David E Nix

Interests

Research

Drug Development - Currently working on an orphan drug (Nikkomycin Z) for treatment of Valley FeverInterested in Pharmacokinetics, Pharmacodynamics and Drug Interactions involving anti-infective drugs.

Teaching

Infectious Diseases - Pharmacology of anti-infective drugs and therapeutics relating to treatment of infectious diseases.Application of pharmacokinetics in treatment of infectious diseases

Courses

Scholarly Contributions

Books

• Nix, D. E. (2021). 2021 PSAP Infectious Diseases. American College of Clinical Pharmacy.
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  Series of books/on line case studies that provide continuing education for pharmacotherapy specialists. Note role was listed at "editor" however the role is actually Faculty Panel Chair for the Infectious Disease Book in the series.

Chapters

• Juan, V. E., & Nix, D. E. (2021). Infection in Patients receiving Biologic Agents for Inflammatory Diseases. In 2021 PSAP Infections Diseases(pp 105-128). ACCP.
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  Chapter for Pharmacotherapy specialty continuing education
• Nix, D. E. (2020). Gonorrhea, Chlamydia, and Herpes Simplex Type 2.. In Pharmacotherapy Principles and Practice Study Guide: A Case Based Care Plan Approach. In: Katz MD, Matthias KR, eds. Pharmacotherapy Principles and Practice Study Guide: A Case Based Care Plan Approach, 5th ed.: McGraw Hill Medical.
• Nix, D. E. (2016). Toxicokinetics and Toxicodynamics of Anti-infective Drugs. In Antibiotic Pharmacodynamics(pp 159-173). Springer. doi:10.1007/978-1-4939-3323-5
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  Chapter in John C. Rotschafer et al. (Eds): Antibiotic Pharmacodynamics, 978-1-4939-3321-1, 318193_1_En, (7)Galley proof finalized 11/2015.

Journals/Publications

• Al-Obaidi, M. M., Ostrosky-Zeichner, L., & Nix, D. E. (2023). Trends of Azole Antifungal Prescription in the United States: Medicare Part D Provider Utilization and Payment Data Analysis. Open forum infectious diseases, 10(8), ofad345.
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  Invasive fungal infections carry a substantial risk of mortality and morbidity. Azole antifungals are used in the treatment of such infections; however, their extensive use can lead to the emergence of antifungal resistance and increased costs to patients and healthcare systems. The aim of this study is to evaluate trends in these antifungals use and costs.
• Erstad, B. L., & Nix, D. E. (2023). Considerations When Using Body Mass Index as a Size Descriptor. The Annals of pharmacotherapy, 57(1), 107-109.
• John, P., Shahbazian, S., Lainhart, W. D., Hayes, J., Mochon, B., & Nix, D. E. (2023). Risk for primary cephalosporin resistance in Gram-negative bacteremia. Antimicrobial stewardship & healthcare epidemiology : ASHE, 3(1), e121.
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  This study aimed to examine the clinical risk factors for cephalosporin resistance in patients with Gram-negative bacteremia caused by (EC), (KP), (ENC), and (PS).
• Salehpour, N., Riley, L. D., Gonzales, M. J., Kobic, E., & Nix, D. E. (2023). Performance of Bayesian Area Under the Concentration-Time Curve-Based Pharmacokinetic Dosing Based on a One-Compartment Model and Trough-Only Monitoring for Vancomycin. Antimicrobial agents and chemotherapy, 67(6), e0017223.
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  A novel Bayesian method was developed to interpret serum vancomycin concentrations (SVCs) following the administration of one or more vancomycin doses with potential varying doses and intervals based on superposition principles. The method was evaluated using retrospective data from 442 subjects from three hospitals. The patients were required to receive vancomycin for more than 3 days, have stable renal function (fluctuation in serum creatinine of ≤0.3 mg/dL), and have at least 2 trough concentrations reported. Pharmacokinetic parameters were predicted using the first SVC, and the fitted parameters were then used to predict subsequent SVCs. Using only covariate-adjusted population prior estimates, the first two SVC prediction errors were 47.3 to 54.7% for the scaled mean absolute error (sMAE) and 62.1 to 67.8% for the scaled root mean squared error (sRMSE). "Scaled" refers to the division of the MAE or RMSE by the mean value. The Bayesian method had minimal errors for the first SVC (by design), and for the second SVC, the sMAE was 8.95%, and the sRMSE was 36.5%. The predictive performance of the Bayesian method did degrade with subsequent SVCs, which we attributed to time-dependent pharmacokinetics. The 24-h area under the concentration-time curve (AUC) was determined from simulated concentrations before and after the first SVC was reported. Prior to the first SVC, 170 (38.4%) patients had a 24-h AUC of 600 mg · h/L. After the first SVC was reported, 322 (72.9%) had a 24-h AUC within the target range, 68 (15.4%) had low values, and 52 (11.8%) had high values based on the model simulation. Target attainments were 38% before the first SVC and 73% after the first SVC. The hospitals had no policies or procedures in place for targeting 24-h AUCs, although the trough target was typically 13 to 17 mg/L. Our data provide evidence of time-dependent pharmacokinetics, which will require regular therapeutic drug monitoring regardless of the method used to interpret SVCs.
• Butkiewicz, C. D., Shubitz, L. F., & Nix, D. E. (2022). A preliminary study of the plasma concentrations of orally administered fluconazole in alpacas (Vicugna pacos). Journal of veterinary pharmacology and therapeutics, 45(1), 99-106. doi:https://dx.doi.org/10.1111/jvp.12994
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  Alpacas residing in the region endemic for Coccidioides spp. are susceptible to serious, disseminated coccidioidomycosis that may result in death. There is currently no oral antifungal dose recommendation for this species. We used a steady-state study design to assess the pharmacokinetics of oral generic fluconazole in alpacas dosed q 24 h for 14 days. Cohorts of 2-3 animals received fluconazole from 6 to 15 mg/kg/day, and pharmacokinetic analysis was performed after each group of animals in order to make dose adjustments for the next group. The final three animals were used as confirmation of our dose recommendation. The median T was 7 h, and the median C was 1.25 µg/ml per mg/kg dose. The mean dose-normalized 24-h AUC was 41.7 µg h/ml per mg/kg dose (CV = 72%). Based on these results, we recommend alpacas receive a starting dose of oral fluconazole at 10-15 mg/kg/day based on the fluconazole AUC in humans (313-625 µg h/ml). Testing to ascertain putative therapeutic plasma concentrations and monitoring of serum transaminases should be performed.
• Erstad, B. L., Matthias, K. R., & Nix, D. E. (2022). Vancomycin dosing in patients with obesity. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 79(22), 2058-2069. doi:https://dx.doi.org/10.1093/ajhp/zxac229
• Kim, Y., Edwards, C., Nix, D. E., & Erstad, B. L. (2022). Accuracy and reproducibility of injections from prefilled "code cart" syringes compared to standard polypropylene syringes. The American journal of emergency medicine, 62, 124-126. doi:https://dx.doi.org/10.1016/j.ajem.2022.08.043
• Nix, D. E., & Erstad, B. L. (2022). Considerations When Using Body Mass Index as a Size Descriptor. Annals of Pharmacotherapy, 57(1), 107-109. doi:10.1177/10600280221097968
• Nix, D. E., Davis, L. E., & Matthias, K. R. (2022). Response to Rybak et al. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 79(16), 1308-1311. doi:https://dx.doi.org/10.1093/ajhp/zxac126
• Nix, D. E., Matthias, K. R., & Davis, L. (2022). The relationship of vancomycin 24-hour AUC and trough concentration. American Journal of Health-System Pharmacy, 79(7), 534-539.
• Nix, D. E., Matthias, K. R., & Erstad, B. L. (2022). Vancomycin Dosing in Patients with Obesity. American Journal of Health-System Pharmacists, 79(22), 2058-2069. doi:10.1093/ajhp/zxac229
• Al-Obaidi, M. M., Nematollahi, S., Nix, D. E., & Zangeneh, T. T. (2021). The benefits of using mold-active triazoles. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.
• Erstad, B. L., & Nix, D. E. (2021). Assessment of Kidney Function in Patients With Extreme Obesity: A Narrative Review. The Annals of pharmacotherapy, 55(1), 80-88.
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  To discuss the evidence and caveats associated with estimated and measured creatinine clearance (eClCr and mClCr) and glomerular filtration rate (eGFR and mGFR) assessments of kidney function in patients with more extreme forms of obesity.
• Erstad, B. L., & Nix, D. E. (2021). Caveats in Kidney Function Assessment. The Annals of pharmacotherapy, 55(11), 1419-1422.
• Grace, C., Larriva, M. M., Steiner, H. E., Marupuru, S., Campbell, P. J., Patterson, H., Cropp, C. D., Quinn, D., Klimecki, W., Nix, D. E., Warholak, T., & Karnes, J. H. (2021). Efficacy of personal pharmacogenomic testing as an educational tool in the pharmacy curriculum: A nonblinded, randomized controlled trial. Clinical and translational science, 14(6), 2532-2543.
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  Personal genomic educational testing (PGET) has been suggested as a strategy to improve student learning for pharmacogenomics (PGx), but no randomized studies have evaluated PGET's educational benefit. We investigated the effect of PGET on student knowledge, comfort, and attitudes related to PGx in a nonblinded, randomized controlled trial. Consenting participants were randomized to receive PGET or no PGET (NPGET) during 4 subsequent years of a PGx course. All participants completed a pre-survey and post-survey designed to assess (1) PGx knowledge, (2) comfort with PGx patient education and clinical skills, and (3) attitudes toward PGx. Instructors were blinded to PGET assignment. The Wilcoxon Rank Sum test was used to compare pre-survey and post-survey PGx knowledge, comfort, and attitudes. No differences in baseline characteristics were observed between PGET (n = 117) and NPGET (n = 116) participants. Among all participants, significant improvement was observed in PGx knowledge (mean 57% vs. 39% correct responses; p 
• Grizzle, A. J., Wilson, L., Nix, D. E., & Galgiani, J. N. (2021). Clinical and Economic Burden of Valley Fever in Arizona: An Incidence-Based Cost-of-Illness Analysis. Open forum infectious diseases, 8(2), ofaa623.
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  Coccidioidomycosis, ie, Valley fever, is an important fungal infection in the Southwest, with half to two thirds of all cases occurring in Arizona. This endemic respiratory disease can range from primary uncomplicated pneumonia to disseminated infection such as meningitis with chronic pulmonary complications. Valley fever diagnoses have risen over recent years and cause substantial morbidity and economic burden in Arizona.
• Nix, D. E., & Blomquist, K. C. (2021). A Critical Evaluation of Newer β-Lactam Antibiotics for Treatment of Pseudomonas aeruginosa Infections.. The Annals of pharmacotherapy, 55(8), 1010-1024. doi:10.1177/1060028020974003
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  This article critically evaluates common Pseudomonas aeruginosa resistance mechanisms and the properties newer β-lactam antimicrobials possess to evade these mechanisms..An extensive PubMed, Google Scholar, and ClinicalTrials.gov search was conducted (January 1995 to July 2020) to identify relevant literature on epidemiology, resistance mechanisms, antipseudomonal agents, newer β-lactam agents, and clinical data available pertaining to P aeruginosa..Relevant published articles and package inserts were reviewed for inclusion..Therapeutic options to treat P aeruginosa infections are limited because of its intrinsic and acquired resistance mechanisms. The goal was to identify advances with newer β-lactams and characterize improvements in therapeutic potential for P aeruginosa infections..Multidrug-resistant (MDR) P aeruginosa isolates are increasingly encountered from a variety of infections. This review highlights potential activity gains of newer β-lactam antibacterial drugs and the current clinical data to support their use. Pharmacists will be asked to recommend or evaluate the use of these agents and need to be aware of information specific to P aeruginosa, which differs from experience derived from Enterobacterales infections..Newer agents, including ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and cefiderocol, are useful for the treatment of MDR P aeruginosa infections. These agents offer improved efficacy and less toxicity compared with aminoglycosides and polymyxins and can be used for pathogens that are resistant to first-line antipseudomonal β-lactams. Selection of one agent over another should consider availability, turnaround of susceptibility testing, and product cost. Efficacy data specific for pseudomonal infections are limited, and there are no direct comparisons between the newer agents.
• Nix, D. E., & Erstad, B. L. (2021). Caveats in Kidney Function Assessment. Annals of Pharmacotherapy, 55(11), 1419-1422. doi:10.1177/10600280211000347
• Nix, D. E., & Erstad, B. L. (2021). Creatinine Assessment in Non-Steady-State Conditions: A Critical Review. The Annals of pharmacotherapy, 55(12), 1536-1544.
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  To discuss methods for the assessment of creatinine clearance (Cl) when serum creatinine (SCr) is not at steady state in order to estimate kidney function and apply the estimate to kidney function staging for clinical assessment or drug dosing.
• Nix, D. E., Al-Obaidi, M. M., Nematollahi, S., & Zangeneh, T. T. (2021). Remarks on the Universal Lifelong Coccidioidomycosis Prophylaxis in Lung Transplant Recipients. Clinical Infectious Diseases, 74(10), 1885-1886. doi:10.1093/cid/ciab878
• Nix, D. E., Butkiewicz, C. D., & Shubitz, L. F. (2021). A preliminary study of the plasma concentrations of orally administered fluconazole in alpacas ( Vicugna pacos ). Journal of Veterinary Pharmacology and Therapeutics, 45(1), 99-106. doi:10.1111/jvp.12994
• Nix, D. E., Davis, L. E., & Matthias, K. R. (2021). The relationship of vancomycin 24-hour AUC and trough concentration. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.
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  In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
• Nix, D. E., Hayes, J. F., Al Obaidi, M., & Tirdad, Z. (2021). Fixed dosing of amphotericin B in morbidly obese individuals. Clin Infect Dis., 72(9), e431.. doi:doi.org/10.1093/cid/ciaa1076
• Nix, D., Naderi, M., Welker, K., & Chan, G. (2021). 148. Implementation of Restriction Criteria within an Electronic Medical Record and Its Impact on Carbapenem Prescribing. Open Forum Infectious Diseases, 8(Supplement_1), S186-S186. doi:10.1093/ofid/ofab466.350
• Blomquist, K. C., & Nix, D. E. (2020). A Critical Evaluation of Newer β-Lactam Antibiotics for Treatment of Infections. The Annals of pharmacotherapy, 1060028020974003.
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  This article critically evaluates common resistance mechanisms and the properties newer β-lactam antimicrobials possess to evade these mechanisms.
• Heil, E. L., Aitken, S. L., Nix, D. E., Drew, R., Rose, W. E., Davis, S. L., Justo, J. A., Fish, D. N., Pogue, J. M., & , S. o. (2020). Recommended Revisions to the National SEP-1 Sepsis Quality Measure: A commentary by the Society of Infectious Diseases Pharmacists on the Infectious Diseases Society of America Position Paper. Pharmacotherapy, 40(4), 368-371.
• Hooten, R., Luis Marquez, J., Goldlist, K., Urcis, R., Adams, M., Matthias, K. R., Nix, D. E., & Al Mohajer, M. (2020). Overprescription of antibiotics in patients with community-acquired pneumonia in the intensive care unit. Avicenna journal of medicine, 9(3), 107-110.
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  We aimed to assess factors associated with therapy failure in patients with community-acquired pneumonia in the intensive care unit (ICU).
• Nix, D. E., & Erstad, B. L. (2020). Assessment of Kidney Function in Patients With Extreme Obesity: A Narrative Review. Annals of Pharmacotherapy, 55(1), 80-88. doi:10.1177/1060028020935580
• Nix, D. E., Hayes, J. F., Al Obaidi, M., & Zangeneh, T. (2020). Fixed Dosing of Amphotericin B in Morbidly Obese Individuals. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.
• Villanueva, J., Nix, D. E., Komatsu, K., Kim, E., & Bhattarai, R. (2020). Antimicrobial Stewardship Approach: Strategy to Enhance Antimicrobial Stewardship Programs in Arizona Long-Term Care. Infection Control and Hospital Epidemiology, 41(S1), s122-s123. doi:10.1017/ice.2020.631
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  Background: Implementing robust antimicrobial stewardship programs within long-term care facilities (LTCFs) presents unique challenges not typically seen in other healthcare settings. These facilities tend to care for older adults, rely on limited on-site clinician availability and experience higher-than-normal staff turnover. Many LTCFs lack the resources and expertise to track and analyze antibiotics usage. Through a collaborative effort between the Arizona Department of Health Services and the University of Arizona College of Pharmacy, support for carrying out stewardship activities was provided to these healthcare facilities. Our objective was to assess the viability of using pharmacy prescribing data to evaluate antibiotics usage among LTCFs throughout Arizona to assist in development of antimicrobial stewardship interventions. Methods: We invited interested LTCFs to participate in the development and enhancement of antimicrobial stewardship programs. We analyzed antibiotic prescribing data from November 2017 through November 2018 to assess the types and quantities of antibiotics prescribed. We worked with pharmacies to obtain a deidentified dataset that included unique patient identifiers, transaction (start) date, agent name, directions for use, route of administration, quantity dispensed, and stop dates. We estimated duration of treatment by assessing antibiotic starts using the number of transaction dates and unique patient identifiers for repeat prescriptions. Each agent was evaluated individually and assigned to an antibiotic category to better assess cumulative prescribing. Results: Through assistance from our community partners, we recruited 11 facilities to participate and worked with 5 servicing pharmacies to obtain a complete dataset for 6 LTCFs. For the facilities evaluated, there were a total of 4,654 antibiotic prescriptions. The most commonly prescribed antibiotic categories were fluroquinolones (24.3% of prescriptions) and oral β-lactams (17.8% of prescriptions). The third most commonly prescribed antibiotics were agents utilized against methicillin-resistant Staphylococcus aureus (MRSA) (13.7% of prescriptions). Antibiotic duration ranged from 1 to 304 days of therapy. Conclusions: Working directly with servicing pharmacies is an efficient way to obtain antibiotic prescribing data for LTCFs. During the 1-year period evaluated, antibiotic prescription rates varied between LTCFs. Despite numerous warnings, the fluroquinolone class continue to be among the most commonly prescribed antibiotics. Visualizing trends in LTCFs antibiotic data is an optimal way to develop and enhance antimicrobial stewardship programs in LTCFs. This fundamental information can help identify areas in which a facility can focus their stewardship efforts and provide a baseline for monitoring progress over time.Funding: NoneDisclosures: None
• Villanueva, J., Nix, D. E., Matthias, K. R., & Hayes, J. (2020). 737. A Descriptive Analysis of Fluconazole Utilization at Two Academic Medical Centers in the Valley Fever Corridor of Arizona. Open Forum Infectious Diseases, 7(Supplement_1), S417-S418. doi:10.1093/ofid/ofaa439.928
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  Abstract Background Fluconazole (fluc) is a common antifungal used at hospitals and is an important target for antimicrobial stewardship (AS). Fluc is also used for management of coccidioidomycosis (C). The objective of our study was to describe fluc prescribing patterns at two academic centers in Arizona. Methods We conducted a retrospective analysis of fluc usage in adult patients. One month from each quarter in a one-year period (November 2017-November 2018) was selected (4 months in total). All adult patients that received fluc at Hospital A and Hospital B in the selected months were identified. Patient demographic information and Charlson comorbidity index (CCI) to quantify the degree of comorbidity were collected. We then analyzed patients in the study by defining the fluc usage as directed towards C management or non-C management (e.g., candidiasis). In the C management group, we characterized the initial fluc dose during the patient’s course as directed for empiric, targeted, or prophylaxis treatment. Finally, we performed further analysis of the empiric C group. The study received IRB approval from our institution. Results During our study period, 1239 patients were included in the analysis. Patient information is shown in Table 1. Overall, most of the fluc usage was directed towards C management (63.5%, 787/1239). A significant amount of that usage was directed towards C prophylaxis at both Hospital A and B (67.4% (234/347) and 75% (330/440), respectively). In addition, fluc usage directed towards empiric C management was higher at Hospital A versus Hospital B (18.4% (64/347) versus 9.5% (42/440), respectively). Further patient data for the empiric C group is shown in Table 2. Conclusion We report the results of a descriptive study that demonstrate that 63.5% of fluc usage in adults at two academic medical centers in Arizona was directed for C management. In addition to traditional fluc targets for AS, our study highlights C prophylaxis in solid organ transplant recipients and empiric C management as AS targets in endemic regions. These targets are especially important due to the risk for selection of azole-resistant Candida species and invasive molds with increased antifungal exposure. Disclosures All Authors: No reported disclosures
• Wilson, L., Nix, D. E., Grizzle, A. J., & Galgiani, J. N. (2020). Clinical and Economic Burden of Valley Fever in Arizona: An Incidence-Based Cost-of-Illness Analysis. Open Forum On Infectious Diseases, 1-32. doi:https://doi.org/10.1093/ofid/ofaa623
• Matthias, K. R., Villanueva, J. E., & Nix, D. E. (2020). The importance of dosing interval in AUC-based vancomycin dosing. American Journal of Health-System Pharmacists, 77(6), 487-492. doi:10.1093/ajhp/zxz180
• Nix, D. E., Villanueva, J. E., & Matthias, K. R. (2019). The importance of dosing interval in limiting vancomycin AUC with trough monitoring. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, Not assigned(Not assigned), 1-6. doi:https://doi.org/10.1093/ajhp/zxz180
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  This is a commentary on the proposed AUC dosing for vancomycin. The article has been accepted and is available on-line. We suspect that the publication is being held until the new Guideline is published.
• Patanwala, A. E., Radosevich, J. J., Meshay, I., Naderi, M., Culver, M. A., Lee, Y. G., Weinberg, J. A., Khobrani, M., & Nix, D. E. (2019). Cefazolin Monotherapy Versus Cefazolin Plus Aminoglycosides for Antimicrobial Prophylaxis of Type III Open Fractures. American journal of therapeutics, Unassigned(Unassigned), 1-8. doi:DOI: 10.1097/MJT.0000000000001121
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  There are conflicting recommendations between organizations regarding aminoglycoside use for the prophylaxis of type III open fractures.
• Thompson, G. R., Lewis, J. S., Nix, D. E., & Patterson, T. F. (2019). Current Concepts and Future Directions in the Pharmacology and Treatment of Coccidioidomycosis. Medical mycology, 57(Supplement_1), S76-S84.
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  Coccidioidomycosis remains a significant clinical problem with substantial morbidity and mortality. The vast majority of infections are asymptomatic and the need for early primary therapy remains controversial. The use of triazole antifungals has improved tolerability of therapy but concerns about acute and long-term toxicities among available agents limit their use. In addition, recent findings of decreased in vitro fluconazole susceptibility to as many as 37% of Coccidioides spp. isolates raises concerns regarding optimal therapy for these infections as fluconazole is commonly used for therapy including central nervous system disease. Thus, new agents from novel antifungal classes are currently in preclinical and clinical development aimed at reducing toxicity and improving outcomes of these serious infections.
• Al Mohajer, M., Joiner, K. A., & Nix, D. E. (2018). Are Teaching Hospitals Treated Fairly in the Hospital-Acquired Condition Reduction Program?. Academic medicine : journal of the Association of American Medical Colleges, 93(12), 1827-1832.
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  To identify the factors associated with total Hospital-Acquired Condition Reduction Program (HACRP) score and with receiving a Centers for Medicare and Medicaid Services (CMS) penalty (1% reduction in payment to those hospitals in the lowest-performing quartile of HACRP scores) for fiscal years (FYs) 2015-2017 with a particular focus on trends over this period.
• Al Mohajer, M., Nix, D. E., Matthias, K. R., Mora, F., McKeown, K. R., Hager, K. M., & Beatty, N. L. (2018). Influenza Vaccine Availability at Urgent Care Centers in the State of Arizona. American Journal of Infection Control, 46(8), 946-948. doi:https://dx-doi-org.ezproxy4.library.arizona.edu/10.1016/j.ajic.2018.02.005
• Al, M. M., Joiner, K. A., & Nix, D. E. (2018). Are Teaching Hospitals Treated Fairly in the Hospital-Acquired Condition Reduction Program?. ACADEMIC MEDICINE, 93(12), 1827-1832.
• Beatty, N., August, J., Saenz, J. A., Nix, D. E., Matthias, K. R., & Al Mohajer, M. (2018). Knowledge, Attitudes, and Practices Associated with the Diagnosis and Management of Skin and Soft Tissue Infections Among Medical Students, Residents, and Attending Physicians. Avicenna Journal of Medicine, 8(3), 104-106. doi:10.4103/ajm.AJM_200_17
• Eljaaly, K., Elarabi, S., Alshehri, S., & Nix, D. E. (2018). Impact of requiring re-authorization of restricted antibiotics on day 3 of therapy. The Journal of antimicrobial chemotherapy, 73(2), 527-530.
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  Pre-authorization of restricted antibiotics is a core component of an antibiotic stewardship programme (ASP). On day 3, information about culture results and clinical status is typically available. Our objective was to compare an ASP that requires initial authorization alone with one requiring initial authorization and re-authorization on day 3 of therapy.
• Norman, B., Jessica, A., Joe, S. A., Nix, D. E., Kathryn, M. R., & Mayar, A. A. (2018). Knowledge, attitude, and practices associated with the diagnosis and management of skin and soft-tissue infections among medical students, residents, and attending physicians. Avicenna Journal of Medicine, 8(3), 104-106. doi:https://dx-doi-org.ezproxy4.library.arizona.edu/10.4103/ajm.A.
• Taweel, I., Beatty, N., Duarte, A., Nix, D. E., Matthias, K. R., & Al Mohajer, M. (2018). Significance of Bacteriuria in Patients With End-Stage Renal Disease on Haemodialysis. Avicenna Journal of Medicine, 8(2), 51-54. doi:10.4103/ajm.AJM_199_17
• Adams, M. D., Al Mohajer, M., Althaghfi, A., Nix, D. E., Bach, M., Matthias, K. R., Bach, M., Matthias, K. R., Althaghfi, A., Nix, D. E., Adams, M. D., & Al Mohajer, M. (2017). Impact of Verigene Multiplex PCR on Antibiotic Stewardship In Patients with Gram-Negative Bacteremia. Open Forum Infectious Diseases, 4(Suppl 1), S625. doi:10.1093/ofid/ofx163.1654
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  Presented at IDWeek2017
• Al Mohajer, M., Matthias, K. R., & Nix, D. E. (2017). Improving The Knowledge Of Students And Physicians Regarding Appropriate Use Of Antibiotics For Respiratory Infections Through Online Educational Module. American Journal of Infection Control, 45(1), e15-e17. doi:http://dx.doi.org/10.1016/j.ajic.2016.09.027
• Al Mohajer, M., Matthias, K. R., & Nix, D. E. (2017). Improving the knowledge of students and physicians regarding appropriate use of antibiotics for respiratory infections through an online educational module. American journal of infection control, 45(1), e15-e17.
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  We developed an interactive online module to improve the knowledge of students and physicians regarding respiratory infections. Our study showed that the completion of this module was associated with substantial improvement in knowledge, with modest retention after 2 months.
• Al Mohajer, M., Matthias, K. R., Petty, W. G., Alshibani, M., McKeown, K., August, J., Nix, D. E., & Beatty, N. (2017). Rapid Multiplex Gastrointestinal Pathogen Panel Testing Improves Antibiotic Stewardship in Patients with Suspected Infectious Diarrhea Compared to Conventional Methods. Open Forum Infectious Diseases, 4(Suppl 1), S624. doi:10.1093/ofid/ofx163.1652
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  Project was presented at IDWeek2017
• Al Mohajer, M., Matthias, K. R., Petty, W., Alshibani, M., Mckeown, K., Kottey, J., Swazo, R., August, J., Nix, D. E., & Beatty, N. (2017). Appropriateness of a Rapid Multiplex Gastrointestinal Panel in the Investigation of Suspected Infectious Diarrhea After Implementation at an Academic Medical Center. Open Forum Infectious Diseases, 4(Suppl 1), S361-362. doi:10.1093/ofid/ofx163.878
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  Presented at IDWeek2017
• Al Mohajer, M., Matthias, K., Kottey, J., Nix, D., Beatty, N., August, J., Swazo, R., Mckeown, K., Alshibani, M., & Petty, W. (2017). Appropriateness of a Rapid Multiplex Gastrointestinal Panel in the Investigation of Suspected Infectious Diarrhea After Implementation at an Academic Medical Center. Open Forum Infectious Diseases, 4(suppl_1), S361-S362. doi:10.1093/ofid/ofx163.878
• Al Mohajer, M., Nix, D. E., Matthias, K. R., Mora, F., Mckeown, K., Hager, K., & Beatty, N. (2017). 2016–2017 Seasonal Influenza Vaccine Availability at Urgent Care Centers in the state of Arizona, USA. Open Forum Infectious Diseases, 4(Suppl 1), S520. doi:https://doi.org/10.1093/ofid/ofx163.1354
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  Presented at IDWeek 2017https://idsa.confex.com/idsa/2017/webprogram/Paper63723.html
• Cardenas-Trowers, O. O., Malekzadeh, P., Nix, D. E., & Hatch, K. D. (2017). Vaginal Mesh Removal Outcomes: Eight Years of Experience at an Academic Hospital. Female pelvic medicine & reconstructive surgery, 23(6), 382-386. doi:DOI: 10.1097/SPV.0000000000000419
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  The purpose of this study is to describe the clinical history leading up to and the outcomes after vaginal mesh removal surgery at an academic hospital.
• Eljaaly, K., Alshehri, S., Aljabri, A., Abraham, I., Al Mohajer, M., Kalil, A. C., & Nix, D. E. (2017). Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: a systematic review and meta-analysis. BMC infectious diseases, 17(1), 385. doi:DOI 10.1186/s12879-017-2495-5
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  Both typical and atypical bacteria can cause community-acquired pneumonia (CAP); however, the need for empiric atypical coverage remains controversial. Our objective was to evaluate the impact of antibiotic regimens with atypical coverage (a fluoroquinolone or combination of a macrolide/doxycycline with a β-lactam) to a regimen without atypical antibiotic coverage (β-lactam monotherapy) on rates of clinical failure (primary endpoint), mortality, bacteriologic failure, and adverse events, (secondary endpoints).
• Nix, D. E., Matthias, K. R., Giovinco, N., Ong, E., Farran, S., Salloum, M., Gardner, S., Armstrong, D. G., & Al Mohajer, M. (2017). Does Everything That’s Counted Count? Value of Inflammatory Markers for Following Therapy and Predicting Outcome in Diabetic Foot Infection. The International Journal of Lower Extremity Wounds, 16(2), 104-107. doi:10.1177/1534734617700539
• Nix, D. E., Mayersohn, M., & Erstad, B. L. (2017). Should estimates of glomerular filtration rate and creatinine clearance be indexed to body surface area for drug dosing?. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 74(21), 1814-1819.
• Ong, E., Farran, S., Salloum, M., Gardner, S., Giovinco, N., Armstrong, D. G., Matthias, K. R., Nix, D. E., & Al Mohajer, M. (2017). Does Everything That's Counted Count? Value of Inflammatory Markers for Following Therapy and Predicting Outcome in Diabetic Foot Infection. The international journal of lower extremity wounds, 16(2), 104-107.
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  To assess the severity of inflammation associated with diabetic foot infection (DFI), values of inflammatory markers such as white blood count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR) are often measured and tracked over time. It remains unclear if these markers can aid the clinician in the diagnosis and management of DFI, and ensure more rational use of antibiotics. Hospitalized adult patients (n = 379) with DFI were retrospectively assessed for abnormal inflammatory markers, correlation between values of inflammatory markers, and clinical diagnosis on initial admission and on last follow-up. At admission, WBC, ESR and NLR were each elevated in patients with osteomyelitis and only ESR was significantly elevated in patients with soft tissue infection only. Only WBC was significantly elevated in patients with osteomyelitis compared with uninfected diabetic feet on last follow-up. Considering the predictive performance of these inflammatory markers, they demonstrated excellent positive predictive value at admission, and excellent negative predictive value at the last follow-up visit. Moreover, the number of elevated markers was further associated with probability of infection both at admission and last follow-up.
• Abraham, I., Nix, D. E., Eljaaly, K., Alshehri, S., Aljabri, A., & Abraham, I. (2016). Clinical Failure Rates With and Without Atypical Coverage in Hospitalized Adults With Community-Acquired Pneumonia: A Meta-analysis. Open Forum Infectious Diseases, 3(suppl_1). doi:10.1093/ofid/ofw172.941
• Al Mohajer, M., Matthias, K. R., & Nix, D. E. (2016). Improving The Knowledge Of Students And Physicians Regarding Appropriate Use Of Antibiotics For Respiratory Infections Through Online Educational Module. American Journal of Infection Control. doi:http://dx.doi.org/10.1016/j.ajic.2016.09.027
• Al Mohajer, M., Petty, W. G., Matthias, K. R., Nix, D. E., & Beatty, N. (2016). Efficacy and cost comparison between a rapid multiplex polymerase chain reaction (PCR) gastrointestinal (GI) pathogen panel versus conventional stool analysis techniques in suspected cases of infectious Diarrheal disease at a tertiary medical center. Open Forum Infectious Diseases, 3(Suppl 1). doi:10.1093/ofid/ofw172.81
• Eljaaly, K., & Nix, D. E. (2016). Voriconazole Dosing in Obese Patients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 63(2), 286-7.
• Matthias, K., Nix, D., Beatty, N., & Mohajer, M. A. (2016). Efficacy and Cost Comparison Between a Rapid Multiplex Polymerase Chain Reaction Gastrointestinal Pathogen Panel Versus Conventional Stool Analysis Techniques in Suspected Cases of Infectious Diarrheal Disease at a Tertiary Medical Center. Open Forum Infectious Diseases, 3(suppl_1). doi:10.1093/ofid/ofw172.81
• Jarrell, D. H., Matthias, K. R., & Nix, D. E. (2015). Incidence and risk factors for persistent Staphylococcus aureus bacteremia. Current Trends in Microbiology, 9, 65-71.
• Jarrell, D. H., Matthias, K. R., & Nix, D. E. (2014). Incidence and risk factors for persistent Staphylococcus aureus bacteremia. Current Trends in Microbiology, 9, 65-71.
• Nix, D. E. (2014). Cardiotoxicity Induced by Antifungal Drugs. Current Fungal Infection Reports.
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  Abstract: This review addresses the potential of antifungal drugs to cause cardiac toxicity. Many antifungal drugs, especially antifungal azoles, rarely cause torsades de pointes (TdP) and carry the risk of sudden death. Interventions to avoid TdP should include cautious use of azoles in combination with other drugs that cause QTc prolongation, and elimination of risk factors for TdP whenever possible. These risk factors include: hypokalemia, hypomagnesemia, severe bradycardia, and preexisting long QT syndrome. ECG monitoring should be considered when the use of multiple QT-prolonging drugs is unavoidable and TdP risk factors cannot be resolved. Itraconazole exhibits negative inotropic activity which may present as worsening heart failure in patients with preexisting heart failure. A few cases of severe bradycardia have also been described with voriconazole. Most cases of cardiac toxicity associated with amphotericin B are due to severe electrolyte abnormalities, rapid administration or overdose. Although cardiac toxicity is not common with the use of antifungal drugs, recognition of the potential to cause serious cardiac-related outcomes, evaluation of risk factors, and monitoring is warranted. © 2014 Springer Science+Business Media New York.
• Shubitz, L. F., Trinh, H. T., Perrill, R. H., Thompson, C. M., Hanan, N. J., Galgiani, J. N., & Nix, D. E. (2014). Modeling nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials. The Journal of infectious diseases, 209(12), 1949-54.
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  Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Coccidioides species that is being developed as a first-in-class orphan product for treatment of coccidioidomycosis. It has previously been shown to reduce lethal respiratory infections in mice to undetectable levels when treatment is begun 48 hours after infection. The studies described here focus on bracketing NikZ doses for phase 2 and 3 clinical trials, using an established mouse respiratory infection as a model and starting treatment 120 hours after infection. A dose of 80 mg/kg/day, divided into 2 doses, nearly eradicated infection, and larger doses did not improve fungal clearance. Increasing the duration of treatment from 1 week to 3 weeks resulted in a greater percentage of culture-negative mice. Comparative data show that plasma levels of NikZ that nearly eradicate Coccidioides in mice are achievable in patients and provide a plausibly effective dose range for initial phase 2 clinical studies.
• Nguyen, C., Barker, B. M., Hoover, S., Nix, D. E., Ampel, N. M., Frelinger, J. A., Orbach, M. J., & Galgiani, J. N. (2013). Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clinical microbiology reviews, 26(3), 505-25.
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  Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii. This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.
• Shubitz, L. F., Roy, M. E., Nix, D. E., & Galgiani, J. N. (2013). Efficacy of Nikkomycin Z for respiratory coccidioidomycosis in naturally infected dogs. Medical mycology, 51(7), 747-54.
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  Nikkomycin Z (NikZ) is a chitin synthase inhibitor with antifungal efficacy against Coccidioides spp. and other endemic fungi. Dogs suffer a rate and range of natural coccidioidomycosis similar to humans and were considered an excellent model for initially testing NikZ against naturally acquired disease. Twelve dogs with coccidioidal pneumonia that had been present for an average of three months were treated with 250 mg (5-15 kg) or 500 mg (> 15-30 kg) twice daily for 60 days. Nine dogs completed the course of treatment and seven dogs had improvement in disease based on radiographs, clinicopathological parameters, physical examination findings, and subjective assessment by owners; three dogs had resolution or near resolution of disease. Based on this small study, NikZ shows efficacy to treat naturally acquired coccidioidomycosis and merits further development for trials in humans.
• R, K., Nix, D. E., Peloquin, C. A., & Graham, M. L. (2012). Poor absorption of high-dose posaconazole in pediatric bone marrow transplant patients. Annals of Pharmacotherapy, 46(9), e22.
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  PMID: 22872751;Abstract: OBJECTIVE: To describe the use of high-dose posaconazole in 2 pediatric patients who received bone marrow transplant (BMT) and highlight concerns regarding posaconazole absorption. CASE SUMMARY: We present 2 pediatric BMT patients in whom prescribed high doses of posaconazole (120-300 mg/kg/day for >3 months) provided serum concentrations less than 1 μg/mL. Both patients received posaconazole with other antifungal therapy and surgical debridement for Rhizopus spp. infections after allogeneic BMTs. Various alternative dosing strategies to potentially enhance posaconazole absorption to increase serum concentrations were attempted, including higher daily doses, frequent or continuous oral administration via feeding tube, use of enteral nutrition, and limiting use of acid-blocking agents. During highdose therapy, frequent posaconazole serum concentration measurement and other monitoring techniques, such as continuous telemetry, were used. While the fungal infections resolved in both patients and no serious adverse effects could be attributed to high-dose posaconazole administration, posaconazole therapy may have contributed to nausea and vomiting in 1 of the patients. DISCUSSION: These 2 cases describe complex circumstances, with several reasons that may have affected the patients' posaconazole serum concentrations. Both patients received significantly higher doses than those recommended in the posaconazole prescribing information, but potentially serious adverse events were not observed since serum concentration measurements were rarely more than 0.5 μg/mL. CONCLUSIONS: The safety of high-dose posaconazole therapy was not determined in these 2 patients. However, given that limited alternative therapy options are available for severely ill patients with suspected posaconazole malabsorption, research regarding dosing strategies should be considered.
• Nix, D. E. (2010). Appropriateness of ciprofloxacin dosing based on a population pharmacokinetic model. Hospital Pharmacy, 45, 237-43.
• Nix, D. E., Swezey, R. R., Hector, R., & Galgiani, J. N. (2009). Pharmacokinetics of nikkomycin Z after single rising oral doses. Antimicrobial agents and chemotherapy, 53(6), 2517-21.
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  Nikkomycin Z is an antifungal drug that inhibits chitin synthase. This agent is under development as an orphan product for treatment of coccidioidomycosis. Safety and pharmacokinetics of nikkomycin Z were evaluated in healthy male subjects following single, rising oral doses ranging from 250 mg to 2,000 mg. A total of 12 subjects were recruited and divided into two groups. Group 1 (n = 6) received two out of three doses of 250 mg, 1,000 mg, or 1,750 mg and a placebo randomly in place of one of the doses. Group 2 (n = 6) received two out of three doses of 500 mg, 1,500 mg, or 2,000 mg and a placebo in place of one of the doses. Subjects were confined to the study unit overnight prior to dosing, and 12 blood samples were collected over 24 h postdosing while subjects were confined. Subjects returned for additional blood samples and safety evaluations at 48 h and 72 h after each dose. There was a 2-week washout period between doses. Plasma drug concentrations were determined using a validated high-performance liquid chromatography method. Nikkomycin Z was absorbed after oral administration, reaching a maximum concentration in serum of 2.21 microg/ml at 2 h postdose and an area under the concentration-time curve from 0 h to infinity of 11.3 microg x h/ml for the 250-mg dose. Pharmacokinetics appeared linear over the range of 250 to 500 mg; however, relative bioavailability was about 62 to 70% for the 1,000-mg dose and 42 to 47% for doses between 1,500 and 2,000 mg. The mean terminal half-life ranged from 2.1 to 2.5 h and was independent of dose. No serious or dose-related adverse events were observed. This study provides a basis for pharmacokinetic simulations and continued studies of nikkomycin Z administered in multiple doses.
• Nix, D., Fernandez, J., Erstad, B. L., Petty, W., & Nix, D. E. (2009). Time to positive culture and identification for Candida blood stream infections. Diagnostic microbiology and infectious disease, 64(4).
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  Candidemia and delay to appropriate therapy contribute to increased morbidity and mortality. Current literature addresses the delay between blood culture collection and final identification; however, it fails to delineate differences among species. The purpose of this study was to quantify the time to yeast detection and identification relative to blood culture collection and determine whether differences exist among species. In this retrospective study, all cases of Candida isolation for 2 years were reviewed. The time delays between blood culture and detection of Candida growth were quantified as well as the additional time required for final species identification. Initiation of antifungal therapy was assessed in relation to culture collection, detection of yeast, and final identification. The appropriateness of therapy at each time point was also analyzed. Most Candida infections were caused by either Candida albicans (n = 43) or Candida glabrata (n = 27). Mean time to positive yeast detection for C. albicans was 35.3 +/- 18.1 h, whereas that of C. glabrata was 80.0 +/- 22.4 h (P < 0.0001). Mean time to final identification for C. albicans was 85.8 +/- 30.9, whereas that of C. glabrata was 154 +/- 43.8 h (P < 0.0001). Mean time to appropriate therapy for C. albicans isolates was 43.3 +/- 27.6 h compared with 98.1 +/- 38.3 h (P < 0.0001) for C. glabrata isolates. The time delay between blood culture collection and yeast detection as well as final identification was significantly longer for C. glabrata isolates when compared with C. albicans. As a result, mean time to appropriate antifungal therapy was significantly longer in patients with C. glabrata isolates.
• Patanwala, A. E., Norris, C. J., Nix, D. E., Kopp, B. J., & Erstad, B. L. (2009). Vancomycin dosing for pneumonia in critically ill trauma patients. The Journal of trauma, 67(4), 802-4.
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  Vancomycin has been recommended as the treatment of choice for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia with a desired trough concentration of 15 to 20 mg/L. The purpose of this study was to evaluate the initial dosing of vancomycin for MRSA pneumonia in critically ill adult trauma patients.
• Stein, G. E., Schooley, S. L., Havlichek, D. H., & Nix, D. E. (2008). Outpatient intravenous antibiotic therapy compared with oral linezolid in patients with skin and soft tissue infections: A pharmacoeconomic analysis. Infectious Diseases in Clinical Practice, 16(4), 235-239.
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  Abstract: Background: In patients with skin or soft tissue infections that do not require hospitalization, the choice between oral therapy and outpatient parenteral antimicrobial therapy (OPAT) depends on several factors. Oral linezolid is an effective antibiotic for skin or soft tissue infections and may be a suitable alternative to OPAT in this patient population. Objective: The aim of the study was to analyze the potential cost-effectiveness of oral linezolid compared with OPAT in adult patients with moderately severe skin or soft tissue infections referred to a hospital-based infusion center. Methods: Twenty patients with skin or soft tissue infections referred to an infusion center for OPAT were enrolled into a prospective, randomized, pilot clinical trial comparing OPAT to oral linezolid. Patients received their prescribed intravenous antibiotic (normal care group) or oral linezolid (600 mg every 12 hours) for a duration decided by their primary or emergency department physician and followed up for 4 weeks. Outcome measures recorded for the economic analysis included all clinic, emergency department, wound care, and infusion center visits as well as hospitalizations. Any additional medical care, including the number of doses of all antibiotics, was documented for each subject. The costs of care were standardized using Medicare reimbursement payments. Results: Most infections in each group involved cellulitis of the abdomen or the lower extremities. In the 10 patients who received OPAT, 2 received no additional antibiotics, 4 received additional oral therapy, and 4 were subsequently hospitalized due to lack of improvement. In the 10 patients who received linezolid, 9 were cured and 1 patient received additional oral antibiotics. None of these patients were hospitalized, but 3 received outpatient wound care. The costs for care in this pilot study, based on Medicare reimbursement payments, would average $1855 in the OPAT group compared with $1038 in patients who received oral linezolid. Conclusions: Oral linezolid can be a cost-effective alternative to OPAT in patients with skin or soft tissue infections, but its use could shift a significant amount of cost for care to the patient. Copyright © 2008 by Lippincott Williams & Wilkins.
• Koopman, E., Nix, D. E., Erstad, B. L., Demeure, M. J., Hayes, M. M., Ruth, J. T., & Matthias, K. R. (2007). End-of-procedure cefazolin concentrations after administration for prevention of surgical-site infection. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 64(18), 1927-34.
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  The adequacy of end-of-procedure free cefazolin concentrations after administration for the prevention of surgical-site infection (SSI) and compliance with national guidelines for antimicrobial prophylaxis for SSI were assessed.
• Nix, D., Patanwala, A. E., Erstad, B. L., & Nix, D. E. (2007). Cost-effectiveness of linezolid and vancomycin in the treatment of surgical site infections. Current medical research and opinion, 23(1).
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  This decision-analytic study was intended to determine the expected cost-effectiveness of linezolid compared to vancomycin for treating surgical site infections (SSIs) caused by methicillin-resistant Staphyloccocus aureus (MRSA) from the perspective of a tertiary-care academic medical center.
• Slade, D. S., Friday, J. W., Snyder, R. W., Nix, D. E., Kleinert, L. B., & Patula, V. B. (2007). Prophylactic gatifloxacin therapy in prevention of bacterial keratitis in a rabbit laser in situ keratomileusis model. Journal of Cataract and Refractive Surgery, 33(5), 888-892.
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  PMID: 17466866;Abstract: Purpose: Use the ID50 (infectious dose to 50% of experimental animals) to quantify the most effective prophylactic dosing regimen to use with gatifloxacin 0.3% (Zymar) for the prevention of keratitis in a rabbit laser in situ keratomileusis model of Staphylococcus epidermidis infection. Setting: University Laboratory, University of Arizona, Tucson, Arizona, USA. Methods: Two groups of rabbits were compared in each of 2 experiments that were separated by 12 months. In the first experiment, rabbits receiving no postoperative antibiotic therapy (Group 1) were compared with rabbits receiving postoperative antibiotic therapy (Group 2). In the second experiment, postoperative antibiotic therapy (Group 3) was compared with preoperative and postoperative antibiotic therapy (Group 4). All antibiotic regimens used gatifloxacin 0.3%. Before antibiotic therapy began, corneal pockets were created in the right eye of each rabbit and all rabbits received balanced salt solution (BSS) only or BSS and S epidermidis inoculations in the corneal pocket. Rabbits were monitored for corneal infiltrates after surgery. Results: The ID50 of the first, second, third, and fourth groups of rabbits was 102, 104, 105, and 107 organisms, respectively. The data showed a statistically significant difference between rabbits receiving BSS only and most rabbits receiving BSS plus inoculate at each postoperative measurement (P
• Erstad, A. J., Erstad, B. L., & Nix, D. E. (2006). Accuracy and reproducibility of small-volume injections from various-sized syringes. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 63(8), 748-50.
• Erstad, B. L., Nix, D. E., Nakazato, P. Z., Barletta, J. F., Matthias, K. R., & Krueger, T. S. (2006). Estimation of Creatinine Clearance in End-Stage Liver Disease. Annals of Pharmacotherapy, 40(5), 900-908. doi:10.1345/aph.1g594
• Nix, D. E., Erstad, B. L., Nakazato, P. Z., Barletta, J. F., Matthias, K. R., & Krueger, T. S. (2006). Estimation of creatinine clearance in end-stage liver disease. The Annals of pharmacotherapy, 40(5), 900-8.
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  Estimation of renal function in patients with end-stage liver disease (ESLD) is complicated by several factors.
• Stoff, J. A., Nix, D. E., & DeYoung, D. W. (2006). A pilot study of an anti-MRSA bio-engineered lacteal complex (anti-MRSA BLC) in a murine septicemia model. Immunopharmacology and immunotoxicology, 28(4), 601-7.
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  Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen of humans and other animals, causing septicemia, abcessation, toxemia, and other infectious diseases. Refined bioengineered lacteal complex (BLC), made specifically against MRSA, is a novel complex of low molecular weight immunogenic and antimicrobial molecules. It was evaluated in vivo using a mouse model of MRSA-induced peritonitis. Intraperitoneal dosing of anti-MRSA BLC demonstrated a therapeutic effect (83% survival) against an intraperitoneal MRSA challenge that caused 100% mortality in untreated animals. Anti-MRSA BLC is a promising therapeutic modality for MRSA infection.
• Valdivia, L., Nix, D., Wright, M., Lindberg, E., Fagan, T., Lieberman, D., Stoffer, T., Ampel, N. M., & Galgiani, J. N. (2006). Coccidioidomycosis as a common cause of community-acquired pneumonia. Emerging Infectious Diseases, 12(6), 958-962.
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  PMID: 16707052;PMCID: PMC3373055;Abstract: The early manifestations of coccidioidomycosis (valley fever) are similar to those of other causes of community-acquired pneumonia (CAP). Without specific etiologic testing, the true frequency of valley fever may be underestimated by public health statistics. Therefore, we conducted a prospective observational study of adults with recent onset of a lower respiratory tract syndrome. Valley fever was serologically confirmed in 16 (29%) of 55 persons (95% confidence interval 16%-44%). Antimicrobial medications were used in 81% of persons with valley fever. Symptomatic differences at the time of enrollment had insufficient predictive value for valley fever to guide clinicians without specific laboratory tests. Thus, valley fever is a common cause of CAP after exposure in a disease-endemic region. If CAP develops in persons who travel or reside in Coccidioides-endemic regions, diagnostic evaluation should routinely include laboratory evaluation for this organism.
• Kopp, B. J., Nix, D. E., & Armstrong, E. P. (2004). Clinical and economic analysis of methicillin-susceptible and -resistant Staphylococcus aureus infections. The Annals of pharmacotherapy, 38(9), 1377-82.
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  The rate of methicillin-resistant Staphylococcus aureus (MRSA) has increased significantly over the last decade. Previous cohort studies of patients with MRSA bacteremia have reported higher mortality rates, increased morbidity, longer hospital length of stay (LOS), and higher costs compared with patients with methicillin-susceptible S. aureus (MSSA) bacteremia. The clinical and economic impact of MRSA involving other sites of infection has not been well characterized.
• Levine, J. M., Noecker, R. J., Lane, L. C., Herrygers, L., Nix, D., & Snyder, R. W. (2004). Comparative penetration of moxifloxacin and gatifloxacin in rabbit aqueous humor after topical dosing. Journal of Cataract and Refractive Surgery, 30(10), 2177-2182.
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  PMID: 15474833;Abstract: Purpose: To evaluate the aqueous penetration of the fourth-generation fluoroquinolones moxifloxacin and gatifloxacin. Setting: University of Arizona, Tucson, Arizona, USA. Methods: Forty eyes of 20 New Zealand white rabbits were divided into 2 experimental groups. In Experiment I rabbits (20 eyes), a commercial preparation of topical gatifloxacin 0.3% was administered to 9 eyes and moxifloxacin 0.5% to 9 eyes; 2 eyes served as a control. Eyes were dosed according to a keratitis protocol; ie, every 15 minutes for 4 hours. The aqueous humor was sampled 10 minutes after the last dose. Experiment II rabbits (20 eyes) were dosed according to a cataract prophylaxis protocol; ie, 4 times a day for 10 days. The aqueous humor was sampled 1 hour after the last dose of antibiotic in 12 eyes and 24 hours after the last dose in 8 eyes. High-performance liquid chromatography was used to determine the fluoroquinolone concentration. Results: In the keratitis dosing protocol, the mean concentration of moxifloxacin in the aqueous (n = 9) was 11.057 μg/mL (range 7.66 to 18.87 μg/mL), which was significantly higher than the mean concentration of gatifloxacin (n = 8) (7.570 μg/mL [range 4.75 to 10.86 μg/mL]) (P = .030). In the cataract prophylaxis dosing protocol, the mean aqueous concentration of moxifloxacin (n = 6) was 1.745 μg/mL (range 0.92 to 3.87 mg/mL). The mean concentration of gatifloxacin (n = 6) was 1.207 μg/mL (range 0.44 to 2.44 μg/mL). The difference was not statistically significant (P = .359). Conclusions: Higher mean levels (×1.46) of aqueous penetration were achieved with moxifloxacin than with gatifloxacin in the keratitis-dosing model. There was no statistically significant difference between the 2 drugs in the cataract prophylaxis dosing model. Both antibiotics had aqueous levels in excess of the minimum inhibitory concentration for most pathogenic organisms in both models. © 2004 ASCRS and ESCRS.
• Nix, D. E. (2004). Clinical and economic analysis of methicillin-susceptible and -resistant Staphylococcus aureus infections. Annals of Pharmacotherapy, 38(9), 1377-82.
• Nix, D. E., Adam, R. D., Auclair, B., Krueger, T. S., Godo, P. G., & Peloquin, C. A. (2004). Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid. Tuberculosis, 84(6), 365-373.
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  PMID: 15525560;Abstract: Background: Clofazimine is potentially useful for the treatment of disease due to multidrug resistant Mycobacterium tuberculosis, as well as leprosy and certain chronic skin diseases. Its pharmacokinetics have been incompletely characterized. This study was conducted to explore issues relating to bioavailability in the presence of food, orange juice, and antacid. Methods: A 5 drug regimen consisting of clofazimine, cycloserine, ethionamide, para-aminosalicyclic acid, and pyridoxime was administered to healthy subjects four times using a four period cross-over design with two weeks washout between treatments. Subjects also received orange juice, a high fat meal, aluminum/magnesium antacid, or only water in random order with the drug regimen. The pharmacokinetics of clofazimine were assessed using individual- and population-based methods and relative bioavailability compared to fasting administration was determined. Results: Clofazimine exhibited a sometimes prolonged and variable lag-time and considerable variability in plasma concentrations. From the population analysis (one-compartment model), the mean oral clearance was 76.7l/h (CV=74.2%) and mean apparent volume of distribution was 1470l (CV=36.3%). The first-order absorption rate constant ranged from 0.716 to 1.33h-1 (pooled CV=61.7%). Residual (proportional) error was 49.1%. Estimates of bioavailability compared to fasting administration were 145% (90% CI, 107-183%) for administration with high fat food, 82.0% (63.2-101%) for administration with orange juice, and 78.5% (55.1-102%) for administration with antacid. Conclusion: Administration of clofazimine with a high fat meal provides the greatest bioavailability, however, bioavailability is associated with high inter- and intra-subject variability. Both orange juice and aluminum-magnesium antacid produced a reduction in mean bioavailability of clofazimine. © 2004 Elsevier Ltd. All rights reserved.
• Nix, D. E., Majumdar, A. K., & DiNubile, M. J. (2004). Pharmacokinetics and pharmacodynamics of ertapenem: An overview for clinicians. Journal of Antimicrobial Chemotherapy, 53(SUPPL. 2), ii23-ii28.
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  PMID: 15150180;Abstract: Ertapenem, a Group 1 carbapenem, is a once-a-day parenteral β-lactam antibiotic recently licensed in the USA and Europe. Monotherapy with ertapenem dosed as 1 g once a day has been shown to be highly effective in clinical trials for the treatment of complicated infections of skin and skin structures, complicated intra-abdominal infections, community-acquired pneumonia, acute pelvic infections and complicated urinary tract infections. Dosing modifications have not been recommended for adults on the basis of gender, age, weight or liver disease. Presently there are no data regarding the use of ertapenem in children. Dose reductions are indicated for patients with advanced renal insufficiency. Ertapenem is neither a substrate nor an inhibitor of P-glycoprotein or cytochrome P450 enzymes; significant drug interactions between ertapenem and drugs handled by these systems are not expected. JAC © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
• Nix, D. E., Majumdar, A. K., & DiNubile, M. J. (2004). Pharmacokinetics and pharmacodynamics of ertapenem: an overview for clinicians. The Journal of antimicrobial chemotherapy, 53 Suppl 2, ii23-8.
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  Ertapenem, a Group 1 carbapenem, is a once-a-day parenteral beta-lactam antibiotic recently licensed in the USA and Europe. Monotherapy with ertapenem dosed as 1 g once a day has been shown to be highly effective in clinical trials for the treatment of complicated infections of skin and skin structures, complicated intra-abdominal infections, community-acquired pneumonia, acute pelvic infections and complicated urinary tract infections. Dosing modifications have not been recommended for adults on the basis of gender, age, weight or liver disease. Presently there are no data regarding the use of ertapenem in children. Dose reductions are indicated for patients with advanced renal insufficiency. Ertapenem is neither a substrate nor an inhibitor of P-glycoprotein or cytochrome P450 enzymes; significant drug interactions between ertapenem and drugs handled by these systems are not expected.
• Nix, D. E., Matthias, K. R., & Ferguson, E. C. (2004). Effect of ertapenem protein binding on killing of bacteria. Antimicrobial agents and chemotherapy, 48(9), 3419-24.
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  The effect of protein binding on the antimicrobial activity of ertapenem was evaluated using the bacterial kill rate and concentration-response studies. Various proportions of human serum were utilized to determine the total and free-drug concentrations using a validated high-performance liquid chromatography assay. The MICs and kill curves were determined for test isolates of Enterobacter cloacae and Staphylococcus aureus at various percentages of human serum. The killing of bacteria was analyzed in relation to the free and total concentrations of ertapenem at various proportions of human serum. It was determined that unbound ertapenem was responsible for the antimicrobial activity against the test isolates.
• Nix, D. E. (2003). Book Review: Pharmacokinetics in Drug Discovery and Development. Annals of Pharmacotherapy, 37(3), 455-456. doi:10.1345/aph.1c406
• Snyder, R. W., Nix, D. E., Nedrud, C., Lee, J. H., & Chang, M. (2003). Comparing Kill Rates for Two New Fluoroquinolones to Ofloxacin and Vancomycin Against Staphylococcal Endophthalmitis Isolates. Investigative Ophthalmology & Visual Science, 44(13), 2120-2120.
• Downhour, N. P., Petersen, E. A., Krueger, T. S., Tangella, K. V., & Nix, D. E. (2002). Severe cellulitis/myositis caused by Stenotrophomonas maltophilia. Annals of Pharmacotherapy, 36(1), 63-66.
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  PMID: 11816260;Abstract: OBJECTIVE: To present a case of cellulitis/myositis due to Stenotrophomonas maltophilia in the absence of trauma and to discuss a potentially novel treatment option. CASE SUMMARY: A 57-year-old white man, having undergone an allogeneic bone marrow transplant, developed myositis with S. maltophilia of the left soleus muscle; there had been no trauma. Risk factors for infection included neutropenia, prolonged hospitalization and intensive care unit stay, and broad-spectrum antibiotic exposure. The affected area of muscle was resected and the patient successfully treated with trimethoprim/sulfamethoxazole (TMP/SMX), ticarcillin/clavulanate, and aztreonam. DISCUSSION: In severe myositis/cellulitis caused by S. maltophilia, TMP/SMX is considered the drug of choice. However, bacteriostatic agents such as TMP/SMX are less than ideal in neutropenic patients. The combination of ticarcillin/clavulanate plus aztreonam has been shown to improve activity in vitro against this organism compared with TMP/SMX. This is likely due to inhibition of the 2 β-lactamases this organism produces by clavulanate and aztreonam. In our study of clinical isolates of S. maltophilia, this combination reduced the minimum inhibitory concentration at 90% by 128-fold and was synergistic against 10 of 12 isolates tested in time-kill analysis. CONCLUSIONS: S. maltophilia is emerging as an important pathogen in patients with compromised immunity, leading to severe infections that are difficult to treat. Based on in vitro synergy studied, we recommend considering ticarcillin/clavulanate plus aztreonam as a potential treatment option in immunocompromised patients with S. maltophilia infection.
• Nix, D. E., Downhour, N. P., Petersen, E. A., Krueger, T. S., & Tangella, K. V. (2002). Severe Cellulitis/Myositis Caused by Stenotrophomonas Maltophilia. Annals of Pharmacotherapy, 36(1), 63-66. doi:10.1345/aph.1a148
• Auclair, B., Nix, D. E., Adam, R. D., James, G. T., & Peloquin, C. A. (2001). Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids. Antimicrobial Agents and Chemotherapy, 45(3), 810-814.
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  PMID: 11181366;PMCID: PMC90379;Abstract: This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA (Cmax), time to maximum concentration (Tmax), or area under the concentration-time curve from 0 h to infinity (AUCo-∞) between the four treatments (P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for Cmax were 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUCo-∞ were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean Tmax was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows: Ka = 0.37 to 0.48 h-1, V/F = 2.0 to 2.8 liters/kg, CL/F = 56.5 to 72.2 liters/h, and terminal half-life = 1.7 to 2.1 h, where Ka is the absorption rate constant, V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.
• Krueger, T. S., Clark, E. A., & Nix, D. E. (2001). In vitro susceptibility of Stenotrophomonas maltophilia to various antimicrobial combinations. Diagnostic Microbiology and Infectious Disease, 41(1-2), 71-78.
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  PMID: 11687317;Abstract: Stenotrophomonas maltophilia has emerged as a significant pathogen in compromised patients, causing infections which are difficult to treat. Clinical isolates from patients in the Tucson area were tested against single and combination antibiotics using three testing methods. Ticarcillin/clavulanate, trimethoprim/sulfamethoxazole and trovafloxacin provided comparable inhibitory activity, in vitro. Ciprofloxacin, imipenem and ticarcillin were active less often. Agreements between disk diffusion and broth microdilution results were poor for ciprofloxacin and trimethoprim/sulfamethoxazole; however, agreement was ≥ 90% for the other drugs tested. Major or very major errors were observed with ticarcillin, ticarcillin/clavulanate, and trovafloxacin. The addition of aztreonam to ticarcillin/clavulanate enhanced the activity compared to ticarcillin/clavulanate alone using the double-disk diffusion, broth microdilution (checkerboard), and time-kill testing methods. Trovafloxacin exhibited good activity by all three methods, with bactericidal activity at ≥ 2× MIC. These results indicate that the newer fluoroquinolones or the triple combination of ticarcillin/clavulanate plus aztreonam may be potential options for treatment of infection caused by S. maltophilia in patients who are intolerant to or fail trimethoprim/sulfamethoxazole therapy. © 2001 Elsevier Science Inc. All rights reserved.
• Nix, D. E., Peloquin, C. A., Zhu, M., Adam, R. D., & Singleton, M. D. (2001). Pharmacokinetics of para-Aminosalicylic Acid Granules under Four Dosing Conditions. Annals of Pharmacotherapy, 35(11), 1332-1338. doi:10.1345/aph.1a088
• Peloquin, C. A., Zhu, M., Adam, R. D., Singleton, M. D., & Nix, D. E. (2001). Pharmacokinetics of para-aminosalicylic acid granules under four dosing conditions. Annals of Pharmacotherapy, 35(11), 1332-1338.
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  PMID: 11724078;Abstract: OBJECTIVE: To determine the pharmacokinetics and relative bioavailability of para-aminosalicylic acid (PAS) granules. DESIGN: Phase I pharmacokinetics study. SETTING: University of Arizona School of Pharmacy. PARTICIPANTS: Sixteen healthy male and female volunteers aged 36 ± 8 years. INTERVENTIONS: Subjects received single doses of PAS granules (6 g) combined with cycloserine 500 mg, clofazimine 200 mg, ethionamide 500 mg, and pyridoxine 100 mg. Drugs were given on an empty stomach after an overnight fast (reference) with high-fat food, with orange juice, and with antacids. MEASUREMENTS AND RESULTS: Four subjects did not complete all four treatments due to adverse events or personal reasons. Plasma and urine samples were collected for 48 hours and measured by a validated HPLC assay. Pharmacokinetic data analysis was performed with WinNonlin using noncompartmental methods and a one-compartmental model. Bioequivalence testing was performed using the mean ratios of the maximum concentrations (Cmax) and AUC0-∞ of PAS, with 90% confidence intervals. Compared with the fasted condition, food increased Cmax 1.5-fold and AUC0-∞ 1.7-fold, and it doubled the time to maximum concentration (tmax). The least-squares mean ratios (treatment/reference) for Cmax were 0.90 (58% to 139% CI), 1.16 (75% to 179% CI), and 0.82 (52% to 127% CI) with orange juice, food, or antacid treatment, respectively. Corresponding ratios for AUC0-∞ were 1.05 (71% to 155% CI), 1.52 (103% to 224% CI), and 0.84 (57% to 125% CI), respectively. CONCLUSIONS: Food significantly enhanced the absorption of PAS, while orange juice and antacids had minor effects.
• Zhu, M., Nix, D. E., Adam, R. D., Childs, J. M., & Peloquin, C. A. (2001). Pharmacokinetics of cycloserine under fasting conditions and with high-fat meal, orange juice, and antacids. Pharmacotherapy, 21(8), 891-897.
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  PMID: 11718495;Abstract: Study Objectives. To determine the effect of a high-fat meal, orange juice, and antacids on absorption of a single oral dose of cycloserine and to estimate its population pharmacokinetic parameters. Design. Randomized, four-period, crossover study. Setting. Clinical research center. Patients. Twelve healthy volunteers. Interventions. Subjects received single doses of cycloserine 500 mg after a 12-hour fast (reference), with a high-fat meal, with orange juice, and with antacids. They also received clofazimine 200 mg, ethionamide 500 mg, and p-aminosalicylic acid granules 6000 mg. Measurements and Main Results. Plasma samples were collected for 48 hours and assayed by validated high-performance capillary electrophoresis assay. Concentration-time data were analyzed with noncompartmental, one-compartment, and population methods. The maximum concentration (Cmax) of cycloserine was decreased (p=0.02) by the high-fat meal. No other statistically significant differences were observed for Cmax and area under the curve from time zero to infinity across the four treatments. The high-fat meal significantly (p
• Barletta, J. F., Johnson, S. B., Nix, D. E., Nix, L. C., & Erstad, B. L. (2000). Population pharmacokinetics of aminoglycosides in critically ill trauma patients on once-daily regimens. The Journal of trauma, 49(5), 869-72.
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  Once-daily dosing regimens of aminoglycosides are routinely used in critically ill trauma patients. However, the pharmacokinetic parameters are variable in these patients. The purpose of this study was to evaluate the pharmacokinetics of aminoglycosides in critically ill trauma patients receiving once-daily dosing regimens.
• Birmingham, M. C., Guarino, R., Heller, A., Wilton, J. H., Shah, A., Hejmanowski, L., Nix, D. E., & Schentag, J. J. (1999). Ciprofloxacin concentrations in lung tissue following a single 400 mg intravenous dose. Journal of Antimicrobial Chemotherapy, 43(SUPPL. A), 43-48.
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  PMID: 10225571;Abstract: Intravenous ciprofloxacin is frequently prescribed for the treatment of infections due to nosocomially acquired Gram-negative organisms, including those originating in the respiratory tract. In this study, the concentrations of ciprofloxacin in serum and lung tissue were determined by HPLC in patients undergoing lung surgery. A total of 22 patients scheduled for lung surgery received a single 400 mg iv dose of ciprofloxacin administered as a 1 h infusion. A specimen of healthy lung tissue was obtained from resected lung from 18 of the patients for analysis of ciprofloxacin concentration during the following time intervals after infusion (one sample/patient): 0-2, 2-4, 4-8 and 8-12 h. Corresponding mean serum and tissue concentrations were 2.37 mg/L and 3.84 mg/kg (0-2 h), 1.18 mg/L and 1.92 mg/kg (2-4 h), 0.69 mg/L and 1.77 mg/kg (4-8 h), and 0.13 mg/L and 0.67 mg/kg (8-12 h). Ciprofloxacin distributed rapidly to lung tissue, as seen by the high concentrations in the lung tissue as early as 2 h after infusion. Concentrations in lung tissue were generally higher than those in serum (tissue:serum ratios ranged from 1.7 to 7.1). The mean tissue concentrations found in this study remained above the MIC for most susceptible organisms.
• Nix, D. E., Cicco, R. D., Miller, A. K., Boyle, D. A., Boike, S. C., Zariffa, N., Jorkasky, D. K., & Schentag, J. J. (1999). The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline. Journal of Clinical Pharmacology, 39(8), 855-865.
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  PMID: 10434239;Abstract: The potential for nonprescription cimetidine (200 mg twice daily) to affect the pharmacokinetics of sustained-release (SB) theophylline was assessed in 26 male subjects, 13 smokers and 13 nonsmokers. This was a concentration-controlled drug interaction study in which the subjects were administered a dose of SR theophylline every 12 hours to provide a mean steady-state concentration between 8 and 15 μg/ml. To determine individual theophylline dose, a test dose of aminophylline was administered, and baseline theophylline pharmacokinetics were determined. Subjects remained on SR theophylline for 23 days and were treated in the following sequence: run-in phase (4 days), treatment 1 (7 days), washout (5 days), and treatment 2 (7 days). During the treatment phases, subjects received cimetidine (200 mg at approximately 08:00 and 12:00) or placebo for 7 days in a randomized crossover fashion. Theophylline pharmacokinetics were determined on days 1, 4, and 7 of both treatment phases. A large day-to-day variability in the oral clearance of theophylline was evident for the theophylline-placebo treatment and the theophylline-cimetidine treatment. Nonprescription strength cimetidine resulted in a mean 5% decrease in theophylline oral clearance on day 1 and a mean 12% decrease on days 4 and 7 combined. There were no significant differences in the cimetidine-theophylline interaction between smokers and nonsmokers. Oral clearance during the nighttime dosing interval was 13% greater than the daytime oral clearance for nonsmokers and 22% greater for smokers, showing a greater circadian rhythm for smokers. In summary, nonprescription doses of cimetidine (400 mg/day) have the potential to produce small changes in theoophylline concentrations during steady-state dosing with SR theophylline; however, this effect appears less than changes that occur as a consequence of theophylline's intrasubject variability. (C) 1999 the American College of Clinical Pharmacology.
• Pcloquin, C. A., Namdar, R., Singleton, M. D., & Nix, D. E. (1999). Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids. Chest, 115(1), 12-18.
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  PMID: 9925057;Abstract: Study objectives: Determine the intrasubject and intersubject variability in, and the effects of food or antacids on, the pharmacokinetics of rifampin (RIF). Design: Randomized, four-period crossover phase I study. Subjects: Fourteen healthy male and female volunteers. Interventions: Subjects ingested single doses of RIF, 600 mg, under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. They also received standard doses of isoniazid, pyrazinamide, and ethambutol. Measurements and main results: Serum was collected for 48 h and assayed by high-pressure liquid chromatography. Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean RIF maximal serum concentration (Cmax) of 10.54 ± 3.18 μg/mL, the time at which it occurred (Truax) of 2.42 ± 1.32 h, and the area under the curve from time zero to infinity (AUC(0-∞)) of 57.15 ± 13.41 μg · h/mL. These findings are similar to those reported previously. Antacids did not alter these parameters (Cmax of 10.89 ± 5.22 μg/mL, Tmax of 2.36 ± 1.28 h, and AUC(0-∞) of 58.37 ± 18.49 μg · h/mL). In contrast, the Food and Drug Administration high-fat meal reduced RIF Cmax by 36% (7.27 ± 2.29 μg/mL), nearly doubled Tmax (4.43 ± 1.09 h), but reduced AUC(0-∞) by only 6% (55.20 ± 14.48 μg · h/mL). Conclusions: These changes in Cmax, Tmax, and AUC(0- ∞) can be avoided by giving RIF on an empty stomach whenever possible.
• Peloquin, C. A., Bulpitt, A. E., Jaresko, G. S., Jelliffe, R. W., Childs, J. M., & Nix, D. E. (1999). Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids. Antimicrobial Agents and Chemotherapy, 43(3), 568-572.
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  PMID: 10049268;PMCID: PMC89161;Abstract: Ethambutol (EMB) is the most frequent 'fourth drug' used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (± standard deviation) EMB maximum concentration of drug in serum (C(max)) of 4.5 ± 1.0 μg/ml, time to maximum concentration of drug in serum (T(max)) of 2.5 ± 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) of 28.9 ± 4.7 μg · h/ml. In the presence of antacids, subjects had a mean C(max) of 3.3 ± 0.5 μg/ml, T(max) of 2.9 ± 1.2 h, and AUC(0-∞) of 27.5 ± 5.9 μg · h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean C(max) of 3.8 ± 0.8 μg/ml, T(max) of 3.2 ± 1.3 h, and AUC(0- ∞) of 29.6 ± 4.7 μg · h/ml. These reductions in C(max), delays in T(max), and modest reductions in AUC(0-∞) can be avoided by giving EMB on an empty stomach whenever possible.
• Peloquin, C. A., Namdar, R., Dodge, A. A., & Nix, D. E. (1999). Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids. International Journal of Tuberculosis and Lung Disease, 3(8), 703-710.
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  PMID: 10460103;Abstract: STUDY OBJECTIVES: To determine the intra- and intersubject variability in and the effects of food or antacids on the pharmacokinetics of isoniazid (INH). DESIGN: Randomized, four-period cross-over Phase I study in 14 healthy male and female volunteers. Subjects ingested single doses of INH 300 mg under fasting conditions twice, with a high-fat meal, and with aluminum- magnesium antacid. They also received standard doses of rifampin, pyrazinamide, and ethambutol. RESULTS: Serum was collected for 48 hours, and assayed by high performance liquid chromatography (HPLC). Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean INH C(max) of 5.53 ± 2.92 μg/ml, T(max) of 1.02 ± 1.10 hours, and AUC(0-∞) of 20.16 ± 12.45 μg* hr/ml. These findings are similar to those reported previously. Antacids did not alter these parameters significantly (C(max) of 5.62 ± 2.53 μg/ml, T(max) of 0.71 ± 0.56 hours, and AUC(0-∞) of 20.27 ± 11.39 μg* hr/ml). In contrast, the high-fat meal recommended by the Food and Drug Administration reduced INH C(max) by 51% (2.73 ± 1.70 μg/ml), nearly doubled T(max) (1.93 ± 1.61 hours), and reduced AUC(0-∞) by 12% (17.72 ± 10.32 μg*hr/ml). CONCLUSIONS: These changes in C(max), T(max), and AUC(0-∞) can be avoided by giving INH on an empty stomach whenever possible.
• Nix, D. E. (1998). Intrapulmonary concentrations of antimicrobial agents. Infectious Disease Clinics of North America, 12(3), 631-646.
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  PMID: 9779382;Abstract: The delivery of antimicrobial agents to the site of infection has always been considered important. Lung infections are typically localized to the bronchial mucosa, endothelial lining fluid, and/or alveolar macrophages. Significant advances have been made in measuring antimicrobial concentrations at these sites, although some of the methods need further refinement and standardization. Relating various intrapulmonary site concentrations to efficacy or treatment failure requires further study. This article reviews the theory and methods relating to the measurement of intrapulmonary delivery of antimicrobial agents, and compares the intrapulmonary delivery of agents commonly used for the treatment of lower respiratory infections.
• Peloquin, C. A., Bulpitt, A. E., Jaresko, G. S., Jelliffe, R. W., James, G. T., & Nix, D. E. (1998). Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids. Pharmacotherapy, 18(6 I), 1205-1211.
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  PMID: 9855317;Abstract: Study Objectives. To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA). Design. Randomized, four-period, crossover phase I study. Subjects. Fourteen healthy men and women volunteers. Interventions. Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high-fat meal and with an aluminum-magnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol. Measurements and Main Results. Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA C(max) 53.4 ± 10.4 μg/ml, T(max) 1.43 ± 1.06 hours, and AUC(0- ∞) 673 ± 79.7 μg·hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean C(max) of 55.6 ± 9.0 μg/ml, T(max) of 1.43 ± 1.23 hours, and AUC(0-∞) of 628 ± 88.4 μg·hr/ml. In the presence of the high-fat meal, mean C(max) was 45.6 ± 9.44 μg/ml, T(max) 3.09 ± 1.74 hours, and AUC(0-∞) 687 ±116 μg·hr/ml. Conclusions. These small changes in C(max), T(max), and AUC(0-∞) can be avoided by giving PZA on an empty stomach whenever possible.
• Schentag, J. J., Strenkoski-Nix, L. C., Nix, D. E., & Forrest, A. (1998). Pharmacodynamic interactions of antibiotics alone and in combination. Clinical Infectious Diseases, 27(1), 40-46.
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  PMID: 9675447;Abstract: Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacterial killing rates in patients with nosocomial pneumonia and is useful for predicting clinical or microbiological outcomes and making dosage adjustments with β-lactams, quinolones, aminoglycosides, and vancomycin. The AUIC values of two antibiotics are additive, and since antibiotics are often given in combination, determining the AUIC for antibiotic combinations could potentially predict the microbiological outcomes for patients given these combinations. To further address this question, mathematical modeling was used to study in vitro pharmacokinetic and pharmacodynamic interactions of the antimicrobials piperacillin and ciprofloxacin. These agents were also studied in vivo in healthy volunteers. Blood samples were obtained for analysis of serum drug concentrations, and serum inhibitory titers were determined against eight common bacterial pathogens, chosen to reflect the range of MIC values to ciprofloxacin and piperacillin. Additive AUIC relationships predictive of bacterial killing rates were typical in patients given these antibiotics in combination.
• Shah, A., Nix, D. E., Heller, A. H., Hejmanowski, L. G., Guarino, R. L., & Birmingham, M. C. (1998). CIPROFLOXACIN (CIPRO) CONCENTRATIONS IN LUNG TISSUE FOLLOWING A SINGLE 400 MG INTRAVENOUS DOSE. Critical Care Medicine, 26(Supplement), 100A. doi:10.1097/00003246-199801001-00275
• Strenkoski-Nix, L. C., Forrest, A., Schentag, J. J., & Nix, D. E. (1998). Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers. Journal of Clinical Pharmacology, 38(11), 1063-1071.
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  PMID: 9824789;Abstract: Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill- type model where E(max), was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.
• Dieterich, D. T., Poles, M. A., Lew, E. A., Martin-Munley, S., Johnson, J., Nix, D., & Faust, M. J. (1997). Treatment of gastrointestinal cytomegalovirus infection with twice- daily foscarnet: A pilot study of safety, efficacy, and pharmacokinetics in patients with AIDS. Antimicrobial Agents and Chemotherapy, 41(6), 1226-1230.
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  PMID: 9174175;PMCID: PMC163891;Abstract: Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 μM following the first dose and 687 μM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose I and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose I and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients.
• Nix, D. E., Symonds, W. T., Hyatt, J. M., Wilton, J. H., Teal, M. A., Reidenberg, P., & Affrime, M. B. (1997). Comparative pharmacokinetics of oral ceftibuten, cefixime, cefaclor, and cefuroxime axetil in healthy volunteers. Pharmacotherapy, 17(1), 121-125.
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  PMID: 9017772;Abstract: Study Objective. To compare the pharmacokinetics of ceftibuten, cefixime, cefuroxime axetil, and cefaclor after oral administration. Design. Randomized, four-period, crossover study. Setting. Hospital-based clinical research center. Subjects. Healthy adult men and women volunteers. Interventions. Single 400-mg doses of cefixime and ceftibuten, and 500-mg doses of cefuroxime axetil and cefaclor. Measurements and Main Results. Serum concentrations were determined by high-performance liquid chromatography methods. The mean oral clearances of cefixime, cefuroxime axetil, and cefaclor were similar, ranging from 20.4-27.0 L/hour; clearance of ceftibuten was approximately 4-fold less, 5.45 L/hour. The serum half-lives of ceftibuten (2.35 hrs) and cefixime (2.38 hrs) were prolonged compared with those of cefuroxime axetil (1.30 hrs) and cefaclor (0.693 hr). These agents also differed in terms of time to maximum concentration, time to peak plasma level, area under the curve, and apparent volume of distribution, the last reflecting differences in bioavailability. Conclusion. Ceftibuten had a relatively high time to maximum concentration and long half-life, resulting in a 3.5-fold higher area under the curve than cefixime, cefuroxime axetil, and cefaclor. These pharmacokinetic data can be used as a basis to compare the four oral cephalosporins; however, comparative susceptibility data must also be considered.
• Nix, D. E., Thomas, J. K., Symonds, W. T., Spivey, J. M., Wilton, J. H., Gagliardi, N. C., & Schentag, J. J. (1997). Assessment of the enzymuria resulting from gentamicin alone and combinations of gentamicin with various β-lactam antibiotics. Annals of Pharmacotherapy, 31(6), 696-703.
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  PMID: 9184707;Abstract: OBJECTIVE: To determine the propensity of β-lactam antimicrobials to ameliorate or potentiate aminoglycoside-induced renal enzymuria. DESIGN: Two open, randomized, double-blind, parallel-group studies were conducted in young, healthy, male volunteer subjects. Using a common protocol, 24-hour urine collections were analyzed for the renal tubular enzymes alanine aminopeptidase (AAP) and N-acetyl-β-D-glucosaminidase (NAG), as well as for creatinine. Antimicrobial combinations studied included gentamicin plus placebo and gentamicin plus ticarcillin/clavulanate (protocol 1); and gentamicin plus placebo, gentamicin plus piperacillin, and gentamicin plus ceftazidime (protocol 2). The antimicrobial regimens were administered for 7 days. Eight subjects completed each treatment group. RESULTS: There were no significant differences between treatment groups with regard to urine creatinine excretion or serum gentamicin concentrations in either protocol. Enzymuria (AAP [p = 0.039] and NAG [p = 0.337]) was decreased in the gentamicin plus ticarcillin/clavulanate treatment compared with that in the gentamicin plus placebo treatment. Increased enzymuria, as indicated by increased urine concentrations of AAP and NAG, was observed in the gentamicin plus ceftazidime treatment (p < 0.05) compared with the other two treatments. CONCLUSIONS: Based on relative enzymuria, ticarcillin/clavulanate may be renal protective. Piperacillin neither potentiated nor ameliorated aminoglycoside-induced enzymuria. Since acute elevations in AAP and NAG reflect insults to the kidney these studies suggest that ceftazidime may enhance aminoglycoside-induced renal injury. Piperacillin had no effect on enzymuria and would appear not to enhance or protect against aminoglycoside- induced renal injury.
• Nix, D. E., Wilton, J. H., Hyatt, J., Thomas, J., Strenkoski-Nix, L. C., Forrest, A., & Schentag, J. J. (1997). Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers. Antimicrobial Agents and Chemotherapy, 41(5), 1108-1114.
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  PMID: 9145877;PMCID: PMC163858;Abstract: The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid E(max) model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, θ, defined the type and relative extent of interaction. The range of observed θ values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.
• Jusko, W. J., Nix, D. E., Kotas, T., Khaliq, S. L., & Jusko, W. J. (1996). Effect of Methylprednisolone (MP) on Endotoxin‐Induced TNFα Production in Whole Blood. Clinical Pharmacology & Therapeutics, 59(2), 193-193. doi:10.1038/sj.clpt.1996.270
• Li, R. C., Nix, D. E., & Schentag, J. J. (1996). Performance of the fractional maximal effect method: Comparative interaction studies of ciprofloxacin and protein synthesis inhibitors. Journal of Chemotherapy, 8(1), 25-32.
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  PMID: 8835104;Abstract: The performance of the recently developed Fractional Maximal Effect (FME) method was evaluated along with the conventional checkerboard technique and time-kill method. Ciprofloxacin in combination with tobramycin was tested against Escherichia coli and Pseudomonas aeruginosa and in combination with tetracycline, chloramphenicol, erythromycin against Escherichia coli. Two combinations, amoxicillin-tetracycline (antagonistic) and tobramycin-ticarcillin (synergistic), were included as reference interactions. The FME method unequivocally showed an antagonistic interaction between ciprofloxacin and all the protein synthesis inhibitors (PSIs) tested, while the other two methods yielded variable results. At a total FME (TFME) level of 1, the FME method demonstrated a similar degree of antagonism against ciprofloxacin by tetracycline, chloramphenicol, and erythromycin, and much lower by tobramycin. Internal consistency of the FME operation was demonstrated by the identical conclusions obtained at both TFME levels of 0.5 and 1. The FME method appears to be a practical alternative for resolving the inconsistencies observed in conventional methods of antibiotic combination testing.
• Schentag, J. J., Forrest, A., Nix, D. E., & Ballow, C. H. (1996). Relationships between serum, intracellular, and infection site concentrations of macrolide and azalide antibiotics: A theoretical exploration of the concept of white blood cell drug delivery to infection sites. Antiinfective Drugs and Chemotherapy, 14(2), 137-146.
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  Abstract: A new theoretical model is proposed to describe the contribution of white blood cell (WBC) drug delivery to the total amount of available macrolide or azalide antibiotic at the infection site. This model was based on the serum concentration versus time courses of azithromycin (an azalide) and erythromycin (a macrolide) and their respective tissue: serum ratios in WBCs and in other tissues. This infection site model also incorporates a pharmacokinetic evaluation of the time course of WBCs at infection sites during active infection and during resolution. The primary discoveries of this exercise were that tissue homogenate:serum ratios could be described for both antibiotics, and that both antibiotics could achieve mass balance of drug distribution among the various body sites in the absence of infection. In the presence of infection, drug delivery by WBCs was predicted to add about 10-fold greater amounts of drug than serum to local erythromycin concentrations, as the amount delivered by WBCs at a highly inflammatory (109 WBCs) site resulted in a 10-fold increase in the amount of erythromycin at the infection site. Drug delivery by WBCs was predicted to be even more important for azithromycin. In the presence of large numbers of WBCs (109 cells), local infection site azithromycin concentrations rose over 100-fold. The phenomenon of WBC delivery increased the area under the inhibitory time curve (AUIC) at infection sites to values in excess of the 125 threshold for activity. While this was of importance for both antibiotics, the contribution of WBC delivery to infection site AUIC was greater for azithromycin than for erythromycin. In summary, this theoretical model may account for the high degree of success of macrolides and particularly azalides at tissue infection sites in spite of their generally low serum concentrations. The property of WBC delivery may be an important contributor to the total antimicrobial action of these antibiotics.
• Schentag, J. J., Nix, D. E., Forrest, A., & Adelman, M. H. (1996). AUIC - The universal parameter within the constraint of a reasonable dosing interval. Annals of Pharmacotherapy, 30(9), 1029-1031.
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  PMID: 8876868;
• Hyatt, J. M., Nix, D. E., Stratton, C. W., & Schentag, J. J. (1995). In vitro pharmacodynamics of piperacillin, piperacillin-tazobactam, and ciprofloxacin alone and in combination against Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 39(8), 1711-1716.
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  PMID: 7486906;PMCID: PMC162813;Abstract: The time-kill curve methodology was used to determine the pharmacodynamics of piperacillin, ciprofloxacin, piperacillin-tazobactam and the combinations piperacillin-ciprofloxacin and ciprofloxacin-piperacillin-tazobactam. Kill curve studies were performed for piperacillin, ciprofloxacin, and piperacillin-tazobactam at concentrations of 0.25 to 50 times the MICs for 13 strains of bacteria: four Pseudomonas aeruginosa, three Enterobacter cloacae, three Klebsiella pneumoniae, and three Staphylococcus aureus isolates (tazobactam concentrations of 0.5, 4, and 12 μg/ml). By using a sigmoid E(max) model and nonlinear least squares regression, the 50% lethal concentrations and the maximum lethal rates of each agent were determined for each bacterial strain. For piperacillin-ciprofloxacin and ciprofloxacin- piperacillin-tazobactam, kill curve studies were performed with concentrations obtained by the fractional maximal effect method (R. C. Li, J. J. Schentag, and D. E. Nix, Antimicrob. Agents Chemother. 37:523-531, 1993) and from individual 50% lethal concentrations and maximum lethal rates. Ciprofloxacin-piperacillin-tazobactam was evaluated only against the four P. aeruginosa strains. Interactions between piperacillin and ciprofloxacin were generally additive. At physiologically relevant concentrations of piperacillin and ciprofloxacin, ciprofloxacin had the highest rates of killing against K. pneumoniae. Piperacillin-tazobactam (12 μg/ml) had the highest rate of killing against E. cloacae. Piperacillin-ciprofloxacin with relatively higher ciprofloxacin concentrations had the greatest killing rates against S. aureus. This combination had significantly higher killing rates than piperacillin (P < 0.002). For all the bacterial strains tested, killing rates by ciprofloxacin were significantly higher than those by piperacillin (P < 0.001). Piperacillin-tazobactam (4 and 12 μg/ml) had significantly higher killing rates than piperacillin alone (P < 0.02 and P < 0.004, respectively). The effect of the combination of piperacillin-ciprofloxacin, in which piperacillin concentrations were relatively higher, was not statistically different from that of piperacillin alone (P ≥ 0.71). The combination of ciprofloxacin-piperacillin-tazobactam achieved greater killing than other combinations or monotherapies against P. aeruginosa. The reduction in the initial inoculum was 1 to 4 logs greater with ciprofloxacin- piperacillin-tazobactam at 4 and 12 μg/ml than with any other agent or combination of agents. On the basis of the additive effects prevalently demonstrated in the in vitro study, the combinations piperacillin- ciprofloxacin and piperacillin-tazobactam are rational therapeutic options. Greater killing of P. aeruginosa was demonstrated with ciprofloxacin- piperacillin-tazobactam. Since treatment failure of P. aeruginosa pneumonia is a significant problem, clinical studies are warranted.
• Kazierad, D. J., Wojcik, G. J., Nix, D. E., Goldfarb, A. L., & Schentag, J. J. (1995). The effect of verapamil on the nephrotoxic potential of gentamicin as measured by urinary enzyme excretion in healthy volunteers. Journal of Clinical Pharmacology, 35(2), 196-201.
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  PMID: 7751432;Abstract: The effects of verapamil on the nephrotoxic potential of multiple-dose gentamicin were studied in healthy adult male volunteers. Subjects received a gentamicin infusion every 8 hours for 19 doses. Gentamicin dosage was adjusted to maintain peak concentrations of 5.5 mg/L and trough concentrations of 0.5 mg/L. Verapamil was given as a sustained release preparation of 180 mg twice daily starting 2 days before the aminoglycoside, and continued for 4 days post-gentamicin therapy. Nephrotoxicity was assessed by measuring 24-hour urinary alanine aminopeptidase excretion (AAP). The urinary AAP results of six subjects given gentamicin with verapamil were compared with urinary AAP from nine subjects treated with gentamicin alone. These nine subjects were matched with the verapamil-treated subjects on the basis of gentamicin area-under-the-curve (AUC). After matching AUC, gentamicin exposure was virtually identical between the two groups with an average gentamicin AUC of 26.61 ± 1.49 and 27.51 ± 1.25 mg · hr/L for the gentamicin/verapamil and gentamicin only groups respectively. Verapamil retarded the rise in mean daily AAP excretion on days 1 to 6 of gentamicin therapy, with a significant difference with respect to AAP urinary excretion (P < .05) observed on day 2. There was no significant difference in total cumulative AAP excretion or in the time to return to baseline AAP excretion. Therefore, verapamil was effective in reducing AAP excretion associated with gentamicin therapy.
• Nix, D. E. (1995). Management of common infections in the elderly. Journal of Geriatric Drug Therapy, 10(1), 5-28.
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  Abstract: Infections are responsible for a large proportion of morbidity and mortality in elderly patients. Immunosenescence and the frequent presence of chronic illnesses increase the susceptibility of elderly patients to infection, as well as the consequences of infection. Elderly patients may exhibit different symptoms than young patients, which complicates the diagnosis of infection. This review discusses common infections in the elderly including pneumonia, urinary tract infection, skin and soft tissue infection, and intraabdominal infection. Antimicrobial regimens are reviewed as are common adverse events related to individual agents.
• Nix, D. E. (1995). The effect of fluconazole on the pharmacokinetics of caffeine in young and elderly subjects. Journal of Infection Disease Pharmacotherapy, 1(1), 1-11.
• Nix, D. E., & Schentag, J. J. (1995). Role of pharmacokinetics and pharmacodynamics in the design of dosage schedules for 12-h cefotaxime alone and in combination with other antibiotics. Diagnostic Microbiology and Infectious Disease, 22(1-2), 71-76.
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  PMID: 7587053;Abstract: Pharmacodynamic principles have provided important tools to evaluate and compare antimicrobial agents, and well as to guide dosing. For β-lactams, time above the minimum inhibitory concentration (MIC) has surfaced as the most important factor. However, the area under the inhibitory serum concentration time-curve (AUIC) may be superior when appropriate dosing intervals are selected. Although the target time over the MIC is unclear in humans even when concentrations remain continuously above the MIC, a higher AUIC predicts better clinical outcome up to a maximum. This article provides a pharmacodynamic assessment of 1- and 2-g doses of cefotaxime every 12 h. AUIC24 values and published MIC values for common pathogens (grouped into four groups based on MIC90) were used to predict organisms suitable for treatment with every-12-h regimens. Cefotaxime was inadequate for group 4 organisms including: Pseudomonas aeruginosa, Acienetobacter sp., and Enterococcus sp. Organisms such as Enterobacter cloacae, Serratia marcescens, Staphylococcus aureus, and B. fragilis may be suboptimally treated with cefotaxime every 12 h. Cefotaxime in doses of 1-2 g every 12 h should be useful in patients with normal renal function infected with organisms having MICs < 0.5 μg/ml This regimen should obtain AUIC24 values > 125 and ensure adequate time above the MIC. In patients with impaired renal function, because of a longer half-life and higher area under the curve, pathogens with MIC values in the 0.5-2 μg/ml range may be treated with cefotaxime every 12 h while maintaining AUICs >125. Data are also presented for cefotaxime 2 g every 8 h alone and in combination with ofloxacin. Measured serum inhibitory titers show strengths and weakness of cefotaxime and ofloxacin monotherapies, and show that the combination often provided greater inhibitory activity than monotherapy with either agent. © 1995.
• Nix, D. E., Tyrrell, R., & Muller, M. (1995). Pharmacodynamics of metronidazole determined by a time-kill assay for Trichomonas vaginalis. Antimicrobial Agents and Chemotherapy, 39(8), 1848-1852.
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  PMID: 7486930;PMCID: PMC162837;Abstract: The pharmacodynamic effects of metronidazole on Trichomonas vaginalis have been poorly characterized. The present in vitro study was performed to characterize the relationship between killing of trichomonads and metronidazole exposure (metronidazole concentration and time of exposure). Five laboratory strains and five relent clinical isolates of T. vaginalis were studied. The minimum lethal concentrations (MLCs) of metronidazole for the strains ranged from 0.8 to 25 μg/ml under anaerobic conditions. Metronidazole exhibited concentration-dependent killing against T. vaginalis at concentrations ranging from 0.1 to > 10 times the MLC. The endpoint measurement, the kill rate constant, which was derived from the reduction in the logarithm of the colony count divided by exposure time, compared with the kill rate constant for the growth control was not affected by the time of assessment between 2 and 24 h. The kill rate constant-versus-metronidazole exposure curves were similar when concentration was expressed as a multiple of the MLC. There were no apparent differences between the clinical isolates and laboratory strains. These data suggest that peak metronidazole concentration and/or area under the plasma concentration-versus-time curve are the important pharmacodynamic parameters to be optimized.
• Oh, Y. -., Nix, D. E., & Straubinger, R. M. (1995). Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection. Antimicrobial Agents and Chemotherapy, 39(9), 2104-2111.
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  PMID: 8540724;PMCID: PMC162889;Abstract: Mycobacterium avium is an intracellular pathogen that can invade and multiply within macrophages of the reticuloendothelial system. Current therapy is not highly effective. Particulate drug carriers that are targeted to the reticuloendothelial system may provide a means to deliver antibiotics more efficiently to M. avium-infected cells. We investigated the formulation of the antibiotics ciprofloxacin and azithromycin in liposomes and tested their antibacterial activities in vitro against M. avium residing within J774, a murine macrophage-like cell line. A conventional passive.entrapment method yielded an encapsulation efficiency of 9% for ciprofloxacin and because of aggregation mediated by the cationic drug, was useful only with liposomes containing ≤50 mol% negatively charged phospholipid. In contrast, ciprofloxacin was encapsulated with >90% efficiency, regardless of the content of negatively charged lipids, by a remote-loading technique that utilized both pH and potential gradients to drive drug into preformed liposomes. Both the cellular accumulation and the antimycobacterial activity of ciprofloxacin increased in proportion to the liposome negative charge; the maximal enhancement of potency was 43-fold in liposomes of distearoylphosphatidylglycerol-cholesterol (DSPG-Chol) (10:5). Azithromycin liposomes were prepared as a freeze-dried preparation to avoid chemical instability during storage, and drug could be incorporated at 33 mol% (with respect to phospholipid). Azithromycin also showed enhanced antimycobacterial effect in liposomes, and the potency increased in parallel to the moles percent of negatively charged lipids; azithromycin in DSPG-Chol (10:5) liposomes inhibited intracellular M. avium growth 41-fold more effectively than did free azithromycin. Thus, ciprofloxacin or azithromycin encapsulated in stable liposomes having substantial negative surface charge is superior to nonencapsulated drug in inhibition of M. avium growth within cultured macrophages and may provide more effective therapy of M. avium infections.
• Shah, A., Lettieri, J., Nix, D., Wilton, J., & Heller, A. H. (1995). Pharmacokinetics of high-dose intravenous ciprofloxacin in young and elderly and in male and female subjects. Antimicrobial Agents and Chemotherapy, 39(4), 1003-1006.
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  PMID: 7785969;PMCID: PMC162672;Abstract: The effects of age and gender on the pharmacokinetics of high-dose intravenous ciprofloxacin in a healthy volunteer study were investigated. Plasma ciprofloxacin concentrations were higher in the elderly than in the young, and the pharmacokinetic parameters were not significantly different between the genders. Ciprofloxacin was well tolerated, with the majority of adverse events related to local reactions at the IV site.
• Teng, R., Harris, S. C., Nix, D. E., Schentag, J. J., Foulds, G., & Liston, T. E. (1995). Pharmacokinetics and safety of trovafloxacin (CP-99,219), a new quinolone antibiotic, following administration of single oral doses to healthy male volunteers. Journal of Antimicrobial Chemotherapy, 36(2), 385-394.
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  PMID: 8522468;Abstract: Trovafloxacin (CP-99,219) is a new fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria. The pharmacokinetics and safety of trovafloxacin were characterised in healthy male volunteers after administration of single oral doses of 30, 100, 300, 600 and 1000 mg. trovafloxacin was rapidly absorbed and serum concentrations reached a maximum approximately 1 h after dosing. The corresponding mean C(max) values (mean ± SD) were 0.3 ± 0.0, 1.5 ± 0.5, 4.4 ± 1.1, 6.6 ± 1.4 and 10.1 ± 0.5 mg/L. Terminal-phase half-life was independent of dose, with an overall mean of 9.9 ± 2.5 h. Generally, C(max) and AUC(0-∞) increased linearly with dose. Less than 10% of the administered dose was recovered unchanged in urine. Over the dosing range, trovafloxacin renal clearance was fairly constant, averaging 0.67 ± 0.36 L/h. Trovafloxacin binding to serum proteins was moderate (70%). Trovafloxacin was well tolerated at doses of 300 mg or below. There were no significant changes in the clinical chemistry or haematology parameters evaluated over the entire dosing range.
• Dandona, P., Nix, D., Wilson, M. F., Aljada, A., Love, J., Assicot, M., & Bohuon, C. (1994). Procalcitonin increase after endotoxin injection in normal subjects. Journal of Clinical Endocrinology and Metabolism, 79(6), 1605-1608.
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  PMID: 7989463;Abstract: As procalcitonin concentrations have been shown to be elevated in patients with septicemia and gram-negative infections in particular, we proceeded to investigate the effect of endotoxin, a product of gram- negative bacteria, on procalcitonin concentrations in normal human volunteers. Endotoxin from Escherichia coli 0113:H10:k, was injected iv at a dose of 4 mg/kg BW into these healthy volunteers. Blood samples were obtained before and 1, 2, 4, 6, 8, and 24 h after injection of the endotoxin. Each patient's cardiovascular and overall clinical status was monitored over this period. The patients developed chills and rigors, myalgia, and fever between 1-3 h. Tumor necrosis factor-α levels increased sharply at 1 h and peaked at 90 min, reaching the baseline concentration thereafter by 6 h. Interleukin-6 levels increased more gradually, peaking at 3 h and reaching the baseline concentration at 8 h. The procalcitonin concentration, which was undetectable (
• Goss, T. F., Forrest, A., Nix, D. E., Ballow, C. H., Birmingham, M. C., Cumbo, T. J., & Schentag, J. J. (1994). Mathematical examination of dual individualization principles (II): The rate of bacterial eradication at the same area under the inhibitory curve is more rapid for ciprofloxacin than for cefmenoxime. Annals of Pharmacotherapy, 28(7-8), 863-868.
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  PMID: 7949501;Abstract: OBJECTIVE: To compare two antibiotics at equal ranges of area under the inhibitory curve (AUIC) exposure to determine if the rate of bacterial eradication differed between these antibiotics. DESIGN: Retrospective comparison of two previously collected studies of similar patients with nosocomial pneumonia. SETTING: Hospitalized patients, most intubated in critical care units with nosocomial pneumonia. PARTICIPANTS: Patients treated with either iv ciprofloxacin (n=74) or the iv third-generation cephalosporin cefmenoxime (n=43) were compared for their length of treatment required to eradicate bacterial pathogens from their respective infection sites, using serial cultures from the site of infection. All patients were also assessed for clinical outcomes. Serum samples were obtained to evaluate individual patient antibiotic pharmacokinetics, which were used to model pharmacodynamics of response. The HPLC assay used for each antibiotic had interday coefficients of variation 250) required six days to achieve the same result. CONCLUSIONS: We conclude that the more rapid in vitro bacterial killing, which is characteristic of ciprofloxacin at optimal AUIC values, can manifest in vivo as more rapid clearance of bacteria from the respiratory tract of patients, even when both agents are controlled for initial antibacterial exposure (i.e., same AUIC).
• Huh, K., Wilton, J. H., Nix, D. E., & Schentag, J. J. (1994). Structures and biological activities of tobramycin-ticarcillin adducts. Journal of Pharmaceutical Sciences, 83(6), 763-767.
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  PMID: 9120803;Abstract: Aminoglycosides and penicillins chemically interact when they are combined in vitro or in vivo. The resulting adducts are considered to be biologically inactive. The major adducts formed in the interaction between tobramycin and ticarcillin have been recently isolated in pure form in our laboratory. On the basis of mass, infrared, and proton magnetic resonance spectra, the major adducts appeared to be amides formed by an attack of the β-lactam carbonyl group of ticarcillin by an amino group of tobramycin. All other moieties of ticarcillin were intact except that the β-lactam ring was opened and was rotated by 120-130°. The minimum inhibitory concentrations (MICs) of the adducts, tobramycin, and ticarcillin were 20.0, 0.25, and 2.0 μg/mL for Staphylococcus aureus and Escherichia coli, and 160.0, 0.5, and 8.0 μg/mL for Pseudomonas aeruginosa. Thus, the major adducts possessed some antimicrobial activity, but not enough to be active in the treatment of infections. As shown by fluorescence polarization immunoassay (FPIA), the adducts demonstrate some cross-reactivity in the assay of tobramycin. However, it was insufficient to cause significant error in the measurement of tobramycin in human serum.
• Hyatt, J. M., Nix, D. E., & Schentag, J. J. (1994). Pharmacokinetic and pharmacodynamic activities of ciprofloxacin against strains of Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa for which MICs are similar. Antimicrobial Agents and Chemotherapy, 38(12), 2730-2737.
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  PMID: 7695254;PMCID: PMC188277;Abstract: The serum bactericidal activity of ciprofloxacin against strains of Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa for which MICs are similar (0.4 μg/ml) was assessed with serum ultrafiltrates from five healthy volunteers receiving ciprofloxacin at 400 mg intravenously every 8 h. In addition, human serum was supplemented with ciprofloxacin to achieve a mean steady-state concentration (C(ss)) that might be achieved in patients with renal failure, with total clearances of 3 to 4 liters/h (elimination rate constant, 0.08 h-1). The area under the inhibitory titer curve from 0 to 24 h (AUIC24) and the area under the bactericidal titer curve from 0 to 24 h (AUBC24) were both measured and predicted as the area under the concentration-time curve from 0 to 24 h (AUC24)/MIC and AUC24/MBC, respectively. We previously demonstrated that a breakpoint AUC24/MIC of 125 for ciprofloxacin had a significantly higher probability of treatment success than lower values, with 250 to 500 being optimal. Volunteer sera (mean C(ss), 1.55 to 2.48 μg/ml) achieved AUC24/MICs of 90 to 145. Supplemented serum (mean C(ss), 6.00 to 7.42 μg/ml) achieved AUC24/MICs of 350 to 450. Correlation coefficients for measured and predicted values of AUC24/MIC and AUC24/MBC were 0.826 and 0.941, respectively. The mean percent errors were not significantly different from zero for either AUIC24 or AUBC24 values (P > 0.1, P > 0.04). Time- kill curve studies were performed with low (1.55 to 2.48 μg/ml), intermediate (6.00 to 7.42 μg/ml), and high (15 to 25 μg/ml) concentrations of ciprofloxacin for the three organisms. At low concentrations (3 to 6 times the MIC) AUC24/MICs were
• Li, R. C., Nix, D. E., & Schentag, J. J. (1994). Interaction between ciprofloxacin and metal cations: Its influence on physicochemical characteristics and antibacterial activity. Pharmaceutical Research, 11(6), 917-920.
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  PMID: 7937536;
• Li, R. C., Nix, D. E., & Schentag, J. J. (1994). Pharmacodynamic modeling of bacterial kinetics: β-Lactam antibiotics against Escherichia coli. Journal of Pharmaceutical Sciences, 83(7), 970-975.
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  PMID: 7965677;Abstract: A simple pharmacodynamic model has been developed to describe the bacterial kinetics exhibited by β-lactam antibiotics. In contrast with previous models that only characterized the early killing phase of a time- kill curve, the present model is capable of simultaneously describing both the killing and regrowth phases. The model relied on the use of both first- order bactericidal and resistance formation rate constants to accurately define the time-dependent changes in the bacterial populations of an antibiotic-treated culture. The concentration dependency of the bactericidal rate constant was further delineated using a saturable-receptor model. Furthermore, an exponential decrease in the resistance formation rate with increasing antibiotic concentrations was demonstrated. The evolving pharmacodynamic model was also explored via computer simulations by perturbing the two governing rate constants. The model was subsequently applied to the description of time-kill data for amoxicillin, penicillin G, and cephalexin against Escherichia coli. The description of amdinocillin's action against E. coli was not as comprehensive because of the existence of a second killing phase. However, this model can be applicable to many classes of antibiotics that display the usual killing and regrowth phases in time- kill studies. The pharmacodynamic model can potentially improve the prediction of bacterial killing and regrowth and foster an improved understanding of complex antimicrobial pharmacodynamics.
• Birmingham, M. C., Nix, D. E., Cumbo, T. J., Collins, D. A., Wels, P. B., & Schentag, J. J. (1993). The development of a bedside algorithm capable of targeting anti- endotoxins to the responder subpopulations. Therapeutic Drug Monitoring, 15(6), 503-509.
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  PMID: 8122285;Abstract: The published selection criteria for use of anti-endotoxin antibodies are modeled on the criteria used in protocol enrollment of patients. These criteria are not suitable for therapeutic decision-making, because the trials themselves prove that the enrollment criteria have both low sensitivity and low specificity. In order to develop a selection method with greater sensitivity and specificity, we examined the charts and records of 23 patients that we enrolled in the multicenter trials of E5 and HA-1A. We retrospectively determined that seven of our 23 enrolled patients were optimal candidates, based on a pattern of rapid clinical deterioration followed by improvement in 24-96 h. We then explored a variety of different modes of bedside patient selection, in search of a method to select as many of the seven optimal candidates as possible while at the same time rejecting the greatest number of the 16 who showed no benefit when treated. None of the resulting selection methods has perfect performance, but nearly all were better than the original protocol enrollment criteria. In our patients, bacteremia had 57% sensitivity and 56% specificity, which was quite similar to the findings in the HA-1A multicenter trial. Shock had 100% sensitivity and 44% specificity, while a baseline organ dysfunction score of ≥5 had 100% sensitivity and 69% specificity. A new algorithm that we developed based on a patient's need for vasopressors and baseline organ dysfunction had 100% sensitivity and 81% specificity. This algorithm could identify all seven of the optimal candidates, plus three more. We propose that there are bedside methods capable of considerably more specific identification of patients who would respond to treatment with anti-endotoxin antibodies.
• Forrest, A., Ballow, C. H., Nix, D. E., Birmingham, M. C., & Schentag, J. J. (1993). Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin. Antimicrobial Agents and Chemotherapy, 37(5), 1065-1072.
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  PMID: 8517693;PMCID: PMC187899;Abstract: Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean ± standard deviation = 7 ± 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CL(T) in liters per hour) was related to body size and renal function (creatinine clearance [CL(CR)] in milliliters per minute per 1.73 m2) by the equation CL(T) = (0.00145 · CL(CR) + 0.167) · weight. However, only 30% of the variance in CL(T) was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CL(T) (by 44%; P < 0.001) than weight- and CL(CR)-matched stable volunteers. The OSSs provided parameter estimates that showed good to excellent concordance with those obtained from all available data. Even with only two well-timed plasma samples, estimates of CL(T) (or area under the concentration-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was >0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.
• Forrest, A., Nix, D. E., Ballow, C. H., Goss, T. F., Birmingham, M. C., & Schentag, J. J. (1993). Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrobial Agents and Chemotherapy, 37(5), 1073-1081.
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  PMID: 8517694;PMCID: PMC187901;Abstract: Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two- compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1 · h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days; and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatinine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.
• Li, R. C., Nix, D. E., & Schentag, J. J. (1993). New turbidimetric assay for quantitation of viable bacterial densities. Antimicrobial Agents and Chemotherapy, 37(2), 371-374.
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  PMID: 8452373;PMCID: PMC187673;Abstract: A turbidimetric assay was developed and validated against Escherichia coli for the quantitation of viable bacterial densities. The Abbott MS-2 research system was employed for continuous 5-min measurements of optical density. A linear standard curve was obtained by regressing the initial bacterial density (log CFU per milliliter) against the time required for bacterial growth causing a 5% decrease in optical transmittance. Slope and intercept values obtained from eight standard curves showed excellent assay reproducibility. Results obtained by the turbidimetric assay compared favorably to those obtained by the conventional pour plate assay. Prior to the application of the new assay, possible interferences of postantibiotic effect induced by the test antibiotics were excluded. The turbidimetric assay, which is presumably more efficient and less expensive, was implemented for the time-kill studies of three different β-lactams against E. coli.
• Li, R. C., Schentag, J. J., & Nix, D. E. (1993). The fractional maximal effect method: A new way to characterize the effect of antibiotic combinations and other nonlinear pharmacodynamic interactions. Antimicrobial Agents and Chemotherapy, 37(3), 523-531.
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  PMID: 8460921;PMCID: PMC187702;Abstract: The checkerboard technique leading to the fractional inhibitory concentration indexes and the killing curve method are currently the most widely used methods to study antibiotic combinations. For both methods, experimental conditions and interpretation criteria are somewhat arbitrary. The relevance of the fractional inhibitory concentration index computation, in the classic case of additivity [P = d1/(D1)(p) + d2/(D2)(p), where d1 and d2 are the doses of drugs 1 and 2 in combination to produce an effect at a percent level (P) and (D1)(p) and (D2)(p) are the doses required for the two respective drugs alone to produce the same effect] relies on the assumption of a linear relationship between the MIC and the concentration of the test antibiotics. In addition, there is no consensus as to the definition of synergy in killing curve interpretation. The fractional maximal effect (FME) method is a new approach which was developed to handle the nonlinear pharmacodynamics exhibited by antibiotics and other drugs. This method relies on the mathematical linearization of the nonlinear concentration-effect scales and eventual construction of an isobologram-type data plot. The FME method was applied to study interactions between several antibiotic combinations: amoxicillin and tetracycline, ciprofloxacin and erythromycin, and ticarcillin and tobramycin. These combinations were selected because the pharmacologic basis for their interactions has been previously described. The FME method correctly identified antagonism for the first two combinations and synergism for the last combination. Conclusions were reproducible across the range of concentrations studied. Besides providing information on the nature of the interaction, the method can rapidly explore the effect of changing concentration ratios of two antimicrobial agents on the degrees of interaction. The FME method may be applied to interactions between drugs or agents with either a linear or nonlinear endpoint measurement. Methods frequently used for drug combination testing are also discussed in the paper.
• Nix, D. E., Lebsack, M. E., Chapelsky, M., Sedman, A. J., Busch, J., & Norman, A. (1993). Effect of oral antacids on disposition of intravenous enoxacin. Antimicrobial Agents and Chemotherapy, 37(4), 775-777.
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  PMID: 8494374;PMCID: PMC187758;Abstract: The effect of an intensive aluminum-magnesium hydroxide antacid regimen (Maalox TC) on the disposition of intravenous enoxacin was studied in six male and six female volunteers. A single 400-mg dose of enoxacin was administered intravenously over 30 min on two occasions separated by a 1- week washout period. Thirty milliliters of Maalox TC was administered at -8, -2.5, -0.5, 1.5, 3.5, 5.5, 7.5, 9.5, 11.5, 13.5, and 15.5 h relative to the start of one enoxacin infusion. The enoxacin dose in which antacid was coadministered was randomly selected. Fourteen plasma samples were collected over 24 h, and urine was collected in two divided intervals over 48 h. Enoxacin concentrations in plasma and urine samples were determined by high- performance liquid chromatographic assays. The intensive antacid regimen did not change the total clearance (P = 0.058) or steady-state volume of distribution (P = 0.516) for enoxacin. However, the nonrenal clearance and half-life were significantly altered (P < 0.05). The mean nonrenal clearance increased from 13.27 ± 3.33 to 15.68 ± 2.35 liters/h (18.2%) following the antacid regimen. This effect of antacid is unlikely to be of clinical significance. Enoxacin may be administered intravenously, but not orally, without regard to antacid treatment.
• Schentag, J. J., Forrest, A., Goss, T. F., Luzier, A., Nix, D. E., Cumbo, T. J., Fracasso, J. E., Sands, M. F., & Vance, J. W. (1993). Ciprofloxacin eradicates respiratory tract bacteria more rapidly than cephalosporins in patients with nosocomial pneumonia. Drugs, 46(SUPPL. 3), 473-.
• Strenkoski, L. C., & Nix, D. E. (1993). Cefpirome clinical pharmacokinetics. Clinical Pharmacokinetics, 25(4), 263-273.
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  PMID: 8261711;Abstract: Cefpirome is a new cephalosporin that exhibits similar in vitro potency to ceftazidime against Gram-negative organisms but has significantly greater in vitro potency against Gram-positive organisms. Cefpirome differs from cefotaxime in that a 3'-pyridinium moiety replaces the acetoxy moiety of cefotaxime. This structural change imparts greater β-lactamase stability, increases the ability to penetrate the outer membrane of Gram-negative bacteria, and enhances activity against Gram-positive organisms. The pharmacokinetic properties of cefpirome are typical of cephalosporins. The drug can be administered by intravenous or intramuscular injection, but is not well absorbed after oral administration. Bioavailability following intramuscular injection exceeds 90%. Cefpirome exhibits low protein binding (≃10%) and has a volume of distribution similar to extracellular fluid volume. Cefpirome penetrates the prostate gland, lung, blister fluid, cerebrospinal fluid and peritoneal fluid, reaching concentrations that are similar to those achieved by other later generation cephalosporins. Approximately 80% of an intravenous dose is eliminated unchanged in the urine. No active metabolites of cefpirome have been identified. The elimination half-life of cefpirome is approximately 2 hours. Elimination appears to be primarily by glomerular filtration since the total clearance of cefpirome is approximately equal to creatinine clearance. The time during which drug concentrations exceed the minimum inhibitory concentration (MIC) represents the most clinically important pharmacodynamic parameter for β-lactam agents. When cefpirome is administered at a dosage of 2g every 12 hours to patients without renal insufficiency [creatinine clearance 70 ml/min (4.2 L/h)], drug concentrations continuously remain above the MIC for pathogens with MIC values of ≤2 μg/ml. With this dosage regimen, drug concentrations will be above the MIC for a pathogen with an MIC of 4 μg/ml for 80% of the dosage interval. The time above MIC for pathogens with an MIC of 8 μg/ml is only 60% of the dosage interval.
• Symonds, W. T., O'Connor, G., & Nix, D. E. (1993). Focus on itraconazole: A broad-spectrum antifungal agent for treatment of blastomycosis and histoplasmosis. Hospital Formulary, 28(1), 23-26+28+33.
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  Abstract: Itraconazole is a new azole antifungal agent active against many common fungal pathogens. The agent was recently approved by the FDA for the treatment of blastomycosis and histoplasmosis, although no controlled, comparative trials have been published. Itraconazole possesses a favorable pharmacokinetic and safety profile and can be administered once or twice daily. Absorption of itraconazole from the gastrointestinal tract is greatly enhanced by the presence of food; therefore, the drug should be administered following meals. Unlike ketoconazole, itraconazole has minimal effects upon the metabolism of endogenous steroids and other drugs. Compared with other available agents useful for the treatment of blastomycosis and histoplasmosis, itraconazole appears to be well tolerated, equally efficacious, and less toxic.
• Chapelsky, M. C., Nix, D. E., Cavanaugh, J. C., Wilton, J. H., Norman, A., & Schentag, J. J. (1992). Renal tubular enzyme effects of clarithromycin in comparison with gentamicin and placebo in volunteers. Drug Safety, 7(4), 304-309.
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  PMID: 1355971;Abstract: This study assessed the potential nephrotoxicity of clarithromycin in comparison with gentamicin and placebo. Increased urinary excretion of alanine aminopeptidase (AAP) and N-acetyl β-D-glucosaminidase (NAG) served as markers of renal tubular injury. The study utilised a mutiple-dose, double-blind, randomised, parallel group design. 14 healthy male subjects received of 3 treatment regimens: (a) clarithromycin 500 mg orally every 12 h for 13 doses and intravencus placebo every 8 h (n = 5); (b) oral placebo every 12 h and intravenous placebo every 8 h (n = 4 and (c) intravenous gentamicin 1.7 mg/kg every 8 h for 19 doses and oral placebo every 12 h (p = 5). 24h urine collections were obtained daily for determinations of AAP and NAG activities. Gentamicin produced statistically significant increases (p < 0.0001) in AAP and NAG excretion, with increases as early as the first and second day of dosing. Clarithromycin, when compared with placebo, did not produce significant elevations in AAP or NAG activity. On the basis of these data, it is unlikely that usual doses of clarithromycin have significant potential for causiag nephrotoxicity.
• Lebsack, M. E., Nix, D., Ryerson, B., Toothaker, R. D., Welage, L., Norman, A. M., Schentag, J. J., & Sedman, A. J. (1992). Effect of gastric acidity on enoxacin absorption. Clinical Pharmacology and Therapeutics, 52(3), 252-256.
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  PMID: 1526081;Abstract: The effect of gastric acidity on the oral absorption of the quinolone antibiotic enoxacin was evaluated in 12 healthy volunteers. In a randomized, crossover design, single 400 mg oral enoxacin doses were administered on four occasions: alone, after 50 mg intravenous ranitidine, after 2 μg/kg subcutaneous pentagastrin, and after combined ranitidine and pentagastrin treatment. Gastric pH was monitored by radiotelemetry capsule for 4 hours after enoxacin administration. Ranitidine pretreatment reduced enoxacin oral-bioavailability by an average of 26%. This effect was abolished when pentagastrin was used to maintain low gastric pH. Thus the ranitidine-induced decrease in enoxacin oral bioavailability probably results from a decrease in gastric acidity rather than from an interaction with ranitidine itself.
• Nix, D. E., Spivey, J. M., Norman, A., & Schentag, J. J. (1992). Dose-ranging pharmacokinetic study of ciprofloxacin after 200-, 300-, and 400-mg intravenous doses.. The Annals of pharmacotherapy, 26(1), 8-10.
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  PMID: 1606348;Abstract: OBJECTIVE: To assess the pharmacokinetics and tolerance of ciprofloxacin after the administration of single intravenous doses of 200, 300, and 400 mg. DESIGN: Double-blind, three-period, randomized, crossover trial. SETTING: Private, university-affiliated, hospital-based, clinical research center. PATIENTS: Normal healthy male volunteers, 18-40 years of age. INTERVENTIONS: Subjects received 200-, 300-, and 400-mg single intravenous doses of ciprofloxacin via 30-minute infusions in random sequence. MAIN OUTCOME MEASURES: Serum ciprofloxacin concentrations were determined by HPLC after each dose and the results were used to derive pharmacokinetic parameters. Tolerance was assessed by reported and observed adverse events, urine microscopic examinations for crystals, and examination of intravenous infusion sites. RESULTS: The mean area under the time curve (AUC) values displayed linearity with respect to the administered dose. No statistical differences were observed in total body clearance, steady-state volume of distribution, or elimination half-life with respect to dose administered. The mean total body clearance, steady-state volume of distribution, or elimination half-life ranged from 36 to 41 L/h, 146 to 169 L, and 3.5 to 3.7 h for the 200-, 300-, and 400-mg doses, respectively. Adverse effects, including venous irritation (four subjects) and crystalluria (two subjects), were mild and did not require withdrawal of any subject from the study. CONCLUSIONS: Intravenous ciprofloxacin in doses ranging from 200 to 400 mg demonstrated linear pharmacokinetics. These single doses were well tolerated, although cases of transient venous irritation and crystalluria were observed.
• Nix, D. E., Wilton, J. H., Velasquez, N., Budny, J. L., Lassman, H. B., Mitchell, P., Divan, K., & Schentag, J. J. (1992). Cerebrospinal fluid penetration of cefpirome in patients with non-inflamed meninges. Journal of Antimicrobial Chemotherapy, 29(SUPPL. A), 51-57.
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  PMID: 1601757;Abstract: Twenty patients (mean age 52 ± 12 years, mean weight 75 ± 15 kg) scheduled for elective myelogram or spinal anaesthesia were enrolled to determine the cerebrospinal fluid (CSF) penetration of a new expanded spectrum cephalosporin antibiotic, cefpirome (HR-810). A single 2 g intravenous dose of cefpirome was administered as a bolus between 1 and 8 h before lumbar puncture. Blood samples were collected at 15 pre-determined times and a single CSF sample was obtained at the time of lumbar puncture. Serum and CSF cefpirome concentrations were determined by high performance liquid chromatography. The mean maximal serum concentration of cefpirome was 264 ± 76 mg/L. A mean steady-state volume of distribution of 20 ± 4 L, clearance of 7.4 ± 1.3 L/h, and half-life of 2.5 ± 0.5 h were determined. Mean CSF concentrations were 0.50 ± 0.11 mg/L at 1-2 h post dose (n = 4), 0.57 ± 0.13 mg/L at 2-4 h post dose (n = 4), 0.76 ± 0.34 mg/L at 4-6 h post dose (n= 7), and 0.83 ± 0.29mg/L at 6-8.3 h post dose (n = 5). Blood:brain barrier permeability to cefpirome may not be a limiting factor as CSF concentrations were rapidly attained. Further studies are required to determine the mechanism of cefpirome transport between plasma and CSF.
• Spivey, J. M., Blum, R. A., & Nix, D. E. (1992). Mathematic modeling of drug disposition and postdialysis rebound in patients requiring hemodialysis. Pharmacotherapy, 12(3), 201-206.
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  PMID: 1608853;Abstract: We developed a model to describe intradialysis and postdialysis serum concentration changes and, in concert with nonlinear regression, to estimate drug removal during hemodialysis. A Lotus-based computer simulation program was developed that describes drug disposition in this therapy. The hemodialysis removal rate constant and β were two important factors identified that influence postdialysis rebound. Also, a nonlinear regression routine using PCNONLIN was developed that enables simultaneous fitting of predialysis, intradialysis, and postdialysis drug concentration data. Data from four patients who received intravenous sulbactam were analyzed using this model. The mean measured amount of sulbactam removed by hemodialysis was 446 ± 32 mg versus predicted amounts of 456 ± 92 mg from model estimates, and 449 ± 33 mg when dialysate recovery of drug was included in the input. This program will be useful in characterizing pharmacokinetic constants and predicting hemodialysis drug removal.
• Symonds, W. T., & Nix, D. E. (1992). Lomefloxacin and temafloxacin: Two new fluoroquinolone antimicrobials. Clinical Pharmacy, 11(9), 753-766.
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  PMID: 1325892;Abstract: The chemistry; mechanism of action, antimicrobial spectrum, pharmacokinetics, clinical efficacy, safety, drug interactions, and dosage and administration of lomefloxacin and temafloxacin, two new antimicrobials, are presented. Lomefloxacin and temafloxacin exhibit activity comparable to that of ciprofloxacin against the Enterobacteriaceae. Lomefloxacin has only modest activity against common gram-positive organisms. Temafloxacin exhibits increased activity against the streptococci and moderate activity against many anaerobes, as compared with ciprofloxacin. Lomefloxacin and temafloxacin have only moderate antipseudomonal activity. Their elimination half-lives are 6-10 hours and they have good oral absorption, excellent penetration into many tissues and fluids, and a better drug-interaction profile than other similar agents. Lomefloxacin has demonstrated comparable efficacy to other therapies in the treatment of lower respiratory-tract infections and urinary- tract infections (UTIs) and for prophylaxis before surgical procedures in the urinary tract. Temafloxacin has been shown to be effective in the treatment of lower respiratory-tract infections, infections of the skin and associated structures, uncomplicated and complicated UTIs, bacterial prostatitis, and gonococcal and nongonococcal urethritis and cervicitis. The most frequent adverse effects with lomefloxacin are gastrointestinal upset and headache; with temafloxacin, gastrointestinal complaints. Lomefloxacin's dosage is 400 mg p.o. daily for 10 days for treatment of acute bacterial exacerbations in chronic bronchitis or simple cystitis and for 14 days for treatment of complicated UTIs. Lomefloxacin is a new oral fluoroquinolone that is indicated for the treatment of various bacterial infections. Temafloxacin, another new fluoroquinolone, appeared to have some favorable characteristics but was withdrawn from the market.
• Dolgin, J. G., Nix, D. E., Sanchez, J., & Watson, W. A. (1991). Pharmacokinetic simulation of the effect of multiple-dose activated charcoal in phenytoin poisoning - Report of two pediatric cases. DICP, Annals of Pharmacotherapy, 25(6), 646-649.
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  PMID: 1877275;Abstract: Activated charcoal is commonly used to inhibit the absorption of phenytoin after acute overdose. There are also reports of multiple-dose activated charcoal (MDAC) increasing the clearance of phenytoin in adults. We describe our experience modeling phenytoin pharmacokinetics during therapy with MDAC in the treatment of two cases of acute phenytoin poisoning in children. After extensive attempts at modeling the serum phenytoin concentrations, simulations were performed to identify the possible consequences of MDAC administration. Phenytoin elimination was more rapid than was expected, based on previously reported phenytoin pharmacokinetic parameters. Moreover, the time to peak phenytoin concentration and time course of phenytoin intoxication appeared to be shorter than available reports of phenytoin intoxication treated with a single dose of activated charcoal. MDAC may prevent continued phenytoin absorption and increase phenytoin elimination rate via gastrointestinal dialysis. The effect of MDAC on the clearance of phenytoin can be described by a first-order elimination rate constant of approximately 0.02-0.04/h.
• Goodwin, S. D., Nix, D. E., Heyd, A., & Wilton, J. H. (1991). Compatibility of ciprofloxacin injection with selected drugs and solutions. American Journal of Hospital Pharmacy, 48(10), 2166-2171.
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  PMID: 1781473;Abstract: The compatibility of ciprofloxacin injection with selected antimicrobials and aminophylline was studied. Ciprofloxacin, amikacin sulfate, aminophylline, clindamycin phosphate, gentamicin sulfate, and tobramycin sulfate were mixed separately in minibags containing 0.9% sodium chloride injection or 5% dextrose injection; admixtures were stored for up to 48 hours at either 4 °C or 25 °C. Ciprofloxacin was also combined separately with each of the other drugs and solutions and stored under the same conditions. In addition, ciprofloxacin was combined with metronidazole in ready-to-use minibags of the latter drug and stored at 25 °C. Drug concentrations were measured by fluorescence polarization immunoassay or high-performance liquid chromatography. All admixtures were also examined visually. Stability was defined as retention of at least 90% of the original drug concentration with no visual evidence of incompatibility. With one exception, drugs in all single-drug admixtures were stable for 48 hours. The drug concentration eight hours after amikacin was mixed in 0.9% sodium chloride and refrigerated was 89% of the original concentration. When ciprofloxacin was combined with gentamicin, metronidazole, or tobramycin, all of the involved drugs were stable for 48 hours. Compatibility of ciprofloxacin-amikacin admixtures depended on the fluid and storage temperature; all such admixtures were stable for at least eight hours. A precipitate formed immediately whenever ciprofloxacin was mixed with clindamycin and within four hours after ciprofloxacin was mixed with aminophylline. Ciprofloxacin injection was compatible with gentamicin, metronidazole, and tobramycin and incompatible with aminophylline and clindamycin. The compatibility of ciprofloxacin-amikacin admixtures depended on the i.v. solution and storage temperature.
• Nix, D. E., Goodwin, S. D., Peloquin, C. A., Rotella, D. L., & Schentag, J. J. (1991). Antibiotic tissue penetration and its relevance: Impact of tissue penetration on infection response. Antimicrobial Agents and Chemotherapy, 35(10), 1953-1959.
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  PMID: 1759813;PMCID: PMC245307;
• Nix, D. E., Goodwin, S. D., Peloquin, C. A., Rotella, D. L., & Schentag, J. J. (1991). Antibiotic tissue penetration and its relevance: Models of tissue penetration and their meaning. Antimicrobial Agents and Chemotherapy, 35(10), 1947-1952.
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  PMID: 1759812;PMCID: PMC245306;
• Schentag, J. J., Nix, D. E., & Adelman, M. H. (1991). Mathematical examination of dual individualization principles (I): Relationships between AUC above MIC and area under the inhibitory curve for cefmenoxime, ciprofloxacin, and tobramycin. DICP, Annals of Pharmacotherapy, 25(10), 1050-1057.
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  PMID: 1803788;Abstract: Traditional antibiotic dosage adjustments target predetermined serum concentrations, whereas a host of in vitro studies and recent clinical trials establish that bacteria vary in their susceptibility. Dual individualization, which considers the variance in both antibiotic pharmacokinetics and bacterial susceptibility, has been employed to describe different rates of bacterial eradication in relation to varying serum concentrations. In patients with nosocomial pneumonia, one of the model compounds studied was cefmenoxime, where a target six-hour area under the serum concentration-time curve (AUC) of 140 μg · h/mL above minimum inhibitory concentration (MIC) was previously associated with bacterial eradication in an average of four days. The target AUC value of 140 μg · h/mL above MIC is unique to cefmenoxime. Ideally, there should be a dual individualized target useful to adjust the dose of any antibiotic. Computer simulations performed to evaluate this hypothesis suggested that each antibiotic had a unique value for target AUC above MIC. These simulations indicated that an optimal AUC above MIC was about 80 percent of the total AUC above the MIC. Predictable rates of bacterial eradication would presumably result from maintaining these relationships across the range of bacterial susceptibility and the range of serum concentration profiles. Each antibiotic has a unique and different 24-hour AUC over MIC value associated with bacterial eradication in 4 days. For cefmenoxime, the target was 540 area units over MIC per 24 hours, tobramycin with 34 area units, and ciprofloxacin with 23 area units per 24 hours. Because it would clearly be desirable to have a target for dosing adjustment that is independent of the particular antibiotic, we then used computer simulations to determine whether the AUIC (area under the inhibitory curve, or integrated AUC above MIC vs. time) could be descriptive of bacterial eradication with the cephalosporin, cefmenoxime; the aminoglycoside, tobramycin; and the fluoroquinolone, ciprofloxacin. Computer simulation revealed that appropriate doses of all three of these antibiotics yield 24-hour AUIC values in the range of 125. On the basis of these simulations, we propose that target AUIC values are likely to be applicable across antibiotic classes, whereas AUC above MIC targets must be unique values to the particular antibiotic. Furthermore, these relationships can be used to make comparisons of antibiotic activity either across different antibiotic classes or within the same class.
• Slooten, A. V., Nix, D. E., Wilton, J. H., Love, J. H., Spivey, J. M., & Goldstein, H. R. (1991). Combined use of ciprofloxacin and sucralfate. DICP, Annals of Pharmacotherapy, 25(6), 578-582.
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  PMID: 1877263;Abstract: The effect of sucralfate on the bioavailability of ciprofloxacin hydrochloride was assessed in 12 healthy male volunteers. The study was a four-period crossover design where subjects were randomized to one of four treatment sequences at entry. Treatments A, B, and C included sucralfate 2 g q12h for five doses. For treatment A, the fifth dose of sucralfate was administered concurrendy with ciprofloxacin 750 mg. For treatment B, 750 mg of ciprofloxacin was administered two hours before the fifth dose of sucralfate. Treatment C consisted of ciprofloxacin 750 mg six hours before the fifth dose of sucralfate. A 750-mg dose of ciprofloxacin was administered alone for treatment D. Blood and urine samples were collected at predetermined time intervals for 24 hours. Ciprofloxacin concentrations were determined by HPLC. The area under the concentration versus time curve from zero to infinity and the urinary recovery of ciprofloxacin were used for determining relative bioavailability. Concurrent administration of ciprofloxacin and sucralfate (treatment A) resulted in a significant decrease (p < 0.05) in ciprofloxacin absorption. The relative bioavailabilities for treatments A, B, and C were 0.0429 ± 0.0202, 0.829 + 0.21, and 0.965 + 0.32, respectively, relative to ciprofloxacin alone. In normal volunteers, ciprofloxacin may be administered between two and six hours before sucralfate, allowing sufficient time for ciprofloxacin absorption prior to the sucralfate dose and thereby minimizing the chance of a significant interaction. In patients with decreased gastric emptying the interaction may be more difficult to avoid.
• Spivey, J. M., Laughlin, P. H., Goss, T. F., & Nix, D. E. (1991). Theophylline toxicity secondary to ciprofloxacin administration. Annals of Emergency Medicine, 20(10), 1131-1134.
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  PMID: 1928889;Abstract: We report the case of a 79-year-old woman who presented from a skilled nursing facility to the emergency department with signs and symptoms of theophylline toxicity and a serum theophylline concentration of 53.7 mg/L. The patient had been on a regular regimen of aminophylline for two months, with the addition of ciprofloxacin three days before arrival as the only identifiable potential cause of theophylline intoxication. She was monitored and treated conservatively with serial doses of activated charcoal, which resulted in a reduction of her serum theophylline level to a therapeutic concentration in 15 hours without adverse sequelae. The number of cases of theophylline intoxication secondary to concurrent ciprofloxacin administration is likely to increase, especially in nursing home populations, and it should be suspected when these patients present to the ED with the appropriate signs and symptoms. Management of theophylline intoxication should be based on clinical presentation as well as concentrations of the drug. © 1991 American College of Emergency Physicians.
• Cook, J. A., Silverman, M. H., Schelling, D. J., Nix, D. E., Schentag, J. J., Brown, R. R., & Stroshane, R. M. (1990). Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers. Antimicrobial Agents and Chemotherapy, 34(6), 974-979.
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  PMID: 2393295;PMCID: PMC171741;Abstract: The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in health male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquidh chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean ± standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 ± 1.12, 4.98 ± 1.44, 5.40 ± 2.02, 4.59 ± 2.17, 6.53 ± 2.44, and 8.01 ± 3.00 μg/ml after the initial dose and 2.30 ± 0.98, 5.41 ± 0.74, 8.05 ± 1.68, 6.87 ± 2.81, 9.53 ± 0.50, and 11.9 ± 1.92 μg/ml on day 11 of the study for the 200-, 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 μg/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinar tract infections.
• Haas, C. E., Nix, D. E., & Schentag, J. J. (1990). In vitro selection of resistant Helicobacter pylori. Antimicrobial Agents and Chemotherapy, 34(9), 1637-1641.
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  PMID: 2285275;PMCID: PMC171897;Abstract: Four strains of Helicobacter pylori were subjected to an in vitro serial passage technique to compare the propensity of the organisms to develop resistance to seven classes of antibacterial agents. The passages were made on serially doubling concentrations of antibacterial agents incorporated into agar starting at one-half the base-line MIC. The frequency of spontaneous resistance was also determined for each strain at four and eight times the MIC of each antibacterial agent. Strains resistant to ciprofloxacin, metronidazole, erythromcyin, and tobramycin were isolated. The experiments failed to select organisms resistant to bismuth subsalicylate, furazolidone, or amoxicillin, althought the MIC of amoxicillin was increased 4- to 16-fold. With the exception of erythromycin, organisms with the selected resistance were stable after at least three passages on antibacterial agent-free medium. Spontaneous resistance rates were generally of a low magnitude and were not predictive of the serial passage results.
• Nix, D. E., Wilton, J. H., Ronald, B., Distlerath, L., Williams, V. C., & Norman, A. (1990). Inhibition of norfloxacin absorption by antacids. Antimicrobial Agents and Chemotherapy, 34(3), 432-435.
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  PMID: 2334155;PMCID: PMC171610;Abstract: The effects of antacids on the systemic absorption of oral norfloxacin was evaluated in 12 healthy volunteers. Subjects were given each treatment in a balanced sequence at 7-day intervals. Treatments included 400 mg of norfloxacin alone, 400 mg of norfloxacin 5 min after aluminium-magnesium hydroxide (Maalox), Maalox 2 h after 400 mg of norfloxacin, and 400 mg of norfloxacin 5 min after calcium carbonate (Titralac). Blood and urine samples were collected at predetermined time intervals for 24 and 48 h, respectively. Norfloxacin concentrations in plasma and urine were determined by high-pressure liquid chromatography. The area under the plasma concentration-versus-time curve from time zero to infinity and urinary recovery were used to compare the relative bioavailability of norfloxacin with antacids with that of norfloxacin alone. Norfloxacin bioavailability was markedly reduced when subjects received antacid pretreatment. When norfloxacin was given 5 min after Maalox and Titralac, the bioavailabilities were 9.02 and 37.5%, respectively, relative to that for 400 mg of norfloxacin alone. When Maalox was given 2 h after norfloxacin, maximal concentrations of norfloxacin in plasma occurred between 1 and 1.5 h postdose, and absorption was reduced to a lesser extent, with a relative bioavailability of 81.31%. Norfloxacin concentrations in urine were also reduced as a result of antacid administration. Antacids containing aluminium and magnesium salts and calcium carbonate should be avoided by patients taking norfloxacin.
• Nguyen, V. X., Nix, D. E., Gillikin, S., & Schentag, J. J. (1989). Effect of oral antacid administration on the pharmacokinetics of intravenous doxycyline. Antimicrobial Agents and Chemotherapy, 33(4), 434-436.
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  PMID: 2729939;PMCID: PMC172455;Abstract: The effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline was studied. In a randomized crossover design, six healthy male volunteers received an infusion of 200 mg of doxycycline hyclate on two occasions separated by 7 days. On one occasion, subjects were given 30 ml of aluminum hydroxide orally four times a day for 4 days, beginning 2 days prior to doxycycline dosing. Blood and urine samples were collected up to 48 and 96 h after the infusion, respectively, and were analyzed by a microbial assay. Values for volume of distribution at steady state, nonrenal clearance, urine recovery, and urine pH were not statistically different among treatment groups. With concomitant antacid therapy, the half-life of intravenous doxycycline was shortened from 16.2 ± 2.6 to 11.2 ± 1.2 h (P = 0.003), and total body clearance increased from 37.4 ± 6.5 to 54.1 ± 12.3 ml/min (P = 0.008). Area under the concentration-time curve for serum was decreased by 18 to 44%, with a 22 to 41% increase in renal clearance. Although the increase in nonrenal clearance ranged from 11 to 128%, the high variability led to a nonsignificant difference (P = 0.07). Concomitant oral antacid therapy may significantly enhance the clearance of intravenous doxycycline.
• Nix, D. E. (1989). Pharmacokinetics and clinical effects of caffeine alone and in combination with oral enoxacin. Reviews in Infectious Diseases, 11(Suppl 5), S1095-6..
• Nix, D. E., Norman, A., & Schentag, J. J. (1989). Effect of lomefloxacin on theophylline pharmacokinetics. Antimicrobial Agents and Chemotherapy, 33(7), 1006-1008.
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  PMID: 2675751;PMCID: PMC176053;Abstract: A study involving 25 healthy male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 ± 3.0 years, and the mean weight was 77.3 ± 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentration in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 ± 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 ± 1.63 to 7.02 ± 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.
• Nix, D. E., Watson, W. A., Handy, L., Frost, R. W., Rescott, D. L., & Goldstein, H. R. (1989). The effect of sucralfate pretreatment on the pharmacokinetics of ciprofloxacin. Pharmacotherapy, 9(6), 377-380.
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  PMID: 2616352;Abstract: Based on the results of our study of norfloxacin-sucralfate coadministration, we suspected that sucralfate would interact also with ciprofloxacin if the drugs were administered concurrently. Therefore, we decided to give a 1-g dose of sucralfate at 6 and 2 hours before a single 750-mg dose of ciprofloxacin and evaluate its effect on the bioavailability of ciprofloxacin. Twelve healthy, male volunteers received ciprofloxacin alone and with sucralfate pretreatment in a randomized, balanced, crossover design. Blood and urine samples were collected over 24 hours after ciprofloxacin administration, and drug concentrations were assayed by high-performance liquid chromatography. When sucralfate was given at 6 and 2 hours before ciprofloxacin, an average 30% decrease in ciprofloxacin, an average 30% decrease in ciprofloxacin's bioavailability was noted (p < 0.05). Four of the 12 subjects, however, had decreases in the agent's area under the curve of more than 50% with sucralfate pretreatment. The results of this study suggest that ciprofloxacin and sucralfate should not be administered concurrently until a dosing interval is found that will avoid this potential interaction.
• Nix, D. E., Watson, W. A., Lener, M. E., Frost, R. W., Krol, G., Goldstein, H., Lettieri, J., & Schentag, J. J. (1989). Effects of aluminum and magnesium antacids and ranitidine on the absorption of ciprofloxacin. Clinical Pharmacology and Therapeutics, 46(6), 700-705.
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  PMID: 2598571;Abstract: The effect of an antacid (Maalox) and ranitidine administration on the absorption of ciprofloxacin was evaluated in healthy male volunteers who were enrolled in three separate studies. Each study was designed as a three- or four-period crossover and included the administration of 750 mg ciprofloxacin alone as a control treatment. Treatments that were evaluated included the administration of ciprofloxacin 5 to 10 minutes, 2 hours, 4 hours, and 6 hours after a single 30 ml dose of antacid; the administration of antacid 2 hours after ciprofloxacin was given; and the administration of ciprofloxacin 2 hours after a 200 mg ranitidine tablet. Administration of antacid within 4 hours before ciprofloxacin dose resulted in a significant decrease in ciprofloxacin absorption (p < 0.05). Percentages of relative bioavailability compared with control values were 15.1%, 23.2%, and 70% for the 5 to 10 minute, 2 hour, and 4 hour antacid pretreatments, respectively. Administration of antacid 6 hours before or 2 hours after the ciprofloxacin dose did not affect absorption. Ranitidine did not alter ciprofloxacin absorption. Antacids that contain magnesium and aluminum salts may reduce the absorption of ciprofloxacin. The extent of this interaction appears to increase as the time between administration of the two drugs decreases. Ranitidine is suggested as an alternative to antacids for patients receiving treatment with ciprofloxacin. © 1989.
• Parpia, S. H., Nix, D. E., Hejmanowski, L. G., Goldstein, H. R., Wilton, J. H., & Schentag, J. J. (1989). Sucralfate reduces the gastrointestinal absorption of norfloxacin. Antimicrobial Agents and Chemotherapy, 33(1), 99-102.
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  PMID: 2712548;PMCID: PMC171428;Abstract: The effect of sucralfate on the bioavailability of norfloxacin after single 400-mg doses of norfloxacin was evaluated in eight healthy males. Subjects received each of the following treatments in random sequence: (i), norfloxacin, 400 mg alone; (ii) sucralfate, 1 g, concurrently with norfloxacin, 400 mg; and (iii) sucralfate, 1 g, followed by norfloxacin, 400 mg, 2 h later. One day before administration of treatments 2 and 3, 1 g of sucralfate was given at 7 a.m., 11 a.m., 5 p.m., and 10 p.m. Blood samples were collected immediately before the norfloxacin dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 h postdose. Urine was collected in divided intervals: from 0 to 12, from 12 to 24, and from 24 to 48 h. Norfloxacin concentrations in plasma and urine were determined by high-performance liquid chromatography. Mean area under the plasma concentration-versus-time curve extrapolated to infinity decreased significantly (P < 0.001) after norfloxacin was given with and 2 h after sucralfate. The relative bioavailabilities were 1.8% when norfloxacin was taken with sucralfate and 56.6% when it was taken 2 h after sucralfate. After norfloxacin was given alone, the mean norfloxacin concentrations in urine collected during intervals of 0 to 12, 12 to 24, and 24 to 28 h were 118.9 ± 72.3, 18.8 ± 12.5, and 2.4 ± 2.2 μg/ml, respectively. After norfloxacin was given with sucralfate, however, the mean norfloxacin concentrations in urine collected during the same time intervals were 6.8 ± 4.7, 1.8 ± 1.4, and 0 ± 0 μg/ml, respectively. Because of low pH and relatively high magnesium concentration in urine, susceptibilities of bacteria in urine are 8- to 32-fold lower than in broth. This fact, in combination with the reduced bioavailability of norfloxacin in the presence of sucralfate or antacids, is likely to result in treatment failure. The effect of sucralfate given after norfloxacin was not examined, nor was the effect of sucralfate given more than 2 h before norfloxacin. Administration of norfloxacin with sucralfate should therefore be avoided.
• Peloquin, C. A., Cumbo, T. J., Nix, D. E., Sands, M. F., & Schentag, J. J. (1989). Evaluation of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections. Impact of plasma concentrations, organism, minimum inhibitory concentration, and clinical condition on bacterial eradication. Archives of Internal Medicine, 149(10), 2269-2273.
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  PMID: 2508586;Abstract: Fifty patients with gram-negative lower respiratory tract infections were treated with intravenous ciprofloxacin to evaluate efficacy and safety. Relationships between individual pharmacokinetics and clinical and bacteriologic outcome were studied. Ciprofloxacin concentrations in plasma were determined by high-performance liquid chromatography. Respiratory secretion cultures were obtained daily to determine the eradication day of the infecting organism. Susceptibility (minimum inhibitory concentration) to ciprofloxacin and other antimicrobials was determined using standard microdilution techniques. The mean age of the patients was 70 years. They had multiple underlying diseases, and two thirds of them were ventilator dependent at entry. Approximately 50% of the patients had failed previous treatment for the same infections. Patients infected with Enterobacteriaceae or Haemophilus influenzae with minimum inhibitory concentrations of less than 0.25 mg/L responded well to intravenous ciprofloxacin therapy (200 mg every 12 hours). The organisms were eradicated from sputum cultures usually within 1 day after ciprofloxacin therapy was started. Most clinical failures occurred in patients who were infected with Pseudomonas aeruginosa and had multiple underlying diseases. Pseudomonas aeruginosa was isolated from 10 patients with pneumonia, 2 patients with lung abscess, and 1 patient with bronchiectasis. The Pseudomonas isolate acquired resistance during ciprofloxacin treatment in 7 patients with pneumonia and in all of the remaining 3 patients. We conclude that ciprofloxacin is safe and effective at a dosage of 200 mg administered intravenously every 12 hours for nosocomial lower respiratory tract infections caused by Enterobacteriaceae or Haemophilus species. Many patients who had failed previous antibiotic treatment for Enterobacteriaceae infections had good clinical response to ciprofloxacin therapy. Studies using either higher dosages of ciprofloxacin or combination therapy should be conducted to determine if acquired resistance can be avoided in Pseudomonas infections.
• Nix, D. E., & Peloquin, C. A. (1988). Storing extra calibration curves in the TDx assay system.. Clinical pharmacy, 7(11), 792-793.
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  PMID: 3197380;
• Nix, D. E., & Schentag, J. J. (1988). The quinolones: an overview and comparative appraisal of their pharmacokinetics and pharmacodynamics.. Journal of Clinical Pharmacology, 28(2), 169-178.
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  PMID: 3283180;
• Nix, D. E., Schultz, R. W., Frost, R. W., Sedman, A. J., Thomas, D. J., Kinkel, A. W., & Schentag, J. J. (1988). The effect of renal impairment and haemodialysis on single dose pharmacokinetics of oral enoxacin. Journal of Antimicrobial Chemotherapy, 21(SUPPL. B), 87-95.
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  PMID: 3162906;Abstract: The effect of renal impairment on the single dose pharmacokinetics of oral enoxacin was studied in 28 volunteers with creatinine clearances ranging from less than 15 to 120 ml/min, including patients undergoing chronic haemodialysis. Following an overnight fast, 400 mg of enoxacin was administered orally to each subject. Blood and urine samples were collected at predetermined times for 48 and 72 h, respectively. Plasma and urine samples were assayed for enoxacin and for oxo metabolite concentrations by a specific high performance liquid chromatographic method. Area under the concentration-time curve from time 0 to infinity (AUC(0-∞)) was increased in subjects with renal impairment. Plasma half-life (10.6-11.6 h) in volunteers with severe renal impairment was approximately double the 5.2 h half-life found in subjects with normal renal function, and this should result in steady-state enoxacin concentrations approximately double those measured in normal subjects given equivalent doses. Haemodialysis did not remove significant amounts of enoxacin. A significant correlation between creatinine clearance and enoxacin renal clearance was observed (r = 0.97).
• Rescott, D. L., Nix, D. E., Holden, P., & Schentag, J. J. (1988). Comparison of two methods for determining in vitro postantibiotic effects of three antibiotics on Escherichia coli. Antimicrobial Agents and Chemotherapy, 32(4), 450-453.
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  PMID: 3288112;PMCID: PMC172199;Abstract: The postantibiotic effect (PAE) for 10 isolates of Escherichia coli was measured by two methods after 1 h of exposure to ampicillin, ciprofloxacin, or tobramycin. The reference method involved serial colony counting to determine growth after antibiotic exposure in relation to control growth. A spectrophotometric procedure was developed with the Abbott MS-2 research system. This method measured the time to detection of growth after exposure and compared this with the time for growth detection in control chambers having the same initial colony count. A reference curve of time to growth versus log initial CFU per milliliter was used to standardize control growth. PAE was determined after exposure to antibiotic at two and six times the MIC and with inocula ranging from 103 to 109 CFU/ml. There was statistically significant correlation between PAE measured by the spectrophotometric and the reference methods, and the residuals about the regression line were normally distributed. The mean PAE determined by both methods was statistically different for tobramycin-exposed, but not for ampicillin-or ciprofloxacin-exposed, organisms. There was a concentration-dependent PAE for ciprofloxacin and tobramycin. The PAEs for ciprofloxacin (151 min) and tobramycin (108 min) at concentrations six times the MIC were prolonged compared with those measured at two times the MIC (69 and 66 min, respectively). PAE was inversely related to the exposed inoculum for ciprofloxacin and tobramycin. The PAE for E. coli exposed to ampicillin was minimal and was not affected by either concentration or inoculum. The MS-2 method for determining PAE yields similar results, but is less laborious than the reference method.
• Rescott, D. L., Nix, D. E., Holden, P., & Schentag, J. J. (1988). Comparison of two methods for determining in vitro postantibiotic effects of three antibiotics on Escherichia coli. Antimicrobial agents and chemotherapy, 32(4), 450-3.
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  The postantibiotic effect (PAE) for 10 isolates of Escherichia coli was measured by two methods after 1 h of exposure to ampicillin, ciprofloxacin, or tobramycin. The reference method involved serial colony counting to determine growth after antibiotic exposure in relation to control growth. A spectrophotometric procedure was developed with the Abbott MS-2 research system. This method measured the time to detection of growth after exposure and compared this with the time for growth detection in control chambers having the same initial colony count. A reference curve of time to growth versus log initial CFU per milliliter was used to standardize control growth. PAE was determined after exposure to antibiotic at two and six times the MIC and with inocula ranging from 10(3) to 10(9) CFU/ml. There was a statistically significant correlation between PAE measured by the spectrophotometric and the reference methods, and the residuals about the regression line were normally distributed. The mean PAE determined by both methods was statistically different for tobramycin-exposed, but not for ampicillin- or ciprofloxacin-exposed, organisms. There was a concentration-dependent PAE for ciprofloxacin and tobramycin. The PAEs for ciprofloxacin (151 min) and tobramycin (108 min) at concentrations six times the MIC were prolonged compared with those measured at two times the MIC (69 and 66 min, respectively). PAE was inversely related to the exposed inoculum for ciprofloxacin and tobramycin. The PAE for E. coli exposed to ampicillin was minimal and was not affected by either concentration or inoculum. The MS-2 method for determining PAE yields similar results, but is less laborious than the reference method.
• Nix, D. E., & DeVito, J. M. (1987). Ciprofloxacin and norfloxacin, two fluoroquinolone antimicrobials. Clinical Pharmacy, 6(2), 105-117.
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  PMID: 3311572;Abstract: The chemistry, mechanism of action, antimicrobial spectrum, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of ciprofloxacin and norfloxacin are reviewed, and mechanisms of antimicrobial resistance and drug and laboratory interactions are described. Norfloxacin is the first antimicrobial in the fluoroquinolone class to be marketed in the United States; ciprofloxacin is under investigation in clinical trials. The fluoroquinolones are structurally related to nalidixic acid. The activity and spectrum are enhanced by the addition of 6-fluoro and 7-piperazino substituents. Quinolone antimicrobials appear to inhibit DNA gyrase, an enzyme specific and essential for all bacteria, as their primary mechanism of action. As a result, DNA synthesis is inhibited. Ciprofloxacin and norfloxacin are active against gram-negative enteric bacteria, Pseudomonas aeruginosa, Haemophilus influenzae, and Neisseria gonorrhoeae. Ciprofloxacin has good activity against Staphylococcus spp., including methicillin-resistant Staph. aureus. Norfloxacin generally is less potent than ciprofloxacin, particularly against Ps. aeruginosa and Staph. aureus. Peak concentrations occur about one to two hours after an oral administration of either drug. Both drugs are widely distributed in body fluids and tissues and are eliminated by renal excretion, metabolism, and biliary excretion. Dosage reductions are required in several renal dysfunction. Ciprofloxacin and norfloxacin are effective agents for treating urinary-tract infections, including infections caused by Ps. aeruginosa. The recommended dosage of norfloxacin for urinary-tract infections in adults is 400 mg orally every 12 hours; the drug should be given for 7 to 10 days in uncomplicated infections and for 10 to 21 days in complicated ones. The fluoroquinolones may be useful for treating chronic bacterial prostatitis. Ciprofloxacin is potentially useful for treating sexually transmitted diseases. Ciprofloxacin is active against N. gonorrhoeae, including β-lactamase-producing strains and strains that are resistant to tetracycline, and Chlamydia spp. Use of ciprofloxacin for treating gastrointestinal infections and for selective decontamination of the gastrointestinal tract is promising. In open studies, ciprofloxacin has been effective against a variety of infections caused by susceptible organisms. Resistance to ciprofloxacin has developed during treatment of infections caused by Ps. aeruginosa, Staph. aureus, and Serratia marcescens. The most frequently reported adverse effects of either drug are gastrointestinal complaints, headache, and dizziness. Ciprofloxacin and norfloxacin are promising new antimicrobial agents that have potent activity against a broad spectrum of bacterial pathogens. Norfloxacin is currently marketed for the treatment of urinary-tract infections in adults. The exact role of the fluoroquinolones relative to other antimicrobial agents should become clearer as comparative efficacy studies are performed.
• Nix, D. E., Cumbo, T. J., Kuritzky, P., Devito, J. M., & Schentag, J. J. (1987). Oral ciprofloxacin in the treatment of serious soft tissue and bone infections. Efficacy, safety, and pharmacokinetics. American Journal of Medicine, 82(4 A), 146-153.
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  PMID: 3555029;Abstract: Forty-eight patients were enrolled in a clinical study of oral ciprofloxacin for the treatment of soft tissue or bone infections. Patients received 500 to 750 mg of ciprofloxacin every 12 hours. In the predominately older population studied, there were 13 patients with osteomyelitis, 24 diabetic patients with soft tissue infection and probable osteomyelitis, and 11 patients with other soft tissue infections. Infecting pathogens included Pseudomonas aeruginosa in 25 patients, Serratia species in nine patients, Staphylococcus aureus in 13 patients, and other aerobic gram-negative rods in 21 patients. Clinical response (defined as resolution or improvement) was noted in 84 percent of patients with non-diabetic osteomyelitis, in 79 percent of patients with diabetic infections, and in 91 percent of patients with soft tissue infections. Microbiologic outcome was very favorable in 75 percent of cases, and Pseudomonas responded as well as any other pathogen. Pharmacokinetic properties of ciprofloxacin were evaluated in 12 patients, and the data were analyzed using both compartmental and non-compartmental analyses. Mean values for compartmental rate constants (hours-1) were as follows: absorption rate constant = 1.15; intercompartmental rate constants, k12 = 0.48, and k21 = 0.58; elimination rate constant = 0.46; distribution rate constant = 1.31; and terminal elimination rate constant = 0.19. The apparent volume of distribution at steady state/bioavailability was 196 liters and total body clearance/bioavailability was 45.9 liters/hour. The mean time to peak concentration was 1.3 hours. The mean peak concentration as determined by compartmental fitting (2.4 μg/ml) underestimated the observed peak (3.2 μg/ml) by 24.8 percent. Clearance of ciprofloxacin was similar regardless of the method used to fit the data, whereas the volume of distribution was significantly different when the two analysis techniques were compared. Ciprofloxacin was well tolerated, with the most frequent adverse reactions being rash, gastrointestinal intolerance, and increased levels of liver enzymes, each of which occurred in five patients.
• Nix, D. E., Sands, M. F., Peloquin, C. A., Vari, A. J., Cumbo, T. J., Vance, J. W., Fracasso, J. E., & Schentag, J. J. (1987). Dual individualization of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections. American Journal of Medicine, 82(4 A), 352-356.
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  PMID: 3555060;Abstract: Dual individualization is the integration of patient-specific pharmacokinetic parameters with the pharmacodynamics (concentration versus response) of the infecting pathogen. This technique allows description of the time of in vivo bacterial eradication, and allows estimation of optimal dosages using small numbers of seriously ill patients. In an ongoing study, 11 patients with nosocomial lower respiratory tract infections were given 200 mg of intravenous ciprofloxacin every 12 hours. Ten blood samples were taken after the first dose, with additional peaks and troughs measured on Day 4 and at the end of treatment. Bacterial isolates had minimal inhibitory concentrations (MICs) determined by standard microdilution techniques. In the 11 patients, there were 14 bacterial isolates, of which seven were Pseudomonas aeruginosa and the remainder were other pathogens. Ciprofloxacin MICs ranged from 0.008 to 1.0 μg/ml. The pharmacokinetics of ciprofloxacin in these patients varied with renal function, and average peak serum concentrations ranged from 1.7 to 4.9 μg/ml. Eradication of bacteria from tracheal aspirates occurred between Days 1 and 7, except in four patients in whom the organism persisted. Correlations were observed between the day of eradication and the length of time ciprofloxacin concentrations remained above the minimal inhibitory concentration (MIC). Essentially all bacteria with MICs of less than 0.25 were eradicated. Of the non-eradicated bacteria, most had either MICs of more than 0.25, or less than 100 percent time above the MIC. The clinical response was satisfactory. It is concluded that 200 mg of intravenous ciprofloxacin every 12 hours is highly effective for bacteria with MICs less than 0.25 μg/ml, but higher dosages may be required to eradicate organisms with higher MICs.
• Nix, D. E., Vito, J. D., Whitbread, M. A., & Schentag, J. J. (1987). Effect of multiple dose oral ciprofloxacin on the pharmacokinetics of theophylline and indocyanine green. Journal of Antimicrobial Chemotherapy, 19(2), 263-269.
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  PMID: 3571046;Abstract: Interaction between ciprofloxacin and theophylline was studied in eight male volunteers, who were randomly divided into two groups. All subjects were given intravenous theophylline and indocyanine green (ICG) on study days 0, 7 and 14. Group I subjects received ciprofloxacin 750 mg orally every 12 h on days 1-7. Group II subjects received ciprofloxacin 750 mg every 12 h on days 6-14. No significant changes in ICG clearance or half-life were noted. A significant increase in theophylline half-life and volume of distribution was observed (P < 0.05); however, clearance was not significantly decreased (P = 0.1). A potentially clinically significant interaction was detected in three subjects whose theophylline clearance decreased by 42-113%. Until further clinical experience is gained, we advise caution when these agents are coadministered. Some adjustment in theophylline dosage may be required; therefore, these patients should have serum theophylline concentration measurements and careful clinical assessement for theophylline toxicity.
• Jones, S., DiPiro, J. T., Nix, D. E., & Bhatti, N. A. (1985). Cephalosporins for prophylaxis in operative repair of femoral fractures. Levels in serum, muscle, and hematoma. Journal of Bone and Joint Surgery - Series A, 67(6), 921-924.
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  PMID: 4019541;Abstract: We conducted a prospective controlled study of thirty patients who had an open reduction with internal fixation of a closed fracture of the femur. Each patient received cefamandole, cefazolin, or cefoxitin intravenously (twenty-five milligrams per kilogram of body weight) on entry into the operating room. Intraoperatively, samples of blood, muscle, and organizing hematoma were collected for determination of levels of the antimicrobial agent. Throughout the operation, cefazolin was shown to result in significantly higher levels in serum. The mean concentrations in muscle were similar for all three drugs, but the levels in the hematoma were twice as high with cefazolin as with cefamandole or cefoxitin. No correlation was evident between the concentration of any of these antibiotics in the hematoma and the interval between injury and operation.
• Nix, D. E., DiPiro, J. T., Bowden Jr., T. A., & Vallner, J. J. (1985). Cephalosporins for surgical prophylaxis: Computer projections of intraoperative availability. Southern Medical Journal, 78(8), 962-966.
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  PMID: 4023790;Abstract: Cephalosporin antibiotics are the most frequently used agents for surgical prophylaxis. Within this class are considerable pharmacokinetic variations that could have significant implications. We used a computer simulation of cephalosporin serum levels to describe concentrations achieved and maintained intraoperatively when the agents are given intravenously 'on call' to the operating room or with induction of anesthesia. Intraoperative serum concentrations fall below 1 μg/ml if an operation lasts longer than 2.3, 2.7, 3.8, or 4.0 hours when cephalothin. cephapirin, cefamandole, or cefoxitin, respectively, is given in usual doses upon induction of anesthesia. When the same agents are given intravenously on call to the operating room, intraoperative serum concentrations fall below 1 μg/ml for operations lasting longer than 1.1, 1.5, 2.6, or 2.8 hours, respectively. If cephalothin, cephapirin, cefamandole, or cefoxitin is used, it should be given at induction of anesthesia to provide maximal intraoperative serum concentrations. The longer half-life of cefazolin, ceforanide, cefonicid, and cefuroxime is a potential advantage because serum concentrations of these agents are well above 1 μg/ml for as long as 8 to 22 hours even after on-call administration.
• Nix, D. E., Durrence, C. W., & May, J. R. (1985). Amphotericin B bladder irrigations. Drug Intelligence and Clinical Pharmacy, 19(4), 299-300.
• Nix, D. E., Tharpe, W. N., & Francisco, G. E. (1985). Intravenous nitroglycerin delivery: Dynamics and cost considerations. Hospital Pharmacy, 20(4), 230-232.
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  PMID: 10311085;
• Nix, D. E., Vito, J. D., & Schentag, J. J. (1985). Liquid-chromatographic determination of ciprofloxacin in serum and urine. Clinical Chemistry, 31(5), 684-686.
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  PMID: 3157505;Abstract: We describe the liquid-chromatographic determination of ciprofloxacin in patients' serum and urine. Serum samples were prepared by precipitating protein with perchloric acid. Urine samples were diluted 100-fold with mobile phase. The mobile phase, consisting of pH 3 phosphate buffer/acetonitrile/methanol (81/5/14, by vol), was pumped through a μBondapak C18 reversed-phase column at 1.5 mL/min. Fluorescence of the effluent was monitored, at wavelengths for excitation and emission of 270 and 440 nm, respectively. Standard curves were linearly related to concentration from 0.08 to 10 mg/L for serum, 1 to 20 mg/L for urine. The procedure was evaluated in a clinical setting to determine its usefulness in studying the pharmacokinetics of ciprofloxacin in patients with concurrent diseases and receiving multiple drug therapies.
• DeVito, J. M., Nix, D. E., & Schentag, J. J. (1984). No false 'Hemoccult' reaction with ranitidine. New England Journal of Medicine, 311(13), 861-.
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  PMID: 6088982;
• Nix, D. E., Tharpe, W. N., & Francisco, G. E. (1984). Effects of presaturation on nitroglycerin delivery by polyvinyl chloride infusion sets. American Journal of Hospital Pharmacy, 41(9), 1835-1837.
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  PMID: 6437222;

Presentations

• Villanueva, J. E., Matthias, K. R., & Nix, D. E. (2019, June). Antibiotic Stewardship Roundtable Sessions. Arizona Infectious Diseases Training and Exercise. Phoenix, AZ: Arizona Department of Health Services.
• Beatty, N. L., Swazo, R. C., August, J. A., McKeown, K., Kottey, J., Alshibani, M., Petty, W., Nix, D. E., Matthias, K. R., & Al Mohajer, M. (2017, Spring). Appropriateness of a Rapid Multiplex Gastrointestinal Panel in the Investigation of Suspected Infectious Diarrhea. The Society for Healthcare Epidemiology of America Spring 2017 Conference. St Louis, MO: The Society for Healthcare Epidemiology of America.
• Cardenas-Trowers, O., Malekzadeh, P., Nix, D. E., & Hatch, K. D. (2017, May 12-16). Vaginal Mesh Removal Outcomes: Eight years of experience at an academic hospital. American Urological Association Education and Research Inc.. Boston, MA: American Urological Association.
• Nix, D. E., Matthias, K. R., Elliott, S. P., & Roller, B. (2017, April). Update on diagnosis for several healthcare-associated infections. UA Department of Surgery Grand Rounds. Tucson, AZ: University of Arizona Department of Surgery.
• Al Mohajer, M., Matthias, K. R., & Nix, D. E. (2016, October). Improving the knowledge and attitudes of students and physicians regarding appropriate use of antibiotics for respiratory infections through online CME modules. IDWeek 2016. New Orleans, LA: Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), and the Pediatric Infectious Diseases Society (PIDS).
• Beatty, N., August, J., Saenz, A., Nix, D. E., Matthias, K. R., & Al Mohajer, M. (2016, October). Knowledge, attitudes, and practices associated with the diagnosis and management of skin and soft tissue infections among medical students, residents, and attending physicians. IDWeek 2016. New Orleans, LA: Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), and the Pediatric Infectious Diseases Society (PIDS).
• Beatty, N., Nix, D. E., Matthias, K. R., Petty, W. G., & Al Mohajer, M. (2016, October). Efficacy and cost comparison between a rapid multiplex polymerase chain reaction (PCR) gastrointestinal (GI) pathogen panel versus conventional stool analysis techniques in suspected cases of infectious Diarrheal disease at a tertiary medical center. IDWeek 2016. New Orleans, LA: Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), and the Pediatric Infectious Diseases Society (PIDS).
• Gaynor, P., Matthias, K. R., Nix, D. E., Tsui, T. Y., & Al Mohajer, M. (2016, May). The role of infectious disease consultation in patients with enterococcus bacteremia. SHEA Spring 2016. Atlanta, GA: The Society for Healthcare Epidemiology of America.
• Hooten, R., Marquez, J. L., Goldlist, K., Urcis, R., Adams, M., Matthias, K. R., Nix, D. E., & Al Mohajer, M. (2016, October). Overprescription of antibiotics in patients with community-aquired pneumonia in the ICU. IDWeek 2016. New Orleans, LA: Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), and the Pediatric Infectious Diseases Society (PIDS).
• Nix, D. E. (2015, February, 14). Adaptive Resistance in Staphylococcus aureus. Annual Portal Conference - Division of Infectious Disease Retreat.. Portal, Arizona: Division of Infectious Diseases.
• Nix, D. E. (2015, February, 22). Fungus Among Us (Coccidioidomycosis) - Fungal Infection in the Southwest. 2015 SW Clinical Pharmacy Seminar. Tucson, AZ: AZPA/University of Arizona.

Poster Presentations

• Nix, D. E., Nix, D. E., Villanueva, J. E., Villanueva, J. E., Matthias, K. R., Matthias, K. R., Hayes, J., & Hayes, J. (2020, Oct). A Descriptive Analysis of Fluconazole Utilization at Two Academic Medical Centers in the Valley Fever Corridor of Arizona. IDWeek 2020. Virtual conference: Infectious Diseases Society of America.
• Villanueva, J. E., & Nix, D. E. (2020, March). Antimicrobial Stewardship Approach: Strategy to Enhance Antimicrobial Stewardship Program in Arizona Long-term Care. Decennial International Conference on Healthcare Associated Infections. Atlanta, GA: The Society for Healthcare Epidemiology of America.
• Al Mohajer, M., Matthias, K. R., August, J., Nix, D. E., & Beatty, N. (2018, April). Rapid multiplex Gastrointestinal Pathogen Panel Improves Antibiotic Stewardship In Patients with Suspected Infectious Diarrhoea. European Congress of Clinical Microbiology and Infectious Diseases. Madrid, Spain: European Society of Clinical Microbiology.
• Al Mohajer, M., Althaghfi, A., Bach, M., Matthias, K. R., Nix, D. E., & Adams, M. D. (2017, October). Impact of Verigene Multiplex PCR on Antibiotic Stewardship In Patients with Gram-Negative Bacteremia. IDWeek 2017. San Diego, California: Infectious Diseases Society of America.
• Al Mohajer, M., Matthias, K. R., Petty, W. G., Alshibani, M., McKeown, K., August, J., Nix, D. E., & Beatty, N. (2017, October). Rapid Multiplex Gastrointestinal Pathogen Panel Testing Improves Antibiotic Stewardship in Patients with Suspected Infectious Diarrhea Compared to Conventional Methods. IDWeek 2017. San Diego, California: Infectious Diseases Society of America.
• Gandhi, R., Matthias, K. R., & Nix, D. E. (2015, May). Identifying adaptive vancomycin-resistant Staphylococcus aureus from blood cultures. 18th Annual MAD-ID Meeting. Orlando, Florida.
• Karnes, J. H., Klimecki, W., Quinn, D., Nix, D. E., Campbell, P., & Larriva, P. M. (2017, October). Efficacy of personal pharmacogenomic testing as an educational tool in the pharmacy curriculum. American College of Clinical Pharmacy Annual Meeting. Phoenix, AZ.
• Bastani, R., Condon, A., Matthias, K. R., & Nix, D. E. (2014, December). Evaluation of time to appropriate therapy for Stenotrophomonas maltophilia infections using rapid species identification. 49th American Society of Health-System Pharmacists Midyear Clinical Meeting & Exhibition. Anaheim, California: American Society of Health-System Pharmacists (ASHP).
• Matthias, K. R., Nguyen, L., Nkemzi, G., Yee, B. M., & Nix, D. E. (2014, August). Evaluation of sulfamethoxazole concentrations in treatment with high-dose trimethoprim-sulfamethoxazole. Skaggs Biomedical Research Symposium. Missoula, Montana.
• Matthias, K. R., Nix, D. E., Hoover, S., & Galgiani, J. N. (2014, April). Comparison of Nikkomycin Z bioavailability after single dose administration under fed and fasting conditions. 58th Annual Coccidioidomycosis Study Group Meeting. Phoenix, Arizona: Coccidioidomycosis Study Group.

Reviews

• Erstad, B. L., & Nix, D. E. (2023. Medication dosing in adult patients with reduced lean body mass and kidney injury: A focus on cystatin C(pp 712-718).
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  Creatinine-based estimates of glomerular filtration rate (GFR) have been the standard for classifying kidney function and guiding drug dosing for over 5 decades. There have been many efforts to compare and improve different methods to estimate GFR. The National Kidney Foundation recently updated the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without race for creatinine (CKD-EPIcr_R) and creatinine and cystatin C (CKD-EPIcr-cys_R), and the 2012 CKD-EPI equation based on cystatin C (CKD-EPIcys) remains. The focus of this review is to highlight the importance of muscle atrophy as a cause for overestimation of GFR when using creatinine-based methods.

Case Studies

• Matthias, K. R., Nix, D. E., Peloquin, C. A., & Graham, M. L. (2012. Poor absorption of high-dose posaconazole in pediatric bone marrow transplant patients(pp e22).
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  To describe the use of high-dose posaconazole in 2 pediatric patients who received bone marrow transplant (BMT) and highlight concerns regarding posaconazole absorption.

Other Teaching Materials

• Al Mohajer, M., Matthias, K. R., & Nix, D. E. (2015. Diagnosis and Management of Common Respiratory Infections. College of Medicine Continuing Medical Education.

Others

• Stein, G. E., Schooley, S., Walker, R. D., & Strenkoski-Nix, L. (2015). Pharmacodynamic activity of five oral cephalosporins against Haemophilus influenzae. Pharmacotherapy.
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  To determine the time above minimum inhibitory concentration (T > MIC) and serum bactericidal activity of five oral cephalosporins against two strains of Haemophilus influenzae.
• Nix, D. E., Matthias, K. R., & Erstad, B. L. (2011, Oct). Vancomycin clearance in overweight and obese patients. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.
• Nix, D. E., & Matthias, K. R. (2010, Jun). Should tigecycline be considered for urinary tract infections? A pharmacokinetic re-evaluation. The Journal of antimicrobial chemotherapy.
• Nix, D. E., Adam, R. D., Auclair, B., Krueger, T. S., Godo, P. G., & Peloquin, C. A. (2004). Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid. Tuberculosis (Edinburgh, Scotland).
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  Clofazimine is potentially useful for the treatment of disease due to multidrug resistant Mycobacterium tuberculosis, as well as leprosy and certain chronic skin diseases. Its pharmacokinetics have been incompletely characterized. This study was conducted to explore issues relating to bioavailability in the presence of food, orange juice, and antacid.
• Auclair, B., Nix, D. E., Adam, R. D., James, G. T., & Peloquin, C. A. (2001, Mar). Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids. Antimicrobial agents and chemotherapy.
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  This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA (C(max)), time to maximum concentration (T(max)), or area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) between the four treatments (P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for C(max) were 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUC(0-infinity) were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean T(max) was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows: K(a) = 0.37 to 0.48 h(-1), V/F = 2.0 to 2.8 liters/kg, CL/F = 56.5 to 72.2 liters/h, and terminal half-life = 1.7 to 2.1 h, where K(a) is the absorption rate constant, V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.
• Peloquin, C. A., Zhu, M., Adam, R. D., Singleton, M. D., & Nix, D. E. (2001, Nov). Pharmacokinetics of para-aminosalicylic acid granules under four dosing conditions. The Annals of pharmacotherapy.
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  To determine the pharmacokinetics and relative bioavailability of para-aminosalicylic acid (PAS) granules.
• Zhu, M., Nix, D. E., Adam, R. D., Childs, J. M., & Peloquin, C. A. (2001, Aug). Pharmacokinetics of cycloserine under fasting conditions and with high-fat meal, orange juice, and antacids. Pharmacotherapy.
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  To determine the effect of a high-fat meal, orange juice, and antacids on absorption of a single oral dose of cycloserine and to estimate its population pharmacokinetic parameters.
• Strenkoski-Nix, L. C., Forrest, A., Schentag, J. J., & Nix, D. E. (1998, Nov). Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers. Journal of clinical pharmacology.
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  Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill-type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.