Implementation of an Automated Antibiotic Time-out at a Comprehensive Cancer Center.

Background: Antimicrobial stewardship programs can optimize antimicrobial use and have been federally mandated in all hospitals. However, best stewardship practices in immunocompromised patients with cancer are not well established. Methods: An antimicrobial time out, in the form of an email, was sent to physicians caring for hospitalized patients reaching 5 days of therapy for targeted antimicrobials (daptomycin, linezolid, tigecycline, vancomycin, imipenem/cilastatin, meropenem) in a comprehensive cancer center. Physicians were to discontinue the antimicrobial if unnecessary or document a rationale for continuation. This is a quasi-experimental, interrupted time series analysis assessing antimicrobial use during the following times: period 1 (before time-out: January 2007-June 2010) and period 2 (after time-out: July 2010-March/2015). The primary antimicrobial consumption metric was mean duration of therapy. Days of therapy per 1000 patient-days were also assessed. Results: Implementation of the time-out was associated with a significant decrease in mean duration of therapy for the following antimicrobials; daptomycin: -0.89 days (95% confidence interval [CI], -1.38 to -.41); linezolid: -0.89 days (95% CI, -1.27 to -.52); meropenem: -0.97 days (95% CI, -1.39 to -.56); tigecycline: -1.41 days (95% CI, -2.19 to -.63); P < .001 for each comparison. Days of therapy/1000 patient-days decreased significantly for meropenem (-43.49; 95% CI, -58.61 to -28.37; P < .001), tigecycline (-35.47; 95% CI, -44.94 to -26.00; P < .001), and daptomycin (-9.47; 95% CI, -15.25 to -3.68; P = .002). Discussion: A passive day 5 time-out was associated with reduction in targeted antibiotic use in a cancer center and could potentially be successfully adopted to several settings and electronic health records.

Temporal dynamics of genetically heterogeneous extended-spectrum cephalosporin-resistant Escherichia coli bloodstream infections.

Extended-spectrum cephalosporin-resistant Escherichia coli (ESC-R-Ec) is an urgent public health threat with sequence type clonal complex 131 (STc131), phylogroup B2 strains being particularly concerning as the dominant cause of ESC-R-Ec infections. To address the paucity of recent ESC-R-Ec molecular epidemiology data in the United States, we used whole-genome sequencing (WGS) to fully characterize a large cohort of invasive ESC-R-Ec at a tertiary care cancer center in Houston, Texas, collected from 2016 to 2020. During the study time frame, there were 1,154 index E. coli bloodstream infections (BSIs) of which 389 (33.7%) were ESC-R-Ec. Using time series analyses, we identified a temporal dynamic of ESC-R-Ec distinct from ESC-susceptible E. coli (ESC-S-Ec), with cases peaking in the last 6 months of the calendar year. WGS of 297 ESC-R-Ec strains revealed that while STc131 strains accounted for ~45% of total BSIs, the proportion of STc131 strains remained stable across the study time frame with infection peaks driven by genetically heterogeneous ESC-R-Ec clonal complexes. bla CTX-M variants accounted for most ß-lactamases conferring the ESC-R phenotype (89%; 220/248 index ESC-R-Ec), and amplification of bla CTX-M genes was widely detected in ESC-R-Ec strains, particularly in carbapenem non-susceptible, recurrent BSI strains. Bla CTX-M-55 was significantly enriched within phylogroup A strains, and we identified bla CTX-M-55 plasmid-to-chromosome transmission occurring across non-B2 strains. Our data provide important information regarding the current molecular epidemiology of invasive ESC-R-Ec infections at a large tertiary care cancer center and provide novel insights into the genetic basis of observed temporal variability for these clinically important pathogens. IMPORTANCE Given that E. coli is the leading cause of worldwide ESC-R Enterobacterales infections, we sought to assess the current molecular epidemiology of ESC-R-Ec using a WGS analysis of many BSIs over a 5-year period. We identified fluctuating temporal dynamics of ESC-R-Ec infections, which have also recently been identified in other geographical regions such as Israel. Our WGS data allowed us to visualize the stable nature of STc131 over the study period and demonstrate a limited but genetically diverse group of ESC-R-Ec clonal complexes are detected during infection peaks. Additionally, we provide a widespread assessment of ß-lactamase gene copy number in ESC-R-Ec infections and delineate mechanisms by which such amplifications are achieved in a diverse array of ESC-R-Ec strains. These data suggest that serious ESC-R-Ec infections are driven by a diverse array of strains in our cohort and impacted by environmental factors suggesting that community-based monitoring could inform novel preventative measures.

Temporal Dynamics of Genetically Heterogeneous Extended-Spectrum Cephalosporin Resistant Escherichia coli Bloodstream Infections.

Extended-spectrum cephalosporin resistant Escherichia coli (ESC-R- Ec ) is an urgent public health threat with sequence type clonal complex 131 (STc131), phylogroup B2 strains being particularly concerning as the dominant cause of ESC-R- Ec infections. To address the paucity of recent ESC-R- Ec molecular epidemiology data in the United States, we used whole genome sequencing (WGS) to fully characterize a large cohort of invasive ESC-R- Ec at a tertiary care cancer center in Houston, Texas collected from 2016-2020. During the study timeframe, there were 1154 index E. coli bloodstream infections (BSIs) of which 389 (33.7%) were ESC-R- Ec . Using time series analyses, we identified a temporal dynamic of ESC-R- Ec distinct from ESC-susceptible E. coli (ESC-S- Ec ), with cases peaking in the last six months of the calendar year. WGS of 297 ESC-R- Ec strains revealed that while STc131 strains accounted for ∼45% of total BSIs, the proportion of STc131 strains remained stable across the study time frame with infection peaks driven by genetically heterogeneous ESC-R- Ec clonal complexes. Bla CTX-M variants accounted for most ß-lactamases conferring the ESC-R phenotype (89%; 220/248 index ESC-R -Ec ), and amplification of bla CTX-M genes was widely detected in ESC-R- Ec strains, particularly in carbapenem non-susceptible, recurrent BSI strains. Bla CTX-M-55 was significantly enriched within phylogroup A strains, and we identified bla CTX-M-55 plasmid-to-chromosome transmission occurring across non-B2 strains. Our data provide important information regarding the current molecular epidemiology of invasive ESC-R- Ec infections at a large tertiary care cancer center and provide novel insights into the genetic basis of observed temporal variability for these clinically important pathogens. IMPORTANCE: Given that E. coli is the leading cause of worldwide ESC-R Enterobacterales infections, we sought to assess the current molecular epidemiology of ESC-R- Ec using a WGS analysis of many BSIs over a five-year period. We identified fluctuating temporal dynamics of ESC-R- Ec infections, which has also recently been identified in other geographical regions such as Israel. Our WGS data allowed us to visualize the stable nature of STc131 over the study period and demonstrate a limited, but genetically diverse group of ESC-R- Ec clonal complexes are detected during infection peaks. Additionally, we provide a widespread assessment of ß-lactamase gene copy number in ESC-R- Ec infections and delineate mechanisms by which such amplifications are achieved in a diverse array of ESC-R- Ec strains. These data suggest that serious ESC-R- Ec infections are driven by a diverse array of strains in our cohort and impacted by environmental factors suggesting that community-based monitoring could inform novel preventative measures.

Significant Publications on Infectious Diseases Pharmacotherapy in 2020.

Purpose. To summarize the most highly esteemed, peer-reviewed, infectious diseases (ID) pharmacotherapy articles published in 2020. Summary. Members of the Houston Infectious Diseases Network (HIDN) nominated articles that were deemed to have noteworthy contributions to ID pharmacotherapy in 2020, including those on coronavirus disease 2019 (COVID-19) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). To select the most significant articles of 2020, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) to vote on their top 10 articles of general ID and COVID-19 pharmacotherapy and one noteworthy HIV/AIDS publication. A total of 40 articles were nominated by HIDN: 35 articles pertaining to general ID/COVID-19 pharmacotherapy and 5 articles with HIV/AIDS involvement. Of the 247 SIDP members who responded to the survey, 205 and 42 members voted for general ID/COVID-19 pharmacotherapy articles and HIV/AIDS related articles, respectively. The top publications are summarized. Conclusion. In a taxing year of a global pandemic, the abundant and rapid distribution of ID literature has made it challenging for clinicians to stay informed of significant publications across the ID spectrum. This review summarizes significant ID-related publications in 2020 with the goal of aiding clinicians in staying up to date on the most relevant publications in ID pharmacotherapy.

Improving the safety of outpatient parenteral antimicrobial therapy for patients with solid tumors.

BACKGROUND AND OBJECTIVES: Outpatient parenteral antimicrobial therapy (OPAT) for infections has been in use for nearly 40 years, and although it has been found safe and efficacious, its use has been studied primarily among otherwise healthy patients. We aimed to develop and evaluate an OPAT program for patients with cancer, particularly solid tumors. METHODS: We implemented multiple quality improvement interventions between June 2018 and January 2020. We retrospectively and prospectively collected data on demographics, the completeness of infectious diseases (ID) physician consultation notes, rates of laboratory test result monitoring, ID clinic follow-up, and 30-day outcomes, including unplanned OPAT-related readmissions, OPAT-related emergency center visits, and deaths. RESULTS: Completeness of ID provider notes improved from a baseline of 77 to 100% (p < .0001) for antimicrobial recommendations, 75 to 97% (p < .0001) for follow-up recommendations, and 19 to 98% (p < .0001) for laboratory test result monitoring recommendations. Completion of laboratory tests increased from a baseline rate of 24 to 56% (p = .027). Thirty-day unplanned OPAT-related readmission, ID clinic follow-up, 30-day emergency center visit, and death rates improved without reaching statistical significance. CONCLUSIONS: Sustained efforts, multiple interventions, and multidisciplinary engagement can improve laboratory test result monitoring among solid tumor patients discharged with OPAT. Although demonstrating a decrease in unplanned readmissions through institution of a formal OPAT program among patients with solid malignancies may be more difficult compared with the general population, the program may still result in improved safety.

Effect of High-Dose Posaconazole on Serum Levels in Adult Patients with Hematologic Malignancy.

Posaconazole (POS) appears to have dose-proportional pharmacokinetics; however, there is a paucity of real-life data. We retrospectively evaluated 67 patients with hematologic cancer who had POS dose increases from 300 mg/day to either 400 mg/day (n = 52) or 300 mg twice daily (BID) (n = 15) and for whom POS serum levels were measured. Median POS levels were 840 ng/ml, 1,625 ng/ml, and 2,710 ng/ml for the dosages of 300 mg/day, 400 mg/day, and 300 mg BID, respectively. Significant interpatient variability in serum levels was noted.

Significant Publications on Infectious Diseases Pharmacotherapy in 2019.

PURPOSE: To provide a summary of the most prominent peer-reviewed infectious diseases (ID) pharmacotherapy and Human Immunodeficiency Virus (HIV)-related articles published in 2019. SUMMARY: Houston Infectious Diseases Network (HIDN) members were asked to nominate articles that they believed were most influential within the ID and HIV pharmacotherapy science communities. A total of 48 general ID and 6 HIV-related articles were nominated. Following nominations, an online survey was distributed via e-mail to Society of Infectious Diseases Pharmacists (SIDP) members, with a total of 156 and 54 members voting for general ID and HIV-related articles, respectively. The results of this survey were ranked to determine the top 10 general ID and top HIV articles. The top articles were then summarized by HIDN members, including residents, fellows, and clinical pharmacists. CONCLUSION: This review covers many of the most influential ID articles published in 2019, including 3 practice guideline updates. Due to the high rate of ID literature published each year, this review continues to help summarize these articles for the ID community, allowing clinicians to remain up-to-date on practice-changing publications in ID and HIV pharmacotherapy.

Significant Publications on Infectious Diseases Pharmacotherapy in 2018.

PURPOSE: To summarize the top 10 most influential peer-reviewed infectious diseases (ID) pharmacotherapy articles published in the year 2018. SUMMARY: Members of the Houston Infectious Diseases Network (HIDN) nominated articles that were thought to have most notably contributed to ID pharmacotherapy in 2018, including those related to human immunodeficiency virus (HIV). A total of 26 articles were nominated: 22 articles pertaining to general ID pharmacotherapy and 4 articles involving HIV/AIDS. To select the most significant articles of 2018, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) asking members to vote on their top 10 general ID publications and 1 HIV publication. Of the 462 members surveyed, 213 (46%) and 108 (23%) voted for general ID pharmacotherapy- and HIV-related articles, respectively. The top article(s) for both categories are summarized. CONCLUSION: With the increased emphasis on antimicrobial stewardship initiatives and the growing problem of multidrug-resistant (MDR) organisms, the amount of ID literature centered on stewardship, appropriate treatment durations, and newly approved antimicrobial agents continues to expand, making it challenging for clinicians to stay informed on the most relevant publications. This review summarizes significant ID-related publications in 2018 with the goal of aiding clinicians in staying up to date on the most noteworthy publications in ID pharmacotherapy.

Carbapenem versus Cefepime or Piperacillin-Tazobactam for Empiric Treatment of Bacteremia Due to Extended-Spectrum-ß-Lactamase-Producing Escherichia coli in Patients with Hematologic Malignancy.

Infections with extended-spectrum-ß-lactamase (ESBL)-producing Escherichia coli are common in patients with hematologic malignancy. The utility of cefepime and piperacillin-tazobactam as empiric therapy for ESBL-producing E. coli bacteremia in patients with hematologic malignancy is largely unknown. We conducted a single-center, retrospective cohort review of 103 adult inpatients with leukemia and/or hematopoietic stem cell transplant (HCT) recipients with monomicrobial ESBL-producing E. coli bacteremia. No association between increased 14-day mortality and empiric treatment with cefepime (8%) or piperacillin-tazobactam (0%) relative to that with carbapenems (19%) was observed (P = 0.19 and P = 0.04, respectively). This observation was consistent in multivariate Cox proportional hazards models adjusted for confounding and an inverse probability of treatment-weighted (IPTW) Cox proportional hazards model. Both fever and persistent bacteremia were more common in patients treated empirically with cefepime or piperacillin-tazobactam. Empiric treatment with cefepime or piperacillin-tazobactam did not result in increased mortality relative to that with treatment with carbapenems in patients with hematologic malignancy and ESBL-producing E. coli bacteremia, although most patients were changed to carbapenems early in treatment. However, due to prolonged fever and persistent bacteremia, their role may be limited in this patient population.

Significant Publications on Infectious Diseases Pharmacotherapy in 2016.

PURPOSE: This is a summary of the most important articles on infectious diseases (ID) pharmacotherapy published in peer-reviewed literature in 2016 as selected by clinical pharmacists with ID expertise. SUMMARY: The Houston Infectious Diseases Network (HIDN) was asked to identify articles published in peer-reviewed literature in 2016 that were believed to contribute significantly to ID pharmacotherapy, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 46 articles on general ID pharmacotherapy and 8 articles on HIV/AIDS were nominated. Members of the Society of Infectious Diseases Pharmacists (SIDP) were surveyed to select 10 general ID articles believed to have made a significant impact on general ID pharmacotherapy and 1 article most significant to HIV/AIDS pharmacotherapy. Of 445 SIDP members surveyed, 212 (47.6%) and 95 (21.3%) members voted for general ID pharmacotherapy- and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the large number of ID-related articles published each year, it can be challenging to stay current with the most relevant ID publications. This review of significant publications in 2016 may provide a starting point for that process.

Outcomes and metrics for antimicrobial stewardship: survey of physicians and pharmacists.

We conducted a survey to compare antimicrobial stewardship outcomes considered to be most important with those used in practice as metrics. Respondent opinion of important outcomes compared with those collected as metrics were antimicrobial use (15% vs 73%), antimicrobial cost (10% vs 73%), appropriateness of antimicrobial use (56% vs 51%), infection-related mortality rate (34% vs 7%), and antibiotic-associated length of stay (22% vs 12%). Patient outcomes are important to many practitioners but are rarely used as metrics.

Assessing appropriateness of antimicrobial therapy: in the eye of the interpreter.

To address the increase of drug-resistant bacteria and widespread inappropriate use of antimicrobials, many healthcare institutions have implemented antimicrobial stewardship programs to promote appropriate use of antimicrobials and optimize patient outcomes. However, a consensus definition of appropriate use is lacking. We conducted a multicenter observational study to compare 4 definitions of appropriateness--a study site-specific definition, use supported by susceptibility data, use supported by electronic drug information resources (Clinical Pharmacology/Micromedex), or study site principal investigator (PI) opinion-among patients receiving 1 or more of 13 identified antimicrobials. Data were collected for 262 patients. Overall, appropriateness with the 4 definitions ranged from 79% based on PI opinion to 94% based on susceptibility data. No single definition resulted in consistently high appropriate use for all target antimicrobials. For individual antimicrobials, the definitions with the highest rate of appropriate use were Clinical Pharmacology/Micromedex support (6 of 7 antimicrobials) and susceptibility data (5 of 7 antimicrobials). For specific indications, support from susceptibility data resulted in the highest rate of appropriate use (4 of 7 indications). Overall comparisons showed that appropriateness assessed by PI opinion differed significantly compared with other definitions when stratified by either target antimicrobial or indication. The significant variability in the rate of appropriate use highlights the difficulty in developing a standardized definition that can be used to benchmark judicious antimicrobial use.

Breaking down the barriers: challenges with development and implementation of an industry-sponsored antimicrobial stewardship data collection and analysis tool.

Partnership between clinicians and the pharmaceutical industry with a focus on antimicrobial stewardship research initiatives is a necessary step toward meeting the shared goals of combating inappropriate antimicrobial use, improving patient outcomes, and minimizing resistance development. Achieving these goals requires outcomes-focused data collection and monitoring tools for antimicrobial stewardship programs (ASP) that consider real-world data about how antimicrobials are used to treat patients. Here we highlight the experiences and challenges associated with the development and implementation of an industry-sponsored electronic antimicrobial stewardship data collection and analysis tool (AS-DCAT). The benefits and risks of the industry-sponsored AS-DCAT from the perspectives of the sponsoring company and participating sites are discussed. Barriers encountered as well as general considerations and recommendations for preventing or overcoming those barriers for future studies and tool development are provided.

Dosing strategy to allow continued therapy with daptomycin after asymptomatic increases in creatine kinase levels.

PURPOSE: A case series in which a novel dosing strategy for managing mild, asymptomatic creatine kinase (CK) increases associated with daptomycin therapy is presented. SUMMARY: Eight patients received a mean daptomycin dosage of 7.75 mg/kg/day for a median duration of 42 days. Seven of the eight patients were being treated for a bone and joint infection, and all but one had methicillin-resistant Staphylococcus aureus. All patients had asymptomatic increases in CK concentrations during daptomycin therapy (peak range, 400-1200 IU/L). A single daptomycin dose was withheld from each patient, and therapy was resumed 24 hours later, most often at the same dosage. The elevated CK values in these patients resolved, and all patients were able to complete daptomycin therapy without further increases in CK elevations. These findings indicate that withholding one dose of daptomycin during treatment may allow patients with asymptomatic, elevated CK concentrations to continue therapy with CK level normalization. Although the mechanism of daptomycin-mediated muscle injury is not fully understood, a reduction in daptomycin exposure via a one-dose cessation of therapy may allow for physiological restoration of sarcolemma membrane integrity that may be disrupted by daptomycin in individuals exhibiting CK elevation. CONCLUSION: A single daptomycin dose was withheld from eight patients with asymptomatic increases in serum CK concentrations, then daptomycin therapy was resumed 24 hours later, most often at the previous dosage. The CK concentrations returned to normal, and all patients were able to complete daptomycin therapy without further increases in CK concentrations.

In vitro assessment and multicenter cohort study of comparative nephrotoxicity rates associated with colistimethate versus polymyxin B therapy.

Despite concerns of nephrotoxicity, polymyxin antibiotics often remain the only susceptible agents for multidrug-resistant (MDR) Gram-negative bacteria. Colistin has been more commonly used clinically due to a perceived safety benefit. We compared the nephrotoxicity of colistin to polymyxin B. The in vitro cytotoxicity of colistin was compared to polymyxin B in two mammalian renal cell lines. To validate the clinical relevance of the findings, we evaluated adult patients with normal renal function who received a minimum of 72 h of polymyxin therapy in a multicenter study. The primary outcome was the prevalence of nephrotoxicity, as defined by the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. Colistin exhibited an in vitro cytotoxicity profile similar to polymyxin B. A total of 225 patients (121 receiving colistimethate, 104 receiving polymyxin B) were evaluated. Independent risk factors for colistimethate-associated nephrotoxicity included age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00 to 1.07; P = 0.03), duration of therapy (OR 1.08; 95% CI, 1.02 to 1.15; P = 0.02), and daily dose by ideal body weight (OR 1.40; 95% CI, 1.05 to 1.88; P = 0.02). In contrast, cystic fibrosis was found to be a protective factor in patients who received colistimethate (OR, 0.03; 95% CI, 0.001 to 0.79; P = 0.04). In a matched analysis based on the risk factors identified (n = 76), the prevalence of nephrotoxicity was higher with colistimethate than with polymyxin B (55.3% versus 21.1%; P = 0.004). Polymyxin B was not found to be more nephrotoxic than colistin and may be the preferred polymyxin for MDR infections. A prospective study comparing the two polymyxins directly is warranted.

Use of daptomycin to treat infections with methicillin-resistant Staphylococcus aureus isolates having vancomycin minimum inhibitory concentrations of 1.5 to 2 µg/mL.

OBJECTIVE: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL. DATA SOURCES: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013). STUDY SELECTION AND DATA EXTRACTION: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included. DATA SYNTHESIS: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d). CONCLUSIONS: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area.

Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors.

OBJECTIVES: The objective of this study was to compare atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors. METHODS: HIV-negative adult volunteers were pre-screened for CYP3A5 *3, *6 and *7 polymorphisms and enrollment was balanced for CYP3A5 expressor status, gender and race (African-American versus non-African-American). Participants received atazanavir 400 mg daily for 7 days followed by atazanavir/ritonavir 300 mg/100 mg daily for 7 days with pharmacokinetic studies on days 7 and 14. Other measures collected were bilirubin, UGT1A1 *28, and ABCB1 1236C > T, 2677G > T/A and 3435C > T genotypes. Data analyses utilized least squares regression. RESULTS: Fifteen CYP3A5 expressors and 16 non-expressors participated. The day 7 atazanavir oral clearance (CL/F) was 1.39-fold faster (0.25 versus 0.18 L/h/kg; P = 0.045) and the C(min) was half (87 versus 171 ng/mL; P = 0.044) in CYP3A5 expressors versus non-expressors. Non-African-American CYP3A5 expressor males had 2.1-fold faster CL/F (P = 0.003) and <20% the C(min) (P = 0.0001) compared with non-African-American non-expressor males. No overall CYP3A5 expressor effects were observed during the ritonavir phase. One or two copies of wild-type ABCB1 haplotype (1236C/2677G/3435C) was predictive of slower atazanavir and ritonavir CL/F compared with zero copies (P < 0.06). Indirect bilirubin increased 1.6- to 2.8-fold more in subjects with UGT1A1 *28/*28 versus *1/*28 or *1/*1. CONCLUSIONS: CYP3A5 expressors had faster atazanavir CL/F and lower C(min) than non-expressors. The effect was most pronounced in non-African-American men. Ritonavir lessened CYP3A5 expressor effects. The wild-type ABCB1 CGC haplotype was associated with slower CL/F and the UGT1A1 *28 genotype was associated with increased bilirubin. Thus, CYP3A5, ABCB1 and UGT1A1 polymorphisms are associated with atazanavir pharmacokinetics and pharmacodynamics in vivo.