Fecal Microbiota, Live-jslm for the Prevention of Recurrent Clostridioides difficile Infection : Subgroup Analysis of PUNCH CD2 and PUNCH CD3.

GOALS: To assess fecal microbiota, live-jslm (REBYOTA, abbreviated as RBL, formerly RBX2660) efficacy and safety in participants grouped by recurrent Clostridioides difficile infection (rCDI) risk factors and treatment-related variables. BACKGROUND: RBL is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration for the prevention of rCDI in adults after antibiotic treatment for rCDI. STUDY: Treatment success rates across subgroups for PUNCH CD3 (NCT03244644) were estimated using a Bayesian hierarchical model, borrowing data from PUNCH CD2 (NCT02299570). Treatment-emergent adverse events were summarized for the double-blind treatment period within 8 weeks. RESULTS: Treatment differences between RBL and placebo at 8 weeks were similar to the total population for most subgroups. Treatment effect sizes were similar between CDI tests, higher for oral vancomycin courses >14 days versus ≤14 days and higher for antibiotic washout periods of 3 days versus ≤2 days. The largest reductions in the rate of rCDI with RBL versus placebo were observed for participants with a 3-day CDI antibiotic washout period and participants with ≥4 previous CDI episodes. Most RBL-treated participants experienced TEAEs that were mild or moderate in severity and related to preexisting conditions. CONCLUSION: This analysis provides further evidence of RBL efficacy and safety across subgroups, including those at high risk for rCDI.

Therapeutic drug monitoring of flucytosine in a cardiac transplant patient receiving continuous veno-venous hemofiltration and intermittent hemodialysis: A case report.

Invasive candidiasis is one of the common infections in solid organ transplant recipients. Guidelines recommend echinocandins or liposomal amphotericin with consideration of flucytosine (5-fluorocytosine; 5-FC) as synergistic therapy for treatment of select deep-seated Candida infections, including complex endovascular infections. Flucytosine undergoes extensive renal elimination; however, optimal dosing in patients with renal impairment, or those requiring renal replacement therapy (RRT), is not well-established. We describe a case of a 60-year old female who underwent orthotopic heart transplant complicated by Candida parapsilosis complex fungemia with mediastinitis and development of end-stage renal disease requiring RRT. Flucytosine therapeutic drug monitoring was performed on continuous veno-venous hemofiltration (CVVH) and intermittent hemodialysis (iHD) to guide appropriate dosing. Our results support 5-FC doses of 25 mg/kg daily while undergoing CVVH with a low fluid replacement rate and 21 mg/kg post-iHD or 17 mg/kg daily while receiving thrice weekly iHD.

Optimal treatment of MSSA bacteraemias: a meta-analysis of cefazolin versus antistaphylococcal penicillins.

Background: Bacteraemias caused by MSSA are associated with significant morbidity and mortality. Controversy exists over the optimal treatment of severe infections caused by MSSA. This systematic review and meta-analysis aims to identify whether differences in clinical outcomes exist between cefazolin and antistaphylococcal penicillins (ASPs). Methods: PubMed, Cochrane Library and Embase were systematically searched for publications reporting clinical outcomes of cefazolin and ASPs for adult patients with MSSA bacteraemias throughout November 2017. Comparative studies reporting 90 day mortality associated with each treatment were included. Random effects models were used to evaluate the impact of directed treatment agent on the odds of 30 and 90 day mortality, clinical failure, discontinuation due to adverse effects and infection recurrence. Results: Five hundred and ninety-nine articles were evaluated for inclusion, of which seven met all inclusion criteria. Across all studies, 1589 patients received cefazolin and 2802 received an ASP. All-cause 90 day mortality was lower in patients who received cefazolin (OR 0.63, 95% CI 0.41-0.99; I2 = 58%). Odds of discontinuation due to adverse events was significantly lower in patients receiving cefazolin (OR 0.25, 95% CI 0.11-0.56; I2 = 13%). No differences in clinical failure were observed (OR 0.85, 95% CI 0.41-1.76; I2 = 74%). Conclusions: This meta-analysis identified a significant decrease in mortality associated with cefazolin therapy for MSSA bacteraemia compared with ASPs, though no differences in clinical failure were observed. Additionally, cefazolin appeared to be better tolerated. These results should be interpreted with caution given the uncontrolled and retrospective nature of the included studies.

Effect of prior receipt of antibiotics on the pathogen distribution and antibiotic resistance profile of key Gram-negative pathogens among patients with hospital-onset urinary tract infections.

BACKGROUND: This retrospective cohort study characterized the impact of prior antibiotic exposure on distribution and nonsusceptibility profiles of Gram-negative pathogens causing hospital-onset urinary tract infections (UTI). METHODS: Hospital patients with positive urine culture for Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae ≥3 days after hospital admission were included. Assessment outcomes included the distribution of bacteria in urine cultures, antibiotic susceptibility patterns, and the effect of prior antibiotic exposure, defined as 0, 1, or ≥2 prior antibiotics, on the distribution and antibiotic susceptibility profiles of the Gram-negative organisms. RESULTS: The most commonly isolated pathogens from 5574 unique UTI episodes (2027 with and 3547 without prior antibiotic exposure) were E. coli (49.5%), K. pneumoniae (17.1%), and P. aeruginosa (8.2%). P. aeruginosa was significantly more commonly isolated in patients with ≥2 prior antibiotic exposures (12.6%) compared with no exposure (8.2%; p = 0.036) or 1 prior exposure (7.9%; p = 0.025). Two or more prior antibiotic exposures were associated with slightly higher incidences of fluoroquinolone nonsusceptibility, multidrug resistance, and extended-spectrum ß-lactamase phenotype compared with 0 or 1 exposure, suggesting an increased risk for resistant Gram-negative pathogens among hospital patients with urinary tract infections occurring ≥3 days after admission. CONCLUSIONS: Clinicians should critically assess prior antibiotic exposure when selecting empirical therapy for patients with hospital-onset urinary tract infections caused by Gram-negative pathogens.

Relationship between day 1 and day 2 Vancomycin area under the curve values and emergence of heterogeneous Vancomycin-intermediate Staphylococcus aureus (hVISA) by Etest® macromethod among patients with MRSA bloodstream infections: a pilot study.

BACKGROUND: In vitro data suggests that suboptimal initial vancomycin exposure may select for heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections. However, no clinical studies have evaluated the relationship between initial vancomycin exposure and emergence of hVISA. This pilot study seeks to assess the relationship between day 1 and day 2 vancomycin area under the curve (AUC) and emergence of hVISA bloodstream infections (BSIs) by Etest® macromethod among patients with a non-hVISA BSI at baseline. METHODS: This was a retrospective cohort study of patients with methicillin-resistant Staphylococcus aureus (MRSA) BSIs at Albany Medical Center Hospital (AMCH) between January 2005 and June 2009. The vancomycin AUC exposure variables on day 1 (AUC0-24h) and day 2 (AUC24-48h) were estimated using the maximal a posteriori probability (MAP) procedure in ADAPT 5. RESULTS: There were 238 unique episodes of MRSA BSIs during the study period, 119 of which met inclusion criteria. Overall, hVISA emerged in 7/119 (5.9%) of patients. All 7 cases of hVISA involved patients who did not achieve area under the curve over broth microdilution minimum inhibitory concentration (AUC0-24h/MICBMD) ratio of 521 or an AUC24-48h/MICBMD ratio of 650. No associations between other day 1 and day 2 AUC variables and emergence of hVISA were noted. CONCLUSIONS: Although more data are needed to draw definitive conclusions, these findings suggest that hVISA emergence among patients with non-hVISA MRSA BSIs at baseline may be partially explained by suboptimal exposure to vancomycin in the first 1 to 2 days of therapy. At a minimum, these findings support further study of the relationship between initial vancomycin exposure and hVISA emergence among patients with MRSA BSIs in a well-powered, multi-center, prospective trial.

Fluoroquinolone and Third-Generation-Cephalosporin Resistance among Hospitalized Patients with Urinary Tract Infections Due to Escherichia coli: Do Rates Vary by Hospital Characteristics and Geographic Region?

This analysis of nearly 10,000 hospital-associated urinary tract infection (UTI) episodes due to Escherichia coli showed that fluoroquinolone and third-generation-cephalosporin resistance rates were 34.5% and 8.6%, respectively; the rate of concurrent resistance to both agents was 7.3%. Fluoroquinolone resistance rates exceeded 25% regardless of geographic location or hospital characteristics. The findings suggest that fluoroquinolones should be reserved and third-generation cephalosporins be used with caution as empirical agents for hospitalized patients with UTIs due to E. coli.

Characterization of the haematological profile of 21 days of tedizolid in healthy subjects.

OBJECTIVES: Tedizolid is a novel oxazolidinone antibacterial. Oxazolidinones carry concerns for time-dependent myelosuppression. To further explore tedizolid's haematological tolerability, we analysed data from a 21 day study comparing safety and pharmacokinetics of tedizolid and linezolid. METHODS: This was a Phase 1 study in healthy volunteers comparing five treatments (each n = 8) over 21 days: tedizolid at 200, 300 or 400 mg once daily; linezolid at 600 mg twice daily; and placebo. Routine laboratory haematological parameters (platelet, absolute neutrophil, white blood cell, red blood cell and reticulocyte counts) were compared between groups. Adverse haematological outcomes were pre-specified as any parameter below the standard lower limits of normal (LLN), substantially abnormal (<50% LLN for neutrophils; <75% LLN for other parameters) or ≥50% below baseline (platelets only). ClinicalTrials.gov identifier: NCT00671814. RESULTS: During the 21 day study period, pre-specified adverse platelet outcomes were observed in the linezolid (n = 2), tedizolid 300 mg (n = 1) and tedizolid 400 mg (n = 3) groups. Mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with higher doses being similar to linezolid. The magnitude of platelet count decreases from baseline was influenced by unbound drug trough plasma concentrations, which were generally higher in subjects with at least a 20% decrease in platelet count. Substantially abnormal haematological parameters were only observed with linezolid and tedizolid 400 mg. One linezolid and two tedizolid 400 mg subjects discontinued due to meeting criteria for pre-specified adverse haematological outcomes. CONCLUSIONS: Although limited to small groups of healthy volunteers, these exploratory results support clinical study of extended treatment durations with tedizolid at 200 mg once daily.

Efficacy of Fecal Microbiota, Live-jslm (REBYOTA®), Among Patients Exposed to Non-Clostridioides difficile Infection Antibiotics: Post Hoc Subgroup Analysis of a Phase 2 Open-Label Study.

Background: Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after. Methods: Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration. Results: Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212-648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic. Conclusions: RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure. Clinical Trials Registration: NCT02589847 (https://clinicaltrials.gov/study/NCT02589847).

Fidaxomicin-Associated Hypersensitivity Reactions: Report of a Morbilliform Drug Eruption.

PurposeWe report a probable case of morbilliform drug eruption secondary to fidaxomicin in a patient with Clostridioides difficile infection (CDI). Summary: A 62-year-old female presented to our institution's emergency department (ED) with symptoms consistent with Clostridioides difficile infection. The patient was prescribed 2 weeks of oral vancomycin for CDI prior to presentation. Given insufficient response to vancomycin, the patient was started on fidaxomicin with a planned 10-day course. After 2 doses of fidaxomicin, the patient developed a rash on her back that spread within 24 hours. The patient did not experience relief upon administration of a variety of medications for allergic reaction. Improvement was noted upon discontinuation of fidaxomicin. The Food and Drug Administration reports that < 2% of adults treated with fidaxomicin experience a rash as an adverse effect. Conclusion: Fidaxomicin was a probable cause of morbilliform drug eruption in our patient with CDI. The patient improved upon discontinuation of fidaxomicin.

A Case Series of Rifabutin Use in Staphylococcal Prosthetic Infections.

This case series describes seven patients who received rifabutin in place of rifampin combined with conventional antimicrobial therapy for treatment of hardware-associated staphylococcal infections. Infection recurrence, defined as need for unplanned surgical intervention within the evaluable follow up period after starting rifabutin, occurred in two patients. Two patients experienced possible treatment-associated adverse effects. Findings support future work to examine rifabutin use, when rifampin is not suitable, for adjunctive treatment of staphylococcal hardware infections. IMPORTANCE This work evaluates real-world data and clinical outcomes when rifabutin is used in place of rifampin for adjunctive management of staphylococcal hardware-associated infections. This is the second case study looking at this specific use of rifabutin, signifying the current lack of clinical data in this area. Assessing use of rifabutin in this capacity is clinically important given its lower propensity for drug interactions compared to rifampin.

Gut microbiome health and dysbiosis: A clinical primer.

The gut microbiome has been referred to as the "forgotten organ." Although much about the gut microbiome remains incompletely understood, data on its clinical importance is emerging at rapid speed. Many practicing clinicians may be unaware of the essential role that the microbiome plays in both health and disease. This review aims to improve clinical understanding of the gut microbiome by discussing key terminology and foundational concepts. The role of a healthy microbiome in normal host function is described, as well as the consequences of a disrupted microbiome (i.e., dysbiosis). Management strategies to restore the gut microbiome from a disrupted to a healthy state are also briefly discussed. Lastly, we review emerging areas for therapeutic potential and opportunity to bring determinants of microbiome health from the bench to bedside.

Baseline procalcitonin as a predictor of bacterial infection and clinical outcomes in COVID-19: A case-control study.

PURPOSE: Coronavirus disease-2019 (COVID-19) is associated with a wide spectrum of clinical symptoms including acute respiratory failure. Biomarkers that can predict outcomes in patients with COVID-19 can assist with patient management. The aim of this study is to evaluate whether procalcitonin (PCT) can predict clinical outcome and bacterial superinfection in patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). METHODS: Adult patients diagnosed with SARS-CoV-2 by nasopharyngeal PCR who were admitted to a tertiary care center in Boston, MA with SARS-CoV-2 infection between March 17 and April 30, 2020 with a baseline PCT value were studied. Patients who were presumed positive for SARS-CoV-2, who lacked PCT levels, or who had a positive urinalysis with negative cultures were excluded. Demographics, clinical and laboratory data were extracted from the electronic medical records. RESULTS: 324 patient charts were reviewed and grouped by clinical and microbiologic outcomes by day 28. Baseline PCT levels were significantly higher for patients who were treated for true bacteremia (p = 0.0005) and bacterial pneumonia (p = 0.00077) compared with the non-bacterial infection group. Baseline PCT positively correlated with the NIAID ordinal scale and survival over time. When compared to other inflammatory biomarkers, PCT showed superiority in predicting bacteremia. CONCLUSIONS: Baseline PCT levels are associated with outcome and bacterial superinfection in patients hospitalized with SARS-CoV-2.

Use of oral tetracyclines in the treatment of adult outpatients with skin and skin structure infections: Focus on doxycycline, minocycline, and omadacycline.

Oral tetracyclines have been used in clinical practice for over 60 years. One of the most common indications for use of oral tetracyclines is for treatment of adult outpatients with skin and soft infections (SSTIs), including acute bacterial skin and skin structure infections (ABSSSIs). The 2014 Infectious Diseases Society of America (IDSA) skin and soft tissue guideline strongly recommends sulfamethoxazole/trimethoprim, clindamycin, and tetracyclines as oral treatment options for patients with purulent SSTIs, especially when methicillin-resistant Staphylococcus aureus is of clinical concern. Despite the long-standing use of tetracyclines, practice patterns indicate that they are often considered after other guideline-concordant oral options for the treatment of patients with SSTIs. Clinicians may therefore be less familiar with the clinical data associated with use of commercially available tetracycline agents for treatment of patients with SSTI. This review summarizes the literature on the use of oral tetracyclines (ie, doxycycline, minocycline, and omadacycline) for the treatment of adult patients with SSTIs. As part of this review, we describe their common mechanisms of resistance, susceptibility profiles against common SSTI pathogens, pharmacokinetics and pharmacodynamics, and comparative clinical data.

Colistin Nephrotoxicity: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Nephrotoxicity is a known adverse effect of polymyxin antibiotics, including colistin. Although previous meta-analyses have aimed to characterize colistin-associated nephrotoxicity risk relative to other antibiotics, included studies were observational in nature with high risk of confounding and heterogeneity. We conducted this systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to evaluate the incidence of nephrotoxicity associated with colistin versus minimally nephrotoxic antibiotics. METHODS: We searched PubMed, EMBASE, Cochrane Library, and 3 trial registries for RCTs comparing the nephrotoxicity of colistin to nonpolymyxin antibiotics. Randomized controlled trials that used aminoglycosides were excluded. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. The study outcome was the rate of nephrotoxicity. RESULTS: Five RCTs with a total of 377 patients were included. Most patients received colistin for pneumonia in the intensive care unit, and the comparators were ß-lactam-based regimens. Colistimethate sodium was dosed at 9 million units/day (300 mg/day of colistin base activity), with administration of a loading dose in 4 studies. The nephrotoxicity incidence in patients who received colistin was 36.2% (95% CI, 23.3% to 51.3%). The nephrotoxicity rate was significantly higher in the colistin arm than comparators (RR, 2.40; 95% CI, 1.47 to 3.91; P ≤ .001; I2 = 0%), and the number needed to harm was 5. Findings persisted upon one-study-removed-analysis. CONCLUSIONS: This meta-analysis of RCTs found a colistin-associated nephrotoxicity rate of 36.2% and an increase in this risk compared with ß-lactam-based regimens by 140%. Colistin should be regarded as a last-line agent and safer alternatives should be considered when possible.

Remdesivir use and outcomes during the FDA COVID-19 emergency use authorization period.

BACKGROUND: Remdesivir (RDV) was approved for treatment of coronavirus disease 2019 (COVID-19), in May 2020 under US Food and Drug Administration emergency use authorization (EUA). Clinical outcomes related to RDV use in hospitalized patients during the EUA period are not well described. METHODS: We conducted a retrospective study of patients who received RDV under EUA. The primary outcome was clinical recovery by day 14 as determined by an eight-category ordinal scale. Secondary outcomes included recovery and survival to day 28, and adverse events. Recovery and survival were calculated using a stratified log-rank Kaplan-Meier estimator and a Cox proportional hazards model. RESULTS: Overall, 164 patients received RDV between May and October 2020, and 153 (93.3%) had evaluable data. Most (77.1%) were hospitalized within 10 days of symptom onset, and 79.7% started RDV within 48 hours. By days 14 and 28, 96 (62.7%) and 117 patients (76.5%) met the definition of clinical recovery, respectively. Median time to recovery was 6 days [interquartile range (IQR) 4-12]. Mortality rates were 6.5% and 11.8% by days 14 and 28, respectively. Age and time to start of RDV after hospital admission were predictive of recovery and 28-day mortality. CONCLUSIONS: In this real-world experience, outcomes after 5 days of RDV therapy were comparable to those of clinical trials. Disease severity, age, and dexamethasone use influenced clinical outcomes. Time to RDV initiation appeared to affect recovery and 28-day mortality, a finding that should be explored further. Mortality rate decreased over the analysis period, which could be related to dexamethasone use and improved management of COVID-19.

Effect of oral vancomycin dose on outcomes in patients with Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality. Oral vancomycin is a cornerstone of CDI treatment, but dosing strategies in clinical practice may differ from guideline recommendations. This study aimed to determine differences in outcomes between patients treated with standard (125 mg QID) and high-dose (≥250 mg QID) oral vancomycin. This dual-centre study evaluated adult patients admitted between January 2013 and July 2017. Patients were included in the study if they had a positive C. difficile toxin PCR, symptomatic infection and received ≥48 h of oral vancomycin. Disease severity was characterised using a variety of classifiers, including guideline definitions. The primary outcome was 90-day CDI recurrence; secondary outcomes included clinical failure, in-hospital mortality and 90-day re-admission. Inverse probability of treatment weighting (IPTW) was conducted to balance differences between groups. A total of 535 patients were included; 261 received standard and 274 received high-dose vancomycin. Baseline demographics were similar between groups, except that patients receiving high-dose vancomycin were more likely to have more severe disease and to be admitted to the ICU. Few patients had fulminant disease (14.4%). No significant differences in recurrence (OR, 1.52, 95% CI 0.82-2.84), clinical failure (OR, 0.64, 95% CI 0.328-1.26), mortality (OR, 1.44, 95% CI 0.78-2.66) or re-admission (OR, 1.03, 95% CI 0.70-1.51) were identified between patients receiving standard and high-dose vancomycin in the IPTW analyses. No differences in recurrence, mortality or re-admission were identified between standard and high-dose vancomycin for the treatment of CDI not requiring surgery.

Approach to the Treatment of Patients with Serious Multidrug-Resistant Pseudomonas aeruginosa Infections.

Multidrug resistance(MDR) among Pseudomonas aeruginosa (PSA) isolates presents a significant clinical challenge and can substantially complicate the approach to selection of optimal antibiotic therapy. This review addresses major considerations in antibiotic selection for patients with suspected or documented serious MDR-PSA infections. Common mechanisms contributing to MDR among clinical PSA isolates are summarized. Empiric and definitive therapy considerations are addressed including the potential role of combination therapy. Newer agents with in vitro activity against MDR-PSA (e.g., ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and cefiderocol) and their potential roles in clinical settings are discussed. Although these newer agents are promising options for the treatment of MDR-PSA, clinical data remain generally limited. Future studies are needed to determine optimal agents for the empiric and definitive treatment of MDR-PSA.

Use of Oral Tetracyclines in the Treatment of Adult Patients with Community-Acquired Bacterial Pneumonia: A Literature Review on the Often-Overlooked Antibiotic Class.

Oral tetracyclines have been used in clinical practice for over 60 years. Overall, one of the most common indications for use of oral tetracyclines is for treatment of adult outpatients with lower respiratory tract infections, including community-acquired pneumonia (CAP). Despite the longstanding use of oral tetracyclines, practice patterns indicate that they are often considered after other guideline-concordant oral CAP treatment options (namely macrolides, fluoroquinolones, and ß-lactams). However, there are growing resistance or safety concerns with the available oral agents listed for outpatients with CAP in the updated American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) CAP guidelines, especially among patients with comorbidities or notable risk factors for resistant pathogens. Given the need for alternative oral agents to macrolides, fluoroquinolones, and beta-lactams for adult outpatients with CAP, this review summarizes the literature on the use of oral tetracyclines (i.e., doxycycline, minocycline, and omadacycline) for this indication. As part of this review, we described their mechanism of action, common mechanisms of resistance, susceptibility profiles against common CAP pathogens, pharmacokinetics, pharmacodynamics, clinical data, and safety. The intent of the review is to highlight the important considerations when deciding between doxycycline, minocycline, and omadacycline for an adult outpatient with CAP in situations in which use of an oral tetracycline is warranted.

Suboptimal Clinical Response Rates with Newer Antibiotics Among Patients with Moderate Renal Impairment: Review of the Literature and Potential Pharmacokinetic and Pharmacodynamic Considerations for Observed Findings.

A number of antibacterial agents have emerged into the U.S. market in the last 2 decades to address growing concerns of antimicrobial resistance. These agents have demonstrated noninferiority to comparators for treatment of a range of complicated infections in their respective clinical trials. However, with select agents, a trend of reduced therapeutic efficacy was observed among study patients with baseline renal impairment. This phenomenon was seen in phase III studies involving ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin. Although these were largely post hoc findings among small subpopulations, this observation is still concerning, given that renal impairment is a common occurrence among patients in real-world care settings. Cautions for use in this population are featured in the prescribing information of all four agents. Although well-defined reasons for these findings across trials are diverse or unknown, several potential pharmacokinetic and pharmacodynamic explanations for these discordant response rates exist. In this review, we summarize the phase III studies that observed lower response rates with ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin relative to their comparators among patients with moderate renal impairment, discuss potential explanations for the observed findings, provide considerations for future antibiotic development, and offer strategies for optimizing antibiotic dosage selection among patients with moderate renal impairment in clinical settings. Although all of these agents are discussed, ceftazidime-avibactam is used as a motivating example to demonstrate the implications of inappropriate dosage selection.