Cristina Miglis

Investigating the Extremes of Antibiotic Use with an Epidemiologic Framework

ABSTRACT Benchmarks for judicious use of antimicrobials are needed. Metrics such as defined daily doses (DDDs) and days of therapy (DOTs) quantify antimicrobial consumption. However, benchmarking with these metrics is complicated by interhospital variability. Thus, it is important for each hospital to monitor its own temporal consumption trends. Time series analyses allow trends to be detected; however, many of these methods are complex. We present simple regressive methods and caveats in using them to define potential antibiotic over- and underutilizations.

Population pharmacokinetics of Polymyxin B in acutely Ill adult patients

ABSTRACT Polymyxin B (PB) has reemerged as a common treatment against multidrug-resistant Gram-negative pathogens. However, nephrotoxicity remains a significant dose-limiting side effect, and contemporary pharmacokinetic (PK) data are limited. This study sought to evaluate PB exposure differences in various loading and nonloading strategies according to total body weight (TBW) and adjusted body weight (ABW). Patients treated with PB had plasma samples obtained for clinical care and analyzed using liquid chromatography-tandem mass spectrometry. Compartmental PK models with linear and allometric scaling of TBW were explored. Semiparametric Monte Carlo simulation evaluated the total (i.e., protein bound plus unbound) area under the plasma concentration-time curve (AUCtotal) during the first 24 h of therapy and at 96 h posttherapy for each regimen at the 10th, 50th, and 90th percentiles of TBW and ABW in the derivation cohort. Literature-based values of the 24-h total AUC/MIC ratio (AUC/MICtotal) of ≥50 defined efficacy, and literature-based values of the 72- to 96-h AUCtotal of ≥100 μg · h/ml defined toxicity. Fifty-two patients contributed 156 PB plasma samples. A two-compartment model with allometric scaling of TBW produced a comparable fit (Akaike information criterion [AIC] = 376.7) to that achieved with linear scaling (AIC = 378). The regimen of a loading dose of 2.5 mg/kg of body weight plus a fixed dose of 100 mg every 12 h had the highest probability of achieving a 24-h AUC/MICtotal of ≥50 with the lowest probability of toxicity in all groups at 24 h, aside from those with the lowest 10th percentile of body weight. This is the first study to suggest that a weight-based loading and fixed maintenance (i.e., weight-independent) dosing strategy for polymyxin B may maximize efficacy while balancing toxicity concerns for most patients.

Carbapenem susceptibility breakpoints, clinical implications with the moving target

ABSTRACT Carbapenems are primary agents used to treat a variety of Gram-negative multi-drug resistant infections. In parallel with increasing use, increasing resistance to carbapenem agents has manifested as increased minimum inhibitory concentrations (MICs). To attempt to improve clinical outcomes with carbapenems, the Clinical Laboratory Standards Institute and the Food Drug Administration decreased susceptibility breakpoints. The European equivalent expert committee, the European Committee on Antimicrobial Susceptibility Testing, also utilizes lower MIC susceptibility breakpoints. This review focuses on the rationale for recent breakpoint changes and the associated clinical outcomes for patients treated with carbapenems for infections with varying MICs proximal to the breakpoint. Supporting pharmacokinetics and pharmacodynamics that underpin the breakpoints are also reviewed.

Doses, durations, and gender predict vancomycin-induced kidney injury in pre-clinical studies

BACKGROUND Although the exposure-dependent efficacy thresholds of vancomycin have been probed, less is known about acute kidney injury (AKI) thresholds for this drug. Sensitive urinary biomarkers, such as kidney injury molecule 1 (KIM-1), have shown high sensitivity and specificity for vancomycin-associated AKI. The aims of the study were to determine if there were dose-response curves with urinary KIM-1, and to evaluate the impact of therapy duration and sex on observed relationships. METHODS A systematic review was conducted via PubMed/MEDLINE. Data were compiled from preclinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and sex. Sigmoidal Hill-type models were fit to the individual dose-response data. RESULTS A total of 15 studies were identified, 6 of which reported vancomycin dose and KIM-1 data. Of these, three included individual animal-level data suitable for analysis. For all pooled rats, increasing total daily vancomycin doses displayed a dose-response curve with urinary KIM-1 concentrations (50% maximal toxic response=130.4 mg/kg/day). Dose-response curves were shifted left for females vs. males (P = 0.05) and for long (i.e. ≥7 days) vs. short (i.e. <4 days) duration of vancomycin therapy (P=0.02). CONCLUSIONS The collective findings demonstrate a clear dose-response relationship between vancomycin dose and AKI. As these analyses focused exclusively on dose-response relationships, additional preclinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI.

A simple microsoft excel method to predict antibiotic outbreaks and underutilization

Benchmarking strategies are needed to promote the appropriate use of antibiotics. We have adapted a simple regressive method in Microsoft Excel that is easily implementable and creates predictive indices. This method trends consumption over time and can identify periods of over- and underuse at the hospital level. Infect Control Hosp Epidemiol 2017;38:860-862.

Correlation between hospital-level antibiotic consumption and incident health care facility-onset Clostridium difficile infection

Background: The purpose of this single‐center, ecologic study is to characterize the relationship between facility‐wide (FacWide) antibiotic consumption and incident health care facility‐onset Clostridium difficile infection (HO‐CDI). Methods: FacWide antibiotic consumption and incident HO‐CDI were tallied on a monthly basis and standardized, from January 2013 through April 2015. Spearman rank‐order correlation coefficients were calculated using matched‐months analysis and a 1‐month delay. Regression analyses were performed, with P < .05 considered statistically significant. Results: FacWide analysis identified a matched‐months correlation between ceftriaxone and HO‐CDI (&rgr; = 0.44, P = .018). A unit of stem cell transplant recipients did not have significant correlation between carbapenems and HO‐CDI in matched months (&rgr; = 0.37, P = .098), but a significant correlation was observed when a 1‐month lag was applied (&rgr; = 0.54, P = .014). Discussion: Three statistically significant lag associations were observed between FacWide/unit‐level antibiotic consumption and HO‐CDI, and 1 statistically significant nonlagged association was observed FacWide. Antibiotic consumption may convey extended ward‐level risk for incident CDI. Conclusions: Consumption of antibiotic agents may have immediate and prolonged influence on incident CDI. Additional studies are needed to investigate the immediate and delayed associations between antibiotic consumption and C difficile colonization, infection, and transmission at the hospital level.

Polymyxin B Pharmacokinetics in Adult Cystic Fibrosis Patients

Polymyxin B pharmacokinetics (PK) in adults with cystic fibrosis (CF) are not well described. The goals of this pilot study were to identify a PK model for patients with CF receiving polymyxin B with exploration of covariate relationships of the PK parameters, to compare polymyxin B PK parameters in adults without CF, and to probe exposures associated with different dosing schemes through simulation.

Effect of elevated imipenem/cilastatin minimum inhibitory concentrations on patient outcomes in Gram-negative bloodstream infections

OBJECTIVES Carbapenem minimum inhibitory concentration (MICs) are known to predict outcomes for patients with Gram-negative bacteraemia. However, limited data exist on how MICs influence such outcomes when organisms are classified as carbapenem-resistant. The purpose of this study was to evaluate the effect of increasing imipenem/cilastatin MICs on mortality in patients with Gram-negative bloodstream infection (BSI). METHODS Patients with an imipenem/cilastatin-resistant (MIC>4mg/L) monomicrobial Gram-negative BSI were eligible for inclusion in the study and were assessed for baseline characteristics, organ function, microbiological data, timing and type of therapeutic treatment, and in-hospital mortality. RESULTS A total of 62 patients with imipenem/cilastatin-resistant bacterial isolates (MIC>4mg/L) were retrospectively studied. Time to event analyses found no difference between patients who received carbapenem therapy and those who did not (P=0.10). After adjustment, patients receiving directed therapy were less likely to die (adjusted hazard ratio=0.35, 95% confidence interval 0.15-0.83; P<0.01), whereas higher modified Acute Physiology and Chronic Health Evaluation (APACHE) II score and days to positive culture were associated with non-survival. CONCLUSION This study did not demonstrate a relationship between receipt of a carbapenem and mortality in patients with carbapenem-resistant Gram-negative BSI.

24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury.

ABSTRACT Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (Cmax), and the minimum concentration. Spearmans rank correlation coefficient (rs) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and Cmax were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for Cmax). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or Cmax.