Nathaniel J. Rhodes

Treatment Outcomes with Cefazolin versus Oxacillin for Deep-Seated Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections

ABSTRACT Clinical preference for a semisynthetic penicillin (oxacillin or nafcillin) over cefazolin for deep-seated methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSI) perseveres despite limited data to support this approach. A retrospective cohort study of patients treated for MSSA BSI with either oxacillin or cefazolin was performed across two medical centers in Chicago, IL. The outcome measures included documented in-hospital treatment failure, all-cause in-hospital mortality, duration of MSSA BSI, and incidence of documented adverse events. Of 161 patients with MSSA BSI, 103 (64%) received cefazolin, and 58 (36%) received oxacillin. The identified sources of BSI were central line (37.9%), osteoarticular (18%), and skin and soft tissue (17.4%). Patients with endocarditis (29/52 [44.2%]) and other deep-seated infections (23/52 [55.8%]) were classified under the subset of deep-seated infections (52/161 [32.3%]). Multivariate models found deep-seated infection (adjusted odds ratio [aOR], 4.52; 95% confidence interval [CI], 1.23 to 16.6; P = 0.023), metastatic disease (aOR, 4.21; 95% CI, 1.13 to 15.7; P = 0.033), and intensive care unit (ICU) onset of infection (aOR, 4.80; 95% CI, 1.26 to 18.4; P = 0.022) to be independent risk factors for in-hospital treatment failure. Treatment group was not an independent predictor of failure (aOR, 3.76; 95% CI, 0.98 to 14.4; P = 0.053). The rates of treatment failure were similar among cefazolin-treated (5/32 [15.6%]) and oxacillin-treated (4/20 [20.0%]) patients (P = 0.72) in the subset of deep-seated infections. Mortality was observed in 1 (1%) and 3 (5.2%) cases of cefazolin- and oxacillin-treated patients, respectively (P = 0.13). Cefazolin was not associated with higher rates of treatment failure and appears to be an effective alternative to oxacillin for treatment of deep-seated MSSA BSI.

Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis

OBJECTIVES As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. METHODS Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. RESULTS Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. CONCLUSIONS Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L.

Defining clinical exposures of cefepime for Gram negative bloodstream infections that are associated with improved survival

ABSTRACT The percentage of time that free drug concentrations remain above the MIC (fT>MIC) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds for fT>MIC were identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A total of 180 patients were included in the analysis, of whom 13.9% died and 86.1% survived. Many patients (46.7% [n = 84/180]) received combination therapy with cefepime. Survivors had higher mean (standard deviation [SD]) fT>MIC than those who died (model 1, 74.2% [29.6%] versus 52.1% [33.8%], P < 0.001; model 2, 85.9% [24.0%] versus 64.4% [31.4%], P < 0.001). CART identified fT>MIC threshold values for greater survival according to models 1 and 2 at >68% and >74%, respectively. Survival was improved for those with fT>MIC of >68% (model 1 adjusted odds ratio [aOR], 7.12; 95% confidence interval [CI], 1.90 to 26.7; P = 0.004) and >74% (model 2 aOR, 6.48; 95% CI, 1.90 to 22.1) after controlling for clinical covariates. Similarly, each 1% increase in cefepime fT>MIC resulted in a 2% improvement in multivariate survival probability (P = 0.015). Achieving a cefepime fT>MIC of 68 to 74% was associated with a higher odds of survival for patients with GNBSI. Regimens targeting this exposure should be aggressively pursued.

Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

ABSTRACT Vancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocols final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearmans nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0–24), the maximum concentration in plasma during the first 24 h (Cmax0–24), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0–24). A total of 52 rats received vancomycin (n = 42) or NS (n = 10). The strongest exposure-response correlations were observed between AUC0–24 and Cmax0–24 and urinary AKI biomarkers. Exposure-response correlations (rs values) for AUC0–24, Cmax0–24, and Cmin0–24 were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0–24 or Cmax0–24 correlates with increases in urinary AKI biomarkers.

Evaluation of clinical outcomes in patients with Gram-negative bloodstream infections according to cefepime MIC.

Predicted and observed failures at higher cefepime MICs have prompted the Clinical and Laboratories Standards Institute (CLSI) to lower the susceptible breakpoint for Enterobacteriaceae to ≤2mg/L, with dose-dependent susceptibility at 4-8mg/L, while the susceptibility breakpoint for nonfermentative organisms remain unchanged at ≥8mg/L. The contribution of increasing cefepime MIC to mortality risk in the setting of aggressive cefepime dosing is not well defined. Patients who were treated with cefepime for Gram-negative blood stream infections (GNBSIs), including both Enterobacteriaceae and nonfermentative organisms, were screened for inclusion in this retrospective cohort study. Demographic and microbiologic variables were collected, including pathogen, cefepime MIC, dosage, and interval. The objective was to define a risk-adjusted mortality breakpoint for cefepime MICs. Secondarily, we looked at time to death and length of stay (LOS) postculture. Ninety-one patients were included in the analysis. Overall, 19 patients died and 72 survived. Classification and Regression Tree analysis identified an inhospital mortality breakpoint at a cefepime MIC between 2 and 4mg/L for patients with a modified Acute Physiology and Chronic Health Evaluation II score ≤16.5 (4.2% versus 25%, respectively). Multivariate logistic regression revealed increased odds of mortality at a cefepime MIC of 4mg/L (adjusted odds ratio [aOR] 6.47; 95% confidence interval [CI] 1.25-33.4) and 64mg/L (aOR 6.54, 95% CI 1.03-41.4). Those with cefepime MICs ≥4mg/L experienced a greater median intensive care unit LOS for survivors (16 versus 2days; P=0.026). Increasing cefepime MIC appears to predict inhospital mortality among patients who received aggressive doses of cefepime for GNBSIs, supporting a clinical breakpoint MIC of 2mg/L.

Unacceptably High Error Rates in Vitek 2 Testing of Cefepime Susceptibility in Extended-Spectrum-β-Lactamase-Producing Escherichia coli

ABSTRACT While a lack of concordance is known between gold standard MIC determinations and Vitek 2, the magnitude of the discrepancy and its impact on treatment decisions for extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli are not. Clinical isolates of ESBL-producing E. coli were collected from blood, tissue, and body fluid samples from January 2003 to July 2009. Resistance genotypes were identified by PCR. Primary analyses evaluated the discordance between Vitek 2 and gold standard methods using cefepime susceptibility breakpoint cutoff values of 8, 4, and 2 μg/ml. The discrepancies in MICs between the methods were classified per convention as very major, major, and minor errors. Sensitivity, specificity, and positive and negative predictive values for susceptibility classifications were calculated. A total of 304 isolates were identified; 59% (179) of the isolates carried blaCTX-M, 47% (143) carried blaTEM, and 4% (12) carried blaSHV. At a breakpoint MIC of 8 μg/ml, Vitek 2 produced a categorical agreement of 66.8% and exhibited very major, major, and minor error rates of 23% (20/87 isolates), 5.1% (8/157 isolates), and 24% (73/304), respectively. The sensitivity, specificity, and positive and negative predictive values for a susceptibility breakpoint of 8 μg/ml were 94.9%, 61.2%, 72.3%, and 91.8%, respectively. The sensitivity, specificity, and positive and negative predictive values for a susceptibility breakpoint of 2 μg/ml were 83.8%, 65.3%, 41%, and 93.3%, respectively. Vitek 2 results in unacceptably high error rates for cefepime compared to those of agar dilution for ESBL-producing E. coli. Clinicians should be wary of making treatment decisions on the basis of Vitek 2 susceptibility results for ESBL-producing E. coli.

Impact of Loading Doses on the Time to Adequate Predicted Beta-Lactam Concentrations in Prolonged and Continuous Infusion Dosing Schemes

TO THE EDITOR—We applaud the work by Roberts et al that was recently published in the Journal [1].As shown in this work and others, achievement of pharmacokinetic– pharmacodynamic (PK/PD) targets for beta-lactam antibiotics has been correlated with improved mortality among the critically ill [1, 2]. Similarly, hastening time to effective antimicrobial therapy in the setting of septic shock has been shown to improve the probability of survival [3–5]. For beta-lactams, maintenance of free ( f ) drug concentrations above an organism’s minimum inhibitory concentration (MIC) for a given proportion of the dosing interval ( f T > MIC) has been shown to predict clinical and microbiologic success [1]. To improve the likelihood of achieving PK/PD targets for these agents, beta-lactams are often administered as prolonged (PI) or continuous infusions (CI); though, time to activity has not been well described nor

Prolonged Infusion Piperacillin-tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients: Results of a Systematic Review and Meta-analysis

Objective: Piperacillin-tazobactam is a commonly used antibiotic in critically ill patients; however, controversy exists as to whether mortality in serious infections can be decreased through administration by prolonged infusion compared with intermittent infusion. The purpose of this systematic review and meta-analysis was to describe the impact of prolonged infusion piperacillin-tazobactam schemes on clinical endpoints in severely ill patients. Design: We conducted a systematic literature review and meta-analysis searching MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to April 1, 2017, for studies. Interventions: Mortality rates were compared between severely ill patients receiving piperacillin-tazobactam via prolonged infusion or intermittent infusion. Included studies must have reported severity of illness scores, which were transformed into average study-level mortality probabilities. Measurements and Main Results: Two investigators independently screened titles, abstracts, and full texts of studies meeting inclusion criteria for this systematic review and meta-analysis. Variables included author name, publication year, study design, demographics, total daily dose(s), average estimated creatinine clearance, type of prolonged infusion, prevalence of combination therapy, severity of illness scores, infectious sources, all-cause mortality, clinical cure, microbiological cure, and hospital and ICU length of stay. The review identified 18 studies including 3,401 patients who received piperacillin-tazobactam, 56.7% via prolonged infusion. Across all studies, the majority of patients had an identified primary infectious source. Receipt of prolonged infusion was associated with a 1.46-fold lower odds of mortality (95% CI, 1.20–1.77) in the pooled analysis. Patients receiving prolonged infusion had a 1.77-fold higher odds of clinical cure (95% CI, 1.24–2.54) and a 1.22-fold higher odds of microbiological cure (95% CI, 0.84–1.77). Subanalyses were conducted according to high (≥ 20%) and low (< 20%) average study-level mortality probabilities. In studies reporting higher mortality probabilities, effect sizes were variable but similar to the pooled results. Conclusions: Receipt of prolonged infusion of piperacillin-tazobactam was associated with reduced mortality and improved clinical cure rates across diverse cohorts of severely ill patients.

Student Characteristics Associated with Successful Matching to a PGY1 Residency Program

Objective. To identify predictors for postgraduate matching success. Methods. In April 2014, a survey was distributed to students at five schools of pharmacy in the United States assessing organizational involvement, research and work experience, postgraduation plans, match status, and demographics. Results. Five hundred seventy-seven students (82%) completed the survey. Applicants who matched had a higher median number of interview offers compared to those who did not match. Significantly more females than males applied for a residency program. Those who matched had a higher median pharmacy school grade point average (GPA) compared to those who did not. No differences were observed in the rates of matching when leadership positions, student organizational membership, or previous work experience were considered. Conclusion. For pharmacy students in this study, number of applications and interviews, pharmacy school GPA, and female gender were associated with a higher likelihood of matching.

Tree-Based Models for Predicting Mortality in Gram-Negative Bacteremia: Avoid Putting the CART before the Horse.

ABSTRACT Increasingly, infectious disease studies employ tree-based approaches, e.g., classification and regression tree modeling, to identify clinical thresholds. We present tree-based-model-derived thresholds along with their measures of uncertainty. We explored individual and pooled clinical cohorts of bacteremic patients to identify modified acute physiology and chronic health evaluation (II) (m-APACHE-II) score mortality thresholds using a tree-based approach. Predictive performance measures for each candidate threshold were calculated. Candidate thresholds were examined according to binary logistic regression probabilities of the primary outcome, correct classification predictive matrices, and receiver operating characteristic curves. Three individual cohorts comprising a total of 235 patients were studied. Within the pooled cohort, the mean (± standard deviation) m-APACHE-II score was 13.6 ± 5.3, with an in-hospital mortality of 16.6%. The probability of death was greater at higher m-APACHE II scores in only one of three cohorts (odds ratio for cohort 1 [OR1] = 1.15, 95% confidence interval [CI] = 0.99 to 1.34; OR2 = 1.04, 95% CI = 0.94 to 1.16; OR3 = 1.18, 95% CI = 1.02 to 1.38) and was greater at higher scores within the pooled cohort (OR4 = 1.11, 95% CI = 1.04 to 1.19). In contrast, tree-based models overcame power constraints and identified m-APACHE-II thresholds for mortality in two of three cohorts (P = 0.02, 0.1, and 0.008) and the pooled cohort (P = 0.001). Predictive performance at each threshold was highly variable among cohorts. The selection of any one predictive threshold value resulted in fixed sensitivity and specificity. Tree-based models increased power and identified threshold values from continuous predictor variables; however, sample size and data distributions influenced the identified thresholds. The provision of predictive matrices or graphical displays of predicted probabilities within infectious disease studies can improve the interpretation of tree-based model-derived thresholds.