Quantifying the importance of active antimicrobial therapy among patients with Gram-negative bloodstream infections: Cefepime as a representative agent.

The quantitative importance of active antimicrobial treatment relative to other modifiable and non-modifiable risk factors for mortality has not been well defined in the literature. Here we quantify the impact of active antimicrobial treatment on mortality relative to other disease modifiers in patients with Gram-negative bloodstream infection (GNBSI). Patients with at least one positive blood culture who were treated with ≥24 h of cefepime for GNBSI were included in the study. To examine in-hospital survival, a full primary model and a base model with the least significant covariate from the primary model were established. Relative importance of covariates was calculated using percentages of difference in log-likelihood values when each covariate was iteratively added to the base model. A total of 154 unique patients with GNBSI were included. The primary model included active cefepime therapy (P = 0.004), normalised days to positive culture (P = 0.091), intensive care unit (ICU) at time of treatment (P = 0.001), modified Acute Physiology and Chronic Health Evaluation (APACHE) II score on day zero (P = 0.025), history of leukaemia (P = 0.008) and prior immunosuppressive therapy (P = 0.088). Active antimicrobial therapy displayed a relative importance of 32.2%, which was second to ICU residence at the time of culture. Amongst all covariates in the model, active antimicrobial therapy was the only modifiable variable and contributed significantly to in-hospital survival in acutely ill patients with GNBSI.

High-Performance Liquid Chromatography Method for Rich Pharmacokinetic Sampling Schemes in Translational Rat Toxicity Models With Vancomycin.

A translational need exists to understand and predict vancomycin-induced kidney toxicity. We describe: (i) a vancomycin high-performance liquid chromatography (HPLC) method for rat plasma and kidney tissue homogenate; (ii) a rat pharmacokinetic (PK) study to demonstrate utility; and (iii) a catheter retention study to enable future preclinical studies. Rat plasma and pup kidney tissue homogenate were analyzed via HPLC for vancomycin concentrations ranging from 3-75 and 15.1-75.5 µg/mL, respectively, using a Kinetex Biphenyl column and gradient elution of water with 0.1% formic acid: acetonitrile (70:30 v/v). Sprague-Dawley rats (n = 10) receiving 150 mg/kg of vancomycin intraperitoneally had plasma sampled for PK. Finally, a catheter retention study was performed on polyurethane catheters to assess adsorption. Precision was <6.1% for all intra-assay and interassay HPLC measurements, with >96.3% analyte recovery. A two-compartment model fit the data well, facilitating PK exposure estimates. Finally, vancomycin was heterogeneously retained by polyurethane catheters.

Relationship between vancomycin exposure and outcomes among patients with MRSA bloodstream infections with vancomycin Etest® MIC values of 1.5mg/L: A pilot study.

Data suggest that vancomycin is less effective for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) with vancomycin Etest® MIC (MICEtest) ≥1.5 mg/L. No published studies have evaluated the relationship between vancomycin exposure and outcomes among patients with MRSA BSIs vancomycin MICEtest ≥1.5 mg/L. This study was a retrospective cohort of 71 hospitalized, adult, non-dialysis patients with MRSA BSIs treated with vancomycin. All but three patients had a vancomycin MICEtest of 1.5 mg/L. Achievement of CART-derived AUC24-48h of at least 550 mg*h/L (AUC24-48h/MIC of 366 mg*h/L) was associated with a lower incidence of treatment failure. In multivariate analyses, the risk ratio was 0.45 for the CART-derived AUC24-48h threshold, indicating that achievement of the CART-derived AUC24-48h threshold of 550 was associated with a 2-fold decrease in treatment failure. These findings suggest a potential association between vancomycin exposure and outcomes in patients with MRSA BSIs with MICEtest ≥1.5 mg/L. As this study was retrospective, these findings provide the basis for a future large-scale, multi-center prospective study.

Resolution of acyclovir-associated neurotoxicity with the aid of improved clearance estimates using a Bayesian approach: A case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVE: Neurotoxicity is a side effect of acyclovir. We report the first case, to our knowledge, whereby Bayesian-informed clearance estimates supported a therapeutic intervention for acyclovir-associated neurotoxicity. CASE SUMMARY: A 62-year-old male with the diagnosis of disseminated zoster was being treated with intravenous (IV) acyclovir when he developed symptoms of acute neurotoxicity. Acyclovir had been dose-adjusted for renal dysfunction according to traditional creatinine clearance estimates; however, as the patient was also on vancomycin, Bayesian estimates of vancomycin clearances were performed, which revealed a 2-fold lower creatinine clearance. In response to the Bayesian estimates, acyclovir was discontinued, and improvements in mentation were noted within 24 hours. WHAT IS NEW AND CONCLUSION: Alternate approaches to estimate renal function beyond Cockcroft-Gault, such as a Bayesian approach used in our patient, should be considered when population estimates are likely to be inaccurate and potentially dangerous to the patient.

Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients.

This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CL(CR)) on overall clearance, TZP clearance was made proportional to the estimated CL(CR). A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CL(CR). The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CL(CR). In contrast, the PTA for the extended-infusion TZP regimen exceeded >or=80% for MIC values of or=32 mg/liter irrespective of the CL(CR). The CL(CR) adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CL(CR) of

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring.

Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day -1 (30% lesser than the usual starting dose). The dose was reduced by 30-40% if the 48-h steady-state concentration was 7-10 ng/ml, and by 40-50% if it was 10-15 ng/ml. No change was made if the concentration was <7 ng/ml. Subsequently, concentrations were generally monitored 2-3 times a week with dose adjustments as necessary. None of the 170 levels (3-12 per patient; median 5) obtained between days +1 and +16 were subtherapeutic (<5 ng/ml) and only 34 levels (20%) were >15 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent.

Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy.

Zygomycosis is increasingly reported as a cause of life-threatening fungal infections. A higher proportion of cases reported over the last decades have been in cancer patients, with or without hematopoietic stem cell transplantation (HSCT). The new anti-fungal agent voriconazole is a recently identified risk factor for developing zygomycosis. We reviewed the clinical characteristics and outcomes of a large cohort of cancer patients who developed zygomycosis after exposure to voriconazole. Health care professionals at 13 large cancer centers provided clinical information on cancer patients with zygomycosis and prior exposure to voriconazole. Criteria for inclusion were 5 days or more of voriconazole use and diagnostic confirmation with tissue or histology. Fifty-eight cases were identified among patients with hematologic malignancies, 62% including patients who underwent a HSCT procedure. Fifty-six patients received voriconazole for primary or secondary prophylaxis against fungal infection. In addition to prior exposure to voriconazole, patients also had several of the previously established risk factors for zygomycosis. Amphotericin B was the most commonly prescribed anti-fungal therapy. Overall mortality was 73%. We conclude that zygomycosis after exposure to voriconazole is a recently described entity that is frequently fatal, despite treatment with currently available anti-fungal agents and surgery.