David W. Kubiak

Reactivity of (1→3)-β-d-Glucan Assay with Commonly Used Intravenous Antimicrobials

ABSTRACT Forty-four intravenous antimicrobials were tested for the presence of (1→3)-β-d-glucan (BG). Colistin, ertapenem, cefazolin, trimethoprim-sulfamethoxazole, cefotaxime, cefepime, and ampicillin-sulbactam tested positive for BG at reconstituted-vial concentrations but not when diluted to usual maximum plasma concentrations. False-positive BG assays may occur when some antimicrobials are administered; however, this needs to be confirmed.

Invasive fungal infections and antifungal therapies in solid organ transplant recipients.

This manuscript will review the risk factors, prevalence, clinical presentation, and management of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients. Primary literature was obtained via MEDLINE (1966–April 2007) and EMBASE. Abstracts were obtained from scientific meetings or pharmaceutical manufacturers and included in the analysis. All studies and abstracts evaluating IFIs and/or antifungal therapies, with a primary focus on solid organ transplantation, were considered for inclusion. English‐language literature was selected for inclusion, but was limited to those consisting of human subjects. Infectious complications following SOT are common. IFIs are associated with high morbidity and mortality rates in this patient population. Determining the best course of therapy is difficult due to the limited availability of data in SOT recipients. Well‐designed clinical studies are infrequent and much of the available information is often based on case‐reports or retrospective analyses. Transplant practitioners must remain aware of their therapeutic options and the advantages and disadvantages associated with the available treatment alternatives.

Evaluation of Caspofungin or Micafungin as Empiric Antifungal Therapy in Adult Patients With Persistent Febrile Neutropenia: A Retrospective, Observational, Sequential Cohort Analysis

BACKGROUND Caspofungin is approved in the United States for empiric antifungal therapy for persistent febrile neutropenia (FN). There are limited data about the use of other echinocandins in this setting. OBJECTIVE After a formulary change, we retrospectively evaluated the safety and effectiveness of caspofungin and micafungin as empiric antifungal therapy for FN at Brigham and Womens Hospital (Boston, Massachusetts). METHODS This was a retrospective, observational, sequential cohort study. We identified patients who had received >or=2 doses on concurrent days of either caspofungin (between November 2005 and October 2006) or micafungin (between November 2006 and October 2007) for empiric FN therapy. Patients were included for analysis if they were neutropenic (absolute neutrophil count <500 cells/microL) and febrile (temperature >or=100.5 degrees F [>or=38 degrees C]). Patients without previous exposure to an echinocandin were included; those included in the caspofungin cohort were excluded from the micafungin cohort. Those who had previously received another systemic antifungal agent for FN therapy (except fluconazole for mucosal candidiasis) were excluded. Patients were followed through hospital discharge. Outcomes analyzed were successful treatment of baseline invasive fungal disease (IFD), incidence of breakthrough IFD, overall mortality, and discontinuation because of adverse events (AEs). IFD was diagnosed and classified according to current European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group criteria. RESULTS Three hundred twenty-three patients met inclusion criteria (caspofungin, n = 149; micafungin, n = 174). Median age was 49 years in both the caspofungin and micafungin groups; 80 (53.7%) and 99 (56.9%) patients in each group, respectively, were men. Fluconazole prophylaxis had been administered to 30 patients (20.1%) treated with caspofungin and 21 patients (12.1%) treated with micafungin. Caspofungin was administered at 70 mg for one dose, followed by 50 mg daily; micafungin was administered at 100 mg daily. The median duration of therapy and of hospitalization were 10 days and 29 days, respectively, with caspofungin, and 9 days and 28 days with micafungin (both, P = NS between groups). Twelve patients (8.1%) in the caspofungin cohort and 13 (7.5%) in the micafungin cohort died during the study period (P = NS). There were 3 cases (2.0%) of baseline IFD in the caspofungin cohort and 6 (3.4%) in the micafungin cohort (P = NS); 6 were successfully treated (caspofungin, 2 [1.3% of entire group]; micafungin, 4 [2.37% of entire group]; P = NS). Breakthrough IFD was diagnosed in 16 patients (10.7%) receiving caspofungin and 21 (12.1%) receiving micafungin (P = NS). AEs requiring echinocandin discontinuation were uncommon (caspofungin, 2 cases of rash and 1 anaphylactoid infusion reaction [2.0%]; mica-fungin, 1 liver function test elevation >or=5 times the upper limit of normal and 1 maculopapular rash [1.1%]; P = NS). CONCLUSION Micafungin, as empiric antifungal therapy for persistent FN, did not appear to differ significantly from caspofungin in terms of safety profile or efficacy in the adult patients included in this sequential cohort analysis at one institution. ClinicalTrials.gov identifier: NCT00723073.

Cefepime vs Other Antibacterial Agents for the Treatment of Enterobacter Species Bacteremia

BACKGROUND Carbapenems are recommended for treatment of Enterobacter infections with AmpC phenotypes. Although isolates are typically susceptible to cefepime in vitro, there are few data supporting its clinical efficacy. METHODS We reviewed all cases of Enterobacter species bacteremia at 2 academic hospitals from 2005 to 2011. Outcomes of interest were (1) persistent bacteremia ≥1 calendar day and (2) in-hospital mortality. We fit logistic regression models, adjusting for clinical risk factors and Pitt bacteremia score and performed propensity score analyses to compare the efficacy of cefepime and carbapenems. RESULTS Three hundred sixty-eight patients experienced Enterobacter species bacteremia and received at least 1 antimicrobial agent, of whom 52 (14%) died during hospitalization. Median age was 59 years; 19% were neutropenic, and 22% were in an intensive care unit on the day of bacteremia. Twenty-nine (11%) patients had persistent bacteremia for ≥1 day after antibacterial initiation. None of the 36 patients who received single-agent cefepime (0%) had persistent bacteremia, as opposed to 4 of 16 (25%) of those who received single-agent carbapenem (P < .01). In multivariable models, there was no association between carbapenem use and persistent bacteremia (adjusted odds ratio [aOR], 1.52; 95% CI, .58-3.98; P = .39), and a nonsignificant lower odds ratio with cefepime use (aOR, 0.52; 95% CI, .19-1.40; P = .19). In-hospital mortality was similar for use of cefepime and carbapenems in adjusted regression models and propensity-score matched analyses. CONCLUSIONS Cefepime has a similar efficacy as carbapenems for the treatment of Enterobacter species bacteremia. Its use should be further explored as a carbapenem-sparing agent in this clinical scenario.

A targeted peritransplant antifungal strategy for the prevention of invasive fungal disease after lung transplantation: a sequential cohort analysis.

Background Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach. Methods We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate. Results IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality. Conclusions The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.

High-Dose Intravenous Vancomycin Therapy and the Risk of Nephrotoxicity

PURPOSE National guidelines recommend higher serum trough concentrations when using vancomycin to treat certain clinical conditions, but there is concern that higher-dose vancomycin therapy causes nephrotoxicity. We evaluated risk factors associated with nephrotoxicity in patients receiving high-dose intravenous vancomycin. METHODS This retrospective cohort study evaluated the clinical outcome of 80 hospitalized adult patients with normal baseline renal function who received ≥4 g/d of intravenous vancomycin for ≥48 hours between January 1, 2011, and December 31, 2011. After abstracting clinical risk factors, we used an analysis by methods of best clinical subsets to develop a multivariable model predicting nephrotoxicity in patients receiving high-dose vancomycin. FINDINGS The overall rate of nephrotoxicity in the study population was 6%. Trough concentrations >20 mg/L were identified in a similar proportion of patients who did and did not develop nephrotoxicity. Patients who developed nephrotoxicity trended toward having a lower body mass index, higher daily dose, longer duration of therapy, and greater exposure to intravenous contrast and nephrotoxic medications. In a multivariable model, the combination of intravenous contrast and nephrotoxic medications was a significant predictor of nephrotoxicity, and duration of high-dose vancomycin was a significant confounder. IMPLICATIONS Administration of high-dose intravenous vancomycin may have less associated nephrotoxicity than previously reported, although duration of vancomycin therapy may play a role. Concomitant exposure to intravenous contrast and other nephrotoxic medications is a more significant predictor of developing nephrotoxicity than vancomycin dose or trough.

High incidence of neutropenia in patients with prolonged ceftaroline exposure

OBJECTIVES We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline. METHODS We retrospectively identified adult patients who received ceftaroline for ≥7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia. RESULTS The overall rate of incident neutropenia was 10%-14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22-44; range 13-68) in patients who developed neutropenia and 15 days (IQR 9-29; range 7-64) in patients without neutropenia] was associated with incident neutropenia (P = 0.048). The median total number of ceftaroline doses received [63 (IQR 44-126; range 36-198) by neutropenic patients and 32 (IQR 22-63; range 14-180) by non-neutropenic patients] was also associated with incident neutropenia (P = 0.023). CONCLUSIONS The overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use.

Safety of Posaconazole and Sirolimus Coadministration in Allogeneic Hematopoietic Stem Cell Transplants

Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patients sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation.

Extensive Prolongation of aPTT with Argatroban in an Elderly Patient with Improving Renal Function, Normal Hepatic Enzymes, and Metastatic Lung Cancer

OBJECTIVE: To report a case of an elderly male with improving renal function and normal hepatic function who sustained an elevated activated partial thromboplastin time (aPTT) after an infusion of argatroban was discontinued. CASE SUMMARY: A 77-year-old white male with a history of heparin-induced thrombocytopenia (HIT) and metastatic lung disease was started on argatroban for treatment of a right upper-extremity deep vein thrombosis (DVT). The infusion was initiated at 2.0 μg/kg/min and was titrated to a goal aPTT of 60–80 seconds. Argatroban was discontinued due to an aPTT elevated to >100 seconds; the aPTT remained elevated for 130 hours after discontinuation of the infusion. DISCUSSION: Argatroban dose reductions in patients with impaired liver and renal function test values have been reported. Elderly subjects may have a prolonged clearance compared with young healthy subjects, although the duration of effect has not been established. As of April 18, 2005, the effect of liver metastasis on argatroban pharmacokinetics in the setting of normal liver function enzyme levels has not been reported. An objective causality assessment using the Naranjo probability scale showed that the prolonged aPTT was probably attributable to argatroban. CONCLUSIONS: Clinicians should exercise caution when initiating argatroban at a dose of 2.0 μg/kg/min in elderly patients with underlying comorbidities, such as metastatic disease and renal impairment, since this may lead to excessive and prolonged anticoagulation and increased risk of bleeding.

Evaluation of a Pharmacist-Directed Vancomycin Dosing and Monitoring Pilot Program at a Tertiary Academic Medical Center

Background: Consensus guidelines recommend vancomycin doses of 15 to 20 mg/kg every 8 to 12 hours in patients with normal renal function. Objective: To evaluate the effect of a pharmacist-directed vancomycin dosing and monitoring pilot program on the percentage of patients receiving targeted weight-based dosing recommendations. Methods: This was a pre-/postevaluation study, approved by the institutional review board at our institution, comparing retrospectively reviewed vancomycin dosing practices hospital-wide between September 1 and September 30, 2010 to patients prospectively managed by a pharmacist-directed vancomycin pilot program between February 1 and April 26, 2011. All adult inpatients receiving intravenous vancomycin were included, unless patients had a creatinine clearance less than or equal to 60 mL/min or indication for therapy was surgical prophylaxis or febrile neutropenia. The primary outcome was the percentage of patients who received optimal vancomycin dosing defined as ≥30 mg/kg/d within 24 hours of initiation of therapy. Secondary outcomes included number of pharmacist interventions, length of therapy and incidence of nephrotoxicity while receiving vancomycin. Results: A total of 319 patients were analyzed, 161 preimplementation and 158 postimplementation. The percentage of patients who received optimal vancomycin dosing was significantly higher postimplementation of the pilot program, 96.8 versus 40.4% (P < 0.001). Pharmacist-directed interventions postimplementation, resulted in 50% more patients being dosed optimally (P < 0.001). Patients in the pilot program also had a shorter length of therapy (10.0 vs 8.4 days, P < 0.003) and a lower incidence of nephrotoxicity (8.7% vs 3.2%, P = 0.006). Conclusions: This pharmacist-directed vancomycin pilot program significantly increased the percentage of patients optimally dosed according to consensus guidelines within 24 hours of initiation of therapy.