Faculty Bibliography

STUDY OBJECTIVE: Despite recent reports of relatively high rates (16-37%) of acute kidney injury (AKI) in patients receiving the combination of intravenous piperacillin-tazobactam (PTZ) and vancomycin, data are limited evaluating the impact of PTZ infusion strategy on the occurrence of nephrotoxicity. The objective of this study was to compare the rates of nephrotoxicity in patients receiving vancomycin in combination with PTZ administered as an extended infusion (EI) versus a standard infusion (SI). DESIGN: Single-center, retrospective, matched-cohort study. SETTING: Large academic tertiary care hospital. PATIENTS: Two hundred eighty adults with a creatinine clearance (CrCl) of 40 ml/minute or higher who received at least 96 hours of vancomycin plus PTZ EI (140 patients) or vancomycin plus PTZ SI (140 patients) between January 1, 2009, and December 31, 2011, and between January 1, 2013, and December 31, 2014 (year 2012 was skipped due the closure of inpatient units following Superstorm Sandy); 48 patients in each group were admitted to the intensive care unit. MEASUREMENTS AND MAIN RESULTS: The median age of all patients was 67 (interquartile range [IQR] 54-77) years, and CrCl was 75 (IQR 55-107) ml/minute. Nephrotoxicity was assessed by the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) criteria. Rates of AKI, according to these criteria, were similar between groups: 17.9% versus 17.1% (p=1) and 32.9% versus 29.3% (p=0.596) for the PTZ EI and PTZ SI groups, respectively. When controlling for residual differences between groups in a conditional logistic regression analysis, no association was observed between receipt of PTZ EI and RIFLE-defined AKI (odds ratio 0.522, 95% confidence interval 0.043-6.295, p=0.609). Time to onset of nephrotoxicity was 4 (IQR 3-6) days, with no significant difference noted between groups (p=0.887). CONCLUSION: Our findings suggest a similar rate of nephrotoxicity between patients who received vancomycin in combination with PTZ EI versus PTZ SI. These results need to be further validated in a prospective randomized controlled study.

BACKGROUND: Cefepime and meropenem are used frequently in hospitalized patients for broad-spectrum empiric coverage, however, practitioners are often reluctant to prescribe these antibiotics for patients with a self-reported nonsevere, nontype I allergic reaction to penicillin. METHODS: Retrospective review of electronic medical records of adults with a self-reported allergy to penicillin who received at least 1 dose of cefepime, ceftriaxone, cefoxitin, cephalexin, or meropenem to assess incidence and type of allergic reactions. RESULTS: Of 175 patients included, 10 (6%) patients experienced an allergic reaction. The incidence for individual study drugs were cefepime 6% (6 of 96), meropenem 5% (3 of 56), cefoxitin 8% (1 of 13), ceftriaxone 0% (0 of 69), and cephalexin 0% (0 of 8). The majority of patients experienced a rash with or without pruritus and fever. Patients with a concomitant "sulfa" allergy (odds ratio [OR] 5.4, 95% confidence interval [CI] 1.4-21, P = .02) or >/=3 other drug allergies (OR 6.4, 95% CI 1.3-32, P = .025) were more likely to have an allergic reaction. CONCLUSIONS: In one of the largest retrospective reviews of hospitalized patients who received full dose therapy with cefepime, ceftriaxone, and meropenem, the incidence of allergic reactions was low and reactions were mild. Cefepime, ceftriaxone, and meropenem can be considered for use in patients with a self-reported nontype I penicillin allergy.

The mainstay treatment of Clostridium difficile infections (CDI) is antimicrobials with growing support for fecal microbiota transplants. We report the first case of an elderly man with severe refractory NAP-1 pseudomembranous CDI who failed all medical therapy and two fecal transplants with response only seen after administration of intravenous immunoglobulin.

Treatment of Legionnaires' disease in severely ill or immunosuppressed patients presents a clinical challenge. Tigecycline (TG) achieves high concentrations intracellularly and has been shown to be effective against L. pneumophila in animal and cell models. We report our experience using TG as second-line therapy. Clinical response was seen in most patients after switching to TG alone or as a combination therapy.

We describe a case of a 72-year-old man with early-stage chronic lymphocytic leukemia (CLL) who presented with invasive nontyphoidal Salmonella (iNTS) infection, necrotizing pneumonia, and chronic infection of a hilar lymph node. Infection is a major cause of death in patients with CLL. Though few cases of iNTS infection associated with CLL have been described in the literature, to our knowledge this is the first reported case of iNTS-associated necrotizing pneumonia. Immunocompromised state in patients, even with early-stage CLL, likely predisposes them to invasive infection with intracellular organisms, such as Salmonella spp. In this case, successful treatment was achieved with prolonged course of intravenous followed by oral antibiotics without any surgical removal of infected focus.

Molecular epidemiological assessments, drug treatment optimization, and development of immunological interventions all depend on understanding pathogen adaptation and genetic variation, which differ for specific pathogens. Mycobacterium tuberculosis is an exceptionally successful human pathogen, yet beyond knowledge that this bacterium has low overall genomic variation but acquires drug resistance mutations, little is known of the factors that drive its population genomic characteristics. Here, we compared the genetic diversity of the bacteria that established infection to the bacterial populations obtained from infected tissues during murine M. tuberculosis pulmonary infection and human disseminated M. bovis BCG infection. We found that new mutations accumulate during in vitro culture, but that in vivo, purifying selection against new mutations dominates, indicating that M. tuberculosis follows a dominant lineage model of evolution. Comparing bacterial populations passaged in T cell-deficient and immunocompetent mice, we found that the presence of T cells is associated with an increase in the diversity of the M. tuberculosis genome. Together, our findings put M. tuberculosis genetic evolution in a new perspective and clarify the impact of T cells on sequence diversity of M. tuberculosis.

Background. Mortality due to severe LD remains high with 20-25% of patients requiring mechanical ventilation. TG, a minocycline derivative, is active against L. pneumophila in animal and cell models, achieves high concentrations intracellularly and demonstrated minimal in vitro synergy with levofloxacin (LVX). Clinical data on TG for LD are limited to two case reports in immunocompromised hosts. We describe our experience with TG as salvage therapy in severely ill patients with LD. Methods. Patient demographics, clinical data and treatment details were collected retrospectively. Clinical failure was defined based on vital signs (temperature >=37.2degreeC, heart rate >=100 beats/min, respiratory rate >=24 breath/min, systolic <=100 mm Hg, oxygen saturation on room air <90%) and/or physician-documented deterioration in clinical parameters or death. Results. At our University Medical Center 12 patients with severe LD (positive Legionella urinary antigen n = 8, elevated L. pneumophilia antibody n = 4) received TG salvage therapy after failure of initial treatment with azithromycin (AZ) n = 6 or LVX and AZ n = 6 between January 2008 and February 2016. Median age of these patients was 81 (37-90) years. More than half had >=2 comorbidities, with cardiovascular and pulmonary being more common. Two patients were immunocompromised due to active chemotherapy. PSI score on admission was 130 (97-223); at the time of switch to TG, SOFA score was 6 (1-9) with respiratory worsening present in 11/12 patients after median of 4 (2-8) days of initial therapy. Seventy percent of patients required intensive care unit stay for 12 (1-18) days, 42% (5/12) had septic shock and were intubated for 10 (1-22) days. These patients received salvage therapy with TG 100 mg x 1 dose, followed by 50 mg IV q12h in addition to LVX n = 5, AZ n = 3, LVX and AZ n = 3, or as monotherapy n = 1 for median of 8 (4-17) days. After TG salvage therapy, clinical improvement was seen in 67% (8/12). Two patients died and 2 were made comfort care. No patients experienced adverse events attributable to TG salvage therapy. Total duration of therapy was 18 (9-24) days. Conclusion. This small cohort of patients provides evidence that TG can be considered for salvage therapy in patients failing macrolide or fluoroquinolone therapy

Scedosporium apiospermum, a ubiquitous environmental mold, is increasingly reported as causing invasive fungal disease in immunocompromised hosts. It poses a therapeutic challenge due to its intrinsic resistance to traditional antifungals and ability to recur despite demonstrating susceptibility. We present an immunocompromised patient with a cutaneous S. apiospermum infection that disseminated despite treatment with voriconazole, the drug of choice. Adding echinocandins and GM-CSF provided partial recovery, indicating a potential synergistic role of dual-antifungal and immunotherapeutic agents.