Samuel L. Aitken

Clinical Practice Patterns in Hospitalized Patients at Risk for Invasive Candidiasis Role of Antifungal Stewardship Programs in an Era of Rapid Diagnostics

Background: Rapid diagnostic tests for Candida are becoming available that may supplement traditional microbiological identification. Objective: Assess clinical practice patterns in patients with or at risk of candidiasis who may benefit from the use of rapid diagnostic tests. Methods: This was a prospective cohort study of patients with candidemia or receiving systemic antifungals conducted at a university-affiliated tertiary care hospital. Time to initiation of therapy, Candida species, time to identification, and indications for antifungal use were assessed. Results: A total of 162 patients with candidemia aged 58 ± 17 years were identified. Average time to yeast identification yeast was 2.2 ± 1.3 days and varied by Candida species (range = 0.6-7.9 days). Average time for patient to start antifungal therapy was 3.5 ± 2.1 days. In Monte Carlo simulations, average time to initiation of antifungal therapy was 0.6 ± 0.2 days for T2Candida, 2.6 ± 1.3 days for PNA-FISH (fluorescence in situ hybridization using peptide nucleic acid probes), and 2.5 ± 1.4 days for MALDI-TOF (matrix-assisted laser desorption/ionization time of flight). Use of T2Candida on the day of the blood culture collection resulted in 3136 to 6078 fewer doses of echinocandins annually per 5000 patients. Conclusion: Many interventions are possible for antifungal stewardship programs to improve care of patients at risk for systemic candidiasis, including rapid identification of yeast species and limiting unnecessary antifungal agents. Technology enabling rapid diagnosis of Candida will be paramount to appropriate, cost-effective treatment of patients with or at risk for candidiasis.

Multicenter Evaluation of Ceftolozane/Tazobactam for Serious Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa

A multicenter, retrospective study of patients infected with carbapenem-resistant Pseudomonas aeruginosa who were treated with ceftolozane/tazobactam was performed. Among 35 patients, pneumonia was the most common indication and treatment was successful in 26 (74%). Treatment failure was observed in all cases where isolates demonstrated ceftolozane-tazobactam minimum inhibitory concentrations ≥8 μg/mL.

Real-world performance of a microarray-based rapid diagnostic for Gram-positive bloodstream infections and potential utility for antimicrobial stewardship.

The Verigene Gram-positive blood culture assay (BC-GP) is a microarray-based rapid diagnostic test, which includes targets for 12 bacterial species and 3 resistance determinants. We prospectively compared the diagnostic accuracy of the BC-GP to routine microbiologic methods and evaluated the potential of the BC-GP for antimicrobial stewardship programs. A total of 143 consecutive patients with Gram-positive bacteremia were included in the analysis. BC-GP correctly identified 127/128 (99.2%) of organisms from monomicrobial blood cultures and 9/14 (64.3%) from polymicrobial, including all methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Stewardship interventions were possible in 51.0% of patients, most commonly stopping or preventing unnecessary vancomycin or starting a targeted therapy. In Monte Carlo simulations, unnecessary antibiotics could be stopped at least 24 hours earlier in 65.6% of cases, and targeted therapy could be started at least 24 hours earlier in 81.2%. BC-GP is a potentially useful test for antibiotic stewardship in patients with Gram-positive bacteremia.

High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-β-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center

Resistance to the novel β-lactam/β-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-β-lactamase in diverse Enterobacteriaceae species.

Aerosolized ribavirin: the most expensive drug for pneumonia.

Dramatic, overnight cost increases of important orphan and generic medications have recently come under public and government scrutiny. We highlight the case of aerosolized ribavirin, an important antiviral agent in hematopoietic stem cell transplantation which, because of substantial price increases, may now cost more than the transplant procedure itself.

Healthcare resource utilization for recurrent Clostridium difficile infection in a large university hospital in Houston, Texas.

Background There are limited data examining healthcare resource utilization in patients with recurrent Clostridium difficile infection (CDI). Methods Patients with CDI at a tertiary-care hospital in Houston, TX, were prospectively enrolled into an observational cohort study. Recurrence was assessed via follow-up phone calls. Patients with one or more recurrence were included in this study. The location at which healthcare was obtained by patients with recurrent CDI was identified along with hospital length of stay. CDI-attributable readmissions, defined as a positive toxin test within 48 hours of admission and a primary CDI diagnosis, were also assessed. Results 372 primary cases of CDI were identified of whom 64 (17.2%) experienced at least one CDI recurrence. Twelve of 64 patients experienced 18 further episodes of CDI recurrence. Of these 64 patients, 33 (50.8%) patients with recurrent CDI were readmitted of which 6 (18.2%) required ICU care, 29 (45.3%) had outpatient care only, and 2 (3.1%) had an ED visit. Nineteen (55.9%) readmissions were defined as CDI-attributable. For patients with CDI-attributable readmission, the average length of stay was 6±6 days. Conclusion Recurrent CDI leads to significant healthcare resource utilization. Methods of reducing the burden of recurrent CDI should be further studied.

Successful Treatment of Bloodstream Infection Due to Metallo-β-Lactamase-Producing Stenotrophomonas maltophilia in a Renal Transplant Patient

ABSTRACT Stenotrophomonas maltophilia is an emerging multidrug-resistant (MDR) opportunistic pathogen for which new antibiotic options are urgently needed. We report our clinical experience treating a 19-year-old renal transplant recipient who developed prolonged bacteremia due to metallo-β-lactamase-producing S. maltophilia refractory to conventional treatment. The infection recurred despite a prolonged course of colistimethate sodium (colistin) but resolved with the use of a novel drug combination with clinical efficacy against the patients S. maltophilia isolate.

Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia

Cefepime is an antibiotic commonly used in nosocomial infections. The objective of this study was to elucidate the relationship between cefepime exposure and clinical outcome in patients with Gram-negative bacterial pneumonia. A previously published population pharmacokinetic model of cefepime was validated in 12 adult patients with normal renal function by measuring plasma concentrations at steady-state. Additionally, clinical outcomes for 33 patients with Gram-negative bacterial pneumonia who received cefepime monotherapy were determined. The free minimum concentration (fCmin) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CLCr), dosing regimen and cefepime MIC of the organism isolated, and was subsequently correlated with clinical failure. Classification and regression tree (CART) analysis was used to determine the most significant drug exposure breakpoint. Mean±S.D. CLCr and cefepime Cmin in the 12 patients were 87.5±21.2mL/min and 6.2±3.8mg/L, respectively. In comparison, the Cmin predicted by the pharmacokinetic model was 5.8mg/L using a CLCr of 90mL/min. MICs of organisms ranged from 0.5mg/L to 8mg/L. Percent time free drug above MIC of 100% was achieved in 32/33 patients, but 12 patients experienced clinical failure. CART analysis determined patients with an fCmin/MIC≥2.1 had a significantly lower risk of clinical failure (OR=0.11, 95% CI 0.02-0.67; P=0.017). The fCmin/MIC ratio is a useful predictor of clinical failure in Gram-negative bacterial pneumonia. The clinical utility of fCmin/MIC in therapeutic drug monitoring should be further explored.

Colonic immunopathogenesis of Clostridium difficile infections.

ABSTRACT There are major gaps in our understanding of the immunopathogenesis of Clostridium difficile infections (CDIs). In this study, 36 different biomarkers were examined in the stools of CDI and non-CDI patients using the Proteome Profiler human cytokine array assay and quantitative enzyme-linked immunosorbent assay. Diarrheal stools from patients with CDI (CDI-positive diarrheal stools) showed higher relative amounts of the following inflammatory markers than the diarrheal stools from CDI-negative patients (CDI-negative diarrheal stools): C5a, CD40L, granulocyte colony-stimulating factor, I-309, interleukin-13 (IL-13), IL-16, IL-27, monocyte chemoattractant protein 1, tumor necrosis factor alpha, and IL-8. IL-8 and IL-23 were present in a larger number of CDI-positive diarrheal stools than CDI-negative diarrheal stools. Th1 and Th2 cytokines were not significantly different between the CDI-positive and CDI-negative diarrheal stools. Lactoferrin and calprotectin concentrations were also higher in the CDI-positive diarrheal stools. Our results demonstrate that CDI elicits a proinflammatory host response, and we report for the first time that IL-23 is a major marker in CDI-positive diarrheal stools. IL-23 may explain the lack of a robust immunological response exhibited by a proportion of CDI patients and may relate to recurrence; the IL-23 levels induced during CDI in these patients may be inadequate to sustain the cellular immunity conferred by this cytokine in promoting the induction and proliferation of effector memory T cells.

Regional and seasonal variation in Clostridium difficile infections among hospitalized patients in the United States, 2001-2010

BACKGROUND This study identified national regional and seasonal variations in Clostridium difficile infection (CDI) incidence and mortality among hospitalized patients in the United States over a 10-year period. METHODS This was a retrospective cohort study of the U.S. National Hospital Discharge Survey from 2001-2010. Eligible cases had an ICD-9-CM discharge diagnosis code for CDI (008.45). Data weights were used to derive national estimates. CDI incidence and mortality were presented descriptively. Regions were as defined by the U.S. Census Bureau. Seasons included the following: winter (December-February), spring (March-May), summer (June-August), and fall (September-November). RESULTS These data represent 2.3 million CDI discharges. Overall, CDI incidence was highest in the Northeast (8.0 CDIs/1,000 discharges) and spring (6.2 CDIs/1,000 discharges). CDI incidence was lowest in the West (4.8 CDIs/1,000 discharges) and fall (5.6 CDIs/1,000 discharges). Peak CDI incidence among children occurred in the West (1.7 CDI/1,000 discharges) and winter (1.5 CDI/1,000 discharges). Mortality among all CDI patients was highest in the Midwest (7.3%) and during the winter (7.9%). CONCLUSION The region and season with the highest CDI incidence rates among patients hospitalized in U.S. hospitals were the Northeast and spring, respectively. The highest CDI mortality rates were seen in the Midwest and winter. Children exhibited different regional and seasonal CDI variations compared with adults and older adults.