Elie Saade

High Proportion of False-Positive Clostridium difficile Enzyme Immunoassays for Toxin A and B in Pediatric Patients

OBJECTIVES To determine the frequency of false-positive Clostridium difficile toxin enzyme immunoassay (EIA) results in hospitalized children and to examine potential reasons for this false positivity. DESIGN Nested case-control. SETTING Two tertiary care pediatric hospitals. METHODS As part of a natural history study, prospectively collected EIA-positive stools were cultured for toxigenic C. difficile, and characteristics of children with false-positive and true-positive EIA results were compared. EIA-positive/culture-negative samples were recultured after dilution and enrichment steps, were evaluated for presence of the tcdB gene by polymerase chain reaction (PCR), and were further cultured for Clostridium sordellii, a cause of false-positive EIA toxin assays. RESULTS Of 112 EIA-positive stools cultured, 72 grew toxigenic C. difficile and 40 did not, indicating a positive predictive value of 64% in this population. The estimated prevalence of C. difficile infection (CDI) in the study sites among children tested for this pathogen was 5%-7%. Children with false-positive EIA results were significantly younger than those with true-positive tests but did not differ in other characteristics. No false-positive specimens yielded C. difficile when cultured after enrichment or serial dilution, 1 specimen was positive for tcdB by PCR, and none grew C. sordellii. CONCLUSIONS Approximately one-third of EIA tests used to evaluate pediatric inpatients for CDI were falsely positive. This finding was likely due to the low prevalence of CDI in pediatric hospitals, which diminishes the tests positive predictive value. These data raise concerns about the use of EIA assays to diagnosis CDI in children.

Appropriateness of empiric therapy in patients with suspected Clostridium difficile infection

Abstract Objective: The objective of this study was to test the hypothesis that many patients with suspected Clostridium difficile infection (CDI) receive inappropriate empiric therapy and/or receive continued therapy despite negative test results. Methods: We performed a 3 month prospective cohort study at the Cleveland Veteran Affairs Medical Center to assess the appropriateness of empiric CDI therapy for all patients with stool samples submitted for CDI testing. Empiric therapy for CDI was considered appropriate if patients with suspected CDI had findings suggestive of severe or complicated illness. Results: Of 251 patients tested for CDI, 53 (21%) received empiric treatment, including 45 (85%) treated with metronidazole and 8 (15%) treated with vancomycin. Of the 53 empirical therapy regimens, only 20 (38%) were deemed appropriate based on criteria for severe or severe, complicated CDI and 39 (74%) had negative laboratory testing for CDI. Twenty-one of 39 (54%) patients with negative testing were continued on therapy for three or more days despite the negative results. The key limitations of the study are the fact that it was conducted in a single institution and had a small sample size. Conclusion: In our facility, empiric treatment for CDI was common and more than half of empirical treatment was deemed inappropriate because patients did not meet criteria for severe CDI. Because CDI therapy may be associated with adverse effects, there is a need for interventions to improve the appropriateness of empiric CDI treatment.

Specialty Care Delivery: Bringing Infectious Disease Expertise to the Residents of a Veterans Affairs Long‐Term Care Facility

To initiate a long‐term care facility (LTCF) infectious disease (LID) service that provides on‐site consultations to LTCF residents to improve the care of residents with possible infections.

Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward ‘molecularly targeted’ therapy

ABSTRACT Introduction: Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of ‘serious’ by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients. Areas covered: In this review, we summarize the clinical impact, presentations, and mechanisms of resistance of these four major groups of non-fermenting Gram-negative bacilli. We also describe available and promising novel therapeutic options and strategies, particularly combination antibiotic strategies, with a focus on multidrug resistant variants. Expert commentary: We finally advocate for a therapeutic approach that incorporates in vitro antibiotic susceptibility testing with molecular and genotypic characterization of mechanisms of resistance, as well as pharmacokinetics and pharmacodynamics (PK/PD) parameters. The goal is to begin to formulate a precision medicine approach to antimicrobial therapy: a clinical-decision making model that integrates bacterial phenotype, genotype and patient’s PK/PD to arrive at rationally-optimized combination antibiotic chemotherapy regimens tailored to individual clinical scenarios.

A 17-Year Nationwide Study of Burkholderia cepacia Complex Bloodstream Infections Among Patients in the United States Veterans Health Administration

Background Burkholderia cepacia complex (Bcc) are a group of multidrug-resistant gram-negative bacteria rarely reported in patients without cystic fibrosis (CF) or immunocompromising conditions. We investigated Bcc bloodstream infections (BSIs) in a cohort of non-CF patients from the US Veterans Health Administration (VHA). Methods Using VHA databases, we identified patients with Bcc BSI at facilities nationwide from 1999 through 2015. We ascertained clinical characteristics, treatments, and outcomes and identified factors associated with 30-day mortality in logistic regression analysis. Results We identified 248 patients with Bcc BSI, who were of advanced age (mean, 68 years), chronically ill, and had severe disease. The most common sources were central venous catheters (41%) and pneumonia (20%). Most cases were hospital-acquired (155 [62%]) or healthcare-associated (70 [28%]). Mortality at 14, 30, and 90 days was 16%, 25%, and 36%, respectively. Trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones were active against 94% and 88% of isolates, respectively. Susceptibility to ceftazidime and meropenem occurred in approximately 70% of the isolates. The most prescribed antibiotics were fluoroquinolones (35%), followed by carbapenems (20%), TMP-SMX (18.5%), and ceftazidime (11%). In regression analysis, age (OR, 1.06 [95% confidence interval {CI}, 1.02-1.10], per added year) and the Pitt bacteremia score (OR, 1.65 [95% CI, 1.44-1.94], per unit increase) were associated with higher 30-day mortality. Conclusions In this large cohort of BSIs caused by Bcc, cases were mostly hospital-acquired and we observed high mortality, significant resistance to ceftazidime, and limited use of TMP-SMX. These observations add to our understanding of Bcc infection in non-CF patients and highlight the need for interventions to improve their outcome.

The Use of Rifampin Therapy to Treat Diabetic Patients with Osteomyelitis of the Foot in the Veterans Health Administration: Patient Characteristics and Clinical Outcomes

Abstract Background Nearly 25% of Veterans Health Administration (VHA) patients are diagnosed with diabetes mellitus (DM). Among DM patients, the lifetime incidence of foot ulcers is 15%. Infection is a common complication of foot ulcers and 20–60% of infections result in diabetic foot osteomyelitis (DFO). Current treatment guidelines do not endorse any specific antibiotic agent for DFO, but small clinical trials suggest the addition of rifampin to antimicrobial regimens results in improved cure rates for osteomyelitis. Methods Using VHA databases, we identified index DFO cases from 2009 to 2013 and extracted patient and infection characteristics including demographics, comorbidities, chronic medications, antibiotic regimens, and microbiology data when present. We analyzed the subset of patients alive, without high-level amputation, and treated with antibiotics at 90 days after diagnosis. We summarized patient characteristics and compared a composite endpoint of amputation or death within 2 years of DFO diagnosis among those treated with rifampin to those not treated with rifampin. Results In total, 10,736 DFO cases met our criteria (Figure). Of these, 151 were considered treated with rifampin, based on 14 or more days of rifampin initiated within 90 days of diagnosis; 10,551 were unexposed to rifampin; and 34 were excluded for late or short treatment with rifampin. We observed significant differences between patients treated with and without rifampin (Table) and 44% of rifampin-treated patients were seen in 14 facilities. Amputation or death at 2 years was observed in 44 (29%) of patients treated with rifampin and 4,007 (38%) of patients not treated with rifampin (P = 0.03). Conclusion Rifampin was rarely used in the treatment of DFO in the VHA and a few facilities accounted for a large proportion of rifampin-treated cases. We observed higher rates of amputation-free survival in patients treated with rifampin, but in the presence of notable confounders including age, comorbidities, and organism. Not treated with rifampin N = 10,551 Treated with rifampin N = 151 P-value Age (mean) 65 62 <0.01 Charlson comorbidity (mean) 4.0 3.5 <0.01 Warfarin (prior 6 months) (%) 9.7 6.6 0.25 S. aureus identified (%) 33.9 45.7 <0.01 Complex VA Medical Center (%) 39.4 45.0 0.19 Disclosures E. Saade, Steris: Grant Investigator, Grant recipient. Janssen: Grant Investigator, Research grant. Sequiris: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. R. A. Bonomo, Entasis: Grant Investigator, Research grant. Allecra: Grant Investigator, Research grant. Wockhardt: Grant Investigator, Research grant. Merck: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. GSK: Grant Investigator, Research grant. Allergan: Grant Investigator, Research grant. Shionogi: Grant Investigator, Research grant

Healthcare Facility-Associated Clostridium difficile Infection in Hospitalized Patients Receiving Intravenous Beta-Lactam Antibiotics in the Veterans Affairs Healthcare System (VHA)

Background • Antibiotic exposure in the intestinal tract is the most important risk factor for Clostridium difficile infection (CDI) • Oral administration of beta-lactamase enzymes such as SYN-004 (Synthetic Biologics, Inc) has been effective in eliminating the portion of intravenous beta-lactam antibiotics excreted into the intestinal tract, preserving the microbiota during therapy • We examined patterns of use of beta-lactams and the relative frequency of healthcare facilityassociated (HCFA)-CDI associated with them given alone or combined with other antibiotics

PHOTO QUIZ: Immunosuppressed Patient Presenting With Fever, Interstitial Pneumonia, and Brain Lesions.

A 23-year-old man presented to the emergency room in August 2013 with a fever of 38.2°C, tachycardia, weakness, dizziness, syncope, and diffuse abdominal pain with nausea. He had been diagnosed with Philadelphia chromosome-positive chronic myelogenous leukemia in January 2012, and had failed treatment with tyrosine kinase inhibitors. He had received hemopoietic stem cell transplants in April and June 2013 (conditioning chemotherapy with busulfan, cytarabine and antithymocyte globulin; and fludarabine and total body irradiation, respectively, were used), both of which failed to engraft. Prior to transplantation, he was seropositive for Toxoplasma and cytomegalovirus. A matched, related donor peripheral stem cell transplant following conditioning with fludarabine and cyclophosphamide in July 2013 was successful, and the patient was discharged in August 2013 on tacrolimus, mycophenolate, prednisone, foscarnet, pentamidine, and voriconazole. The patient was readmitted due to syncope 1 day after discharge, and physical examination showed fever, hypotension, and right-sided rhonchi on chest auscultation. Chest radiograph demonstrated bilateral interstitial lung infiltrates. Admission leukocyte count was 41.6 × 10 cells/L, with 89% neutrophils and 3% lymphocytes, and the platelet count was 71 × 10 cells/L. Magnetic resonance imaging of the brain showed abnormal increased signal involving the right parieto-occipital lobe and small scattered focal lesions in the subcortical white matter and cortex within the posterior left parietal lobe. Lumbar puncture was performed and cerebrospinal fluid (CSF) showed 139 leukocytes/μL (95% neutrophils), protein of 90 mg/dL, and glucose of 67 mg/dL. Microscopic examination of a cytospin CSF preparation (Wright stain) showed a few intracellular organisms, predominantly in neutrophils, as well as occasional extracellular organisms (Figure 1). Empiric treatment with amphotericin B, azithromycin, acyclovir, pyrimethamine, meropenem, metronidazole, and vancomycin was initiated. The patient became increasingly hypoxic (partial pressure of oxygen declined to 45 mm Hg) and was intubated, and bronchoalveolar lavage (BAL) was performed. No malignant cells, viral inclusions, or organisms were identified on BAL fluid. Despite aggressive treatment, the patient was unable to maintain his oxygen saturation; his leukocyte count increased to 96.2 × 10 cells/L (88% neutrophils) and his platelet count decreased to 26 × 10 cells/L, and he died from progressive respiratory failure on hospital day 3.