Julie E. Mangino

A Prospective Observational Study of Candidemia: Epidemiology, Therapy, and Influences on Mortality in Hospitalized Adult and Pediatric Patients

We conducted a prospective, multicenter observational study of adults (n=1447) and children (n=144) with candidemia at tertiary care centers in the United States in parallel with a candidemia treatment trial that included nonneutropenic adults. Candida albicans was the most common bloodstream isolate recovered from adults and children (45% vs. 49%) and was associated with high mortality (47% among adults vs. 29% among children). Three-month survival was better among children than among adults (76% vs. 54%; P<.001). Most children received amphotericin B as initial therapy, whereas most adults received fluconazole. In adults, Candida parapsilosis fungemia was associated with lower mortality than was non-parapsilosis candidemia (24% vs. 46%; P<.001). Mortality was similar among subjects with Candida glabrata or non-glabrata candidemia; mortality was also similar among subjects with C. glabrata candidemia who received fluconazole rather than other antifungal therapy. Subjects in the observational cohort had higher Acute Physiology and Chronic Health Evaluation II scores than did participants in the clinical trial (18.6 vs. 16.1), which suggests that the former subjects are more often excluded from therapeutic trials.

Antifungal Susceptibility Survey of 2,000 Bloodstream Candida Isolates in the United States

ABSTRACT Candida bloodstream isolates (n = 2,000) from two multicenter clinical trials carried out by the National Institute of Allergy and Infectious Diseases Mycoses Study Group between 1995 and 1999 were tested against amphotericin B (AMB), flucytosine (5FC), fluconazole (FLU), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), caspofungin (CFG), micafungin (MFG), and anidulafungin (AFG) using the NCCLS M27-A2 microdilution method. All drugs were tested in the NCCLS-specified RPMI 1640 medium except for AMB, which was tested in antibiotic medium 3. A sample of isolates was also tested in RPMI 1640 supplemented to 2% glucose and by using the diluent polyethylene glycol (PEG) in lieu of dimethyl sulfoxide for those drugs insoluble in water. Glucose supplementation tended to elevate the MIC, whereas using PEG tended to decrease the MIC. Trailing growth occurred frequently with azoles. Isolates were generally susceptible to AMB, 5FC, and FLU. Rates of resistance to ITR approached 20%. Although no established interpretative breakpoints are available for the candins (CFG, MFG, and AFG) and the new azoles (VOR and POS), they all exhibited excellent antifungal activity, even for those strains resistant to the other aforementioned agents.

Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study.

BACKGROUND The American Thoracic Society and Infectious Diseases Society of America provide guidelines for management of hospital-acquired, ventilator-associated, and health-care-associated pneumonias, consisting of empirical antibiotic regimens for patients at risk for multidrug-resistant pathogens. We aimed to improve compliance with these guidelines and assess outcomes. METHODS We implemented a performance-improvement initiative in four academic medical centres in the USA with protocol-based education and prospective observation of outcomes. Patients were assessed for severity of illness and followed up until death, hospital discharge, or day 28. We included patients in intensive-care units who were at risk for multidrug-resistant pneumonia and were treated empirically. FINDINGS 303 patients at risk for multidrug-resistant pneumonia were treated empirically, and prescribed treatment was guideline compliant in 129 patients and non-compliant in 174 patients. 44 (34%) patients died before 28 days in the compliance group and 35 (20%) died in the non-compliance group. Five patients in the compliance group and seven in the non-compliance group were lost to follow-up after day 14. Kaplan-Meier estimated survival to 28 days was 65% in the compliance group and 79% in the non-compliance group (p=0·0042). This difference persisted after adjustment for severity of illness. Median length of stay and duration of mechanical ventilation did not differ between groups. Compliance failures included non-use of dual treatment for Gram-negative pathogens in 154 patients and absence of meticillin-resistant Staphylococcus aureus coverage in 24 patients. For patients in whom pathogens were subsequently identified, empirical treatment was active in 79 (81%) of 97 of patients receiving compliant therapy compared with 109 (85%) of 128 of patients receiving non-compliant therapy. INTERPRETATION Because adherence with empirical treatment was associated with increased mortality, we recommend a randomised trial be done before further implementation of these guidelines. FUNDING Pfizer, US Medical.

Administrative coding data, compared with CDC/NHSN criteria, are poor indicators of health care–associated infections

BACKGROUND ICD-9-CM coding alone has been proposed as a method of surveillance for health care-associated infections (HAIs). The accuracy of this method, however, relative to accepted infection control criteria is not known. METHODS Retrospective analysis of patients at an academic medical center in 2005 who underwent surgical procedures or who were at risk for catheter-associated bloodstream infections or ventilator-associated pneumonia was performed. Patients previously identified with HAIs by Centers for Disease Control and Preventions National Healthcare Safety Network surveillance methods were compared with those of the same risk group identified by secondary infection ICD-9-CM codes. Discordant cases identified by only coding were all rereviewed and adjusted prior to final analysis. When coding and surveillance were both negative, a sample of patients was used to estimate the proportion of false negatives in this group. RESULTS The positive predictive values (PPVs) ranged from 0.14 to 0.51 with an aggregate of 0.23, even after adjustment for additional cases detected on subsequent medical record review. The negative predictive values (NPVs) ranged from 0.91 to 1.00, with an aggregate of 0.96. The estimates of the true variance of PPVs and NPVs across surgical procedures were small (0.0129, standard error, 0.009; 0.000145, standard error, 0.00019, respectively) and could be mostly explained by variation in prevalence of surgical site infections. CONCLUSION Administrative coding alone appears to be a poor tool to be used as an infection control surveillance method. Its proposed use for routine HAI surveillance, public reporting of HAIs, interfacility comparisons, and nonpayment for performance should be seriously questioned.

Early experience with tigecycline for ventilator-associated pneumonia and bacteremia caused by multidrug-resistant Acinetobacter baumannii

Study Objective. To evaluate early experience with tigecycline alone or in combination with other antimicrobials for treatment of ventilator‐associated pneumonia (VAP) and/or bacteremia caused by multidrug‐resistant Acinetobacter baumannii.

Synergy Testing by Etest, Microdilution Checkerboard, and Time-Kill Methods for Pan-Drug-Resistant Acinetobacter baumannii

ABSTRACT Pan-drug-resistant (PDR) Acinetobacter baumannii is an important nosocomial pathogen that poses therapeutic challenges. Tigecycline alone or in combination with agents such as colestimethate, imipenem, and/or amikacin is being used clinically to treat PDR A. baumannii infections. The purpose of this study was to compare in vitro susceptibility testing by epsilometric (Etest) methods and the checkerboard (CB) method with testing by time-kill analysis. PDR A. baumannii clinical strains representing eight unique pulsed-field gel electrophoresis clones selected from a total of 32 isolates were tested in vitro with tigecycline, colestimethate, imipenem, and amikacin in single- and two-drug combinations by using two different methods of Etest (with a fixed ratio method [method 1] and with the incorporation of the active drug in medium [method 2]) and by using CB. The three-drug combination of imipenem, tigecycline, and amikacin was also tested by CB. These results were compared to time-kill results. Synergy was consistently detected with the imipenem plus colestimethate and tigecycline plus imipenem combinations. The Etest method with active drug incorporated into the agar allowed us to detect synergy even in the presence of the active drug and was more comparable to CB and time-kill tests. Synergy was detected with the three-drug combination of imipenem, tigecycline, and amikacin by both CB and time-kill methods among several tested clones. These findings indicate the utility of synergy testing to predict activity of specific antibiotic combinations against PDR A. baumannii.

Relationship of Vancomycin Minimum Inhibitory Concentration to Mortality in Patients With Methicillin-Resistant Staphylococcus aureus Hospital-Acquired, Ventilator-Associated, or Health-care-Associated Pneumonia

BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health-care-associated pneumonia (HCAP). These infections are associated with significant morbidity, mortality, and cost. The impact of vancomycin minimum inhibitory concentration (MIC) on mortality for patients with MRSA pneumonia has not been determined. METHODS Adult patients in ICUs with a diagnosis of MRSA HAP, VAP, or HCAP were entered in the study. Clinical and laboratory information were prospectively collected. Vancomycin MIC and heteroresistance were determined for each MRSA isolate. Data were collected from February 2006 through August 2007. The primary outcome variable was all-cause mortality at day 28. A propensity score approach was used to adjust for confounding variables. RESULTS The study sample consisted of 158 patients. All-cause mortality at day 28 was 32.3%. The majority of MRSA isolates had a vancomycin MIC ≥ 1.5 mg/mL (115/158, 72.8%). Propensity score analysis demonstrated an increase in 28-day mortality as vancomycin MIC increased from 0.75 to 3 mg/mL (P ≤ .001). Heteroresistance to vancomycin, demonstrated in 21.5% isolates, was not associated with mortality. CONCLUSIONS Mortality in patients with MRSA HAP, VAP, and HCAP increases as a function of the vancomycin MIC, even for strains with MIC values within the susceptible range. Evaluation of vancomycin MICs should be contemplated at the institutional level and for individual cases of MRSA pneumonia. The use of vancomycin therapy in patients with MRSA pneumonia caused by isolates with MICs between 1 and 2 mg/mL should be undertaken with caution, and alternative therapies should be considered.

Clinical Experience in Adults and Children Treated with Intravenous Peramivir for 2009 Influenza A (H1N1) Under an Emergency IND Program in the United States

Peramivir, an investigational intravenous neuraminidase inhibitor, was given to 31 hospitalized patients with severe viral pneumonia during the 2009 H1N1 influenza pandemic under the Emergency IND regulations. The drug was generally well tolerated and associated with recovery in most patientes.

Multicenter Study of Clostridium difficile Infection Rates from 2000 to 2006

OBJECTIVE To compare incidence rates of Clostridium difficile infection (CDI) during a 6-year period among 5 geographically diverse academic medical centers across the United States by use of recommended standardized surveillance definitions of CDI that incorporate recent information on healthcare facility (HCF) exposure. METHODS Data on C. difficile toxin assay results and dates of hospital admission and discharge were collected from electronic databases. Chart review was performed for patients with a positive C. difficile toxin assay result who were identified within 48 hours after hospital admission to determine whether they had any HCF exposure during the 90 days prior to their hospital admission. CDI cases, defined as any inpatient with a stool toxin assay positive for C. difficile, were categorized into 5 surveillance definitions based on recent HCF exposure. Annual CDI rates were calculated and evaluated by use of the chi(2) test for trend and the chi(2) summary test. RESULTS During the study period, there were significant increases in the overall incidence rates of HCF-onset, HCF-associated CDI (from 7.0 to 8.5 cases per 10,000 patient-days; P < .001); community-onset, HCF-associated CDI attributed to a study hospital (from 1.1 to 1.3 cases per 10,000 patient-days; P = .003); and community-onset, HCF-associated CDI not attributed to a study hospital (from 0.8 to 1.5 cases per 1,000 admissions overall; P < .001). For each surveillance definition of CDI, there were significant differences in the total incidence rate between HCFs. CONCLUSIONS The increasing incidence rates of CDI over time and across healthcare institutions and the correlation of CDI incidence in different surveillance categories suggest that CDI may be a regional problem and not isolated to a single HCF within a community.

Multicenter study of surveillance for hospital-onset Clostridium difficile infection by the use of ICD-9-CM diagnosis codes.

OBJECTIVE To compare incidence of hospital-onset Clostridium difficile infection (CDI) measured by the use of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis codes with rates measured by the use of electronically available C. difficile toxin assay results. METHODS Cases of hospital-onset CDI were identified at 5 US hospitals during the period from July 2000 through June 2006 with the use of 2 surveillance definitions: positive toxin assay results (gold standard) and secondary ICD-9-CM discharge diagnosis codes for CDI. The chi(2) test was used to compare incidence, linear regression models were used to analyze trends, and the test of equality was used to compare slopes. RESULTS Of 8,670 cases of hospital-onset CDI, 38% were identified by the use of both toxin assay results and the ICD-9-CM code, 16% by the use of toxin assay results alone, and 45% by the use of the ICD-9-CM code alone. Nearly half (47%) of cases of CDI identified by the use of a secondary diagnosis code alone were community-onset CDI according to the results of the toxin assay. The rate of hospital-onset CDI found by use of ICD-9-CM codes was significantly higher than the rate found by use of toxin assay results overall (P < .001), as well as individually at 3 of the 5 hospitals (P < .001 for all). The agreement between toxin assay results and the presence of a secondary ICD-9-CM diagnosis code for CDI was moderate, with an overall kappa value of 0.509 and hospital-specific kappa values of 0.489-0.570. Overall, the annual increase in CDI incidence was significantly greater for rates determined by the use of ICD-9-CM codes than for rates determined by the use of toxin assay results (P = .006). CONCLUSIONS Although the ICD-9-CM code for CDI seems to be adequate for measuring the overall CDI burden, use of the ICD-9-CM discharge diagnosis code for CDI, without present-on-admission code assignment, is not an acceptable surrogate for surveillance for hospital-onset CDI.