Screening for extended-spectrum beta-lactamase-producing Enterobacteriaceae among high-risk patients and rates of subsequent bacteremia.

BACKGROUND: Bloodstream infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae have been associated with increased hospital costs, length of stay, and patient mortality. However, the role of routine inpatient surveillance for ESBL colonization in predicting related infection is unclear. METHODS: From 2000 through 2005, we screened 17,872 patients hospitalized in designated high-risk units for rectal colonization with vancomycin-resistant enterococci and ESBL-producing Enterobacteriaceae using a selective culture medium. In patients with a bloodstream infection due to ESBL-producing Enterobacteriaceae (ESBL-BI) during the study period, surveillance results were evaluated for evidence of antecedent ESBL-producing Enterobacteriaceae colonization. RESULTS: The rate of ESBL-producing Enterobacteriaceae colonization doubled during the 6-year study period, increasing from 1.33% of high-risk patients in 2000 to 3.21% in 2005. Among patients with ESBL-producing Enterobacteriaceae colonization, 49.6% also carried vancomycin-resistant enterococci. The number of ESBL-BIs increased >4-fold in 5 years, from 9 cases in 2001 to 40 cases in 2005. Of 413 patients colonized with ESBL-producing Enterobacteriaceae, 35 (8.5%) developed a subsequent ESBL-BI. Of concern, more than one-half of all ESBL-BIs occurred in patients who were not screened. These 56 patients received a diagnosis of ESBL-BI in the emergency department, when hospitalized in low-risk medical units, or at transfer from an acute or long-term health care facility. CONCLUSIONS: Colonization with ESBL-producing Enterobacteriaceae is increasing at a rapid rate, and routine rectal surveillance for ESBL-producing Enterobacteriaceae may have clinical implications. However, in our experience, over one-half of patients with an ESBL-BI did not undergo screening through our current surveillance measures. As a result, targeted screening for ESBL-producing Enterobacteriaceae among additional patient populations may be integral to future ESBL-BI prevention and management efforts.

A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.

BACKGROUND: The empirical treatment of febrile, neutropenic patients with cancer requires antibacterial regimens active against both gram-positive and gram-negative pathogens. This study was performed to demonstrate the noninferiority of monotherapy with piperacillin-tazobactam, compared with cefepime. METHODS: We conducted a randomized-controlled, open-label, multicenter clinical trial among high-risk patients from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia who were undergoing treatment for leukemia or hematopoietic stem cell transplantation and were hospitalized for empirical treatment of febrile neutropenic episodes. Patients received piperacillin-tazobactam (4.5 g every 6 h) or cefepime (2 g every 8 h) intravenously. The primary outcome was success (defined by defervescence without treatment modification) at 72 h of treatment, end of treatment, and test of cure in the modified intent-to-treat analysis. Secondary outcomes included time to defervescence, microbiological efficacy, the additional use of glycopeptide antibiotics, emergence of resistant bacteria, and safety. RESULTS: For 528 subjects (265 received piperacillin-tazobactam and 263 received cefepime), success rates were 57.7% and 48.3%, respectively (P = .04) at the 72-h time point, 39.6% and 31.6% (P = .06) at end of treatment, and 26.8% and 20.5% (P = .11) at the test-of-cure visit. The analyses demonstrated noninferiority for piperacillin-tazobactam at all time points (P< or = .0001). Treatment with piperacillin-tazobactam was independently associated with treatment success in multivariate analysis (odds ratio, 1.65; 95% confidence interval, 1.04-2.64; P = .035). Both regimens were well tolerated. CONCLUSIONS: This study demonstrates the noninferiority and safety of piperacillin-tazobactam monotherapy, compared with cefepime, for the empirical treatment of high-risk febrile neutropenic patients with cancer.

Active surveillance using electronic triggers to detect adverse events in hospitalized patients.

BACKGROUND: Adverse events (AEs) occur with alarming frequency in health care and can have a significant impact on both patients and caregivers. There is a pressing need to understand better the frequency, nature, and etiology of AEs, but currently available methodologies to identify AEs have significant limitations. We hypothesized that it would be possible to design a method to conduct real time active surveillance and conducted a pilot study to identify adverse events and medical errors. METHODS: Records were selected based on 21 electronically obtained triggers, including abnormal laboratory values and high risk and antidote medications. Triggers were chosen based on their expected potential to signal AEs occurring during hospital admissions. Each AE was rated for preventability and severity and categorized by type of event. Reviews were performed by an interdisciplinary patient safety team. RESULTS: Over a 3 month period 327 medical records were reviewed; at least one AE or medical error was identified in 243 (74%). There were 163 preventable AEs (events in which there was a medical error that resulted in patient harm) and 138 medical errors that did not lead to patient harm. Interventions to prevent or ameliorate harm were made following review of the medical records of 47 patients. CONCLUSIONS: This methodology of active surveillance allows for the identification and assessment of adverse events among hospitalized patients. It provides a unique opportunity to review events at or near the time of their occurrence and to intervene and prevent harm.

Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia.

BACKGROUND: Linezolid is a recently approved oxazalidinone with extended activity against Gram-positive bacteria. We evaluated the results of linezolid therapy in neutropenic cancer patients with Gram-positive bacterial infections from a compassionate-use program. PATIENTS AND METHODS: This was a prospective, multicenter, open-label, non-comparative, non-randomized compassionate-use treatment program in patients with serious Gram-positive infections. To qualify for enrollment patients were required to have an infection resistant to available antimicrobial agents, or in whom available agents had failed or to which they were intolerant. Patients with absolute neutrophil counts (ANC) <500 cells/mm(3) or <1000 cells/mm(3) and expected to decrease to <500 cells/mm(3), and who received linezolid 600 mg twice daily were included. Plasma samples for population pharmacokinetic analysis were collected. Clinical and microbiological assessments of outcomes were made at the end of therapy and at short-term follow-up. RESULTS: Of the patients in the compassionate-use trial, 103 were neutropenic. The mean [standard deviation (SD)] age was 50.1 (17.5) years, 47% were female, and 47.6% had a baseline ANC

Contamination of the clinical microbiology laboratory with vancomycin-resistant enterococci and multidrug- resistant Enterobacteriaceae: implications for hospital and laboratory workers.

We surveyed environmental surfaces in our clinical microbiology laboratory to determine the prevalence of vancomycin-resistant enterococci (VRE) and multidrug-resistant Enterobacteriaceae (MDRE) during a routine working day. From a total of 193 surfaces, VRE were present on 20 (10%) and MDRE were present on 4 (2%) of the surfaces tested. In a subsequent survey after routine cleaning, all of the 24 prior positive surfaces were found to be negative. Thus, those in the laboratory should recognize that many surfaces may be contaminated by resistant organisms during routine processing of patient specimens.

Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion.

The aim of this study was to review the characteristics and outcome of 21 patients with invasive mucormycosis treated with amphotericin B colloidal dispersion (ABCD) in five phase I and phase II studies. Mucormycosis is an increasing concern in immunocompromised patients, in whom mortality exceeds 60%. The standard treatment has been amphotericin B combined with surgical debridement. Twenty-one patients with invasive mucormycosis treated with ABCD, a lipid complex of amphotericin B and cholesteryl sulfate, were identified. Patients were given ABCD on the basis of pre-existing renal insufficiency, development of nephrotoxicity during amphotericin B therapy, or fungal infection that failed to respond to amphotericin B. Response could be evaluated in 20 patients, all of whom had bone marrow or organ transplantation, haematologic malignancies, or diabetes. Infection was disseminated in six patients and localised to the sinuses, lower respiratory tract, or skin in the other patients. ABCD was given at a mean dose of 4.8 mg/kg per infusion for a mean duration of 37 days. Twelve of 20 patients responded to ABCD therapy. Response rates were similar when patients were treated with ABCD alone (4/7) and ABCD combined with surgery (8/13), with more complete response obtained in the latter group. No difference in response rate was observed in leukaemic patients (3/5) or transplant recipients (6/10) compared to diabetics (3/5). No renal or hepatic toxicity was observed. These results compare favourably with the results of standard treatment and suggest that ABCD combined with surgery may be a useful therapy in patients with mucormycosis.

Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: emerging problems and new prospects for management.

INTRODUCTION: Infections due to multidrug-resistant Gram-positive bacteria are a growing worldwide problem, particularly among seriously ill patients. A number of studies have demonstrated that patients infected with either methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) are at higher risk for mortality and medical resource expenditures. METHODS: A non-systematic evidence-based review of linezolid, the first commercially available oxazolidinone, and quinupristin/dalfopristin, the first injectable streptogramin, for management of these multidrug-resistant infections was conducted. RESULTS: As infections due to VRE increase and vancomycin-insensitive MRSA emerge, vancomycin is becoming less effective for managing Gram-positive infections. Preclinical comparative studies demonstrated that linezolid and quinupristin/dalfopristin are highly effective in eradicating both susceptible and resistant staphylococci, streptococci, and enterococci. Clinical experience, including phase III and compassionate-use data, with these newer agents in the treatment of MRSA and VRE infections are discussed. CONCLUSIONS: The clinical experiences thus far with linezolid and quinupristin/dalfopristin for MRSA and VRE infections have demonstrated efficacy, making these agents important additions to the limited number of therapeutic alternatives for Gram-positive infections.

Fluoroquinolone resistance is a poor surrogate marker for type II topoisomerase mutations in clinical isolates of Streptococcus pneumoniae.

The association between fluoroquinolone susceptibility and DNA mutations coding for amino acid substitutions in the quinolone resistance-determining region was assessed with 44 clinical isolates of Streptococcus pneumoniae. Twenty-three strains bore at least one amino acid substitution. Only seven strains with mutations were suggested by diminished susceptibility to ciprofloxacin (MIC, > or =2 microg/ml).

Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci.

To assess the potential for emergence of resistance during the use of linezolid, we tested 10 clinical isolates of vancomycin-resistant enterococci (VRE) (four Enterococcus faecalis, five Enterococcus faecium, and one Enterococcus gallinarum) as well as a vancomycin-susceptible control (ATCC 29212) strain of E. faecalis. The enterococci were exposed to doubling dilutions of linezolid for 12 passes. After the final passage, the linezolid plate growing VRE contained a higher drug concentration with E. faecalis than with E. faecium. DNA sequencing of the 23S rRNA genes revealed that linezolid resistance in three E. faecalis isolates was associated with a guanine to uracil transversion at bp 2576, while the one E. faecium isolate for which the MIC was 16 microg/ml contained a guanine to adenine transition at bp 2505.

New technology for detecting multidrug-resistant pathogens in the clinical microbiology laboratory.

Northwestern Memorial Hospital instituted in-house molecular typing to rapidly assess microbial clonality and integrated this typing into an infection control program. We compared data on nosocomial infections collected during 24 months before and 60 months after implementing the new program. During the intervention period, infections per 1,000 patient-days fell 13% (p=0.002) and the percentage of hospitalized patients with nosocomial infections decreased 23% (p=0.000006). In our hospital, the percentage of patients with nosocomial infections is 43% below the U.S. rate. Our typing laboratory costs approximately $400,000 per year, a savings of $5.00 for each dollar spent.

Engineering infection control through facility design.

Many medical centers have modified their facility design to provide a safer environment for patients. From an infection control perspective, the primary objective of hospital design is to place the patient at no risk for infection while hospitalized. We describe historical landmarks about hospital design, modern facility design, and specific designs to prevent acquisition and spread of infections such as tuberculosis and aspergillosis.

Paenibacillus macerans pseudobacteremia resulting from contaminated blood culture bottles in a neonatal intensive care unit.

Paenibacillus species are gram-positive, rod-shaped, spore-forming aerobes that are abundant in nature and closely related to Bacillus. Between June 24 and June 30, 1999, 8 neonates in our neonatal intensive care unit had positive blood cultures for Paenibacillus macerans. This cluster of positive blood cultures with an unusual pathogen suggested a pseudoepidemic. Investigation revealed that the most likely etiology of the pseudobacteremia was environmental contamination of the rubber stoppers in blood culture bottles. This was confirmed by environmental sampling and simulated inoculation studies. This pseudobacteremia outbreak highlights the importance of adhering to well-established methods for blood culture collection and ongoing infection control surveillance.

Yield of vancomycin-resistant enterococci and multidrug-resistant Enterobacteriaceae from stools submitted for Clostridium difficile testing compared to results from a focused surveillance program.

It has been suggested that a method of performing surveillance for vancomycin-resistant enterococci (VRE) is to screen specimens submitted for Clostridium difficile testing. We compared this approach to our focused surveillance program of high-risk units during October 1997 to compare the yield of VRE and multidrug-resistant Enterobacteriaceae (MDRE) with both methods. Of the stools submitted for C. difficile testing, 14% were positive for VRE or MDRE, whereas rectal swabs from routine surveillance yielded 11% VRE- or MDRE-positive results. Although stools submitted for C. difficile testing resulted in a higher percentage of positive cultures, 14 VRE- and 2 MDRE-positive patients from our high-risk population were missed because many patients had no stool submitted for C. difficile testing. Therefore, while screening stools submitted for C. difficile testing cannot replace our focused surveillance program, it appears advantageous to assess these stools at various intervals to detect new patient reservoirs of drug-resistant organisms that may benefit from routine surveillance cultures.

Comparison of the Rodac imprint method to selective enrichment broth for recovery of vancomycin-resistant enterococci and drug-resistant Enterobacteriaceae from environmental surfaces.

We compared the Rodac imprint technique to selective enrichment broth for detecting vancomycin-resistant enterococci (VRE) and multidrug-resistant Enterobacteriaceae (MDRE) on surfaces. Rodac plates contained tryptic soy agar with 5% sheep blood, vancomycin (6 microg/ml), ceftazidime (2 microg/ml), amphotericin B (2 microg/ml), and clindamycin (1 microg/ml). Two types of broth were used: brain heart infusion (BHI) and BHI plus vancomycin (6 microg/ml) and ceftazidime (2 microg/ml) (BHIVC). Of the 46 surfaces cultured for VRE, 12 (26%) were positive. Of the 12 VRE-positive surfaces, 11 (92%) grew from Rodac, 8 (67%) grew from BHIVC, and 7 (58%) grew from BHI. A larger study is needed for MDRE, as only 4 of 43 surfaces were MDRE positive. The Rodac imprint technique successfully recovered VRE from environmental surfaces.

Activity of voriconazole against Candida albicans and Candida krusei isolated since 1984.

With the recent dramatic rise in fluconazole use, there has been an increase in Candida species resistant to that agent. This has led to the clinical development of newer triazoles such as voriconazole that have greater potency and a broader spectrum of activity. We therefore hypothesized that fluconazole-resistant Candida albicans and Candida krusei would be susceptible to voriconazole. Susceptibility testing was performed on 205 isolates of C. albicans collected from 1984 to 1995, and on C. albicans and C. krusei that were identified as fluconazole resistant since 1995. The anti fungal agents used were amphotericin B, 5-flucytosine, itraconazole, ketoconazole, fluconazole and voriconazole. Three C. albicans and 26 C. krusei isolates had a minimum inhibitory concentration (MIC) >/=20 mg/l and were defined as fluconazole resistant. Of these, 28 isolates were susceptible to 2 mg/l) but all were susceptible to

The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance.

BACKGROUND: The development of antimicrobial guidelines is one way in which institutions attempt to control emerging resistance, but the real challenge falls on promoting and ensuring adherence to these guidelines. Investigating reasons for the prescribing of alternative antimicrobial agents outside of these guidelines is crucial for modifying practices that may adversely impact institutional antimicrobial goals. METHODS: Retrospective cross-referencing of computerized pharmacy printouts and concurrent manual medical record review. RESULTS: Approximately 25% (470/1893) of the patients requiring antimicrobial therapy reported an allergy to at least 1 antimicrobial agent. The most commonly reported antimicrobial allergy was penicillin (295/1893 [15.6%]). Eighty-five patients (18.1%) reported having an allergy to 2 or more antimicrobial agents. Only 4% (27/601) of the reported antimicrobial allergies contained documentation as to the nature of the specific allergic reactions, while a manual medical record review revealed that 32% (23/73) of the antimicrobial allergies contained documentation of the specific allergic reaction. Ninety-eight (39. 7%) of 247 patients reporting an allergy only to penicillin and/or cephalosporin received vancomycin in comparison with 247 (17.4%) of 1423 patients without any antimicrobial allergies (P<.001). Similarly, 53 (21.5%) of 247 patients with reported penicillin and/or cephalosporin allergies received levofloxacin compared with 114 (8.0%) of 1423 patients without any antimicrobial allergy (P<. 001). CONCLUSION: The incidence of penicillin allergy at our institution exceeds population averages. This finding, in combination with limited documentation of drug allergies, appears to lead to the prescribing of alternative antimicrobial agents that do not fit into institutional antimicrobial guidelines and, in some instances, may put the patient at risk for infection and/or colonization with resistant organisms. Use of these alternative agents may adversely impact the ability to manage emerging antimicrobial resistance.

Changing patterns of infections and antimicrobial susceptibilities.

Nosocomial bloodstream infections across the United States and in Europe are increasingly attributable to gram-positive species--a trend that represents a reversal of the gram-negative predominance of the previous decades. Data from Memorial Sloan-Kettering Cancer Center and elsewhere show that patients with hematologic malignancies or patients who are immunocompromised because of anticancer treatments are experiencing this shift in microbial spectrum. Most common among gram-positive species are coagulase-negative Staphylococci. Antimicrobial resistance continues to increase, which makes treatment more difficult for infections caused by some species, especially vancomycin-resistant enterococcal species. The underlying causes of changes in microbial spectrum and drug-resistance patterns are incompletely understood, but it is clear that antibiotic exposure exerts a significant selective pressure on pathogens, resulting in partial or complete resistance. New drugs or drug combinations will be necessary to treat drug-resistant infections in cancer patients.

Persistent contamination of fabric-covered furniture by vancomycin-resistant enterococci: implications for upholstery selection in hospitals.

Vancomycin-resistant enterococci (VRE) have emerged as important nosocomial pathogens in hospitals throughout the United States. An increasing concern with respect to VRE dissemination is survival on, and potential transmission from, environmental surfaces within health care institutions. Therefore, we assessed survival of VRE on fabric chairs in an attempt to determine the optimal upholstery for the health care setting. VRE was identified on 3 of 10 seat cushions sampled, including 2 chairs in a room of a patient with known VRE. After performing simulated contamination experiments, all samples were positive at 72 hours and 1 week after inoculation. Contamination of the upholstery could be prevented by placing a sheet folded 4 times or a bath blanket folded in half on the seat cushion. In conclusion, VRE are capable of prolonged survival on fabric seat cushions and can be transferred to hands. Environmental surfaces such as chairs may serve as a potential reservoir for nosocomial transmission of VRE, and an easily cleanable, nonporous material is the preferred upholstery in hospitals.

Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones.

The in vitro activity of the novel 8-methoxyquinolone, moxifloxacin, against Streptococcus pneumoniae was evaluated, and the intracellular targets of this agent were studied. Analysis of mutant strains selected with moxifloxacin demonstrated that first-step mutants bore amino acid substitutions at position 81 in the GyrA subunit of DNA gyrase. This suggests that, unlike older fluoroquinolone agents such as ciprofloxacin and levofloxacin, but similar to other C-8 substituted quinolones like sparfloxacin and gatifloxacin, moxifloxacin targets the GyrA subunit of DNA gyrase as an initial lethal event. Such a mechanism results in high activity against increasingly common S. pneumoniae strains bearing substitutions in DNA topoisomerase IV. Moxifloxacin was active with an MIC of Phe/Tyr substitution in ParC. The moxifloxacin MIC for strains with mutations in the structural genes for both DNA gyrase subunit GyrA and DNA topoisomerase IV subunit ParC did not exceed 2 mg/L, a level within clinically achievable serum concentrations for this agent. We also found that moxifloxacin is a poor substrate for active efflux in S. pneumoniae. Therefore, the high activity of moxifloxacin against S. pneumoniae appears to be a result of both enhanced activity against DNA gyrase and topoisomerase IV, and reduced efflux from the bacterial cell.

A convenient assay for estimating the possible involvement of efflux of fluoroquinolones by Streptococcus pneumoniae and Staphylococcus aureus: evidence for diminished moxifloxacin, sparfloxacin, and trovafloxacin efflux.

We developed a simplified assay for estimating efflux by measuring the effect of reserpine on the growth of Streptococcus pneumoniae and Staphylococcus aureus over 7 h. Reserpine enhanced ciprofloxacin and levofloxacin 17 to 68%. The hydrophobic drug trovafloxacin and the drug moxifloxacin, with a bulky C-7 substituent but hydrophilicity similar to that of levofloxacin, showed little (0 to 11%) reserpine-enhancing effect. The ease of resistant mutant strain selection correlated with efflux susceptibility.