Mary K. Hayden

Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.

Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

Targeted versus Universal Decolonization to Prevent ICU Infection

BACKGROUND Both targeted decolonization and universal decolonization of patients in intensive care units (ICUs) are candidate strategies to prevent health care-associated infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS We conducted a pragmatic, cluster-randomized trial. Hospitals were randomly assigned to one of three strategies, with all adult ICUs in a given hospital assigned to the same strategy. Group 1 implemented MRSA screening and isolation; group 2, targeted decolonization (i.e., screening, isolation, and decolonization of MRSA carriers); and group 3, universal decolonization (i.e., no screening, and decolonization of all patients). Proportional-hazards models were used to assess differences in infection reductions across the study groups, with clustering according to hospital. RESULTS A total of 43 hospitals (including 74 ICUs and 74,256 patients during the intervention period) underwent randomization. In the intervention period versus the baseline period, modeled hazard ratios for MRSA clinical isolates were 0.92 for screening and isolation (crude rate, 3.2 vs. 3.4 isolates per 1000 days), 0.75 for targeted decolonization (3.2 vs. 4.3 isolates per 1000 days), and 0.63 for universal decolonization (2.1 vs. 3.4 isolates per 1000 days) (P=0.01 for test of all groups being equal). In the intervention versus baseline periods, hazard ratios for bloodstream infection with any pathogen in the three groups were 0.99 (crude rate, 4.1 vs. 4.2 infections per 1000 days), 0.78 (3.7 vs. 4.8 infections per 1000 days), and 0.56 (3.6 vs. 6.1 infections per 1000 days), respectively (P<0.001 for test of all groups being equal). Universal decolonization resulted in a significantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or screening and isolation. One bloodstream infection was prevented per 54 patients who underwent decolonization. The reductions in rates of MRSA bloodstream infection were similar to those of all bloodstream infections, but the difference was not significant. Adverse events, which occurred in 7 patients, were mild and related to chlorhexidine. CONCLUSIONS In routine ICU practice, universal decolonization was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical isolates and bloodstream infection from any pathogen. (Funded by the Agency for Healthcare Research and the Centers for Disease Control and Prevention; REDUCE MRSA ClinicalTrials.gov number, NCT00980980).

Epidemiology of colonisation of patients and environment with vancomycin-resistant enterococci

BACKGROUND Vancomycin-resistant enterococci (VRE) have emerged as nosocomial pathogens during the past 5 years, but little is known about the epidemiology of VRE. We investigated colonisation of patients and environmental contamination with VRE in an endemic setting to assess the importance of different sources of colonisation. METHODS Between April 12, and May 29, 1995, cultures from body sites (rectum, groin, arm, oropharynx, trachea, and stomach) and from environmental surfaces (bedrails, drawsheet, blood-pressure cuff, urine containers, and enteral feed) were obtained daily from all newly admitted ventilated patients in our medical intensive-care unit (MICU). Rectal cultures were obtained from all non-ventilated patients in the MICU. Strain types of VRE were determined by pulsed-field gel electrophoresis. FINDINGS There were 97 admissions of 92 patients, of whom 38 required mechanical ventilation. Colonisation with VRE on admission was more common in ventilated than in non-ventilated patients (nine [24%] vs three [6%], p < 0.05). Of the nine ventilated patients colonised with VRE on admission, one acquired a new strain of VRE in the MICU. Of the 29 ventilated patients who were not colonised with VRE on admission, 12 (41%) acquired VRE in the MICU. The median time to acquisition of VRE was 5 days (interquartile range 3-8). Of the 13 ventilated patients who acquired VRE, 11 (85%) were colonised with VRE by cross-colonisation. VRE were isolated from 157 (12%) of 1294 environmental cultures. The rooms of 13 patients were contaminated with VRE, but only three (23%) of these patients subsequently acquired colonisation with VRE. Pulsed-field gel electrophoresis of 262 isolates showed 20 unique strain types of VRE. INTERPRETATION Frequent colonisation with VRE on MICU admission and subsequent cross-colonisation are important factors in the endemic spread of VRE. Persistent VRE colonisation in the gastrointestinal tract and on the skin, the presence of multiple-strain types of VRE, and environmental contamination may all contribute to the spread of VRE.

Determinants of Vancomycin Resistance and Mortality Rates in Enterococcal Bacteremia: A Prospective Multicenter Study

Enterococcus species have become increasingly prominent as etiologic agents of nosocomial bacteremia (19). Enterococcal bacteremia has a mortality rate of 42% to 73% (10, 11) and is common among debilitated patients and those with severe underlying illnesses (5, 6, 1217). Enterococci have low-level resistance to penicillins, aminoglycosides, and clindamycin and are intrinsically resistant to cephalosporins. Enterococci may acquire resistance to additional antibiotics, including -lactams, aminoglycosides, and glycopeptides (18). Resistance to multiple antibiotics, in particular vancomycin coupled with high-level ampicillin and aminoglycoside, has been reported with increasing frequency (19). At present, more than 20% of enterococci isolated from intensive care units exhibit vancomycin resistance. The addition of vancomycin resistance to high-level ampicillin and aminoglycoside resistance limits available therapeutic options (20). To investigate the clinical implications of antibiotic resistance in enterococci, we instituted a prospective, multicenter observational study of outcome in patients with enterococcal bacteremia. We sought to determine 1) factors associated with infection with vancomycin-resistant enterococci [VRE], 2) factors predictive of death in patients with enterococcal bacteremia, 3) the effect of vancomycin resistance on mortality rates, and 4) the effect of antibiotic therapy on outcome. Methods All patients with enterococcal bacteremia were hospitalized at the University of Pittsburgh Medical Center and the Veterans Affairs (VA) Medical Center (Pittsburgh, Pennsylvania), Detroit Medical Center and John D. Dingell VA Medical Center (Detroit, Michigan), Rush-Presbyterian-St. Lukes Medical Center (Chicago, Illinois), New England Medical Center (Boston, Massachusetts), and William Beaumont Hospital (Royal Oak, Michigan). Clinical data were obtained from review of medical records. The institutional review boards of four participating institutions approved the study. At the fifth institution, the study was considered exempt from review because it involved confidential use of existing records and bacterial isolates. Microbiology Blood for culture was obtained by venipuncture or through central venous catheters. Enterococcal species were determined by using either VITEK (bioMerieux Vitek, Inc., Hazelwood, Missouri) or MicroScan (MicroScan, Inc., West Sacramento, California) systems according to the manufacturers recommendations. Identification of species other than E. faecalis and E. faecium was confirmed as reported elsewhere (21). One of the authors standardized antimicrobial susceptibilities by using Etest strips (AB BIODISK North America, Inc., Piscataway, New Jersey). Enterococcus faecium isolates showing resistance or intermediate susceptibility to quinupristindalfopristin were tested by broth microdilution and disk diffusion to confirm reduced susceptibility. If the isolate was unavailable, antimicrobial susceptibilities reported by the submitting microbiology laboratories were used. Minimum inhibitory concentration (MIC) breakpoints from the Ninth National Committee for Clinical Laboratory Standards (NCCLS) were used (22). Because imipenem MIC values for enterococci are not defined, NCCLS breakpoints for Enterobacteriaceae were used (22). Quality control was monitored by using E. faecalis American Type Culture Collection (ATCC) 29212. Nine enterococcal isolates displayed intermediate susceptibility to vancomycin (MIC, 8 to 16 g/mL) but were considered resistant for the purposes of analysis. Vancomycin resistance genotypes of selected clinical isolates were determined by using polymerase chain reaction (PCR) amplification with primers specific for intragenic sequences of the vanA and vanB genes (23, 24). Control strains included vancomycin-susceptible E. faecalis ATCC 29212, E. faecium BM4147 (vanA) (25), and E. faecalis V583 (vanB) (26). For determination of aminoglycoside resistance genes, genomic DNA for PCR amplification was prepared with the InstaGene Matrix kit (BioRad Laboratories, Hercules, California) and PCR performed as reported elsewhere (27). Aminoglycoside resistance genes detected included aac(6)-Ie-aph(2)-Ia (28), aph(2)-Ic (29), aph(2)-Id (30), and aph(2)-Ib (31). Definitions Clinically significant bacteremia was defined as isolation of enterococci in two or more separately obtained blood cultures or from a single blood culture and from a concomitant site of infection in a clinical scenario compatible with bacteremic infection (6). Endocarditis was defined by using the Duke criteria (32). Polymicrobial bacteremia was defined as isolation from blood culture of one or more additional species of bacteria concomitantly with enterococci (same blood culture or another blood culture within 24 hours of the initial blood culture yielding enterococci). A single concomitant isolation of another bacterial species was sufficient, except for isolation of coagulase-negative staphylococci, diphtheroids, -hemolytic streptococci, and Bacillus species that required isolation from two blood cultures. Length of hospitalization was defined as the time in days from hospital admission to development of clinically significant enterococcal bacteremia. Enterococcal bacteremia occurring 60 days or more from a previous episode in patients already enrolled was counted as a separate episode. The end point was survival at 14 days from the first positive blood culture. Patients discharged from the hospital before 14 days were considered survivors. Medical records were reviewed at entry, at 2 weeks, at 4 weeks, and at 6 weeks (or at time of discharge or death if earlier than 6 weeks). We collected information on patient demographic characteristics, underlying disease, Acute Physiology and Chronic Health Evaluation (APACHE) II scores at bacteremia onset, antibiotic use, use of glucocorticosteroids and other immunosuppressive drugs, and receipt of invasive devices and procedures in the 2 weeks before bacteremia onset. Antibiotic therapy during the 6 weeks after the onset of bacteremia was recorded. Beyond 6 weeks, patients were followed for evidence of relapse of bacteremia and for survival to discharge or death. Immunosuppressive drugs included cyclosporine, cyclophosphamide, azathioprine, tacrolimus, methotrexate, and cytotoxic chemotherapy. Appropriate antibiotic therapy was defined as treatment with at least one antibiotic that had in vitro activity (as defined by Etest) against the enterococcal isolate, initiated within 48 hours of the initial positive enterococcal blood culture and continuing for at least 72 hours. Antibiotics considered potentially active included penicillin, ampicillin, ureidopenicillin, vancomycin, quinupristindalfopristin, chloramphenicol, doxycycline, and rifampin. Statistical Analysis For categorical variables, proportions were compared by using the Fisher exact test. Continuous variables were analyzed with the MannWhitney rank-sum test. Multivariate analysis was done by using logistic regression. Variables with a two-tailed P value of 0.05 were included in stepwise logistic regression models for vancomycin resistance and 14-day mortality. The initial bacteremic episode for each patient (n = 398) was used for the evaluation of risk factors for bacteremia caused by VRE. Patients who were alive 14 days after the onset of enterococcal bacteremia (n = 321) were evaluated for factors associated with microbiological failure. Statistical analysis of the data was performed by using the Prophet system (MarketMiner, Inc., Charlottesville, Virginia) and Epistat (Epistat Services, Richardson, Texas). Results Enterococcal Bacteremia We studied hospitalized patients 16 years of age or older with clinically significant hospital- or community-acquired enterococcal bacteremia. From February 1995 through March 1997, 391 consecutive patients from five participating institutions were entered into the study. An additional 9 patients from Pittsburgh were entered into the study over a 6-month period (October 1998 through March 1999) to increase the total number of patients to 400. These patients were consecutive and unselected. Two patients younger than 16 years of age were excluded, leaving 398 patients for evaluation. Eighty-nine patients were from the University of Pittsburgh Medical Center and the VA Medical Center, 97 were from Rush-Presbyterian-St. Lukes Medical Center, 95 were from the Detroit Medical Center and John D. Dingell VA Medical Center, 61 were from New England Medical Center, and 56 were from the William Beaumont Hospital. Blood cultures yielded 398 enterococcal isolates. Of these, 60% (239 of 398) were E. faecalis and 37% (148 of 398) were E. faecium. Three percent (10 of 398) of the isolates belonged to the less common enterococcal species, which include E. avium, E. casseliflavus, E. durans, E. gallinarum, and E. raffinosus. The species of one isolate could not be identified. Seventeen recurrences were seen at 60 or more days after the initial bacteremia. Of these, 14 were caused by the same enterococcal species as the initial episode. In 12 of these 14 episodes, the pair of isolates had the same susceptibilities to vancomycin. Overall, 35% of the 398 enterococcal isolates were resistant to vancomycin (MIC 32 g/mL), 63% were susceptible to vancomycin (MIC 4 g/mL), and 2% displayed intermediate susceptibility (MIC, 8 to 16 g/mL). Table 1 shows the susceptibility patterns of the two major Enterococcus species. Eight percent of the E. faecalis isolates were resistant to vancomycin, 91% were susceptible, and 1% displayed intermediate susceptibility. In contrast, 80% of the E. faecium isolates were resistant to vancomycin, 18% were susceptible, and 2% displayed intermediate susceptibility. Of the 11 isolates of other species, none were resistant to vancomycin, 73% (8 of 11) were susceptible to vancomycin, and 27% (3 of 11) displayed intermediate susceptibility to vancomycin. Table 1. Pr

Development of Daptomycin Resistance In Vivo in Methicillin-Resistant Staphylococcus aureus

ABSTRACT Daptomycin is a new lipopeptide antibiotic that is rapidly bactericidal against Staphylococcus aureus. We report daptomycin resistance and treatment failure in 2 patients with osteomyelitis due to methicillin-resistant S. aureus. Disk diffusion susceptibility testing failed to detect resistance. Daptomycin at high concentration retained bactericidal activity against resistant isolates.

Effectiveness of Gloves in the Prevention of Hand Carriage of Vancomycin-Resistant Enterococcus Species by Health Care Workers after Patient Care

Gloving reduces acquisition of vancomycin-resistant Enterococcus species (VRE) on the hands, and it should be considered for routine inpatient care, even for contact with the intact skin of patients who may be colonized with VRE. However, gloving does not completely prevent contamination of the hands, and hand washing is necessary after glove removal.

Effectiveness of routine patient cleansing with chlorhexidine gluconate for infection prevention in the medical intensive care unit.

BACKGROUND Controlled studies that took place in medical intensive care units (MICUs) have demonstrated that bathing patients with chlorhexidine gluconate (CHG) can reduce skin colonization with potential pathogens and can lessen the risk of central venous catheter (CVC)-associated bloodstream infection (BSI). OBJECTIVE To examine, without oversight of practice by research study staff, the effectiveness or real-world effect of patient cleansing with CHG on rates of CVC-associated BSI. DESIGN In the fall of 2005, the MICU at Rush University Medical Center discontinued bathing patients daily with soap and water and substituted skin cleansing with no-rinse, 2% CHG-impregnated cloths. This change was a clinical management decision without research input. SETTING A 21-bed MICU at Rush University Medical Center. PATIENTS Patients hospitalized in the MICU during the period from September 2004 through October 2006. METHODS In a pre-post study design, we gathered data from administrative and laboratory databases, infection control practitioner logs, and patient medical charts to compare rates of CVC-associated BSI and blood culture contamination between the baseline soap-and-water bathing period (September 2004-October 2005) and the CHG bathing period (November 2005-October 2006). Rates of secondary BSI, Clostridium difficile infection (CDI), ventilator-associated pneumonia (VAP), and urinary tract infection (UTI) served as control variables that were not expected to be affected by CHG bathing. RESULTS Bathing with CHG was associated with a statistically significant decrease in the rate of CVC-associated BSI (from 5.31 to 0.69 cases per 1,000 CVC-days; P = .006) and in the rate of blood culture contamination (from 6.99 to 4.1 cases per 1,000 patient-days; P = .04). Rates of secondary BSI, CDI, VAP, and UTI did not change significantly. CONCLUSIONS In our analysis of real-world practice, daily bathing of MICU patients with CHG was effective at reducing rates of CVC-associated BSI and blood culture contamination. Controlled studies are needed to determine whether these beneficial effects extend outside the MICU.

Insights into the epidemiology and control of infection with vancomycin-resistant enterococci.

Despite control efforts, the incidence of nosocomial infections due to vancomycin-resistant enterococci (VRE) continues to increase in the United States. VRE are thought to spread primarily by cross-contamination. Recent molecular epidemiologic studies have refined our understanding of this phenomenon. If VRE are not controlled soon after introduction into a hospital, sporadic cases may evolve into a monoclonal outbreak, which may then evolve to polyclonal endemicity. An intervention that is effective in containing VRE in one setting may be ineffective in another. Control of VRE where they are endemic is particularly challenging. Although eradication of endemic VRE may not be possible, aggressive, multifaceted programs have been successful in diminishing the problem. A mathematical model of transmission of VRE and the effect of infection control measures in settings where they are endemic has been reported. The use of such a model may allow more precise determination of the impact of control strategies in the future.

Successful control of an outbreak of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae at a long-term acute care hospital.

OBJECTIVE To determine the effect of a bundle of infection control interventions on the horizontal transmission of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae during an outbreak. DESIGN Quasi-experimental study. Setting. Long-term acute care hospital. Intervention. On July 23, 2008, a bundled intervention was implemented: daily 2% chlorhexidine gluconate baths for patients, enhanced environmental cleaning, surveillance cultures at admission, serial point prevalence surveillance (PPS), isolation precautions, and training of personnel. Baseline PPS was performed before the intervention was implemented. Any gram-negative rod isolate suspected of KPC production underwent a modified Hodge test and, if results were positive, confirmatory polymerase chain reaction testing. Clinical cases were defined to occur for patients whose samples yielded KPC-positive gram-negative rods in clinical cultures. RESULTS Baseline PPS performed on June 17, 2008, showed a prevalence of colonization with KPC-producing isolates of 21% (8 of 39 patients screened). After implementation of the intervention, monthly PPS was performed 5 times, which showed prevalences of colonization with KPC-producing isolates of 12%, 5%, 3%, 0%, and 0% (P < .001). From January 1, 2008, until the intervention, 8 KPC-positive clinical cases--suspected to be due to horizontal transmission--were detected. From implementation of the intervention through December 31, 2008, only 2 KPC-positive clinical cases, both in August 2008, were detected. From January 1 through December 31, 2008, 8 patients were detected as carriers of KPC-producing isolates at admission to the institution, 4 patients before and 4 patients after the intervention. CONCLUSION A bundled intervention was successful in preventing horizontal spread of KPC-producing gram-negative rods in a long-term acute care hospital, despite ongoing admission of patients colonized with KPC producers.

Multicenter intervention program to increase adherence to hand hygiene recommendations and glove use and to reduce the incidence of antimicrobial resistance.

OBJECTIVE To determine whether a multimodal intervention could improve adherence to hand hygiene and glove use recommendations and decrease the incidence of antimicrobial resistance in different types of healthcare facilities. DESIGN Prospective, observational study performed from October 1, 1999, through December 31, 2002. We monitored adherence to hand hygiene and glove use recommendations and the incidence of antimicrobial-resistant bacteria among isolates from clinical cultures. We evaluated trends in and predictors for adherence and preferential use of alcohol-based hand rubs, using multivariable analyses. SETTING Three intervention hospitals (a 660-bed acute and long-term care hospital, a 120-bed community hospital, and a 600-bed public teaching hospital) and a control hospital (a 700-bed university teaching hospital).Intervention. At the intervention hospitals, we introduced or increased the availability of alcohol-based hand rub, initiated an interactive education program, and developed a poster campaign; at the control hospital, we only increased the availability of alcohol-based hand rub. RESULTS We observed 6,948 hand hygiene opportunities. The frequency of hand hygiene performance or glove use significantly increased during the study period at the intervention hospitals but not at the control hospital; the maximum quarterly frequency of hand hygiene performance or glove use at intervention hospitals (74%, 80%, and 77%) was higher than that at the control hospital (59%). By multivariable analysis, preferential use of alcohol-based hand rubs rather than soap and water for hand hygiene was more likely among workers at intervention hospitals compared with nonintervention hospitals (adjusted odds ratio, 4.6 [95% confidence interval, 3.3-6.4]) and more likely among physicians (adjusted odds ratio, 1.4 [95% confidence interval, 1.2-1.8]) than among nurses at intervention hospitals. A significantly reduced incidence of antimicrobial-resistant bacteria among isolates from clinical culture was found at a single intervention hospital, which had the greatest increase in the frequency of hand hygiene performance. CONCLUSIONS During a 3-year period, a multimodal intervention program increased adherence to hand hygiene recommendations, especially to the use of alcohol-based hand rubs. In one hospital, a concomitant reduction was found in the incidence of antimicrobial-resistant bacteria among isolates from clinical cultures.