Curtis J. Donskey

Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients.

BACKGROUND Colonization and infection with vancomycin-resistant enterococci have been associated with exposure to antibiotics that are active against anaerobes. In mice that have intestinal colonization with vancomycin-resistant enterococci, these agents promote high-density colonization, whereas antibiotics with minimal antianaerobic activity do not. METHODS We conducted a seven-month prospective study of 51 patients who were colonized with vancomycin-resistant enterococci, as evidenced by the presence of the bacteria in stool. We examined the density of vancomycin-resistant enterococci in stool during and after therapy with antibiotic regimens and compared the effect on this density of antianaerobic agents and agents with minimal antianaerobic activity. In a subgroup of 10 patients, cultures of environmental specimens (e.g., from bedding and clothing) were obtained. RESULTS During treatment with 40 of 42 antianaerobic-antibiotic regimens (95 percent), high-density colonization with vancomycin-resistant enterococci was maintained (mean [+/-SD] number of organisms, 7.8+/-1.5 log per gram of stool). The density of colonization decreased after these regimens were discontinued. Among patients who had not received antianaerobic antibiotics for at least one week, 10 of 13 patients who began such regimens had an increase in the number of organisms of more than 1.0 log per gram (mean increase, 2.2 log per gram), whereas among 10 patients who began regimens of antibiotics with minimal antianaerobic activity, there was a mean decrease in the number of enterococci of 0.6 log per gram (P=0.006 for the difference between groups). When the density of vancomycin-resistant enterococci in stool was at least 4 log per gram, 10 of 12 sets of cultures of environmental specimens had at least one positive sample, as compared with 1 of 9 sets from patients with a mean number of organisms in stool of less than 4 log per gram (P=0.002). CONCLUSIONS For patients with vancomycin-resistant enterococci in stool, treatment with antianaerobic antibiotics promotes high-density colonization. Limiting the use of such agents in these patients may help decrease the spread of vancomycin-resistant enterococci.

Antimicrobial-Associated Risk Factors for Clostridium difficile Infection

Antimicrobial therapy plays a central role in the pathogenesis of Clostridium difficile infection (CDI), presumably through disruption of indigenous intestinal microflora, thereby allowing C. difficile to grow and produce toxin. Investigations involving animal models and studies performed in vitro suggest that inhibitory activity against C. difficile and differences in the propensity to stimulate toxin production may also influence the likelihood that particular drugs may cause CDI. Although nearly all antimicrobial classes have been associated with CDI, clindamycin, third-generation cephalosporins, and penicillins have traditionally been considered to harbor the greatest risk. Recent studies have also implicated fluoroquinolones as high-risk agents, a finding that is most likely to be related in part to increasing fluoroquinolone resistance among epidemic strains (i.e., restriction-endonuclease analysis group BI/North American PFGE type 1 strains) and some nonepidemic strains of C. difficile. Restrictions in the use of clindamycin and third-generation cephalosporins have been associated with reductions in CDI. Because use of any antimicrobial has the potential to induce the onset of CDI and disease caused by other health care-associated pathogens, antimicrobial stewardship programs that promote judicious use of antimicrobials are encouraged in concert with environmental and infection control-related efforts.

Analysis of Antibiotic Resistance Genes in Multidrug-Resistant Acinetobacter sp. Isolates from Military and Civilian Patients Treated at the Walter Reed Army Medical Center

ABSTRACT Military medical facilities treating patients injured in Iraq and Afghanistan have identified a large number of multidrug-resistant (MDR) Acinetobacter baumannii isolates. In order to anticipate the impact of these pathogens on patient care, we analyzed the antibiotic resistance genes responsible for the MDR phenotype in Acinetobacter sp. isolates collected from patients at the Walter Reed Army Medical Center (WRAMC). Susceptibility testing, PCR amplification of the genetic determinants of resistance, and clonality were determined. Seventy-five unique patient isolates were included in this study: 53% were from bloodstream infections, 89% were resistant to at least three classes of antibiotics, and 15% were resistant to all nine antibiotics tested. Thirty-seven percent of the isolates were recovered from patients nosocomially infected or colonized at the WRAMC. Sixteen unique resistance genes or gene families and four mobile genetic elements were detected. In addition, this is the first report of blaOXA-58-like and blaPER-like genes in the U.S. MDR A. baumannii isolates with at least eight identified resistance determinants were recovered from 49 of the 75 patients. Molecular typing revealed multiple clones, with eight major clonal types being nosocomially acquired and with more than 60% of the isolates being related to three pan-European types. This report gives a “snapshot” of the complex genetic background responsible for antimicrobial resistance in Acinetobacter spp. from the WRAMC. Identifying genes associated with the MDR phenotype and defining patterns of transmission serve as a starting point for devising strategies to limit the clinical impact of these serious infections.

The Role of the Intestinal Tract as a Reservoir and Source for Transmission of Nosocomial Pathogens

The intestinal tract provides an important reservoir for many nosocomial pathogens, including Enterococcus species, Enterobacteriaciae, Clostridium difficile, and Candida species. These organisms share several common risk factors and often coexist in the intestinal tract. Disruption of normal barriers, such as gastric acidity and the indigenous microflora of the colon, facilitates overgrowth of pathogens. Factors such as fecal incontinence and diarrhea contribute to the subsequent dissemination of pathogens into the health care environment. Selective pressure exerted by antibiotics plays a particularly important role in pathogen colonization, and adverse effects associated with these agents often persist beyond the period of treatment. Infection-control measures that are implemented to control individual pathogens may have a positive or negative impact on efforts to control other pathogens that colonize the intestinal tract.

Reduction of Clostridium Difficile and vancomycin-resistant Enterococcus contamination of environmental surfaces after an intervention to improve cleaning methods

BackgroundContaminated environmental surfaces may play an important role in transmission of some healthcare-associated pathogens. In this study, we assessed the adequacy of cleaning practices in rooms of patients with Clostridium difficile-associated diarrhea (CDAD) and vancomycin-resistant Enterococcus (VRE) colonization or infection and examined whether an intervention would result in improved decontamination of surfaces.MethodsDuring a 6-week period, we cultured commonly touched surfaces (i.e. bedrails, telephones, call buttons, door knobs, toilet seats, and bedside tables) in rooms of patients with CDAD and VRE colonization or infection before and after housekeeping cleaning, and again after disinfection with 10% bleach performed by the research staff. After the housekeeping staff received education and feedback, additional cultures were collected before and after housekeeping cleaning during a 10-week follow-up period.ResultsOf the 17 rooms of patients with VRE colonization or infection, 16 (94%) had one or more positive environmental cultures before cleaning versus 12 (71%) after housekeeping cleaning (p = 0.125), whereas none had positive cultures after bleach disinfection by the research staff (p < 0.001). Of the 9 rooms of patients with CDAD, 100% had positive cultures prior to cleaning versus 7 (78%) after housekeeping cleaning (p = 0.50), whereas only 1 (11%) had positive cultures after bleach disinfection by research staff (p = 0.031). After an educational intervention, rates of environmental contamination after housekeeping cleaning were significantly reduced.ConclusionOur findings provide additional evidence that simple educational interventions directed at housekeeping staff can result in improved decontamination of environmental surfaces. Such interventions should include efforts to monitor cleaning and disinfection practices and provide feedback to the housekeeping staff.

Gene Dosage and Linezolid Resistance in Enterococcus faecium and Enterococcus faecalis

ABSTRACT Resistance to linezolid has been associated with a G2576U mutation in domain V of the 23S rRNA. We analyzed nine clinical isolates of linezolid-resistant enterococci and showed a clear association between the number of 23S rRNA genes containing this mutation and the level of linezolid resistance expressed.

Persistence of Skin Contamination and Environmental Shedding of Clostridium difficile during and after Treatment of C. difficile Infection

BACKGROUND Current guidelines for control of Clostridium difficile infection (CDI) suggest that contact precautions be discontinued after diarrhea resolves. However, limited information is available regarding the frequency of skin contamination and environmental shedding of C. difficile during and after treatment. DESIGN We conducted a 9-month prospective, observational study involving 52 patients receiving therapy for CDI. Stool samples, skin (chest and abdomen) samples, and samples from environmental sites were cultured for C. difficile before, during, and after treatment. Polymerase chain reaction ribotyping was performed to determine the relatedness of stool, skin, and environmental isolates. RESULTS Fifty-two patients with CDI were studied. C. difficile was suppressed to undetectable levels in stool samples from most patients during treatment; however, 1-4 weeks after treatment, 56% of patients who had samples tested were asymptomatic carriers of C. difficile. The frequencies of skin contamination and environmental shedding remained high at the time of resolution of diarrhea (60% and 37%, respectively), were lower at the end of treatment (32% and 14%, respectively), and again increased 1-4 weeks after treatment (58% and 50%, respectively). Skin and environmental contamination after treatment was associated with use of antibiotics for non-CDI indications. Ninety-four percent of skin isolates and 82% of environmental isolates were genetically identical to concurrent stool isolates. CONCLUSIONS Skin contamination and environmental shedding of C. difficile often persist at the time of resolution of diarrhea, and recurrent shedding is common 1-4 weeks after therapy. These results provide support for the recommendation that contact precautions be continued until hospital discharge if rates of CDI remain high despite implementation of standard infection-control measures.

Both Oral Metronidazole and Oral Vancomycin Promote Persistent Overgrowth of Vancomycin-Resistant Enterococci during Treatment of Clostridium difficile-Associated Disease

ABSTRACT For treatment of mild to moderate Clostridium difficile-associated disease (CDAD), oral metronidazole has been recommended as the preferred agent, in part due to concern that vancomycin may be more likely to promote colonization by vancomycin-resistant enterococci (VRE). We performed a prospective observational study to examine the effects of oral metronidazole or vancomycin treatment of CDAD on acquisition and concentration of VRE stool colonization. Before, during, and after 90 courses of CDAD therapy, stool samples were cultured for VRE, and the concentrations were quantified. Eighty-seven subjects (97%) had received antibiotics within the past month. For 56 treatment courses in which preexisting VRE colonization was present, metronidazole (n = 37 courses) and vancomycin (n = 19 courses), each promoted persistent VRE overgrowth during therapy, and the concentration decreased significantly in both groups by ∼2 weeks after completion of treatment (P <0.049). For 34 treatment courses in which baseline cultures were negative for VRE, new detection of VRE stool colonization occurred during 3 (14%) of the 22 courses of metronidazole and 1 (8%) of the 12 courses of vancomycin (P = 1.0). These results demonstrate that both oral metronidazole and oral vancomycin promote the overgrowth of VRE during treatment of CDAD. New CDAD treatments are needed that are less likely to disrupt the intestinal microflora and promote overgrowth of healthcare-associated pathogens.

Vegetative Clostridium difficile Survives in Room Air on Moist Surfaces and in Gastric Contents with Reduced Acidity: a Potential Mechanism To Explain the Association between Proton Pump Inhibitors and C. difficile-Associated Diarrhea?

ABSTRACT Proton pump inhibitors (PPIs) have been identified as a risk factor for Clostridium difficile-associated diarrhea (CDAD), though the mechanism is unclear because gastric acid does not kill C. difficile spores. We hypothesized that the vegetative form of C. difficile, which is killed by acid, could contribute to disease pathogenesis if it survives in room air and in gastric contents with elevated pH. We compared the numbers of C. difficile spores and vegetative cells in stools of patients prior to and during the treatment of CDAD. We assessed the survival of vegetative cells on moist or dry surfaces in room air versus anaerobic conditions and in human gastric contents, in pH-adjusted gastric contents, and in gastric contents from individuals receiving PPI therapy. Stool samples obtained from patients prior to the initiation of antibiotic treatment for C. difficile contained ∼10-fold more vegetative cells than spores. On dry surfaces, vegetative C. difficile cells died rapidly, whereas they remained viable for up to 6 h on moist surfaces in room air. Vegetative C. difficile cells had only marginal survival in gastric contents at low pH; adjustment to a pH of >5 resulted in survival similar to that in the phosphate-buffered saline control. The survival of vegetative C. difficile in gastric contents obtained from patients receiving PPIs was also increased at a pH of >5. The ability of the vegetative form of C. difficile to survive on moist surfaces and in gastric contents with an elevated pH suggests a potential mechanism by which PPI therapy could increase the risk of acquiring C. difficile.

Community-associated Clostridium difficile infection and antibiotics: a meta-analysis

OBJECTIVES Antibiotic exposure is the most important risk factor for Clostridium difficile infection (CDI). Most evaluations of antimicrobial risk factors have been conducted in healthcare settings. The objective of this meta-analysis was to evaluate the association between antibiotic exposure and community-associated CDI (CA-CDI) (i.e. symptom onset in the community with no healthcare facility admission within 12 weeks) and to determine the classes of antibiotics posing the greatest risk. METHODS We searched four electronic databases for subject headings and text words related to CA-CDI and antibiotics. Studies that investigated the risk of CA-CDI associated with antibiotic usage were considered eligible. Data from the identified studies were combined using a random-effects model and ORs were calculated. RESULTS Of 910 citations identified, eight studies (n = 30 184 patients) met our inclusion criteria. Antibiotic exposure was associated with an increased risk of CA-CDI (OR 6.91, 95% CI 4.17-11.44, I(2) = 95%). The risk was greatest with clindamycin (OR 20.43, 95% CI 8.50-49.09) followed by fluoroquinolones (OR 5.65, 95% CI 4.38-7.28), cephalosporins (OR 4.47, 95% CI 1.60-12.50), penicillins (OR 3.25, 95% CI 1.89-5.57), macrolides (OR 2.55, 95% CI 1.91-3.39) and sulphonamides/trimethoprim (OR 1.84, 95% CI 1.48-2.29). Tetracyclines were not associated with an increased CDI risk (OR 0.91, 95% CI 0.57-1.45). CONCLUSIONS Antibiotic exposure was an important risk factor for CA-CDI, but the risk was different amongst different antibiotic classes. The risk was greatest with clindamycin followed by fluoroquinolones and cephalosporins, whereas tetracyclines were not associated with an increased risk.