Yoav Golan

Fidaxomicin versus Vancomycin for Clostridium difficile Infection

BACKGROUND Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection. METHODS Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence). RESULTS A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies. CONCLUSIONS The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)

Prior Environmental Contamination Increases the Risk of Acquisition of Vancomycin-Resistant Enterococci

BACKGROUND Patients colonized with vancomycin-resistant enterococci (VRE) frequently contaminate their environment, but the environmental role of VRE transmission remains controversial. METHODS During a 14-month study in 2 intensive care units, weekly environmental and twice-weekly patient surveillance cultures were obtained. VRE acquisition was defined as a positive culture result >48 h after admission. To determine risk factors for VRE acquisition, Cox proportional hazards models using time-dependent covariates for colonization pressure and antibiotic exposure were examined. RESULTS Of 1330 intensive care unit admissions, 638 patients were at risk for acquisition, and 50 patients (8%) acquired VRE. Factors associated with VRE acquisition included average colonization pressure (hazard ratio [HR], 1.4 per 10% increase; 95% confidence interval [CI], 1.2-1.8), mean number of antibiotics (HR, 1.7 per additional antibiotic; 95% CI, 1.2-2.5), leukemia (HR, 3.1; 95% CI, 1.2-7.8), a VRE-colonized prior room occupant (HR, 3.1; 95% CI, 1.6-5.8), any VRE-colonized room occupants within the previous 2 weeks (HR, 2.5; 95% CI, 1.3-4.8), and previous positive room culture results (HR, 3.4; 95% CI, 1.2-9.6). In separate multivariable analyses, a VRE-colonized prior room occupant (HR, 3.8; 95% CI, 2.0-7.4), any VRE-colonized room occupants within the previous 2 weeks (HR, 2.7; 95% CI, 1.4-5.3), and previous positive room culture results (HR, 4.4; 95% CI, 1.5-12.8) remained independent predictors of VRE acquisition, adjusted for colonization pressure and antibiotic exposure. CONCLUSIONS We found that prior room contamination, whether measured via environmental cultures or prior room occupancy by VRE-colonized patients, was highly predictive of VRE acquisition. Increased attention to environmental disinfection is warranted.

Listeria monocytogenes infection in Israel and review of cases worldwide.

Listeria monocytogenes, an uncommon foodborne pathogen, is increasingly recognized as a cause of life-threatening disease. A marked increase in reported cases of listeriosis during 1998 motivated a retrospective nationwide survey of the infection in Israel. From 1995 to 1999, 161 cases were identified; 70 (43%) were perinatal infections, with a fetal mortality rate of 45%. Most (74%) of the 91 nonperinatal infections involved immunocompromised patients with malignancies, chronic liver disease, chronic renal failure, or diabetes mellitus. The common clinical syndromes in these patients were primary bacteremia (47%) and meningitis (28%). The crude case-fatality rate in this group was 38%, with a higher death rate in immunocompromised patients.

Efficacy of Fidaxomicin Versus Vancomycin as Therapy for Clostridium difficile Infection in Individuals Taking Concomitant Antibiotics for Other Concurrent Infections

Concomitant antibiotic (CA) use compromised initial response to Clostridium difficile infection therapy and durability of that response. Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in the presence of CAs and preventing recurrence regardless of CA use.

Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit.

BACKGROUND Candida albicans has been the most common cause of fungal bloodstream infections (BSIs) in intensive care units (ICUs); however, infections due to non-albicans Candida species have been increasing in prevalence. We examined factors associated with BSIs due to non-albicans Candida species, compared with C. albicans BSIs, in an ICU patient population. METHODS For our case-comparator study, we identified consecutive adult ICU patients with BSIs due to non-albicans Candida species or C. albicans at 2 tertiary care hospitals during the period 1995-2005. Data collected included demographic characteristics, comorbidities, exposure to antibiotics and antifungals, and ICU-related factors, such as total parenteral nutrition, blood product transfusions, invasive procedures, central venous catheter use, hemodialysis, and mechanical ventilation. We built a multivariable logistic regression model that identified variables that differentiate BSIs due to non-albicans Candida species from BSIs due to C. albicans. RESULTS There were 67 patients with BSIs due to non-albicans Candida species and 79 patients with C. albicans BSIs. Variables were adjusted for time at risk. In multivariable models, factors associated with an increased risk of BSIs due to non-albicans Candida species, compared with C. albicans BSIs, included fluconazole exposure (odds ratio, 11.6; 95% confidence interval, 2.28-58.8), central venous catheter exposure (odds ratio, 1.95; 95% confidence interval, 1.10-3.47), and mean number of antibiotics per day (odds ratio, 2.31; 95% confidence interval, 0.71-7.54). Total parenteral nutrition exposure was associated with a decreased risk (odds ratio, 0.16; 95% confidence interval, 0.05-0.47) of BSIs due to non-albicans Candida species, compared with C. albicans BSIs. Duration of stay in the ICU was not significantly different between the 2 groups. Specific antibiotics, such as vancomycin and piperacillin-tazobactam, were not independently associated with BSI due to non-albicans Candida species. CONCLUSIONS Receipt of fluconazole and central venous catheter exposure were associated with an increased risk of BSI due to non-albicans Candida species, and total parenteral nutrition was associated with a decreased risk of BSI due to non-albicans Candida species, compared with BSI due to C. albicans. Patients without characteristics of infection due to non-albicans Candida species might benefit from empirical antifungal therapy with fluconazole.

Reappraisal of Community-Acquired Bacteremia: A Proposal of a New Classification for the Spectrum of Acquisition of Bacteremia

In recent years, dramatic changes in health care systems have shifted much of the care of sick individuals from hospitals to the community. Consequently, infections traditionally classified as community-acquired or hospital-acquired infections cannot now be readily classified into either category. We thus propose a new classification based on a wider spectrum of acquisition. A total of 1028 episodes of bloodstream infection (BSI) were divided into 5 categories: true community-acquired infections (370 episodes [36%]), infections in recently discharged patients (110 [11%]), infections associated with invasive procedures performed just before or at the time of admission (56 [5%]), infections in patients admitted from nursing homes (68 [7%]), and hospital-acquired infections (424 [41%]). Thus, 234 (39%) of the 604 bloodstream infections traditionally defined as community acquired were reclassified into 3 newly defined groups, each of which has distinct epidemiologic, clinical, and bacteriologic characteristics, as well as distinct antimicrobial susceptibility profiles. There is a conceptual and practical need for such a new classification.

National Survey on the Susceptibility of Bacteroides fragilis Group: Report and Analysis of Trends in the United States from 1997 to 2004

ABSTRACT The susceptibility trends for the species of the Bacteroides fragilis group against various antibiotics from 1997 to 2004 were determined by using data for 5,225 isolates referred by 10 medical centers. The antibiotic test panel included ertapenem, imipenem, meropenem, ampicillin-sulbactam, piperacillin-tazobactam, cefoxitin, clindamycin, moxifloxacin, tigecycline, chloramphenicol, and metronidazole. From 1997 to 2004 there were decreases in the geometric mean (GM) MICs of imipenem, meropenem, piperacillin-tazobactam, and cefoxitin for many of the species within the group. B. distasonis showed the highest rates of resistance to most of the β-lactams. B. fragilis, B. ovatus, and B. thetaiotaomicron showed significantly higher GM MICs and rates of resistance to clindamycin over time. The rate of resistance to moxifloxacin of B. vulgatus was very high (MIC range for the 8-year study period, 38% to 66%). B. fragilis, B. ovatus, and B. distasonis and other Bacteroides spp. exhibited significant increases in the rates of resistance to moxifloxacin over the 8 years. Resistance rates and GM MICs for tigecycline were low and stable during the 5-year period over which this agent was studied. All isolates were susceptible to chloramphenicol (MICs < 16 μg/ml). In 2002, one isolate resistant to metronidazole (MIC = 64 μg/ml) was noted. These data indicate changes in susceptibility over time; surprisingly, some antimicrobial agents are more active now than they were 5 years ago.

Lessons Learned from the Anaerobe Survey: Historical Perspective and Review of the Most Recent Data (2005–2007)

BACKGROUND The rationale and lessons learned through the evolution of the National Survey for the Susceptibility of Bacteroides fragilis Group from its initiation in 1981 through 2007 are reviewed here. The survey was conceived in 1980 to track emerging antimicrobial resistance in Bacteroides species. METHODS Data from the last 11 years of the survey (1997-2007), including 6574 isolates from 13 medical centers, were analyzed for in vitro antimicrobial resistance to both frequently used and newly developed anti-anaerobic agents. The minimum inhibitory concentrations of the antibiotics were determined using agar dilution in accordance with Clinical and Laboratory Standards Institute recommendations. RESULTS The analyses revealed that the carbapenems (imipenem, meropenem, ertapenem, and doripenem) and piperacillin-tazobactam were the most active agents against these pathogens, with resistance rates of 0.9%-2.3%. In the most recent 3 years of the survey (2005-2007), resistance to some agents was shown to depend on the species, such as ampicillin-sulbactam against Bacteroides distasonis (20.6%) and tigecycline against Bacteroides uniformis and Bacteroides eggerthii ( approximately 7%). Very high resistance rates (>50%) were noted for moxifloxacin and trovafloxacin, particularly against Bacteroides vulgatus. During that period of study, non-B. fragilis Bacteroides species had >40% resistance to clindamycin. Metronidazole-resistant Bacteroides strains were also first reported during that period. CONCLUSIONS In summary, resistance to antibiotics was greater among non-B. fragilis Bacteroides species than among B. fragilis and was especially greater among species with a low frequency of isolation, such as Bacteroides caccae and B. uniformis. The emergence of resistance among the non-B. fragilis Bacteroides species underscores the need for speciation of B. fragilis group isolates and for clinicians to be aware of associations between species and drug resistance.

Risk factors for albicans and non-albicans candidemia in the intensive care unit.

Objective:To determine risk factors for bloodstream infections (BSI) with Candida non-albicans (C-NA) species and Candida albicans (CA) among critically ill patients. Design:Case-control study. Setting:Adult medical and surgical intensive care units (ICUs) at two university hospitals. Patients:Consecutive patients with C-NA and CA BSIs from 1995–2005 formed the two case groups. Controls were patients without candidemia who were randomly selected in a ratio of 5:1 and matched by study hospital, ICU type (medical vs. surgical) and by ICU admission date within a 3-month period. Interventions:Data collected included demographics, comorbidities, exposure to antibiotics and antifungals, and ICU factors such as total parenteral nutrition (TPN), blood product transfusions, invasive procedures, central venous catheters, hemodialysis, and mechanical ventilation. We built multivariable logistic regression models, which identified risk factors for C-NA or CA BSIs compared with controls. Variables were adjusted for time-at-risk. Measurements and Main Results:There were 67 patients with C-NA BSIs, 79 patients with CA BSIs, and 780 controls. In multivariable models, factors associated with an increased risk of C-NA compared with controls included major pre-ICU operations [odds ratio; (95% confidence interval)] [2.12; (1.14–3.97)], gastrointestinal procedures [2.24; (1.49–3.38)], enteric bacteremia [3.43; (1.39–8.48)], number of hemodialysis days [6.20; (2.67–14.4)], TPN duration [2.87; (1.40–5.90)], and mean number of red blood cell transfusions [2.72; (1.33–5.58)]. Factors associated with an increased risk of CA BSIs compared to controls were very similar and included major ICU operations [1.26; (1.14–3.97)], enteric bacteremia [3.45; (1.38–8.63)], number of hemodialysis days [3.84; (1.75–8.40)], TPN duration [11.0; (5.52–21.7)] and mean number of red blood cell transfusions [1.97; (0.98–3.99)]. Conclusions:We found multiple common risk factors for both non-C. albicans and C. albicans BSIs, however we could not differentiate between these two groups based on clinical characteristics alone.

Empirical Anti-Candida Therapy among Selected Patients in the Intensive Care Unit: A Cost-Effectiveness Analysis

Context Invasive candidiasis has several treatments. How to balance their costs and effectiveness is not known. Contribution According to this cost-effectiveness analysis, empirical caspofungin therapy is the most effective strategy for patients in the intensive care unit (ICU) with suspected infection that has not responded to antibacterial therapy. However, because of its high cost, caspofungin is less cost-effective than empirical fluconazole (incremental cost of