Antimicrobial Susceptibility Pattern of
            <i>Clostridium difficile</i>
            and Its Relation to PCR Ribotypes in a Swedish University Hospital

134

103

Since 2002, an epidemic of Clostridium difficile infections has occurred in southern Quebec, Canada. At Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada, the incidence of C. difficile infections increased from 11/1,000 admissions (1999 to 2002) to 27/1,000 admissions (2003 to 2005). We compared the exposures and outcomes for patients infected with strains with different ribopatterns isolated before (n ‫؍‬ 55) and during (n ‫؍‬ 175) the epidemic, as well as the in vitro activities of antibiotics against those isolates. During the preepidemic period, 46 isolates (84%) were of ribotype 001, 1 was of ribotype 027, and 8 were of other ribopattern types. During the epidemic period, ribotype 027 strains accounted for 140 (80%) isolates; 26 (15%) were of ribotype 001, and 7 were of other ribopattern types. Ribotype 027 strains were highly resistant to fluoroquinolones (FQs) but were susceptible to clindamycin. A pattern of prior specific antibiotic exposure that selected for antibiotic-resistant ribotype C. difficile infections was observed for FQs (ribotype 027) and clindamycin (ribotype 001). The rate of mortality was higher among older patients, those with a high Charlson comorbidity index, and those with longer previous hospitalizations. By multivariate analysis, patients infected with ribotype 027 were twice as likely to die within 30 days of diagnosis than patients infected with other ribotypes (adjusted odds ratio, 2.06; 95% confidence interval, 1.00 to 4.22). The observations from this study support the notion that continued selective antibiotic pressure resulted in the superimposition of the hypertoxigenic ribotype 027 clone on top of the prior dominant ribotype 001 clone in a setting of preexisting high endemicity, thus leading to the high rates of morbidity and mortality seen in the Quebec outbreak. Stringent antibiotic stewardship measures, combined with aggressive infection control, are required to curtail the epidemic of C. difficile infections.

Section: Discussionsupporting

confidence: 61%

Clostridium difficile Infections in a Canadian Tertiary Care Hospital before and during a Regional Epidemic Associated with the BI/NAP1/027 Strain

Labbé

Poirier

MacCannell

et al. 2008

134

103

“…In keeping with many historic studies of CDI risk and outbreaks of the disease, clindamycin was found to have the strongest association with risk. One must note however, that clindamycin has not been associated with the greatest risk enhancement in every study (28); variability in effects may be due to true biological heterogeneity of effect (e.g., variable strain susceptibility to clindamycin [29], timing of inoculation relative to the end of antibiotic exposure), or it could be an artifact of the different methods used for outcome ascertainment (see below).…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Antibiotics and the Risk of Community-Associated Clostridium difficile Infection

Brown

Khanafer

Daneman

et al. 2013

500

357

The rising incidence of Clostridium difficile infection (CDI) could be reduced by lowering exposure to high-risk antibiotics. The objective of this study was to determine the association between antibiotic class and the risk of CDI in the community setting. The EMBASE and PubMed databases were queried without restriction to time period or language. Comparative observational studies and randomized controlled trials (RCTs) considering the impact of exposure to antibiotics on CDI risk among nonhospitalized populations were considered. We estimated pooled odds ratios (OR) for antibiotic classes using random-effect metaanalysis. Our search criteria identified 465 articles, of which 7 met inclusion criteria; all were observational studies. We noted no effect of tetracyclines on CDI risk (OR ‫؍‬ 0.92; 95% CI, 0.61 to 1.40). In the community setting, there is substantial variation in the risk of CDI associated with different antimicrobial classes. Avoidance of high-risk antibiotics (such as clindamycin, CMCs, and fluoroquinolones) in favor of lower-risk antibiotics (such as penicillins, macrolides, and tetracyclines) may help reduce the incidence of CDI.C lostridium difficile, a toxin-producing bacterium that causes diarrhea, is the largest single cause of morbidity and mortality among hospital-acquired infections (1). In hospitals, C. difficile infection (CDI) is generally acquired when patients with predisposing factors such as advanced age and antibiotic use are exposed to C. difficile spores emanating from other hospitalized infected patients (2). With the emergence of increasingly virulent C. difficile strains have come reports of CDIs in patients previously considered to be at low risk of this infection, including those living in the community (3-5). Spore exposure may occur outside inpatient settings, since river water, soil, and foods can be contaminated (6, 7), outpatient exposures to the health care system are common, and transmission may occur within households (8). A recent study noted that the population-based incidence of community-acquired CDI (11.2 cases per 100,000 person-years) was on par with hospital-acquired CDI (12.1 cases per 100,000 personyears) (9).One published meta-analysis and one systematic review have considered the impact of antibiotic exposure on CDI (10, 11) risk among hospital inpatients. The meta-analytic study noted that tetracyclines and penicillins were associated with the lowest risk, while fluoroquinolones, clindamycin, and expanded-spectrum cephalosporins were associated with the highest risk of CDI acquisition, despite considerable confidence interval overlap (10). The systematic review established that the strongest evidence of risk existed for penicillins and clindamycin and that effect estimates for other antibiotic classes were liable to bias (11).In addition to yielding accurate adjusted effect estimates, a systematic review of the association between exposure to antibiotics and community-associated CDI is necessary, since the risk profile is different among nonhospitalized...

“…The C. difficile MIC 90 values for 5FDQD are equivalent to those reported for metronidazole, vancomycin, and surotomycin, a phase III investigational agent for CDI therapy (56,69). Although 5FDQD is less potent against C. difficile than fidaxomicin is, the available cecal concentration of 5FDQD after a single oral dose is well above the MIC and at a concentration that rapidly kills C. difficile in vitro.…”

Section: Resultsmentioning

confidence: 56%

Novel Riboswitch-Binding Flavin Analog That Protects Mice against Clostridium difficile Infection without Inhibiting Cecal Flora

Blount

Megyola

Plummer

et al. 2015

Despite nearly 85 years of successful antibacterial chemotherapy, bacterial infections still pose a serious threat to human health. Continually emerging drug-resistant bacteria make existing agents less effective, and a paucity of new agents and decreased development effort from the pharmaceutical industry provide little hope of replenishing the arsenal (1, 2). Complications and mortality due to bacterial infections continue to increase, already reaching epidemic proportions in some areas of the world. If humans are to regain the upper hand in fighting bacterial infections, then innovation, investment, and new antibacterial agents will be needed. Although some of the barriers to the discovery and approval of new compounds are economic or policy related, there is also a desperate need for new targets and new mechanisms of action. A renewed effort to expand our knowledge of bacterial physiology and to translate discoveries into the clinic will be needed to address these challenges and to reinvigorate antibiotic development pipelines.Recent advances in our understanding of how bacteria maintain physiological homeostasis revealed a promising class of potential antibiotic targets called riboswitches-noncoding mRNAs that form a structured receptor (or aptamer) which can directly bind to a specific small-molecule ligand or ion and thereby regulate gene expression (3-5). Ligand binding to a riboswitch aptamer stabilizes a conformationally distinct architecture in the mRNA that modulates the expression of the adjacent coding region(s) (4-8). To date, more than 35 riboswitch classes have been discovered and characterized (7). Three of these riboswitch classes have been revealed as important cellular targets of antibacterial small molecules whose mechanism of action had not been previously defined (9-13). More recently, several publications have demonstrated that novel small molecules that bind to selected riboswitch aptamers with affinities comparable to that of the cognate ligand can be rationally identified and optimized (14-21).In some cases, synthetic or natural riboswitch ligand analogs have demonstrated potent antibacterial activity (12-15, 20, 22). For example, the phosphorylated form of roseoflavin (RoF) (