Larry K. Kociolek

Breakthroughs in the treatment and prevention of Clostridium difficile infection

This Review summarizes the latest advances in the treatment and prevention of Clostridium difficile infection (CDI), which is now the most common health-care-associated infection in the USA. As traditional, standard CDI antibiotic therapies (metronidazole and vancomycin) are limited by their broad spectrum and further perturbation of the intestinal microbiota, which result in unacceptably high recurrence rates, novel therapeutic strategies for CDI are needed. Emerging CDI therapies are focused on limiting further perturbation of the intestinal microbiota and/or restoring the microbiota to its pre-morbid state, reducing colonization of the intestinal tract by toxigenic strains of C. difficile and bolstering the host immune response against C. difficile toxins. Fidaxomicin is associated with reduced CDI recurrences, and other emerging narrow-spectrum CDI antibiotic therapies might eventually demonstrate a similar benefit. Prevention of intestinal colonization of toxigenic strains of C. difficile can be achieved through restoration of the intestinal microbiota with faecal microbiota transplantation, as well as by colonizing the gut with nontoxigenic C. difficile strains. Finally, emerging immunological therapies, including monoclonal antibodies and vaccines against C. difficile toxins, might protect against CDI and subsequent CDI recurrences. The available clinical data for these emerging therapies, and their relative advantages and disadvantages, are described.

Molecular Epidemiology of Clostridium difficile Infections in Children: A Retrospective Cohort Study

OBJECTIVE The molecular epidemiology of pediatric Clostridium difficile infection (CDI) is poorly understood. We aimed to identify the restriction endonuclease analysis (REA) groups causing CDI and to determine risk factors and outcomes associated with CDI caused by epidemic strains in children. DESIGN Retrospective cohort study. PATIENTS Inpatients and outpatients >1 year old receiving care between December 2012 and December 2013. SETTING An academic childrens hospital in Chicago, Illinois. METHODS C. difficile PCR-positive stools were cultured, and C. difficile isolates were typed by REA. REA of isolates from patients with multiple CDIs was performed to differentiate relapse (infection with same strain) from reinfection (different strains) irrespective of time between CDIs. RESULTS A total of 189 CDIs occurred among 145 patients. REA groups were widely distributed. The BI/NAP1/027 strain caused CDI in only 1 patient. DH/NAP11/106, the predominant epidemic strain identified, was associated with the use of third- or fourth-generation cephalosporins (risk ratio [RR], 3.2; 95% confidence interval [CI], 1.1-9.9; P=.04). CDI relapse commonly occurred up to 20 weeks later. Compared with CDI caused by non-DH/NAP11/106 strains, CDI caused by DH/NAP11/106 was more likely to result in multiple CDI relapses (40% vs 8%; P=.05) among children with multiple CDIs. CONCLUSIONS REA identified the exceedingly low prevalence of BI/NAP1/027 and the high prevalence of DH/NAP11/106, a common epidemic strain in the United Kingdom that is less often reported in the United States. CDI relapse commonly occurred up to 20 weeks from the previous CDI. Defining recurrent CDI as that occurring only within 8 weeks of the original infection may lead to misclassification of some recurrent CDIs as new CDIs in children.

Clinical and Microbiologic Assessment of Cases of Pediatric Community-associated Clostridium difficile Infection Reveals Opportunities for Improved Testing Decisions.

Background: Most children with Clostridium difficile infection (CDI) experience community onset of CDI symptoms. Methods: We retrospectively compared hospital-onset healthcare facility–associated CDI cases to community-associated (CA) CDI cases diagnosed by Cepheid Xpert tcdB polymerase chain reaction (PCR) at an academic children’s hospital over a 1-year period. Saved stools from CDI cases additionally underwent anaerobic stool culture and multiplex gastrointestinal pathogen PCR testing. Results: Compared with 25 hospital-onset healthcare facility–associated CDI cases, the 74 CA-CDI cases were more frequently <2 years old (18% vs. 0%, P = 0.034) and less frequently had antibiotic exposure in the past 30 days (26% vs. 88%, P < 0.0001), proton pump inhibitor exposure (16% vs. 36%, P = 0.036) or a gastrostomy tube (11% vs. 32%, P = 0.013). Among children diagnosed with CA-CDI, 19 (26%) had no identified CDI risk factors (immunocompromised; gastrostomy tube; recent antibiotic, proton pump inhibitor or inpatient/outpatient healthcare exposures). Clinical testing for viral pathogens was uncommon among children thought to have CA-CDI. Multiplex PCR testing of saved stool samples failed to identify C. difficile among 23% of cases diagnosed with CA-CDI by the Cepheid Xpert tcdB PCR assay. CDI antibiotic therapy was provided to nearly all patients testing positive by tcdB PCR irrespective of CDI risk factors. Conclusions: Many children diagnosed with CA-CDI by PCR lack CDI risk factors and have discordant results when additional CDI testing methods are performed, suggesting overdiagnosis of CDI in children with community-onset diarrhea. More selective CDI testing of low-risk pediatric patients is needed to more accurately diagnose CDI and limit unnecessary CDI antibiotic treatment in children.

Risk Factors for Recurrent Clostridium difficile Infection in Children: A Nested Case-Control Study.

OBJECTIVE To identify risk factors for recurrent Clostridium difficile infection (RCDI) in children. STUDY DESIGN A nested case-control study was performed to identify RCDI risk factors using a pediatric cohort of inpatients and outpatients diagnosed with Clostridium difficile infection by tcdB polymerase chain reaction (PCR) at an academic childrens hospital between December 9, 2012, and June 30, 2014. Strict inclusion criteria were adopted to limit selection bias related to inappropriate inclusion of patients with probable C difficile colonization. RESULTS Thirty children with RCDI were compared with 94 children with non-RCDI. Statistically significant associations were identified between RCDI and malignancy (OR 2.8, 95% CI 1.0-7.4, P = .044), tracheostomy tube dependence (OR 5.2, 95% CI 1.1-24.7, P = .037), and tcdB PCR cycle threshold (OR 0.87, 95% CI 0.78-0.97, P = .01) using multivariable logistic regression modeling. The receiver operator characteristic curve for PCR cycle threshold as a predictor of RCDI demonstrated area under the curve = 0.67. The highest predictive rate (75%) for RCDI was demonstrated at cycle threshold cutpoint ≤ 20. The difference between sensitivity (64%) and specificity (68%) was minimized at cycle threshold cutpoint ≤ 23. Compared with controls with non-RCDI, children excluded because of probable C difficile colonization had a similar cycle threshold value (27.5 vs 27.2, P = .77). CONCLUSIONS Malignancy and tracheostomy tube dependence were identified as RCDI risk factors. Although RCDI was associated with positivity at a lower tcdB PCR cycle threshold, the clinical utility of cycle threshold as a tool to predict recurrence was limited. Better methods to predict RCDI are needed to prioritize pediatric populations to target for RCDI prevention efforts.

Infection Prevention and Control in Residential Facilities for Pediatric Patients and Their Families

The Society for Healthcare Epidemiology of America (SHEA) guideline “Infection Prevention and Control in Residential Facilities for Pediatric Patients and Their Families” is the first infection prevention and control (IPC) guideline to address preventing transmission of infectious agents in “home away from home” residential settings, of which the Ronald McDonald Houses (RMHs) serve as a prototype. These types of facilities provide support services, including overnight lodging, for ill and injured children and their families. Food preparation occurs in common areas, and cleaning of rooms or apartments is performed by the occupants during their stay and before departure. Pediatric patients are frequent guests of the family-centered facilities while receiving or recovering from specialized medical therapy. Examples of high-risk populations served in these facilities include families of patients with cancer, recipients of stem cell or solid organ transplants, surgical and/or very-low-birthweight infants who receive care in neonatal intensive care units (NICUs), those with cystic fibrosis, and women with high-risk pregnancies awaiting delivery in a nearby medical center. Such facilities are located worldwide and vary in their physical structure and the predominant population served.

Clinical utility of laboratory detection of Clostridium difficile strain BI/NAP1/027

ABSTRACT Clostridium difficile strain BI/NAP1/027 is associated with increased C. difficile infection (CDI) rates and severity, and the efficacy of some CDI therapies may be strain dependent. Although cultured C. difficile isolates can be reliably subtyped by various methods, the long turnaround times, high cost, and limited availability of strain typing preclude their routine use. Nucleic acid amplification tests identify BI/NAP1/027 rapidly from stool, but the emergence of closely related strains compromises test specificity. Although detection of epidemiologically significant pathogens is generally useful for infection control programs, specific data supporting use of rapid detection of BI/NAP1/027 as an infection control tool are still awaited.

Strategies for Optimizing the Diagnostic Predictive Value of Clostridium difficile Molecular Diagnostics

ABSTRACT Because nucleic acid amplification tests (NAATs) do not distinguish Clostridium difficile infection (CDI) and asymptomatic C. difficile carriage, the diagnostic predictive value of NAATs is limited when used in patients with a low probability of CDI. In this issue of the Journal of Clinical Microbiology, Truong et al. (J. Clin. Microbiol., 55:1276–1284, 2017, https://doi.org/10.1128/JCM.02319-16 ) report significant reductions in hospital-onset CDI and oral vancomycin utilization at their institution following implementation of a novel intervention that leveraged their clinical bioinformatics resources to prevent C. difficile testing of stools from patients without clinically significant diarrhea and in patients with recent laxative use.

Differences in the Molecular Epidemiology and Antibiotic Susceptibility of Clostridium difficile Isolates in Pediatric and Adult Patients.

ABSTRACT The rising incidence of Clostridium difficile infections (CDIs) in adults is partly related to the global spread of fluoroquinolone-resistant strains, namely, BI/NAP1/027. Although CDIs are also increasingly diagnosed in children, BI/NAP1/027 is relatively uncommon in children. Little is known about the antibiotic susceptibility of pediatric CDI isolates. C. difficile was cultured from tcdB-positive stools collected from children diagnosed with CDI between December 2012 and December 2013 at an academic childrens hospital. CDI isolates were grouped by restriction endonuclease analysis (REA). MICs were measured by agar dilution method for 7 antibiotics. Susceptibility breakpoints were based on guidelines from CLSI and/or the European Committee on Antimicrobial Susceptibility Testing (EUCAST). MICs and REA groupings of C. difficile isolates from 74 adult patients (29 isolates underwent REA) from a temporally and geographically similar adult cohort were compared to those of pediatric isolates. Among 122 pediatric and 74 adult isolates, respectively, the rates of resistance were as follows: metronidazole, 0% and 0%; vancomycin, 0% and 8% (P = 0.003); rifaximin, 1.6% and 6.7% (P = 0.11); clindamycin, 18.9% and 25.3% (P = 0.29); and moxifloxacin, 2.5% and 36% (P = <0.0001). Only 1 of 122 (0.8%) BI/NAP1/027 isolates was identified among the children, compared to 9 of 29 (31%) isolates identified among the adults (P = <0.0001). The 3 moxifloxacin-resistant pediatric isolates were of REA groups BI and CF and a nonspecific group. The 2 rifaximin-resistant pediatric isolates were of REA groups DH and Y. The 21 clindamycin-resistant pediatric isolates were distributed among 9 REA groups (groups A, CF, DH, G, L, M, and Y and 2 unique nonspecific REA groups). These data suggest that a diverse array of relatively antibiotic-susceptible C. difficile strains predominate in a cohort of children with CDI compared to adults.

Impact of a Healthcare Provider Educational Intervention on Frequency of Clostridium difficile Polymerase Chain Reaction Testing in Children: A Segmented Regression Analysis

Background. Although Clostridium difficile infections (CDIs) are increasingly diagnosed in children, many children diagnosed with CDI lack classic risk factors. Frequent use of highly sensitive tcdB polymerase chain reaction (PCR) testing in low-risk patients leads to CDI misdiagnosis and unnecessary CDI antibiotic use in children with C difficile carriage. Methods. For this quasi-experimental study, we developed and implemented an educational intervention (EI) to inform healthcare providers (HCPs) about tcdB PCR test limitations. We provided HCP didactic education and built an electronic notification into the tcdB PCR test order that describes scenarios in which carriage is more likely than CDI. Segmented regression analysis assessed changes in level (ie, overall rates) and trend of C difficile testing rate ([TR] number of tests performed per 1000 patient encounters) and test positivity rate ([PR] number of positive tests per 1000 patient encounters) between the pre- (August 2009-August 2013) and postintervention (February 2014-July 2015) periods. Results. Hospital-wide, absolute TR reduction was 0.71 (P[level] = .0067; P[trend] = .0042) and absolute PR reduction was 0.14 (P[level] = .22; P[trend] = .018). In the outpatient setting, absolute TR reduction was 0.30 (P[level] = .0015; P[trend] < .001) and absolute PR reduction was 0.09 (P[level] = .0069; P[trend] = .046). The incidence density of healthcare facility-associated CDI did not significantly change after the EI. The EI was associated with avoidance of 574 tests and 113 positive tests (and subsequent antibiotic courses) during the postintervention period, which saved approximately

Concomitant Medical Conditions and Therapies Preclude Accurate Classification of Children With Severe or Severe Complicated Clostridium difficile Infection

250 000 in patient charges related to CDI testing and treatment. Conclusions. Healthcare provider education can cost-effectively reduce the frequency of C difficile testing and CDI misdiagnosis by improving test utilization among low-risk children.