Antimicrobial Drugs Increase C. difficile Hospital Occurrences; Transmission Questions

Infection with the nosocomial pathogen Clostridium difficile is a major risk in healthcare settings and long-term care facilities (LTCFs) and has an increasing prevalence in the broader community. More than 250,000 hospitalized persons are diagnosed with C. difficile infection annually in the United States. Colonization of the gut microbiota with C. difficile can be innocuous and asymptomatic. However, antimicrobial drugs disrupt the normal intestinal microbial architecture and can enable proliferation of C. difficile. An insufficient host antibody response to C. difficile toxins A and B can then lead to C. difficile infection (CDI). CDI is a severe diarrheal disease that is concentrated among elderly persons and those with extended hospital stays or residing in LTCFs. The relative risk for CDI, given recent antimicrobial drug exposure, differs greatly among antimicrobial drug classes and ranges from no relative risk when receiving tetracyclines to a 20-fold relative risk when receiving clindamycin. Despite an increasing interest in C. difficile biology and the epidemiology of CDI, fundamental questions about reservoirs and routes of transmission remain unanswered.


Studies have estimated that 10%–38% of CDI cases that occur more than 48 hours after hospital admission (termed hospital-onset CDI) can be attributed to transmission from known symptomatic contacts within the hospital. These estimates suggest that a substantial proportion of CDI arises from other sources, such as transmission from patients with asymptomatic colonization or community acquisition. The relative role of these routes of transmission to the epidemiology of C. difficile is crucial for determining effectiveness of hospital-based measures to control infection. In addition, toxin-targeting treatments, such as vaccines, nontoxigenic C. difficile, and monoclonal antibodies, might protect against CDI but are unlikely to prevent asymptomatic colonization with C. difficile. To predict the effectiveness of these emerging therapies, it is critical to understand the role of asymptomatic carriers in CDI epidemiology.


To fully understand the epidemiology of the pathogen and to inform decisions regarding control strategies, it is crucial to quantify the relative transmission of C. difficile in the hospital and in the broader community.


Researchers found that a person with CDI in an LTCF transmits at a rate 27% that for a comparable patient in the hospital, and a colonized person or a person with CDI in the community transmits C. difficile to others at a rate <0.1% that of a comparable patient in the hospital. Despite the lower community transmission rate, researchers found that because of the much larger pool of colonized persons in the community, interventions that reduce community transmission hold substantial potential to reduce hospital-onset CDI by reducing the number of patients entering the hospital with asymptomatic colonization. Moreover, their results show that in the hospital, symptomatic CDI patients under isolation and infection control measures nonetheless transmit CDI to uncolonized patients at a rate that is 15 times greater than that of asymptomatic carriers. This higher rate of transmission indicates that toxin-targeting treatments (such as vaccines); nontoxigenic C. difficile; and monoclonal antibodies, which might protect against symptomatic CDI but not against asymptomatic colonization, could be effective tools for reducing not only primary CDI cases but also for further transmission.


These epidemiologic results underscore the need for incorporating and understanding transmission dynamics within and outside healthcare settings when evaluating C. difficile control strategies. Although C. difficile transmission rates are lower among asymptomatically colonized persons, residents of LTCFs, and persons in the community than in hospitalized patients with symptomatic CDI, overall CDI incidence is driven by several factors: transmission, antimicrobial drug use, and underlying population health. The researchers found that, per unit increase in relative antimicrobial drug risk, CDI incidence increases by a factor of 160% in the hospital and 33% in the LTCF but only by a factor of 6.4% in the community. This finding is a consequence of amplification by concentration.


When the researchers compared patients in the hospital and LTCF with persons in the community, they found that patients are closer to each other, are more frequently receiving antimicrobial drugs, and tend to have poorer overall health or may be immunocompromised. These attributes combine to yield a greater risk for infection and transmission. This finding of amplification-by-concentration has major implications for antimicrobial drug risk management: those antimicrobial drugs strongly associated with CDI, such as clindamycin, cephalosporins, and fluoroquinolones, will have a more detrimental effect on overall CDI incidence in a high-transmission setting, such as a hospital, than they will in a moderate-transmission setting, such as an LTCF, or in a low-transmission setting, such as the community.


The researchers found no major effect of hospital-based transmission interventions on LTCF-onset CDI or of LTCF-based transmission interventions on hospital-onset CDI. This finding suggests that although C. difficile can be introduced by a patient who acquired the bacteria in the hospital, CDI outbreaks in LTCFs are driven primarily from within and are best mitigated by targeted transmission interventions within the facility. Likewise, any interventions to reduce transmission within an LTCF will have limited effect on hospital-onset CDI because LTCF transmission interventions will not influence continued introduction of C. difficile to the hospital from the community.


The control strategies the researchers evaluated are representative of a broad range of interventions. For example, an improvement in hospital isolation effectiveness could be achieved through enhanced hospital staff adherence to precautions, or alternatively through an increased capacity to keep a patient with CDI in isolation for the duration of the disease. An improvement in the LTCF transmission rate could be achieved through an improvement to LTCF staff hygiene and cleanliness, through an increased availability of private facilities for residents, or through the isolation of LTCF residents with CDI.


The researchers’ analyses demonstrated that C. difficile transmission among healthcare settings and the community is interconnected, and there are comparable effects of community-based transmission and hospital-based transmission on hospital-onset CDI. The researchers found that the effect of antimicrobial drug use on CDI incidence is modulated by transmission dynamics, with specific antimicrobial drugs exacerbating incidence, and doing so to a greater degree in high-transmission settings than in low-transmission settings. These results underscore the need for empirical quantification of community-associated transmission and the need of understanding transmission dynamics in all settings when evaluating C. difficile interventions and control strategies.


See the CDC Report


See also Medical Law Perspectives, January 2012 Report: Hospital-Acquired Infections: Who Is Liable and Why?