Defining the Vulnerable Period for Re-Establishment of Clostridium difficile Colonization after Treatment of C. difficile Infection with Oral Vancomycin or Metronidazole

Abstract

Background Clostridium difficile is an anaerobic, spore-forming bacterium that is the most common cause of healthcare-associated diarrhea in developed countries. A significant proportion of patients receiving oral vancomycin or metronidazole for treatment of Clostridium difficile infection (CDI) develop recurrences. However, the period of vulnerability to re-establishment of colonization by C. difficile after therapy is not well defined.Principal FindingsIn a prospective study of CDI patients, we demonstrated that most vancomycin-treated patients maintained inhibitory concentrations of vancomycin in stool for 4 to 5 days after therapy, whereas metronidazole was only detectable during therapy. From the time of elimination of the antibiotics to 14 to 21 days after therapy, a majority of stool suspensions supported growth of C. difficile and deep 16S rRNA sequencing demonstrated persistent marked alteration of the indigenous microbiota. By 21 to 28 days after completion of CDI treatment, a majority of stool suspensions inhibited growth of C. difficile and there was evidence of some recovery of the microbiota.ConclusionsThese data demonstrate that there is a vulnerable period for re-establishment of C. difficile colonization after CDI treatment that begins within a few days after discontinuation of treatment and extends for about 3 weeks in most patients.

Disease Progression and Resolution in Rodent Models of Clostridium difficile Infection and Impact of Antitoxin Antibodies and Vancomycin

“…6B and C. Since colonization of the gut by C. difficile is facilitated by antibiotic-mediated disruption of the normal gut biota, there is a period of time, following successful cure of an initial episode of CDI with standardof-care antibiotics such as vancomycin (the "at-risk window" in Fig. 6B and C), during which the gut microbiome has not yet recovered and patients are at risk for recurrence (9,10,36). Paradoxically, the standard of care for recurrent episodes of CDI consists of a new course of antibiotics, including vancomycin, perpetuating a recurrence cycle that can be difficult to break (Fig.…”

“…The infection is normally treated with antibiotics such as vancomycin and metronidazole which have potent activity against C. difficile (1,8). However, the broad antibacterial spectra of these agents perpetuate gut dysbiosis, leading to high rates of disease recurrence following withdrawal of therapy, during which surviving or newly acquired C. difficile spores take advantage of persistent disruption of the gut microbiome to cause another episode of CDI (9)(10)(11). The risk of recurrence following a first episode is around 25% but increases significantly with each subsequent episode, often leading to a cycle of recurrence which can be difficult to break (11)(12)(13).…”

“…The mechanism of protection is thought to be through direct competition for nutrients and environmental niches within the gut, as well as through production of secondary bile acid metabolites that directly inhibit germination of C. difficile spores and growth of vegetative C. difficile (4,5). Furthermore, several studies over the last few years have demonstrated that the initial effects of antibiotics on the microbiota are reversible and that the period of recovery is anywhere between a few days and several weeks (9,19,20). This period of recovery is hypothesized to correspond to the window of susceptibility to recurrence that follows successful cure of a primary episode with antibiotics such as vancomycin.…”

Preclinical Studies of Amixicile, a Systemic Therapeutic Developed for Treatment of Clostridium difficile Infections That Also Shows Efficacy against Helicobacter pylori

“…In contrast, many of these bacteria are susceptible to fidaxomicin and vancomycin (21). Several studies found a greater abundance of members of the genus Bifidobacterium in the feces of individuals considered resistant to CDI infection than in the feces of those susceptible to recurrence (22,23). Many of these human microbiome studies of CDI and controls reveal substantial changes in the complex gut microflora but have yet to correlate these changes with specific antibiotic therapy.…”

An in vitro culture model to study the dynamics of colonic microbiota in Syrian golden hamsters and their susceptibility to infection with Clostridium difficile

“…Fecal extracts from naïve hamsters were inhibitory for C. difficile growth while extracts obtained from clindamycin-treated hamsters supported C. difficile growth. Using fecal extracts from samples collected in a longitudinal study, a plot was generated which strongly resembled the theoretical plot of C. difficile risk presented by Rupnik et al (2009) as well as results reported by Abujamel et al (2013), which demonstrated that stool suspensions collected from patients undergoing antibiotic therapy were permissive to C. difficile growth for a period of B14 to 21 days after the clearance of the antibiotics.…”