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

Turki Abujamel,Sirisha Kundrapu,Robin L Jump,Alain C Stintzi,Curtis J Donskey,Venkata C K Sunkesula,Jennifer L Cadnum,Lucy A Jury,Daniel Paredes-Sabja

doi:10.1371/journal.pone.0076269

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.

Highlights

Clostridium difficile is the most important cause of healthcare-associated diarrhea in developed countries [1]
76 Clostridium difficile infection (CDI) patients had stool samples available for analysis, including 42 (55%) patients treated with oral vancomycin and 34 (45%) patients treated with oral metronidazole
More than half of C. difficile isolates from both treatment groups were North American pulsed-field gel electrophoresis type 1 (NAP1)/ ribotype 027 isolates based on Polymerase chain reaction (PCR) ribotyping and amplification of the binary toxin gene cdtB

Summary

Introduction

Clostridium difficile is the most important cause of healthcare-associated diarrhea in developed countries [1]. Oral vancomycin and metronidazole are the agents most often used to treat Clostridium difficile infection (CDI) [1] These antibiotics are effective in suppressing C. difficile, but they are nonselective agents that cause significant disruption of the indigenous microbiota of the colon [2,3,4]. It is known that recurrences may occur days to weeks after completion of CDI therapy, the period of vulnerability to re-establishment of colonization by C. difficile after therapy is not well defined. In theory, this period will extend from the time vancomycin or metronidazole levels reach subinhibitory concentrations in the colon to the time when the intestinal microbiota recovers sufficiently to inhibit C. difficile growth. Conclusions: These 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

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