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Probiotics for recurrent Clostridium difficile disease

¹Division of Infectious Diseases, Washington University School of Medicine, Box 8051, 660 South Euclid Avenue, St. Louis, MO 63110, USA ²Division of Gastroenterology, Harvard Medical School, Boston, MA, USA ³Philadelphia FIGHT, Philadelphia, PA, USA ⁴Saint Louis University School of Public Health, St. Louis, MO, USA

Correspondence: Steven J. Lawrence (slawrenc{at}im.wustl.edu)

In this journal's recent review of Clostridium difficile-associated disease (CDAD) management, McFarland (2005) emphasized the need for definitive efficacy trials to test recurrent CDAD (RCDAD) therapies. To address this recommendation, we report results and feasibility issues learned from a pilot trial of adjunctive Lactobacillus rhamnosus GG (LGG) for prevention of RCDAD.

Adults presenting with RCDAD (i.e. diarrhoea, enzyme immunoassay detection of stool C. difficile toxin A or B, and history of CDAD in the preceding year) were recruited from two hospitals and an extended care facility in St. Louis, Missouri, USA, over 9 months. Exclusion criteria included critical or terminal illness, compromised immunity, prosthetic heart valves, >5 days of anti-C. difficile antibiotic therapy, recent probiotic use and confounding diarrhoeal illness. Informed consent was obtained from all participants or their proxies, and the study was approved by the institutional review board of each institution.

Participants were randomized to receive one LGG capsule (40 mg lyophilized LGG and 320 mg inulin) or one placebo capsule (360 mg inulin) orally twice daily, adjunctively with anti-C. difficile antibiotics as chosen by the primary clinician, for the duration of antibiotic therapy and for an additional 21 days. The LGG and placebo capsules were donated by CAG Functional Foods, Omaha, Nebraska, USA. Investigators and participants were blinded to the treatment assignment. Randomly selected LGG capsules were analysed and contained 2.8 x 10¹¹ c.f.u. per capsule of Gram-positive bacilli with uniform colony morphology at study initiation and 4.0 x 10¹⁰ c.f.u. after 8 months stored at 4 °C. The primary outcome was subsequent RCDAD within 60 days of completing anti-C. difficile antibiotic therapy. Participants were analysed within their assigned treatment arm in an intention-to-treat analysis, using t-tests and Mann-Whitney U tests for continuous variables and Fisher's Exact tests for categorical variables in Statistical Package for the Social Sciences version 12.0.

Among the 15 enrolled participants, the mean age was 77.9 years, 13 (86.7 %) were women, five (33.3 %) demonstrated cognitive dysfunction and the median number of prior CDAD episodes was 1.0 (maximum of three) (see Table 1). Eight participants (53.3 %) received LGG and were similar to placebo recipients with respect to demographic and clinical features. Three (37.5 %) cases of RCDAD were observed in the LGG arm and one (14.3 %) in the placebo arm [risk ratio 2.6 (95 % confidence intervals 0.3–19.9)]. The median duration of the anti-C. difficile antibiotic regimens was 18.0 days and similar between arms; 12 (80 %) of the participants received metronidazole monotherapy. Notably, 10 (66.7 %) of the participants received concurrent systemic antimicrobials unrelated to CDAD. Clinical features of the presenting episode associated with subsequent RCDAD included presence of nausea or vomiting (100 % vs 27.3 % for RCDAD vs no RCDAD, P = 0.026) and a lower peak white blood cell count (12.3 x 10³ vs 20.5 x 10³ µl^–1, P = 0.025). More participants with RCDAD received gastric acid suppression therapy after enrolment (100 % vs 54.5 % for RCDAD vs no RCDAD, P = not significant). There were no Lactobacillus infections, LGG-related serious adverse events or intolerances leading to study discontinuation. Mild to moderate adverse effects attributed to LGG included bloating (25 % incidence) and excessive flatulence (37.5 % incidence). Reported adherence to the assigned study capsules was 90 % for all but two study participants (one in each arm).

Evidence for efficacious treatments of RCDAD is sparse. Our study findings complement another small-scale trial that reported no benefit from a yogurt formulation of adjunctive LGG (Pochapin, 2000; McFarland, 2005). Although our study was not powered to detect a difference in outcomes for RCDAD, the data spotlight several feasibility challenges relevant to the launch of a large-scale probiotic efficacy trial. First, the majority of participants were prescribed concurrent systemic antimicrobial therapy for non-CDAD indications and gastric acid suppressive therapy, both of which interfere with the normal gut flora and its ability to inhibit C. difficile colonization (McFarland, 2005; Dial et al., 2004). Avoidance of these drugs is often not feasible in frequently hospitalized older adults with multiple comorbidities, thus introducing an important source of confounding that can be difficult to quantify. Second, 60-day retention in this study was arduous for many of the frail, elderly participants, and was often further complicated by concomitant cognitive dysfunction. Also, most study participants were presenting with a first recurrence of CDAD, unlike the patients with recalcitrant disease who were previously reported in case series of successful adjunctive LGG treatment (Gorbach et al., 1987; Bennett et al., 1996). Lastly, the participants were conservatively chosen to be at low risk for infectious complications from the study probiotic. Compared to previous RCDAD cohorts, the subsequent exclusion of younger immunocompromised patients resulted in an older study population with age-related gut flora changes possibly influencing the underlying risk for CDAD recurrence (McFarland et al., 1994; Surawicz et al., 2000; Wullt et al., 2003; Hopkins & Macfarlane, 2002).

Together, these findings suggest that future probiotic studies should be designed to carefully measure and control for the receipt of confounding drugs that impact the gut flora, and should have end points that distinguish outcomes in time-to-event analyses. Careful consideration must also be made in choosing the study population to account for heterogeneous risk attributable to immune status, age, cognitive function and prior CDAD history. As emphasized by McFarland (2005), effective adjunctive treatments for preventing CDAD recurrence are lacking, and we echo the call for full-scale clinical trials to investigate those that appear promising.

	ACKNOWLEDGEMENTS

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S. J. L. received salary support from National Research Service Award #5 T32 AI07 172-24. The probiotic and placebo capsules were donated by CAG Functional Foods, Omaha, Nebraska, USA. Potential conflict of interest: J. R. K. has received research support from Rhodia Pharma Solutions; S. J. L and L. M. M., no conflict.

	References

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