Clostridium difficile–Associated Diarrhea after Antibiotic Treatment for Traveler's Diarrhea

Traveler's diarrhea, defined as the passage of at least 3 unformed stools in 24 h in association with es;1 other gastrointestinal symptom, constitutes an important health problem. It affects up to 40% of individuals traveling from low-risk countries to high-risk developing areas. The illness usually resolves within a few days without treatment, but in some cases, infection causes significant morbidity. Consequently, there has been increasing interest in strategies for prevention, prophylaxis, and self-treatment with antimicrobials, as well as the development of new treatments and potential vaccines. According to published data, 8%–15% of affected travelers may remain symptomatic for >1 week, with some developing persistent diarrhea (duration, >14 days) or even chronic diarrhea (duration, >1 month) [1, 2].

Many causes have been identified that may account for prolonged diarrhea in the returning traveler. The presence of antibiotic-resistant enteric bacteria, parasitic infection (typically infection due to Giardia lamblia, Cryptosporidium parvum, Cyclospora cayetanensis, or Entamoeba histolytica), acquired disaccharidase deficiency, postinfectious irritable bowel syndrome, preexisting HIV infection, intake of certain treatments, inflammatory bowel disease, bowel carcinoma, and tropical sprue have been reported in the literature as potential causes of ongoing diarrhea in travelers [1–4].

Bacterial pathogens are known to cause acute traveler's diarrhea in up to 80% of cases; thus, antibiotics are commonly administered for the treatment of this entity [2]. In addition, antimicrobial chemoprophylaxis has been shown to reduce the incidence of traveler's diarrhea by 90% [3]. Both of these factors may contribute to the development of Clostridium difficile–associated diarrhea (CDAD), for which prior antibiotic use is a known risk factor, because of the disruption of normal flora. Therefore, this disease should also be considered as a cause of persistent or chronic diarrhea in travelers.

Case reports. Cases were identified retrospectively at a Tropical Medicine Referral Unit in Madrid, Spain during the period 2001–2007 when an episode of traveler's diarrhea treated with antibiotics failed to resolve or when a second episode of diarrhea occurred after receipt of antibiotic treatment. In total, 2133 travelers had attended the unit during this period, and of these, 239 had been diagnosed with traveler's diarrhea. Six travelers who had previously taken antimicrobial treatment for an acute diarrheal episode presented with prolonged or recurrent gastrointestinal symptoms, including diarrhea, in association with C. difficile. None of the patients had been hospitalized, but 1 of the patients (patient 4) had briefly attended the emergency department twice, and antibiotics had been prescribed before CDAD was diagnosed in the unit. Although unlikely, nosocomial acquisition of C. difficile may have been theoretically possible for this patient.

The results of stool C. difficile toxin assays (Vidas C. difficile Toxin A; bioMacute;rieux) and cultures on selective media for C. difficile (incubated in anaerobic conditions at 37eg;C for 7 days) were positive in all cases. Conventional stool cultures were also performed, as were examinations for ova, cysts, and parasites and Kinyoun stains for acid-fast organisms. The results of these tests were all negative, so other infectious causes were excluded.

We identified an additional patient with positive C. difficile stool culture and toxin assay results who only experienced self-limiting abdominal pain and tenesmus after an episode of treated diarrhea. A clear etiologic role for C. difficile was difficult to establish, and the patient was excluded from the series. This patient had been hospitalized in Venezuela during the acute episode, also raising the possibility of nosocomial C. difficile infection.

The main epidemiological, clinical, and laboratory findings (including treatment regimens and outcome) for the 6 patients in the study are summarized in table 1. All of the patients had visited countries classically deemed to be high-risk regions for acquiring traveler's diarrhea. Areas visited included Peru, Bolivia, Cambodia, Myanmar, India, Morocco, and Kenya. For 4 patients, additional risk factors were also identified, including the consumption of ice or nonbottled water, consumption of food from local street vendors, or history of staying in jungle areas. All of the patients had received previous antibiotic therapy for their acute diarrheal episodes. Four of the patients had been treated with ciprofloxacin followed by a second or even a third antibiotic when symptoms did not improve. For 2 of the patients who were treated abroad, determination of the exact antibiotic treatment administered initially was not possible.

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Table 1

Epidemiological, clinical, and laboratory findings for cases of Clostridium difficile-associated diarrhea after receipt of antibiotics for treatment of traveler's diarrhea.

One of the patients had persistent diarrhea (duration, 2–4 weeks), and 3 patients had chronic diarrhea (duration, >4 weeks) These patients described initial improvement after treatment but presented to the hospital because symptoms failed to resolve completely. The other 2 patients experienced recurrent diarrhea.

Once the diagnosis of CDAD was established, 5 patients were treated with metronidazole (500 mg 3 times per day for 5–7 days). One patient (patient 1) was treated with metronidazole (250 mg 3 times per day for 10 days). A second course of metronidazole was prescribed for 1 patient (patient 2). For patient 4, a 5-day course of metronidazole was followed by oral vancomycin before symptoms resolved. Interestingly, the latter patient had received a short course of oral metronidazole for treatment of the initial episode of diarrhea. Given that metronidazole treatment failure in CDAD appears to be more frequent than was previously recognized [5], this could well have accounted for the initial treatment failure.

Regarding outcome after CDAD, all patients experienced improvement, although microbiological confirmation of cure was only obtained for 2 patients. The patient who had received 2 courses of metronidazole (patient 2), experienced mild improvement of symptoms only; a lactose-free diet was initiated, and additional investigations were scheduled, but the patient did not return for follow-up.

Discussion. Several publications consider CDAD to be a rare cause of prolonged diarrhea in previously treated, returning travelers, especially as a potential complication of long-term prophylaxis [1]. However, to the authors' knowledge, this is the first reported series of CDAD after receipt of specific treatment for traveler's diarrhea. In 1995, Golledge and Riley [6] reported 3 cases of laboratory-proven CDAD after administration of malaria prophylaxis with doxycycline. Stool cultures yielded toxigenic C. difficile only (results of free toxin assays were not published), and gastrointestinal parasites were not found. The authors postulated that, because C. difficile cultures were not routinely requested for these patients, other cases of CDAD resulting from tetracycline therapy in travelers may be going undiagnosed. This may also be the case for persons who receive antibiotics for traveler's diarrhea, especially because mild CDAD symptoms may resolve without treatment after withdrawal of the initial antibiotic therapy [7]. This may well have occurred in the patient with positive C. difficile toxin and stool culture results who was excluded from this report. Therapy with metronidazole, which may be used as an empirical antiparasitic agent once initial standard antibacterial treatment has failed, may also inadvertently treat unrecognized CDAD.

Fluoroquinolones are still recommended as one of the first-line treatment and prophylaxis options for traveler's diarrhea, especially given the greater activity provided by this class of drugs against invasive bacterial pathogens [1, 3, 8, 9]. Virtually all antimicrobial agents have been linked to the development of CDAD, and historically, use of cephalosporin and clindamycin in hospitals has constituted a major risk factor. There has been renewed interest in the role of fluoroquinolones in CDAD. Recent studies of the disease-especially for cases caused by the NAP1/027 strain, a hypervirulent strain linked to recent outbreaks in North America, Japan, and Europe-have found that fluoroquinolones in particular were most closely associated with the development of CDAD [10, 11]. Although the new strain has not been linked thus far to prior antibiotic use in travelers, it is noteworthy that, even in this small series, the majority of the travelers (at least 4) with CDAD had received fluoroquinolones as part of their initial treatment. The use of rifaximin, a poorly absorbed oral antibiotic shown to have low potential for inducing disruption of the intestinal flora, for the treatment of traveler's diarrhea may change the incidence of CDAD in this clinical scenario [9, 12]. However, there are ongoing concerns about the development of resistance to this agent.

The importance of careful assessment of the patient's history, with emphasis on prior antibiotic use, should be highlighted, because this may well lead to the diagnosis of CDAD in travelers with prolonged diarrhea. The incidence of the disease in this context may be higher than has previously been believed. As illustrated by this report, patients may often experience improvement of an acute diarrheal episode with antibiotic treatment, followed by persistence of symptoms or the appearance of a second episode. Clinicians should be aware of CDAD as a potential complication, especially if there is a history of prior fluoroquinolone use, because current trends in antibiotic prescribing policies may well be changing the epidemiology of the disease. The diagnostic methods involved are simple and inexpensive, and timely diagnosis may avoid many unnecessary investigations. Although antibacterials have been shown to be effective for a majority of cases of traveler's diarrhea, keeping prophylaxis short term, judiciously using antibiotics, and searching for specific causes of prolonged or recurrent diarrhea in travelers are advocated to minimize the risk of CDAD in such patients.

• Received October 15, 2007.
• Accepted December 3, 2007.

• © 2008 by the Infectious Diseases Society of America