Clostridium difficile (CD) is a potentially deadly,1–5 spore-forming bacterium1 that is emerging as a leading cause of life-threatening, healthcare-acquired infections worldwide.3–11 Pathogenic strains of CD produce potent toxins (e.g. toxA, toxB) that cause the clinical manifestations in humans known as symptomatic CD infection (CDI),4,8,12,13 especially in vulnerable individuals and mostly in hospitals and long-term care facilities.1,2,5,7,13–18 An increased prevalence of CDI associated with an increase in disease severity and mortality has been documented in the United States, Canada and Europe.

Individuals most at-risk for CDI have a generally weakened condition,4,7,19,20 have received antibiotics,1,4,7,9,12,15,17,18,21,22 and are likely to have been hospitalized or residing in long-term care facilities,1,2,7,12,13,15,17,18,22 where they could have been exposed to environmental spores. Also, age correlates with increased incidence, severity of disease, the likelihood of recurrences, and CDI related-death.2–4,7,9,12,13,21–25Despite the availability of antibiotics to treat CDI, there is a disturbingly large proportion of patients (i.e. 20–30%) who experience recurrences of CDI,9,12,13,16,19,20,25 which lead to re-hospitalizations20 and longer hospital stays.4,18,20,25 Since transmission of CD is difficult to control14 and treatment options for CDI are less than ideal,4,13,19,20 vaccination could be an efficacious,13,16 cost-effective1,4,17,19,20,24–26 and complementary public health measure12,13 to protect vulnerable individuals from this devastating disease, in whom the attributable mortality is 8–15%.3,5 Sanofi Pasteur is developing a toxoid vaccine for the prevention of primary CDI in at-risk individuals. In addition, a number of other groups, both public agencies and private corporations, are developing and evaluating a number of other prophylactic approaches and management strategies.

Data on the frequency and impact of CDI in Latin America are sparse6,27–33; however the disease has been reported from prospective laboratory surveillance and in outbreaks.6 Moreover, more virulent CD ribotype 027 has been isolated in Costa Rica32 and in Chile.34 We therefore conducted a prospective epidemiological study in order to estimate the incidence of symptomatic laboratory-confirmed CDI cases in Argentina and Mexico among newly hospitalized patients considered at risk (≥40 years of age who have commenced in-hospital antibiotic treatment) and to describe the characteristics of these patients, as a prelude for potential vaccine trials in this region.

A total of 466 patients were enrolled in the study and 414 (89%) completed the follow-up. Among the 52 (11%) patients who discontinued the study, the most common reasons for discontinuation were death during hospitalization (n=32; 7%) and lost to follow-up (n=12; 3%).

This prospective multicenter study confirmed the presence of CDI in at-risk patients hospitalized in tertiary centers in Argentina and Mexico, with an incidence of 1.1 per 1000 patient days within 30 days after initiation of antibiotic treatment. CDI episodes also occurred after discharge from hospital, suggesting that follow-up of at-risk patients is essential to estimate the rate of CDI. In addition, the REA CF group observed predominantly in this study is also known as ribotype 017 and toxinotype VIII and was previously reported in outbreaks worldwide.15

Data on the frequency and impact of CDI in Latin America are sparse and comparison between studies is difficult due to the variety of study designs. One study conducted among 113 patients in Mexico and Latin America from 2003 to 200727 identified use of H2 blockers, prior hospitalization within 12 weeks of diagnosis, prior use of cephalosporins and fluoroquinolones, stay at an ICU, extended hospital stay, and antimicrobial use before diagnosis as risk factors for CDI. In our study, neither cephalosporins nor fluoroquinolones were found associated with CDI. From 1998 to November 1999, 245 fecal specimens from hospitalized and ambulatory patients were tested to confirm the diagnosis of CDI in a medical center in Buenos Aires (28, 29) and 16 (6.5%) were identified as positive by isolation of cytotoxigenic CD among hospitalized patients (81.3%) and outpatients (18.7%) with a mean age of 72.9 years. All patients had received two or more antimicrobial agents, mainly beta-lactams, two months before the appearance of diarrhea. In Argentina, 104 consecutive stool samples from 87 patients with diarrhea were screened for toxigenic CD between April 2000 and April 2001.31,33 The study reported that 38.5% of the samples and 36.8% of the patients were positive for CD. Another study performed in a 200-bed general hospital in Buenos Aires35 showed incidence rates of CDI ranging from 37 to 84 per 10,000 admissions between years 2000 and 2005. Finally, Quesada-Gomez and co-workers32 reported the emergence of CD NAP1 strain in a Costa Rican hospital.

Some limits and strengths of this descriptive study should be discussed. Data were collected in two geographical areas and four centers, which may limit the generalization of the risk estimates to Latin America. Outbreaks have been previously reported in Brazil and Argentina6 and ribotype 027 was already isolated in Costa Rica32 and in Chile.34 This suggested that CDI could tend to occur in outbreaks in Argentina, and this may explain why more cases were observed in this country than in Mexico after only one year of surveillance. Therefore, a longer surveillance period over a larger number of study sites and countries may be needed in order to have a more generalizable estimation of CDI in the region. In our study, results were consolidated by the prospective nature of the study design with laboratory confirmation of CDI using two complementary laboratory techniques (ELISA and REA). While polymerase chain reaction (PCR)-based methods may have allowed for an increased detection rate of toxigenic C. difficile than ELISAs for Toxin A and B, such methods were not in routine practice at the sites at the time of this study. In addition, these methods may fail to discriminate between CDI and asymptomatic colonization with C. difficile, potentially leading to an over detection of cases whereas ELISA-based toxin testing offers strong evidence of clinical disease despite its shortcomings with regards to sensitivity.36

While antibiotic therapy using fidaxomicin (approved in 2011 and not available at the time of this study), metronidazole, vancomycin, and rifampicin is often used in treating the principal episodes of diarrhea, these agents are of no benefit in the treatment of asymptomatic carriers and in the eradication of spores, which are the main transmissible form of this organism.37,38 In addition, 20% of patients treated with metronidazole or vancomycin will have a symptomatic recurrence when treatment is discontinued, and are at increased risk for multiple recurrences.12 Patients who suffer two recurrences have an approximate risk of 65% for further recurrence of CDI, and this form of CDI is a substantial clinical management problem.37 The limitations of conventional therapy, the incongruity of treating antibiotic-associated diarrhea with additional antibiotics, the rapid increase in the incidence of CDI over the past decade, and the risk of inducing antibiotic resistance, require the development of new strategies to limit the impact of this opportunistic pathogen.15

In conclusion, the results of this study added further elements to the existing but limited data regarding CDI in Argentina and Mexico. Caution should be exercised when extrapolating these data to the country level or to Latin America as a whole due to the epidemiological heterogeneity of the disease within and across countries in that region. However, these data confirm the presence of C. difficile in both countries and support the need to further assess the overall burden of the disease in this region.

The study sponsor, Sanofi Pasteur, was involved in the trial design, the management and analysis of data and in the decision to publish. This manuscript was prepared with the assistance of Nicolas Voirin, funded by Sanofi Pasteur.

The authors declare no conflicts of interest.