Clostridioides difficile is an anaerobic, Gram-positive bacterium that undergoes fecal–oral transmission leading to colonization of the large intestine and release of protein exotoxins.1C. difficile infection (CDI) can manifest as a broad spectrum of symptoms, ranging from mild diarrhea to serious and life-threatening conditions, such as pseudomembranous colitis and toxic megacolon.1,2

Antibiotic exposure, which alters the natural flora of the intestines and in turn allows the bacterium to proliferate, is the most important risk factor for CDI.1,3 Other factors associated with CDI include advanced age, prior healthcare exposure, and increased number of comorbid conditions.3

The epidemiology of CDI is temporally and geographically variable; however, incidence rates have generally been increasing over the past 20 years.1,4 In high-income countries, CDI has been most common in healthcare settings and is the most frequent cause of hospital-acquired infectious diarrhea and healthcare-associated infections.5–7 Notably, a growing proportion of CDI cases are now community associated.1,8 In 2017, the incidence of all CDIs, healthcare-associated CDIs, and community-associated CDIs in the United States was 130.3, 67.0, and 63.3 per 100,000, respectively; in EU countries participating in healthcare-associated infections surveillance, the mean hospital incidence density was 3.2 and 2.4 per 10,000 patient-days for total CDI and hospital-associated CDI, respectively, in 2016.8,9 Additionally, a recent meta-analysis estimated 2.24 healthcare-associated CDI cases per 1000 admissions based on reports published between 2005 and 2015 from 41 countries, most of which were from Europe and North America.10

CDI can result in substantial morbidity and mortality1,11 and is associated with prolonged length of stay (LOS) in the hospital, as well as other healthcare utilizations, including direct costs for treating the patient and indirect costs to prevent spread of the infection.11 Additionally, although antibiotic treatment of acute CDI infections is indicated, including use of metronidazole and vancomycin, continued antibiotic treatment during and after initial CDI infection can result in poor outcomes, including recurrence.1,12,13 Concurrently with the observed increase in CDI incidence rates, CDI associated mortality has risen in the past two decades.4,14 Based predominantly on Western data sets, mortality from CDI is estimated at 6.0% and is highest in older individuals.14

As available investigations of the epidemiology of CDI have focused on resource-rich settings, comparatively less is known about the burden in other regions.15 In a recent review of the epidemiology of CDI in low- and middle-income countries, the prevalence of CDI varied considerably in South America, which is likely attributed to differences in diagnostic approaches, study populations, and study design. In a systematic review and meta-analysis of CDI epidemiology in developing countries among patients with diarrhea, the prevalence of a first episode of community- and hospital-onset CDI was 19% (95% CI: 13, 27) in Latin America compared with a prevalence of 15% (95% CI: 13, 17) among all regions included in the analysis (ie, Africa/Middle East, developing countries in Asia, Latin America, and China).16

Unfortunately, little is known about CDI occurring in Latin America because of a paucity of published data.17 Available studies from Latin America have focused predominantly on CDI incidence rates,18–28 and limited data are available on risk factors associated with CDI or its consequences, such as mortality and healthcare utilization. Therefore, this hospital-based, nested case-control study assessed the risk factors and burden, including in-hospital mortality and LOS, associated with nosocomial CDI in four countries in Latin America.

This hospital-based, case-control assessment conducted in Argentina, Brazil, Chile, and Mexico identified antibiotic exposure, existing medical conditions, and recent hospital admission as major risk factors for healthcare-associated CDI. These risk factors are consistent with those identified in Western and Latin American populations as described in this discussion.

Antibiotic exposure is thought to increase the risk of CDI via alterations of the normal intestinal flora, leading to overgrowth or new infection of C. difficile species.3 This risk is greatest at the start of antibiotic initiation but can persist for several months after discontinuation of the antimicrobial agent. Antibiotic exposure was identified as a major risk factor for healthcare-associated CDI in the current study, with use of ≥3 antibiotics and ≥15-day duration of antibiotic treatment having the strongest associations with CDI occurrence. These findings are comparable to those from Western and Latin American data sets. For instance, a US retrospective cohort study found that this risk appears to increase with a greater cumulative number of doses, number of antibiotics used, and duration of antimicrobial therapy; these factors were postulated by the authors to increase depletion of the normal gut flora, conferring greater risk of CDI development.31 Additionally, in a case-control study conducted at a tertiary hospital in Mexico, previous antibiotic use was more frequent (95.9% vs 79.9%; p < 0.001) and the number of antibiotics used was higher (3 vs 2; p < 0.001) in cases versus controls, respectively.32 Similarly, another case-control study conducted at a tertiary care hospital in Mexico found that prior antibiotic exposure was the most significant risk factor associated with CDI.33 A systematic review of studies in Brazil from 1988 to 2018 also concluded that the major risk factors for CDI were the number of previous antibiotics and duration of therapy.34

Use of high-risk antibiotics (clindamycin, carbapenem, fluoroquinolone, or any cephalosporin) also showed a strong association with CDI in this study. These findings are comparable to those from Western and Latin American data sets. In a US study, receipt of certain antibiotics, including cephalosporins and fluoroquinolones, resulted in greater risk of developing CDI.31 Additionally, multivariate analyses of a prospective cross-sectional study of three tertiary care hospitals in Colombia found exposure to third-generation cephalosporins to be a significant risk factor for CDI.35 In a prospective surveillance study of hospitals in Argentina and Mexico, several antibiotics were used significantly more among laboratory-confirmed cases of CDI compared with patients without CDI, including clindamycin and carbapenem.28 Similarly, hospital-based studies from Brazil and Mexico found a significant association with development of CDI and carbapenem use.32,36 Conversely, a study of eight university hospitals in Brazil found exposure to fluoroquinolones to be the only variable associated with development of CDI, whereas carbapenem exposure was not significantly associated.37

Patients with more comorbid conditions and with specific comorbidities are more susceptible to CDI.3 For instance, pre-existing inflammatory bowel disease is associated with increased incidence and severity of CDI.38 Other comorbidities demonstrably associated with CDI include chronic liver and kidney disease.3 In the current study, a CCI > 3, indicative of a greater number of comorbidities, was one of the factors most strongly associated with CDI occurrence. Additionally, multivariate analyses found substantially increased odds of developing CDI in patients with comorbid dementia or moderate/severe renal disease compared with patients who did not have these pre-existing conditions. Consistent with these findings, a hospital-based study in Brazil found that comorbidity severity, as measured by CCI at the time of hospital admission, was a strong independent predictor of CDI-associated diarrhea.36 Similarly, a US retrospective cohort study of healthcare-associated CDI found that patients with a greater number of comorbidities had a greater risk of CDI, even after controlling for potentially confounding variables, including antibiotic therapy and age.39 In a case-control study conducted at a tertiary care hospital in Mexico, patients with chronic kidney disease were the largest proportion of hospitalized patients with CDI.33

The current study found that the risk of developing CDI in patients with a recent hospitalization (within three months of current hospitalization) was more than two-fold higher compared to patients who had not been recently discharged from a hospital. This higher risk may reflect that patients with a recent hospitalization were sicker and with more comorbidities, thus more susceptible to CDI. Another factor for the increased risk in healthcare settings is associated with the more likely prevalence of C. difficile spores in locations such as hospitals and long-term care facilities.3 For instance, in a study of a tertiary hospital in Mexico, referral from another hospital resulted in a significant adjusted OR of 1.99 for development of hospital-onset, healthcare facility―associated CDI.32

Advanced age is a reported risk factor for CDI development and CDI-associated death, with the risk of developing CDI estimated to increase by 2% per year after 65 years of age.3,7 The reported high burden of CDI in older populations is multifactorial, with physiologic changes associated with ageing that may predispose elderly individuals to CDI (eg, immunosenescence and intestinal flora changes), frequent interaction with healthcare systems, increased use of antibiotics, and higher likelihood of comorbid conditions thought to be contributing factors.3,10 However, because no difference between the ages of cases and controls was observed in the current study, age as a risk factor for CDI could not be shown. Based on the preponderance of data from Western settings, future study of age-related effects on CDI risk in Latin America is warranted.

Our study found a considerable burden of disease in the study population; CDI was associated with increased in-hospital risk of death and longer LOS. Specifically, patients with CDI had a risk of dying in the hospital more than three-fold higher and an increased overall LOS of 14.5 days compared with patients without CDI. These findings are consistent with those in the existing literature showing that CDI can cause substantial morbidity and mortality, including within Latin America.1,11,27,32,40 For instance, in a hospital study from Colombia, the mortality rate from CDI was 13%.40 In a study of four Mexican hospitals, patients with a CDI diagnosis had a mortality rate of 9.0% and increased LOS of 15 days.27 Similarly, in a tertiary hospital in Mexico, LOS was 15 days longer in patients with CDI versus controls (25 vs 10 days, respectively; p < 0.001).32

The findings from this study indicate that CDI management in Latin America is complex, and unfavorable outcomes are frequent. All patients with CDI were treated with metronidazole, alone or combined with vancomycin, the most common antibiotic regimens. Although the majority of patients were cured of their infection, 16% experienced either treatment failure or recurrence during the same hospitalization. Consistent with this study, a publication of data from four Mexican hospitals found that 48% of patients with CDI were initially treated with vancomycin combined with metronidazole and 35% with metronidazole alone.40 Available guidance from Latin America recommends the use of vancomycin, with metronidazole considered as an alternative therapy.41–43 Notably, the choice of therapy varies by recommending body according to severity of CDI and availability of the various antimicrobials. The current study also showed that metronidazole was used more often among patients with less severe CDI; more severe cases tended to be treated with vancomycin alone or in combination with metronidazole. It is possible that the severity of CDI was more associated with treatment failure than attributed to the specific antibiotic regimen used. However, because the study was not powered to assess associations between type of antibiotic therapy and outcomes, it is not possible to determine the effect the common use of metronidazole-based regimens had on patient outcomes.

The strengths of this study are the relatively large sample size and that, to the best of our knowledge, it is one of the few studies from Latin America assessing risk factors associated with nosocomial CDI or consequences of CDI, such as mortality. In addition, cases and controls were selected from the same population with a risk-set sampling approach applied for matching, thereby minimizing the risk of bias.

This study was limited by the use of hospital databases and medical records, where the clinical aspects might not be fully captured and thus may introduce bias, and incompleteness of data capture could vary between countries and study centers. The study was also limited by the availability of data in medical records (eg, lack of follow-up data on readmission at other healthcare facilities), which may have caused the estimation of CDI recurrence to be biased. The use of hospital databases and medical records also precluded assessment of some outcomes of interest, such as the prevalence of antibiotic resistance by treatment received and type of ribotype circulating. Additionally, because the study was only conducted in four Latin American countries, generalizability to other countries in the region may be limited because of differences in diagnostic and treatment practices. For instance, testing for anaerobic pathogens, such as C. difficile, is not routine in many laboratories in Latin America.17 Accordingly, because underdiagnosis of CDI is problematic in Latin America, misclassification of cases might occur. However, this was addressed in the study in that patients with diarrhea were excluded from the control group, thereby avoiding misclassification.

In conclusion, this study found that antibiotic exposure, existing medical conditions, and recent hospital admission were major risk factors for healthcare-associated CDI in select countries in Latin America. Because of the limited data available on CDI epidemiology and risk factors within this region, these findings further emphasize the importance of improved surveillance to better characterize and understand the burden of CDI in Latin America. Such information is critical to identify and implement effective prevention and infection control measures.

H Yu and D Curcio are employees of Pfizer Inc and hold stocks and stock options. N Flaster and A Casanello have no competing interests to declare.