Candidemia Subsequent to Severe Infection Due to Clostridium difficile: Is There a Link?

To the Editor—We read with great interest the article by Nerandzic et al [1] reporting pretreatment prevalence and posttreatment acquisition of Candida species stool colonization in patients who were administered antimicrobial agents for Clostridium difficile infection (CDI). We also took into account the reply letter by Manian and Bryant [2], and we agree with the conclusion that Candida species overgrowth may protect against CDI. However, the intriguing finding of Nerandzic et al, showing a 29% prevalence of patients who acquired Candida species stool colonization after oral vancomycin treatment, led us to speculate about the opposite point of view. We are carrying out an observational study on Candida bloodstream infection in patients admitted to the 1300-bed teaching hospital Policlinico “Umberto I,” in Rome. Since December 2012, we have been recording prospectively 23 consecutive cases. Among 7 infected patients of Internal Medicine wards, 4 patients, hospitalized in 3 different wards, developed at least 1 episode of candidemia after severe CDI (white blood cell count >15,000 cells/µL or a serum creatinine level ≥1.5 times the premorbid level) [3]. One of them developed Candida bloodstream infection after the first episode of CDI; the other 3 patients, after CDI relapse (Table 1). In one case, ribotyping assay was performed and the specific 027 ribotype of C. difficile, which is known to be associated with an increased frequency of therapeutic failure and poor outcome, was recognized (case 3, Table 1). This is not surprising as this 027 ribotype has been recently described in our geographic area [4]; of importance, culture of all the peripheral lines (including peripherally inserted central catheter) did not show growth of Candida, reinforcing the idea of an intestinal source of the candidemia. Characteristics of Patients With Clostridium difficile Infection and Subsequent Candida Species Bloodstream Infection PICC TPN Type 2 diabetes mellitus PICC TPN Chronic renal failure Glucocorticoids PICC TPN Chronic renal failure PICC TPN PICC TPN Type 2 diabetes mellitus PICC TPN Chronic renal failure Glucocorticoids PICC TPN Chronic renal failure PICC TPN Abbreviations: CDI, Clostridium difficile infection; HCAP, healthcare-associated pneumonia; IV, intravenous; PICC, peripherally inserted central catheter; qd, 1 time a day; qid, 4 times a day; TPN, total parenteral nutrition. a Number of days from primary CDI to first CDI relapse. b Number of days from primary CDI to the development of the first blood culture growing Candida species. Characteristics of Patients With Clostridium difficile Infection and Subsequent Candida Species Bloodstream Infection PICC TPN Type 2 diabetes mellitus PICC TPN Chronic renal failure Glucocorticoids PICC TPN Chronic renal failure PICC TPN PICC TPN Type 2 diabetes mellitus PICC TPN Chronic renal failure Glucocorticoids PICC TPN Chronic renal failure PICC TPN Abbreviations: CDI, Clostridium difficile infection; HCAP, healthcare-associated pneumonia; IV, intravenous; PICC, peripherally inserted central catheter; qd, 1 time a day; qid, 4 times a day; TPN, total parenteral nutrition. a Number of days from primary CDI to first CDI relapse. b Number of days from primary CDI to the development of the first blood culture growing Candida species. Using murine models of gastrointestinal candidiasis to investigate mechanisms of invasion, Cole et al [5] demonstrated that, to have a hematogenous candidiasis, 3 conditions are necessary: colonization of gastrointestinal mucosa, alterations of the normal integrity of the mucosal epithelium, and impairment of mucosal immunity (particularly neutrophils, which play a crucial role in clearing gastrointestinal candidiasis). As a matter of fact, severe CDI is characterized by an intense host inflammatory response provoked by toxin hyperproduction [6], persisting despite the administration of appropriate antibiotic therapy [7]. Toxin production is directly involved in intestinal mucosal epithelium injury [8, 9] and exerts mucosal immunity impairment also by modification of neutrophils morphology and function [10]. CDI treatment, primarily oral vancomycin, may favor Candida species stool colonization [1]. Therefore, severe CDI and specific antibiotic treatment could predispose patients to develop Candida bloodstream infections. There are 2 important limitations in our observations: first, possible Candida colonization preceding CDI was not assessed in our patients; second, several other risk factors for candidemia were simultaneously present (Table 1). In conclusion, in patients who were administered specific treatment for primary severe or relapsing CDI, it is possible to hypothesize an increased risk of candidemia. To the best of our knowledge, this is the first report of a putative link between CDI and Candida species bloodstream infections. Further studies are needed to confirm this assumption. Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.