Antibiotics Associated With Clostridium difficile Infection

Introduction Clostridium difficile (C. difficile) is one of the major causes of diarrhea transmitted by the fecal-oral route. C. difficile type BI/NAP1/027 is responsible for the most severe C. difficile infection (CDI). It is a major cause of antibiotic-associated diarrhea followed by Clostridium perfringens, Staphylococcus aureus,and Klebsiella oxytoca. Historically, clindamycin, cephalosporins, penicillins, and fluoroquinolones were related to CDI. We conducted this study to evaluate the antibiotics associated with CDI in recent times. Methods We conducted a retrospective, single-center study over a period of eight years. A total of 58 patients were enrolled in the study. Patients with diarrhea and positive C. difficile toxin in stool were evaluated for antibiotics given, age, presence of malignancy, previous hospital stay for more than three days in the last three months, and any comorbidities. Results Among patients who developed CDI, prior antibiotics for at least four days duration were given in 93% (54/58) of patients. The most common antibiotics associated with C. difficile infection were piperacillin/tazobactam in 77.60% (45/58), meropenem in 27.60% (16/58), vancomycin in 20.70% (12/58), ciprofloxacin in 17.20% (10/58), ceftriaxone in 16% (9/58), and levofloxacin in 14% (8/58) of patients, respectively. Seven percent (7%) of patients with CDI did not receive any prior antibiotics. Solid organ malignancy was present in 67.20% and hematological malignancy in 27.60% of CDI patients. Ninety-eight percent (98%, 57/58) of patients treated with proton pump inhibitors, 93% of patients with a previous hospital stay for more than three days, 24% of patients with neutropenia, 20.1% of patients aged more than 65 years, 14% of patients with diabetes mellitus, and 12% of patients with chronic kidney disease also developed C. difficile infection. Conclusion The antibiotics associated with C. difficile infection are piperacillin/tazobactam, meropenem, vancomycin, ciprofloxacin, ceftriaxone, and levofloxacin. Other risk factors for CDI are proton pump inhibitor use, prior hospital admission, solid organ malignancy, neutropenia, diabetes mellitus (DM), and chronic kidney disease (CKD).


Introduction
Clostridioides difficile was previously known as Clostridium difficile (C. difficile). It is one of the major causes of diarrhea in the Western world [1] and is a Gram-positive, anaerobic, toxin-producing bacteria whose spores are transmitted by the fecal-oral route. The main protective barrier against C. difficile infection (CDI) is the normal indigenous intestinal microflora [2][3][4]. Bile acids play an important role in spore germination [4]. Virulence factors are enzymes including collagenase, hyaluronidase, chondroitin-sulfatase, and two types of toxins, A and B, causing intestinal damage [3,5]. C. difficile type BI/NAP1/027 is resistant to fluoroquinolones and causes the most severe CDI [6,7].
Bacteria other than C difficile that cause antibiotic-associated diarrhea are Clostridium perfringens, Staphylococcus aureus, and Klebsiella oxytoca [17].
Limited data are available regarding CDI in Asia. Recently rates of CDI in Asia are becoming equal to Europe and North America [18].
We conducted this study to evaluate recent antibiotics associated with a C. difficile infection in Pakistan.

Materials And Methods
We conducted a retrospective, single-center study at Shaukat Khanum Memorial Cancer Hospital and Research Center (SKMCH&RC), which is a tertiary care cancer center in Lahore, Pakistan. We included patients over a period of eight years from January 1, 2015, to September 30, 2022, and reviewed their medical records. This study was approved by the Institutional Review Board at SKMCH&RC with a waiver of informed consent. We included all patients (all ages and both inpatients and outpatients) with diarrhea and positive C. difficile toxin in stool, detected via nucleic acid amplification using a real-time polymerase chain reaction (PCR) assay (the GeneXpert technique). We evaluated patients regarding antibiotics given for at least four days [15] in the last three months and features of severe infection or not [19]. We also evaluated patients for other characteristics, including age, type of malignancy, presence of neutropenia, previous hospital stay for more than three days in the last three months, and any comorbidities. Frequencies and proportions were reported for categorical variables. Mean and standard deviation was reported for continuous variables.

Results
A total of 58 patients were evaluated in the study, further supporting the rarity of C. difficile infection in the Asian subcontinent [20].  Prior antibiotics for at least four days duration in the last three months were given in 93% (54/58) of patients. The most common antibiotics given in patients with C. difficile infection were piperacillin/tazobactam given in 77.60% (45/58), followed by meropenem given in 27.60% (16/58), vancomycin given in 20.70% (12/58), ciprofloxacin given in 17.20% (10/58), ceftriaxone given in 16% (9/58) and levofloxacin given in 14% (8/58) of patients respectively. These antibiotics were given in recommended standard doses and adjusted for renal or hepatic failure if present. Results are summarized in Table 2.

Discussion
The results of our study showed that the most common antibiotics associated with C. difficile infection were piperacillin/tazobactam, meropenem, vancomycin, ciprofloxacin, ceftriaxone, and levofloxacin. Seven percent (7%, 4/58) of patients with CDI did not receive any prior antibiotics. Males were affected more than females and adults were affected more than children. Most CDI occurred in patients with solid organ tumors and neutropenia (14%, 14/58). The use of proton pump inhibitors and prior hospital admission was the most common risk factors for CDI, other than antibiotics exposure.
The major strengths of our study are its duration and the highlighting of a complex issue often neglected in complicated hospitalized patients in Pakistan.
As our study population consisted of complicated cancer patients on treatment as well as other complications, the risk of CDI was increased not only because of antibiotics use but also because of malignancy, age, comorbidities, and surgery, thus confounding the culprit antibiotics. The major weakness of our study is its retrospective single-center design with a relatively small sample size. We recommend multicenter retrospective or prospective cohort studies for further research purposes.

Conclusions
The most common antibiotics associated with C. difficile infection are piperacillin/tazobactam, meropenem, vancomycin, ciprofloxacin, ceftriaxone, and levofloxacin. Few patients with CDI did not receive any prior antibiotics but had other risk factors of proton pump inhibitor use, prior hospital admission, solid organ malignancy, neutropenia, DM, and CKD. If patients with these risk factors develop diarrhea, they should be evaluated for CDI.