Early diagnosis of monomicrobial Clostridioides difficile bacteremia in a patient without colitis

Abstract

Bacteremia is a rare finding among Clostridioides difficile infections. We describe a case of a 67-year-old man with resected colorectal cancer with colostomy who presented with small bowel obstruction and was admitted for lysis of adhesions. On day 8 of admission, he developed leukocytosis and raised inflammatory markers with isolation of Gram-positive bacilli in several blood cultures, which was presumptively identified through blood culture pelleting and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) as C. difficile. The diagnosis was confirmed with conventional culture and reference lab identification and the patient demonstrated clinical response with parenteral then oral vancomycin that briefly worsened when therapy was switched to parenteral metronidazole and then improved once oral vancomycin was resumed. Our case was notable in that the combination of pelleting and MALDI-TOF offered early diagnosis in this patient whose positive blood cultures were suspicious for contamination and in whom there was an absence of diarrheal illness or features of colitis on abdominal imaging. Early diagnosis is critical for the timely initiation of therapy, implementation of infection prevention and control measures and in selection of appropriate therapy for antimicrobial stewardship.

Case Presentation

A 67-year-old man with a history of resected sigmoid adenocarcinoma with end colostomy, alcohol use disorder with cirrhosis, moderate dementia and Parkinson's disease presented with small bowel obstruction and acute kidney injury (AKI) secondary to rhabdomyolysis from crush injury to the arm after becoming hooked to a commode handle for greater than 16 hours. On admission, he was afebrile, had mild leukocytosis of 14 × 10⁹/L (normal 4.5-10.5 × 10⁹/L) and was not on any medications. Admission blood cultures were positive for Enterococcus casseliflavus and coagulase-negative staphylococcus. Abdominal computed tomography (CT) scan revealed a proximal high small intestine obstruction. He received perioperative cefazolin prophylaxis and the small bowel was resected with a primary anastomosis and lysis of adhesions on the first day of admission. Repeat blood cultures were negative and the enterococcus was susceptible to ampicillin, E. casseliflavus was presumed to be reflective of a transient bacteremia secondary to the intra-abdominal infection. He was empirically treated with 1 g IV ceftriaxone daily and 500 mg IV metronidazole every 12 hours rather than piperacillin-tazobactam due to AKI. On the eighth day of admission, he developed marked leukocytosis (32 × 10⁹/L) and elevation of both C-reactive protein (81.2 mg/L; normal < 3 mg/L) and procalcitonin (0.65 μg/L; normal ≤ 0.50 μg/L). He was afebrile (37.1° C) and blood cultures grew Gram-positive bacilli (GPB) in multiple bottles. CT abdomen demonstrated ileus with no signs of colitis or abscess.

Diagnosis

Blood culture pelleting (lysis-centrifugation of an aliquot of positive blood culture fluid from BD BACTEC FX) was performed (1) and was identified via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Bruker MALDI-TOF MS) as Clostridioides difficile (C. difficile, formerly Clostridium difficile, score 2.15) which was confirmed by a reference lab and consistent with subsequent features in conventional culture: non-hemolytic, large fried egg colonies with a strong, characteristic odour were observed from only the anaerobic plates. The isolate was susceptible to metronidazole, piperacillin-tazobactam and meropenem and resistant to cefoxitin. Liquid stool collected from colostomy five days later also tested positive for C. difficile with glutamate dehydrogenase and toxin A/B detected (C. DIFF QUIK CHEK COMPLETE, TechLab). The patient did not have prior history of C. difficile infection or colonization.

Discussion

C. difficile infection (CDI) most commonly presents as an antibiotic-associated enteritis that ranges in severity from benign self-limiting diarrhea to toxic megacolon and death. Extra-intestinal CDI is rare, making up 0.17% of CDIs in a 10-year single-center Finnish study (2/31 cases with a single monomicrobial case (2)) and the least frequent manifestation is bacteremia which has been reported in 0.01% of CDI (3), with 137 cases of bacteremia reported in literature (4). In Ontario, 30 cases from sterile sources were reported between 2012-2017 (5). These are likely underestimated due to the challenges associated with extra-intestinal C. difficile isolation which can vary greatly depending on specimen type, presence of other microbes and recovery method.

In this case, the preliminary finding of GPB in blood culture was regarded as a possible contaminant, as diphtheroid bacilli like corynebacteria are part of commensal skin flora. Fortunately, with the practice of pelleting blood culture bottles and preliminary identification using MALDI-TOF MS, the lab was able to provide an earlier diagnosis of CDI, described in literature as an average of 12 hours faster than conventional subculture (6). Earlier diagnosis of CDI for our patient may have led to numerous significant clinical implications; timely initiation of therapy (with downstream effects in improving patient outcome, decreasing length of stay and improving patient flow), initiation of infection prevention and control precautions to minimize the spread of C. difficile in the intensive care unit, and antibiotic stewardship in narrowing therapy.

The patient experienced a fluctuating clinical course. Initially, there was clinical response to combination therapy with intravenous (IV) vancomycin 1 gram every 12 hours, oral vancomycin 500 mg every 6 hours and IV piperacillin-tazobactam 3.375 grams every 8 hours (Figure 1). However, the patient's condition worsened with increased abdominal pain and increasing leukocytosis (Figure 1) upon transfer to the ward when therapy was switched from IV vancomycin to IV metronidazole 500 mg every 8 hours (Figure 1). The patient improved clinically with combination therapy (IV metronidazole and oral vancomycin) and leukocytosis decreased (13 × 10⁹/L) after several days and the patient continued this regimen to complete a 14-day course. The isolate demonstrated susceptibility to metronidazole and vancomycin susceptibility was not reported. Oral fidaxomicin was not utilized in consideration of the cost and improvement on combination therapy with metronidazole and vancomycin. C. difficile bacteremia is too uncommon and heterogenous an entity to ascertain whether outcomes are improved with treatment with IV metronidazole or vancomycin monotherapy or combination therapy (7). Pulse field gel electrophoresis was performed and revealed the patient's C. difficile as toxigenic (toxin A/B/binary toxin gene positive) B1/NAP1/027 ribotype (NAP1). NAP1 is a well-described epidemic strain in Canada that has been decreasing in prevalence in recent years but continues to be regarded with caution as it is known to cause more severe disease, has greater resistance to antibiotics and is more likely to relapse compared to other ribotypes (8). In this case, there was no recurrence one month following the completion of therapy.

Figure 1:

Timeline of antibiotic therapy and trend of white blood cell (WBC) count and C-reactive protein (CRP) with clinical worsening Oct 20-22 2021

Numerous risk factors were present in this case; a history of intestinal malignancy with end colostomy, alcohol misuse and cirrhosis, recent exposure to broad-spectrum antibiotics and recent intestinal surgery. In a 10-year single-center study of extra-intestinal CDI, intestinal surgery, abscess or perforation was associated with 14/31 (45%) likely due to direct spread from the intestine and 9/31 (29%) patients had an alcohol use disorder, which is theorized to be linked to intestinal dysbiosis resembling that of patients who are colonized with C. difficile (2). In another review, 7/60 (12%) of patients with C. difficile bacteremia were observed to have liver cirrhosis (4), which is plausible considering that patients with cirrhosis possess independent risk factors for C. difficile infection; they are frequently hospitalized, are regularly exposed to antibiotics and proton pump inhibitors and have impaired immune function.

There has been a decreasing rate of hospital-associated CDI reported in Canada from 2016-2020 while community-acquired CDI rates have decreased in Eastern and Central Canada and have remained steady in the Western regions (9). Employing rapid identification strategies like pelleting or early subculture with MALDI-TOF MS can expedite rapid identification of positive blood cultures (5) and many clinical microbiology labs have adopted these strategies to accelerate the time to pathogen identification.

In summary, our case features multiple interesting teaching points: the rare entity of C. difficile bacteremia, the early diagnosis provided by blood culture pelleting and MALDI-TOF, and the potential positive downstream effects of rapid diagnostic methods on improved patient care and flow, initiation of optimized therapy and appropriate IPAC precautions to help prevent outbreaks.

Acknowledgements:

The authors would like to thank the following individuals for their contributions to the manuscript: the patient for their unique case and consent to contributing to the scientific community, clinical pharmacists Abdulhadi Abdulhadi and Michael Wan for their aid in providing antibiotic history, and the laboratory assistants and medical technologists in the microbiology laboratory for their stellar efforts during and beyond the COVID-19 pandemic.

Funding Statement

Funding: No funding was received for this work.

Contributors:

Conceptualization, J Tat, GJ German; Methodology, J Tat, S Krajden, GJ German; Formal Analysis, J Tat, S Krajden, GJ German; Investigation, J Tat, S Krajden, GJ German; Resources, S Patel, GJ German; Supervision, GJ German; Data Curation, J Tat, GJ German, S Patel; Writing – Original Draft, J Tat, GJ German; Writing – Review & Editing, J Tat, S Krajden, GJ German; Visualization, GJ German; Project Administration, GJ German.

Ethics Approval:

All research meets the ethical guidelines, including adherence to the legal requirements of the study country.

Informed Consent:

Informed consent was obtained.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

All data will not be made publicly available. Researchers who require access to the study data can contact the corresponding author for further information.

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A