CLINICAL SOLVING PROBLEM Clostridium difficile in the ICU The Struggle Continues Vladimir Krajinovic, MD, PhD

History and clinical exam 68-year old female patient was transferred to our hospital for infectious disease due to fever of 39 °C, diarrhea and abdominal pain Previously, she was treated on the psychiatric ward because of chronic psychosis for one month There she acquired UTI with E. coli and was treated with cefuroxim for 14 days Past medical history: arterial hypertension, hyperlipoproteinaemia, anemia On admission, she was hypotensive 90/50, adynamic, moderately dehydrated, with diffuse abdominal pain, tenderness upon palpation, slightly reduced bowel sounds Differential diagnoses: infectious colitis (bacteria, viruses, parasites) sepsis postantimicrobial colitis (C. difficile) – CD noninfectious diarrhea All of the above

Acute diarrhea The initial evaluation of patients who present to medical care with acute diarrhea should include a careful history to determine the duration of symptoms, the frequency and characteristics of the stool, and associated symptoms. Additionally, there should be an attempt to elicit evidence of dehydration (eg, dark yellow or scant urine, decreased skin turgor, orthostatic hypotension). Questioning about potential exposures, such as food history, residence, occupational exposure, recent and remote travel, previous antimicrobial treatment, can also provide further diagnostic clues. Most cases of acute diarrhea in adults are of infectious etiology, and most cases resolve with symptomatic treatment alone. When clinicians care for adults with diarrhea, two important decision points are when to perform stool testing and whether to initiate empiric antimicrobial therapy.

INITIAL EVALUATION What lab and microbiological tests should be performed initially: a) CBC and C- reactive protein b) blood cultures c) stool analysis for viruses, bacteria and CD toxin d) stool ova and parasites (O&P) test e) a+b+c

Correct answer: In initial lab and microbiology evaluation should be performed: a) CBC and C- reactive protein b) bloodcultures c) stool analysis for viruses, bacteria and CD toxin d) stool ova and parasites (O&P) test e) a+b+c

Lab tests and microbology findings L 42.91 x 109, with 89% neutrophils . E 3.69, Hb 109, Trc 199 BUN 19.8 mmol/L, creatinin 246 mcmol/L C-reactive protein 202.4 mg/dL albumins 20 g/L lactate 2.4 mmol/L. Stool: C. difficile toxin A positive. The drug of choice: a) metronidazole po b) vancomycin po c) vancomycin iv d) ceftriaxone iv e) vancomycin po + metronidazole iv

Correct answer: The drug of choice for treatment: a) metronidazole po b) vancomycin po c) vancomycin iv d) ceftriaxone iv e) vancomycin po + metronidazole iv Since the patient had severe form of CD colitis (high leukocytosis, severe hypoalbuminaemia, high creatinine, hypovolemia) it is important to treat the patient with two antibiotics.

Antimicrobial treatment for severe CDI Patients with severe or fulminant CDI may have delayed passage of oral antibiotics from the stomach to the colon; these individuals may benefit from the addition of intravenous metronidazole. Fecal metronidazole concentrations in the therapeutic range can be achieved with this regimen because of biliary and intestinal excretion of the drug. However, it is uncertain whether intravenous metronidazole alone is effective as oral vancomycin or oral fidaxomicin therapy, so oral therapy should be administered together with intravenous therapy whenever feasible. Intravenous vancomycin has no effect on C. difficile colitis since vancomycin is not excreted into the colon.

PATIENT MENAGEMENT Your next diagnostic step: a) abdominal ultrasound Despite proper antimicrobial and supportive treatment the patient was still hypotensive and oliguric, and transferred to ICU where she was treated with antibiotics, vasopressors, albumins and other supportive care. In the ICU, diarrhea continued, abdominal distension appeared with reduced bowel sounds. The patient became anuric and CVVHD was started. Your next diagnostic step: a) abdominal ultrasound b) abdominal MRI c) repeat stool culture d) abdominal CT scan e) nothing of the above

Correct answer: Radiographic imaging of the abdomen and pelvis is warranted for patients with clinical manifestations of severe disease (severe abdominal pain, abdominal distention with apparent ileus, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and/or marked leukocytosis) or fulminant colitis (characterized by hypotension or ileus) to evaluate for presence of toxic megacolon, bowel perforation, or other findings warranting surgical intervention. Computed tomography (CT) of the abdomen and pelvis with oral and intravenous contrast is the preferred imaging modality. Your next diagnostic step: a) abdominal ultrasound b) abdominal MRI c) repeat stool culture d) abdominal CT scan e) nothing above

Toxic megacolon images Abdominal CT scan Abdominal X-ray www. radiopaedia.org

PATIENT MENAGEMENT Your next step: Abdomen CT scan showed the colonic dilatation (> 10 cm in diameter) with air-fluid levels, without free air in the abdomen. Lab test showed persistent leukocytosis with high lactate (4.5 mmol/L) Your next step: a) change antibiotic treatment b) consult abdominal surgeon c) colonoscopy d) nothing above e) all of the above

Correct answer: Your next step: a) change antibiotic treatment b) consult abdominal surgery c) colonoscopy d) nothing above e) all true Some studies have used a white blood cell threshold ≥15,000 cells/microL for diagnosis of severe disease and need for surgical evaluation. In a retrospective review of a C. difficile outbreak in Canada®, colectomy was most beneficial for immunocompetent patients aged ≥65 years with a white blood cell count ≥20,000 cells/microL and/or a plasma lactate between 2.2 and 4.9 mEq/L.  ®Lamontagne F, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg. 2007

The patient died in ICU in refractory septic shock… OUTCOME The surgeon deffered operation cause patient’s severe condition and haemodynamic instability. The patient died in ICU in refractory septic shock… All cause 30 day mortality of CDI colitis appeared to be high, with 15 studies indicating a mortality of 15% or greater.* *Mitchell BG, Gardner A. Mortality and Clostridium difficile infection: a review. Antimicrob Resist Infect Control. 2012