Sandbox Yaz

Resident Survival Guide

C. difficile Infection Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Guillermo Rodriguez Nava, M.D. [2]; Yazan Daaboul, M.D.

Overview

Treatment is generally recommended for average-risk patients who are symptomatic with positive lab findings for C. difficile infection. For patients with C. difficile risk factors, empiric therapy is recommended for symptomatic patients regardless of lab findings. Antimicrobial therapy is tailored acccording to the clinical severity of the infection. Administration of oral metronidazole is recommended for patients with mild symptoms, whereas oral vancomycin is recommended for severe disease.

Indications for Treatment

Symptomatic vs. Asymptomatic Individuals

• Treatment is recommended only for average-risk, symptomatic patients (usually diarrhea) with positive lab findings (either ELISA or PCR) of C. difficile infection

• In contrast, treatment is not recommended for average-risk, asymptomatic individuals OR patients with diarrhea and negative lab findings (either ELISA or PCR).

Average Risk vs. High Risk Patients

• The negative predictive values of the diagnostic lab tests (either ELISA or PCR) are sufficiently high > 95% for patients among patients with average risk of developing C. difficile infection. Accordingly, empiric therapy is not recommended if diagnostic lab tests yield negative findings among average-risk patients.

• In contrast the negative predictive values of the diagnostic lab tests (either ELISA or PCR) are NOT sufficiently high for patients at high risk of C. difficile infection. Accordingly, empiric therapy is recommended for high risk patients with high pre-test probability even when lab findings yield negative results. Common risk factors for the development of C. difficile infection are history of antibiotic administration within the past 12 weeks, advanced age > 65 years, immunodeficiency, exposure to healthcare facilities, or inflammatory bowel disease.

For more detailed list of C. difficile risk factors, click here

Principles of Antimicrobial Therapy for Clostridium difficile infection

According to the 2013 practice guidelines for the diagnosis, treatment, and prevention of C. difficile infections, the choice of antimicrobial therapy is based on the severity of the clinical disease. Shown below is a table that defines the severity of C. difficile infection based on clinical features and lab findings:

▸ Click on the following categories to expand treatment regimens.

Initial episode   ▸  Mild to moderate   ▸  Severe   ▸  Severe complicated Recurrence   ▸  First recurrence   ▸  Second recurrence

Mild to moderate Recommended treatment ▸ Metronidazole 500 mg orally q8h If no improvement in 5-7 days ▸ Vancomycin 125 mg orally q6h Severe Recommended treatment ▸ Vancomycin 125 mg orally q6h Severe complicated Recommended treatment† ▸ Vancomycin 500 mg orally q6h PLUS ▸ Metronidazole 500 mg IV q8h † If ileus present, add Vancomycin 500 mg in 100 mL normal saline per rectum q6h as retention enema. First recurrence Recommended treatment ▸ Same as first episode but stratified by severity Second recurrence Recommended treatment ▸ Vancomycin in tapered and pulsed doses 125 mg 4 times daily for 14 days 125 mg 2 times daily for 7 days 125 mg once daily for 7 days 125 mg once every 2 days for 8 days (4 doses) 125 mg once every 3 days for 15 days (5 doses)

Duration of antimicrobial therapy

• Administer antimicrobial therapy for 10-14 days.
• Continue antimicrobial therapy only for 10 days if there is clinical improvement within 5 to 7 days.

Do's

• Suspend other antibiotic therapies during administration of antibiotics to treat C. difficile infection.
• Administer vancomycin for mild-to-moderate patients who are intolerant/allergic to metronidazole and for pregnant/breastfeeding women..
• Deliver supportive care to patients with severe or severe complicated CDI .
• Perform diagnostic abdominal CT scan for patients with worsening diarrhea and/or abdominal pain to rule out C. difficile-associated complications.
• Request surgical consultation and perform routine pre-surgical work-up for patients suspected to have complicated C. difficile infection. To view indications for surgical management of C. difficile infection, click here.
• Consider fecal microbiota transplant if there is a third recurrence after a pulsed vancomycin regimen.
• Consider vancomycin enema for patients whose oral antibiotic regimen cannot reach a segment of the colon, such as patients with Hartman's pouch, ileostomy, or colon diversion.
• Administer intravenous immunoglobulins for recurrent C. difficile infection only if patient has hypogammaglobulinemia.
• Manage C. difficile infection simultaneously with inflammatory bowel disease (IBD) flare-up among patients with IBD.
• Continue immunosuppressive medications for IBD patients with C. difficile infection.

Don'ts

• Do not administer metronidazole for a second recurrence episode of CDI or for long-term therapy because of the risk of neurotoxicity.

• Do not administer anti-peristaltic agents to treat diarrhea in patients with CDI.
• Do not administer intravenous immunoglobulins for recurrent C. difficile infection, except if patient has hypogammaglobulinemia.
• Do not increase dose of immunosuppressive medications for IBD patients with untreated C. difficile infection.

Novel Pharmacologic Therapies

• In 2011, fidaxomicin was FDA-approved for the treatment of C. difficile infection.
  • Fidaxomicin is a poorly absorbed, bactericidal, macrocyclic antibiotic that acts against anaerobic, gram-positive bacteria.
  • Fidaxomicin demonstrated non-inferior to vancomycin in the treatment of primary infection.
  • Fidaxomicin was associated with significantly reduced rate of recurrence compared with vancomycin (15% vs. 25%), except among patients infected with BI/NAP1/027 strain where the recurrence rate was statistically similar between both therapies.

Fecal Bacteriotherapy

• Fecal bacteriotherapy is a procedure related to probiotic research. It has been suggested as a potential cure for C. difficile infection.
• It involves infusion of bacterial flora acquired from the feces of a healthy donor in an attempt to reverse bacterial imbalance responsible for the recurring nature of the infection.

Classification

Abdominal aortic aneurysms may be classified based on the size of the aneurysm:

• Small aneurysm: Diameter < 4.0 cm
• Medium aneurysm: Diameter between 4.0 and 5.5 cm
• Large aneurysm: Diameter ≥ 5.5 cm
• Very large aneurysm: Diameter ≥ 6.0 cm

Abdominal aortic aneurysms may also be classified based on the rate of aneurysm expansion:

• Non-rapidly expanding aneurysm: Diameter increase of ≤ 0.5 cm within 6 months OR ≤ 1.0 cm within 12 months
• Rapidly expanding aneurysm: Diameter increase of > 0.5 cm within 6 months OR > 1.0 cm within 12 months

Causes

Life Threatening Causes

• Ruptured AAA
• Infected (mycotic) aneurysm
• Inflammatory AAA
• Aortovenous fistula
• Aortoenteric fistula
• Lower extremity thromboembolism

Risk Factors for Development of AAA

• Old age 50 > years
• Greater height
• Male gender
• Caucasian race
• Smoking
• History of CAD and atherosclerotic cardiovascular disease
• History of hypertension
• Dyslipidemia
• Family history of AAA
• Personal history of peripheral artery aneurysms

Risk Factors for Rapid Expansion or Rupture of AAA

• Female gender
• Advanced age > 50 years
• Smoking
• Advanced atherosclerosis
• History of prior stroke
• Hypertension
• Transplantation (cardiac or renal)
• Known reduced FEV1 (obstructive pulmonary disease)

FIRE: Focused Initial Rapid Evaluation

A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate surgical intervention. Boxes in red signify that an urgent management is needed.

Identify cardinal findings that increase the pre-test probability of abdominal aortic aneurysm (AAA) rupture and development of complications ❑ Known large AAA > 5.5 cm ❑ Known rapid AAA expansion rate > 0.5 cm/6 months OR 1.0 cm/year ❑ Known infective endocarditis (high risk for infected aneurysm) ❑ Acute abdominal/back pain that may radiate to buttocks, groin region, or lower extremities ❑ Tearing/sharp quality ❑ Increasing in intensity ❑ Pulsating abdominal mass ❑ Hypotension or shock ❑ Oliguria or anuria ❑ Muscular weakness ❑ Lower extremity numbness and/or tingling ❑ Cold extremities ❑ Peripheral cyanosis ❑ Acute limb pain ❑ Fever or sepsis ❑ Altered mental status ❑ Unexplained syncope ❑ Coma ❑ Presence of risk factors associated with rapid expansion or rupture of AAA ❑ Female gender ❑ Advanced age > 50 years ❑ Smoking ❑ Advanced atherosclerosis ❑ History of prior stroke ❑ Hypertension ❑ Transplantation (cardiac or renal) ❑ Known reduced FEV1 (obstructive pulmonary disease)

Rule out life threatening alternative diagnoses: ❑ Acute coronary syndromes (suggestive findings: Chest pain, Abdominal pain, back pain, interscapular pain, Hypotension, Dyspnea, Nausea, Cold sweats ❑ Peritonitis (suggestive findings: Abdominal pain, Abdominal guarding, Abdominal rigidity, Fever, Hypotension ❑ Bowel ischemia (suggestive findings: Abdominal pain, Vomiting, Fever, Absence of abdominal tenderness ❑ Perforated ulcer (suggestive findings: Abdominal pain, Vomiting, Hematemesis, Fever ❑ Intestinal obstruction (suggestive findings: Abdominal pain, Bilious vomiting, Abdmoninal tenderness, Fever, Abdmoninal distention ❑ Aortic dissection (suggestive findings: back pain, interscapular pain, aortic regurgitation, pulsus paradoxus, blood pressure discrepancy between the arms) ❑ Pulmonary embolism (suggestive findings: acute onset of dyspnea, tachypnea, hemoptysis, previous DVT) ❑ Cardiac tamponade (suggestive findings: hypotension, jugular venous distention, muffled heart sounds, pulsus paradoxus) ❑ Tension pneumothorax (suggestive findings: sudden dyspnea, tachycardia, chest trauma, unilateral absence of breath sound) ❑ Esophageal rupture (suggestive findings: vomiting, subcutaneous emphysema)

Stabilize and resuscitate the patient ❑ Attend to the patient's ABCs (Airway, Breathing, Circulation) ❑ Consider endotracheal intubation if the patient's airway is compromised, has a Glasgow coma scale (GCS < 8) or profound hemodynamic instability ❑ Administer oxygen and maintain a saturation >90% ❑ Secure 2 large-bore intravenous (IV) lines ❑ Administer fluids to reach a target systolic blood pressure (SBP) of 70 to 100 mm Hg. Excessive fluid administration in AAA is associated with worse outcomes ❑ Do NOT routinely administer vasopressors if patient is hypotensive at presentation. Vasopressor administration in AAA is controversial. Consider ANY of the following vasopressors only if patient remains hypotensive despite fluids ❑ Norepinephrine 0.05 microgram/kg/minute IV; titrate by 0.02 microgram/kg/minute every 5 minutes, OR ❑ Phenylephrine 100-180 microgram/minute; titrate by 25 microgram/minute every 10 minutes, OR ❑ Dopamine 5 microgram/kg/minute; titrate by 5 microgram/kg/minute every 10 minutes ❑ Obtain 12 lead ECG and place the patient on a cardiac monitor ❑ Place an indwelling urethral catheter and monitor urine output ❑ Frequently assess mental status and check for focal neurologic deficits ❑ Type and crossmatch 6 to 10 units of PRBC. FFP may also be needed in cases of massive transfusion ❑ Do not administer pre-op transfusions except if patient is unconscious or has signs or myocardial infarction ❑ Withdraw blood for CBC, electrolytes, BUN, serum creatinine, LFTS, PT, PTT, troponin I, CK, CK-MB, CRP or ESR, and multiple blood cultures Pain management ❑ Assess pain severity (self-report NRS scale 0 to 10; unconscious BPS 3-12 or CPOT 0-8). Pain considered significant if NRS≥4, BPS<5, or CPOT≥3 ❑ Administer IV opioids: Morphine 4-10 mg IV every 4 hours, infused over 4-5 minutes (dose range: 5-15 mg) ❑ Consider pre-op epidural catheter if patient meets ALL of the following criteria ❑ Patient hemodynamically stable, AND ❑ Contained leak, AND ❑ Satisfactory coagulation profile ❑ Maintain patient in a conscious state ❑ Monitor any significant undesired drop in blood pressure as pain medications are administered

Patient hemodynamically unstable despite resuscitation? ❑ Hypotension (SBP < 90 mm Hg) despite resuscitation ❑ Tachycardia (HR > 100 bpm) despite resuscitation

Yes. Patient is still hemodynamically unstable despite resuscitation.

No. Patient is hemodynamically stable following resuscitation

Is the patient known to have an AAA?

Can patient have CT scan with contrast?

Yes

No

Yes

No

❑ Proceed to operating room without further work-up

❑ Obtain focused bedside ultrasound

❑ Obtain CT scan with IV contrast of abdominal aorta and iliac arteries

❑ Obtain CT scan without IV contrast of abdominal aorta and iliac arteries

AAA confirmed on imaging?

Yes

No

Consider alternative diagnoses

Evaluate need for further management of the following AAA complications For patients suspected to have thromboembolism ❑ Obtain Duplex ultrasound of affected extremities ❑ Consider CT scan of aorta from aortic valves to iliac bifurcation For patients suspected to have infected (mycotic) aneurysm ❑ Consider gallium scanning or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate disease activity For patients suspected to have aortovenous fistula ❑ Obtain CT angiography For patients suspected to have aortoenteric fistula ❑ Perform EGD to rule out other possible etiologies of GI bleed among hemodynamically stable patients ❑ Obtain CT scan with IV contrast of the abdomen and iliac arteries ❑ Consider arteriography

Administer antimicrobial therapy Once diagnosis of complicated AAA is confirmed, all patients require blood cultures and empirical antibiotic therapy for gram-positive and gram-negative coverage (even if afebrile at presentation) ❑ Withdraw multiple sets of blood culture (if blood cultures were not withdrawn initially) ❑ Administer empiric combination antibiotic therapy ❑ Vancomycin 1-1.5g IV every 12 hours PLUS only one of the following: ❑ Ceftriaxone 2 g IV every 12 hours, OR ❑ Cefuroxime 1.5 g IV every 4 hours, OR ❑ Piperacillin-tazobactam

Proceed to further management

Treatment

Shown below is an algorithm summarizing the management of abdominal aortic aneurysm.

Confirmed AAA

Symptoms present?

No

Yes

❑ Perform imaging using ANY of the following imaging modalities for the abdominal aorta and iliac arteries: ❑ Ultrasound ❑ CT Scan ❑ MRI

Hemodynamically stable?

Adequate imaging?

No

Yes

Stabilize and resuscitate the patient ❑ Attend to the patient's ABCs (Airway, Breathing, Circulation) ❑ Consider endotracheal intubation if the patient's airway is compromised, has a Glasgow coma scale (GCS < 8) or profound hemodynamic instability ❑ Administer oxygen and maintain a saturation >90% ❑ Secure 2 large-bore intravenous (IV) lines ❑ Administer fluids to reach a target systolic blood pressure (SBP) of 70 to 100 mm Hg. Excessive fluid administration in AAA is associated with worse outcomes ❑ Do NOT routinely administer vasopressors if patient is hypotensive at presentation. Vasopressor administration in AAA is controversial. Consider ANY of the following vasopressors only if patient remains hypotensive despite fluids ❑ Norepinephrine 0.05 microgram/kg/minute IV; titrate by 0.02 microgram/kg/minute every 5 minutes, OR ❑ Phenylephrine 100-180 microgram/minute; titrate by 25 microgram/minute every 10 minutes, OR ❑ Dopamine 5 microgram/kg/minute; titrate by 5 microgram/kg/minute every 10 minutes ❑ Place an indwelling urethral catheter and monitor urine output ❑ Frequently assess mental status and check for focal neurologic deficits

No

Yes

Repeat imaging

AAA meets AT LEAST ONE of the following criteria for surgical or endovascular intervention? ❑ AAA > 5.5 cm, OR ❑ Rapidly expanding AAA, OR ❑ AAA plus peripheral arterial aneurysm or peripheral artery disease

Perform pre-operative work-up ❑ Obtain 12 lead ECG and place the patient on a cardiac monitor ❑ Perform CT scan of the abdominal aorta and iliac arteries. (CT scan preferably WITH contrast, but may be WITHOUT contrast for patients at high risk of contrast-induced complications). ❑ Type and crossmatch 6 to 10 units of PRBC. FFP may also be needed in cases of massive transfusion ❑ Do not administer pre-op transfusions except if patient is unconscious or has signs or myocardial infarction ❑ Withdraw blood for CBC, electrolytes, BUN, serum creatinine, LFTS, PT, PTT, troponin I, CK, CK-MB, CRP or ESR, and multiple blood cultures

No

Yes

Pain management ❑ Assess pain severity (self-report NRS scale 0 to 10; unconscious BPS 3-12 or CPOT 0-8). Pain considered significant if NRS≥4, BPS<5, or CPOT≥3 ❑ Administer IV opioids: Morphine 4-10 mg IV every 4 hours, infused over 4-5 minutes (dose range: 5-15 mg) ❑ Consider pre-op epidural catheter if patient meets ALL of the following criteria ❑ Patient hemodynamically stable, AND ❑ Contained leak, AND ❑ Satisfactory coagulation profile ❑ Maintain patient in a conscious state ❑ Monitor any significant undesired drop in blood pressure as pain medications are administered

Manage modifiable risk factors of asymptomatic AAA ❑ Administer aspirin 80 to 100 mg once daily if patient has no contraindication to aspirin therapy ❑ Administer statin therapy (e.g. simvastatin 40 mg once daily) if patient has no contraindication to statin therapy ❑ Manage hypertension based on guidelines for the management of hypertension (There are currently no recommended antihypertensive pharmacologic therapies for the management of AAA) ❑ Recommend smoking cessation ❑ Recommend moderate physical activity at least 4 times per week (e.g. running, swimming, golfing) ❑ Do NOT recommend intense physical activity (e.g. heavy lifting) due to increased risk of AAA rupture ❑ Provide appropriate counseling for patients at high risk of AAA expansion and rupture

Administer antimicrobial therapy Once diagnosis of complicated AAA is confirmed, all patients require blood cultures and empirical antibiotic therapy for gram-positive and gram-negative coverage (even if afebrile at presentation) ❑ Withdraw multiple sets of blood culture (if blood cultures were not withdrawn initially) ❑ Administer empiric combination antibiotic therapy ❑ Vancomycin 1-1.5g IV every 12 hours PLUS only one of the following: ❑ Ceftriaxone 2 g IV every 12 hours, OR ❑ Cefuroxime 1.5 g IV every 4 hours, OR ❑ Piperacillin-tazobactam

Follow-Up ❑ Schedule routine follow-up visits with abdominal ultrasound imaging at regular time intervals to monitor patients who are candidates for surgical or endovascular repair. ❑ Do NOT schedule follow-up visits for patients who refuse either surgical or endovascular repair or who are not adequate candidates for either surgical or endovascular repair. Optimal interval between visits has not yet been established and is controversial. Aneurysm size should determine the frequency of follow-up ultrasound, and the following intervals may be considered based on various guidelines.

Evaluate need for further management of the following AAA complications For patients suspected to have thromboembolism ❑ Obtain Duplex ultrasound of affected extremities ❑ Consider CT scan of aorta from aortic valves to iliac bifurcation For patients suspected to have infected (mycotic) aneurysm ❑ Consider gallium scanning or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate disease activity For patients suspected to have aortovenous fistula ❑ Obtain CT angiography For patients suspected to have aortoenteric fistula ❑ Perform EGD to rule out other possible etiologies of GI bleed among hemodynamically stable patients ❑ Obtain CT scan with IV contrast of the abdomen and iliac arteries ❑ Consider arteriography

Aneurysm size between 5 and 5.5 cm ❑ Consider routine ultrasound every 3 months

Aneurysm size between 4.5 and 4.9 cm ❑ Consider routine ultrasound every 12 months (1 year)

Aneurysm size between 4.0 and 4.4 cm ❑ Consider routine ultrasound every 24 months (2 years)

Aneurysm size between 3.5 to 3.8 cm ❑ Consider routine ultrasound every 36 months (3 years)

Aneurysm size between 2.6 to 2.9 cm ❑ Consider routine ultrasound every 60 months (5 years)

Evaluate patient's surgical risk

High surgical risk

Low to moderate surgical risk

Patient performed CT scan of the abdominal aorta and iliac arteries WITH contrast?

Yes

No

CT scan demonstrated adequate aortic anatomy and integrity suitable for endovascular procedure?

Yes

No

Consider any of the following: ❑ Endovascular repair, OR ❑ Open AAA repair

Open AAA Repair

Screening

Screening for AAA is currently recommended only once in the following patient groups:

• Men between the age of 65 and 75 years and who have ever smoked
• Men aged 60 years or older with a sibling or a parent with abdominal aortic aneurysm

There are currently no recommendations to screen AAA in women, but women are at increased risk of AAA expansion or rupture. Some experts recommend one-time screening in women with risk factors of developing AAA (such as smoking or positive family history)