Clostridioides difficile

Aka: Clostridioides difficile, Clostridium difficile, Pseudomembranous colitis, Pseudomembranous Enterocolitis

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II. Background

  1. First recognized in 1978 as a cause of Antibiotic-Associated Diarrhea in 1978
  2. Clostridium difficile was reclassified as Clostridioides difficile in 2016
    1. Initially included in genus Clostridium due to shared properties
    2. Later reclassified to be included in a completely different Bacterial family, Peptostreptococcaceae
    3. New genus was named Clostridioides to preserve similar naming (C. Diff) and reduce clinician confusion

III. Epidemiology

  1. Incidence
    1. U.S. Adults: 14 cases per 1000 persons
    2. Marked increase from the 65 per 100,000 in 1991, and 156 per 100,000 in 2003 in U.S.
    3. Most common Nosocomial Infection in the United States
  2. Mortality:
    1. Of >450,000 cases per year, nearly 30,000 died in 2011 (6% mortality)
  3. References
    1. Kelly (2008) N Engl J Med 359(18): 1932-40 [PubMed]

IV. Pathophysiology

  1. Obligate, anaerobic, Gram Positive, spore-forming, motile Bacillus
    1. Causes Secretory Diarrhea and mucosal injury with colitis
    2. Two toxins are typically produced
      1. Enterotoxin A (causes Diarrhea, accompanies Toxin B in some cases)
      2. Cytotoxin B (cytotoxic to colon cells, present in all cases)
  2. New virulent epidemic strain: NAP1/B1/027
    1. Strain responsible for the 5 fold increase in C. difficile infections from 1999 to 2007
    2. Toxin A/B levels are >16 fold higher than other strains
    3. Produces binary toxin in addition to typical toxins A and B
    4. Higher rate of associated Toxic Megacolon
    5. Highly Fluoroquinolone resistant
  3. Sequence of infection
    1. Normal colonic Bacteria disturbed (e.g. Antibiotics)
    2. Exposure to C. difficile
      1. C. difficile is acquired in health care settings in 94% of cases
        1. However presentation is delayed until after hospitalization in 75% of cases
      2. C. difficile is commensal in only 3% of patients
      3. C. difficile survives in hospital room >40 days
        1. Occupying a room of a prior patient with C. difficile more than doubles the C. difficile risk
        2. Flushing a toilet in a C difficile patient's room disperses contaminated bioaerosol throughout room
        3. Wilson (2020) Infect Control Hosp Epidem, published online
      4. Colonization occurs in 7 to 26% of acute care facilities
      5. Colonization risk increases for each day of hospitalization
        1. Occurs in 50% of those hospitalized >4 weeks
      6. Colonization is community acquired in 41% of cases
        1. More common young, female with few comorbidities and less severe infection
        2. Occurs without Antibiotic exposure frequently
        3. Khanna (2012) Am J Gastroenterol 107(1): 89-95 [PubMed]
    3. Colonization with Clostridium difficile
      1. Asymptomatic (carrier state)
        1. Up to 15% of healthy adults are colonized with C difficile
        2. Asymptomatic patients account for >50% C. difficile colonization cases
        3. As many as 63% of healthy newborns are colonized with C. difficile
          1. Most strains in infants are non-toxic, and likely due to peripartum hospitalization
      2. Symptomatic (typically symptoms start 3-7 days after exposure)
        1. Mild Diarrheal illness or
        2. Severe illness (Pseudomembranous colitis)

V. Risk Factors

  1. Highest risk patients
    1. Older patients over age 64 years old, and especially over age 70 years
      1. Risk of C. difficile infection increases 2% for each year over age 18 years old
    2. Debilitated patients
    3. Immunocompromised patients
      1. Includes Hematopoietic Stem Cell Transplant and Solid Organ Transplant
      2. Includes Corticosteroid use
    4. Cystic Fibrosis patients (high risk for fulminant infection)
    5. Obesity
    6. Female Gender
    7. Chronic Kidney Disease (esp. Serum Creatinine >2)
    8. Gastrointestinal conditions
      1. Enteral feeding
      2. Gastrointestinal surgery
      3. Small Bowel Obstruction or Adynamic Ileus
      4. Inflammatory Bowel Disease
      5. Cirrhosis
      6. Malnutrition or low Serum Albumin
  2. Acid suppression
    1. Proton Pump Inhibitors (e.g. Omeprazole)
      1. Highest risk as they raise gastric pH most significantly
    2. H2 Blockers (e.g. Ranitidine)
      1. Less risk than with Proton Pump Inhibitors
    3. Consider stopping indefinately following diagnosis of Clostridium difficile (due to higher risk of recurrence)
  3. Recent Antibiotic use within last 3 months (especially last 7-10 days)
    1. General
      1. All Antibiotics can cause C. difficile Diarrhea (even single dose perioperative Antibiotics)
      2. Broad-spectrum agents are highest risk
      3. Risk increases with combination Antibiotic regimens, frequent dosing and longer therapy duration
      4. Up to 40% of C. difficile are in patients without recent Antibiotic use
    2. Most common Antibiotic causes
      1. Clindamycin
        1. ClindamycinOdds Ratio 16
        2. More common cause again since resurgence for MRSA management
      2. Fluoroquinolones (e.g. Ciprofloxacin, Levofloxacin)
        1. FluoroquinoloneOdds Ratio 5.5
        2. Emerging as very common cause
      3. Broad-spectrum Cephalosporins
        1. Odds Ratio 5.7
      4. Ampicillin or Amoxicillin (most common cause in United States)
        1. Odds Ratio 2.7
      5. Macrolides (e.g. Erythromycin, Azithromycin)
        1. Odds Ratio 2.7
      6. Carbapenems (Ertapenem)
        1. Odds Ratio 1.5 to 5.7
    3. Less common Antibiotic causes
      1. Tetracycline Antibiotics (e.g. Doxycycline)
      2. Sulfonamides (e.g. Bactrim)
      3. Trimethroprim
    4. Rare Antibiotic causes
      1. Parenteral Aminoglycosides
      2. Metronidazole (used for treatment)
      3. Vancomycin (used for treatment)
    5. References
      1. Brown (2013) Antimicrob Agents Chemother 57(5): 2326-32 +PMID:23478961 [PubMed]

VI. Symptoms

  1. Asymptomatic carrier state is common
  2. Megacolon may be present without Diarrhea
  3. Inflammatory Diarrhea (variably present)
    1. Timing
      1. Incubates for 2-7 days after colonization
      2. Most cases occur on days 4-9 of Antibiotic course
      3. Onset <14 days after Antibiotics in 96% of cases
      4. All cases occur within 3 months of Antibiotics
      5. Olson (1994) Infect Control Hosp Epidemiol 15:371 [PubMed]
    2. Characteristics
      1. Frequent, watery Bowel Movements to profuse Diarrhea up to 20-30 stools daily
      2. Foul, characteristic odor may be present, but not shown in studies to be sensitive or specific
        1. Rao (2013) Clin Infect Dis 56(4):615-6 [PubMed]
      3. Mucus and occult blood often present
  4. Acute inflammatory symptoms (<50% of cases)
    1. Fever (>38.5 C in 15% of cases)
    2. Crampy Abdominal Pain
    3. Decreased appetite
    4. Malaise
    5. Nausea or Vomiting may be present in 2 to 30% of patients
    6. In severe cases, Pseudomembranous colitis and Toxic Megacolon occurs
    7. Melana and Hematochezia are uncommon (although occult blood in stool is more often present)
  5. Extraintestinal symptoms
    1. Asymmetric Oligoarticular large joint Arthralgia

VII. Labs: Diagnosis

  1. Indications: Screening
    1. At least 3 unformed stools in 24 hours (required)
    2. Antibiotic use in last 3 months
    3. Inflammatory Bowel Disease with acute exacerbation
  2. Contraindications to testing
    1. Formed stool (no Diarrhea)
    2. Recent Laxative use in prior 48 hours
    3. Testing for cure in asymptomatic patients (following treatment of active infection) is NOT recommended
    4. Children <12 months of age
      1. Infants are frequently and asymptomatically colonized with C. difficile
      2. Children 1-2 years old with prolonged Diarrhea, no other causes and who have risk factors may be tested
  3. Clostridium difficile testing
    1. Clostridium difficile PCR or Nucleic Acid Amplification Tests or NAAT (preferred)
      1. Best test efficacy and recommended by American College Gastroenterology
      2. Increased risk of overdiagnosis of asymptomatic carrier state (esp. in lower probability cases)
      3. Sufficient as single test in Immunocompromised patients (assume toxigenic in these cases)
    2. Glutamate dehydrogenase (GDH) Antigen
      1. Highly sensitive and rapid assay for Antigen produced by all C. difficile isolates
      2. Does not distinguish between toxigenic and nontoxigenic strains
      3. Positive tests are then reflexed to PCR or ELISA testing (see above)
    3. Clostridium difficile A and B toxin ELISA (or EIA)
      1. Used in combination with PCR to reduce risk of over-diagnosis
      2. Preferred over Clostridium difficile culture, and widely available
      3. Replaced the cell cytotoxicity neutralization assay (CCNA)
      4. Test Sensitivity: 75-95%
      5. Test Specificity: 83-98%
      6. Available within 2 hours of obtaining sample
      7. Aldeen (2000) Diagn Microbiol Infect Dis 36(4): 211-3 [PubMed]
  4. IDSA recommends multistep protocols (screening with GDH EIA or PCR/NAAT and reflexing to toxin EIA)
    1. GDH EIA and Toxin A/B EIA (with or without PCR/NAAT)
    2. NAAT/PCR reflex to Toxin A/B EIA
      1. NAAT/PCR alone is suffiicient in Immunocompromised patients (treat all positive cases)

VIII. Labs: Markers of Severe Infection

  1. Hypoalbuminemia
  2. Lactic Acidosis
  3. Serum Creatinine >1.5 mg/dl
  4. White Blood Cell Count >15,000 cells/uL
    1. Leukocytosis variably present (<50% of cases)
    2. White Blood Cell Count may be greater than 20,000, or even 40,000 cells/uL
    3. White Blood Cell Count greater than 30,000 is related to C. difficile in 25% of cases

IX. Imaging

  1. CT Abdomen
    1. Indications
      1. Severe complicated C. difficile colitis (e.g. severe Abdominal Pain, ileus, fever, Lactic Acidosis, severe Leukocytosis)
      2. Evaluate differential diagnosis
      3. Prior Small Bowel Obstruction or surgery
      4. Inflammatory Bowel Disease (e.g. Ulcerative Colitis, Crohn's Disease)
      5. Medical complications (e.g. Diabetes Mellitus)
    2. General Findings
      1. Colon wall thickening
      2. Pericolonic stranding may be present
      3. Low attenuation mural thickening with mucosal or submucosal edema
        1. Target sign or double halo sign (2-3 concentric rings of varying attenuation)
    3. Toxic Megacolon Findings
      1. Colon dilitation >7 cm diameter
      2. Small Bowel dilation
      3. Small Bowel air fluid levels
      4. Submucosal edema (thumb printing or bowel wall scalloping)
  2. Abdominal XRay Findings (not typically indicated)
    1. Dilated colon: >7 cm in greatest diameter (Toxic Megacolon)
    2. Small Bowel dilation or air-fluid levels may be present
    3. Mucosal edema or thumbprinting may also be present

X. Diagnostics

  1. Endoscopy (Flexible Sigmoidoscopy or Colonoscopy)
    1. Not recommended in most cases
    2. May be indicated if diagnosis is unclear
    3. Findings: Mucosal lesions with pseudomembranes

XI. Differential Diagnosis

  1. Antibiotic intolerance (resolves off Antibiotics)
  2. Infectious enteritis
    1. Acute Gastroenteritis
    2. Amebic Dysentery
    3. Klebsiella oxytoca
      1. Like Clostridium difficile, causes Antibiotic-Associated Diarrhea, that may be hemorrhagic
      2. Improves after stopping Antibiotics and NSAIDs
  3. Inflammatory Bowel Disease
  4. Ischemic Colitis

XII. Evaluation: Severe Infection Criteria

  1. See ATLAS Bedside Score System for Clostridium Difficile Infection
  2. Severe infection criteria risk stratify management (e.g. Vancomycin selection for treatment)
  3. High risk patients of severe, fulminant disease (with 2 or more of the following risk factors)
    1. Age over 60 years old
    2. Temperature >38.3 C (100.9 F)
    3. Albumin <2.5 g/dl
    4. Leukocytosis with White Blood Cell Count >15,000/L
    5. Serum Creatinine >50% increase over baseline or >1.5 mg/dl
    6. Pseudomembranous colitis on endoscopy
    7. Intensive Care unit management
    8. Zar (2007) Clin Infect Dis 45(3): 302-7 [PubMed]

XIII. Management: General Measures

  1. Discontinue Antibiotics
    1. Diarrhea resolves in up to 25% of cases with stopping
    2. If Antibiotic required, choose one with lower risk
  2. Indications to start C. difficile Antibiotics immediately (empiric while awaiting test results)
    1. Older patients
    2. Multiple comorbid conditions
    3. Antibiotics can not be discontinued
    4. Severe disease
      1. Persistent Diarrhea
      2. Dysentery (fever, Leukocytosis)
  3. Avoid and stop medications that could worsen condition
    1. Proton Pump Inhibitors
    2. Opioid
    3. Antidiarrheal agents
    4. Cholestyramine (Questran)
      1. Binds Vancomycin and Metronidazole in the Intestine lowering their efficacy against C. difficile
  4. Do not retest for toxin post-treatment if asymptomatic
    1. May be positive, but does not require treatment

XIV. Management: Adults

  1. Background
    1. Antibiotic course is typically 10 days (extend to 14 days if needed)
  2. Fidaxomicin (Dificid)
    1. Considered first-line, preferred over Vancomycin due to lower recurrence rates
    2. Dose: 200 mg orally twice daily for 10 days
    3. Macrolide that inhibits RNA Polymerase, and in turn Protein synthesis, leading to Bacterial cell death
    4. Advantages
      1. Narrow spectrum Antibiotic (C. difficile, Staphylococcus, Enterococcus)
        1. Does not affect Gram Negative Bacteria including normal bowel flora
      2. High efficacy (90% cure rate, similar to Vancomycin)
      3. Lower C. difficile recurrence rates than with Vancomycin
      4. Minimal systemic absorption when taken orally
        1. As with Vancomycin, oral Fidaxomicin primarily stays in the Gastrointestinal Tract
    5. Disadvantages
      1. Very expensive ($250/dose or $3000 to $4300 for a 10 day course)
  3. Vancomycin
    1. Precaution: Only effective for C. difficile if dosed orally or rectally
    2. Indications
      1. As of 2018, a first-line agent for C. difficile, replacing Metronidazole even in mild-moderate cases
      2. Drug of choice for severe C. difficile infection
        1. Still with risk of promoting Vancomycin resistance
        2. Had been very expensive ($600-800 per course)
          1. Inexpensive if pharmacist compounds the intravenous form into oral formulation
          2. As of 2021, Vancomycin capsules are $75 to 300 per course
          3. Firvanq oral Vancomycin solution is also available $125 per course
    3. Dose: 125-500 mg orally (or rectally) four times daily for 10-14 days (10 days is often sufficient)
      1. Use low dose (125 mg) in most patients
        1. Studies suggest 125 mg four times daily is as effective as higher doses
      2. Use high dose Vancomycin 500 mg four times daily with Metronidazole in severe, fulminant disease
        1. May deliver via Nasogastric Tube in severe cases
        2. Consider using via rectal retention enema in ileus
        3. High dose enteral doses may require serum Vancomycin level monitoring (esp. Kidney disease)
      3. Extended course may be used for persistent Diarrhea
        1. See Vancomycin recurrence protocol below
  4. Bezlotoxumab (Zinplava)
    1. Monoclonal Antibody against C. Difficile
    2. Consider in the prevention of recurrent infection (adjunctive to Antibiotics) if at least one risk factor for recurrence
      1. Age 65 years or older
      2. Immunocompromised state
      3. Severe C. Difficile infection
    3. Dose: 10 mg/kg IV infusion over 60 minutes
    4. Risk of worsening Congestive Heart Failure
  5. Metronidazole
    1. No longer recommended by IDSA as first line protocol for mild to moderate Clostridium difficile
      1. Replaced by Vancomycin and Fidaxomicin as first-line agents
      2. Resistance is growing and may approach 30% in some regions
        1. IDSA shifted to recommending oral Vancomycin as first-line in 2018
      3. Not recommended for c. difficile recurrence treatment
        1. If repeated after being used for prior management, neurotoxicity risk
    2. Metronidazole has historically been preferred for mild to moderate infection (WBC <15k, creat<1.5 mg/dl)
      1. Metronidazole is much lower cost (~$20/course) than oral Vancomycin (~$400/course)
      2. May still be a reasonable alternative in mild-moderate first cases in younger patients where first-line agents are unavailable
    3. Dose
      1. Typical: 500 mg orally every 6-8 hours for 10-14 days
      2. Lower dose: 250 mg orally q6 hours for 10-14 days
      3. Parenteral dose: 500 mg IV q8 hours for 10-14 days

XV. Management: Child

  1. Mild to Moderate disease: Metronidazole (Flagyl)
    1. Metronidazole 7 mg/kg (maximum 500 mg) orally three times daily for 7-10 days
  2. Severe disease: Vancomycin
    1. Vancomycin 5 mg/kg (to maximum 125 mg) every 6 hours for 7-10 days

XVI. Management: Recurrence - General

  1. Recurrence risk doubles with each episode
    1. Follows clearance of prior episode on appropriate Antibiotics
    2. Initial recurrence risk is 20-30% (typically within 2 months)
    3. After third episode, recurrence is virtually assured
  2. Recurrence risk factors
    1. Prolonged Antibiotic use
    2. Prolonged hospitalization course
    3. Diverticulosis
    4. Multiple comorbid illnesses
    5. Elderly patients
    6. Immunocompromised
  3. Management
    1. Vancomycin is preferred Antibiotic for recurrence management
    2. Metronidazole is not recommended for recurrence due to neurotoxicity risk
  4. Fidaxomicin (Dificid)
    1. Start: 200 mg orally twice daily for 10 days
    2. Next: 200 mg orally once every other day for 20 days
  5. Vancomycin taper
    1. Start 125 mg orally four times daily for 10-14 days,
    2. Then 125 mg orally twice daily for 7 days
    3. Then 125 mg orally daily for 7 days
    4. Then 125 mg orally once every 2-3 days for up to 8 weeks
  6. Vancomycin AND Rifamaxin
    1. Vancomycin 125 mg orally four times daily for 10 days and THEN
    2. Rifaxamin 400 mg orally three times daily for 20 days
  7. Bezlotoxumab (Zinplava)
    1. Monoclonal Antibody against C. Difficile
    2. Indicated in the prevention of recurrent infection (adjunctive to Antibiotics) if last infection in prior 6 months
    3. Dose: 10 mg/kg IV infusion over 60 minutes
    4. Risk of worsening Congestive Heart Failure
  8. Probiotics
    1. Precautions
      1. Avoid if Immunocompromised (risk of Septicemia)
      2. Take Probiotics 2 hours after Antibiotic dose
    2. Saccharomyces boulardii
      1. Dose 250 mg PO bid to tid for 1 month
      2. Has also been used with Vancomycin 500 mg PO qid
    3. Lactobacillus (Culturelle)
  9. Fecal Microbiota Spores
    1. Live-brpk (Vowst)
      1. Indicated for 3 or more C. difficile episodes within 12 months
      2. Purified, Firmicutes Bacterial spore suspension in oral capsule, from human donor feces
      3. Take 2-4 days following Antibiotic treatment of recurrent C. difficile
      4. Effective in C. difficile prevention, but at nearly $20,000 per full 12 capsule course
      5. Smith (109) Am Fam Physician 109(5): 472-3 [PubMed]

XVII. Management: Recurrence - Fecal Transfer (Stool Transplant, Fecal Bacteriotherapy, Intestinal Microbiota Transplant)

  1. See Intestinal Microbiota Transplant

XVIII. Management: Fulminant disease (high mortality rate)

  1. Background
    1. Complicates 1-3% of C. difficile cases
  2. Indications
    1. Intractable colitis, Toxic Megacolon, ileus or bowel perforation
    2. Severe Leukocytosis (e.g. White Blood Cell Count to 30,000)
    3. Serum Lactate >5
    4. Multi-system organ failure or other shock-like state
  3. Management
    1. Consult general surgery
      1. Total abdominal colectomy may be indicated in the most severe diseases
      2. Other surgical management options include diverting loop ileostomy with colonic lavage
    2. Consult gastroenterology
      1. Emergent endoscopic Stool Transplant may spare both surgery and the patient's life
    3. Antibiotic Protocol
      1. Metronidazole IV 500 mg every 8 hours AND
      2. Vancomycin 500 orally four times daily AND
      3. Vancomycin enema 500 mg in 100 cc NS q6 hours
        1. Delivered by foley in Rectum, 30 cc balloon
        2. Balloon inflated for 60 minutes after dose

XIX. Prognosis

  1. See ATLAS Bedside Score System for Clostridium Difficile Infection
  2. Findings of improvement (assess on day 5)
    1. Fever resolves within first 2 days
    2. Diarrhea resolves within first 4 days
  3. Recurrence rates
    1. After episode 1: Recurrence in up to 25%
    2. After episode 2: Recurrence in up to 65%

XX. Complications

  1. Toxic Megacolon
    1. Severe systemic toxicity AND Large Bowel dilation (>7 cm diameter colon or >12 cm diameter cecum)
  2. Bowel perforation
  3. Dehydration
  4. Electrolyte abnormality

XXI. Prevention

  1. Avoid Proton Pump Inhibitors (or other acid suppression such as H2 Blocker use) unless absolutely indicated
  2. Antibiotic Stewardship
    1. Antibiotic Stewardship decreases c. difficile infection rates by >50%
      1. Dancer (2013) J Antimicrob Agents 41(2): 137-42 [PubMed]
    2. Avoid broad-spectrum Antibiotic use if possible
      1. Narrow Antibiotic spectrum based on ongoing findings such as culture results
    3. Use Antibiotics only when indicated, and no longer than the necessary duration
  3. Probiotic Indications
    1. Recurrent C. difficile (see above)
    2. Concurrent use with Antibiotics (start while patients hospitalized)
      1. Dosing
        1. Start within 1-2 days of Antibiotic initiation
        2. Continue for 5 days beyond Antibiotic course
        3. Take 2 hours after each Antibiotic dose
      2. Probiotic species appear to be equally effective
        1. Saccharomyces boulardii (e.g. Florastor)
        2. Lactobacillus (e.g. Culturelle)
      3. Multiple studies demonstrate significant reduction in C. difficile infection following Antibiotic use
      4. Hempel (2012) JAMA 307(18): 1959-69 [PubMed]
      5. Hickson (2007) BMJ 335(7610): 80 [PubMed]
      6. Gao (2010) Am J Gastroenterol 105(7): 1636-41 [PubMed]
      7. Goldenberg (2017) Cochrane Database Syst Rev (12):CD006095 [PubMed]
  4. Prevent Clostridium difficile spore spread
    1. Spores are resistant to Alcohol, Antibiotics and antiseptics
      1. Chlorhexidine and soap are effective
    2. Contact Isolation of patient
      1. Use personal protective gear including Hand Hygiene, gowns and gloves
      2. Use disposable stethoscopes and Thermometers
      3. Continue contact precautions for at least 48 hours after Diarrhea has resolved
      4. C. difficile should not share a bathroom with other people in hospital or at home
      5. Bathroom and kitchen surfaces should be cleaned with bleach solutions
    3. Practice good hygiene
      1. Hand Washing with soap and water
      2. Hand sanitizers (e.g hand gels) are not effective against Clostridium difficile
      3. C. difficile survives outside colon as spores that are Antibiotic, heat and acid resistant
      4. Disinfect surfaces and equipment with sporicidal disinfectants
        1. Bleach
        2. Alkaline glutaraldehyde
        3. Ethylene oxide
        4. Disinfecting Ultraviolet light system (used in combination with surface cleaners)

XXII. References

  1. (2018) Presc Lett 25(4)
  2. Herbert (2012) EM:RAP C3 2(4): 3
  3. Long and Swaminathan in Swadron (2022) EM:Rap 23(1): 5-11
  4. Suntharam (2006) First 24 hours, Park Nicollet Lecture
  5. Cagle (2022) Am Fam Physician 105(3): 262-70 [PubMed]
  6. Hookman (2009) World J Gastroenterol 15(13): 1554-80 [PubMed]
  7. Hsu (2014) Am Fam Physician 90(6): 377-82 [PubMed]
  8. Jabbar (2003) Prim Care 30(1):63-80 [PubMed]
  9. Johnson (2021) Clin Infect Dis 73(1): e1029-44 [PubMed]
  10. Kyne (2001) Gastroenterol Clin North Am 30(3):753-77 [PubMed]
  11. Mounsey (2020) Am Fam Physician 101(3): 168-75 [PubMed]
  12. Schroeder (2005) Am Fam Physician 71(5):921-8 [PubMed]
  13. Winslow (2014) Am Fam Physician 89(6): 437-42 [PubMed]

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