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CADTH » Resources » Academic Detailing Templates » Supporting Information - Appendices » Appendix 16a : ADUP CAP FastFacts - Macrolides

Appendix 16a : ADUP CAP FastFacts - Macrolides

How do the macrolides fit in the therapy of Community Acquired Pneumonia?

  • Macrolides are attractive agents for the treatment of CAP because of their spectrum of activity. Of the 6 pathogens that cause most CAP (S. pneumoniae, M. pneumoniae, C. pneumoniae, Legionella species, H. influenzae and influenza A virus), all but influenza viruses are usually susceptible to macrolides including erythromycin. Their advantage over penicillin is their coverage of the “atypical” organisms (Mycoplasma pneumoniae and Chlamydia pneumoniae).
  • Of the 5 main bacterial causes of CAP, H. influenzae is the least susceptible to macrolides. Erythromycin has the least H. influenzae activity in vitro, clarithromycin is of intermediate activity and azithromycin is the most active. Because of reduced H. influenzae coverage, erythromycin is not recommended as empiric therapy for patients with co-morbid factors.
  • In most CAP guidelines, including the TOP recommendations, macrolides are recommended as first line empiric therapy in otherwise healthy adults.
  • For children, macrolides are recommended as first line empiric therapy in patients age 5 to 16 years (the most common pathogens in this age group is M. pneumonia and C. pneumonia).

Is resistance an issue with these agents?

  • The rate of erythromycin resistant S. pneumoniae in Canada increased from 16% in 2003 to 18.3% in 2004. These rates are considerably lower than those in other countries including the US [29%] and Japan [71%].
  • The mechanism of resistance is either target site modification or an efflux pump mechanism. The efflux mechanism is much more common in N. America and is associated with a lower level of resistance (i.e. lower concentrations of antibiotic are required to overcome the resistance). Note that pneumococci resistant to erythromycin (by either mechanism) are also resistant to azithromycin and clarithromycin.
  • Despite the rated reports of in vitro resistance, very few cases have been reported in which the presence of macrolide resistance has led to clinical failure during macrolide therapy. This should be considered in light of the several million numbers of prescriptions written yearly to treat outpatient pneumonia.
  • The low number of case failures may be attributed to these factors: 1) low level resistance predominates in N. America; 2) macrolides are actively accumulated into tissue fluids and macrophages (in vitro susceptibility may not accurately predict in vivo activity).

Are there disadvantages to use of macrolides in CAP?

  • Patients at risk of infection with macrolide resistant S. pneumoniae should receive an alternate agent (or additional coverage for S. pneumoniae). Patients at risk include those with previous antibiotic exposure (within the last 3 months), recent hospitalization, attendance at daycare centres, immunosuppression, age > 65 years and resident of a long term care facility.

Key Talking Points

  • “It is true that increasing resistance to the macrolides has been documented. However, there have been very few reports of treatment failures. This may be attributed to the low level of resistance in N. America and the high concentration macrolides achieve in tissue fluids and macrophages. At this point, guidelines (Canadian and American) are still recommending macrolides as first line. The guidelines do recognize those patients that should be considered for alternate therapies.”
  • “Even in the U.S. where resistance rates are recorded as considerably higher to macrolides than here in Canada, the macrolides are still recommended as first line therapy.”

Other key FastFACTS:

1. Major Drug Interactions

  • Erythromycin and clarithromycin are potent inhibitors of CYP450 3A4 therefore caution should be exercised in combining drugs metabolized by this isoenzyme.
  • Erythromycin, clarithromycin and azithromycin can increase the QT interval (less potential with azithromycin). Caution in combining with other agents with this effect.
  • Examples of drugs that interact with -
    • erythromycin: atorvastatin, BDZs, carbemazepine, digoxin, ergot alkaloids, felodipine, sertraline, simvastatin, warfarin, zolmitriptan.
    • clarithromycin: similar drug interactions to erythromycin
    • azithromycin: digoxin, warfarin, Al/Ca/Mg containing products (decreased azithro absorption due to chelation), ergot alkaloids. In contrast to the other macrolides, azithro is unlikely to interact with drugs metabolized by CYP 3A4 (however elevations of phenytoin have been reported).

2. Tolerability

  • Macrolides are generally well tolerated. Some nausea, diarrhea, abdominal pain, headache and dizziness can occur. Erythromycin has a higher incidence of GI upset than the other macrolide agents which can make it hard to take.
  • Clarithromycin can cause abnormal taste and can rarely cause liver failure.
  • Food decreases the absorption of erythromycin stearate and non-enteric coated dosage forms. It should be given 2 hours before or after food.

3. CAP Dose and Dosage Forms

  • See RxFiles document “Oral anti-infectives”

4. Alberta Drug Benefits Coverage

  • See AH&W Drug Benefit List
  • Azithromycin (tablets and suspension), clarithromycin (regular release tabs & suspension) and erythromycin (various formats) are covered
  • Biaxin XL (clarithromycin extended release 500 mg tablets) were reviewed and will NOT be covered.

References

Alberta Clinical Practice Guideline Working Group. Diagnosis and management of community acquired pneumonia: Adults. 2005 Update. [TOP Guidelines]. Available from: www.topalbertadoctors.org

Mandell LA et al. Canadian Guidelines for the Initial Management of Community-Acquired Pneumonia: An Evidence-Based Update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infectious Dis 2000; 31:383-421.

File TJ, Tan JS. International guidelines for the treatment of community-acquired pneumonia in adults: the role of macrolides. Drugs 2003; 63(2):181-205.

Lynch JP, Martinez FJ. Clinical relevance of macrolide-resistant Streptococcus pneumoniae for community-acquired pneumonia. Clin Infect Dis 2002; 34(Suppl 1): S27-46.

The Medical Letter. Treatment Guidelines: Drugs for Pneumonia. The Medical Letter Sept 2003; (13): 83-88.