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azithromycin (Zithromax, Zmax, Z-pak, AzaSite)

Tradenames: Zithromax, Zmax. Indications: - bacterial infections due to susceptible organisms, including - gastrointestinal infections - traveler's diarrhea - enterocolitis - proctitis - acute otitis media - upper respiratory tract infections - acute sinusitis - lower respiratory tract infections - pertussis - pneumonia - eye infections - conjunctivitis - urogenital infections - urethritis - pelvic inflammatory disease - gonorrhea - chancroid - boutonneuse fever - toxoplasmosis - prevention of COPD exacerbations [10] - prophylaxis for bacterial endocarditis [14] - empiric treatment of fever of unknown origin - Mycobacterium avium complex [14] Contraindications: - long-term use after stem-cell transplantation for hematologic malignancy [19] Benefit/risk: - in combination with a beta-lactam antibiotic for community-acquired pneumonia in the elderly - number needed to treat to reduce 90 day mortality = 21 - number need to harm to cause 1 MI = 144 [16] Dosage: 1) 10 mg/kg up to 500 mg PO on day 1, then 5 mg/kg 250 mg QD for 4 days. (Zithro-pak Z-pak) 2) Pharyngitis: 12 mg/kg up to 500 mg PO QD for 5 days 3) Chlamydia: 1 g PO single dose 4) Mycobacterium avium a) treatment 600-1200 mg PO/IV QD for 6 weeks b) prophylaxis: 1200 mg PO weekly 5) 500 mg IV QD 6) new 3 day regimen [6] 7) 2000 mg (Zmax) one-time dose [7] 8) Z-pak 500 PO day 1, the 250 mg QD for 4 days Tabs: 250, 500 mg. Suspension: 100 & 200 mg/5 mL (15 mL). Extended-release: Zmax: 200 mg (oral suspension) [7] Ophthalmic: (AzaSite) 1% opthalmic solution [9] - 1 drop BID for 2 days, then 1 drop QD for next 5 days Pharmacokinetics: 1) rapid oral absorption 2) food decreases absorption by 40-50% 3) tissue distribution: a) good: skin, lungs, sputum, tonsils, cervix b) poor CSF penetration c) leukocytes concentrate azithromycin, resulting in high levels of drug at the site of infection d) tissue levels exceed serum levels by an order of magnitude e) elimination from tissues lags behind elimination from blood 4) terminal 1/2life is 68 hours 5) biliary elimination of unchanged drug; only 6% eliminated in the urine Antimicrobial activity: Gram positive - Streptococcus - Streptococcus group A - Streptococcus group B - Streptococcus group C - Streptococcus group G - Streptococcus pneumonia* - Staphylococcus aureus (MSSA) (+/-) - Staphylococcus epidermidis (+/-) Gram negative - Neisseria gonorrhoeae (+/-) - Moraxella catarrhalis - Haemophilus influenzae - Legionella - Haemophilus ducreyi - Campylobacter Atypical bacteria - Chlamydia species (FDA approved for urethritis/cervicitis) - Chlamydophila pneumoniae [14] - Mycoplasma pneumonia, Mycoplasma hominis - Mycobacterium avium Anaerobes - Actinomyces - Bacteroides melaninogenicus - Clostridium species * community-acquired resistant pneumococcus has been reported [5] Adverse effects: 1) not common (1-10%) - diarrhea, nausea/vomiting, abdominal pain, cramping - hearing loss with chronic use [10] 2) uncommon (< 1%) - thrombophlebitis, ventricular arrhythmias, fever, skin rash, eosinophilia, increased aspartate transaminase (AST), & cholestatic jaundice less than erythromycin, ototoxicity (transient deafness), hypertrophic pyloric stenosis 3) allergic reactions (rare) 4) unlikely among macrolides to cause QT prolongation or interact with other drugs inhibiting or metabolized by cyt P450 3A4 5) azithromycin is associated with increased risk for cardiovascular death [11,12,20] a) risk of potentially fatal arrhythmia [12] - no increased risk of ventricular arrhythmia [17]; - 2-fold risk in ventricular arrhythmia associated with underlying infection, not azithromycin [17] b) excess cardiovascular mortality is attributable to the infection being treated, not the antibiotic [13] c) higher risk of arrhythmia & mortality than amoxicillin [15] d) increased risk of cardiovascular death (RR=1.8) within 5 days of outpatient treatment (relative to amoxicillin) [20] - no increased risk 6-10 days after treatment [20] e) benefits outweigh risks in elderly hospitalized with commmunity-acquired pneumonia [16] 6) other - 2-fold increased risk of miscarriage [18] Drug interactions: 1) Al+3 & Mg+2 containing antacids decrease serum levels by 24% 2) increased effect/toxicity & or serum levels with: - alfentanil, anticoagulants, astemizole, terfenadine, loratadine, bromocryptine, carbamazepine, cyclosporine, digoxin, disopyramide, theophylline, phenytoin, ergotamine, triazolam 3) unlikely among macrolides to cause QT prolongation or interact with other drugs inhibiting or metabolized by cyt P450 3A4 Laboratory: - azithromycin in serum/plasma

Interactions

drug interactions drug adverse effects of macrolide(s)

Specific

Azithromycin Ophthalmic

General

macrolide (macrolide antibiotic)

Properties

MISC-INFO: elimination route LIVER pregnancy-category B safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Sanford Guide to antimicrobial therapy 1997
  3. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 165
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Journal Watch 20(24):194, 2000 Kelley et al, Clin Infect Dis Oct 31:1008, 2000
  6. Prescriber's Letter 11(2):12 2004
  7. Prescriber's Letter 12(8): 2005 Zmax (Azithromycin Extended Release for Oral Suspension) Detail-Document#: 210310 (subscription needed) http://www.prescribersletter.com
  8. Department of Veterans Affairs, VA National Formulary
  9. Prescriber's Letter 14(9): 2007 New dosage form: AzaSite (azithromycin 1% ophthalmic solution) Detail-Document#: 230909 (subscription needed) http://www.prescribersletter.com
  10. Prescriber's Letter 18(10): 2011 Azithromycin to Prevent COPD Exacerbations Detail-Document#: 271004 (subscription needed) http://www.prescribersletter.com
  11. Ray WA et al Azithromycin and the Risk of Cardiovascular Death N Engl J Med 2012; 366:1881-1890 PMID: 22591294 http://www.nejm.org/doi/full/10.1056/NEJMoa1003833 - FDA MedWatch, 05/18/2012 Zithromax (azithromycin): FDA Statement on risk of cardiovascular death http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm304503.htm - Prescriber's Letter 19(6): 2012 Azithromycin (Zithromax) and the Risk of Cardiovascular Death Detail-Document#: 280603 (subscription needed) http://www.prescribersletter.com
  12. FDA MedWatch. March 12, 2013 Azithromycin (Zithromax or Zmax): Drug Safety Communication - Risk of Potentially Fatal Heart Rhythms http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm343350.htm
  13. Svanstrom H et al Use of Azithromycin and Death from Cardiovascular Causes. N Engl J Med 2013; 368:1704-1712. May 2, 2013 PMID: 23635050 http://www.nejm.org/doi/full/10.1056/NEJMoa1300799 - Mosholder AD et al Cardiovascular Risks with Azithromycin and Other Antibacterial Drugs. N Engl J Med 2013; 368:1665-1668. May 2, 2013 PMID: 23635046 http://www.nejm.org/doi/full/10.1056/NEJMp1302726
  14. Deprecated Reference
  15. Rao GA et al Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death. Ann Fam Med 2014 vol. 12 no. 2 121-127 PMID: 24615307 http://annfammed.org/content/12/2/121
  16. Mortensen EM et al Association of Azithromycin With Mortality and Cardiovascular Events Among Older Patients Hospitalized With Pneumonia. JAMA. 2014;311(21):2199-2208 PMID: 24893087 http://jama.jamanetwork.com/article.aspx?articleid=1877208
  17. Trifiro G, de Ridder M, Sultana J et al Use of azithromycin and risk of ventricular arrhythmia. CMAJ April 18, 2017 vol. 189 no. 15 E560-E568 PMID: 28420680 http://www.cmaj.ca/content/189/15/E560
  18. Muanda FT, Sheehy O, Berard A Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ 2017 May 1;189:E625-33 PMID: 28461374 http://www.cmaj.ca/content/189/17/E625.full.pdf+html
  19. Walker M FDA Warns Against Long-Term Zmax Use in Certain Cancer Patients. Heightened risk of relapse, death seen in study of stem cell transplant recipients. MedPage Today. August 03, 2018 https://www.medpagetoday.com/hematologyoncology/hematology/74403
  20. Zaroff JG, Cheetham C, Palmetto N et al Association of Azithromycin Use With Cardiovascular Mortality. JAMA Netw Open. 2020;3(6):e208199. June 17. PMID: 32585019 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767245