Azithromycin

• Azithromycin is a macrolide antibiotic used to treat a wide range of clinical conditions, including bacterial conjunctivitis, upper respiratory tract bacterial infections, some patients with bacterial community-acquired pneumonia (CAP), disseminated Mycobacterium avium complex (MAC), pertussis, Chlamydia, gonococcal STDs, and cat scratch disease.
• Mechanism of resistance: Methylation of ribosomal target and activation of efflux pump.
• Various pharmaceutical preparations:
• Oral tabs: 250 mg, 500 mg, 600 mg
• Oral single-dose suspension: 1 gm
• Pediatric immediate-release suspension: 100 mg/5 mL and 200 mg/5 mL
• Ophthalmic solution, 1%
• Powder for reconstitution and IV use, 500 mg vials
• Evaluate risk of prolongation of QTc before prescribing; details under adverse effects

• None

• None

• Treatment stopped due to adverse effects (1%), rash (rare), neutropenia (rare), thrombocytopenia (rare), nausea/vomiting (3%), diarrhea (5%), increased LFTs (rare), increased BUN/Creatinine (rare).
• Variety of other laboratory abnormalities (e.g., lymphopenia, eosinophilia, electrolytes and liver function abnormalities), which may or may not be drug related, have been reported at a frequency of 1% or less.
• Transient reversible hearing loss from Azithromycin (J Otolaryngol 36:257, 2007).
• QTc interval prolongation: Any of the macrolides (Azithromycin, Clarithromycin, and Erythromycin) have the potential of increasing the QTc interval and predispose to ventricular tachycardia.
• QTc prolongation may be congenital or acquired (N Engl J Med 358:169, 2008). Variable prevalence of mutations associated with long QT: 11% in Denmark vs. 20% in New Zealand or Minnesota (J Cardiovasc Electrophysiol 23:1092, 2012).

• In retrospective controlled study from Tennessee, 5 days of Azithromycin increased the risk of cardiovascular death (hazard ratio 2.88, p 0.001); compared to Amoxicillin, estimated 47 additional cardiovascular deaths per 1 million courses of therapy (N Engl J Med 366:1881, 2012). Subsequent larger study in generally younger population from Denmark showed CV mortality in Azithromycin recipients was only 15.4/million courses vs. 85.2/million courses in the Tennessee study (N Engl J Med 368:1704, 2013; N Engl J Med 368:1665, 2013).

• Risk of ventricular arrhythmia and/or cardiac death studied in 2 million Taiwanese outpatients treated within 7 days with amox/clav, oral FQ, or oral macrolide (Azithromycin/Clarithromycin). Although the number of events was low, compared to Amoxicillin-clavulanate, the highest propensity score adjusted odds ratios were 2.74 for Moxifloxacin, and 3.4 for Azithromycin (Clin Infect Dis 60: 566, 2015).

• Hence, Azithromycin may increase risk of CV death in patients with congenital or acquired cardiovascular disease risk factors. Caution indicated in patients with history of unexplained syncope, family history of unexplained sudden cardiac death, known electrolyte abnormalities, or the need for concomitant administration of other drugs known to potentially prolong the QTc.

• Prolonged QTc defined as > 470 ms for men; > 480 ms for women, and > 500 ms for either men or women.
• Review with balance of benefits vs risk see Am J Med 128: 1362.e1, 2015.
  

• Mycoplasma species are generally susceptible to azithromycin and other macrolides. The exception is Mycoplasma hominis which is resistant to macrolides.

Footnotes:

1: Refers to adult oral preparations unless otherwise noted; + food = take with food, no food = take without food, ± food = take with or without food

2: SD = after a single dose, SS = at steady state

3: V/F = Vd/oral bioavailability; Vss = Vd at steady state; Vss/F = Vd at steady state/oral bioavailability

4: Assumes CrCl >80 mL/min

5: (Peak concentration in bile/peak concentration in serum) x 100. If blank, no data.

6: CSF concentrations with inflammation.

7: Judgment based on drug dose and organism susceptibility. CSF concentration ideally ≥10x MIC.

8: AUC = area under serum concentration vs. time curve; 12 hr = AUC 0-12, 24 hr = AUC 0-24