Azithromycin

by Helen Boucher, M.D. last updated Mar 26, 2024 09:48 AM
Azithromycin
Zithromax
Prep Started At Notes
injection
1% ophthalmic solution Unavailable -1% ophthalmic solution

Usage and Dosing

  • 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

Adult Dose

Bacterial conjunctivitis Azithromycin ophthalmic solution 1 drop bid x 2 days,
then 1 drop once daily x 5 days
Respiratory tract
(mild/moderate infection)
500 mg po day 1,
then 250 mg po once daily, days 2-5
Community-acquired pneumonia (CAP) 500 mg IV once daily
(often combined with beta-lactam)
Chancroid 1 gm po single dose
C. trachomatis 1 gm po single dose
N. gonorrhoeae 2 gm po single dose

Pediatric Dose

Dose (Age >28 Days) Max/Day
(po) 5-12 mg/kg/day (once daily) -
(IV) 10 mg/kg/day (once daily) -

Renal Adjustment

  • Body weight and Creatinine Clearance calculations
  • CrCl = Creatinine clearance level (mL/min) CAPD = Continuous Ambulatory Peritoneal Dialysis CRRT = Continuous Renal Replacement Therapy AD = after hemodialysis SLED = sustained low efficiency dialysis
Half-life, hrs (renal function normal) 68
Half-life, hrs (ESRD) Unchanged
Dose (renal function normal) 250-500 mg IV/po q24h
CrCl or eGFR No dosage adjustment for renal impairment
Hemodialysis No dosage adjustment
CAPD No dosage adjustment
CRRT No dosage adjustment
SLED No data

Hepatic Adjustment

  • None

Adverse Effects

  • 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.

Pregnancy Risk

FDA Risk Category 1 B
Use during Lactation Safe, monitor infant for GI toxicity

Footnotes:

1 : Capital letter = Old FDA risk category; Text = New FDA risk category

Antimicrobial Spectrum

Agent is a first line therapy: reliably active in vitro, clinically effective, guideline recommended, recommended as a first-line agent or acceptable alternative agent in the Sanford Guide

Active + ( 14 )

Agent is a potential alternative agent (active in vitro, possesses class activity comparable to known effective agents or a therapeutically interchangeable agents and hence likely to be clinically effective, but second line due to overly broad spectrum, toxicity, limited clinical experience, or paucity of direct evidence of effectiveness)

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

Pharmacology

PK/PD Index 24-hr AUC/MIC
Pharmaceutical Preparations Tab (250, 500, 600 mg), oral susp (1 gm pkt), oral susp (100 mg/5 mL, 200 mg/5 mL), 1% oph soln, injection
Food Rec (PO Drugs) 1 All preps ± food
Oral Absorption (%) 37
Tmax (hr) po 2.5
Peak Serum Conc (µg/mL) 2 0.4 (500 mg po, SD)
3.6 (500 mg IV, SD)
Peak Urine Conc (µg/mL) No data
Protein Binding (%) 7-51
Volume of Distribution (Vd) 3 31.1-33.3 L/kg
Avg Serum T½ (hr) 4 68
Elimination Biliary
Bile Penetration (%) 5 High
CSF/blood (%) 6 No data
Therapeutic Levels in CSF 7 No data
AUC (µg*hr/mL) 8 4.3 (500 mg po, 0-inf)
9.6 (500 mg IV, 0-24 hr, pre-SS)

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. KEY: 0-inf = AUC 0 to infinity; 0-xh = AUC 0 to x hours.

Enzyme- Transporter-mediated Interactions

Drug is a substrate of CYP450
Drug is a substrate of Transporter PGP
CYP450 Inhibited by drug
Transporter Inhibited by drug PGP (weak)
CYP450 Induced by drug
Transporter Induced by drug
Impact on Serum Drug Concentrations 1 mild ↑

Footnotes:

1 : Impact on Serum Drug Concentrations refers to serum concentrations of companion drugs that may be affected by the listed antimicrobial. ↑=increase; ↓=decrease; blank=no drugs should be affected

Major Drug Interactions

Drug Effect on concentration (or other) Suggested management
Amiodarone ↑QT interval Monitor or avoid
Apixaban ↑apixaban Monitor or avoid
Betrixaban ↑betrixaban Monitor or avoid
Cyclosporine ↑cyclosporine Monitor or avoid
Dabigatran ↑dabigatran Monitor or avoid
Digoxin ↑digoxin Monitor, adjust dosage
Dofetilide ↑QT interval Monitor or avoid
Edoxaban ↑edoxaban Monitor or avoid
Everolimus ↑everolimus Monitor or avoid
Nelfinavir ↑azithromycin Monitor
Procainamide ↑QT interval Monitor or avoid
Quinidine ↑QT interval Monitor or avoid
Rivaroxaban ↑rivaroxaban Monitor or avoid
Sirolimus ↑sirolimus Monitor or avoid
Sotalol ↑QT interval Monitor or avoid
Tacrolimus ↑tacrolimus Monitor or avoid