Sanford Guide: Azithromycin

Drug Shortages

Prep	Started At	Notes
Oral susp, 1 gm packets	2024-11-20

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.
Available in multiple pharmaceutical preparations (see Pharmacology).
Evaluate risk of prolongation of QTc before prescribing; details under adverse effects

Adult Dose

Bacterial conjunctivitis	1% oph solution: 1 drop bid x2 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 (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

Mild impairment (Child-Pugh Class A)	No dosage adjustment
Moderate impairment (Child-Pugh Class B)	No dosage adjustment
Severe impairment (Child-Pugh Class C)	No dosage adjustment

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	Humans: no evidence of toxicity. Animals: some evidence of decreased viability and delayed development in rats.
Use during Lactation	Safe, monitor infant for GI toxicity

Footnotes:

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

Antimicrobial Spectrum

Preferred ++ ( 10 )

Agent is a first line therapy: reliably active in vitro, clinically effective, guideline recommended, recommended as a primary or acceptable alternative agent in the Sanford Guide. See pathogen page for specific recommendations.

Alternative + ( 13 )

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

CYP450s that drug is a substrate for:	-
Transporters that drug is a substrate for:	PGP
UGTs that drug is a substrate for:	-
CYP450s inhibited by drug:	-
Transporters inhibited by drug:	PGP (weak)
UGTs inhibited by drug:	-
CYP450s induced by drug:	-
Transporters induced by drug:	-
UGTs induced by drug:	-
Impact on serum drug concentrations ¹	mild ↑

Footnotes:

Refers to serum concentrations of companion drugs that may be affected by the listed antimicrobial. ↑=increase, ↓=decrease.

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