Azithromycin (Zithromax®) versus Amoxicillin/Clavulanate (Augmentin®)

Based on "Antibiotic and Chemotherapy"
written by Roger G. Finch

Generally, azithromycin is significantly better tolerated and has shorter duration of therapy than amoxicillin/clavulanate.

Azithromycin Amoxicillin/ Clavulanate
Brand names
• Zithromax®
• Z-pak®
• Co-Amoxiclav
• Augmentin®
Drug class
Macrolide antibiotic Penicillin antibiotic and beta-lactamase inhibitor combination
Mode of action
Bacteriostatic Bactericidal
Side effects
• Minimal toxicity -
excellent safety and tolerability
• Clavulanic acid may be hepatotoxic6
• High rate of diarrhea7
Pregnancy category

Azithromycin vs Co-amoxiclav for Sinusitis

Amoxicillin with clavulanate is recommended by Clinical Practice Guideline as a first-line therapy for acute sinusitis8. Co-amoxiclav is safe and cost-effective initial therapy. This combination antibiotic covers all pathogens responsible for acute sinusitis (S. pneumoniae, H. influenzae, β-hemolytic streptococcus, and M. catarrhalis).

Azithromycin was recommended as alternative treatment in the past. Currently azithromycin is not recommended for empiric treatment of sinus infections due increasing rate of S. pneumoniae resistance.

Head-to-head comparative trials

Azithromycin and amoxicillin/clavulanate have similar efficacy in the treatment of sinusitis2, but azithromycin is better tolerated.

Results of randomized, double-blind, multicenter study of adults with acute bacterial sinusitis2 Azithromycin ER Amoxicillin Clavulanate
Regimen 500 mg/day once daily for 3 days (AZM-3)
or 6 days (AZM-6)
500/125 mg 3 times daily for 10 days
Clinical success rates the end of therapy

88.8% (AZM-3)
89.3% (AZM-6)

Clinical success rates the end of study 71.7% (AZM-3)
73.4% (AZM-6)
Incidence of side effects 31.1% (AZM-3)
37.6% (AZM-6)
Number of patients who discontinued study 7 (AZM-3)
11 (AZM-6)

Azithromycin extended release provides earlier resolution of acute sinusitis symptoms than amoxicillin/clavulanate 5.

Results of prospective, randomized, open-label, observational study of patients with symptoms of acute bacterial sinusitis5 Azithromycin ER Amoxicillin Clavulanate
Regimen single 2 g dose 875/125 mg every 12 hours for 10 days
Resolution of symptoms at day 5, number of patients (%) 70 of 236
45 of 238
Number of patients who needed additional antibiotics by day 28 26 of 236 (11.0%) 27 of 238 (11.3%)
Additional physician visits, quality of life, and overall satisfaction


Otitis media

Azithromycin and amoxicillin/clavulanate have similar efficacy in the treatment of acute otitis media in children1. Also, azithromycin provides more complete resolution of tympanic membrane disease, and is better tolerated.

Results of randomized, double-blind study of azithromycin comparing with co-amoxiclav for acute otitis media1 Azithromycin Co-amoxiclav
Regimen 10 mg/kg/day x 3 days 45 mg/kg/day x 10 days
Clinical success rate at day 10, number of patients (%) 153 of 185 (83%) 159 of 181 (88%)
Cure rate at day 28, number of patients (%) 134 of 182 (74%) 124 of 180 (69%)
Signs of AOM at day 28:
abnormal reflectometry
bulging of the eardrum
loss of tympanic membrane landmarks


Adverse events 11% 20%

More recent study4 found that single dose of azithromycin extended-release (ER) is slightly less effective than amoxicillin/clavulanate in the treatment of middle ear infections in children.

Results of randomized, double-blind, double-dummy, multicenter international study of azithromycin versus amoxicillin/clavulanate in children with acute otitis media. 4 Azithromycin ER Amoxicillin Clavulanate
Regimen single 60-mg/kg dose 90/6.4 mg/kg per day for 10 days
Clinical response at the test-of-cure visit 80.5% 84.5%
Bacteriologic eradication (actual killing of the bacteria) 82.6% 92%
Rates of dermatitis and diarrhea, and other adverse events higher in the amoxicillin/clavulanate group
Compliance to the medication higher in the azithromycin ER group

Lower respiratory tract infections

Azithromycin and amoxicillin/clavulanate have similar efficacy in the treatment of lower respiratory tract infections3.

Results of multicentre randomized double-blind, double-dummy study of children with acute lower respiratory tract infections 3 Azithromycin Co-Amoxiclav
Regimen 10 mg/kg daily for 3 days 45/11.25 mg/kg daily in 3 doses for 10 days
Percentage of patients cured or clinically improved at days 10-13 91% 87%
Adverse events significantly more were reported in the co-amoxiclav group
Gastrointestinal complaints rate 19% 43%

Further reading


  • 1. Dunne MW, Latiolais T, Lewis B, Pistorius B, Bottenfield G, Moore WH, Garrett A, Stewart TD, Aoki J, Spiegel C, Boettger D, Shemer A. Randomized, double-blind study of the clinical efficacy of 3 days of azithromycin compared with co-amoxiclav for the treatment of acute otitis media. J Antimicrob Chemother. 2003 Sep;52(3):469-72.
  • 2. Henry DC, Riffer E, Sokol WN, Chaudry NI, Swanson RN. Randomized double-blind study comparing 3- and 6-day regimens of azithromycin with a 10-day amoxicillin-clavulanate regimen for treatment of acute bacterial sinusitis. Antimicrob Agents Chemother. 2003 Sep;47(9):2770-4.
  • 3. Ferwerda A, Moll HA, Hop WC, Kouwenberg JM, Tjon Pian Gi CV, Robben SG, de Groot R. Efficacy, safety and tolerability of 3 day azithromycin versus 10 day co-amoxiclav in the treatment of children with acute lower respiratory tract infections. J Antimicrob Chemother. 2001 Apr;47(4):441-6.3 Nov-Dec;21(6):367-72.
  • 4. Arguedas A, Soley C, Kamicker BJ, Jorgensen DM. Single-dose extended-release azithromycin versus a 10-day regimen of amoxicillin/clavulanate for the treatment of children with acute otitis media. Int J Infect Dis. 2011 Apr;15(4):e240-8.
  • 5. Marple BF, Roberts CS, Frytak JR, Schabert VF, Wegner JC, Bhattacharyya H, Piccirillo JF, Sanchez SP. Azithromycin extended release vs amoxicillin/clavulanate: symptom resolution in acute sinusitis. Am J Otolaryngol. 2010 Jan-Feb;31(1)
  • 6. Cundiff J, Joe S. Amoxicillin-clavulanic acid-induced hepatitis.Am J Otolaryngol. 2007 Jan-Feb;28(1):28-30. PubMed
  • 7. Kuehn J, Ismael Z, Long PF, Barker CI, Sharland M. Reported rates of diarrhea following oral penicillin therapy in pediatric clinical trials. J Pediatr Pharmacol Ther. 2015 Mar-Apr;20(2):90-104 PubMed
  • 8. IDSA Clinical Practice Guideline for Acute. Bacterial Rhinosinusitis in Children and Adults.

Published: January 12, 2014
Last reviewed: January 23, 2018


More Comparisons
Home | Contact Us | Cookies Policy

This website is certified by Health On the Net Foundation. Click to verify. This site complies with the HONcode standard for trustworthy health information: verify here

Copyright 2007-2019 All rights reserved.
All information is for educational purposes only.