Drug Review: Clarithromycin in Upper Respiratory Tract Infections

Continuously rising antimicrobial resistance to beta-lactam drugs, which are used commonly against upper respiratory tract infections, has shifted the focus on viable alternative antimicrobial agents. Macrolides, being safe and well-tolerated antibiotics, serve an essential role in treating community-acquired upper respiratory tract infections. Due to their broad-spectrum activity against gram-positive cocci such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, macrolides are now widely used as empiric treatment of upper respiratory tract infections. (3)

Role of Clarithromycin in Managing URTI-Attributes that make the antibiotic a promising therapy in URTIs

• Clarithromycin, a second-generation macrolide which is more potent than its predecessor erythromycin offers significant improvements with an expanded spectrum of activity and improved tolerability and can be opted for in patients having acute bacterial pharyngitis. (4)
• Clarithromycin's bacteriological superiority over erythromycin is attributed to the drug's pharmacokinetics and metabolism, which include tissue penetration and the formation of 14-hydroxy metabolite which acts as the prime bacteriocide, as well as findings from pharmacodynamic modelling, which opines that clarithromycin has the least potential for promoting the emergence of unrecognized resistant strains within a susceptible strain. (4)
• Evidence from various clinical trials and experimental research suggests that clarithromycin possesses anti-inflammatory and immunomodulatory benefits that may be relevant to respiratory infections. (4)
• Inhibiting the development of microbial toxins and other virulence factors, thereby attenuating the pro-inflammatory host response, suppressing immune cell activity, and modulating the cytokine profile towards more anti-inflammatory states are other possible mechanisms. (4)

Scientific Evidence supporting Clarithromycin: Clinical Evidence in Respiratory Infections-

• In sinusitis- A comprehensive evaluation of published trials highlighted that there were no significant differences in effectiveness between clarithromycin and amoxicillin-clavulanic acid for upper respiratory infections. The report also revealed that clarithromycin was more efficacious than beta-lactam antibiotics for sinusitis (OR: 1.27, 95% CI: 1.01-1.61). Regarding safety, the incidence of adverse events was significantly lower for clarithromycin than for beta-lactams (amoxicillin and amoxicillin-clavulanic acid). (5)
• In acute otitis media-Clarithromycin has been demonstrated to attain high concentrations in the middle ear and to be clinically helpful in individuals with acute otitis media (AOM). Clinical trials have consistently affirmed that clarithromycin, as a newer generation macrolide, is equally effective as amoxicillin/clavulanic acid and cefaclor in the treatment of AOM and is preferable due to the less frequent administration, shorter length of treatment, and reduced frequency of recurrence. (3)
• In pharyngitis-A meta-analysis assessing the evidence base for clarithromycin in patients with URTIs, specific pharyngitis due to group A beta-hemolytic Streptococci (GABHS pharyngitis) concluded that the rates of bacteriological cure were higher with clarithromycin than with either comparator agents (penicillin, erythromycin). (4)
• In pediatric populations-Corroborating with the above results, clarithromycin has emerged as a practical option for treating URTIs in pediatric patients (5,6). Clarithromycin is a safe and effective option for the treatment of URTIs in pediatric patients, given the fact that URTIs are among the most commonly encountered pediatric infections. High-quality research affirms that clarithromycin is more effective than other antibiotics at eradicating bacteria and exhibits a therapeutically equivalent profile in terms of clinical cure, clinical success, and relapse risk. (6)
• In COVID-19-related URTI-Study results indicate that treatment of COVID-19 with clarithromycin may reduce the host's hyper-inflammatory reactions and the likelihood of progression to severe respiratory failure (SRF). The ACHIEVE trial (Anti-inflammatory Clarithromycin to Improve SARS CoV 2 Infection Early) was designed as a proof-of-concept study to determine whether early administration of oral clarithromycin amongst patients with respiratory tract infection (URTI) due to SARS CoV-2 could reduce the inflammatory burden, modulate the host immune response, and result in early clinical improvement. The results highlighted that early clarithromycin treatment in patients with moderate COVID-19 leads to the most clinical improvement. Treatment should start in the first five days from symptoms onset. The effect of clarithromycin is associated with an increase in interferon-gamma production, a decrease in interleukin-6 production and a decrease in viral load. (7)

• Clarithromycin is now included in the World Health Organisation (WHO) Essential List of Medicines. (8)
• The ICMR (Indian Council of Medical Research) guidelines recommend the use of clarithromycin in Streptococcal pharyngitis and acute otitis media for patients allergic to penicillin. (2)

• URTIs continue to be a frequently encountered infection across OPDs, with massive use of antibiotic prescriptions. (1,9)
• Spiking resistance against beta-lactams has put the focus on other important antibiotic therapies. Macrolides have now gained popularity in managing URTIs effectively.(3)
• Newer generation macrolide clarithromycin has proven to be clinically effective and is very well tolerated for treating patients with URTIs. (3)
• With the newer generation of macrolides exhibiting a better pharmacodynamic, clinical efficacy, and safety profile, managing URTIs with clarithromycin is a promising option for managing upper respiratory tract infections. (3)

Adapted from

1. Md.Zulqarnain, Singh S, Prasad A, Abdullah, Palit T, Use of Antibiotics in Upper Respiratory Tract Infections in Tertiary Care Teaching Hospital of Delhi, Journal of drug delivery and Therapeutics. 2021; 11(2-s):36-40

2. Indian Council of Medical Research. (2019). Treatment guidelines for antimicrobial use in common syndromes. Indian Counc Med Res Dep Heal Res New Delhi, India [Internet]., 1-106.

3. Aleksandra K. Wierzbowski; Daryl J. Hoban; Tamiko Hisanaga; Mel DeCorby; George G. Zhanel (2006). The use of macrolides in the treatment of upper respiratory tract infections. , 6(2), 171–181. doi:10.1007/s11882-006-0056-x

4. Hoban DJ, Nauta J. Clinical And Bacteriological Impact Of Clarithromycin In Streptococcal Pharyngitis: Findings From A Meta-Analysis Of Clinical Trials. Drug Des Devel Ther. 2019;13:3551-3558 https://doi.org/10.2147/DDDT.S205820

5. Abad-Santos F, Gálvez-Múgica MA, Espinosa de Los Monteros MJ, Gallego-Sandín S, Novalbos J. [Meta-analysis of clarithromycin compared with other antimicrobial drugs in the treatment of upper respiratory tract infections]. Rev Esp Quimioter. 2003;16(3):313–324. Spanish.

6. Gutiérrez-Castrellón P, Mayorga-Buitron JL, Bosch-Canto V, Solomon-Santibañez G, de Colsa-Ranero A. Efficacy and safety of clarithromycin in pediatric patients with upper respiratory infections: a systematic review with meta-analysis. Rev Invest Clin. 2012;64:126–135.

7. Tsiakos, K., Tsakiris, A., Tsibris, G., Voutsinas, P. M., Panagopoulos, P., Kosmidou, M., ... & Giamarellos-Bourboulis, E. J. (2021). Early start of oral clarithromycin is associated with better outcomes in COVID-19 of moderate severity: the ACHIEVE open-label single-arm trial. Infectious diseases and therapy, 10(4), 2333-2351.

8. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.02

9. Thomas M, Bomar PA. Upper Respiratory Tract Infection. [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532961