Clarithromycin Effective and Safe Choice of Antibiotic in Pediatric Out-patient Settings: Review

Pediatric outpatient settings encounter many infections daily. Healthcare professionals must consider various factors, including safety, approval, dosage regime, and adverse reactions, before prescribing medications for these infections, as it is for a vulnerable population. The decision is often empirical, based on clinical symptoms and history due to the lack of feasibility of diagnostic tests. Respiratory infections are pervasive in children, and antibiotics are commonly prescribed in pediatric outpatient settings. (1) Antibiotics are the fundamental treatment for bacterial infections, and macrolides are considered one of the preferred antimicrobial agent options. (2) Clarithromycin is a broad-spectrum macrolide antibacterial agent effective against the major pathogens responsible for respiratory tract infections in immunocompetent patients. (3)

Antimicrobial activity of Clarithromycin

Clarithromycin is semi-synthetic, a 14-membered ring macrolide antibiotic. It is an acid-stable orally administered macrolide antimicrobial drug structurally associated with erythromycin. Clarithromycin binds to the 50S ribosomal subunit and inhibits RNA-dependent protein synthesis in susceptible organisms. It exhibits a broad spectrum of antimicrobial activity and inhibits Gram-positive and Gram-negative organisms, atypical pathogens, and some anaerobes. (4)

Therapeutic indications of Clarithromycin in children

The U.S. Food and Drug Administration (FDA) has approved clarithromycin as an antibiotic in treating acute and chronic infections caused by clarithromycin susceptible organisms in pediatrics. (5)

• Upper respiratory tract infections include tonsillitis/pharyngitis and acute maxillary sinus infections.
• Acute otitis media.
• Mycobacterium avium complex (MAC) infection.
• Skin infections and soft tissue infections of mild to moderate severity.
• As an alternative to beta-lactam antibiotics.
• Infections of the lower respiratory tract like community-acquired pneumonia in children older than two years old, pneumonia, and acute bronchitis. (6)

Let's take a Peak at the Pharmacology of Clarithromycin (7,8,9)

• It possesses high oral bioavailability (52 to 55%), and it exhibits higher plasma concentrations compared to erythromycin.
• It has a longer elimination half-life, which permits its twice-daily administration
• Primarily metabolized into an active metabolite, 14-hydroxyclarithromycin.
• Reaches significantly higher drug concentrations in the epithelial lining fluid and alveolar macrophages, the potential sites of extracellular and intracellular respiratory tract pathogens respectively.
• Approximately one-third of the drug is excreted by the kidney and the remaining is metabolized in the liver.
• The absorption of clarithromycin is not affected by the presence of the food.
• Clarithromycin is a weak inducer of CYP and exhibits fewer drug-drug interactions, but its use with theophylline, carbamazepine, and terfenadine is contraindicated.

Pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug interactions are demonstrated with clarithromycin than with older macrolides.

Why choose Clarithromycin over Other Antibiotics? (10)

• The efficacy of clarithromycin oral suspension is equivalent to amoxicillin/clavulanate oral suspension in the treatment of acute otitis media in children.
• Clarithromycin is better tolerated than amoxicillin/clavulanate with a lower incidence of gastrointestinal side effects.
• Clarithromycin has similar efficiency as standard oral therapies against respiratory tract and soft tissue infections. (11)
• Clarithromycin has a longer serum half-life and better tissue penetration allowing twice-a-day dosing for most common infections. (11)
• Gastrointestinal distress is relatively uncommon with Clarithromycin
• Clarithromycin is active against some unexpected pathogens (e.g., B burgdorferi, T gondii, M avium complex, and M leprae).
• Clarithromycin is highly active against atypical mycobacteria.
• Clarithromycin tended to produce better clinical success and bacteriological eradication than amoxicillin/clavulanic acid and also phenoxymethylpenicillin in patients with streptococcal pharyngitis (3, 11)
• Clarithromycin has a superior pharmacokinetic profile to that of erythromycin. (12)
• Clarithromycin is metabolized into an active compound with twice the in vitro activity of the parent drug against H influenza. (11)

Dosage and Route of Administration in Paediatric Patients (13)

The dose and duration of clarithromycin treatment depend on the clinical condition of the patient.

• Children 6 months to 12 years of age: Clarithromycin 125 mg/5 ml Oral Suspension, the recommended dose is 7.5 mg/kg twice a day for 5 to 10 days

Infants <6 months: There is limited experience in this population

What do studies reveal about clarithromycin in Paediatric patients?

• Safe and effective for the treatment of upper respiratory infections in pediatric patients: In a systematic review with meta-analysis of randomized controlled trials (RCTs) which included 24 studies, it was reported that Clarithromycin was safe and effective for treating URIs in pediatric patients of age < or = 12 years with upper respiratory infections. (2)
• Clarithromycin - 10 days of treatment in children with acute otitis media with effusion: In another research, scientists allocated children aged six months to 12 years with acute otitis media with effusion to azithromycin at 10 mg/kg once daily for three days or to clarithromycin at 15 mg/kg day divided into two equal doses for ten days. Clarithromycin showed a satisfactory clinical response in the study and can be considered for treating children with acute otitis media. (14)
• Low-dose macrolide given for the long term presented a good recovery rate for otitis media with effusion in pediatric patients: A study enrolled children with otitis media with effusion, prescribed macrolides according to a designed protocol, and followed up for 8-12 weeks. The result noted that almost 72.1% of chronic otitis media with effusion patients recovered after an 8-week course of low-dose macrolides. In this study, clarithromycin was selected as the first-line macrolide for its efficacy on OME in previous studies and clinical safety. (15)
• Clarithromycin has very less allergenic activity compared to Azithromycin in children with suspected hypersensitivity reaction to macrolide: A study was conducted on 90 children aged 1-17 years with symptoms suggestive of hypersensitivity reaction to clarithromycin or azithromycin to evaluate the safety of macrolide. Results showed that clarithromycin is safer than azithromycin, as it exhibited less allergenic activity. (16)

Takeaway Points

• Clarithromycin reaches significantly higher drug concentrations in the epithelial lining fluid and alveolar macrophages, the potential sites of extracellular and intracellular respiratory tract pathogens, making it a clinically relevant antimicrobial agent in respiratory infections.
• Due to the risk of antibiotic resistance and side effects, macrolides should be prescribed with care and judiciously in the pediatric population. Clinicians should apply precise diagnostic criteria, weigh the benefits and harms of antibiotic therapy, and understand situations regarding the indications of the antibiotics.
• Clarithromycin 125 mg/5 ml oral suspension should be considered, as it is safe and well-tolerated in the pediatric population. (17)
• Clarithromycin can be given irrespective of food intake as the extent of its bioavailability is not affected by food.
• Clarithromycin remains active against clinically relevant respiratory tract pathogens. It shows better efficacy and tolerance than amoxicillin- clavulanic acid in specific respiratory infections.

References:

1. Saleh EA, Schroeder DR, Hanson AC, Banerjee R. Guideline-concordant antibiotic prescribing for pediatric outpatients with otitis media, community-acquired pneumonia, and skin and soft tissue infections in a large multispecialty healthcare system. Clin Res Infect Dis. 2015 Jan 10;2(1):1010.

2. 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 Mar-Apr;64(2):126-35.

3. Langtry, H.D., Brogden, R.N. Clarithromycin. Drugs 53, 973–1004 (1997). https://doi.org/10.2165/00003495-199753060-00006

4. Peters DH, Clissold SP. Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties, and therapeutic potential. Drugs. 1992 Jul;44(1):117-64. doi: 10.2165/00003495-199244010-00009)(Drug Database, Clinicalinfo.hiv.gov https://clinicalinfo.hiv.gov//en/drugs/clarithromycin/patient.

5. National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 84029, Clarithromycin. Retrieved August 5, 2022, from https://pubchem.ncbi.nlm.nih.gov/compound/Clarithromycin.) ((Langtry, H.D., Brogden, R.N. Clarithromycin. Drugs 53, 973–1004 (1997). https://doi.org/10.2165/00003495-199753060-00006.

6. Block S, Hedrick J, Hammerschlag MR, Cassell GH, Craft JC. Mycoplasma pneumoniae and Chlamydia pneumoniae in pediatric community-acquired pneumonia: comparative efficacy and safety of clarithromycin vs. erythromycin ethylsuccinate. Pediatr Infect Dis J. 1995 Jun;14(6):471-7. doi: 10.1097/00006454-199506000-00002.

7. Rodvold KA. Clinical pharmacokinetics of clarithromycin. Clin Pharmacokinet. 1999 Nov;37(5):385-98. doi: 10.2165/00003088-199937050-00003.

8. King SM. Clarithromycin for children. Can J Infect Dis. 1995 Mar;6(2):69-70. doi: 10.1155/1995/820963

9. Principi N, Esposito S. Comparative tolerability of erythromycin and newer macrolide antibacterials in pediatric patients. Drug Saf. 1999 Jan;20(1):25-41. doi: 10.2165/00002018-199920010-00004. PMID: 9935275.

10. McCarty JM, Phillips A, Wiisanen R. Comparative safety and efficacy of clarithromycin and amoxicillin/clavulanate in the treatment of acute otitis media in children. Pediatr Infect Dis J. 1993 Dec;12(12 Suppl 3):S122-7. doi: 10.1097/00006454-199312003-00006. PMID: 8295813.

11. Whitman MS, Tunkel AR. Azithromycin and clarithromycin: overview and comparison with erythromycin. Infect Control Hosp Epidemiol. 1992 Jun;13(6):357-68. doi: 10.1086/646545.

12. Peters DH, Clissold SP. Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties, and therapeutic potential. Drugs. 1992

13. https://www.medicines.org.uk/emc/product/515/smpc#gref

14. Arguedas A, Loaiza C, Rodriguez F, Herrera ML, Mohs E. Comparative trial of 3 days of azithromycin versus 10 days of clarithromycin in the treatment of children with acute otitis media with effusion. J Chemother. 1997 Feb;9(1):44-50. doi: 10.1179/joc.1997.9.1.44. PMID: 9106017.

15. Chen K, Wu X, Jiang G, Du J, Jiang H. Low dose macrolide administration for long term is effective for otitis media with effusion in children. Auris Nasus Larynx. 2013 Feb;40(1):46-50. doi: 10.1016/j.anl.2012.05.008. Epub 2012 Jun 4. PMID: 22673738

16. Barni S, Butti D, Mori F, Pucci N, Rossi ME, Cianferoni A, Novembre E. Azithromycin is more allergenic than clarithromycin in children with suspected hypersensitivity reaction to macrolides. J Investig Allergol Clin Immunol. 2015;25(2):128-32. PMID: 25997306.

17. Craft JC, Siepman N. Overview of the safety profile of clarithromycin suspension in pediatric patients. The Pediatric Infectious Disease Journal. 1993 Dec;12(12 Suppl 3):S142-7. DOI: 10.1097/00006454-199312003-00009. PMID: 8295816.