Clarithromycin-Quick Review of Its Unique Antibiotic Spectrum and Therapeutic Use

A significant quest for newer macrolides with enhanced tolerance and favorable pharmacokinetic features has been prompted by the recurrent gastrointestinal side effects caused by older macrolide antibiotics and their adverse pharmacokinetic profile. This led to synthesizing the second generation of macrolides, including the well-known member, Clarithromycin. (1)

The following review will give insight into Clarithromycin's clinical applicability, backed by scientific evidence for its use in different conditions.

Macrolide Antibiotics Challenges: Overcoming with Clarithromycin:

Clarithromycin, one of several new macrolide antibiotics, is known for its stability in gastric acid and favorable pharmacokinetic properties following oral administration. It is not associated with macrolide-induced GI irritation. The increased acid stability of Clarithromycin not only results in improved oral bioavailability but may also lead to improved intracellular bioactivity. (1)

Clarithromycin concentrations in lung tissue are ten times higher than those in serum, demonstrating that the drug is clinically relevant during pulmonary infections. (1)

The superiority of Clarithromycin over other Macrolides Antibiotics in Upper Respiratory Tract Infections (URTI): Several studies have demonstrated the effectiveness of macrolides against the most frequently isolated bacterial causes of pharyngitis, otitis media, and sinusitis. (2)

• Clarithromycin vs. Commonly Used Antibiotics in URTI: A meta-analysis assessed the efficacy of Clarithromycin versus the most commonly used treatment for URTI (including amoxicillin, amoxicillin plus clavulanic acid). It is even more effective than beta-lactam antibiotics for treating sinusitis (OR: 1.27, 95% CI: 1.01-1.61 in intent-to-treat analysis). 1.12, 95% Cl: 1.01-1.25). Regarding safety, the incidence of adverse events was significantly lower for clarithromycin compared to amoxicillin and amoxicillin-clavulanic acid. The finding concluded that Clarithromycin is effective and safe in treating URTI. (3)
• Acute Bacterial Sinusitis: A controlled, multicenter, investigator-blinded study compared the efficacy and tolerability of Clarithromycin [1000mg once daily] to amoxicillin/ clavulanate [875mg/125mg] (N=437, aged above 12 years). A clinical cure rate was observed at 98% with Clarithromycin and 97% with amoxicillin/clavulanate within 14 days of treatment. Clarithromycin showed symptomatic improvement or relief as early as 2 days-5 days after initiating the drug, with a statistically significantly higher resolution rate of sinus pressure (p=0.027) and improvement/resolution rate of nasal congestion (p = 0.035). The study concluded that Clarithromycin was comparable, and for selected measures superior to amoxicillin/clavulanate for treating bacterial sinusitis. (4)
• Acute Bacterial Pharyngitis: A meta-analysis of 5 randomized, multi-center outpatient trials (N= 1184; participants above 12 years) evaluated the efficacy and safety of Clarithromycin in treating pharyngitis due to Group A beta-hemolytic Streptococci (GABHS). Penicillin VK and erythromycin were the active competitors in the trials. The numerical findings for bacteriological cure are notably in favor of Clarithromycin; the clinical outcomes of the post-treatment at 4-6 days showed that the cure rate of Clarithromycin (250 mg twice daily for ten days) was 84.9%, while it was 83.6% with penicillin VK (250 mg three or four times daily). Comparison of the cure rate of Clarithromycin (250 mg twice daily for ten days) and erythromycin (500 mg twice daily) was 81.9% and 79.6%, respectively. Clarithromycin was well tolerated, with a low incidence of adverse events. The results of this analysis indicate that Clarithromycin is an effective and largely well-tolerated treatment option for GABHS pharyngitis patients who cannot benefit from other agents. (5)

Evidence in Pediatric Patients:

A systematic review of meta-analysis (24 studies from 76 RCTs) analyzed the safety and efficacy of Clarithromycin in pediatric patients (below 12 years) with URTI. Clarithromycin showed better bacteriological eradication [RR 1.06 (1.02 to 1.09), p=0.001] and a lower risk for related adverse events [RR 0.77 (0.65 to 0.90), p = 0.001]. The study concluded that Clarithromycin is superior to other antibiotics for bacterial eradication and is safe and effective in pediatric patients with URTI. (6)

Acute Otitis Media (AOM): A single-blind, randomized, multicentre clinical trial compared the safety and efficacy of Clarithromycin and amoxicillin in pediatric AOM patients (N=259). Both suspensions were prescribed at 125 mg for children weighing less than 25 kg or 250 mg for children weighing more than 25 kg for five days. Clarithromycin showed 80% clinical cures against 68% with amoxicillin (p = 0.057). Adverse events were observed in 3% with Clarithromycin and 6% with amoxicillin. At the doses administered, Clarithromycin given twice daily was as safe and effective as given three times daily in treating AOM pediatric patients. (7)

Indian Evidence: A six-month prospective observational study compared and assessed the efficacy of the three antibiotics: Clarithromycin, cefuroxime, and levofloxacin. The study included 99 subjects, under the age of 14 years attending the outpatient pediatric department URTI. Clarithromycin (125 mg/5 ml) has shown cure [patient is completely relieved from symptoms by the treatment] before completing three days in 73% of individuals, whereas cefuroxime (125 mg/5ml] has shown 73% within five days. The treatment time is longer in the levofloxacin group (125 mg/5 ml) as most patients took more than 5 days for improving symptoms. Clarithromycin and cefuroxime showed an equal efficacy rate of 94%, but Clarithromycin showed a shorter duration of the outcome, i.e., three days. A significant difference of p<0.05 (p=0.00) was observed, and no adverse events were noted. The study indicated that among the three antibiotics, Clarithromycin is preferable as it is more effective than the other two drugs in the treatment of pediatric URTI. (8)

Clinical Message:

Clarithromycin is one of the most commonly prescribed macrolide antibiotics. The incidence of adverse events with Clarithromycin is significantly lower than other antibiotics such as amoxicillin and amoxicillin-clavulanic acid. Clarithromycin offers advantages in the form of improved pharmacokinetics, pharmacodynamics, and higher tissue concentration. The bacteriological superiority of Clarithromycin over erythromycin may partly reside in the drug’s metabolism, including tissue penetration and the formation of a bacteriologically relevant 14-hydroxy metabolite. Considering these advantages, Clarithromycin may be considered for empirical use in patients with URTIs.

Reference-

1. Sturgill MG, Rapp RP. Clarithromycin: review of a new macrolide antibiotic with improved microbiologic spectrum and favorable pharmacokinetic and adverse effect profiles. Ann Pharmacother. 1992;26(9):1099-1108. doi:10.1177/106002809202600912

2. Davidson RJ. In vitro activity and pharmacodynamic/pharmacokinetic parameters of clarithromycin and azithromycin: why they matter in the treatment of respiratory tract infections. Infect Drug Resist.2019;12:585-596. Published 2019 Mar 8. doi:10.2147/IDR.S187226

3. Abad-Santos, F., Gálvez-Múgica, M. A., Espinosa de los Monteros, et.al. Meta-analysis of clarithromycin compared with other antimicrobial drugs in the treatment of upper respiratory tract infections. 2003. Rev Esp Quimioter. 2003 Sep;16(3):313-24.

4. Riffer E, Spiller J, Palmer R, et al. Once daily clarithromycin extended-release vs twice-daily amoxicillin/clavulanate in patients with acute bacterial sinusitis: a randomized, investigator-blinded study. Current Medical Research and Opinion. 2005 Jan;21(1):61-70. DOI: 10.1185/030079904x18009.

5. 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. Published 2019 Oct 16. doi:10.2147/DDDT.S205820

6. Gutiérrez-Castrellón P, Mayorga-Buitron JL, Bosch-Canto V, et.al. Efficacy and safety of clarithromycin in pediatric patients with upper respiratory infections: a systematic review with meta-analysis. Rev Invest Clin. 2012;64(2):126-135.

7. Coles SJ, Addlestone MB, Kamdar MK, Macklin JL. A comparative study of clarithromycin and amoxicillin suspensions in the treatment of pediatric patients with acute otitis media. Infection. 1993;21(4):272-278. doi:10.1007/BF01728911

8. Padugundla G, Jyothirmayee V, Ravali B et.al. A Randomised Control Study To Compare The Efficacy Of Cefuroxime, Clarithromycin, And Levofloxacin In The Management Of Paediatric Upper Respiratory Tract Infection. Asian J Pharm Clin Res.2021.DOI: http://dx.doi.org/10.22159/ajpcr.2021v14i10.42957