Clarithromycin in outpatient ENT settings: A Review

In outpatient care settings, otorhinolaryngologists and head and neck surgeons encounter many complex ears, nose, and throat (ENT) infectious conditions. Left untreated, ENT infections can rapidly snowball into complex sequels leading to recurrent infections and disturbing ear, nose, and throat functions. These morbidities may occasionally result in social awkwardness and professional, academic, and financial losses for patients and their families. (1)

Determining the Right Antimicrobial Agent is Prudent

Because of the serious morbidities that ENT infections can cause due to the impairment of the innate physiologic functions (that often occur in the head and neck region), knowledge of the optimal therapy for ear, nose, and throat infections is of prime importance. (1)

Based on expert choices, knowledge, and drug availability, managing these ENT-related diseases differs in a community hospital or an OPD setup. (1)

Macrolide antibiotics are most often used for managing ENT diseases, particularly in ambulatory care settings. Based on current guidelines, macrolide antibiotics are essential to their optimum therapeutic efficacy while avoiding drug resistance. (2) This article aims to elaborate on the specific benefits of clarithromycin over other macrolides, its unique mechanism of action, and studies supporting a rationale use of this antimicrobial agent for clinical application in ENT infections.

Clarithromycin -A summary of the Drug and its uses

• Clarithromycin is an antibiotic prescription medicine approved by the United States Food and Drug Administration (FDA) to treat certain bacterial infections caused by specific types of bacteria, such as community-acquired pneumonia, throat infections (pharyngitis), acute sinus infections, and others. (3)
  
• The FDA also licenses clarithromycin to prevent and treat Mycobacterium avium complex (MAC) infection, a complex, bacterial respiratory infection. (3)

Is clarithromycin a better choice among macrolides?

Clarithromycin's unique benefits explain why it is effective and of clinical utility, for treating respiratory tract infections, in both adults and children. (2)

• High activity against numerous Gram-positive and Gram-negative bacteria as well as atypical and common pathogens.
• High concentrations in cells and tissues, which encourages a high level of clinical and microbiological activity;
• High action against Haemophilus influenza infections (acts twice as strongly as clarithromycin itself via its metabolite, 14-hydroxy-clarithromycin);
• Beta-lactamase resistance (a pharmacologic category distinct from beta-lactams);
• The availability of oral and intravenous forms, enabling so-called sequence treatment;
• The dosage is administered twice or once daily;
• Less chance of selection of strains that are resistant to macrolides than azithromycin.

Among popular macrolides, clarithromycin, has higher and more constant absorption, resulting in bioavailability ranging from 50 to 55 percent, compared to only 18 to 45 percent (depending on the salt derivative) for erythromycin. While erythromycin requires to be given 3-4 times a day, research suggests that a twice-daily dose of clarithromycin (for similar periods) is sufficient to fight gram-positive and gram-negative respiratory tract infections; thus highlighting the difference in microbiological potency of the two drugs. (4)

Position of Clarithromycin in the outpatient ENT scenario-

Owing to the lack of feasibility for bacterial culture findings and drug sensitivity testing, the primary decision-making regarding the choice of antimicrobial treatment for ENT outpatients is predominantly empirical. (5)

Clarithromycin: Review of Clinical Studies in URTIs

• Clinical Practice Trend of Using Clarithromycin: In 2017, a survey about the use of clarithromycin in the Ear, Nose, and Throat (ENT) Outpatient Department of Fudan University Hospital in China was undertaken to understand its utilization patterns and rational use. The team concluded that 82.5% of the clarithromycin prescriptions were for treating acute and chronic rhinosinusitis. The research team elaborated that the clarithromycin dosage regimen varied in outpatient clinical practice. For chronic rhinosinusitis, the preferred duration of treatment was usually between 8 and 16 days. Interestingly, clarithromycin was also prescribed in 11.7% of the cases for the treatment of secretory otitis media, owing to its anti-biofilm and anti-inflammatory functions. (5)
• Anti-inflammatory Effect of Clarithromycin: A study by Zeng et al. highlights that clarithromycin demonstrated a dexamethasone-like anti-inflammatory impact in patients with chronic rhinosinusitis(CRS), with an increase in anti-inflammatory mediators and a reduction in the generation of Th1 and Th2 responses of the sinonasal mucosa. Although the use of clarithromycin by patients with Chronic Rhinosinusitis (CRS) with Nasal Polyps(CRSwNP) is contentious, new studies now indicate that patients with CRSwNP benefit greatly from long-term usage of this antibiotic. The results noted that long-term adjuvant use of low-dose clarithromycin for chronic rhinosinusitis patients with recurrent sinonasal polyposis (resistant to therapeutic and surgical therapy) resulted in a better quality of life and nasal endoscopy results. Further, the team concluded that this improvement was sustained in the patient group tested 12 weeks after therapy ended. Interestingly, despite chronic use, medication withdrawal had no adverse reactions or side effects. (6)
• A non-comparative trial was conducted in primary care settings; among patients with upper or lower respiratory tract infections treated with Clarithromycin 250 mg twice daily for 6 to 12 days. Excellent results were reported in 76.1% of cases, while good results were reported in another 20.7% of patients. It was reported that sore throat improved in the majority of patients within 48 hours and cough was absent in most patients within 7 days. (7)
• The most consequential form of bacterial upper respiratory tract infection (UTRI) is pharyngitis caused by Group A beta-hemolytic Streptococci (GABHS). (8) A study review (9) highlighted the comparative efficacy and safety of clarithromycin in pediatric patients with URTIs. Echoing a similar result, a later published eminent Cochrane systematic review, (10) concluded that macrolides and penicillin showed comparable efficacy in treating GABHS pharyngitis in adults.
• With the aim to evaluate the effectiveness of Clarithromycin versus most commonly used drugs for upper respiratory infections, a meta-analysis (11) was conducted by Abad-Santos F et al. Comparing Clarithromycin to other drugs (amoxicillin-clavulanic acid for upper respiratory infections, cephalosporins, amoxicillin or amoxicillin-clavulanic acid for otitis media, or oral penicillin for classic streptococcal tonsillitis) revealed comparable clinical efficacy. For treating sinusitis, Clarithromycin performed better than beta-lactam antibiotics.
• It was noted that among macrolides, Clarithromycin had higher efficacy as compared to azithromycin. In terms of safety, compared to amoxicillin and amoxicillin-clavulanic acid, Clarithromycin had a much-reduced frequency of adverse effects. It was thus concluded that Clarithromycin is a safe and effective therapy for upper respiratory infections. Furthermore, its once-daily dosage may increase therapeutic compliance among patients. (11)

Administration-The most commonly used clarithromycin doses are-125mg / 250mg / 500mg / 1000mg (extended-release) – oral tablets. (12)

Depending on the treatment needed and the targeted pathology, clarithromycin can be administered in a variety of ways. The most often used form of these medications is oral tablets, also available as topical creams, injectable medications, and ophthalmic preparations. (12)

Long Term Safety profile of Clarithromycin is Established-Kadota and colleagues (13) investigated the safety and efficacy of once-daily clarithromycin administered at a low dose in patients with chronic respiratory infections for four years. They discovered that most of these individuals improved pulmonary function within six months and, in many cases, within 2 to 3 months. Within six months, 90% of the patients had improved oxygen saturation at rest and quality of life. These benefits lasted at least four years, with no documented adverse effects.

FDA recommends patients with heart problems should exercise caution when using the antibiotic clarithromycin. (14)

Classified as a category C drug, clarithromycin, should be used with great caution in pregnant women. (14)

Key pointers-

• ENT infections, when left untreated, may lead to severe complications, specifically in the head-neck region.
• Macrolides are among the most popular antibiotics in managing ENT diseases.
• Studies consistently highlight that clarithromycin, owing to its unique features, is a popular and well-accepted macrolide for managing ENT infections.
• Evidence affirms that clarithromycin, whether used for short-term or long-term therapy, exhibits a relatively good safety profile, with minimal adverse effects.

Take home message-With growing evidence backing the use of clarithromycin safely and efficiently in treating ear and nose throat diseases; ENT specialists may like to consider judicious use of clarithromycin in out-patient settings.

References:

1. Fasunla AJ, Samdi M, Nwaorgu OG. An audit of ear, nose, and throat diseases in a tertiary health institution in Southwestern Nigeria. Pan Afr Med J. 2013;14:1. doi: 10.11604/pamj.2013.14.1.1092. Epub 2013 Jan 1. PMID: 23503692; PMCID: PMC3597854.

2. Emeryk, A., Mazurek, H., Pirożyński, M., Klatka, J., Służewski, W., Antczak, A., ... & Dutkowska, A. (2016). Macrolide antibiotics in respiratory diseases. Recommendations of the Polish Expert Group—AD 2015. Advances in Respiratory Medicine, 84(1), 62-80.

3. National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 84029, Clarithromycin. Retrieved July 5, 2022 from https://pubchem.ncbi.nlm.nih.gov/compound/Clarithromycin

4. Amsden, G. W. (1996). Erythromycin, clarithromycin, and azithromycin are the differences real?. Clinical therapeutics, 18(1), 56-72.

5. Yan, J., Shen, J., Li, Y., Tang, F., & Chen, N. (2017). Survey about the use of clarithromycin in an ENT outpatient department of a tertiary hospital. European Archives of Oto-Rhino-Laryngology, 274(8), 3103-3107.

6. Zeng, M., Li, ZY., Ma, J. et al. Clarithromycin and dexamethasone show similar anti-inflammatory effects on distinct phenotypic chronic rhinosinusitis: an explant model study. BMC Immunol 16, 37 (2015). https://doi.org/10.1186/s12865-015-0096-

7. Bogossian M. Use of clarithromycin for respiratory infections in general practice Iin Portuguese I.Rev Bras Med 1995 May; 52: 500-9

8. 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

9. 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.

10. van Driel ML, De Sutter A, Habraken H, Thorning S, Christiaens T. Different antibiotic treatments for group A streptococcal pharyngitis. Cochrane Database Syst Rev. 2016;9:CD004406.

11. 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]. Revista Espanola de Quimioterapia : Publicacion Oficial de la Sociedad Espanola de Quimioterapia. 2003 Sep;16(3):313-324. PMID: 14702124.

12. Patel PH, Hashmi MF. Macrolides. [Updated 2022 Feb 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551495/

13. Kadota, J., Mukae, H., Ishii, H., Nagata, T., Kaida, H., Tomono, K., & Kohno, S. (2003). Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. Respiratory medicine, 97(7), 844–850. https://doi.org/10.1016/s0954-6111(03)00042-8

14. US Food and Drug Administration. (2018). FDA drug safety communication: FDA review finds additional data supports the potential for increased long-term risks with antibiotic clarithromycin (Biaxin) in patients with heart disease. US Food and Drug Administration, Silver Spring, MD.