Approach to Treatment of Acute Upper Respiratory Tract Infections and Scientific Spectacle on Clarithromycin

Overview of Acute URTI

Upper respiratory tract infections (URTI) are infections affecting the upper airways, including the nasal passages, sinuses, throat, larynx, and pharynx. They encompass conditions like acute rhinitis, pharyngitis, sinusitis and otitis media, often causing symptoms such as sore throat, nasal congestion, cough, and systemic manifestations like fever and malaise.[1,2] The Global Burden of Disease Study 2019 reported that the incidence of URTI in India between 1990 and 2019 amounted to a staggering 2.70 billion cases.[3] According to the National Family Health Survey 5, conducted during 2019–2020, the prevalence of Acute Respiratory Infections in India was reported to be between 2.4%- 3.8%.[4]

A variety of viruses and bacteria can cause upper respiratory tract infections. Bacteria may cause roughly 15% of sudden-onset pharyngitis presentations. The most common is S. pyogenes, a Group A streptococcus.(1) The risk factors encompass close contact with children, underlying conditions like asthma, immunocompromised states, and anatomical anomalies. URTIs can significantly impact the health-related quality of life, leading to discomfort and reduced physical activity. In India, URTIs exhibit seasonal variations influenced by climate and population density, peaking during monsoon and winter months of the year[1,5,6]

Challenges Pertaining to URTI In the Indian Context

URTIs pose unique challenges in India due to the country’s large population, seasonal variations, and straining healthcare resources. Limited rural healthcare access, low public awareness of preventive measures, and inaccurate diagnosis further add to the burden of disease and its outcomes. [6,7] In India, challenges related to URTIs include limited awareness of appropriate antibiotic use and their resistance and poor knowledge. Factors like age, gender, education, occupation, and awareness contribute to this issue. [8,9]

URTI Management: Review of Scientific Evidence

In India, URTI management evidence-based guidelines emphasize accurate diagnosis, symptom relief, and prudent antibiotic use. The Standard Treatment Workflow (STW) for managing acute respiratory infections by the Indian Council of Medical Research (ICMR) recommends symptomatic treatment, rest, hydration, and antibiotic considerations, including clarithromycin as a treatment option for URTI where bacterial infection is confirmed. Monitoring for complications and reducing antibiotic resistance is integral to URTI management's balanced and effective approach. [10,2]

Rationale for Considering Clarithromycin in Acute URTI

The human upper respiratory tract hosts a diverse mix of commensal and potentially harmful microorganisms, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. A study conducted on Indian patients with URTIs found S. aureus as the predominant bacterial strain, followed by β-hemolytic Streptococci, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli and H. influenzae highlighting the diverse microbial landscape of URTIs.[11,12]

Common microbes associated with respiratory infections include Staphylococcus aureus, Streptococcus pyogenes, M. catarrhalis, and S. pneumoniae. Atypical pathogens such as Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella spp. can also contribute to respiratory illnesses. These often necessitate targeted treatments like clarithromycin, an antibiotic effective against a broad spectrum of bacterial URTI pathogens, to combat the infections effectively and ensure patient recovery.

Clarithromycin, a versatile macrolide antibiotic, effectively targets a range of pathogens responsible for URTI. It combats bacteria by inhibiting bacterial protein synthesis through binding to the 50S subunit of the ribosome. Its key metabolites, including 14-(R)-hydroxyclarithromycin(CAM), contribute to its antibacterial activity. With a favourable pharmacokinetic profile, including acid stability and a 5–7-hour half-life, clarithromycin's twice-daily dosing ensures both convenience and effectiveness in combating bacterial infections.[13,14]

Beyond-Anti-microbial Properties of Clarithromycin

Clarithromycin, a versatile macrolide antibiotic, has garnered significant attention not only for its potent antibacterial properties but also for its remarkable pleiotropic benefits [15]

• Anti-Inflammatory: Clarithromycin exhibits anti-inflammatory effects by inhibiting specific cytokines and modulating immune responses.
• Mucociliary Enhancement: It can enhance mucociliary transport, improve nasal secretion volume, and normalize nasal mucus rheology.[15]
• Immunomodulatory Effect: They exhibit a modulating effect by influencing the the majority of the cells involved in innate and adaptive immune responses. (16)

Clinical Evidence for Use of Clarithromycin Acute URTI

• Effectiveness of Clarithromycin in URTI: A meta-analysis of 33 clinical trials conducted by Santos A. et al assessed the effectiveness of clarithromycin compared to common treatments for URTI. Clarithromycin demonstrated more effectiveness than beta-lactam antibiotics such as cephalosporins, amoxicillin, and amoxicillin-clavulanic acid for sinusitis (OR: 1.27, 95% CI: 1.01-1.61 in intent-to-treat analysis). In the overall analysis, clarithromycin showed a statistically significant benefit (OR: 1.12, 95% CI: 1.01-1.25, p<0.05). In conclusion, clarithromycin is an effective and safe treatment for URTI. [17]
• Clarithromycin Beneficial for Streptococcus Pharyngitis: In an eight-centre in vivo study conducted by Levenstein J H, oral clarithromycin 500 mg/day (250 mg every 12 hours) was evaluated for its efficacy in treating S. pyogenes pharyngitis. A total of 67 patients were enrolled in the clarithromycin group. The study demonstrated that clarithromycin was highly effective, with a clinical cure rate of 96% during the initial post-treatment period (between two & ten days post-treatment). This study highlights that oral clarithromycin is a highly effective and safe treatment for S. pharyngitis.[18]
• Three-Day Clarithromycin Beneficial for Upper Respiratory Infection in Children: Gouthami P et al conducted a 6-month prospective observational study at a paediatric department of an Indian hospital. The study enrolled and examined 99 outpatients under 14 who received antibiotics for URTI. The participants were divided into three groups: clarithromycin (n=33), cefuroxime (n=33) and levofloxacin (n=33). Both clarithromycin (cure rate of 94% in 3 days) and cefuroxime (cure rate of 94% in 5 days) exhibited similar effectiveness, while levofloxacin, administered over 3-5 days, showed a 52% cure rate.(p<0.05). Clarithromycin demonstrated a shorter treatment duration, indicating its efficacy in managing URTI.[19]

Clinical Benefits of Clarithromycin in URTI

• Broad-Spectrum Antibacterial Activity: Clarithromycin can effectively target a wide range of bacteria, including S. pneumoniae, H. influenzae, and M. catarrhalis, common pathogens causing URTIs.[13,14]
• Anti-Inflammatory Action: Beyond its antibacterial effects, clarithromycin possesses anti-inflammatory properties. They can help alleviate symptoms associated with URTIs, such as sore throat, cough, and congestion, by reducing inflammation in the upper respiratory tract.[15]
• Shorter Treatment Duration: Studies have suggested that clarithromycin may lead to a shorter duration of illness and faster recovery than other antibiotics, such as amoxicillin, cephalosporins. [18,19]
• Tolerability: Clarithromycin is generally well-tolerated, with a lower incidence of adverse effects than certain other antibiotics such as amoxicillin, cephalosporins, and levofloxacin. The well-accepted safety profile makes it a favourable choice for patients sensitive to other medications. [13,14,15,17,18,19]

Take Home Message

• URTIs encompass infections of the upper air passages, affecting parts like the nose, sinuses, throat, and voice box. URTIs account for a substantial portion of global health concerns, with billions of cases reported annually, impacting patients' quality of life. [1,2,3,4]
• Clarithromycin effectively targets many bacteria commonly associated with URTIs, including S. pneumoniae and H. influenzae. [13,14]
• Beyond antibacterial effects, clarithromycin possesses anti-inflammatory properties, helping alleviate URTI symptoms such as sore throat, cough, and congestion. [15]
• The ICMR provides guidelines and recommendations for considering clarithromycin for managing upper respiratory tract infections. [10]
• The recommended dose is 250 to 500 mg every 12 hours (or 500 mg once daily) for 7 to 14 days. [2,14,18]

Clarithromycin is a valuable therapeutic consideration in managing acute URTIs. Its broad-spectrum antibacterial activity, including efficacy against common URTI pathogens and its anti-inflammatory properties, contributes to its effectiveness in alleviating symptoms and reducing the duration of illness. [13,14,15,17,18,19]

References:

1. Thomas M, Bomar PA. Upper Respiratory Tract Infection. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532961/

2. Indian Council of Medical Research (2019). Treatment Guidelines for antimicrobial use in common syndromes. Indian Council Of Medical Research Department Of Health Research New Delhi, India 1-106 https://main.icmr.nic.in/sites/default/files/guidelines/Treatment_Guidelines_2019_Final.pdf

3. Qiao Liu, Chenyuan Qin, Min Du, Yaping Wang, Wenxin Yan, Min Liu and Jue Liu. Incidence and Mortality Trends of Upper Respiratory Infections in China and Other Asian Countries from 1990 to 2019. Viruses,2022;14:2550 https://doi.org/10.3390/v14112550

4. Sujata Murarkar, Jayashree Gothankar, Prakash Doke, Girish Dhumale, Prasad D. Pore, Sanjay Lalwani, Sanjay Quraishi, Reshma S. Patil, Vivek Waghachavare, Randhir Dhobale, Kirti Rasote, Sonali Palkar, Nandini Malshe and Rupeshkumar Deshmukh. Prevalence of the Acute Respiratory Infections and Associated Factors in the Rural Areas and Urban Slum Areas of Western Maharashtra, India: A Community-Based Cross-Sectional Study. Frontiers in Public Health, 2021;9. https://doi.org/10.3389/fpubh.2021.723807

5. Rushabh Waghmode, Sushama Jadhav and Vijay Nema. The Burden of Respiratory Viruses and Their Prevalence in Different Geographical Regions of India: 1970–2020. Frontiers in Microbiology,2021;12. https://doi.org/10.3389/fmicb.2021.723850

6. Mridu Anand and Pavani Nimmala. Seasonal incidence of respiratory viral infections in Telangana, India: utility of a multiplex PCR assay to bridge the knowledge gap. Tropical Medicine and International Health,2020;25(12):1503-09. https://doi.org/10.1111/tmi.13501

7. Anand Krishnan, Ritvik Amarchand, Vivek Gupta, Kathryn E. Lafond, Rizwan Abdulkader Suliankatchi, Siddhartha Saha, Sanjay Rai, Puneet Misra, Debjani Ram Purakayastha, Abhishek Wahi, Vishnubhatla Sreenivas, Arti Kapil, Fatimah Dawood, Chandrakant S. Pandav, Shobha Broor, Suresh K. Kapoor, Renu Lal and Marc-Alain Widdowson. Epidemiology of acute respiratory infections in children - preliminary results of a cohort in a rural north Indian community. BMC Infectious Diseases,2015; 15:462. https://doi.org/10.1186/s12879-015-1188-1

8. Ngoc V. Nguyen, Yogyata Marothi and Megha Sharma. Knowledge, Attitude, and Practice Regarding Antibiotic Use and Resistance for Upper Respiratory Tract Infections among the Population Attending a Mass Gathering in Central India: A Cross-Sectional Study. Antibiotics,2022;11:1473. https://doi.org/10.3390/antibiotics11111473

9. N.J. Gogtay , H.A. Bhatt, S.S. Dalvi & N.A. Kshirsagar. The Use and Safety of Non-Allopathic Indian Medicines. Drug Safety: An International Journal of Medical Toxicology and Drug Experience,2002;25(14):1005–1019. https://doi.org/10.2165/00002018-200225140-00003

10. Indian Council of Medical Research. (Year). Pulmonology: Acute Respiratory Infections. https://stw.icmr.org.in/images/pdf/Pulmonology/Pulmonology_Acute_Respiratory_Infections.pdf

11. Astrid A. T. M. Bosch, Giske Biesbroek, Krzysztof Trzcinski, Elisabeth A. M. Sanders, Debby Bogaert Viral and Bacterial Interactions in the Upper Respiratory Tract PLOS Pathogens,2013;9(1): e1003057 https://doi.org/10.1371/journal.ppat.1003057

12. K. Kousalya, S. Thirumurugu, D. C. Arumainayagam, R. Manavalan, Vasantha.J, C. Uma Maheswara Reddy ANTIMICROBIAL RESISTANCE OF BACTERIAL AGENTS OF THE UPPER RESPIRATORY TRACT IN SOUTH INDIAN POPULATION Journal of Advanced Pharmaceutical Technology & Research,2010;1(2) https://pubmed.ncbi.nlm.nih.gov/22247847/

13. Langtry, H. D., & Brogden, R. N. Clarithromycin: A review of its efficacy in the treatment of respiratory tract infections in immunocompetent patients. Drugs, 1997;53(6):973–1004. https://doi.org/10.2165/00003495-199753060-00006

14. Nobuo Takemori1a , Hong-Kean Ooi, Goro Imai, Kazuo Hoshino and Masanao Saio. Possible mechanisms of action of clarithromycin and its clinical application as a repurposing drug for treating multiple myeloma. Ecancermedicalscience,2020;14:1088 https://doi.org/10.3332/ecancer.2020.1088

15. Soichiro Kanoh and Bruce K. Rubin. Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications. CLINICAL MICROBIOLOGY REVIEWS,2010;23(3):590-615 https://doi.org/10.1128/cmr.00078-09

16. J. Altenburg, C.S. de Graaff, T.S. van der Werf, W.G. Boersma; Immunomodulatory Effects of Macrolide Antibiotics – Part 1: Biological Mechanisms. Respiration 1 December 2010; 81 (1): 67–74. https://doi.org/10.1159/000320319

17. F Abad-Santos, M A Gálvez-Múgica, M J Espinosa de los Monteros, S Gallego-Sandín, J Novalbos [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;16(3):313-324 https://pubmed.ncbi.nlm.nih.gov/14702124/

18. J H Levenstein Clarithromycin versus penicillin in the treatment of streptococcal pharyngitis The Journal of Antimicrobial Chemotherapy,1991;27:67-74 https://doi.org/10.1093/jac/27.suppl_a.67

19. Gouthami Padugundla, Jyothirmayee V, Bethala Ravali, Jagillapuram Arundhathi, Thakur Srilatha, Noorbasha Nissi2, Arshiya Anjum A Randomised Control Study To Compare The Efficacy Of Cefuroxime, Clarithromycin, And Levofloxacin In The Management Of Paediatric Upper Respiratory Tract Infection Asian Journal Of Pharmaceutical And Clinical Research,2021;14(10):103-106 https://doi.org/10.22159/ajpcr.2021v14i10.42957