Understanding the scope of Faropenem in Lower Respiratory Tract Infections(LRTIs)

Lower Respiratory Infections(LRIs): Complexities in the Indian Context

In India, the burden of lower respiratory tract infections (LRTIs) is substantial, more so among the elderly population. The reported incidence of LRTIs in older adults is found to be 248 per 1000 person-years, while LRTI-related hospitalizations account for 12 per 1000 person-years. Patients with pre-existing chronic bronchitis are five times more likely to develop LRTI. Patients aged > 75 years and poor socio-economic status are additional major risk factors associated with increased risk of LRTI. Viral etiology could be detected in only about 11% of LRTI episodes; the commonest being influenza, underlying the likely burden of predominant bacterial as primary or precipitating causes. Notably, the 30-day all-cause mortality after an LRTI episode is recorded as up to 3.5% in elderly Indian patients. (1)

Such evidence points towards the need for 'appropriate treatment of lower respiratory infections among specific vulnerable Indian patients. The scientific evidence and clinical utility supporting the potential use of Faropenem are reviewed.

Faropenem: Unique Fusion Chemical Structure Leading to Better Bacteriological Coverage

Faropenem is a novel oral penem with a structure unique from the rest of beta-lactams including carbapenems. Faropenem contains an unsaturated thiazole ring, making it a structural hybrid between penicillin and cephalosporin. Importantly, the faropenem is resistant to the effects of many bacterial beta-lactamases. This microbiological property is likely attributed to its unique chemical structure i.e. the presence of 1-(R)-hydroxyethyl group at carbon-6 (C6) of its bicyclic molecule. (2) Additionally, faropenem is characterized by potent penicillin-binding protein (PCP) activity. The antibacterial spectrum of faropenem includes gram-positive, gram-negative, and some anaerobic bacteria. Faropenem typically shows a high affinity for PBPs making it a relevant consideration in the management of complex respiratory infections. (3)

Acceptance & Opportunity for Faropenem: The Most Prescribed Penem in India

India has reported one of the highest rates of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae organisms in the world (4). Carbapenems are a reliable treatment option for serious infections caused by ESBL-producing organisms but the need for intravenous administration and high costs make them less feasible for use in outpatient therapy (5).In India, an alternative that is often considered by clinicians is faropenem, an oral antibiotic that belongs to the "penems" class of beta-lactam antibiotics. Faropenem has broad antimicrobial activity and is active against aerobic gram-positive, gram-negative, and anaerobic bacteria. In addition, the faropenem is resistant to TEM, SHV, and CTXM types of ESBLs. Faropenem is approved for the treatment of respiratory tract infections in India. As cited in an article published by Sumantha G et al, more than 18 million units of Faropenem have been utilized until the last decade in Indian settings. (6)

Antibiotic Resistance in India: Drivers are Beyond Antibiotic Overuse

The high burden of infectious diseases, antibiotic use for growth promotion in livestock, and low awareness of antibiotic resistance notably together form major contributors to antibiotic resistance in India. Initiatives to prevent antibiotic resistance in India include surveillance of antibiotic resistance, infection prevention, and control, and improving the use of antibiotics Improving the use of antibiotics practically implies appropriate use of antibiotics, in terms of selection and time of its use, striking the clinical balance between abuse and lack of its use. (7)

Faropenem: Justified Consideration in Lower Respiratory Infections

Several surveillance studies evaluating community-acquired respiratory pathogens have pointed out resistance to beta-lactams, azithromycin, and trimethoprim-sulfamethoxazole (SXT) was higher among S. pneumoniae isolates in humans. Beta-Lactamase production rates among H. influenzae and M. catarrhalis isolates were 27.4 and 91.6%, respectively. Faropenem minimum inhibitory concentration (MICs) at which 90% of isolates are inhibited were 0.5 mcg/ml for S. pneumoniae, 1 mcg/ml for H. influenzae, and 0.5 mcg/ml for M. catarrhalis, suggesting that faropenem shows promise as a treatment option for respiratory infections caused by contemporary resistant phenotypes. (8) Time kill experiments conducted at 2, 4, and 10 times the MICs, carried out on six representative isolates of H. influenzae and M. catarrhalis (4 beta-lactamase-producing & 2 non-producing strains) revealed an excellent bactericidal activity of faropenem. (9) F Wall et al, published a study comparing the in vitro activity of Faropenem against S. pneumoniae, M. catarrhalis, and H. influenzae with amoxicillin, amoxiclav, clarithromycin, levofloxacin, and ciprofloxacin activity and inferred that faropenem has significant activity (MIC90 <1 mg/l) against respiratory tract infections' pathogens such as S. pneumoniae, M. catarrhalis and H. influenza. (3)

Faropenem in Lower Respiratory Infections: Clinical Review

A respiratory scientific forum report published Journal of Antimicrobial Chemotherapy by Glenn S. Tillotson et al, have cited in the testimony of Faropenem that it had excellent activity against respiratory isolates, notably S. pneumoniae, was resistant to degradation by almost all b-lactamases, with a high oral bioavailability of up to 84%. Clinical efficacy in Community-Acquired Pneumonia (CAP) was 86% to 91% and this agent clearly offers a potential further oral option for the management of Respiratory Tract Infections (RTIs). (10)

Faropenem – Activity Against Common and Complex Respiratory Pathogens (added as per scientific data traceable)

Faropenem has demonstrated excellent activity against common respiratory pathogens, many aerobic gram-positive organisms, and anaerobic pathogens. including penicillin-sensitive,-intermediate, and -resistant strains of S. pneumonia (11). Furthermore, Faropenem has also demonstrated useful bactericidal activity against Haemophillus influenzae and Moraxella catarrhalis (12).

Faropenem had invitro demonstrated considerable inhibitory activities against 56 strains of rapidly growing mycobacteria, including Mycobacterium peregrinum, Mycobacterium chelonae, Mycobacterium fortuitum, and Mycobacterium abscessus. Thus, faropenem has the potential to be used as an adjunctive drug with clarithromycin for the treatment of infection with rapidly growing mycobacteria. Case reports have reported favorable clinical and microbiological responses to faropenem treatment. (13)

Clinical Summary

Lower respiratory infections are a significant burden in the Indian population, especially with increased hospitalization and mortality associated with geriatric patients. (1)In the Indian context, there may be logistic and cost implications for the patients with timely initiation of parenteral antibiotics (6). Faropenem, by virtue of its unique fusion structure between penicillin and cephalosorin, allows resistance to the effects of many bacterial beta-lactamases (2) and offers an antibacterial spectrum against gram-positive, gram-negative, and certain anaerobic bacteria (3). Faropenem is a unique oral penem allowing an easy oral route of administration, and may play a role in the treatment of outpatient respiratory tract infections. It may also be of clinical utility in follow-up treatment after parenteral drug administration following hospital discharge in several complex respiratory infections. (9)

References:

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2. Jeremy M. T. Hamilton-Miller, Chemical and Microbiologic Aspects of Penems, a Distinct Class of b-Lactams: Focus on Faropenem, Pharmacotherapy 2003;23(11):1497–1507

3. Walsh F, Amyes AK, Amyes SG. The in vitro effects of faropenem on lower respiratory tract pathogens isolated in the United Kingdom. Int J Antimicrob Agents. 2003 Jun;21(6):581-4. doi: 10.1016/s0924-8579(03)00049-9. PMID: 12791474.

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9. Marchese A, Debbia EA, Bryskier A, Schito GC. Antimicrobial activity of faropenem, a new oral penem, against lower respiratory tract pathogens. Clin Microbiol Infect. 1999 May;5(5):282-287. doi: 10.1111/j.1469-0691.1999.tb00142.x. PMID: 11856268.

10. Tillotson GS, Ball P. Meeting report: Fourth Forum on Respiratory Tract Infections, Sitges, Spain, 8 11 February 2007. J Antimicrob Chemother. 2007 Sep;60(3):464-9. doi: 10.1093/jac/dkm216. Epub 2007 Jun 26. PMID: 17595283.

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12. Mignon P et al, In vitro activity of Faropenem against respiratory pathogens, J Antimicrob Chemother 2002;49:575-577

13. Tanaka E, Kimoto T, Tsuyuguchi K, Suzuki K, Amitani R. Successful treatment with faropenem and clarithromycin of pulmonary Mycobacterium abscessus infection. J Infect Chemother. 2002 Sep;8(3):252-5. doi: 10.1007/s10156-002-0176-8. PMID: 12373490.