Faropenem: Decoding the Therapeutic Potential in Acute Bacterial Sinusitis

Bacterial Sinusitis in Indian Practice Settings

Acute bacterial sinusitis (ABS) - defined as inflammation or infection of the mucosa of the nasal passages and at least one of the paranasal sinuses. The ostiomeatal complex, an area at the confluence of drainage from the sinuses, is specifically vulnerable to inflammatory changes, swelling, and obstruction. Anatomical variations often predispose patients to ABS by causing inflammation in the ostiomeatal complex (1).  Acute sinusitis is the second most common infectious disease seen by General Practitioners (GPs) (2). The published epidemiological studies regarding sinusitis in India have indicated that it mainly affects adults in their mid-thirties, with about 70% of patients suffering from chronic maxillary sinusitis. Indian patients do generally have a family history of sinusitis in about 20% of cases and exposure to cold and allergy in approximately 30% of patients (3). In India, it is a common practice for most diagnoses of upper respiratory tract infections to receive prescriptions for antibiotics from primary care physicians without a diagnosis of sinusitis. Most patients going to primary care physicians receive prescriptions for antimicrobial agents (2). To avoid the emergence and spread of antibiotic-resistant bacteria, a judicious approach to the use of antimicrobial agents among patients with ABS symptoms is critical (3). The scientific evidence for consideration of the use of Faropenem in acute bacterial sinusitis is reviewed.

Faropenem: Most well-studied Member of Penem Class of Antibiotics

Penems tend to have a broader spectrum than do penicillins and cephalosporins. They have potent antibacterial activity against gram-positive and gram-negative pathogens mainly responsible for a wide range of community infections and are stable to beta-lactamases. Faropenem is cited to be the most well-studied member of the penem class (4) . The bioavailability of faropenem medoxomil is proposed to be 70–80% (5) . Importantly, faropenem is resistant to the effects of many bacterial beta-lactamases. This microbiological property is attributed to its unique chemical structure i.e. the presence of 1-(R)-hydroxyethyl group at carbon-6 (C6) of its bicyclic molecule (4).

Bacteriological Susceptibility of Faropenem in Acute Bacterial Sinusitis

Faropenem has reportedly exhibited bactericidal activity against clinical isolates of a variety of organisms, including Bacteroides fragilis, E. coli, Klebsiella pneumoniae, Proteus mirabilis, S. aureus, Staphylococcus saprophyticus, Streptococcus milleri, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes (6). Amongst beta-lactams, Faropenem has demonstrated better bactericidal activity against Staphylococcus aureus, as compared to Amoxicillin, Amoxicillin-Clavulanate, Cefaclor, and Cefixime. Faropenem is active against the major bacterial pathogens which could lead to community-acquired respiratory tract infections. Faropenem reported, had similar MICs to those of imipenem against these isolates (S. pneumoniae, H. influenzae, and Moraxella catarrhalis), some of which were b-lactamase producers, and had lower MICs than those of penicillin, ampicillin, amoxicillin plus clavulanate, cefuroxime, ceftriaxone, trimethoprim-sulfamethoxazole, and levofloxacin. This is suggestive that faropenem may have clinical utility in the outpatient treatment of respiratory infections, including those that are resistant to other therapies. The potent activity of faropenem may be due to its stability in the presence of B- lactamases produced by H. influenzae and M. catarrhalis strains (4).

Faropenem had lower MICs compared to amoxicillin plus clavulanate and second-and third-generation cephalosporins against most members of the Enterobacteriaceae (MICs < 4 mg/L), as well as Neisseria sp, E. faecalis, Streptococci, and beta-lactamase producing and non-beta-lactamaseproducing isolates of H. influenzae and M. catarrhalis (7). Of the anaerobic bacteria studied, faropenem had the lowest MICs against Clostridium perfringens and peptostreptococci (MIC90< 1 mg/L), and B. fragilis (MIC90 = 4 mg/L). Faropenem was also found to be 4–8-fold more active against Methicillin Susceptible Staphylococcus aureus (MSSA) compared with amoxicillin, cefuroxime, and vancomycin (8).

Clinical Efficacy Evidence with Use of Faropenem in Acute Bacterial Sinusitis (ABS)

Faropenem has excellent activity against major pathogens causing acute bacterial sinusitis. The isolates obtained from major Phase 3 trials for ABS reported MIC90 to S. pneumoniae, H influenza, and M catarrhalis were 0.25, 0.5, and 0.5 mcg/ml respectively. This evidence has been reported to be consistent with surveillance across 273 in-patient settings (9) . The major symptoms benefited by faropenem reportedly, include purulent nasal discharge and nasal congestion. The benefit included patients with mucoperiosteal thickening, opacifications, and air-fluid levels (10).

Seven Day Faropenem Treatment Effective as 10-Day Treatment with Cefuroxime

Upchurch et al conducted a study to compare the efficacy and safety of faropenem with cefuroxime in adults with acute bacterial sinusitis (ABS). A prospective, double-blind, phase III trial was conducted with enrolment criteria consistent with Infection Disease Society of America (IDSA) guidelines for the diagnosis of ABS. The intervention included faropenem, 300 mg twice daily (group 1) for seven or ten days, or cefuroxime 250 mg twice daily (group 2) for ten days among adults treated for acute bacterial sinusitis (ABS). The primary efficacy parameter considered was clinical response at 7 to 21 days after treatment. One thousand ninety-nine subjects were randomized and treated; of which 861 were valid for final efficacy analysis. The results of the study indicated that clinical cure rates were 80.3% & 81.8% with seven and ten days of faropenem, and 74.5% with 10 days of cefuroxime, respectively. There was no difference in the incidence of adverse events or premature discontinuation rates across the treatment regimens. It was thus inferred that seven- and ten-day faropenem regimens were similar to a ten-day cefuroxime regimen based on clinical response in patients with ABS. Thus, a seven-day therapeutic regimen of faropenem 300 mg twice-daily could be a promising management option for the treatment of ABS (10).

Summary

Acute bacterial sinusitis is common in India and the use of antibiotics is rampant (2). To avoid the emergence and spread of antibiotic-resistant bacteria, a judicious approach to antibiotic use in patients may be necessary (4). Faropenem – the most extensively studied member of penem class, is efficacious across the clinical spectrum of severity of acute bacterial sinusitis (10). The consideration for use of faropenem among selected complex infections like acute bacterial sinusitis in outpatient settings may be clinically useful.

References:

1.Dewey C. Scheid et al, Acute Bacterial Rhinosinusitis in Adults: Part I. Evaluation, American Family Physician 2004;70(9):1685-1692

2.National Health Systems Resource Centre, (NHSRC) Ministry of Health & Family Welfare, Government Of India. Guidelines on Acute Sinusitis 2017, 1-40

3.Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a global multifaceted phenomenon. Pathog Glob Health. 2015;109(7):309-318. doi:10.1179/2047773215Y.0000000030

4.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

5.Jacob P Gettig, Christopher W Crank, and Alexander H Philbrick, Faropenem Medoxomil, The Annals of Pharmacotherapy 2008, 42:80-90

6.Boswell FJ, Andrews JM, Wise R. Pharmacodynamic properties of faropenem demonstrated by studies of time-kill kinetics and postantibiotic effect. J Antimicrob Chemother 1997;39:415-8.

7.Woodcock JM, Andrews JM, Brenwald NP, et al. The in vitro activity of faropenem, a novel oral penem. J Antimicrob Chemother 1997;39:35–43

8.Von Eiff C, Schepers S, Peters G. Comparative in-vitro activity of faropenem against staphylococci. J Antimicrob Chemother 2002;50:277–80

9.Hadley JA, Tillotson GS, Tosiello R, Echols RM. Faropenem medoxomil: a treatment option in acute bacterial rhinosinusitis. Expert Rev Anti Infect Ther. 2006 Dec;4(6):923-37. doi: 10.1586/14787210.4.6.923. PMID: 17181408.

10.Upchurch J, Rosemore M, Tosiello R, Kowalsky S, Echols R. Randomized double-blind study comparing 7- and 10-day regimens of faropenem medoxomil with a 10-day cefuroxime axetil regimen for treatment of acute bacterial sinusitis. Otolaryngol Head Neck Surg. 2006 Oct;135(4):511-7. doi: 10.1016/j.otohns.2006.05.034. PMID: 17011409.