Faropenem: review of a new oral penem

Abstract

Faropenem medoxomil is a new orally administered penem antibiotic. Its chiral tetrahydrofuran substituent at position C2 is responsible for its improved chemical stability and reduced CNS effects, compared with imipenem. Faropenem demonstrates broad-spectrum in vitro antimicrobial activity against many Gram-positive and -negative aerobes and anaerobes, and is resistant to hydrolysis by nearly all beta-lactamases, including extended-spectrum beta-lactamases and AmpC beta-lactamases. However, faropenem is not active against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, Pseudomonas aeruginosa or Stenotrophomonas maltophilia. Prospective, multicenter, randomized, double-blind, comparative (not vs placebo) clinical trials of acute bacterial sinusitis (ABS), acute exacerbations of chronic bronchitis (AECB), community-acquired pneumonia (CAP) and uncomplicated skin and skin structure infections (uSSSIs) have demonstrated that faropenem medoxomil has equivalent efficacy and safety compared with cefuroxime, clarithromycin, azithromycin, amoxicillin, cefpodoxime and amoxicillin-clavulanate. The evidence supports faropenem medoxomil as a promising new oral beta-lactam with proven efficacy and safety for the treatment of a variety of community-acquired infections. However, the US FDA recently rejected faropenem for all four indications stating that the clinical trials in ABS and AECB should have been performed versus a placebo. In the CAP studies, the FDA stated that they could not be certain of the validity of the study population actually having the disease and for uSSSI, the FDA stated that only a single trial was not adequate evidence of efficacy for this indication.

Rapid Cytolysis of Mycobacterium tuberculosis by Faropenem, an Orally Bioavailable β-Lactam Antibiotic

“…Although encouraging results have recently been obtained using meropenem for the treatment of XDR-TB in humans (18)(19)(20), the instability and poor bioavailability of this compound, which necessitate frequent or continuous intravenous administration, will likely restrict its broader clinical application. Faropenem is an orally bioavailable penem antibiotic that is more resistant to hydrolysis by ␤-lactamases than cephalosporins and carbapenems are (21)(22)(23)(24). As demonstrated here, faropenem exhibits potent biochemical activity and inactivates M. tuberculosis L,D-transpeptidase enzymes more efficiently than meropenem.…”

“…While plating for determination of the numbers of CFU at defined time points cannot distinguish between these possibilities, it might be possible to resolve this issue in the future using single-cell time-lapse microscopy of infected macrophages. The hurdle to launching clinical studies of faropenem against human tuberculosis should be low because this compound has already been approved for human use and its pharmacokinetics in humans are known (23,24,49,50). Indeed, the data presented in this paper were the basis for the regulatory approval of a phase II clinical trial aimed at evaluating the efficacy of faropenem in patients with drug-resistant TB and performed under the auspices of the European and Developing Countries Clinical Trials Partnership.…”

“…Faropenem is an orally bioavailable (72 to 84% bioavailability) penem antibiotic that is more resistant to hydrolysis by ␤-lactamases than cephalosporins and carbapenems are (21,22). This unconventional ␤-lactam has demonstrated excellent activity against common respiratory pathogens, and it has already been approved for use in humans (23,24). Based on these favorable characteristics, we decided to evaluate the efficacy of faropenem against M. tuberculosis in order to ascertain its potential as an alternative therapeutic agent against MDR-and XDR-TB.…”

Use of Faropenem as an Indicator of Carbapenemase Activity in the Enterobacteriaceae

“…However, inferring carbapenemase activity from an antibiogram is not always straightforward because some isolates of CPE appear susceptible to carbapenems, while isolates without carbapenemases may appear resistant (2). Faropenem medoxomil is an oral penem antibiotic with efficacy for the treatment of community-acquired infections caused by Enterobacteriaceae, including strains with AmpC or extended-spectrum ␤-lactamases (ESBLs) (9). In the first part of this study, we evaluated the effectiveness of disc susceptibility testing with faropenem as a means of predicting carbapenemase activity and compared it with four carbapenems using a collection of 248 Enterobacteriaceae with defined ␤-lactamases.…”

Binding of Faropenem and Other β-Lactam Agents to Penicillin-Binding Proteins of Pneumococci with Various β-Lactam Susceptibilities

“…Faropenem is an oral penem with excellent activity against the primary bacterial pathogens responsible for communityacquired respiratory tract infections, including non-penicillinsusceptible S. pneumoniae, ␤-lactamase-producing Haemophilus influenzae, and ␤-lactamase-producing Moraxella catarrhalis isolates (6,12,25,28). Faropenem demonstrates lower MICs (MIC 90 , 1 g/ml) than other ␤-lactams and macrolides for panresistant non-vaccine serotype 19A S. pneumoniae strains, which are spreading in the United States (5,22).…”