Chemical and Microbiologic Aspects of Penems, a Distinct Class of β-Lactams: Focus on Faropenem

Jeremy M. T. Hamilton-Miller, D.Sc., FRCPath


Pharmacotherapy. 2003;23(11) 

In This Article

Faropenem: A Representative of the Penem Class

In general, penems have demonstrated a broad spectrum of activity and high potency. However, as a consequence of wrongly aligning penems with carbapenems, issues associated with carbapenems, such as renal DHP stability, are often misapplied to the penem class. So far, in vitro studies of activity against antimicrobial-resistant clinical isolates and in vivo studies of stability to DHP and safety issues have indicated that, as a class, the penems have a favorable profile.

Faropenem (previously known as SUN5555, SY5555, WY49605, RU67655, ALP201, BLA 857, YM 044, farom, fropenem, and furopenem) is the most well-studied member of the penem class. Three forms of faropenem have been described: free acid, sodium salt, and daloxate prodrug derivative (Figure 3). Faropenem originally was synthesized as the sodium salt, but the oral bioavailability of this compound was only 20-30%. In contrast, the daloxate ester has an oral bioavailability of 70-80%.[19] This ester is hydrolyzed rapidly in vivo to release the active free acid. At the time of this writing, faropenem daloxate was in phase III clinical trials for the treatment of a range of community-acquired infections including respiratory tract infections.

Structures of the three forms of faropenum.

Faropenem daloxate (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-(5R,6S)-6-[(R)-1-hydroxyethyl]-7-oxo-3-[(R)-2-tetrahydrofuryl]-4-thia-1-aza-bicyclo[3,2,0]hept-2-ene-carboxylate) (C17H19NO8S) exists as a single pure enantiomer with a molecular weight of 397.41 daltons. It is classed as an arylpenem, with the aryl side chain, a saturated, oxygen-containing tetrahydrofuran group, substituted at position 2 of the thiazoline nucleus.[3] The daloxate moiety of faropenem is attached by an ester link to C3of the thiazoline ring. Faropenem daloxate is a nonhygroscopic, yellowish white crystalline solid that is light sensitive and stable at pH 4 and 25°C.[41]

As with other penems, faropenem induces bactericidal effects by binding to PBPs and inhibiting bacterial cell wall synthesis. These bactericidal effects were found to be affected by the nature of the tetrahydrofuran side chain, with an unsaturated derivative showing reduced activity compared with that of the saturated derivative (faropenem).[42] Faropenem is also less susceptible to the actions of DHP-1 than are the carbapenems imipenem and meropenem[41]; it has been proposed that the absence of a protonable group in the 2-side chain of faropenem, in contrast to the presence of such groups in the equivalent side chains of the carbapenems, is responsible for this phenomenon.[41] Finally, faropenem is resistant to the effects of many bacterial β-lactamases. This property is thought to be due to the 1-(R)-hydroxyethyl group at C6 of the bicyclic molecule.

A summary of the antibacterial activity is illustrated in Table 2 , which show MIC90 values against a selection of clinically important bacteria. As an important indication for faropenem is likely to be respiratory tract infections, the activity against these organisms is discussed first.

Respiratory Tract Pathogens. Faropenem is active against the major bacterial causes of community-acquired respiratory tract infections. In a recent study, 4725 S. pneumoniae, 2614 H. influenzae, and 1193 Moraxella catarrhalis nonrepeat isolates were collected from patients across 273 hospitals in the United States.[43] Faropenem had similar MICs to those of imipenem against these isolates, some of which were β-lactamase producers, and had lower MICs than those of penicillin (S. pneumoniae isolates tested only), ampicillin, amoxicillin plus clavulanate, cefuroxime-axetil, ceftriaxone, trimethoprim-sulfamethoxazole, and levofloxacin. This indicates that faropenem may have 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 β-lactamases produced by H. influenzae and M. catarrhalis strains.[44] Like other β-lactams, faropenem was not found to be active against atypical respiratory tract pathogens.[19]

Activity against drug-resistant strains also was investigated in a number of studies. In vitro activity was compared with that of 21 other antimicrobials against 385 genetically characterized isolates of S. pneumoniae resistant to tetracycline, trimethoprim-sulfamethoxazole, levofloxacin, erythromycin and clindamycin, or erythromycin but not clindamycin.[45] Faropenem was the most potent of all the agents tested, with an MIC90 of 0.25 mg/L or less. Significantly, faropenem expressed activity against isolates that were not susceptible to antimicrobials commonly used to treat pneumococcal infections. In another study, faropenem exhibited excellent activity against penicillin-susceptible, -intermediate, and -resistant S. pneumoniae (MIC50, 90 = ≤ 0.015, 0.03; 0.12, 0.5; 1, and 1 mg/L, respectively), H. influenzae (MIC50, 90 = 0.5, 1 mg/L), and M. catarrhalis (MIC50, 90 = 0.12, 0.5 mg/L).[18]

In an in vitro study, faropenem was found to be highly stable to the group 2b β-lactamases TEM-1 and SHV-1, group 2be β-lactamases TEM-3 and TEM-9, and a penicillinase from S. aureus NCTC 11561.[46,47]

Other Pathogens. Faropenem had lower MICs than those of 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 β-lactamase-producing and non-β-lactamase-producing isolates of H. influenzae and M. catarrhalis.[48] 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 exhibited reduced activity against Serratia sp, and activity was weak against P. aeruginosa and S. maltophilia. Faropenem was also found to be 4-8-fold more active against methicillin-susceptible S. aureus compared with amoxicillin, cefuroxime, and vancomycin, showing similar MICs as those of clindamycin (MIC90 = 0.25 mg/L).[49] In the same study, faropenem was found to be active in a subset of methicillin-resistant S. aureus strains (MIC90 = 2 mg/L, 18 isolates), although when all data were analyzed, the MIC90 was greater than 128 mg/L (31 isolates). For coagulase-negative staphylococci, faropenem was found to have an MIC90 of 1 mg/L.

Another group of authors showed that faropenem is active against unusual aerobic and anaerobic organisms isolated from bite wounds.[50] These included Eikenella corrodens (MIC90 = 0.25 mg/L) and Pasteurella sp (MIC90 = 0.25 mg/L).

In clinical trials, faropenem daloxate was administered at oral dosages of 300, 600, and 1200 mg twice/day. In these studies, the maximum concentration (Cmax) was found to be approximately 13 mg/L (300-mg dose), half-life was 0.9-1.3 hours, urinary elimination accounted for 14-20% of the dose, and renal clearance was 1.6-2.9 L/hour (depending on patient's age and sex). Protein binding was approximately 95%, and metabolism involved the opening of the β-lactam ring to yield two diastereoisomers.[19] Coadministration with furosemide, probenecid (an inhibitor of tubular excretion), or antacids (which theoretically might inhibit the conversion of the daloxate to the free acid) did not produce any pharmacokinetic changes that warranted dosage adjustment.[51,52]

Adverse events were similar to those seen with other β-lactams, but gastrointesinal effects were less common,[19] and headache was occasionally seen.[51,52] In healthy volunteers, administration of faropenem did not result in the overgrowth of resistant microbial strains in the oropharynx, or select for Clostridium difficile or overgrowth of Candida or P. aeruginosa, or multiresistant Enterobacteriaceae in the feces.[51,52]