Faropenem, a Stable and Orally Bioavailable β-Lactam, to Counteract Resistant Pathogens and Infectious Diseases

Therapeutic Options for Treating Severe and Resistant Bacterial Infections

Several hundred β-lactam antibiotics exist, but the carbapenems have the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacterial species [6]. • For this reason, when treatment with other antibiotics fails, carbapenems are used as the last-line antibiotics for treating severe and resistant bacterial infections that often are associated with high morbidity and mortality. Carbapenems as IV formulations are available in most countries for the treatment of severe, complicated and resistant bacterial infections, including those affecting the respiratory, abdominal and urinary tracts, and the skin. While faropenem demonstrates high oral bioavailability (around 70%–80% in its ester prodrug form), carbapenems must be administered parenterally. Efforts to improve the oral bioavailability of carbapenems are ongoing [7].

An oral penem, faropenem, is available in Japan and India for the treatment of urinary tract infections (UTIs), respiratory tract infections, skin and skin structure infections and gynaecological infections [8, 9]. This narrative review aims to profile the only available oral penem that addresses the challenge of resistant infectious diseases.

Pharmacodynamics

Faropenem is characterized by pronounced β-lactamase stability compared to other cephalosporins and imipenem. It is highly stable against hydrolysis by various β-lactamases from Bacteroides fragilis strains and the rate of faropenem hydrolysis by metallo-β-lactamases is 5 times lower than that for imipenem [12]. Faropenem, like other β-lactam antibiotics, interferes with penicillin-binding proteins (PBPs) activity involved in the final phase of peptidoglycan synthesis. PBPs catalyze a pentaglycine crosslink between alanine and lysine residues providing additional strength to the cell wall. Without a pentaglycine crosslink, the integrity of the cell wall is severely compromised and ultimately leads to cell lysis and death [13].

Spectrum activity of faropenem:

• Gram-positive bacteria: Faropenem is highly potent against S. pneumoniae, [14] and in vitro activity has been noted against many methicillin-sensitive and methicillin-resistant strains of S. aureus and coagulase- negative Staphylococci.
• Gram-negative bacteria: Faropenem has good in vitro activity against E. coli and Klebsiella spp. with ESBLs, including the CTX-M types [3]. Furthermore, it has significant activity against the common respiratory pathogens, H. influenzae and M. catarrhalis.

Anaerobes: Against Clostridium perfringens, faropenem is as active as metronidazole and clindamycin. Faropenem also has activity against Peptostreptococci and B. fragilis.

As depicted in (Table 1) faropenem exhibited better inhibitory potential compared to other antimicrobials like cefuroxime and Co-amoxiclav.

Pharmacokinetics

Orally administered faropenem medoxomil is readily absorbed. The addition of the medoxomil ester to the faropenem moiety improves bioavailability. The bioavailability of faropenem medoxomil is proposed to be 70–80%, which is approximately four times that of faropenem sodium [17]. The half-life of faropenem medoxomil is estimated to be

0.9 hours. Administration of faropenem medoxomil under fasting and postprandial conditions resulted in no significant difference in Cmax and AUC.

Clinical Evidence For Faropenem

7-day Regimen of faropenem for the treatment of cystitis: Acute uncomplicated cystitis is a common disease in women, and the increasing prevalence of resistant bacteria including ESBL-producing strains in pathogens causing acute uncomplicated cystitis has been of concern. Hamasuna evaluated the efficacy of faropenem against cystitis, and compared 3- and 7-day administration regimens in a multicenter, randomized, controlled, open-label study. Women aged ≥20 years, with any cystitis symptoms, such as micturition pain, urinary frequency, urge to urinate, or lower abdominal pain with pyuria and bacteriuria were included in this study. The target bacteria were Staphylococcus spp., Enterococcus faecalis, Streptococcus agalactiae and Enterobacteriaceae [18]. Faropenem sodium was administered three times daily (600 mg/day) for 3 days (n=97) or 7 days (n=103).

Clinical efficacy in the two groups was not significantly different when evaluated at 5–9 days after treatment completion, and at 4–6 weeks after treatment completion. The microbiological non-recurrence rate was 80.8% (21/26) in the 3-day treatment group and 79.4% (27/34) in the 7-day treatment group (p=1.0). The MIC90 for E. coli, K. pneumoniae, Staphylococcus and Enterococcus was 1, 0.5, 1 and 0.03 mg/L, respectively. Adverse events (AEs) were reported in 9.5% of patients (19/200) and there was no significant difference between the 3- and 7-day treatment groups. The most common AE was diarrhea (7.5%, 15/200). AE severity was mild-to-moderate.

The 7-day regimen of faropenem showed a superior rate of microbiological response. E. coli strains were, in general, susceptible to faropenem, including fluoroquinolone- and cephalosporin-resistant strains.

Faropenem for patients with acute cystitis caused by ESBL-producing E.coli: Fujino retrospectively reviewed the medical charts of patients with acute cystitis caused by ESBL- producing E. coli who was treated with the oral antimicrobial agent faropenem (FRPM) in their institution from June 2011 to May 2015 [19] Ten patients with acute cystitis caused by ESBL-producing E.coli were treated with FRPM. Although a clinical cure was achieved in 9 of them, it reoccurred in 3. This study revealed that the treatment regimen with FRPM for patients with acute cystitis caused by ESBL-producing E.coli is promising. However, a non-negligible number of recurrences were caused by ESBL-producing E.coli because of the nature of underlying diseases or pathologies in the urinary tract.

Faropenem for the management of urinary tract infection: Real-world experience from India [20]: To record the real- world evidence on the use of faropenem in the management of UTIs, the responses of Indian urologists were obtained on the usage of faropenem in the management of complicated urinary tract infection (cUTI) after providing a set of eight questions having both multiple-choice responses and open- ended answers. Results: Responses from 391 participants were collected. In the majority of the urology clinics prevalence of cUTI was 5-10% whereas others found it to be 10-20%. A majority believed that faropenem was an effective pharmacotherapy for the management of UTIs (66.4%) including cUTI as a step-down therapy (66.4%). Faropenem 300 mg provided more compliance. The overall perception of the use of faropenem in their practice was that (out of 391 responses) the majority found it to be effective (72.7%) and 4.6% of participants have used faropenem as an alternative for cUTI. The majority found it safe (68.5) to be used in cUTI. It was shown that faropenem was preferred for the treatment of urinary tract infections due to its effectiveness, ability to cause less resistance and safety profile.

A faropenem regimen of 200-300 mg twice daily is recommended by Medindia for treating genitourinary infections [21].

Faropenem as an alternative to cefuroxime for the treatment of acute bacterial sinusitis: Siegert, et al. compared the efficacy and safety of 7-day courses of faropenem medoxomil (300 mg twice daily; n=228) and cefuroxime axetil (250 mg twice daily; n=224) in adult patients with acute bacterial sinusitis in a prospective, multinational, multicenter, double-blind, comparative study [11].

S. pneumoniae, H. influenzae, S. aureus and M. catarrhalis were the most common organisms isolated at baseline. Four out of 36 H. influenzae, 9 out of 10 M. catarrhalis and 11 out of 19 S. aureus strains were β-lactamase producers. At 7-16 days post-therapy, clinical cure was reported in 89.0% of faropenem medoxomil and 88.4% of cefuroxime axetil-treated patients, while the corresponding rates for bacteriological success were 91.5% and 90.8%. AEs were reported by 46 (16.8%) of the faropenem medoxomil-treated patients and 49 (17.9%) of the cefuroxime axetil-treated patients.

In a study by Upchurch, et al. the efficacy and safety of faropenem medoxomil was compared with cefuroxime axetil in adults with acute bacterial sinusitis. This phase III, prospective, randomized, double-blind, multicenter trial included patients aged ≥18 years with a clinical diagnosis of acute sinusitis and duration of signs and symptoms >7 days but <28 days. Patients were randomly assigned in a 1:1:1 proportion to faropenem medoxomil 300 mg twice daily for 7 days (n=366) or 10 days (n=363) or cefuroxime axetil 250 mg twice daily for 10 days (n=370) [14].

Clinical cure rates for the 7-day and 10-day faropenem medoxomil regimens were non-inferior to that of the 10-day cefuroxime axetil regimen for the efficacy-valid population. The continued cure rates at the late follow-up visit showed that both faropenem medoxomil regimens had higher success rates than cefuroxime axetil. At least one AE was reported by 39%, 34% and 41% of patients in the faropenem medoxomil 7-day and 10-day groups and the cefuroxime axetil group, respectively. The majority of the AEs was mild or moderate in severity (∼87%) and improved or resolved after treatment.