Novel Carbapenem Antibiotics for Parenteral and Oral Applications: In Vitro and In Vivo Activities of 2-Aryl Carbapenems and Their Pharmacokinetics in Laboratory Animals

Abstract

b SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae (including ␤-lactamase-negative ampicillin-resistant strains), and Neisseria gonorrhoeae (including ciprofloxacin-resistant strains), with MIC 90 s of <1 g/ml. Unlike tebipenem (MIC 50 , 8 g/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC 50 , >128 g/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and ␤-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren. The therapeutic efficacies of intravenous administrations of SM-295291 and SM-369926 against experimentally induced infections in mice caused by penicillin-resistant S. pneumoniae and ␤-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren, respectively, reflecting their in vitro activities. SM-295291 and SM-369926 showed intravenous pharmacokinetics similar to those of meropenem in terms of half-life in monkeys (0.4 h) and were stable against human dehydropeptidase I. SM-368589 and SM-375769, which are medoxomil esters of SM-295291 and SM-369926, respectively, showed good oral bioavailability in rats, dogs, and monkeys (4.2 to 62.3%). Thus, 2-aryl carbapenems are promising candidates that show an ideal broad spectrum for the treatment of community-acquired infections, including infections caused by penicillin-resistant S. pneumoniae and ␤-lactamase-negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapies.

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

“…These include several new fluoroquinolones (142–145), tetracyclines (146, 147), carbapenems (148), macrolides (149, 150), and the lipoglycopeptide dalbavancin (151). These and some additional antimicrobials or therapeutic compounds have been recently reviewed elsewhere (11, 12, 22).…”

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

“…The semisynthetic lipoglycopeptide dalbavancin recently showed potent activity against a small number of gonococcal isolates (314). Two new broad-spectrum parenteral 2-acyl carbapenems, SM-295291 and SM-369926, showed high in vitro antimicrobial activities against gonococci, including ciprofloxacin-resistant isolates (315). Two novel broad-spectrum fluoroquinolones, avarofloxacin (JNJ-Q2) (316) and delafloxacin (317), also displayed high in vitro activities against gonococcal isolates, including ciprofloxacin-resistant isolates.…”

β-Lactams and β-Lactamase Inhibitors: An Overview

“…Although its antibacterial spectrum is similar to the other carbapenems against Enterobacteriaceae, ertapenem differs from imipenem, meropenem, and doripenem in that it has no useful activity against P. aeruginosa (Kohler et al 1999). Two carbapenems approved for use only in Japan include biapenem, with an antimicrobial spectrum similar to meropenem and doripenem (Neu et al 1992; Papp-Wallace et al 2011), and tebipenem, which lacks appreciable antipseudomonal activity (Fujimoto et al 2013) (Table 4). Tebipenem is notable for its dosing as the pivoxil ester, rendering it orally bioavailable for use in pediatric respiratory infections (Kato et al 2010).…”