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

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 β-lactamase-negative ampicillin-resistant strains), and Neisseria gonorrhoeae (including ciprofloxacin-resistant strains), with MIC(90)s of ≤ 1 μg/ml. Unlike tebipenem (MIC(50), 8 μg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC(50), ≥ 128 μg/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and β-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 β-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 β-lactamase-negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapies.

Fig 1

Chemical structures of 2-aryl carbapenems.

Fig 2

Bactericidal activities of SM-295291 and reference antimicrobial agents against PRSP strain 18280 (A) and BLNAR strain 17051(B). Symbols: ○, control; ▲, 1/4× the MIC; ■, 1/2× the MIC; ●, 1× the MIC; ◆, 2× the MIC; □, 4× the MIC; ♢, IPM concentration at 32 μg/ml.

Fig 3

Effects of antimicrobial agents on the bacterial burden in the lungs of mice infected intranasally with PRSP strain 18280 at 1.7 × 10⁶ CFU/mouse (A) and BLNAR strain 17051 at 4.4 × 10⁷ CFU/mouse (B). Antibacterial agents were administered intravenously thrice daily 1 day and 2 days after infection (n = 6). Cilastatin at a dose of 100 mg/kg was administered subcutaneously 5 min before carbapenem treatment. The lungs were removed 3 days after infection. The values represent the means and standard deviations. The dotted line represents the mean bacterial burden in the lungs for the control group. *, significantly different from control (P < 0.01 by Dunnett's test for multiple comparisons).

Fig 4

In vitro serial passage study of P. aeruginosa PAO1.