In Vitro and In Vivo Antibacterial Activities of L-084, a Novel Oral Carbapenem, against Causative Organisms of Respiratory Tract Infections

Abstract

L-084 (a prodrug of LJC 11,036 [L-036]) is a new oral carbapenem.Here we compared the in vitro and in vivo antibacterial activities of L-036 with those of imipenem, faropenem, ceditoren-pivoxil, cefdinir, amoxicillin, and levofloxacin. The MICs at which 90% of the isolates were inhibited of L-036 against methicillinsusceptible staphylococci, Streptococcus pneumoniae including penicillin-resistant organisms, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae including ampicillin-resistant organisms, Legionella pneumophila, and Moraxella catarrhalis were equal to or less than 1 g/ml. In pharmacokinetics studies of L-084 in lungs of mice, the maximum concentration in serum, half-life, and area under the concentration-time curve of this drug were 9.09 g/g of tissue, 6.18 h, and 31.0 g ⅐ h/ml, respectively. In murine respiratory infection models of penicillin-susceptible and -resistant S. pneumoniae and H. influenzae, the efficacies of L-084 were better than those of reference drugs. Our results indicate that the in vitro high potency and good distribution in the lungs might be the underlying mechanisms of its efficacy in the murine model of pneumonia.Carbapenems such as imipenem, meropenem, and panipenem, which are commercially available parenteral drugs, have broad-spectrum activity against both gram-positive and gram-negative bacteria. To date, there are many types of oral antimicrobial agents such as ␤-lactams, fluoroquinolones, and penems with broad antibacterial activities. Recently, there has been an increase in the incidence of community-acquired respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae, penicillinase-producing Haemophilus influenzae, and ␤-lactamase-nonproducing ampicillin-resistant H. influenzae (3,13,18). In addition, the incidence of infections caused by fluoroquinolone-resistant organisms also seems to have increased (1,5,14). These conditions highlight the need for novel antimicrobial agents active against these problematic pathogens. At present, various oral carbapenems such as GV118819X, CS-834, DZ-2640, and CL191,121 remain under development (12, 15, 16, 19, 20).hept-2-ene-2-carboxylate, is a novel oral carbapenem synthesized at the Medical Research Laboratories, Lederle (Japan), Ltd., Saitama, Japan. In the study described here, we evaluated the in vitro antibacterial properties of LJC 11,036 (L-036) and the in vivo activities of L-084 (a prodrug of L-036) by using models of murine bronchopneumonia caused by H. influenzae and pneumonia caused by S. pneumoniae. We also compared the potency of this drug with those of faropenem, imipenem, levofloxacin, cefditoren-pivoxil (a prodrug of cefditoren), cefdinir, and amoxicillin. MATERIALS AND METHODSAntimicrobial agents. The following antimicrobial agents, used in this study, were obtained from the indicated sources: L-036 and L-084, Wyeth Lederle Japan, Tokyo, Japan; faropenem, Suntory, Tokyo, Japan; imipenem, Banyu Pharmaceutical Co., Tokyo, Japan; levofloxacin, Daiichi Pharmaceutical Co., Tokyo, J...

Detection of Haemophilus influenzae type B DNA in a murine pneumonia model by in situ PCR

“…ml 21 (study group A of 20 mice, study group B of 10 mice), a heat-inactivated Hib suspension at 10 9 c.f.u. ml 21 (control group A of 6 mice) or sterilized saline (control group B of 6 mice) (Miyazaki et al, 2001;Xu et al, 2008). After inoculation, the animals were observed continuously for 7 days.…”

Novel prodrugs of meropenem with two lipophilic promoieties: synthesis and pharmacokinetics

“…Synthetic procedures in Scheme 3 (14). To a solution of 13 (440 mg, 0.91 mmol) in EtOAc (3.5 ml) at 50 1C was added [(AcO) 2 Rh] 2 Á2H 2 O (22 mg, 0.05 mmol), and the mixture was stirred for 20 min, and then evaporated under reduced pressure.…”

“…[13][14][15] In the present study, we attempted to apply our double-promoiety prodrug method to MEPM to increase its bioavailability. We succeeded in modifying ceftizoxime, a parenteral cephalosporin, to orally bioavailable double-promoiety prodrugs, in which the appropriate balance of lipophilicity and hydrophilicity was achieved by the introduction of both lipophilic promoiety and hydrophilic promoiety.…”

“…Recently, tebipenem was developed in Japan and approved as a new orally active carbapenem ( Figure 1). Tebipenem showed potent activity against penicillin-resistant S. pneumoniae, b-lactamase-negative ampicillin-resistant H. influenzae, H. influenzae and E. coli; [13][14][15] however, unlike MEPM, tebipenem has no activity against b-lactamase-producing P. aeruginosa 2 and its therapeutic use is still limited to pediatric otitis media, rhinitis and pneumonia. In the present study, we attempted to increase the oral bioavailability of MEPM by chemical modification to a double-promoiety prodrug, because MEPM is chemically and biologically more stable than imipenem and panipenem, and has a lower molecular weight than doripenem.…”

Improved Selective Isolation of Bordetella pertussis by Use of Modified Cyclodextrin Solid Medium

“…To address this problem, we have attempted to improve the selective isolation of B. pertussis when performing direct plating of clinical specimens. Modified CS medium (MCS medium) was prepared by replacing cephalexin with cefdinir (Asteras Pharma Inc., Tokyo, Japan), which inhibits the growth of M. catarrhalis (9,16); vancomycin; and amphotericin B at final concentrations of 4 g/ml, 8 g/ml, and 4 g/ml, respectively. For making MCS medium, all of the ingredients except antibiotics were autoclaved for 15 min at 121°C.…”