The in vitro activities of the novel 1␤-methylcarbapenems J-111,225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 g/ml (MICs at which 90% of isolates are inhibited [MIC 90 s]), respectively, indicating that these agents were 32-to 64-fold more potent than imipenem, which has an MIC 90 of 128 g/ml. Although these drugs were less active in vitro than vancomycin, which had MIC 90 s of 1 and 2 g/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.The emergence of multidrug-resistant microorganisms has caused serious concern about infectious diseases worldwide. Although more than three decades have passed since the first report of methicillin-resistant Staphylococcus aureus (MRSA), MRSA still presents a serious problem worldwide as a cause of nosocomial infections (7, 12). Vancomycin, a cyclic glycopeptide antibiotic, has been extensively used in the clinic to treat MRSA infections. However, it is not an ideal antibiotic because of the slow clinical response (6) and potential adverse effects (3). Furthermore, the emergence of MRSA strains with reduced susceptibility to vancomycin accelerated an urgent need for new chemotherapeutic agents for the treatment of MRSA infections (5).Previously reported ␤-lactam antibiotics with activity against methicillin-resistant staphylococci (MRS) such as L-695,256 (2), SM-17466 (13), BO-3482 (8), TOC-39 (4), MC-02,479/ RWJ-54428 (F. Malouin, C. Chan, S. Bond, S. Chamberland, and V. J. Lee, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-177, p. 176, 1997), Ro 63-9141 (P. Hohl, P. Angehrn, R. L. Then, P. Hebeisen, and I. Heinze-Krauss, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-24, p. 239, 1998), and L-786,392 (J. Huber, K. L. Dorso, J. Koheler, H. Kropp, H. Rosen, and L. L. Silver, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-30, p. 240, 1998) all had weak activities against gram-negative organisms and/or a lack of antipseudomonal activity.In the course of our derivatization study of 1␤-methylcarbapenems, a novel trans-3,5-...

The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1beta-methyl-carbapenem, was compared with those of vancomycin and imipenem in murine models of septicemia and thigh infection with methicillin-resistant Staphylococcus aureus (MRSA). Because BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeutic efficacy of BO-3482 was determined during coadministration with cilastatin. In the septicemia models, which involved two homogeneous MRSA strains and one heterogeneous MRSA strain, the 50% effective doses were, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-3482; 5.56, 2.15, and 1.79 mg/kg for vancomycin; and >200, >200, and 15.9 mg/kg for imipenem. BO-3482 was also as effective as vancomycin in an MRSA septicemia model with mice with cyclophosphamide-induced immunosuppression. In the thigh infection model with a homogeneous MRSA strain, the bacterial counts in tissues treated with BO-3482-cilastatin were significantly reduced in a dose-dependent manner compared with the counts in those treated with vancomycin and imipenem-cilastatin (P < 0.001). These results indicate that BO-3482-cilastatin is as effective as vancomycin in murine systemic infections and is more bactericidal than vancomycin in local-tissue infections. The potent in vivo activity of BO-3482-cilastatin against such MRSA infections can be ascribed to the good in vitro anti-MRSA activity and improved pharmacokinetics in mice when BO-3482 is combined with cilastatin and to the bactericidal nature of the carbapenem.

Summary. The adherence of Serratia marcescens to bladder epithelial cells of mice with alloxan-induced diabetes was studied. S . marcescens adhered more strongly to the bladder epithelial cells of diabetic mice than to those of normal mice both in vitro and in uiuo. The susceptibility of diabetic mice to urinary tract infection may be due to an increased adhesive capacity of bladder epithelial cells.

In a murine model of systemic infection with methicillin-resistant Staphylococcus aureus (MRSA), J-111,225 showed an ED(50) value of 5. 83 mg/kg, which was comparable to vancomycin (ED(50) 4.84 mg/kg), whereas imipenem failed to cure infected mice (ED(50) >100 mg/kg). Against a mixed infection caused by MRSA and Pseudomonas aeruginosa, monotherapy with J-111,225 showed an ED(50) value of 7.23 mg/kg, whereas combined treatment with vancomycin plus imipenem (1:1) had an ED(50) of 20.86 mg/kg. J-111,225 showed good therapeutic efficacy against methicillin-susceptible S. aureus, penicillin-resistant Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae and P. aeruginosa. The unusually broad spectrum suggests that monotherapy with this novel carbapenem may be suitable for polymicrobial infections associated with MRSA.

The in vitro and in vivo activity of BO-2727,a carbapenem antibiotic, against resistant clinical isolates of Pseudomonasaeruginosa was studied. The geometric meanMICsagainst three groups of clinical isolates resistant to imipenem, meropenem and both carbapenems were 4.28, 4.08 and 5.44 /zg/ml, respectively. BO-2727 also inhibited multiply antibiotic resistant isolates and laboratory mutants including a nalB-typQ mutant, which showed resistance to antibiotics such as imipenem, meropenem, ceftazidime, and/or ciprofloxacin, at less than 1.56 /ig/ml. Overall, BO-2727 was 4-fold more active than biapenem, meropenem, panipenem and imipenem with an MIC90of less than 6.25/Lig/mlThe presence of basic amino acids in minimal mediumless affected the antipseudomonal activity to a minimal extent, suggesting that BO-2727has diverse penetration routes through the outer membraneother than OprDchannel, which facilitates the diffusion of basic amino acids and carbapenems. The in vitro activity of BO-2727reflected well in its therapeutic efficacy in experimental systemic infection in mice. These results suggest a possibility for the development of antipseudomonal carbapenems having activity against imipenem-and/or meropenem-resistant P. aeruginosa as well as a broad spectrum encompassing Gram-positive and -negative bacteria.Since the discovery of thienamycin1^carbapenem antibiotics are knownto have a broad spectrum encompassing both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. However, the recent problems are the emergenceof carbapenem-resistant P. aeruginosa, in which the mechanismsof resistance are a) deficiency or decreased amount of OprDof the outer membrane, which facilitates the diffusion of carbapenem and basic amino acids2~5), b) nalB mutation responsible for multiple resistance to cephems, quinolones, tetracyclines as well as meropenem5) and c) the evolution of a class B metallo-/Mactamase capable of hydrolyzing carbapenems6).