In Vivo Antibacterial Activity of S-3578, a New Broad-Spectrum Cephalosporin: Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa Experimental Infection Models

Abstract

The in vivo antibacterial activity of S-3578, a new parental cephalosporin, was compared with those of cefepime, ceftriaxone, ceftazidime, imipenem-cilastatin, and vancomycin. The efficacy of S-3578 against systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA) SR3637 (50% effective dose [ED 50 ], 7.21 mg/kg of body weight) was almost the same as that of vancomycin. In contrast, cefepime and imipenemcilastatin were less active against this pathogen (ED 50 s, >100 and >100 mg/kg, respectively). S-3578 was the most effective compound against penicillin-resistant Streptococcus pneumoniae SR20946 (ED 50 , 1.98 mg/kg). S-3578 (10 mg/kg) induced a significant reduction in the numbers of viable MRSA SR17764 and Pseudomonas aeruginosa SR10396 organisms in polymicrobial pulmonary infections. The therapeutic efficacy of S-3578 was more potent than that of the combination of vancomycin and ceftazidime. High levels of S-3578 were detected in plasma in vivo, and its efficacy against experimentally induced infections in mice caused by MRSA and P. aeruginosa reflected its potent in vitro activity. We conclude that S-3578 is a promising new cephalosporin for the treatment of infections caused by gram-positive and -negative bacteria, including MRSA and P. aeruginosa.Drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci, are widespread throughout the world. MRSA constitutes 50 to 70% of all S. aureus isolates and are also prevalent in Japan (10). MRSA infections are becoming a serious clinical problem. Recently, new cephalosporins with potent activities against MRSA, such as Ro 63-9141 and BMS-247243, have been developed (5, 7). However, the clinical therapeutic options for MRSA infections are scarce or are limited to glycopeptide-type drugs, such as vancomycin or, more recently, oxazolidinones, such as linezolid.To find a cephalosporin with higher levels of activity against MRSA, a program was launched at Shionogi Co., Ltd. (Osaka, Japan). It led to the discovery of S-3578, (6R,oct-2-ene-2-carboxylate monosulfate, an inner salt monosulfate and a novel parental cephalosporin that displays broad and potent activities in vitro against both MRSA and Pseudomonas aeruginosa (4,20). In the present study, we compared the in vivo efficacy of S-3578 with those of cefepime (6), ceftazidime, imipenemcilastatin, vancomycin, and linezolid using experimental mouse models.(This work was presented in part at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., 16 to 19 December 2001.) MATERIALS AND METHODSAntibiotics. S-3578 and vancomycin were supplied by Shionogi Co., Ltd. Cefepime was obtained from Bristol-Myers Squibb Co. (Tokyo, Japan), ceftriaxone was obtained from Hoechst Japan Co. (Tokyo, Japan), ceftazidime was obtained from Glaxo Wellcome Co., (Tokyo, Japan), ampicillin was obtained from Meiji Seika (Tokyo, Japan), imipenem-cilastatin was obtained from B...

Murine Immune Response to a Chronic Staphylococcus aureus Biofilm Infection

“…The left leg of each mouse was cleansed with povidone iodine and rinsed with 70% ethanol before surgical implantation of an S. aureus-coated or uninfected control pin, according to the methods previously described by Li et al (28). For antimicrobial efficacy experiments, mice were treated via subcutaneous (s.c.) injection of 50 mg of vancomycin/kg twice daily for 10 days beginning on day 14 postimplantation, which is approximately 10-fold higher than that used in previous studies (9,24,45). All other mice did not undergo any additional treatments after surgery until sacrifice.…”

Pharmacodynamics of S-3578, a Novel Cephem, in Murine Lung and Systemic Infection Models

“…In addition, in patients with polymicrobial infections, Pseudomonas aeruginosa may be isolated in conjunction with MRSA (11). It has been reported that S-3578 has potent in vitro and in vivo activities not only against gram-negative bacteria but also against gram-positive bacteria, including MRSA (6,16).…”

Novel antimicrobial peptide&ndash;modified azithromycin-loaded liposomes against methicillin-resistant <em>Staphylococcus aureus</em>

“…In order to find this, a model using MRSA, a major cause of nosocomial infections, which is widely used to assess antibiotic efficacy, was established. 23,43 PBS or D-LPs (DP7-C dosage of 0.1 or 2.5 mg/kg) was given by IV injection, 1 hour after MRSA challenge. Animals were sacrificed 20 hours later, and the number of the bacteria in the peritoneal lavage fluid was counted.…”

“…aureus is a major cause of nosocomial infections, which is widely used to assess the antibiotic efficacy. 23,43 In vivo antibacterial experiments showed that D-LPs had potent antibacterial effect and showed significant synergistic effects with AZT, which markedly potentiate the antibacterial activity of AZT. Treatment with AZT-D-LPs showed a more positive therapeutic effect in mice than treatment with AZT-LPs or D-LPs alone (Figure 3).…”