Although antibiotic-loaded hydroxyapatite blocks have been used for the treatment of chronic osteomyelitis, their long-term potential for releasing antibiotic into human bones is not well known. Five patients with chronic osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA) infection were effectively treated with local implantation of vancomycin-loaded hydroxyapatite blocks. Blocks were removed during the following reconstructive surgeries when the releasing capability of the blocks, and the bacteriocidal activity of the remaining vancomycin in these blocks could be evaluated. Vancomycin was rapidly released within 1 month after implantation, and by 3 months 90% of vancomycin had leaked from the blocks. At 18 months vancomycin still remained in a bacteriocidal form in the hydroxyapatite blocks, though the blocks had no releasing potential or the eluted vancomycin had been changed to a different form. Vancomycin-loaded porous hydroxyapatite blocks would be useful for the treatment of chronic osteomyelitis or implant-associated osteomyelitis due to MRSA.

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...

The in vitro growth of tumor cells infected with mycoplasmas was suppressed by macrophages pretreated with interferon (IFN), but the growth of mycoplasma-free tumor cells was not suppressed. Pretreatment of macrophages with IFN plus mycoplasmas or their soluble factors either simultaneously or sequentially, IFN first and mycoplasmas second, but not in the reverse order, was effective in activating macrophages to suppress the growth of mycoplasma-free tumor cells. Macrophages from C3H/HeJ mice (which respond only slightly to lipopolysaccharide) were activated by IFN plus mycoplasmas or their soluble factor, and their action was not influenced by the addition of a lipopolysaccharide-neutralizing agent, polymyxin B. These results suggest that the macrophage-activating agent in mycoplasmas does not mimic lipopolysaccharide. The administration of mycoplasmas plus IFN to mice with ascitic or solid tumors resulted in the reduction of tumor growth. The survival rate of tumor-bearing mice was improved by the administration of mycoplasmas, and this was synergistically enhanced by the addition of IFN. These results indicate (a) that mycoplasmas can be useful as a biological response modifier, and (b) that care should be taken to prevent contamination with mycoplasmas in experiments on macrophage activation.