The spiropiperidylrifamycin LM 427 (4-deoxo-3,4-[2-spiro-N-isobutyl-4-piperidyl]-(1H)-imidazo-(2,5-dihydro)rifamycin S) displays a broad spectrum of potent antibacterial activity in vitro. In vivo it is particularly effective in the therapy of experimental tubercular infections of mice.Three schedules of treatment were employed and the best results were obtained when intermittent administrations were used (ED51 of LM 427; 7 times lower than rifampicin).LM 427 is well distributed in tissues of mice and rats, with lung concentrations 10-20 times higher than plasma levels.In a previous papery we described the antibacterial activity of a new class of rifamycin S derivatives: the spiropiperidylrifamycins.One member of this class (4-N-isobutylspiropiperidylrifamycin S; see structure below) whose code number is LM 427 (compound 11 in the earlier paper), showed remarkable activity against Mycobacterium tuberculosis in vitro and in vivo, together with an interesting profile of tissue distribution in rats.Recent research') carried out at the Center for Disease Control in Atlanta, Georgia, USA, demon- Portions of these data were presented at the 12th International Congress of Chemotherapy (Florence, 1981, Abstracts No. 956 & 960). Materials and MethodsIn Vitro Activity The minimal inhibitory concentration (MIC) on Gram-positive and Gram-negative bacteria, both standard and clinical isolates, was determined by the serial dilution technique in Bacto Antibiotic Medium No. 3 (Difco) supplemented with 1.5 % of Agar (Difco) for aerobic strains and in Bacto FTM (Difco) for the anaerobic strains. The inoculum consisted of about 105 cells per plate or per ml. Incubation was at 37°C for 1-2 days. The MIC on M. tuberculosis was determined by the serial dilution technique in Bacto Albumin Dubos Medium (Difco) inoculated with about 101 cells/ml and incubated for 7-10 days at 37°C.Rifampicin was taken as a reference compound. The antibiotics were dissolved in dimethylform-
The ever-increasing incidence of tuberculosis calls for the implementation of control measures, including new efficient, short-term preventive therapies to replace 6 to 12 months of isoniazid therapy. The efficacies of 12-week regimens of rifabutin or isoniazid given daily and the combination of the two drugs administered intermittently were evaluated in mice infected with Mycobacterium tuberculosis after vaccination with the bacillus Calmette-Guerin (BCG) to imitate some features of the natural infection in humans with a low number of persisting bacteria. Rifabutin at 10 mg/kg of body weight per day was highly effective as early as the eighth week of treatment: all spleens were sterilized and the number of bacteria was drastically reduced in the lungs (mean ± standard deviation log CFU, 0.2 ± 0.3, compared with 5.9 ± 0.6 for untreated controls). No bacilli were found in the spleens or lungs of any of the animals treated for 12 weeks. The combination of rifabutin at 10 mg/kg plus isoniazid at 25 mg/kg twice weekly was almost as effective as rifabutin daily: after 8 weeks of treatment only two of six mice harbored a small number of mycobacteria in their spleens and lungs; at week 12, all spleens were sterilized and a total of eight colonies were isolated from the lungs of two of six mice. Daily isoniazid and once-weekly rifabutin plus isoniazid therapies were less effective. Colonies randomly isolated from the spleens and lungs of mice from different experimental groups were also tested for their susceptibilities to the two drugs. The three surviving colonies from rifabutin-treated mice and all colonies from those administered rifabutin plus isoniazid remained fully susceptible to either drug. In contrast, 2 (18%) of the 11 colonies randomly selected from isoniazid-treated mice became resistant to isoniazid (MIC, > 2 ,ug/ml), although they were still susceptible to rifabutin.
The most efficient routes for the synthesis of FCE 22101, a penem antibiotic characterized by a carbamoyloxymethyl sidechain at C-2 identical to that of cefuroxime and cefotaxime, and of FCE 22891, its orally absorbed pro-drug, are described. On the basis of in-vitro antimicrobial profile and other characteristics the compounds have been considered worthy of further development.
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