Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice

Abstract

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDSassociated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracelulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracelulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDSassociated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in the present study.Rifampin (RMP) and other rifarmycins, including rifabutin (RBT), rifapentine, and so on, are highly active against slowly growing mycobacteria, particularly Mycobacterium tuberculosis and some nontuberculous mycobacteria (1,3,5,7,14,18,24,28,29,36). However, they are not so excellent in their in vitro activity against M. avium complex (MAC) (5,19,28), supposedly because of the permeability barrier of the organisms (11,25). Moreover, it is not known whether RMP and other rifamycins are really efficacious in the treatment of patients with MAC infections. Some investigators have reported that multidrug chemotherapy, including treatment with RMP, has been used in many cases of clinical management of AIDS-or non-AIDS-associated MAC patients with success (4, 6). In contrast, others have reported unavoidable difficulty in clinical control of MAC, even by using RMP combined with other drugs (36). For instance, Rosenzweig (27) reported that sustained conversion of sputum with such chemotherapy alone was achieved in only 41% of patients and, after a 6-month trial of drugs including RMP, 33% of the patients experienced relapse.Because rifamycin with a high in vitro anti-MAC activity and superior pharmacokin...

In vitro antimicrobial activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex, determined by the radiometric method

“…Previously, 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin (KRM-1648; KANEKA Corporation, Hyogo, Japan) demonstrated excellent in vitro activity against slowly growing mycobacteria, especially Mycobacterium avium complex (MAC), in our experiment to determine its MICs for various mycobacterial strains by the agar dilution method using Middlebrook 7H11 agar plates (7). KRM-1648 also exhibited excellent therapeutic efficacy against MAC infections induced in BALB/c and NK-deficient beige mice (12) and in rabbits (unpublished observation) and also demonstrated potent therapeutic activity against M. marinum infection induced in BALB/c mice (14). The MICs of KRM-1648 for various MAC strains isolated from AIDS and non-AIDS patients were determined by using the BACTEC 460 TB system by the method of Heifets et al (1,2,4).…”

Interaction of Antimycobacterial Drugs with the Anti-Mycobacterium aviumComplex Effects of Antimicrobial Effectors, Reactive Oxygen Intermediates, Reactive Nitrogen Intermediates, and Free Fatty Acids Produced by Macrophages

“…A great discrepancy is known for the in vitro and in vivo anti-MAC activities of rifamycins, especially in the case of RLZ. That is, the therapeutic efficacy of rifamycins against MAC infections is much weaker than that expected from their MICs for MAC isolates (22,(26)(27)(28). This enigmatic situation may be in part explained by using the present finding that rifamycins antagonize the ROI-mediated antimicrobial mechanisms of host M⌽s.…”

“…First, although RLZ has a much lower MIC against MAC than other antituberculosis drugs, its therapeutic efficacy against MAC infection is not as good as expected based on its low MIC (22,(26)(27)(28). In contrast, the bacteriological response in the patients with MAC infection to treatment with CLR depends on the in vitro susceptibility (based on the CLR MIC) of individual MAC pathogens to the drug (26,27).…”

Antimycobacterial activity of a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9)

“…At similar doses of RIF administered to mice, the maximum concentration in plasma observed was 7.85 g/ml at 1 h (2). Pharmacokinetic studies by Tomioka et al (11) have shown maximum concentrations in plasma of 0.60, 12.73, and 0.92 g/ml for KRM-1648, RIF, and rifabutin, respectively, for mice receiving 20-mg/kg doses of each of the compounds. The comparison of the pharmacokinetics of some of the RIF derivatives with respect to their MICs against mycobacteria indicates that T9 has good therapeutic value.…”