Susceptibility of Mycobacterium avium Complex to Various Two-drug Combinations of Antituberculosis Agents

Disseminated Mycobacterium avium infection is the major cause of bacteremia in patients with acquired immunodeficiency syndrome. We present here a new animal model of this disease, thymectomized C57BL/6 mice that were intravenously infused with monoclonal antibody to selectively deplete CD4+ T cells. The increased susceptibility of such animals to M. avium infection is comparable to that of C57BL/6 beige mice and thus may provide a viable alternative to the latter model. Further, using representative strains of acquired immunodeficiency syndrome-associated M. avium (serotypes 1, 4, and 8 and a rough isolate), we show that the course of such infections in thymectomized, CD4-deficient mice can be markedly restrained and in some cases the infections can be sterilized by treatment over a 120-day period with a regimen containing 40 mg of the new antimycobacterial agent rifabutin per kg (body weight).Once a fairly uncommon occurrence, infections caused by members of the Mycobacterium avium complex have increased enormously over the past few years as a result of the acquired immunodeficiency syndrome (AIDS) epidemic to the extent that they now represent the most common form of bacteremia in patients with AIDS (1, 16). Chemotherapy of such infections has proved difficult not only because of resistance of these organisms to conventional antimycobacterial therapy but because diagnosis is usually made only when bacterial numbers reach very high, potentially untreatable, levels (16).We report here a new animal model of M. avium infections, mice specifically depleted of CD4+ T cells in an attempt to model the specific immunological defect in AIDS. Such mice are significantly more susceptible to M. avium infections than control mice and thus may provide a more immunologically accurate alternative to the C57BL/6 beige mouse model (5) in the sense that they mimic AIDS in terms of specific CD4 T-cell-mediated immune depression while beige mice possess biochemical lesions at the level of intracellular bacterial killing, similar to Chediak-Higashi syndrome (11). In addition, we show that treatment of infected, thymectomized, CD4-deficient (TxCD4-) mice with the new antimycobacterial drug rifabutin substantially reduced the growth of and in some cases sterilized three of four M. avium isolates tested. MATERIALS AND METHODSMice. Specific-pathogen-free female C57BL/6J and C57BL/ 6J-bglbg (beige) mice were purchased from the Jackson Laboratory, Bar Harbor, Maine, and maintained under isolated barrier conditions in our facility. Because of their poor natural killer cell activity (11-13), we routinely autopsied beige mice at each harvest time point for evidence of tumor growth; data from 16% of the mice in our colony harvested at the last time points (i.e., when they were about 6 months of age) were excluded for this reason. One group of C57BL/6 mice were thymectomized at 4 weeks of age, followed 1 week later by intravenous infusion with 200 ,ug of purified monoclonal GK1.5 (anti-CD4) anti-* Corresponding author.body (3) in 200 ,ul of...

Section: Discussionmentioning

confidence: 82%

Effect of rifabutin on disseminated Mycobacterium avium infections in thymectomized, CD4 T-cell-deficient mice

Furney

Roberts

Orme

1990

“…Less consistent results have been noted with combinations of ETA and RIF against MAC in vitro. Kuze et al (14) and Heifets (8) have noted an additive or synergistic effect against MAC with the combination of ETA and RIF, while Ozenne et al (15) noted an antagonistic effect with this combination. The combination of ETA and RPT in vivo was antagonistic against this particular isolate.…”

Section: Discussionmentioning

confidence: 99%

In vivo activities of newer rifamycin analogs against Mycobacterium avium infection

Klemens

Cynamon

1991

The comparative activities of newer rifamycin analogs and the activity of rifabutin or rifapentine in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J; bgilbg') mouse model of disseminated Mycobacterium avium infection. Rifabutin and rifapentine at 20 mg/kg of body weight had comparable activities. P/DEA and CGP 7040 at 20 mg/kg were less active. The combination of ethambutol at 125 mg/kg and rifabutin at 20 mg/kg resulted in a slight increase in activity beyond that seen with rifabutin alone against organisms in the spleens. The combination of ethambutol and rifapentine at 20 mg/kg resulted in a modest increase in activity beyond that seen with rifapentine alone against organisms in the lungs. The combination of ethionamide at 125 mg/kg and rifapentine resulted in a decrease in activity compared with that for rifapentine alone. The combination of clofazimine at 20 mg/kg and rifapentine resulted in increased activity in the mouse model. The combination of clofazimine and rifapentine (or rifabutin) appears to be an attractive regimen that should be evaluated for the treatment of human infections due to M. avium complex.Rifampin (RIF) has modest activity against Mycobacterium avium complex (MAC) in vitro and limited activity in murine models of disseminated MAC infection (3,17,18). Newer rifamycin analogs such as rifabutin (RBT), rifapentine (RPT), CGP 7040, CGP 29,861, and P/DEA (MDL 62,769) have greater intrinsic activities than rifampin against MAC in vitro (2, 5, 11, 20) and offer pharmacokinetic advantages such as higher peak serum or tissue levels and longer plasma elimination half-lives than rifampin (1, 21). The purpose of the present study was to determine the comparative in vivo activities of the newer rifamycin analogs against MAC and to evaluate the activities of newer rifamycins in combination with other antimycobacterial agents. MATERIALS AND METHODSDrugs. RBT was provided by Adria Laboratories, Dublin, Ohio. RPT was provided by Merrell Dow Pharmaceuticals, Cincinnati, Ohio. P/DEA (MDL 62,769)

“…The antimicrobial agents tested were chosen because they showed activity against MAC inside J774 cells (15) or because they have been suggested for use in treatment of MAC or M. tuberculosis infection (7,9,15,16). They included clofazimine (1 jig/ml), ethambutol (EMB; 4 ,ug/ml), rifampin (RIF; 8 ,ug/ml), rifabutin (RBT [Ansamycin]; 0.5 ,ug/ml), ciprofloxacin (CIP; 2 ,ug/ml), amikacin (AMI; 32 jig/ml), and streptomycin (STR; 16 ,g/ml).…”

Section: Methodsmentioning

confidence: 99%

Effects of antimicrobial agents on survival of Mycobacterium avium complex inside alveolar macrophages obtained from patients with human immunodeficiency virus infection

Yajko

Nassos

Sanders

et al. 1991

Measurements of the activities of antimicrobial agents against the Mycobacterium avium complex (MAC) usually do not take into consideration the intracellular location of the organism. A recent study using mouse macrophage continuous cell line J774 (D. M. Yajko, P. S. Nassos, C. A. Sanders, and W. K. Hadley, Am. Rev. Respir. Dis. 140:1198-1203 showed that certain combinations of antimicrobial agents are able to kill MAC inside macrophages and suggested that the J774 cell line could be used as a model for screening of drugs for intracellular activity against MAC. As a test of the validity of this model, alveolar macrophages were isolated from the bronchoalveolar lavages of 36 patients who had AIDS or an AIDS-related condition or were considered to be at risk for AIDS. The macrophages were infected with MAC and then treated with a drug or drug combination for 48 to 72 h. Survival of MAC was measured over time in drug-treated macrophages and untreated control macrophages. No single drug or two-drug combination that was tested was able to cause a decrease in the survival of every one of the MAC strains used in the study. However, several three-drug combinations that had been shown to cause a decrease in survival of all MAC strains inside J774 cells also caused a decrease in survival of all MAC strains inside alveolar macrophages from patients. The good agreement between these results and those obtained previously with J774 cells gives further evidence of the usefulness of the simpler J774 model for screening of drugs for intracellular activity against MAC.