Use of normal C57BL/6 mice with established Mycobacterium avium infections as an alternative model for evaluation of antibiotic activity

Abstract

Several murine models have been used to evaluate the activities of antimicrobial agents against Mycobacterium avium infection. The main model used is the beige mouse model, but beige mice are expensive and not easily available. Thus, we developed a model of infection in wild C57BL/6 mice. The drugs that exhibited some activity in a previous model of early infection were evaluated in a new model of established infection. Sparfloxacin (50 mg/kg of body weight), ethambutol (50 mg/kg), minocycline (25 mg/kg), and the inhibitor of the cortisol receptors RU-40555 (100 mg/kg) were compared with clarithromycin (50 mg/kg). Treatments were started 5 weeks after the inoculation and were continued for 21 days. Sparfloxacin and RU-40555, which exhibited a moderate activity in the model of early infection, were not effective in this model of established infection. Clarithromycin and combinations with clarithromycin kept their activities against M. avium infection, both in the spleen and in lungs. The present model of established infection of normal C57BL/6 mice is more relevant than the model of early infection for a stringent evaluation of drugs.Disseminated Mycobacterium avium complex (MAC) infection is one of the most common bacterial infections in patients with AIDS (7). The experimental evaluation of the activities of antimicrobial agents against MAC is done in cellular models using macrophages or in animal models. The main animal model used is the beige mouse model (1,5). This model uses mice that are deficient in natural killer cells, providing a kind of immunodeficiency different from that of AIDS in humans. Beige mice, which often develop spontaneous tumors, are expensive and not easily available. Alternative models of mice with cellular immunodeficiency, such as TxCD4 Ϫ mice, Thxb mice, or nude mice, have been suggested (3, 4). TxCD4 Ϫ mice are C57BL/6 mice thymectomized at 4 weeks of age and treated intravenously with anti-CD4 antibodies. Thxb mice are adult thymectomized BALB/c mice that are subjected to lethal whole-body gamma irradiation and are reconstituted with syngeneic bone marrow cells. Nude mice require a sterile environment. These models, difficult to realize, are not easily used for routine investigations. We have shown that the CFU counts of MAC in organs of untreated wild C57BL/6 mice progressively rose after an initial 4-week plateau (10). The bacterial load reaches concentrations higher than 10 8 CFU/g of spleen and higher than 10 7 CFU/g of lung after 6 months of infection, without the spontaneous clearance of bacteria observed with Swiss Webster mice (4-6). The model of early infection of normal C57BL/6 mice may be used for a rapid screening of drugs (8,9,10). In patients with AIDS, MAC infection has a subacute or a chronic clinical course. Thus, a model of established infection of C57BL/6 mice should be more relevant than the model of early infection for mimicking human infection and should represent a more stringent model for the evaluation of antimicrobial agents.Clarithromycin is now considere...

Drug Evaluation of Concurrent Pneumocystis carinii , Toxoplasma gondii , and Mycobacterium avium Complex Infections in a Rat Model

“…The combination of a macrolide (clarithromycin or roxithromycin) with a sulfonamide or dapsone reduced the burdens of the three microorganisms and prevented mortality. The eradication of M. avium complex infection from tissues was not achieved, although bacteremia was abolished, which is consistent with observations with other animal models and for humans (6,7,13,18,26,30). Clarithromycin plus atovaquone or rifabutin plus atovaquone was as effective as the previous combinations and could avoid the frequent undesirable sulfonamide-or dapsone-related side effects which are particularly common in HIV-infected patients (38).…”

Multidrug therapy ofMycobacterium aviumsubsp.aviuminfection in experimentally inoculated budgerigars (Melopsittacus undulatus)

“…Most of these types of study have been carried out in rodents (Cohen et al, 1995;Vrioni, Nauciel et al, 1998) in which, however, vomiting does not occur. Therefore, they cannot be compared with birds in this respect.…”

“…Among the drugs most commonly used in the treatment of mycobacteriosis in humans are clarithromycin and azithromycin (Tartaglione, 1997). Drug combinations also frequently include ethambutol and quinolones (Cohen et al, 1995;Rieder, 2009). In the studies conducted by Koh et al (2013), the use of moxifloxacin improved by onethird the efficiency of the treatment of refractory mycobacteriosis caused by M. avium Complex in humans (Koh et al, 2013).…”

Mycobacterial infection models

“…An easy model uses normal wild‐type C57BL/6 mice. The bacterial concentration in the spleen reaches levels higher than 10 6 CFU per organ, without the spontaneous clearance of bacteria that is observed in Swiss‐Webster mice [17,18]. Because the death of animals is not an indispensable endpoint for the evaluation of drugs, those model can be used for the evaluation of antibiotics.…”