Confirmation of the Beige Mouse Model for Study of Disseminated Infection with Mycobacterium avium Complex

Bertram, Miriam; Inderlied, Clark B.; Yadegar, Sasan; Kolanoski, Peter; Yamada, J K; Young, Lowell S.

doi:10.1093/infdis/154.1.194

Cited by 81 publications

(43 citation statements)

References 2 publications

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“…Moreover, the liposomal form of capreomycin had a better in vivo activity than the free form against MAC isolates. The bacterial counts obtained for controls were concordant with those reported in the literature (2,3,20) in the beige mouse model. The difference in the mean CFU for each organ was slight (0.6 to 0.9 log1o CFU/g of organ for the 120-mg/kg dose by the curative procedure); thus, the antibacterial activity observed was a bacteriostatic effect.…”

Section: Discussionsupporting

confidence: 86%

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Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

Conte¹,

Gallou²,

Potel³

et al. 1994

Antimicrob Agents Chemother

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Capreomycin was incorporated into multilamellar vesicles of pure dipalmitoylphosphatidylcholine. The pharmacokinetics and nephrotoxicity of capreomycin in the free and liposomal forms were studied in normal mice. The efficacies of the two forms were evaluated by using the Mycobacterium avium complex beige mouse model. Approximately 107 viable M. avium cells were injected intravenously. Seven days later, treatment with either liposomal or free capreomycin at 60 or 120 mg/kg of body weight was administered daily for 5 days. Mice were sacrificed 5 days after the end of treatment, and the viable bacteria in liver, spleen, lungs, and blood were counted. After 5 days of treatment with dosages of 60 or 120 mg/kg/day, the level of blood urea nitrogen increased in the group treated with free capreomycin but not in the group treated with liposomal capreomycin. After intravenous injection of 120 mg/kg, liposomes enhanced the diffusion of capreomycin in the spleen, lungs, and kidneys and increased the half-life in serum. The 120-mg/kg dose of liposomal capreomycin significantly reduced the number of viable mycobacteria in the liver, spleen, and blood compared with those in the controls. Although these results are promising, further studies are needed to assess the efficacy of liposomal capreomycin for the treatment of M. avium complex infections.Since the appearance of the human immunodeficiency virus (HIV), the incidence of Mycobacterium avium complex (MAC) infections has increased considerably and has involved between 18 and 50% of HIV-infected patients (17,24,33). Treatment is difficult because of the weakened immune defense system of the host and the resistance of MAC strains to many classic antituberculous agents. Moreover, the phenotypes of resistance of these strains are very heterogeneous (25,26,49).Experimental infection models involving animal or human macrophage cultures and acute or chronic infections in the mouse have been developed to assess the activities of antiinfectious agents against MAC (32). Numerous studies have been performed either in vitro (25,28,36,49) or on macrophages (46) and in animal models (6,21,34,38,39) with classic or more recent antituberculous agents (ciprofloxacin, sparfloxacin, azithromycin, and clarithromycin) alone or in combi-

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Section: Discussionsupporting

confidence: 86%

“…The disseminated MAC infection model in the beige mouse has been described in detail (3,20). Mice were infected by injecting approximately 107 CFU of MAC in 0.1 ml of 7H9 broth into the tail vein.…”

mentioning

confidence: 99%

Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

Conte¹,

Gallou²,

Potel³

et al. 1994

Antimicrob Agents Chemother

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“…Of these murine systems, the most frequently used system has been the beige mouse model of disseminated MAC disease (52,160). There has been some debate about whether the beige mouse, infected intravenously with MAC, truly mimics disseminated MAC infection in patients with AIDS.…”

Section: In Vitro Susceptibility Testing Backgroundmentioning

confidence: 99%

The Mycobacterium avium complex

1993

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Mycobacterium avium complex (MAC) disease emerged early in the epidemic of AIDS as one of the common opportunistic infections afflicting human immunodeficiency virus-infected patients. However, only over the past few years has a consensus developed about its significance to the morbidity and mortality of AIDS. M. avium was well known to mycobacteriologists decades before AIDS, and the MAC was known to cause disease, albeit uncommon, in humans and animals. The early interest in the MAC provided a basis for an explosion of studies over the past 10 years largely in response to the role of the MAC in AIDS opportunistic infection. Molecular techniques have been applied to the epidemiology of MAC disease as well as to a better understanding of the genetics of antimicrobial resistance. The interaction of the MAC with the immune system is complex, and putative MAC virulence factors appear to have a direct effect on the components of cellular immunity, including the regulation of cytokine expression and function. There now is compelling evidence that disseminated MAC disease in humans contributes to both a decrease in the quality of life and survival. Disseminated disease most commonly develops late in the course of AIDS as the CD4 cells are depleted below a critical threshold, but new therapies for prophylaxis and treatment offer considerable promise. These new therapeutic modalities are likely to be useful in the treatment of other forms of MAC disease in patients without AIDS. The laboratory diagnosis of MAC disease has focused on the detection of mycobacteria in the blood and tissues, and although the existing methods are largely adequate, there is need for improvement. Indeed, the successful treatment of MAC disease clearly will require an early and rapid detection of the MAC in clinical specimens long before the establishment of the characteristic overwhelming infection of bone marrow, liver, spleen, and other tissue. Also, a standard method of susceptibility testing is of increasing interest and importance as new effective antimicrobial agents are identified and evaluated. Antimicrobial resistance has already emerged as an important problem, and methods for circumventing resistance that use combination therapies are now being studied.

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“…Murine models of disseminated M. avium infection have been developed since 1983 (2,3,10) and used extensively in the investigation of host response and in the screening of active therapeutic agents (1). In these models, bacterial burden and histopathology changes in the abdominal organs and lymph nodes had been thoroughly studied, but the neuraxes have not been evaluated.…”

mentioning

confidence: 99%

“…Our results suggest that M. avium infection of the CNS during AIDS is an underrecognized entity. We used strain 101, which is a well-characterized virulent strain of M. avium (3). Other strains, such as the virulent strain 724 (22), however, may prove to be more invasive of the CNS or trigger a greater inflammatory response than strain 101 and should be investigated in this model in the future.…”

mentioning

confidence: 99%

Invasion of the Brain and Chronic Central Nervous System Infection after SystemicMycobacterium aviumComplex Infection in Mice

Wu¹,

Kolonoski²,

Chang³

et al. 2000

Infect Immun

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Central nervous system (CNS) infections caused by nontuberculous mycobacteria have been described previously, especially in patients with AIDS. To investigate specific aspects of the pathogenesis of this entity, C57BL bg ؉ /bg ؊ mice were infected intravenously with Mycobacterium avium, and cultures of blood and brain as well as histopathology examination of brain tissue were carried out at several time points up to 6 months after infection. Low-grade inflammatory changes with small aggregates of lymphocytes and macrophages as well as perivascular cuffing were seen early in the infection. A small number of bacteria could be observed in the parenchyma of the choroid plexus. Six months after infection, numerous bacteria were present within the foamy macrophage of the granulomatous lesions along the ventricle and meninges. None of the mice developed clinical signs of meningitis or encephalitis or even died spontaneously during the period of observation. Use of CD18؊/؊ knockout mice indicated that transport of the bacterium within neutrophils or monocytes into the brain is unlikely. Mild chronic CNS infection developed in the mice during sustained systemic M. avium infection, similar to what has been reported in most human cases.Central nervous system (CNS) infections due to nontuberculous mycobacteria (NTBM) usually manifest as meningitis or meningoencephalitis, but occasionally pure encephalitis or abscesses along neuraxes are found (5, 9). NTBM brain diseases are most often described in patients with AIDS or other immune-compromised patients, but it had also been reported in individuals without obvious underlying disease (5,26,28). CNS infections with NTBM can sometimes be misdiagnosed as Mycobacterium tuberculosis infection, resulting in incorrect treatment and death (11,28). As the epidemic of human immunodeficiency virus infection and the application of immunosuppressive treatment expand, it has become more likely that doctors might come in contact with these usually infrequent infections. A suitable animal model may therefore help us to understand the immunopathophysiology of this disease, as well as to develop an effective therapy.The Mycobacterium avium complex is the most common organism causing systemic opportunistic bacterial infections in patients with AIDS (13,14,29). It is also the leading cause of the NTBM brain disease in this population (5). Patients with M. avium infection usually have disseminated disease with bacteremia and frequently liver, spleen, bone marrow, and lymph node involvement. In addition, a variable percentage of these patients can have invasive infection in the brain (6,11,12,15,17,27).Murine models of disseminated M. avium infection have been developed since 1983 (2, 3, 10) and used extensively in the investigation of host response and in the screening of active therapeutic agents (1). In these models, bacterial burden and histopathology changes in the abdominal organs and lymph nodes had been thoroughly studied, but the neuraxes have not been evaluated.The CNS is confined to an ...

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Confirmation of the Beige Mouse Model for Study of Disseminated Infection with Mycobacterium avium Complex

Cited by 81 publications

References 2 publications

Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

The Mycobacterium avium complex

Invasion of the Brain and Chronic Central Nervous System Infection after SystemicMycobacterium aviumComplex Infection in Mice

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