A Comparison of Two Regimens for the Treatment of<i>Mycobacterium avium</i>Complex Bacteremia in AIDS: Rifabutin, Ethambutol, and Clarithromycin versus Rifampin, Ethambutol, Clofazimine, and Ciprofloxacin

Shafran, Stephen D.; Singer, Joel; Zarowny, Donald P.; Phillips, Peter; Salit, Irving E.; Walmsley, Sharon; Fong, I. W.; Gill, M. John; Rachlis, Anita; Lalonde, Richard; Fanning, Mary M.; Tsoukas, Christos

doi:10.1056/nejm199608083350602

Cited by 282 publications

(90 citation statements)

References 26 publications

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“…Curiously, similar to our present findings, IL-10 seems not to underlie the susceptibility to tuberculosis in the mouse model (52). Since long-term treatment of both tuberculosis and M. avium infection with the appropriate conventional chemotherapy usually leads to severe side effects (11,12), the possibility of improving antimycobacterial activity of current antibiotics by interfering with IL-10 signaling may help circumvent these problems.…”

Section: Discussionsupporting

confidence: 85%

“…Long-term treatment with macrolides such as clarithromycin, which is highly effective in the treatment of MAC infections (4,5), leads to the emergence of resistant forms (6 -8), which can be prevented by combining at least two or three drugs (9,10). However, this in turn can lead to severe side effects (11,12). Ways to shorten therapeutical courses as well as increasing efficacy of the treatment are thus needed.…”

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confidence: 99%

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Blocking the Receptor for IL-10 Improves Antimycobacterial Chemotherapy and Vaccination

Silva

Pais

Appelberg

2001

The Journal of Immunology

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Novel approaches are required for the prevention and therapy of mycobacterial infections since the only vaccine in use, bacillus Calmette-Guérin, is poorly effective and chemotherapy is long and often ineffective in sterilizing the infection. We used a mouse model of Mycobacterium avium infection to address the usefulness of a mAb able to block IL-10R both in treatment of primary infections and in conventional multidrug therapy and subunit vaccination. Treatment of infected mice with this mAb during the entire period of experimental infection had little impact on the course of M. avium infection, with a slight improvement in the resistance of infected mice observed in the liver and spleen at day 30 of infection, which was associated with increased macrophage activation and priming of CD4+ T cells for IFN-γ production. Administration of this mAb later in infection had no effect on its course, but improved the effectiveness of chemotherapy when the latter was started in a chronic phase of infection. Also, the anti-IL-10R mAb acted as an adjuvant in the induction of protective immunity upon vaccination with a mycobacterial subunit preparation.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Blocking the Receptor for IL-10 Improves Antimycobacterial Chemotherapy and Vaccination

Silva

Pais

Appelberg

2001

The Journal of Immunology

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“…The drug was shown to be even more bactericidal than isoniazid when tested in a mouse model of tuberculosis chemotherapy (2). For reasons that are not well documented, clofazimine was not advanced for the treatment of human tuberculosis but was used for the treatment of leprosy and later, unsuccessfully, for the treatment of Mycobacterium avium complex infection in patients with AIDS (3,4). The unfortunate development of multidrug-and extensively drug-resistant tuberculosis has kindled a worldwide push for the development of new therapy options for this disease, including a renewed interest in clofazimine (5).…”

mentioning

confidence: 99%

Assessment of Clofazimine Activity in a Second-Line Regimen for Tuberculosis in Mice

Grosset

Tyagi

Almeida

et al. 2013

Am J Respir Crit Care Med

109

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Rationale: Although observational studies suggest that clofaziminecontaining regimens are highly active against drug-resistant tuberculosis, the contribution of clofazimine for the treatment of this disease has never been systematically evaluated. Objectives: Our goal was to directly compare the activity of a standard second-line drug regimen with or without the addition of clofazimine in a mouse model of multidrug-resistant tuberculosis. Our comparative outcomes included time to culture conversion in the mouse lungs and the percentage of relapses after treatment cessation. Methods: Mice were aerosol-infected with an isoniazid-resistant (as a surrogate of multidrug-resistant) strain of Mycobacterium tuberculosis. Treatment, which was administered for 5 to 9 months, was initiated 2 weeks after infection and comprised the following second-line regimen: daily (5 d/wk) moxifloxacin, ethambutol, and pyrazinamide, supplemented with amikacin during the first 2 months. One-half of the mice also received daily clofazimine. The decline in lung bacterial load was assessed monthly using charcoal-containing agar to reduce clofazimine carryover. Relapse was assessed 6 months after treatment cessation. Measurements and Main Results: After 2 months, the bacillary load in lungs was reduced from 9.74 log 10 at baseline to 3.61 and 4.68 in mice treated with or without clofazimine, respectively (P , 0.001). Mice treated with clofazimine were culture-negative after 5 months, whereas all mice treated without clofazimine remained heavily culturepositive for the entire 9 months of the study. The relapse rate was 7% among mice treated with clofazimine for 8 to 9 months. Conclusions: The clofazimine contribution was substantial in these experimental conditions. Keywords: tuberculosis; multidrug-resistant tuberculosis; clofazimine; inbred BALB/c mice Clofazimine, also known as B.663 or Lamprene, is a fat-soluble riminophenazine dye developed in the 1950s by Vincent Barry and colleagues (1, 2) as a drug for the treatment of tuberculosis. The drug was shown to be even more bactericidal than isoniazid when tested in a mouse model of tuberculosis chemotherapy (2). For reasons that are not well documented, clofazimine was not advanced for the treatment of human tuberculosis but was used for the treatment of leprosy and later, unsuccessfully, for the treatment of Mycobacterium avium complex infection in patients with AIDS (3, 4). The unfortunate development of multidrug-and extensively drug-resistant tuberculosis has kindled a worldwide push for the development of new therapy options for this disease, including a renewed interest in clofazimine (5). Although several groups have characterized clofazimine activity for in vitro and animal models of tuberculosis (6), a seminal publication by van Deun and colleagues in 2010 reported for the first time that a 9-month drug regimen including gatifloxacin, ethambutol, pyrazinamide, and clofazimine throughout plus a 4-month initial supplement of kanamycin, prothionamide, and a high dose of isoniazid achi...

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“…Clinical trials have supported the superiority of clarithromycin, ethambutol, and rifabutin over rifampicin, ethambutol, clofazimine, and ciprofloxacin (56). A compara- Uncorrected Proof Copy 258 Gillespie tive trial suggested that lower doses of rifabutin (300 mg daily) together with ethambutol are more effective than a four-drug regimen of rifampicin, ethambutol, clofazimine, and ciprofloxacin, still retaining much of the activity of clarithromycin (1000 mg twice daily) and rifabutin (600 mg daily) doses (56).…”

Section: Management Of Disseminated Infection In Hiv-seropositive Patmentioning

confidence: 99%

Management of Infection With Nontuberculosis Mycobacteria

Gillespie¹

2004

Management of Multiple Drug-Resistant Infections

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A Comparison of Two Regimens for the Treatment ofMycobacterium aviumComplex Bacteremia in AIDS: Rifabutin, Ethambutol, and Clarithromycin versus Rifampin, Ethambutol, Clofazimine, and Ciprofloxacin

Cited by 282 publications

References 26 publications

Blocking the Receptor for IL-10 Improves Antimycobacterial Chemotherapy and Vaccination

Blocking the Receptor for IL-10 Improves Antimycobacterial Chemotherapy and Vaccination

Assessment of Clofazimine Activity in a Second-Line Regimen for Tuberculosis in Mice

Management of Infection With Nontuberculosis Mycobacteria

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