Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis [PublishAheadOfPrint]

More permissive preclinical models may be useful in evaluating anti-tuberculosis regimens for their propensity to select drug-resistant mutants. To evaluate whether acquired rifamycin monoresistance could be recapitulated in mice and, if so, to evaluate the effects of immunodeficiency, intermittent dosing and drug exposures. Athymic nude and BALB/c mice were infected. Controls received daily rifapentine alone or 2 months of rifampin, isoniazid, pyrazinamide and ethambutol, followed by 4 months of rifampin/isoniazid, either daily or twice-weekly with one of two isoniazid doses. Test groups received the same intensive regimen followed by once-weekly rifapentine, or isoniazid/rifapentine with rifapentine doses of 10, 15 or 20 mg/kg plus one of two isoniazid doses. All combination regimens rendered BALB/c mice culture-negative, but selected mutants resistant to isoniazid (8.5%, 12/140) or rifampin (3.5%, 5/140) in nude mice (P < 0.001). Intermittent intensive phase therapy selected isoniazid and rifampin resistance in 10% (8/80, P < 0.001) and 20% (16/80, P = 0.009) of nude mice, respectively, compared to 0% treated with a daily regimen. Once-weekly rifapentine-containing continuation phase regimens selected rifampin-resistant mutants in 18.0% (18/100, P = 0.035) compared to rifampin/isoniazid regimens. Higher isoniazid doses in the intermittent control regimen and higher rifapentine doses in once-weekly regimens were associated with less selection of isoniazid resistance. Acquired resistance, including rifamycin monoresistance, was more likely to occur in nude mice despite combination therapy. These results recapitulate clinical outcomes, and indicate that nude mice may be useful for evaluating the ability of novel regimens to prevent the selection of resistance.

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