Imipenem for treatment of tuberculosis in mice and humans

Abstract

Chemotherapy of tuberculosis caused by multiple-drug-resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta-lactam antibiotics are active against Mycobacterium tuberculosis in vitro. We investigated the efficacy of imipenem in a mouse model of tuberculosis and in humans with MDR tuberculosis. Mice infected with M. tuberculosis strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenem-treated mice were compared to those of untreated or isoniazid-treated mice. Ten patients with MDR tuberculosis also were treated with imipenem in combination with other first- or second-line agents; elimination of M. tuberculosis from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. tuberculosis organisms in lungs and spleens and improved survival of mice. Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. Seven remained culture-negative off of therapy. There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log10 CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with M. tuberculosis. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.

FIG. 1.

Mean burdens of M. tuberculosis strain H37Rv as log₁₀ CFU/g in spleen and lung tissues. The numbers of mice are as follows: for untreated mice (black diamonds), 14, 19, and 14 on days 0, 14, and 28, respectively; for imipenem-treated mice (open circles), 22 and 15 for days 14 and 28, respectively; and for isoniazid-treated (black squares), 14 and 15 for days 14 and 28, respectively. The standard errors of the means are indicated by the bars.

FIG. 2.

Survival curves for untreated mice (black diamonds), imipenem-treated mice (open circles), and isoniazid-treated mice (black squares).

FIG. 3.

Results of quantitative sputum cultures indicating M. tuberculosis burdens, expressed as log₁₀ CFU/ml, over time in sputa of individual patients (numbers correspond to patient numbers in Table 1) (A) and as a calculation of the overall elimination rate by linear regression for those patients who responded to treatment (B). The linear regression equation is shown.

FIG. 4.

Means and standard errors for proportional growth indices (GI) (the ratio of counts per minute on each day to counts per minute for the strain at day 0) for three separate experiments performed with starting growth indices ranging between 100 and 300. The open triangles indicate the prestudy isolate, and the closed triangles indicate the 18-week isolate for untreated cultures (A) or cultures to which imipenem at concentrations of 4 μg/ml (B), 8 μg/ml (C), or 16 μg/ml (D) had been added on day 0.