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 log 10 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.Treatment of tuberculosis caused by multiple-drug-resistant (MDR) (i.e., resistant to both isoniazid [INH] and rifampin) strains of Mycobacterium tuberculosis (MDR TB) is a challenge. Second-line antituberculous agents are less efficacious and more toxic than first-line drugs (5, 13). Fluoroquinolones, which can significantly improve response rates, are an important recent addition to the therapeutic armamentarium (13, 17), but other alternatives are desperately needed.Beta-lactams have not been regarded as useful drugs for treatment of tuberculosis because M. tuberculosis is naturally resistant to most of these antibiotics in vitro. Resistance is thought to be mediated by a class A beta-lactamase that hydrolyzes penicillins and cephalosporins (4,6,8). Resistance may be overcome by two means. One is inhibition of the beta-lactamase, and the other is the use of an antibiotic that is not a substrate for it. An example of the former is the use of the beta-lactam-beta-lactamase inhibitor combination amoxicillin-clavulanate, which is active in vitro (3) and has early bactericidal activity in patients with pulmonary tuberculosis (1). Anecdotally, amoxicillin-clavulanate in combination with other second-line agents has been successfully used in selected patients infected with MDR strains (11,19). This approach has met considerable skepticism, and the role, if any, of amoxicillin-clavulanate rem...

A Rare Cause of Acute Respiratory Distress Syndrome

“…Initial mortality due to ARDS in our patient was averted possibly because of anti micro bacterial action of gentamicin [10], levofloxacin and imipenem [11]. Partial response of ARDS and miliary TB can only be explained by anti micro bacterial action of antibiotics, as she had no evidence of pyogenic infection.…”

Potentiation of Available Antibiotics by Targeting Resistance – An Emerging Trend in Tuberculosis Drug Development

“…Encouraging results were also reported in animal models. Although less effective than the first-line anti-TB drug INH, imipenem significantly reduced M. tuberculosis counts in the lungs and spleens of infected mice (Chambers et al, 2005). As a result, imipenem doubled the survival rate of infected mice (35% mortality vs. 70%).…”

“…While only a very few cases in which TB patients treated with lactams in conjunction with or without potentiators have been reported, the results were always promising. One study using imipenem alone in MDR-TB patients with poor predicted outcomes achieved a 70% cure rate (Chambers et al, 2005). Another study showed that treatment of TB patients with an amoxicillin/clavulanate combination significantly reduced M. tuberculosis counts with early bactericidal activity comparable to patients treated with the frontline drug INH (Chambers et al, 1998).…”

Rational Use of Anti-Tuberculosis Drugs in the Chemotherapy Era of Drug-Resistant Tuberculosis

“…For RR-TB, MDR-TB and XDR-TB patients, off-label uses will be inevitable. Several clinical off-label experiences demonstrated the efficacy, safety, and tolerability profile of some antibiotics prescribed for other infectious diseases [14,15]. Among them, the drug most frequently prescribed is the linezolid, which is originally an antibiotic to treat infection caused by Grampositive bacteria.…”