Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters.
The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse.



We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively.



The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug.



Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.
United States Centers for Disease Control and Prevention, Atlanta, GA, USA.
Joseph S
JS
Cavanaugh
Taiwan Centers for Disease Control, Taipei, Taiwan, Republic of China.
Ruwen
R
Jou
Taiwan Centers for Disease Control, Taipei, Taiwan, Republic of China.
Mei-Hua
MH
Wu
United States Centers for Disease Control and Prevention, Atlanta, GA, USA.
Tracy
T
Dalton
United States Centers for Disease Control and Prevention, Atlanta, GA, USA.
Ekaterina
E
Kurbatova
United States Centers for Disease Control and Prevention, Atlanta, GA, USA.
Julia
J
Ershova
United States Centers for Disease Control and Prevention, Atlanta, GA, USA.
J Peter
JP
Cegielski
D019980:Amoxicillin-Potassium Clavulanate Combination / Q000494:pharmacology; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019818:Clavulanic Acid / Q000494:pharmacology; D002991:Clofazimine / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D007917:Leprostatic Agents / Q000494:pharmacology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology
D000995:Antitubercular Agents; D007917:Leprostatic Agents; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D019980:Amoxicillin-Potassium Clavulanate Combination; D002991:Clofazimine; D000077731:Meropenem