Is there a place for β-lactams in the treatment of multidrug-resistant/extensively drug-resistant tuberculosis? Synergy between meropenem and amoxicillin/clavulanate.
OBJECTIVE
To: (i) assess if amoxicillin/clavulanate is a useful option for the management of multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB); (ii) assess if meropenem/clavulanate is active against Mycobacterium tuberculosis at concentrations achievable in vivo; and (iii) determine whether there was inhibition of meropenem/clavulanate activity in the presence of amoxicillin.


METHODS
Twenty-eight M. tuberculosis strains (7 susceptible, 2 monoresistant, 16 MDR and 3 XDR) were included in the study and tested against different concentrations of meropenem, meropenem/clavulanate, amoxicillin/meropenem, amoxicillin/clavulanate and amoxicillin/meropenem/clavulanate using the Bactec 960 MGIT(®) system.


RESULTS
All 28 strains were resistant to meropenem at the highest concentration tested (5 mg/L). Although 24 strains were susceptible to amoxicillin/clavulanate, 7 strains were susceptible only to 7.2/2.5 mg/L amoxicillin/clavulanate, 10 strains were susceptible to 3.6/2.5 mg/L amoxicillin/clavulanate, 6 strains were susceptible to 1.8/2.5 mg/L amoxicillin/clavulanate and 1 strain was susceptible to 0.9/2.5 mg/L amoxicillin/clavulanate. Therefore, 4/28 strains (14.29%) were resistant to the highest concentration of amoxicillin tested (7.2 mg/L); all of them were MDR. All of the 11 strains resistant to amoxicillin or susceptible only to 7.2 mg/L amoxicillin increased their susceptibility to amoxicillin/clavulanate after the addition of meropenem. The addition of clavulanate to meropenem reduced the MIC of meropenem by an average of over 1.8 dilutions.


CONCLUSIONS
The combination of amoxicillin/clavulanate plus meropenem is active against MDR/XDR-TB in vitro, and this triple therapy could be a useful therapy for MDR/XDR-TB and possibly help to reduce the development of further resistance. The drug susceptibility technique used here is routinely used, with modification, in mycobacteriology laboratories.
Health Protection Agency National Mycobacterium Reference Laboratory, 2 Newark Street, Whitechapel, London E1 2AT,  UK.
Ximena
X
Gonzalo
Francis
F
Drobniewski
D000658:Amoxicillin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019818:Clavulanic Acid / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D013845:Thienamycins / Q000494:pharmacology*; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology*; D047090:beta-Lactams / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D047090:beta-Lactams; D019818:Clavulanic Acid; D000658:Amoxicillin; D000077731:Meropenem