European Society of Mycobacteriology - Instituto Nacional de Saúde ...

PP-107
SYNERGISTIC ACTIVITY OF TWO ANTITUBERCULOUS
DRUG COMBINATIONS AGAINST CLINICAL ISOLATES OF
Mycobacterium tuberculosis RESISTANT TO ISONIAZID.
Emma Rey, Griselda Tudó and Julià González-Martín
Servei de Microbiologia. Hospital Clínic-IDIBAPS. Dept. Microbiologia i Parasitologia Sanitaria, Universitat de Barcelona.
Spanish Network for the Research in Infectius Diseases (REIPI, RD06/0008).
Objective
To determine the synergistic activity of 2 drug combinations: isoniazid (H)+rifampicin (R)+ethambutol (E) and ofloxacin
(O)+R against M. tuberculosis clinical isolates resistant to H versus drug susceptible isolates.
Methods
Individual MICs of the strains were studied. Both combinations were studied crossing 7 concentrations of each antibiotic
(including their MIC). The inoculum was of 10 4 CFU/ml. All cultures were performed with the proportional method in
Middlebrook 7H11 medium and incubated 4 weeks. On analysing the results of the combinations, the fractional inhibitory
concentration (FIC) was interpreted: FIC≤0.5, synergistic activity; FIC from 1-4 indifference and FIC>4 antagonistic activity.
Results
H+R+E Combination: 11 H resistant isolates were studied: 4 (36%) isolates had MIC=52µg/ml and 7 (64%) had MIC=0.8µg/
ml. 9 drug-susceptible isolates were also studied. Among the 20 isolates the individual MIC for R ranged from 1-2 µg/ml,
from 2.5-5 µg/ml for E, being 0.05µg/ml for H in susceptible isolates. In H-resistant isolates, the MIC in combination for
H and R decreased up to 3 dilutions (average) respect to their individual MIC. A lesser decrease (2-3 dilutions) was observed
for E. In H-resistant isolates, 9/11 (81.1%) showed synergistic activity while 2/11 (18.18%) of the resistant isolates
indicated indifference (FIC index =0.7). MICs in combination of susceptible strains decreased an average of 2 dilutions
compared to their individual MIC. The susceptible strains had FIC indices ≥ 0.748. O+R Combination: 21 isolates were
studied:11 had MIC≤1µg/ml, 4 MIC=1-6.4 µg/ml and 6 MIC>6.4. 9 drug-susceptible isolates were studied. Individual MICs
for R ranged from 1-2, with 1 for O. MICs in combination of all strains were the same or decreased up to 1 dilution with
regard to their individual MIC. The combination of OR in 21 strains did not show synergism or antagonism in either the
resistant or the susceptible strains being the FIC values mainly 1.5.
Conclusions
1)These results suggest that in strains resistant to H with an MIC of 0.8µg/ml in vitro, the standard antibiotic regimen, including
H, would be effective due to the possible compensatory effects of R and E. 2) Although strains resistant to H with
an MIC of 51.2 µg/ml showed synergism, these strains would be within the range of resistance. 3)The combination of HRE
against susceptible strains and that of OR did not show synergism probably because of high individual bactericide action.
European Society of Mycobacteriology | 30 th Annual Congress | July 2009 | Porto - Portugal
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