GENOME AND MIC STABILITY IN MYCOBACTERIUM-TUBERCULOSIS AND INDICATIONS FOR CONTINUATION OF USE OF ISONIAZID IN MULTIDRUG-RESISTANT TUBERCULOSIS

Mycobacterium tuberculosis strains resistant to two or more of the fir st line antituberculosis drugs (MDR) are a serious threat to successfu l tuberculosis control programmes, For this retrospective study, 85 fo llow-up drug resistant isolates from 23 patients residing in a communi ty with a high incidence of tuberculosis were collected and the level of in-vitro resistance to antibiotics determined quantitatively, PCR-S SCP and sequencing techniques were used to screen for gene mutations a ssociated with resistance in 31 follow-up samples from a smaller group of eight patients, DNA fingerprint analysis was done on sequential is olates to confirm identity, Although treatment had a profound effect o n changes in drug resistance patterns, the MIC for a particular agent remained constant in follow-up isolates. DNA fingerprinting and mutati onal analysis (14 different loci) showed that the genome of MDR strain s of M, tuberculosis is relatively stable during the course of therapy , The rpoB gene was the most frequently mutated structural gene involv ed in drug resistance and a novel C to T mutation upstream of open rea ding frame (ORF)1 of the inhA operon was detected, No evidence was fou nd of the presence of strain W (New York) in this group of MDR strains , The results stress the importance of confirming individuality of str ains for the accurate calculation of frequencies of particular mutatio ns associated with drug resistance, particularly in a high incidence a rea, Approximately one-half (47.8%) of the patients had isolates resis tant to concentrations just above the critical concentration for isoni azid (MICs of 0.2-5 mg/L), Therefore, these patients and their contact s who develop primary drug-resistant tuberculosis may respond to highe r dosages of treatment which could have a considerable impact on the c ost and the ease of management of resistant tuberculosis.