The bactericidal activity of gatifloxacin, alone and in combination with isoniazid and rifampin, was studied on both exponential-and stationary-phase cultures of Mycobacterium tuberculosis strain H37Rv. On log-phase cultures, the bactericidal activity of gatifloxacin at 4 g/ml was rapid and was very similar to that of isoniazid. At concentrations of 0.25 and 4 g/ml, gatifloxacin enhanced the activity of isoniazid. Killing of the stationaryphase culture was biphasic. During the first 2 days, gatifloxacin at 4 g/ml slightly increased the limited bactericidal activities of isoniazid and rifampin. However, no further additional bactericidal activity was found during further incubation with isoniazid alone or when gatifloxacin was added to either isoniazid or rifampin. This suggested that the stationary-phase culture contained a mixture of occasionally dividing bacilli that were killed during the first 2 days and true static persisters in the residual population that mimicked those in human lesions. In view of the failure of gatifloxacin to add to the sterilizing activity of isoniazid or rifampin during days 2 to 6 of exposure in the stationary-phase culture, it is unlikely to be a sterilizing drug that can be used to shorten the duration of treatment appreciably when it is added to present treatment regimens.Tuberculosis continues to be one of the leading causes of death in the world. Although directly observed treatment, short course (DOTS), contributes to the control of the disease, noncompliance with treatment continues to be the main cause of poor results. Even in places where the DOTS strategy is reported to be a success, the main reason cited for noncompliance is the long, 6-month duration of treatment (17). Hence, shortening of the duration of treatment without compromising the cure and relapse rates still remains a major goal for control policies. Evidence that the addition of fluoroquinolones to present treatment regimens might shorten their duration has been provided by studies of experimental murine tuberculosis (14) and by a clinical trial at the Tuberculosis Research Centre, Chennai, India (16). Further clinical trials of fluoroquinolones aimed at shortening treatment, with backing in the United States (14) and from the European Commission (10), are proceeding. Among the fluoroquinolones, those with the greatest activity in tuberculosis are ofloxacin (OFX), levofloxacin, which should act in the same manner, and the newer quinolones such as 8-methoxy derivatives gatifloxacin (GAT) and moxifloxacin. In vitro studies have compared the in vitro bactericidal actions of each of these four quinolones and suggest that among the fluoroquinolones GAT and moxifloxacin have the greatest activities, even though they are still limited, against static bacterial populations of Mycobacterium tuberculosis that might resemble those in human lesions (5).During the initial phase of chemotherapy, which lasts for about 2 days, bacilli are killed exponentially at a rapid rate, followed by a further lengthy period of much slowe...
The in vitro activity of fluoroquinolones, including lomefloxacin, ofloxacin, ciprofloxacin, sparfloxacin, moxifloxacin and gatifloxacin, was evaluated against 55 clinical isolates of Mycobacterium tuberculosis by absolute concentration method on Lowenstein-Jensen (L-J) and Middlebrook's 7H11 media. Both ofloxacin susceptible and ofloxacin resistant strains of M. tuberculosis isolates were tested. The in vitro activities of these fluoroquinolones on the M. tuberculosis isolates were in the order: lomefloxacin < ciprofloxacin < or = ofloxacin < sparfloxacin < moxifloxacin = gatifloxacin. Gatifloxacin and moxifloxacin showed low minimal inhibitory concentrations (MIC) for both ofloxacin resistant and ofloxacin susceptible strains even though some cross resistances were observed.
Studies in the mouse and in humans suggest that use of moxifloxacin and gatifloxacin may shorten the duration of treatment of pulmonary tuberculosis. We describe here the in vitro findings with gatifloxacin and moxifloxacin in regimens similar to those that might be used in the treatment of tuberculosis. The bactericidal activities of moxifloxacin and gatifloxacin were measured alone and in different combinations with isoniazid, rifampicin and pyrazinamide against a 30-day, stationary phase culture, at a pH of 5.9. There was a rapid, irregular fall in colony counts during the first 4 days followed by a slower consistent kill during days 4-21 with a mean kill of -0.36 (SD=2.74) and -0.106 (SD=0.011) log(10)CFU/ml/day, respectively. The 4-21-day kill is considered the best assessment of bactericidal activity against persisting bacilli that prolong treatment. The substitution of either of the quinolones for isoniazid in the control regimen of rifampicin, pyrazinamide and isoniazid did not increase bactericidal activity with log CFU of 5.00 and 4.88, but did result in increased bactericidal action with the log CFU of 4.11 and 4.10 for moxifloxacin and gatifloxacin respectively. Moxifloxacin and gatifloxacin had closely similar activities in all drug combinations. Adding moxifloxacin or gatifloxacin to the control regimen resulted in a significant increase in bactericidal action, considered sufficient to reduce the treatment duration.
The bactericidal activity of moxifloxacin, alone and in combination with isoniazid and rifampin, was studied on exponential and stationary phase cultures of Mycobacterium tuberculosis H37 Rv strain, the standard strain which is a wild type of M. tuberculosis strain, not exposed to any environment, susceptible to all anti-tuberculosis drugs. Moxifloxacin alone was highly bactericidal, being intermediate in activity between isoniazid and rifampin on both types of culture. The speed of activity was slow with the stationary phase culture, causing a reduction from 6.41 log(10)cfu/ml to 2.70 log(10)cfu/ml on day 6 with the higher moxifloxacin concentration of 4 microg/ml and to 4.08 log(10)cfu/ml with the lower concentration of 0.25 microg/ml. When added to isoniazid, its activity against both exponential and stationary phase cultures was increased. However, when it was added to rifampin, no increase in activity was found with either type of culture. Addition of moxifloxacin to isoniazid and rifampin resulted in a slight increase in activity against the exponential culture but a considerable increase against the stationary culture with counts below the limit of detection at 4 and 6 days with both moxifloxacin concentrations. The synergism found with isoniazid, but not with rifampin, supports the view that isoniazid should be included in combinations with moxifloxacin during the therapy of pulmonary tuberculosis.
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