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 bactericidal actions of ofloxacin and sulbactam-ampicillin, alone and in combination with rifampin and isoniazid, on exponential-phase and stationary-phase cultures of a drug-susceptible isolate of Mycobacterium tuberculosis were studied in vitro. In exponential-phase cultures, all drugs were bactericidal, with the higher concentrations of ofloxacin (5 g/ml) and sulbactam-ampicillin (15 g of ampicillin per ml) being as bactericidal as 1 g of isoniazid per ml or 1 g of rifampin per ml. In two-drug combinations, both drugs increased the levels of activity of isoniazid and rifampin and were almost as bactericidal as isoniazid-rifampin; they also appeared to increase the level of activity of isoniazid-rifampin in three-drug combinations. In contrast, ofloxacin and sulbactam-ampicillin had little bactericidal activity against stationary-phase cultures and were less active than isoniazid or rifampin alone. Furthermore, in two-drug or three-drug combinations, they did not increase the level of activity of isoniazid, rifampin, or isoniazid-rifampin. These findings suggest that ofloxacin and sulbactam-ampicillin are likely to be most useful in the early stages of treatment and in preventing the emergence of resistance to other drugs but are unlikely to be effective as sterilizing drugs helping to kill persisting lesional bacilli.
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.
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