This article throws light upon the four chemicals originating from existing families of drugs. The chemicals are: 1. Fluoro Quinolones 2. Gatifloxacin 3. Moxifloxacin 4. New Quinolones.
Contents
Chemical # 1. Fluoro Quinolones:
Fluoro quinolones were introduced into clinical practice in the 1980’s. They are characterised by broad spectrum antimicrobial activity and are recommended and widely used for the treatment of bacterial infection of the respiratory, gastrointestinal and urinary tracts.
Fluor quinolones have been also found to have activity against M. tuberculosis and are currently part of the recommended regimen as second line drugs.
Since Fluoro quinolones share the same molecular targets, it is highly probable that they will trigger the same mechanisms of resistance. The major concern is that widespread use of Fluoro quinolones for treatment of other bacterial infections may select for resistant strains of M. tuberculosis.
In a study conducted in USA and Canada, among referral samples isolates between 1996 and 2000, resistance to ciprofloxacin was assessed and was found to occur in 1.8% of isolates and 75.8% were also MDR.
The authors concluded that despite the widespread use of Fluoro quinolones for treatment of common bacterial infection in USA and Canada, resistance to Fluoro quinolones remains rare and occurs mainly in MDR strains.
In contrast, in a different study conducted by Ginsburg and collaborators between 1998 and 2002, the incidence of M. tuberculosis Fluoro quinolones resistance in a small sample of patients with newly diagnosed TB was found to be high among patients with prior Fluoro quinolones exposure.
The risk of selecting Fluoro quinolones-resistant M. tuberculosis strains by empirically treating with Fluoro quinolones for presumed infections before a diagnosis of TB established is of great concern.
For this reason, some investigators in the TB field argue that the use of Fluoro quinolones might be better reserved for specific serious infection such as TB rather than becoming the workhorse of antimicrobial treatment, however given the current widespread use of quinolones this might not be realistic.
The interest in Fluoro quinolones as anti-tuberculosis agents has focused on the new Fluoro quinolones moxifloxacin and gatifloxacin.
Despite a lack of a comprehensive work comparing the activities of old and new classes of Fluoro quinolones in M. tuberculosis, what can be inferred from published sources are that moxifloxacin and gatifloxacin are characterised by a higher activity against M. tuberculosis in vitro when compared to the old Fluoro quinolones of loxacin and ciprofloxacin.
Chemical # 2. Gatifloxacin:
Gatifloxacin is a new Fluoro quinolones marketed in the U.S. by Bristol-Myers Squibb as Tequin. GAT has been found to have in vitro and in vivo bactericidal activity against M. tuberculosis.
In an in vivo study, GAT showed the highest bactericidal activity during the first 2 days but not thereafter. Similar results were obtained when GAT was used in combination with INH or RIF, GAT was able to slightly increase the bactericidal activity of INH or RIF only during the first 2 days.
One paper reported that when tested in mice in combination with ethionamide and PZA (high doses: 450 mg/kg, 5 days per week) GAT was able to clear lungs of infected mice after 2 months of treatment.
Current available data on GAT does not support the hypothesis that introduction of GAT with first-line drugs will-impressively contribute to shorten TB treatment. Further investigation should be done to properly assess the activity of GAT in vitro and in animal models.
GAT is currently in Phase II Clinical Trials (Table 6.1), conducted under the supervision of the European Commission of lotub Consortium (Hu et al., 2003). The aim of like trial is to evaluate the efficacy and safety of a four months gatifloxacin-containing regimen for treatment of pulmonary TB.
Chemical # 3. Moxifloxacin:
Moxifloxacin is produced by Bayer Pharmaceuticals and marketed as Avelox in the USA. MXF is the most promising of the new Fluoro quinolones being tested against M. tuberculosis.
In vitro, MXF appeared to kill a subpopulation of tubercle bacilli not killed by RIF, i.e. rifampicin-tolerant persisters, while other Fluoro quinolones ciprofloxacin and of loxacin did not have any significant bactericidal effect on the same subpopulation. One possibility is that MXF interferes with protein synthesis in slowly metabolizing bacteria, through a mechanism that differs from that used by RIF.
In mice models, the activity of MXF against tubercle bacilli was comparable to that of INH. When used in combination with MXF and PZA, MXF has been reported to kill the bacilli more effectively that the INH+RIF+PZA combination.
In conclusion, in vitro and in vivo studies suggest that MXF might be a promising candidate drug to shorten TB treatment. MXF is currently in Phase III Clinical Trials (Table 6.1). A trial substituting EMB with MXF during intensive phase was initiated before the animal models and showed no advantage over EMB.
Chemical # 4. New Quinolones:
In 2003, the TB Alliance launched a project in collaboration with the Korean Research Institute of Chemical Technology (KRCT) and the Yonsei University aimed to synthesise and evaluate novel and more effective quinolone compounds that could shorten first-line treatment. To date, 450 compounds have been synthesised and tested for their anti-tuberculosis activity.
During the research, the sub-class termed 2-pyridones was identified as being the one showing the most potent activity against M.tuberculosis in both its growing and persistent states.
This sub-class of compounds was already identified by Abbott in 1998 and found to have activity against drug-susceptible and drug-resistant M. tuberculosis in both its growing and persistent states. The lead compounds identified so far, showed sub-class of compounds was already identified by better activity than GZF and MXF.
