Cadrofloxacin Hydrochloride

The global resurgence of tuberculosis and the emergence of multidrug-resistant tuberculosis have emphasized an urgent need for new, effective antimycobacterial drugs. A new antimycobacterial drugs should have a different mechanism of action to the standard drugs and should not show cross-resistance with them. Favorable pharmacokinetic properties, low incidence of side effects and low cost are the characteristics that would make antimycobacterial drugs suitable for extensive use. The fluoroquinolones would appear to fulfill most of the criteria for an ideal class of antimycobacterial drugs. The fluoroquinolones have been proposed for the treatment of Mycobacterium tuberculosis (M. tuberculosis) infections, with the results of in vitro, animal model and clinical studies suggesting that ofloxacin, ciprofloxacin, sparfloxacin and levofloxacin are the most promising of these drugs. However, these fluoroquinolones should not be used as first-line drugs, but rather, they should be reserved for treatment of tuberculosis that is resistant to rifampicin and isoniazid. Recently, a new investigational fluoroquinolone derivative, AM-1155, DU-6859a and CS-940, have excellent in vitro activity against M. tuberculosis, further studies are required to assess its clinical activity. We discussed the future of view of development of fluoroquinolones for mycobacterial diseases on the basis of structure-activity and structure-side-effect relationship studies. The comparative analysis enabled us to elucidate the structural requirements for the antimycobacterial activity and side-effects of fluoroquinolones. In addition, we summarized the newer methods for high-throughput screening of compounds against M. tuberculosis and discussed the problem of development of fluoroquinolones for mycobacterial diseases.

Compared with the recent rapid advances in the diagnosis of tuberculosis, advances in the treatment of tuberculosis have been quite slow. For example, as long as six months are required for initial treatment, even with addition of pyrazinamide in the first two months to isoniazid, rifampicin, and streptomycin or ethambutol. Moreover, it is not always easy to treat patients who cannot receive standard agents including isoniazid and rifampicin due to adverse effects of these drugs or drug resistance. For these reasons, the development of new agents with potent antituberculosis activities and fewer adverse effects is urgently desired. However, at present, few new antituberculosis agents are being developed, and new quinolones are considered the most promising new antituberculosis agents due to their lack of cross-resistance to previously existing antituberculosis agents, their excellent in vitro and in vivo antituberculous activities, and good pharmacokinetics. We therefore reviewed experimental studies and clinical reports useful for evaluation of potential clinical use of new quinolones as antituberculosis drugs. Our conclusions are summarized below: 1) Of nine new quinolones on the market, ofloxacin, ciprofloxacin, aparfloxacin and levofloxacin have excellent in vitro and in vivo antituberculous activities without cross-resistance to previously existing antituberculosis agents. 2) Ofloxacin appears to be useful clinically for intractable multidrug-resistant tuberculosis. The incidence and severity of adverse effects of ofloxacin were very low on longterm administration. 3) Ofloxacin resistance emerged from two to four months after initiation of administration of ofloxacin, and ofloxacin exhibited cross-resistance to other new quinolones. 4) The usefulness of new quinolones for initial treatment of tuberculosis is unclear. 5) New quinolones should be used to treat patients with drug-resistant tuberculosis and those patients for whom adverse effects have limited the use of standard agents. However, monotherapy with new quinolones is not recommended, due to the significant risk of emergence of quinolone resistance. 6) Not only ofloxacin, ciprofloxacin, sparfloxacin and levofloxacin, which are on the market, but also gatifloxacin, CS-940, Du-6859a and other newly developed new quinolones are candidates for new antituberculosis agents. However, careful study not only of antituberculous activities and pharmacokinetic but also drug interactions and chronic cumulative toxicities due to long-term administration are needed prior to clinical application of these drugs.