Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the beta-lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg.h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (delta log10 CFU/ml.h, +0.20 +/- 0.14). Ofloxacin (delta log10 CFU/ml.h, -0.13 +/- 0.12), temafloxacin (delta log10 CFU/ml.h, -0.19 +/- 0.18), and levofloxacin (delta log10 CFU/ml.h, -0.24 +/- 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (delta log10 CFU/ml.h, -0.59 +/- 0.21) and Win 57273 (delta log10 CFU/ml.h, -0.72 +/- 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg.h (delta log10 CFU/ml.h, -0.80 +/- 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone.

01 Jan 1995·DrugsQ1 · MEDICINE

Quinolone Activity against Anaerobes

Q1 · MEDICINE

Review

Author: Appelbaum, P C

Currently available quinolones are either inactive or marginally active against anaerobic bacteria. This review summarises the in vitro activity of currently available as well as experimental quinolones against clinically significant anaerobic bacteria. Quinolones with low activity against anaerobes include ciprofloxacin, ofloxacin, levofloxacin, fleroxacin, pefloxacin, enoxacin, lomefloxacin and probably E 4868 and NM 441. Compounds with intermediate anaerobe activity include sparfloxacin, grepafloxacin, PD 131628 and AM 1155. Quinolones that are very active against anaerobes include clinafloxacin and DU 6859a. CP 99,219, a naphthyridone, is also very active against anaerobes. Toxicity problems have necessitated the withdrawal of some quinolones shown to have intermediate activity (temafloxacin and tosufloxacin) and the discontinuation of the development of some investigational agents (Win 57273 and BAY Y 3118) with high activity. Conclusions regarding the therapeutic value of quinolones against human anaerobic infections await further clinical toxicological and pharmacokinetic studies.

01 Jan 1994·International Journal of Antimicrobial AgentsQ2 · MEDICINE

Treatment and developmental therapeutics of Mycobacterium avium complex (MAC) infections

Q2 · MEDICINE

Article

Author: Georgiev, V S

Opportunistic infections associated with AIDS pose very serious problems because of their exceedingly high morbidity and mortality. For their part, Mycobacterium avium and M. intracellulare, two organisms belonging to M. avium complex (MAC), are the most often isolated bacteria from AIDS patients. Although in recent years, some progress has been made, by and large, there is no viable drug and /or combinations of drugs effective against MAC, especially in AIDS patients. Conventional therapies with multiple drug combinations involving isoniazid, rifampin, ethambutol, streptomycin, ethionamide, and cycloserine are still widely used, as well as prophylactic treatment with rifabutin. The use of clofazimine and ciprofloxacin has also been reported. Studies on new quinolones (sparfloxacin, difloxacin, WIN 57273), macrolides, folate antagonists and antimcobacterial anitbiotics are being actively pursued along with novel strategies involving drugs inhibiting mycobacterial cell wall biosynthesis. The role of various cytokines in enhancing host immune defenses against MAC infections is also discussed.

100 Deals associated with WIN-57273

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Discovery	US	Sanofi Winthrop LP	-

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