rifampin and sitafloxacin

Highly virulent, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strains with Panton-Valentine leucocidin (PVL) genes have been found increasingly worldwide. Among a total of 2,101 MRSA strains isolated from patients in hospitals in Japan, two were positive for PVL genes. One strain was identified as a community-acquired MRSA strain with genotype sequence type 30 (ST30) and spa (staphylococcal protein A gene) type 19 from Japan and was resistant only to beta-lactam antimicrobial agents. The other strain was closely related to PVL+ multidrug-resistant, hospital-acquired MRSA strains (ST30, spa type 43) derived from nosocomial outbreaks in the 1980s to 1990s in Japan but with a divergent sequence type, ST765 (a single-locus variant of ST30). Twenty-two PVL+ MRSA strains, including those from Japan and those from other countries with various sequence types (ST1, ST8, ST30, ST59, and ST80) and genotypes, were examined for susceptibility to 31 antimicrobial agents. Among the agents, DX-619, a des-fluoro(6) quinolone, showed the greatest activity, followed by rifampin and sitafloxacin, a fluoroquinolone. The data suggest that DX-619 exhibits a superior activity against PVL+ MRSA strains with various virulence genetic traits from the community as well as from hospitals.

Topics: Anti-Bacterial Agents; Bacterial Toxins; Community-Acquired Infections; Cross Infection; Drug Resistance, Bacterial; Exotoxins; Fluoroquinolones; Hospitals; Humans; Leukocidins; Methicillin Resistance; Microbial Sensitivity Tests; Pyrrolidines; Quinolones; Rifampin; Staphylococcus aureus

The antimicrobial effects of sitafloxacin (DU-6859a) against Mycobacterium leprae, either singly or in combination with either rifampicin, rifabutin or KRM-1648, were studied using a mouse footpad assay technique and the results were compared with those obtained with ofloxacin. When used singly, the minimum concentrations of sitafloxacin and ofloxacin needed to inhibit completely the growth of M. leprae were 25 and 100 mg per kg body weight per day, respectively, and the effects were bactericidal. Both sitafloxacin and ofloxacin exhibited excellent synergistic effects when combined with either rifabutin or KRM-1648, but not with rifampicin. Thus, incorporation of sitafloxacin and rifabutin (or KRM-1648) in the multidrug regimen for treating leprosy patients is suggested.

Topics: Animals; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Fluoroquinolones; Leprostatic Agents; Leprosy; Mice; Mice, Inbred BALB C; Mycobacterium leprae; Ofloxacin; Rifampin

The in-vitro antibacterial activity of sitafloxacin (DU-6859a) against Mycobacterium leprae was evaluated and compared with those of ofloxacin, levofloxacin, and ciprofloxacin. Two biochemical indicators (intracellular ATP and uptake of [(3)H]-thymidine) were used to measure the in-vitro growth of M. leprae in Dhople-Hanks (DH) medium. Sitafloxacin was found to be more potent than the other three commonly used fluoroquinolones, with the minimum inhibitory concentration (MIC) against M. leprae being 0.1875 microg/ml and the action being bactericidal. The MICs of ofloxacin, levofloxacin, and ciprofloxacin were 1.5, 0.75, and 3.0 microg/ml, respectively. Similar to ofloxacin and levofloxacin, sitafloxacin also exhibited synergistic activity when combined with either rifabutin or KRM-1648, but not with rifampin. Thus, further studies on the incorporation of sitafloxacin in multidrug therapy regimens in treating leprosy patients are suggested.

Topics: Animals; Anti-Infective Agents; Armadillos; Drug Synergism; Drug Therapy, Combination; Fluoroquinolones; Humans; Leprostatic Agents; Microbial Sensitivity Tests; Mycobacterium leprae; Rifabutin; Rifampin; Rifamycins

Efficacy of a new fluoroquinolone, sitafloxacin (DU-6859a), against Mycobacterium ulcerans was evaluated in vivo using the mouse footpad system. The growth of M. ulcerans in mouse footpads was completely inhibited when mice were fed with sitafloxacin at a dose of 25 mg/kg body weight per day; on the other hand similar effects were observed with ofloxacin at a dose of 100 mg/kg body weight per day. In the presence of rifampin, the above dose of sitafloxacin could be reduced by 75% to achieve total inhibition, while, under similar circumstances, the dose of ofloxacin could be reduced by only 50%. Either used singly or in combination with rifampin, the effects of sitafloxacin were bactericidal. The results suggest that sitafloxacin should be evaluated as a chemotherapeutic agent against M. ulcerans infection.

Topics: Animals; Anti-Infective Agents; Antibiotics, Antitubercular; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluoroquinolones; Foot; Mice; Mice, Inbred BALB C; Mycobacterium Infections, Nontuberculous; Mycobacterium ulcerans; Rifampin

The antimicrobial effect of sitafloxacin (DU-6859a), used either singly or in combination with rifampicin, was evaluated in vitro against Mycobacterium ulcerans. Growth of M. ulcerans was measured by plate counts and the BACTEC radiometric method. The MICs and MBCs of sitafloxacin for M. ulcerans were in the range 0.125-0.5 mg/L. The values for other fluoroquinolones were two- to four-fold higher than for sitafloxacin. Combination of sitafloxacin and rifampicin exhibited synergy with five of the eight strains, whereas the combination of ofloxacin and rifampicin resulted in additive effects only. These results suggest that the combination of sitafloxacin and rifampicin has potential in the treatment of M. ulcerans infection.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Drug Therapy, Combination; Fluoroquinolones; Humans; Microbial Sensitivity Tests; Mycobacterium ulcerans; Rifampin

Sitafloxacin (DU-6859a) and trovafloxacin are novel quinolones potent on methicillin-resistant Staphylococcus aureus (MRSA) that are designed for once daily administration. In order to define the adequacy of the above regimen for the therapy of infections by multiple drug-resistant MRSA, their postantibiotic effect (PAE), their bactericidal activity, and their interactions with rifampin were determined on 14 MRSA isolates resistant to both ciprofloxacin and rifampin. PAE was defined after 1-h exposure to 1x, 4x, and 10x MIC and the killing effect after exposure to 1x and 4x MIC. Rifampin was applied for interactive studies at a concentration of 2 micrograms/mL, which is equal to its mean serum level. Median PAEs produced by 1x, 4x, and 10x MIC of sitafloxacin were 1.39, 3.75, and 6.61 h respectively, and by 1x, 4x, and 10x MIC of trovafloxacin 0.87, 2.07, and 2.23 h respectively. PAEs achieved by sitafloxacin were statistically shown to be longer than those achieved by trovafloxacin; PAEs achieved by a concentration of 10x MIC of each quinolone did not differ significantly from those achieved by a concentration of 4x MIC. Both the 4x and 10x MIC concentrations produced a more prolonged PAE than the 1x MIC concentration. A rapid bactericidal activity was expressed over the first 6 h of growth by each quinolone involving 80% of isolates enhanced in some isolates by their interaction with rifampin. The above findings revealed an extended PAE and a rapid killing effect of both sitafloxacin and trovafloxacin on MRSA resistant to ciprofloxacin and to rifampin, thus supporting their once daily administration in the therapy of infections by multiple drug-resistant MRSA. However little in vitro benefit is derived by their interaction with rifampin.

Topics: Anti-Infective Agents; Drug Interactions; Fluoroquinolones; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Naphthyridines; Rifampin; Staphylococcus aureus

The in vitro activity of DU-6859a (DU) alone and in combination with various antimicrobials was evaluated against multiresistant enterococci including some isolates with defined gyrA mutations. DU produced rapid in vitro killing against most enterococci that lacked resistance to ciprofloxacin, but it was not bactericidal against strains with MICs of ciprofloxacin of > or = 8 micrograms/ml, or against one of four strains with an MIC of ciprofloxacin of 4 micrograms/ml. The combination of DU with rifampin was antagonistic against two of two isolates tested. Combinations of DU and novobiocin, gentamicin, or a beta-lactam (amoxicillin, ampicillin-sulbactam, or amoxicillin-clavulanate) were generally indifferent. When different beta-lactams were used together, with or without DU, bactericidal activity was observed against some isolates. Despite the absence of synergistic interactions with other agents, DU is a promising fluoroquinolone for use against enterococci, although prior development of resistance to currently available fluoroquinolones diminishes some of its effect.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Ciprofloxacin; DNA Gyrase; DNA Topoisomerases, Type II; Drug Antagonism; Drug Combinations; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Synergism; Enterococcus; Fluoroquinolones; Genetic Variation; Gentamicins; Lactams; Microbial Sensitivity Tests; Novobiocin; Quinolones; Rifampin