In Vitro Activity of Garenoxacin against
            <i>Streptococcus pneumoniae</i>
            Mutants with Characterized Resistance Mechanisms

Yamamoto, Kazuko; Yanagihara, Katsunori; Sugahara, Kazuyuki; Imamura, Yoshifumi; Seki, Masafumi; Izumikawa, Koichi; Kakeya, Hiroshi; Yamamoto, Yoshihiro; Hirakata, Yoichi; Kamihira, Shimeru; Kohno, Shigeru

doi:10.1128/aac.00176-09

Cited by 8 publications

(5 citation statements)

References 22 publications

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“…These results further suggest that GyrA was the most crucial target for development of high-level resistance reflected in high MIC and MPC values for these three fluoroquinolones and the only target sensitive to prolonged antibiotic pressure in MPC experiments. These results are in agreement with previous findings (1,4,18,23,25,27). No clear relationship was found between the MPCs or their ratios to the MICs and the existence of gyrB, parC, or parE mutations.…”

Section: Resultssupporting

confidence: 83%

“…The MPC/MIC ratio defines the concentration range in which resistant mutant subpopulations are selectively amplified, with the lower values suggesting a better ability to prevent mutant emergence (4,13,23,25). In the current study, moxifloxacin and levofloxacin MPC/MIC ratios were within the same range for most strains; Ͼ80% of strains had ratios of 2 to 4.…”

Section: Resultsmentioning

confidence: 69%

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Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Credito

Kosowska-Shick

McGhee

et al. 2010

Antimicrob Agents Chemother

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We tested the propensity of three quinolones to select for resistant Streptococcus pneumoniae mutants by determining the mutant prevention concentration (MPC) against 100 clinical strains, some of which harbored mutations in type II topoisomerases. Compared with levofloxacin and gemifloxacin, moxifloxacin had the lowest number of strains with MPCs above the susceptibility breakpoint (P < 0.001), thus representing a lower selective pressure for proliferation of resistant mutants. Only moxifloxacin gave a 50% MPC (MPC 50 ) value (1 g/ml) within the susceptible range.The only three quinolones currently approved to treat community-acquired respiratory tract infections in adults are levofloxacin (500 and 750 mg), moxifloxacin (400 mg), and gemifloxacin (320 mg). When free area under the curve (AUC)/MIC data are compared, moxifloxacin and gemifloxacin yield similar values and are superior to levofloxacin (15,16). These pharmacokinetic/pharmacodynamic considerations relate to efficacy against the susceptible portion of the bacterial population (9, 10). Another criterion, the mutant prevention concentration (MPC), may also impact clinical efficacy by relating to the resistant mutant subpopulations. The MPC, which is the MIC of the least susceptible resistant mutant subpopulation, represents a threshold above which the selective proliferation of the resistant mutant subpopulation is expected to rarely occur. Using this method, Blondeau and colleagues (4) proposed that moxifloxacin and gatifloxacin (a drug no longer available) are more active than levofloxacin in the treatment of pneumococcal pneumonia. Since the least susceptible mutant is usually a drug target mutant, MPC values can be regarded as a measure of the interaction of the quinolone with the mutant target enzyme. However, clinical isolates may contain additional efflux mechanism and/or permeability alterations that potentially may raise the MPC. Thus, measurement of MPC with clinical isolates and integrating that information with pharmacokinetics is important for comparing compounds.In the current study, the MIC and MPC values for 100 recent clinical pneumococcal isolates, each with different ␤-lactam, quinolone, and macrolide phenotypes, were determined for levofloxacin, moxifloxacin, and gemifloxacin. All quinolonenonsusceptible (intermediate as well as resistant) strains, as well as 13 randomly selected quinolone-susceptible strains were tested for the presence of mutations in the quinolone resistance-determining regions (QRDRs) of the gyrA, gyrB, parC, and/or parE genes. MATERIALS AND METHODSMIC and MPC determination. The initial determinations of the MICs for all strains were made using standard agar dilution methodology (5). MICs were also tested during MPC determinations that were performed as follows. Starter cultures were generated by inoculating 12 blood Trypticase soy agar (TSA) plates (BD Diagnostics, Sparks, MD) with pure cultures of each test isolate and incubated overnight at 35°C in air. The cells were then transferred from plates and suspended...

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 69%

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Credito

Kosowska-Shick

McGhee

et al. 2010

Antimicrob Agents Chemother

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“…In addition to their antimicrobial properties, certain quinolones have significant immunomodulatory activities in vitro and in vivo (Dalhoff, 2005). A newly developed fluoroquinolone, garenoxacin mesilate hydrate (GRNX), has a low mutant prevention concentration (the concentration that prohibits the growth of mutants from a susceptible population of more than 10 10 cells) and a narrow mutant selection window (defined as the range between the minimum inhibitory concentration and the mutant prevention concentration, provides a means for defining the ability of an antibiotic to prevent the emergence of mutants) and is useful for minimizing the selection of quinolone-resistant mutants of pneumococcal strains (Yamamoto et al, 2009). However, the immunomodulatory properties of GRNX in human lung cells have not previously been examined.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory effects of garenoxacin on IL-8 production and ERK1/2 activation induced by lipopolysaccharides in A549 and THP-1 cells

Hara

Ishimatsu

Mukae

et al. 2011

European Journal of Pharmacology

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“…Determination of antimicrobial susceptibility is important, particularly when treatment has failed. According to studies, the level of resistance to quinolones in Asian countries, especially in the Middle East, is significantly higher than that in other parts of the world; quinolone resistance has been reported in Korea (6.1%), the Philippines (9.1%), and Hong Kong (14.3%) was reported, and the development of strains resistant to levofloxacin in Qatar, Kuwait, Lebanon raised serious concerns [12,13] . In addition, a research in southern Nigeria confirmed that the level of resistance to first-generation quinolones is relatively higher than that to third-generation quinolones, i.e., the highest resistance is to nalidixic acid and the least resistance is to levofloxacin [14] .…”

Section: Discussionmentioning

confidence: 99%

Molecular Investigation of Quinolone Resistance of Quinolone Resistance-Determining Region in Streptococcus pneumoniae Strains Isolated from Iran Using Polymerase Chain Reaction–Restriction Fragment Length Polymorphism Method

Kargar¹,

Jahromi²,

Doosti³

et al. 2014

Osong Public Health and Research Perspectives

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ObjectivesThe resistance of Streptococcus pneumoniae to the recently available antibiotic treatment has been a growing problem. The aim of the study was to determine the quinolone-resistant strains and detect the presence of mutations in the quinolone resistance-determining regions of the gyrA, parE, and parC genes.MethodsIn this study, for the first time in Iran, the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method was used to investigate the presence of mutations at quinolone resistance-determining regions of topoisomerase IV and DNA gyrase on 82 S. pneumoniae strains, among them 45 clinical samples were from patients and 37 from healthy carriers (control group).ResultsIn clinical samples, 34 (75.56%) strains contained mutations in the parC gene, 31 (68.89%) carried mutations in the gyrA gene, and 14 (31.11%) had parE gene mutations. Antibiotic susceptibility test was performed using the CLSI (Clinical and Laboratory Standards Institute) criteria on three different generations of quinolone family, with nalidixic acid (82.22%) showing the highest resistance and levofloxacin (42.22%) the least resistance.ConclusionResults indicated that there is a significant correlation between quinolone resistance development and mutations in the parE gene as well as in the parC and gyrA genes.

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In Vitro Activity of Garenoxacin against Streptococcus pneumoniae Mutants with Characterized Resistance Mechanisms

Cited by 8 publications

References 22 publications

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Anti-inflammatory effects of garenoxacin on IL-8 production and ERK1/2 activation induced by lipopolysaccharides in A549 and THP-1 cells

Molecular Investigation of Quinolone Resistance of Quinolone Resistance-Determining Region in Streptococcus pneumoniae Strains Isolated from Iran Using Polymerase Chain Reaction–Restriction Fragment Length Polymorphism Method

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