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International Journal of Chronic... 2009The newest generation of fluoroquinolones have proven efficacy against bacterial organisms associated with acute exacerbation of chronic bronchitis (AECB). Gemifloxacin,... (Review)
Review
The newest generation of fluoroquinolones have proven efficacy against bacterial organisms associated with acute exacerbation of chronic bronchitis (AECB). Gemifloxacin, as one of the quinolones in this class, exhibits many of the pharmacokinetic and pharmacodynamic characteristics of the class with a few notable differences. Against Streptococccus pneumoniae it has a lower minimal inhibitory concentration (MIC) than the other respiratory fluoroquinolones and it has activity against both bacterial DNA gyrase and topoisomerase IV. The increased activity of gemifloxacin against both enzymes may be associated with decreased rates of resistance. Clinically, gemifloxacin has been shown to have positive effects on length of hospitalization and increased success at long-term follow-up in AECB patients. These associations were observed in noninferiority comparison studies. Although an advantage with the use of gemifloxacin in AECB is suggested, there are no comparison data is available to conclude that gemifloxacin is superior to the other respiratory fluoroquinolones. Gemifloxacin is generally well tolerated, but is associated with a characteristic rash and gastrointestinal upset as its most common observed side effects.
Topics: Animals; Anti-Bacterial Agents; Bronchitis, Chronic; Cost-Benefit Analysis; Disease Models, Animal; Drug Costs; Drug Resistance, Bacterial; Fluoroquinolones; Gemifloxacin; Humans; Microbial Sensitivity Tests; Naphthyridines; Treatment Outcome
PubMed: 19684863
DOI: 10.2147/copd.s3903 -
Antimicrobial Agents and Chemotherapy Nov 2000The activities of two investigational fluoroquinolones and three fluoroquinolones that are currently marketed were determined for 182 clinical isolates of Streptococcus... (Comparative Study)
Comparative Study
The activities of two investigational fluoroquinolones and three fluoroquinolones that are currently marketed were determined for 182 clinical isolates of Streptococcus pneumoniae. The collection included 57 pneumococcal isolates resistant to levofloxacin (MIC >/= 8 microg/ml) recovered from patients in North America and Europe. All isolates were tested with clinafloxacin, gatifloxacin, gemifloxacin, levofloxacin, and trovafloxacin by the National Committee for Clinical Laboratory Standards broth microdilution and disk diffusion susceptibility test methods. Gemifloxacin demonstrated the greatest activity on a per gram basis, followed by clinafloxacin, trovafloxacin, gatifloxacin, and levofloxacin. Scatterplots of the MICs and disk diffusion zone sizes revealed a well-defined separation of levofloxacin-resistant and -susceptible strains when the isolates were tested against clinafloxacin and gatifloxacin. DNA sequence analyses of the quinolone resistance-determining regions of gyrA, gyrB, parC, and parE from 21 of the levofloxacin-resistant strains identified eight different patterns of amino acid changes. Mutations among the four loci had the least effect on the MICs of gemifloxacin and clinafloxacin, while the MICs of gatifloxacin and trovafloxacin increased by up to six doubling dilutions. These data indicate that the newer fluoroquinolones have greater activities than levofloxacin against pneumococci with mutations in the DNA gyrase or topoisomerase IV genes. Depending upon pharmacokinetics and safety, the greater potency of these agents could provide improved clinical efficacy against levofloxacin-resistant pneumococcal strains.
Topics: Anti-Bacterial Agents; Fluoroquinolones; Gatifloxacin; Gemifloxacin; Humans; Levofloxacin; Microbial Sensitivity Tests; Naphthyridines; Ofloxacin; Streptococcus pneumoniae
PubMed: 11036007
DOI: 10.1128/AAC.44.11.2962-2968.2000 -
ACS Omega Nov 2021Environmental protection and the necessity of green energy have become fundamental concerns for humankind. However, rapid recombination of photoexcitons in...
Environmental protection and the necessity of green energy have become fundamental concerns for humankind. However, rapid recombination of photoexcitons in semiconductors often gets in the path of photocatalytic reactions and annoyingly suppresses the photocatalytic activity. In this study, a polypyrrole (PPY)-supported step-scheme (S-scheme) ZnFeO@WO (PZFW15) ternary composite was fabricated by a multistep process: hydrothermal and calcination processes, followed by polymerization. During the formation of the heterojunction, the oxygen vacancy (OV) on WO promotes effective separation and increases the redox power of the photogenerated excitons via the built-in internal electric field of S-scheme pathways between ZnF and WO The successful construction of the S-scheme heterojunction was substantiated through X-ray photoelectron spectroscopy, experimental calculations, radical trapping experiment, and liquid electron spin resonance (ESR) characterization, whereas the existence of OVs was well confirmed by EPR and Raman analyses. Meanwhile, the PPY served as a supporter, and the polaron and bipolaron species of PPY acted as electron and hole acceptors, respectively, which further enhances the charge-carrier transmission and separation in the ternary PZFW15 photocatalyst. The designed ternary nanohybrid (PZFW15) displays outstanding gemifloxacin detoxification (95%, 60 min) and hydrogen generation (657 μmol h), i.e., 1.5 and 2.2 times higher than the normal S-scheme ZFW15 heterostructure and pure ZnFeO (ZnF), respectively, with an apparent conversion efficiency of 4.92%. The ESR and trapping experiments indicate that the generated OH and O radicals from the PZFW15 photocatalyst are responsible for gemifloxacin degradation. This unique PPY-supported S-scheme heterojunction is also beneficial for the enhanced electron-transfer rate and provides abundant active sites for photocatalytic reactions.
PubMed: 34805671
DOI: 10.1021/acsomega.1c03705 -
MSphere Jul 2019The objectives of this study were to perform genomic and phenotypic characterization of antimicrobial resistance in isolates recovered from urine samples from patients...
Genotypic and Phenotypic Characterization of Antimicrobial Resistance in Neisseria gonorrhoeae: a Cross-Sectional Study of Isolates Recovered from Routine Urine Cultures in a High-Incidence Setting.
The objectives of this study were to perform genomic and phenotypic characterization of antimicrobial resistance in isolates recovered from urine samples from patients in St. Louis, MO, USA. Sixty-four clinical isolates were banked over a 2-year period and subjected to antimicrobial susceptibility testing (AST) by Kirby-Bauer disk diffusion (penicillin, tetracycline, cefuroxime, and ciprofloxacin) and gradient diffusion (tetracycline, doxycycline, azithromycin, ceftriaxone, cefixime, ciprofloxacin, gemifloxacin, and delafloxacin). The medical records for the patients were evaluated to determine the demographics, location, and prescribed treatment regimen. Isolate draft genomes were assembled from Illumina shotgun sequencing data, and resistance determinants were identified by ResFinder and PointFinder. Of the 64 isolates, 97% were nonsusceptible to penicillin, with resistant isolates all containing the gene; 78 and 81% of isolates were nonsusceptible to tetracycline and doxycycline, respectively, with resistant isolates all containing the (M) gene. One isolate was classified as non-wild-type to azithromycin, and all isolates were susceptible to ceftriaxone; 89% of patients received this combination of drugs as first-line therapy. Six percent of isolates were resistant to ciprofloxacin, with most resistant isolates containing multiple and mutations. Correlation between disk and gradient diffusion AST devices was high for tetracycline and ciprofloxacin ( > 99% for both). The rates of antibiotic resistance in St. Louis are comparable to current rates reported nationally, except ciprofloxacin resistance was less common in our cohort. Strong associations between specific genetic markers and phenotypic susceptibility testing hold promise for the utility of genotype-based diagnostic assays to guide directed antibiotic therapy. causes the sexually transmitted infection gonorrhea, which is most commonly diagnosed using a DNA-based detection method that does not require growth and isolation of in the laboratory. This is problematic because the rates of antibiotic resistance in are increasing, but without isolating the organism in the clinical laboratory, antibiotic susceptibility testing cannot be performed on strains recovered from clinical specimens. We observed an increase in the frequency of urine cultures growing after we implemented a total laboratory automation system for culture in our clinical laboratory. Here, we report on the rates of resistance to multiple historically used, first-line, and potential future-use antibiotics for 64 isolates. We found that the rates of antibiotic resistance in our isolates were comparable to national rates. Additionally, resistance to specific antibiotics correlated closely with the presence of genetic resistance genes, suggesting that DNA-based tests could also be designed to guide antibiotic therapy for treating gonorrhea.
Topics: Adolescent; Adult; Anti-Bacterial Agents; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Female; Genotype; Gonorrhea; Humans; Incidence; Male; Middle Aged; Neisseria gonorrhoeae; Phenotype; Sequence Analysis, DNA; Whole Genome Sequencing; Young Adult
PubMed: 31341071
DOI: 10.1128/mSphere.00373-19 -
Antimicrobial Agents and Chemotherapy Feb 2002Gemifloxacin is a recently developed fluoroquinolone with potent activity against Streptococcus pneumoniae. We show that the drug is more active than moxifloxacin,...
Gemifloxacin is a recently developed fluoroquinolone with potent activity against Streptococcus pneumoniae. We show that the drug is more active than moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin against S. pneumoniae strain 7785 (MICs, 0.03 to 0.06 microg/ml versus 0.25, 0.25, 1, and 1 to 2 microg/ml, respectively) and against isogenic quinolone-resistant gyrA-parC mutants (MICs, 0.5 to 1 microg/ml versus 2 to 4, 2 to 4, 16 to 32, and 64 microg/ml, respectively). Gemifloxacin was also the most potent agent against purified S. pneumoniae DNA gyrase and topoisomerase IV in both catalytic inhibition and DNA cleavage assays. The drug concentrations that inhibited DNA supercoiling or DNA decatenation by 50% (IC(50)s) were 5 to 10 and 2.5 to 5.0 microM, respectively. Ciprofloxacin and levofloxacin were some four- to eightfold less active against either enzyme; moxifloxacin and gatifloxacin showed intermediate activities. In assays of drug-mediated DNA cleavage by gyrase and topoisomerase IV, the same order of potency was seen: gemifloxacin > moxifloxacin > gatifloxacin > levofloxacin approximately ciprofloxacin. For gemifloxacin, the drug concentrations that caused 25% linearization of the input DNA by gyrase and topoisomerase IV were 2.5 and 0.1 to 0.3 microM, respectively; these values were 4-fold and 8- to 25-fold lower than those for moxifloxacin, respectively. Each drug induced DNA cleavage by gyrase at the same spectrum of sites but with different patterns of intensity. Finally, for enzymes reconstituted with quinolone-resistant GyrA S81F or ParC S79F subunits, although cleavable-complex formation was reduced by at least 8- to 16-fold for all the quinolones tested, gemifloxacin was the most effective; e.g., it was 4- to 16-fold more active than the other drugs against toposiomerase IV with the ParC S79F mutation. It appears that the greater potency of gemifloxacin against both wild-type and quinolone-resistant S. pneumoniae strains arises from enhanced stabilization of gyrase and topoisomerase IV complexes on DNA.
Topics: Amino Acid Substitution; Anti-Infective Agents; Catalysis; DNA Gyrase; DNA Topoisomerase IV; DNA Topoisomerases, Type II; DNA, Bacterial; Drug Resistance, Bacterial; Enzyme Stability; Fluoroquinolones; Gemifloxacin; Microbial Sensitivity Tests; Naphthyridines; Streptococcus pneumoniae; Topoisomerase II Inhibitors
PubMed: 11796351
DOI: 10.1128/AAC.46.2.413-419.2002 -
Antimicrobial Agents and Chemotherapy Sep 2009Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of... (Randomized Controlled Trial)
Randomized Controlled Trial
Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated K(m) and Vmax for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an approximately 200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.
Topics: Adjuvants, Pharmaceutic; Female; Fluoroquinolones; Gemifloxacin; Humans; Kidney Function Tests; Kidney Tubules; Male; Metabolic Clearance Rate; Naphthyridines; Probenecid
PubMed: 19564368
DOI: 10.1128/AAC.01200-08 -
Antimicrobial Agents and Chemotherapy Jan 2003Gemifloxacin, a novel quinolone with potent activity against Staphylococcus aureus, was 8- to 16-fold more active against wild-type S. aureus than ciprofloxacin. The...
Gemifloxacin, a novel quinolone with potent activity against Staphylococcus aureus, was 8- to 16-fold more active against wild-type S. aureus than ciprofloxacin. The two- to fourfold increase in the MIC of gemifloxacin in genetically defined grlBA mutants and the twofold increase in a single gyrA mutant, supported by the low frequency of selection of resistant mutants at twice the MIC (7.4 x 10(-11) to 1.1 x 10(-10)), suggested similar targeting of the two enzymes by gemifloxacin. Dual mutations in both gyrase and topoisomerase IV caused a 64- to 128-fold increase in the MIC of gemifloxacin, similar to that seen with ciprofloxacin. Gemifloxacin also had similar activity in vitro against topoisomerase IV and gyrase purified from S. aureus (50% inhibitory concentrations of 0.25 and 0.31 micro g/ml, respectively). This activity was 10- to 20-fold higher than that of ciprofloxacin for topoisomerase IV and 33-fold higher than that for gyrase. In contrast to the in vitro findings, only topoisomerase IV mutants were selected in first-step mutants. Overexpression of the NorA efflux pump had a minimal effect on resistance to gemifloxacin, and a mutation in the promoter region of the gene for NorA was selected only in the sixth step of serial selection of mutants. Our data show that although gemifloxacin targets purified topoisomerase IV and gyrase similarly in vitro, topoisomerase IV is the preferred target in the bacteria. Selection of novel resistance mutations in grlA requires further expansion of quinolone-resistance-determining regions, and their study may provide increased insight into enzyme-quinolone interactions.
Topics: Anti-Infective Agents; DNA Topoisomerases; Drug Resistance, Bacterial; Fluoroquinolones; Gemifloxacin; Microbial Sensitivity Tests; Mutation; Naphthyridines; Plasmids; Staphylococcus aureus
PubMed: 12499202
DOI: 10.1128/AAC.47.1.274-282.2003 -
Antimicrobial Agents and Chemotherapy Mar 2005Gemifloxacin is a novel fluoronaphthyridone quinolone with enhanced in vitro activity against Streptococcus pneumoniae. We investigated the activities of gemifloxacin...
Gemifloxacin is a novel fluoronaphthyridone quinolone with enhanced in vitro activity against Streptococcus pneumoniae. We investigated the activities of gemifloxacin and trovafloxacin, their abilities to select for resistance in vitro and in vivo, and their efficacies in a mouse model of acute pneumonia. Immunocompetent Swiss mice were infected with 10(5) CFU of a virulent, encapsulated S. pneumoniae strain, P-4241, or its isogenic parC, gyrA, parC gyrA, and efflux mutant derivatives (serotype 3); and leukopenic mice were infected with 10(7) CFU of two poorly virulent clinical strains (serotype 11A) carrying either a parE mutation or a parC, gyrA, and parE triple mutation. The drugs were administered six times every 12 h, starting at either 3 or 18 h postinfection. In vitro, gemifloxacin was the most potent agent against strains with and without acquired resistance to fluoroquinolones. While control mice died within 6 days, gemifloxacin at doses of 25 and 50 mg/kg of body weight was highly effective (survival rates, 90 to 100%) against the wild-type strain and against mutants harboring a single mutation, corresponding to area under the time-versus-serum concentration curve at 24 h (AUC(24))/MIC ratios of 56.5 to 113, and provided a 40% survival rate against a mutant with a double mutation (parC and gyrA). A total AUC(24)/MIC ratio of 28.5 was associated with poor efficacy and the emergence of resistant mutants. Trovafloxacin was as effective as gemifloxacin against mutants with single mutations but did not provide any protection against the mutant with double mutations, despite treatment with a high dose of 200 mg/kg. Gemifloxacin preferentially selected for parC mutants both in vitro and in vivo.
Topics: Animals; Area Under Curve; Drug Resistance, Bacterial; Fluoroquinolones; Gemifloxacin; Mice; Microbial Sensitivity Tests; Mutation; Naphthyridines; Pneumonia, Pneumococcal; Streptococcus pneumoniae
PubMed: 15728901
DOI: 10.1128/AAC.49.3.1046-1054.2005 -
Asia Pacific Allergy Oct 2012Anaphylaxis have been documented as adverse effects of ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, and moxifloxacin. However resistant and biphasic...
Anaphylaxis have been documented as adverse effects of ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, and moxifloxacin. However resistant and biphasic anaphlylactic reactions to gemifloxacin have not been reported to date. Management of severe anaphylaxis in the elderly can be complicated by concurrent medications such as beta (β) adrenergic, alpha (α) adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors. We report here in the case of a 60-year-old male who was taking on ACE inhibitor, α and β blockers and experienced a severe, resistant and biphasic anaphlylactic reaction to gemifloxacin mesylate.
PubMed: 23130335
DOI: 10.5415/apallergy.2012.2.4.280 -
Antimicrobial Agents and Chemotherapy Nov 2000We investigated the roles of DNA gyrase and topoisomerase IV in determining the susceptibility of Streptococcus pneumoniae to gemifloxacin, a novel fluoroquinolone which... (Comparative Study)
Comparative Study
Potent antipneumococcal activity of gemifloxacin is associated with dual targeting of gyrase and topoisomerase IV, an in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro.
We investigated the roles of DNA gyrase and topoisomerase IV in determining the susceptibility of Streptococcus pneumoniae to gemifloxacin, a novel fluoroquinolone which is under development as an antipneumococcal drug. Gemifloxacin displayed potent activity against S. pneumoniae 7785 (MIC, 0.06 microgram/ml) compared with ciprofloxacin (MIC, 1 to 2 microgram/ml). Complementary genetic and biochemical approaches revealed the following. (i) The gemifloxacin MICs for isogenic 7785 mutants bearing either parC or gyrA quinolone resistance mutations were marginally higher than wild type at 0.12 to 0.25 microgram/ml, whereas the presence of both mutations increased the MIC to 0.5 to 1 microgram/ml. These data suggest that both gyrase and topoisomerase IV contribute significantly as gemifloxacin targets in vivo. (ii) Gemifloxacin selected first-step gyrA mutants of S. pneumoniae 7785 (gemifloxacin MICs, 0.25 microgram/ml) encoding Ser-81 to Phe or Tyr, or Glu-85 to Lys mutations. These mutants were cross resistant to sparfloxacin (which targets gyrase) but not to ciprofloxacin (which targets topoisomerase IV). Second-step mutants (gemifloxacin MICs, 1 microgram/ml) exhibited an alteration in parC resulting in changes of ParC hot spot Ser-79 to Phe or Tyr. Thus, gyrase appears to be the preferential in vivo target. (iii) Gemifloxacin was at least 10- to 20-fold more effective than ciprofloxacin in stabilizing a cleavable complex (the cytotoxic lesion) with either S. pneumoniae gyrase or topoisomerase IV enzyme in vitro. These data suggest that gemifloxacin is an enhanced affinity fluoroquinolone that acts against gyrase and topoisomerase IV in S. pneumoniae, with gyrase the preferred in vivo target. The marked potency of gemifloxacin against wild type and quinolone-resistant mutants may accrue from greater stabilization of cleavable complexes with the target enzymes.
Topics: Anti-Infective Agents; Ciprofloxacin; DNA Gyrase; DNA Topoisomerase IV; DNA Topoisomerases, Type II; Drug Resistance, Microbial; Fluoroquinolones; Gemifloxacin; Humans; Microbial Sensitivity Tests; Mutation; Naphthyridines; Streptococcus pneumoniae
PubMed: 11036032
DOI: 10.1128/AAC.44.11.3112-3117.2000