Levofloxacin and Sparfloxacin: New Quinolone Antibiotics

After oral administration of 500 mg of levofloxacin to 12 volunteers, we investigated the pharmacokinetics and serum bactericidal activities (SBAs) against five strains of members of the family Enterobacteriaceae. Pharmacokinetic data were as follows: maximum concentration in serum, 6.36 ؎ 0.57 mg/liter; area under the concentration-time curve, 43.6 ؎ 6.23 mg ⅐ h/liter; elimination half-life 4.23 ؎ 0.87 h. SBAs were present for 24 h against Escherichia coli and Citrobacter freundii. The SBAs at 1, 12, and 24 h after administration against E. coli were 1:108, 1:29, and 1:7, respectively, and those against Citrobacter freundii were 1:74, 1:25, and 1:7, respectively. The SBAs were present for 12 h against the other three organisms tested. The SBAs against Serratia marcescens were 1:28 and 1:9 at 1 and 12 h, respectively; the SBAs against Klebsiella pneumoniae were 1:25 and 1:7 at 1 and 12 h, respectively; and the SBAs against Enterobacter cloacae were 1:24 and 1:10 at 1 and 12 h, respectively.Levofloxacin is the active L-isomer of the racemate ofloxacin, a fluoroquinolone with a broad spectrum of activity (5,14). We assessed the pharmacokinetics of levofloxacin and the serum bactericidal activities (SBAs) against five different species of members of the family Enterobacteriaceae. Twelve healthy female volunteers (mean age, 33.8 Ϯ 6.1 years; mean body weight, 64.1 Ϯ 10.2 kg) were included after they provided written informed consent. Exclusion criteria were hypersensitivity to quinolones, pregnancy, drug or alcohol abuse, or the use of a concomitant medication except for contraceptives. The study was approved by the ethical committee of the Physicians' Association of Hessen, Frankfurt, Germany.Levofloxacin (lot HR355/1014, batch no. 20; Hoechst, Frankfurt, Germany) was administered orally as an open single dose of 500 mg (in tablet form) on an empty stomach after 10 h of fasting. Blood samples were collected just before medication and at 0.5, 1,2,4,6,8,12, and 24 h after medication. Serum levofloxacin concentrations were determined enantioselectively by high-performance liquid chromatography by a previously described method (12). The assay was linear over the concentration range studied, and the lower limit of quantitation was 20 ng/ml. The inter-and intraday coefficients of variation were both Ͻ3%.We analyzed 10 clinically relevant strains of five different species of the family Enterobacteriaceae isolated by the Department of Clinical Microbiology of the City Hospital Zehlendorf/ Heckeshorn and of the Departments of Microbiology of the University Hospitals Benjamin-Franklin and Charité-Virchow, Berlin, Germany. The species of all isolates were determined with the API 20E system (API BioMérieux, Nürtingen, Germany). The minimal bactericidal concentrations (MBCs) of levofloxacin were determined in triplicate by the standardized microdilution method described in the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS) (16). All samples were serially diluted in a 96-well plate (Falcon; Becton...

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confidence: 89%

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confidence: 99%

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Levofloxacin Pharmacokinetics and Serum Bactericidal Activities against Five Enterobacterial Species

Geerdes-Fenge¹,

Wiedersich²,

Wagner³

et al. 2000

“…However, increased macrolide resistance among GBS isolates, especially in CPS type V isolates largely represented in adult infections, can lead to therapeutic issues (3,4,7,13). Therefore, fluoroquinolones (FQ), especially levofloxacin (LVX), moxifloxacin (MXF), and gatifloxacin, which exhibit improved Gram-positive activity compared to other FQ such as norfloxacin and ciprofloxacin, emerged as an important alternative for the treatment of adult GBS infections (14,15). FQ inhibit bacterial growth primarily by binding to enzymes involved in DNA replication, the DNA gyrase and DNA topoisomerase IV encoded by the gyr and par genes, respectively.…”

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confidence: 99%

Changing Epidemiology of Group B Streptococcus Susceptibility to Fluoroquinolones and Aminoglycosides in France

Hays

Louis

Plainvert

et al. 2016

Group B Streptococcus (GBS) is the leading cause of neonatal invasive infections and an emerging pathogen in the elderly. Our objectives were to describe the evolution of GBS resistance to antibiotics in France and to investigate the emergence of fluoroquinolone (FQ)-resistant isolates. A total of 8,757 unrelated GBS isolates were collected and tested for antibiotic susceptibility from 2007 to 2014 according to EUCAST recommendations. All isolates were susceptible to penicillin G, amoxicillin, and vancomycin. Resistance to macrolides decreased from 47.0% to 30.0%, whereas high-level resistance to aminoglycosides, especially amikacin, increased from 6.4% to 8.8% and 24 isolates (0.3%) were highly resistant to gentamicin. FQ resistance gradually increased from 0.2% in 2007 (n ‫؍‬ 1) to 1.5% in 2014 (n ‫؍‬ 18, P < 0.01). Capsular polysaccharide (CPS) genotyping, multilocus sequence typing, and sequencing of the quinolone resistance-determining region (QRDR) showed that GBS isolates of sequence type 19 (ST-19) CPS type V were largely overrepresented in FQ-resistant isolates (n ‫؍‬ 30, 45.5%). All 30 strains displayed the same QRDR mutations and were often associated with cross-resistance to macrolides (93.3%) and gentamicin (30%). In conclusion, we report the rise of FQ-and aminoglycoside-resistant GBS in France over an 8-year study period, an evolution likely linked to the clonal expansion of ST-19 CPS V-resistant isolates. This study emphasizes the need for a continuous surveillance of GBS epidemiology and antibiotic susceptibility. G roup B Streptococcus (Streptococcus agalactiae; GBS) is aGram-positive encapsulated bacterium colonizing the intestinal and vaginal tracts of 10 to 30% of healthy adults. This commensal bacterium is also the leading cause of neonatal invasive infections (bacteremia and meningitis) in industrialized countries and a pathogen of growing importance in the elderly, especially in people suffering from underlying diseases such as diabetes or cancer (1-5). The mortality rate of neonatal infections reaches approximately 10%, and up to 40% of infants who survive meningitis are left with permanent neurologic sequelae, making the global burden of GBS infections significant (2,5,6). Epidemiological studies based on capsular polysaccharide (CPS) typing revealed that GBS isolates are not similarly represented among colonizing and infectious strains. Among the 10 serotypes described to date (Ia, Ib, and II to IX), CPS types Ia, II, III, and V are almost equally prevalent among colonizing strains and are responsible for 70% of adult invasive infections worldwide (3-5, 7, 8). Conversely, CPS type III has been identified since the 1970s as strongly associated with neonatal infections and is currently responsible for more than 60% of these (1-3, 7).Penicillins or aminopenicillins are recommended as the firstline antibiotics against GBS infections (9). These antibiotics remain highly active, even though strains with reduced susceptibility were recently described in Asia and North America (10-12). Macroli...

“…Although the fluoroquinolones (FQ) are used against multidrug-resistant Mycobacterium tuberculosis (1), initial experience with ciprofloxacin (CIP) and ofloxacin (OFX) resulted in the rapid development of resistance (27,34) and the use of the more effective sparfloxacin (SPX) is limited by toxicity (24). Nevertheless, newer drugs, such as moxifloxacin and gatifloxacin, have higher therapeutic ratios (8) and appear promising.…”

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confidence: 99%

Intrinsic Resistance of Mycobacterium smegmatis to Fluoroquinolones May Be Influenced by New Pentapeptide Protein MfpA

Montero

Mateu

Rodríguez

et al. 2001

109

The fluoroquinolones (FQ) are used in the treatment of Mycobacterium tuberculosis, but the development of resistance could limit their effectiveness. FQ resistance (FQ R ) is a multistep process involving alterations in the type II topoisomerases and perhaps in the regulation of efflux pumps, but several of the steps remain unidentified. Recombinant plasmid pGADIV was selected from a genomic library of wild-type (WT), FQsensitive M. smegmatis by its ability to confer low-level resistance to sparfloxacin (SPX). In WT M. smegmatis, pGADIV increased the MICs of ciprofloxacin (CIP) by fourfold and of SPX by eightfold, and in M. bovis BCG it increased the MICs of both CIP and SPX by fourfold. It had no effect on the accumulation of 14 C-labeled CIP or SPX. The open reading frame responsible for the increase in FQ R , mfpA, encodes a putative protein belonging to the family of pentapeptides, in which almost every fifth amino acid is either leucine or phenylalanine. Very similar proteins are also present in M. tuberculosis and M. avium. The MICs of CIP and SPX were lower for an M. smegmatis mutant strain lacking an intact mfpA gene than for the WT strain, suggesting that, by some unknown mechanism, the gene product plays a role in determining the innate level of FQ R in M. smegmatis.Although the fluoroquinolones (FQ) are used against multidrug-resistant Mycobacterium tuberculosis (1), initial experience with ciprofloxacin (CIP) and ofloxacin (OFX) resulted in the rapid development of resistance (27,34) and the use of the more effective sparfloxacin (SPX) is limited by toxicity (24). Nevertheless, newer drugs, such as moxifloxacin and gatifloxacin, have higher therapeutic ratios (8) and appear promising. Therefore, continued study of the mechanisms by which FQ resistance (FQ R ) develops in mycobacteria seems warranted. Other bacteria, such as Escherichia coli, Streptococcus pneumoniae, and Staphylococcus aureus, develop FQ R in a stepwise process, principally involving alterations in the A and B subunits of both gyrase and topoisomerase IV (30). However, there appear to be other elements involved in FQ R , because a very high level of resistance may not be completely explained by mutations in topoisomerase genes and strains with a low level of resistance may lack mutations in these genes (39). The only other mechanism that has been implicated in FQ R is the increased expression of FQ-transporting efflux pumps (29), which could play a role in both low-level and very high-level resistance (25).Mycobacteria do not contain topoisomerase IV (7), and strains with moderate levels of resistance to CIP, OFX, or levofloxacin (LVX) (Ͼ3 g) or SPX (Ͼ1 g) all contain gyrA mutations (36 MATERIALS AND METHODSBacterial strains and growth conditions. Wild-type (WT), FQ-sensitive M. smegmatis strain mc 2 155 was used for genetic selections (14). Some plasmids were also tested for the ability to confer resistance in M. bovis BCG Pasteur. Mycobacteria were grown in 7H9 oleic acid-albumin-dextrose-0.05% Tween 80 (OAD-TW) liquid or on 7H10 ...