Antimicrobial Agents and Chemotherapy

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Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model
Antimicrobial Agents and Chemotherapy - Tập 61 Số 1 - 2017
Cornelia B. Landersdorfer, Tri‐Hung Nguyen, Linh Thuy Lieu, Gary Nguyen, Robert J. Bischof, Els Meeusen, Jian Li, Roger L. Nation, Michelle P. McIntosh
ABSTRACT

Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.

Plasmid-mediated ROB-1 beta-lactamase in Pasteurella multocida from a human specimen
Antimicrobial Agents and Chemotherapy - Tập 35 Số 11 - Trang 2419-2422 - 1991
A Rosenau, A. Labigne, F. Escande, P Courcoux, A. Philippon

A Pasteurella multocida human isolate was resistant to beta-lactams because of production of ROB-1 beta-lactamase. The beta-lactamase was encoded by a 4.3-kb plasmid closely related to that of a Pasteurella bovine strain, as shown by Sau3A restriction profile and hybridization with a plasmid probe containing the blaROB-1 gene.

A New Approach to In Vitro Comparisons of Antibiotics in Dynamic Models: Equivalent Area under the Curve/MIC Breakpoints and Equiefficient Doses of Trovafloxacin and Ciprofloxacin against Bacteria of Similar Susceptibilities
Antimicrobial Agents and Chemotherapy - Tập 42 Số 11 - Trang 2841-2847 - 1998
Alexander A. Firsov, Sergey N. Vostrov, Alexander Alekseevich Shevchenko, Yury A. Portnoy, Stephen H. Zinner
ABSTRACT

Time-kill studies, even those performed with in vitro dynamic models, often do not provide definitive comparisons of different antimicrobial agents. Also, they do not allow determinations of equiefficient doses or predictions of area under the concentration-time curve (AUC)/MIC breakpoints that might be related to antimicrobial effects (AMEs). In the present study, a wide range of single doses of trovafloxacin (TR) and twice-daily doses of ciprofloxacin (CI) were mimicked in an in vitro dynamic model. The AMEs of TR and CI against gram-negative bacteria with similar susceptibilities to both drugs were related to AUC/MICs that varied over similar eight-fold ranges [from 54 to 432 and from 59 to 473 (μg · h/ml)/(μg/ml), respectively]. The observation periods were designed to include complete bacterial regrowth, and the AME was expressed by its intensity (the area between the control growth in the absence of antibiotics and the antibiotic-induced time-kill and regrowth curves up to the point where viable counts of regrowing bacteria equal those achieved in the absence of drug [ I E ]). In each experiment monoexponential pharmacokinetic profiles of TR and CI were simulated with half-lives of 9.2 and 4.0 h, respectively. Linear relationships between I E and log AUC/MIC were established for TR and CI against three bacteria: Escherichia coli (MIC of TR [MIC TR ] = 0.25 μg/ml; MIC of CI [MIC CI ] = 0.12 μg/ml), Pseudomonas aeruginosa (MIC TR = 0.3 μg/ml; MIC CI = 0.15 μg/ml), and Klebsiella pneumoniae (MIC TR = 0.25 μg/ml; MIC CI = 0.12 μg/ml). The slopes and intercepts of these relationships differed for TR and CI, and the I E -log AUC/MIC plots were not superimposed, although they were similar for all bacteria with a given antibiotic. By using the relationships between I E and log AUC/MIC, TR was more efficient than CI. The predicted value of the AUC/MIC breakpoint for TR [mean for all three bacteria, 63 (μg · h/ml)/(μg/ml)] was approximately twofold lower than that for CI. Based on the I E -log AUC/MIC relationships, the respective dose ( D )-response relationships were reconstructed. Like the I E -log AUC/MIC relationships, the I E -log D plots showed TR to be more efficient than CI. Single doses of TR that are as efficient as two 500-mg doses of CI (500 mg given every 12 h) were similar for the three strains (199, 226, and 203 mg). This study suggests that in vitro evaluation of the relationships between I E and AUC/MIC or D might be a reliable basis for comparing different fluoroquinolones and that the results of such comparative studies may be highly dependent on their experimental design and datum quantitation.

Inhibition of the Emergence of Ciprofloxacin Resistance in Streptococcus pneumoniae by the Multidrug Efflux Inhibitor Reserpine
Antimicrobial Agents and Chemotherapy - Tập 43 Số 4 - Trang 988-989 - 1999
Penelope N. Markham
ABSTRACT

Recent evidence supports the contribution of a multidrug efflux mechanism to fluoroquinolone resistance in Streptococcus pneumoniae . In this paper I show that reserpine, an inhibitor of multidrug transporters in gram-positive bacteria, dramatically suppresses the in vitro emergence of ciprofloxacin-resistant variants of S. pneumoniae , suggesting that the combination of a fluoroquinolone with an inhibitor of multidrug transport may help preserve the efficacy of this class of antibiotics.

Comparison of high-pressure liquid chromatography and microbiological assay for the determination of biliary elimination of ciprofloxacin in humans
Antimicrobial Agents and Chemotherapy - Tập 28 Số 2 - Trang 311-314 - 1985
J.M. Brogard, F. Jehl, H. Monteil, M Adloff, Jean‐Frédéric Blickle, Patrick Lévy

Serum kinetics and biliary, urinary, and fecal elimination of ciprofloxacin, a new quinolone derivative, were studied in 12 recently cholecystectomized patients provided with T-tube drainage during 24 h after oral administration of a single 500-mg dose of this substance. Drug concentrations were measured by both high-pressure liquid chromatography (HPLC) and microbiological assay. The results were comparable for the concentrations in serum (average of peaks, 2.0 +/- 0.2 micrograms/ml by HPLC and 2.3 +/- 0.3 micrograms/ml by the microbiological method) and urine (0 to 6 h, 267 +/- 74 and 241 +/- 58 micrograms/ml, respectively). This was not the case for biliary values, for which the microbiological assay yielded significantly higher concentrations than did HPLC (average of peak concentrations, 21.2 +/- 2.6 and 16.0 +/- 2.5 micrograms/ml, respectively [P less than 0.02]), nor for total 24-h biliary output (2,167 +/- 288 and 1,587 +/- 222 micrograms, respectively [P less than 0.01]). This suggests hepatic biotransformation of ciprofloxacin into microbiologically active metabolites. The apparent broad antibacterial spectrum of ciprofloxacin and its higher biliary levels than simultaneously determined serum concentrations suggest that this derivative is suitable for the treatment of biliary tract infections.

A Mutation in Escherichia coli DNA Gyrase Conferring Quinolone Resistance Results in Sensitivity to Drugs Targeting Eukaryotic Topoisomerase II
Antimicrobial Agents and Chemotherapy - Tập 48 Số 12 - Trang 4495-4504 - 2004
Thomas Grüger, John L. Nitiss, Anthony Maxwell, Lynn Zechiedrich, Peter Heisig, S. Seeber, Yves Pommier, Dirk Strumberg
ABSTRACT

Fluoroquinolones are broad-spectrum antimicrobial agents that target type II topoisomerases. Many fluoroquinolones are highly specific for bacterial type II topoisomerases and act against both DNA gyrase and topoisomerase IV. In Escherichia coli , mutations causing quinolone resistance are often found in the gene that encodes the A subunit of DNA gyrase. One common site for resistance-conferring mutations alters Ser 83 , and mutations to Leu or Trp result in high levels of resistance to fluoroquinolones. In the present study we demonstrate that the mutation of Ser 83 to Trp in DNA gyrase (Gyr S83W ) also results in sensitivity to agents that are potent inhibitors of eukaryotic topoisomerase II but that are normally inactive against prokaryotic enzymes. Epipodophyllotoxins, such as etoposide, teniposide and amino-azatoxin, inhibited the DNA supercoiling activity of Gyr S83W , and the enzyme caused elevated levels of DNA cleavage in the presence of these agents. The DNA sequence preference for Gyr S83W -induced cleavage sites in the presence of etoposide was similar to that seen with eukaryotic type II topoisomerases. Introduction of the Gyr S83W mutation in E. coli strain RFM443-242 by site-directed mutagenesis sensitized it to epipodophyllotoxins and amino-azatoxin. Our results demonstrate that sensitivity to agents that target topoisomerase II is conserved between prokaryotic and eukaryotic enzymes, suggesting that drug interaction domains are also well conserved and likely occur in domains important for the biochemical activities of the enzymes.

Quinolone-Binding Pocket of DNA Gyrase: Role of GyrB
Antimicrobial Agents and Chemotherapy - Tập 46 Số 6 - Trang 1805-1815 - 2002
Jonathan G. Heddle, Anthony Maxwell
ABSTRACT

DNA gyrase is a prokaryotic type II topoisomerase and a major target of quinolone antibacterials. The majority of mutations conferring resistance to quinolones arise within the quinolone resistance-determining region of GyrA close to the active site (Tyr 122 ) where DNA is bound and cleaved. However, some quinolone resistance mutations are known to exist in GyrB. Present structural data suggest that these residues lie a considerable distance from the quinolone resistance-determining region, and it is not obvious how they affect quinolone action. We have made and purified two such mutant proteins, GyrB(Asp 426 →Asn) and GyrB(Lys 447 →Glu), and characterized them in vitro. We found that the two proteins behave similarly to GyrA quinolone-resistant proteins. We showed that the mutations exert their effect by decreasing the amount of quinolone bound to a gyrase-DNA complex. We suggest that the GyrB residues form part of a quinolone-binding pocket that includes DNA and the quinolone resistance-determining region in GyrA and that large conformational changes during the catalytic cycle of the enzyme allow these regions to come into close proximity.

Antimicrobial Resistance of Diarrheagenic Escherichia coli Isolated from Children under the Age of 5 Years from Ifakara, Tanzania
Antimicrobial Agents and Chemotherapy - Tập 43 Số 12 - Trang 3022-3024 - 1999
Jordi Vilà, Martha Vargas, Climent Casals‐Pascual, Honorato Urassa, Hassan Mshinda, David Schellemberg, Joaquím Gascón
ABSTRACT

Diarrhea caused by multidrug-resistant bacteria is an important public health problem among children in developing countries. The prevalence and antimicrobial susceptibility of diarrheagenic Escherichia coli in 346 children under 5 years of age in Ifakara, Tanzania, were studied. Thirty-eight percent of the cases of diarrhea were due to multiresistant enterotoxigenic E. coli , enteroaggregative E. coli , or enteropathogenic E. coli . Strains of all three E. coli categories showed high-level resistance to ampicillin, tetracycline, co-trimoxazole, and chloramphenicol but were highly susceptible to quinolones. Guidelines for appropriate use of antibiotics in developing countries need updating.

Clinical relevance of antibiotic-induced endotoxin release
Antimicrobial Agents and Chemotherapy - Tập 38 Số 6 - Trang 1211-1218 - 1994
Jan M. Prins, S J van Deventer, Ed J. Kuijper, Peter Speelman
Transcriptional Inhibitor of Virulence Factors in EnteropathogenicEscherichia coli
Antimicrobial Agents and Chemotherapy - Tập 49 Số 10 - Trang 4101-4109 - 2005
Annick Gauthier, Marilyn L. Robertson, Michael J. Lowden, J. Antonio Ibarra, José L. Puente, B. Brett Finlay
ABSTRACT

The type III secretion system (TTSS) is a key virulence mechanism of many important gram-negative bacterial pathogens. The TTSS is conserved among different bacterial pathogens, and mutations and deletions to the system significantly decrease virulence, making the TTSS an important potential therapeutic target. We have developed a high-throughput assay to search for inhibitors of the TTSS. We screened a commercial library of 20,000 small molecules for their ability to inhibit type III secretion by enteropathogenicEscherichia coli(EPEC). After discarding compounds that had no effect on secretion, inhibited bacterial growth, and/or caused degradation of EPEC-secreted proteins, the search was focused on a class of compounds that, while not direct inhibitors of type III secretion, inhibit expression of TTSS-related genes and other genes involved in virulence. This class of compounds does not affect bacterial viability or motility, indicating that it is not significantly affecting the expression of essential genes and is specific to virulence-associated genes. Transcriptional fusion assays confirmed that virulence-associated promoters were more sensitive to inhibition by this class of compounds. Overall, we have identified a class of compounds that can be used as a tool to probe the mechanism(s) that regulates virulence gene expression in EPEC.

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