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1.
The pharmacokinetics after oral application of the fluoroquinolones (FQs), enrofloxacin, difloxacin, marbofloxacin and orbifloxacin were compared in independent crossover studies in Beagle dogs. Commercially available tablet formulations were given at common dosage recommended by the manufacturers which were 2.0 mg/kg body weight (bw) for marbofloxacin, 2.5 mg/kg bw for orbifloxacin and 5.0 mg/kg bw for enrofloxacin and difloxacin. Analysis was performed by an agar diffusion assay. Pharmacokinetic parameters were calculated by noncompartmental methods. All FQs were rapidly absorbed and achieved average peak serum concentrations of 1.41, 1.11, 1.47 and 1.37 mug/mL for enrofloxacin, difloxacin, marbofloxacin and orbifloxacin, respectively. Enrofloxacin was eliminated at a terminal half-life (t(1/2)) of 4.1 h, difloxacin at 6.9 h, orbifloxacin at 7.1 h and marbofloxacin at 9.1 h. While the area under the serum concentration-time curve of the 24-h dosing interval (AUC0--24) for marbofloxacin and orbifloxacin were similar (approximately 13 microg x h/mL), enrofloxacin attained an AUC(0-24) of 8.7 and difloxacin of 9.3 microg x h/mL. Because of its favourable pharmacokinetics combined with excellent in vitro activity, enrofloxacin exhibited superior pharmacodynamic predictors of in vivo antimicrobial activity as C(max)/MIC (maximum serum concentration/minimum inhibitory concentration) and AUC(0-24)/MIC (area under the 24-h serum concentration--time curve/minimum inhibitory concentration) compared with other FQs.  相似文献   

2.
Background – The problem of antibacterial drug resistance is increasing worldwide, in part due to the therapeutic concentrations currently used based on the minimal inhibitory concentration (MIC) as a measure of potency are often the very concentrations required to selectively enrich the resistant mutant portion of the population. A mutant prevention concentration (MPC)‐based dosing strategy is suggested to improve the therapeutic outcome based on the MIC. Objective – Our aim was to investigate the MPC and mechanism of resistance to various fluoroquinolones using recent Staphylococcus pseudintermedius isolates from canine pyoderma. Methods – The broth microdilution method for MIC and a series of agar plates containing different concentrations of fluoroquinolones were inoculated with ～1010 colony‐forming units of the bacterial culture for MPC were used. PCR was used to identify mutation in the resistant isolates. Results – The rank order of potency based on MIC and MPC was ciprofloxacin = enrofloxacin ≥ marbofloxacin > difloxacin ≥ orbifloxacin. Integrating our data with reported pharmacokinetic data at the recommended dose ranges revealed that only high doses of ciprofloxacin, enrofloxacin and marbofloxacin could achieve a maximal plasma concentration (Cmax) greater than the MPC of 90% of isolates (Cmax/MPC90). The overall rank of potency against S. pseudintermedius, based on Cmax/MIC, Cmax/MPC, the area under concentration–time curve (AUC)/MIC and AUC/MPC values, was in decreasing order: enrofloxacin > ciprofloxacin ≥ marbofloxacin ≥ orbifloxacin = difloxacin. Sequencing of the quinolone resistant determining region of gyrA, gyrB, grlA and grlB of resistant strains showed a base‐pair substitution in both gyrA and gyrB that resulted in Ser‐84 to Leu and Ser‐80 to Arg amino acid changes, respectively. Conclusions and clinical importance – High doses of ciprofloxacin, enrofloxacin and marbofloxacin could minimize the selection of resistant mutants, whereas the possibility of selecting mutants with the conventional doses of difloxacin and orbifloxacin, and low clinical doses of all fluoroquinolones, seems high.  相似文献   

3.
BACKGROUND: Fluoroquinolones are often used interchangeably in dogs and cats. HYPOTHESIS: Predicted therapeutic efficacy differs among fluoroquinolones. ANIMALS: Bacterial pathogens isolated from dogs and cats. METHODS: Using microtube-dilution procedures, percent resistance and 2 pharmacodynamic/pharmacokinetic indices (maximum concentration/minimum inhibitory concentration [Cmax/MIC] [target 0.10] and area under curve/minimum inhibitory concentration [AUC/MIC] [target 0.125]) were compared prospectively at low and high doses (mg/kg) for ciprofloxacin (5 and 20), difloxacin (5 and 10), enrofloxacin (including enrofloxacin+ciprofloxacin) (5 and 20), marbofloxacin (2.5 and 5), and orbifloxacin (2.5 and 7.5). Indices were calculated for organisms represented by < or = 15 isolates. RESULTS: Percent resistance for all Gram-negative (n = 180; 20+/-3%; 39+/-5% for Escherichia coli) and Gram-positive isolates (n = 66; 18+/-3%) did not differ among drugs or organisms. The pattern of Cmax/MIC was generally enrofloxacin+ciprofloxacin > or = enrofloxacin or ciprofloxacin > or = marbofloxacin > or = orbifloxacin > or = difloxacin; and for AUIC/ MIC, enrofloxacin+ciprofloxacin > or = marbofloxacin > or = ciprofloxacin > or = enrofloxacin > difloxacin > orbifloxacin. Among susceptible Gram-negative isolates studied (n = 117), targeted Cmax/MIC or AUC/MIC were achieved in 88% of E. coli, 53% of Proteus mirabilis, and 35% of Pseudomonas aeruginosa; and for susceptible Gram-positive isolates studied (n = 49), 53% of Streptotoccus spp. and Staphylococcus intermedius and 27% of Staphylococcus spp. At the high dose, the proportion of isolates for which a target was reached was: ciprofloxacin, enrofloxacin+ciprofloaxin, and marbofloxacin (77%), enrofloxacin (73%), orbifloxacin (51%), and difloxacin (40%); and at the low dose, enrofloxacin+ciprofloxacin and enrofloxacin (43%), ciprofloxacin (40%), marbofloxacin (39%), orbifloxacin (29%), and difloxacin (28%). CONCLUSIONS: E. coli resistance to fluoroquinolones approximated 40%. For susceptible isolates, enrofloxacin, marbofloxacin, and ciprofloxacin more consistently reached indices associated with predicted efficacy, but only at the high dose.  相似文献   

4.
OBJECTIVE: To investigate the development of enrofloxacin resistance among Escherichia coli isolates obtained from chickens by determining mutant-prevention concentrations (MPCs) and sequence the quinolone resistance-determining regions (QRDRs) of gyrA and parC genes in selected isolates. SAMPLE POPULATION: 15 chicken-derived E coli isolates. PROCEDURES: For all isolates, MPC and minimal inhibition concentration (MIC) of enrofloxacin were determined. The MPCs and maximum serum drug concentrations attained with enrofloxacin doses recommended for treatment of E coli infections in chickens were compared. Mutation frequencies and QRDR sequence changes in gyrA and parC were also determined. RESULTS: In 2 of 15 E coli strains, MPCs were low (0.016 and 0.062 microg/mL), MPC:MIC ratios were 2 and 4, and the GyrA and ParC proteins had no mutations. In 9 susceptible isolates with a GyrA point mutation, MPCs ranged from 2 to 16 microg/mL. For isolates with double mutations in GyrA and a single mutation in ParC, MPCs were > 32 microg/mL (several fold greater than the maximal plasma concentration of enrofloxacin in chickens); mutation frequencies were also much lower, compared with frequencies for single-mutation isolates. CONCLUSIONS AND CLINICAL RELEVANCE: For E coli infections of chickens, MPC appears to be useful for determining enrofloxacin-dosing strategies. The high MPC:MIC ratio may result in enrofloxacin-treatment failure in chickens infected with some wild-type gyrA E coli isolates despite the isolates' enrofloxacin susceptibility (MICs 0.125 to 1 microg/mL). For infections involving isolates with high MPCs, especially those containing mutations in gyrA and parC genes, treatment with combinations of antimicrobials should be adopted.  相似文献   

5.
A 3‐day course of oral enrofloxacin is effective for treating uncomplicated urinary tract infection (UTI) in dogs when administered 20 mg/kg Q24H. However, emergence of fluoroquinolone‐resistant mutants of uropathogens is a concern. Urine concentrations of enrofloxacin and ciprofloxacin were measured in six healthy dogs following dose of enrofloxacin 20 mg/kg. Mutant prevention concentrations of Escherichia coli isolated from canine UTI were also determined against ciprofloxacin. Urine AUC(24)/MPC ratios considering ciprofloxacin concentrations ranged 3819–7767, indicating that selection of resistant E. coli mutants in dogs with uncomplicated UTIs is unlikely in the bladder given that an AUC(24)/MPC = 39 is considered to be protective against mutant selection for ciprofloxacin. However, additional studies are required to evaluate the effects of this enrofloxacin treatment protocol on bacteria that colonize anatomic sites where fluoroquinolones achieve lower concentrations compared to the urinary bladder.  相似文献   

6.
Orbifloxacin is a fluoroquinolone drug used widely in companion animal medicine. In this study, we firstly determined post-antibiotic effects (PAEs) and post-antibiotic sub-minimum inhibitory concentrations (MIC) effects (PA-SMEs) of orbifloxacin for two strains each of Escherichia coli and Pseudomonas aeruginosa from dogs, and these parameters were compared with those of enrofloxacin. At twice the MIC, the PAEs of orbifloxacin ranged from -0.28-0.93 h (mean, 0.29 h) for E. coli and -0.18-1.18 h (mean, 0.37 h) for P. aeruginosa. These parameters were not significantly different for E. coli and shorter for P. aeruginosa, compared to enrofloxacin (P < 0.05). Continued exposure to 0.1, 0.2, and 0.3 the MIC of orbifloxacin resulted in average PA-SMEs of 0.55, 1.11, and 2.03 h, respectively, for E. coli, and 1.04, 1.40, and 2.47 h, respectively, for P. aeruginosa. These PA-SMEs, which had no significant differences with those of enrofloxacin, were significantly longer than the corresponding PAEs (P < 0.05). These results suggest that the PA-SME of orbifloxacin for E. coli and P. aeruginosa can be meaningfully prolonged by increase of sub-MICs.  相似文献   

7.
The mutant prevention concentration (MPC) is a new concept meant to face the increased prevalence of antibiotic resistance by using antibiotic concentrations able to prevent the selection of single-step resistant mutants. In the present study, the MPCs of ciprofloxacin and enrofloxacin were evaluated against fully susceptible strains of Escherichia coli, Salmonella Typhimurium and Pseudomonas aeruginosa. Additionally, representative single-step mutants arising after exposure to sub-MPC antibiotic concentrations were investigated for molecular basis of their fluoroquinolone resistance phenotypes. MPC value was recorded when more than 1010 CFU/mL were spread on Muëller Hinton Agar supplemented with different antibiotic concentrations (from 1X to 16X MIC value). MICs of original strains as well as single-step mutants were determined in presence or absence of the Efflux Pump Inhibitor Phe-Arg-β-naphthylamide (PAβN). Moreover point mutations in the QRDR of the gyrA and parC genes were investigated by sequencing. The enrofloxacin MPC values were 4–16-fold higher than ciprofloxacin values. E. coli and S. Typhimurium representative single-step mutants showed reduced susceptibilities associated with point mutations in the QRDR of the gyrA gene or efflux pump system. P. aeruginosa mutants showed resistance phenotypes associated predominantly with efflux pump system activity. According to in vitro MPC data, ciprofloxacin showed a better efficacy than enrofloxacin, in preventing the selection of E. coli, S. Typhimurium and P. aeruginosa single-step mutants. However, in relation to AUC/MPC ratio, the MPC concept can be applied in vivo to ciprofloxacin and enrofloxacin for E. coli and S. Typhimurium but not for P. aeruginosa.  相似文献   

8.

Background

The mutant prevention concentration (MPC) is an important parameter to evaluate the likelihood of growth of fluoroquinolone-resistant mutants for antimicrobial-pathogen combinations. The MPCs of fluoroquinolones for different canine pathogens have not been compared. In this study, we compared for the first time orbifloxacin MPCs between susceptible strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus pseudintermedius of canine origin.

Methods

More than 1010 CFU/ml of 10 strains of each bacterial species were inoculated onto Muller-Hinton agar supplemented with different concentrations of orbifloxacin from 1× to 64× minimum inhibitory concentration (MIC) and the MPCs were recorded. MICs of original strains and of mutants arising after exposure to sub-MPC concentrations (one per original strain) were determined in the presence or absence of efflux pump inhibitors (EPIs). The effects of quinolone resistance-determining region (QRDR) mutations were also examined.

Results

MPCs were significantly higher for P. aeruginosa (16–128 μg/ml) than for E. coli (0.5–32 μg/ml). MPCs for S. pseudintermedius varied between the low-susceptible (16–128 μg/ml) and the high-susceptible strains (4–16 μg/ml) and were the most broadly distributed among the three species. Regarding resistance mechanisms, only one QRDR mutation in gyrA was found in all of the 10 mutants of E. coli and in 4 of the 10 mutants of P. aeruginosa, whereas mutations in both grlA and gyrA were found in 3 mutants and one mutation in grlA was found in 2 mutants among the 10 mutants of S. pseudintermedius. In the presence of an EPI, the MICs of P. aeruginosa mutants decreased markedly, those of E. coli mutants decreased moderately, and those of S. pseudintermedius mutants were unaffected.

Conclusions

MPCs of orbifloxacin vary between bacterial species of canine pathogens, possibly due to the diversity of the main fluoroquinolone resistance mechanism among these species. Therefore, the type of bacterial species should be taken into consideration when using fluoroquinolone drugs such as orbifloxacin in canines.  相似文献   

9.
Niwa H  Hobo S  Anzai T 《Veterinary microbiology》2006,115(1-3):264-268
In this study, the quinolone resistance-determining region (QRDR) in gyrA and gyrB of in vitro fluoroquinolone-resistant Rhodococcus equi mutants was sequenced. These mutants were selected from four R. equi strains on blood agar plates containing ciprofloxacin or enrofloxacin. Each mutant became 8- to 64 or greater-fold resistant to fluoroquinolones compared with their parent strains. From the results of sequence analysis of QRDR in gyrA and gyrB, a nucleotide mutation of codon GAC for GGC in gyrA was detected in all mutants, but no mutation was observed in gyrB. This mutation leads to amino acid substitution of Asp for Gly in putative GyrA in R. equi. The position of this substitution corresponds to position 87 of GyrA in Escherichia coli. Our results suggest that the mutation of QRDR in gyrA, which was observed in in vitro fluoroquinolone-resistant R. equi mutants in this study, is closely associated with fluoroquinolone resistance.  相似文献   

10.
The pharmacokinetics and pharmacodynamics of orbifloxacin were studied in six clinically healthy Hanwoo cows after intravenous (i.v.) and intramuscular (i.m.) administration at a dose of 3 mg/kg. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Steady-state volume of distribution and clearance of orbifloxacin after i.v. administration were 0.92 L/kg and 0.24 L/h·kg, respectively. Following i.m. administration, a slow and complete absorption with absolute bioavailability of 101.4%, and a maximum concentration ( C max) of 1.17 μg/mL at 1.04 h were observed. The in vitro serum protein binding was 14.76%. The in vitro antibacterial activity of orbifloxacin against a pathogenic strain of Mannheimia haemolytica ( M. haemolytica ), Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ) was determined . The ex vivo activity of orbifloxacin against M. haemolytica strain was also determined , and these data were integrated with the ex vivo bacterial counts to establish AUC 24h/ MIC values producing bacteriostatic action, bactericidal action and elimination of bacteria. Mean values were 32.7, 51.6 and 102.6 h, respectively. From these data, we predict that orbifloxacin, when administered i.m. at a dosage of 2.5–5 mg/kg once a day, would be effective against bovine pathogens, such as M. haemolytica. Additional studies may be needed to confirm its efficacy in a clinical setting, and to evaluate the penetration of the drug in diseased tissues.  相似文献   

11.
Nine quinolone resistant (minimal inhibitory concentration [MIC] was > 32 microg/mL for nalidixic acid, > 1 microg/mL for ciprofloxacin) isolates of Escherichia coli have been found in wild birds with septicemia. All of the isolates were aerobactin positive. The mechanisms of resistance were characterised by sequencing the quinolone resistance-determining region (QRDR) of the gyrA, gyrB, parC, and parE genes. Sequence analysis of the gyrA gene in all isolates identified only 1 nucleotide substitution at codon Serine-83 for Leucine-83. Sequence analysis of the gyrB, parC, and parE QRDR genes revealed no mutations in any of the isolates. This study was conducted to determine the importance of these genes in the susceptibility of E. coli strains isolated from wild birds to quinolones.  相似文献   

12.
The aim of this study were to detect the gyrA, parC and marR mutations and qnr genes (qnrA, qnrB and qnrS) in 120 strains of Escherichia coli isolated from animals. European Committee on Antimicrobial Susceptibility Testing and Clinical Laboratory Standards Institute disc diffusion and minimum inhibitory concentration (MIC) tests, respectively, were used to determine fluoroquinolone (FQ) resistance, and molecular methods were used to detect the mutations and the genes. E coli isolates with an MIC of ≥8 mg/l had mutation at Ser-80 in parC in addition to mutations at Ser-83, Asp-87 or both in gyrA. The nucleotide change was detected in marR (Ser-3?→?Asn, Ala-53?→?Glu, Gly-103?→?Ser, Tyr-137?→?His). Only four E coli isolates (3.3 per cent) contained qnrA and qnrS, and qnrB was not detected. Two E coli isolates from healthy calves also contained qnrA and qnrS. The MICs of enrofloxacin and danofloxacin for qnr-containing E coli isolates ranged from 32 mg/l to 256 mg/l. The results of this study indicated that the FQ-resistant E coli isolates presented an alteration in gyrA (Ser-83?→?Leu, Asp-87?→?Asn) and parC (Ser-80?→?Ile) with high MICs (8-256 mg/l), and there was a low prevalence of qnr genes among E coli isolated from animals.  相似文献   

13.
The single-dose disposition kinetics of orbifloxacin were determined in clinically normal rabbits (n=6) after intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration of 5 mg/kg bodyweight. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of orbifloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The concentration-time data were analysed by compartmental and noncompartmental kinetic methods. Steady-state volume of distribution (V(ss)) and total body clearance (Cl) of orbifloxacin after i.v. administration were estimated to be 1.71+/-0.38 L/kg and 0.91+/-0.20 L/h x kg, respectively. Following s.c. and i.m. administration orbifloxacin achieved maximum plasma concentrations of 2.95+/-0.82 and 3.24+/-1.33 mg/L at 0.67+/-0.20 and 0.65+/-0.12 h, respectively. The absolute bio-availabilities after s.c. and i.m. routes were 110.67+/-11.02% and 109.87+/-8.36%, respectively. Orbifloxacin showed a favourable pharmacokinetic profile in rabbits. However, on account of the low AUC/MIC and C(max)/MIC indices obtained, its use by i.m. and s.c. routes against the S. aureus strains assayed in this study cannot be recommended given the risk of selection of resistant populations.  相似文献   

14.
The pharmacokinetics and pharmacodynamics of danofloxacin were studied in the camel in a two period cross-over study. After intravenous (i.v.) administration at a dose rate of 1.25 mg/kg, the pharmacokinetics of danofloxacin indicated a high volume of distribution (V(d(area))=3.43 L/kg), relatively rapid clearance (0.44 L/kg/h) and half-life of 5.37 h. After intramuscular (i.m.) dosing absorption was complete (F=114.5) and rapid (T((1/2)abs)=0.12 h) and terminal half-life was 5.71 h. Danofloxacin penetrated fairly slowly into both inflamed (exudate) and non-inflamed (transudate) tissue cage fluids and was cleared slowly from these fluids, elimination half-life being at least twice that for serum for both exudate and transudate after both i.v. and i.m. dosing. The antibacterial actions of danofloxacin against the camel pathogen Escherichia coli 0157-H7 were determined by measurement of minimum inhibitory concentration (MIC) in vitro (single measurement) and ex vivo measurements of bacterial count at nine times between one and 48 h after i.m. dosing in each of the fluids, serum, exudate, and transudate. Using in vitro MIC data and in vivo pharmacokinetic parameters, the surrogate markers of antimicrobial activity, C(max)/MIC, AUC/MIC and T>MIC, were determined for all three fluids. The ex vivo serum AUC(24 h)/MIC data were integrated with reduction in bacterial count to provide values producing a bacteriostatic action (no change in bacterial count), inhibition of bacterial count by 50%, reduction in bacterial count by 99.9% (bactericidal action) and elimination of bacteria. Mean AUC(24h)/MIC values were 17.20, 20.07, 21.24, and 68.37 h, respectively. To describe the latter, the introduction of a new term to supplement MIC and minimum bactericidal concentration (MBC) is proposed, namely minimum elimination concentration (MEC). A novel means of designing antimicrobial drug dosage schedules for evaluation in clinical trials is proposed, using ex vivo AUC(24h)/MIC values for bactericidal activity and elimination of bacteria together with MIC(90) data for camel pathogens.  相似文献   

15.
Pharmacokinetics and distribution of orbifloxacin into body fluids and endometrium was studied in 6 mares after intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. Orbifloxacin concentrations were serially measured in serum, synovial fluid, peritoneal fluid, urine, cerebrospinal fluid, and endometrial tissues over 24 hours. Minimum inhibitory concentrations of orbifloxacin were determined for 120 equine pathogens over an 11-month period. The mean peak serum concentration (Cmax) was 2.41+/-0.30 microg/mL at 1.5 hours after administration and decreased to 0.17+/-0.01 microg/mL (Cmin) at 24 hours. The mean elimination half-life (t1/2) was 9.06+/-1.33 hours and area under the serum concentration vs time curve (AUC) was 20.54+/-1.70 mg h/L. Highest mean peritoneal fluid concentration was 2.15+/-0.49 microg/mL at 2 hours. Highest mean synovial fluid concentration was 1.17+/-0.28 microg/mL at 4 hours. Highest mean urine concentration was 536.67+/-244.79 microg/mL at 2 hours. Highest mean endometrial concentration was 0.72+/-0.23 microg/g at 1.5 hours. Mean CSF concentration was 0.46+/-0.55 microg/mL at 3 hours. The minimum inhibitory concentration of orbifloxacin required to inhibit 90% of isolates (MIC90) ranged from < or = 0.12 to > 8.0 microg/mL, with gram-negative organisms being more sensitive than gram-positive organisms. Orbifloxacin was uniformly absorbed in the 6 mares and was well distributed into body fluids and endometrial tissue. At a dosage of 7.5 mg/kg once a day, many gram-negative pathogens, such as Actinobacillus equuli, Escherichia coli, Pasteurella spp., and Salmonella spp. would be expected to be susceptible to orbifloxacin.  相似文献   

16.
The pharmacodynamic properties of a new veterinary fluoroquinolone antimicrobial agent, ibafloxacin, were evaluated. Minimal inhibitory concentrations (MIC), time-kill kinetics, postantibiotic effect (PAE) and postantibiotic subminimal inhibitory concentration effects (PA-SME) were determined against pathogenic canine Gram-negative and Gram-positive bacterial isolates from dermal, respiratory and urinary tract infections. The synergistic interactions between ibafloxacin and its main metabolite, 8-hydroxy-ibafloxacin were investigated. Finally, the efficacy of ibafloxacin was tested in in vivo canine infection models. Ibafloxacin had good activity against Pasteurella spp., Escherichia coli, Klebsiella spp., Proteus spp. and Staphylococcus spp. (MIC90=0.5 microg/mL), moderate activity against Bordetella bronchiseptica, Enterobacter spp. and Enterococcus spp. (MIC50=4 microg/mL) and low activity against Pseudomonas spp. and Streptococcus spp. The time-killing analysis confirmed that ibafloxacin was bactericidal with a broad spectrum of activity. The PAE and PA-SME were between 0.7-2.13 and 1-11.5 h, respectively. Finally, studies in dog models of wound infection and cystitis confirmed the efficacy of once daily oral ibafloxacin at a dosage of 15 mg/kg. Additional studies are needed to better define the importance of AUC/MIC (AUIC) and Cmax/MIC ratios on the outcome of fluoroquinolone therapy in dogs.  相似文献   

17.
Thirty-seven fluoroquinolone-resistant Escherichia coli strains from ruminants (according to Clinical and Laboratory Standards Institute guidelines) were screened by molecular methods for mutations in the quinolone resistance-determining region (QRDR) of the gyrA and parC genes and for the presence of the qnrA gene. One of the strains studied was an enterohemorrhagic E. coli (EHEC) strain potentially pathogenic for humans. Three E. coli strains resistant to enrofloxacin (minimal inhibitory concentration [MIC] = 2 microg/ml) but not to ciprofloxacin (MIC = 1 microg/ml) presented single mutations in the gyrA and parC genes, while 34 strains resistant to both fluoroquinolones presented double and single mutations in gyrA and parC, respectively (31 strains), or double mutations in gyrA and parC (3 strains). The EHEC strain presented a double amino acid substitution in the GyrA protein (Ser-83-->Leu and Asp-87-->Gly) and a double amino acid substitution in the ParC protein (Gly-78-->Cys and Ser-80-->Arg), one of which has not been previously described. The present study shows that most of the mutations in the QRDR of the gyrA and parC genes of fluoroquinolone-resistant E. coli strains from ruminants are the same as those seen in E. coli strains from other animal species and humans and that there are no differences in mutation patterns in the QRDR of E. coli strains from healthy ruminants and those with diarrhea. No strains carried qnrA, which indicates that this gene does not play an important role in the selection of fluoroquinolone-resistant E. coli strains from ruminants.  相似文献   

18.
The pharmacokinetics of enrofloxacin (EFL) and its active metabolite ciprofloxacin (CIP) was investigated in 7-8 month old turkeys (6 birds per sex). EFL was administered intravenously (i.v.) and orally (p.o.) at a dose 10 mg kg(-1) body weight. Blood was taken prior to and at 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h following drug administration. The concentrations of EFL and CIP in blood serum were determined by high-performance liquid chromatography (HPLC). Serum concentrations versus time were analysed by a noncompartmental analysis. The elimination half-live and the mean residence time of EFL after i.v. injection for the serum were after oral administration 6.64+/-0.90 h, 8.96+/-1.18 h and 6.92+/-0.97 h, 11.91+/-1.87 h, respectively. After single p.o. administration, EFL was absorbed slowly (MAT=2.76+/-0.48 h) with time to reach maximum serum concentrations of 6.33+/-2.54 h. Maximum serum concentrations was 1.23+/-0.30 microg mL(-1). Oral bioavailability for for EFL after oral administration was found to be 69.20+/-1.49%. The ratios C(max)/MIC and AUC(0 --> 24)/MIC were respectively from 161.23+/-5.9 h to 12.90+/-0.5 h for the pharmacodynamic predictor C(max)/MIC, and from 2153.44+/-66.6 h to 137.82+/-4.27 h for AUC(0 --> 24)/MIC, for the different clinically significant microorganisms, whose values for MIC varies from 0.008 microg L(-1) to 0.125 microg mL(-1).  相似文献   

19.
The single-dose disposition kinetics of orbifloxacin were determined in clinically normal rabbits ( n  = 6) after intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration of 5 mg/kg bodyweight. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Minimal inhibitory concentrations ( MIC s) assay of orbifloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The concentration–time data were analysed by compartmental and noncompartmental kinetic methods. Steady-state volume of distribution ( V ss) and total body clearance ( Cl ) of orbifloxacin after i.v. administration were estimated to be 1.71 ± 0.38 L/kg and 0.91 ± 0.20 L/h·kg, respectively. Following s.c. and i.m. administration orbifloxacin achieved maximum plasma concentrations of 2.95 ± 0.82 and 3.24 ± 1.33 mg/L at 0.67 ± 0.20 and 0.65 ± 0.12 h, respectively. The absolute bio-availabilities after s.c. and i.m. routes were 110.67 ± 11.02% and 109.87 ± 8.36%, respectively. Orbifloxacin showed a favourable pharmacokinetic profile in rabbits. However, on account of the low AUC / MIC and C max/ MIC indices obtained, its use by i.m. and s.c. routes against the S. aureus strains assayed in this study cannot be recommended given the risk of selection of resistant populations.  相似文献   

20.
旨在了解猪链球菌对氟喹诺酮类药物耐药性与parC、gyrA基因突变的相关性,通过微量稀释法测定34株猪链球菌对4种氟喹诺酮类药物的MIC值,采用PCR方法扩增并测序分析了临床分离的猪链球菌对氟唪诺酮类约物10株耐药株和9株敏感株的parC和gyrA基因喹诺酮耐药决定区(QRDRs).在氟喹诺酮类药物耐药菌株parC基因QRDRs发生Ser79→Phe、Arg 87→Leu的氨基酸突变,在4株高度耐药菌株gyrA基因QRDRs发生Arg66→Ser,Ser81→Arg氨基酸突变;当菌株对氟喹诺酮类药物敏感时,parC和gyrA基因的QRDR区均未有突变;而当MIC≥32 μg·L-1 时,parC的氨基酸发生了 Ser79→Phe的突变,同时发生gyrA氨基酸Arg66→Ser,Set81→Arg突变.结果表明,猪链球菌对氟喹诺酮类药物低水平类耐药是由parC单一位点突变引起,而高水平耐药是由parC和gyrA双位点突变引起.  相似文献   

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