Pharmacokinetics of a single bolus intravenous, intramuscular and subcutaneous dose of disodium fosfomycin in horses.

Pharmacokinetic parameters of fosfomycin were determined in horses after the administration of disodium fosfomycin at 10 mg/kg and 20 mg/kg intravenously (IV), intramuscularly (IM) and subcutaneously (SC) each. Serum concentration at time zero (C(S0)) was 112.21 +/- 1.27 microg/mL and 201.43 +/- 1.56 microg/mL for each dose level. Bioavailability after the SC administration was 84 and 86% for the 10 mg/kg and the 20 mg/kg dose respectively. Considering the documented minimum inhibitory concentration (MIC(90)) range of sensitive bacteria to fosfomycin, the maximum serum concentration (Cmax) obtained (56.14 +/- 2.26 microg/mL with 10 mg/kg SC and 72.14 +/- 3.04 microg/mL with 20 mg/kg SC) and that fosfomycin is considered a time-dependant antimicrobial, it can be concluded that clinically effective plasma concentrations might be obtained for up to 10 h administering 20 mg/kg SC. An additional predictor of efficacy for this latter dose and route, and considering a 12 h dosing interval, could be area under the curve AUC(0-12)/MIC(90) ratio which in this case was calculated as 996 for the 10 mg/kg dose and 1260 for the 20 mg/kg dose if dealing with sensitive bacteria. If a more resistant strain is considered, the AUC(0-12)/MIC(90) ratio was calculated as 15 for the 10 mg/kg dose and 19 for the 20 mg/kg dose.

Pharmacokinetics of disodium-fosfomycin in mongrel dogs.

Pharmacokinetic variables of fosfomycin were determined after administration of buffered disodium-fosfomycin intravenously (IV), intramuscularly (IM), subcutaneously (SC) and orally (PO), in mongrel dogs, at 40 and 80 mg/kgday for three days. Renal integrity was also assessed by measuring key serum variables. Day 1, day 2 and day 3 plasma concentration vs. time profiles were undistinguishable, but there appears to be a lineal increase in serum concentrations vs. time with the dose. A non-accumulative kinetic behavior was observed after three days with both doses and most pharmacokinetic variables remain unaltered. Considering a MIC range from 1 mirog/mL to 16 microg/mL of fosfomycin in serum for sensitive bacteria, and a negligible plasma protein binding of fosfomycin (<0.5%), useful plasma concentrations can only be achieved after the SC injection of 80 mg/kg every 12h, having a C(max)=18.96+/-0.3 microg/mL; a T(1/2beta)=2.09+/-0.06 microg/mL and a bioavailability of 84-85%. No alterations were observed in serum variables of kidney-related biochemical values.

Intravenous and intramuscular pharmacokinetics of a single-daily dose of disodium-fosfomycin in cattle, administered for 3 days.

Pharmacokinetic parameters of fosfomycin in cattle were determined after administration of buffered disodium fosfomycin either intravenously (i.v.) or intramuscularly (i.m.) at a dose of 20 mg/kg/day for 3 days. Calculated concentrations at time zero and maximum serum concentrations were 34.42 and 10.18 mug/mL, respectively. The variables determined, the elimination half-life of the drug remained unchanged during the 3 days ( = 1.33 +/- 0.3 h for the i.v. route and = 2.17 +/- 0.4 h for the i.m. route). Apparent volumes of distribution suggest moderated distribution out of the central compartment (V(darea) = 673 mL +/- 27 mL/kg and V(dss) = 483 +/- 11 mL/kg). Bioavailability after i.m. administration was 74.52%. Considering fosfomycin as a time-dependent antibacterial drug, plasma concentration vs. time profiles obtained in this study, suggest that clinically effective plasma concentrations of fosfomycin could be obtained for up to 8 h following i.v. administration and approximately 10 h after i.m. injection of 20 mg/kg, for susceptible bacteria. In addition to residue studies in milk and edible tissues, a series of clinical assessments, using fosfomycin at 20 mg/kg b.i.d. or t.i.d. are warranted before this antibacterial drug should be considered for use in cattle.

Pharmacokinetics of a cephalone (CQ-M-EPCA) in rats after oral, intraduodenal and intravenous administration.

As part of the development of a new series of antibacterial agents derived from coupling a beta-lactamic precursor with a fluoroquinolone and named cephalones, the pharmacokinetics of one derivate: CQ-M-EPCA in rats after intravenous, intragastric and intraduodenal routes, was carried out. After the IV injection of 20 mg/kg or 40 mg/kg of this cephalone, plasma concentrations at the time zero (Cp0) were 3.1 and 11.26 microg/ml, respectively. Plasma concentrations decreased rapidly to almost disappear in both instances. Forty-five minutes later, a surge in concentrations, in the 40 mg/kg group, with a maximal plasma concentration (Cpmax) of 2.97 microg/ml was observed. An elimination half-life (T1/2el) of 2.36 +/- 0.33 h. was calculated. The drug was undetected by the ninth hour. Intragastric administration of the drug resulted in Cpmax of 3.78 +/- 0.26 microg/ml with a time to reach Cpmax (Tmax) of 25 min and T1/2el = 3.22 h. Same variables after intraduodenal administration were Cpmax 4.71 microg/ml; Tmax 1h, and T1/2el 3.41 h. Outstandingly high bioavailabilities after intragastric and intraduodenal administration (169 and 246%, respectively), together with the shape of the concentration versus time profiles after IV administration suggest that the drug undergoes a complex redistribution phenomenon, while showing high tissue diffusion with an apparent volume of distribution of 3.33 l/kg.

Non-bioequivalence of various trademarks of enrofloxacin and Baytril in cows.

Including Baytril, in various parts of the world many commercial preparations of enrofloxacin for parenteral administration are being employed for the treatment of bacterial diseases in cows. To optimize clinical responses and to minimize development of bacterial resistance to this agent, the copied pharmaceutical preparations must comply with some key pharmacokinetic features when bioequivalence studies are performed. To assess whether or not there was bioequivalence among nine commercial preparations of enrofloxacin and the original one, a controlled pharmacokinetic study was carried out. These was done utilizing the microbiological agar-diffusion test as quantitative/qualitative analytical method. A non-compartmental model defined kinetic variables. Results for Baytril revealed that maximal serum concentration (Csmax) was only matched by one preparation while area under the curve (AUC) of the serum concentration/activity of enrofloxacin and metabolites in time was not matched by any preparation. Time to Csmax (Tmax), elimination half-life, and shape of the time-serum concentrations of enrofloxacin profiles obtained for the nine generic preparations differ significantly somehow from the corresponding data obtained for the reference enrofloxacin. The need for studies to demonstrate bioequivalence becomes mandatory if similar preparations of enrofloxacin become commercially available. Enrofloxacin should be used selectively and cautiously to limit development of bacterial resistance. Non-bioequivalence of relevant pharmacokinetic values, such as Csmax and bioavailability (AUC) would facilitate development of bacterial resistance and limit the useful life span of this antibacterial agent.

Effectiveness of two fluoroquinolones for the treatment of chronic respiratory disease outbreak in broilers.

1. Chronic respiratory disease (CRD) caused by Mycoplasma synoviae in association with Escherichia coli is the disease most frequently encountered in poultry in Mexico. 2. Differences of antimycoplasmal activity, pharmacokinetics and cost among fluoroquinolones were the impetus for this clinical evaluation of efficacy of enrofloxacin and norfloxacin-nicotinate in broilers with CRD. 3. A total of 99,600 broilers, naturally infected with M. synoviae and E. coli, were treated with enrofloxacin (10 mg/kg/d for 3 d) (n = 49,800) or norfloxacin-nicotinate (20 mg/kg/d for 3 d) (n = 49,800). 4. Based on survivor analysis, there were no significant differences of efficacy of the 2 drugs. Survivor probabilities were above 0.99. 5. These results indicate that enrofloxacin and norfloxacin-nicotinate are efficacious for treatment of CRD. Questions remaining to be answered by other studies include: public health concern about the use of fluoroquinolones for the treatment of CRD; clinical superiority of one of these drugs on the basis of an attribute other than antimicrobial activity, such as cost:benefit ratio or ability to prevent bacterial resistance. 6. Clinical efficacy is not a relevant variable in assessing whether norfloxacin-nicotinate or enrofloxacin should be used for the treatment of CRD associated with E. coli in broilers.