Pharmacokinetics of Immediate and Sustained Release Cephalexin Administered by Different Routes to Llamas (Lama glama).

We investigate the pharmacokinetics of two different cephalexin formulations administered to llamas by the intravenous (IV), intramuscular (IM), and subcutaneous (SC) routes, the minimum inhibitory concentration (MIC) of cephalexin against some Escherichia coli and staphylococci isolated from llamas, and we apply the PK/PD modelling approach, so that effective dosage recommendations for this species could be made. Six llamas received immediate (10 mg/kg, IV, IM, and SC) and sustained (8 mg/kg IM, SC) release cephalexin. Pharmacokinetic parameters were calculated by noncompartmental approach. Immediate release SC administration produced a significantly longer elimination half-life as compared with the IV and IM administration (1.3 ± 0.2 versus 0.6 ± 0.1 and 0.6 ± 0.1 h, resp.) and higher mean absorption time as compared with the IM administration (1.7 ± 0.5 versus 0.6 ± 0.4 h). Absolute bioavailability was in the range of 72-89% for both formulations and routes of administration. Cephalexin MIC90 values against staphylococci and E. coli were 1.0 and 8.0 µg/mL, respectively. Our results show that the immediate release formulation (10 mg/kg) would be effective for treating staphylococcal infections administered every 8 h (IM) or 12 h (SC), whereas the sustained release formulation (8 mg/kg) would require the IM or SC administration every 12 or 24 h, respectively.

A population pharmacokinetic approach to describe cephalexin disposition in adult and aged dogs.

This study was conducted in order to characterize the pharmacokinetics of orally administered cephalexin to healthy adult and aged dogs, using a population pharmacokinetic approach. Two hundred and eighty-six cephalexin plasma concentrations obtained from previous pharmacokinetic studies were used. Sex, age, pharmaceutical formulation, and breed were evaluated as covariates. A one-compartment model with an absorption lag-time (Tlag) best described the data. The final model included age (adult; aged) on apparent volume of distribution (Vd/F), apparent elimination rate (ke/F), and Tlag; sex (female; male) on ke/F, and breed (Beagle; mixed-breed) on Vd/F. Addition of the covariates to the model explained 78% of the interindividal variability (IIV) in Vd/F, 36% in ke/F, and 24% in Tlag, respectively. Formulation did not affect the variability of any of the pharmacokinetic parameters. Tlag was longer, whereas Vd/F and ke/F were lower in aged compared to adult animals; in female aged dogs ke/F was lower than in male aged dogs; however, the differences were of low magnitude. Different disposition of cephalexin may be expected in aged dogs.

Chronokinetics of ceftazidime after intramuscular administration to dogs.

Ceftazidime, a third-generation cephalosporin, is widely used for the treatment of Pseudomonas aeruginosa infections. The aims of the present study were to characterize the pharmacokinetics of ceftazidime and to estimate the T > MIC against P. aeruginosa, after its intramuscular (i.m.) administration at two different dosing times (08:30 h and 20:30 h) to dogs, in order to determine whether time-of-day administration modifies ceftazidime pharmacokinetics and/or predicted clinical antipseudomonal efficacy. Six female healthy beagle dogs were administered ceftazidime pentahydrate by the intramuscular route in a single dose of 25 mg/kg at both 08:30 and 20:30 h, two weeks apart. Plasma ceftazidime concentrations were determined by microbiological assay. Pharmacokinetic parameters and time above the minimum inhibitory concentration (T > MIC) and 4xMIC for Pseudomonas aeruginosa were calculated from the disposition curve of each dog. No differences between the daytime and nighttime administrations were found for the main pharmacokinetic parameters, including C(max), t(max), t((1/2) lambda), AUC, and MRT; however, the high interindividual variability shown by these values and the small number of individuals may account for this lack of difference. Rate of absorption (k(a)) was significantly higher after the 20:30 h than 08:30 h administration. No significant differences between T > MIC were found when comparing the 08:30 h and 20:30 h administrations. Mean T > MIC values predicted a favorable bacteriostatic effect for all susceptible strains of P. aeruginosa for the 12 h dosing interval at both dosing times. Our results suggest that similar antipseudomonal activity may be expected when ceftazidime is administered at 8:30 and 20:30 h; however, as only two timepoints of drug administration were explored, we are unable to draw any conclusions for other treatment times during the 24 h.

Antibiotic Treatment of Dogs and Cats during Pregnancy.

The use of pharmacological agents in pregnant females poses a major clinical challenge due to the marked physiological changes that may modify the pharmacokinetics of drugs and to the potential effects on the fetus. The purpose of this paper is to review briefly our knowledge on the use of antibacterial drugs during pregnancy and to provide information for the judicious selection of an antimicrobial treatment for use in pregnant bitches and queens. The risk to the fetus is a result of the ability of a drug to reach the fetal circulation and to produce toxic effects. The placenta functions as a barrier that protects the fetus due to the presence of transporters and metabolising enzymes; however, during pregnancy, the presence and activity of both enzymes and transporters may change. Antimicrobial agents that have been shown to be safe for use during pregnancy include betalactams, macrolides, and lincosamides. Pharmacotherapy during pregnancy in all species may affect adversely the developing fetus; therefore, it should be avoided when possible.

Chronopharmacological study of cephalexin in dogs.

Recent studies have identified a 24 h rhythm in the expression and function of PEPT1 in rats, with significantly higher levels during the nighttime than daytime. Similarly, temporal variations have been described in glomerular filtration rate and renal blood flow, both being maximal during the activity phase and minimal during the rest phase in laboratory rodents. The aim of this study was to assess the hypothesis that the absorption of the first-generation cephalosporin antibiotic cephalexin by dogs would be less and the elimination would be slower after evening (rest span) compared to morning (activity span) administration, and whether such administration-time changes could impair the medication's predicted clinical efficacy. Six (3 male, 3 female; age 4.83+/-3.12 years) healthy beagle dogs were studied. Each dog received a single dose of 25 mg/kg of cephalexin monohydrate per os at 10:00 and 22:00 h, with a two-week interval of time between the two clock-time experiments. Plasma cephalexin concentrations were determined by microbiological assay. Cephalexin peak plasma concentration was significantly reduced to almost 77% of its value after the evening compared to morning (14.52+/-2.7 vs. 18.77+/-2.8 microg/mL) administration. The elimination half-life was prolonged 1.5-fold after the 22:00 h compared to the 10:00 h administration (2.69+/-0.9 vs. 1.79+/-0.2 h). The area under the curve and time to reach peak plasma concentration did not show significant administration-time differences. The duration of time that cephalexin concentrations remained above the minimal inhibitory concentrations (MIC) for staphylococci susceptiblity (MIC=0.5 microg/mL) was>70% of each of the 12 h dosing intervals (i.e., 10:00 and 22:00 h). It can be concluded that cephalexin pharmacokinetics vary with time of day administration. The findings of this acute single-dose study require confirmation by future steady-state, multiple-dose studies. If such studies are confirmatory, no administration-time dose adjustment is required to ensure drug efficacy in dogs receiving an oral suspension of cephalexin in a dosage of 25 mg/kg at 12 h intervals.

Ciprofloxacin and norfloxacin pharmacokinetics and prostatic fluid penetration in dogs after multiple oral dosing.

The aims of this study were to assess the pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) indices predictive of clinical outcome of ciprofloxacin (CIP) and norfloxacin (NOR) after multiple oral dosing, and to investigate their penetration into prostatic fluid in dogs. Eight dogs received seven oral doses b.i.d. of NOR (20 mg/kg) and CIP (15 mg/kg). Drug concentrations were determined in blood and in two prostatic fluid samples. Prostatic fluid concentrations were lower than plasma concentrations for both drugs. No statistically significant differences were determined between the pharmacokinetic parameters calculated after the first and seventh doses for either CIP or NOR. The PK/PD indices were found to be useful for predicting bacteriological outcome for fluoroquinolones (area under the disposition curve/minimum inhibitory concentration [MIC] and peak plasma concentration/MIC) and indicate that with this dose regimen CIP presents a more favourable disposition than NOR for successful clinical outcome.

Chronopharmacology and antimicrobial therapeutics.

Chronobiology studies the phenomenon of rhythmicity in living organisms. Circadian rhythms are genetically determined and are regulated by external synchronizers (i.e. light/day cycle). Several biological processes involved in the pharmacokinetics and pharmacodynamics of drugs are subject to circadian variations. Chronopharmacology studies how biological rhythms impact on drug pharmacokinetic (chronokinetics), pharmacodynamics (chronoesthesy) and toxicity and determines whether time of day administration modifies drug's pharmacological characteristics. Chronotherapy applies chronopharmacological studies to clinical treatments, determining the best biological time for its dosing, i.e. when beneficial effects are maximal and incidence and/or intensity of related side-effects and toxicity are minimal. Significant variations in the pharmacokinetics and toxicity of antibiotics (aminoglycosides, beta-lactams and fluoroquinolones) related to administration time are well known. The aims of this review are to discuss, briefly, the currently accepted model of the circadian system that substantiates endogenous rhythmicity and to provide an update on the knowledge of circadian rhythms applied to drugs used as medicines, with a special mention to the possible impact on antimicrobial treatments. It is concluded that the dosing time of an antimicrobial agent might be clinically relevant in some treatments, thus, clinicians should be aware that the dosing time might affect the clinical response of a drug.

Chronopharmacokinetic study of gentamicin in dogs.

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed-breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p < 0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady-state, and total body clearance (1.73+/-0.55 at 20:00 h versus 3.31+/-0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p < 0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.