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The Pharmacokinetic/Pharmacodynamic (PK/PD) relationship of antimicrobial drugs (AMD) for surgical prophylaxis has been poorly studied, hampering evidence-based decision making around AMD dosing and timing. Our objective is to use PK/PD principles to inform (1) the timing of administration and (2) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cefalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. E. coli and methicillin-susceptible staphylococci were identified as possible intraoperative contaminants and their epidemiological cut-offs (ECOFF) were retrieved from the EUCAST database. Individual PK data were refitted with non-linear mixed effect models (Phoenix®). We performed Monte Carlo simulation to compute i) the 95 th percentile of time of peak concentration in the peripheral compartment (informing timing between administration and first incision) and ii) the duration for which at least 90% of dogs maintain a free plasma concentration above ECOFF (informing timing of re-administration: 1.5-4 h). Cefazolin (22-25 mg/kg), cefuroxime (20 mg/kg), cefalexin (15 mg/kg) and amoxicillin (16.7 mg/kg) reached peak peripheral concentrations within 30 min, but ampicillin (20 mg/kg) required 82 min, respectively. For methicillin-susceptible staphylococci, cefazolin and cefuroxime require re-administration every 2 h, whereas cefalexin and both amoxicillin and ampicillin can be readministered every 3 and 4 h, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cefalexin failed uniformly. Alternatively, ampicillin and amoxicillin (critically ill dogs) may cover E. coli contaminations, but only if readministered every 1.5 h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing., Competing Interests: Declaration of Competing Interest The authors of the manuscripts are members of ENOVAT working groups (WG1: FA, WG2: LP, WG3: LP, PC and WG4: LP, TMS, FA) and the veterinary subcommittee of EUCAST named VetCAST (LP, PC, PLT). None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the pharmacokinetics of cefovecin sodium after SC administration to Hermann's tortoises (Testudo hermanni)., Animals: 23 healthy adult Hermann's tortoises (15 males and 8 females)., Procedures: Cefovecin (8.0 mg/kg) was injected once in the subcutis of the neck region of Hermann's tortoises, and blood samples were obtained at predetermined time points. Plasma cefovecin concentrations were measured via ultraperformance liquid chromatography coupled to tandem mass spectrometry, and pharmacokinetic parameters were calculated with a noncompartmental model. Plasma protein concentration was quantified, and the percentage of cefovecin bound to protein was estimated with a centrifugation technique., Results: Cefovecin was absorbed rapidly, reaching maximum plasma concentrations between 35 minutes and 2 hours after administration, with the exception of 1 group, in which it was reached after 4 hours. The mean ± SD time to maximum concentration was 1.22 ± 1.14 hours; area under the concentration-time curve was 220.35 ± 36.18 h•μg/mL The mean protein-bound fraction of cefovecin ranged from 41.3% to 47.5%. No adverse effects were observed., Conclusions and Clinical Relevance: Administration of a single dose of cefovecin SC appeared to be well-tolerated in this population of tortoises. Results of pharmacokinetic analysis indicated that the 2-week dosing interval suggested for dogs and cats cannot be considered effective in tortoises; however, further research is needed to determine therapeutic concentrations of the drug and appropriate dose ranges.

Erythromycin (ERY) is an antibiotic effective against Streptococcus iniae, a microorganism responsible for significant losses in aquaculture. No data are available on the pharmacokinetics and residue depletion of ERY in sea bream. The aim of this study was thus to evaluate the pharmacokinetics of ERY in this species after a single oral administration at 75 mg kg(-1) b.w. and to assess its residue depletion from tissues after prolonged treatment for 10 days. ERY was rapidly absorbed in sea bream (Cmax  = 10.04 μg g(-1) and Tmax =1 h), with a half-life of 9.35 h and an AUC0-24 of 56.81 (h μg mL(-1) ). The data obtained and the evaluation of pharmacokinetic/pharmacodynamic parameters allowed us to hypothesize that dosage used in this study should be effective against S. iniae. A rapid reduction in erythromycin concentrations was observed in tissues, with the drug being detectable only during the first day post-treatment. In Europe, the use of ERY in aquaculture is allowed by off-label prescription with a withdrawal time of 500 °C day(-1) . The absence of ERY residues in tissues already at 24 h post-treatment suggests that ERY in sea bream should not pose human food safety issues., (© 2013 John Wiley & Sons Ltd.)

The efficacy of enrofloxacin (ENRO) was evaluated against multidrug-resistant avian pathogenic Escherichia coli correlating the minimum inhibitory concentrations (MIC) of 235 E. coli field strains with its pharmacokinetics (PK) in 50 healthy turkeys (5 groups) with a PK/pharmacodynamic approach. The treatments were as follows: a) single oral gavage and b) single subcutaneous (SC) treatment at the recommended dose of 10 mg/kg; c) single oral gavage, d) 5 d of 10-h pulsed water medication, and e) 5 d of 24-h continuous water medication at the doubled dose of 20 mg/kg. Blood samples were collected at established times over 24 h. Plasma was analyzed using a liquid chromatography tandem mass spectrometry method that was validated in house. A monocompartmental and a noncompartmental model were applied to the data to obtain the PK results. After gavage administration, the mean maximum concentration Cmax/MIC50 and area under the curve AUC0-24/MIC50 ratios were, respectively, 3.07 ± 0.62 and 7.01 ± 1.03 and 25.48 ± 3.04 and 57.2 ± 3.73 for the 10 and 20 mg/kg doses, respectively. After SC administration of 10 mg/kg, Cmax/MIC50 and AUC0-24/MIC50 ratios were 3.45 ± 0.75 and 33.96 ± 7.46, respectively. After the administration of 10-h pulsed or 24-h continuous medicated water at 20 mg/kg, lower values of Cmax/MIC50 (10-h pulsed: 3.45 ± 0.7; 24-h continuous: 3.05 ± 0.48) and AUC0-24/MIC50 (10-h pulsed: 42.42 ± 6.17; 24-h continuous: 53.32 ± 5.55) were obtained. Based on these results, the European Union-recommended dosage of 10 mg/kg seems ineffective to achieve adequate drug plasma concentrations and even the 20 mg/kg by 10 h pulsed or continuous medicated water administration did not reach completely efficacious concentrations in plasma against colibacillosis. Although the results obtained were not completely encouraging, the medicated water should preferably be provided continuously. To conclude about the efficacy of ENRO treatment against colibacillosis, target tissue concentration should be extensively considered., (© 2014 Poultry Science Association Inc.)

Escherichia coli are a common inhabitant of the gastrointestinal tract of mammals and birds; nevertheless, they may be associated with a variety of severe and invasive infections. Whereas fluoroquinolones (FQ) have been banned in the United States for use in poultry production, the use of these antimicrobials in poultry husbandry is still possible in the European Union, although with some restrictions. The aim of this study was to investigate the FQ resistance of 235 E. coli isolates recovered from chickens and turkeys. Minimum inhibitory concentrations were determined by a microdilution method, whereas mutations in the quinolone resistance-determining regions of the target genes, gyrA and parC, were detected by a PCR-based method. High resistance rates (>60%) were observed for nalidixic acid, flumequine, and difloxacin, whereas resistance to ciprofloxacin, danofloxacin, enrofloxacin, marbofloxacin, and sarafloxacin was less frequently reported (<40%). Sixty-four isolates (27.2%) showed full susceptibility toward the tested FQ, but 57 isolates (24.2%) were resistant to all tested FQ. The remaining 114 E. coli isolates (48.5%) were grouped in 5 different resistance patterns. Isolates resistant only to flumequine or nalidixic acid or both possessed 1 gyrA mutation, whereas isolates with further resistance to enrofloxacin, difloxacin, danofloxacin, and sarafloxacin had in addition 1 or 2 parC substitutions. Two gyrA mutations coupled with 1 substitution in parC were detected in isolates resistant to all tested FQ. The number of mutations and their correlation with the in vitro activity of FQ reflected the currently accepted model, according to which a single gyrA substitution is associated with resistance or decreased susceptibility to older quinolones, whereas further gyrA or parC substitutions are needed for a higher level of resistance.

Erythromycin (ERY) is a drug active against Gram-positive bacteria such as Lactococcus garvieae, a pathogen responsible for an important disease that may cause a substantial decrease in rainbow trout Oncorhynchus mykiss (Walbaum) production, the species of fish most commonly produced in Italy. In the literature, studies on the kinetics behaviour of ERY in fish are limited. Therefore, the aim of the present study was to evaluate the pharmacokinetics of ERY in rainbow trout after a single oral treatment with 75 mg kg⁻¹ body weight (b.w.) of ERY and the residue depletion after multiple oral administration of 75 mg kg⁻¹ b.w. day⁻¹ of ERY for 10 days. Blood concentrations of ERY increased up to 20.24 ± 13.32 μg mL⁻¹ at 6 h, then decreased to 5.97 ± 3.89 μg mL⁻¹ at 24 h. The time during which the antibiotic remains in the bloodstream at concentrations exceeding the MIC (T > MIC) and the area under the serum concentration-time curve (AUC)/MIC are both pharmacokinetic-pharmacodynamic (PK/PD) predictors of ERY efficacy, and the data obtained allowed us to hypothesize that a dosage of 75 mg kg⁻¹ b.w. day⁻¹ of ERY could treat the lactococcosis in trout. Regarding the study of ERY depletion, rapid elimination was observed in tissue (muscle plus adherent skin); in fact the concentrations were below the limit of quantification in all samples (except two) by day 10 post-treatment. ERY is not licensed in Europe for use in aquaculture, and its use is possible only by off-label prescription with a precautionary withdrawal time of 500 degree-days, as established by Directive 2004/28/EC. From the data obtained in this study, a withdrawal time of 8.90 days was calculated, corresponding, in our experimental conditions, to 117.5 degree-days, a value significantly lower than that established by the European directive., (© 2013 John Wiley & Sons Ltd.)

Flumequine (FLU) is used in the treatment of systemic bacterial infections in poultry, including colibacillosis, which is a common disease in turkeys. The pharmacokinetic (PK) behavior of FLU administered to 32 healthy turkeys as an oral bolus via gavage or as 10-h pulsed administration in drinking water were compared, using the authorized dose of 15 mg/kg and the double dose of 30 mg/kg. The minimum inhibitory concentrations (MIC) of 235 Escherichia coli field strains isolated from poultry were determined for pharmacodynamics (PD) to develop a PK/PD model. Blood samples were collected at established times over 24 h, and the obtained plasma was analyzed using a liquid chromatography tandem mass spectrometry method that was validated in-house. A monocompartmental model and a noncompartmental model were applied to the data to obtain the PK results. For both types of administration and both dosages, the ratios of the maximum concentration (Cmax)/MIC50 and the area under the plasma concentration-time curve (AUC)/MIC50 achieved were considerably lower than the fluoroquinolone breakpoints usually adopted for efficacy. The Cmax/MIC50 and AUC0-24/MIC50 ratios were, respectively, 0.67 ± 0.09 and 4.76 ± 0.48 and 1.18 ± 0.35 and 7.05 ± 2.40 for the 15 and 30 mg/kg bolus doses, respectively. After 10-h pulsed administration of 15 mg/kg, values of Cmax/MIC50, 0.19 ± 0.02 on d 1 and 0.30 ± 0.08 on d 5 of therapy were obtained, the AUC/MIC50 ratios were 2.09 ± 0.29 and 3.22 ± 0.93 on d 1 and 5, respectively. Higher values were obtained with the doubled dose of 30 mg/kg: the Cmax/MIC50 ratios were 0.49 ± 0.11 on d 1 and 0.69 ± 0.18 on d 5; the AUC/MIC50 ratios were 5.15 ± 1.15 and 6.57 ± 1.92 on d 1 and 5, respectively. Based on these results, FLU administration should be adopted when specific diagnostic findings indicate its efficacy, and revising the dosage scheme to comply with the prudent and responsible use of antimicrobials in veterinary medicine is advisable.

The efficacy of administering enrofloxacin at 10mg/kg in medicated water to turkeys was evaluated by applying a PK/PD approach to the kinetic parameters obtained after oral pulsed administration and to the MIC values of avian pathogenic Escherichia coli (APEC) strains isolated from commercial turkey flocks. The kinetic parameters of enrofloxacin were evaluated in 10 healthy and 10 colisepticemic turkeys that received the drug dissolved in medicated water at 89 μg/mL and 71 μg/mL, respectively, for 10h/day for 5 days. Blood samples were collected for 24h from all turkeys on the last day of treatment, and the serum was analysed by HPLC with fluorimetric detection. The mean AUC (7374.53±1067.64 h ng/mL and 7656.95±1460.61 h ng/mL) and C(max) values (673.09±186.18 ng/mL and 543.50±68.75 ng/mL) obtained for healthy and sick turkeys were not significantly different. High-level resistance was observed in 30.3% of strains, 40.5% exhibited intermediate resistance, and only 29.2% were susceptible; the MIC(50) and MIC(90) values were 1mg/L and 32 mg/L, respectively. The PK/PD parameters C(max)/MIC(50) (0.67 and 0.54 for healthy and sick turkeys, respectively) and AUC/MIC(50) (7.37 and 7.66) were lower than the efficacy breakpoints reported for fluoroquinolones. These results indicate that authorised dosage of enrofloxacin used in pulsed medicated water administration could be ineffective against more than the 70% of circulating APEC strains, indicating the need to test the drug susceptibility of APEC prior to administering the drug and adopting a more convenient medication schedule for mass treatment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Maintenance of adequate drug concentration at the site of infection is an important problem in mastitis antibiotic therapy, and the efficacy of intramammary β-lactams can be optimized by maintaining the drug concentration at the site of infection above the minimum inhibitory concentration (MIC) as long as possible. The most important pharmacokinetic and pharmacodynamic parameter for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). In this study, we assessed the pharmacokinetic profile of cefquinome (CFQ) after repeated intramammary administration in healthy cows and cows subclinically infected with Staphylococcus aureus as well as the MIC of Staph. aureus field strains. In addition, the degree of drug passage was investigated from udder to bloodstream by measuring systemic drug absorption in healthy and infected animals. Cefquinome concentrations were quantified by HPLC (UV-visible detection) in milk samples collected from quarters and from blood serum samples. The systemic drug absorption was negligible in healthy and subclinically infected animals (maximum concentration 0.09±0.02 and 0.1±0.01 μg/mL in healthy and subclinically infected animals, respectively). The MIC(90) value for CFQ in Staph. aureus field strains (n=20) was 0.24 μg/mL. The pharmacokinetic and pharmacodynamic evaluation, determined by t>MIC, showed an equal persistence of CFQ in all quarters, indicating an equivalent activity of the drug regardless of the pathological status of the udder. Moreover, with literature data regarding CFQ MIC, the t>MIC has been calculated for other bacterial species., (Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Selection of the antimicrobial agent and maintenance of adequate drug concentrations at the site of infection are the most relevant problems in mastitis antibiotic therapy. Intramammary drug efficacy can be maximized by keeping drug concentrations at the site of infection above the minimum inhibitory concentration (MIC) as long as possible; the most important pharmacokinetic and pharmacodynamic (PK/PD) measure for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). To evaluate this measure, the PK profile of cefoperazone (CFP) after single intramammary administration in healthy and subclinical infected Staphylococcus aureus cows and the MIC of Staph. aureus field strains were assessed. In addition, the degree of drug passage from udder to bloodstream was investigated by measuring systemic drug absorption in healthy and infected animals. Cefoperazone concentrations were quantified by HPLC in quarter milk samples and blood serum samples. Systemic drug absorption was negligible in healthy animals (0.020+/-0.006 microg/mL serum at 4 h), whereas it was higher in infected animals (0.102+/-0.079 microg/mL at 4h and 0.025 microg/mL at 24 h), probably due to the damage of epithelial cell junctions caused by subclinical infections. The MIC90 value for CFP in Staph. aureus field strains (n=24) was 0.64 microg/mL. The PK/PD evaluation, determined by t>MIC, showed a longer persistence of CFP in infected quarters than in healthy ones (mean residence time was 8.37+/-1.51 vs. 11.42+/-5.74 h in September and 2.07+/-0.43 vs. 3.31+/-0.91 h in October), with a t>MIC of 45+/-6 h for infected quarters versus 38+/-5 h for healthy quarters different only in October. This could mean a prolonged time in which microorganisms are exposed to drug activity and thus, a greater efficacy of the drug., (Copyright (c) 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The pharmacokinetics of teicoplanin were evaluated in 10 healthy sheep. After intravenous injection it showed monophasic behaviour, with a short mean (sd) elimination half-life (5 [0.24] hours). After intramuscular injection its bioavailability was 100 per cent but it was absorbed slowly; its elimination half-life was satisfactorily slow (9.23 [0.74] hours). Its efficacy was evaluated in 26 crossbreed sheep with milk positive to strains of Staphylococcus aureus, coagulase-negative staphylococci and Streptococcus agalactiae, and clinical signs of disease. In 19 of them a single intramuscular dose of 6 mg/kg bodyweight resulted in a complete resolution of the clinical signs, and no microorganisms were detected in milk by the fifth day; in the other seven sheep, with more severe intramammary infections, three consecutive daily intramuscular doses of 6 mg/kg bodyweight were necessary. There were no local or systemic side effects and no relapses during 30 days after the treatments in any of the sheep.