Population pharmacokinetic meta-analysis of five beta-lactams antibiotics to support dosing regimens in dogs for surgical antimicrobial prophylaxis.

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 95th 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 to 4h). Cefazolin (22-25mg/kg), cefuroxime (20mg/kg), cefalexin (15mg/kg) and amoxicillin (16.7mg/kg) reached peak peripheral concentrations within 30min, but ampicillin (20mg/kg) required 82min, respectively. For methicillin-susceptible staphylococci, cefazolin and cefuroxime require re-administration every 2h, whereas cefalexin and both amoxicillin and ampicillin can be readministered every 3 and 4h, 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 1.5h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing.

Antimicrobial prophylaxis in companion animal surgery: A scoping review for European Network for Optimization of Antimicrobial Therapy (ENOVAT) guidelines.

Surgical antimicrobial prophylaxis (SAP) is widely used to reduce the risk of surgical site infections (SSI), but there is uncertainty as to what the proportion of SSI reduction is. Therefore, it is difficult for surgeons to properly weigh the costs, risks and benefits for individual patients when deciding on the use of SAP, making it challenging to promote antimicrobial stewardship in primary practice settings. The objective of this study was to map the veterinary evidence focused on assessing the effect of SAP on SSI development and in order to identify surgical procedures with some research evidence and possible knowledge gaps. In October 2021 and December 2022, Scopus, CAB Abstracts, Web of Science Core Collection, Embase and MEDLINE were systematically searched. Double blinded screening of records was performed to identify studies in companion animals that reported on the use of SAP and SSI rates. Comparative data were available from 34 out of 39123 records screened including: eight randomised controlled trials (RCT), 23 cohort studies (seven prospective and 16 retrospective) and three retrospective case series representing 12476 dogs and cats in total. Extracted data described peri- or post-operative SAP in nine, and 25 studies, respectively. In the eight RCTs evaluating SAP in companion animals, surgical procedure coverage was skewed towards orthopaedic stifle surgeries in referral settings and there was large variation in SAP protocols, SSI definitions and follow-up periods. More standardized data collection and agreement of SSI definitions is needed to build stronger evidence for optimized patient care.

Quality of amoxicillin/clavulanic acid oral formulations for intended veterinary use in the UK, Malaysia, Serbia and Thailand.

OBJECTIVES: Amoxicillin/clavulanate is the most commonly used oral antimicrobial drug in companion animals. The objective of the study was to detect types and frequency of deficits in the quality of veterinary oral formulations of amoxicillin/clavulanate in various countries. MATERIALS AND METHODS: In a prospective study with purposive sampling, amoxicillin/clavulanate tablet formulations for canine use were collected in four countries (wholesalers or veterinary practice) and shipped to a central bioanalytical laboratory. Twenty-four samples were collected from the UK (nine), Malaysia (nine), Serbia (four) and Thailand (two), yielding 18 different formulations (10 veterinary). Packaging inspection, tablet disintegration and content assay were conducted (validated high-performance liquid chromatography with ultra-violet detection); content was acceptable when within the 90% to 120% pre-specified range (US Pharmacopeia). RESULTS: Secondary packaging was present for 13 of 24 samples and primary packaging integrity was verified for all but one sample. Amoxicillin trihydrate/potassium clavulanate label ratio was 4:1, except for three formulations (2:1). Tablet dose strength ranged from 250 to 625 mg. All formulations contained both analytes. For amoxicillin, two of 24 samples were out of specification with 72.8% (Malaysia) and 82.3% (Thailand) of labelled content. For clavulanate, four of 24 samples were out of specification with 46.9% (Serbia), 79.0% (UK), 84.3% (Serbia) and 86.5% (Thailand) of labelled content. One formulation (Thailand) failed for both analytes. CLINICAL SIGNIFICANCE: Antimicrobial formulations of substandard quality have negative consequences for efficacy in patients and potentially promote antimicrobial resistance. There was evidence of substandard formulations in all countries, not only for amoxicillin but especially for clavulanate; this could compromise equitable access to acceptable quality essential veterinary medicines worldwide.

A Protocol for Prolonged Surgical Anaesthesia with Recovery in Fire Salamanders Using Tricaine Mesylate (MS-222): A Case Series.

The objective of this study was to describe prolonged surgical anaesthesia and recovery in fire salamanders (Salamandra salamandra) using tricaine methanesulfonate (MS-222). A total of 14 salamanders were anaesthetised for electromyography wire implantation. Sodium bicarbonate buffered solutions (0.5-4 g l-1) of MS-222 were prepared (adjusted to pH 7.0). Anaesthesia was induced by partial immersion in pre-oxygenated 3 g l-1 solution for 20 min. Buprenorphine (0.5 mg kg-1) was administered subcutaneously. During microsurgery, heart rate (HR), solution pH and temperature were recorded. Reflectance pulse oximeter (SpO2) (Masimo Rad-57) was recorded in two salamanders. Anaesthetic plane and MS-222 pH stability (pH 7.6) were maintained by renewing administration of oxygenated MS-222 solution (0.5-3 g l-1) onto swabs that partially covered the body. Recovery started at the end of surgery (MS-222 0 g l-1). Postoperatively, salamanders were given oral meloxicam (0.2 mg kg-1). Mean time for loss of righting reflex during induction was 13.7 ± 2.2 min. Duration of anaesthesia and time to recovery were 111 ± 24.2 and 31 ± 10.3 min, respectively. Due to complications, two salamanders did not recover. Baseline HR was 67.4 ± 34.5 beats/min, and it decreased significantly until recovery (p ≤ 0.0001). In two salamanders, baseline SpO2 was 85.5% ± 14.5, SpO2 during surgery was 61% ± 6.4, improving to 80.5% ± 2.1 on recovery.In conclusion, prolonged recovery anaesthesia is achievable with MS-222 dilutions in salamander. Reflectance SpO2 could prove valuable during immersion anaesthesia.

The use of ondansetron for the treatment of nausea in dogs with vestibular syndrome.

BACKGROUND: Vestibular syndrome is often accompanied by nausea. Drugs currently approved for its treatment have been developed to stop vomiting but not nausea. The efficacy of 5-HT3 receptor antagonists to reduce nausea has been described for chemotherapy, but not for nausea secondary to vestibular disorders. METHODS: Sixteen dogs with vestibular syndrome-associated nausea were included in the open-label, multicentre study. The intensity of nausea-like behaviour was analysed before ondansetron administration (0.5 mg/kg i.v.) and 2 h afterwards, using a validated 5-point-scale. The occurrence and frequency of salivation, lip licking, restlessness, vocalisation, lethargy, and vomiting were assessed. RESULTS: All dogs initially showed signs of nausea, whereas only 31% showed vomitus. The intensity of nausea was significantly reduced in all dogs (p ≤ 0.0001) 2 h after ondansetron administration, including the clinical signs of nausea analysed in 11 dogs (salivation [p = 0.0078], lip licking [p = 0.0078], restlessness [p = 0.0039], and lethargy [p = 0.0078]) except for vocalisation (p > 0.9999). CONCLUSIONS: The results provide preliminary evidence of the potential benefit of ondansetron in the treatment of nausea, which was present in all examined dogs. Vomiting was only observed in 5 dogs indicating that nausea can occur separately and should not be perceived only as a preceding stimulation of the vomiting centre.

Patterns of Limb and Epaxial Muscle Activity During Walking in the Fire Salamander, Salamandra salamandra.

Salamanders and newts (urodeles) are often used as a model system to elucidate the evolution of tetrapod locomotion. Studies range from detailed descriptions of musculoskeletal anatomy and segment kinematics, to bone loading mechanics and inferring central pattern generators. A further area of interest has been in vivo muscle activity patterns, measured through electromyography (EMG). However, most prior EMG work has primarily focused on muscles of the forelimb or hindlimb in specific species or the axial system in others. Here we present data on forelimb, hindlimb, and epaxial muscle activity patterns in one species, Salamandra salamandra, during steady state walking. The data are calibrated to limb stride cycle events (stance phase, swing phase), allowing direct comparisons to homologous muscle activation patterns recorded for other walking tetrapods (e.g., lizards, alligators, turtles, mammals). Results demonstrate that Salamandra has similar walking kinematics and muscle activity patterns to other urodele species, but that interspecies variation does exist. In the forelimb, both the m. dorsalis scapulae and m. latissimus dorsi are active for 80% of the forelimb swing phase, while the m. anconaeus humeralis lateralis is active at the swing-stance phase transition and continues through 86% of the stance phase. In the hindlimb, both the m. puboischiofemoralis internus and m. extensor iliotibialis anterior are active for 30% of the hindlimb swing phase, while the m. caudofemoralis is active 65% through the swing phase and remains active for most of the stance phase. With respect to the axial system, both the anterior and posterior m. dorsalis trunci display two activation bursts, a pattern consistent with stabilization and rotation of the pectoral and pelvic girdles. In support of previous assertions, comparison of Salamandra muscle activity timings to other walking tetrapods revealed broad-scale similarities, potentially indicating conservation of some aspects of neuromuscular function across tetrapods. Our data provide the foundation for building and testing dynamic simulations of fire salamander locomotor biomechanics to better understand musculoskeletal function. They could also be applied to future musculoskeletal simulations of extinct species to explore the evolution of tetrapod locomotion across deep-time.

Padrones de actividad muscular epaxial y apendicular durante la cursorialidad de la salamandra-de-fuego, Salamandra salamandra Las salamandras y los tritones (urodelos) son utilizados con frecuencia como un sistema modelo para dilucidar la evolución de la locomoción en los tetrápodos. Los estudios previos varían de descripciones detalladas de la anatomía musculoesquelética y cinemática de los segmentos del cuerpo, a la mecánica de la capacidad de soporte de carga estructural ósea y la generación de padrones centrales. Otra área de interés ha sido los padrones de actividad muscular in vivo, medidos por electromiografía (EMG). Sin embargo, la mayoría de los trabajos anteriores con EMG se han centrado principalmente en los músculos de los miembros anteriores o posteriores en especies específicas o en el sistema axial de otras. En este trabajo, presentamos datos sobre los padrones de actividad muscular en los músculos de los miembros anteriores, posteriores y de la musculatura epaxial en una especie, Salamandra salamandra, durante la marcha continua. Los datos se calibran para los períodos del ciclo de caminar de los miembros (fase de soporte, fase de movimiento), lo que permite comparaciones directas con padrones de activación muscular homólogos registrados para otros tetrápodos cursoriales (por ejemplo, lagartos, caimanes, tortugas y mamíferos). Los resultados demuestran que Salamandra tiene padrones de cinemática cursorial y actividad muscular similares a otras especies de urodelos, pero con variación interespecífica. En los miembros anteriores, ambos los m. dorsalis scapulae y m. latissimus dorsi están activos en 80% de la fase de movimiento del miembro anterior, mientras que el m. anconaeus humeralis lateralis se activa en la transición de la fase de movimiento-soporte y permanece activo en 86% de la fase de soporte. En los miembros posteriores, ambos m. puboischiofemoralis internus y m. extensor iliotibialis anterior están activos en 30% de la fase de movimiento de los miembros posteriores, mientras que el m. caudofemoralis está activo durante el 65% de la fase de movimiento, permaneciendo activo durante la mayor parte de la fase de soporte. Con respecto al sistema axial, las porciones anterior y posterior del m. dorsalis trunci exhibe dos períodos de activación, un padrón consistente con la estabilización y rotación de la cintura pélvica y pectoral. Como sugirido anteriormente, la comparación de los tiempos de actividad muscular de Salamandra con otros tetrápodos cursoriales reveló similitudes en gran escala, lo que podría indicar la conservación de algunos aspectos de la función neuromuscular entre los tetrápodos. Nuestros datos proporcionan una base para la construcción y prueba de simulaciones dinámicas de la biomecánica locomotora de salamandras-de-fuego para comprender mejor las funciones musculoesqueléticas. Nuestros resultados también se pueden aplicar a futuras simulaciones musculoesqueléticas de especies extintas para explorar la evolución de la locomoción de tetrápodos en el tiempo profundo.

Padrões de atividade muscular epaxial e apendicular durante a cursorialidade da salamandra-de-fogo, Salamandra salamandra Salamandras e tritões (urodelos) são freqüentemente utilizados como um sistema modelo para elucidar a evolução da locomoção em tetrápodes. Estudos anteriores variam de descrições detalhadas da anatomia musculoesquelética e cinemática dos segmentos corporais, a mecânica da capacidade de carga estrutural óssea e geradora de padrões centrais. Uma outra área de interesse tem sido os padrões de atividade muscular in vivo, medidos por eletromiografia (EMG). No entanto, a maioria dos trabalhos anteriores de EMG concentrou-se principalmente nos músculos dos membros anteriores ou posteriores em espécies específicas ou no sistema axial de outras. Nesse trabalho, apresentamos dados sobre os padrões de atividade muscular nos membros anteriores, posteriores e musculatura epaxial em uma espécie, Salamandra salamandra, durante caminhada em modo contínuo. Os dados são calibrados para os períodos do ciclo de caminhada dos membros (fase de apoio, fase de movimento), permitindo comparações diretas com padrões de ativação muscular homólogos registrados para outros tetrápodes cursoriais (por exemplo, lagartos, jacarés, tartarugas e mamíferos). Os resultados demonstram que Salamandra possui padrões de cinemática cursorial e atividade muscular semelhantes à outras espécies de urodelos, mas com variação interespecífica. Nos membros anteriores, ambos os m. dorsalis scapulae e m. latissimus dorsi estão ativos em 80% da fase de movimento do membro anterior, enquanto o m. anconaeus humeralis lateralis é ativado na transição da fase de movimento-apoio e continua ativo em 86% da fase de apoio. Nos membros posteriores, ambos m. puboischiofemoralis internus e m. extensor iliotibialis anterior estão ativos em 30% da fase de movimento dos membros posteriores, enquanto o m. caudofemoralis está ativo por 65% da fase de movimento, permanecendo ativo na maior parte da fase de apoio. No que diz respeito ao sistema axial, as porções anterior e posterior do m. dorsalis trunci exibe dois períodos de ativação, um padrão consistente com a estabilização e rotação da cintura peitoral e pélvica. Como préviamente sugerido, a comparação dos tempos de atividade muscular de Salamandra com outros tetrápodes cursoriais revelou similaridades em larga escala, potencialmente indicando a conservação de alguns aspectos da função neuromuscular entre tetrápodes. Os nossos dados fornecem uma base para a construção e testagem de simulações dinâmicas da biomecânica locomotora de salamandras-de-fogo para se entender melhor as funções músculo-esqueléticas. Nossos resultados também podem ser aplicados a futuras simulações músculo-esqueléticas de espécies extintas para explorar a evolução da locomoção de tetrápodes no tempo profundo.

Pregabalin for the treatment of syringomyelia-associated neuropathic pain in dogs: A randomised, placebo-controlled, double-masked clinical trial.

Pregabalin is the first-line treatment for neuropathic pain (NeP) in humans. Dogs with Chiari-like malformation and syringomyelia (CM/SM) associated with NeP could benefit from pregabalin. The aim of this study was to evaluate the efficacy of pregabalin for NeP in dogs with CM/SM. Eight dogs with symptomatic CM/SM were included in a double-masked, randomised, crossover placebo-controlled clinical trial. All dogs received anti-inflammatory drugs as base-line treatment during placebo or pregabalin phase of 14±4 days each. Analgesic efficacy was assessed with a daily numerical rating scale (NRS) recorded by dog owners (0-10, 10=worst pain) and quantitative sensory testing at baseline, placebo and pregabalin phases. Blood samples were collected to report pregabalin exposure and to assess renal function. Daily NRS scores recorded by dog owners in the pregabalin group were lower than in the placebo group (P=0.006). Mechanical thresholds were higher with pregabalin compared to baseline or placebo (P=0.037, P<0.001). Cold latency at 15°C was prolonged on the neck and humeri with pregabalin compared to baseline (P<0.001 for both) or placebo (P=0.02, P=0.0001). Cold latency at 0°C was longer on pregabalin compared to baseline and placebo (P=0.001, P=0.004). There was no pregabalin accumulation between first and last dose. This study demonstrates the efficacy of pregabalin for the treatment of NeP due to CM/SM on daily pain scores recorded by dog owners. Pregabalin significantly reduced mechanical hyperalgesia, cold hyperalgesia (0°C) and allodynia (15°C) compared to placebo. Pregabalin was non-cumulative and well tolerated with occasional mild sedation.

Sedative and antinociceptive effects of different detomidine constant rate infusions, with or without methadone in standing horses.

BACKGROUND: Standing surgery avoids the risks of general anaesthesia in horses. OBJECTIVES: To assess sedation, antinociception and gastrointestinal motility in standing horses after a detomidine loading dose and 2-h constant rate intravenous (i.v.) infusion, with or without methadone. STUDY DESIGN: Blinded, randomised, crossover with seven healthy adult cross-bred horses, three geldings and four females (404 ± 22 kg). METHODS: Five i.v. treatments were administered to all horses with 1-week washout period: saline (SAL), detomidine low (2.5 µg/kg bwt + 6.25 µg/kg bwt/h) (DL) and high doses (5 µg/kg bwt + 12.5 µg/kg bwt/h) (DH) alone or combined with methadone (0.2 mg/kg bwt + 0.05 mg/kg bwt/h), (DLM) and (DHM), respectively. Height of head above the ground (HHAG), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility were evaluated at predetermined times between 5 and 240 min. A mixed effect model and Kruskal-Wallis test were used to analyse normally and non-normally distributed data, respectively. RESULTS: Sedation (<50% basal HHAG) was achieved for the duration of the infusion, and for an additional 15 min in DH and DHM groups. Nociceptive thresholds were higher than baseline, to the greatest degree and the longest duration, with DHM (ET and TT for 135 min and MT for 150 min). After DH, TT was significantly higher than baseline from 30 to 120 min and MT from 15 to 135 min. After DLM, ET was increased at 90 min, TT at 30 min and MT for 120 min. Gastrointestinal motility was reduced for up to 135 min after DL, 150 min after DLM and 210 min after DH and DHM. MAIN LIMITATIONS: Nociceptive thresholds are not equivalent to surgical stimuli. CONCLUSION: Methadone with the highest detomidine dose (DHM) may provide sufficient sedation and analgesia for standing surgical procedures and warrants further investigation.

Characterisation of the in vivo interactions between detomidine and methadone in horses: Pharmacokinetic and pharmacodynamic modelling.

BACKGROUND: Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. OBJECTIVES: To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. STUDY DESIGN: Randomised, placebo-controlled, blinded, crossover. METHODS: Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 µg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] µg/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) [1]. RESULTS: Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (α = -1.33), VAS (α = -0.98) and GIM (α = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (α = 0.78). MAIN LIMITATIONS: This is a small experimental study. CONCLUSIONS: Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations.

Pharmacokinetic-pharmacodynamic integration and modelling of oxytetracycline for the calf pathogens Mannheimia haemolytica and Pasteurella multocida.

A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-∞ )/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC0-∞ /MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24 hr /MIC ratios for 3log10 decrease in bacterial count of 27.5 hr (M. haemolytica) and 60.9 hr (P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197 mg/kg (M. haemolytica) and 314 mg/kg (P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively.

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed-effects to characterize and quantify variability in drug pharmacokinetics.

A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between-patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food-producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population-associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.

Comparison of veterinary drugs and veterinary homeopathy: part 1.

For many years after its invention around 1796, homeopathy was widely used in people and later in animals. Over the intervening period (1796-2016) pharmacology emerged as a science from Materia Medica (medicinal materials) to become the mainstay of veterinary therapeutics. There remains today a much smaller, but significant, use of homeopathy by veterinary surgeons. Homeopathic products are sometimes administered when conventional drug therapies have not succeeded, but are also used as alternatives to scientifically based therapies and licensed products. The principles underlying the veterinary use of drug-based and homeopathic products are polar opposites; this provides the basis for comparison between them. This two-part review compares and contrasts the two treatment forms in respect of history, constituents, methods of preparation, known or postulated mechanisms underlying responses, the legal basis for use and scientific credibility in the 21st century. Part 1 begins with a consideration of why therapeutic products actually work or appear to do so.

Comparison of veterinary drugs and veterinary homeopathy: part 2.

Part 2 of this narrative review outlines the theoretical and practical bases for assessing the efficacy and effectiveness of conventional medicines and homeopathic products. Known and postulated mechanisms of action are critically reviewed. The evidence for clinical efficacy of products in both categories, in the form of practitioner experience, meta-analysis and systematic reviews of clinical trial results, is discussed. The review also addresses problems and pitfalls in assessing data, and the ethical and negative aspects of pharmacology and homeopathy in veterinary medicine.

Pharmacokinetic/pharmacodynamic integration and modelling of oxytetracycline for the porcine pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida.

Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules of oxytetracycline for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in broth and porcine serum. PK/PD integration established ratios of average concentration over 48 h (Cav0-48 h )/MIC of 5.87 and 0.27 µg/mL (P. multocida) and 0.70 and 0.85 µg/mL (A. pleuropneumoniae) for broth and serum MICs, respectively. PK/PD modelling of in vitro time-kill curves established broth and serum breakpoint values for area under curve (AUC0-24 h )/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4 log10 reductions in bacterial count. Doses were then predicted for each pathogen, based on Monte Carlo simulations, for: (i) bacteriostatic and bactericidal levels of kill; (ii) 50% and 90% target attainment rates (TAR); and (iii) single dosing and daily dosing at steady-state. For 90% TAR, predicted daily doses at steady-state for bactericidal actions were 1123 mg/kg (P. multocida) and 43 mg/kg (A. pleuropneumoniae) based on serum MICs. Lower TARs were predicted from broth MIC data; corresponding dose estimates were 95 mg/kg (P. multocida) and 34 mg/kg (A. pleuropneumoniae).

Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf.

The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller-Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC(0-24 h) /MIC) to achieve a bactericidal effect was estimated from in vitro time-kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single-dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts.

A large potentiation effect of serum on the in vitro potency of tulathromycin against Mannheimia haemolytica and Pasteurella multocida.

The antimicrobial properties of tulathromycin were investigated for M. haemolytica and P. multocida. Three in vitro indices of antimicrobial activity, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time-kill curves, were established for six isolates of each organism. Each index was measured in two growth media: Mueller-Hinton broth (MHB) and calf serum. It was shown that MICs and MBCs were markedly lower in serum than in MHB. MHB:serum ratios for MIC were 47:1 (M. haemolytica) and 53:1 (P. multocida). For both serum and MHB, adjustment of pH led to greater potency at alkaline compared to acid pH. Tulathromycin MIC was influenced by size of inoculum count, being 4.0- to 7.7-fold greater for high compared to low initial counts. It was concluded that for the purpose of determining dosages for therapeutic use, pharmacodynamic data for tulathromycin should be derived in biological fluids such as serum. It is hypothesized that in vitro measurement of MIC in broth, conducted according to internationally recommended standards, may be misleading as a basis for estimating the in vivo potency of tulathromycin.

Comparison of standardised versus non-standardised methods for testing the in vitro potency of oxytetracycline against Mannheimia haemolytica and Pasteurella multocida.

The in vitro pharmacodynamics of oxytetracycline was established for six isolates of each of the calf pneumonia pathogens Mannheimia haemolytica and Pasteurella multocida. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and bacterial time-kill curves were determined in two matrices, Mueller Hinton broth (MHB) and calf serum. Geometric mean MIC ratios, serum:MHB, were 25.2:1 (M. haemolytica) and 27.4:1 (P. multocida). The degree of binding of oxytetracycline to serum protein was 52.4%. Differences between serum and broth MICs could not be accounted for by oxytetracycline binding to serum protein. In vitro time-kill data suggested a co-dependent killing action of oxytetracycline. The in vitro data indicate inhibition of the killing action of oxytetracycline by serum factor(s). The nature of the inhibition requires further study. The outcome of treatment with oxytetracycline of respiratory tract infections in calves caused by M. haemolytica and P. multocida may not be related solely to a direct killing action.