Augusto Matías Lorenzutti

Metoclopramide is used for prevention or treatment of emesis and gastroesophageal reflux in dogs. Historically, it has been administered three to four times a day. However, reports of adverse reactions associated with intravenous boluses raise concerns. A more modern trend is to administer the total daily dose as a constant rate infusion of 1 to 2 mg/kg/day. A loading dose prior to the infusion is often omitted, which can delay the onset of action. Adequate loading doses for these constant rate infusions are not known. We have reanalysed pharmacokinetic data from dogs receiving metoclopramide and modelled its behaviour when administered as a constant rate infusion, with and without loading doses. We have quantified the delay expected if loading doses are not administered and calculated appropriate loading doses designed to reach the target concentration while omitting unnecessarily high plasma levels. If a loading dose is omitted, a delay of 3.25 hours for reaching a steady state can be expected. Loading doses of 0.05 and 0.1 mg/kg are recommended for infusions of 1 and 2 mg/kg/day, respectively, in order to reach targeted plasma levels almost immediately.

Background/Objectives: The expansion of intensive swine production in Córdoba, Argentina, underscores the need to assess the risks associated with antimicrobial (AM) use, whose extensive application has driven antimicrobial resistance, a major global threat within the One Health framework. This study aimed to characterize AM use practices and evaluate the epidemiological resistance profiles (non-wild-type phenotypes, NWT) of commensal Escherichia coli of fecal origin from swine farms, using epidemiological cut-off values (ECOFFs) as a surveillance criterion. Methods: An observational cross-sectional study was conducted in 19 farrow-to-finish farms in Córdoba during 2023. Information on AM use (prophylaxis, metaphylaxis, treatment) across production categories was collected. A total of 437 E. coli isolates were obtained from fecal samples, and minimum inhibitory concentrations (MICs) were determined for 10 AMs of critical importance for human and animal health. NWT phenotypes were classified according to EUCAST ECOFFs, and multidrug resistance (MDR) was assessed. Results: AM use was frequent and predominantly prophylactic (89.5% of farms), mainly through mass medication (66.3%), with macrolides and amoxicillin being the most commonly administered AMs. NWT proportions were extremely high (90–92%) for ampicillin, tetracyclines, and chloramphenicol and substantial for ciprofloxacin (50.6%), sulfamethoxazole (68.2%), and trimethoprim (44.9%). Extended-spectrum β-lactamase (ESBL)-producing phenotypes were detected. Alarmingly, 92% of isolates were classified as MDR E. coli, with homogeneous distribution across production categories. Conclusions: Findings reveal intensive and largely empirical AM use that has consolidated a stable intestinal resistome in the swine population. High MDR levels, even in categories with limited direct AM exposure or involving banned compounds, suggest that co-selection and horizontal gene transfer are key drivers of resistance. This scenario highlights the urgent need to strengthen integrated surveillance and promote prudent AM use strategies under the One Health approach to preserve therapeutic efficacy.

La diarrea posdestete (DPD) es un importante problema sanitario y económico en la producción porcina, donde Escherichia coli enterotoxigénica (ETEC) constituye uno de los principales agentes causales, provocando diarrea y retraso en el crecimiento, lo que conlleva un mayor uso de antimicrobianos y, en consecuencia, un incremento del riesgo de resistencia bacteriana. El objetivo de este estudio fue aislar cepas de E. coli a partir de muestras fecales de lechones con DPD en granjas de la provincia de Córdoba, Argentina, describir su perfil de resistencia a antimicrobianos de importancia crítica en salud pública y/o animal, y realizar su caracterización genotípica. Se recolectaron 69 muestras de hisopado rectal en seis establecimientos, con una tasa de aislamiento de E. coli del 97%. Se observó un perfil de resistencia preocupante, con altos niveles frente a betalactámicos (98,5%), fenicoles (88%), tetraciclinas (86,6%) y aminoglucósidos (34,3%). Además, 62 cepas (92,5%) fueron clasificadas como multirresistentes. De los 67 aislamientos obtenidos, el 70% correspondió a cepas ETEC, con alta prevalencia de los genes estII (74,5%) y estI (63,8%), asociados a la producción de toxinas. También se detectaron genes de adhesión como fedA (21,3%), faeG (14,9%), aidA (25,5%) y astA (14,9%). Estos resultados evidencian la fuerte presión de selección ejercida sobre las poblaciones bacterianas en los sistemas productivos, favoreciendo la persistencia y diseminación de cepas multirresistentes, y subrayan la necesidad de implementar medidas de control más estrictas para reducir su propagación en la producción porcina, con implicancias directas para la salud pública y bajo el enfoque de Una Salud.

The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin, as well as the placental transfer of enrofloxacin and ciprofloxacin, have not been studied. The aims of this study were (1) to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin by intravenous and intramuscular administration of 7.5 mg/kg in pregnant goats; (2) to determine the placental transfer of enrofloxacin and ciprofloxacin; (3) to conduct a PK/PD analysis to calculate the PK/PD cutoff of different dose regimens; and (4) to evaluate the tentative epidemiological cutoff values for coagulase-negative staphylococci wild-type isolates from goats. Plasmatic concentrations of enrofloxacin and ciprofloxacin in pregnant goats were well described by the parent–metabolite model. Simultaneous modeling of enrofloxacin and ciprofloxacin in each individual allowed for a PK/PD analysis that considered both drugs with antimicrobial activity. Our results show that both enrofloxacin and ciprofloxacin crossed the placenta in goats: fetal/maternal concentration ratio were 0.58 ± 0.05 and 0.03 ± 0.01 for enrofloxacin and ciprofloxacin. MIC values of coagulase-negative staphylococci isolates (n = 90) were obtained, and tentative epidemiological cutoffs were calculated at 0.25 and 0.5 mg/L for enrofloxacin and ciprofloxacin. According to PK/PDco values, an intravenous dose regimen of 10 mg/kg/day was considered the most appropriate, but based on the PK/PDco, culture, and AST data, an effective dosing regimen with the lowest possible dose could be selected to minimize the potential risk of fetal exposure to enrofloxacin.

Coagulase-negative staphylococci are main pathogens that produce goat mastitis. Marbofloxacin is a third-generation fluoroquinolone approved for treat mastitis in animals. The objectives of this study were: (i) to determine the pharmacokinetics of marbofloxacin (10 mg/kg/24 h) in serum and milk administered intramuscularly for five days in goats with mastitis induced by coagulase-negative staphylococci; (ii) to characterize the concentration–effect relationship of marbofloxacin against coagulase-negative staphylococci in Mueller Hinton broth and goat milk; (iii) to determine AUC/MIC cutoff values of marbofloxacin, and (iv) to perform a PK/PD analysis to evaluate the efficacy of the dose regimen for the treatment of goat mastitis produced by coagulase-negative staphylococci. Marbofloxacin presented context-sensitive pharmacokinetics, influenced by the evolution of the disease, which decreased marbofloxacin disposition in serum and milk. Marbofloxacin showed a median (95% CI) fAUC/MIC values for MIC of 0.4 and 0.8 µg/mL of 26.66 (22.26–36.64) and 32.28 (26.57–48.35) related with −2 log₁₀CFU/mL reduction; and 32.26 (24.81–81.50) and 41.39 (29.38–128.01) for −3 log₁₀CFU/mL reduction in Mueller Hinton broth. For milk, −2 log₁₀CFU/mL reduction was achieved with 41.48 (35.29–58.73) and 51.91 (39.09–131.63), and −3 log₁₀CFU/mL reduction with 51.04 (41.6–82.1) and 65.65 (46.68–210.16). The proposed dose regimen was adequate for the treatment of goat mastitis produced by coagulase-negative staphylococci, resulting in microbiological and clinical cure of all animals. The animal model used in this study provided important pharmacokinetic information about the effect of the infection on the pharmacokinetics of marbofloxacin. Pharmacodynamic modeling showed that fAUC/MIC cutoff values were higher in goat milk compared with Mueller Hinton broth.

Staphylococcus aureus (S. aureus) is an important pathogen that causes clinical mastitis in goats and produces infections difficult to cure. Different antimicrobials as fluoroquinolones have been used against S. aureus. However, the studies developed to evaluate the bacterial drug interaction only have used the MIC as a single reference point with artificial growth media. The aims of this study were to describe the effect of marbofloxacin on S. aureus isolated from mastitis goats’ milk by different approaches as the minimum inhibitory and bactericidal concentrations (MIC and MBC) in cation adjusted Mueller–Hinton broth (CAMHB), serum and milk of goats at two inoculum sizes of 10⁵ and 10⁸ CFU/mL, the determination and analysis of the time kill curves (TKC) by non-linear mixed effect models in each growth medium and inoculum size, as well as the estimation of their pharmacokinetics/pharmacodynamics (PK/PD) cutoff values. The results obtained indicate that MIC values were higher and increases 2,4-fold in serum and 3,6-fold in milk at high inoculum, as well as the EC₅₀ values determined by each pharmacodynamics model. Finally, the PK/PD cutoff values defined as fAUC₂₄/MIC ratios to achieve clinical efficacy were highly dependent on inoculum and growth medium, with median values of 60–180, especially at high inoculum in milk, suggesting that further studies are necessary to evaluate and optimize the best therapeutic strategies for treating S. aureus in lactating goats.