Pharmacokinetics of multiple doses of chloramphenicol in fed adult horses.

To the authors' knowledge, there have been no studies evaluating the pharmacokinetics of chloramphenicol administered orally to horses at the currently recommended dose of 50 mg/kg PO q6 h for multiple days. The published antimicrobial susceptibility breakpoint is 8.0 ug/mL; it is unknown if this concentration is achievable at the recommended dose rate in horses. The aim of this prospective multi-dose pharmacokinetic study was to perform pharmacokinetic analysis of chloramphenicol after multiple doses. The authors hypothesize that the antimicrobial susceptibility breakpoint will not be reached. Seven healthy adult horses were administered 50 mg/kg chloramphenicol base tablets PO q6 h for 4 days. Blood was collected via venipuncture daily at 4 and 6 h after administration for the first 15 doses. After the 16th dose, an IV catheter was aseptically placed in the right jugular vein and blood was collected at regular intervals for pharmacokinetic analysis. Maximum chloramphenicol concentration was variable between horses (2.1-42.7 µg/mL). The highest average chloramphenicol concentration was just below the susceptibility breakpoint at 7.7 ug/mL while the lowest was well below the breakpoint at 1.5 ug/mL. On average, the time above 8.0 µg/mL was 75 min, considerably less than the recommended 50% of the dosing interval. When chloramphenicol is administered at a dose of 50 mg/kg PO q6 h in horses, the highest reliably achievable steady state concentration for at least half of the dosing interval is 2.0 µg/mL. The established susceptibility breakpoint of 8.0 ug/mL is not achievable in adult horses, and should be re-evaluated.

Enterococcus infections in foals.

Enterococci have been increasing in prevalence in foal sepsis over the past three decades. There are no published studies in the peer-reviewed literature documenting common sites of infection, antimicrobial susceptibility, or outcome specifically associated with enterococcal infections in foals. Our objectives were to evaluate the sites of origin, antimicrobial susceptibility, and survival outcome to discharge in foals with enterococcal infections compared with foals with sepsis of another bacterial etiology. Seventy-five foals 0-30 days of age with cultures positive for Enterococcus and 170 control foals 0-30 days of age with cultures positive for other bacteria were included. Enterococcus was 2.67 times (95% confidence interval [CI], 1.49-4.80; P = 0.0012) more likely to be isolated from the lower urogenital tract of foals than were other bacteria. Enterococci were less likely to be isolated from blood cultures than other bacteria, with an odds ratio (OR) of 0.17 (95% CI 0.09-0.35; P < 0.0001). For Enterococcus isolates, 48% (n = 29/61) had a multiple antimicrobial resistance (MAR) index of ≥30% and 46% (n = 28/61) had a multiple drug resistance (MDR) index of ≥30%. Foals with enterococcal infections were less likely to survive to discharge (49.9% vs. 63.5%; P = 0.03). Enterococcus is commonly isolated from the lower urogenital tract of foals, is often multidrug resistant, and foals with enterococcal infections were less likely to survive. Multidrug resistance is common among enterococcal isolates, and therefore antimicrobial susceptibility testing of cultured isolates is warranted.

Temporal trends in in vitro antimicrobial susceptibility patterns of bacteria isolated from foals with sepsis: 1979-2010.

REASONS FOR PERFORMING THE STUDY: Monitoring the development of antimicrobial resistance is important for the rational selection of appropriate antimicrobial drugs to initiate treatment of foals with sepsis. OBJECTIVES: To identify temporal trends in antimicrobial susceptibility patterns of bacteria isolated from foals with sepsis. STUDY DESIGN: Retrospective review of medical records. METHODS: Foals aged <30 days with a diagnosis of sepsis, confirmed by culture of bacteria, were included. Susceptibility data, expressed as minimum inhibitory concentrations (MICs) (MIC50 , MIC90 , MIC range) and percent of isolates that were susceptible to a particular antimicrobial drug, were compared for bacteria isolated from foals during 3 different time periods: 1979-1990, 1991-1997 and 1998-2010. The Cochran-Armitage trend test and the Jonckheere-Terpstra test were used for statistical analysis. RESULTS: A total of 1091 bacterial isolates were cultured from 588 foals. Enterobacteriaceae, Actinobacillus spp. and ß-haemolytic Streptococcus spp. showed a decrease in percent of isolates susceptible to gentamicin over time. Enterobacteriaceae, Actinobacillus spp. and ß-haemolytic Streptococcus spp. showed an increase in MIC values for amikacin. Enterobacteriaceae showed a decrease in percent of isolates susceptible to ceftiofur. Enterococcus spp. and Pseudomonas spp. showed increased MIC values to ceftiofur. Enterobacteriaceae showed increased MIC values to ceftizoxime. Enterococcus spp. became more resistant to imipenem and showed increased MIC values to ticarcillin/clavulanic acid. In contrast, several trends in increased susceptibility were also seen. CONCLUSIONS: Based on these in vitro results, the combination of amikacin and ampicillin remains an appropriate choice for initiating treatment of sepsis in foals while awaiting culture and susceptibility test results, although increasing development of resistance to amikacin was demonstrated. The decrease in in vitro activity of ceftiofur against Enterobacteriaceae is of concern. Similarly, the development of resistance of Enterococcus spp. to imipenem is an important finding that warrants monitoring in the future. Judicious use of antimicrobials is therefore crucial.

Temporal trends in prevalence of bacteria isolated from foals with sepsis: 1979-2010.

REASONS FOR PERFORMING STUDY: Sepsis is an important cause of death in foals. Knowledge of which pathogens are likely to be involved is important for selection of antimicrobial drugs for initial treatment. OBJECTIVES: To identify temporal trends in prevalence of bacteria isolated from foals with sepsis between 1979 and 2010. STUDY DESIGN: Retrospective review of medical records. METHODS: All foals ≤30 days of age presented to the Veterinary Medical Teaching Hospital (VMTH) at the University of California, Davis between 1979 and 2010, with a diagnosis of sepsis confirmed by culture of bacteria from blood or internal organs (antemortem or at necropsy), were included in the study. Conventional microbiological methods were used to identify isolated organisms. The Cochran-Armitage trend test was used for statistical analysis. RESULTS: The percentage of Gram-positive isolates increased significantly over the years. The percentage Enterobacteriacea, and Klebsiella spp. in particular, decreased over time. Enterococcus spp. isolates were cultured more often in recent years. CONCLUSIONS: Whereas Gram-negative bacteria, particularly Enterobacteriaceae, remain the most common isolates from neonatal foals with sepsis, the prevalence of Gram-positive bacteria is increasing. This trend underlines the importance of including antimicrobial drugs active against both Gram-positive and Gram-negative bacteria in treatment protocols while awaiting the results of bacteriological culture and susceptibility tests. The increased prevalence of Enterococcus spp. is of concern because antimicrobial susceptibility patterns for enterococci are unpredictable and enterococci can also act as donors of antimicrobial resistance genes to other bacteria.