Comparison of two indirect techniques for local delivery of a high dose of an antimicrobial in the distal portion of forelimbs of horses

OBJECTIVE: To compare isolated limb retrograde venous injection (ILRVI) and isolated limb infusion (ILI) for delivery of amikacin to the synovial fluid of the distal interphalangeal and metacarpophalangeal joints and to evaluate the efficacy of use of an Esmarch tourniquet in standing horses. ANIMALS: 6 healthy adult horses. PROCEDURES: Horses were randomly assigned in a crossover design. In ILRVI, the injection consisted of 1 g of amikacin diluted to a total volume of 60 mL administered during a 3-minute period. In ILI, the infusion consisted of 1 g of amikacin diluted to 40 mL administered during a 3-minute period followed by administration of boluses of diluent (82 mL total) to maintain vascular pressure. During ILI, the infusate and blood were circulated from the venous to the arterial circulation in 5-mL aliquots. Synovial fluid and serum samples were obtained to determine maximum amikacin concentrations and tourniquet leakage, respectively. RESULTS: Both techniques yielded synovial concentrations of amikacin > 10 times the minimum inhibitory concentration (MIC) for 90% of isolates (80 microg/mL) and > 10 times the MIC breakpoint (160 microg/mL) of amikacin-susceptible bacteria reported to cause septic arthritis in horses. These values were attained for both joints for both techniques. Esmarch tourniquets prevented detectable loss of amikacin to the systemic circulation for both techniques. CONCLUSIONS AND CLINICAL RELEVANCE: Both techniques reliably achieved synovial fluid concentrations of amikacin consistent with concentration-dependent killing for bacteria commonly encountered in horses with septic arthritis. Esmarch tourniquets were effective for both delivery techniques in standing horses.     

Efficacy of three tourniquet types for intravenous antimicrobial regional limb perfusion in standing horses

Objective: To determine (1) if clinically useful concentrations of amikacin sulfate can be obtained in synovial fluid during regional limb perfusion (RLP) performed above the carpus in standing sedated horses and (2) to determine the efficacy of 3 tourniquet types (narrow rubber [NR], wide rubber [WR], pneumatic [PN]). Animals: Horses (n=9). Methods: Bilateral forelimb RLP with amikacin sulfate (2.5 g) were administered through the cephalic vein in standing sedated horses. Limbs were randomly assigned to the 3 tourniquet types (NR, WR, PN) applied above the carpus. Metacarpophalangeal synovial fluid was obtained 0.5 hour after perfusion. Amikacin concentration in the synovial fluid was detected using fluorescence polarization immunoassay. Results: Mean synovial concentrations of amikacin in the PN (mean 236 μg/mL; range 23–913 μg/mL) and WR (mean 64.2 μg/mL; range 7–315 μg/mL) were significantly higher (P=.000 and .032, respectively) than the NR tourniquet (mean 2.1 μg/mL; range 0.9–3.3 μg/mL). Conclusions: The PN tourniquet resulted in the highest synovial fluid amikacin concentrations in all horses, although administration with PN and WR tourniquets achieved adequate amikacin concentrations. NR tourniquet is ineffective and should not be used for RLP above the carpus in the standing horse.     

Comparison of intraosseous or intravenous infusion for delivery of amikacin sulfate to the tibiotarsal joint of horses

OBJECTIVE: To establish the route of infusion (IV or intraosseous) that results in the highest concentration of amikacin in the synovial fluid of the tibiotarsal joint and determine the duration of peak concentrations. ANIMALS: 21 horses. PROCEDURE: Regional perfusion of a limb on 15 horses was performed. Amikacin sulfate was infused into the saphenous vein or via intraosseous infusion into the distal portion of the tibia (1 g in 56 ml of lactated Ringer's solution) or proximal portion of the metatarsus (1 g of amikacin in 26 ml of lactated Ringer's solution). Amikacin concentrations were measured in sequential samples from tibiotarsal joint synovial fluid and serum. Samples were obtained immediately prior to release of the tourniquet and 0.5, 1, 4, 8, 12, and 24 hours after the tourniquet was released. Radiographic contrast material was infused into the same locations as the antibiotic perfusate to evaluate distribution in 6 other horses. RESULTS: Infusion into the saphenous vein produced the highest concentration of amikacin in the tibiotarsal joint, compared with the distal portion of the tibia (mean +/- SE, 701.8 +/- 366.8 vs 203.8 +/- 64.5 microg/ml, respectively). Use of a lower volume of diluent in the proximal portion of the metatarsus produced a peak value of 72.2 +/- 23.4 microg/ml. CONCLUSIONS AND CLINICAL RELEVANCE: For regional perfusion of the tarsus, IV infusion is preferred to intraosseous infusion, because higher concentrations are achieved in the synovial fluid, and the procedure is easier to perform.     

Intraosseous gentamicin perfusion of the distal metacarpus in standing horses

OBJECTIVE: To report tissue gentamicin concentrations after intraosseous (IO) perfusion in standing horses. STUDY DESIGN: In vivo study. ANIMALS OR SAMPLE POPULATION: Twelve horses. METHODS: Sedated horses had a cannulated cortical bone screw inserted into the dorsolateral aspect of the treated metacarpus and a tourniquet applied proximally. Gentamicin (2.2 mg/kg) diluted in sterile saline solution (0.1 mL/kg) was infused through the screw. Two horses were euthanatized at each time interval: 0, 2, 6, 12, 24, and 36 hours. Synovial fluid and bone samples were collected distal to the screw from both forelimbs. Gentamicin concentrations were measured using fluorescence polarization immunoassay. RESULTS: The highest synovial fluid gentamicin concentrations were 385+/-273 microg/mL (mean+/-SD) in the metacarpophalangeal joint, 225+/-205 microg/mL in the proximal interphalangeal joint, 215+/-205 microg/mL in the distal interphalangeal joint, 382+/-195 microg/mL in the digital flexor tendon sheath, and 206+/-161 microg/mL in the navicular bursa. The highest bone concentrations of gentamicin were 55+/-30 microg/g in the distal metacarpus, 34+/-27 microg/g in the proximal, 16+/-15 microg/g in the middle, and 16+/-2.2 microg/g in the distal phalanges, and 27+/-17 microg/g in the proximal and 24+/-11 microg/g in the distal sesamoid bones. CONCLUSION: Standing IO perfusion of gentamicin resulted in local antibiotic concentrations in the synovial structures and bones of the distal aspect of the limb that exceed the reported minimum inhibitory concentration of pathogens commonly implicated in equine orthopedic infections. CLINICAL RELEVANCE: Standing IO perfusion of gentamicin in the distal aspect of the limb should be considered for treatment of orthopedic infections of this region in horses.     

Pharmacokinetics of ceftiofur in the metacarpophalangeal joint after standing intravenous regional limb perfusion in horses

This study investigated the pharmacokinetics of ceftiofur after intravenous regional limb perfusion (IVRLP). Six horses were involved in 3 IVRLP sessions. For each session, operators with varying clinical experience placed the tourniquet. A wide-rubber tourniquet was applied in the antebrachium as 2 g of ceftiofur in a total volume of 100 mL was injected into the cephalic vein. Plasma and metacarpophalangeal synovial fluid samples were obtained to evaluate perfusate leakage and synovial fluid concentrations of ceftiofur over 24 h. Overall, mean plasma concentrations were not significantly different before and after tourniquet removal. Mean synovial fluid ceftiofur concentrations were significantly higher 5 min and 8 h after tourniquet removal versus 24 h, after which values above the minimum inhibitory concentration (MIC) (1 μg/mL) were not detected. Concentrations above the MIC were detected in 72% and 50% of the horses at 5 min and 8 h, respectively. Overall, higher synovial fluid concentrations were obtained for the operator with the most recent clinical experience performing IVRLP.     

Synovial fluid and plasma concentrations of ceftiofur after regional intravenous perfusion in the horse

OBJECTIVE: To determine radiocarpal (RC) joint synovial fluid and plasma ceftiofur concentrations after regional intravenous perfusion (RIP) and systemic intravenous (IV) administration. STUDY DESIGN: Experimental cross-over study. ANIMALS: Five normal adult horses. METHODS: One RC joint was randomly selected for RIP and the contralateral RC joint was sampled to determine intrasynovial ceftiofur concentrations after IV administration. Wash-out between IV and RIP was > or = 14 days. After surgical introduction of an intraarticular catheter, ceftiofur (2 g) was administered under general anesthesia either IV or by RIP after tourniquet application. Plasma and synovial fluid were collected over 24 hours. Samples were analyzed using high-performance liquid chromatography with ultraviolet detection and the results were statistically analyzed using a linear mixed effect model. RESULTS: Mean synovial fluid ceftiofur concentrations were consistently higher after RIP than after IV administration and were > 1 mug/mL (minimal inhibitory concentration [MIC] for common pathogens) for >24 hours. Mean synovial fluid peak concentration of ceftiofur after RIP and IV administration was 392.7+/-103.29 microg/mL at 0.5 hours postinjection (HPI) and 2.72+/-0.31 mug/mL at 1 HPI, respectively. Large variations in synovial fluid and plasma ceftiofur concentrations were observed between horses regardless of administration technique. RIP did not cause adverse effects. CONCLUSIONS: Under the present experimental conditions RIP with ceftiofur (2 g) induced significantly higher intraarticular antibiotic concentrations in the RC joint in comparison with IV administration. Moreover, after RIP, synovial fluid ceftiofur concentrations remain above the MIC for common pathogens (1 microg/mL) for > 24 hours. No adverse effects from the technique or the antibiotic were observed. CLINICAL RELEVANCE: RIP with high doses of ceftiofur may be a beneficial adjunctive therapy when treating equine synovial infections which are caused by cephalosporin susceptible microorganisms.     

Determination of synovial fluid and serum concentrations, and morphologic effects of intraarticular ceftiofur sodium in horses

OBJECTIVES: To determine the serum and synovial fluid concentrations of ceftiofur sodium after intraarticular (IA) and intravenous (IV) administration and to evaluate the morphologic changes after intraarticular ceftiofur sodium administration. STUDY DESIGN: Strip plot design for the ceftiofur sodium serum and synovial fluid concentrations and a split plot design for the cytologic and histopathologic evaluation. ANIMALS: Six healthy adult horses without lameness. METHODS: Stage 1: Ceftiofur sodium (2.2 mg/kg) was administered IV. Stage 2: 150 mg (3 mL) of ceftiofur sodium (pHavg 6.57) was administered IA into 1 antebrachiocarpal joint. The ceftiofur sodium was reconstituted with sterile sodium chloride solution (pH 6.35). The contralateral joint was injected with 3 mL of 0.9% sterile sodium chloride solution (pH 6.35). Serum and synovial fluid samples were obtained from each horse during each stage. For a given stage, each type of sample (serum or synovial fluid) was collected once before injection and 12 times after injection over a 24-hour period. All horses were killed at 24 hours, and microscopic evaluation of the cartilage and synovium was performed. Serum and synovial fluid concentrations of ceftiofur sodium were measured by using a microbiologic assay, and pharmacokinetic variables were calculated. Synovial fluid was collected from the active joints treated during stage 2 at preinjection and postinjection hours (PIH) 0 (taken immediately after injection of either the ceftiofur sodium or sodium chloride), 12, and 24, and evaluated for differential cellular counts, pH, total protein concentration, and mucin precipitate quality. RESULTS: Concentrations of ceftiofur in synovial fluid after IA administration were significantly higher (P = .0001) than synovial fluid concentrations obtained after IV administration. Mean peak synovial fluid concentrations of ceftiofur after IA and IV administration were 5825.08 microg/mL at PIH .25 and 7.31 microg/mL at PIH 4, respectively. Mean synovial fluid ceftiofur concentrations at PIH 24 after IA and IV administration were 4.94 microg/mL and .12 microg/mL, respectively. Cytologic characteristics of synovial fluid after IA administration did not differ from cytologic characteristics after IA saline solution administration. White blood cell counts after IA ceftiofur administration were < or =3,400 cells/ML. The mean synovial pH of ceftiofur treated and control joints was 7.32 (range, 7.08-7.5) and 7.37 (range, 7.31-7.42), respectively. Grossly, there were minimal changes in synovium or cartilage, and no microscopic differences were detected (P = .5147) between ceftiofur-treated joints and saline-treated joints. The synovial half-life of ceftiofur sodium after IA administration joint was 5.1 hours. CONCLUSIONS: Synovial concentrations after intraarticular administration of 150 mg of ceftiofur sodium remained elevated above minimal inhibitory concentration (MIC90) over 24 hours. After 2.2 mg/kg IV, the synovial fluid ceftiofur concentration remained above MIC no longer than 8 hours. CLINICAL RELEVANCE: Ceftiofur sodium may be an acceptable broad spectrum antimicrobial to administer IA in septic arthritic equine joints.     

Gentamicin concentrations in synovial fluid and joint tissues during intravenous administration or continuous intra-articular infusion of the tarsocrural joint of clinically normal horses

OBJECTIVE: To compare gentamicin concentrations achieved in synovial fluid and joint tissues during IV administration and continuous intra-articular (IA) infusion of the tarsocrural joint in horses. ANIMALS: 18 horses with clinically normal tarsocrural joints. PROCEDURE: Horses were assigned to 3 groups (6 horses/group) and administered gentamicin (6.6 mg/kg, IV, q 24 h for 4 days; group 1), a continuous IA infusion of gentamicin into the tarsocrural joint (50 mg/h for 73 hours; group 2), or both treatments (group 3). Serum, synovial fluid, and joint tissue samples were collected for measurement of gentamicin at various time points during and 73 hours after initiation of treatment. Gentamicin concentrations were compared by use of a Kruskal-Wallis ANOVA. RESULTS: At 73 hours, mean +/- SE gentamicin concentrations in synovial fluid, synovial membrane, joint capsule, subchondral bone, and collateral ligament of group 1 horses were 11.5 +/- 1.5 microg/mL, 21.1 +/- 3.0 microg/g, 17.1 +/- 1.4 microg/g, 9.8 +/- 2.0 microg/g, and 5.9 +/- 0.7 microg/g, respectively. Corresponding concentrations in group 2 horses were 458.7 +/- 130.3 microg/mL, 496.8 +/- 126.5 microg/g, 128.5 +/- 74.2 microg/g, 99.4 +/- 47.3 microg/g, and 13.5 +/- 7.6 microg/g, respectively. Gentamicin concentrations in synovial fluid, synovial membrane, and joint capsule of group 1 horses were significantly lower than concentrations in those samples for horses in groups 2 and 3. CONCLUSIONS AND CLINICAL RELEVANCE: Continuous IA infusion of gentamicin achieves higher drug concentrations in joint tissues of normal tarsocrural joints of horses, compared with concentrations after IV administration.     

Pharmacokinetics of amikacin in plasma and selected body fluids of healthy horses after a single intravenous dose

Reasons for performing study: No studies have determined the pharmacokinetics of low‐dose amikacin in the mature horse. Objectives: To determine if a single i.v. dose of amikacin (10 mg/kg bwt) will reach therapeutic concentrations in plasma, synovial, peritoneal and interstitial fluid of mature horses (n = 6). Methods: Drug concentrations of amikacin were measured across time in mature horses (n = 6); plasma, synovial, peritoneal and interstitial fluid were collected after a single i.v. dose of amikacin (10 mg/kg bwt). Results: The mean ± s.d. of selected parameters were: extrapolated plasma concentration of amikacin at time zero 144 ± 21.8 µg/ml; extrapolated plasma concentration for the elimination phase 67.8 ± 7.44 µg/ml, area under the curve 139 ± 34.0 µg*h/ml, elimination half‐life 1.34 ± 0.408 h, total body clearance 1.25 ± 0.281 ml/min/kg bwt; and mean residence time (MRT) 1.81 ± 0.561 h. At 24 h, the plasma concentration of amikacin for all horses was below the minimum detectable concentration for the assay. Selected parameters in synovial and peritoneal fluid were maximum concentration (C_max) 19.7 ± 7.14 µg/ml and 21.4 ± 4.39 µg/ml and time to maximum concentration 65 ± 12.2 min and 115 ± 12.2 min, respectively. Amikacin in the interstitial fluid reached a mean peak concentration of 12.7 ± 5.34 µg/ml and after 24 h the mean concentration was 3.31 ± 1.69 µg/ml. Based on a minimal inhibitory concentration (MIC) of 4 µg/ml, the mean C_max : MIC ratio was 16.9 ± 1.80 in plasma, 4.95 ± 1.78 in synovial fluid, 5.36 ± 1.10 in peritoneal fluid and 3.18 ± 1.33 in interstitial fluid. Conclusions: Amikacin dosed at 10 mg/kg bwt i.v. once a day in mature horses is anticipated to be effective for treatment of infection caused by most Gram‐negative bacteria. Potential relevance: Low dose amikacin (10 mg/kg bwt) administered once a day in mature horses may be efficacious against susceptible microorganisms.     

Comparison of 2 techniques for regional antibiotic delivery to the equine forelimb: intraosseous perfusion vs. intravenous perfusion

The purpose of this study was to compare the synovial fluid concentrations and pharmacokinetics of amikacin in the equine limb distal to the carpus following intraosseous and intravenous regional perfusion. The front limbs of 6 horses were randomly assigned to either intraosseous or intravenous perfusion. A tourniquet was placed distal to each carpus and the limb perfused with 500 mg of amikacin. Systemic blood samples and synovial fluid samples were collected over 70 min from the distal interphalangeal (DIP) joint, metacarpophalangeal joint, and digital flexor sheath. The tourniquet was removed following the 30 min sample collection. The mean peak amikacin concentration for the DIP joint was significantly higher with intravenous perfusion. There were no significant differences in time to peak concentration or elimination half-life between methods at each synovial structure. Each technique produced mean peak concentrations ranging from 5 to 50 times that of recommended peak serum concentrations for therapeutic efficacy.     

The influence of perfusate volume on antimicrobial concentration in synovial fluid following intravenous regional limb perfusion in the standing horse

This study investigated the influence of perfusate volume on antimicrobial concentration in synovial fluid following intravenous regional limb perfusion (IVRLP) and assessed the efficacy of low volume IVRLP. The front limbs of 9 horses were randomly assigned to 1 of 3 volume groups: 10 mL (Group 1), 30 mL (Group 2), or 60 mL (Group 3). A tourniquet was applied distal to the carpus and the limbs were perfused with 500 mg genta-micin diluted to the assigned volume via a catheter placed in the lateral palmar digital vein at the level of the proximal sesamoid bones. Synovial fluid samples were collected from the metacarpophalangeal joint at 30 minutes, followed by removal of the tourniquet. Gentamicin concentration in synovial fluid was detected using a fluorescence polarization immunoassay. There were no statistically significant differences among gentamicin concentrations in synovial fluid among perfusate volume groups. Mean gentamicin concentration in Group 1 (125.9 μg/mL) was higher than Group 2 (82.7 μg/mL) and Group 3 (56.1 μg/mL).     

Pharmacokinetics and tissue distribution of enrofloxacin and its active metabolite ciprofloxacin in calves

The purpose of this study was to establish the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in the plasma and interstitial fluid (ISF) following subcutaneous (s.c.) administration of enrofloxacin. Ultrafiltration probes were placed in the s.c. tissue, gluteal musculature, and pleural space of five calves. Each calf received 12.5 mg/kg of enrofloxacin. Plasma and ISF samples were collected for 48 h after drug administration and analyzed by high pressure liquid chromatography. Plasma protein binding of enrofloxacin and ciprofloxacin was measured using a microcentrifugation system. Tissue probes were well tolerated and reliably produced fluid from each site. The mean +/- SD plasma half-life was 6.8 +/- 1.2 and 7.3 +/- 1 h for enrofloxacin and ciprofloxacin, respectively. The combined (ciprofloxacin + enrofloxacin) peak plasma concentration (Cmax) was 1.52 microg/mL, and the combined area under the curve (AUC) was 25.33 microg/mL. The plasma free drug concentrations were 54% and 81% for enrofloxacin and ciprofloxacin, respectively, and free drug concentration in the tissue fluid was higher than in plasma. We concluded that Cmax/MIC and AUC/MIC ratios for free drug concentrations in plasma and ISF would meet suggested ratios for a targeted MIC of 0.06 microg/mL.     

Pharmacokinetics of voriconazole following intravenous and oral administration and body fluid concentrations of voriconazole following repeated oral administration in horses

OBJECTIVE: To determine the pharmacokinetics of voriconazole following IV and PO administration and assess the distribution of voriconazole into body fluids following repeated PO administration in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURES: All horses received voriconazole (10 mg/kg) IV and PO (2-week interval between treatments). Plasma voriconazole concentrations were determined prior to and at intervals following administration. Subsequently, voriconazole was administered PO (3 mg/kg) twice daily for 10 days to all horses; plasma, synovial fluid, CSF, urine, and preocular tear film concentrations of voriconazole were then assessed. RESULTS: Mean +/- SD volume of distribution at steady state was 1,604.9 +/- 406.4 mL/kg. Systemic bioavailability of voriconazole following PO administration was 95 +/- 19%; the highest plasma concentration of 6.1 +/- 1.4 microg/mL was attained at 0.6 to 2.3 hours. Mean peak plasma concentration was 2.57 microg/mL, and mean trough plasma concentration was 1.32 microg/mL. Mean plasma, CSF, synovial fluid, urine, and preocular tear film concentrations of voriconazole after long-term PO administration were 5.163 +/- 1.594 microg/mL, 2.508 +/- 1.616 microg/mL, 3.073 +/- 2.093 microg/mL, 4.422 +/- 0.8095 microg/mL, and 3.376 +/- 1.297 microg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that voriconazole distributed quickly and widely in the body; following a single IV dose, initial plasma concentrations were high with a steady and early decrease in plasma concentration. Absorption of voriconazole after PO administration was excellent, compared with absorption after IV administration. Voriconazole appears to be another option for the treatment of fungal infections in horses.     

Serum concentrations and pharmacokinetics of enrofloxacin after intravenous and intragastric administration to mares.

Serum concentrations and pharmacokinetics of enrofloxacin were studied in 6 mares after intravenous (IV) and intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. In experiment 1, an injectable formulation of enrofloxacin (100 mg/mL) was given IV. At 5 min after injection, mean serum concentration was 9.04 microg/mL and decreased to 0.09 microg/mL by 24 h. Elimination half-life was 5.33 +/- 1.05 h and the area under the serum concentration vs time curve (AUC) was 21.03 +/- 5.19 mg x h/L. In experiment 2, the same injectable formulation was given IG. The mean peak serum concentration was 0.94 +/- 0.97 microg/mL at 4 h after administration and declined to 0.29 +/- 0.12 microg/mL by 24 h. Absorption of this enrofloxacin preparation after IG administration was highly variable, and for this reason, pharmacokinetic values for each mare could not be determined. In experiment 3, a poultry formulation (32.3 mg/mL) was given IG. The mean peak serum concentration was 1.85 +/- 1.47 microg/mL at 45 min after administration and declined to 0.19 +/- 0.06 microg/mL by 24 h. Elimination half-life was 10.62 +/- 5.33 h and AUC was 16.30 +/- 4.69 mg x h/L. Bioavailability was calculated at 78.29 +/- 16.55%. Minimum inhibitory concentrations of enrofloxacin were determined for equine bacterial culture specimens submitted to the microbiology laboratory over an 11-month period. The minimum inhibitory concentration of enrofloxacin required to inhibit 90% of isolates (MIC90) was 0.25 microg/mL for Staphylococcus aureus, Escherichia coli, Salmonella spp., Klebsiella spp., and Pasteurella spp. The poultry formulation was well tolerated and could be potentially useful in the treatment of susceptible bacterial infections in adult horses. The injectable enrofloxacin solution should not be used orally.     

Effect of intrathecal amikacin administration and repeated centesis on digital flexor tendon sheath synovial fluid in horses

OBJECTIVE: To determine the effect of intrathecal amikacin administration and repeated tenovaginocentesis on the total nucleated cell count (TNCC), total protein (TP) concentration and cytologic characteristics of synovial fluid of the equine digital flexor tendon sheath (DFTS). STUDY DESIGN: Randomized, cross-over experimental design. ANIMALS: Adult horses (n=8). METHODS: Synovial fluid was aseptically collected from the DFTS and either 1 mL amikacin sulfate (250 mg/mL) or lactated Ringer's solution (LRS) was injected into the DFTS. Serial synovial fluid samples were obtained at 0, 12, 24, 48, and 72 hours. The opposite treatment was administered to the contralateral DFTS after a washout period of 2 weeks. RESULTS: Treatment increased TP concentration, TNCC, percentage of neutrophils, and neutrophil counts from baseline levels. There was no difference between treatment of the DFTS with amikacin or LRS. Values peaked at 12-24 hours after the initial centesis and then declined toward baseline levels. CONCLUSIONS: Injection and repeat centesis of the normal DFTS with 250 mg amikacin or an equivalent volume of LRS resulted in mild increases in synovial fluid analytes from baseline. Synovial inflammation in this study was not accompanied by lameness at the walk and measured analytes returned toward baseline levels within 12-24 hours of first injection. CLINICAL RELEVANCE: The effect of tenovaginocentesis and intrathecal administration of amikacin or LRS on DFTS synovial fluid values are modest in most horses; however, some horses can develop marked increases in synovial fluid values that may be interpreted as sepsis.     

Gentamicin concentrations in synovial fluid obtained from the tarsocrural joints of horses after implantation of gentamicin-impregnated collagen sponges

OBJECTIVE: To determine synovial fluid gentamicin concentrations and evaluate adverse effects on the synovial membrane and articular cartilage of tarsocrural joints after implantation of a gentamicin-impregnated collagen sponge. ANIMALS: 6 healthy adult mares. PROCEDURES: A purified bovine type I collagen sponge impregnated with 130 mg of gentamicin was implanted in the plantarolateral pouch of 1 tarsocrural joint of each horse, with the contralateral joint used as a sham-operated control joint. Gentamicin concentrations in synovial fluid and serum were determined for 120 hours after implantation by use of a fluorescence polarization immunoassay. Synovial membrane and cartilage specimens were collected 120 hours after implantation and evaluated histologically. RESULTS: Median peak synovial fluid gentamicin concentration of 168.9 microg/mL (range, 115.6 to 332 microg/mL) was achieved 3 hours after implantation. Synovial fluid gentamicin concentrations were < 4 microg/mL by 48 hours. Major histologic differences were not observed in the synovial membrane between control joints and joints implanted with gentamicin-impregnated sponges. Safranin-O fast green stain was not reduced in cartilage specimens obtained from treated joints, compared with those from control joints. CONCLUSIONS AND CLINICAL RELEVANCE: Implantation of a gentamicin-impregnated collagen sponge in the tarsocrural joint of horses resulted in rapid release of gentamicin, with peak concentrations > 20 times the minimum inhibitory concentration reported for common pathogens that infect horses. A rapid decrease in synovial fluid gentamicin concentrations was detected. The purified bovine type I collagen sponges did not elicit substantial inflammation in the synovial membrane or cause mechanical trauma to the articular cartilage.     

Plasma and synovial fluid endothelin-1 and nitric oxide concentrations in horses with and without joint disease

OBJECTIVE: To compare plasma and synovial fluid endothelin-1 (ET-1) and nitric oxide (NO) concentrations in clinically normal horses and horses with joint disease. ANIMALS: 36 horses with joint disease, and 15 horses without joint disease. PROCEDURE: Horses with joint disease were assigned to 1 of the 3 groups (ie, synovitis, degenerative joint disease [DJD], or joint sepsis groups) on the basis of findings on clinical and radiographic examination and synovial fluid analysis. Endothelin-1 and NO concentrations were measured in plasma from blood samples, collected from the jugular vein and ipsilateral cephalic or saphenous vein of the limb with an affected or unaffected joint, as well as in synovial fluid samples obtained via arthrocentesis from the involved joint. RESULTS: Plasma ET-1 concentrations between affected and unaffected groups were not significantly different. Median concentration and concentration range of ET-1 in synovial fluid obtained from the joint sepsis group (35.830 pg/mL, 7926 to 86.614 pg/mL; n = 7) were significantly greater than values from the synovitis (17.531 pg/mL, 0.01 to 46.908 pg/mL; 18), DJD (22.858 pg/mL, 0.01 to 49.990 pg/mL; 10), and unaffected (10.547 pg/mL, 0.01 to 35.927 pg/mL; 10) groups. Plasma and synovial fluid NO concentrations between affected and unaffected groups were not significantly different. CONCLUSIONS AND CLINICAL RELEVANCE: Endothelin-1 is locally synthesized in the joints of horses with various types of joint disease. Synovial fluid concentrations of ET-1 varied among horses with joint disease, with concentrations significantly higher in the synovial fluid of horses with joint sepsis. These results indicate that ET-1 may play a role in the pathophysiologic mechanism of joint disease in horses.     

Pharmacokinetics of once-daily amikacin in healthy foals and therapeutic drug monitoring in hospitalized equine neonates

The objectives of this study were to investigate the pharmacokinetics of once-daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram-negative isolates from blood cultures in septic foals. Median half-life, clearance, and volume of distribution of amikacin in healthy 2- to 3-day-old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86-5.45 hours), 1.82 mL/min/kg (1.35-1.97 mL/min/kg), and 0.785 L/kg (0.638-0.862 L/kg), respectively. Statistically significant (P <.05) decreases in area under the curve (14% decrease), mean residence time (19% decrease), and C24h plasma amikacin concentrations (29% decrease) occurred between days 2-3 and 10-11. Plasma amikacin concentrations in healthy foals at 0.5 hours (C0.5h) were significantly higher (P = .02) than those of hospitalized foals. Sepsis, prematurity, and hypoxemia did not alter amikacin concentrations. The MIC at which 90% of all gram-negative isolates from equine neonatal blood cultures were inhibited by amikacin was 4 microg/mL, suggesting that amikacin C0.5h of 40 microg/mL should be targeted to achieve a maximum serum concentration to MIC ratio of 10:1. The proportion of foals with C0.5h 40 microg/mL was significantly higher (P < .0001) in hospitalized foals receiving a dose of amikacin at 25 mg/kg (22/24 or 92%) than in foals receiving a dose at 21 mg/kg (9/25 or 36%), whereas no difference was found in the proportion of foals with C24h concentrations > or = 3 microg/mL between the 2 groups. An initial dose at 25 mg/kg is recommended for once-daily amikacin in equine neonates.     

The effect of implanting gentamicin-impregnated polymethylmethacrylate beads in the tarsocrural joint of the horse

OBJECTIVE: To determine the effect of intra-articular gentamicin-impregnated polymethylmethacrylate (PMMA) beads inserted in the equine tarsocrural joint on the synovial fluid, synovial lining, and cartilage, and to determine the peak and sustainable gentamicin concentrations in synovial fluid and plasma. STUDY DESIGN: Pharmacokinetic, cytologic, and histologic study of the effect of gentamicin-impregnated PMMA on normal equine tarsocrural joints. ANIMALS: Five healthy adult horses. METHODS: Gentamicin-impregnated PMMA bead strands (3 strands each of 40 beads, with each strand containing 100 mg gentamicin) were surgically inserted into one radiographically normal tarsocrural joint in 5 horses. Each horse had both joints flushed with 1 L of lactated Ringer's solution before bead administration. Synovial fluid total protein concentration, white blood cell (WBC) count, gentamicin concentration, synovial histology, cartilage integrity, and cartilage glycosaminoglycan (GAG) concentrations were determined. RESULTS: Gentamicin concentration (mean +/- SEM peak concentration, 27.9 +/- 2.27 microg/mL) occurred in the first 24 hours and remained above 2 microg/mL for 9 days. Gentamicin concentrations in control joints and the plasma remained below detectable levels. The synovial fluid WBC count for treated joints was increased compared with control joints for 72 hours, but was similar at day 6. The synovial protein concentration in gentamicin-treated joints remained increased for 21 days. Synovium in treated joints had diffuse synovitis, whereas control joints had less fibrovascular proliferation. Superficial cartilage erosion was present in all treated joints. There was no difference in the GAG content of treated and control joint cartilage. CONCLUSIONS: Short-term implantation of gentamicin (300 mg)-impregnated PMMA beads can provide therapeutic levels of gentamicin (>2 microg/mL) in the normal tarsocrural joint for 9 days; however, gentamicin-impregnated PMMA beads induce synovitis and superficial cartilage erosion. CLINICAL RELEVANCE: Temporary intra-articular administration of antibiotic-impregnated PMMA may be an effective way to treat septic joints that require constant high concentrations of antibiotics.     

Evaluation of safety and pharmacokinetics of vancomycin after intraosseous regional limb perfusion and comparison of results with those obtained after intravenous regional limb perfusion in horses

OBJECTIVE: To evaluate the clinical effects and pharmacokinetics of vancomycin in plasma and synovial fluid after intraosseous regional limb perfusion (IORLP) in horses and to compare results with those obtained after IV regional limb perfusion (IVRLP). ANIMALS: 6 horses. PROCEDURES: 1 forelimb of each horse received vancomycin hydrochloride (300 mg in 60 mL of saline [0.9% NaCl] solution) via IORLP; the contralateral limb received 60 mL of saline solution (control). Solutions were injected into the medullary cavity of the distal portion of the third metacarpal bone. Synovial fluid from the metacarpophalangeal (MTCP) and distal interphalangeal (DIP) joints and blood were collected prior to perfusion and 15, 30, 45, 65, and 90 minutes after beginning IORLP, and synovial fluid from the MTCP joint only and blood were collected 4, 8, 12, and 24 hours after beginning IORLP. Plasma urea and creatinine concentrations and clinical appearance of the MTCP joint region and infusion sites were determined daily for 7 days. Results were compared with those of a separate IVRLP study. RESULTS: Clinical complications were not observed after IORLP. Mean vancomycin concentration in the MTCP joint was 4 microg/mL for 24 hours after IORLP. Compared with IORLP, higher vancomycin concentrations were detected in the DIP joint after IVRLP. Compared with IVRLP, higher vancomycin concentrations were detected in the MTCP joint for a longer duration after IORLP. CONCLUSIONS AND CLINICAL RELEVANCE: IORLP with 300 mg of vancomycin in a 0.5% solution was safe and may be clinically useful in horses. Intravenous and intraosseous routes may be better indicated for infectious processes in the DIP and MTCP joints, respectively.