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.     

Pharmacokinetics and pharmacodynamics of enrofloxacin and a low dose of amikacin administered via regional intravenous limb perfusion in standing horses

OBJECTIVE: To evaluate the pharmacokinetic-pharmacodynamic parameters of enrofloxacin and a low dose of amikacin administered via regional IV limb perfusion (RILP) in standing horses. ANIMALS: 14 adult horses. PROCEDURES: Standing horses (7 horses/group) received either enrofloxacin (1.5 mg/kg) or amikacin (250 mg) via RILP (involving tourniquet application) in 1 forelimb. Samples of interstitial fluid (collected via implanted capillary ultrafiltration devices) from the bone marrow (BMIF) of the third metacarpal bone and overlying subcutaneous tissues (STIF), blood, and synovial fluid of the radiocarpal joint were collected prior to (time 0) and at intervals after tourniquet release for determination of drug concentrations. For pharmacokinetic-pharmacodynamic analyses, minimum inhibitory concentrations (MICs) of 16 microg/mL (amikacin) and 0.5 microg/mL (enrofloxacin) were applied. RESULTS: After RILP with enrofloxacin, 3 horses developed vasculitis. The highest synovial fluid concentrations of enrofloxacin and amikacin were detected at time 0; median values (range) were 13.22 microg/mL (0.254 to 167.9 microg/mL) and 26.2 microg/mL (5.78 to 50.0 microg/mL), respectively. Enrofloxacin concentrations exceeded MIC for approximately 24 hours in STIF and synovial fluid and for 36 hours in BMIF. After perfusion of amikacin, concentrations greater than the MIC were not detected in any samples. Effective therapeutic concentrations of enrofloxacin were attained in all samples. CONCLUSIONS AND CLINICAL RELEVANCE: In horses with orthopedic infections, RILP of enrofloxacin (1.5 mg/kg) should be considered as a treatment option. However, care must be taken during administration. A dose of amikacin > 250 mg is recommended to attain effective tissue concentrations via RILP in standing horses.     

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.     

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.     

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).     

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.     

Evaluation of regional limb perfusion with amikacin using the saphenous,cephalic, and palmar digital veins in standing horses

Previous studies have shown that regional limb perfusion (RLP) using the palmar digital (PD) vein delivers therapeutic concentration of amikacin to the distal limb. Our hypothesis was that using the cephalic and saphenous veins for RLP will enable delivery of therapeutic concentrations of amikacin to the distal limb. Nineteen healthy horses participated in the study. The cephalic, saphenous, or PD vein was used to perfuse the limb with amikacin. Two grams of amikacin was used for RLP using the saphenous and the cephalic veins, and one gram was used in the PD vein. Synovial samples were collected from the metacarpo‐/metatarsophalangeal (MCP/MTP) joint, and blood samples were collected from the jugular vein. Maximum concentration (Cmax) of amikacin in the MCP/MTP joint using the cephalic and the saphenous vein was 277 and 363 mg/L, respectively. The amikacin concentrations achieved in the synovial fluid of the MCP/MTP joint in the current study were between 69 and 91 times the minimally inhibitory concentration of common susceptible bacterial pathogens causing orthopedic infections in horses. To conclude, this study shows that use of the proximal veins for RLP to treat distal limb infections is a viable alternative to using the palmar or plantar digital vein.     

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.     

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.     

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.     

In Vitro and In Vivo Evaluation of Ferric-Hyaluronate Implants for Delivery of Amikacin Sulfate to the Tarsocrural Joint of Horses

Objective— To assess the antimicrobial elution characteristics, toxicity, and antimicrobial activity of amikacin‐impregnated ferric‐hyaluronate implants (AI‐FeHAI) for amikacin delivery to the tarsocrural joint of horses. Study Design— Experimental study. Sample Population— AI‐FeHAI implants, equine cartilage, and synovium, and horses (n=6). Methods— In vitro study: Five AI‐FeHAI were placed in saline solution with daily replacement until implant degradation. Eluent was tested for amikacin concentration and bioactivity. Synovial and cartilage explants were incubated in the presence or absence of AI‐FeHAI for 72 hours and subsequently assessed for morphology, viability, and composition. Synovial explants were incubated with Staphylococcus aureus in the presence or absence of AI‐FeHAI. Spent medium was cultured daily and explants were assessed for morphology and viability after 96 hours. In vivo study: AI‐FeHAI were placed in 6 tarsocrural joints. Standard cytologic analysis and amikacin concentration (SFAC) were determined in synovia obtained regularly for 28 days thereafter. Similar analyses were conducted after a single intra‐articular injection of amikacin 6 months later. Results— In vitro study: Amikacin concentrations exceeded 16 μg/mL and inhibited S. aureus growth for 8 days. AI‐FeHAI had no effect on cartilage explants. AI‐FeHAI eliminated bacteria from synovial explants. In vitro study: After AI‐FeHAI placement, SFAC was highest (140.78+63.81 μg/mL) at first sampling time. By 24 hours SFAC was <16 μg/mL. After intra‐articular injection, SFAC was the highest (377.91 ± 40.15 μg/mL) at first sampling time. By 48 hours SFAC was <16 μg/mL. Conclusions— A single intra‐articular amikacin injection demonstrated superior pharmacokinetics than AI‐FeHAI prepared as described. Clinical Relevance— AI‐FeHAI cannot be recommended for clinical use.     

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.     

Evaluation of regional limb perfusion with chloramphenicol using the saphenous or cephalic vein in standing horses

Regional limb perfusion (RLP) significantly decreases morbidity and mortality associated with distal limb injuries in horses. There is an urgent need for finding additional effective antimicrobial drugs for use in RLP. In this study, we tested the pharmacokinetics (PK) of chloramphenicol in RLP. Eight horses participated in the study, which was approved by the University Animal Care and Use Committee. The cephalic and the saphenous veins were used to perfuse the limbs. Synovial samples were collected from the metacarpo/metatarsophalangeal (MCP/MTP) joint. The Friedman Test was applied for assessing change in PK concentration over time, for all time points. The Wilcoxon Signed Ranks Test was used to test the difference between PK concentration in joint & serum as well as concentration in joint vs. MIC. The comparison of measurements between measurements taken on hind vs. front legs was carried out using the Mann–Whitney Test. A P‐value of 5% or less was considered statistically significant. After RLP, the concentration of chloramphenicol in the synovial fluid of the MCP/MTP joint using either the cephalic or the saphenous vein was initially far above the minimal inhibitory concentration (MIC) of most susceptible pathogens and remained above the MIC for approximately 6 h. The results indicate that performing RLP using the cephalic and saphenous veins enables reaching concentrations of chloramphenicol in the MCP/MTP joint that are well above the MIC of most susceptible pathogens. The chloramphenicol concentrations achieved in the synovial fluid of the MCP/MTP joint in the current study were between 1.5 (MTP) and 7 (MCP) times the MIC of MRSA in horses. These results are encouraging since MRSA infections are becoming far more common, causing considerable morbidity. To the best of our knowledge, this is the first study to evaluate the pharmacokinetics of chloramphenicol following RLP in the horse and the results are positive.     

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.     

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.     

Single-dose pharmacokinetics of cefazolin in bovine synovial fluid after intravenous regional injection

Gagnon, H., Ferguson, J.G., Papich, M.G., Bailey, J.V. Single-dose pharmacokinetics of cefazolin in bovine synovial fluid after intravenous regional injection. J. vet. Pharmacol. Therap. 17, 31–37.
The pharmacokinetic properties of cefazolin in the synovial fluid of the tibiotarsal joint were determined in 10 healthy mature cattle after intravenous regional injection of 2 50 mg cefazolin. A pneumatic tourniquet was positioned proximal to the tibiotarsal joint and the intravenous injection was performed distal to the tourniquet. Synovial fluid concentrations of cefazolin increased in the first 30 mm and fluctuated between 54.7 ± 11.0 g/ml (mean ± SEM) and 73.2 ± 13.2 g/ml in the following 90 min while the tourniquet remained inflated. After tourniquet removal, synovial fluid concentration-time curves followed first-order one-compartment model decay in most of the animals with an elimination half-life of 0.82 h (harmonic mean). Therapeutic concentrations of cefazolin in the synovial fluid of normal joints were reached and this injection technique could be used as an alternative to systemic administration of antibiotics to provide adequate concentrations in a localized area.     

Regional Perfusion of the Equine Carpus for Antibiotic Delivery

Regional perfusion of carpal tissues by forced intramedullary administration of fluids was evaluated in 10 horses. Results of subtraction radiography after perfusion with a contrast medium demonstrated that perfusate was delivered to the carpal tissues by the venous system. Perfused India ink was distributed uniformly in the antebrachiocarpal and middle carpal synovial membranes. Histologically, the ink was within the venules of the synovial villi. Immediately after perfusion with gentamicin sulfate (1 g), the gentamicin concentrations in the synovial fluid and synovial membrane of the antebrachiocarpal joint were 349 +/- 240 micrograms/mL and 358 +/- 264 micrograms/g, respectively. When gentamicin concentrations in the synovial fluid of the antebrachiocarpal joint and serum were measured 0, 0.5, 1, 4, 8, 12, and 24 hours after carpal perfusion, the mean peak gentamicin concentration in the synovial fluid was 589 +/- 429 micrograms/mL. At hour 24, the mean gentamicin concentration in the synovial fluid was 4.8 +/- 2.0 micrograms/mL. The resulting peak gentamicin concentration in the serum was 23.7 +/- 14.5 micrograms/mL immediately after the perfusion; it decreased below the desired trough level of 1 micrograms/mL between hours 4 and 8.     

Regional limb perfusion for antibiotic treatment of experimentally induced septic arthritis.

Septic arthritis was induced in one antebrachiocarpal joint of seven horses by the intra-articular injection of 1 mL Staphylococcus aureus suspension containing a mean of 10(5) colony-forming units. Twenty-four hours after inoculation, four horses were treated by regional perfusion with 1 g of gentamicin sulfate, and three horses received 2.2 mg/kg gentamicin sulfate intravenously (IV) every 6 hours. Synovial fluid was collected for culture and cytology at regular intervals, and the synovial membranes were collected for culture and histologic examination at euthanasia 24 hours after the first treatment. Gentamicin concentration in the septic synovial fluid after three successful perfusions was 221.2 +/- 71.4 (SD) micrograms/mL; after gentamicin IV, it was 7.6 +/- 1.6 (SD) micrograms/mL. The mean leukocyte count in the inoculated joints decreased significantly by hour 24 in the successfully perfused joints. Terminal bacterial cultures of synovial fluid and synovial membranes were negative in two horses with successfully perfused joints. S. aureus was isolated from the infected joints in all three horses treated with gentamicin IV.     

Pharmacokinetics of cefoperazone in horses

The pharmacokinetics and bioavailabilty of cefoperazone (CPZ) were studied following intravenous (IV) and intramuscular (IM) administration of single doses (30 mg/kg) to horses. Concentrations in serum, urine and synovial fluid samples were measured following IV administration. CPZ concentrations in serum, synovial fluid and spongy bone samples were measured following IM administration. After IV administration a rapid distribution phase ( t _1/2(α):4.22 ± 2.73 min) was followed by a slower elimination phase ( t 1/2(β) 0.77 ± 0.19 h). The apparent volume of distribution was 0.68 ± 0.10 L/kg. Mean synovial fluid peak concentration was 5.76 ± 0.74 μg/mL. After IM administration a bioavailability of 42.00±5.33% was obtained. Half-life of absorption was 2.51 ± 0.72 min and t _1/2(β) was 1.52±0.15 h. The mean synovial fluid and spongy bone peak concentrations at 2 h after IM administration were 2.91±0.85 μg/mL and 5.56±0.70 μg/mL, respectively.