SINGLE-DOSE, MULTIPLE-DOSE, AND THERAPEUTIC DRUG MONITORING PHARMACOKINETICS OF FIROCOXIB IN ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Firocoxib is a COX-2-selective nonsteroidal anti-inflammatory drug (NSAID) with limited effects on COX-1, which means it likely has fewer side effects than typically associated with other NSAIDs. This study determined possible doses of firocoxib based on single- and multidose pharmacokinetic trials conducted in 10 Asian elephants (Elephas maximus). Initially, two single oral dose trials (0.01 and 0.1 mg/kg) of a commercially available tablet (n = 6) and paste (n = 4) formulation were used to determine a preferred dose. The 0.1 mg/kg dose was further evaluated via IV single dose (n = 3) and oral multidose trials (tablets n = 6; paste n = 4). Serum peak and trough firocoxib concentrations were also evaluated in Asian elephants (n = 4) that had been being treated for a minimum of 90 consecutive days. Key pharmacokinetic parameters for the 0.1 mg/kg single-dose trials included mean peak serum concentrations of 49 ± 3.3 ng/ml for tablets and 62 ± 14.8 ng/ml for paste, area under the curve (AUC) of 1,332 ± 878 h*mg/ml for tablets and 1,455 ± 634 h*mg/ml for paste, and half-life (T1/2) of 34.3 ± 30.3 h for tablets and 19.9 ± 12.8 h for paste. After 8 d of dosing at 0.1 mg/kg every 24 h, pharmacokinetic parameters stabilized to an AUC of 6,341 ± 3,003 h*mg/ml for tablets and 5,613 ± 2,262 for paste, and T1/2 of 84.4 ± 32.2 h for tablets and 62.9 ± 2.3 h for paste. Serum COX inhibition was evaluated in vitro and ex vivo in untreated elephant plasma, where firocoxib demonstrated preferential inhibition of COX-2. No adverse effects from firocoxib administration were identified in this study. Results suggest administering firocoxib to Asian elephants at a dose of 0.1 mg/kg orally, using either tablet or paste formulations, every 24 h.

SERUM DISPOSITION OF A SINGLE DOSE OF ORALLY ADMINISTERED FIROCOXIB IN AFRICAN ELEPHANTS (LOXODONTA AFRICANA).

The time course of serum firocoxib concentrations was described after administration of two single oral doses (0.01 and 0.1 mg/kg) of commercially available firocoxib tablet (n = 4) and paste (n = 2) formulations to six healthy adult female African (Loxodonta africana) elephants. Firocoxib was quantitated by high-performance liquid chromatography. Firocoxib serum concentrations were below detectable levels after administration of 0.01 mg/kg of both formulations. A dose of 0.1 mg/kg (n = 4) of the tablet formulation had the following mean ± SD of pharmacokinetic parameters: area under the curve (AUC) 1,588 ± 362 h × ng/ml, maximum plasma concentration (Cmax) 31 ± 6.6 ng/ml at 6.4 ± 1.8 h, and disappearance half-life (T1/2) 66 ± 59 h, Elephant compliance to oral administration of the paste formulation was challenging, with only two elephants accepting administration of the paste at 0.1 mg/kg. Pharmacokinetic parameters determined included AUC of 814 h × ng/ml, Cmax of 44 ng/ml at Tmax of 7.0 h, and T1/2 of 36.4 h. Based on mean AUC, the relative bioavailability of paste compared to tablet formulations was 50%. Limitations of this study were the small number of participants and elephant compliance with the paste formulation. This study supports an oral dose of 0.1 mg/kg every 24 h. Multidose and IV trials are indicated to confirm firocoxib dosing requirements for African elephants.

Genomic and in vitro pharmacodynamic analysis of rifampicin resistance in multidrug-resistant canine Staphylococcus pseudintermedius isolates.

BACKGROUND: Antimicrobial resistance is a growing concern in canine Staphylococcus pseudintermedius dermatitis. Treatment with rifampicin (RFP) is considered only in meticillin-resistant and multidrug-resistant S. pseudintermedius (MDR-MRSP). HYPOTHESIS/OBJECTIVES: To determine an optimal RFP dosing for MDR-MRSP treatment without induction of RFP resistance and identify causal mutations for antimicrobial resistance. METHODS AND MATERIALS: Time-kill assays were performed in a control isolate and three MDR-MRSP isolates at six clinically relevant concentrations [32 to 1,024 × MIC (the minimum inhibitory concentration)]. Whole-genome resequencing and bioinformatic analysis were performed in the resistant strains developed in this assay. RESULTS: The genomic analysis identified nine antimicrobial resistance genes (ARGs) in MDR-MRSP isolates, which are responsible for resistance to seven classes of antibiotics. RFP activity against all four isolates was consistent with a time-dependent and bacteriostatic response. RFP resistance was observed in six of the 28 time-kill assays, including concentrations 64 × MIC in MDR-MRSP1 isolates at 24 h, 32 × MIC in MDR-MRSP2 at 48 h, 32 × MIC in MDR-MRSP3 at 48 h and 256 × MIC in MDR-MRSP3 at 24 h. Genome-wide mutation analyses in these RFP-resistant strains discovered the causal mutations in the coding region of the rpoB gene. CONCLUSIONS AND CLINICAL RELEVANCE: A study has shown that 6 mg/kg per os results in plasma concentrations of 600-1,000 × MIC of S. pseudintermedius. Based on our data, this dose should achieve the minimum MIC (×512) to prevent RFP resistance development; therefore, we recommend a minimum daily dose of 6 mg/kg for MDR-MRSP pyoderma treatment when limited antibiotic options are available.

PHARMACOKINETICS OF ORALLY ADMINISTERED FLUNIXIN MEGLUMINE IN AFRICAN (LOXODONTA AFRICANA) AND ASIAN (ELEPHAS MAXIMUS) ELEPHANTS.

Flunixin meglumine is the most commonly used nonsteroidal anti-inflammatory drug used to treat elephants; however, no pharmacokinetic study for flunixin has yet been conducted in these species, and dosages used range widely. Pharmacokinetic parameters of flunixin were determined in African (Loxodonta africana) and Asian (Elephas maximus) elephants after single-dose oral administration of 0.8 and 1.5 mg/kg flunixin paste in each species. Elephant compliance to oral administration of banamine was occasionally challenging, especially among older, female African elephants. After administration of 0.8 mg/kg flunixin, mean serum concentrations peaked in approximately 1.3 hr at 2.1 ± 0.8 µg/ml for Asian (n = 8) and 2.8 hr at 2.5 ± 0.7 µg/ml for African (n = 8) elephants. Dosages of 1.5 mg/kg flunixin resulted in mean serum concentration peaks of 7.2 ± 1.5 µg/ml in Asian elephants (n = 7) and 4.4 ± 0.7 µg/ml in African elephants (n = 6). However, multiple-dose trials using 1.1 mg/kg flunixin resulted in peak serum concentrations that were again less in Asian than African elephants (2.7 µg/ml versus 4.4 µg/ml, respectively). Asian elephants consistently had lower time to maximal concentration, greater area under the curve, and longer mean residence times compared with African elephants. In other species, flunixin is excreted unchanged primarily via hepatic routes with small amounts in the urine. Asian elephants may engage in some level of enterohepatic recycling of flunixin, as was previously reported for phenylbutazone. This study supports that different oral dosing regimens should be used for Asian (1.0 mg/kg SID) and African (1.2 mg/kg SID) elephants, and oral administration techniques used should ensure complete dosage delivery.

PHARMACOKINETICS OF PRIMAQUINE PHOSPHATE AFTER A SINGLE ORAL ADMINISTRATION TO AFRICAN PENGUINS (SPHENISCUS DEMERSUS).

Primaquine is an 8-aminoquinolone drug commonly used for the chemoprophylaxis and treatment of avian malarial infections in managed penguin populations worldwide. Little is known about its pharmacokinetic properties in avian species. The objective of this study was to describe the disposition of primaquine phosphate after a single oral dose in 15 healthy African penguins (Spheniscus demersus). A single tablet containing 26.3 mg of primaquine phosphate (equivalent to 15 mg primaquine base) was administered orally to each bird in a herring fish. Blood samples were collected prior to drug administration and at predetermined timepoints through 144 hr postadministration. Plasma was analyzed for drug concentration by high-performance liquid chromatography with ultraviolet detection. Mean maximum plasma concentration of primaquine phosphate was 277 ± 96 ng/ml at approximately 3.1 hr following oral administration. The mean disappearance half-life was 3.6 ± 1.6 hr. Plasma concentrations were below detectable limits in all but one penguin by 36 hr. A single oral administration of 26.3 mg of primaquine phosphate in African penguins resulted in a pharmacokinetic profile comparable to those attained in human studies. These results suggest that a dosing interval similar to human regimens may be of potential use in the prevention and treatment of avian malaria in penguins. Additional clinical studies are needed to determine the efficacy and safety of this regimen.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs are of a significant health concern. Illicit substances are taken by healthy individuals as well as by patients with medical conditions such as mental illnesses, acquired immunodeficiency syndrome, diabetes mellitus and cancer. Many individuals that use illicit substances simultaneously take clinical drugs meant for targeted treatment. This concomitant usage can lead to life-threatening pharmacokinetic interactions between illicit substances and clinical drugs. Optimal levels and activity of drug-metabolizing enzymes and drug-transporters are crucial for metabolism and disposition of illicit substances as well as clinical drugs. However, both illicit substances and clinical drugs can induce changes in the expression and/or activity of drug-metabolizing enzymes and drug-transporters. Consequently, with concomitant usage, illicit substances can adversely influence the therapeutic outcome of coadministered clinical drugs. Likewise, clinical drugs can adversely affect the response of coadministered illicit substances. While the interactions between illicit substances and clinical drugs pose a tremendous health and financial burden, they lack a similar level of attention as drug-drug, food-drug, supplement-drug, herb-drug, disease-drug, or other substance-drug interactions such as alcohol-drug and tobacco-drug interactions. This review highlights the clinical pharmacokinetic interactions between clinical drugs and commonly used illicit substances such as cannabis, cocaine and 3, 4-Methylenedioxymethamphetamine (MDMA). Rigorous efforts are warranted to further understand the underlying mechanisms responsible for these clinical pharmacokinetic interactions. It is also critical to extend the awareness of the life-threatening adverse interactions to both health care professionals and patients.

Regulation of the neuroendocrine axis in male rats by soy-based diets is independent of age and due specifically to isoflavone action†.

Soy-based foods are consumed for their health beneficial effects, implying that the population is exposed to soy isoflavones in the diet. Herein, male rats at 21, 35, and 75 days of age were maintained either on a casein control diet, soybean meal (SBM), or control diet supplemented with daidzin and genistin (G + D) for 14 days. Feeding of SBM and G + D diets decreased testicular testosterone (T) secretion regardless of age. Altered androgen secretion was due to decreased (P < 0.05) Star and Hsd17ß protein in the testes and was associated with increased (P < 0.05) Lhß and Fshß subunit protein expression in pituitary glands. Second, male rats were fed either a casein control diet, control diet + daidzin, control diet + genistin, or control diet + genistin + daidzin (G + D). Compared to control, feeding of all isoflavone-containing diets decreased (P < 0.05) testicular T concentrations, and more so in the G + D diet group. Interestingly, Esr1 and androgen receptor protein and pituitary Fshß with Lhß subunit protein were increased (P < 0.05) by feeding of genistin and G + D diets, but not the daidzin diet. However, daidzein and genistein both caused a concentration dependent inhibition (P < 0.05) of T secretion by Leydig cells in vitro with IC50 of 184 ηM and 36 ηM, respectively. Results demonstrated that altered testicular steroidogenic capacity and pituitary FSHß and LHß subunit expression due to soy-based diets result from specific actions by genistein and daidzein. Experiments to assess effects of isoflavone regulation of intratesticular androgen concentrations on male fertility are warranted.

Excessive Cyclosporine-Associated Immunosuppression in a Dog Heterozygous for the MDR1 (ABCB1-1Δ) Mutation.

Pharmacodynamic monitoring was used to titrate cyclosporine dosing in a dog with immune-mediated hemolytic anemia. Development of a suspected secondary infection, with subsequent discovery of an unexpectedly high level of T-cell suppression despite a relatively low cyclosporine dose, prompted an investigation into the cause of possible excessive immunosuppression. Blood cyclosporine concentrations were within expected target ranges, and the dog was determined to be heterozygous for the multidrug resistance protein 1 (MDR1; ATP-binding cassette sub family B member 1-1Δ) gene mutation. The MDR1 mutation was suspected to have contributed to the excessive immunosuppression experienced by this patient. This case highlights the need to monitor immunosuppressive therapy in the individual patient, especially when the patient is not responding to therapy at typical dosages or when secondary infections develop at dosages lower than expected to cause significant immunosuppression. Pharmacodynamic monitoring can be used to help identify unexpected excessive immunosuppression in dogs receiving cyclosporine, and MDR1 genotyping should be further explored as a potential method of predicting and preventing its occurrence.

Comparison of predicted intrinsic hepatic clearance of 30 pharmaceuticals in canine and feline liver microsomes.

1. Known cytochrome P450 (CYP) substrates in humans are used in veterinary medicine, with limited knowledge of the similarity or variation in CYP metabolism. Comparison of canine and feline CYP metabolism via liver microsomes report that human CYP probes and inhibitors demonstrate differing rates of intrinsic clearance (CLint). 2. The purpose of this study was to utilize a high-throughput liver microsome substrate depletion assay, combined with microsomal and plasma protein binding to compare the predicted hepatic clearance (CLhep) of thirty therapeutic agents used off-label in canines and felines, using both the well-stirred and parallel tube models. 3. In canine liver microsomes, 3/30 substrates did not have quantifiable CLint, while midazolam and amitriptyline CLint was too rapid for accurate determination. A CLhep was calculated for 29/30 substrates in feline microsomes. Overall, canine CLhep was faster compared to the feline, with fold differences ranging from 2-20-fold. 4. A comparison between the well-stirred and parallel tube model indicates that the parallel tube model reports a slighter higher CLhep in both species. 5. The differences in CYP metabolism between canine and feline highlight the need for additional research into CYP expression and specificity.

Identification and quantification of domestic feline cytochrome P450 transcriptome across multiple tissues.

Understanding of cytochrome P450 (CYP) isoform distribution and function in the domestic feline is limited. Only a few studies have defined individual CYP isoforms across metabolically relevant tissues, hampering the ability to predict drug metabolism and potential drug-drug interactions. Using RNA sequencing (RNA-seq), transcriptomes from the 99 Lives Cat Genome Sequencing Initiative databank combined with experimentally acquired whole transcriptome sequencing of healthy, adult male (n = 2) and female (n = 2) domestic felines, expression of 42 CYP isoforms were identified in 20 different tissues. Thirty-seven of these isoforms had not been previously reported in cats. Depending on the tissue, three to twenty-nine CYP isoform transcripts were expressed. The feline genome annotations did not differentiate CYP2E1 and 2E2 genes, demonstrating poor annotation for this gene using the reference genome. As the majority of the sequences are based on automated pipelines, complete cDNA sequences for translation into CYP protein sequences could not be determined. This study is the first to identify and characterize 37 additional CYP isoforms in feline tissues, increasing the number of identified CYP from the previously reported seven isoforms to 42 across 20 tissues.

Minimum inhibitory concentration and killing properties of rifampicin against canine Staphylococcus pseudintermedius isolates from dogs in the southeast USA.

BACKGROUND: Meticillin-resistant (MR) staphylococcal pyoderma in dogs has led to increased use of alternate antibiotics such as rifampicin (RFP). However, little information exists regarding its pharmacodynamics in MR Staphylococcus pseudintermedius. HYPOTHESIS/OBJECTIVES: To determine the minimum inhibitory concentration (MIC) and killing properties of RFP for canine Staphylococcus pseudintermedius isolates. METHODS: The MIC of RFP was determined using the ETEST® for 50 meticillin-susceptible (MS) and 50 MR S. pseudintermedius isolates collected from dogs. From these isolates, two MS isolates (RFP MIC of 0.003 and 0.008 µg/mL, respectively) and two MR isolates (RFP MIC of 0.003 and 0.012 µg/mL, respectively) were subjected to time-kill studies. Mueller-Hinton broth was supplemented with RFP at 0, 0.5, 1, 2, 4, 8, 16 and 32 times the MIC for 0, 2, 4, 10, 16 and 24 h. The number of viable colony forming units in each sample was determined using a commercial luciferase assay kit. RESULTS: The MIC50 and MIC90 were the same for MS and MR isolates, at 0.004 µg/mL and 0.008 µg/mL, respectively. Rifampicin kill curves were not indicative of concentration-dependency, suggesting time-dependent activity. Two isolates (MS 0.003 and 0.008 µg/mL) exhibited bacteriostatic activity, whereas two others (MR 0.003 and 0.012 µg/mL) exhibited bactericidal activity. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrated that MS and MR S. pseudintermedius isolates were equally susceptible to rifampicin and that dosing intervals should be designed for time-dependent efficacy. These data can support pharmacokinetic studies of RFP in dogs with susceptible infections caused by S. pseudintermedius.

THE PHARMACOKINETICS OF TOPICAL ITRACONAZOLE IN PANAMANIAN GOLDEN FROGS (ATELOPUS ZETEKI).

Chytridiomycosis is caused by the fungus Batrachochytrium dendrobatidis and is one of the primary causes of the global decline in amphibian populations and specifically of the Panamanian golden frog ( Atelopus zeteki ). Itraconazole has been demonstrated to be an effective treatment for chytridiomycosis by inhibiting cytochrome P450, a major enzyme important for the structure of B. dendrobatidis zoospores' plasma membranes. However, anecdotal reports of toxicity in this and other amphibian species have been reported at the 0.01% concentration. This study is the first to determine pharmacokinetics of 0.01% and 0.001% itraconazole in the Panamanian golden frog. Frogs were bathed 10 min, euthanized, and skin, liver, and heart were collected at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 36 hr. Itraconazole concentrations were measured using high performance liquid chromatography, and the minimum inhibitory concentration (MIC) of itraconazole (0.032 µg/ml) for B. dendrobatidis was used to determine whether therapeutic concentrations were attained. Itraconazole was detected in all tissues at both concentrations, indicating systemic absorption. At the 0.01% itraconazole bath, itraconazole concentrations in all tissues exceeded the MIC at all time points, and the lack of decline until the end of the study at 36 hr precluded determining a disappearance half-life. With the 0.001% bath, itraconazole exceeded the MIC and declined with a disappearance half-life that markedly varied (14.1-1,244 min). This study augments the growing literature base on chytridiomycosis and seeks to aid in further experimental attempts to find the most-optimal treatment protocol for this disease.

RESULTS OF THE MEGAVERTEBRATE ANALGESIA SURVEY: ELEPHANTS AND RHINO.

An online survey utilizing Survey Monkey linked through the American Association of Zoo Veterinarians listserve examined current practices in megavertebrate analgesia. Data collected included drugs administered, dosing regimens, ease of administration, efficacy, and adverse events. Fifty-nine facilities (38 housing elephants, 33 housing rhinoceroses) responded. All facilities administered nonsteroidal anti-inflammatory drugs (NSAIDs), with phenylbutazone (0.25-10 mg/kg) and flunixin meglumine (0.2-4 mg/kg) being most common. Efficacy was reported as "good" to "excellent" for these medications. Opioids were administered to elephants (11 of 38) and rhinoceroses (7 of 33), with tramadol (0.5-3.0 mg/kg) and butorphanol (0.05-1.0 mg/kg) being most common. Tramadol efficacy scores were highly variable in both elephants and rhinoceroses. While drug choices were similar among institutions, substantial variability in dosing regimens and reported efficacy between and within facilities indicates the need for pharmacokinetic studies and standardized methods of analyzing response to treatment to establish dosing regimens and clinical trials to establish efficacy and safety.

RESULTS OF THE MEGAVEREBRATE ANALGESIA SURVEY: GIRAFFE AND HIPPOPOTAMUS.

Results of an online survey posted on the American Association of Zoo Veterinarians listserv examined the patterns of analgesic medication and pain management modalities used for captive giraffe and hippopotami. Compiled data included signalment, drugs administered, dosing regimens, subjective efficacy scores, ease of administration, and adverse events. Nineteen institutions exhibiting hippopotami ( Hippopotamus amphibious ) and pygmy hippopotami (Choeropsis liberiensis) and 45 exhibiting giraffe ( Giraffa camelopardalis spp.) responded. Phenylbutazone was the most-commonly administered nonsteroidal anti-inflammatory drug (NSAID), followed by flunixin meglumine, but doses varied widely. Eight institutions reported adverse events from NSAID administration. Tramadol was the most-commonly administered opioid followed by butorphanol. Only one adverse event was reported for opioids. Twenty-three of 45 institutions exhibiting giraffe utilized alternative analgesia methods including gabapentin, glucosamine-chondroitin, local anesthetics, and low level laser therapy. Six of 19 institutions exhibiting hippopotami administered omega 3-6 fatty acids, gabapentin, glucosamine-chondroitin, and α-2 adrenergics to provide analgesia. While all reporting zoological institutions administered similar drugs, there was substantial variation and diversity in both dosing regimens and frequencies, indicating the need for both preclinical and clinical studies supporting dosing regimens.

A novel alanine to serine substitution mutation in SoxS induces overexpression of efflux pumps and contributes to multidrug resistance in clinical Escherichia coli isolates.

OBJECTIVES: The purpose of this study was to describe a putative role for a novel soxS mutation in contributing to multiple-antibiotic resistance in canine fluoroquinolone-associated MDR (FQ-MDR) Escherichia coli. This soxS mutation was discovered in canine faecal E. coli isolates during a study investigating the effect of oral fluoroquinolone administration on faecal E. coli in healthy dogs. METHODS: We determined via quantitative real-time RT-PCR that both soxS and acrB were overexpressed in the clinical soxS Ala-12→Ser (soxS(A12S)) mutants and this may account for their FQ-MDR phenotype. We validated the FQ-MDR phenotype of the clinical isolates by reconstructing the WT and the soxS(A12S) mutation in the E. coli soxS null mutant JW4023 (soxS::kn) via allelic exchange. RESULTS: The JW4023 soxS(A12S) derivative showed an increase in MICs of ciprofloxacin, enrofloxacin and chloramphenicol compared with the JW4023 derivative in which the WT soxS had been restored. The soxS and acrB genes were overexpressed in the JW4023 soxS(A12S) mutant compared with JW4023 with WT soxS. A similar overexpression of efflux pump genes and an increase in antibiotic resistance were observed upon stimulation with paraquat to resemble the phenotype of the clinical soxS(A12S) isolates. CONCLUSIONS: Our data suggest that the soxS(A12S) substitution mutation is selected in clinical isolates when dogs are exposed to a fluoroquinolone and that this mutation contributes to the FQ-MDR phenotype of E. coli isolates.

Determining canine skin concentrations of terbinafine to guide the treatment of Malassezia dermatitis.

BACKGROUND: Terbinafine (TBF) is known to concentrate and persist in human skin. Its use is increasing in veterinary medicine, but there are limited data concerning its tissue concentration and efficacy in dogs. HYPOTHESIS/OBJECTIVES: (i) Describe TBF accumulation in canine skin; (ii) Integrate pharmacokinetic data with historical minimum inhibitory concentration (MIC) results for Malassezia pachydermatis to verify the currently used dosage of TBF for the treatment of Malassezia dermatitis. ANIMALS: Ten healthy, client-owned dogs. METHODS: Dogs were given TBF (generic preparation, 250 mg tablets) 30 mg/kg per os (p.o.) once daily for 21 days. Serum, sebum and stratum corneum (SC) samples were collected on days 1, 5, 7, 11, 14, 21, 28 and 35. High-pressure liquid chromatography was used to determine drug concentrations in samples. RESULTS: Relevant (mean ± standard deviation) parameters for TBF in serum, paw SC, thorax SC and sebum, respectively, were: maximum concentration (Cmax , µg/mL) 23.59 ± 10.41, 0.31 ± 0.26, 0.30 ± 0.32 and 0.48 ± 0.25; half-life (t1/2 , d) 4.49 ± 2.24, 6.34 ± 5.33, 4.64 ± 3.27 and 5.12 ± 3.33; time to maximum concentration (Tmax , d) 10.40 ± 6.98, 13.20 ± 5.16, 11.90 ± 8.62 and 10.60 ± 3.69. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that TBF does not achieve high concentrations in canine SC or sebum compared to serum. The mean Cmax of all skin tissues (paw SC, thorax SC and sebum) barely exceeded the reported Malassezia MIC90, of 0.25 µg/mL, which indicates that doses higher than 30 mg/kg p.o. once daily may be necessary.

Elution of Clindamycin and Enrofloxacin From Calcium Sulfate Hemihydrate Beads In Vitro.

OBJECTIVE: To compare the in vitro elution characteristics of clindamycin and enrofloxacin from calcium sulfate hemihydrate beads containing a single antibiotic, both antibiotics, and each antibiotic incubated in the same eluent well. STUDY DESIGN: Experimental in vitro study. METHODS: Calcium sulfate hemihydrate beads were formed by mixing with clindamycin and/or enrofloxacin to create 4 study groups: (1) 160 mg clindamycin/10 beads; (2) 160 mg enrofloxacin/10 beads; (3) 160 mg clindamycin + 160 mg enrofloxacin/10 beads; and (4) 160 mg clindamycin/5 beads and 160 mg enrofloxacin/5 beads. Chains of beads were formed in triplicate and placed in 5 mL phosphate buffered saline (PBS; pH 7.4 and room temperature) with constant agitation. Antibiotic-conditioned PBS was sampled at 14 time points from 1 hour to 30 days. Clindamycin and enrofloxacin concentrations in PBS were determined using high-performance liquid chromatography. RESULTS: Eluent concentrations from clindamycin-impregnated beads failed to remain sufficiently above minimum inhibitory concentration (MIC) for common infecting bacteria over the study period. Enrofloxacin eluent concentrations remained sufficiently above MIC for common wound pathogens of dogs and cats and demonstrated an atypical biphasic release pattern. No significant differences in elution occurred as a result of copolymerization of the antibiotics into a single bead or from individual beads co-eluting in the same eluent well. CONCLUSION: Clindamycin-impregnated beads cannot be recommended for treatment of infection at the studied doses; however, use of enrofloxacin-impregnated beads may be justified when susceptible bacteria are cultured.

DISPOSITION OF CEFTIOFUR AND ITS ACTIVE METABOLITES IN FALLOW DEER (DAMA DAMA) FOLLOWING SINGLE-DOSE INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION.

Septicemia and foot infections associated with Fusobacterium necrophorum , Pasturella multocida, and Streptococcus suis in captive fallow deer (Dama dama) are reasonably treated with ceftiofur hydrochloride. This study describes the disposition of ceftiofur after single-dose intravenous and intramuscular administration of 3.65±0.1678 mg/kg in six female adult fallow deer using a nonrandomized crossover design and a 7-day washout period. Serial blood samples were collected for 12 hr postdrug administration. Ceftiofur bioactivity, including its active metabolite desfuroylceftiofur, was quantitated in serum using a microbiologic assay. After i.v. administration, the extrapolated serum drug concentration reported as median (range) was 52.83 (43.32-57.49) µg/ml and elimination half-life was 178.36 (19.75-217.22) min. The volume of distribution at steady-state was 0.171 (0.101-0.229) L/kg and serum clearance was 0.97 (0.48-4.3) ml/min per kg. After i.m. administration, median peak plasma concentration (Cmax) was 14.37 (9.00-32.00) µg/ml at 54.5 (11.00-95.00) min. The median elimination half-life and mean residence time were 128.32 (38.03-242.40) and 203.65 (62.48-347.15) min, respectively. The median absorption time after i.m. administration was 14.77 (-57.74 to 94.79) min. Bioavailability of ceftiofur following i.m. administration was 78.00 (58.00-137.00) percent. Based on this study, a mean i.m. dose of ceftiofur of 3.65±0.1678 mg/kg every 12 hr is recommended for maintaining serum concentrations above MIC90 levels for infections associated with F. necrophorum, P. multocida, and S. suis, in addition to other susceptible infectious bacteria.

Pharmacokinetics of Amitriptyline HCl and Its Metabolites in Healthy African Grey Parrots ( Psittacus erithacus ) and Cockatoos (Cacatua Species).

Amitriptyline, a tricyclic antidepressant, is used clinically to treat feather-destructive behavior in psittacine birds at a recommended dosage of 1-5 mg/kg PO q12-24h, which has been extrapolated from human medicine and based on anecdotal reports. The purpose of this pilot study was to describe the individual and population pharmacokinetic parameters of amitriptyline after a single oral dose at 1.5 mg/kg, 4.5 mg/kg, and 9 mg/kg in healthy African grey parrots ( Psittacus erithacus , n = 3) and cockatoos (Cacatua species, n = 3). Three birds received an initial 1.5 mg/kg oral dose, and blood samples were collected for 24 hours at fixed time intervals. Serum concentrations of amitriptyline and its metabolites were determined by polarized immunofluorescence. After determining the initial parameters and a 14-day washout period, 2 African grey parrots and 1 cockatoo received a single oral dose at 4.5 mg/kg, and 3 cockatoos and 1 African grey parrot received a single oral dose at 9 mg/kg. Concentrations reached the minimum therapeutic range reported in people (60 ng/mL) in 4 of 10 birds (4.5 and 9.0 mg/kg). Concentrations were within the toxic range in 1 African grey parrot (9 mg/kg), with regurgitation, ataxia, and dullness noted. Serum concentrations were nondetectable in 3 birds (1.5 and 4.5 mg/kg) and detectable but below the human therapeutic range in 3 birds (1.5 mg/kg and 9 mg/kg). Drug concentrations were continuing to increase at the end of the study (24 hours) in 1 bird. Elimination half-life varied from 1.6 to 91.2 hours. Population pharmacokinetics indicated significantly varied absorption, and elimination constants varied between species. Although amitriptyline appeared to be tolerated in most birds, disposition varies markedly among and within species, between the 2 genera, and within individual birds. The current recommended dosage of 1-5 mg/kg q12h in psittacine birds appears insufficient to achieve serum concentrations within the human therapeutic range and does not yield predictable concentrations. Results of this study suggest doses of up to 9 mg/kg may be necessary, although that dose may produce adverse events in some birds, and elimination half-life is sufficiently variable that dosing intervals are not predictable. Therapeutic drug monitoring combined with response to therapy is indicated to determine individual therapeutic ranges.

Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases).

BACKGROUND: Superficial bacterial folliculitis (SBF) is usually caused by Staphylococcus pseudintermedius and routinely treated with systemic antimicrobial agents. Infection is a consequence of reduced immunity associated with alterations of the skin barrier and underlying diseases that may be difficult to diagnose and resolve; thus, SBF is frequently recurrent and repeated treatment is necessary. The emergence of multiresistant bacteria, particularly meticillin-resistant S. pseudintermedius (MRSP), has focused attention on the need for optimal management of SBF. OBJECTIVES: Provision of an internationally available resource guiding practitioners in the diagnosis, treatment and prevention of SBF. DEVELOPMENT OF THE GUIDELINES: The guidelines were developed by the Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases, with consultation and advice from diplomates of the American and European Colleges of Veterinary Dermatology. They describe optimal methods for the diagnosis and management of SBF, including isolation of the causative organism, antimicrobial susceptibility testing, selection of antimicrobial drugs, therapeutic protocols and advice on infection control. Guidance is given for topical and systemic modalities, including approaches suitable for MRSP. Systemic drugs are classified in three tiers. Tier one drugs are used when diagnosis is clear cut and risk factors for antimicrobial drug resistance are not present. Otherwise, tier two drugs are used and antimicrobial susceptibility tests are mandatory. Tier three includes drugs reserved for highly resistant infections; their use is strongly discouraged and, when necessary, they should be used in consultation with specialists. CONCLUSIONS AND CLINICAL IMPORTANCE: Optimal management of SBF will improve antimicrobial use and reduce selection of MRSP and other multidrug-resistant bacteria affecting animal and human health.