Randomized, Controlled, Crossover trial of Prevention of Clindamycin-Induced Gastrointestinal Signs Using a Synbiotic in Healthy Research Cats.

BACKGROUND: Synbiotics often are prescribed to limit antibiotic-associated gastrointestinal signs (AAGS) in cats, but data to support this recommendation are lacking. OBJECTIVE: To determine whether synbiotic co-administration mitigates AAGS in healthy research cats treated with clindamycin. ANIMALS: 16 healthy research cats. METHODS: A randomized, double-blinded, placebo-controlled, 2-way, 2-period, crossover study with a 6-week washout was performed. Each study period consisted of a 1-week baseline and a 3-week treatment period. Cats received 75 mg clindamycin with food once daily for 3 weeks, followed 1 hour later by either 2 capsules of a synbiotic or placebo. Food consumption, vomiting, fecal score, and completion of treatment were compared using repeated measures split plot or crossover designs with covariates, with P < 0.05 considered significant. RESULTS: Cats that received the synbiotic were more likely to complete treatment in period 1 (100% vs. 50%, P = 0.04). Cats vomited less when receiving the synbiotic but this was not significant, but there were significant period effects (F-value = 11.4, P < 0.01). Cats had higher food intake while receiving the synbiotic (F-value = 31.1, P < 0.01) despite period effects (F-value = 8.6, P < 0.01). There was no significant effect of treatment on fecal scores, which significantly increased over time (F-value = 17.9, P < 0.01). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of a synbiotic 1 hour after clindamycin administration decreased hyporexia and vomiting in healthy cats. Additionally, significant period effects suggest that clinical benefits of synbiotic administration persist for at least 6 weeks after discontinuation, decreasing the severity of AAGS in cats that subsequently received clindamycin with placebo. Unlike in people, synbiotic administration did not decrease antibiotic-associated diarrhea.

Extended low-dose dexamethasone suppression test for diagnosis of atypical Cushing's syndrome in dogs.

The purpose of this study was to evaluate extension of the low-dose dexamethasone suppression (LDDS) test from 8 h to 12 h to detect possible hypercortisolemia associated with atypical hyperadrenocorticism (AHAC). Twelve client-owned dogs were enrolled in the study: 6 healthy dogs (group 1) and 6 dogs with suspected AHAC (group 2). Baseline EDTA plasma samples were collected for endogenous ACTH determination using an immunoradiometric assay. Serum samples were collected before and at 4, 8, 10, and 12 h post-administration of 0.01 mg/kg dexamethasone IV for cortisol concentration determination via chemiluminescent assay. Mean endogenous ACTH concentration did not differ between groups (group 1: 22.4 pg/mL, group 2: 20.0 pg/mL; P > 0.2). Mean baseline cortisol concentration also did not differ significantly between groups (group 1: 3.03 µg/dL, group 2: 4.95 µg/dL; P > 0.2) nor was there any difference in mean cortisol concentration between the groups at any other time point (P > 0.2). The cortisol concentration from 1 dog in group 2 suppressed to 0.7 µg/dL at 8 h but increased to 1.5 µg/dL at 10 h and 3.7 µg/dL at 12 h post-dexamethasone. Based on results of this study, use of an extended LDDS test could not differentiate between healthy dogs and dogs with AHAC. Diagnosis of AHAC should continue to be based on prior established criteria until new testing has been identified.

Presumed primary immune-mediated neutropenia in 35 dogs: a retrospective study.

OBJECTIVES: To describe, in a cohort of dogs with presumed primary immune-mediated neutropenia, the presenting clinical characteristics, haematology results, bone marrow characteristics, therapies used (drugs and doses), clinical response to treatment, relapse and outcome at six months and one year. METHODS: Multi-institutional recruited retrospective descriptive case series with voluntary submissions. Presumed immune-mediated neutropenia was diagnosed based on a neutrophil concentration <1·5×109 cells/L on a minimum of two complete blood counts, exclusion of other causes of neutropenia based on a diagnostic bone marrow aspirate or biopsy, and exclusion of secondary immune-mediated neutropenia. Dogs meeting these diagnostic criteria between 2006 and 2013, and that had a haematocrit of ≥29% and minimum of two complete blood clounts performed after initiation of therapy, were included. RESULTS: Information on 35 dogs was included. Neutropenia was less than 0·5×109 cells/L in most cases (21 dogs), 0·5 to ·99×109 cells/L in 11, and 1.0 to 1·49×109 cells/L in three. Eight dogs had thrombocytopenia, which was severe (<49·9×109 cells/L) in three. [Correction added on 23 May 2017, after first online publication: the cell numbers were incorrect due to errors in the conversion of cell measurements to international units. The numbers have been corrected throughout the article and Table 2.] Twenty-three dogs had myeloid hyperplasia, 10 dogs had myeloid hypoplasia and two dogs had normal myelopoiesis. Neutropenia resolved in 32 of 33 dogs within two weeks of starting corticosteroid therapy and in all dogs within one month. Relapse of neutropenia occurred in 12 cases within one year. CLINICAL SIGNIFICANCE: Initial response of presumed primary immune-mediated neutropenia cases to corticosteroid therapy can be excellent. Long-term monitoring for relapse is warranted because 34% of cases relapsed during or after taper of immunosuppressive medications.

Posaconazole Pharmacokinetics in Healthy Cats after Oral and Intravenous Administration.

BACKGROUND: Posaconazole is the most active available azole antifungal drug, but absorption and pharmacokinetics are not available to guide dosing regimens in cats. OBJECTIVE: To determine the pharmacokinetics of posaconazole in cats given an IV solution and PO suspension. ANIMALS: Six healthy, adult research cats. METHODS: After a 12-hour fast, each cat received 15 mg/kg of posaconazole PO suspension with food. Four cats also received 3 mg/kg IV posaconazole after a 7-day washout period. Plasma was collected at predetermined intervals for analysis using high-pressure liquid chromatography (HPLC). Concentration data were analyzed using a 2-compartment pharmacokinetic analysis for IV administration data and a 1-compartment analysis with first-order input for PO administration data using Phoenix® software. RESULTS: After IV dosing, volume of distribution (VSS ) was 1.9 (0.3) L/kg (mean, standard deviation), terminal half-life (T½ ) was 57.7 (28.4) hours, and clearance was 28.1 (17.3) mL/kg/h. After PO dosing, peak concentration (CMAX ) was 1.2 (0.5) µg/mL and T½ was 38.1 (15.0) hours. Bioavailability of PO suspension was 15.9% (8.6). No adverse effects were observed with either route of administration. CONCLUSION AND CLINICAL IMPORTANCE: Despite low PO absorption, these data allow for simulation of PO dosage regimens that could be explored in clinical studies. Two regimens can be considered to maintain targeted trough concentrations of 0.5-0.7 µg/mL as extrapolated from studies in humans: (1) 30 mg/kg PO loading dose followed by 15 mg/kg q48h, or (2) 15 mg/kg PO loading dose followed by 7.5 mg/kg q24h.

Serum cortisol concentrations in dogs with pituitary-dependent hyperadrenocorticism and atypical hyperadrenocorticism.

BACKGROUND: Atypical hyperadrenocorticism (AHAC) is considered when dogs have clinical signs of hypercortisolemia with normal hyperadrenocorticism screening tests. HYPOTHESIS/OBJECTIVES: To compare cortisol concentrations and adrenal gland size among dogs with pituitary-dependent hyperadrenocorticism (PDH), atypical hyperadrenocorticism (AHAC), and healthy controls. ANIMALS: Ten healthy dogs, 7 dogs with PDH, and 8 dogs with AHAC. METHOD: Dogs were prospectively enrolled between November 2011 and January 2013. Dogs were diagnosed with PDH or AHAC based on clinical signs and positive screening test results (PDH) or abnormal extended adrenal hormone panel results (AHAC). Transverse adrenal gland measurements were obtained by abdominal ultrasound. Hourly mean cortisol (9 samplings), sum of hourly cortisol measurements and adrenal gland sizes were compared among the 3 groups. RESULTS: Hourly (control, 1.4 ± 0.6 µg/dL; AHAC, 2.9 ± 1.3; PDH, 4.3 ± 1.5) (mean, SD) and sum (control, 11.3 ± 3.3; AHAC, 23.2 ± 7.7; PDH, 34.7 ± 9.9) cortisol concentrations differed significantly between the controls and AHAC (P < .01) and PDH (P < .01) groups. Hourly (P < .01) but not sum (P = .27) cortisol concentrations differed between AHAC and PDH dogs. Average transverse adrenal gland diameter of control dogs (5.3 ± 1.2 mm) was significantly less than dogs with PDH (6.4 ± 1.4; P = .02) and AHAC (7.2 ± 1.5; P < .01); adrenal gland diameter did not differ (P = .18) between dogs with AHAC and PDH. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum cortisol concentrations in dogs with AHAC were increased compared to controls but less than dogs with PDH, while adrenal gland diameter was similar between dogs with AHAC and PDH. These findings suggest cortisol excess could contribute to the pathophysiology of AHAC.

Hepatic lesions in 90 captive nondomestic felids presented for autopsy.

Hepatic lesions in nondomestic felids are poorly characterized. The purpose of this study was to evaluate hepatic lesions in 90 captive, nondomestic felids including tigers, cougars, and lions. Hepatic lesions were histologically characterized as vacuolar change (lipidosis or glycogenosis), biliary cysts, biliary hyperplasia, hepatitis, necrosis, neoplasia, fibrosis, veno-occlusive disease, cholestasis, hematoma, congestion, or hemorrhage. Stepwise logistic regression analyses were performed for vacuolar change, benign biliary lesions, hepatitis, lipogranulomas, extramedullary hematopoiesis, and hepatic stellate cell hypertrophy and hyperplasia, with species as the outcome variable. Ninety cats met the inclusion criteria. Seventy livers (78%) contained 1 or more lesions. Hepatocellular vacuolar change (41/90 [46%]) was the most common lesion overall. Extramedullary hematopoiesis, lipogranulomas, and hepatic stellate cell hyperplasia were also common. One snow leopard had veno-occlusive disease. Tigers were more likely than other felids to have no significant hepatic histologic lesions (odds ratio [OR], 12.687; P = .002), and lions were more likely to have biliary cysts (OR, 5.97; P = .021). Six animals (7%) died of hepatic disease: cholangiocellular carcinoma (n = 2) and 1 each of hepatic lipidosis, hepatocellular necrosis, pyogranulomatous hepatitis, and suppurative cholecystitis. Hepatocellular iron and copper accumulations were present in 72 of 90 (80%) and 10 of 90 (11%) sections, respectively. Sinusoidal fibrosis was common (74/90 [82%]) and primarily centrilobular (65/74 [88%]). Hepatocellular iron, copper, and fibrosis were not significantly associated with hepatic lesions. Primary hepatic disease was not a common cause of death in nondomestic felids in this study.

Canine pancreatic-specific lipase concentrations in clinically healthy dogs and dogs with naturally occurring hyperadrenocorticism.

BACKGROUND: Specificity of canine pancreatic lipase immunoreactivity (cPLI) assays in dogs with hyperadrenocorticism (HAC) is unknown. HYPOTHESIS: Results of cPLI assays differ for clinically healthy dogs and dogs with HAC. ANIMALS: Seventeen healthy dogs and 20 dogs with HAC diagnosed by ACTH stimulation test results without evidence of clinical pancreatitis. METHODS: Dogs were enrolled between December 2009 and November 2010. Serum cPLI concentrations were determined by quantitative (Spec cPL test, SPEC) and semiquantitative (SNAP cPL test, SNAP) assays. Results were categorized as normal, equivocal, or abnormal (SPEC) or negative or positive (SNAP). Associations between group and cPLI were assessed using Fisher's exact test or the Mann-Whitney U-test. Spearman rank correlation coefficients (ρ) were determined for SNAP and SPEC results. Significance was set at P < .05. RESULTS: Spec cPL test concentrations were significantly (P < .001) higher in dogs with HAC (491.1 µg/L) than in healthy dogs (75.2 µg/L), with more abnormal SPEC results in HAC dogs (P < .001). There were more (P = .002) positive SNAP results in dogs with HAC (55%) than in healthy dogs (6%). SNAP and SPEC results were highly correlated (ρ = 0.85; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with HAC had higher SPEC concentrations and more positive SNAP results than clinically healthy dogs with normal ACTH stimulation test results. Specificity of SPEC and SNAP assays in HAC dogs without clinical pancreatitis were 65 and 45%, respectively. Pending further study, SNAP and SPEC results should be interpreted cautiously in dogs with HAC to avoid false diagnosis of concurrent pancreatitis.

Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs.

BACKGROUND: Itraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost. OBJECTIVE: To determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs. ANIMALS: Nine healthy, adult research Beagle dogs. METHODS: A randomized, 3-way, 3-period, crossover design with an 8-day washout period. After a 12-hour fast, each dog received 100 mg (average: 10.5 mg/kg) of either innovator itraconazole, an approved human generic capsule, or compounded itraconazole (compounded using a commercially available compounding vehicle) with a small meal. Plasma was collected at predetermined intervals for high pressure liquid chromatography analysis. Concentration data were analyzed using noncompartmental pharmacokinetics to determine area under the curve (AUC), peak concentration (C(MAX)), and terminal half-life. Bioequivalence tests compared generic and compounded itraconazole to the reference formulation. RESULTS: Average ratios of compounded and generic formulations to the reference formulation of itraconazole for AUC were 5.52% and 104.2%, respectively, and for C(MAX) were 4.14% and 86.34%, respectively. A test of bioequivalence using 2 one-sided tests and 90% confidence intervals did not meet bioequivalence criteria for either formulation. CONCLUSION AND CLINICAL IMPORTANCE: Neither generic nor compounded itraconazole is bioequivalent to the reference formulation in dogs. However, pharmacokinetic data for generic formulation were similar enough that therapeutic concentrations could be achieved. Compounded itraconazole produced such low plasma concentrations, it is unlikely to be effective; therefore, compounded itraconazole should not be used in dogs.

Bartonella species antibodies and hyperglobulinemia in privately owned cats.

BACKGROUND: Bartonella species are zoonotic agents and primary pathogens in cats. Hyperglobulinemia has been associated with bartonellosis in humans and cats. HYPOTHESIS/OBJECTIVES: To evaluate for associations between Bartonella species immunoglobulin G (IgG) antibodies and serum biochemistry panel results in privately owned cats. ANIMALS: 1,477 privately owned cats. METHODS: Residual sera were collected after biochemical evaluation for this prospective, cross-sectional serosurvey. Bartonella species IgG ELISA was performed with a cutoff value of ≥ 1 : 64. Stepwise logistic regression analysis was performed with the endpoint titer as the outcome variable. The final statistical model included age, albumin, ALP activity, ALT activity, bilirubin, creatinine, glucose, and globulin as covariates. Serum protein electrophoresis was performed with serum from 50 cats with and without antibodies to Bartonella species and hyperglobulinemia. Sera from cats seropositive to Bartonella species and with hyperglobulinemia were assessed for evidence of exposure to other infectious agents associated with hyperglobulinemia. RESULTS: Risk of seropositivity to Bartonella species was positively associated with the natural log of globulin concentration (OR = 11.90, 95% CI 6.15-23.02, P < .0001), and inversely associated with the natural log of glucose concentration (OR = 0.66, 95% CI 0.50-0.87, P = .004). Another explanation for hyperglobulinemia was not identified for most cats with Bartonella species antibodies. Hyperglobulinemia was primarily caused by polyclonal gammopathy in cats that were seronegative and seropositive for Bartonella species. CONCLUSIONS AND CLINICAL IMPORTANCE: Hyperglobulinemia was significantly associated with seropositivity to Bartonella species. Testing for bartonellosis is warranted in cats with unexplained hyperglobulinemia and clinical or laboratory findings suggestive of bartonellosis.

Associations among albuminuria, C-reactive protein concentrations, survival predictor index scores, and survival in 78 critically ill dogs.

BACKGROUND: Microalbuminuria and C-reactive protein (CRP) are predictors of morbidity and survival in critically ill human patients. HYPOTHESIS/OBJECTIVES: To evaluate results of microalbuminuria assays (untimed single-sample urine albumin concentration [U-ALB] and the urine albumin:creatinine ratio [UACR]), serum CRP, and survival predictor index (SPI2) scores as predictors of survival in critically ill dogs. ANIMALS: Seventy-eight dogs admitted to intensive care units at University of Tennessee (UT) and Colorado State University (CSU). METHODS: Prospective observational study. Critically ill dogs were eligible for enrollment, unless euthanized because of financial constraints. Samples were collected within 3 hours of admission. Spearman's rank-correlation coefficients were determined for U-ALB, UACR, CRP, and SPI2. U-ALB, UACR, CRP, and SPI2 were assessed for associations with 7- and 30-day survival by Mann-Whitney U-tests and receiver operating characteristic (ROC) curves. P-values < .0125 were considered significant. RESULTS: UT (n = 49) and CSU (n = 29) patients did not differ significantly. Forty percent (31/78) of dogs died. SPI2 was inversely correlated with U-ALB (r(s) = -0.39, P < .001) and UACR (r(s) = -0.41, P < .001). CRP was not correlated with SPI2 (P = .019), U-ALB (P > .1), or UACR (P > .1). U-ALB and UACR had very high correlation (r(s) = 0.95, P < .001). SPI2, U-ALB, and UACR differed significantly for survivors and nonsurvivors. SPI2, U-ALB, and UACR had areas under the ROC curve (AUC) from 0.68 to 0.74 for survival prediction. CONCLUSIONS AND CLINICAL IMPORTANCE: Albuminuria and SPI2, but not CRP, are associated with survival in critically ill dogs. Suboptimal AUCs limit the value of microalbuminuria testing for clinical risk assessment. Additional studies are necessary to determine the usefulness of microalbuminuria testing in patient risk stratification for prospective research.

Comparison of signalment, clinicopathologic findings, histologic diagnosis, and prognosis in dogs with glomerular disease with or without nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) develops most commonly in people with glomerular diseases associated with marked albuminuria. Hypernatremia, hypertension, and progressive renal failure are more prevalent in nephrotic than nonnephrotic human patients. HYPOTHESIS/OBJECTIVES: Dogs with NS have higher serum cholesterol, triglyceride, and sodium concentrations, higher urine protein:creatinine ratios (UPC) and systolic blood pressure, and lower serum albumin concentrations than dogs with nonnephrotic glomerular disease (NNGD). NS is associated with membranous glomerulopathy and amyloidosis. Affected dogs are more likely to be azotemic and have shorter survival times. ANIMALS: Two hundred and thirty-four pet dogs (78 NS dogs, 156 NNGD dogs). METHODS: Multicenter retrospective case-control study comparing time-matched NS and NNGD dogs. NS was defined as the concurrent presence of hypoalbuminemia, hypercholesterolemia, proteinuria, and extravascular fluid accumulation. Signalment, clinicopathologic variables, histopathologic diagnoses, and survival time were compared between groups. RESULTS: Age, serum albumin, chloride, calcium, phosphate, creatinine, and cholesterol concentrations, and UPC differed significantly between NS and NNGD dogs. Both groups were equally likely to be azotemic at time of diagnosis, and NS was not associated with histologic diagnosis. Median survival was significantly shorter for NS (12.5 days) versus NNGD dogs (104.5 days). When subgrouped based on serum creatinine (< or ≥1.5 mg/dL), survival of NS versus NNGD dogs was only significantly different in nonazotemic dogs (51 versus 605 days, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Presence of NS is associated with poorer prognosis in dogs with nonazotemic glomerular disease. Preventing development of NS is warranted; however, specific interventions were not evaluated in this study.

Antibodies against Crandell Rees feline kidney (CRFK) cell line antigens, alpha-enolase, and annexin A2 in vaccinated and CRFK hyperinoculated cats.

BACKGROUND: Cats inoculated with feline herpesvirus 1, calicivirus, and panleukopenia (FVRCP) vaccines grown on the Crandell Rees feline kidney (CRFK) cell line have been shown to develop anti-CRFK antibodies. The identities of common CRFK antigens are unknown. HYPOTHESIS: Cats inoculated with CRFK lysates and FVRCP vaccines will develop autoantibodies measurable by Western blot immunoassay. Antigens associated with these antibodies can be isolated for further study. ANIMALS: One CRFK hyperinoculated rabbit, 44 age-matched unvaccinated kittens purchased from a commercial vendor. METHODS: Commonly recognized CRFK antigens were identified by comparison of Western blot immunoassays using sera from a hyperinoculated rabbit and kittens inoculated with CRFK lysate or 1 of 4 commercially available FVRCP vaccines. Antigens were purified from CRFK lysates and sequenced. Antigen recognition was confirmed by Western blot immunoassay and indirect ELISA for 2 proteins using sera from CRFK and FVRCP inoculated kittens. RESULTS: CRFK antigens 47, 40, and 38 kD in size were identified. Protein isolation and sequencing identified 3 CRFK proteins as alpha-enolase, annexin A2, and macrophage capping protein (MCP). Sera from FVRCP and CRFK inoculated cats were confirmed to recognize annexin A2 and alpha-enolase by Western blot immunoassay and indirect ELISA. CONCLUSIONS AND CLINICAL RELEVANCE: This study validated the use of Western blot immunoassay for detection of antibodies against CRFK proteins and identified 3 CRFK antigens. In humans, alpha-enolase antibodies are nephritogenic; alpha-enolase and annexin A2 antibodies have been associated with autoimmune diseases. Further research will be necessary to determine the clinical relevance of these findings.

Nontraumatic rupture of an adrenal gland tumor causing intra-abdominal or retroperitoneal hemorrhage in four dogs.

Diagnosis and surgical management of intra-abdominal or retroperitoneal hemorrhage in 4 dogs with rupture of an adrenal gland tumor were determined. All 4 dogs were lethargic and weak with pale mucous membranes on initial examination. Three dogs did not have any history of clinical signs of hyperadrenocorticism or pheochromocytoma prior to examination. In 3 of the dogs, a mass in the area of the adrenal gland was identified with ultrasonography prior to surgery. All dogs developed ventricular premature contractions before or during anesthesia. Three dogs survived adrenalectomy; 1 dog was euthanatized during surgery because of an inability to achieve adequate hemostasis. The remaining 3 dogs all survived more than 5 months after surgery; 1 was euthanatized 9 months after surgery because of rupture of a hepatic mass. On the basis of these results, we suggest that hemodynamic stabilization followed by adrenalectomy is the treatment of choice for dogs with nontraumatic rupture of an adrenal gland tumor and resulting life-threatening hemorrhage.