Efficacy of antimicrobial and nutraceutical treatment for canine acute diarrhoea: A systematic review and meta-analysis for European Network for Optimization of Antimicrobial Therapy (ENOVAT) guidelines.

Systemic antimicrobial treatments are commonly prescribed to dogs with acute diarrhoea, while nutraceuticals (prebiotics, probiotics, and synbiotics) are frequently administered as an alternative treatment. The aim of this systematic review and meta-analysis was to assess the effectiveness of antimicrobials and nutraceutical preparations for treatment of canine acute diarrhoea (CAD). The results of this study will be used to create evidence-based treatment guidelines. PICOs (population, intervention, comparator, and outcome) were generated by a multidisciplinary expert panel taking into account opinions from stakeholders (general practitioners and dog owners). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to evaluate the certainty of the evidence. The systematic search yielded six randomised controlled trials (RCT) for antimicrobial treatment and six RCTs for nutraceutical treatment meeting the eligibility criteria. Categories of disease severity (mild, moderate, and severe) were created based on the presence of systemic signs and response to fluid therapy. Outcomes included duration of diarrhoea, duration of hospitalization, progression of disease, mortality, and adverse effects. High certainty evidence showed that antimicrobial treatment did not have a clinically relevant effect on any outcome in dogs with mild or moderate disease. Certainty of evidence was low for dogs with severe disease. Nutraceutical products did not show a clinically significant effect in shortening the duration of diarrhoea (based on very low to moderate certainty evidence). No adverse effects were reported in any of the studies.

Azithromycin concentration in severely inflamed canine external ear canals - a case series.

OBJECTIVE: To determine azithromycin concentration in severely inflamed canine external ear canals. MATERIAL AND METHODS: Five dogs of various breeds and ages with severe and chronic otitis externa underwent ear canal reconstruction surgery. A single oral dose of azithromycin at 10 mg/kg was administered 12 to 24 hours prior to surgery. Tissue samples were collected from the excised external ear canals and azithromycin concentration was determined using a liquid chromatography-tandem mass spectrometry method. RESULTS: Azithromycin concentrations ranging from 11.4 to 107.0 µg/g (mean 59.2 ± 44.6 µg/g, median 50.9 µg/g) were detected in the chronically infected external ear canal tissue 12 to 24 hours after administration. CLINICAL SIGNIFICANCE: Little information exists on antibiotic concentrations in pathological tissues of dogs. Macrolides are known to concentrate in skin tissue. In light of the present results, investigation of clinical efficacy of azithromycin in chronic canine otitis externa is warranted.

Microbial composition affects the performance of an artificial Tephritid larval diet.

The present study investigated the patterns of microorganisms in an artificial larval diet during Dacus ciliatus (Diptera; Tephritidae) larval development. Microbial population contents in the diet of total heterotrophic bacteria, yeast and molds, coliform and lactobacilli, and their dynamics during development, were monitored. Initially, the microbial composition in diet trays failing to produce viable pupae and in trays successfully producing pupae and adult flies was characterized. The failing diet trays contained large populations of lactobacilli that increased during larval development, and low populations of coliforms. In contrast, the successful diet showed an increasing population of coliforms and a low, or undetected, population of lactobacilli. To study the hypothesis that lactobacilli affect D. ciliatus larval development, we conducted controlled inoculation experiments in which Lactobacillus plantarum was added into fresh diet at the time of egg seeding. L. plantarum inoculated trays showed no production of D. ciliatus. Control trays without lactobacilli inoculation showed variable results. One tray successfully produced viable pupae and adults, and showed a slight and slow increase in the indigenous populations of lactobacilli. The second tray, however, failed to produce pupae and showed a fast increase of the indigenous lactobacilli to very high levels. Monitored pH trends in L. plantarum-inoculated diet showed a sharp pH decrease during the first 4 days of larval development from 5 to less than 4 units, while successful diet, producing viable D. ciliatus pupae and adults, showed a moderate pH drop during most of the larval development period. The paper discusses the possible ecological interactions between D. ciliatus larvae, the microbial content of the diet and the physical properties of the diet. The discussion also points out at the usefulness of this approach in understanding and managing mass production parameters of tephritid fruit flies industrial diets used for Sterile Insect Technique.

In vitro lectin binding to the outer surface of Spirocerca lupi at different life-stages.

Spirocerca lupi is the esophageal nematode of dogs. Early, transient eosinophilia occurs in experimentally infected dogs, but is absent in advanced cases, suggesting that the nematode evades the dog's immune system. Lectins are proteins or glycoproteins of plant or animal origin, binding different saccharides, with varying specificities and avidities, used to characterize surface haptens in plant and animal parasitic helminths. This study investigated the in vitro binding of six lectins (Concanavalin A [ConA], wheat germ agglutinin [WGA], peanut agglutinin [PNA], soybean agglutinin [SBA], Dolichus biflorus agglutinin [DBA] and Ulex earopaeus agglutinin I [UEA]) to the surface of S. lupi nematodes at different life stages, the L2 and L3 larvae (dead and alive) and to dead adult worms, with negative controls, with and without addition of the six respective inhibitory sugar haptens. Con A moderately bound to surfaces of both live and frozen L3, to the stoma and excretory pores of adult worms, and to the outer surface nematode's eggs, within a female worm, but not to L2. PNA bound only to stoma and excretory pores surfaces in both frozen and live L3. WGA bound strongly to the outer surfaces of live and dead L2 and L3, which resulted in molting of live larvae. These results suggest that the nematode's surface content change during its development. Such changes may play roles in the nematode's interactions with the intermediate and definitive hosts' tissues, and in its ability to evade the immune response, its long survival within the host, and even induce neoplastic transformation.

Laboratory longevity and competitiveness of Dacus ciliatus Loew (Diptera: Tephritidae) following sub-sterilizing gamma irradiation.

The effect of a sub-sterilizing gamma radiation dose on Dacus ciliatus adults was investigated to assess the suitability of the sterile insect technique (SIT) as an alternative method to control this pest. Late pupae (48 h prior to adult emergence) from a laboratory strain were irradiated with 120 Gy of gamma rays emitted by a 60Co source. Following adult emergence, the mortality of irradiated and non-irradiated cohorts was recorded. Over a period of 50 days after emergence, no significant negative effects of irradiation upon the longevity of male or female laboratory flies were observed. A laboratory competitiveness study (Fried test), using irradiated laboratory and wild males at a ratio of 3:1 was conducted to assess the ability of irradiated males to reduce the egg hatch rates of a wild population. The overall competitiveness was found to be ca. 0.32, suggesting a reduced, but satisfactory, quality of irradiated laboratory as compared with wild males. Based on the above findings, we calculated and proposed effective male release ratios for field application of SIT against D. ciliatus.

Long-term outcome of transendoscopic oesophageal mass ablation in dogs with Spirocerca lupi-associated oesophageal sarcoma.

Oesophageal sarcoma is a potential sequel of Spirocerca lupi infection. Oesophageal mass excision can be performed by open chest surgery. The objectives of this observational study were to evaluate the feasibility, short-term morbidity and long-term outcome of transendoscopic oesophageal mass ablation in dogs with spirocercosis-associated oesophageal neoplasia. A 9 mm video-endoscope and laser or electrocauterisation were used to debulk the oesophageal mass. Long-term follow-up was done by telephonic interviews. Fifteen dogs were included. The median tumour size was 5 cm (range 3.5-9). The median procedure time was 75 minutes (range 35-165) and was deemed successful in 12/15 dogs (80 per cent). Recovery was uneventful in all dogs. Immediate complications included oesophageal damage (two dogs) oesophageal perforation (one dog) and a focal thermal damage (one dog). The median hospitalisation time of all dogs was less than one day, with all but two discharged on the procedure day. The median survival time, available in nine dogs that were followed, was 202 days (range 51-691). Four of these dogs (44 per cent) survived more than six months, of which three survived more than one year. In conclusion, transendoscopic oesophageal mass ablation might be considered an alternative, palliative procedure for open-chest oesophageal surgery. It has comparable long-term survival, lower morbidity, short hospitalisation time and relatively low cost.

Temporal association of ambient temperature and relative humidity with Spirocerca lupi infection of Onthophagus sellatus: a 14-year longitudinal study.

The parasitic nematode Spirocerca lupi causes major morbidity and mortality in dogs. The scarab beetle Onthophagus sellatus is its major intermediate host in Israel. We investigated the prevalence of beetle infection by S. lupi in different years between 1994 and 2008. The average monthly maximum and minimum relative humidity (RH) and ambient temperature (AT) throughout the study period were calculated based on daily meteorological data. The infection prevalence decreased over the study period, possibly due to a chronological change resulting from increased preventive treatment of dogs against S. lupi, or climate change. Multivariate analysis was performed for these two hypotheses. Under the first hypothesis, chronological change was forced into the model, and environmental variables were inserted stepwise. The final model included beetle-collection date, minimum RH (RH min) during the month preceding beetle collection, its interaction with maximal AT (AT max) during that same month, and the interaction of maximal RH (RH max) and AT max, during the month of beetle collection. Under the second hypothesis, chronological change was not forced. The final model included RH max during the month of beetle collection, average RH (RHave) during the month preceding beetle collection, and its interaction with AT max during the latter month. The results suggest that under both hypotheses, RH and AT during the month preceding beetle collection influence S. lupi's ability to develop and survive in O. sellatus, and may be used to predict the risk to dogs of S. lupi infection.

Use of the novel atypical opioid tapentadol in goats (Capra hircus): pharmacokinetics after intravenous, and intramuscular administration.

The objective of the present study was to assess the pharmacokinetics of the novel atypical drug tapentadol (TAP) after intravenous (I.V.) and intramuscular (I.M.) injections in clinically healthy goats. A 2 × 2 cross-over design study was carried out. Six local adult Nubian nonlactating, nonpregnant female goats, were given 5 mg/kg body weight of TAP by I.V. and I.M. routes. The concentrations of TAP in plasma were evaluated using a validated HPLC method. Transient adverse effects were noticed in some animals, especially after I.V. administration (tremors and ataxia). Three days after drug administration, severe hair loss was also recorded. The plasma concentrations after the two routes of administration were best described by a bi-compartmental model. After I.M. injection, TAP showed a very fast absorption (Tmax  = 0.17 h) and a short half-life (1.29 h). The I.M. bioavailability was quite high, despite being variable (87.8 ± 35.6%). This is the first pharmacokinetic study of TAP in goats but due to its unknown safety profile and efficacy, it is premature to recommend the use of this drug in clinical ovine practice.

Intravenous infusion of electrolyte solution changes pharmacokinetics of drugs: pharmacokinetics of ampicillin.

The pharmacokinetics of ampicillin in dogs was determined after intravenous (i.v.) bolus and constant rate infusion. Ampicillin was administered to six beagle dogs as an i.v. bolus at 20 mg/kg and as a constant rate i.v. infusion (CRI) at 20 mg/kg during 8 h (0.042 mL/min/kg) in Ringer's lactate (Hartmann's) solution. The concentrations were determined by an LC/MS/MS method. After i.v. bolus, ampicillin total body clearance, apparent volume of distribution at steady-state, mean residence time (MRT), and half-life were 4.53 ± 0.70 mL/min/kg, 0.275 ± 0.044 L/kg, 61 ± 13 min, and 111 (85-169) min, respectively. The corresponding parameters calculated after CRI were 13.5 ± 1.06 mL/min/kg, 0.993 ± 0.415 L/kg, 73 ± 27 min, and 49 (31-69) min. Ampicillin concentration decreased by 30% in the Ringer's lactate infusion solution mostly during the first hour after preparation of the solution. Constant rate infusion of Ringer's lactate solution during 8 h caused significant changes in ampicillin pharmacokinetics. The results suggested that special attention should be given to drug pharmacokinetics when co-administered intravenously with electrolyte solutions.

Evaluation of urinary catheters coated with sustained-release varnish of chlorhexidine in mitigating biofilm formation on urinary catheters in dogs.

BACKGROUND: Biofilm formation occurs commonly on urinary catheters. OBJECTIVES: To assess the efficacy of urinary catheters coated with sustained-release varnish of chlorhexidine in decreasing catheter-associated biofilm formation in dogs. ANIMALS: Thirty client-owned dogs. METHODS: Prospective study. Thirteen dogs were catheterized with urinary catheters coated with sustained-release varnish of chlorhexidine (study group), and 13 dogs were catheterized with an untreated urinary catheter (control group). Presence and intensity of biofilm formation on the urinary catheters were assessed and compared between the groups by evaluating colony-forming units (CFU) of biofilm bacteria, and semiquantitatively, using confocal laser scanning microscopy and electron microscopy. RESULTS: None of the dogs experienced adverse effects associated with the presence of the urinary catheters. Median CFU count of biofilm bacteria at all portions of the urinary catheter was significantly (P < .001) lower in the study compared with the control group. The degree of biofilm formation on the urinary catheters, as evaluated by confocal laser scanning microscopy and electron microscopy, was significantly lower in the study compared with the control group. Electron microscopy examination identified crystals on some of the urinary catheters. The proportion of catheters on which crystals were observed was significantly lower on the distal part of the urinary catheter in the study group compared with the control group (16.7% versus 66.7%, respectively; P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE: Chlorhexidine sustained-release varnish-coated urinary catheters effectively decrease urinary catheter-associated biofilm formation in dogs.

Serum gastrin concentrations in dogs with liver disorders.

Dogs with liver disorders often display gastrointestinal signs that may be triggered by ulceration. The liver is important for inactivation of some forms of gastrin. Therefore, hypergastrinaemia has been implicated in the pathogenesis of gastrointestinal ulcerations related to liver dysfunction. The aim of this study was to determine serum gastrin concentrations in dogs with liver disease. Fasted blood samples were collected from 15 dogs with newly diagnosed liver disease and 18 healthy dogs. Gastrin concentrations were significantly lower in dogs with congenital portosystemic shunt compared with healthy dogs (P=0.003). No significant difference (P=0.6) in gastrin concentration was revealed between dogs with hepatocellular disease and healthy dogs. Serum gastrin concentrations were not significantly associated with the occurrence of vomiting, anorexia, diarrhoea, or melaena in dogs with liver disorders. These findings did not provide support for the role of hypergastrinaemia in the development of gastrointestinal signs associated with liver disease in dogs. Decreased serum concentrations of gastrin in a dog with liver disease may suggest the presence of portosystemic shunt. Further investigation is warranted to determine the importance of hyopogastrinaemia in congenital postosystemic shunts in dogs and to evaluate potential alterations in serum gastrin concentrations in specific hepatocellular diseases.

Pharmacokinetics of intravenous and intramuscular parecoxib in healthy Beagles.

Parecoxib is an inactive pro-drug that is rapidly converted to valdecoxib, a selective cyclooxygenase (COX)-2 inhibitor registered for the management of post-operative pain in humans. Recent studies have suggested that parecoxib has excellent clinical efficacy and safety in veterinary species. The aim of the current study was to assess the pharmacokinetics of parecoxib and valdecoxib after intravenous (i.v.) and intramuscular (i.m.) administration. Seven healthy male Beagle dogs received 2.5 mg/kg parecoxib by either the i.v. or i.m. route in a cross-over design, with the alternative route of administration used 1 week later. The plasma concentrations of both analytes were detected according to a previously validated method using high performance liquid chromatography with fluorescence detection (HPLC-FL). No adverse effects were observed in any animal during the study. For both routes of administration, parecoxib was rapidly and almost completely converted to valdecoxib. The parecoxib/valdecoxib area under the curve (AUC) ratio for both routes of administration was 1.4. The half-life of valdecoxib was about 2 h, which was shorter than reported for humans, although the plasma concentrations following both routes of administration were likely to be effective for analgesia. The absolute bioavailability of parecoxib was 66%. The pharmacokinetic features of parecoxib make it suitable for treatment of acute pain in the canine species.

Novel gastroretentive controlled-release drug delivery system for amoxicillin therapy in veterinary medicine.

Beta-lactam antimicrobials, commonly used in both veterinary and human medicine, generally present short biologic half-lives, whereas their activity is enhanced as pathogen exposure is prolonged. These properties necessitate multiple-dose regimens of standard dosage forms, thereby hampering pet owner adherence, frequently resulting in therapeutic failure. This study presents a novel controlled-release gastroretentive oral drug delivery system for beta-lactams with which single-dose administration provides an effective antimicrobial course, optimizing pharmacokinetic (PK)-pharmacodynamic (PD) profiles, minimizing adverse effects and emergence of antimicrobial resistance and facilitating adherence. Our prototype sustained-delivery swelling-tablet (SDST), based on a degradable hydrophilic polymeric matrix, was designed to enable continuous input of these drugs to their absorption sites over several days. Several SDST formulations of the beta-lactam amoxicillin were evaluated in in vitro dissolution studies. Two formulations were selected for further in vivo canine studies, for determination of gastric retention and PK-PD profiling. Prolonged gastric retention times maintaining allowed for maintained effective drug concentrations against many clinically relevant pathogens for more than 48 h for one formulation and more than 5 days for the other. Both SDST formulations offer significant advantages over standard immediate-release therapy in achieving PK-PD goals and enhancing adherence. The prototypical formulations represent a novel platform which may be modified to meet various clinical requirements.

A novel subcutaneous controlled-release amoxicillin degradable implant for extended-interval administration in veterinary medicine.

Dosage forms of antimicrobials play a critical role in facilitating the attainment of pharmacokinetic-pharmacodynamic (PK-PD) targets as well as adherence in both veterinary and human medicine. The purpose of this study was to develop and evaluate a controlled-release subcutaneous amoxicillin implant for single-dose therapy of large ruminants such as goats, sheep, and deer. The degradable implant, designed to attain PK-PD targets following single administration, was evaluated for amoxicillin release rate and time-concentration profile. In vitro release studies demonstrated constant-rate release of approximately 40% of amoxicillin content within 96 h. In an in vivo study in goats, serving as a model for target animals, a serum concentration of approximately 0.4 mg/L was achieved within 8 h of implant insertion and maintained for >6 days. In comparison, in control goats given a standard single intramuscular amoxicillin dose of 15 mg/kg, amoxicillin peaked at 1.2 mg/L after 1 h, rapidly dropping to below detection level at 8 h. These results suggest that the proposed implant offers a unique modality for animal caregivers to conveniently administer a full antimicrobial course following a single dose of an efficient PK-PD-optimized dosage form. Furthermore, modifications of implant composition may allow for tailoring of its characteristics to various PK, PD, microbiological, and clinical requirements.

Pharmacokinetics of methylphenidate after oral administration of immediate and sustained-release preparations in Beagle dogs.

Methylphenidate (MPH) is a drug administered either as an immediate- or sustained-release preparation for the treatment of attention deficit hyperactivity disorder in humans. The aim of this study was to determine the pharmacokinetics of two different MPH formulations in the dog. Eight dogs were randomly assigned to two treatment groups using a two-part randomised, cross-over experimental design. Each subject received a single dose of 20 mg d,l-MPH as an immediate- (IR) or sustained-release (SR) tablet. Blood was collected at specific times, and the plasma concentrations of d,l-MPH were evaluated using high performance liquid chromatography. There were no adverse effects following the oral administration of d,l-MPH in either the IR or SR groups, apart from mild hyperkinesia which was observed in some of the IR group. The plasma concentration data of d,l-MPH were best described by a one-compartment model. There were significant differences in the maximum concentration (C(max)), time to C(max) (T(max)), area under the curve (AUC) and clearance (Cl) between the two formulations. The relative bioavailability of the SR formulation was 30.58±13.73% and, despite low drug plasma concentrations, the SR formulation resulted in uniform plasma concentrations of d,l-MPH. However, the dose rate of the SR formulation used in this study resulted in plasma concentrations that were below effective levels for clinical efficacy, so further studies are required to confirm the suitability of higher dose rates for clinical use.

Pharmacokinetics of methylphenidate following two oral formulations (immediate and sustained release) in the dog.

Methylphenidate (MPH) is an immediate-release (IR) or sustained-release (SR) drug used to treat attention-deficit hyperactivity disorder. Eight dogs were randomly assigned to two treatment groups, using an open, single-dose, two-treatment, two-period, randomized, crossover design. Each subject received a single dose of 20 mg d,l-MPH IR or SR tablet. After blood collections at specific times, the concentrations of d,l-MPH in plasma were evaluated by high-performance liquid chromatography. Following both IR and SR oral administration of d,l-MPH, the animals did not show any side effects, except that mild hyperkinesia was observed in a few subjects belonging to the IR treatment group. After both administrations, the concentration data for d,l-MPH in plasma displayed a characteristic, one-compartment drug model. The relative bioavailability of the SR formulation was 30.58 +/- 13.73%. Significant differences between the two administrations were found in T(max), C(max), AUC, and Cl. Despite low drug concentrations in the blood, the SR formulation ensured uniformity of d,l-MPH plasma concentrations and, thus, a simpler and easier titration. In conclusion, the tested dosage appears to be too low for clinical application in canines, and an increase in dosing is suggested. Further pharmacodynamics studies are necessary to support this speculation.

Spirocerca lupi in dogs: prophylactic effect of doramectin.

Spirocerca lupi is primarily a parasite of dogs, which typically causes oesophageal nodules, aortic aneurysms, and spondylitis. This study investigated the efficacy of doramectin as a prophylactic agent for canine spirocercosis. Five beagle dogs were injected subcutaneously with doramectin (400 microg/kg on 3 occasions 30 days apart q30d), while 5 other beagle dogs served as untreated controls. All dogs were inoculated with 40 infectious S. lupi larvae (L3) one month after the last doramectin treatment. All control dogs and 4/5 treated dogs became infected. Two control dogs died of ruptured aortic aneurysms, while no deaths occurred in treated dogs. Oesophageal nodules appeared 40-103 day later in treated as compared to control dogs, and eggs appeared in the faeces 49-106 day later in treated as compared to control dogs. The mean faecal egg count on day 223 in the treatment group was reduced by 99.77%. All control dogs had thoracic radiographic changes during the study, while only 2/5 study dogs showed radiographic changes. This study shows that although doramectin did not entirely prevent canine spirocercosis it reduced the clinical signs associated with infection and delayed and reduced egg output.

Retrospective study of 46 cases of feline haemobartonellosis in Israel and their relationships with FeLV and FIV infections.

Forty-six cats with clinical haemobartonellosis were studied; 75 per cent of the cats of known age were two-and-a-half years old or younger, 50 per cent were intact males and 19.5 per cent were castrated males. The predominant signs of the disease were tachypnoea, lethargy, depression, anorexia, infestation with fleas, pale mucous membranes, icterus, emaciation, dehydration, splenomegaly, anaemia, leucocytosis, increased activities of alanine aminotransferase and aspartate aminotransferase, and azotaemia. Thirty-eight per cent of the cats that were tested for feline leukaemia virus (FeLV) antigen were positive, and 22 per cent of those tested for feline immunodeficiency virus (FIV) antibodies were positive. The prevalence of both FeLV and FIV was much higher than in the general Israeli cat population. The cats infected with both Haemobartonella felis and FeLV had a significantly lower body temperature, were more anaemic and the mean cell volume of their erythrocytes was greater than in the cats with haemobartonellosis alone.