Keven Flammer

Disposition and Analgesic Effects of Fentanyl in White Cockatoos (Cacatua alba)

Abstract Fentanyl is a mu opioid agonist with 80–100 times the analgesic potency of morphine. Fentanyl is used in several mammalian species for relief of severe pain, but its use has not been investigated in psittacine birds. To determine the pharmacologic disposition of fentanyl in healthy white cockatoos (Cacatua alba), we measured fentanyl plasma concentrations in sequentially collected samples after administration of fentanyl at 0.01 or 0.02 mg/kg IM. To investigate the analgesic effects of fentanyl in conscious cockatoos, we compared the change in pre- and posttreatment levels of electrical and thermal noxious stimuli necessary to elicit a withdrawal response in birds administered fentanyl at 2 different doses (0.02 mg/kg IM or 0.2 mg/kg SC) and those given saline. Fentanyl was rapidly absorbed and plasma concentrations declined with an elimination half-life of 1.2–1.4 hours. Plasma concentrations considered to be analgesic in humans were maintained for at least 2 hours with the 0.02 mg/kg dose. However, no significant difference was found in analgesic response between birds given saline and those given fentanyl at 0.02 mg/kg IM. Although the 0.2 mg/kg SC dose provided significant analgesia in some birds, fentanyl at this dose is not recommended as a routine analgesic agent because a large volume of drug must be injected and this dose causes hyperactivity in some birds.

Species-Related Differences in the Incidence of Gram-Negative Bacteria Isolated from the Cloaca of Clinically Normal Psittacine Birds

Cloacal swabs from 506 clinically normal psittacine birds of 22 species were aerobically cultured for bacteria and yeasts. In 45 (9%) samples, no microbial organisms were recovered. Gram-positive bacteria were recovered from 474 (91%) samples. The incidences of gram-negative bacteria and yeasts were: Escherichia coli 157 (31%), Enterobacter sp. 21 (4%), Klebsiella sp. 3 (0.6%), Pseudomonas sp. 4 (0.8%), and yeasts 26 (5%). Differences were noted in the recovery rate of E. coli among the various species of birds cultured. Escherichia coli was recovered from 101 of 168 cockatoos (60%) of the genus Cacatua but from only 18% of 338 non-Cacatua species. As all birds were housed in the same facility under similar conditions, this difference in the incidence rate of E. coli cannot be explained on the basis of differences in husbandry or diet alone.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh)

OBJECTIVE To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. ANIMALS 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). PROCEDURES In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). RESULTS Voriconazoles elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. CONCLUSIONS AND CLINICAL RELEVANCE In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole < or = 0.4 microg/mL. Higher doses may be needed to maintain plasma voriconazole concentrations during long-term treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.

Pharmacokinetics of Butorphanol After Intravenous, Intramuscular, and Oral Administration in Hispaniolan Amazon Parrots (Amazona ventralis)

Abstract Previous studies have validated the clinical use of opioids with κ-receptor affinities for pain management in birds. Butorphanol, a κ opioid receptor agonist and a μ opioid receptor antagonist, is currently considered by many clinicians to be the opioid of choice for this use. However, despite studies reporting the analgesic properties of butorphanol in psittacine birds, dosing intervals have not been established for any psittacine species. The goals of this study in the Hispaniolan Amazon parrot (Amazona ventralis) were to evaluate the pharmacokinetics of butorphanol tartrate after intravenous (IV), intramuscular (IM), and oral (PO) administration and to determine the bioavailability of butorphanol tartrate after oral administration. Twelve Hispaniolan Amazon parrots were used in the study, with a complete-crossover experimental design and a 3-month period separating each part of the study. The birds were randomly assigned to 3 groups (n  =  4) for each stage. Butorphanol tartrate was administered once at a dose of 5 mg/kg in the basilic vein or pectoral muscles or as an oral solution delivered via feeding tube into the crop for the IV, IM, and PO studies, respectively. After butorphanol administration, blood samples were collected at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes for the IV and IM studies and at 5, 15, 30, 60, 90, 120, 180, 240, and 300 minutes for the PO study. Because of the size limitation of the birds, naïve pooling of datum points was used to generate a mean plasma butorphanol concentration at each time point. For each study, birds in each group (n  =  4) were bled 3 times after dosing. Plasma butorphanol concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were calculated. Butorphanol tartrate was found to have high bioavailability and rapid elimination following IM administration. In contrast, oral administration resulted in low bioavailability (<10%), thus precluding the use of this route of administration for clinical purposes. Based on these results, in Hispaniolan Amazon parrots, butorphanol tartrate dosed at 5 mg/kg IV or IM would have to be administered every 2 and 3 hours, respectively, to maintain plasma concentrations consistent with published therapeutic levels. To our knowledge, this is the first published study presenting the pharmacokinetic analysis of butorphanol tartrate in a psittacine species as well as the first study presenting pharmacokinetic analysis of butorphanol after oral administration in any avian species.

Plasma Concentrations of Doxycycline in Selected Psittacine Birds When Administered in Water for Potential Treatment of Chlamydophila psittaci Infection

Abstract Infection by Chlamydophila psittaci (formerly Chlamydia psittaci) is a common cause of morbidity and mortality in companion psittacine birds and is transmissible to humans. Replication of Chlamydophila is inhibited by plasma doxycycline concentrations greater than 1 μg/ml, but prolonged treatment periods of 30–45 days are needed to eliminate infection. Medication of birds for this prolonged period is difficult with current treatment methods. In this study, drinking water medicated with doxycycline hyclate at 800 mg/L was provided ad libitum to healthy African grey parrots (Psittacus erithacus timneh) and Goffins cockatoos (Cacatua goffini) for 42 days. Blood samples for doxycycline analysis were collected on treatment days 4, 7, 14, 21, 28, 35, and 42. Mean doxycycline concentrations exceeded 1 μg/ml throughout the 42-day treatment period. In the African grey parrots, the mean doxycycline concentration (± SD) for all plasma samples collected during the study was 1.51 ± 0.68 μg/ml and doxycycline concentrations were greater than 1 μg/ml in 73% of the samples. In the Goffins cockatoos, the overall mean was 2.78 ± 1.00 μg/ml and doxycycline concentrations exceeded 1 μg/ml in all samples. No adverse effects were noted in the African grey parrots. All of the 8 treated Goffins cockatoos were physically healthy, but changes in plasma biochemical analyses suggested mild hepatic damage in 3 birds. Results of plasma biochemical analyses in these cockatoos were within reference ranges when retested 7 days after doxycycline treatment ended. The results of this study suggest that doxycycline-medicated water can safely maintain plasma concentrations adequate for treating avian Chlamydophila infections in African grey parrots and Goffins cockatoos housed under standardized conditions.

Preliminary Investigation of Doxycycline Plasma Concentrations in Cockatiels (Nymphicus hollandicus) After Administration by Injection or in Water or Feed

Abstract Chlamydiosis is an important cause of morbidity and mortality in cockatiels (Nymphicus hollandicus); however, little published information is available regarding effective treatment options for this species. This preliminary study was conducted to determine if adequate plasma concentrations of doxycycline, the antibiotic of choice for treating chlamydiosis in pet birds, could be achieved in cockatiels by using different methods of administration. Doxycycline hyclate was administered to 5 groups comprising 3 to 6 birds each by intramuscular injection (100 mg/kg IM every 10 days for 5 injections) or by mixing with drinking water (0.28 or 0.83 mg/ml), seeds (500 mg/kg wet weight), or mash (1000 mg/kg). Three additional groups of birds received unmedicated food and water and served as controls. Plasma doxycycline concentrations were measured periodically during the 45-day trial. Birds given doxycycline by intramuscular injection had variable, localized tissue reactions and a mean trial plasma concentration <1 μg/ml, the value considered therapeutic for treating chlamydiosis. Birds that received doxycycline in drinking water and in seeds maintained group mean doxycycline concentrations >1 μg/ml. Birds that received doxycycline in mash had high plasma doxycycline concentrations and showed severe clinical illness, suggesting doxycycline toxicosis; drug administration was discontinued on day 3. Therefore, in this study, drinking water and seeds were effective vehicles for doxycycline administration to clinically healthy cockatiels under controlled conditions. However, mash combined with doxycycline resulted in severe toxicosis, whereas doxycycline hyclate by intramuscular injection did not achieve desired therapeutic plasma concentrations. Further studies are needed to examine efficacy and safety of food- and water-based doxycycline regimens in clinically ill birds and those housed under different environmental conditions.

Evaluating 21-day doxycycline and azithromycin treatments for experimental Chlamydophila psittaci infection in cockatiels (Nymphicus hollandicus).

Abstract To determine the efficacy of 21-day therapy with azithromycin and doxycycline in the treatment of experimental infection with Chlamydophila psittaci in cockatiels (Nymphicus hollandicus), 30 birds randomly assigned to 3 treatment groups and 1 control group were inoculated with C psittaci by combined intranasal and ocular routes. Morbidity, mortality, and results of polymerase chain reaction testing confirmed that infection was successful. Birds in group 1 (n  =  8) received azithromycin at 40 mg/kg PO q48h for 21 days; in group 2 (n  =  8), doxycycline at 35 mg/kg PO q24h for 21 days; in group 3 (n  =  8), doxycycline at 35 mg/kg PO q24h for 45 days; and, in group 4 (controls; n  =  6), no treatment. Six birds died either before or within 2 days of initiating treatment: 4 in the 3 treatment groups and 2 in the control group. Clinical signs resolved and mortality ceased 2–6 days after treatment was initiated in all treatment groups, whereas birds in the control group exhibited clinical signs for the duration of the study. Plasma doxycycline concentrations were measured during the treatment period and exceeded 1 µg/mL at all time points. The absence of clinical signs and mortality in the treatment groups, even after inducing an immunocompromised state with dexamethasone (3 mg/kg IM q24h for 5 days), starting on day 70 postinoculation, suggested that treatment resulted in elimination of the pathogen. After euthanasia of the remaining 24 birds, 23 of the carcasses were submitted for necropsy. Spleen and liver samples from the birds in all treatment and control groups were polymerase chain reaction negative for C psittaci nucleic acid, and organisms were not detected by Gimenez stain. No gross or histologic differences were observed in the livers and spleens of treated and untreated infected birds. Lesions consistent with avian chlamydiosis (hystiocytosis) were seen in all birds and were considered residual. In this study, a 21-day course of either doxycycline or azithromycin was effective in eliminating C psittaci infection in experimentally inoculated cockatiels. Additional studies are necessary to evaluate the efficacy of these treatments in naturally infected cockatiels as well as other species of birds.

Potential use of long-acting injectable oxytetracycline for treatment of chlamydiosis in Goffin's cockatoos.

To determine the potential use of parenteral therapy in the treatment of chlamydiosis in psittacine birds, the disposition and toxicity of a long-acting oxytetracycline (OTC) was evaluated in Goffins cockatoos. Following intramuscular and subcutaneous administration of 50 to 100 mg/kg body weight, plasma OTC concentrations of 7 to 15 micrograms/ml were obtained 3 hr following injection and declined with a terminal half-life between 8.9 to 14.7 hr. Plasma concentrations in excess of 1.0 microgram/ml were maintained for 48 to 68 hr. Multiple-dose treatment of 100 mg/kg subcutaneously every 3 days for 30 days caused focal necrosis and scabs at the injection site but no other clinical or serological evidence of adverse effects. Long-term treatment did not result in accumulation or alteration in the disposition of OTC. Based on this study, a dosage regimen of 50 to 100 mg/kg of OTC subcutaneously every 2-3 days would safely maintain plasma concentrations in excess of 1.0 microgram/ml and could potentially be used as an alternative to medicated feeds or daily oral dosing regimens for the treatment of chlamydiosis in psittacine birds.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis).

OBJECTIVE To determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 15 clinically normal adult Hispaniolan Amazon parrots. PROCEDURES Single doses of voriconazole (12 or 24 mg/kg) were administered orally to 15 and 12 birds, respectively; plasma voriconazole concentrations were determined at intervals via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) or water was administered orally to 6 and 4 birds, respectively, every 8 hours for 11 days (beginning day 0); trough plasma voriconazole concentrations were evaluated on 3 days. Birds were monitored daily, and clinicopathologic variables were evaluated before and after the trial. RESULTS Voriconazole elimination half-life was short (0.70 to 1.25 hours). In the single-dose experiments, higher drug doses yielded proportional increases in the maximum plasma voriconazole concentration (C(max)) and area under the curve (AUC). In the multiple-dose trial, C(max), AUC, and plasma concentrations at 2 and 4 hours were decreased on day 10, compared with day 0 values; however, there was relatively little change in terminal half-life. With the exception of 1 voriconazole-treated parrot that developed polyuria, adverse effects were not evident. CONCLUSIONS AND CLINICAL RELEVANCE In Hispaniolan Amazon parrots, oral administration of voriconazole was associated with proportional kinetics following administration of single doses and a decrease in plasma concentration following administration of multiple doses. Oral administration of 18 mg of voriconazole/kg every 8 hours would require adjustment to maintain therapeutic concentrations during long-term treatment. Safety and efficacy of voriconazole treatment in this species require further investigation.

Mycotic Keratitis in a Blue-fronted Amazon Parrot (Amazona aestiva)

Abstract Mycotic keratitis is most commonly reported in horses and humans and is rarely reported in birds. We diagnosed mycotic keratitis, localized to the left eye, in an adult blue-fronted Amazon parrot (Amazona aestiva). The ophthalmic examination revealed a diffuse yellow-green haze encompassing the entire surface of the left cornea. Diffuse fluorescein uptake occurred in the entire cornea. The right eye appeared normal. Aspergillus fumigatus was isolated on conjunctival culture. The affected eye was enucleated because of the birds discomfort and the poor prognosis for successful treatment. Histopathologic examination revealed a severe granulomatous keratitis with intracorneal fungal hyphae and corneal perforation. Multinucleated giant cells and fungal hyphae were present within the anterior chamber. Aspergillus fumigatus is an uncommon cause of keratitis in birds but should be considered as a potential cause of refractory ulcers.