Pharmacokinetics of Fluconazole in Alpacas
Alpacas and llamas suffer severe disease from Valley Fever and the limited evidence available suggests treatment is not very effective. Because of their ruminant digestive system, alpacas and llamas often absorb oral medication poorly. Fluconazole is the most common oral medication used to treat valley fever in humans and other animals and it is very well-absorbed (~100%) in most species tested. The objective of this research was to determine the dose of oral fluconazole that would produce therapeutic drug levels in alpacas.
Healthy alpacas were enrolled and given fluconazole once a day by crushing tablets with water and corn syrup and syringing the mixture into the mouth. On the 14th day, a blood sample was collected before the last dose was given, then 3 more times in the next 24 hours. The blood levels of fluconazole over the 24 hours was used to calculate a drug concentration curve to estimate the daily dose needed to produce fluconazole blood levels expected to treat Valley Fever.
Nine alpacas were tested with low, medium, and high doses of fluconazole. A low dose of 6 mg/kg/day resulted in blood levels below therapeutic. A dose of 15 mg/kg/day produced higher than necessary doses. 10 mg/kg/day generated therapeutic drug levels in 2 animals but levels that were too low in 3 animals. Though some alpacas absorb fluconazole well enough for treatment to be effective, the ability to absorb the drug (called bioavailability) appears to be variable. In the 14 days of treatment, none of the alpacas had adverse effects from the fluconazole.
The recommendations from this study include:
1) Alpacas need a dose of 10-12 mg/kg/day to develop therapeutic blood levels. If they absorb the drug poorly, they may need a higher dose.
2) Because of the unpredictable absorption of the drug, checking a blood level after 2-3 weeks on the fluconazole to determine if the alpaca has a therapeutic level in the blood is advisable. If not, the dose should be increased. Checking the blood level could be triggered by a poor response to treatment, but time in getting the animal back to health is lost by this approach.
3) An incidental finding from the pre-enrollment health testing of the alpacas in this study is that 3/12 animals had blood work abnormalities and/or clinical signs that led to testing for valley fever. All of the animals were seropositive. There are currently no recommendations regarding testing of asymptomatic animals, but it is possible that annual complete blood work could detect healthy-appearing alpacas that should be tested for valley fever.
This study was funded by the Morris Animal Foundation. [Grant # D19LA-005]
A Survey of the Experience of Alpaca Owners with Valley Fever in Their Herds
An anonymous, web-based survey was created to learn more the experiences of alpaca owners with Valley Fever in their herds. The survey included questions about housing, general location, herd size, and the clinical signs, diagnosis, and treatment of Valley Fever in affected animals.
Survey respondents represented Arizona, California, New Mexico, and Texas. Of all the alpacas included in the survey, 4.6% received a diagnosis of Valley Fever between 2005 and 2016. Owners noted weight loss, decreased energy, and decreased appetite as the most common clinical signs seen in their sick animals.
Mortality was high for the alpacas included in the survey. 92% of the sick alpacas that went untreated died or were euthanized. For the total population, including animals for which treatment was attempted, 78% died or were euthanized, while the remaining 22% were reported as recovered, improving, or stable at the time of the survey.
Valley Fever appears to cause significant disease in alpacas that are infected and become ill. There are currently no treatment guidelines for the disease in this species. Additional research looking at the rate of infection and the development of treatment protocols would be useful for alpacas residing in the region endemic for Valley Fever.
Spherusol Skin Testing
Skin tests were once widely used as a means of assessing infection with the fungus that causes Valley Fever in people. The benefit of a skin test is that it is easier and more cost-effective than running blood tests on a large population. This makes it particularly useful when trying to study the epidemiology, or distribution, of the disease. Spherusol is a new skin test reagent that has shown good efficacy in people. We wanted to know if the reagent is similarly effective in dogs.
We enrolled dogs that had been diagnosed with Valley Fever within the last five years. Dogs did not need to be currently treated for Valley Fever to be eligible for participation in the study. Enrolled dogs received two intradermal skin tests, one on each flank, which were then read 48 hours later.
Utility of Skin Testing for Epidemiological Survey of Coccidioides Infection in Dogs
Our primary goal was to evaluate the usefulness of Spherusol, a commercially available skin test reagent, in the identification of a delayed type hypersensitivity reaction in dogs known to have been diagnosed with Valley Fever. Twenty-two dogs were tested with both Spherusol and coccidioidin, a historically used skin test reagent. We combined this data with previously unpublished work evaluating coccidioidin.
We found that the sensitivity of coccidioidin and Spherusol in the detection of dogs infected with the Coccidioides spp. was 49.1% and 18.2%, respectively. Coccidioidin was highly specific, but our small study could not determine the specificity for Spherusol. We conclude that skin tests are not a sensitive marker of infection in the dog.
Incidence and Risk Factors Study
In order to better understand the number of dogs that become infected with Valley Fever, blood was sampled from dogs in Pima and Maricopa counties. One group of dogs was enrolled between 4 and 6 months of age and received a blood test every six months. The other group of dogs was enrolled between 4 and 18 months of age and received a single blood test for Valley Fever. All owners were questioned about the health status of their dog and were asked to complete a questionnaire about potential risk factors for infection by the fungus.
We found that dogs in Pima and Maricopa counties had a 28% chance of becoming infected with Valley Fever in the first two years of life. During that time, the chance of a dog becoming ill was 6%. The results of the Valley Fever test were reported as a titer, or dilution of the sample that still tested positive for the presence of antibodies to the fungus. Dogs that were infected but not sick had titers ranging from <1:2 to 1:16, while dogs that were ill at the time of the blood sample had titers ranging from <1:2 to 1:32, indicating an overlap in titers between sick and healthy dogs.
The risk of infection was 4.9 times greater for dogs that spent more than 80% of their time outdoors as compared to predominantly indoor dogs. Dogs with more than an acre of land to roam were found to have a risk of infection 6.2 times greater than dogs with a smaller roaming area. No relationship was found between infection and breed, age of home, yard cover, digging behavior, or proximity to construction. Details of this study can be found here.
Nikkomycin Z is a chitin synthase inhibitor, meaning that it works by disrupting the fungal cell wall. A study of the effectiveness of nikkomycin Z was completed using twelve dogs. All of the dogs enrolled in the study had been diagnosed with respiratory Valley Fever. Study dogs were treated with nikkomycin Z for 60 days, and clinical signs, blood results, and Xrays were compared from the start and end of the study period. Nine of the dogs finished the entire course of the medication. Of those 9, 7 dogs showed improvement in their clinical signs and Xrays. No dogs exhibited any adverse effects to the medication.
Nikkomycin Z appears to have good potential as a new therapeutic for the treatment of Valley Fever in dogs. It is currently awaiting clinical trials in humans and is unavailable for commercial use at this time. More detailed information about this study is available: here
VT-1161 is a new antifungal medication designed to interfere with the fungal cell membrane. It has demonstrated a low number of drug interactions while being non-toxic to mammals. Twenty-four dogs with respiratory Valley Fever were enrolled into this study and randomized to receive either a high or low dose of VT-1161. Twenty-two dogs completed the full 60 day course of the medication. Clinical signs, X-rays, and bloodwork were compared from the start to the end of the study. 20 of 23 dogs (83%) had at least a 50% reduction in disease scores at the end of the study. Only 2 dogs exhibited mild adverse effects. VT-1161 appeared to have very low toxicity in dogs as previously shown in other animals and humans.
VT-1161 has demonstrated efficacy against Valley Fever but is not currently commercially available.
Shubitz, L.F., et. al. Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs. 2017. Antimicrobial Agents and Chemotherapy, Vol 61(5): DOI: 10.1128/aac.00111-17