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Treatment of Refractory Coccidioidomycosis in Dogs | VETgirl Veterinary Continuing Education Podcasts

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In this VETgirl online veterinary continuing education podcast, we discuss the treatment of refractory coccidioidomycosis in dogs. Coccidioidomycosis, also known as Valley Fever, is a common fungal infection in the southwestern United States that is caused by the organisms Coccidioides immitis and Coccidioides posadasii. Pulmonary infections leading to fungal pneumonia are the most common presentation, though roughly a quarter of dogs will suffer from a disseminated infection, such as infection of the central nervous system and/or skeletal system (Johnson). Itraconazole and fluconazole are common first-line treatment choices, and treatment can be quite prolonged depending on the case. Unfortunately, some patients with this disease are refractory to standard antifungal treatment, and these dogs may require amphotericin B or other antifungal regimens. Additional therapeutic strategies are urgently needed for these patients!

So, Shubitz et al wanted to evaluate this in a study entitled Posaconazole treatment of refractory coccidioidomycosis in dogs. In this study, authors retrospectively described treatment outcomes and therapeutic monitoring of dogs with refractory coccidioidomycosis that were treated with posaconazole. Posaconazole is a second generation triazole antifungal therapy that has been used to treat refractory coccidioidomycosis in humans, though only limited information is available for its use in dogs.

This was a retrospective study performed at the Veterinary Specialty Center of Tucson. Medical records were searched, and dogs with refractory coccidioidomycosis that had been treated with posaconazole were included. Dogs were recruited over a seven-year period, ranging from 2011 to 2018. The authors defined refractory cases as dogs with confirmed coccidioidomycosis that failed to respond to at least 2 antifungal therapies. To be a confirmed case of coccidioidomycosis, dogs must have had positive serology testing with concurrent evidence of clinical disease based on imaging, clinical presentation, and clinicopathological findings. Alternatively, dogs with cytological or culture proof of infection were also included. The authors extracted detailed information about the dogs’ medical history leading up to posaconazole administration, as well as a thorough review of the dogs’ response to posaconazole, therapeutic monitoring, and survival status.

Overall, 8 dogs were identified that fit the inclusion criteria. Seven of these dogs were females (6 spayed, 1 intact), and 1 was a neutered male. Half of the dogs were mixed breed, and no breed was represented more than once. Ages ranged from 1 to 11 years. Seven of the 8 dogs had been diagnosed at an external clinic prior to presentation, with the original diagnosis ranging from 1 to 9 months prior to referral. The diagnosis was made based on a combination of patient clinical signs and history, diagnostic imaging findings, and serology. Serology was assessed via agar gel immunodiffusion assay (AGID). One dog was seronegative, but this dog had fungal spherules identified on lung cytology after fine needle aspiration of a lesion was performed. Serum anti-coccidioidal AGID antibody titers at the dogs’ initial assessments ranged from this one negative result to ≥ 1:256 (median 1:32).

Recall that to be included, all dogs must have failed prior treatment. Therefore, all 8 dogs had been treated with and failed to respond to at least 2 antifungal medications prior to starting posaconazole. All dogs received fluconazole and itraconazole as components of their previous therapy. The authors report that no dogs had lasting improvement with either medication, or dogs developed an intolerance. Four dogs were also treated with generic voriconazole, but 3 had to discontinue the medication due to either hepatotoxicosis or neurologic effects. Finally, 6 of the 8 dogs also received amphotericin B lipid complex. Not surprisingly, all 8 dogs suffered from pulmonary disease, though 2 of the dogs also had bone and lymph node involvement. Thoracic radiographs showed pulmonary infiltrates, characterized as regional or diffuse bronchointerstitial infiltrates, and tracheobronchial lymphadenopathy, characterized commonly as moderate to severe. Less common radiographic findings included pulmonary nodules (5), mild pleural effusion (2), alveolar infiltrates or lobar consolidation (2), sternal lymphadenopathy (2), and one dog had multiple cavitary lesions observed. CT scans were performed in 5 of the 8 dogs, which demonstrated consistent findings as radiography. Two dogs also demonstrated skeletal lesions, including lytic-proliferative long bone lesions, joint effusion, and erosive arthritis. One dog demonstrated cervical vertebral lesions, in addition to bilateral humeral lesions.

Clinical pathology abnormalities were consistent with systemic inflammatory responses, and included neutrophilia (6), monocytosis (6), hyperglobulinemia (5), and hypoalbuminemia (4). Other diagnostic results included pyogranulomatous inflammation from bronchial washes in 3 dogs and from pulmonary aspirates in 3 dogs. Of note, spherules were also observed on cytology from 2 dogs with pulmonary aspirates, and these samples were taken from nodular lesions or areas of lung consolidation. Anterior uveitis was diagnosed in 2 dogs, and in 1 dog, Coccidioides posadasii was diagnosed via lymph node culture and PCR. Finally, one dog had joint aspirates performed, which demonstrated non-degenerate neutrophils, but no visible organisms.

Okay, let’s hear more about the posaconazole administration in these dogs. One dog received a posaconazole suspension (10 mg/kg/day), whereas the remaining dogs received an oral tablet or capsule (5 mg/kg/day). In this study, therapeutic posaconazole monitoring protocols were also reviewed. For determining trough posaconazole concentrations, clinicians collected serum samples within an hour of the next scheduled dose of medication, and serum levels were measured roughly 1 month after starting treatment or 2 weeks after dose adjustments. The clinicians used this monitoring tool to make dose adjustments as needed. Importantly, all dogs had posaconazole levels in the therapeutic range. However, some were much higher than the range and even required dose reductions. One dog with high serum concentrations was tolerating the medication clinically, yet had elevated liver enzymes. Another dog had a decreased appetite initially while taking posaconazole, but this was managed with an appetite stimulant. This dog also suffered from several other comorbidities. The remaining 7 dogs did not have any clinically apparent adverse reactions to posaconazole.

Chemistry panels were performed one month after starting posaconazole. Assessing clinicopathologic abnormalities secondary to posaconazole was somewhat tricky because mild-moderate liver enzyme elevations were most common, yet 7 of the dogs were receiving concurrent prednisone. For instance, 5 of the 8 dogs had elevations in ALP, though this could have been secondary to the prednisone. Of note, 2 dogs had greater than 3-fold elevations in ALT, though 1 normalized after discontinuing prednisone alone. The other dog had persistently elevated ALT until discontinuation of posaconazole. This dog also demonstrated previous hepatic intolerance to fluconazole and voriconazole.

Treatment duration in these 8 dogs ranged from 14 to 19 months (median 18 months), and all dogs improved initially after starting posaconazole. In fact, 6 of the 8 dogs (75%) experienced disease resolution or remission. Those are encouraging results! Five of the 8 dogs (63%) were still alive at the time the authors wrote this manuscript. The sixth dog had resolution of disease, but was euthanized for unrelated reasons 4 months after discontinuing posaconazole. The remaining 2 dogs were euthanized after prolonged treatment, due to progressive pain secondary to osteomyelitis in 1 dog and pneumothorax in the other.

Let’s look more closely at the 5 dogs that survived. The authors characterized 4 of the 5 dogs in remission, meaning complete resolution of all radiographic, clinicopathologic, and clinical abnormalities, in addition to serum antibody titers that ranged from <1:2 to only 1:4. Only 1 of these 4 dogs was still receiving posaconazole (2.8 mg/kg, every 48 hours), though the authors note that this continued therapy was due to the owner’s reluctance to discontinue treatment. One dog was receiving no antifungal therapies, and the other 2 dogs were receiving fluconazole. The fifth dog that survived but that was not characterized as in remission had unresolved skeletal lesions. However, this patient did demonstrate radiographic resolution of pulmonary lesions, reduced antibody titers (>1:256 to 1:16), and resolution of clinical signs. It was noted that the patient transitioned from posaconazole to fluconazole after 17 months of therapy due to concern for hepatotoxicosis, and the dog continued to do well in the year following this change.

The authors note several limitations to this study, such as its retrospective nature and the fact that this is an observational case series lacking a control group. It is also important to remember that this is off-label use of posaconazole, and that the formulations used were not controlled for in this study. That said, what can we take away from this VETgirl podcast? First of all, posaconazole led to clinical remission or resolution in 75% of dogs in this population! Admittedly this is a small study population, but recall that these are dogs that failed previous therapies. This is promising news! Posaconazole also appeared to be well tolerated. The primary adverse effects observed in this study were 1 dog with concern for hepatotoxicosis based on serum biochemistries, and another dog that had transient inappetence. In addition to monitoring clinical response and assessing for hepatotoxicosis, therapeutic drug monitoring may help guide treatment adjustments. Hopefully moving forward, we will see larger, controlled studies evaluating posaconazole in more depth. For now, however, this VETgirl will remember posaconazole as an option if faced with a refractory coccidioidomycosis case!

References:
Shubitz L, Schlacks S, Vishkautsan P, et al. Posaconazole treatment of refractory coccidioidomycosis in dogs. J Vet Intern Med. 2021; 35(6): 2772-2777.

Johnson LR, Herrgesell EJ, Davidson AP, et al. Clinical, clinicopathologic, and radiographic findings in dogs with coccidioidomycosis: 24 cases (1995-2000). J Am Vet Med Assoc. 2003;222: 461-466.

Abbreviations:
AGID – Agar gel immunodiffusion assay

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