Oral voriconazole therapy in cats with histoplasmosis yielded mild side effects and a favorable outcome

Loren F. Easterwood BluePearl Veterinary Hospital for Pets, Overland Park, KS

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Kenneth R. Harkin Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Amy J. Rankin Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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 DVM, MS, DACVO

Abstract

OBJECTIVE

Infection by Histoplasma organisms most commonly results in disseminated systemic infection in cats. Relapse during therapy with itraconazole and fluconazole has been reported. The aim of this study was to report the clinical response, duration of therapy, side effects, and outcome in cats with histoplasmosis that were treated with voriconazole.

ANIMALS

6 client-owned cats.

CLINICAL PRESENTATION

Medical records were reviewed of cats with confirmed histoplasmosis that presented to the Kansas State University Veterinary Health Center and received voriconazole therapy (n = 6 cats).

RESULTS

4 cats were switched to voriconazole from fluconazole (n = 2), itraconazole (1), or both (1), and 2 cats received voriconazole as initial therapy. Median starting dosage was 3.51 mg/kg PO every 72 hours. Two cats required a change in dosing interval from every 72 hours to every 96 hours due to hyporexia (n = 2) and an elevated ALT (1). Remission was documented in all 6 cats with a median time to a negative urine antigen of 256 days (range, 94 to 494 days).

CLINICAL RELEVANCE

Voriconazole therapy in 6 cats with histoplasmosis yielded mild side effects and a favorable outcome. Reported dosages provide a feasible alternative to daily dosing for owners of feline patients.

Abstract

OBJECTIVE

Infection by Histoplasma organisms most commonly results in disseminated systemic infection in cats. Relapse during therapy with itraconazole and fluconazole has been reported. The aim of this study was to report the clinical response, duration of therapy, side effects, and outcome in cats with histoplasmosis that were treated with voriconazole.

ANIMALS

6 client-owned cats.

CLINICAL PRESENTATION

Medical records were reviewed of cats with confirmed histoplasmosis that presented to the Kansas State University Veterinary Health Center and received voriconazole therapy (n = 6 cats).

RESULTS

4 cats were switched to voriconazole from fluconazole (n = 2), itraconazole (1), or both (1), and 2 cats received voriconazole as initial therapy. Median starting dosage was 3.51 mg/kg PO every 72 hours. Two cats required a change in dosing interval from every 72 hours to every 96 hours due to hyporexia (n = 2) and an elevated ALT (1). Remission was documented in all 6 cats with a median time to a negative urine antigen of 256 days (range, 94 to 494 days).

CLINICAL RELEVANCE

Voriconazole therapy in 6 cats with histoplasmosis yielded mild side effects and a favorable outcome. Reported dosages provide a feasible alternative to daily dosing for owners of feline patients.

Introduction

Organisms in the genus Histoplasma are found worldwide, including throughout the US.1,2 Although infections have been documented in areas in the US that are not considered endemic, the vast majority of infectious outbreaks in people have centered around the Missouri, Mississippi, and Ohio river valleys.2,3 On the basis of available published case series, histoplasmosis appears to be the most prevalent systemic fungal infection in cats with the majority of reported cases from Oklahoma and Kansas, although infection in cats from nonendemic areas has been documented.412 Infection is suspected to be from inhalation of airborne mold spores in cats with variable systemic dissemination after pulmonary inoculation.1 Clinical signs can include labored breathing and tachypnea, fever, ocular disease, and lameness. Gastrointestinal disease without pulmonary involvement can lead to chronic weight loss, diarrhea, and vomiting. Pathology can result in hepatic and splenic infection, bone marrow infiltration with anemia, thrombocytopenia, and/or leukopenia.49 A definitive diagnosis can be achieved with microbiological or molecular techniques as well as pathology; however, when samples cannot be obtained safely or are devoid of organisms, detection of Histoplasma antigen in urine by enzyme immunoassay has been shown to be highly sensitive (94%) and specific (97% to 100%) in diagnosing feline histoplasmosis cases.6,13 Itraconazole and fluconazole, sometimes in combination with amphotericin B, are most commonly used for the treatment of histoplasmosis in cats, with 6-month survival rates of 60% to 70%.4,9,10 Up to 31% of cats require a change from itraconazole to fluconazole, or vice versa, due to toxicity, side effects, or apparent organism resistance, with no significant difference depending on which triazole is started.4 Hepatotoxicity is a reported side effect of azole therapy and may be managed with a change in azole (eg, itraconazole to fluconazole) or a dose reduction.4,10,14

When cats fail to respond to both itraconazole and fluconazole, alternative azole therapy needs to be considered. Posaconazole pharmacokinetics have been reported in healthy cats with 2 dosing regimens; however, posaconazole is considerably more expensive than fluconazole or itraconazole and there are no published reports of its use in cats with histoplasmosis.15

Voriconazole is a second-generation triazole synthesized from fluconazole. The pharmacokinetics of IV and PO (suspension and tablet) administration of voriconazole were evaluated in healthy cats and demonstrated similar excellent bioavailability with the oral tablet and commercially available suspension, rapid absorption, a gradual increase over time in plasma concentration when administered PO every 48 hours, and a half-life of > 43 hours after oral administration.16 The side effects noted were hypersalivation immediately after administration of the oral solution and transient miosis. The authors of that study suggested that a dosage of 12.5 mg/cat every 72 hours should be investigated, and therapeutic drug monitoring was recommended.

The objective of this study was to report the clinical response, duration of therapy, side effects, and outcome in feline patients with histoplasmosis that were presented to the Kansas State University Veterinary Health Center (KSUVHC) and treated with oral voriconazole.

Methods

Cats included in this study were identified from the personal case logs of 2 veterinarians (KRH and AJR) at KSUVHC, and the medical records of those cats were obtained for evaluation. Cats were included if histoplasmosis was confirmed via cytology, histopathology, or urine antigen. The medical record was searched for signalment, duration of illness, prior diagnoses of histoplasmosis and antifungal therapy, and physical examination findings. If available from the medical record, clinicopathological findings and results from imaging, histopathology, and other diagnostics were recorded. Additionally, information regarding dosing regimen, side effects, treatment duration, and outcome were included.

All written radiograph reports and abdominal ultrasound imaging at the KSUVHC were completed or approved by a board-certified veterinary radiologist. Histoplasmosis urine antigen quantification by enzymatic immunoassay (UA-EIA) was performed at a commercial laboratory (MVista Histoplasma quantitative antigen test; MiraVista Diagnostics) with a reported reference interval for quantifiable antigen level at 0.4 to 19.0 ng/mL. An antigen level above 0.4 ng/mL was considered a positive result.

Results

Study cohort

Between January of 2020 and September of 2021, oral voriconazole therapy was initiated in the 6 cats included in this report. One additional cat was prescribed voriconazole for a third relapse of histoplasmosis but was switched to fluconazole after 2 doses of voriconazole at the request of the owner due to unspecified behavior change and is not included in the analyses. At the initiation of voriconazole therapy, the median age was 11 years (range, 10 months to 13 years) and the median weight was 3.62 kg (range, 2.45 to 9.32 kg). There were 5 spayed female cats and 1 castrated male cat. Breeds included domestic shorthair (n = 3) and 1 each of domestic longhair, Persian, and Siamese mix. Four of 6 cats had received antifungal therapy prior to initiation of voriconazole therapy, including fluconazole (n = 2), itraconazole (1), and itraconazole and fluconazole (1). Two cats had not received any antifungal therapy prior to the initiation of voriconazole.

Historical, clinical, and diagnostic findings

Three cats (Cats 1, 2, and 3) in this study had been previously diagnosed with histoplasmosis and treated and had gone into remission. These cats were initially diagnosed 1.25, 3, and 9 years earlier, respectively, and had been treated successfully with itraconazole (Cat 1, dose and formulation not specified) and fluconazole (Cat 2, 25 mg [50-mg tablet], PO, q 12 h; and Cat 3, 50-mg tablet, PO, q 12 h). Cat 2 was first diagnosed 3 years earlier, relapsed 17 months later, and was put into remission a second time again with fluconazole (same dose and formulation). Cat 3 failed itraconazole therapy initially (dose and formulation not specified) prior to achieving remission with fluconazole. All 3 cats relapsed and were being treated at the time voriconazole was initiated. Relapse occurred 1, 1.8, and 8 years after their last remission. These cats were being treated with itraconazole (Cat 1) and fluconazole (Cats 2 and 3) for 1, 2, and 11 months, respectively, with deterioration noted in the previous 1, 2, and 6 weeks. Cat 3 was switched from fluconazole to itraconazole (Itrafungol itraconazole oral solution; 5 mg/kg, PO, q 24 h, oral suspension) 6 weeks prior to initiation of voriconazole therapy, with continued deterioration during itraconazole therapy. Deterioration consisted of acute-onset blindness found to be secondary to diffuse severe chorioretinitis in both eyes and anemia (Hct, 24%; reference interval, 35% to 50%; Cat 1); progressive lethargy, weight loss, and hyporexia (Cat 2); and progressively worsening nodular pulmonary lesions, tachypnea, and persistent unilateral submandibular lymphadenomegaly from which Histoplasma spp organisms were identified on cytologic evaluation of a fine-needle aspirate (Cat 3). For Cat 1, the UA-EIA was reported to be 4.2 ng/mL at the time of relapse and 0.42 ng/mL 1 month prior to presentation for acute blindness, but the test was not repeated prior to initiation of voriconazole therapy. For Cat 2, a UA-EIA was performed 2 months prior to initiation of voriconazole and was positive, but below the limit of detection, and was not repeated. Cat 3 had no prior UA-EIA tests performed and was found to be positive but above the limit of quantification.

Cat 4 was diagnosed at 7 months of age with a 3-week history of stiffness, reluctance to move, lethargy, and hyporexia and subcutaneous nodules on the bridge of the nose and tail that had been present for 4 to 7 days. This cat had peripheral lymphadenomegaly of multiple lymph nodes and tachypnea and was found to be leukopenic (3.9 X 103/μL; reference interval, 4.2 X 103 to 19.1 X 103/μL), anemic (Hct, 12%), and thrombocytopenic (29 X 103/μL; reference interval, 140 X 103 to 400 X 103/μL), with circulating Histoplasma spp organisms seen in monocytes on a blood smear. A mild diffuse interstitial pulmonary pattern and moderate hepatosplenomegaly were found on radiographs, and Histoplasma spp organisms were identified on cytologic evaluation of lymph node aspirates. The UA-EIA was positive but above the level of quantification. This cat was initially treated with fluconazole (25 mg [50-mg tablet], PO, q 12 h) and was returned for reevaluation 90 days later with a 1-week history of acute-onset blindness and a draining lesion from the bridge of the nose. The UA-EIA was 4.25 ng/mL 1 week earlier. This cat was diagnosed with bilateral retinal detachments with panuveitis. Peripheral lymphadenomegaly was still present, and cytologic evaluation of the draining lesion revealed Histoplasma spp organisms.

For the 2 cats that had not been previously diagnosed with histoplasmosis or treated with antifungal therapy, the duration of clinical signs was 3 weeks (Cat 5) and 4 months (Cat 6). Cat 5 presented for tachypnea, weight loss, and becoming reclusive. This cat was found to be leukopenic (3.2 X 103/μL), anemic (Hct, 25%), and thrombocytopenic (126 X 103/μL). No pulmonary lesions were identified, but hepatosplenomegaly was detected radiographically. Despite no reported abnormalities on the appearance of the liver and spleen on ultrasound, aspirates of the spleen revealed Histoplasma spp organisms. Cat 6 had no abnormalities noted on physical examination and was mildly anemic (29%), and radiographs revealed a moderately severe diffuse reticulonodular pulmonary pattern. No cytological diagnosis was obtained in Cat 6. The UA-EIA was positive in both cats and above the level of quantification in Cat 5 and 16.57 ng/mL in Cat 6.

Voriconazole treatment and side effects

Four cats were switched to voriconazole due to lack of response to therapy with fluconazole (Cats 2, 3, and 4) or itraconazole (Cats 1 and 3), and 2 cats were prescribed voriconazole as the initial therapy (Cats 5 and 6). Five cats that weighed between 2.45 and 4.36 kg were started on 12.5 mg, PO, every 72 hours. One cat (Cat 6) that weighed 9.32 kg was started on 25 mg, PO, every 72 hours. The median starting dosage was 3.51 mg/kg, PO, every 72 hours (range, 2.68 to 5.10 mg/kg, PO, q 72 h).

Two cats had a dosing interval increase from every 72 hours to every 96 hours. The owners of Cat 2 modified the dosing interval after 3 doses due to a poor appetite perceived to be caused by voriconazole. The appetite had reportedly improved when the cat was reevaluated 10 days later and serum ALT was normal (36 U/L; reference interval, 36 to 181 U/L). Cat 3 was reevaluated 28 days after starting voriconazole, at which time the cat had gained 0.02 kg and cytological evaluation of the enlarged submandibular lymph node failed to demonstrate any organisms. Serum ALT at that visit was 84 U/L. The cat was returned 85 days after starting voriconazole, at which time it was reported that the cat had been anorexic for 3 days. Weight loss of 0.55 kg was documented, and serum ALT was 194 U/L. Voriconazole dosing was changed to every 96 hours at that time, the appetite returned, and 18 days later serum ALT had fallen to 61 U/L.

Appetite was generally reported as good in all cats throughout treatment with the exception of the 2 cats requiring a dosing interval increase. Weight loss was documented in 3 of 5 cats with a weight history. Cats 3, 5, and 6 lost 0.69, 0.16, and 1.14 kg, respectively, between initiation and discontinuation of voriconazole. Cat 5 lost 0.6 kg after 128 days of voriconazole therapy but regained 0.44 kg over the subsequent 366 days of therapy. Cats 2 and 4 gained 0.07 and 0.55 kg, respectively, during the treatment period. Cat 6 was notoriously aggressive and difficult to handle when healthy but was described by the owner as “mellow” and “laid-back” and was amenable to handling and examination by the veterinarian (KRH) during voriconazole therapy. Cat 6 was eating and active at home, and this change in behavior was not attributed to histoplasmosis or any other illness. Serial CBCs and serum biochemistry profiles were performed on 5 cats (Cat 1 was managed elsewhere, and test results were not provided). All previous abnormalities noted on CBC prior to voriconazole therapy normalized over time, and no abnormalities developed during therapy. An increase in ALT was noted in only 1 cat (Cat 3), as described above. There were no other abnormalities noted on any serum biochemistry analysis in these 5 cats during therapy.

Outcome

The median time to a negative UA-EIA in Cats 2 through 6 after initiation of voriconazole therapy was 256 days (range, 94 to 494 days). Cat 1 was reported to have achieved a negative UA-EIA, but the time frame was not reported. In Cat 3, there was resolution of the nodular pulmonary pattern and enlarged submandibular lymph node 9 months after initiation of voriconazole therapy. Thoracic radiographs were not repeated in any other cat. Bilateral anterior uveitis, retinal detachments, peripheral lymphadenomegaly, and the draining lesion on the nose were no longer present in Cat 4 after 55 days of therapy. This cat also received 1% prednisolone acetate ophthalmic solution topically to address the uveitis. The cat was blind due to advanced retinal degeneration.

The end point of therapy in the study was a negative urine antigen test. Five cats were treated with voriconazole 1 month beyond a negative test result. One cat (Cat 5) was treated with voriconazole 2 months beyond a negative test result because of the long duration of therapy (494 days) required to achieve a negative result. For Cats 1, 2, and 4, the first UA-EIA performed after initiating voriconazole therapy was negative. For Cats 3, 5 and 6, the last positive UA-EIA was recorded 120, 79, and 76 days, respectively, prior to a negative UA-EIA. Cats 2, 3, and 6 had repeat urine antigen testing performed 129, 145, and 66 days, respectively, after discontinuation of voriconazole, and all were negative. Cat 6 had an additional negative result on UA-EIA performed 405 days after the last negative result. At the time of last follow-up, Cats 1, 4, and 5 were in remission for 560, 196, and 60 days, respectively, since discontinuing voriconazole therapy. Cats 2, 3, and 6 relapsed 416, 418, and 679 days, respectively, after the last voriconazole dose, and all 3 are in remission and receiving voriconazole at the time of manuscript preparation.

Discussion

The results of this study support the use of voriconazole in cats as an alternative treatment option for histoplasmosis. Voriconazole was used as rescue therapy in 4 cats that were receiving azole therapy (fluconazole or itraconazole) and clinically deteriorating at the time voriconazole therapy was initiated. Voriconazole was also used safely as a first-line therapy in 2 cats upon the diagnosis of histoplasmosis. Transient clinical remission was achieved in all cats.

Voriconazole is less expensive than posaconazole, and there are limited reports on its use in cats. In 1 report,17 2 cats with orbital aspergillosis treated with noncommercial compounded voriconazole (9.5 to 10 mg/kg, PO, q 24 h of a 100 mg/mL oral solution) developed severe systemic reactions that necessitated discontinuation of voriconazole. Lethargy, hyporexia, and weight loss were seen in both cats, whereas one cat developed a presumed cutaneous drug reaction while the other developed ataxia and hind limb paresis. Discontinuation of voriconazole resulted in improvement and/or resolution of both paresis and suspected cutaneous reaction. Similarly, administration of voriconazole to 3 cats at 10 to 13 mg/kg PO every 24 hours resulted in pelvic limb paresis with proprioceptive deficits between 5 and 16 days after initiation of therapy.18 Additional findings in these cats included lethargy and hyporexia (n = 2 cats), mydriasis with diminished or absent menace response (2), nystagmus and tremors (1), and paresis (3). The 2 cats that received voriconazole as a tablet had onset of paresis within 5 to 6 days, while the remaining cat that received a suspension presented for paresis 16 days after the start of therapy. Paraparesis improved or resolved after discontinuation of voriconazole in these 3 cats. Even at a lower dose (4.2 mg/kg, PO, q 24 h), hyporexia and lethargy were reported in a cat treated with voriconazole after 14 days of therapy.19 Based on these reports, it was recommended that voriconazole not be administered to cats due to neurotoxicity.20

Previously reported toxic side effects of voriconazole therapy in cats include lethargy, hyporexia, weight loss, pelvic limb paresis with ataxia and proprioceptive deficits, nystagmus, tremors, apparent blindness with mydriasis, cutaneous drug reaction, and azotemia.16,1719 All cats in those reports were receiving daily voriconazole with doses as low as 4.32 mg/kg/d and as high as 10.5 mg/kg/d. Side effects in the present study were mild. Hyporexia necessitating a change in the frequency of dosing from every 72 hours to every 96 hours was noted in 2 cats only. Weight loss was reported in only 3 cats, although it was substantial (1.14 kg) in 1 cat despite maintenance of a good appetite throughout therapy. Cat 3 had substantial weight loss (0.55 kg) in a short period (57 days) prior to changing the dose frequency from every 72 hours to every 96 hours. This cat lost only an additional 0.14 kg over the remaining duration of voriconazole therapy. All cats that lost weight during therapy had documented weight gain after discontinuing voriconazole. Behavioral change was noted in 1 cat (Cat 6), although this was deemed to be beneficial as it facilitated administration of medication and examination. Still, this could be interpreted as a neurological side effect to voriconazole. Subtle behavioral change may have been present but interpreted as slow recovery from illness by the other cat owners. Differentiating changes in behavior due to side effects or illness could be difficult but should be taken in context of appetite and the pet owner’s perception of the cat’s attitude along with the results of diagnostic tests (eg, CBC and serum biochemistry profile). Hepatotoxicity, recognized by an increase in ALT, was noted in only 1 cat and resolved with a change in dose frequency. None of the other previously reported side effects were noted in these 6 cats.

Although voriconazole was administered on the basis of the dosing recommendation of 12.5 mg/cat PO every 72 hours by Vishkautsan et al,16 therapeutic drug monitoring was not performed in any cat. Likewise, the median dose of voriconazole used in this report (3.51 mg/kg) exceeded the dose range (2.05 to 2.7 mg/kg) from that pharmacokinetic study, although the smallest cat in this report (2.45 kg) receiving the highest dose (5.1 mg/kg, q 72 h) did not demonstrate any adverse side effects. Measuring serum voriconazole levels could have helped guide therapy in these 6 cats; however, modifications in dosing interval based on a suspicion of elevated serum drug levels successfully mitigated observed side effects in 2 cats. A perceived need for a change in dosage was not recognized in any other cat, as side effects were deemed minimal and clinical response was good.

Relapse was recognized in 3 cats (Cats 2, 3, and 6) more than a year after the last voriconazole dose. Cats 2 and 3 had prior relapses of previously diagnosed and successfully treated histoplasmosis. One cat (Cat 1) that had a prior diagnosis of histoplasmosis and relapsed prior to treatment with voriconazole has remained in remission 560 days following discontinuation of voriconazole therapy. Relapse is reported in up to 40% of cases, although the true relapse rate may be higher when cats are followed long-term.4 In the current study, Cat 2 was in remission for 8 years prior to relapse, a period of follow-up that is rarely achieved in most retrospective or prospective studies. It is unknown how long azole therapy needs to be continued following resolution of clinical disease (resolution of radiographic changes, disappearance of organisms on cytology) or upon achieving a negative UA-EIA to minimize relapse in cats.10 In this report, the time frame by which organisms could be identified cytologically was shorter than the time frame to achieve a negative UA-EIA. Even in the 1 cat with nodular pulmonary infiltrates, the UA-EIA was positive long past resolution of thoracic radiographic changes (239 days). In cats with a positive UA-EIA, the authors of the current report have traditionally treated cats with azoles for 1 month beyond a negative UA-EIA and then repeated the UA-EIA 1 to 2 months after discontinuation of therapy. This treatment and monitoring protocol also did not prove to be successful in preventing relapse in 3 cats. Even cat 6, with an additional negative UA-EIA more than a year after the previous negative test result, relapsed 274 days after that negative test result.

Voriconazole therapy as described in this report is an attractive alternative to the once- to twice-daily dosing required with itraconazole or fluconazole. The need to dose the cat once every 3 days was the rationale for choosing voriconazole therapy in Cat 6 that was known to be difficult to handle. Cat owners report a number of unpleasant experiences while attempting to medicate their cats, including being bitten or scratched.21,22 Owner preference of liquids versus tablets is unclear, and available surveys state conflicting results. Although owner compliance is apparently similar with once- versus twice-daily dosing, most cat owners would likely appreciate a longer interval between doses, such as dosing intervals of every 72 or 96 hours.2123

In conclusion, voriconazole should be considered an alternative antifungal treatment option for histoplasmosis in cats at 12.5 mg/cat PO every 72 hours, with exceptions for unusually large (or small) cats. Voriconazole administration resulted in remission of histoplasmosis and was associated with infrequent mild adverse effects.

Acknowledgments

None reported.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.

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  • 1.

    Teixeira MM, Patané JS, Taylor ML, et al. Worldwide phylogenetic distributions and population dynamics of the genus Histoplasma. PLoS Negl Trop Dis. 2016;10(6):e0004732. doi:10.1371/journal.pntd.0004732

    • Search Google Scholar
    • Export Citation
  • 2.

    Histoplasmosis maps. CDC. January 14, 2021. Accessed February 16, 2023. https://www.cdc.gov/fungal/diseases/histoplasmosis/maps.html

  • 3.

    Nett RJ, Skillman D, Riek L, et al. Histoplasmosis in Idaho and Montana, USA, 2012-2013. Emerg Infect Dis. 2015;21(6):1071-1072. doi:10.3201/eid2106.141367

    • Search Google Scholar
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