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This study evaluated the effect of 1% bifonazole cream in the treatment of canine sino-nasal aspergillosis (SNA). The cream was instilled through perendoscopically placed catheters into the frontal sinuses and was used either as single therapy after debridement (DC) or as adjunctive therapy after 2% enilconazole infusion (DEC). Twelve dogs were treated initially with DEC: 7 and 3 of these dogs were free of disease after 1 and 2 procedures, respectively, while 2 dogs were cured after DC was used as a second procedure. Five dogs were treated with DC only: in 3 dogs with moderate disease, cure was obtained after a single procedure while, in 2 debilitated patients, cure could not be confirmed. Topical administration of 1% bifonazole cream appears as an effective therapy in SNA, either as an adjunctive therapy to enilconazole infusion or as sole therapy in moderately affected patients.
Efficacité de l’administration intrasinusale d’une crème de bifonazole seule ou en combinaison avec l’irrigation à l’enilconazole pour l’aspergillose sino-nasale canine : 17 cas. Cette étude a évalué l’effet d’une crème de bifonazole 1 % pour le traitement de l’aspergillose sino-nasale (ASN). La crème a été instillée par des cathéters placés par endoscopie dans les sinus frontaux et a été utilisée soit comme thérapie unique après débridement (DC) ou comme traitement auxiliaire après une infusion d’enilconazole 2 % (DEC). Douze chiens ont été traités initialement par DEC : 7 et 3 de ces chiens étaient exempts de maladie après 1 et 2 procédures, respectivement, tandis que 2 chiens ont été guéris après le recours au DC comme deuxième procédure. Cinq chiens ont été traités par DC seulement : chez 3 chiens avec une maladie modérée, la guérison a été obtenue après une seule procédure tandis que, chez deux patients débilités, la guérison n’a pas pu être confirmée. L’administration topique d’une crème de bifonazole 1 % semble être une thérapie efficace pour l’ASN, soit comme traitement auxiliaire à l’infusion d’enilconazole ou comme thérapie unique chez des patients modérément affectés.
(Traduit par Isabelle Vallières)
Sino-nasal aspergillosis (SNA) is a common disease that affects between 12% and 34% of dogs evaluated for chronic sino-nasal disease (1). This disease is often suspected based on history and clinical signs, and the diagnosis is confirmed by a combination of results obtained by rhinoscopy, computed tomography, cytology/histology, fungal culture, and serology (2–7).
Effective treatment of canine SNA including surgery and systemic and topical administration of antimycotic medication is a challenge (3). Systemic treatment with oral antimycotic agents is costly and requires prolonged administration (8). The efficacy of these drugs varies from 40% to 50% for thiabendazole and ketoconazole to 60% to 70% for fluconazole and itraconazole (9–12). Topical treatment with clotrimazole or enilconazole has a higher success rate and has improved the management of this previously intractable condition (13,14). Various procedures developed to administer medication topically vary in invasiveness and ease of performance. Surgical tube implantation and irrigation of the nasal cavities and frontal sinuses twice daily for 7 to 14 d with antifungal agents has been the standard treatment for many years (14). More recently, however, minimally invasive techniques using non-surgically placed tubes have ensured better distribution of the drugs into the sinuses. These techniques have been equally effective and have fewer complications (13,15,16). Several studies have evaluated non-invasive infusion techniques in order to improve treatment success, toleration by the animal, and compliance by the owners (13,17–19). Although the use of topical antifungal agents via non-invasive methods is well tolerated and shows a high success rate, the procedures are time-consuming and require a long anesthesia time.
A recent study was conducted to evaluate prospectively the use of invasively administered 1% clotrimazole cream instilled into the frontal sinus after trephination. The cream acted as a depot agent to minimize anesthesia time while providing extended period of drug contact; a good response was shown in most dogs (20).
The aim of the present study was to evaluate the effect of 1% bifonazole cream instilled non-invasively through perendoscopically placed catheters as a single therapy or after instillation with 2% enilconazole in the treatment of 17 dogs with SNA.
Seventeen dogs with aspergillosis in the nasal cavities and frontal sinus were included in this retrospective study. The diagnosis of SNA was based on the presence of compatible clinical findings and endoscopic observation of typical intrasinusal or intranasal fungal plaques associated with turbinate destruction.
Each dog underwent a complete physical examination, general blood work, and rhinoscopy. Serology results (agar gel double immunodiffusion; Meridian Diagnostics, Cincinnati, Ohio, USA) were also recorded. For rhinoscopy, all dogs were sedated with medetomidine (Domitor, Pfizer Animal Health SA, Louvain-La-Neuve, Belgium), 25 to 35 μg/kg, IM, or acepromazine (Combistress; Phenix SA, Brussels, Belgium), 0.025 to 0.05 mg/kg, IM, and methadone (Mephenon; Federa SC, Brussels, Belgium), 0.2 to 0.4 mg/kg, IM, and anesthetized with thiopentone (Nesdonal; Rhône-Poulenc SA, Lyon, France), 5 to 10 mg/kg, IV, or propofol (Diprivan; AstraZeneca SA, Brussels, Belgium), 2 to 6 mg/kg, IV. Anesthesia was maintained with isoflurane (Forene; Abott SA, Ottignies-LLN, Belgium) in oxygen. Both nasal cavities were explored with a rigid endoscope (Cystoscope K Storz SL 30°, Ref BA 3059308; Karl-Storz-Endoscopy Belgium SA, Strombeek Bever, Belgium) as well as with a pediatric bronchoscope (Fujinon EB-4105; Onys SA, Brussels, Belgium) allowing exploration of the frontal sinus, sampling of nasal biopsies and fungal plaques, and endoscopically guided debridement. Plaque-like specimens were incubated at 37°C on Sabouraud’s-dextrose-agar containing chloramphenicol (0.5 g/L) and actidione (0.5 g/L).
A meticulous debridement (D) was performed endoscopically in all dogs by means of forceps, suction catheter, and copious lavage with saline (0.9% NaCl) solution until most fungal plaques and necrotic material were removed from the sinus and nasal cavity. Most dogs were then treated with a 1-h infusion of 2% enilconazole (E), instilled through catheters placed into the frontal sinus under endoscopic guidance in the affected nasal cavity and in the dorsal meatus in the non-affected nasal cavity. This was followed by administration of a 1% bifonazole cream (C) as a depot agent in the affected frontal sinus through the catheter (treatment protocol DEC). Alternatively, dogs with only moderate amounts of fungal material (few fungal colonies all restricted to a demarcated area of the nasal cavity or sinus) and debilitated patients (in order to decrease the duration of anesthesia) were treated with local deposits of cream without infusion with enilconazole (treatment protocol DC). All patients underwent follow-up rhinoscopy at 3 wk intervals until cure was established. An additional treatment procedure was applied during rhinoscopy if the dog was not free of aspergillosis.
For the DEC protocol, after debridement, the dog was positioned in dorsal recumbency with the hard palate parallel to the table, and a 20/24-F Foley catheter was inserted into the nasopharynx with a right-angle forceps. Gauze sponges were placed around the base of the catheter in the pharynx. The 30-mL balloon was inflated with saline solution to occlude the nasopharynx. The balloon was palpated through the soft palate to confirm its position just caudal to the hard palate. In the affected nasal cavity, a 12-F fenestrated catheter was placed under endoscopic guidance into the caudal part of the frontal sinus. In the non-affected nasal cavity, a 12-F fenestrated catheter was inserted blindly dorsomedially to the level of the medial canthus of the ipsilateral palpebral fissure. The 12-F fenestrated catheters were the infusion catheters and were connected via a T-shaped connecting piece to a 60-mL infusion syringe. Each nostril was occluded by use of an 8/12-F Foley catheter (with a 1.5/3-mL balloon) and towel clamps. Finally, all Foley catheters were occluded by clamps. Slow infusion of approximately 120 mL of 2% enilconazole (Imaverol; Janssen-Cilag SA, Berchem, Belgium) (~60 mL for each nasal cavity) was administered over a 1-h period. The head of the dog was rotated 90° every 15 min (dorsal recumbency — lateral recumbency (affected side) — ventral recumbency, lateral recumbency (non-affected side)) to ensure maximal contact between enilconazole and the sino-nasal mucosa. At the end of the intranasal infusion, the head was tilted downwards at an angle of 30°, the nasal Foley catheters were removed and enilconazole was allowed to drain rostrally through the nostrils for 10 min. The content of a 15-g tube of 1% bifonazole cream (Canestene; Bayer, Brussels, Belgium) was then transferred to a 60-mL nutrition syringe, which was placed at the end of the infusion catheter of the affected side, and instilled directly into the frontal sinus. The head of the dog was positioned with the nose above the level of the frontal sinus for at least 10 min. When both sinuses were involved, the content of another tube was infused into the 2nd frontal sinus. Finally, all remaining catheters and gauze sponges were removed and the pharynx and larynx were examined and cleaned. In the DC protocol, bifonazole cream was administered directly after debridement through the infusion catheter into the affected frontal sinus as described above.
The duration of the whole procedure was obtained from the anesthetic report, but the duration of each part of the procedure (debridement, enilconazole infusion, and cream deposit) was not recorded and could only be estimated. Antibiotic therapy was initiated at the end of the procedure with cefazo-line (Cefacidal; Bristol-Myers Squibb Belgium SA, Brussels, Belgium), 20 mg/kg, IV, followed by 1 injection after 6 h at the same dose, and continued with cefalexine (Keforal; Eli Lilly Benelux SA, Brussels, Belgium), 20 mg/kg, q12h, administered PO for 5 d. All dogs also received oral antifungal medication until cure was confirmed by rhinoscopy: ketoconazole (Nizoral; Janssen-Cilag SA, Berchem, Belgium), 10 mg/kg, PO, q12h or itraconazole (Sporanox; Janssen-Cilag SA, Berchem, Belgium), 5 mg/kg, PO, q12h, according to previous administration of antifungal therapy or according to the veterinary surgeon.
Ten breeds were represented among the 17 dogs in this study (Table 1). The most frequent breeds were rottweilers (n = 3), Labrador retrievers (n = 2), and beauceron sheep-dogs (n = 2). There were 8 females (3 intact) and 9 males (7 intact). Age at the time of diagnosis ranged from 1 to 15 y (mean ± s: 6.4 ± 4.5 y). In 3 dogs (no. 5, 7, and 12), SNA had been suspected based on the results of a CT-scan of the head. Involvement of the cribriform plate was not detected in any of these dogs. Current treatment at the time of referral included oral antimycotic drugs in 1 dog (no. 7), antibiotics in 7 dogs (no. 3, 4, 8, 10, 11, 13, and 16) and a combination of oral antifungal therapy and antibiotics in 4 animals (no. 2, 5, 14, and 15). In most cases, no or weak transitory improvement had been observed.
Duration of clinical signs ranged from 1 to 11 mo (mean ± s: 3.8 ± 2.5 mo). At the time of diagnosis, clinical features included nasal discharge and sneezing or reverse sneezing in all dogs, signs of nasal pain (n = 10), illness or signs of depression (n = 11), ulceration of the nares (n = 12), and increased nasal airflow (n = 12). The nasal discharge was at least partly hemorrhagic in 14 patients. Four dogs had epiphora present on the same side as the affected sinus. Rhinoscopic findings included in all dogs destruction of turbinates (bilateral in 8), intranasal mucopurulent secretions (bilateral in 8), presence of fungal plaques in one (n = 11) or both (n = 6) nasal cavities and intense intranasal remodeling. Frontal sinus was involved in 16 dogs; dog 13 was the only patient in which the disease was limited to the nasal cavity. Destruction of the nasal septum was seen in 6 dogs, although it was visualized in 2 additional dogs during the control rhinoscopy. Fungal culture was positive for Aspergillus fumigatus in 11 dogs (nos. 2–9, 13, 14, 16), negative in 2 dogs (nos. 1 and 10) and was not available for the 4 other animals. Serology was positive, negative, and not available in 11 dogs (nos. 1–4, 7, 8, 11, 13–16), 2 dogs (nos. 6 and 10), and 4 dogs, respectively.
The DEC protocol was used as 1st treatment procedure in 12 dogs (nos. 1 to 12) and as 2nd treatment protocol in 3 dogs (nos. 8 to 10), in which cure was not reached after the first DEC protocol (Table 1). The duration of the DEC protocol, from the beginning of rhinoscopic debridement until the pharynx and larynx were cleaned, ranged from 135 to 225 min (mean ± s: 176 ± 32.1 min). Dogs recovered very slowly from anesthesia and were hospitalized until the next day. They exhibited signs of sino-nasal pain for 2 to 3 d after discharge. Nasal discharge stopped or was greatly reduced within 1 to 3 d, and the general condition improved markedly within 3 d. Dogs 1 to 7 were cured after the 1st treatment, while dogs 8 to 10 were cured after the 2nd treatment.
The DC protocol was used as a 2nd treatment procedure in 2 dogs that were not cured after a single DEC protocol (dogs 11 and 12). The DC protocol was also applied as a 1st treatment protocol in 5 dogs (nos. 13 to 17) for various reasons (Table 1). Dogs 13 to 15 were atypical nonsevere cases. In dog 13, DC was chosen because the animal was old (15 y) and suffered from chronic renal failure; moreover, fungal plaques were limited to the nasal cavity. In dog 14, despite intensive bilateral turbinate lysis, only a reduced amount of fungal material was found, and in dog 15, plaques were localized around a vegetal foreign body which was easily retrieved during diagnostic rhinoscopy. Dog 16 was a 12.5 year-old Labrador retriever with pyelonephritis. Prolonged anesthesia was not recommended and the owners opted for the DC protocol. Dog 17 was suffering from leishmaniasis and tissue was biopsied during rhinoscopy as a nasal tumor was suspected. Treatment with the DC protocol was elected in view of the possible poor prognosis.
Overall, the duration of the DC protocol ranged from 35 to 120 min (mean ± s: 73.3 ± 27.9 min). Dogs recovered slowly from anesthesia but could be discharged from the hospital the same day. They exhibited signs of sinonasal pain for 2 to 3 d after discharge as well. Dogs 11 to 15 were cured. Dog 16 was not cured, although related clinical symptoms improved. Some intranasal plaques were still visualized during control rhinoscopy and the owners elected euthanasia. In dog 17, histopathological examination of the biopsied mass failed to reveal a neoplastic process, but the animal developed neurological signs (seizures and Horner’s syndrome) 4 d after treatment and was euthanatized by the referring veterinarian at the owner’s request.
Seven dogs received ketoconazole (nos. 4, 5, 9–12, and 17) and the other 10 dogs received itraconazole, as oral antifungal therapy, until the final checkup.
The aim of the present study was to evaluate the effect of 1% bifonazole cream instilled non-invasively into the frontal sinuses after extensive perendoscopical debridement either as a single therapy or after instillation of 2% enilconazole in the treatment of canine SNA.
The choice of the drugs and treatment procedures used was based on the efficacy of a technique previously reported that uses topical intranasal infusion of 2% enilconazole (17) and on a recent publication using clotrimazole cream as topical treatment (20). The infusion technique using enilconazole is associated with few complications and has shown good efficacy (17). Our goal was to improve the success rate and decrease the number of therapeutic procedures by adding 1% bifonazole cream instilled non-invasively through the perendoscopically placed catheters into the frontal sinuses. This was based on the hypothesis that viscosity of the cream might provide greater persistence in the frontal sinus, thereby increasing drug contact time with possible persistent fungal colonies (20). Besides, although safe and efficacious, the DEC protocol is a time-consuming and laborious procedure which entails a very long anesthesia period. The DC protocol, therefore, appeared be an interesting alternative in debilitated patients and dogs with only moderate amounts of fungal material as both a second and first therapeutic procedure. As adding oral systemic antifungal therapy to topical antifungal therapy may enhance the efficacy of the treatment (21), itraconazole/ketoconazole was continued until checkup in dogs that were already receiving it and was administered concomitantly in other patients until control rhinoscopy.
In the present study, instillation of 1% bifonazole cream through the catheters after infusion with 2% enilconazole (protocol DEC) was successful without complication in 100% of the dogs treated, after 1 (7/10 dogs) or 2 (3/10 dogs) therapeutic procedures. This confirms and even improves results from previous studies assessing the efficacy of non-invasive enilconazole infusion in dogs with SNA. Zonderland et al (17) reported a combined 100% cure after 1 (53% of dogs), 2 (35%), or 3 treatments (12%), while McCullough et al (19) reported 100% cure after 2 to 3 treatments. This also compares very favorably with the success rates relative to any other non-invasive/medical (13,22,23) or invasive/surgical therapeutic trial (13,14,20,21,24).
Although tested in a relative low number of cases in the present study, the success rate of a single DC protocol, whether applied as a second or first therapeutic option, was excellent in the 5 dogs with moderate amounts of mycotic material. Results from the present study suggest that in case of failure after one procedure, and persistence of few Aspergillus plaques, the repeated classical DEC protocol could advantageously be replaced by the much shorter and less invasive DC protocol.
The use of the DC protocol as a first treatment option in the 2 older dogs with systemic disease and severe SNA was not successful. This could have been related to an insufficient effect of the local drug against the fungus. Very little information is available on the stability and retention time of bifonazole cream inside the canine frontal sinus. The hypothesis is that retention would be prolonged due to the viscosity of the product, but no study has been conducted to verify this hypothesis. In contrast to a more liquid antifungal solution (5% clotrimazole or 2% enilconazole), the increased viscosity of the bifonazole cream may prevent the antifungal agent from contacting all fungal material that may be hidden within crevices of the frontal sinus and/or nasal cavity. Another hypothesis to explain treatment failure would be the lack of complete debridement when very large fungal plaques and/or abundant necrotic material are impacted in the frontal sinuses. In these 2 older dogs, complete debridement with retrieval of all fungal material could not be achieved during rhinoscopy. In our experience, extensive debridement prior to infusion is critical in achieving cure and this step may be quite challenging in severe cases. Current evidence suggests that canine SNA is not associated with significant tissue invasion of either mucosa or bone, making the disease in dogs resemble chronic non-invasive destructive fungal rhinosinusitis in human patients (25–28). It appears that in humans with this condition, extensive debridement by endoscopic sinus surgery is the major success factor in achieving a cure as the concomitant use of oral antifungal medications is only occasionally reported (26–28). One could imagine treating dogs with SNA only with extensive debridement. However, despite extensive debridement and enilconazole infusion in some cases, as well as in other dogs with severe impaction treated with surgical debridement through trepanation followed by infusion of antifungal drug (29), some dogs are still not cured. Therefore, it seems not ethically justified to investigate whether debridement alone can be an effective therapeutic option.
As expected, the DC protocol (73.3 ± 27.9 min) was much shorter than the DEC protocol (176 ± 32.1 min), thus allowing a significant reduction in the duration of anesthesia. Moreover, since the dogs were discharged on the same day with most patients being discharged within 6 h of treatment, the costs of the treatment were significantly reduced. Nevertheless, the DC protocol is still longer than the combined invasive clotrimazole irrigation and depot therapy (mean duration 31.7 min) through frontal sinus trephination as described by Sissener et al (20). This is due to the absence of meticulous perendoscopical debridement of the sino-nasal cavities in that method.
Adverse effects after DEC protocol were mild and identical to those previously reported (17). The major concern for topical application techniques is the risk of contamination of the brain either by fungal invasion or by topical drug overflowing across a damaged cribriform plate (30). In the present study, a CT scan of the skull was performed in only 2 cases and the cribriform plate appeared to be intact in those patients. Dog 17 had seizures 4 d after treatment, possibly due to central nervous system contamination by drug or fungi. It is not known whether the use of bifonazole cream, by hypothetical prolonged retention time within the frontal sinus, may have resulted in increased risk of contamination of the brain or in increased inflammatory reaction in that dog.
In conclusion, the DEC therapeutic protocol lead to cure in 100% of cases in this series, after 1 or 2 procedures. The DC protocol was successfully used as a 2nd protocol when the 1st DEC had not totally cured the dog. The DC protocol, therefore, may also offer a promising alternative as a primary therapeutic protocol in dogs with only few fungal plaques. Finally, the DC protocol was a much quicker procedure than the DEC protocol, thereby requiring a shorter anesthesia time and only brief hospitalization. A prospective clinical trial, however, is necessary to draw definitive conclusions on the superiority of this protocol. CVJ
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