Cécile Clercx, DVM, PhD, dipl ECVIM-CA
Departement of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, University of Liège, Sart Tilman, B44, 4000 Liège Belgium
Effective treatment of nasal aspergillosis in dogs has proved difficult. Therapeutic considerations have included surgery as well as systemic and topical antimycotic medications. The systemic administration of antifungal agents requires prolonged medication due to their poor efficacy, and clinical cures are obtained in only about 50% of patients. Topical treatment has been associated with greater therapeutic success, and has improved management of this previously intractable condition. Different procedures, with varying degrees of invasiveness, have been developed to administer the topical medication. For several years, the standard treatment was an enilconazole emulsion delivered via tubes surgically implanted into the nasal cavities and frontal sinuses with twice daily irrigation for 7 days (Sharp and Sullivan, 1992). More recently, a non-invasive technique using nonsurgically placed catheters has been developed to infuse the topical drug into the nasal cavities and frontal sinuses under general anaesthesia (Davidson 1995). Many trials with variables of the latest techniques (such as regime of drug administration, concentration, volume, formula of the drug, etc.) are at present under investigation in order to improve the therapeutic success and to improve the tolerance by the animal and the owners. For dogs that are confirmed to be free of fungus at the end of antifungal drug therapy the long-term prognosis seems to be good after treatment.
Systemically active therapies are the least-invasive treatments available, although they are not the most successful. Moreover, the drugs are expensive and are potentially hepatotoxic. Treatment of nasal aspergillosis with systemic antifungal medications, such as thiabendazole at 10 mg twice daily for six to eight weeks (Cervantes 1983) or ketoconazole at 5 mg twice daily for six to eight weeks (Sharp and Sullivan, 1989) has been disappointing because, even associated with surgery (rhinotomy and turbinectomy), administration of these drugs results in improvement in at most 50% of cases (Sharp et al, 1984; Harvey 1984).
Two drugs that are reported to be more effective are itraconazole, at a dosage of 5 mg/kg PO BID, and fluconazole, at a dosage of 2.5 mg / kg PO BID, both for a minimum of 10 weeks (Legendre 1995; Sharp et al,1991). Response to oral administration of itraconazole has been observed in approximately 60 to 70% of cases (Legendre, 1995).
Topical administration of enilconazole, or clotrimazole is more effective than orally administered antifungal medications (Sharp and Sullivan, 1989; Sharp et al, 1991; Sharp et al, 1993; Davidson et al, 1992; Mathews et al,1998).
Topical enilconazole is a very effective treatment for canine nasal aspergillosis although it is not effective in dogs in which the organism had invaded adjacent soft tissues (Sharp et al, 1993); in such cases, enilconazole combined with a systemically active drug is indicated. Enilconazole is considered an ideal topical agent because it is also active in the vapor phase, which enhances its distribution throughout the nasal chamber (Sharp et al, 1993). In a technique described by Sharp et al in 1993, the drug is administered through separate tubes that have been implanted surgically into both nasal chambers by means of trephine holes in the frontal sinuses, as well as into the infected sinus or sinuses. The procedure is performed twice daily at a dosage of 10 mg/kg for a total of 7 to 10 days. Although most patients tolerate treatment well, hospitalization is usually required and this type of treatment is far less convenient than that which consists of orally administered antifungal drugs. Common complications include: premature removal of catheters necessitating additional anesthetic episodes for catheter replacement, transient postoperative subcutaneous emphysema, inappetence, and ptyalism. Treatment may also have to be abandoned if the patient becomes aggressive and intolerant of the procedure. Using this technique, nasal discharge resolved in 19 of 24 (80%) dogs treated solely with topical administration of enilconazole (Sharp et al, 1993).
Some studies were conducted on cadavers to evaluate the effect of different factors on the distribution of infusate into the nasal chambers and sinuses.
In 1995, Richardson, (Vet Sur 1995) studied the distribution of dye injected into cadaver skulls of dogs without sinonasal disease using a noninvasive technique for intranasal infusion. They found that this technique resulted in better distribution of infusate into the nasal cavity and frontal sinuses than did techniques that used surgically placed catheters. Larger volumes of infusate may be administered and leakage is minimal, thereby decreasing the risk of aspiration, if the nares and nasapharynx are occluded during intranasal infusion. With cadaver skulls placed in dorsal recumbency, bilateral administration of 50 ml (100 ml total) resulted in excellent distribution of infusate to the entire nasal cavity and frontal sinuses with minimal leakage into the pharynx.
However, the volume of the nasal cavity and frontal sinuses depends on the size of the dog, extent of turbinate destruction, and volume of accumulated exudate. On the basis of a study on cadavers (Mathews et al, 1996), the average volume of frontal sinuses in breeds predisposed to fungal disease was 25 ml / side. The nasal cavity and sinuses can be flooded with a larger volume of infusate (50 or 60 ml / side), which results in distribution of infusate to all areas of the nasal cavity and frontal sinuses. Recommendations from this study were to use 50 to 60 ml / side in middle- to large-breed dogs regardless of head size.
Intranasal pressures, evaluated in the same study to determine if pressure could be used to predict distribution of infusate, were cumbersome to measure and, in many cases, were not useful.
A 1-hour infusion of clotrimazole administered to dogs under general anaesthesia also results in resolution of clinical signs in many dogs with nasal aspergillosis (Davidson and Pappagianis, 1995; Davidson 1997). Although a surgical procedure is still necessary for catheter placement in the frontal sinus, multiple treatments are not required, complications associated with indwelling catheters are eliminated, and hospitalization time is substantially reduced.
Therapy consists of bilateral infusion of a total of 1 gm clotrimazole, dissolved in 1 dl propylene glycol 200 into the frontal sinuses and nasal passages through infant feeding tubes placed into the frontal sinuses by trephination. The 1% clotrimazole solution has a moderate viscosity, enabling coating of mucous membranes, yet passes through infant feeding tubes without difficulty. As compared to the twice-daily infusion of an antimycotic solution, patient discomfort is minimized, the contact of clotrimazole with the affected mucosal surfaces is maximized, and hospitalisation time and expense are markedly reduced. Concurrent systemic antifungal therapy has not been found to be advantageous, and may interfere with the proposed fungicidal effect of the drug. Again, cases selected for topical clotrimazole therapy should have aspergillosis limited to the frontal sinuses and nasal passages.
Adverse reactions to this treatment have been described (Caulkett et al, 1997) and recognized (Zonderland et al, 2000); these include severe pharyngitis and oedema and prolonged recovery, presumably as a result of the vehicles present in the clotrimazole formulation, and of microsomal enzyme inhibition by the clotrimazole respectively. Indeed, in the original protocol, powdered clotrimazole was formulated in polyethylene glycol (Davidson and Pappagianis, 1995) while in the described case, a commercial preparation (1% Topical solution, Miles Canada, Etobiocoke,Ontacontains propylene glycol, isopropyl alcohorio, Canada) marketed for external use only was used. This preparation contains propylene glycol, isopropyl alcohol and polyethylene glycol. Polyethylene glycol is considered to be a relatively nonirritant vehicle, but propylene glycol and isopropyl alcohol produce local irritation when applied to the mucous membranes. In his report, Caulkett concluded that clotrimazole solutions formulated in the propylene glycol, isopropyl alcohol and polyethylene glycol vehicles should not be used for intranasal instillation. Barbiturate anesthesia or sedation should be used cautiously when clotrimazole is administered by the intranasal route due to the potential interaction between barbiturates and clotrimazole.
In a study designed to examine the clinical response to topical administration of clotrimazole in dogs with nasal aspergillosis, and to compare the effects of surgically placed versus nonsurgically placed catheters used for administration on outcome, it was found that topical administration of clotrimazole, using either technique, is an effective treatment for nasal aspergillosis in dogs (Mathews et al, 1998). Use of noninvasive intranasal infusion of clotrimazole eliminates the need for surgical trephination of frontal sinuses in many dogs and was associated with fewer complications (Mathews et al, 1998). In this study, twenty-seven dogs were anaesthetized and treated with 1 topical administration of clotrimazole delivered via surgically placed catheters. A 1% solution of clotrimazole in polyethylene glycol was evenly divided among four 30 ml-syringes and slowly infused during a 1-hour period. After treatment, excess medication was allowed to drain rostrally, and the pharynx and proximal portion of the oesophagus were suctioned to decrease the risk of aspiration.. Eighteen dogs were treated with 1 intranasal infusion of clotrimazole, delivered via nonsurgically placed catheters. In this technique, a 24-F Foley catheter is placed per os so that the tip of the catheter is dorsal to the soft palate and the balloon is inflated. Sponges are placed in the pharynx. One 10-F polypropylene infusion catheter is advanced through each nostril and a 12-F Foley catheter is inserted into each nostril and balloons are inflated and positioned just caudal to the nostrils. The clotrimazole is administered similarly. Each dog's head is rotated and maintained in the following positions to ensure contact of clotrimazole with all nasal surfaces: dorsal recumbency (15 min), left lateral recumbency (15 min), right lateral recumbency (15 min) and dorsal recumbency (15 min). Changing the dog's head position periodically during infusion is required to ensure adequate contact between antifungal medication and all surfaces of the frontal sinuses. Post treatment procedures were the same as in group 1. In a third goup, the dogs received several infusions. Of the 27 group-1 dogs, 4 were considered treatment failures and were not retreated with clotrimazole. Of the 18 group-2 dogs, 2 were considered treatment failures and were not retreated with clotrimazole. In summary, of the 60 dogs of this report, 8 (13%) were considered treatment failures. This compares favorably with the 80% resolution rate previously reported for multidose topical administration of enilconazole and the 43 to 70% resolution rate reported for oral treatment with a variety of antifungal medications (Harvey, 1984; Sharp and Sullivan, 1989; Sharp et al, 1991; Sharp et al, 1991, Sharp et al, 1993)
Severe complications leading to euthanasia included neurological signs compatible with cortical encephalopathy and suppurative meningitis. (Other less severe complications were similar to those previously described).
Enilconazole has also been used through nonsurgically placed catheters. Enilconazole is available as different formulations (Clinifar-EC, which contains alcohol and Imaverol). Clinifar was administered after endoscopic placement of lavage tubes in the caudal portion of the nasal cavity and frontal sinuses (McCullough et al, 1998). Enilconazole in a final concentration of 5% and 50 to 200 ml-volume was used in the treatment, during general anaesthesia, of 6 dogs with nasal aspergillosis. The dogs received two or three treatments with each one lasting 45 to 60 minutes. All the dogs showed favorable clinical response soon after treatment. Three dogs that were followed for a mean of 16.5 months had marked clinical improvement.
More recently, imaverol has been used as a one-hour infusion but has produced disappointing results, according to the authors (Bray et al, 1998a; Bray et al, 1998b). In one study involving four dogs, none were cured by the one-hour infusion of imaverol and three even appeared to be worse. Two of these dogs did respond to subsequent twice daily irrigation with the drug. Three other dogs were randomly assigned a one-hour infusion with clotrimazole during the same period, and all were cured.
Their results are in disagreement with others. In our own experience, treatment with a 2% imaverol solution infused during one hour through nonsurgically placed catheters gives encouraging results. This treatment was used in 20 dogs. The success rate was 50% after the first treatment, and 75% after the second treatment (Zonderland et al., 2000), which can be compared with results previously reported with clotrimazole using a similar technique.
Rhinotomy and turbinectomy followed by topical treatment and/or systemic therapy are considered by some clinicians as a very efficacious method. On the other hand, other authors suggest that turbinectomy is of no benefit in controlling the nasal discharges and is often detrimental (Sharp, 1995). Invasive surgical exposure of the nasal passages and frontal sinuses (open nasal cavity treatment), therefore should not be recommended as first line therapy, topical 10% povidone -iodine application, and delayed closure 6 to 8 weeks postoperatively is recommended for refractory cases, but has poor client acceptance (Pavletic and Clark, 1991), and therefore should not be recommended as first line therapy.
case study with rhinoscopic images
table of therapies for canine nasal aspergillosis
There are images of canine nasal aspergillosis here
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Cervantes ÐOlivaries RA. PhD 1983
Lotrimin solution, Schering Plough Corp, Kenilworth, NJ
Canesten solution, Miles Canada, Etobicoke, Ont, Canada.
Clinifarm-EC, 13.8% concentrate, sterwin labs, Inc, Millsboro, DE
June 13, 2000