Treatment of
Canine Nasal Aspergillosis
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
E-mail: cclercx@ulg.ac.be
Introduction
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 anesthesia
(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.
Systemic therapy
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 therapy
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.
Surgery
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.
