Successful treatment of invasive Aspergillus sinusitis with caspofungin and voriconazole.

Abstract

Chronic invasive Aspergillus sinusitis is a rare andpotentially devastating infection. Management typically requires extensive surgical debridement followed by long-term antifungal therapy, primarily with intravenous amphotericin B. We describe the case of an elderly woman who had been diagnosed with extensive Aspergillus sinusitis that had invaded critical structures. The extensiveness of the infection and the patient's frailty and unwillingness to undergo a disfiguring procedure precluded surgery, and her medical condition was too fragile to wlthstand amphotericin B therapy. Therefore, we decided to treat her with a combination of caspofungin and voriconazole, two relatively nontoxic antifungal agents that have different mechanisms o faction. After administration of this novel regimen, the infection resolved rapidly.

Introduction

Fungal sinusitis is classified as invasive or noninvasive and chronic or acute. (1) Acute invasive fungal rhinosinusitis occurs more often in immunocompromised patients, and symptoms develop rapidly over days to weeks. Chronic invasive fungal sinusitis occurs in patients with little or no evidence of immunocompromise, and it tends to present more insidiously over weeks to months. (1) The prognosis generally depends more on the host's immune status than on the specific causative organism.

Traditionally, invasive Aspergillus sinusitis has been treated with extensive surgical debridement followed by long-term antifungal therapy, primarily with intravenous amphotericin B. We describe a case in which the patient's fragile condition and refusal to undergo surgery necessitated a novel approach to therapy.

Case report

An 89-year-old woman with asthma presented to our hospital with a 1-year history of facial and tooth pain and a runny nose. Both her dentist and her primary care physician had treated her with multiple courses of oral antibiotics without any discernible improvement. She eventually underwent computed tomography (CT), which detected marked sinusitis with opacification of the left ethmoid and frontal sinuses. After consultation with an otolaryngologist, she underwent sinus surgery. The left ethmoid and maxillary sinuses were drained, and an inferior meatus antrostomy was performed. Extensive necrosis and debris were noted intraoperatively. Subsequent findings on pathologic examination--hyphae associated with tissue necrosis, acute and chronic inflammation, and fungus balls--were consistent with a fungal infection. Six days after surgery, Aspergillus fumigatus grew on culture. After the patient underwent inhaled amphotericin therapy for several weeks, she developed ocular immobility, increased tearing, and subsequent loss of vision in the left eye.

At that point, the patient was referred to the emergency department at our hospital, where she underwent ophthalmologic and otolaryngologic evaluations. These examinations revealed left-sided blindness, ptosis, and a complete paralysis of the extraocular muscles (figure 1). Soft-tissue swelling and erythema were noted on the left side of the face in the area surrounding the eye. A repeat CT (figure 2, A) and magnetic resonance imaging with gadolinium contrast both detected extensive invasive disease involving the nasopharynx, infratemporal fossa, orbit, and cavernous sinus. No evidence of parenchymal disease was seen.

The infection rapidly worsened over the first 24 hours of hospitalization. The extensive involvement of critical structures and the patient's frailty and unwillingness to undergo a disfiguring procedure precluded surgery, and we believed that her medical condition was too fragile to withstand IV amphotericin B therapy. Therefore, we consuited the literature for guidance. Although the literature supporting combination therapy with an echinocandin and a triazole for invasive aspergillosis was limited at the time, we decided that it was sufficient to justify a trial of combination caspofungin and voriconazole. Our decision was based on studies showing that these two agents had a beneficial synergistic effect in animals with experimental pulmonary aspergillosis. (2)

Initially, the patient received a loading dose of caspofungin (70 mg IV) and two doses of voriconazole (6 mg/kg IV). Thereafter, she was administered IV caspofungin at 50 mg/day and IV voriconazole at 4 mg/kg twice daily. The voriconazole was later administered as an oral formulation (100 mg twice daily). The patient remained on both medications for several months. The concentration of caspofungin was eventually increased to minimize fluid overload.

After only one dose of this combination, the course of the infection stabilized. The patient experienced no further progression of her neurologic symptoms, and her facial edema and erythema abated. Serial follow-up CTs confirmed the considerable improvement (figure 2, B), which allowed us to perform a limited surgical debridement. Subsequent cultures were negative for Aspergillus. With the exception of the blindness in her left eye, the patient experienced a complete resolution of symptoms. Drug toxicity was minimal.

Discussion

Chronic invasive fungal sinusitis is generally difficult to eradicate, it recurs frequently, and it carries a poor prognosis. Patients may develop symptoms over prolonged periods; in such cases, the slow progression of disease hinders a diagnosis, as was the case with our patient. Frequently, in fact, a diagnosis is made only after the infection has invaded critical structures, which can take months to years to occur. Symptoms may not develop until the orbit or skull base becomes involved. (3) Erosion of fungal hyphae into the orbit from the maxillary sinus mayproduce proptosis. Invasion of the cribriform plate can cause headaches, seizures, mental deterioration, or focal deficits. Extension through the sphenoid sinus may lead to cavernous sinus syndrome and cranial nerve deficits--again, as happened to our patient. (3) Patients can experience cata strophic complications, including carotid artery rupture, mycotic aneurysms, and cavernous sinus thrombosis. (3)

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It is interesting that most patients with chronic invasive fungal sinusitis are immunologically intact, as was our patient. Washburn et al performed extensive testing on patients with invasive disease; these evaluations included measurements of absolute neutrophil and monocyte counts, the phagocytic and fungicidal activity of peripheral blood monocytes, total lymphocyte counts, natural killer-cell activity, and immunoglobulin levels. (4) No uniform deficits were identified in that study.

[FIGURE 1 OMITTED]

Aspergillus species carry specific virulence factors that may explain their propensity to cause invasive disease, even in the otherwise normal host. Spores produced by Aspergillus are tiny (3 to 5 [micro]m), which allows them to penetrate deep into tissues. These spores may withstand extraordinary atmospheric conditions owing to their coating layer of hydrophobic protein. The organisms efficiently bind laminin and fibrinogen, and they produce various proteases, phospholipases, hemolysin, and aflatoxin. (5)

Left untreated, invasive Aspergillus sinusitis carries a nearly 100% mortality. However, treatment has been historically difficult and inconsistently successful. Following debridement, an induction phase of treatment with high doses of IV amphotericin B is generally initiated to achieve high drug concentrations. This is followed by a consolidation or maintenance phase, which sometimes includes the addition of oral agents such as itraconazole. (5) Amphotericin is a polyene macrolide that binds preferentially to ergosterol in the fungal cell membrane; it also binds human cholesterol. It is difficult to administer and to tolerate because of frequent infusion reactions, electrolyte wasting, and severe renal toxicity. The various liposomal derivatives of amphotericin have been less toxic and easier to use, and the introduction of newer agents in different classes has broadened our range of options for treating this disease. The two agents that we used--caspofungin and voriconazole--are among these newly developed drugs.

Caspofungin. Caspofungin was the first of the echinocandin class of drugs. It inhibits beta-glucan synthesis for fungal cell wall formation. It is considerably less toxic than amphotericin B, as humans lack a comparable target structure--namely, a cell wall structure. Also, its dose is adjustable for patients with hepatic function abnormalities. In 2002, Arikan et al demonstrated in vitro synergy between caspofungin and amphotericin against Aspergillus and Fusarium spp. (6) Moreover, the authors of several case reports have described the successful use of this combination, particularly in neutropenic patients with invasive pulmonary aspergillosis.(7,8)

Voriconazole. Voriconazole is a triazole antifungal that inhibits the cytochrome p450-dependent enzyme lanosterol 14 alpha-demethylase, thereby disrupting cell membrane synthesis. It is fungicidal for most Aspergillus isolates, and it is well tolerated; its most common side effects relate to liver function abnormalities and visual disturbances in patients on long-term therapy. Few studies have focused on the use of voriconazole for invasive sinus disease thus far. In one randomized multicenter trial published in 2002, Herbrecht et al compared voriconazole with amphotericin as a primary therapy for invasive aspergillosis; they found that voriconazole significantly improved response and survival rates and caused fewer adverse events. (9)

Combination therapy. In recent years, investigators have studied the effectiveness of combining an echinocandin with a triazole. (2,7,10-12) These two classes of drugs have different sites of action; echinocandins inhibit fungal cell wall formation, and triazoles inhibit cell membrane synthesis. The simultaneous inhibition of the biosynthesis of key components of the fungal cell wall and membrane could theoretically result in a synergistic interaction and increased killing.

Petraitis et al tested this theory by performing in vitro and animal studies of experimentalinvasive pulmonaryaspergillosis in neutropenic rats. (2) These experiments demonstrated that combination treatment caused concentration-dependent synergistic hyphal damage (p < 0.001). In addition, rats with invasive disease that received combination therapy experienced a significant reduction in fungal burden in lung tissue, greater survival, and less pulmonary injury.

In vitro synergy between caspofungin and voriconazole was demonstrated by Perea et al in their test of 48 clinical isolates of Aspergillus species obtained from patients with invasive aspergillosis. (10) Synergy, defined as a fractional inhibitory concentration (FIC) index of less than 1, was detected in 87.5% of interactions. No antagonism was observed, although 4.2% of interactions demonstrated an additive effect (FIC index: 1.0) and 8.3% demonstrated a subadditive effect (FIC index: 1 to 2). The authors speculated that one explanation for this synergy or additivity might be the simultaneous disruption of the fungal cell membrane and cell wall, which decreases cell stability and viability.

Manavathu et al investigated the in vitro susceptibility of 20 clinical isolates of A fumigatus to combinations of caspofungin and several different triazoles (voriconazole, itraconazole, posaconazole, and ravuconazole).(11) They found that the isolates were highly susceptible to each of the several triazoles and to caspofungin individually. It is interesting that the authors documented a synergistic interaction between caspofungin and itraconzole or posaconazole, but no interaction between caspofungin and ravuconazole or voriconazole. Further studies in animal models and in humans are necessary to confirm the observation that there may be differences in synergistic interactions between the various triazoles and caspofungin.

Kirkpatrick et al evaluated the antifungal activities of caspofungin and voriconazole, alone and in combination, against invasive disseminated aspergillosis in a guinea pig model. (12) Immunosuppression was induced in the animals via the administration of steroids and cyclophosphamide. Then a lethal bolus of A fumigatus conidia was inoculated intravenously, which disseminated disease to multiple organs, including the liver, kidney, lung, and brain. All 36 animals that were treated with either caspofungin alone or voriconazole alone and all 12 control animals had at least one positive culture of organ tissue. The animals that received combination treatment had significantly fewer positive cultures of liver, lung, kidney, and brain tissues (p < 0.0025).

Marr et al retrospectively studied the combination of caspofungin and voriconazole as salvage therapy in 47 patients with proven or probable invasive aspergillosis (including extrapulmonary disease) who had failed to respond to amphotericin B. (7) Multivariate analyses showed that the patients who received combination therapy had a significantly greater 3-month survival than did those who had received voriconazole only (p = 0.011). The results of this study, which was conducted at a large cancer center, are impressive, and they provide further evidence that the combination may prove to be a safe and effective alternative to traditional treatment modalities. Further data from larger randomized trials are necessary to confirm its efficacy as a primary and salvage therapy.

Finally, our comprehensive literature review identified one other case report in which combination treatment with caspofungin and voriconazole resulted in clinical and microbiologic cure of invasive sinus aspergillosis without the need for radical surgery. (13) Tsiodras et al treated a patient who had refused to undergo surgery, including eye enucleation. Instead the patient received combination therapyand repeated local debridements, and he recovered completely. However, this case differs from ours in that this patient had several predisposing factors for invasive fungal sinusitis; he was diabetic, and he had received a liver transplant for hepatitis C-related cirrhosis. Also, this patient had developed fungal sinusitis while receiving systemic liposomal amphotericin B, whereas our patient had received only inhaled amphotericin.

While our case and the case reported by Tsiodras et al (13) are rare and were characterized by somewhat extenuating circumstances, each represents a clear case of successful treatment of this invasive disease with relatively nontoxic medications that spared both patients radical, disfiguring surgery.

Our experience suggests that combination therapy with caspofungin and voriconazole may prove to be safe and effective in the management of invasive Aspergillus sinusitis, and we believe it should be considered a therapeutic option in the future.

References

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(2.) Petraitis V, Petraitiene R, Sarafandi AA, et al. Combination therapy in treatment of experimental pulmonary aspergillosis: Synergistic interaction between an antifungal triazole and an echinocandin. J Infect Dis 2003; 187(12): 1834-43.

(3.) Stringer SP, Ryan MW. Chronic invasive fungal rhinosinusitis. Otolaryngol Clin North Am 2000;33(2):375-87.

(4.) Washburn RG, Kennedy DW, Begley MG, et al. Chronic fungal sinusitis in apparently normal hosts. Medicine (Baltimore) 1988;67(4):231-47.

(5.) Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26(4):781803.

(6.) Arikan S, Lozano-Chiu M, PaetznickV, Rex JH. In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob Agents Chemother 2002;46(1):245-7.

(7.) Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39(6):797802.

(8.) Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006;107(12):2888-97.

(9.) Herbrecht R, Denning DW, Patterson TF, et al; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347(6):408-15.

(10.) Perea S, Gonzalez G, Fothergill AW, et al. In vitro interaction of caspofimgin acetate with voticonazole against clinical isolates of Aspergillus spp. Antimicrob Agents Chemother 2002;46(9):303941.

(11.) Manavathu EK, Alangaden GJ, Chandrasekar PH. Differential activityoftriazoles in two-drug combinations with the echinocandin caspofungin against Aspergillus fumigatus. JAntimicrob Chemother 2003;51 (6):1423-5.

(12.) KirkpatrickWR, Perea S, Coco B J, Patterson TE Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother 2002;46(8):2564-8.

(13.) Tsiodras S, Zafiropoulou R, GiotakisJ, et al. Deep sinus aspergillosis in a liver transplant recipient successfully treated with a combination of caspofungin and voriconazole. Transpl Infect Dis 2004;6(1): 37-40.

From the Division of Infectious Diseases, Department of Internal Medicine (Dr. Chirch and Dr. Fuhrer), and the Department of Radiology (Dr. Roche), Stony Brook (N.Y.) University School of Medicine.

Corresponding author: Lisa M. Chirch, MD, Division of Infectious Diseases, Stony Brook University Medical Center, T15-080, Stony Brook, NY 11794-8153. Phone: [phone], ext. 18; fax: [phone]; e-mail: [e-mail]