Successful treatment of invasive Aspergillus sinusitis with caspofungin and voriconazole.Abstract
Chronic invasive Aspergillus Aspergillus
Any fungus of the genus Aspergillus of the Fungi Imperfecti (form-class Deuteromycetes). Species for which the sexual phase is known are placed in the order Eurotiales. A. niger causes black mold on some foods; A. niger, A. flavus, and A. sinusitis sinusitis
Inflammation of the sinuses. Acute sinusitis, usually due to infections such as the common cold, causes localized pain and tenderness, nasal obstruction and discharge, and malaise. is a rare andpotentially devastating infection. Management typically requires extensive surgical debridement Debridement Definition
Debridement is the process of removing nonliving tissue from pressure ulcers, burns, and other wounds.
Debridement speeds the healing of pressure ulcers, burns, and other wounds. 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.
Fungal sinusitis is classified as invasive or noninvasive and chronic or acute. (1) Acute invasive fungal rhinosinusitis occurs more often in immunocompromised immunocompromised /im·mu·no·com·pro·mised/ (-kom´pro-mizd) having the immune response attenuated by administration of immunosuppressive drugs, by irradiation, by malnutrition, or by certain disease processes (e.g., cancer). 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.
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 ethmoid /eth·moid/ (eth´moid)
1. sievelike; cribriform.
2. the ethmoid bone; see Table of Bones. .ethmoi´dal
eth·moid or eth·moi·dal
adj. 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 Ptosis Definition
Ptosis is the term used for a drooping upper eyelid. Ptosis, also called blepharoptosis, can affect one or both eyes.
The eyelids serve to protect and lubricate the outer eye. , and a complete paralysis of the extraocular muscles (figure 1). Soft-tissue swelling and erythema erythema (ĕr'əthē`mə), more or less diffuse redness of the skin due to concentration of an abnormally large amount of blood within the small vessels of the skin (hyperemia), as in burns. 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 magnetic resonance imaging (MRI), noninvasive diagnostic technique that uses nuclear magnetic resonance to produce cross-sectional images of organs and other internal body structures. with gadolinium gadolinium (gădəlĭn`ēəm), metallic chemical element; symbol Gd; at. no. 64; at. wt. 157.25; m.p. 1,312°C;; b.p. 3,233°C;; sp. gr. 7.898 at 25°C;; valence +3. contrast both detected extensive invasive disease involving the nasopharynx nasopharynx /na·so·phar·ynx/ (-far´inks) the part of the pharynx above the soft palate.nasopharyn´geal
n. , infratemporal fossa, orbit, and cavernous sinus. No evidence of parenchymal pa·ren·chy·ma
1. Anatomy The tissue characteristic of an organ, as distinguished from associated connective or supporting tissues.
2. 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 triazole /tri·a·zole/ (tri´ah-zol) (tri-a´zol)
1. a five-membered heterocyclic ring containing two carbon and three nitrogen atoms.
2. for invasive aspergillosis Aspergillosis Definition
Aspergillosis refers to several forms of disease caused by a fungus in the genus Aspergillus. Aspergillosis fungal infections can occur in the ear canal, eyes, nose, sinus cavities, and lungs. 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 edema (ĭdē`mə), abnormal accumulation of fluid in the body tissues or in the body cavities causing swelling or distention of the affected parts. 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.
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 hy·pha
n. pl. hy·phae
Any of the threadlike filaments forming the mycelium of a fungus.
[New Latin, from Greek huph into the orbit from the maxillary sinus mayproduce proptosis proptosis /prop·to·sis/ (prop-to´sis) forward displacement or bulging, especially of the eye.
n. pl. . 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 cavernous sinus syndrome
A syndrome caused by thrombosis of the cavernous intracranial sinus and characterized by edema of the eyelids and conjunctivae and by paralysis of the third, fourth, and sixth nerves. and cranial nerve deficits--again, as happened to our patient. (3) Patients can experience cata strophic stro·phic
1. Relating to or consisting of strophes.
2. Music Having the same melody used for each strophe. complications, including carotid artery rupture, mycotic aneurysms, and cavernous sinus thrombosis Cavernous sinus thrombosis (CST) is the formation of a blood clot within the cavernous sinus. One possible cause may be the spread of a dental infection in a tooth of the maxilla (upper jaw). In these cases, Staphylococcus aureus is the associated bacteria. . (3)
[FIGURE 2 OMITTED]
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 monocyte /mono·cyte/ (mon´o-sit) a mononuclear, phagocytic leukocyte, 13µ to 25µ in diameter, with an ovoid or kidney-shaped nucleus, and azurophilic cytoplasmic granules. counts, the phagocytic phag·o·cyt·ic
1. Of or relating to phagocytes.
2. Of, relating to, or characterized by phagocytosis.
emanating from or pertaining to phagocytes. and fungicidal activity of peripheral blood monocytes monocytes,
n.pl the largest of the white blood cells. They have one nucleus and a large amount of grayish-blue cytoplasm. Develop into macrophages and both consume foreign material and alert T cells to its presence. , 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 Spores
A state of "suspended animation" that some bacteria can adopt when conditions are not ideal for growth. Spores are analogous to plant seeds and can germinate into growing bacteria when conditions are right. 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 laminin
(lam´n and fibrinogen Fibrinogen
The major clot-forming substrate in the blood plasma of vertebrates. Though fibrinogen represents a small fraction of plasma proteins (normal human plasma has a fibrinogen content of 2–4 mg/ml of a total of 70 mg protein/ml), its conversion , and they produce various proteases, phospholipases, hemolysin hemolysin /he·mol·y·sin/ (he-mol´i-sin) a substance that liberates hemoglobin from erythrocytes by interrupting their structural integrity.
n. , 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 itraconazole /it·ra·co·na·zole/ (it?rah-kon´ah-zol) a triazoleantifungal used in a variety of infections.
n. . (5) Amphotericin is a polyene polyene /pol·y·ene/ (pol´e-en)
1. a chemical compound with a carbon chain of four or more atoms and several conjugated double bonds.
2. any of a group of antifungal antibiotics with such a structure (e.g. macrolide that binds preferentially to ergosterol ergosterol /er·gos·te·rol/ (er-gos´te-rol) a sterol occurring mainly in yeast and forming ergocalciferol (vitamin D2) on ultraviolet irradiation or electronic bombardment.
n. 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 Fusarium
a genus of fungi; some species are plant pathogens and some are opportunistic infectious agents of humans and animals. Many also produce trichothecene toxins which cause poisoning of animals if the infected material, usually stored feed, is eaten. 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 ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. 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 Biosynthesis
The synthesis of more complex molecules from simpler ones in cells by a series of reactions mediated by enzymes. The overall economy and survival of the cell is governed by the interplay between the energy gained from the breakdown of compounds 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 FIC First International Computer
FIC Fogarty International Center (John E. Fogarty International Center for Advanced Study in the Health Sciences; National Institutes of Health)
FIC Fellowship for Intentional Community ) 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 immunosuppression
Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim is to allow the recipient to accept the organ permanently with no unpleasant side effects. was induced in the animals via the administration of steroids and cyclophosphamide cyclophosphamide /cy·clo·phos·pha·mide/ (-fos´fah-mid) a cytotoxic alkylating agent of the nitrogen mustard group; used as an antineoplastic, as an immunosuppressant to prevent transplant rejection, and to treat some diseases . Then a lethal bolus bolus /bo·lus/ (bo´lus)
1. a rounded mass of food or pharmaceutical preparation ready to swallow, or such a mass passing through the gastrointestinal tract.
2. a concentrated mass of pharmaceutical preparation, e. of A fumigatus conidia co·nid·i·a
Plural of conidium. 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 enucleation /enu·cle·a·tion/ (e-noo?kle-a´shun) removal of an organ or other mass intact from its supporting tissues, as of the eyeball from the orbit.
Surgical removal of the eyeball. . 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.
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(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 füh·rer also fueh·rer
A leader, especially one exercising the powers of a tyrant.
[German, from Middle High German vüerer, from vüeren, to lead, from Old High German ), 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 The State University of New York at Stony Brook (SUNYSB), also known as Stony Brook University (SBU) is a public research university located in Stony Brook, New York (on the north side of Long Island, about 55 miles east of Manhattan, New York). Medical Center, T15-080, Stony Brook, NY 11794-8153. Phone: (631) 287-5990, ext. 18; fax: (631) 287-5995; e-mail: firstname.lastname@example.org