Invasive fungal sinusitis caused by Pseudallescheria boydii: case report and literature review.

Abstract

Fungal sinusitis secondary to Pseudallescheria boydii is rare, as only 25 cases have been previously reported in the literature. Although P boydii resembles Aspergillus on pathologic examination, it is typically resistant to amphotericin B. Therefore, culture is necessary to differentiate the two. Patients with P boydii sinusitis should generally be treated with a combination of surgery and antifungal therapy. Combination treatment is particularly important for immunocompromised patients with fungal invasion because mortality among these patients is high. The prognosis is better for immunocompetent patients, even those with fungal invasion. We describe a new case of invasive fungal sinusitis secondary to P boydii infection, and we review the literature on this emerging pathogen.

Introduction

Pseudallescheria boydii--a ubiquitous, saprophytic fungus in the class Ascomycetes--is an emerging pathogen found worldwide. It is commonly isolated in soil, in polluted and coastal waters, and in animal manure. (1) Siebenmann first isolated the organism in the 1880s as a pathogen in the ear of a child with chronic otitis externa. (2) The first complete description of the organism was published in 1922 by Shear. (3)

P boydii is associated with Madura foot (maduromycosis), a cutaneous and subcutaneous suppurative disease that affects farmers in tropical and subtropical countries. (4) Historically, Madura foot has accounted for 99% of all P boydii infections. (1) The organism has also been identified in specimens obtained from pulmonary cavities and pulmonary infiltrates. It has been shown to cause sinusitis, corneal infections, endophthalmitis, parotitis, skin infections, arthritis, osteomyelitis, brain and thyroid abscesses, endocarditis, chronic prostatitis, and disseminated infection?

In this article, we describe a case of P boydii invasive fungal sinusitis in a diabetic patient who died before the pathogen was identified. As we discuss, this organism can be mistaken for Aspergillus on fungal smear, but it is typically resistant to amphotericin B, the antifungal medication that is commonly started empirically for patients with invasive fungal sinusitis. Thus, in cases of invasive fungal sinusitis, proper identification via culture is imperative to ensure effective pharmacotherapy.

Case report

A 76-year-old man with non-insulin-dependent (type 2) diabetes mellitus presented with a 4-month history of intractable temporal and occipital headaches. Since the onset of the headaches, he had been diagnosed with sinusitis and treated twice with a penicillin derivative, but his headaches did not resolve. Two subsequent courses of a steroid taper provided no relief. At that point, the patient was admitted to our hospital for a further workup.

Upon admission, the patient was dehydrated and hyperglycemic; a finger-stick blood test revealed that his glucose level was 477 mg/dl. He had discontinued his oral hypoglycemic medication prior to admission, despite being on a steroid course. The early part of his hospitalization was complicated by the medical and later surgical treatment of diverticulitis. After one of his abdominal surgeries, he awoke from surgery confused and combative and complaining of blindness in both eyes. Prior to the onset of the blindness, the patient's visual acuity had been 20/60 in the right eye and 6/200 in the left eye; he had also had a left relative afferent pupillary defect. However, after the onset of the blindness, he was found to have a disconjugate gaze with poor extraocular motility (worse in the left eye), and he was not able to perceive hand movements in front of his eyes.

The laboratory workup revealed an elevated white blood cell (WBC) count of 12.6 x [10.sup.9]/L (normal: 4.8 to 10.8), an elevated erythrocyte sedimentation rate of 81 mm/hr (normal: 0 to 20), and an elevated glycosylated hemoglobin concentration of 11.2% (normal: 4.5 to 6.4%). The rapid plasma reagin test was nonreactive, and the vitamin [B.sub.12] level was elevated at 1,143 pg/ml (normal: 210 to 705). Alumbar puncture revealed a low cerebrospinal fluid (CSF) glucose concentration of 104 mg/dl (normal: 239 to 358 for a blood glucose level of 477 mg/dl) and an elevated CSF protein level of 49.2 mg/dl (normal: 15 to 45); no WBCs were found in the CSF.

Noncontrast computed tomography (CT) of the head showed at partial opacification at the sphenoid sinus. Contrast-enhanced magnetic resonance imaging (MRI) of the brain demonstrated enhancement of the dura along the planum sphenoidale, the anterior frontal lobes bilaterally, and the orbital apices bilaterally (figure 1). Enhancement was also noted along the anterior clinoid. Bilateral engorgement of the superior orbital veins was noted.

[FIGURE 1 OMITTED]

Nasal endoscopy detected no necrosis of any turbinate or of the rostra of the sphenoid sinuses (figure 2). Contrast-enhanced CT of the sinuses revealed mucoperiosteal thickening of the right sphenoid and frontal sinuses and opacification of the left sphenoid sinus (figure 3). Enhancing soft tissue was seen at the posterior wall of the frontal sinus, and it extended along the planum sphenoidale and through the fovea ethmoidalis; intracranial extension was seen along the dura at the anterior cranial fossa and the anterior aspect of the interhemispheric falx (figure 4). Additionally, the process extended anteriorly through the optic nerve foramina and superior orbital fissures and was associated with a loss of normal fat planes bilaterally in the pterygopalatine fossae. Bone erosion accompanied the abnormal soft-tissue extension from the ethmoid air cells and frontal sinuses through the adjacent anterior cranial floor and cribriform plate.

[FIGURES 2-4 OMITTED]

In light of these findings, the patient was placed on empiric piperacillin/tazobactam and amphotericin B lipid complex to cover bacterial skull base osteomyelitis and invasive fungal sinusitis. He was then taken to the operating room for image-guided bilateral endoscopic sphenoidotomy with biopsy. Operative findings included minimally inflamed mucosa within the nasal cavity. No necrotic tissue was present on the right or left sphenoid rostrum, and no purulent or necrotic debris was present in either sphenoid sinus (figure 5). A frozen-section biopsy of the right sphenoid sinus was reported as only inflamed mucosa with no evidence of invasive fungal disease. A Gram's stain of the sinus contents identified gram-positive cocci and yeast. Final pathology identified a mass of fungal hyphae in 1 of 5 specimens that were morphologically consistent with the presence of Aspergillus spp. Culture grew 2+ coagulase-negative staphylococci and 1+ multidrug-resistant Klebsiella pneumoniae. Based on these findings, the antibacterial coverage was changed to vancomycin and meropenem.

[FIGURE 5 OMITTED]

Over the next several days, the patient's mental status worsened. A cerebral angiogram showed an area of opacification within the anterior aspect of the left cavernous sinus consistent with thrombosis. Hence, the patient was started on heparin anticoagulation. However, his mental status continued to worsen, and he developed epistaxis that required packing of the left nasal cavity. The heparin drip was discontinued, but soon thereafter, he developed worsening respiratory distress and died. Of note, he had been switched from amphotericin B lipid complex to voriconazole approximately 3 days prior to his death because the maximum amphotericin B dosage had been reached.

At autopsy, the dura of the anterior falx cerebri was indurated and thickened (as much as 0.5 cm). Microscopic examination of this area detected acute and chronic inflammation associated with necrosis and a granulomatous component. Silver stains showed septate fungal hyphae. Fungal cultures from the sphenoid biopsies performed at surgery grew P boydii in the postmortem period.

Literature review

For our literature review, we searched the PubMed database, using the keywords Pseudallescheria, boydii, Verticillium graphii, Allescheria, Glenospora, Indiella americanus, Acremoniella lusii, Petriellidium, Scedosporium apiospermum, monosporium, and sinusitis. We found 25 reported cases of sinusitis that were caused by P boydii. (5-29) The case described in this article brings to 26 the total number of cases documented in the literature (table). These patients included 17 women and 9 men, aged 20 to 85 years (mean: 48.3). The first case was reported by Gluckman et al in 1977; their patient was a 58-year-old diabetic man on hemodialysis who ultimately died of a cause unrelated to his P boydii infection. (6)

Of the 26 cases, mucosal invasion by fungal organisms was proven or suspected in 12 patients, excluded or not suspected in 9 patients, and unknown in the remaining 5 patients. Of the 12 patients with proven or suspected invasive disease, 9 were immunocompromised; 4 patients had leukemia, 3 were diabetics, and 2 had acquired immunodeficiency syndrome (AIDS). All 9 of these patients either died of infection or another cause or had persistent or recurrent infection at the time the case was reported. Six of these 9 immunocompromised patients were treated with surgery and antifungal therapy, 1 was treated with surgery and antibacterial therapy, and 2 were treated with antifungal therapy alone. Of the 3 immunocompetent patients with proven or suspected invasive disease, 1 experienced a complete resolution of disease after undergoing combined surgery and antifungal therapy, 1 responded completely to surgery alone, and 1 died of infection after being treated with combined surgery and antifungal therapy.

Five of the 9 patients without evidence or suspicion of invasion were immunocompetent, and all 5 experienced a complete resolution of their infection; 4 patients had been treated with surgery alone and the other with combined surgery and antifungal therapy. Of the 4 patients without signs of invasion who were immunocompromised (1 case each of adrenocortical insufficiency, sickle cell anemia, diabetes, and organ transplantation), 1 patient experienced a full resolution with combined surgery and antifungal therapy, 1 recovered completely with surgery alone, 1 died of squamous cell carcinoma of the sinuses following surgery, and the outcome of the other patient, who had undergone surgery, was not reported.

Among the 5 patients in whom the presence or absence of fungal invasion was not reported, 2 were immunosuppressed (1 case of diabetes and 1 case of bone marrow transplantation); the diabetic patient was treated with surgery alone and his outcome was not reported, and the post-transplant patient was treated with combined surgery and antifungal therapy but died of a related cause. Of the 3 immunocompetent patients in whom the presence or absence of fungal invasion was not reported, all experienced a complete resolution of symptoms; 2 had been treated with surgery alone, and 1 had been treated with combined surgery and antifungal therapy.

Among the 26 cases, the maxillary sinuses were involved in 15 cases, the sphenoid sinuses in 14, the ethmoid sinuses in 9, the frontal sinuses in 2, and the nasal cavity only in 1. Seven of the 14 patients with sphenoid sinus involvement had isolated sphenoid disease.

Of the 26 patients, 13 had concomitant bacterial infections; these pathogens included K pneumoniae (n = 3), Staphylococcus aureus (3), Citrobacter freundii (3), Staphylococcus epidermidis (3), Proteus mirabilis (2), Enterobacter cloacae (2), anaerobic gram-positive rods (1), Serratia liquefasciens (1), and Klebsiella oxytoca (1). Fungal coinfection (Candida albicans) was seen in 1 patient.

Discussion

Fungal infection of the paranasal sinuses includes a broad spectrum of disease processes. At one end of the spectrum is allergic fungal sinusitis, which represents an immune reaction to noninvading fungal colonizers that was first associated with Aspergillus. (30) At the other end of the spectrum is acute invasive fungal sinusitis, which is usually caused by Mucor or Aspergillus spp. Intermediate disease processes include chronic invasive fungal sinusitis and chronic noninvasive fungal sinusitis (fungus ball). In 1997, deShazo et al proposed that invasive fungal sinusitis be classified into three categories: granulomatous, acute fulminant, and chronic. (31) They described 2 cases of chronic invasive sinusitis in middle-aged adults with well-controlled non-insulin-dependent diabetes mellitus and apical orbital syndrome. The 2 patients had a similar course: protracted disease for more than 6 months with proptosis, vision changes, and late neurologic symptoms reflecting cavernous sinus invasion. Both patients died of their infection. Our patient followed a similar course with several months of protracted headache.

Aspeligillus, Mucor, and Candida spp. are responsible for most pathologic fungal sinus infections. (32) However, improvements in the medical management of immunosuppressed patients and the wider use of immunosuppressive therapies has led to the identification of a long list of unusual fungal pathogens, some of which were previously thought to be solely commensal. Specifically, rare fungal pathogens have been isolated in AIDS patients, (22) in cancer patients (particularly those being treated for leukemia (33)), and in transplant recipients. (34) One of these emerging pathogens is P boydii.

P boydii has undergone many name changes over the years. In his original report, Siebenmann called it Verticillium graphii. (2) It has since been referred to as Allescheria boydii, Glenospora boydii, Indiella americanus, and Acremoniella lusii. (14) In 1970, Malloch suggested that the species be transferred from the genus Allescheria to Petriellidium. (35) This change was later thought to be an error, and the organism was placed in the valid and previously described genus Pseudallescheria. (1) The anamorph (imperfect) form of the organism is called Scedosporium apiospermum (formerly Monosporium apiospermum), and was shown by Emmons (36) in 1944 to be the same organism as P boydii. Both forms have been implicated as pathogens.

Of the 26 cases (5-29) of fungal sinusitis secondary to P boydii infection that have now been reported in the literature, fungal invasion was proven or suspected in 12 patients, 9 of whom were immunocompromised. It is interesting that the other 3 patients with invasive disease were immunocompetent: 2 experienced a full resolution of infection (1 with combination surgery and antifungal therapy and the other with surgery alone). Among the 13 patients with immunosuppression whose outcome was reported, I 1 either died or had persistent or recurrent infection by the time the case was reported. Two patients with immunosuppression experienced a complete resolution of the infection, but neither had evidence of invasion: 1 of these patients had been treated with combined surgery and antifungal therapy and the other had been treated with surgery alone. These data suggest that our patient's prognosis probably would have been poor even if he had been diagnosed sooner.

Identification of P boydii by fungal culture is essential to selecting effective pharmacotherapy. The hyphae of P boydii can resemble those of Aspergillus on fungal stains, and their tropism for blood vessels is similar. (15) But unlike Aspergillus, P boydii is typically resistant to amphotericin B. (37) This can be problematic because amphotericin B is often the first-line pharmacologic therapy for suspected invasive fungal sinusitis. Miconazole is the antifungal of choice for P boydii, (38) and several authors have reported successful treatment with ketoconazole. (12,14,17,19) In 1978, Cosgrove et al theorized that combining amphotericin B with an imidazole antifungal might result in antagonism because the two agents competed for the same binding sites on cell membranes. (39) However, Walsh et al challenged that theory in 1995 when they reported that in vitro studies specific for P boydii showed that the two compounds actually might have a synergistic relationship. (40) More recently, the results of other in vitro studies have supported the use of voriconazole, a new triazole antifungal agent, in the treatment of P boydii infections. (41-43)

Our patient presented with a 4-month history of vague headaches, which are often characteristic of chronic sphenoid sinusitis. (28) He underwent an extensive workup, but the diagnosis was elusive. Only alter orbital apex syndrome had developed was the diagnosis of chronic sinusitis with skull base osteomyelitis made. Even then, the organisms responsible were not known. Pathologic specimens from sphenoid sinus biopsies yielded a mass of fungal hyphae that resembled Aspergillus. It was for this reason that amphotericin B was started. It was not until alter the patient had died that P boydii was grown in cultures of the sphenoid sinus. As discussed, P boydii is typically resistant to amphotericin B, so this patient received inadequate pharmacologic therapy. As for surgical therapy, by the time this patient had been diagnosed, imaging had already demonstrated erosion of a significant part of his anterior skull base and enhancement of the dura of the anterior cranial fossa. An earlier diagnosis and the use of miconazole or voriconazole as the initial therapy might have changed this patient's outcome. However, the literature suggests that patients with invasive P boydii who are immunocompromised have a high mortality rate regardless of therapy.

In conclusion, fungal sinusitis secondary to P boydii infection is rare. When it does occur, it can appear in both immunosuppressed and immunocompetent patients. Although the organism resembles Aspergillus on pathologic examination, P boydii is typically resistant to amphotericin B. Therefore, culture and a definitive identification of the organism are crucial to selecting adequate pharmacologic therapy. Sensitivity testing will help direct antifungal therapy. In general, patients should be treated with a combination of surgery and antifungal therapy, particularly those patients with immunosuppression and fungal invasion. Immunocompetent patients with P boydii fungal sinusitis have a better prognosis, even when invasion is present.

References

(1.) Rippon JW. Pseudallescheriasis. In: Wonsiewicz M, ed. Medical Mycology: The Pathogenic Fungi and the Pathogenic Actinomycetes. 3rd ed. Philadelphia: W.B. Saunders: 1988:651-3.

(2.) Siebenmann F. Die Schimmelmykosen des menschlichen Ohnes. Wiesbaden, Germany: Bergmann: 1889:95.

(3.) Shear CL. Life history of an undescribed ascomycete isolated from a granular mycetoma of man. Mycologia 1922:14:239-43.

(4.) Green WO Jr., Adams TE. Mycetoma in the United States: a review and report of seven additional cases. Am J Clin Pathol 1964:42: 75-91.

(5.) Travis LB, Roberts GD, Wilson WR. Clinical significance of Pseudallescheria boydii: A review of 10 years experience. Mayo Clin Proc 1985:60:531-7.

(6.) Gluckman SJ, Ries K, Abrutyn E. Allescheria (Petriellidium) boydii sinusitis in a compromised host. J Clin microbiol 1977:5:481-4.

(7.) Winston DJ, Jordan MC, Rhodes J. Allescheria boydii infections in the immunosuppressed host. Am J Med 1977:63:830-5.

(8.) Hecht R, Montgomerie JZ. Maxillary sinus infection with Allescheria boydii (Petriellidium boydii). Johns Hopkins Med J 1978:142: 107-9.

(9.) Mader JT, Ream RS, Heath PW. Petriellidium boydii (Allescheria boydii) sphenoidal sinusitis. JAMA 1978:239:2368-9.

(10.) Bark CJ, Zaino LJ, Rossmiller K. Copper CL. Petriellidium boydii sinusitis. JAMA 1978:240:1339-40.

(11.) Bryan CS, DiSalvo AF, Kaufman L. et al. Petriellidium boydii infection of the sphenoid sinus. Am J Clin Pathol 1980:74:846-51.

(12.) Bloom SM. Warner RR, Weitzman I. Maxillary sinusitis: Isolation of Scedosporium (Monosporium) apiospermum, anamorph of Petriellidium (Allescheria) boydii. Mt Sinai J Med 1982:49:492-4.

(13.) Winn RE. Ramsey PD, McDonald JC, Dunlop KJ. Maxillary sinusitis from Pseudallescheria boydii. Efficacy of surgical therapy. Arch Otolaryngol 1983:109:123-5.

(14.) Schiess RJ, Coscia MF, McClellan GA. Petriellidium boydii pachymeningitis treated with miconazole and ketoconazole. Neurosurgery 1984:14: 220-4.

(15.) Morgan MA, Wilson WR, Neel HB III, Roberts GD. Fungal sinusitis in healthy and immunocompromised individuals. Am J Clin Pathol 1984:82:597-601.

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

(17.) Salitan ML, Lawson W, Sore PM, et al. Pseudallescheria sinusitis with intracranial extension in a nonimmunocompromised host. Otolaryngol Head Neck Surg 1990; 102:745-50.

(18.) Terris DJ, Steiniger JR. Scedosporium apiospermum: Fungal sinusitis in an immunocompetent patient. Am J Rhinol 1992:6:49-53.

(19.) Stamm MA, Frable MA. Invasive sinusitis due to Pseudallescheria boydii in an immunocompetent host. South Med J 1992;85: 439-41.

(20.) Watters GW, Milford CA. Isolated sphenoid sinusitis due to Pseudallescheria boydii. J Laryngol Otol 1993; 107:344-6.

(21.) Grigg AP. Phillips P, Durham S, Shepherd JD. Recurrent Pseudallescheria boydii sinusitis in acute lenkemia. Stand J Infect Dis 1993:25:263-7.

(22.) Meyer RD, Gaultier CR, Yamashita JT. et al. Fungal sinusitis in patients with AIDS: Report of 4 cases and review of the literature. Medicine (Baltimore) 1994:73:69-78.

(23.) Fiero RA, Groth M, Hurewitz A, et al. Chronic hemoptysis: An unusual manifestation of fungal sinusitis. South Med J 1995:88: 782-5.

(24). Machado CM. Martins MA, Heins-Vaccari EM, et al. Scedosporium apiospermum sinusitis after bone marrow transplantation: Report of a case. Rev Inst Med Trop Sao Paulo 1998:40:321-3.

(25.) Tadros TS, Workowski KA, Siegel RJ. et al. Pathology of hyalohyphomycosis caused by Scedosporium apiospermum (Pseudallescheria boydii): An emerging mycosis. Hum Pathol 1998:29:1266-72.

(26.) Jones J, Katz SE, Lubow M. Scedosporium apiospermum of the orbit. Arch Ophthalmol 1999:117:272-3.

(27.) Horton CK. Huaug L, Gooze L. Pseudallescheriu boydii infection in AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20: 209-11.

(28.) Shaw CL. McCleave M, Worlnuld PJ. Unusual presentations of isolated sphenoid fungal sinusitis. J Laryngol Otol 2000:114: 385-8.

(29.) Castiglioni B, Sutton DA, Rinaldi MG. et al. Pseudallescheria boydii (Anamorph Scedosporium apiospermum). Infection in solid organ transplant recipients in a tertiary medical center and review of the literature. Medicine (Baltimore) 2002:81:333-48.

(30.) Katzenstein AL, Sale SR, Greenberger PA. Allergic Aspergillus sinusitis: A newly recognized form of sinusitis. J Allergy Clin Immunol 1983;72:89-93.

(31.) deShazo RD, O'Brien M, Chapin K, et al. A new classification and diagnostic criteria for invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 1997;123:1181-8.

(32.) Oliverio PJ. Zinreich SJ. Radiology of the nasal cavity and paranasal sinuses. In: Cummings CW, ed. Otolaryngology-Head and Neck Surgery. 3rd ed. St. Louis: Mosby: 1998: 1082-3.

(33.) Anaissie E, Bodey GR Kantarjian H, el al. New spectrum of fungal infections in patients with cancer. Rev Infect Dis 1989:11:369-78.

(34.) Walsh TJ, Groll AH. Emerging fungal pathogens: Evolving challenges to immunocompromised patients for the twenty-first century. Transpl Infect Dis 1999:1:247-61.

(35.) Malloch D, New concepts in the Microascaceae illustrated by two new species. Mycologia 1970;62:727-40.

(36.) Emmons CW. Allescheria boydii and Monosporium apiospermum Mycologia 1944:36:188-93.

(37.) Mohr JA, Muchmore HG. Susceptibility of Allescheria boydii to amphotericin B. Antimicrobial Agents Chemother (Bethesda) 1968:30:429-30.

(38.) Lutwick LI, Galgiani JN, Johnson RH. Stevens DA. Visceral fungal infections due to Petriellidium boydii (allescheria boydii). In vitro drug sensitivity studies. Am J Med 1976;61:632-40.

(39.) Cosgrove RK Beezer AE, Miles RJ. In vitro studies of amphotericin B in combination with the imidazole antilungal compounds clotrimazole and miconazole. J Infect Dis 1978:138:681-5.

(40.) Walsh TJ, Peter J. McGough DA. et al. Activities of amphotericin B and antifungal azoles alone and in combination against Pseudallescheria boydii. Antimicrob Agents Chemother 1995:39: 1361-4.

(41.) Radford SA, Johnson EM, Warnock DW. In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent. against emerging and less-common mold pathogens. Antimicrob Agents Chemother 1997:41:841-3.

(42.) McGinnis MR, Pasarell L, Sutton DA, et al. In vitro evaluation of voriconazole against some clinically important fungi. Antimicrob Agents Chemother 1997:41:1832-4.

(43.) Cuenca-Estrella M, Ruiz-Diez B, Martinez-Suarez JV, et al. Comparative in-vitro activity of voriconazole (UK-109,496) and six other antifungal agents against clinical isolates of Scedosporium prolificans and Scedosporium apiospermum. J Antimicrob Chemother 1999:43:149-51.

Dwight D. Bates, MD; J. Whitman Mires, MD

From the Department of Otolaryngology, Wake Forest University School of Medicine, Winston-Salem, N.C.

Reprint requests: J. Whitman Mires. MD, Department of Otolaryngology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. Phone: [phone]: fax: [phone]; e-mail: [e-mail]

Originally presented as a poster at the 108th annual meeting of the Triological Society; May 13-16, 2005: Boca Raton, Fla.

Table. Summary of the 26 cases of sinonasal infection with P boydii
reported in literature

                             Sinus(es)    Immune status     Fungal
Author             Age/sex   involved     (cause)           invasion

Gluckman           58/M      Maxillary,   Compromised       Proven
et al, (6) 1977              ethmoid,     (diabetes)
                             sphenoid

Winston            57/F      None         Compromised       Proven
et al, 1977                  (nasal       (leukemia)
                             cavity)

Hecht and          20/M      Maxillary    Compromised       Proven
Montgomerie, (8)                          (leukemia)
1978

Mader et al, (9)   33/F      Sphenoid     Competent         Proven
1978

Bark et al, (10)   28/F      Maxillary    Compromised       Unknown
1978                                      (diabetes)

Bryan              47/F      Sphenoid     Competent         Proven
et al, (11)
1980

Bloom              57/F      Maxillary    Compromised       Excluded
et al, (12)                               (adrenocortical
1982                                      Insufficiency)

Winn et al, (13)   43/F      Maxillary    Competent         Unknown
1983

Schiess            61/F      Maxillary,   Compromised       Proven
et al, (14) 1984             ethmoid,     (diabetes)
                             frontal,
                             sphenoid

Morgan             45/M      Maxillary    Competent         Proven
et al, (15)
1984

Travis             47/M      Maxillary    Competent         Unknown
et al, (5)
1985

Washburn           77/F      Maxillary    Competent         Excluded
et al, (16) 1988

Salitan            28/F      Ethmoid,     Competent         Unknown
et al, (17)                  sphenoid
1990

Terris and         69/F      Sphenoid     Competent         Excluded
Steiniger, (18)
1992

Stamm and          23/F      Maxillary,   Competent         Excluded
Frable, (19)                 ethmoid,
1992                         sphenoid

Watters and        52/F      Ethmoid,     Competent         Excluded
Milford, (20)                sphenoid
1993

Grigg              35/F      Maxillary,   Compromised       Proven
et al, (21)                  ethmoid      (leukemia)
1993

Meyer              44/M      Maxillary,   Compromised       Suspected,
et al, (22)                  ethmoid,     (AIDS)            after
1994                         frontal,                       initially
                             sphenoid                       excluded

Fiero              28/F      Ethmoid,     Competent         Excluded
et al, (23)                  sphenoid
1995

Machado            40/M      Maxillary    Compromised       Unknown
et al, (24) 1998                          (bone marrow
                                          transplant)

Tadros             33/F      Maxillary    Compromised       Excluded
et al, (25)                               (sickle cell
1998                                      anemia)

Jones              68/M      Maxillary,   Compromised       Suspected
et al, (26)                  ethmoid      (leukemia)
1999

Horton             44/M      Sphenoid     Compromised       Suspected
et al, (27)                               (AIDS)
1999

Shaw et al, (28)   85/F      Sphenoid     Compromised       Excluded
2000                                      (diabetes)

Castiglioni        58/F      Sphenoid     Compromised       Not
et al, (29) 2002                          (post-            suspected
                                          transplant)

Bates and          76/M      Sphenoid     Compromised       Proven
Mims, ([dagger])                          (diabetes)
2006

                   Concomitant
Author             bacteria          Treatment            Outcome

Gluckman           Staphylococcus    Surgery, *           Died of an
et al, (6) 1977    aureus, Proteus   antifungal           unrelated
                   mirabilis         therapy              cause
                                     (amphotericin B)

Winston            S aureus,         Surgery,             Died of
et al, 1977        P mirabilis       antibacterial        disease
                                     therapy

Hecht and          Staphylococcus    Surgery,             Died of
Montgomerie, (8)   epidermidis,      antifungal therapy   disease
1978               Enterobacter      (5-fluorocytosine,
                   cloacae           amphotericin B)

Mader et al, (9)   Citrobacter       Surgery,             Infection
1978               freundii          antifungal therapy   resolved
                                     (miconazole)

Bark et al, (10)   Klebsiella        Surgery              Unknown
1978               pneumoniae,
                   E cloacae,
                   anaerobic gram-
                   positive rods

Bryan              None              Surgery,             Died of
et al, (11)                          antifungal therapy   disease
1980                                 (amphotericin B,
                                     then miconazole)

Bloom              Klebsiella        Surgery              Infection
et al, (12)        oxytoca                                resolved
1982

Winn et al, (13)   None              Surgery              Infection
1983                                                      resolved

Schiess            K pneumoniae,     Surgery,             Died of an
et al, (14) 1984   S epidermidis     antifungal therapy   unknown
                   (also Candida     (miconazole, then    cause
                   albicans)         ketoconazole)

Morgan             C freundii        Surgery              Infection
et al, (15)                                               resolved
1984

Travis             C freundii        Surgery              Infection
et al, (5)                                                resolved
1985

Washburn           No                Surgery              Infection
et al, (16) 1988                                          resolved

Salitan            S aureus          Surgery,             Infection
et al, (17)                          antifungal therapy   resolved
1990                                 (amphotericin B,
                                     switched to
                                     miconazole then
                                     ketoconazole)

Terris and         Serratia          Surgery              Infection
Steiniger, (18)    liquefasciens                          resolved
1992

Stamm and          None              Surgery,             Infection
Frable, (19)                         antifungal therapy   resolved
1992                                 (amphotericin B,
                                     switched to
                                     ketoconazole)

Watters and        None              Surgery              Infection
Milford, (20)                                             resolved
1993

Grigg              None              Surgery,             Infection
et al, (21)                          antifungal therapy   persisted a
1993                                 (amphotericin B,     the most
                                     switched to          recent
                                     miconazole,          follow-up
                                     rifampin)

Meyer              S epidermidis     Surgery,             Infection
et al, (22)                          antifungal therapy   recurred;
1994                                 (ketoconazole)       died of a
                                                          related
                                                          cause

Fiero              None              Surgery              Infection
et al, (23)                                               resolved
1995

Machado            None              Surgery,             Died of a
et al, (24) 1998                     antifungal therapy   related
                                     (itraconazole)       cause

Tadros             None              Surgery              Unknown
et al, (25)
1998

Jones              None              Antifungal therapy   Died of
et al, (26)                          (amphotericin B,     leukemia
1999                                 itraconazole)

Horton             None              Surgery,             Died of an
et al, (27)                          antifungal therapy   unknown
1999                                 (amphotericin B,     cause
                                     switched to
                                     itraconazole)

Shaw et al, (28)   None              Surgery              Died,
2000                                                      probably of
                                                          squamous
                                                          cell
                                                          carcinoma

Castiglioni        None              Surgery,             Infection
et al, (29) 2002                     antifungal therapy   resolved
                                     (miconazole, then
                                     itraconazole)

Bates and          K pneumoniae      Antifungal therapy   Died of
Mims, ([dagger])                     (amphotericin B)     disease
2006

* Surgical drainage and/or debridement.

([dagger]) Present report.