The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–4, 2014 Copyright Ó 2014 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2014.01.036
Clinical Communications: Pediatrics ORBITOCRANIAL COMPLICATIONS OF ACUTE SINUSITIS IN CHILDREN Pradeep Kumar Sharma, MD, Bhaskar Saikia, MD, and Rachna Sharma, MD Pediatric Intensive Care Unit, B L Kapur Super Specialty Hospital, New Delhi, India Reprint Address: Pradeep Kumar Sharma, MD, Pediatric Intensive Care Unit, B L Kapur Super Specialty Hospital, Flat no 48, Pocket 7, Sector 21, Rohini, New Delhi 110086, India
, Abstract—Background: Orbitocranial complications (OCCs) of sinusitis are uncommon but potentially life threatening. OCCs carry high morbidity, mortality, and significant long-term sequelae. Late recognition leads to even worse outcomes. Objective: To present four case reports showing that aggressive management of complications of sinusitis-like OCC decreases long-term sequelae and mortality in pediatric patients. Case Reports: Four pediatric patients diagnosed with OCC were treated at our institution from April 2012 to March 2013. Three were boys and one was a girl; ages ranged from 4–14 years. Magnetic resonance imaging and computed tomography were the most useful imaging modalities. All patients received broad-spectrum antibiotics. Additional interventions consisted of endoscopic sinus surgery, subdural empyema drainage, and orbital decompression. Conclusion: The difficult complications of acute sinusitis in the pediatric age group should be anticipated, recognized early, and aggressively managed to prevent morbidity and a fatal outcome. Ó 2014 Elsevier Inc.
are observed more in younger children, whereas intracranial complications occur preferentially in older children (2,3). Boys are predominantly affected (2,3). We report four cases of pediatric orbitocranial complications (OCC): one had subdural empyema, two had orbital involvement, and one had both intracranial and orbital involvement. CASE REPORTS Case 1 A 9-year-old boy presented with fever, headache, vomiting, and seizure. On arrival, the child was drowsy (Glasgow Coma Scale score of 15), febrile (38.9 C/102 F), had photophobia and brisk reflexes with no meningeal signs. The illness began 18 days prior with fever and headache, and he was taken to his primary physician on day 6. The white blood cell (WBC) count was 14,190 with 79% polymorphs. He was started on amoxicillinclavulanate. The symptoms persisted and the child was referred for magnetic resonance imaging (MRI) by a neurologist on day 10. The MRI of the brain revealed bilateral sphenoidal and left ethmoidal sinusitis. The antibiotic was changed to cefaclor by an otolaryngologist. Over the next 3 days, partial symptomatic improvement was seen, however, high-grade fever, headache, and vomiting recurred. The antibiotic was stopped at 48 h and a plan was made for further investigations. The child had seizures and was admitted on day 18. Investigations revealed WBC count of 26,000 with 89% polymorphs,
, Keywords—orbitocranial complications (OCC); sinusitis; early recognition
INTRODUCTION Sinusitis accounts for 21% of antibiotic prescriptions in the pediatric population (1). Sinus infection can spread to involve orbital and intracranial structures through either direct, hematogenous, or by retrograde extension, along the valve-less diploic veins. Orbital complications
RECEIVED: 3 May 2013; FINAL SUBMISSION RECEIVED: 11 December 2013; ACCEPTED: 30 January 2014 1
2
C-reactive protein (CRP) 152 mg/L, erythrocyte sedimentation rate 110, and sodium 127 mEq/L. A brain MRI scan was suggestive of sphenoidal sinusitis, leftsided cavernous sinus thrombophlebitis, narrowing of the internal carotid artery, and subdural empyema (Figure 1A, B). Cerebrospinal fluid analysis showed 20 cells with 90% polymorphs; biochemistry and culture were normal. The patient was managed with ceftriaxone, vancomycin, metronidazole, endoscopic sinus surgery (ESS), intracranial decompression, and supportive measures. Antibiotics were given for a total of 6 weeks. The child was discharged on an anticonvulsant. Follow-up MRI after 4 weeks was normal. Case 2 A 13-year-old, type I diabetic boy presented to an outlying hospital with complaints of headache and vomiting for the past 15 days, and proptosis of the right eye for the previous 3 days. Brain MRI and paranasal sinuses (PNS) computed tomography (CT) revealed pansinusitis, right cavernous sinus thrombosis, and optic
P. K. Sharma et al.
nerve and medial rectus inflammatory edema. The child was managed conservatively for diabetic ketoacidosis with the addition of ceftriaxone and vancomycin. Voriconazole was added on the 7th day. He was referred to our center on day 12 in light of persistent proptosis and ophthalmoplegia. On admission, the patient had right proptosis, complete right ophthalmoplegia, and no perception of light. Blood sugar was 248 mg/dL. Investigation revealed WBC 9800 with 60% polymorphs and CRP 60 mg/L. MRI of the brain and CT of the PNS revealed pansinusitis, most pronounced on the right side, right cavernous sinus thrombophlebitis, optic neuritis, and orbital myositis (Figure 1C, D). Ceftriaxone, vancomycin, metronidazole, and amphotericin B were started. High-dose methylprednisolone was given for the optic neuritis and the patient underwent ESS on day 2. Perception of light and hand movement was noticed after 2 days of treatment. A histopathology sample showed the presence of zygomycoses with vascular invasion. He underwent repeat ESS after 2 weeks. Amphotericin B was given for 6 weeks. After 8 weeks of follow-up, the eye
Figure 1. (A, B) Case 1: Shows sphenoid sinusitis, left cavernous sinus thrombophlebitis, narrowing of left internal carotid artery (encircled), and subdural empyema (arrows). (C, D) Case 2: Shows bilateral sphenoid sinusitis, right orbital cellulitis, optic neuritis, and cavernous sinus thrombophlebitis.
OCC in Acute Sinusitis
was moving partially in the lateral direction, with visual acuity of 1/60. Case 3 A 4-year-old girl had fever and runny nose for the previous 6 days. On day 4 her physician started her on oral cefixime. Over the next 24 to 48 h, she developed redness and rapidly progressing painful swelling of the right eye. On admission she had fever, right proptosis, and chemosis. Her eye movements were painful and restricted, but vision and light reflex were preserved. Investigations revealed WBC count of 14,600 with 72% polymorphs and CRP 65 mg/ L. MRI of the brain and orbit revealed right-sided paranasal sinusitis with erosion of the lamina papyracea and orbital cellulitis. Ceftriaxone, cloxacillin, and metronidazole along with supportive measures were started. She underwent intranasal orbital decompression with ESS. Endoscopic suctioning and cleaning was done on the 4th postoperative day due to fluid collection. She was discharged on the 7th day on cefuroxime for 7 days. Case 4 A 12½-year-old boy presented with fever and headache for 5 days. On day 3 he developed swelling and pain in the right eye. At admission, the child had fever, right proptosis, and chemosis. Vision and eye movements were normal. Investigations revealed WBC 12,100 with 79% polymorphs and CRP 185 mg/L. MRI of the brain and orbit revealed right-sided pan-sinusitis with extension into the preseptal space. The patient was managed with ceftriaxone, cloxacillin, metronidazole, ESS, and supportive measures. He was discharged on the 5th day on cefuroxime for 10 days. DISCUSSION OCC usually occurs as a direct extension of infected paranasal sinuses. Orbital complications are seen more commonly with frontal sinusitis and intracranial complications are commonly associated with frontal sinusitis; however, most of these children have opacification of multiple sinuses (4). Orbital complications comprise about 80% of all OCC (2,3). As per Chandler classification, orbital findings include proptosis, retro-orbital phlegmon, lateral displacement of the medial rectus muscle, subperiosteal phlegmon or abscess, and intraorbital cellulitis or abscess (5). The average duration of illness from presentation is 3–5 days (3). Orbital infection often coexists with intracranial extension, and leads to an early diagnosis and better outcome (6).
3
Intracranial extension was defined by radiographic evidence of epidural abscess, subdural empyema, dural enhancement, intracerebral abscess, venous sinus thrombosis, or frontal bone osteomyelitis. OCC may present with fever, headache, vomiting, chemosis, eye pain, proptosis, cranial nerve palsy, seizures, and focal neurological deficit. Red flag signs for orbital involvement are swollen eye, proptosis, or impaired function of the extraocular muscles. Children with intracranial complication usually have several encounters with health care providers prior to admission (2,6). Persistent headache and vomiting favors intracranial extension. The diagnosis of sinusitis is clinical as per recent guidelines (7). Emergency physicians should suspect OCC in the presence of red flag signs and worsening of symptoms despite appropriate treatment. Urgent radiological imaging is recommended, and a multi-specialty team including pediatrician, neurosurgeon, ophthalmologist, and otolaryngologist should be involved in acute management. CTand MRI are useful imaging modalities in OCC. MRI is superior for intracranial pathology and CT is required to delineate bony anatomy for guiding ESS. MRI and CT complement each other for evaluation of OCC. Pus cultures usually reveal polymicrobial flora and are sterile in about 25% of cases (2,3,6). Treatment includes broad-spectrum antibiotics comprising ceftriaxone/cefotaxime, cloxacillin/clindamycin, and metronidazole. Vancomycin is used for intracranial extension or methicillin-resistant Staphylococcus aureus. Surgical management includes ESS, orbital decompression, and neurosurgical intervention. ESS is recommended in patients with intracranial extension as it accelerates clinical improvement, however, its use in extracranial complications should be individualized (6). Outcomes are favorable with early recognition and aggressive medical and surgical management. Mortality has declined significantly over the years, to about 4–6% (6). However, long-term sequelae such as epilepsy, visual deficits, hearing loss, hemiparesis, cognitive deficits, cranial nerve palsy, and aphasia range from 7–35% in recent literature (2,3,6–9). In our cases 1 and 2, late recognition and delayed surgical management caused prolonged hospitalization, multiple surgical interventions, and neurological sequelae. Also, these complications have high mortality (subdural empyema 12–28% and mucormycosis 40–65%) (10–13).
CONCLUSION Acute sinusitis is an innocuous disease, but OCC carries high morbidity, a higher rate of surgical intervention, increased health care costs, and increased mortality.
4
P. K. Sharma et al.
Emergency physicians should be prepared to anticipate, recognize, and treat these complications at the earliest to minimize adverse outcomes. REFERENCES 1. Anon JB, Jacobs MR, Poole MD, et al. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;130:1–45. 2. Goytia VK, Giannoni CM, Edwards MS. Intraorbital and intracranial extension of sinusitis: comparative morbidity. J Pediatr 2011; 158:486–91. 3. Lance E, Oxford MD, McClay J. Complications of acute sinusitis in children. Otolaryngol Head Neck Surg 2005;133:32–7. 4. DeMuri GP, Wald ER. Complications of acute bacterial sinusitis in children. Pediatr Infect Dis J 2011;30:701–2. 5. Chandler JR, Langenbrunner DJ, Stevens ER. The pathogenesis of orbital complications in acute sinusitis. Laryngoscope 1970;80: 1414–28.
6. Germiller JA, Monin DL, Sparano AM, et al. Intracranial complications of sinusitis in children and adolescents and their outcomes. Arch Otolaryngol Head Neck Surg 2006;132:969–76. 7. Wald ER, Applegate KE, Bordley C, et al. Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. Pediatrics 2013;132: e262–80. 8. Giannoni C, Sulek M, Friedman EM. Intracranial complications of sinusitis: a pediatric series. Am J Rhinol 1998;12:173–8. 9. Gallagher RM, Gross CW, Phillips CD. Suppurative intracranial complications of sinusitis. Laryngoscope 1998;108:1635–42. 10. Agrawal A, Timothy J, Pandit L, Shetty L, Shetty JP. A review of subdural empyema and its management. Infect Dis Clin Pract 2007;15:149–53. 11. Nathoo N, Nadvi SS, van Dellen JR, et al. Intracranial subdural empyemas in the era of computed tomography: a review of 699 cases. Neurosurgery 1999;44:529–36. 12. Anane S, Kaouech E, Belhadj S, et al. Rhino-orbito-cerebral mucormycosis in the diabetic: a better known pathology in Tunisia. Ann Biol Clin 2009;67:325–32. 13. Thomas R, Rogers TR. Treatment of zygomycosis: current and new options. J Antimicrob Chemother 2008;61:i35–9.
http://dx.doi.org/10.1016/j.jemermed.2014.01.036
Clinical Communications: Pediatrics ORBITOCRANIAL COMPLICATIONS OF ACUTE SINUSITIS IN CHILDREN Pradeep Kumar Sharma, MD, Bhaskar Saikia, MD, and Rachna Sharma, MD Pediatric Intensive Care Unit, B L Kapur Super Specialty Hospital, New Delhi, India Reprint Address: Pradeep Kumar Sharma, MD, Pediatric Intensive Care Unit, B L Kapur Super Specialty Hospital, Flat no 48, Pocket 7, Sector 21, Rohini, New Delhi 110086, India
, Abstract—Background: Orbitocranial complications (OCCs) of sinusitis are uncommon but potentially life threatening. OCCs carry high morbidity, mortality, and significant long-term sequelae. Late recognition leads to even worse outcomes. Objective: To present four case reports showing that aggressive management of complications of sinusitis-like OCC decreases long-term sequelae and mortality in pediatric patients. Case Reports: Four pediatric patients diagnosed with OCC were treated at our institution from April 2012 to March 2013. Three were boys and one was a girl; ages ranged from 4–14 years. Magnetic resonance imaging and computed tomography were the most useful imaging modalities. All patients received broad-spectrum antibiotics. Additional interventions consisted of endoscopic sinus surgery, subdural empyema drainage, and orbital decompression. Conclusion: The difficult complications of acute sinusitis in the pediatric age group should be anticipated, recognized early, and aggressively managed to prevent morbidity and a fatal outcome. Ó 2014 Elsevier Inc.
are observed more in younger children, whereas intracranial complications occur preferentially in older children (2,3). Boys are predominantly affected (2,3). We report four cases of pediatric orbitocranial complications (OCC): one had subdural empyema, two had orbital involvement, and one had both intracranial and orbital involvement. CASE REPORTS Case 1 A 9-year-old boy presented with fever, headache, vomiting, and seizure. On arrival, the child was drowsy (Glasgow Coma Scale score of 15), febrile (38.9 C/102 F), had photophobia and brisk reflexes with no meningeal signs. The illness began 18 days prior with fever and headache, and he was taken to his primary physician on day 6. The white blood cell (WBC) count was 14,190 with 79% polymorphs. He was started on amoxicillinclavulanate. The symptoms persisted and the child was referred for magnetic resonance imaging (MRI) by a neurologist on day 10. The MRI of the brain revealed bilateral sphenoidal and left ethmoidal sinusitis. The antibiotic was changed to cefaclor by an otolaryngologist. Over the next 3 days, partial symptomatic improvement was seen, however, high-grade fever, headache, and vomiting recurred. The antibiotic was stopped at 48 h and a plan was made for further investigations. The child had seizures and was admitted on day 18. Investigations revealed WBC count of 26,000 with 89% polymorphs,
, Keywords—orbitocranial complications (OCC); sinusitis; early recognition
INTRODUCTION Sinusitis accounts for 21% of antibiotic prescriptions in the pediatric population (1). Sinus infection can spread to involve orbital and intracranial structures through either direct, hematogenous, or by retrograde extension, along the valve-less diploic veins. Orbital complications
RECEIVED: 3 May 2013; FINAL SUBMISSION RECEIVED: 11 December 2013; ACCEPTED: 30 January 2014 1
2
C-reactive protein (CRP) 152 mg/L, erythrocyte sedimentation rate 110, and sodium 127 mEq/L. A brain MRI scan was suggestive of sphenoidal sinusitis, leftsided cavernous sinus thrombophlebitis, narrowing of the internal carotid artery, and subdural empyema (Figure 1A, B). Cerebrospinal fluid analysis showed 20 cells with 90% polymorphs; biochemistry and culture were normal. The patient was managed with ceftriaxone, vancomycin, metronidazole, endoscopic sinus surgery (ESS), intracranial decompression, and supportive measures. Antibiotics were given for a total of 6 weeks. The child was discharged on an anticonvulsant. Follow-up MRI after 4 weeks was normal. Case 2 A 13-year-old, type I diabetic boy presented to an outlying hospital with complaints of headache and vomiting for the past 15 days, and proptosis of the right eye for the previous 3 days. Brain MRI and paranasal sinuses (PNS) computed tomography (CT) revealed pansinusitis, right cavernous sinus thrombosis, and optic
P. K. Sharma et al.
nerve and medial rectus inflammatory edema. The child was managed conservatively for diabetic ketoacidosis with the addition of ceftriaxone and vancomycin. Voriconazole was added on the 7th day. He was referred to our center on day 12 in light of persistent proptosis and ophthalmoplegia. On admission, the patient had right proptosis, complete right ophthalmoplegia, and no perception of light. Blood sugar was 248 mg/dL. Investigation revealed WBC 9800 with 60% polymorphs and CRP 60 mg/L. MRI of the brain and CT of the PNS revealed pansinusitis, most pronounced on the right side, right cavernous sinus thrombophlebitis, optic neuritis, and orbital myositis (Figure 1C, D). Ceftriaxone, vancomycin, metronidazole, and amphotericin B were started. High-dose methylprednisolone was given for the optic neuritis and the patient underwent ESS on day 2. Perception of light and hand movement was noticed after 2 days of treatment. A histopathology sample showed the presence of zygomycoses with vascular invasion. He underwent repeat ESS after 2 weeks. Amphotericin B was given for 6 weeks. After 8 weeks of follow-up, the eye
Figure 1. (A, B) Case 1: Shows sphenoid sinusitis, left cavernous sinus thrombophlebitis, narrowing of left internal carotid artery (encircled), and subdural empyema (arrows). (C, D) Case 2: Shows bilateral sphenoid sinusitis, right orbital cellulitis, optic neuritis, and cavernous sinus thrombophlebitis.
OCC in Acute Sinusitis
was moving partially in the lateral direction, with visual acuity of 1/60. Case 3 A 4-year-old girl had fever and runny nose for the previous 6 days. On day 4 her physician started her on oral cefixime. Over the next 24 to 48 h, she developed redness and rapidly progressing painful swelling of the right eye. On admission she had fever, right proptosis, and chemosis. Her eye movements were painful and restricted, but vision and light reflex were preserved. Investigations revealed WBC count of 14,600 with 72% polymorphs and CRP 65 mg/ L. MRI of the brain and orbit revealed right-sided paranasal sinusitis with erosion of the lamina papyracea and orbital cellulitis. Ceftriaxone, cloxacillin, and metronidazole along with supportive measures were started. She underwent intranasal orbital decompression with ESS. Endoscopic suctioning and cleaning was done on the 4th postoperative day due to fluid collection. She was discharged on the 7th day on cefuroxime for 7 days. Case 4 A 12½-year-old boy presented with fever and headache for 5 days. On day 3 he developed swelling and pain in the right eye. At admission, the child had fever, right proptosis, and chemosis. Vision and eye movements were normal. Investigations revealed WBC 12,100 with 79% polymorphs and CRP 185 mg/L. MRI of the brain and orbit revealed right-sided pan-sinusitis with extension into the preseptal space. The patient was managed with ceftriaxone, cloxacillin, metronidazole, ESS, and supportive measures. He was discharged on the 5th day on cefuroxime for 10 days. DISCUSSION OCC usually occurs as a direct extension of infected paranasal sinuses. Orbital complications are seen more commonly with frontal sinusitis and intracranial complications are commonly associated with frontal sinusitis; however, most of these children have opacification of multiple sinuses (4). Orbital complications comprise about 80% of all OCC (2,3). As per Chandler classification, orbital findings include proptosis, retro-orbital phlegmon, lateral displacement of the medial rectus muscle, subperiosteal phlegmon or abscess, and intraorbital cellulitis or abscess (5). The average duration of illness from presentation is 3–5 days (3). Orbital infection often coexists with intracranial extension, and leads to an early diagnosis and better outcome (6).
3
Intracranial extension was defined by radiographic evidence of epidural abscess, subdural empyema, dural enhancement, intracerebral abscess, venous sinus thrombosis, or frontal bone osteomyelitis. OCC may present with fever, headache, vomiting, chemosis, eye pain, proptosis, cranial nerve palsy, seizures, and focal neurological deficit. Red flag signs for orbital involvement are swollen eye, proptosis, or impaired function of the extraocular muscles. Children with intracranial complication usually have several encounters with health care providers prior to admission (2,6). Persistent headache and vomiting favors intracranial extension. The diagnosis of sinusitis is clinical as per recent guidelines (7). Emergency physicians should suspect OCC in the presence of red flag signs and worsening of symptoms despite appropriate treatment. Urgent radiological imaging is recommended, and a multi-specialty team including pediatrician, neurosurgeon, ophthalmologist, and otolaryngologist should be involved in acute management. CTand MRI are useful imaging modalities in OCC. MRI is superior for intracranial pathology and CT is required to delineate bony anatomy for guiding ESS. MRI and CT complement each other for evaluation of OCC. Pus cultures usually reveal polymicrobial flora and are sterile in about 25% of cases (2,3,6). Treatment includes broad-spectrum antibiotics comprising ceftriaxone/cefotaxime, cloxacillin/clindamycin, and metronidazole. Vancomycin is used for intracranial extension or methicillin-resistant Staphylococcus aureus. Surgical management includes ESS, orbital decompression, and neurosurgical intervention. ESS is recommended in patients with intracranial extension as it accelerates clinical improvement, however, its use in extracranial complications should be individualized (6). Outcomes are favorable with early recognition and aggressive medical and surgical management. Mortality has declined significantly over the years, to about 4–6% (6). However, long-term sequelae such as epilepsy, visual deficits, hearing loss, hemiparesis, cognitive deficits, cranial nerve palsy, and aphasia range from 7–35% in recent literature (2,3,6–9). In our cases 1 and 2, late recognition and delayed surgical management caused prolonged hospitalization, multiple surgical interventions, and neurological sequelae. Also, these complications have high mortality (subdural empyema 12–28% and mucormycosis 40–65%) (10–13).
CONCLUSION Acute sinusitis is an innocuous disease, but OCC carries high morbidity, a higher rate of surgical intervention, increased health care costs, and increased mortality.
4
P. K. Sharma et al.
Emergency physicians should be prepared to anticipate, recognize, and treat these complications at the earliest to minimize adverse outcomes. REFERENCES 1. Anon JB, Jacobs MR, Poole MD, et al. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;130:1–45. 2. Goytia VK, Giannoni CM, Edwards MS. Intraorbital and intracranial extension of sinusitis: comparative morbidity. J Pediatr 2011; 158:486–91. 3. Lance E, Oxford MD, McClay J. Complications of acute sinusitis in children. Otolaryngol Head Neck Surg 2005;133:32–7. 4. DeMuri GP, Wald ER. Complications of acute bacterial sinusitis in children. Pediatr Infect Dis J 2011;30:701–2. 5. Chandler JR, Langenbrunner DJ, Stevens ER. The pathogenesis of orbital complications in acute sinusitis. Laryngoscope 1970;80: 1414–28.
6. Germiller JA, Monin DL, Sparano AM, et al. Intracranial complications of sinusitis in children and adolescents and their outcomes. Arch Otolaryngol Head Neck Surg 2006;132:969–76. 7. Wald ER, Applegate KE, Bordley C, et al. Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. Pediatrics 2013;132: e262–80. 8. Giannoni C, Sulek M, Friedman EM. Intracranial complications of sinusitis: a pediatric series. Am J Rhinol 1998;12:173–8. 9. Gallagher RM, Gross CW, Phillips CD. Suppurative intracranial complications of sinusitis. Laryngoscope 1998;108:1635–42. 10. Agrawal A, Timothy J, Pandit L, Shetty L, Shetty JP. A review of subdural empyema and its management. Infect Dis Clin Pract 2007;15:149–53. 11. Nathoo N, Nadvi SS, van Dellen JR, et al. Intracranial subdural empyemas in the era of computed tomography: a review of 699 cases. Neurosurgery 1999;44:529–36. 12. Anane S, Kaouech E, Belhadj S, et al. Rhino-orbito-cerebral mucormycosis in the diabetic: a better known pathology in Tunisia. Ann Biol Clin 2009;67:325–32. 13. Thomas R, Rogers TR. Treatment of zygomycosis: current and new options. J Antimicrob Chemother 2008;61:i35–9.
