01Approach to the Critical Patient/attcp45

Immediate priorities

›Life-threatening features requiring immediate action

›Airway patency

›Altered mental status with inability to protect airway (cerebral extension)

›Angioedema or orbital swelling causing stridor

›If airway compromised, immediate definitive airway control

›Hemodynamic state

›SBP < 90 mmHg or MAP < 65 mmHg

›Signs of septic physiology with angioinvasive infection

›If septic shock, broad-spectrum antifungal within 1 hour of recognition

›Neurologic status

›GCS change from baseline

›Seizures

›Focal cranial nerve deficits (CN III, IV, V, VI)

›If GCS < 13 or focal deficit, emergent CT/MRI brain

Recognition and escalation

›High-suspicion pattern

›Immunocompromised or uncontrolled diabetic patient with facial pain

›Unilateral periorbital swelling, proptosis, or ptosis

›Black necrotic eschar on nasal mucosa or palate

›Rapid progression over hours to days

›Failure to improve on antibiotics in immunocompromised patient

›Any sinusitis syndrome not responding within 24–48 hours in a diabetic patient

›Consider ROCM until proven otherwise

›Immediate escalation triggers

›Any vision change (diplopia, blurred vision, loss of light perception)

›Emergent ophthalmology consult

›Altered mental status or new focal neurologic deficit

02History/hx60

Presenting symptoms

›Core symptom complex

›Unilateral facial pain or pressure

›Onset and rate of progression (hours to days is typical)

›Maxillary, periorbital, or frontal distribution

›Nasal symptoms

›Bloody or dark-colored nasal discharge

›Nasal congestion or obstruction

›Anosmia

›Orbital symptoms

›Periorbital edema or swelling

›Diplopia or restricted eye movement

›Visual blurring or loss of vision

›Proptosis

›Neurologic symptoms

›Headache

›Facial numbness (V2 distribution)

›Altered mental status

›Seizures

›Focal weakness

Alarm features

›Red flag symptoms signaling advanced disease

›Black eschar visible on nasal mucosa, turbinates, or palate

›Pathognomonic for angioinvasive fungal infection

›No light perception in affected eye

›Associated with higher mortality and orbital exenteration consideration

›Rapid progression from mild sinusitis to orbital involvement

›Can evolve within 24–72 hours

03Physical Exam/exam46

Vital signs

›Hemodynamic and metabolic status

›Fever (present in approximately 70% of ROCM cases)

›Tachycardia (DKA or sepsis physiology)

›Kussmaul respirations (metabolic acidosis from DKA)

›Blood pressure for septic shock assessment

Head and neck exam

›Nasal and sinus exam

›Turbinate and septal mucosa inspection

›Black or gray necrotic eschar — pathognomonic finding

›Purulent or bloody nasal discharge

›Septal ulceration or perforation

›Necrotic lesions found in up to 87% in case series

›Anterior rhinoscopy findings

›Turbinate pallor or anesthesia (early ischemia before frank necrosis)

›Pale or gray mucosa before eschar formation

Oral and facial exam

›Palate and gingival inspection

›Palatal ischemia or frank necrosis (maxillary sinus spread)

›Gingivoperiodontal tissue discoloration or ulceration

›Molar and premolar percussion tenderness

›Facial swelling pattern

›Unilateral mid-facial edema

›Cheek induration

Orbital exam

›Periorbital and intraorbital findings

›Periorbital erythema and edema

›Proptosis (exophthalmos)

04Differential Diagnosis/ddx34

Life-threatening mimics

›Invasive aspergillosis (most important mimic)

›ICD-10: B44.1 (Other invasive pulmonary aspergillosis)

›Septate, dichotomously branching hyphae on histopathology (vs. broad pauci-septate in Mucorales)

›Galactomannan and beta-D-glucan positive (negative in mucormycosis)

›Differentiating pearl: negative galactomannan in angioinvasive mold strongly favors mucormycosis

›Cavernous sinus thrombosis

›ICD-10: G08 (Intracranial phlebitis and thrombophlebitis)

›Can coexist with ROCM

›Bilateral CN palsy involvement more common in septic cavernous sinus thrombosis

›Bacterial orbital cellulitis

›ICD-10: H05.01 (Cellulitis of orbit)

›Responds to antibiotics; lacks necrotic eschar

›Gram-positive or gram-negative organisms typical

›Epidural or intracranial abscess

›ICD-10: G06.0 (Intracranial abscess and granuloma)

›Bacterial usually; fever with focal neurologic deficit

Other angioinvasive molds

›Invasive fusariosis

›ICD-10: B48.7 (Fusariosis)

›Similar clinical picture; culture and histopathology required for differentiation

›Scedosporiosis and lomentosporosis

›Septate hyphae on histopathology differentiates from Mucorales

›Alternaria and Curvularia sinusitis in immunosuppressed hosts

Non-fungal causes of destructive sinus disease

›Granulomatosis with polyangiitis (GPA/Wegener)

›ICD-10: M31.31 (Wegener granulomatosis with renal involvement)

›Midline destructive lesion; ANCA-positive (c-ANCA/PR3)

05Laboratory Tests/lt47

Essential metabolic panel

›Basic metabolic panel

›Serum glucose

›Hyperglycemia expected in DKA-associated ROCM

›Target glucose 8–10 mmol/l during DKA management

›Serum potassium

›Hypokalemia most common adverse effect of amphotericin B (50–70%)

›Baseline and every 48 hours during amphotericin B therapy

›Serum creatinine and eGFR

›Baseline renal function before initiating liposomal amphotericin B

›Monitor at least every 48 hours during therapy

›Serum bicarbonate and anion gap

›Elevated anion gap metabolic acidosis in DKA

Hematologic and inflammatory markers

›Complete blood count with differential

›Absolute neutrophil count (ANC)

›ANC < 0.5 x 10^9/L — severe neutropenia, highest risk

›Hemoglobin and platelet count for baseline

›Leukocytosis or leukopenia (sepsis physiology)

›Inflammatory markers

›C-reactive protein and ESR

›Elevated but non-specific in invasive fungal infection

›Procalcitonin

›May be elevated but not validated specifically for ROCM

Fungal diagnostics

›Serum galactomannan

›Expected result: negative in mucormycosis (Mucorales lack galactomannan)

›Negative result in suspected invasive mold infection raises suspicion for mucormycosis over aspergillosis

06Diagnostic Tests/dt83

Scoring Systems

›ROCM severity stratification (anatomic extent)

›Isolated sinonasal disease

›Survival approximately 82% (best prognosis)

›Rhino-orbital extension

›Intermediate prognosis

›Rhino-orbito-cerebral (ROCM)

›Survival 27% (lowest prognosis)

›Intracranial extension associated with 71% mortality

›Independent mortality predictors

›HbA1c > 8%

›Age > 60 years

›Impaired CN V2 function

›Vision loss (no light perception)

›EORTC/MSG criteria for proven invasive fungal disease

›Proven: histopathologic demonstration of Mucorales in tissue with positive culture

›Probable: host factor + clinical criteria + mycologic evidence

›Possible: host factor + clinical criteria only

MRI

›MRI with gadolinium — gold standard for orbital and cerebral involvement

›Indications

›Any suspected orbital extension beyond nasal sinuses

›Any neurologic symptoms or cranial nerve deficits

›Pre-operative mapping for surgical planning

›Superior to CT for soft tissue and intracranial detail

›Key MRI findings

›Orbital fat stranding and extraocular muscle thickening

›Cavernous sinus enhancement or thrombosis

›Meningeal enhancement (cerebral extension)

›Perineural spread along cranial nerves

›Frontal lobe infarction from internal carotid artery invasion

›T1 hypointense, T2 heterogeneous sinus masses with restricted diffusion in abscess

›MRI limitations

›May be unremarkable in early disease — normal MRI does NOT exclude ROCM

›Repeat imaging and endoscopy required if high clinical suspicion

›Follow-up imaging

›Weekly MRI recommended in unstable patients during active treatment

CT

›CT paranasal sinuses with contrast — first-line imaging in ED

›Indications

›Initial evaluation of any suspected invasive sinus infection

›Pre-operative surgical planning

›Rapid access in emergency setting

›Key CT findings

›Unilateral sinus opacification (maxillary, ethmoid, sphenoid)

›Mucosal thickening

›Bony erosion (wall of maxillary sinus, lamina papyracea, skull base)

›Peri-antral fat infiltration (soft tissue extension)

›Orbital extension (fat stranding, muscle thickening)

›CT limitations

›Less sensitive than MRI for soft tissue and intracranial involvement

›Early disease may show only mucosal thickening without bony erosion

›Normal CT does not exclude ROCM

›Chest CT

›Obtain once ROCM confirmed to evaluate for pulmonary involvement

›May show nodules, consolidation, pleural effusion in disseminated disease

›Halo sign or reversed halo sign possible but not specific for mucormycosis

Ultrasound

›Ultrasound — limited primary role in ROCM

›Orbital ultrasound

›May identify proptosis, optic nerve sheath dilation

›Useful if CT/MRI not immediately available

›Cannot assess bony or intracranial involvement

›Point-of-care ultrasound for DKA management

›Inferior vena cava diameter for fluid responsiveness assessment

›Cardiac function screening for hypotension evaluation

›Ultrasound not a primary diagnostic tool for ROCM sinuses

›Bone and air barriers limit sinus evaluation

Histopathology and microbiology

›Tissue diagnosis — definitive confirmation

›Nasal endoscopy with biopsy

›Most critical diagnostic procedure

›Brush biopsy of ulcerations and necrotic eschars

›Do not delay antifungal therapy while awaiting biopsy results

›Histopathology staining

›PAS (periodic acid-Schiff) stain

›GMS (Grocott-Gomori methenamine silver) stain

›Characteristic finding: broad (7–15 µm), ribbon-like, pauci-septate hyphae with non-dichotomous (right-angle) branching

›Direct microscopy

›KOH wet mount for rapid identification

›Calcofluor white or Blankophor fluorescence staining

›Fungal culture

›Sabouraud's glucose agar at 25–37°C

›Grows rapidly (24–48 hours) but culture positive in only approximately 50% of cases

›MALDI-TOF MS for species identification from positive cultures

›Molecular diagnostics

›Mucorales-specific PCR on tissue, BAL, or serum

›Emerging as key early diagnostic tool

07Disposition/dispo25

Admission criteria

›All suspected ROCM patients require immediate hospital admission

›No outpatient or ED observation role for any suspected ROCM case

›Minimum step-down unit; ICU preferred for initial stabilization

›ICU-level care indications

›DKA requiring insulin infusion and continuous monitoring

›Hemodynamic instability or septic shock

›Altered mental status or cerebral extension

›Extensive surgical debridement with post-operative monitoring

›Vision loss or rapidly progressing orbital disease

Specialist consultation timing

›Urgent same-day consultations (within hours of presentation)

›Infectious disease — antifungal selection, duration, monitoring

›ENT/otolaryngology — endoscopic evaluation within hours; surgical debridement as soon as feasible

›Ophthalmology — baseline visual acuity; orbital exenteration planning if indicated

›Endocrinology — DKA management and glycemic optimization

›Neurosurgery — if intracranial involvement on imaging or neurologic exam

Transfer criteria

›Transfer indications

›Facilities without ENT surgical capability should transfer immediately

›Neurosurgical capability required for cerebral extension

›Hyperbaric oxygen availability for selected cases if not available on site

›Tertiary referral center with multidisciplinary fungal infection team preferred

Discharge criteria

›Criteria for transition to outpatient management (weeks to months later)

›Clinical stability with resolving imaging findings

›Successfully transitioned to oral step-down antifungal therapy

›Underlying condition controlled (DKA resolved, immunosuppression reduced)

08Treatment/t87

Antifungal therapy — first-line

›Liposomal amphotericin B (L-AmB) — agent of choice

›Standard dosing

›5 mg/kg/day IV

›Dilute in D5W; infuse over 2 hours

›CNS involvement dosing

›10 mg/kg/day IV (based on animal model and clinical data)

›Pre-medication

›Acetaminophen 650 mg PO/IV 30 minutes before infusion

›Diphenhydramine 25–50 mg IV before infusion

›Normal saline 500 mL pre-hydration to reduce nephrotoxicity

›Monitoring

›Serum creatinine and potassium at least every 48 hours

›Magnesium and phosphate weekly

›Duration

›Minimum 4–6 weeks of primary therapy

›Continue until complete imaging resolution AND immune reconstitution

›No fixed maximum duration

Antifungal therapy — alternatives

›Isavuconazole (FDA-approved for mucormycosis)

›Loading dose

›200 mg IV or PO every 8 hours for 6 doses (48 hours)

›Maintenance dose

›200 mg IV or PO once daily

›Indications

›Renal failure precluding amphotericin B use

›Amphotericin B intolerance

›Step-down maintenance after clinical stabilization on L-AmB

›Caution

›Isavuconazole shortens the QTc interval

›Contraindicated in familial short QT syndrome

›Posaconazole delayed-release tablets

›Loading dose

›300 mg PO BID on day 1

›Maintenance dose

›300 mg PO once daily

›Indications

›Step-down oral therapy after stabilization

›Alternative in renal failure

›Requirement

›Delayed-release tablet or IV formulation preferred (oral suspension has variable absorption)

›Antifungals with NO activity against Mucorales (contraindicated)

›Voriconazole

›Echinocandins (caspofungin, micafungin, anidulafungin)

›Fluconazole

›Itraconazole

Surgical intervention

›Urgent surgical debridement — pillar of therapy

›Timing

›As soon as feasible after diagnosis; does not wait for antifungal response

›Preferably within 24 hours of diagnosis

›Approach

›Endoscopic sinus debridement with removal of all necrotic tissue

›Open surgical debridement if endoscopic access insufficient

›Second-look surgery

›Day 7 reassessment recommended to evaluate margins (MICA protocol)

›Repeat until no viable fungal tissue identified

›Orbital exenteration

›Indicated if globe is non-viable (no light perception) with extensive orbital involvement

›Exenteration associated with improved survival in selected patients

›Evidence

›Combined surgical and medical therapy reduces mortality from 88% to 32% versus antifungals alone

DKA and metabolic correction

›Aggressive DKA management — co-equal pillar of therapy

›IV fluid resuscitation

›Normal saline 1 L/hour initial bolus

›Switch to 0.45% NaCl at 250–500 mL/hour after initial correction

›Insulin infusion

›Regular insulin 0.1 units/kg/hour IV infusion

›Target glucose reduction 3–5 mmol/l per hour

›Transition to SubQ when glucose < 13.9 mmol/l and anion gap closing

›Potassium replacement

›Hold insulin if K < 3.5 mmol/l; replace first

›Maintain K 3.5–5.0 mmol/l during infusion

›Bicarbonate

›Sodium bicarbonate only if pH < 6.9

Immunosuppression reversal

›Reduce immunosuppressive burden

›Taper glucocorticoids to lowest effective dose or discontinue if possible

›Discuss reduction of transplant immunosuppression with transplant team

›Reduce or hold voriconazole prophylaxis (no activity; may mask breakthrough)

›Growth factor support

›G-CSF (filgrastim) 5 mcg/kg/day SubQ if neutropenic (ANC < 0.5 x 10^9/L)

›GM-CSF as alternative

›Granulocyte transfusions in selected cases pending neutrophil recovery

Adjunctive therapies

›Hyperbaric oxygen (HBO)

›May be beneficial in selected diabetic patients with sino-orbital disease

›Increases local oxygen tension in ischemic tissue

›Not universally available; use where accessible in appropriate candidates

›Deferasirox (iron chelator)

›NOT recommended — randomized pilot trial showed no mortality benefit

›Deferoxamine contraindicated (increases iron availability to Mucorales)

09Special Populations/sp51

Pregnancy

›ROCM in pregnancy

›Epidemiology

›Rare; isolated case reports; associated with gestational diabetes and immunosuppression

›DKA in pregnancy is a significant risk factor

›Antifungal considerations

›Liposomal amphotericin B is the drug of choice in pregnancy

›Considered relatively safe; documented use in pregnant patients with invasive fungal infections

›Azole antifungals

›Posaconazole and isavuconazole — teratogenic in animal studies

›Avoid in first trimester; use only if L-AmB not available or tolerated

›Surgical considerations

›Surgical debridement required regardless of gestational age

›Multidisciplinary team including obstetrics, maternal-fetal medicine

›Fetal monitoring

›Continuous fetal heart rate monitoring during surgical procedures

›DKA management follows standard obstetric protocol with lower glucose targets

Geriatric

›ROCM in elderly patients

›Risk profile

›Age > 60 years is an independent mortality predictor

›Higher prevalence of DM, CKD, and cardiovascular disease

›Reduced physiologic reserve for amphotericin B nephrotoxicity

›Amphotericin B dosing and monitoring

›Consider starting at 3–5 mg/kg/day in patients with CKD

›More frequent renal function monitoring (every 24–48 hours)

›Aggressive hydration critical to minimize nephrotoxicity

›Azole preference

10Background/b57

Epidemiology

›Incidence and prevalence

›Global incidence estimated at 0.005–1.7 per million population

›Incidence rising due to increasing DM, HCT, solid organ transplant, and COVID-19

›ROCM is the most common clinical form in diabetic patients (approximately 40% of all mucormycosis cases)

›COVID-19-associated mucormycosis caused epidemic wave primarily in India (2021)

›Mortality

›Overall mortality 50–80%

›Disseminated or cerebral involvement: mortality > 90%

›Isolated sinonasal: survival approximately 82%

›Rhino-orbito-cerebral: survival 27%

›Demographics

›Predominantly affects middle-aged adults

›Male predominance in most series

›DM accounts for 40–60% of cases in high-income countries

Pathophysiology

›Causative organisms

›Order Mucorales, family Mucoraceae

›Predominant genera: Rhizopus (most common), Mucor, Lichtheimia, Cunninghamella

›Ubiquitous environmental molds found in soil, decaying organic matter, compost

›Mechanism of infection

›Entry via inhalation of sporangiospores into nasal passages

›Normal immunity clears spores via neutrophil and macrophage phagocytosis

›In hyperglycemia, DKA, or neutropenia: impaired phagocytic killing allows germination

›Iron and acidosis role

›Mucorales thrive in high-iron, acidic environments

›DKA provides both: metabolic acidosis and disrupted transferrin binding releasing free iron

›Deferoxamine (iron chelator metabolized by Rhizopus) acts as a siderophore providing iron

11Patient Discharge Instructions/pdi25

copy discharge instructions

›Discharge instructions for Mucormycosis (Rhino-orbital-cerebral)

›About your infection

›You have been treated for a serious fungal infection of your sinuses, eye area, or brain called mucormycosis

›This infection requires prolonged treatment, usually several months

›Strict control of your blood sugar is essential to prevent the infection from returning

›Your antifungal medication

›Take all antifungal medications exactly as prescribed

›Do not stop taking antifungal medication without consulting your doctor, even if you feel better

›Report any new nausea, vomiting, jaundice, or decreased urine output to your doctor immediately

›Blood sugar control

›Check your blood glucose as directed and keep a log

›Follow your diabetic diet and take all diabetes medications

›High blood sugar can allow this infection to return

›Follow-up appointments

›You must attend all scheduled follow-up appointments with infectious disease, ENT surgery, and eye specialist

›Imaging (CT scan or MRI) will be repeated regularly to monitor your response to treatment

›Do not miss appointments — this infection can return or worsen rapidly

›Return to emergency department immediately for

›Any new or worsening facial pain, numbness, or swelling

›Any change in vision including blurring, double vision, or loss of vision

›New headache that is severe or different from prior headaches

›Confusion, difficulty speaking, seizures, or weakness in any limb

›Fever above 38.5 degrees Celsius

›New black or dark discoloration inside the nose or mouth

›Any wound breakdown or new skin discoloration at surgical site

12References/r38

Guidelines and key sources

›Kontoyiannis DP, Walsh TJ

›Mucormycosis. New England Journal of Medicine. 2026

›NEJM comprehensive review: clinical spectrum, diagnostics, and management

›Cornely OA, Alastruey-Izquierdo A, et al

›Global Guideline for the Diagnosis and Management of Mucormycosis: ECMM/MSGERC Initiative

›Lancet Infectious Diseases. 2019

›Core international guideline for antifungal selection and surgical approach

›Zia Z, Sajadi MJ, et al

›Survival and Prognostic Factors in Rhino-Orbito-Cerebral Mucormycosis: A 3-Year Cohort Study

›Scientific Reports. 2025

›Mortality data by anatomic extent; orbital exenteration survival outcomes

›Douglas AP, Lamoth F, John TM, et al

›ASTCT Series: Management and Prevention of Non-Aspergillus Molds in HCT Recipients

›Transplantation and Cellular Therapy. 2025

›HCT-specific risk period and antifungal management

›Kozan G, Dedeoğlu S, et al

›Impact of Anatomical Extent and Combined Surgical-Medical Therapy on Survival in Sinonasal and ROCM: A 14-Year Retrospective ENT Cohort

›Journal of Clinical Medicine. 2025

›Surgical debridement mortality reduction data

›Brown L, Tschiderer L, Alanio A, et al

›Diagnosis of Mucormycosis by PCR: Systematic Review and Meta-Analysis

›EClinicalMedicine. 2025

›Mucorales PCR sensitivity and performance data

›Gervais M, Aubertin M, Verillaud B, et al

›Systematic Surgical Reassessment Combined With Liposomal Amphotericin B: The MICA Protocol

›Acta Oto-Laryngologica. 2026

›Second-look surgery protocol evidence

Evidence & Review

Evidence & Review