01Approach to the Critical Patient/attcp59

Immediate priorities

›Airway and mental status threats

›GCS < 13 or rapidly declining

›Immediate advanced airway consideration

›Aspiration risk with depressed gag

›RSI preparation if GCS < 8

›Seizure activity

›Independent mortality predictor (OR 3.1)

›Benzodiazepine first-line abortive therapy

›Herniation signs

›Fixed dilated pupils

›Decorticate or decerebrate posturing

›Cushing's triad: hypertension, bradycardia, irregular respirations

›Elevated intracranial pressure recognition

›Papilledema on fundoscopy

›Indicator of significantly elevated ICP

›If present, consider CT before LP

›CN VI palsy (diplopia)

›False localizing sign of elevated ICP

›Abducens nerve most vulnerable

›Opening pressure target on LP

›Measure in all patients

›Drain CSF if >= 25 cm H2O to target < 20 cm H2O

›Circulatory support

›Sepsis physiology screening

›MAP < 65 mmHg triggers resuscitation

›Lactate >= 2 mmol/l as perfusion marker

›IV access and fluid resuscitation

02History/hx93

Presenting symptoms

›Core neurological syndrome

›Headache (most common, ~97% of cases)

›Progressive over median 2 weeks

›Retro-orbital or diffuse quality

›Altered mentation

›Lethargy, personality changes, memory loss

›Often from elevated ICP rather than direct infection

›Nausea and vomiting

›Reflect elevated ICP

›Distinguish from viral gastroenteritis

›Meningeal symptoms

›Neck stiffness

›Present in only 25-33% of HIV-associated cases

›Absence does not exclude diagnosis

›Photophobia and phonophobia

›Variable prevalence

›May be absent in severe immunosuppression

›Cranial nerve symptoms

›Diplopia (CN VI palsy)

›False localizing sign from elevated ICP

›Abducens nerve compression

›Visual changes or vision loss

›Optic nerve involvement

›Risk of permanent blindness without ICP control

›Hearing loss or tinnitus

›CN VIII involvement

›Less common

Systemic and constitutional history

›Constitutional features

›Fever

›Present in ~50-72% of cases

›May be absent particularly in non-HIV patients

›Weight loss and night sweats

›Markers of advanced immunosuppression

›Prolonged subacute course

›Fatigue and malaise

›Weeks-long evolution is characteristic

›Subacute tempo distinguishes from bacterial meningitis

›Pulmonary symptoms

›Cough and dyspnea

›Pulmonary cryptococcosis can precede or co-exist with meningitis

›Can mimic PCP or ARDS

›Respiratory distress

›Rare but high-mortality presentation

›Consider disseminated disease

›Skin findings history

›Umbilicated papules

›Mimic molluscum contagiosum

›Marker of disseminated cryptococcosis

›Nodules, ulcers, or cellulitis-like lesions

›Report any recent skin changes

Risk factors

›Immunodeficiency risk factors

›HIV/AIDS with CD4 < 100 cells/mm3

›Predominant risk factor globally

›CD4 nadir, current CD4 count, viral load

›Solid organ transplant on immunosuppression

›Calcineurin inhibitors: tacrolimus, cyclosporine

›Second most common risk group in high-income countries

›Hematologic malignancy

›Lymphoma, leukemia, myeloma

›Chemotherapy-induced lymphopenia

›Medication and iatrogenic risks

›Glucocorticoid therapy

›Chronic or high-dose use

›Sarcoidosis treatment

›Biologic immunosuppressants

›Anti-TNF agents: infliximab, adalimumab

›Ibrutinib, fingolimod, alemtuzumab

›ART adherence and timing

›Nonadherence or virologic failure

›Recent ART initiation raises IRIS risk

›Epidemiologic exposures

›Travel to endemic areas

›Sub-Saharan Africa (C. neoformans)

›Pacific Northwest, British Columbia, Southeast Asia (C. gattii)

›Occupational exposure

›Pigeon breeders or handlers

›Soil and decaying wood exposure (C. gattii)

›Immunocompetent host

›C. gattii can cause disease without immunosuppression

›Higher rates of cryptococcoma formation

Past medical history

›Relevant prior conditions

›Prior cryptococcal disease

›Relapse risk if maintenance not completed

›ART history and adherence

›Prior opportunistic infections

›CD4 nadir indicator

›PCP, toxoplasmosis, CMV history

›Chronic kidney or liver disease

›Affects amphotericin B and flucytosine dosing

›Baseline creatinine and LFTs essential

›Idiopathic CD4 lymphopenia

›HIV-negative patients with unexplained lymphopenia

›Rare but recognized risk group

03Physical Exam/exam74

Vital signs

›Hemodynamic and fever assessment

›Temperature

›Fever in 50-72% of cases

›Hypothermia as severe sepsis marker

›Blood pressure

›Hypertension can indicate Cushing's response to raised ICP

›Hypotension signals septic shock

›Heart rate

›Tachycardia with sepsis physiology

›Relative bradycardia with Cushing's triad

›Respiratory rate

›Tachypnea with pulmonary involvement

›Irregular respirations as herniation sign

Neurological exam

›Mental status

›Glasgow Coma Scale

›GCS < 13 is independent mortality risk factor

›Trend more important than single value

›Orientation and cognitive assessment

›Confusion, personality change, memory loss

›Encephalopathy from elevated ICP

›Cranial nerve examination

›CN VI (abducens)

›Lateral gaze palsy or diplopia

›False localizing sign of elevated ICP

›CN VIII (vestibulocochlear)

›Hearing loss or vestibular dysfunction

04Differential Diagnosis/ddx57

Life-threatening mimics

›Infectious meningitis spectrum

›Bacterial meningitis

›ICD-10 G00.9

›More acute onset; CSF neutrophilic pleocytosis, very low glucose

›Tuberculous meningitis

›ICD-10 A17.0

›Chronic course with basilar enhancement; AFB smear, TB PCR on CSF

›Viral meningoencephalitis

›HSV (ICD-10 B00.4), CMV, VZV

›CSF PCR panel distinguishes; temporal lobe involvement on MRI for HSV

›CNS mass lesions

›Toxoplasma encephalitis

›ICD-10 B58.2

›Ring-enhancing lesions; serology positive in >95%

›CNS lymphoma

›ICD-10 C85.20

›Mass lesion; CSF cytology; EBV PCR

›Cryptococcoma

›Mass lesion form of cryptococcosis

›More common with C. gattii; CT or MRI shows mass

Other fungal infections

›Endemic mycoses

›Coccidioidomycosis meningitis

›ICD-10 B38.4

›Southwest US endemic; serum and CSF complement fixation

›Histoplasma meningitis

›ICD-10 B39.9

05Laboratory Tests/lt65

CSF analysis

›Lumbar puncture priority tests

›Opening pressure measurement

›>= 25 cm H2O in 60-80% of HIV-associated CM

›Therapeutic drainage if elevated: reduce by >= 50% or to < 20 cm H2O

›Remove 20-25 mL if no manometer available

›CSF cryptococcal antigen (CrAg)

›Sensitivity ~99% in HIV-associated CM

›Lateral flow assay preferred; results in minutes

›Critical test: positive even when routine CSF appears normal

›India ink preparation

›Visualization of encapsulated yeast

›Sensitivity 60-80%; positive in 70-80% of AIDS-associated cases

›Negative result does not exclude diagnosis

›Fungal culture (gold standard)

›Required for confirmatory diagnosis

›Results take days to weeks

›CSF may appear deceptively normal with positive culture

›Routine CSF studies

›Cell count and differential

›Variable lymphocytic pleocytosis; may be minimal in severe immunosuppression

›Neutrophilic pleocytosis rare; consider bacterial co-infection

›Glucose

›Low-to-normal glucose typical

›CSF:serum glucose ratio < 0.5 suggests bacterial meningitis

›Protein

›Mildly elevated protein typical

›CSF can appear entirely normal in severely immunosuppressed patients

06Diagnostic Tests/dt67

Scoring Systems

›IDSA/ECMM risk stratification for CM

›High-risk features

›Altered mental status (GCS < 15)

›Opening pressure >= 25 cm H2O

›Seizures

›Fungemia (positive blood cultures)

›Mortality risk factors from cohort data

›Altered consciousness: OR 6.9 for death

›Seizures: OR 3.1 for death

›Older age, undetectable CSF CrAg, multiple symptoms

›69-73% of survivors have cognitive or physical impairment at 12 months

›ICP monitoring thresholds

›Therapeutic LP threshold

›Opening pressure >= 25 cm H2O with symptoms: drain CSF

›Target pressure < 20 cm H2O

›Repeat LP at 48-72 hours regardless of initial pressure

›Refractory ICP criteria

›Daily LPs still required after 5-7 days

›Triggers neurosurgical consultation for lumbar drain or VP shunt

MRI

›Brain MRI indications and findings

›Indications for MRI in CM

›Focal neurologic deficits to exclude mass lesion

›New seizures

›Failure to improve after antifungal initiation

›Suspected IRIS

›Typical MRI findings in CM

07Disposition/dispo43

Admission criteria

›All patients with confirmed or suspected CM require admission

›Inpatient admission for all cases

›Uniformly fatal without treatment

›IV antifungal initiation requires inpatient monitoring

›Duration typically 1-2 weeks or more for induction phase

›ICU admission indications

›GCS < 13 or rapidly declining mental status

›Refractory elevated ICP not controlled by initial LP

›Hemodynamic instability or septic shock

›Respiratory failure requiring ventilatory support

›Seizures requiring continuous monitoring

Level of care and specialist consultation

›Monitored ward vs ICU

›Monitored ward criteria

›Stable mental status (GCS 14-15)

›ICP controlled after initial LP

›Hemodynamically stable

›ICU transfer triggers

›Any mental status decline

›Recurrent seizures

›ICP uncontrolled after 2-3 serial LPs

›Mandatory specialist consultation

›Infectious disease

›Early and throughout hospitalization

›Antifungal stewardship and monitoring

›Neurosurgery

›Refractory elevated ICP

08Treatment/t119

ED stabilization

›Immediate ED interventions

›Lumbar puncture

›Diagnostic and therapeutic simultaneously

›Measure opening pressure in all patients

›Drain to < 20 cm H2O if >= 25 cm H2O with symptoms

›Remove 20-25 mL if manometer unavailable

›IV access and prehydration

›Normal saline 500-1000 mL before amphotericin B

›Reduces nephrotoxicity

›Electrolyte preparation

›Potassium replacement before and during amphotericin B

›Magnesium replacement before and during amphotericin B

Induction antifungal therapy (2 weeks)

›Preferred induction regimen

›Liposomal amphotericin B

›Dose: 3-4 mg/kg IV daily

›Duration: 2 weeks

›Less nephrotoxic than conventional formulation

›Class I recommendation (IDSA/ECMM/ISHAM 2024 Global Guideline)

›Flucytosine (5-FC) combined with liposomal amphotericin B

›Dose: 25 mg/kg PO every 6 hours (four times daily)

›Duration: 2 weeks

›Dose-adjust for renal impairment (GFR-based dosing)

›Monitor peak levels: target 25-100 mg/L

›Alternative induction regimen

›Amphotericin B deoxycholate (conventional)

›Dose: 0.7-1.0 mg/kg IV daily

›Combined with flucytosine 25 mg/kg PO four times daily

›Greater nephrotoxicity risk than liposomal formulation

›Used when liposomal formulation unavailable

›AMBITION-cm regimen (resource-limited settings)

›Single-dose liposomal amphotericin B 10 mg/kg IV

›Plus flucytosine + fluconazole 1200 mg PO daily x 2 weeks

›Non-inferior to 7-day AmBisome in AMBITION-cm trial

›WHO recommended option for resource-limited settings

Consolidation therapy (8 weeks)

›Fluconazole consolidation

›Fluconazole

›Starting dose: 800 mg PO daily

›Once CSF sterile and ART initiated: reduce to 400 mg PO daily

›Duration: 8 weeks

›Class I recommendation

›Monitoring during consolidation

›CSF culture confirmation of sterility at end of induction

›LFTs and renal function monitoring

›Drug interactions: fluconazole inhibits CYP3A4 and CYP2C9

Maintenance therapy (minimum 12 months)

›Long-term suppressive therapy

›Fluconazole maintenance

›Dose: 200 mg PO daily

›Duration: minimum 12 months

›Class I recommendation

›Discontinuation criteria

›CD4 > 100 cells/mm3 on ART

›HIV viral load suppressed on ART

›Completed minimum 1 year of maintenance

›Failure to complete 1 year is the most common cause of relapse

ICP management

›Therapeutic lumbar punctures

›Daily therapeutic LPs

›Continue until pressure normalizes < 20 cm H2O

›Repeat LP at 48-72 hours regardless of initial pressure

›Symptomatic elevated ICP is the primary indication

›Escalation for refractory ICP

›Lumbar drain if refractory to serial LPs

›VP shunt for definitive ICP control

›Neurosurgery consultation required

›Medications not recommended for ICP

›Corticosteroids contraindicated for ICP management

›Increased mortality in randomized trials

›Not recommended by IDSA or ECMM/ISHAM guidelines

›Mannitol not recommended

›No evidence of benefit in CM

›May worsen electrolyte disturbances

›Acetazolamide not recommended

›Not effective for cryptococcal ICP management

›Avoid unless alternative indication exists

ART timing in HIV-positive patients

›ART initiation timing

›Delay ART: 4-6 weeks from antifungal start

›Standard recommendation (Class I)

›Reduces risk of IRIS

›COAT trial: early ART (1-2 weeks) increased mortality 1.7-fold

›Earlier ART consideration (at 2 weeks)

›Clinical improvement documented

›ICP controlled

›CSF cultures negative

›Do not initiate ART in the ED

›IRIS risk is substantial and potentially fatal

›Initiation decision after ID consultation only

›IRIS management

›Unmasking IRIS

›Occurs when CM diagnosed after ART initiation

›Continue antifungal therapy; do not stop ART

›Paradoxical IRIS

›Worsening symptoms after ART initiation in treated CM

›LP and antifungal optimization

›Short-course corticosteroids considered in selected cases

Antifungal toxicity management

›Amphotericin B toxicity monitoring and mitigation

›Nephrotoxicity prevention

›Normal saline 500-1000 mL prehydration before each dose

›Avoid concomitant nephrotoxins

›Monitor creatinine and GFR daily

›Electrolyte replacement

›Potassium replacement: maintain serum K > 3.5 mmol/l

›Magnesium replacement: maintain serum Mg > 0.8 mmol/l

›Infusion reactions

›Premedicate with acetaminophen and diphenhydramine

›Meperidine for rigors if severe

›Flucytosine toxicity monitoring

›Bone marrow suppression

›CBC weekly during flucytosine therapy

›Thrombocytopenia and leukopenia most common

›Dose reduction if toxicity develops

›Hepatotoxicity

›LFTs baseline and monitoring

›Elevated transaminases require dose review

›Renal dose adjustment

›Reduce dose when GFR < 40 mL/min/1.73m2

›Dose adjustment based on drug levels and renal function

›Echinocandins are not active against Cryptococcus

›Mechanism: no glucan synthase target in Cryptococcus

›Do not use anidulafungin, caspofungin, or micafungin

›Not alternatives to amphotericin B or fluconazole

09Special Populations/sp93

Pregnancy

›Maternal considerations

›Incidence and risk

›Rare in pregnancy unless severely immunocompromised

›HIV-positive pregnant women at highest risk

›Requires urgent multidisciplinary management

›Diagnostic approach

›LP and CSF CrAg as per standard protocol

›Serum CrAg lateral flow assay safe in pregnancy

›MRI preferred over CT to avoid fetal radiation

›Antifungal safety in pregnancy

›Amphotericin B

›Preferred antifungal in pregnancy (FDA Category B)

›Liposomal formulation preferred for reduced toxicity

›Crosses placenta but teratogenicity not demonstrated

›Flucytosine

›Teratogenic in animal studies (FDA Category C)

›Avoid in first trimester if possible

›Use with caution; benefits must outweigh risks in severe disease

›Fluconazole

›High-dose fluconazole (400-800 mg/day) associated with fetal cardiac defects

›Avoid during organogenesis (first trimester)

›Single low-dose (150 mg) considered low risk; high-dose contraindicated

›ART in pregnant HIV-positive women

›Continue ART through pregnancy

›ART initiation timing: same principles apply (delay 4-6 weeks for IRIS risk)

›Fetal and neonatal considerations

›Vertical transmission

›Rare reports of congenital cryptococcosis

›Neonatal evaluation if maternal CM at time of delivery

›Delivery timing

›No specific criteria to alter delivery timing for CM alone

›Maternal stability is primary concern

Geriatric

›Altered presentation in older adults

›Non-HIV risk factors predominate

›Solid organ transplant, glucocorticoids, malignancy

›C. gattii meningitis more common in immunocompetent elderly

›Atypical presentations more common

›Dementia-like presentation

›Falls and functional decline as presenting features

›Fever more often absent

›Diagnostic challenges

›Cognitive baseline difficult to establish

›Comorbid dementia masking encephalopathy

›Treatment modifications in older adults

›Amphotericin B nephrotoxicity risk

›Pre-existing CKD common; baseline GFR essential

›More frequent electrolyte monitoring

›Reduced starting doses may be required

›Fluconazole drug interactions

›Polypharmacy common; CYP2C9 and CYP3A4 inhibition

›Warfarin interaction: INR monitoring required

›QT prolongation with other agents

›Frailty and fluid management

›Cautious prehydration volumes; avoid fluid overload

›Monitor for heart failure exacerbation

›Albumin supplementation if hypoalbuminemia

Pediatrics

›Epidemiology in children

›Primary risk group: HIV-positive children with CD4 < 100 cells/mm3

›Sub-Saharan Africa has highest pediatric burden

›Less common in high-income countries due to ART coverage

›Neonatal cryptococcosis

›Rare; associated with maternal immunosuppression

›Higher mortality than older pediatric groups

›C. gattii in immunocompetent children

›Reported in endemic areas (Pacific Northwest, Australia)

›Cryptococcoma formation more common

›Pediatric antifungal dosing

›Liposomal amphotericin B

›Dose: 3-6 mg/kg IV daily (weight-based)

›Induction duration: 2 weeks (same as adults)

›Monitor renal function closely

›Flucytosine in children

›Dose: 25 mg/kg PO every 6 hours

›Dose-adjust for renal impairment

›Monitor CBC weekly for marrow suppression

›Fluconazole in children

›Consolidation: 12 mg/kg/day PO (max 800 mg/day)

›Maintenance: 6 mg/kg/day PO (max 200 mg/day)

›Duration: 12 months minimum

›Pediatric ICP management

›Therapeutic LP approach

›Same principles as adults

›Volume to drain calculated by weight; drain 10-15 mL or to target pressure

›Daily LP if refractory ICP

›ART timing in HIV-positive children

›Delay ART 4-6 weeks from antifungal initiation

›IRIS risk same as adults

›Pediatric ID specialist consultation essential

›Pediatric-specific guidelines

›DHHS Pediatric OI Guidelines (2025)

›Liposomal AmB + flucytosine induction preferred

›Fluconazole consolidation and maintenance as per adult protocol adjusted for weight

›Prophylaxis for HIV-positive children: fluconazole if CD4 < 100 cells/mm3

10Background/b93

Epidemiology

›Global burden

›Incidence

›Approximately 223,000 cases of CM annually worldwide

›Approximately 180,000 deaths per year attributed to CM

›70-80% of cases in sub-Saharan Africa

›Mortality

›Case fatality rate 10-20% in high-income countries

›Case fatality rate 35-65% in sub-Saharan Africa

›Uniformly fatal without antifungal treatment

›Long-term morbidity

›69-73% of survivors have cognitive or physical impairment at 12 months

›Over one-third report work difficulties at 6 months

›Population distribution

›HIV-associated CM

›CD4 < 100 cells/mm3 in vast majority of HIV-associated cases

›ART nonadherence and virologic failure major drivers

›Screening programs in sub-Saharan Africa detect pre-symptomatic antigenemia

›Non-HIV CM

›Solid organ transplant: second most common risk group in high-income countries

›Glucocorticoid users: sarcoidosis, autoimmune disease

›Idiopathic CD4 lymphopenia: rare but recognized

›Species distribution

›C. neoformans var. grubii (serotype A): predominant globally; HIV-associated

›C. gattii: immunocompetent and immunocompromised; BC/Pacific Northwest, Australia

›C. neoformans var. neoformans (serotype D): Europe predominantly

Pathophysiology

›Organism and infection pathway

›Cryptococcus neoformans biology

›Encapsulated basidiomycete yeast

›Polysaccharide capsule: key virulence factor; inhibits phagocytosis

›Melanin production: antioxidant defense against host immune attack

›Thermal tolerance at 37 degrees Celsius: essential for human pathogenicity

›Portal of entry and dissemination

›Inhalation of desiccated yeast cells or basidiospores from environment

›Primary pulmonary infection: often subclinical

›Hematogenous dissemination to CNS via crossing blood-brain barrier

›Yeasts travel within macrophages using Trojan horse mechanism

›CNS pathology

›Meningitis mechanism

›Accumulation of yeasts and polysaccharide capsule in subarachnoid space

›CSF outflow obstruction causes communicating hydrocephalus

›Elevated ICP: major cause of early mortality and morbidity

›Perivascular space invasion

›Yeast proliferation in Virchow-Robin spaces

›Gelatinous pseudocysts (soap bubble lesions) on imaging

›Basal ganglia predilection

›Immune evasion

›Capsular polysaccharide inhibits complement activation

›Impairs T-cell proliferation and macrophage killing

›Host CD4 T-cell depletion allows unbridled proliferation

›IRIS pathophysiology

›Immune reconstitution inflammatory syndrome

›Paradoxical worsening as immune function recovers with ART

›Heightened inflammatory response to residual Cryptococcus antigens

›Occurs in 10-30% of HIV-positive patients after ART initiation

›Most commonly within first 30 days of ART

Therapeutic Considerations

›Antifungal mechanism and rationale

›Amphotericin B mechanism

›Binds ergosterol in fungal cell membrane

›Forms pores causing cell lysis

›Fungicidal activity; critical for induction clearance

›Liposomal formulation reduces kidney uptake and toxicity

›Flucytosine mechanism

›Prodrug converted to 5-fluorouracil inside fungal cell

›Inhibits RNA and DNA synthesis

›Synergistic with amphotericin B: superior fungicidal activity

›Resistance emerges rapidly as monotherapy; always used in combination

›Fluconazole mechanism

›Inhibits 14-alpha lanosterol demethylase (CYP51)

›Blocks ergosterol biosynthesis

›Fungistatic against Cryptococcus; not fungicidal

›Suitable for consolidation and maintenance; not adequate for induction

›Evidence base

›ACTA trial (2013)

›Amphotericin B deoxycholate + flucytosine superior to amphotericin alone

›Combination reduced early fungal burden and 10-week mortality

›Established combination induction as standard of care

›AMBITION-cm trial (2022)

›Single high-dose liposomal AmB (10 mg/kg) + flucytosine + fluconazole

›Non-inferior to 7-day AmBisome regimen at 10-week mortality

›Shorter inpatient requirement; WHO recommended for resource-limited settings

›COAT trial (2014)

›Early ART (1-2 weeks after antifungal) vs delayed (5 weeks)

›Early ART associated with 1.7-fold increased mortality

›Established delayed ART (4-6 weeks) as standard recommendation

›Treatment targets and monitoring

›CSF sterilization rate

›Target CSF culture negative by end of 2-week induction

›Early fungicidal activity (EFA) predicts 2-week and 10-week mortality

›EFA >= 0.5 log10 CFU/mL/day associated with improved outcomes

›CrAg titer monitoring

›Serum CrAg titer correlates with fungal burden

›Persistent high titer suggests inadequate clearance

›CSF CrAg negativity confirms treatment response

11Patient Discharge Instructions/pdi51

copy discharge instructions

›Diagnosis and treatment explanation

›You have been treated for cryptococcal meningitis

›A fungal infection of the brain and spinal fluid

›Caused by the fungus Cryptococcus, found in soil and bird droppings

›You are being discharged on antifungal medication

›Fluconazole tablet taken by mouth once daily

›This phase of treatment lasts 8 weeks (consolidation phase)

›After that, a lower dose is continued for at least 12 months (maintenance phase)

›Medication instructions

›Fluconazole

›Take exactly as prescribed; do not skip doses

›Do not stop without your doctor's approval

›Take with or without food

›Drug interactions to report

›Blood thinners (warfarin): dose adjustment may be needed

›Other antifungals, certain antibiotics, or heart medications

›Inform all providers you are taking fluconazole

›Activity and lifestyle

›Activity restrictions

›Avoid driving if you experience headache, dizziness, or vision changes

›Light activity as tolerated; avoid strenuous exercise until cleared

›No specific dietary restrictions

›Maintain adequate hydration

›Nutritious diet to support immune recovery

›Follow-up instructions

›Infectious disease follow-up

›Within 1-2 weeks of discharge

12References/r43

Guidelines and key sources

›Global and society guidelines

›Chang CC, Harrison TS, Bicanic TA, et al.

›Global Guideline for the Diagnosis and Management of Cryptococcosis

›ECMM and ISHAM in cooperation with ASM

›Lancet Infectious Diseases. 2024

›IDSA/DHHS Opportunistic Infections Guidelines for Adults with HIV (2025)

›Benson C, Brooks J, Dhanireddy S, et al.

›Infectious Diseases Society of America; Office of AIDS Research Advisory Council

›DHHS Pediatric OI Guidelines (2025)

›Kapogiannis BG, Yates F, Li W, et al.

›Office of AIDS Research Advisory Council

›Key clinical trials

›COAT Trial (2014)

›Early versus delayed ART in HIV-positive CM patients

›Established 4-6 week ART delay recommendation

›Eshun-Wilson I, et al. Cochrane Database Systematic Reviews. 2018

›AMBITION-cm Trial (2022)

›Single-dose liposomal AmB 10 mg/kg + flucytosine + fluconazole

›Non-inferior to 7-day AmBisome for 10-week mortality

›WHO adopted for resource-limited settings

›Systematic reviews and landmark publications

›Stott KE, Loyse A, Jarvis JN, et al.

›Cryptococcal Meningoencephalitis: Time for Action

›Lancet Infectious Diseases. 2021

›Fisher KM, Montrief T, Ramzy M, Koyfman A, Long B

›Cryptococcal Meningitis: A Review for Emergency Clinicians

›Internal and Emergency Medicine. 2021

Evidence & Review