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id.endemic-mycoses.v1PRODUCTION
id.endemic-mycoses.v1

Endemic mycoses (Histoplasmosis / Coccidioidomycosis / Blastomycosis / Paracoccidioidomycosis)

infectious_diseaseacutesubacutechronicadult
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Canonical 12-phase frame with authored status for this dossier.

Current phase

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Detailed

Adult endemic-mycosis engine covering histoplasmosis (Ohio/Mississippi River valleys + bird/bat exposure), coccidioidomycosis (SW US Arizona/California Central Valley + Mexico/Central America), blastomycosis (SE/NC US + Great Lakes + St. Lawrence River), and paracoccidioidomycosis (rural Latin America). Talaromycosis (SE Asia AIDS) noted as sibling but routed separately. Pediatric-isolated forms and isolated chronic-pulmonary subforms flagged for siblings.

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Advance rule
Set
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host + exposure + scope confirmed (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017)

Patient inputs (14)

Endemic distribution defines pretest probability: Ohio/Mississippi River valleys (histo), SW US Arizona/California Central Valley + Mexico (cocci), SE/NC US + Great Lakes + St. Lawrence (blasto), rural Latin America (paracocci), SE Asia (talaromyces sibling) (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238; IDSA blasto 2008 PMID 18462107; Shikanai-Yasuda 2017 PMID 28746570)

HIV CD4 < 150, transplant, biologic-DMARD, chronic steroid, malignancy, age extremes alter disease tempo (progressive disseminated histo, severe cocci, blasto dissemination, paracocci juvenile form) and drug choice (avoid azoles with calcineurin inhibitors; use L-AmB for severe disseminated) (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238)

Azoles (itraconazole, fluconazole, voriconazole, posaconazole, isavuconazole) teratogenic — first-trimester contraindicated; L-AmB is preferred antifungal in pregnancy; coccidioidal-meningitis pregnancy = intrathecal AmB historically (IDSA histo 2007; IDSA cocci 2016 PMID 27470238)

Persistent fever (> 7 days) in endemic-exposure host suggests progressive / disseminated disease vs self-limited pulmonary form (IDSA histo 2007 PMID 17806045)

Urine Histoplasma antigen sens > 90% in disseminated histo, ~80% in acute pulmonary; also cross-reactive with blasto (~80%) and paracocci (variable) — high-yield first-line antigen test (Hage ATS 2019 PMID 31469325; IDSA histo 2007 PMID 17806045)

Coccidioides immunodiffusion (qualitative IgM + IgG) and complement-fixation titer ≥ 1:16 / 1:32 marks active / disseminated cocci; titer trajectory drives treatment monitoring (IDSA cocci 2016 PMID 27470238; Hage ATS 2019 PMID 31469325)

Fungal blood / sputum / BAL / tissue culture — gold standard but slow (2-4 wk); BAL/tissue Grocott-methenamine-silver (GMS) + PAS stains for typical morphology (broad-based budding yeast = blasto; small intracellular yeast = histo; spherules with endospores = cocci; pilot-wheel multiple budding = paracocci) (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017)

Pancytopenia in disseminated histo (bone-marrow involvement); AmB / flucytosine myelosuppression; baseline CBC for progressive-disease assessment (IDSA histo 2007 PMID 17806045)

CXR + CT chest: cavitary upper-lobe (chronic-pulmonary histo), nodular / consolidation (acute pulmonary cocci or blasto), miliary (disseminated histo), mass-like with effusion (blasto), mediastinal adenopathy with hilar fullness (histo) (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017)

Azole hepatotoxicity (itraconazole, fluconazole, voriconazole, posaconazole, isavuconazole) — monthly LFTs during prolonged 6-12 mo therapy (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008)

Hypoxemia (SpO2 < 92%) marks severe / acute respiratory failure in disseminated histo or severe cocci pneumonia — L-AmB induction + ICU (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238)

AmB (especially deoxycholate) nephrotoxic; itraconazole oral solution / fluconazole + tacrolimus / cyclosporine DDI; renal-dose voriconazole IV vehicle (cyclodextrin) (IDSA histo 2007 PMID 17806045)

CNS involvement: histo CNS / cocci basilar meningitis with hydrocephalus / blasto brain abscess / paracocci CNS granulomas — MRI brain with contrast when CNS phenotype suspected (IDSA histo 2007; IDSA cocci 2016 PMID 27470238)

Itraconazole TDM target trough > 1 µg/mL (HPLC) or > 2 µg/mL (bioassay) — sub-therapeutic levels common with capsule formulation; oral solution preferred; food / acid pH affects absorption (IDSA histo 2007 PMID 17806045; IDSA blasto 2008 PMID 18462107)

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Severity triggers (7)

7 need judgement
  • informationallife_threateningsevere_pulmonary_respiratory_failure
    Hypoxic respiratory failure (SpO2 < 92% on supplemental O2), ARDS, or extensive bilateral infiltrates from severe pulmonary endemic mycosis (severe pulmonary cocci, acute pulmonary histo with respiratory failure, severe blasto) (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238; IDSA blasto 2008 PMID 18462107)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningdisseminated_endemic_mycosis
    Disseminated phenotype: fever + weight loss + hepatosplenomegaly + pancytopenia + mucocutaneous lesions ± positive blood fungal culture in immunocompromised or apparently immunocompetent host (IDSA histo 2007 PMID 17806045; IDSA blasto 2008 PMID 18462107; Shikanai-Yasuda 2017 PMID 28746570)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningcns_endemic_mycosis
    CNS involvement: coccidioidal meningitis (subacute basilar meningitis, lymphocytic CSF, positive CSF cocci CF titer or culture), CNS histoplasmosis (encephalitis, focal lesion), blasto brain abscess, paracocci CNS granulomas (IDSA cocci 2016 PMID 27470238; IDSA histo 2007 PMID 17806045; IDSA blasto 2008 PMID 18462107)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningimmunocompromised_progressive_disseminated_histo
    HIV (CD4 < 150), transplant, biologic-DMARD (TNF-α blocker), chronic steroid, or malignancy + disseminated histo / blasto / cocci — highest-mortality phenotype with rapid progression (IDSA histo 2007 PMID 17806045)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecocci_high_risk_ancestry_or_comorbidity
    Cocci with African-American / Filipino / Hispanic ancestry, pregnancy, DM2, chronic steroid, TNF-α blocker, HIV, lymphoma, or SOT — markedly elevated risk for severe / disseminated cocci with extrapulmonary spread (IDSA cocci 2016 PMID 27470238)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepregnancy_in_endemic_mycosis
    Endemic mycosis in pregnancy — azole teratogenicity in 1st trimester (itraconazole, fluconazole, voriconazole, posaconazole, isavuconazole all FDA category C-D); L-AmB preferred; cocci meningitis in pregnancy = intrathecal AmB historically (IDSA cocci 2016 PMID 27470238; IDSA histo 2007 PMID 17806045)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecocci_meningitis_relapse_on_withdrawal
    Coccidioidal meningitis relapse on attempted fluconazole withdrawal — Dewsnup et al CID 1996 showed ~75% relapse rate; therefore LIFELONG fluconazole maintenance (IDSA cocci 2016 PMID 27470238)
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

Endemic mycoses induction → maintenance ladder by organism × severity × host (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017)
axis: endemic_mycoses_severity_organism_ladder
Selected axis "Endemic mycoses induction → maintenance ladder by organism × severity × host (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017)" by default fallback (first axis)
  • itraconazole
    first line
    azole
    Mild-moderate (histo / blasto / paracocci): 200 mg PO TID × 3 d (load) → 200 mg PO BID × 6-12 mo. Severe step-down (after L-AmB): 200 mg PO BID × ≥ 12 mo. Cocci (alternative to fluconazole): 200 mg PO BID-TID × 3-6 mo. • PO • BID-TID
    triggers: mild_moderate_pulmonary_histo_or_blasto_or_paracocci, step_down_from_LAmB_for_severe_disease, itraconazole_preferred_blasto_per_IDSA_2008, paracocci_first_line_per_Brazilian_consensus_2017
    IDSA histo 2007 PMID 17806045 + IDSA blasto 2008 PMID 18462107 + Shikanai-Yasuda 2017 PMID 28746570 — itraconazole is first-line for mild-moderate histo and blasto and paracocci, and is step-down maintenance after L-AmB for severe disease. TDM trough > 1 µg/mL HPLC (> 2 µg/mL bioassay). Oral solution > capsule absorption; food / acid-pH-dependent capsule absorption; avoid PPIs with capsules. Rifampin is absolute contraindication (CYP3A4 induction destroys levels). Capsule-to-oral-solution-to-IV switching requires re-targeting TDM.
    rxcui 28031
  • amphotericin B liposomal
    first line
    polyene_antifungal
    Severe / disseminated: 3-5 mg/kg IV daily × 1-2 wk → step-down to itraconazole or fluconazole. CNS histoplasmosis: 5 mg/kg IV daily × 4-6 wk → itraconazole BID-TID × ≥ 12 mo. Pregnancy preferred antifungal. • IV • daily
    triggers: severe_disseminated_histo_or_blasto_with_respiratory_failure_or_septic_shock, cns_histoplasmosis_or_blasto_brain_abscess, pregnancy_first_trimester_antifungal_choice, cocci_meningitis_refractory_to_fluconazole_or_first_trimester_pregnancy, severe_paracocci_juvenile_form
    Johnson Ann Intern Med 2002 PMID 12118965 RCT — L-AmB superior to AmB-deoxycholate for moderate-severe disseminated histo in AIDS (clinical success 88% vs 64%; less nephrotoxicity 9% vs 37%; less infusion reactions 25% vs 63%; mortality 1/51 vs 3/22). IDSA histo 2007 PMID 17806045 + IDSA blasto 2008 PMID 18462107 — L-AmB induction for severe / disseminated / CNS. Pregnancy preferred per IDSA cocci 2016 PMID 27470238.
    rxcui 236594
  • amphotericin B
    second line
    polyene_antifungal
    AmB deoxycholate 0.7-1 mg/kg IV daily × 1-2 wk + pre-medicate acetaminophen + diphenhydramine + meperidine + IVF. Only when L-AmB unavailable. • IV • daily
    triggers: liposomal_amphotericin_unavailable_resource_limited_setting
    Johnson Ann Intern Med 2002 PMID 12118965 showed inferior to L-AmB (more nephrotoxicity, infusion reactions, mortality); reserved for L-AmB-unavailable settings per IDSA histo 2007 + IDSA blasto 2008.
    rxcui 732
  • fluconazole
    first line
    azole
    Cocci mild-moderate pulmonary: 400-800 mg PO daily × 3-6 mo. Cocci severe / disseminated: 400-1200 mg PO daily × 6-12 mo. Cocci meningitis: 400-1200 mg PO daily LIFELONG (no taper). Histo / blasto: only when itraconazole intolerant — 800 mg PO daily. • PO • daily
    triggers: cocci_first_line_mild_moderate_or_disseminated, cocci_meningitis_lifelong_maintenance, itraconazole_intolerant_alternative_for_histo_or_blasto, cns_blasto_adjunct_after_LAmB
    IDSA cocci 2016 PMID 27470238 — fluconazole first-line for cocci across severity tiers; cocci meningitis requires LIFELONG fluconazole 400-1200 mg/d (relapse common on withdrawal per Dewsnup et al CID 1996). Better CNS penetration than itraconazole. QTc + DDI screen (warfarin, tacrolimus, cyclosporine, sulfonylureas, statins, phenytoin, rifampin).
    rxcui 4450
  • voriconazole
    rescue
    azole
    Load 6 mg/kg IV q12h × 2 doses → 4 mg/kg IV q12h or 200-300 mg PO q12h. TDM trough 1-5.5 µg/mL. • IV/PO • q12h
    triggers: itraconazole_or_fluconazole_resistant_or_intolerant, cns_blasto_or_paracocci_with_fluconazole_failure, breakthrough_endemic_mycosis_on_other_azole
    IDSA blasto 2008 PMID 18462107 + IDSA cocci 2016 PMID 27470238 — voriconazole rescue for CNS blasto and refractory cocci. CYP2C19 metabolism + TDM required (trough 1-5.5 µg/mL); QTc / visual disturbance / skin photo-toxicity / SCC-risk on prolonged therapy.
    rxcui 121243
  • posaconazole
    rescue
    azole
    Delayed-release tablet 300 mg PO BID × 1 d → 300 mg PO daily; suspension 200 mg PO TID with food; IV 300 mg q12h × 2 → 300 mg daily. TDM trough > 1 µg/mL. • PO/IV • daily-TID
    triggers: refractory_endemic_mycosis_after_itraconazole_or_fluconazole, salvage_for_disseminated_cocci_or_paracocci
    IDSA cocci 2016 PMID 27470238 + Restrepo case series — posaconazole salvage for refractory disseminated endemic mycosis. Delayed-release tablet preferred over suspension (better bioavailability + less food dependence). DDI profile mirrors itraconazole (CYP3A4).
    rxcui 282446
  • isavuconazonium
    rescue
    azole
    Load 200 mg IV/PO q8h × 6 doses → 200 mg daily. • IV/PO • daily after load
    triggers: azole_alternative_with_calcineurin_inhibitor_ddi_burden_in_transplant, voriconazole_or_posaconazole_intolerant
    IDSA cocci 2016 + emerging case-series support; fewer DDIs than voriconazole; no QTc prolongation (actually shortens QT); no cyclodextrin vehicle. Limited prospective endemic-mycosis RCT data.
    rxcui 1608322
  • terbinafine
    add on
    allylamine_antifungal
    250-500 mg PO daily, often combined with itraconazole for refractory cutaneous / mucocutaneous paracocci or chromoblastomycosis-overlap • PO • daily
    triggers: refractory_cutaneous_paracocci_or_chromoblastomycosis_overlap
    Shikanai-Yasuda 2017 PMID 28746570 — terbinafine adjunct considered in select refractory paracocci / chromoblastomycosis-overlap; not first-line for systemic endemic mycoses.
    rxcui 37801
  • sulfamethoxazole / trimethoprim (TMP-SMX)
    second line
    sulfonamide_combination
    160 mg / 800 mg PO BID × 12-24 mo (paracocci alternative when itraconazole unavailable) • PO • BID
    triggers: paracocci_alternative_when_itraconazole_unavailable_resource_limited
    Shikanai-Yasuda 2017 PMID 28746570 — TMP-SMX is the historical resource-limited alternative for paracocci; longer duration (12-24 mo) than itraconazole; monitor LFTs + CBC + creatinine + sulfa allergy.
    rxcui 10831

outpatient playbook — drug actions (4)

  1. 1. itraconazole maintenance (histo / blasto / paracocci)
    rxcui 28031
    200 mg PO BID × ≥ 12 mo (histo / blasto); 200 mg PO daily × 6-12 mo (paracocci) • PO • BID-daily
    trigger: Histo / blasto / paracocci outpatient maintenance
    IDSA histo 2007 PMID 17806045 + IDSA blasto 2008 PMID 18462107 + Shikanai-Yasuda 2017 PMID 28746570
  2. 2. fluconazole maintenance (cocci)
    rxcui 4450
    Cocci pulmonary / disseminated 400-800 mg PO daily × 6-12 mo; cocci meningitis 400-1200 mg PO daily LIFELONG • PO • daily
    trigger: Cocci outpatient
    IDSA cocci 2016 PMID 27470238 — meningitis lifelong (Dewsnup withdrawal data)
  3. 3. ART initiation (HIV+ severe disseminated histo) at 4-6 wk
    Per HIV core engine • PO • daily
    trigger: HIV+ severe disseminated histo at 4-6 wk from start of L-AmB
    Extrapolated from COAT NEJM 2014; IDSA histo 2007 PMID 17806045 — defer ART to avoid IRIS
  4. 4. sulfamethoxazole / trimethoprim (TMP-SMX) — paracocci alternative when itraconazole unavailable
    rxcui 10831
    160/800 mg PO BID × 12-24 mo • PO • BID
    trigger: Resource-limited paracocci
    Shikanai-Yasuda 2017 PMID 28746570

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Subacute pneumonia / CAP-mimic with Ohio-Mississippi / Southwest / Great-Lakes / Latin-American exposure (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238; IDSA blasto 2008 PMID 18462107); Fever + weight loss + hepatosplenomegaly + pancytopenia in immunocompromised host — disseminated mycosis (IDSA histo 2007 PMID 17806045); Mucocutaneous oral / nasopharyngeal / verrucous skin lesions in Latin-American or SE-US host — paracocci or blasto (Shikanai-Yasuda 2017 PMID 28746570; IDSA blasto 2008 PMID 18462107).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Endemic mycoses (Histoplasmosis / Coccidioidomycosis / Blastomycosis / Paracoccidioidomycosis)** (id.endemic-mycoses.v1).
Phenotype framing: TB (separate engine; can co-infect histo / blasto), cryptococcosis (separate engine; HIV / immunocompromised, basilar meningitis with CrAg LFA), pneumocystis jirovecii (HIV CD4 < 200; β-glucan + bilateral GGO), aspergillosis (immunocompromised, halo sign + galactomannan), bacterial CAP / atypical pneumonia, sarcoidosis (mediastinal LAD + non-caseating granulomas), lymphoma (B-symptoms + adenopathy + tissue diagnosis), lung cancer (cavitary mass mimicking chronic histo / blasto), tularemia (rabbit exposure + ulceroglandular). Endemic-mycosis differential resolved by antigen + serology + culture + histology trajectory (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238; IDSA blasto 2008 PMID 18462107; Shikanai-Yasuda 2017 PMID 28746570).
Scope: Adult endemic-mycosis engine covering histoplasmosis (Ohio/Mississippi River valleys + bird/bat exposure), coccidioidomycosis (SW US Arizona/California Central Valley + Mexico/Central America), blastomycosis (SE/NC US + Great Lakes + St. Lawrence River), and paracoccidioidomycosis (rural Latin America). Talaromycosis (SE Asia AIDS) noted as sibling but routed separately. Pediatric-isolated forms and isolated chronic-pulmonary subforms flagged for siblings.

No severity triggers fired against current inputs.

Plan

Regimen axis: **Endemic mycoses induction → maintenance ladder by organism × severity × host (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017)**.
1. itraconazole Mild-moderate (histo / blasto / paracocci): 200 mg PO TID × 3 d (load) → 200 mg PO BID × 6-12 mo. Severe step-down (after L-AmB): 200 mg PO BID × ≥ 12 mo. Cocci (alternative to fluconazole): 200 mg PO BID-TID × 3-6 mo. PO BID-TID (azole, first line) — IDSA histo 2007 PMID 17806045 + IDSA blasto 2008 PMID 18462107 + Shikanai-Yasuda 2017 PMID 28746570 — itraconazole is first-line for mild-moderate histo and blasto and paracocci, and is step-down maintenance after L-AmB for severe disease. TDM trough > 1 µg/mL HPLC (> 2 µg/mL bioassay). Oral solution > capsule absorption; food / acid-pH-dependent capsule absorption; avoid PPIs with capsules. Rifampin is absolute contraindication (CYP3A4 induction destroys levels). Capsule-to-oral-solution-to-IV switching requires re-targeting TDM.
2. amphotericin B liposomal Severe / disseminated: 3-5 mg/kg IV daily × 1-2 wk → step-down to itraconazole or fluconazole. CNS histoplasmosis: 5 mg/kg IV daily × 4-6 wk → itraconazole BID-TID × ≥ 12 mo. Pregnancy preferred antifungal. IV daily (polyene_antifungal, first line) — Johnson Ann Intern Med 2002 PMID 12118965 RCT — L-AmB superior to AmB-deoxycholate for moderate-severe disseminated histo in AIDS (clinical success 88% vs 64%; less nephrotoxicity 9% vs 37%; less infusion reactions 25% vs 63%; mortality 1/51 vs 3/22). IDSA histo 2007 PMID 17806045 + IDSA blasto 2008 PMID 18462107 — L-AmB induction for severe / disseminated / CNS. Pregnancy preferred per IDSA cocci 2016 PMID 27470238.
3. amphotericin B AmB deoxycholate 0.7-1 mg/kg IV daily × 1-2 wk + pre-medicate acetaminophen + diphenhydramine + meperidine + IVF. Only when L-AmB unavailable. IV daily (polyene_antifungal, second line) — Johnson Ann Intern Med 2002 PMID 12118965 showed inferior to L-AmB (more nephrotoxicity, infusion reactions, mortality); reserved for L-AmB-unavailable settings per IDSA histo 2007 + IDSA blasto 2008.
4. fluconazole Cocci mild-moderate pulmonary: 400-800 mg PO daily × 3-6 mo. Cocci severe / disseminated: 400-1200 mg PO daily × 6-12 mo. Cocci meningitis: 400-1200 mg PO daily LIFELONG (no taper). Histo / blasto: only when itraconazole intolerant — 800 mg PO daily. PO daily (azole, first line) — IDSA cocci 2016 PMID 27470238 — fluconazole first-line for cocci across severity tiers; cocci meningitis requires LIFELONG fluconazole 400-1200 mg/d (relapse common on withdrawal per Dewsnup et al CID 1996). Better CNS penetration than itraconazole. QTc + DDI screen (warfarin, tacrolimus, cyclosporine, sulfonylureas, statins, phenytoin, rifampin).
5. voriconazole Load 6 mg/kg IV q12h × 2 doses → 4 mg/kg IV q12h or 200-300 mg PO q12h. TDM trough 1-5.5 µg/mL. IV/PO q12h (azole, rescue) — IDSA blasto 2008 PMID 18462107 + IDSA cocci 2016 PMID 27470238 — voriconazole rescue for CNS blasto and refractory cocci. CYP2C19 metabolism + TDM required (trough 1-5.5 µg/mL); QTc / visual disturbance / skin photo-toxicity / SCC-risk on prolonged therapy.
6. posaconazole Delayed-release tablet 300 mg PO BID × 1 d → 300 mg PO daily; suspension 200 mg PO TID with food; IV 300 mg q12h × 2 → 300 mg daily. TDM trough > 1 µg/mL. PO/IV daily-TID (azole, rescue) — IDSA cocci 2016 PMID 27470238 + Restrepo case series — posaconazole salvage for refractory disseminated endemic mycosis. Delayed-release tablet preferred over suspension (better bioavailability + less food dependence). DDI profile mirrors itraconazole (CYP3A4).
7. isavuconazonium Load 200 mg IV/PO q8h × 6 doses → 200 mg daily. IV/PO daily after load (azole, rescue) — IDSA cocci 2016 + emerging case-series support; fewer DDIs than voriconazole; no QTc prolongation (actually shortens QT); no cyclodextrin vehicle. Limited prospective endemic-mycosis RCT data.
8. terbinafine 250-500 mg PO daily, often combined with itraconazole for refractory cutaneous / mucocutaneous paracocci or chromoblastomycosis-overlap PO daily (allylamine_antifungal, add on) — Shikanai-Yasuda 2017 PMID 28746570 — terbinafine adjunct considered in select refractory paracocci / chromoblastomycosis-overlap; not first-line for systemic endemic mycoses.
9. sulfamethoxazole / trimethoprim (TMP-SMX) 160 mg / 800 mg PO BID × 12-24 mo (paracocci alternative when itraconazole unavailable) PO BID (sulfonamide_combination, second line) — Shikanai-Yasuda 2017 PMID 28746570 — TMP-SMX is the historical resource-limited alternative for paracocci; longer duration (12-24 mo) than itraconazole; monitor LFTs + CBC + creatinine + sulfa allergy.

Setting playbook (outpatient) — Complete 6-12 mo azole maintenance (itraconazole for histo / blasto / paracocci; fluconazole for cocci); lifelong fluconazole for cocci meningitis; ART initiation 4-6 wk for HIV+ severe disseminated histo; TDM + LFT + antigen / CF titer surveillance; relapse vigilance + immune-recovery threshold
10. itraconazole maintenance (histo / blasto / paracocci) 200 mg PO BID × ≥ 12 mo (histo / blasto); 200 mg PO daily × 6-12 mo (paracocci) PO BID-daily — Histo / blasto / paracocci outpatient maintenance (IDSA histo 2007 PMID 17806045 + IDSA blasto 2008 PMID 18462107 + Shikanai-Yasuda 2017 PMID 28746570)
11. fluconazole maintenance (cocci) Cocci pulmonary / disseminated 400-800 mg PO daily × 6-12 mo; cocci meningitis 400-1200 mg PO daily LIFELONG PO daily — Cocci outpatient (IDSA cocci 2016 PMID 27470238 — meningitis lifelong (Dewsnup withdrawal data))
12. ART initiation (HIV+ severe disseminated histo) at 4-6 wk Per HIV core engine PO daily — HIV+ severe disseminated histo at 4-6 wk from start of L-AmB (Extrapolated from COAT NEJM 2014; IDSA histo 2007 PMID 17806045 — defer ART to avoid IRIS)
13. sulfamethoxazole / trimethoprim (TMP-SMX) — paracocci alternative when itraconazole unavailable 160/800 mg PO BID × 12-24 mo PO BID — Resource-limited paracocci (Shikanai-Yasuda 2017 PMID 28746570)

Non-pharmacologic actions:
- Counsel exposure avoidance: no spelunking / dusty soil / construction / agricultural work in endemic areas while immunocompromised
- ART adherence counselling (HIV) — sustained viral suppression key to maintenance discontinuation
- Calcineurin-inhibitor dose monitoring in transplant patients (azole DDI reduces CNI dose 40-60%)
- Pregnancy planning + contraception if on azole maintenance
- Functional recovery — pulmonary rehab if fibrotic / cavitary sequelae; PT/OT if disseminated debility
- Mental-health screening
- Patient + family education on relapse signs (return of fever, cough, weight loss, mucocutaneous lesion) → ED

AVOID / contraindication checks:
- Itraconazole rifampin absolute contraindication CYP3A4 induction destroys levels (IDSA histo 2007 PMID 17806045)
- Azoles pregnancy category D or C avoid first trimester prefer LAmB (IDSA cocci 2016 PMID 27470238; FDA / DailyMed)
- Itraconazole capsule requires acidic pH avoid PPI H2 blocker use oral solution (DailyMed itraconazole label)
- Itraconazole TDM trough target >1 µg mL HPLC or >2 µg mL bioassay (IDSA histo 2007 PMID 17806045)
- Fluconazole QTc prolongation monitor with amiodarone methadone ondansetron (DailyMed)
- Fluconazole warfarin tacrolimus cyclosporine statin sulfonylurea phenytoin rifampin DDI (DailyMed)
- Voriconazole CYP2C19 TDM trough 1 to 5.5 µg mL (IDSA cocci 2016 PMID 27470238)
- Voriconazole visual disturbance photo toxicity SCC risk on prolonged therapy (DailyMed)
- Posaconazole tablet preferred over suspension better bioavailability (DailyMed)
- AmB deoxycholate nephrotoxicity monitor Cr K Mg premedicate (IDSA histo 2007; IDSA blasto 2008)
- L AmB preferred over deoxycholate less nephrotoxic less infusion reactions (Johnson Ann Intern Med 2002 PMID 12118965)
- Calcineurin inhibitor dose reduction 40 60 percent with azoles in transplant (IDSA histo 2007 PMID 17806045)
- Cocci meningitis no taper fluconazole lifelong relapse on withdrawal (IDSA cocci 2016 PMID 27470238)
- Defer ART 4 to 6 weeks in HIV with severe disseminated histo to avoid IRIS (extrapolated from COAT cryptococcal data; IDSA histo 2007 PMID 17806045)

Monitoring

Regimen monitoring:
- itraconazole trough at steady state day 14 target >1 µg mL HPLC (IDSA histo 2007 PMID 17806045)
- creatinine K Mg q48h during AmB induction (IDSA histo 2007; IDSA blasto 2008)
- CBC q48h during AmB induction (IDSA histo 2007)
- LFT monthly during 6-12 mo azole therapy (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008)
- cocci CF titer q3 mo rising titer marks progression or relapse (IDSA cocci 2016 PMID 27470238)
- urine histo antigen q3 mo clearance marks response (IDSA histo 2007 PMID 17806045; Hage ATS 2019 PMID 31469325)
- HIV CD4 VL q3 mo for ART efficacy and IRIS surveillance
- pregnancy test repeat if attempting azole switch from LAmB
- voriconazole TDM trough 1-5.5 µg mL if used (IDSA cocci 2016 PMID 27470238)
- posaconazole TDM trough >1 µg mL if used

Setting (outpatient) monitoring:
- LFT monthly × 6-12 mo
- Itraconazole trough q3 mo
- Cocci CF titer q3 mo
- Urine histo antigen q3 mo
- HIV CD4 + VL q3 mo
- Annual MRI brain + neurology for cocci meningitis lifelong

Follow-up plan: ID outpatient q1-3 mo through 6-12 mo of therapy + lifelong for cocci meningitis; HIV / transplant clinic concurrent; vaccinations per ACIP after immune-recovery; exposure-avoidance counselling (no spelunking / dusty soil disruption in endemic areas while immunocompromised); fertility / pregnancy planning if azole maintenance ongoing; mental-health screening for post-critical-illness sequelae; pulmonary rehab for fibrotic / cavitary sequelae; relapse vigilance — return of fever / cough / weight loss / mucocutaneous lesion → re-evaluation (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017).
- Close-out criterion: maintenance plan + relapse-precaution counselling + immune-recovery threshold documented

Monitoring phase: CBC + BMP + LFT q48h during L-AmB induction; itraconazole trough at steady-state (~14 d) target > 1 µg/mL HPLC; LFT monthly during 6-12 mo azole maintenance; cocci CF titer q3 mo (rising titer = progression / relapse); urine histo antigen q3 mo during therapy (clearance marks resolution); HIV CD4 + VL q3 mo for ART efficacy / IRIS surveillance; pregnancy test repeat if azole switch from L-AmB attempted; symptom + functional recovery q1-3 mo. Cocci meningitis lifelong fluconazole — annual neurology + imaging surveillance (Galgiani Dewsnup withdrawal data).

Disposition

Current setting: outpatient — Complete 6-12 mo azole maintenance (itraconazole for histo / blasto / paracocci; fluconazole for cocci); lifelong fluconazole for cocci meningitis; ART initiation 4-6 wk for HIV+ severe disseminated histo; TDM + LFT + antigen / CF titer surveillance; relapse vigilance + immune-recovery threshold

Disposition criteria:
- Maintenance discontinuation (histo / blasto / paracocci): completed 6-12 mo + asymptomatic + clearing antigen + CD4 > 150 sustained on ART (HIV) — per IDSA histo 2007
- Cocci meningitis: LIFELONG fluconazole — no withdrawal (IDSA cocci 2016 PMID 27470238)

Escalation triggers (move to higher acuity):
- Relapse signs → ED for re-evaluation + repeat antigen / serology / imaging + restart induction if disseminated
- Rising cocci CF titer → urgent re-LP + re-imaging + reassess azole + dose
- Severe IRIS post-ART → ID + consider short-course steroid only for severe decompensation
- Pregnancy on azole maintenance → switch to L-AmB during 1st trimester

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Hypoxic respiratory failure (SpO2 < 92% on supplemental O2), ARDS, or extensive bilateral infiltrates from severe pulmonary endemic mycosis (severe pulmonary cocci, acute pulmonary histo with respiratory failure, severe blasto) (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238; IDSA blasto 2008 PMID 18462107)
- [LIFE_THREATENING] Disseminated phenotype: fever + weight loss + hepatosplenomegaly + pancytopenia + mucocutaneous lesions ± positive blood fungal culture in immunocompromised or apparently immunocompetent host (IDSA histo 2007 PMID 17806045; IDSA blasto 2008 PMID 18462107; Shikanai-Yasuda 2017 PMID 28746570)
- [LIFE_THREATENING] CNS involvement: coccidioidal meningitis (subacute basilar meningitis, lymphocytic CSF, positive CSF cocci CF titer or culture), CNS histoplasmosis (encephalitis, focal lesion), blasto brain abscess, paracocci CNS granulomas (IDSA cocci 2016 PMID 27470238; IDSA histo 2007 PMID 17806045; IDSA blasto 2008 PMID 18462107)

Citations

- IDSA histoplasmosis 2007 (Wheat et al CID, PMID 17806045) + IDSA coccidioidomycosis 2016 (Galgiani et al CID, PMID 27470238 / executive summary 27559032) + IDSA blastomycosis 2008 (Chapman et al CID, PMID 18462107) + Brazilian consensus paracoccidioidomycosis 2017 (Shikanai-Yasuda et al RSBMT, PMID 28746570) + ATS Clinical Practice Guideline microbiology of pulmonary fungal infections 2019 (Hage et al Am J Respir Crit Care Med, PMID 31469325) + Johnson et al Ann Intern Med 2002 L-AmB pivotal RCT (PMID 12118965) [PMID:17806045](https://pubmed.ncbi.nlm.nih.gov/17806045/)
- Cited evidence (PMID 27470238) [PMID:27470238](https://pubmed.ncbi.nlm.nih.gov/27470238/)
- Cited evidence (PMID 27559032) [PMID:27559032](https://pubmed.ncbi.nlm.nih.gov/27559032/)
- Cited evidence (PMID 18462107) [PMID:18462107](https://pubmed.ncbi.nlm.nih.gov/18462107/)
- Cited evidence (PMID 28746570) [PMID:28746570](https://pubmed.ncbi.nlm.nih.gov/28746570/)

Last reconciled with current guidelines: 2026-05-26.
References
  • IDSA histoplasmosis 2007 (Wheat et al CID, PMID 17806045) + IDSA coccidioidomycosis 2016 (Galgiani et al CID, PMID 27470238 / executive summary 27559032) + IDSA blastomycosis 2008 (Chapman et al CID, PMID 18462107) + Brazilian consensus paracoccidioidomycosis 2017 (Shikanai-Yasuda et al RSBMT, PMID 28746570) + ATS Clinical Practice Guideline microbiology of pulmonary fungal infections 2019 (Hage et al Am J Respir Crit Care Med, PMID 31469325) + Johnson et al Ann Intern Med 2002 L-AmB pivotal RCT (PMID 12118965) — PMID:17806045
  • Cited evidence (PMID 27470238) — PMID:27470238
  • Cited evidence (PMID 27559032) — PMID:27559032
  • Cited evidence (PMID 18462107) — PMID:18462107
  • Cited evidence (PMID 28746570) — PMID:28746570