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id.toxoplasmosis-cns.v1PRODUCTION
id.toxoplasmosis-cns.v1

Cerebral toxoplasmosis (HIV-associated and immunocompromised) — DHHS 2024 OI + Dannemann ACTG (Ann Intern Med 1992 PMID 1727093) + Katlama European RCT (CID 1996 PMID 8838183)

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12/12 authored

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Adult cerebral toxoplasmosis in HIV (CD4 < 100, especially < 50) and non-HIV immunocompromised hosts (SOT — heart D+/R- highest; alloHSCT; biologic + CAR-T). Congenital + isolated ocular toxoplasmosis out of scope (DHHS 2024 OI; Robert-Gangneux PMID 22491772)

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immunocompromise substrate + scope confirmed

Patient inputs (11)

Defines toxoplasmosis risk profile — advanced HIV (CD4 < 100) most common; SOT (heart D+/R- highest); alloHSCT; biologic/CAR-T; chronic-steroid; drives empiric trial vs early biopsy threshold (DHHS 2024 OI; Robert-Gangneux PMID 22491772)

ART status (HIV) drives IRIS risk + secondary prophylaxis duration; SOT immunosuppression reduction coordination with transplant team; biologic / CAR-T may need temporary hold (DHHS 2024 OI; AST IDCOP transplant ID guidance)

Toxoplasma IgG positive in > 99% of true reactivation toxoplasmosis in HIV — supports empiric trial; IgG-negative argues against toxo and pushes toward upfront biopsy or alternative diagnosis (Luft/Remington PMID 1520757; DHHS 2024 OI)

MRI brain with contrast: ring-enhancing lesions (often multifocal), basal ganglia + corticomedullary junction predilection; superior sensitivity vs CT; lesion count + size + zone informs response assessment (Luft/Remington PMID 1520757)

Pyrimethamine myelosuppression (megaloblastic anemia, neutropenia, thrombocytopenia) — mitigated by leucovorin co-administration; baseline + weekly monitoring (DHHS 2024 OI)

Sulfa-allergy mandates pyrimethamine + clindamycin (Pyr-Cm) regimen vs first-line pyrimethamine + sulfadiazine (Pyr-Sdz); Caumes CID 1995 PMID 8527561 reported Stevens-Johnson / Lyell with Pyr-Sdz; Katlama PMID 8838183 confirmed Pyr-Cm acceptable alternative when sulfa-intolerant

Sulfadiazine crystalluria + AKI risk (especially low urine pH + dehydration); urinary alkalinization + hydration; renal dose-adjust TMP-SMX (DHHS 2024 OI)

Mass effect + edema + midline shift or herniation features drive adjunctive dexamethasone use; otherwise steroids should be AVOIDED as they confound imaging response (DHHS 2024 OI; Luft/Remington PMID 1520757)

CD4 < 100 (especially < 50) is the classic HIV-toxoplasmosis substrate; drives primary prophylaxis (TMP-SMX 1 SS daily when CD4 < 100 + Toxo IgG+) + secondary prophylaxis discontinuation thresholds (DHHS 2024 OI)

ART optimization + IRIS risk + secondary prophylaxis discontinuation when CD4 > 200 × 6 mo on suppressive ART (DHHS 2024 OI)

Pyrimethamine + sulfadiazine hepatotoxicity surveillance; baseline + serial (DHHS 2024 OI)

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (9)

9 need judgement
  • informationallife_threateningmass_effect_or_impending_herniation
    Mass effect (midline shift > 5 mm), edema with focal deficit, Cushing reflex (bradycardia + hypertension), asymmetric pupils, posturing, or GCS drop ≥ 2 (DHHS 2024 OI; Luft/Remington CID 1992 PMID 1520757)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningstatus_epilepticus_at_presentation
    Status epilepticus (continuous seizure activity > 5 min or recurrent without recovery) at presentation (NCS/AAN guidelines)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereempiric_trial_non_response_at_10_14_d
    No clinical OR radiographic improvement at 10-14 d of adherent appropriate anti-toxoplasma therapy (Luft/Remington CID 1992 PMID 1520757; Dannemann Ann Intern Med 1992 PMID 1727093)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveretransplant_recipient_with_cns_lesion
    SOT (especially heart D+/R-), alloHSCT, biologic/CAR-T recipient with new ring-enhancing brain lesion(s) (Cibickova Transpl Infect Dis 2007 PMID 17428279; Robert-Gangneux Clin Microbiol Rev 2012 PMID 22491772)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveresevere_pyrimethamine_cytopenia_despite_leucovorin
    Severe anemia / neutropenia / thrombocytopenia despite leucovorin 25-50 mg daily co-administration (DHHS 2024 OI; FDA pyrimethamine label)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveresulfadiazine_crystalluria_aki
    Sulfadiazine-associated AKI / crystalluria (rising creatinine, hematuria, crystals on UA) (FDA sulfadiazine label)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereconcurrent_cmv_or_pjp_co_infection_in_advanced_hiv
    Concurrent CMV viremia / retinitis OR PJP pneumonia in CD4 < 50 HIV with toxoplasmosis (DHHS 2024 OI)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatesulfa_allergy_severe_or_sjs_ten_history
    History of severe sulfa reaction (SJS/TEN, DRESS, anaphylaxis) (Caumes CID 1995 PMID 8527561)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderateiris_after_art_initiation
    Paradoxical worsening of toxoplasmosis 2-8 wk after ART initiation / re-initiation in HIV (DHHS 2024 OI)
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

Cerebral toxoplasmosis induction (≥6 wk; longer if not improving) — Pyr-Sdz-leucovorin first-line; Pyr-Cm-leucovorin sulfa-allergy alternative; TMP-SMX resource-limited / pyrimethamine-unavailable; atovaquone-based salvage (DHHS 2024 OI; Dannemann Ann Intern Med 1992 PMID 1727093; Katlama CID 1996 PMID 8838183)
axis: toxoplasmosis_cns_inductionstep 1 - Step 1 — Pyrimethamine + sulfadiazine + leucovorin (first-line; Dannemann PMID 1727093; Katlama PMID 8838183)
Selected step "Step 1 — Pyrimethamine + sulfadiazine + leucovorin (first-line; Dannemann PMID 1727093; Katlama PMID 8838183)" — Empiric trial OR biopsy-confirmed cerebral toxoplasmosis; sulfa-tolerant; oral absorption intact; no contraindication to pyrimethamine (severe pancytopenia, pregnancy first trimester)
  • pyrimethamine
    first line
    antiprotozoal_dhfr_inhibitor
    200 mg PO × 1 load → 75 mg PO daily (50 kg-60 kg) OR 100 mg PO daily (> 60 kg) • PO • daily after load (max: 100 mg daily)
    triggers: empiric_trial_or_confirmed_toxoplasmosis, sulfa_tolerant
    DHFR inhibitor (active against tachyzoite); load improves time to therapeutic level; co-administration with leucovorin mitigates myelosuppression (DHHS 2024 OI; Dannemann PMID 1727093)
    rxcui 9010
  • sulfadiazine
    first line
    sulfonamide
    1500 mg PO q6h (> 60 kg) OR 1000 mg PO q6h (< 60 kg) • PO • q6h (max: 6 g/day)
    triggers: empiric_trial_or_confirmed_toxoplasmosis, sulfa_tolerant
    Synergistic DHPS inhibition with pyrimethamine; sulfadiazine specifically (NOT sulfamethoxazole) is the partner of choice in classic Pyr-Sdz regimen; hydrate + alkalinize urine to mitigate crystalluria + AKI; SJS/TEN risk per Caumes CID 1995 PMID 8527561
    rxcui 10171
  • leucovorin
    add on
    folinic_acid
    10-25 mg PO daily; titrate to 50 mg if cytopenias develop • PO • daily (continue 1 wk after pyrimethamine cessation) (max: 50 mg daily)
    triggers: co_administered_with_pyrimethamine
    Mandatory co-therapy with pyrimethamine; rescues host DHFR pathway without rescuing parasite (parasite lacks folinic-acid uptake); reduces megaloblastic anemia / neutropenia / thrombocytopenia (DHHS 2024 OI)
    rxcui 6313

outpatient playbook — drug actions (4)

  1. 1. maintenance Pyr-Sdz-leucovorin (preferred)
    rxcui 9010
    Pyrimethamine 25-50 mg PO daily + sulfadiazine 2-4 g/day in divided doses + leucovorin 10-25 mg PO daily • PO • per agent
    trigger: Post-induction maintenance; sulfa-tolerant
    DHHS 2024 OI — preferred maintenance; continue until CD4 > 200 × 6 mo on suppressive ART (HIV)
  2. 2. maintenance Pyr-Cm-leucovorin (sulfa-allergy alternative)
    rxcui 2582
    Pyrimethamine 25-50 mg + clindamycin 600 mg PO q8h + leucovorin 10-25 mg daily • PO • per agent
    trigger: Sulfa-allergy maintenance
    Katlama PMID 8838183 acceptable alternative; C. difficile risk
  3. 3. primary prophylaxis TMP-SMX SS daily (HIV CD4 < 100 + Toxo IgG+)
    rxcui 10831
    1 SS tab (80/400 mg) PO daily • PO • daily
    trigger: HIV + CD4 < 100 + Toxo IgG+ (NOT already on Toxo therapy)
    DHHS 2024 OI — primary prophylaxis; same drug as PJP prophylaxis; discontinue when CD4 > 200 × 3-6 mo on ART
  4. 4. ART continuation / optimization (HIV)
    per HIV regimen • PO • per regimen
    trigger: All HIV patients with toxoplasmosis
    DHHS 2024 OI — ART is the foundation of long-term outcome; suppression + immune recovery is the threshold for prophylaxis discontinuation

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Focal neurologic deficit (hemiparesis, aphasia, cranial nerve palsy) + headache ± fever in HIV CD4 < 100 or other immunocompromised host — subacute over 2-3 wk (Luft/Remington CID 1992 PMID 1520757); AMS / encephalopathic features + immunocompromise → cerebral toxoplasmosis high on differential when Toxo IgG+ and CD4 < 100 (DHHS 2024 OI; Dannemann Ann Intern Med 1992 PMID 1727093); New-onset seizure in immunocompromised adult — toxoplasmosis is a leading cause of focal seizure in advanced HIV (DHHS 2024 OI).

Objective

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

Assessment

**Cerebral toxoplasmosis (HIV-associated and immunocompromised) — DHHS 2024 OI + Dannemann ACTG (Ann Intern Med 1992 PMID 1727093) + Katlama European RCT (CID 1996 PMID 8838183)** (id.toxoplasmosis-cns.v1).
Phenotype framing: Toxoplasmosis vs primary CNS lymphoma (single lesion + Toxo IgG-negative + hot on FDG-PET / Th-201 SPECT / EBV-positive CSF → lymphoma) vs tuberculoma (TB-endemic exposure + basal enhancement + chest findings) vs cryptococcoma (CrAg + India ink) vs bacterial brain abscess (acute course + parameningeal source) vs PML (no enhancement typically, white matter) vs HIV encephalopathy (DHHS 2024 OI; Luft/Remington PMID 1520757; Atreya Int J STD AIDS 2013 PMID 24108450)
Scope: Adult cerebral toxoplasmosis in HIV (CD4 < 100, especially < 50) and non-HIV immunocompromised hosts (SOT — heart D+/R- highest; alloHSCT; biologic + CAR-T). Congenital + isolated ocular toxoplasmosis out of scope (DHHS 2024 OI; Robert-Gangneux PMID 22491772)

No severity triggers fired against current inputs.

Plan

Regimen axis: **Cerebral toxoplasmosis induction (≥6 wk; longer if not improving) — Pyr-Sdz-leucovorin first-line; Pyr-Cm-leucovorin sulfa-allergy alternative; TMP-SMX resource-limited / pyrimethamine-unavailable; atovaquone-based salvage (DHHS 2024 OI; Dannemann Ann Intern Med 1992 PMID 1727093; Katlama CID 1996 PMID 8838183)** — step "Step 1 — Pyrimethamine + sulfadiazine + leucovorin (first-line; Dannemann PMID 1727093; Katlama PMID 8838183)".
1. pyrimethamine 200 mg PO × 1 load → 75 mg PO daily (50 kg-60 kg) OR 100 mg PO daily (> 60 kg) PO daily after load (antiprotozoal_dhfr_inhibitor, first line) — DHFR inhibitor (active against tachyzoite); load improves time to therapeutic level; co-administration with leucovorin mitigates myelosuppression (DHHS 2024 OI; Dannemann PMID 1727093)
2. sulfadiazine 1500 mg PO q6h (> 60 kg) OR 1000 mg PO q6h (< 60 kg) PO q6h (sulfonamide, first line) — Synergistic DHPS inhibition with pyrimethamine; sulfadiazine specifically (NOT sulfamethoxazole) is the partner of choice in classic Pyr-Sdz regimen; hydrate + alkalinize urine to mitigate crystalluria + AKI; SJS/TEN risk per Caumes CID 1995 PMID 8527561
3. leucovorin 10-25 mg PO daily; titrate to 50 mg if cytopenias develop PO daily (continue 1 wk after pyrimethamine cessation) (folinic_acid, add on) — Mandatory co-therapy with pyrimethamine; rescues host DHFR pathway without rescuing parasite (parasite lacks folinic-acid uptake); reduces megaloblastic anemia / neutropenia / thrombocytopenia (DHHS 2024 OI)

Setting playbook (outpatient) — Complete ≥ 6 wk induction; transition to lifelong (HIV) or per-protocol (SOT/HSCT) maintenance; optimize ART; manage IRIS; surveil for relapse; coordinate ID + ophtho + neuro follow-up; primary prophylaxis re-initiation when CD4 < 100 (HIV)
4. maintenance Pyr-Sdz-leucovorin (preferred) Pyrimethamine 25-50 mg PO daily + sulfadiazine 2-4 g/day in divided doses + leucovorin 10-25 mg PO daily PO per agent — Post-induction maintenance; sulfa-tolerant (DHHS 2024 OI — preferred maintenance; continue until CD4 > 200 × 6 mo on suppressive ART (HIV))
5. maintenance Pyr-Cm-leucovorin (sulfa-allergy alternative) Pyrimethamine 25-50 mg + clindamycin 600 mg PO q8h + leucovorin 10-25 mg daily PO per agent — Sulfa-allergy maintenance (Katlama PMID 8838183 acceptable alternative; C. difficile risk)
6. primary prophylaxis TMP-SMX SS daily (HIV CD4 < 100 + Toxo IgG+) 1 SS tab (80/400 mg) PO daily PO daily — HIV + CD4 < 100 + Toxo IgG+ (NOT already on Toxo therapy) (DHHS 2024 OI — primary prophylaxis; same drug as PJP prophylaxis; discontinue when CD4 > 200 × 3-6 mo on ART)
7. ART continuation / optimization (HIV) per HIV regimen PO per regimen — All HIV patients with toxoplasmosis (DHHS 2024 OI — ART is the foundation of long-term outcome; suppression + immune recovery is the threshold for prophylaxis discontinuation)

Non-pharmacologic actions:
- Patient education on prolonged maintenance + adherence + adverse effect recognition (rash, fever, jaundice → call) (DHHS 2024 OI)
- Counsel on relapse warning signs: new focal deficit, new seizure, headache, AMS — urgent presentation (Luft/Remington PMID 1520757)
- DDI review at each visit (especially atovaquone + ART; sulfadiazine + warfarin) (FDA labels)
- ART adherence support (HIV) (DHHS 2024 OI)
- Transplant team coordination for IS-related decisions (SOT/HSCT) (AST IDCOP)

AVOID / contraindication checks:
- Pyrimethamine pregnancy first trimester avoid or strong leucovorin cover (FDA label; DHHS 2024 OI)
- Sulfadiazine sulfa allergy anaphylactic or SJS TEN AVOID (Caumes CID 1995 PMID 8527561; FDA label)
- Sulfadiazine crystalluria hydration and urinary alkalinization (FDA label)
- Pyrimethamine myelosuppression CBC weekly and leucovorin titrate (DHHS 2024 OI; FDA label)
- Clindamycin c difficile colitis monitoring (FDA label)
- Tmp smx renal dose adjust and hyperkalemia (FDA label)
- Atovaquone absorption fatty meal required (FDA label)
- Dexamethasone avoid unless documented mass effect or herniation (DHHS 2024 OI; Luft/Remington PMID 1520757)

Monitoring

Regimen monitoring:
- Clinical neuro exam daily during induction (DHHS 2024 OI)
- CBC weekly during induction then q 2 4 wk during maintenance (DHHS 2024 OI; FDA pyrimethamine label)
- Creatinine weekly during sulfadiazine use (FDA sulfadiazine label)
- LFT q 2 wk during induction (DHHS 2024 OI)
- MRI brain at 2 4 wk for radiographic response (Luft/Remington PMID 1520757)
- Resistance or alternative diagnosis consideration if no response 10 14 d (Luft/Remington PMID 1520757)
- Minimum induction duration 6 wk longer if not improving (DHHS 2024 OI; Dannemann PMID 1727093)

Setting (outpatient) monitoring:
- CBC + creatinine + LFT q 4-8 wk during maintenance (DHHS 2024 OI; FDA labels)
- CD4 + VL q 3-4 mo (HIV) (DHHS 2024 OI)
- MRI brain q 6 mo or PRN clinical change (Luft/Remington PMID 1520757)
- Ophthalmology q 3-6 mo (DHHS 2024 OI)

Follow-up plan: Maintenance / secondary prophylaxis after ≥6 wk induction: pyrimethamine 25-50 mg PO daily + sulfadiazine 2-4 g/day (in divided doses) + leucovorin 10-25 mg daily (OR pyrimethamine + clindamycin + leucovorin for sulfa-allergic) OR atovaquone 750-1500 mg PO BID; Discontinue secondary prophylaxis when CD4 > 200 × 6 mo on suppressive ART + clinically asymptomatic (DHHS 2024 OI); Primary prophylaxis re-initiate / continue when HIV CD4 < 100 + Toxo IgG+ — TMP-SMX 1 SS PO daily (same as PJP prophylaxis); Transplant recipients: prophylaxis per protocol (TMP-SMX is standard PJP + toxo + Nocardia prophylaxis post-SOT/HSCT). Lifelong ophtho + neurology surveillance for sequelae (DHHS 2024 OI; Luft/Remington PMID 1520757)
- Close-out criterion: maintenance + prophylaxis plan + ART optimization documented; CD4 + VL trending; sequelae surveillance scheduled

Monitoring phase: Clinical response (resolution of focal deficit + AMS) at d 7-14; repeat MRI at 2-4 wk for radiographic response (lesion regression, enhancement decrease); CBC weekly (myelosuppression — anemia/neutropenia/thrombocytopenia — leucovorin titrate up to 25-50 mg daily if cytopenia); creatinine weekly (sulfadiazine crystalluria + AKI); LFT every 2 wk; CD4 + VL trending (HIV); IRIS surveillance ~2-8 wk after ART start (DHHS 2024 OI; Dannemann PMID 1727093)

Disposition

Current setting: outpatient — Complete ≥ 6 wk induction; transition to lifelong (HIV) or per-protocol (SOT/HSCT) maintenance; optimize ART; manage IRIS; surveil for relapse; coordinate ID + ophtho + neuro follow-up; primary prophylaxis re-initiation when CD4 < 100 (HIV)

Disposition criteria:
- Discontinue secondary prophylaxis (HIV): CD4 > 200 × 6 mo on suppressive ART + clinically + radiographically asymptomatic (DHHS 2024 OI)
- Discontinue primary prophylaxis (HIV): CD4 > 200 × 3-6 mo on suppressive ART (DHHS 2024 OI)
- SOT/HSCT: maintain per transplant protocol indefinitely or until IS taper documented (AST IDCOP)

Escalation triggers (move to higher acuity):
- New focal neurologic finding / new seizure / new headache + AMS during maintenance → urgent re-imaging + ED if mass effect (Luft/Remington PMID 1520757)
- AKI / cytopenia / hepatotoxicity from maintenance regimen → switch (DHHS 2024 OI; FDA labels)
- CD4 falling below 100 in previously immune-recovered HIV patient → restart primary prophylaxis (DHHS 2024 OI)
- IRIS at 2-8 wk after ART start → symptomatic; rarely requires steroids (DHHS 2024 OI)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Mass effect (midline shift > 5 mm), edema with focal deficit, Cushing reflex (bradycardia + hypertension), asymmetric pupils, posturing, or GCS drop ≥ 2 (DHHS 2024 OI; Luft/Remington CID 1992 PMID 1520757)
- [LIFE_THREATENING] Status epilepticus (continuous seizure activity > 5 min or recurrent without recovery) at presentation (NCS/AAN guidelines)
- [SEVERE] No clinical OR radiographic improvement at 10-14 d of adherent appropriate anti-toxoplasma therapy (Luft/Remington CID 1992 PMID 1520757; Dannemann Ann Intern Med 1992 PMID 1727093)

Citations

- DHHS/NIH/CDC/IDSA Adult/Adolescent Opportunistic Infection Guidelines 2024 (Toxoplasmosis section; clinicalinfo.hiv.gov web-anchored) + Dannemann ACTG (Ann Intern Med 1992) + Katlama European RCT (CID 1996) + Luft/Remington foundational review (CID 1992) + Robert-Gangneux/Dardé epidemiology (Clin Microbiol Rev 2012) + AST IDCOP transplant ID guidance [PMID:1727093](https://pubmed.ncbi.nlm.nih.gov/1727093/)
- Cited evidence (PMID 8838183) [PMID:8838183](https://pubmed.ncbi.nlm.nih.gov/8838183/)
- Cited evidence (PMID 8527561) [PMID:8527561](https://pubmed.ncbi.nlm.nih.gov/8527561/)
- Cited evidence (PMID 2060529) [PMID:2060529](https://pubmed.ncbi.nlm.nih.gov/2060529/)
- Cited evidence (PMID 1520757) [PMID:1520757](https://pubmed.ncbi.nlm.nih.gov/1520757/)

Last reconciled with current guidelines: 2026-05-26.
References
  • DHHS/NIH/CDC/IDSA Adult/Adolescent Opportunistic Infection Guidelines 2024 (Toxoplasmosis section; clinicalinfo.hiv.gov web-anchored) + Dannemann ACTG (Ann Intern Med 1992) + Katlama European RCT (CID 1996) + Luft/Remington foundational review (CID 1992) + Robert-Gangneux/Dardé epidemiology (Clin Microbiol Rev 2012) + AST IDCOP transplant ID guidance — PMID:1727093
  • Cited evidence (PMID 8838183) — PMID:8838183
  • Cited evidence (PMID 8527561) — PMID:8527561
  • Cited evidence (PMID 2060529) — PMID:2060529
  • Cited evidence (PMID 1520757) — PMID:1520757