Opportunistic infections

How do OIs emerge?

When host defenses are impaired

Which populations are affected by OIs?

• advanced or untreated HIV

• solid organ or stem cell transplantation

• hematologic malignancy

• chemo

• biologic/immunosuppressive therapy

• systemic glucocorticoids

What is Pneumocystis jirovecii pneumonia?

• Opportunistic fungus with protozoan characteristics

• Inhalation of cyst form and the organism is widely present in nature

Who is at risk for PJP?

• HIV

  • greatest risk with advanced immunosuppression

  • CD4<200

• Non-HIV

  • hematologic malignancy

  • solid organ or stem cell transplantation

  • systemic glucocorticoids

  • biologic and other immunosuppressive therapies

  • autoimmune/inflammatory diseases receiving combo immunosuppression

True or false: Non-HIV PJP is increasingly important and may progress more rapidly with worse outcomes

true

What is the typical presentation (days to weeks) of PJP?

• progressive dyspnea

• fever

• nonproductive cough

• hypoxemia

• oral thrush

• extrapulmonary disease (rare)

What do you see on imaging that is consistent with PJP?

• bilateral diffuse ground-glass opacities

• CT more sensitive than CXR

How is PJP diagnosed?

• Respiratory specimen (PCR and/or staining)

• 1,3 B-D-glucan

  • sensitive supportive test, not specific

What drug is preferred in BOTH non HIV and HIV PJP for prophylaxis?

Bactrim

When do you stop prophylaxis for PJP in HIV vs Non-HIV?

HIV: guidelines provide clear start/stop criteria

Non: risk depends on disease + treatment

What is the indication for PJP primary prophylaxis in HIV?

• Not receiving/starting ART: CD4 <200 cells/mL

• If on ART:

  • CD4: <100 regardless of HIV RNA

  • CD4: 100-200 with detectable HIV RNA

What is the preferred therapy for PJP primary prophylaxis in HIV?

• Bactrim 1 DS PO QD

• Bactrim 1 SS PO QD

• Also protect against toxoplasmosis

What is the alternative therapy for PJP primary prophylaxis in HIV?

• Bactrim 1 DS PO 3x/week

• Dapsone

• Aerosolized pentamidine via Respigard II nebulizer monthly

• Atovaquone

What testing is needed before use of dapsone?

G6PD

When do you d/c primary prophylaxis for PJP or toxoplasmosis with HIV?

• CD4 count >200 for >3 months on ART

• Consider when CD4 count is 100-200 and HIV RNA is suppressed for 3-6 months

When do we consider PJP prophylaxis outside HIV? (strongest indications)

• Hematopoietic stem cell transplantation

• Selected solid organ transplantation

• acute leukemia/selected hematologic malignancies

• high-risk immunosuppressive regimens

How do we treat PJP that is mild-moderate?

• Preferred: Oral Bactrim

• Alternative

  • Primaquine + clindamycin

  • Atovaquone

How do we treat PJP that is moderate to severe? (no HIV)

• Preferred: IV Bactrim then switch to oral

• Alternative

  • Primaquine + clindamycin

  • IV Pentamidine

How do we treat moderate-to-severe PJP? (HIV)

Add a 21-day prednisone taper within 72 hours

*Start ART within ~2 weeks when feasible

What classifies someone as moderate to severe PJP?

• PaO2 <70 mmHg

• A-a gradient >35 mmHg

Duration of treatment for PJP

21 days and consideration of secondary prophylaxis after treatment

How is Toxoplasma gondii transmitted?

• undercooked meat (tissue cysts)

• Cat feces (oocysts in the environment)

• Transfusion, transplant, transplacental (less common)

What is the pathogenesis of toxoplasma gondii?

disease usually from reactivation of latent cysts

What is a major manifestation of toxoplasma gonddi

CNS (toxoplasmic encephalitis)

People with HIV with a CD4 cell count < ____ cells/ml is at highest risk for toxoplasma gondii

50

How can you recognize TE? (Toxoplasmic encephalitis)

• Advanced HIV + focal encephalitis

  • HA, confusion, motor weakness, fever

  • focal neurologic deficits ± seizures

• Imaging with CT/MRI

  • multiple contrast-enhancing brain lesions (often surrounding edema)

• Serology

  • toxoplasma IgG +

  • - IgG makes TE less likely

Who is indicated for toxoplasmosis primary prophylaxis in HIV?

• Toxoplasma IgG + AND CD4 count <100 cells/mL

  • At-risk patients should already be on PJP prophylaxis

What is the preferred therapy for toxoplasmosis (prophylaxis)?

Bactrim 1 DS PO QD

Alternatives to primary prophylaxis in HIV for toxoplasmosis

• Bactrim 1 DS PO 3x/week

• Bactrim 1 SS PO QD

• Atovaquone

What is the preferred acute treatment AND chronic maintenance of toxoplasmosis in HIV?

pyrimethamine + sulfadiazine + leucovorin (weight-based)

Why do we use leucovorin?

decreases pyrimethamine-associated bone marrow toxicity

What is alternative therapy in the acute treatment of toxoplasmosis in HIV?

Bactrim IV or PO (if pyrimethamine unavailable or intolerant)

What is the duration of acute treatment of toxoplasmosis in HIV?

• >6 weeks, then chronic maintenance until immune recovery

• HIV: start ART ~2-3 weeks when feasible

What is the alternative therapy in chronic maintenance therapy for toxoplasmosis in HIV?

• pyrimethamine + leucovorin + clindamycin

• Bactrim DS 1 tablet QD or BID

When do you d/c chronic maintenance therapy with toxoplasmosis in HIV?

• Completed initial therapy

• asymptomatic

• CD4 count >200 cells/mL for >6 months on ART

What is MAC (mycobacterium avium complex)

group of non-tuberculous mycobacteria comprised of M. intracellulare and M. avium

What are the reservoirs for MAC?

water, soil, and animals

True or false: MAC is spread person-to-person

false

How is MAC transmitted?

inhalation, ingestion, inoculation (respiratory and GI tract)

What are the clinical features of MAC?

• Fever, night sweats, weight loss, fatigue

• diarrhea, abdominal pain

• hepatomegaly, splenomegaly, lymphadenopathy

What laboratory findings are consistent with MAC?

• anemia (out of proportion to HIV stage)

• leukopenia

• increased alkaline phosphatase

How do we diagnose MAC?

Compatible s/s plus isolation of MAC from blood, bone marrow, lymph node, or other sterile tissue/fluid

What are the indications for MAC primary prophylaxis in HIV?

CD4 count <50 cells/mL AND not receiving ART, or detectable HIV RNA viral load on ART, or no options for a fully suppressive ART regimen

When is MAX primary prophylaxis in HIV NOT recommended?

If starting effective ART immediately

What is the preferred therapy for primary prophylaxis in HIV with MAC?

• Azithromycin PO once weekly or twice weekly

• clarithromycin PO BID

What is the alternative therapy for primary prophylaxis in HIV with MAC?

Rifabutin PO daily

• check for TB first and drug interactions

What should you rule out first prior to starting MAC prophylaxis in HIV?

disseminated MAC

obtain mycobacterial blood cultures

When should you d/c MAC prophylaxis in HIV?

once on effective ART

What is the preferred therapy for MAC treatment in HIV?

• 2 or more drugs to prevent resistance

  • azithromycin + ethambutol

  • clarithromycin + ethambutol

What additional drugs can be considered in MAC treatment in HIV if profound immunosuppression or severe/high-burden disease?

• rifabutin

• amikacin

• streptomycin

• levofloxacin or moxifloxacin

Duration of MAC treatment in HIV

• >12 months and d/c if asymptomatic and CD4 count >100 cells/mL for >6 months

• Start ART ASAP

What is cryptococcus neoformans?

encapsulated environmental yeast found in bird droppings, soil, and decaying wood

How is Cryptococcus neoformans transmitted?

inhalation of infectious propagules

Sub-acute presentation of cryptococcal meningoencephalitis

• fever, malaise HA

• meningeal signs

• encephalopathic symptoms from increased intracranial pressure

  • lethargy, altered mentation, memory loss

CSF findings consistent with cryptococcal meningoencephalitis

• pleocytosis

• increased protein, low-normal glucose

• opening pressure often elevated (> 25 cm H2O in 60-80%)

How is cryptococcal meningoencephalitis diagnosed?

• Culture (CSF, sterile sites)

• Cryptococcal antigen (CrAg)

IS CSF CrAg or serum CrAg highly sensitive in meningoencephalitis?

CSF

What do you do when you get a + serum CrAg?

lumbar puncture to rule out CNS disease

What antifungals are used for cryptococcal meningoencephalitis?

• amphotericin B

• Flucytosine

  • Amphotericin + flucytosine = rapid fungal clearance

• Fluconazole

  • consolidation and long-term suppression

Pearls of amphotericin B

• binds ergosterol

• nephrotoxicity

• decreased K+ and Mg2+

• infusion rxns

• disrupts fungal cell membrane

Pearls of flucytosine

• Converted within fungal cells to metabolites that disrupt DNA/RNA synthesis

• PO use in combo

• bone marrow suppression

• renally eliminated

Pearls of fluconazole

• Inhibits ergosterol synthesis

• PO/IV have excellent bioavailability and CSF penetration

• hepatotoxicity + drug interactions

What are the stages of cryptococcal meningoencephalitis treatment?

1. Induction (>2 weeks)

2. Consolidation (next 8 weeks)

3. Maintenance (>12 months)

Therapy for induction phase for cryptococcal meningoencephalitis

• liposomal amphotericin B (high dose) x 1 + flucytosine x 14 days + fluconazole QD x 14 days

• liposomal amphotericin B (high dose) x 1 + flucytosine x 14 days

• Monitor CBC, electrolytes, and renal function

• Flucytosine - monitor therapeutic drug monitoring if needed

Therapy for consolidation AND maintenance phase for cryptococcal meningoencephalitis

Fluconazole daily

When do you d/c therapy for cryptococcal meningoencephalitis?

• Completed>12 months of maintenance therapy

• asymptomatic

• CD4 count >100 cells/mL for >3 months on ART with virologic suppression

How do we time ART for cryptococcal meningoencephalitis treamtnet?

• delay until after induction

• sometimes defer until after consolidation

True or false: with cryptococcal meningoencephalitis, early initiation of ART worsens outcomes and increases risk of death

true

What medications are NOT effective in intracranial pressure in cryptococcal meningoencephalitis?

• glucocorticoids

• mannitol

• acetazolamide

How do we mitigate nephrotoxicity with amphotericin B?

IV saline pre- and post-infusion

replace electrolytes

How do we help with amphotericin B infusion reaction symptoms?

Pre-medicate with APAP, Benadryl, hydrocortisone

Meperidine for rigors