Opportunistic Infections

What are opportunistic infections?

They are infections that emerge when host defenses are impaired

What are the major populations for opportunistic infections

1. HIV - advanced or untreated

2. Solid organ or stem cell transplants

3. Hematologic malignancy

4. Chemotherapy

5. Biologic/Immunosuppressive therapy

6. Systemic glucocorticoids

Which pathogens did we focus on for opportunistic infections?

1. Pneumocystis jirovecii (PJP)

2. Toxoplasma gondii

3. Mycobacterium avium complex (MAC)

4. Cryptococcus neoformans

What is Pneumocystis jirovecii (PJP)?

an opportunistic fungus with protozoan characteristics

what is the preferred regimen in both HIV and Non-HIV PJP prophylaxis?

Bactrim

PJP prophylaxis in HIV vs Non-HIV

In HIV: need to establish CD4 and viral response. Immune recovery on ART allows discontinuation

Non-HIV: no universal threshold and duration is tied to immunosuppression/risk

Can you apply HIV CD4 thresholds to non-HIV patients?

No

PJP primary prophylaxis in HIV is indicated for who?

1. Patient NOT receiving or starting ART —> with CD4 < 200 cells/uL

2. Patient IS receiving ART —> CD4 count < 100 cells/uL, regardless of HIV RNA viral load, or CD4 count 100–200 cells/µL with detectable HIV RNA

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

Preferred Therapy: TMP/SMX 1 DS PO daily (or 1 SS PO daily), which provides the additional benefit of cross-protecting against Toxoplasma gondii

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

Alternative therapy:

1. TMP/SMX 1 DS PO 3x/week

2. Dapsone *assess G6PD status before starting

3. Aerosolized pentamidine via Respigard II nebulizer monthly

4. Atovaquone

What is the discontinuation criteria for PJP primary prophylaxis in HIV?

1. Discontinue when the CD4 count is ≥ 200 cells/µL for ≥ 3 months on ART

2. Discontinue if the CD4 count is 100–200 cells/µL with suppressed HIV RNA for ≥ 3–6 months

When should you consider PJP prophylaxis outside of HIV? what are the strongest indications?

What is the preferred and alternative therapy for Mild to Moderate PJP treatment outside of HIV

Preferred: Bactrim Oral

Alternative: Primaquine + Clindamycin (check G6PD deficiency for Primaquine) OR use Atovaquone

What is the preferred and alternative therapy for Moderate to Severe (PaO2 < 70 or A-a gradient > 35 mmHg) PJP treatment outside of HIV

Preferred: IV Bactrim initially, then switch to oral when improved

Alternative: Primaquine + Clindamycin (check G6PD deficiency for Primaquine) OR use Pentamidine IV

What is the duration of treatment for PJP outside of HIV

21 days (consider secondary prophylaxis after treatment)

The defined 21-day adjunctive oral prednisone taper (initiated within 72 hours for PaO2 < 70 or an A-a gradient > 35mmHg) is specifically designated for patients with _____

HIV

In ________ patients there is no universal CD4 threshold

non-HIV patients

** the decision to continue or stop secondary prophylaxis is tied entirely to the patient’s net state of immunosuppression and ongoing immunosuppressive therapy

What is Toxoplasma gondii?

Ubiquitous intracellular protozoan parasite

How is Toxoplasma gondii transmitted?

1. undercooked meat (tissue cysts)

2. cat feces

less commonly through transfusion, transplant or trasnplacental

_________ disease usually occurs from reactivation of latent cysts (meaning not a new infection but from reactivation of latent tissue cysts already present in the body)

Toxoplasma gondii

_________ is a major manifestation of Toxoplasma gondii

Toxoplasmic Encephalitis

A CD4 count below _________ represents severe immunosuppression, carrying the highest risk for the reactivation of latent Toxoplasma gondii in patients with HIV

< 50 cells/µL

Central nervous system (CNS) disease—specifically __________—is the primary clinical presentation in HIV

Toxoplasmic Encephalitis (TE)

When recognizing Toxoplasmic Encephalitis (TE), patients with Advanced HIV and Focal encephalitis present with what symptoms?

Headache, confusion, motor weakness and fever

Focal neurologic deficits ± seizures

What tests help us identfiy Toxoplasmic Encephalitis (TE), we use what?

1. CT/MRI imaging → multiple contrast-enhancing brain lesions, frequently accompanied by surrounding vasogenic edema

2. Serology → Patients are usually seropositive for Toxoplasma IgG; a negative IgG antibody result makes a diagnosis of TE substantially less likely

If IgG is _______, Toxoplasmic encephalitis is very unlikely but not completely impossible

negative

Toxoplasmosis primary prophylaxis in HIV is indicated for which patients?

Toxoplasma IgG positive and CD4 count <100 cells/uL

what is the preferred therapy for Toxoplasmosis primary prophylaxis in HIV

Bactrim 1 DS PO daily

Advantage: This regimen simultaneously provides primary prophylaxis against Pneumocystis jirovecii pneumonia (PJP)

what is the alternative therapy for Toxoplasmosis primary prophylaxis in HIV

• TMP/SMX 1 DS PO 3 times weekly

• TMP/SMX 1 SS PO daily

• Atovaquone (for patients intolerant to TMP/SMX)

What is the discontinuation criteria for Toxoplasmosis primary prophylaxis in HIV

• CD4 count > 200 cells/uL for > 3 months on ART

• Can also be considered if the CD4 count is 100–200 cells/µL with suppressed HIV RNA for ≥ 3–6 months

What is the preferred therapy for Acute treatment of Toxoplasmosis in HIV?

Pyrimethamine + Sulfadiazine + Leucovorin (weight-based)

Why do we add Leucovorin?

To reduce pyrimethamine-associated bone marrow toxicity and myelosuppression

What is the alternative therapy for Acute treatment of Toxoplasmosis in HIV?

Bactrim IV or PO

(if pyrimethamine is unavailable or intolerant)

Acute treatment of Toxoplasmosis in HIV must continue for ________, after which the patient transitions to chronic maintenance therapy

≥ 6 weeks

Initiate ART within __________ of starting acute toxoplasmosis therapy when feasible

~2–3 weeks

When do we start Chronic maintenance therapy for Toxoplasmosis in HIV

Following successful completion of the acute ≥6-week treatment course, patients require suppressive maintenance therapy to prevent relapse until immune reconstitution occurs

What is the preferred therapy for Chronic maintenance for Toxoplasmosis in HIV?

Preferred: Pyrimethamine + Leucovorin + Sulfadiazine

(provides PJP prophylaxis)

What is the alternative therapy for Chronic maintenance for Toxoplasmosis in HIV?

• Alternative: Pyrimethamine + Leucovorin + Clindamycin

  • (requires another agent for PJP prophylaxis)

• TMP/SMX DS: 1 tablet once or twice daily

Discontinue chronic maintenance therapy for Toxoplasmosis in HIV only when all three criteria are met:

1. completed intial therapy

2. Asymptomatic

3. CD4 count > 200 cells/uL for > 6months on ART

What is Mycobacterium avium complex?

A group of NON-Tuberculosis mycobacteria comprising M. intracellulare and M. avium

MAC organisms are widely distributed in the environment, with primary reservoirs including _______

water, soil, and animals

How does MAC transmission occur?

Inhalation, ingestion, or direct inoculation through the respiratory and gastrointestinal tracts

T/F: Unlike Mycobacterium tuberculosis, MAC is not spread person-to-person

True

Which distinct clinical syndromes does MAC cause?

** Depending on the patient's underlying host defenses

1. Pulmonary → COPD, CF, prior Pneumonia, chronic glucocorticoids, older women without recognized risk factors

2. Lymphadenitis → mainly children < 5 years

3. Disseminated→ Occurs in patients with advanced or untreated HIV with a CD4 count < 50 cells/µL

What clinical manifestations are seen with Disseminated MAC?

• Systemic symptoms: Persistent high fever, night sweats, unintentional weight loss, and profound fatigue

• Gastrointestinal symptoms: Diarrhea and abdominal pain

• Physical examination findings: Hepatomegaly, splenomegaly, and diffuse lymphadenopathy

what are laboratory abnormalities for Disseminated MAC?

Anemia, leukopenia, and increased alkaline phosphatase.

what is used to diagnose MAC?

Diagnosis requires compatible signs and symptoms alongside isolation of MAC in culture from blood, bone marrow, lymph nodes, or another sterile body tissue/fluid

What is the indication for MAC Primary prophylaxis in HIV?

Indicated only when: The CD4 count is < 50 cells/µL AND the patient is not currently receiving ART, has a detectable HIV RNA viral load while on ART, or has no available options for a fully suppressive ART regimen

What is MAC Primary prophylaxis NOT recommended in HIV?

Not recommended if starting effective ART immediately

What mandatory workup should you perform before MAC primary prophylaxis in HIV?

Rule out active, disseminated MAC (including obtaining baseline mycobacterial blood cultures) before starting prophylactic therapy to avoid under-treating occult disease and driving macrolide resistance

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

Preferred:

Azithromycin PO once weekly

Azithromycin PO twice weekly

Clarithromycin PO BID

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

Alternative:

Rifabutin PO daily

**requires ruling out active TB beforehand and carefully screening for CYP-mediated drug interactions

MAC primary prophylaxis can be discontinued when?

once the patient is established on effective ART

MAC treatment in HIV requires combination therapy with at least two antimicrobials. Why?

to prevent drug resistance

What is the preferred therapy for MAC treatment in HIV (a.k.a treatment of Disseminated MAC)

Preferred: Macrolide + Ethambutol

1. Azithromycin + Ethambutol

2. Clarithromycin + Ethambutol

What are additional (not alternative) therapies for MAC treatment in HIV (a.k.a. treatment of Disseminated MAC)

Rifabutin, an injectable aminoglycoside (Amikacin or Streptomycin), or a Fluroquinolone (Levofloxacin or Moxifloxacin)

When should you consider adding additional drugs to MAC treatment in HIV?

for patients with severe or high-burden disease or profound immunosuppression

What is the duration of therapy for MAC treatment in HIV?

For > 12 months

When can therapy be discontinued for MAC treatment in HIV?

Therapy can only be discontinued once the patient has completed ≥ 12 months of therapy, is completely asymptomatic, and maintains a CD4 count > 100 cells/µL for > 6 months on effective ART

DO NOT give _______ if the patient is starting ART immediately

MAC primary prophylaxis

If your patient is on MAC treatment in HIV (a.k.a Disseminated MAC), when should ART therapy be started?

start ART as soon as possible for patients with MAC

How do you decide whether to start primary prophylaxis for MAC or active treatment for MAC (Disseminated MAC)

Are there hallmark features of active disseminated MAC?

• Systemic symptoms: High persistent fever, drenching night sweats, profound fatigue, unintentional weight loss,

• Gastrointestinal/Organ involvement: Abdominal pain, chronic diarrhea, hepatosplenomegaly, or diffuse lymphadenopathy^.

• Laboratory abnormalities: Anemia out of proportion to the stage of HIV, leukopenia, and markedly elevated alkaline phosphatase.

• Microbiology: Isolation of MAC from blood or another sterile site (e.g., positive mycobacterial blood cultures).

**Do not just look for a CD4 count < 50 only

What is cryptococcus neoformans?

Encapsulated environmental yeast and ubiquitous

Where is Cryptococcus neoformans found?

bird droppings, soil and decaying wood

How is Cryptococcus neoformans transmitted?

Through inhalation of infectious propagules

What populations are at risk for Cryptococcus neoformans infections?

• Advanced HIV

• Solid organ transplants

• Glucocorticoids and other immunosuppressive therapies

• Malignancy and other immune disorders

• Paients without recognized immunocompromising conditions can also occasionally develop cryptococcal disease

What is the path of disease progression for Cryptococcus neoformans infections?

Pulmonary infection —> Disseminated disease —> CNS involvement

How does Cryptococcus neoformans infections present clinically?

• Common Symptoms: Fever, malaise, and headache

• Atypical Feature: Classic meningeal signs (neck stiffness, photophobia) are present in only 25% to 33% of patients

• Elevated Intracranial Pressure (ICP) Signs: Encephalopathic manifestations resulting from elevated ICP include lethargy, altered mentation, and memory loss

Diagnosis of Cryptococcus neoformans infections is done how?

• Lumbar Puncture (LP) & CSF Analysis:

  • Opening pressure: often elevated (>25cm H2O)

  • Pleocytosis (which may be minimal in advanced HIV), mildly elevated protein, and low-to-normal glucose.

• Cryptococcal Antigen (CrAg) Testing:

  • CSF CrAg: Highly sensitive for diagnosing cryptococcal meningoencephalitis.

  • Serum CrAg: Positive in the majority of cases and can precede clinical symptoms

  • Clinical rule: A positive serum CrAg mandates a lumbar puncture to evaluate for and rule out CNS involvement24.

• Fungal Culture: Definitive isolation from CSF, blood, or other sterile sites confirms the diagnosis

What Antifungals are used for Cryptococcosis?

Amphotericin B

Flucytosine

Fluconaozle

Amphotericin B MOA

binds ergosterol —> disrupts fungal cell membrane

Flucytosine MOA:

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

Fluconazole MOA:

-azole that inhibits ergosterol synthesis

Which antifungal is given both IV and PO?

Fluconazole

Which antifungal is given only as IV?

Amphotericin B

Which antifungal is given only orally?

Flucytosine

Which antifungal has nephrotoxicity, decreased K and Mg, and infusion reactions?

Amphotericin B

Which antifungal has bone marrow suppression risk and is renally eliminated and is used in combination because resistance develops when given as monotherapy?

Flucytosine

Which antifungal has excellent bioavailability and CSF penetration, is well tolerated, but has a risk of hepatotoxicity and drug interactions

Fluconazole

__________ —> rapid fungal clearance

___________ —> consolidation and long-term suppression

Amphotericin —> rapid fungal clearance

Fluconazole —> consolidation and long-term suppression

Cryptococcal meningoencephalitis treatment in HIV are what three phase regimens and what is their durations?

Induction ( > 2 weeks) *most intensive phase

Consolidation (next 8 weeks)

Maintenance ( > 12 months)

what is the regimen used in the Induction phase for Cryptococcal meningoencephalitis treatment in HIV?

Inudction Phase:

1. Liposomal Amphotericin B (high dose) x 1 dose + Flucytosine x 14 days + Fluconazole (High dose) daily x 14 days

2. Liposomal Amphotericin B IV daily x 14 days + Flucytosine x 14 days

what is the regimen used in the Consolidation phase for Cryptococcal meningoencephalitis treatment in HIV?

Fluconazole (high dose) daily

what is the regimen used in the Maintenance phase for Cryptococcal meningoencephalitis treatment in HIV?

Fluconazole daily (lower dose)

What is the discontinuation criteria for Cryptococcal meningoencephalitis treatment in HIV?

1. Completed > 12 months of maintenance therapy

2. Asyptomatic

3. CD4 count > 100cells/uL for > 3 months on ART with virologic suppression

What should you consider for ART timing in Cryptococcal meningoencephalitis treatment in HIV?

Antiretroviral therapy must be delayed until after the induction phase (at least 2 weeks), and may be deferred until after consolidation (~10 weeks)

Increased ________ can lead to rapid clinical deterioration despite effective microbiologic killing by antifungals

intracranial pressure

An opening pressure ______ defines significant risk of cryptococcal meningoencephalitis

> 25cm H2O

what are effective management interventions for increased intracranial pressure in cryptococcal meningoencephalitis?

Check opening pressure at initial diagnosis and perform therapeutic repeat lumbar punctures as needed to relieve pressure. Refractory cases require CSF diversion or surgical shunting

What medications would be ineffective for intracranial pressure control in cryptococcal meningoencephalitis?

Glucocorticoids, Mannitol and Acetazolamide would be inneffective

Nephrotoxicity from Amphoetericin B can be mitigated with what?

Mitigate by administering IV normal saline hydration pre- and post-infusion. Replacing electrolytes with Mg or K

Infusion Reactions (fever, chills, headache, vomiting) due to Amphotericin B can be premedicated with what?

Premedicate with Acetaminophen, Diphenhydramine, and Hydrocortisone. **Administer meperidine for rigors

What should you monitor with Flucytosine?

Monitor CBC closely for myelosuppression, track renal function, and use therapeutic drug monitoring (TDM) when available