OPPORTUNISTIC INFECTIONS

• Infections occurring in immunocompromised patients either AIDS or in medically induced immunosuppression.

• In the latter they are temporary but in AIDS the infection is progressive.

THERAPY

• AIDS-different pathophysiology and may require a different therapeutic approach.

• AIDS patients - do not tolerate medications well.

• Increased likelihood of drug interactions in AIDS.

PNEUMOCYSTIS PNEUMONIA (PCP)

PNEUMOCYSTIS PNEUMONIA (PCP)

• The most common opportunistic infection in advanced AIDS (80% of AIDS patients have at least one episode).

• Pneumocystis juroveci.

• Multiple infections are often present simultaneously with the PCP.

PROPHYLAXIS

• Routine prophylaxis has been successful in improving survival.

• PCP prophylaxis is indicated if the patient has a CD4 T lymphocyte count lower than 200 cells/mm3, or has oral candidiasis regardless of the CD4 count.

<200 cells/mm3

DRUGS FOR PROPHYLAXIS

• TMP/SMX- DOC for prevention (used orally).

• DOC for treatment (IV).

TOXICITY

• More common in AIDS patients than in others (dose reduction often eliminates some).

TOXICITY

• Rash (including Stevens-Johnson syndrome).

TOXICITY

• Nausea and fever.

• Bone marrow suppression.

ALTERNATE THERAPY

• For those who can’t tolerate trimethoprim-sulfamethoxazole.

DAPSONE

• A sulfone.

• Dapsone and dapsone+pyrimethamine (and leucovorin) appear to be the most effective alternatives.

MECHANISM OF ACTION

• It is a dicationic diamidine.

• Exact mechanism of action is unknown. It has multiple effects.

– May react with a variety of negatively charged intracellular targets such as phospholipids, enzymes and RNA and DNA.

– Inhibitor of type II topoisomerase as well as ATPase.

PHARMACOKINETICS

• Poorly absorbed from the GI tract and thus is usually given IV (or IM).

• IV pentamidine is given by slow (1-2h) infusion in 5% glucose as a single dose/day.

• Fairly well absorbed from parenteral sites despite the formation of sterile abscesses.

PHARMACOKINETICS

• It achieves therapeutic levels in the lung slowly (5-7 days) due to high levels of extrapulmonary tissue binding.

• Also available as an aerosol which shows little systemic absorption.

PENTAMIDINE AEROSOL

• No longer recommended for routine prophylaxis against PCP but is reserved for those few individuals who can’t tolerate systemic therapy with more effective agents.

DISADVANTAGES OF THE AEROSOL

• Aerosolized pentamidine lacks efficacy against extrapulmonary infections with P.jurevici and it induces an increased incidence of pneumothorax.

• Not well distributed to all lobes of the lungs.

• More expensive than oral regimens.

ADVERSE EFFECTS

• IV- breathlessness, tachycardia, dizziness or fainting, headache or vomiting.

• Pain at the site of IM injection along with erythema and formation of sterile abscesses.

ADVERSE EFFECTS

• Pancreatitis, hypoglycemia and hyperglycemia.

ATOVAQUONE

TREATMENT OF PCP

• Start therapy early (success is related to severity of the disease at the time of initiation of therapy).

• Therapy is individualized (to reflect the immune deficit, tolerance of specific drugs, geographic location and the medical institution).

TMP-SMX

• Treatment of choice.

• Oral (for mild-moderate cases or after initial response to IV therapy and for prophylaxis).

TMP-SMX

• Excellent tissue penetration.

• Produces a rapid clinical response.

ALTERNATE THERAPIES

• Dapsone (+/- pyrimethamine)

• Atovaquone- better tolerated than cotrimoxazole but has unreliable absorption.

• Clindamycin plus primaquine- in mild to moderate infection.

PCP-ALTERNATE THERAPY

• Trimetrexate with folinic acid –for moderate to severe PCP.

• Pentamidine (alternative parenteral agent for the treatment of moderate to severe PCP).

ADJUNCT THERAPY-STEROIDS

• Prednisone-used for moderate to severe PCP and in patients started with anti-PCP therapy.

• Increases survival and prevents development of acute respiratory failure.

TOXOPLASMOSIS

• Caused by Toxoplasma gondii, an intracellular protozoan.

• It is found worldwide and is transmitted orally.

TOXOPLASMOSIS

TOXOPLASMOSIS

• Many people have asymptomatic infections that can have serious consequences in the immunosuppressed.

• Toxoplasmic encephalitis in AIDS.

PROPHYLACTIC THERAPY

• Cotrimoxazole (when the CD4 count <200 cells/mm3).

STANDARD THERAPY

• Pyrimethamine plus sulfadiazine is the treatment of choice for CNS toxoplasmosis.

• Folinic acid is usually given concurrently.

• Standard therapy is often not well tolerated by AIDS patients (50% experience adverse effects).

ALTERNATE THERAPIES

• Clindamycin plus pyrimethamine.

• Azithromycin, clarithromycin, atovaquone.

ADVERSE REACTIONS

• Nausea and headaches.

• Hematological effects: gradual but reversible depression of bone marrow.

• Allergic reactions (when combined with a sulfonamide).

Herpes simplex and Varicella-Zoster Virus Infections

• Common pathogens in HIV-infected patients.

• Severe and prolonged mucocutaneous Herpes virus infections have been reported in AIDS patients.

• Lesions are more frequent, larger and more painful.

TREATMENT

• For mucocutaneous HSV infections treatment is similar to that in the non-immunocompromised.

TREATMENT

• Acyclovir is used but valacyclovir and famciclovir are often preferred for Herpes zoster because of pharmacokinetic reasons.

ACYCLOVIR

• Oral or IV ACV decreases duration and severity of primary varicella or disseminated VZV infection in AIDS and prevent recurrences.

ACYCLOVIR

• Adverse effects include nausea, headache and reversible renal dysfunction with high doses.

• Emergence of resistance is increasingly common in AIDS patients.

USE IN HIV

• In AIDS patients with acyclovir-resistant HSV and VZV infections.

ADVERSE EFFECTS

• Renal toxicity, anemia, nausea, hypokalemia, hypocalcemia, and hypo- and hyperphosphatemia.

VALACYCLOVIR

• Prodrug of acyclovir with better oral bioavailability.

FAMCICLOVIR

• Diacetylester prodrug of penciclovir.

• Similar spectrum of activity to acyclovir.

• Inhibits DNA synthesis.

• Well absorbed orally and rapidly converted to penciclovir.

FAMCICLOVIR

• Used for treating HSV and VZV infections.

• Adverse effects include headache, diarrhea and nausea.

CYTOMEGALOVIRUS INFECTIONS

• In the general population CMV is common and generally benign.

• In AIDS it is severe and can cause considerable morbidity and mortality.

• Site-threatening in HIV- infected patients and a major infectious disease after transplantation.

• CMV retinitis, GI disease and CNS involvement.

TREATMENT OF CMV

• Induction therapy interrupts the ongoing tissue destruction and maintenance therapy prevents relapse.

• Maintenance therapy for CMV disease other than retinitis is controversial.

• Ganciclovir and Foscarnet

CMV TREATMENT

• Although neither ganciclovir nor foscarnet is curative both are equally effective in halting progression.

• Cidofovir-promising alternative.

• Fomiversen.

TOXICITY

• Dose limiting toxicities are frequently observed during treatment.

• The primary toxicities are hematological for ganciclovir and renal for foscarnet and cidofovir.

FUNGAL INFECTIONS

• Advanced AIDS is often complicated by severe fungal infections which may be life-threatening.

• Good response to primary treatment but the relapse rate is very high.

MUCOSAL CANDIDIASIS

• Candidal infections (oral and vaginal) are one of the most prevalent fungal infections in AIDS patients (occurs in 90% of patients at some time).

• Primary prophylaxis is usually not recommended.

OTHER COMMON AND SERIOUS FUNGAL

INFECTIONS IN AIDS• Cryptococcosis

• Histoplasmosis

• Aspergillosis

MUCOSAL CANDIDIASIS-TREATMENT

• Nystatin or clotrimazole-topical therapy, effective for oral thrush, decreases occurrences.

• Fluconazole and itraconazole

• Caspofungin

CLOTRIMAZOLE

• Imidazole derivative.

• Broad spectrum activity.

• Pharmacokinetics and toxicity limit use to topical therapy.

TREATMENT OF SYSTEMIC MYCOSES

• Amphotericin B-standard treatment for systemic fungal infections in AIDS.

• Flucytosine plus amphotericin B

• Fluconazole,itraconazole,voriconazole

• Caspofungin

MYCOBACTERIUM TUBERCULOSIS

• Now a common HIV-related opportunistic infection.

• Very aggressive disease in HIV-infected people.

• Responds well to standard therapy when started promptly.

PROPHYLAXIS

• All HIV-infected patients with a positive tuberculin reaction should take at least one year of isoniazid (INH) for prophylaxis (plus pyridoxine).

• Rifampin plus pyrazinamide.

THERAPY

• Use four drugs.

• INH, rifampin, pyrazinamide plus ethambutol or streptomycin.

• Continue therapy for at least nine months.

THERAPY

• Directly observed therapy is strongly recommended

• Rifampin should not be used if patient is taking protease inhibitors or NNRTIs. (Rifabutin is a less potent inducer).

THERAPY

• For multiple drug resistance the therapeutic options are limited.

• Use an initial 5 or 6 drug regimen.

MYCOBACTERIUM AVIUM COMPLEX (MAC)

• Rarely encountered before the AIDS epidemic (common in HIV).

PROPHYLAXIS

• To reduce the significant morbidity and mortality associated with disseminated MAC.

• First line---Clarithromycin or azithromycin

• Second line---Rifabutin or rifabutin plus azithromycin.

TREATMENT

• Difficult because of resistance to most anti-T.B. drugs.

• Multiple drugs are necessary to overcome intrinsic resistance.

• Treatment of choice is now rifabutin, ethambutol and clarithromycin.

TREATMENT

• Azithromycin is also effective.

• Regimens are suppressive and not curative so continue therapy indefinitely.

RIFABUTIN

• Mechanism of action- Inhibition of DNA-dependent RNA polymerase.

• More active vs. MAC than rifampin.

• Pharmacokinetics---well absorbed from GI tract.

ADVERSE EFFECTS

• Rash.

• GI Distress.

• Neutropenia.

• Uveitis and arthralgias have occurred in patients receiving high doses.

• It can decrease AZT plasma levels.

CLARITHROMYCIN OR AZITHROMYCIN

• Treatment of infection due to MAC (used in combination).

• Clarithromycin or Azithromycin are now considered the drugs of choice for prophylaxis against MAC (in patients with CD4 counts <50/mm3).

ADVERSE EFFECTS

• Primarily GI disturbances.

• They are used in high doses so tinnitus, dizziness and reversible hearing loss occasionally have occurred.

PCP Trimethoprim-Sulfamethoxazole

Toxoplasmosis Trimethoprim-Sulfamethoxazole

HS virus infections Acylcovir, valacyclovir, foscarnet

CMV infections Ganciclovir, foscarnet

Fungal infections Amphotericin B,flucytosine, fluconazole, itraconazole

T.B. INH, rifampin or rifabutin, pyrazinamide + ethambutol or streptomycin

MAC Rifabutin, ethambutol and clarithromycin

DRUGS OF CHOICE FOR OPPORTUNISTIC INFECTIONS