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
