Transcript Opportunistic Infections

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 THERAPYSTEROIDS
• Prednisone-used for moderate to severe
PCP and in patients started with antiPCP 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 VaricellaZoster 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 nonimmunocompromised.
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 hypoand 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 CANDIDIASISTREATMENT
• 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 DNAdependent 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.
DRUGS OF CHOICE FOR OPPORTUNISTIC INFECTIONS
PCP
Toxoplasmosis
Trimethoprim-Sulfamethoxazole
Trimethoprim-Sulfamethoxazole
HS virus infections
Acylcovir, valacyclovir, foscarnet
CMV infections
Ganciclovir, foscarnet
Fungal infections
Amphotericin B,flucytosine,
fluconazole, itraconazole
INH, rifampin or rifabutin,
pyrazinamide + ethambutol or
streptomycin
Rifabutin, ethambutol and
clarithromycin
T.B.
MAC