Professional Documents
Culture Documents
HIV/INFECTIOUS DISEASES
CURTIS L. SMITH, PHARM.D., BCPS
FERRIS STATE UNIVERSITY
LANSING, MICHIGAN
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HIV/Infectious Diseases
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A. Fluconazole 200 mg/day orally. 9. P.I. is a 35-year-old woman who presents to the
B. Amphotericin B 0.3 mg/kg/day alone. clinic with a 2-week history of night sweats,
C. Amphotericin B 0.3 mg/kg/day plus fatigue, weight loss, and a persistent cough. A
flucytosine 37.5 mg/kg every 6 hours. purified protein derivative (PPD) is placed, and
D. Amphotericin B 0.7 mg/kg/day plus a sputum sample is taken; then, P.I. is sent home
flucytosine 25 mg/kg every 6 hours for 2 with a prescription for levofloxacin 750 mg/day
weeks, followed by fluconazole 400 mg/day. orally. Two days later, her PPD is measured at
20-mm induration, and her sputum sample is posi-
6. A study is performed to compare the incidence of tive for acid-fast bacilli. P.I., who has no pertinent
active tuberculosis (TB) infection in patients re- medical history, has never been outside the United
ceiving isoniazid (INH) versus rifampin (RIF) for States. He lives in an area with an extremely low
latent TB infection. After completion of therapy incidence of multidrug-resistant TB. Which of the
(6 months for INH and 4 months for RIF), 0.3% in following is the best therapy for P.I.?
the INH group and 0.8% in the RIF group prog- A. INH 300 mg/day orally for 6 months.
ress to active disease. Which one of the following B. INH, RIF, pyrazinamide (PZA), and
represents how many patients would need to be ethambutol (EMB) for 2 months, followed by
treated with INH over RTF to prevent one progres- INH and RIF for 4 more months.
sion to active disease? C. INH and RIF for 6 months.
A. 5. D. Levofloxacin 750 mg/day orally for both LB
B. 50. and other bacterial causes of pneumonia.
C. 200.
D. Insufficient information to calculate 10. A prospective, double-blind study compared the
this number. effects of two therapies—a potent combination
antiretroviral therapy with a ritonavir-boosted
7. G.T. is a 34-year-old woman positive for HI V who protease inhibitor and a potent combination anti-
is brought to the emergency department by her retroviral therapy with efavirenz—in 350 patients
boyfriend after experiencing headaches, a change in with HIV. Which one of the following statistical
mental status, and loss of feeling on her right side. A tests should be used to compare end points such as
computed tomographic scan shows two large ring- the mean change in viral load or mean change in
enhancing lesions in 3 her brain. Her most recent CD 4 counts?
CD 4 count was 85/mm , but that was 4 months ago. A. Analysis of variance.
She currently takes no antiretroviral agents but B. Chi-square test.
takes dapsone for Pneumocystis pneumonia (PCP) C. Student's t-test.
prophylaxis. Which one of the following therapies D. Wilcoxon rank sum test.
should be used to treat G.T.?
A. Atovaquone for 4-6 weeks.
B. High-dose trimethoprim-sulfamethoxazole (TMP/
SMX) plus clindamycin for 6 weeks.
C. Pyrimethamine plus sulfadiazine for 6 weeks.
D. Pyrimethamine plus clindamycin and
leucovorin for 6 weeks.
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2. Western blot
a. Confirms ELISA
b. False-positive: 1 in 20,000
c. False-negative: 1 in 250,000
3. Rapid HIV tests
a. OraQuick Advance: finger-stick, whole blood, or oral fluid
b. Uni-Gold Recombigen: finger-stick or whole blood
c. Reveal G2, Multispot HIV-l/HIV-2: serum or plasma
4. Test for HIV RNA
a. Detects HIV RNA in serum (tests for the virus, not for antibodies)
b. Branched-chain DNA, VERSANT, and Quantiplex (Bayer)
i. Signal amplification
ii. Sensitive to 75 copies/mL of HIV RNA
c. Reverse transcriptase-polymerase chain reaction, Amplicor HIV-1 Monitor (Roche)
i. Sensitive to 50 copies/mL of HIV RNA
d. Nucleic acid sequence-based amplification (NASBA), NucliSens (Organon Teknika)
i. Sensitive to 40 copies/mL of HIV RNA
e. Values expressed as copies of HIV RNA per milliliter or the log of copies of HIV RNA per
milliliter
f. Changes greater than 3-fold (about 0.5 log) are clinically significant.
5. Use of HIV RNA testing
a. Acute HIV infection (diagnosis is received sooner than with older tests)
b. Newly diagnosed HIV infection (for baseline value to follow)
c. Every 3-4 months without therapy
d. From 2 to 4 (no more than 8) weeks after starting or changing therapy (should detect a
significant decrease)
e. From 3 to 4 months after starting therapy (change therapy if decrease is limited)
f. Every 3-4 months while on therapy (checking for increase—therapy failure)
g. Whenever there is a clinical event or decrease in CD 4 count
6. Who should be screened for HIV?
a. All patients aged 13-64 years (in all health care settings)
b. Adults and adolescents at increased risk of HIV infection should be checked annually
(intravenous drug users, those who have unprotected sex with several partners, men
who have sex with men, men or women who have sex for money or drugs, people
being treated for sexually transmitted diseases, recipients of several blood transfusions
1975-1985)
c. Pregnant women
7. Case definition for HIV - 2008 (Table 2)
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2. Progression of HIV
a. Human immunodeficiency virus replicates actively at all stages of the infection.
b. From 109 to 1010 virions are produced every day.
c. Half-life of virions is about 6 hours.
3. Immunization of patients with HIV (no live virus vaccines if CD 4 count is less than 200/mm3)
a. Influenza virus vaccine: annually (before the influenza season)
b. Pneumococcal vaccine: once (ideally, before CD 4 count is less than 200/mm3)
c. Hepatitis B vaccine: for all susceptible patients
d. Hepatitis A vaccine: for all at-risk patients
D. Treatment of HIV
1. Reverse transcriptase inhibitors (RTIs) (nucleoside [NRTI], nucleotide, and
nonnucleoside [NNRTI])
a. Reverse transcriptase: enzyme required to copy viral RNA to DNA
b. Dideoxynucleoside analogs: inserted in growing DNA chain, terminating elongation
c. See Tables 4 and 5 for RTI characteristics.
d. Nonnucleoside NRTIs and nucleotide RTIs do not require phosphorylation.
2. Protease inhibitors
a. See Table 6 for protease inhibitor characteristics.
3. Entry inhibitors
a. Fusion inhibitors: enfuvirtide (Fuzeon); a.k.a.: T-20 and pentafuside
i. Mechanism of action: HIV envelope protein gpl20 binds to the cell's CD 4 receptor,
resulting in exposure of chemokine coreceptors on the cell; attachment of gpl20
to CD 4 receptor and coreceptors CCR5 or CXCR4 results in exposure of specific
peptide sequence of gp 41; enfuvirtide binds to this gp 41 peptide sequence,
preventing fusion.
ii. Indications - treatment-experienced patients with HIV infection
iii. Adverse effects — hypersensitivity reactions; local injection-site reactions
(98%); pneumonia
iv. Drug interactions - none
v. Dosing - 90 mg (1 mL) 2 times/day subcutaneously (reconstitution required)
b. CCR5 antagonist: maraviroc (Selzentry)
i. Mechanism of action: binds to the CCR5 receptor of the CD 4 T cell
ii. Indications - treatment-experienced patients with HIV infected solely with R5 strains
iii. Adverse effects - abdominal pain, cough, dizziness, musculoskeletal symptoms,
pyrexia, rash, upper respiratory tract infections, hepatotoxicity, orthostatic hypotension
iv. Drug interactions — CYP3A substrate (watch CYP3A inducers and inhibitors)
v. Dosing — 150-600 mg 2 times/day oral (depending on concomitant drug interactions)
4. Integrase inhibitors: raltegravir (Isentress)
a. Mechanism of action: inhibits strand transfer of viral DNA to host cell DNA
b. Indications - treatment-experienced patients with HIV infection
c. Adverse effects - nausea, headache, diarrhea, pyrexia, creatine kinase elevation
d. Drug interactions — metabolized by uridine 5'-diphospho (UDP)-glucuronosyltransferases
(UGTs); inducers of UGT1A1: RIF, efavirenz, tipranavir-ritonavir, and rifabutin
e. Dosing - 400 mg 2 times/day orally
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Table 4. Nucleoside Reverse Transcriptase Inhibitors
Zidovudine Didanosine Stavudine Lamivudine Emtricitabine Abacavir
(AZT, ZDV, Retrovir, (ddl, Videx) (d4T, Zerit) (3TC, Epivir, Combivir, (FTC, Emtriva) (ABC, Ziagen,
Combivir, Trizivir) Epzicom, Trizivir) Epzicom, Trizivir)
Form 100-mg capsules, 125-, 200-, 250-, 15-, 20-, 30-. 150-, 300-mg tablets 200-mg capsules 300-mg tablets
300-mg tablets; 400-mg 40-mg capsules 10 mg/mL liquid 10 mg/mL liquid 20 mg/mL liquid
50 mg/5 mL liquid; enteric-coated 1 mg/mL solution Combivir: 150mg of Truvada: 200 mg of Trizivir: 300 mg
10 mg/mL injection capsules 75, 100 mg extended 3TC/300 mg of ZDV FTC/300 mg of TDF of ABC/150 mg of
release Epzicom: 300 mg of 3TC/300 mg of ZDV
3TC/600 mg of ABC
Dosing 200 mg TID or 300 mg > 60 kg: 200 mg BID > 60 kg: 40 mg BID 150 mg BID or 300 mg/ 200 mg/day or 240 300 mg BID or
BID or 400 mg/day ≤ 60 kg: 30 mg BID day mg liquid/day 600 mg/day
≤ 60 kg: 125 mg BID < 50 kg: 2 mg/kg BID
or 250 mg/day
Oral bioavailability 60% 40% 86% 86% 93% 83%
Empty stomach
Serum half-life 1.1 hours 1.6 hours 1 hour 3-6 hours 10 hours 1.5 hours
Intracellular half-life 7 hours > 20 hours 7.5 hours 18-22 hours 39 hours 12-26 hours
Elimination Metabolized to ZDV Renal excretion 50% Renal excretion 50% Renally excreted Renal excretion Metabolized by
glucuronide (GZDV) unchanged (70%) alcohol dehydrogenase
Renal excretion of GZDV and glucuronyl
transferase
Metabolites—renal
Major toxicity Bone marrow suppression, Pancreatitis (5%) Peripheral Diarrhea, nausea, Diarrhea, nausea, Hypersensitivity,
* All may cause GI intolerance, headache, Peripheral neuropathy abdominal pain, headache, rash, and fever, rash, GI
lactic acidosis with insomnia, asthenia, nail neuropathy (35%) (20%-30%) insomnia, and headaches hyperpigmentation symptoms, malaise,
hepatic steatosis pigmentation, and myalgia Nausea, diarrhea Elevated liver (minimal toxicity) fatigue, anorexia, and
enzymes myocardial infarction
Drug interactions Myelosuppressive agents Fluoroquinolones, TMP/SMX may increase Ethanol may increase
Rifampin tetracycline; 3TC concentrations ABC concentrations
ketoconazole,
dapsone; tenofovir
Miscellaneous Activity in activated Activity in activated Resistance develops Activity in resting Hypersensitivity
information lymphocytes lymphocytes quickly with macrophages reaction may be
monotherapy fatal—discontinue
Activity in resting drug immediately
macrophages Screen for HLA-B*
5701 before initiation;
cross-resistance with
ddl and 3TC
BID = 2 times/day; GI = gastrointestinal; TID = 3 times/day; TMP/SMX = trimethoprim-sulfamethoxazole.
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Table 5. Nonnucleoside and Nucleotide Reverse Transcriptase Inhibitors
Nevirapine (Viramune) Delavirdine Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Tenofovir DF (TDF,
(Rescriptor) Viread, Truvada)
RTI type Nonnucleoside Nonnucleoside Nonnucleoside Nonnucleoside Nucleotide
Form 200-mg tablets 100-, 200-mg tablets 50-, 100-, 200-mg capsules 100 mg tablets 300-mg tablets
600-mg tablets Truvada: 200 mg of
Atripla: 200 mg of FTC/300 FTC/300 mg of TDF
mg of TDF/efavirenz 600 mg
Dosing 200 mg/day for 14 days; 400 mg PO TID (3 600 mg PO qHS 200mg PO BID 300 mg/day PO
then
200 mg PO BID (2 times/day)
times/day)
Oral > 90% 85% 42% Take with food 40%
bioavailability Avoid antacids Avoid with high-fat meal Take with food
Serum half-life 25-30 hours 5.8 hours 40-55 hours 20-60 hours 10-14 hours
Elimination Metabolized by Metabolized by Metabolized by CYP3A4, Metabolized by CYP Eliminated by renal filtration
CYP3A4; 80% CYP3A4, 51% 14%—34% excreted in urine, 3A4, 2C9, 2C19 and active secretion
excreted in urine (< 5% excreted in urine 16%-61% in feces
unchanged), 10% in (< 5% unchanged),
feces 44% in feces
Major toxicity Rash Rash (less than Rash (less than delavirdine) Rash GI toxicity
GI toxicity nevirapine) CNS symptoms (insomnia, Nausea Headache
Increased LFTs- Headache impaired concentration, May cause lactic acidosis
hepatotoxicity nightmares, mania) with hepatic steatosis
Increased LFTs (mitochondrial toxicity
may be less)
Drug interactions Induces CYP3A4 Inhibits CYP3A4 Induces CYP3A4 Induces CYP3A4 Increases didanosine
Watch rifampin, Separate Inhibits CYP 2C9 and concentration—separate
rifabutin, OCs, protease administration with 2C19 administration
inhibitors, triazolam, antacids and ddl
midazolam
Miscellaneous Extensive cross- Extensive cross- Extensive cross-resistance in Can dissolve in water May be effective against
information resistance in class resistance in class class for patients who cannot HIV strains resistant to
Do not initiate in Avoid in first trimester of swallow other RTIs
women with CD 4 + pregnancy; May be effective against
counts > 250 cells/mm 3 do not use Atripla if CrCl < HIV strains resistant to
or in men with CD,+ 50 mL/minute efavirenz or nevirapine
counts > 400 cells/mm 3
(liver toxicity)
BID = 2 times/day; CNS = central nervous system; CrCl = creatinine clearance; CYP = cytochrome P450; DM = diabetes mellitus; GI = gastrointestinal; HIV = human
immunodeficiency virus; LFT = liver function test; OC = oral contraceptive; PO = orally;©qHS = every
2010 night; College
American RTI = reverse transcriptase
of Clinical Pharmacyinhibitor; TID = 3 times/day.
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Table 6. Protease Inhibitors
Indinavir [IDV] Nelfinavir Ritonavir [RTV] Saquinavir Fosamprenavir Lopinavir- Atazanavir Tipranavir Darunavir
(Crixivan) (Viracept) (Norvir) [SQV] [f-APV] (Lexiva) Ritonavir [ATV] (Rcyataz) [TPV] (Aptivus) [TMC 114]
(Invirase) (Kaletra) (Prezista)
Form 200-. 333-, 250-, 625-mg 100-mg capsules; 200-mg 700 mg tablets; 100/25, 200/50 100-, 150-, 200- 250-mg capsules 75-, 150-,
400-mg capsules; tablets; 50 mg/g 80 mg/mL liquid; capsules, 500- 50 mg/mL liquid; mg tablets: 300-mg capsules 400-. 600-mg
refrigerate oral powder refrigerate capsules mg tablets prodrug of 80/20 mg/mL tablets
capsules amprenavir solution
Dosing 800 mg q8h 750 mg TID or 600 mg every 12 1000 mg BID 1400 mg BID 400/100 mg 400 mg/day 500 mg BID 800 mg/day
800 mg + RTV 1250 mg BID hours (300 mg ql2h with ritonavir (or 1400 mg + RTV BID or If taken with with RTV with RTV 100
100 mg or for 2 days, 400 mg 100 mg; take 100-200 mg/day; 800/200 mg/ efavirenz: RTV 200 mg BID mg/dav or 600
200 mg ql2h q 12h for 3 days, 500 within 2 hours or 700 mg + RTV day with food 100 mg + ATV mg BID with
mg ql2h for 8 days) of a meal 100 mg BID). With If taking 400 mg/day RTV
"Boosting dose'' = efavirenz: 700 mg efavirenz or If taken with 100 mg BID
100-400 mg divided + RTV 100 mg BID nevirapine: efavirenz: RTV
1 or 2 times/day 500 mg/125 100 mg + ATV
mg BID 300 mg/day
Oral 65%; 20%-80%; 65%—75%; Invirase: 4% Fosamprenavir: Solution take Food increases Food increases Food
1 hour before take with meal take with food T of amprenavir with food; absorption and absorption and increases
bioavailability or 2 hours after or snack max 1
take tablets bioavailability; bioavailability absorption
meals (may take occurs in 1.5-4 without take with food Take with food and
with low-fat hours; respect to food bioavailability
meal) take without respect Take with
to food food
Serum half-life 1.5-2 hours 3.5-5 hours 3-5 hours 1-2 hours 7-11 hours 5-6 hours 7 hours 6 hours 15 hours
Elimination CYP3A4; CYP3A4 CYP 3A4 > 2D6 > CYP3A4 CYP3A4 CYP3A4 CYP3A4 CYP3A4 CYP3A4
renal—20% 2C9/10
Major toxicity Nephrolithiasis Diarrhea (mild); GI intolerance; GI intolerance GI intolerance; GI intolerance; Indirect Hepatotoxicity; Rash (sulfa);
GI intolerance; endocrine a paresthesias (mild); rash; oral fatigue; hyperbiliru- rash (sulfa); endocrine a
alopecia, disturbances (circumoral and endocrine a paresthesias; asthenia; binemia, endocrine a disturbances
dry skin and lips; extremities); taste disturbances increased LFTs; pancreatitis; prolonged QT disturbances
endocrine a disturbances; endocrine a endocrine a interval/heart
disturbances asthenia; endocrine
a
disturbances disturbances block, endocrine
a
disturbances disturbances
Drug Inhibits CYP3A4 Inhibits Inhibits CYP 3A4, Inhibits Inhibits CYP3A4 Inhibits CYP Inhibits Inhibits CYP Inhibits
(< RTV); CYP3A4 2D6 (potent) CYP3A4 (< RTV) 3A4, 2D6 CYP3A4, PPIs, 3A4, 2D6 CYP3A4
interactions ddl decreases (< RTV) ddl decreases (< RTV) H, blockers,
absorption absorption antacids
Induces glucuronyl
transferases
Miscellaneous Cross-resistance with Do not use with Less lipid effects Good for PI- Good for PI-
information IDV IDV resistant virus resistant virus
"Endocrine disturbances include insulin resistance (type 2 diabetes mellitus in 8%-10%), peripheral fat loss/central fat accumulation (in 50%), and lipid abnormalities (in 70%).
BID = 2 times/day; CYP = cytochrome P450; GI = gastrointestinal; PI = protease inhibitor; q8h = every 8 hours: ql2h = every 12 hours; TID = 3 times/day.
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Patient Case
1. F.G. is a 27-year-old man who is HIV positive but asymptomatic. One year ago, his CD 4 count was 815/mm3 ,
and his viral load was 1500 copies/mL (by reverse transcriptase-polymerase chain reaction). F.G. continues
to be monitored; his CD 4 count has decreased (most recent was 240/mm3 ), and his viral load has increased
(most recent was 60,000 copies/mL by reverse transcriptase-polymerase chain reaction). Which one of the
following treatments should F.G. receive?
A. Antiretroviral therapy should not be given because F.G.'s CD 4 count is still above
3
200/mm3 .
B. Initiate F.G. on zidovudine alone because his CD, count is still above 200/mm .
C. Initiate F.G. on combination therapy of zidovudine, lamivudine, and nevirapine.
D. Initiate F.G. on combination therapy of tenofovir, emtricitabine, and atazanavir-ritonavir.
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Patient Cases
2. Six months after starting appropriate therapy, F.G.'s CD 3 4
count is 620/mm3 , and his viral load is undetectable.
Two years later, his CD 4 count decreases to 310/mm , and his viral load is 15,000 copies/mL. Which one of
the following changes is best to make to F.G.'s therapy?
A. No changes should be made; wait until his viral load is again more than 50,000 copies/mL.
B. Change tenofovir to abacavir because abacavir is a more potent antiretroviral.
C. Change tenofovir and emtricitabine to abacavir and lamivudine.
D. Change the entire regimen to abacavir, lamivudine, and fosamprenavir-ritonavir.
3. Which one of the following should be monitored now that F.G. is receiving fosamprenavir-ritonavir?
A. Peripheral neuropathy.
B. Drug interactions with drugs metabolized by CYP1A2.
C. Endocrine disturbances such as hyperglycemia, fat redistribution, and lipid abnormalities.
D. Nephrolithiasis.
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iv. Extensive therapy with resistance - Resuppress viral load maximally or at least
adequately to prevent clinical progression.
v. New regimen with at least two fully active agents not possible - Continue
current regimen.
j. Resistance testing
i. Types of testing
(a) Genotypic
(1) Testing for the presence of mutations known to cause drug resistance
(2) Comparing the HIV-1 pol gene with a wild-type gene
(3) Recommend to guide therapy in patients with virologic failure while on
their first or second regimen.
(b) Phenotypic
(1) Test for inhibitory concentration needed to decrease HIV replication by
50% (IC 50).
(2) Values are reported as fold changes in sensitivity.
(3) An increase of more than 4-fold in IC 50 = "sensitive."
(4) A 4- to 10-fold increase in IC 50 = "intermediate."
(5) An increase of more than 10-fold in IC 50 = "resistant."
(6) Added to genotypic testing in patients with complex drug resistance
mutation patterns
ii. Indications
(a) Recommended: virologic failure during potent combination antiretroviral therapy
(b) Recommended: suboptimal suppression of viral load after initiation of potent
combination antiretroviral therapy
(c) Recommended: acute HIV infection before initiating therapy to determine
whether a drug-resistant virus was transmitted
iii. Benefits
(a) Resistance testing is an independent indicator of virologic outcome (better short-
term viral load response in those who had testing completed).
(b) May also benefit patients by limiting drug exposures, toxicities, and expense
iv. Limitations
(a) The effect of resistance testing is limited in heavily treated patients.
(b) The HIV RNA value must be 500-1000 copies/mL or more.
(c) Current need for expert interpretation
(d) Difficult-to-detect small mutant populations (less than 20%)
(e) Cost: about $400-$500 per test
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C. Initiating Potent Combination Antiretroviral Therapy in the Setting of A cute Opportunistic Infections
1. Opportunistic infections with no effective therapy require prompt initiation of antiretroviral
therapy: cryptosporidiosis, microsporidiosis, promyelocytic leukemia, and Kaposi sarcoma
2. Antiretroviral therapy should begin within 2 weeks of acute opportunistic infections, except
for TB, in which the infection should be treated first.
Patient Cases
4. Three years later, F.G. (from patient case questions 1-3) has not responded to any of his antiretroviral treat-
ment regimens because of resistance or intolerance. His CD 4 count has decreased to 135/mm3 . Against which
one of the following infections should he receive primary prophylaxis?
A. PCP.
B. Cryptococcal meningitis.
C. Cytomegalovirus (CMV).
D. Mycobacterium avium complex (MAC).
5. B.L. is a 44-year-old man positive for HIV who arrives at the emergency department severely short of
breath. He is an extremely nonadherent patient and has not seen a health care provider in more than 3 years.
A chest radiograph shows pulmonary infiltrates in both lung fields. The following laboratory profile and
tests are performed: sodium = 147 mEq/L; potassium = 4.2 mEq/L; chloride = 104 mEq/L; bicarbonate =
25.2 mEq/L; glucose = 107 mg/dL; blood urea nitrogen = 38 mg/dL; serum creatinine = 1.1 mg/dL; aspar-
tate aminotransferase = 28 IU/L; alanine aminotransferase = 32 IU/L; lactate dehydrogenase = 386 IU/L;
alkaline phosphate = 75 IU/L; pH = 7.45; partial pressure of oxygen = 63 mm Hg; partial pressure of carbon
dioxide = 32 mm Hg; and oxygen saturation = 85%. Sputum Gram's stain is negative; silver stain is also
negative. Which one of the following treatments should B.L. receive?
A. Pentamidine intravenously with adjuvant prednisone therapy.
B. TMP/SMZfor21 days.
C. TMP/SMZ intravenously with adjuvant prednisone therapy for 21 days.
D. Atovaquone for 21 days.
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b. Pentamidine
i. Dose = 4 mg/kg/day for 21 days (intravenously)
ii. Adverse effects
(a) Hypotension
(b) Rash
(c) Electrolyte disturbances
(d) Hypo- or hyperglycemia
(e) Pancreatitis
iii. Prophylaxis dose = 300 mg by nebulization (Respirgard) once monthly (can predose
with ß-agonist to diminish respiratory irritation)
c. Trimethoprim and dapsone
i. Dose = 5 mg/kg of TMP every 8 hours and dapsone 100 mg/day for 21 days (orally
only for mild to moderate PCP)
ii. Adverse effects
(a) Nausea and vomiting
(b) Anemia
iii. Prophylactic dose = dapsone 100 mg/day (pediatric dose = 1 mg/kg/day) or 50 mg/
week with 50—75 mg of pyrimethamine and 25 mg of leucovorin
d. Clindamycin and primaquine
i. Dose = 300-450 mg of clindamycin every 6 hours and primaquine 15-30 mg/day for
21 days (intravenous clindamycin may be used)
ii. Adverse effects
(a) Rash
(b) Anemia, methemoglobinemia
e. Atovaquone (Mepron)
i. Dose = 750 mg 2 times/day for 21 days (orally only for mild to moderate PCP)
ii. Pediatric dose (less than 40 kg [88 lb]) = 40 mg/kg/day divided 2 times/day
iii. Equal to TMP/SMX for PCP but not an antibacterial
iv. Potential for decreased efficacy in patients with diarrhea (because of poor absorption)
v. Adverse effects
(a) Nausea and vomiting
(b) Rash
(c) Transient increase in liver function tests
(d) Insomnia, headache, fever
vi. Prophylactic dose = 1500 mg/day (alternative to TMP/SMX)
f. Adjuvant therapy
i. Corticosteroids
(a) Used in patients with severe PCP (A-a gradient of 35 or more or PaO 2, of 70
or less) — Start within 72 hours.
(b) Decreases mortality
(c) Dose = 40 mg 2 times/day of prednisone for 5 days, followed by 40 mg/day for
5 days, and then 20 mg/day for remainder of PCP therapy (use cautiously in
patients with TB)
4. Prophylaxis
a. Secondary prophylaxis in patients after PCP (may be discontinued if CD 4 count is more
than 200/mm 3 for 3 months or longer because of potent combination antiretroviral therapy)
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b. Primary prophylaxis in patients with CD 4 count less than 200/mm 3 (may be discontinued if
CD4 count is more than 200/mm 3 for 3 months or longer because of potent combination
antiretroviral therapy)
E. Candida Infections
1. Oral Candida infections (thrush)
a. More than 90% of patients with AIDS sometime during their illness
b. Signs and symptoms
i. Creamy white, curdlike patches on the tongue and other oral mucosal surfaces
ii. Pain; decreased food and fluid intake
2. Candida esophagitis
a. Not always an extension of oral thrush (30% do not have oral thrush)
b Signs and symptoms
i. Painful swallowing, obstructed swallowing, substernal pain
3. Diagnosis
a. Signs and symptoms of infection
b. Fungal cultures/potassium hydroxide smear
4. Therapy (oral candidiasis is easy to treat [3-14 days' duration], but it relapses within 30 days)
a. Nystatin
i. Indicated for mucous membrane and cutaneous Candida infections
ii. Use for initial episodes in patients with CD 4 count more than 50/mm 3.
iii. Five milliliters (100,000 units/mL); swish and swallow 4 times/day
iv. Poor adherence
b. Clotrimazole—alternative to nystatin
i. Use for initial episodes in patients with CD 4 count more than 50/mm 3.
ii. Mycelex troches 10 mg 5 times/day
iii. Poor adherence (generally better tolerated than nystatin)
c. Fluconazole
i. Indicated for oropharyngeal and esophageal candidiasis
ii. Two percent relapse on fluconazole versus 28% on placebo
iii. Ten percent of patients develop fluconazole-resistant infections.
iv. A total of 100-200 mg/day
d. Itraconazole
i. Indicated for oropharyngeal and esophageal candidiasis
ii. Oral solution: 200 mg/day
Patient Case
6. G.H. is a 33-year-old man positive for HIV who presents to the clinic with a severe headache that has gradu -
ally worsened during the past 3 weeks. He also has memory problems and is3 always tired. He has refused
antiretroviral therapy in the past, and his most recent CD 4 count was 75/mm . He is given a diagnosis of
Cryptococcal meningitis and is successfully treated. Which one of the following is the best follow-up
therapy for G.H.?
A. No maintenance treatment is required.
B. Administer fluconazole 200 mg/day orally.
C. Administer amphotericin B 1 mg/kg/week intravenously.
D. G.H. is protected as long as he is also receiving PCP prophylaxis.
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F. Cryptococcosis
1. C. neoformans
2. Occurs in 6%-l 0% of patients with AIDS
3. In general, occurs in patients with CD 4 counts less than 100/mm 3
4. Acute mortality is 10%-25%, and 12-month mortality is 30%-60%.
5. Worldwide distribution
Found in aged pigeon droppings and nesting places (e.g., barns, window ledges)
Organism must be aerosolized and inhaled; it then disseminates hematogenously.
6. Signs and symptoms
a. Almost always meningitis (66%-84%)
b. Usually present for weeks or months (1 day to 4 months; average = 31 days)
c. Insidious onset
i. Low-grade fever (80%-90%)
ii. Headaches (80%-90%)
iii. Altered sensorium (20%); irritability, somnolence, clumsiness, impaired memory and
judgment, behavioral changes
iv. Seizures may occur late in the course (less than 10%).
v. Minimal nuchal rigidity, meningismus, photophobia
7. Diagnosis
a. Cerebral spinal fluid (CSF) changes
i. Patients with AIDS often have no CSF abnormalities except:
(a) Positive CSF cultures
(b) Cerebral spinal fluid India ink
(c) Cerbral spinal fluid cryptococcal antigen titer (91%)
b. Serum cryptococcal antigen more than 1:8
8. Therapy
a. Amphotericin B: 0.7—1 mg/kg/day (or liposomal amphotericin 4-6 mg/kg/day) PLUS
flucytosine 25 mg/kg every 6 hours for at least 2 weeks, followed by fluconazole 400 mg/
day for at least 8 weeks—commonly used in patients with AIDS
b. Amphotericin B: 0.7-1 mg/kg/day (or liposomal amphotericin 4-6 mg/kg/day) for 4-6
weeks (or 1 month after negative cultures); alternative in patients with AIDS
c. Amphotericin B: 0.7-1 mg/kg/day PLUS fluconazole 800 mg/day for 2 weeks, followed
by fluconazole 800 mg/day for at least 8 weeks
d. Fluconazole 1200mg/day PLUS flucytosine 25 mg/kg every 6 hours for 6 weeks
e. Fluconazole 800-2000 mg/day for 10-12 weeks
9. Outcome
a. Therapeutic response: 42%-75%
b. Length of therapy is controversial, but antifungals should probably be continued as long
as CSF and other body fluid cultures are positive and for 1 month after negative cultures.
c. Relapse: 50%-90% (with about 100% mortality)
10. Prophylaxis
a. Relapses usually occur within first year after therapy (less often with HAART therapy).
b. Secondary prophylaxis: fluconazole 200 mg/day (may consider stopping if CD 4 count
is more than 100/mm 3 for 3 months or longer after potent combination anti-retroviral
therapy; restart if CD 4 count decreases to less than 100/mm3)
c. Primary prophylaxis: not indicated (decreases the incidence of cryptococcosis but does
not decrease mortality and may lead to resistance)
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Patient Case
7. After treatment of his cryptococcal meningitis, G.H. is initiated on potent combination anti retroviral thera-
py. Two, 6, and 8 months after starting the therapy, his CD 4 counts are 212, 344, and 484/mm3 , respectively.
Which one of the following is the best follow-up therapy for G.H. now?
A. Continue the fluconazole maintenance.
B. Maintenance therapy with fluconazole should be given for at least 1 year; then, it can be discontinued
because the CD 4 counts have increased.
C. Maintenance therapy with fluconazole should be continued until CD 4 counts are greater than 500/mm3 .
D. Maintenance therapy with fluconazole can be discontinued.
8. J.C., a 36-year-old woman positive for HIV, has severe anemia. She has been tested for iron deficiency and
has been taken off zidovudine and TMP/SMZ. She has also started to lose weight and to have severe diar -
rhea. A blood culture is positive for MAC. Which one of the following treatments is best for J.C.?
A. Clarithromycin plus EMB for 2 weeks, followed by maintenance with clarithromycin alone.
B. Azithromycin plus EMB for at least 12 months.
C. Clarithromycin plus INH for 2 weeks, followed by maintenance with clarithromycin alone.
D. EMB plus rifabutin indefinitely.
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5. Prophylaxis
a. Primary prophylaxis in patients with CD 4 counts less than 50/mm 3 (may be discontinued
if CD 4 count is more than 100/mm 3 for 3 months or longer because of potent combination
antiretroviral therapy)
i. Clarithromycin 500 mg orally 2 times/day
(a) Three times lower incidence of MAC bacteremia (vs. placebo)
ii. Azithromycin 1200 mg orally once weekly
iii. Rifabutin 300 mg/day (150 mg orally 2 times/day with food if there are
gastrointestinal adverse effects)
(a) Two times longer until a positive MAC culture (vs. placebo)
(b) Decreased incidence of symptoms related to MAC
(c) Adverse effects: rash, gastrointestinal disturbances, neutropenia, body fluid
discoloration
(d) DO NOT give alone to patients with active TB.
Patient Case
9. P.L. is a 44-year-old man positive for HIV who receives a diagnosis of CMV retinitis. He currently receives
zidovudine, lamivudine, and efavirenz as antiretroviral agents; pyrimethamine-sulfadiazine for toxoplas-
mosis and PCP prophylaxis; and fluconazole for esophageal candidiasis. Which one of the following agents
is the best empiric therapy?
A. Ganciclovir intravenously or valganciclovir orally.
B. Foscarnet intravenously.
C. Cidofovir intravenously.
D. Acyclovir intravenously.
H. Cytomegalovirus (CMV)
1. Characteristics of CMV infection
a. Fifty-three percent of Americans between 18 and 25 years old are CMV+.
b. Eighty-one percent of Americans older than 35 years are CMV+.
c. More than 95% of homosexual men are CMV+.
d. About 90% of CMV infections are asymptomatic (if illness occurs, it resembles
mononucleosis).
e. Virus remains latent in the host after initial infection but may reactivate if patient
becomes immunocompromised (especially cell-mediated immunity).
f. Ninety percent of patients with AIDS develop CMV infections, and 25% experience
life- or sight-threatening disease (pre-HAART [highly active antiretroviral therapy] data:
pre-1996).
2. Diagnosis of CMV infection
a. Serology
i. Detects exposure to CMV
b. Virus isolation
i. Tissue culture—requires up to 6 weeks
ii. Shell vial technique—requires only 16 hours
(a) Organism is incubated overnight and then detected by immunofluorescence
microscopy with monoclonal antibodies.
c. Cytology/histology
i. Large (cytomegalic) cell with a large, central, basophilic, intranuclear inclusion
("owl's eye")
ii. Low yield
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3. Manifestations of CMV
a. Gastrointestinal
i. Colitis: 5%-10% of patients with AIDS
(a) Diarrhea, abdominal pain, weight loss, anorexia, fever
ii. Esophagitis/gastritis uncommon
iii. Hepatitis: 33%-50% with histologic evidence but minimal clinical importance
iv. Maintenance drugs not needed
b. Pneumonia
i. Cytomegalovirus is commonly in bronchial secretions; of questionable importance
ii. Chest radiography results are similar to those seen with PCP.
iii. Symptoms: shortness of breath; dyspnea on exertion; dry, nonproductive cough
iv. Treat if:
(a) Documented tissue infection
(b)Cytomegalovirus is only pathogen
(c)Deteriorating illness
v. About 50%-60% of patients will respond; no need for maintenance
c. Retinitis
i. Occurs in 10%-15% of patients with AIDS; is clinically most important CMV
infection
ii. In general, patients have CD 4 counts less than 100/mm 3 .
iii. Begins unilaterally and spreads bilaterally
iv. Early complaints: "floaters," pain behind the eye
v. In general, progressive; no spontaneous resolution (blindness in weeks to months)
vi. Twenty-six percent progression, even with treatment; retinal detachment very common
4. Therapy for CMV infections
a. Ganciclovir (Cytovene-IV, Cytovene), valganciclovir (Valcyte)
i. Competes with deoxynucleosides, inhibiting viral DNA synthesis
ii. Must be triphosphorylated; the rate-limiting step in this process is the first
phosphorylation. Cytomegalovirus induces the production of the enzymes required to
monophosphorylate ganciclovir but not acyclovir.
iii. Valganciclovir is rapidly converted to ganciclovir in intestinal wall and liver (F of
about 60%).
iv. Adverse effects
(a) A total of 65% have adverse effects, and 76% have moderate to severe
neutropenia (25% less than 1000/mm3 , 16% less than 500/mm3).
(1) In general, after 10 days
(2) Ganciclovir plus zidovudine: 82% will have severe hematologic toxicity
(3) Patients receiving ganciclovir can tolerate only up to 300 mg/day of
zidovudine.
(b) Thrombocytopenia (9% less than 20,000/mm 3)
(c) Confusion; convulsions; dizziness; headache; thinking disorders
(d) Nausea; vomiting; diarrhea; abnormal liver function tests
(e) Possible reproductive toxicity
vi. Dose
(a) Induction: valganciclovir 900 mg orally 2 times/day for 14-21 days (alternative:
ganciclovir 5 mg/kg intravenously every 12 hours for 14-21 days)
(b) Maintenance: valganciclovir 900 mg/day orally (alternative: ganciclovir 5 mg/kg/
day intravenously)
(c) All (100%) patients will relapse in 1-8 weeks without maintenance.
(d) Intravenous maintenance therapy requires establishment of central venous access.
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I. Toxoplasmosis
1. Description
a. Toxoplasma gondii (protozoan)
b. Felines are the hosts for sporozoite production (change litter box daily, wash hands
after changing litter box or have someone else change the litter box, and, ideally, keep
the cat indoors).
c. A total of 15%-68% of adults in the United States are seropositive for T. gondii.
d. Secondary to undercooked beef, lamb, or pork (stress avoidance in patients with HIV)
e. Case-defining illness in 2.1 % of patients with AIDS
2. Signs and symptoms
a. Fever, headache, altered mental status
b. Focal neurologic deficits (60%): hemiparesis; aphasia; ataxia; visual field loss; nerve palsies
c. Seizures (33%)
d. Cerebral spinal fluid: mild pleocytosis, increased protein, normal glucose
3. Diagnosis
a. Brain biopsy: only definitive diagnosis but generally not done
b. Antibodies or T. gondii isolation in serum or CSF
c. Magnetic resonance imaging scan or computerized tomographic scan: multiple, bilateral,
hypodense, ring-enhancing mass lesions (magnetic resonance imaging scan more
sensitive than computerized tomographic scan)
4. Therapy
a. Standard therapy
i. Pyrimethamine 50—75 mg/day (loading dose = 200 mg in two doses) PLUS
ii. Sulfadiazine 1000-1500 mg every 6 hours (watch crystalluria)
(a) Bone marrow suppression: thrombocytopenia, granulocytopenia, anemia
(b) Folinic acid (leucovorin) 10-20 mg/day to reduce bone marrow effects of
pyrimethamine
(c) Duration: 6 weeks or after signs and symptoms resolve
b. Alternative therapy
i. Clindamycin
(a) Dosage: 600-1200 mg intravenously every 6 hours for 6 weeks; after 3 weeks,
can change to oral 600 mg every 8 hours
(b) Used in combination with pyrimethamine-leucovorin for sulfa intolerance or by
itself when bone marrow suppression occurs
ii. Atovaquone
(a) Dosage: 1500 mg orally 2 times/day
(b) Used in combination with pyrimethamine-leucovorin or in combination with
sulfadiazine or alone (monitor plasma concentrations if using alone)
iii. Azithromycin
(a) Dosage: 900-1200 mg/day orally
(b) Used in combination with pyrimethamine (do not use alone for acute therapy)
iv. Other alternatives: clarithromycin plus pyrimethamine, 5-FU (fluorouracil) plus
clindamycin, dapsone plus pyrimethamine plus leucovorin, and minocycline
or doxycycline combined with pyrimethamine plus leucovorin, sulfadiazine, or
clarithromycin
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5. Prophylaxis
b. Relapse rates approach 80% without maintenance therapy.
c. Toxoplasma-seropositive patients with a CD 4 count of 100/mm3 or less should receive
primary prophylaxis. *
d. For primary prophylaxis, use TMP/SMZ or dapsone-pyrimethamine-leucovorin or
atovaquone with or without pyrimethamine at doses used for PCP prophylaxis (may be
discontinued if the CD 4 count is more than 200/mm3 for 3 months or longer because of
potent combination antiretroviral therapy).
e. For secondary prophylaxis, use the following (may be discontinued if the CD 4 count is
more than 200/mm3 for 6 months or longer because of potent combination antiretroviral
therapy):
i. Pyrimethamine 25—50 mg/day plus leucovorin 10-25 mg/day with sulfadiazine
2-4 g/day
ii. Clindamycin 600 mg every 8 hours can be substituted if sulfa intolerance occurs.
iii. Atovaquone 750 mg orally every 6—12 hours with or without pyrimethamine-
leucovorin
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B. Pathophysiology (Figure 3)
1. Person-to-person transmission—Airborne droplets carrying M. tuberculosis are inhaled.
2. Infection primarily pulmonary, although can occur in other organ systems
C. Diagnosis (Table 8)
Table 8. Diagnosis of Tuberculosis
Nonspecific Signs and Symptoms Radiology Microbiology
Cough Chest radiograph Sputum smear for AFB
Malaise patchy or nodular Sputum culture for
Weight loss infiltrates in upper Mycobacterium tuberculosis
Fever, chills lobes; cavitary
Night sweats lesions
Pleuritic pain
AFB = acid-fast bacillus.
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Patient Case
10. J.M. is a 42-year-old man who has a yearly PPD skin test because he works at a long-term care facility. Forty-
eight hours after the PPD was placed, he had an 18-mm induration. This is the first time he has reacted to this
test. His chest radiograph is negative. Which one of the following is best in view of J.M.'s positive PPD?
A. No treatment is necessary, and J.M. should have another PPD skin test in 1 year.
B. Another PPD skin test should be performed in 1 week to see whether this is a booster effect.
C. J.M. should be monitored closely, but no treatment is necessary because he is older than 35 years.
D. J.M. should be initiated on INH 300 mg/day orally for 6 months.
D. Therapy
1. Treatment of latent TB infection
a. The goal is to prevent latent (asymptomatic) infection from progressing to clinical disease.
b. The treatment of latent TB infection should be instituted in the following groups with a
positive PPD skin test:
i. Close contacts of individuals with newly diagnosed infectious TB
ii. Health care workers at facilities treating patients with TB
iii. Foreign-born people from high-prevalence countries (immigration within 5 years)
iv. Homeless people
v. People working at or living in long-term care facilities
vi. Patients with HIV infection
vii. Recent converters (within a 2-year period)
viii. People with abnormal chest radiographs that show fibrotic lesions —likely to
represent old, healed TB
ix. People with medical conditions that have been reported to increase the risk of
TB: intravenous drug use, diabetes mellitus, silicosis, Hodgkin disease, leukemia,
immunosuppressive therapy, corticosteroids, end-stage renal disease
c. Dosing regimens
i. Patients who are not infected with HIV:
(a) Administer INH 300 mg/day or 900 mg 2 times/week for 6-9 months (or RIF alone
for 4 months).
ii. Patients who are infected with HIV:
(a) Administer INH 300 mg/day for 9 months (or RIF alone for 4 months).
iii. Areas with multidrug-resistant isolates:
(a) Two drugs with activity against the isolate for 6-12 months
Patient Case
11. R.J. is a 32-year-old man positive for HIV infection who presents to the clinic with increased weight loss
and night sweats, as well as a cough productive of sputum. He is currently receiving fosamprenavir -ritona-
vir 700 mg/100 mg 2 times/day, zidovudine 300 mg 2 times/day, lamivudine 150 mg 2 times/day, fluconazole
200 mg/day orally, and TMP/SMZ double strength daily. A sputum sample is obtained that is positive for acid -
fast bacillus. R.J. lives in an area with a low incidence of multidrug-resistant TB. Which one of the following is
the initial treatment of choice?
A. Initiate INH, RIF, and PZA with no change in his HIV medications.
B. Initiate INH, RIF, and PZA; increase the dosage of fosamprenavir-ritonavir; and use a higher dosage of RIF.
C. Initiate INH, rifabutin, PZA, and EMB, with a lower dosage of rifabutin.
D. Initiate INH, rifabutin, PZA, and EMB and decrease the dosage of fosamprenavir-ritonavir.
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Patient Case
12. Which one of the following represents the best follow-up for R.J.?
A. Treatment with the initial drugs should continue for 6 months.
B. Treatment can be decreased to just 1NH and a rifamycin after 2 months for a total treatment of 18-24
months.
C. Treatment can be decreased to just INH and a rifamycin after 2 months for a total treatment of 6
months; HIV RNA concentrations should be observed closely during therapy.
D. Treatment can be decreased to INH, a rifamycin, and either PZA or EMB after 2 months for a total
treatment of 6 months; HIV RNA concentrations should be observed closely during therapy.
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iii. Ibuprofen (10 mg/kg up to 600 mg 30 minutes before infusion) - Significantly more
fever/chills in placebo (87%) than in ibuprofen group (48%)
iv. Acetylsalicylic acid, acetaminophen, diphenhydramine—never shown to be effective
(but not specifically studied)
e. Treatment:
i. Meperidine 50 mg—stops reaction within 30 minutes (mean = 10.8 minutes)
ii. If the patient consistently needs meperidine, then prophylactic doses may be
appropriate.
4. Dosing
a. Test dose of 1 mg (in 25-50 mL of 5% dextrose in distilled water [D5W]) or aliquot of
initial dose) for 20-30 minutes
b. If tolerated, prepare dose to a concentration of 0.1 mg/mL in D5W (amphotericin B
potency not affected by light [for 24 hours]).
c. Start therapy with 0.25 mg/kg (some suggest 5-10 mg) administered for 4-6 hours.
d. Increase gradually to desired milligram per kilogram concentration (i.e., 5- to 10-mg
increments).
e. May increase rapidly in fulminant infections or immunocompromised patients
f. Amphotericin can be given on alternate days by doubling the daily dose to a maximum of
1.5 mg/kg.
5. Liposomal amphotericin
a. Liposomal formulations are designed to maintain therapeutic efficacy, but they diminish
renal- and infusion-related toxicity.
Amphotericin B Abelcet Amphotec AmBisome
Liposome Type Multilamellar Colloidal dispersion Unilamellar
vesicle with in aqueous solution liposome
ribbonlike structure (disk-shaped bilayer)
Dose 1 mg/kg/day 5 mg/kg/day 3^1 mg/kg/day 3-5 mg/kg/day
for 2 hours for 3-4 hours
b. Mostly taken up by macrophages in the lung, liver, spleen, bone marrow, and circulating
monocytes
c. Liposomes target fungi cell membranes much more than human cell membranes.
d. Amphotericin dissociates from the liposome over time, decreasing its toxicity (only free
drug is toxic).
e. Primary use in patients with aspergillosis who cannot tolerate amphotericin B
f. Potential use for invasive candidiasis
B. Azole Antifungals
1. Mechanism of action
a. Inhibits the synthesis of ergosterol, a component of the fungal cell membrane, vital for
normal growth
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HIV/Infectious Diseases
2. Ketoconazole (Nizoral)
a. Spectrum of activity
i. In vitro
(a) Candida species, Blastomyces, histoplasmosis, Paracoccidioides, Sporothrix,
dermatophytes
ii. Clinical use
(a) Histoplasmosis, superficial Candida and other infections, blastomycosis,
paracoccidioidomycosis
b. Adverse effects
i. Nausea, abdominal pain, headache, rash
ii. Adrenal insufficiency, decreased libido, impotence, gynecomastia, menstrual
irregularities (inhibits steroidogenesis)
iii. Increased liver function tests, potential fulminate hepatitis
c. Drug interactions (CYP3A4 substrate and inhibitor)
i. Antacids, H 0-blockers, proton pump inhibitors, didanosine (gastrointestinal
absorption)
ii. Rifampin (decreases ketoconazole concentrations)
iii. Cyclosporine
iv. Phenytoin
v. Warfarin
vi. Methylprednisolone, midazolam, alprazolam, simvastatin, lovastatin
vii. Protease inhibitors
d. Dosing
i. 200-400 mg/day
3. Fluconazole (Diflucan)
a. Spectrum of activity
i. In vitro
(a) Candida species (poor activity against C. glabrata and no activity against C.
krusei), Cryptococcus, Blastomyces, histoplasmosis, dermatophytes
ii. Clinical use
(a) Cryptococcal meningitis
(b) Candida infections (primarily C. albicans and C. parapsilosis)
b. Pharmacokinetics
i. Well absorbed orally (F = 100%)—also available intravenously
ii. Half-life is about 30 hours—primarily eliminated unchanged in the urine
c. Adverse effects
i. Nausea, abdominal pain, headache
ii. Increased liver function tests
d. Drug interactions (CYP3A4 inhibitor at more than 400 mg/day and CYP2C9 inhibitor at
lower doses)
i. Cyclosporine
ii. Phenytoin
iii. Warfarin
e. Dosing
i. Oral candidiasis—100—200 mg/day
ii. Esophageal candidiasis—200 mg/day
iii. Invasive candidiasis—400-800 mg/day
iv. Acute cryptococcal meningitis—400 mg/day
v. Cryptococcal meningitis prophylaxis—200 mg/day
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4. Itraconazole (Sporanox)
a. Spectrum of activity
i. In vitro
(a) Candida species (usually just C. albicans), Cryptococcus, Aspergillus,
Blastomyces, histoplasmosis, dermatophytes
ii. Clinical use
(a) Onychomycosis
(b) Histoplasmosis
(c) Aspergillus
b. Pharmacokinetics
i. Oral absorption about 55% when given with food—also available intravenously
ii. Half-life is about 20 hours—extensively metabolized—hydroxyitraconazole is active
c. Adverse effects
i. Nausea, abdominal pain, headache, rash
ii. Increased liver function tests, potential fulminate hepatitis
d. Drug interactions (CYP3A4 inhibitor at more than 400 mg/day and CYP2C9 inhibitor at
lower doses)
i. Antacids, H2-blockers, proton pump inhibitors, didanosine (gastrointestinal
absorption)
ii. Cyclosporine
iii. Digoxin (decreases digoxin volume of distribution)
iv. Phenytoin
v. Warfarin
vi. Protease inhibitors
vii. HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors
e. Dosing
i. 200 mg/day
5. Voriconazole (Vfend)
a. Spectrum of activity
i. In vitro
(a) Candida species, Aspergillus, Fusarium, Scedosporium
ii. Clinical use
(a) Resistant Candida infections (especially C. glabrata and C. krusei)
(b) Aspergillus
b. Pharmacokinetics
i. Oral absorption about 95%—also available intravenously
ii. Half-life is about 6 hours—extensively metabolized—CYP (2C9, 3A4, 2C19)
c. Adverse effects
i. Abnormal vision 30% (abnormal vision, color changes, photophobia). Short-term
(20-30 minutes) effects on retina. Dose related. Not studied for more than 28 days
of therapy
ii. Increased liver function tests, rash, nausea
d. Drug interactions (CYP3A4 inhibitor and substrate; see table)
e. Dosing
Aspergillosis: loading dose = 6 mg/kg 2 times intravenously (infuse for 2 hours);
minimum dose = 4 mg/kg every 12 hours intravenously (infuse for 2 hours)
200 mg every 12 hours orally if more than 40 kg and 100 mg every 12 hours orally if
less than 40 kg (note: oral doses may be increased to 300 mg every 12 hours and 150 mg
every 12 hours, respectively, if necessary)
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HIV/Infectious Diseases
6. Posaconazole (Noxafil)
a. Spectrum of activity
i. In vitro
(a) Candida species, Cryptococcus, Trichosporon, Aspergillus, Fusarium
ii. Clinical use
(a) Candida infections
(b) Aspergillosis
(c) Zygomycoses
(d) Fusariosis
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HIV/Infectious Diseases
b. Pharmacokinetics
i. Oral absorption enhanced by a high-fat meal—no intravenous formulation
ii. Half-life is about 24-30 hours—primarily eliminated unchanged in the feces
c. Adverse effects
i. Nausea, vomiting, diarrhea
ii. Increased liver function tests, rash, hypokalemia, thrombocytopenia
iii. Q-Tc interval prolongation
d. Drug interactions - CYP3A4 inhibitor
e. Dosing
Oropharyngeal candidiasis: loading dose = 200 mg; then 100 mg/day
Refractory oropharyngeal candidiasis: 400 mg 2 times/day
Prophylaxis of invasive fungal infections in neutropenic and graft-versus-host disease
patients: 200 mg 3 times/day
C. Echinocandins
1. Mechanism of action
a. Inhibits the synthesis of l,3-|3 -glucan, an essential component of the fungal cell wall
-D
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REFERENCES
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9. Answer: B
Because the patient is symptomatic and her sputum is
acid-fast bacillus positive, she should be treated for an
active TB infection. Isoniazid, RIF, PZA, and EMB
for 2 months, followed by INH and RIF for 4 more
months, is the recommended therapy for active TB.
Patients should be initiated on at least three antibiotics
for the first 2 months. Although fluoroquinolones have
some activity against TB, their use as first-line mono-
therapy is inappropriate.
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