T RABAJO DE CAMPO

Metronidazole Cefamandole Cefoperazone Cefotetan Chlorpropamide

Tx of MRSA

ORAL:

-TMP/SMX -Clindamycin

Linezolid Doxycycline

OTHER:

Daptomycin Vancomycin Tigecycline

and glucuronyl transferase & 3TC 0sensitized individuals should never be rechallenged (can be genetically screened) Didanosine (DDI) Inosine analogue (precursor for

guanosine/adenosine)→ ddATP in cell

PK: Abs best in fasting state or w/ antacid, crosses CNS (less than AZT)

Greater affinity for mito DNA polymerase→ peripheral neuropathy, lipoatrophy, pancreatitis (…remember valproate)

-Less BMS than AZT

CI: Zalcitabine, stavudine (similar toxicities)

Lamivudine (3TC) MOA: Cytosine analog that terminates synthesis of proviral DNA chain & inhibits HIV & HBV RT (does not affect mito DNA synth or BM precursor cells

-Tx of HIV

-Acitive in hepatitis B -Never used alone→ too weak (should not be used w/

other cytosine analogs Resistance:

-Mutation at viral codon 184 (but restores sensitivity to AZT & tenofovir)

-Least toxic of NRTIs (least potent) -Few significant SE

Emtricitabine -Fluoro-derivative of analog of 3TC

-Taken once a day

-Inhibits HIV and HBV RT -Does not affect CYP450s, no significant interactions w/ other drugs

-Diarrhea, h/a, rash

-Hyperpigmentation of the soles/palms -Lactic acidosis, fatty liver,

hepatomegally Stavudine (D4T) AZT analogue (thymidine alalog)→

binds same site

-Strong inhibitor of β and y DNA polymerases

PK: completely abs PO not affected by food, crosses CNS

Tx HIV Greater affinity for mito DNA

polymerase→ peripheral neuropathy, pancreatitis, lipoatrophy

-Less BMS than AZT -DO NOT USE W/ AZT

Zalcitabine (DDC)

1^st cytosine analog developed, but removed from the market b/c of toxicity

Tx HIV -Peripheral neuropathy (dose limiting) -GI distress

-Pancreatitis, neutropenia, rash CI: Didanosine (similar toxicities) Tenofovir MOA: nucleoTIDE (AMP) analog

PK: take w/ food, long half life→

once daily dosing

Tx HIV GI (n/v/d, flatulence)

CI: only NRTI w/ sig drug interactions (↑DDI, no longer recommended combined use & ↓atazanavir→so ↑ by boosting w/

ritonavir)

NNRTI Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are highly selective, noncompetitive inhibitors of HIV-1 RT do not require metabolic activation. They inhibit reverse transcriptase at a different site from the NRTIs. Since they can be added to the NRTIs, they are synergistic with NRTIs. They lack cross-resistance with NRTIs. These drugs have cross-resistance WITHIN the NNRTI class, drug interactions, and a high incidence of hypersensitivity rxns. These drugs are NOT myelosuppressive.

Nevirapine (NVP)

PK: well abs PO (not affected by food), crosses to CNS, excreted in the urine as metabolites (CYP3A4 + CYP2B6)

Used in combination with other antiretroviral drugs for HIV-1 tx in adults and children

Resistance:

-Target site is HIV-1 specific, not essential to enzyme→ rapid resist

-Potential severe hepatotoxicity (don’t use in women w/ CD4 < 250, male CD4 < 400) CI: induces CYP3A4→→→→ ↑↑↑↑metab of PI’s (no dosage adjust needed), oral

contraceptives, ketoconazole, methadone, metronidazole, quinidine, theophyline, warfarin

Efavirenz (EFV) Preferred NNRTI

PK: ↑bioavail w/ fatty meal; well distrib after PO, 99% plasma albumin bound, half life

-Mostly CNS (50%)→ dizziness, h/a, vivid dreams, loss of concentration→resolves after few weeks

-Rash (25%)

(>40hrs)→once-a-day dosing

CI: Pregnancy; potent inducer of CYP450 Delavirdine

Adefovir Does not require phosphorylation Protease

Inhibitors

Aspartate protease (pol gene encoded) is a viral enzyme that cleaves precursor polypeptides in HIV buds to form the proteins of the mature virus core. The enzyme contains a dipeptide structure not seen in mammalian proteins (important for selectivity). PIs bind to this dipeptide, inhibiting the enzyme. Resistance occurs via specific point mutations in the pol gene, such that there is not complete cross-resistance b/w different PIs. Since PIs have nothing to do with DNA replication, they will NOT cause BMS→thus, good for adding these drugs to the regimen!. Since they have a different MOA, they can only be synergistic with those drugs blocking replication. Most have poor bioavailablity. However, the biggest problem is the inhibition of CYP450s. They also cause disorded lipid and carbohydrate metabolism.

Saquinavir Given w/ low dose RTV; high fat meals enhance absorption

Half life = 7-12 hours

H/A, fatigue, nausea, GI

CI: drugs that enhance metabolism (e.g. rifampin, rifabutin, nevirapine) Indinavir Given w/ RTV to increase absorption,

permit twice daily dosing

-Least protein bound, absorption decreaed when taken w/ meals

-Half life = 1.8hours

-Nephrolithiasis -Hyperbilirubinemia -Fat redistribuation -GI distress -Thrombocytopenia -Inhibition of CYP3A4

CI: dosage should be reduced w/

hepatic insufficiency Ritonavir PK enhancer/ booster of other PI’s

-Potent inhibitor of CYP3A4 -Half life = 3-5 hours

-GI distress

-Asthenia & circumoral paresthesias -Major drug interactions: induces CYP 1A2 & inhibit the major P450s (3A4 & 2D6)→ thus limited use Nelfinavir (NFV) Canot be boosted y RTV; metabol by several

CYPS; major metabolite (CYP2C19) has antiviral activity equal to parent compound -half life = 5h

Diarrhea (controlled by loperamide), nausea, flatulence

CI: can inhibit metabolism of other drugs

Fosamprenavir (fAPV)

Given w/ RTV; prodrug→ amprenavir H/A, fatigue, nausea, vomiting, paresthesias

CI: can inhibit metab of other drugs Lopinavir (LPVr) One of the preferred PIs; given with RTV

-Poor intrinsic bioavailability -half life =1.8 hours

GI, hypertriglyceridemia, insulin resistance

CI: enzyme inducers (avoid St Johns Wort), Oral solution contains EtOH (ovoid disulfiram or metroniadazole) Atazanavir

(ATZ)

ATV + RTV = only once daily preferred PI;

structurally unrelated to other PIs; well absorbed orally (increased by food) -Highly protein bound (86%) -Half life = 7h

-Competitive inhibitor of glucuronyl transferase (benign hyperbilirubinemia + jaundice)

-Prolongs PR intervale + slows HR CI: Metabolized by & inhibits CYP3A4, proton pump inhibitors;

administration must by more than 12h apart from H2 blockers &

antacids Tipranavir (TPV) Inhibits HIV protease resistant to other

PIs

-Twice daily w/ RTV

-Well absorbed when taken with food; half life = 6h

Same as other PIs + severe and fatal hepatitis

-Fatal/nonfatal intracranial hemorrhags

CI:Inducer of CYP 450 Darunavir Inhibits HIV protease resistant to other

PIs; well absorbed when taken w/ food Half life = 15 h (w/ RTV)

Same as other PIs + RASH

CI: metabolized by & inhibits CYP3A4

VIRAL ATTACHMENT

Enfurvitide -Fusion inhibitor; structurally resembles gp41

MOA: Binds gp41 (recognizes chemokine receptrs) and inhibits fusion of HIV-1 to CD4+

(note: gp120 → recognizes CD4+)

-Has to be administered parenterally (twice daily subQ injections)

-Use for

tx-experienced adults w/

evidence of HIV replication

-Injection-related (3% discontinue)

$$$ (estimated at $20,000)

VIRAL ENTRY Maraviroc Blocks CCR5 coreceptor that works w/

gp41 to facilitate HIV entry through cell membrane (only CCR5 expressing virus can be treated w/ maraviroc

-Well tolerated

INTEGRASE INHIBITOR

Raltegravir (RAL)

Specifically inhibts final step in integration of viral DNA into host cell DNA

-Half life = 9h→ twice daily dose -Metabol via UGT1A1-mediated glucuronidation→ no interactions w/

CYP450 inducers, inhibitors

-Give w/ other retrovirals for tx-experienced patients w/ evidenc of viral replication

Well tolerated Nausea, h/a Diarrha