Binds to LPS in Gram - 

(disrupts both the inner and outer membrane)

Binds to cell memb in a calcium-dependent manner via insertion of its lipid tail

(forms pores + loss of memb potential)

Gram -

including P. aeruginosa, enterobacteriacea spp.

Gram + only

including VRSA, VRE

Broad Spectrum

(Gm+ : MRSA, Strep, Nocardia, C. perfringens)

(Gm - : E.coli, Klebsiella, Proteus, Salmonella)

(some Protozoa: plasmodium, toxoplasm gondii)

(Atypical bacteria: chlamydia trachomatis)

Malaria

CNS toxoplasmosis

1. Over-production of PABA

(b/c sulfonamides are structural analogs of PABA, so they compete with PABA as a substrate for the enzyme dihydropteroate synthase)

2. Reduced enzyme affinity

3. Reduced cell permeability to sulfonamides

Crystalluria

(b/c agent is excreted by kidney and is a wek acid, if pH of urine is low (acidic) and sulfonamides are given at high conc., will crystalize b/c of low solubility and cause blockage of nephrons)

Bacteriostatic (alone)

Bacteriocidal (sulfamethoxazole + trimethoprim)

1. Bacterial over-production of DHFR (dihydrofolate reductase)

2. Reduced enzyme affinity (DHFR)

3. Reduced cell permeability to trimethoprim

UTIs

Pneumocystis pneumonia

Sinusitis

Otitis media

Antacids and di-/tri-valent cations

(Ca++, Mg++, Fe) significantly decrease fluoroquinolone absorption

Solution: Must take fluoroquinolone 2 hours before or after these items.

What are the order of potencies of

Ciprofloxacin, Levofloxacin, and Moxifloxacin toward Gm- and Gm+ bacteria?

Gm-  :   Cipro > Levo > Moxi

Gm+  :   Moxi > Levo > Cipro

Complicated UTIs

Community-acquired UTI

Nosocomial infections

(esp. pseudomonas or complicated Gm- inf.)

Fluoroquinolones + Beta-lactams

Combination provides additive effect

(b/c they both affect different pathways)

Tendonitis

Tendon Rupture

Some fluoroquinolones (Cipro > Levo > Moxi) inhibit CYP1A2 enzyme

Effect:

1. Decreases metabolism of

theophylline (mostly) and warfarin

2. Increased risk of torsades de pointes

Inhibit DNA synthesis

Inhibit topoisomerase II (DNA gyrase)

and topoisomerase IV

1. Mutation of target enzymes (topoisomerases)

2. Protection at the active site

3. Enzymatic inactivation of fluoroquinolones

4. Reduced cell permeability to fluoroquinolones

Name the only fluroquinolone that has

hepatic eliminiation?

Moxifloxacin (Avelox)

(the rest have renal elimination)

Are fluoroquinolones

bacteriostatic or bactericidal?

Is fluoroquinolone killing

time- or concentration-dependent?

Which 3 drugs make up the

Echinocandins (anti-fungal)?

Caspofungin

Micafungin

Anidulafungin

IV - systemic infections

(poor GI absorption)

Oral - only effective against fungi

          in the lumen of the GI tract

Amphotericin B has prominent toxicity in humans due to the drug binding to human sterols.

What can be done to eliminate this toxicity?

Local administration of drug

- Optical application

-Joint application

-Bladder irrigation

Broadest spectrum of activity of anti-fungals

Candida albicans

Cryptococcus neoformans

Histoplasm capsulatum

Blasomyces dermatitidis

Coccidioides immitis

Aspergillus fumigatus and Mucor spp.

Amphotericin B has infusion-related (immediate) adverse effects of fever/chills, muscle spasms, vomiting, headache, hypotension.

What 3 things can be done to

combat these effects?

1.  Slower infusion rate

2. Lower dose

3. Premedication

(antipyretics, antihistamines,

corticosteroids, meperidine)

Binds to ergosterol in fungal membranes

Multiple amp B molecules form a pore that leads to cell lysis

Which anti-fungal cannot be used as a

single agent and why?

Which antifungal exhibits synergy

with other antifungals?

(with Amp B for cryptococcus meningitis, with itraconazole for chromoblastomycosis)

Flucytosine is metabolized to

5-fluoruracil (5-FU), which is anti-neoplastic

Have to pay close attention to other drugs the patients are taking due to great risk of

drug-drug interactions

(inhibition of human P450s)

Which oral azole is dependent on

food (high-fat meal) for efficacy?

and

Which anti-fungal's absorption is

improved when given fatty foods?

Posaconazole -- efficacy dependent on

              high-fat meal

Griseofulvin -- absorption is improved when

             given a high-fat meal

Vulvo-vaginal candidiasis

Tinea corporis - ring worm

Tinea pedis - athlete's foot

Tinea cruris - jock itch

(additionally, oral troches of clotrimazole are available for oral thrush)

MOA of Echinocandins (anti-fungals)?

(Caspofungin, Micafungin, Anidulafungin)

Binds to keratin to protect skin from new infection (fungistatic activity)

Interferes with ergosterol synthesis, but interacts with a different fungal enzyme

1.  Shorter treatment periods

(inc. compliance, dec. resistance, lower cost)

2.  Treatments for resistant strains

3. Treatments more compatible

w/existing HIV treatments

1. Mycolic acid

2. Enzymes w/role in essential processes to TB

3. Enzymes that are unique to TB bacteria

Isoniazid

Ethambutol

Rifampin (+ rifabutin, rifapentin)

Pyrazinamide

Streptomycin

Quinolones (moxifloxacin, gatifloxacin)

Ethionamide

Aminosalicylic acid

Cycloserine

IFN-gamma

Amikacin

Kanamycin

 Capreomycin

Linezolid

Ethionamide is second-line

(Ethambutol is first-line)

1.  Damage to skin and peripheral nervous syst.

2.  Affects colder areas of body (fingers/toes/nose/earlobes)

3.  Disfigurement

Dapsone

Clofazimine

Rifampin (also 1st line TB agent)

Treat for minimum of 2 years

Dapsone

Rifampin (also 1st line TB agent)

Treat for 6 months

Dapsone - inhibit folate synthesis

Clofazimine - unknown

Rifampin - inhibits RNA-dependent

                              DNA polymerase

Skin discoloration - ranging from red-brown

                                                 to black

Mycobacterium avium

Mycobacterium intracellularae

Amikacin

Rifabutin, Rifampin

Clarithromycin

Azithromycin

Streptomycin

BOTH

Bacteriostatic - for "resting" bacilli

Bactericidal - for rapidly-dividing bacilli

Isoniazid is a pro-drug.

What enzyme converts it to its active metabolite?

Inhibits synthesis of mycolic acid

by targeting the inhA gene product

that codes fo an enzyme that converts unsaturated FAs to saturated FAs

in the mycolic acid biosynthesis pathway

(if there is a mutation in the inhA gene, the drug will NOT work -- resistance)

Glucuronidation

Acetylation

One of the ways Isoniazid is

metabolized is by acetylation.

 What is significant about this

in this particular drug?

Genetic variations in the NAT2 gene will affect acetylation of isoniazid.

Patients can be fast or slow acetylators

Slow acetylation - recessive (need 2 variant alleles)

Fast acetylation - dominant (1 or 2 copies does this)

BOTH intracellular and extracellular

(b/c can penetrate macrophages)

katG - codes for the enzyme that activates the pro-drug (catalase-peroxidase)

inhA - drug target of isoniazid

ahpC

kasA

ndh

Why should isoniazid be administered with pyridoxine (vit B6)?

and

When is administration of pyridoxine (B6) with isoniazid indicated?

Minimize risk of peripheral neruopathy

and CNS toxicity

Indicated in patients predisposed to neuropathy:

elderly, pregnancy, HIV-infected, diabetic, alcoholic, anemic, uremic, slow acetylators

Which Anti-TB agent can turn

body fluids orange-red?

The half-life of rifampin is usually 1.5 to 5 hours.

What causes either a decrease or increase in half-life of rifampin?

Increased half-life of rifampin

hepatic insufficiency

Patients also taking isoniazid that are slow acetylators

Decreased half-life of rifampin

during first 14 days of treatment

(due to induced liver enzymes)

MOA of Rifampin, Rifabutin, and Rifapentine

(all same MOA)

Inhibits DNA-dependent RNA polymerase of mycobacteria and other Gm+ and Gm- organisms

Suppresses chain formation in RNA synthesis (does NOT affect elongation)

Rifabutin

(b/c is a less-potent inducer of P450s

c/p to rifampin)

polymyalgia

pseudo-jaundice

anterior uveitis (occular inflammation)

Rifamycin family

Rifampin

Rifabutin

Rifapentin

(Has effects on other Gm+ and Gm- bacteria)

Pyrazinamide works inside the M. tuberculosis in the acidic phagosome

(b/c drug is most-effective @ acidic pH)

Which anti-TB first-line agent has adverse effects of

1. Retrobulbar neuritis, resulting in loss of visual acuity and red-green color blindness 

2. Increased urate in the blood due to decreased excretion of uric acid?

Ethambutol

Pyrazinamide

Due to side effect of hyperuricemia

(decreased renal excretion of uric acid)

Targets mycobacterial

fatty acid synthase I gene

involved in myoclic acid synthesis

IFN-gamma activates macrophages to kill TB

Results in enhanced local immune stimulation

(Used in patients with multi-drug resistant TB)

ototoxic (hearing loss)

nephrotoxic

vertigo

activatd by a mycobacterial redox system

(A NADPH-specific, FAD-containing monooxygenase (EtaA) converts ethionamide to 2-3thyl-4-aminopyridine)

What are 3 adverse effects of Cycloserine?

(2nd-line anti-TB agent)

CNS-related effects

(disappear when drug is d/c )

Increased risk of seizures

(not take w/alcohol or in pts with risk of seizure)

Increased risk of suicide in pts w/depression

What 4 species of plasmodium

cause human Malaria?

P. falciparum (most serious cases)

P. vivax

P. ovale

P. malariae

Concentrate in malarial food vacuoles and prevent polymerization of heme into memozoin

(toxic to parasite due to the buildup of free heme)

treatment and prophylaxis of sensitive malaria

Amebic abscesses that have failed initial therapy with metronidazole

Psoriasis

Porphyria

Variety of vision problems

History of liver, neurologic, or hematologic disorders

Quinine and Quinidine are derived from the bark of the cinchona tree and hence have an adverse effect of Cinchonism.

What are the symptoms of cinchonism?

tinnitus

headache

nausea

dizziness

flushing

visual disturbances

Blood Schizonticide

against P. falciparum and P. vivax

Therapy for chloroquine-resistant falciparum malaria

Prophylaxis against falciparum and others

Hematological problems

Pts receiving myelosuppressive drugs

Drug of choice for P. vivax and P. ovale

 Primaquine + Chloroquine = radical cure

(kills both blood and liver stages)

Given after travel to endemic areas

Also treats Pneumocystis jiroveci

Pyrimethamine

Proquanil (Malarone)

Fansidar

Sulfonamides (Sulfamethoxazole, etc.)

Tetracycline, Doxycycline

Clindamycin

Blood Schizonticide

(oral administration only)

Chloroquine

Amodiaquine

Quinidine & Quinine

Mefloquine

Artemisinin

Gametocides

Chloroquine (all except falciparum)

Amodiaquine (all except falciparum)

Quinidine & Quinine (for vivax and ovale)

Primaquine

Primaquine

(also a Gametocide)

Iodoquinol

Diloxanide furorate

Paromomycin sulfate

Extraintestinal infection

(though also works against intestinal infections)

Giardiasis

Trichomoniasis

Not absorbed well

(90% of drug is retained in the intestine, so can stay in the GI tract to kill the parasites)

Trypanosomatid protozoans

P. jiroveci

True

(50% of patients report toxicity)

Severe hypotension

Tachycardia

dizziness, dyspnea

pancreatic toxicity

hypoglycemia

Inhibits the pyruvate/feredoxin oxidoreductase pathway

(whatever that means)

Recently approved for

Giardia lamblia

Cryptosporidium parvum

Also effective against

E. histolytica, H. pylori

Ascaris lumbricoides, Fasciola hepatica

Drug of choice for

Hyatid disease

cysticerosis

Also for... hook/pinworms, ascaris, trichuriasis, strongyloidiasis

Drug of choice for

Facioliasis (sheep liver fluke)

mebendazole

piperazine

Piperazine

Pyrantel pamoate

carbamazepine (decreases)

phenytoin (decreases)

cimetidine (increases)

Pregnancy

Impaierd renal or liver function

History of epilepsy or chronic neurological disea.

Albendazole

Mebendazole

Thiabendazole

Primary = Mebendazole

Alternative = Piperazine

Primary = Ivermectin

Alternative = Thiabendazole

Gm +  (MSSA, MRSA)

Impetigo

Nitrofurantoin

Methenamine mandelate/hipurate

Ganiclovir

Competes with endogenous compounds for DNA polymerase & binds irreversibly to DNA template

**Chain termination when

incorporated into viral DNA

thymidine kinase

DNA polymerase

Valganciclovir

(pro-drug of gancyclovir)

Ganciclovir

(as a result, risk of retinal detachment)

(as well as myelosuppression)

Ganciclovir

Foscarnet (also covers HIV-1)

Inhibits fusion between the

plasma membrane and th HSV envelope, preventing viral entry into cells

Multiple-drug therapy (3 or 4 drugs)

for HIV-patients

Aims to...

reduce viral replication to the lowest possible level

decreases liklihood of resistance

prolong life

prevent disease progression

Emtricitabine

Lamivudine

Zalcitabine

Stavudine

Zidovudine

Didanosine (adenosine analog)

Zalcitabine (cyctosine analog)

Stavudine (thymidine analog)

Bind directly to HIV-1 reverse transcriptase -- resulting in blockade of RNA- and DNA-dependent DNA polymerase

Can NRTIs and NNRTIs be used together?

Why or why not?

Yes, b/c NRTIs and NNRTIs each have different binding sites

(unlike NRTIS, NNRTIs do not compete with nucleotide triphosphates nor do they require activation by phosphorlyation)

Skin rash

GI intolerance

Many potential CYP interactions

Abacavir (guanosine)

Didanosine (adenosine) - need antacid, NO food

Emtricitabine (cytosine)

Lamivudine (cytosine)

Zalcitabine (cytosine)

Stavudine (Thymidine)

Zidovudine (Thymidine)

Tenofovir (AMP) - high-fat meal

Nevirapine

Delavirdine - NO antacids

Efavirenz - high-fat meal

Rilpivirine - normal-to-high-calorie meal

Which is the only NNRTI that has

side effect of fat redistribution?

Which NNRTI has increased bioavailability when..

taken with a high-fat meal?

taken with normal-to high-calorie meal?

Efavirenz - high-fat meal

Rilpivirine - normal- to high-calorie meal

Lopinavir/Ritonavir-moderate- to high-fat meal

Nelfinavir - high-fat meal

Saquinavir - high-fat meal

Amprenavir

(possibly Fosamprenavir, which is pro-drug of amprenavir)

crystalluria

kidney stones (nephrolithiasis)

unconjugated hyperbilirubinemia

blocks viral entry into the cell

(binds to the gp41 viral envelope glycoprotein, prevents fusion fo virus with plasma memb

Blocks the action of integrase

(integrase is involved in incorporating viral DNA into the host chromosome)

False 

Raltegravir can be taken without regard to food

Rhabdomyolysis

Myopathy

Stevens-Johnson Syndrome

increased glucose, lipase, amylase

HBV

HCV

Lamivudine

Adefovir Dipivoxil

Entecavir

Ribavirin (misc. agent)

Telprevir (protease inhibitor)

Boceprevir (protease inhibitor)

Amantadine

Rimantidine

Zanamivir

Oseltamivir

Neuraminidase inhibitor

interferes with release of progeny virus from infected cells to new host cells

Amantadine & Rimantidine

Avoid 48 hours prior and 2 weeks after admin of influenza vaccine

Zanamivir & Oseltamivir

Avoid near vaccination times

Zanamivir - inhalation

Oseltamivir - oral

When therapy is initiated within 1 to 2 days

after onset of illness, the duration

is reduced by 1 to 2 days.

Ribavirin

Palvizumab

IFN-alpha

Imiquimod (Aldara)

Inhibits replication of RNA & DNA viruses

- inhib. virus RNA polymerase

- inhib. initiation & elongation of RNA fragments

- resulting in inhib. of viral protein synthesis

Monoclonal antibody directed at the A antigenic site of the F protein of RSV

Neutralizes and inhibits fusion of RSV