First Aid Micro/immuno Pharm

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Block cell wall synthesis by inhibition of peptidoglycan cross-linking

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PCN, ampicillin, ticarcillin, piperacillin, imipenem, aztreonam, cephalosporins

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Block peptidoglycan synthesis

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Bacitracin, vancomycin

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Disrupt bacterial cell membranes

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Polymyxins

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Block nucleotide synthesis

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Sulfonamides, trimethoprim

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Block DNA topoisomerases

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Quinolones

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Block mRNA synthesis

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Rifampin

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Block protein synthesis at 50S ribosomal subunit

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Chloramphenicol, macrolides, clindamycin, streptogramins (quinupristin, dalfopristin), linezolid

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Block protein synthesis at 30S ribosomal subuni

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Aminoglycosides, tetracyclines

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Bacteriostatic

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Erythromycin, Clindamycin, Sulfamethoxazole, Trimethoprim, Tetracyclines, Chloramphenicol ("We're ECSTaTiC about bacteriostatics")

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Bacteriocidal

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Vancomycin, Fluoroquinolones, Penicillin, Aminoglycosides, Cephalosporins, Metronidazole ("Very Finely Proficient At Cell Murder")

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Penicillin

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PCN G (IV) PCN V (oral). Protype Beta-lactam antibiotics.
1. Bind penicillin-binding proteins
2. Block transpeptidase cross-linking
3. Activate autolytic enzymes

Uses: Bactericidal for gram-positive cocci, gram-pos rods, gram-neg cocci, and spirochetes (SYPHILIS)

Tox: Hypersensitivity reactions, hemolytic anemia

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Methicillin, nafcillin, dicloxacillin (penicillinase-resistant penicillins)

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Mechanism: same as penicillin. Narrow spectrum; penicillinase resistant because of bulkier R group.
Uses: S. aureus (except MRSA; resistant because of altered PBP target site)

Tox: Hypersensitivity reactions; methicillin- interstitial nephritis (see eosinophils in urine)

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Ampicillin, amoxicillin (aminopenicillins)

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Mechanism: Same as PCN. Wider spectrum; penicillinase-sensitiv. Also combine with clavulanic acid (penicillinase inhibitor) to enhance spectrum. AmOxicillin has great Oral bioavailability than ampicillin.

Uses: Extended-spectrum penicillin- certain gram positive bacteria and gram-negative rods (Haemophilus influenzae, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, enterococci) HELPS

Tox: Hypersensitivity reactions; ampicillin rash; pseudomembranous colitis

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Ticarcillin, carbenicillin, piperacillin (antipseudomonals)

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Mechanism: Same as PCN. Extended spectrum.

Uses: Pseudomonas spp. and gram neg rod + bacteriods; susceptible to penicillinase; use with clavulanic acid.

tox: hypersensitivity reactions

(TCP: Takes Care of Pseudomonas)

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Cephalosporins- General mechanism and toxicity

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Beta-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactercidal.

Tox: hypersens. reactions. Cross-hypersensitivity with penicillins occur in 10-15% of patients. Increased nephrotoxicity of aminoglycosides; disulfiram-like reaction with ethanol (in cephalosporins with a methylthiotetrazole group, e.g. cefamandole, cefoperazone, cefotetan)

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Ist generation cephalosporins:
cefazolin, cephalexin

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Gram pos cocci, Proteus mirabilis, E. coli, Klebsiella pneumonia (PEcK) Common causes of UTI's

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2nd generation cephalosporins:
cefoxitin, cefaclor, cefuroxime

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gram-pos cocci, Haemophilis influenzae, Enterobacter aerogenes, Neisseria spp,, Proteus mirabilis, E. coli, Klebsiella pneumoniae, Serratia marcescens (HEN PEcKS)
Cefuroxime enters CNS

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3rd generation cephalosporins: ceftriaxone, cefotaxime, ceftazidime

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serious gram neg infections resistant to other beta-lactams; meningitis (most penetrate BBB) Examples: ceftazidime for Pseudomas; ceftriaxone for gonorrhea

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4th generation cephalosporins: cefepime, cefpirome

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increased activity against Pseudomonas and gram-positive organisms

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Aztreonam

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Mechanism: A monobactam resitant to beta-lactamaes. Inhibits cell wall synthesis (binds to PBP3). Syngergistic with aminoglycosides. No cross allergenicity with penicllins
Clinical use: Gram-neg rods- Klebsiella spp., Pseudomonas spp,, Serratia spp. No actiivty against gram-positive or anaerobe. For penicillin-allergic patients and those with renal insufficiency who cannot tolerate aminoglycosides.

Tox: Usually nontoxic; occasional GI upset. No cross-sensitivity with penicillins or cephalosporins.

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Imipenem/cilstatin, meropenem

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Imipenem is a broad-spectrum beta-lacatamase resistant carbapenem. Always administered with cilastatin (inhibitor of renal dihydropeptidase I) to decrease inactivation in renal tubules.

Uses: Gram pos cocci, gram neg rods, and anaerobes. Drug of choice for Enterobacter. The significant side effects limit use to life-threatening infections or after other drugs have failed. Meropenem, however, has a reduced risk of seizures and is stable to dihydropeptidase I.
Tox: GI distress, skin rash, and CNS toxicity (seizures) at high plasma levels.

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Vancomycin

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Inhibits cell wall mucopeptide formation by binding D-ala D-ala portion of cell wall precursors. Bactericidal. Resistance occurs with amino acid change of D-ala D-ala to D-ala D-lac. (transposons from enterococci can do this)
Uses: Serious, gram-pos multi-drug resistanct organisms including S. aureus and Clostridium difficile (pseudomembrane colitis)
Tox: Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing- "red man syndrome" (can be largely prevented by pretreatment with antihistamines and slow infusion rate) Well tolerated in general- does NOT have many problems.

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Aminoglycosides: Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin ("Mean" GNATS canNOT kill anaerobes)

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Bactericidal. 30S inhibitor. Inhibits formation of initiation complex and causes misreading of mRNA. Requires oxygen for uptake; therefore ineffective against anaerobes.
Use: Severe gram neg infections. Synergistic with beta-lactam antibiotics. Neomycin for bowel surgery.
Tox: Nephrotoxicity (especially when used with cephalosporins). Ototoxicity (especially with loop diuretics). Teratogen.

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Tetracycline, doxycycline, demeclocycline, mincycline

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Bacteriostatic; bind to 30S and prevent attachment of amnoacyl-tRNA; limited CNS penetration. Doxycycline is fecally eliminated and can be used in patients with renal failure. Must NOT take with milk, antacids, or iron-containing preparations because divalent cations inhibit its absorption in the gut. Demeclocycline- ADH antagonist used in SIADH
Uses: Vibrio cholerae, Acne, Chlamydia, Ureaplasma Urealyticum, Mycoplasma pneuomoniae, Tularemia, H. pylori, Borrelia burgorferi (Lyme disese), Rickettsia, (VACUUM THe BedRoom)--think intracellular bugs and tick bites
Tox: GI distress, discoloration of teeth and inhibition of bone growth in children, photosensitivity. Teratogen.

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Macrolides: Erythomycin, azithromycin, clarithromycin

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Inhibit protein synthesis by blocking translocation; bind to the 23S rRNA of the 50S ribosomal subunit. Bacteriostatic. Erthyomycin and clarithomycin but NOT azithromycin are p450 inhibitors.

Uses: URI's, pneumonias, STDs, gram pos cocci (strep infections in patients allergic to penicillins), Mycoplasma, Legionella, Chlamydia, Neisseria

Tox: GI discomfort (most common cause of noncompliance), acute cholestatic hepatitis (seen in pregancy with use of Erythromycin), eosinophilia, skin rashes. Increases serum concentration of theophyllines, oral anticoagulants. Clarithromycin is embryotoxic.

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Chloramphenicol

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Mechanism: Inhibits 50S peptidyltransferase activity. Bacteriostatic.
Uses: Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae). Conservative use due to toxicities.
Tox: Anemia (dose dependent), aplastic anemia (dose independent), gray baby sydrome (in premature babies because they lack liver UDP-glucuronyl transferase)

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Clindamycin

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Blocks peptide bond formation at 50S ribosomal subunit. Binds at same spot as macrolides. Bacteriostatic.

Uses: Treat anaerobic infections (above the diaphragm) and gram pos
Tox: Pseudomembranous colitis (C. difficile overgrowth), fever, diarrhea

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Sulfonamides: Sulfamethozole (SMX), sulfisoxazole, triple sulfas, sulfadiazine

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PABA antimetabolites inhibit dihydropteroate synthetase. Bacteriostatic.
Uses: Gram pos, gram neg, Nocardia, Chlaymdia. Triple sulfas or SMX for simple UTI.
Tox: Hypersens. reactions, hemolysis if G6PD def., nephrotoxicity (tubulointerstitial nephritis), photosens, kernicterus in infants, displaces other drugs from albumin (e.g. warfarin). P450 inhibitor.

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Trimethoprim

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Inhibits bacterial dihydrofolate reductase. Bacteriostatic. Used in combo with sulfonamides causing sequential block of folate synthesis. Combo used for recurrent UTI, Shigella, Salmonella, Pneumocystis jiroveci pneumonia.

Tox: Megaloblastic anemia, leukopenia, granulocytopenia. (May alleviate with supplemental folinic acid)

TMP-treats marrow poorly

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Sulfa drug allergies apply to:

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Sulfonamides, Sulfonylureas, Thiazide diuretics, acetazolamide, and furosemide.

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Fluoroquinolones: Ciprofloxacin, norfloxacin, ofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, enozacin, and nalidixic acid (a quinolone)

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Inhibits DNA gyrase (topo II). Bactericidal. Must NOT be taken with antacids.

Uses: Gram neg rods of urinary and GI tracts (including Pseudomonas), Neisseria, some gram pos organisms

Tox: GI upset, superinfections, skin rashes, headache, dizziness. Contraindicated in pregnant women and children because animal studies show damage to cartilage). Tendonitis and tendon rupture in adults; leg cramps and myalgias in kids.

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Metronidazole

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Forms toxic metabolites in the bacterial cell that damage DNA. Bactericidal.

Uses: Antiprotozoal, Giardia, Entamoeba, Trichomonas, Gardneralla vaginalis, Anaerobes,. Used with bismuth and amoxicillin (or tetracycline) for "triple therapy against H. Pylori. Anaerobic infections below the diaphragm. "GET GAP on the Metro"

Tox: Disulfiram-like reaction with alcohol; headache, metallic taste. Mutagenesis in pregnancy.

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Polymyxins (B and E)

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Bind to cell membranes of bacteria and disrupt their osmotic properties. ("mix up the membrane") Cationic, basic proteins that act like detergents

Uses: Resistant gram-negative infections.

Tox: Neurotoxicity, acute renal tubular necrosis

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M. tuberculosis: Prophylaxis and Treatment

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Pro: INH
Tx: INH, streptomycin,pyrazinamide, rifampin, ethambutol, (INH-SPIRE)
2nd line- Cycloserine
Important side effect of ethambutol is optic neuropathy (red-green color blindness. For all, hepatotoxicty.

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M. avium intracellulare:
Prophylaxis and Treatment

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Pro: Azithromycin with CD4<100 or Clarithromycin with CD4<75
Tx: Azithromycin, rifampin, ethambutol, streptomycin

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M. Leprae: No Prophylaxis
Treatment

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Pro: N/A
Tx: Dapsone, rifampin, clofazimine

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Isoniazid (INH)

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Decrease synthesis of mycolic acids.
Uses: TB
Tox: Hemolysis if G6PD def., neurotoxicity, hepatoxicity, SLE-like syndrome, Pyridoxine (Vitamin B6) can prevent neurotoxicity. (INH injures neurons and hepatocytes) Different half-lives in fast and slow acetylators.

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Rifampin

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Inhibits DNA-dependent RNA polymerase.
Ues: TB, MAC; delays resistance to dapsone when used for leprosy. Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H. flu type B.

Tox: Minor hepatoxicity and drug interactions (P-40 inducer); orange body fluids (nonhazardous)

4 R's:
RNA polymerase inhibitor
Revs up microsomal P-450
Red/orange body fluids
Rapid resistance if used alone

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Resistance mechanism for Penicillins/cephalosporins

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Beta-lactamase cleavage of B-lactam ring or altered PBP in case of MRSA

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Resistance mechanism for Aminoglycosides

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Modification via acetylation, adenylation, or phosphorylation.

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Resistance mechanism for Vancomycin

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Terminal D-ala of cell wall component replaced with D-lac; Decreased affinity

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Resistance mechanism for Chloramphenicol

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Modification via acetylation

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Resistance mechanism for Macrolides

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Methylation of rRNA near erythromycin's ribosome-binding site

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Resistance mechanism for Tetracycline

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Decreased uptake or Increased transport out of cell

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Resistance mechanism for Sulfonamides

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Altered bacterial dihydropteroate synthetase, decreased uptake, or Increased PABA synthesis

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Resistance mechanism for Quinolones

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Altered gyrase or reduce uptake

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Treatment for VRE

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linezolid and streptogramins (quinupristin/dalfopristin)

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Amphotericin B

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Binds ergosterol, forms membrane pores that allow leakage of electrolytes.

Uses: Systemic mycoses of wide spectrum- cryptococcus, Blastomyces, Coccidioides, Aspergillus, Histoplasma, Candida, Mucor. Intrathecally for fungal meningitis; does not cross BBB.

Tox: Fever/Chills, hypotension, nephrotoxicity (great affinity for cells of kidney basement membrane), arrhythmias, anemia, IV phlebitis (venous inflammation). Hydration reduces nephrotoxicity. Liposomal amphotericin reduces toxicity.

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Nystatin

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Binds to ergosterol, disrupting fungal membranes. Too toxic for systemic use. "Swish and swallow" for oral candidiasis (thrush); topical for diaper rash or vaginal candidiasis.

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Azoles

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Inhibits ergosterol synthesis
Uses: Fluconazole for cryptococcal meningitis in AIDS patients because it can cross BBB) and candidal infections of all types. Ketoconazole for Blastomyces, Coccidioides, Histoplasma, Candida albicans; hypercortisolism. Clotrimazole and miconazole for topical fungal infections.

Tox: Hormone synthesis inhibition (gynecomastia), liver dysfunction (inhibits P-450), fever, chills

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Flucytosine

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Inhibits DNA synthesis by conversion of flurouracil, which competes with uracil.

Used in systemic fungal infections (Candida, Cryptococcus) in combination with amphotericin B.

Tox: nausea, vomiting, diarrhea, bone marrow suppression

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Caspofungin, Micafungin

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Inhibits cell wall synthesis by blocking 1,3-beta-D-glucan synthesis

Uses: Invasive aspergillosis, candida
Tox: GI upset, flushing

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Terbinafine

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Inhibits the fungal enzyme squalene epoxidase
Used to treat dermatophytoses (esp. onychomycosis)

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Griseofulvin

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Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues like nails.

Uses: oral treatment for superficial infections; inhibits growth of dermatophytes (tinea, ringworm)
Tox: teratogenic, carcinogenic, confusion, headaches, P-450 inducer; therefore, increases warfarin metabolism.

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Amantadine

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Blocks viral penetration/uncoating (M2 protein); may buffer pH of endosome. Also causes the release of dopamine from intact nerve terminals.

Uses: Prophylaxis and treatment for Influenza A; Rubella; Parkinson's

Tox: Ataxia, dizzines, slurred speech. Rimantidine is a derivative with fewer side effects since it does not cross BBB)

Mechanism of resistance: Mutated M2 protein . 90% of all influenza A strains are resistant so not used.

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Zanamivir, oseltamivir

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Inhibit influenza neuraminadase, decreasing release of viral progeny.
Used for both influenza A and B, avian flu

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Ribavirin

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Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase.
Uses: (RSV), chronic hepatitis C
Tox: Hemolytic anemia. Severe teratogen.

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Acyclovir

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Monophosphorylated by HSV/VZV thymidine kinase. Triphosphate formed by cellular enzymes. Preferentially inhibits viral DNA polymerase by chain termination.

Uses: HSV, VZV, EBV. Used for HSV-induced mucocutaneous and genital lesions as well as encephalitis. Prophylaxis in immunocompromised patients. For herpes zoster, use a related agent, famciclovir. No effect on latent forms of HSV and VZV.
Mechanism of resitance: lack of thymidine kinase-->use cidofovir

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Ganciclovir

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5'-monophosphate formed by a CMV viral kinase or HSV/VZV thymidine kinase. Triphosphate formed by cellular kinases. Preferentially inhibits viral DNA polymerase.

Use: CMV, especially in immunocompromised patients.
Tox: Leukopenia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes than acyclovir.
Mechanism of resistance: Mutated CMV DNA polymerase or lack of viral kinase.

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Foscarnet

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Viral DNA polymerase inhibitor that binds to the pyrophosphate-binding site of the enzyme. Does not require activation by viral kinase.

Uses: CMV retinitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV.

Tox: Nephrotoxicity, chelates divalent cations-->hypocal, hypomag.

Resistance: Mutated DNA polymerase

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Protease Inhibitors: -Navir
Saquinavir, ritonavir, indinavir, nelfinavir, amprenavir

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Inhibit assembly of new virus by blocking protease in progeny virions, inhibit Gag-Pol cleavage

Tox: GI intolerance (nausea, diarrhea), hyperglycemia, lipodystropy (fat redistribution similar to what is seen in Cushing's), thrombocytopenia (indinavir)

(NAVIR (never) TEASE a proTEASE)

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Reverse transcriptase inhibitors: NON-nucleosides

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Nevirapine, Efavirenz, Delavirdine (Never Ever Deliver Nucleosides)

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Reverse transcriptase inhibitors: nucleosides

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Zidovudine (ZDV, formerly AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), Lamivudine (3TC), abacavir

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Reverse transcriptase inhibitors: Mechanism/Uses/Toxicity

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Preferentially inhibit reverse transcriptase of HIV; prevent incorporation of DNA copy of viral genome into host DNA
Tox: Bone marrow suppression (neutropenia, anemia), peripheral neuropathy, lactic acidosis (nucleosides), rash (non-nucleosides), megaloblastic anemia (ZDV)
GM-CSF and erythropoietin can be used to reduce bone marrow suppression.
Uses: Highly active antiretroviral therapy (HAART) generally entails combination therapy with protease inhibitors and reverse trancriptase inhibitors. Initiated when patients have low CD4 counts (<500 cells/mm) or high viral load. ZDV is used for general prophylaxis and during pregnancy to reduce risk of vertical transmission.

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Fusion inhibitors: Enfuvirtide

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Binds viral gp41 subunit; inhibit conformational change required for fusion with CD4 cells. Therefore blocks entry and subsequent replication.
Uses: In patients with persistent viral replication in spite of antiviral therapy, used in combination with other drugs.

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Interferons: Mechanism and Toxicity

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Glycoproteins from human leukocytes that block various stages of viral RNA and DNA synthesis. Induce ribonuclease that degrades viral mRNA.
Tox: neutropenia

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IFN-alpha

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chronic hepatitis B and C, Kaposi's sarcoma.

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IFN-beta

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MS

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IFN-gamma

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NADPH oxidase deficiency (Chronic Granulomatous Disease)

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Tacrolimus (FK506)

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Similar to cyclosporine (calcineurin inhibitor); binds to FK-binding protein, inhibiting secretion of IL-2 and other cytokines
Potent immunosuppressive used in organ transplant recipients
Tox: Significant- nephrotoxicity, peripheral neuropathy, hypertension, pleural effusion, hyperglycemia.

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Azathioprine

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Antimetabolite precursor of 6-mercaptopurine that interferes with the metabolism and synthesis of nucleic acids. Toxic to proliferating lymphocytes.
Uses: Kidney transplantation, autoimmune disorders (including glomerulonephritis and hemolytic anemia)
Tox: Bone marrow suppression. Active metabolite mercaptopurine is metabolized by xanthine oxidase; thus, toxic effects may be increased by allopurinol.

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Muromonab-CD3 (OKT3)

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Monoclonal antibody that binds to CD3 (epsilon chain) on the surface of T cells.
Use: Immunosuppression after kidney transplantation.
Tox: Cytokine release syndrome, hypersensitivity reaction.

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Sirolimus (rapamycin)

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Binds to mTOR. Inhibits T-cell proliferation in response to IL-2.
Use: Immunosuppression after kidney transplantation in combination with cyclosporine and corticosteroids.
Tox: Hyperlipidemia, thrombocytopenia, leukopenia.

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Mycophenolate mofetil

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Inhibits IMP dehydrogenase thereby inhibiting de novo purine synthesis and blocks lymphocyte production.

Uses: lupus nephritis, transplantations

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Daclizumab

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Monoclonal Ab with high affinity for the IL-2 receptor on activated T-cells.

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Palivizumab

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Respiratory syncytial virus- blocks RSV protein

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Rituximab

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Non-Hodgkin Lymphoma- binds to surface protein

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Aldesleukin (IL-2)

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Uses: Renal cell carcinoma, metastatic melanoma

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Erythropoietin (epoetin)

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Uses: Anemias (esp. in renal failure)

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Filgrastim (G-CSF)
Sargramostim (GM-CSF)

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Use: Recovery of bone marrow

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Oprelvekin (IL-11)
Thrombopoietin

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Use: Thrombocytopenia