Inhibition of cell wall synthesis

Penicillins, cephalosporins, imipenem/meropenem, aztreonam, vancomycin

Inhibition of bacterial protein synthesis

Inhibtion of nucleic synthesis

Inhibition of folic acid synthesis

Penicillin & cephalosporins resistance mechanisms

Aminoglycosides resistance

Drugs that bacteria develop resistance to (gentamicin, streptomycin, amikacin)

Forms enzymes that inactivate drugs via conjugation rxns that trasfer acetyl, phosphoryl etc. groups

Macrolides and clindamycin resistance 

Drugs erythromycin, azithromycin, clarithromycin etc.

Forms methyltransferases that alter drug binding sites on the 50S ribosomal subunit, or active transport of the drug out of cells

Tetracyclines resistance

Sulfonamides resistance

Fluoroquinolones

Chloramphenicol resistance

Penicillins

MOA: interact w/ cytoplasmic membrane binding proteins to inhibit transpeptidation rxns involving the bacterial cell wall synthesis

Elimination: most via active tubular secretion in kidney, nafcillin, oxacillin eliminated via bile, benzathine pcn G eliminated via repository form

SE: hypersensitivity can be any of the type I-IV rxns  

Narrow spectrum PCN's

Penicillin G and V

Spectrum: gram (+) cocci (strep/penumo/meningo) + Treponema pallidum (G is DOC for syphilis)

Very narrow spectrum PCN's

nafcillin, methicillin, oxacillin

Spectrum: known or suspected staphylococci (NOT MRSA)

broad spectrum PCN's

beta-lactamase sensitive

Ampicillin & Amoxicillin

Spectrum: gram + cocci (not staph), E.coli, H, influenzae, Listeria monocytogenes (DOC ampicillin) Borrelia burgdorferi, H.pylori (amoxicillin)

Activity enhaced if used w/ clavulanic acid which are inhibitors of beta lactamase

Synergy w/ aminoglycosides (gentamicin) against enterococcal species

Extended spectrum PCN's

Ticarcillin, piperacillin, azlocillin

Spectrum: everything plus gram (-) rods like Pseudomonas aeruginosa

Enhanced activity if used w/ beta-lactamase inhibitors like clavulanic acid and sulbactam

Synergy w/ aminoglycosides against Pseudomonas

Two drug bugs

Pseudomonas

Listeria

Enterococcus

Cephalosporins

MOA: interact w/ cytoplasmic membrane-binding proteins to inhibit transpeptidation rxns w/in bacterial cell walls

Elimination: via active tubular secretion blocked by probenecid, ceftriaxone is eliminated via bile

SE: hypersensitivity (rashes/drug fever),

disulfiram-like rxn (cefotetan, cefoperazone, cefamandole)

hypoprothrombinemia (def. of factor II)  

Organisms not covered by cephalosporins

Listeria monocytogenes (amp + gent)

Atypicals (chlamydia, mycoplasma)

MRSA (vancomycin)

Enterococci (amp +gent)

Narrow spectrum cephalosporins (1st gen.)

cefazolin, cephalexin

Spectrum: gram + cocci, Proteus, E.coli, Klebsiella pneumoniae

Common in surgical prophylaxis, DO NOT enter CNS

Broad spectrum cephalosprorins (2nd gen.)

cefotetan, cefaclor, cefuroxime

Spectrum: increasing gram (-) coverage, some anaerobes (Actinomyces, bacteriodes, clostridium)

Very broad spectrum cephalosporins (3rd gen.)

Ceftriaxone, Cefotaxime, Cefdinir, Cefixime

Spectrum: Less gram (+) more gram (-) cocci & rods

Most enter the CNS

Empiric management of meningitis and sepsis 

very broad spectrum cephalosporins (4th gen.)

Cefepime

Widest spectrum for mostly gram (-) cocci/rods

Resistant to most beta-lactamases

Enters the CNS

Imipenem, Meropenem, Ertapenem

MOA: interact w/ cytoplasmic membrane-binding proteins to inhibit transpeptidation rxns w/in the bacterial cell wall (resistant to beta-lactamases)

Spectrum: broadest we have! use for empiric tx

Imipenem is given w/ cilastatin which inhibits its rapid metabolism by renal dehydropeptidase

SE: GI distress, drug fever, CNS effects

Aztreonam

MOA: interact w/ cytoplasmic mebrane-binding proteins to inhibit transpeptidation of bacterial cell wall synthesis (resistant to beta-lactamases)

Spectrum: IV drug mainly active against gram (-) rods, doesn't kill any gram (+)

Vancomycin

MOA: binds to the D-ala-D-ala muramyl pentapeptide to sterically hinder the transglycosylation rxns involved in peptidoglycan chains

Spectrum: only gram +'s, Enterococci  

DOC: for nosocomial MRSA

used as a backup drug for C. difficile

Enterococcal resistance involves change in the muramyl pentapeptide target via changing the D-ala to a D-lactate

Given IV and orally (not absorbed so good for colitis)

SE: "red man syndrome" from histamine release, otoxicity, nephrotoxicity

Aminoglycosides (MOA)

30s

Inhibits formation of initiation complex, via blocking associaiton of 50s ribosomal subunit w/ mRNA-30s, causes misreading of code, may even incorporate wrong amino acid (if so = bacteriocidal)

Linezolid (MOA) 

50s

Inhibits the formation of the initiation complex by blocking the association of 50s ribosomal subunit w/ mRNA-30s

Tetracyclines (MOA)

30s

Block the attachment of aminoacyl tRNA to the acceptor site = tRNA specific for each AA is not allowed to enter site

Dalfopristin/quinupristin (MOA) 

50s

block the attachment of aminoacyl tRNA to acceptor site  

Chloramphenicol (MOA) 

50s, bacteriostatic

Inhibits the activity of peptidyltransferase (can't form peptide bond w/ elongating chain) 

Macrolides & clindamycin (MOA)

50s, bacteriostatic

Inhibits translocation of peptidyl-tRNA from acceptor to donor site

Aminoglycosides

gentamicin, tobramycin, amikacin, streptomycin

Accumulated intracellularly via an O2-dependent uptake (so anaerobes are innately resistant), spectrum = gram (-) rods only

Streptomycin: used in TB and is DOC for bubonic plague & tularemia

Renal elimination so adjust dose in renal dysfunction

SE: nephrotoxicity (usu reversible but enhanced by vancomycin, amphotericin B, cisplatin, and cyclosporine), ototoxicity (enhanced by loop diuretics)

Tetracyclines

doxycycline, minocycline, demeclocycline

30s, bacteriostatic

Spectrum: "broad" including chlamydial, mycoplasmal species, H.pylori, Rickettsia, Borrelia burgdorferi, Brucella, Vibrio

doxycyline: more activity overall, good for prostatitis b/c reaches high levels there

minocycline: concentrates in saliva/tears

demeclocycline: used in SIADH blocks ADH receptor function in collecting ducts (receptors aka V2)

Elimination: kidney except doxy via liver

chelators: bind divalent cations (Ca2+, Mg2+, Fe2+, Al3+) which decrease their absorption so becareful w/ antacids

SE: Tooth enamel discoloration & dec. bone growth in children (DON'T use)

Phototoxicity

Chloramphenicol

50s, bacteriostatic

Spectrum: wide, used as back up drug for Salmonella typhi, B. fragilis, Rickettsia

Metabolized by hepatic glucuronidation so dec. dose in liver failure/neonates, also inhibits CYP450

SE: dose-dependent bone marrow supression, "gray baby syndrome" in neonates (b/c can't glucuronidate)

Macrolides

erythromycin, azithromycin, clarithromycin

50s, broad spectrum, often used in community acquired pneumonia 

erythromycin: gram + cocci, atypicals (chlamydia, mycloplasma), legionella, Campylobacter jejuni)

liver metabolism, CYP450 inhibitor

azithromycin: above + more active in respiratory infxns Mycobacterium avium

Excreted by kidney, safer in pregnancy

clarithromycin: greater activity against M. avium and H. pylori

liver metabolism, CYP450 inhibitor

SE: stimulate motilin receptor & cause GI distress, reversible deafness a high doses, erythromycin estolate causes cholestasis, jaundice

Clindamycin

50s, not a macrolide

Spectrum: "narrow" gram + cocci (no MRSA), anaerobes including B. fragilis, toxoplasmosis

Concentrates in bone so has value in osteomyelitis

1st known drug to cause pseudomembranous colitis (caused by C. difficile)

Linezolid

50s, inhibits the formation of the initiation complex in bacterial translation systems by preventing formation of the complex

Spectrum: tx of vancomycin resistant Staph & Enterococci, and drug-resistant pneumococci

SE: bone marrow supression (thrombocytopenia- dec. platelets)

Quinupristin-Dalfopristin

MOA: streptogramins that act in concert via several mechanisms (prevent interaction of amino-acyl-tRNA w/ acceptor site and stimulate dissociation from ternary complex & block the extrusion of a completed polypeptide)

Spectrum: parenteral for VRSA & VRE, and other drug-resistant gram + cocci  

Sulfonamides, trimethoprim & pyrimethamine

MOA: folic acid synthesis inhibitors

sulfonamides inhibit the bacterial enzyme dihydropteroate synthetase and trimethoprim & pyrimethamine inhibit the human & bacterial enzyme dihydrofolate reductase

Sulfonamindes alone =limited use

Sulfasalazine = prodrug in UC and RA

Ag sulfadiazine = used topically in burns

TMP-SMX = DOC in nocarida, mycobacteria, gram (-) infxns (E.coli, salmonella, shigella, H.flu) gram (+), fungus (pneumocystis jiroveci), protozoa (toxoplasma gondii - use sulfadiazine + pyrimethamine)

Elimination: sulfonamides are hepatically acetylated, highly protein bound causes kernicterus in neonates (don't use in 3rd trimester)

SE:

Sulfonamides = hypersensitivity (SJS), phototoxicity, hemolysis in G6PD deficiency

Trimethoprim or Pyrimethamine = bone marrow supression (anemias anti-folate)

Drugs that have sulfonamides w/in watch for allergies

1. carbonic anhydrase inhibitors

2. thiazides

3. loops

4. sulfonylureas

5. celecoxib, valdecoxib

Stevens Johnson Syndrome

1. erythema multiforme

2. hemorrhagic crusts of lips and oral mucosa

3. MC in kids

Quinolones

Norfloxacin, ciprofloxacin, ofloxacin, other oxacins

MOA: inhibit topoisomerase II (DNA gyrase) responsible for separation of replicated DNA during cell division (ie: inhibits DNA synthesis)

Spectrum: great gram (-) coverage but not 1st line

Fe2+, Ca2+ limit their absorption (chelators), eliminated via kiney

SE: Phototoxicity, tendonitis/tendon rupture w/ long term use, increase the QT interval (so risk of torsades)

Metronidazole

unclassified ATBX, may produce free radicals?

GET BaC on the Metro

H.pylori regimins

"BMT" regimin = bismuth, metronidazole, and tetracycline

OR

Clarithromycin, amoxicillin, omeprazole

Isoniazid

one of the drugs used for TB, & prophylaxis

MOA: inhibits mycolic acid synthesis, but is a prodrug

Resistance: comes via deletions in the katG gene that encodes the catalase needed for INH bioactivation

SE: Hepatitis, peripheral neuritis, sideroblastic anemia, hemolysis in G6PD def., SLE in slow acetylators

Rifampin

used in TB tx

MOA: inhibits DNA-dependent RNA polymerase (nucleic acid synthesis inhibitor)

SE: hepatitis, induction of CYP450, red-orange metabolites in sweat, urine, tears 

Ethambutol

TB tx. regimin

MOA: inhibits synthesis of arabingalactan (cell wall component)

SE: dose-dependent retrobulbar neuritis --> dec. visual acuity and red-green discrimination

Pyrazinamide

TB tx regimin

MOA: unkown

SE: hepatitis, polyarthralgia, myalgia, rash, hyperuricemia (GOUT!!!), phototoxicity, inc. porphyrin synthesis