Pharmacology: Test 4: Antibiotics Lec 63

Front 1

Bactericidal Antibiotics: Concentration dependant

Back 1

These are classified as Type I, Concentration Dependant effect w/ SIGNIFICANT PAE (post antibiotic effect)

ex:

Lipopeptide daptomycin, aminoglycosides, ketolides, fluoroquinolones, nitroimidazole, rifamycin

FLAK RN

Front 2

Bactericidal Antibiotics: Time dependant

Back 2

These are classified as Type II, time dependant effect w/ NO PAE.

ex:
beta lactams (NONE FOR GRAM -), glycopeptides (vancomycin action on Gram Pos Rods -- it's bacteriostatic against Gram Pos Cocci).

Front 3

Bacteriostatic Antibiotics

Back 3

These are Type III, time dependant with moderate to prolonged PAE.

glycopeptides (Gram Pos Cocci), oxazolidinones, tertracycline, glycylcycline chloramphenicol, macrolides, lincosamine, sulfonamides

some beta-lactams have some PAE effect (none for Gram Neg though).

Front 4

Glycopeptide Antibiotics: VANCOMYCIN

Back 4

STATIC: Gram Pos Cocci
CIDAL: Gram Pos RODS (incl penicillinase producers and methicillin-resistant strains)

Front 5

Glycopeptide Antibiotics: VANCOMYCIN... Mech of Action

Back 5

Binds D-Ala-D-Ala terminus of Murine monomer, and prevents Transglycosylase from attaching disaccharide subunits to pre-existing cell wall. (NO THE NEW NAM-NAG ISN'T ABLE TO JOIN THE PREXISTING CHAIN)

Inhibition by binding the SUBSTRATE (unlike PCN which binds the enzyme)

not effective against Gram Neg

Front 6

Glycopeptide Antibiotics: VANCOMYCIN... Mech of Resistance

Back 6

acquisition of van HAX gene, allows it to replace the terminal D-ala with D-lactate, so vancomycin cannot bind to the end of the pentapeptide chain.

Front 7

Glycopeptide Antibiotics: VANCOMYCIN... Pharmcokinetics

Back 7

Poorly absorbed from GI, orally used to treat pseudomembranous colitis and Staphylococcal enterocolitis

Pri renal elimination.

No cross resistance or sensitivty to beta lactams, so can be used in these individuals to treat SERIOUS STAPHYLOCOCCAL AND STREPTOCOCCAL infections.

Front 8

Glycopeptide Antibiotics: VANCOMYCIN... Adverse effects

Back 8

RED MAN SYNDROME (hypersensitivity rxn: skin flushing, nephro, ototoxicity, neutropenia, tissue necrosis if given IM.

Front 9

Glycopeptide Antibiotics: TEICOPLANIN

Back 9

Since glyopeptide antiobitics are time dependant, and w/out much PAE, TEICOPLANIN is a good drug because:

extended Half-Life of elimination, Once daily dosing, fewer side effects (NO OTOTOXICITY), no tissue necrosis after IM.

Front 10

Beta Lactams

Back 10

Includes Penicillins, cephalosporins, carbapenemes, monobactam

Bactericidal: so requires actively growing infection

Front 11

Beta Lactams: Mechanism of action

Back 11

inhibition by binding the ENZYME (Transpeptidase)

This inhibits synthesis of crosslinks between repeating disaccharide subunits of cell wall.
- These bind the enzyme by mimicing the structure of D-alanyl-D-alanine substrate for transpeptidase.

The second way it works is by activating or disinhibiting autolytic enzymes which normally function to breakdown the cell wall during cell growth and division.

Both result in weakning of cell wall and osmotic pressure outwards causes rupture of the microorganism.

Front 12

Beta lactams: Mech of Resistance

Back 12

4 ways:

1. incrase penicillinase acitivity

2. decrease affinity for PCN binding protein (PBPs) through mutations.

3. decrease cell membrane permeability so drug can't get in.

4. active efflux of the drug out the cell.

Front 13

Beta lactam: Strategy to overcome pencillinase depenant resistance?

Back 13

introduce beta lactams and 'sucidice inhibitors' of pencillinase (beta lactamase) i.e.

AUGMENTIN: amoxcillin plus CLAVULANATE

UNASYN: ampicillin plus SULBACTAM

ZOSYN: pipericillin plus TAZOBACTAM

Front 14

Beta lactams: ADVERSE EFFECTS (except Monobactams)

Back 14

allergic rxn (drug's polymers and metabolites react with bacterial and tissue proteins to form antigenic conjugates).

Diarrhea (kids and children)

Cardiovascular effects due to fluid overload secondary to salts present in drug

CNS especially in renal failure pts (due to GABA inhibition: cause hallucinations and convulsions)

COAGULATION DEFECTS: esp w/ CARBENICILLIN AND TICARCILLIN (anti-pseudomonals). It inhibits platelet activation and conversion of fibrinogen to fibrin.

Front 15

beta lactam: Structure: significance of the B ring

Back 15

the B ring is active center of the drug, site of pencillinases, site of formation of major antigenic determinants

Front 16

beta lactam: Structure: significance of the R group

Back 16

acid stability, sensitivity to pencillinase acitivty, antibacterial spectrum and potency.

Front 17

Beta lactams: Pharmacokinetics

Back 17

good distro except CSF, PCNs organic acids so ionized at physio pH. Therefore, provided as Na or K salts.

Pri Elim: renal secretion of unmetabolized drug (short half life).

Hepatic metab not important for elimination but metabolites generated are important for generation of hypersensitivity reactions.

Front 18

Beta Lactams: Natural PCNs: PCN G and V

Back 18

natural compounds, has 6-aminopenicillanic acid nucleus composed of thaizolidine ring fused to a beta-lactam ring

Front 19

Beta Lactams: Natural PCNs: PCN G

Back 19

PCN G: most active against BROAD spectrum, GRAM POS, non-pencillinase producers. PCN G is acid labile, so only 1/3 oral dose is absorbed

Esp active against Neisseria and some anaerobes

blood levels extended by: delaying absorption by combining with PROCAINE or BENZATHINE (v. effective against SYPHILIS); OR delay elimination by adminstration of PROBENECID, competivite blocker of tubular secretin of organic acids.

Front 20

Testing for PCN Hypersensitivity?

Back 20

Skin testing: challenge with Pre-Pen to predict 95% of IgE mediated hypersensitivtiy. So, NEG test doesn't guarantee absne of anaphylactic response.

Front 21

Beta Lactams: PCNase resistant PCNs

Back 21

Think: i MET NAsty OXen

METhicillin, NAfcillin, OXacillin, clOXacillin, diclOXacillin

Front 22

Beta Lactams: PCNase resistant PCNs: Pathogen spectrum

Back 22

Initial therapy for beta lactamase producing gram positive coccal infection.

NEVER GIVEN WHERE NATURAL PCN ALONE WOULD WORK

Ideal for beta lactamase producing Staph aureus and staph epidermis

NOT active against Gram Negative

Front 23

Methicillin resistance (MRSA)

Back 23

related to failure to bind PCN binding proteins.

These organisms are likely to be resistant to other PCNs and Cephalosporins

Front 24

beta lactams: EXTENDED RANGE PCNS

Back 24

think i AM extended

AMpicillin, AMoxicillin

First PCN effective against Gram Negative (makes sense: it's there long enough to penetrate the Gram Negative. Also due to decrease susceptibility to Gram neg PCNases) These are more susceptible to Gram Pos PCNases though.

Amoxicillin more completely absorbed.

Active against: E. coli, P. mirabilis, H. influenza, Salmonella, Shigella, and Neisseria.

Front 25

beta lactams: Antipseudomonal PCNs

Back 25

think 'pseudo-CARs have tail PIPES'


Extended via carboxylation: CARbenicillin, tiCARcillin; extend range to Pseudomonas aeruginosa, Proteus and Enterobacter. ; OFTEN RESERVED FOR PULMONARY INFXN.

GREAT ADVERSE EFFECT OF COAGULATION DEFECTS WITH ABOVE.

Extended through N-acyl derivaation: PIPEricillin

Front 26

beta lactams: Cephalosporins

Back 26

similar action as PCNs, but wider range of activity due to alteration of R groups, PCNase resistance and pharmakokinetics.

Front 27

Cephalosporins: First Gen

Back 27

CefAzolin

A is the first letter in alphabet, so First Gen

narrow spectrum, Gram Pos

NO active infection, SURGICAL PROPHYLAXIS, does not penetrate CNS

No mrsa, no gram neg

Front 28

Cephalosporin: Second Gen

Back 28

Increased activity against Gram Negative, decreased activity against Gram Pos

CEFOTETAN and CEFOXITIN: Bacterioides fragilis (G-) and other anaerobic organisms, PROPHY during abd surgery

CEFUROXIME: H influenza, K pneumoniae (used in community acquired pneumonia), CROSSES BBB, use IV

LORACARBEF: aka carbacephem, acitivity comparable to amoxicillin/clavualante combo (Augmentin)

Front 29

Cephalosporin: Third Gen

Back 29

Good Penetration of CNS, BONE, LUNGS, URINARY TRACT

Highly active against Gram NEG enteric bacteria

BROADER spectrum: both Gram Neg and Pos.

CEFTRIAXONE: N gonorrhea, B burgdorferi (Lyme Dz)

CEFTAZIDIME, CEFOPERAZONE: indicated for Multi-drug resistant GRAM NEG ifxn esp. P. aeruginosa.

Front 30

Cephalosporins: Fourth Gen

Back 30

CEFEPIME: similar to ceftazidime in activity against P. aeruginosa, and other gram Neg;

better than Third gen against GRAM POS due to resistance to chromosomally encoded Beta lactamase

ORALLY ACTIVE

Front 31

Cephalosporin Adverse effects

Back 31

BLEEDING: (cefoperazone and cefotetan) due to hypothrombinemia, thrombocytopenia, Vit K deficiency

Bleeding common in ELDERS

nephrotoxicity esp. in combo with aminoglycosides

superinfection: wipe out enteric bacteria

Hypersensitivity (same as PCN)

Disulfiram-like Alcohol reaction w/ methylthiotetrazole group. Increased acetal dehydrogenase

Front 32

Carbapenems: Imipenem

Back 32

extremely broad spectrum, resistant to beta lactamase, rapidly hydrolyzed by RENAL dipeptidase so given in COMBO with CILASTATIN (dipeptidase inhibitor) as PRIMAXIN

NOT resistant to metallo-beta-lactamases,

Cross allergencities to PCN.

CNS seizures and renal toxicities

Front 33

Carbapenems: Meropenem

Back 33

similar to imipenem but less susceptible to renal tubule dipeptidase (doesn't require cilastin)

Less nephrotoxic than imipenem

Front 34

Monobactam (aztreonam)

Back 34

excellent activity against Gram Neg bacteria, poor Gram Positive

little cross-allergenicity with other beta lactam antibiotics (THE ONLY ONE)

Can be used in some cases instead of aminoglycosidases.

Front 35

Lipopeptide antibiotic: Daptomycin

Back 35

inhibition of cell membrane potential by forming membrane channels in Ca-dependant manner resulting in depolarization of the membrane inhibiting protein, DNA and RNA synthesis.

Front 36

Lipopeptide antibiotic: Daptomycin... Pathogen spectrum

Back 36

used for complicated skin and skin structure infections by aerobic, Gram Positive incl. resistant gram pos bacteria, also isolates resistant to methicillin, vacomycin, and linezolid (BIG GUN)

synergizes with oxacillin against MRSA.

Bactericidal against VRE (vancomycin resistant enterococci)

Front 37

Lipopeptide antibiotic: Daptomycin... Pharmcokinetics

Back 37

IV only (IM causes tox to muscle), excreted by Kidney (dose adj req'd for renal insufficiency)

Adv effects: irritation to site of injectin, skeletal muscle pain and weakness, increase CPK, renal failure.