Pharmacology 28 & 29 (Penicillins)

obligate intracellular parasites

candida albicans

humans
fungi

bacteria

eukaryotic cell has distinct, membrane bound nucleus

prokaryotic cell has no nuclear membrane

prokaryotes - generate certain vitamins and factors that eukaryotes can't

bacterial (prokaryote) ribosomes have different size and binding capabilities than human (eukaryote) ribosomes

prokaryotes lack sterols in their membranes that eukaryotes have

bacteria (prokaryotes) rely on cell wall integrity to maintain fcn in osmotic pressure changes

peptidoglycan stabilizes cell wall (found in bacteria, spirochetes, actinomycetes, but NOT mycoplasma)

nothing like a peptidoglycan cell wall found in eukaryotes

gram positive bacteria

gram (+) bacteria have much more developed cell wall than do gram (-) bacteria, which makes them more sensitive

chains of alternating N-acetylglucosamine and N-acetylmuramic acid residues cross-linked with a glycine pentapeptide

transpeptidase

different bacteria have different transpeptidases

transpeptidase is one

others are needed for the penicillins to have cidal activity

spectrum
potency
kinetics

beta-lactam ring

penicillinase is a subset of beta-lactamase

bacterial transpeptidase binds to the beta-lactam ring of penicillin molecules, and thereby breaks the beta-lactam ring by cleaving the CO-N bond

the transpeptidase is bound covalently to the penicillin molecules and is therefore permanently lost

since the transpeptidase is lost, you don't have to maintain plasma levels for the penicillin to work; this is the post-antibiotic effect

bacteria need to be growing

at a growth site, the peptidoglycan cell wall is nicked by enzymes called autolysins

peptidoglycan is inserted until the cell has doubled in size

transpeptidase is lost, so that cross-linking of peptidoglycan chains cannot be performed

though the wall cannot be crosslinked, the autolysins continue to nick peptidoglycan in the cell wall and make holes

in isotonic medium, the cell membrane grows out of the cell wall (forming spheroplasts)
in hypo- or hypertonic solutions, the cell membrane is destroyed

dead bacteria and cells are dug out of the abscess and the bacteria start to grow, and then the cell wall inhibitors (e.g. penicillins) start to work again

they have a carboxylic acid group that causes them to be secreted in the proximal tubule of the kidney

**b/c of this the half-life is short**

1) autolysins usually clip strands of peptidoglycan to allow insertion of new material
2) teichoic acid in the cell wall prevents autolysins from acting
3) beta-lactam Abx induce the release of teichoic acid from the cell wall, resulting in unopposed autolysin activity

rapidly excreted by kidneys (90%)
only 10% excreted in bile

half-life is 30 minutes
if renal excretion is blocked with probenacid, half-life extends to 3-4 hours

benzathine penicillin G (long-acting pen G)

requires only one or two IM shots, so don't have to worry about compliance

**causative agent in syphilis = treponema pallidum**

procaine pen G and benzathine pen G

very oily suspensions that are next to insoluble and are dissolved slowly, so must be injected IM (very dangerous if given IV)

upon absorption, both forms are quickly hydrolyzed to pen G

units (1mg = 1667 units)

(4 x MIC) to control systemic infections

(10 x MIC) to control infections in CNS b/c CNS is missing a lot of immune system weapons

MIC = minimum inhibitory concentration

1) streptococcal infections
2) treponema
- even if pt has pen allergy, still use at a slow drip to deplete mast cells - done in hospital
3) Neisseria meningitidis
4) anaerobic bacteria
- clostridium perfringens
- clostridium tetani
- anaerobic strep

hydrolyzes the CO-N bond in the beta lactam rings of penicillins without covalently binding to the penicillin, so the penicillinase can be reused

penicillinase can inactivate 800 molecules of Pen G per second; wipes out entire dose before it ever gets the chance to attach to penicillin binding proteins

add a bulky R group, which creates steric hindrance to penicillinase binding (decreases affinity of penicillinase for the penicillin)

problem: also decreases affinity of penicillin for transpeptidase, so potency is decreased

secrete penicillinase into environment that destroys the pen G

oral penicillins that are stable to staphylococcal penicillinase

"-oxacillins"

vancomycin (IV)

changing the target proteins (penicillin binding proteins)

difficult to treat, requiring different class of antibiotic completely (no beta-lactams will work)

DOC: vancomycin (IV)

prevention: methicillin should only be used for penicillinase-producing S. aureus

outer cell membrane is unique to gram-neg bacteria and proves to be a tough permeability barrier

gram-neg bacteria can express penicillinase, and if they do it is present between the outer membrane and the cytoplasmic membrane (in the periplasmic space) as a bath for the peptidoglycan (if the penicillin gets through outer membrane, it is destroyed before it gets to PG)

proteins called porins are present in the outer membrane for uptake of nutrients

this can be taken advantage of in order for Abx to gain access, but this requires a hydrophilic molecule (charged)

bridges of Braun lipoprotein

amino groups in the R side chain

skin rashes - probably toxic, not allergic
- begins late in Tx (8th-10th day)
- though doesn't imply allergy to pens, best to stop drug

diarrhea
- gut flora dynamics altered considerably
- diminishing of certain organism pops results in enhances other bacteria pops

shows up several months after therapy

C. difficile elaborates a toxin that damages intestinal mucosa
- can result in fatal diarrhea

Tx: oral vancomycin (DO NOT alter intestinal motility b/c it will prolong toxin exposure)

interferes with the dephosphorylation of the C55-isoprenyl pyrophosphate, a molecule that carries the building-blocks of the peptidoglycan bacterial cell wall outside of the inner membrane

acts by inhibiting proper cell wall synthesis in Gram-positive bacteria; due to the different mechanism by which Gram-negative bacteria produce their cell walls and the various factors related to entering the outer membrane of Gram-negative organisms, vancomycin is not active against Gram-negative bacteria (except some non-gonococcal species of Neisseria)

DOC for C. difficile diarrhea

High activity against gram-pos bacteria; low/no activity against gram-neg

Acid-labile (easily destroyed in acid), so oral absorption is poor
- Must use IV or IM injections
Destroyed by beta-lactamase

Side Effects: skin rashes (all pens)

oral Penicillin G

High activity against gram-pos bacteria; low/no activity against gram-neg

Acid resistant (not broken down in acid), so oral absorption is good

Destroyed by beta-lactamase

Side Effects: skin rashes (all pens), diarrhea (all oral Abx)

Lower activity against gram-pos bacteria than Pen G; still low/no activity against gram-neg

Acid labile (easily destroyed in acid), so oral absorption is poor
- Must use IV or IM injections

Resistant to beta-lactamase, including staph beta-lactamase

Indications: skin infections (cellulitis)

Side Effects: skin rashes (all pens)

oral methicillin = isoxazolyl penicillin

Lower activity against gram-pos bacteria than Pen G; still low/no activity against gram-neg

Acid resistant, so oral absorption is good

Resistant to beta-lactamase, including staphylococcal penicillinase

Indications: skin infections (Staph aureus or Staph epidermidis)
- Used before infection gets serious enough to warrant hospital stay (as preventative measure against hospital stay)

Side Effects: skin rashes (all pens), diarrhea (all oral Abx)

oral methicillin = isoxazolyl penicillin

Lower activity against gram-pos bacteria than Pen G; still low/no activity against gram-neg

Acid resistant, so oral absorption is good

Resistant to beta-lactamase, including staphylococcal penicillinase

Indications: skin infections (Staph aureus or Staph epidermidis)
- Used before infection gets serious enough to warrant hospital stay (as preventative measure against hospital stay)

Side Effects: skin rashes (all pens), diarrhea (all oral Abx)

Active against gram-pos bacteria; low/no activity against gram-neg

IV administration

Resistant to staphylococcal beta-lactamase

Indications: skin infections (cellulitis)

Side Effects: Skin rashes

aminopenicillin

Destroyed by beta-lactamase (penicillinase)

High activity against gram-pos; more active against gram-neg

Administered IM/IV

Side Effects: Skin Rashes (all pens)

oral ampicillin = aminopenicillin

Destroyed by beta-lactamase (penicillinase)

High activity against gram-pos; more active against gram-neg

Oral administration

Side Effects: Skin Rashes (all pens), diarrhea (all oral Abx)

High activity against gram-pos; excellent for gram-neg aerobes

IV use only, for really sick patients

Side Effects: Skin Rashes (all pens)

High activity against gram-pos; excellent for gram-neg aerobes

IV use only, for really sick patients

Side Effects: skin rashes

suicide inhibitor of beta-lactamase

Has a beta-lactam ring which is attacked and covalently bound by the beta-lactamase; end up losing one molecule of beta-lactamase and one of clavulanic acid

Creates synergy with penicillins to decrease the minimum inhibitory concentration

suicide inhibitor of beta-lactamase

Has a beta-lactam ring which is attacked and covalently bound by the beta-lactamase; end up losing one molecule of beta-lactamase and one of sulbactam

Creates synergy with penicillins to decrease the minimum inhibitory concentration

suicide inhibitor of beta-lactamase

Has a beta-lactam ring which is attacked and covalently bound by the beta-lactamase; end up losing one molecule of beta-lactamase and one of tazobactam

Creates synergy with penicillins to decrease the minimum inhibitory concentration

uricosuric agent

Blocks renal excretion of Pen G to extend its half life from 30 minutes to 3-4 hrs

long-acting Penicillin G

Very oily suspension that is nearly insoluble and is dissolved slowly from IM sites

Dangerous if injected IV

After absorption, quickly hydrolyzed to Pen G

hospital (nosocomial infections)

has a particularly tough permeability layer

highly effective against Klebsiella and enterococcus

aminoglycosides

allergic rxns (beta lactam hapten)
skin rashes (toxic)
diarrhea (oral Abx)
seizures (blocks GABA with high plasma conc.)

Strep pneumoniae
Klebsiella pneumoniae
Haemophilus influenzae
Mycoplasma pneumoniae

third generation

skin rashes, urticaria, angioedema

anaphylaxis (rare)

"-penems"

carbapenems (imipenem, miropenem)

kills gram-neg and gram-pos, regardless of whether aerobe or anaerobe

beta-lactamases cannot even bind the beta-lactam ring

penicillins
cephalosporins
carbapenems
aztreonam

vancomycin

1) Red Man syndrome
a. Results from rapid IV infusion (over 15 minutes), so infuse a dose slowly over 1-2 hours
b. Caused by huge histamine release, which leads to flushing, itching, redness
c. Very uncomfortable, but not fatal
2) Renal toxicity
a. Monitor peak/trough