Beta Lactams: Penicillins (TEST 3)

Alexander Fleming

Discovered penicillin in 1928

Beta-Lactam

-heart of the pharmacophere

-4 membered lactone ring

Penicillum notatum

Penicillin G "natural Penicillin" originally came from?

Penicillum chrysogenum

from cysteine and valine with 3 stereogenic centers

open ring and "inactivate"

What do beta lactamases do to Penicillin G stability to base and basic enzymes?

Penicillin G stability to acid

intramolecular reaction that forms an intermediate that promotes the hydrolysis reaction

poor

Penicillin G has _________ oral bioavailability due to its instability in acids.

Penicillin G

What is the most potent of all antibiotics against susceptible species?

NO it only will tx inflammation: meningitis

Does Penivillin G have good CNS penetration?

-pneumonia

-endocarditis

-severe infections

-meningitis

-gangrene

-strep

-S. pneumoniae

-S. pyogenes

What are the indications for PenicillinG?

-low toxicity (one of the safest)

-low cost

-most potent

What are some advantages of using Penicillin G?

1st pass urinary excretion

How is Penicillin G excreted?

30 minutes

What is the t1/2 of Penicillin G?

Probenecid

-administered with Penicillin G that increase the blood level of Penicillin G by 2 fold

-it is an agent used to tx gout (decreases tubular excretion)

Beta lactam MOA

-Inhibits transpeptidase and other related enzymes that cross-link mucopeptides of bacterial cell walls” (only inhibits actively dividing bacteria)

-Cells rupture under osmotic stress (especially Gm + have high osmotic stress due to accumulation of AAs, sugars, salts)

Penicillin Binding Proteins (PBPs)

1) high molecular wt

2) low molecule qt

3) Penicillin "drug receptors"

4) beta-lactamase enzymes

5) body proteins

transpeptidases

What is the primary target of mechanism for penicillin binding proteins (PBPs)?

penicillin "drug receptors"

bacteria used to recognize Pens to signal for resistance

beta-lactamase enzymes

penicillanses, cephalosporinases

body proteins

produce allergic reactions (bind to penicillins to form 'allergens')

1) B-lactamase production

2) modification of penicillin binding proteins (PBPs)

3) reduced penetration of antibiotic to reach PBPs

4) multidrug efflux.- active ATP efflux pump

What are the different ways bacterias can have resistance to Penicillins and other B-lactams?

Beta-lactamase production

most frequent among both Gm (+) and Gm (-) species

Modification of penicillin binding proteins

-usually with transpeptidases

-less frequent, but high occurence in certain Gm (+) like staph. (MRSA)

Reduced penetration of antibiotic to reach PBPs

-certain Gm (-) like pseudomonas spp.

-eliminate/decrease # of porins)

Multidrug efflux

-multidrug resistant

-active ATP efflux punmp

-MDR Neisseria gonorrhea

-E. coli

-MDR pseudomonas aurguinosa

B-Lactamase inhibitors (Penicillinase inhibitors)

-no side chain

-no cytoplasmic membrane penetration

-no antibiotic activity

-react with B-lactamases

Unasyn

-Ampicillin + sulbactam Na

-SE: rash and AAD

-tx of severe infections

Augmentin

-Amoxicillin + Clavulanate

-oral

Zosyn

-IV ONLY

-Piperacillin Na + tazobactam

severe kidney failure

What problem can cause high serum levels that may induce seizures with Penicillin G?

serum sickness with Penicillin G

-rash

-fever

-joint pain

-"delayed" onset reaction

antihistamines or steriods

What do you treat serum sickness with?

anaphylactic reactions to Penicillin G

-shock

-massive histamine release

-swelling

-constriction of bronchioles

-heart failure

-circulatory collapse

-death

-primarily obeserved with IM, IV admin of Pen G

epinephrine

How do you treat anaphylactic reactions to Pen G?

NOT

Penicillins are ________ allergens!

haptens

Penicillins act as _________ that react with body proteins to form an allergen.

-cross reactions with other Pens

-exposure from food

-occupational hazards like gloves and masks while formulating

Where can Pen G allergies come from?

1 oxford unit

minimum amount of penicillin that inhibits the growth of a specific strain of Staph. aureus under specific conditions

0.5-2 M units

What is the typical dose of Pen G IV?

NO because other acid or base salts will alter pH and destroy Pen G

Can you admix Pen G with other drugs?

Penicillin G Procaine

-deep IM

-insoluble lipophilic salts

-tx of strep throat

-syphilitic eye disease with Probenicid

Penicillin G Benzathine

-IM or PO

-used for the prevention of rheumatic fever (group A strep)

-tx of syphilis

Bicillin

treats RTI pneumonia or otitis media

-combo of pen G benzathine and Pen G procaine

Penicillin V

-electron withdrawing side chain that prevents catalytic intramolecular reaction

-has acid stability so it can be admin orally

-spectrum about the same as pen G

-tx of minor infections and strep throat

Methicillin

-not available in the US

-work only on methicillin sensitive strains including penicillinase producers

-bulky R group blocks active site of beta-lactamase enzymes

-source of MRSA

Nafcillin

-IV, IM

-tx of severe staph infections

-side effect of decreased WBC count (neutropenia)

Oxacillin

-IV, IM

-tx of severe staph infections

-side effects of rash

Dicloxacillin

-oral (caps)

-tx of mild/moderate staph infections and impetigo

-side effects of abdominal pain and GI bleeding and rash

Ampicillin

-has a positive charge in side chain

-blocks formation of positively charged reaction intermediate required for the intramolecular reaction-catalyzed acid hydrolysis reaction

-used in the tx of RTI, S/SSI, GI, UTI, otitis media

-rash

-antibiotic associated diarrhea

What are the side effects of Ampicillin?

Amoxicillin

-oral

-hydroxylation of phenyl improves GI absorption

-Gm pos and neg

-tx of lyme disease and less severe RTI and otitis media in children

-side effects of rash and antibiotic-associated diarrhea

Aminopenicillins

are not active against most enteric KES (e.g., Klebsiella, Enterobacter), Pseudomonas spp. *Mycoplasma pneumoniae - inherently resistant!

Urido Pencillins

side chain increases GM neg penetration and increases GM neg PBP binding

-Amoxicillin

-Amox/Clav

-Piperacillin

-Ticarcillin

What are the drugs that have kidney impairment adjustment doses?