B-lactam abx and cell wall synthesis inhibitors - Lecture Flashcards Preview

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Flashcards in B-lactam abx and cell wall synthesis inhibitors - Lecture Deck (32):
1

Natural Penicillins

Penicillin G - IV, IM
Penicillin V - PO

2

Anti-Staphylococcals

Methicillin - discontinued
Oxacillin - PO
Dicloxacillin - PO
Nafcillin - IV, PO

3

Extended spectrum and beta-lactamase inhibitors

Ampicillin + sulbactam - IV
Amoxicillin + clavulanic acid - PO

4

Anti-pseudomonals and beta-lactamase inhibitors

Ticarcillin + clavulanic acid - IV
Pipercillin + tazobactam - IV

5

Cell wall biosynthesis in gram + bacteria

Streptococci, Staphylococci, Enterococci

Cell wall synthesis involves cross-linking a unique dipeptide D-ala-D-ala to a string of glycine

1- sub-unit assembly
2- peptidoglycan elongation (transglycosylase)
3- Peptidoglycan cross-linking (transpeptidase PBPs)

6

Beta-lactam MOA

resemble D-ala-D-ala
inhibit cross-linking enzymes/transpeptidases irreversibly

-penicillins - Penicillin G
-Cephalosporins, carbapenems, monolactams

7

Natural Pencillin properties

Penicillin G and V are narrow spectrum

potent and effective against sensitive strains of gram + cocci, certain gram - cocci, certain gram + anaerobic species, spirochetes

8

Clinical indications of gram + cocci

S. pneumoniae- pneumococcal pneumonia

S. pyogenes - pharyngitis, scarlet fever

S. viridans group - endocarditis

9

Clinical indications of spirochetes

T. pallidum - syphilis - single tx

10

Clinical indications of gram - cocci

N. meningitides - meningococcal infection

11

Clinical indications of anaerobes

C. perfringens - gas gangrene

12

Penicillin pharmacokinetics

G - IV, IM, PO (low bioavailability)

V - PO - stable at gastric pH

Distribution into CNS with inflamed meninges

Renal elimination
Tubular secretion

13

Hypersensitivity in Penicillins

All penicillins have risk for hypersensitivity, including anaphylaxis

Penicillin "hapten" reacts with proteins

Happen-Protein adduct is antigenic

Later exposure to "hapten" provokes allergy/anaphylaxis in sensitized host

14

Penicillin conferring vulnerability to drug resistance

B-lactam in Penicillin G/V

B-lactam ring essential for activity but makes it vulnerable to resistance

S. aureus with plasmid encoding b-lactamase --> resistance
-b-lactamase cleaves ring, inactivating penicillin

-Penicillin G, V, ampicillin, amoxicillin, ticarcillin, piperacillin

15

Drugs shielded from degradation by b-lactamase

Methicillin
Nafcillin
Oxacillin
Dicloxacillin

Drugs of choice for penicillin -resistant, methicillin sensitive organisms - S. aureus (MSSA)

16

Methicillin

not clinically used
Renal clearance
Toxicity - Interstitial nephritis

17

Nafcillin

IV
Hepatic, biliary clearance

Toxicity: hypersensitivity, CYP450 induction

18

Oxacillin and Dicloxacillin

PO
Renal, biliary clearance

Toxicity: hypersensitivity

19

Mechanism of methicillin resistance

alteration of mec A gene and PBP2 in S. aureus

includes resistance to methicillin, oxacillin, other 'anti-staphylococcal' penicillins

Use Vancomycin to treat MRSA

20

Vancomycin Uses

Gram + bacteria

MRSA, MRSE
Enterococci (E. faecalis, E. faecium)
C. difficile orally for topical effect in bowel (if metronidazole failed)

No activity against gram - aerobes or anaerobes

21

Vancomycin MOA

glycopeptide cell wall synthesis inhibitor by binding the D-ala-D-ala and sterically hindering transglycosylation and transpeptidation

inhibits transglycosylase

Covers streptococcal or staphylococcal gram + not gram -

22

Vancomycin pharmacokinetics

Not absorbed in intestines - useful for C. diff colitis if metronidazole fails

IV - slow 60-90 min
Distributes into CNS if inflamed meninges

Renal elimination
Glomerular filtration

23

Vancomycin adverse effects

Erythroderma or shock
-manage with anti-histamines/steroids

Nephrotoxicity and ototoxicity
-rare with mono therapy, more common when administered with other nephro- or ototoxins (aminoglycosides)

Dermatologic - rash

Phlebitis at injection site

24

Extended spectrum penicillins

Ampicillin + sulbactam - IV, parenteral
Amoxicillin + clavulanic acid - PO, stabile at gastric pH

absorption --> 100%, too little stays in gut to use for enteritis

Renal elimination, tubular secretion

Enter via porins
Bind to PBPs in periplasm
Disrupt cells all integrity

B-lactmase enzymes will degrade ampicillin and amoxicillin

Use with B-lactamase inhibitor

Use in penicillin resistant/methicillin sensitive S. aureus, S. pneumoniae, H. influenzae, E. coli

25

Clinical indications of Amoxicillin - gram +

Gram + cocci:
-S. pneumoniae
-S. pyogenes
-S. viridans group
-Enterococci

Gram + bacilli:
-Listeria monocytogenes

Diseases:
Respiratory infections:
community acquired pneumonia (CAP), sinusitis, bronchitis, pharyngitis

used in children with pharyngitis because of taste

26

Clinical indications of amoxicillin - gram -

H. influenzae - bronchitis in COPD

E. coli - OM

Proteus mirabilis

27

Sulbactam

inhibits b-lactamase
-irreversibly inactivates enzyme
-depletes b-lactamase activity
-spares ampicillin
-no intrinsic antibiotic effect

28

B-lactamase inhibitors

not antibiotics themselves
augment activity of other antibiotics by neutralizing their enzymatic degradation by b-lactamases

29

Drugs ineffective against Pseudomonas aeruginosa

Penicillin G and V
Nafcillin, Oxacillin, Dicloxacillin
Ampicillin, Amoxicillin

30

Pseudomonas aeruginosa infections

opportunistic gram - rod

burn patients
CF patients
Injection drug users
Immunosuppressed patients

Resistance mechanisms:
Altered PBPs
Porin deficit - MDR
Not mediated by b-lactamase

31

Ticarcillin and Piperacillin

cover gram - rods

Enterobacter spp., E. coli, Proteus mirabillis, H. influenzae, Pseudomonas aeruginosa

Piperacillin most potent

32

Utility of using ticarcillin and piperacillin with a b-lactamase inhibitor

serious infection - pneumonia when gram - suspected and if pseudomonas aeruginosa is a concern

Ex:
-severe pneumonia in hospitalized patient with COPD
-Neutropenic fever - sepsis
-Aspiration pneumonia in hospitalized patient or stroke victim