B-lactam abx and cell wall synthesis inhibitors - Lecture

Question 1

Natural Penicillins

Answer 1

Penicillin G - IV, IM

Penicillin V - PO

Question 2

Anti-Staphylococcals

Answer 2

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

Question 3

Extended spectrum and beta-lactamase inhibitors

Answer 3

Ampicillin + sulbactam - IV

Amoxicillin + clavulanic acid - PO

Question 4

Anti-pseudomonals and beta-lactamase inhibitors

Answer 4

Ticarcillin + clavulanic acid - IV

Pipercillin + tazobactam - IV

Question 5

Cell wall biosynthesis in gram + bacteria

Answer 5

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)

Question 6

Beta-lactam MOA

Answer 6

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

• penicillins - Penicillin G
• Cephalosporins, carbapenems, monolactams

Question 7

Natural Pencillin properties

Answer 7

Penicillin G and V are narrow spectrum

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

Question 8

Clinical indications of gram + cocci

Answer 8

S. pneumoniae- pneumococcal pneumonia

S. pyogenes - pharyngitis, scarlet fever

S. viridans group - endocarditis

Question 9

Clinical indications of spirochetes

Answer 9

T. pallidum - syphilis - single tx

Question 10

Clinical indications of gram - cocci

Answer 10

N. meningitides - meningococcal infection

Question 11

Clinical indications of anaerobes

Answer 11

C. perfringens - gas gangrene

Question 12

Penicillin pharmacokinetics

Answer 12

G - IV, IM, PO (low bioavailability)

V - PO - stable at gastric pH

Distribution into CNS with inflamed meninges

Renal elimination
Tubular secretion

Question 13

Hypersensitivity in Penicillins

Answer 13

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

Question 14

Penicillin conferring vulnerability to drug resistance

Answer 14

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

Question 15

Drugs shielded from degradation by b-lactamase

Answer 15

Methicillin
Nafcillin
Oxacillin
Dicloxacillin

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

Question 16

Methicillin

Answer 16

not clinically used
Renal clearance
Toxicity - Interstitial nephritis

Question 17

Nafcillin

Answer 17

IV
Hepatic, biliary clearance

Toxicity: hypersensitivity, CYP450 induction

Question 18

Oxacillin and Dicloxacillin

Answer 18

PO
Renal, biliary clearance

Toxicity: hypersensitivity

Question 19

Mechanism of methicillin resistance

Answer 19

alteration of mec A gene and PBP2 in S. aureus

includes resistance to methicillin, oxacillin, other ‘anti-staphylococcal’ penicillins

Use Vancomycin to treat MRSA

Question 20

Vancomycin Uses

Answer 20

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

Question 21

Vancomycin MOA

Answer 21

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 -

Question 22

Vancomycin pharmacokinetics

Answer 22

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

Question 23

Vancomycin adverse effects

Answer 23

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

Question 24

Extended spectrum penicillins

Answer 24

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

Question 25

Clinical indications of Amoxicillin - gram +

Answer 25

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

Question 26

Clinical indications of amoxicillin - gram -

Answer 26

H. influenzae - bronchitis in COPD

E. coli - OM

Proteus mirabilis

Question 27

Sulbactam

Answer 27

inhibits b-lactamase

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

Question 28

B-lactamase inhibitors

Answer 28

not antibiotics themselves

augment activity of other antibiotics by neutralizing their enzymatic degradation by b-lactamases

Question 29

Drugs ineffective against Pseudomonas aeruginosa

Answer 29

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

Question 30

Pseudomonas aeruginosa infections

Answer 30

opportunistic gram - rod

burn patients
CF patients
Injection drug users
Immunosuppressed patients

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

Question 31

Ticarcillin and Piperacillin

Answer 31

cover gram - rods

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

Piperacillin most potent

Question 32

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

Answer 32

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