Antibiotics II: Cell Wall Inhibitors

Question 1

What are the Beta-Lactams?

Answer 1

▪ Broad group of antibiotics including the penicillins, cephalosporins and carbapenems

▪ All have a beta-lactam ring (4 membered lactam) with different side chains

▪ Cell wall inhibitors – target bacterial cell walls

▪ Only effective against actively growing
bacteria

▪ Bactericidal, time dependent

▪ Some cross allergenicity between groups – conflicting data (< 1% to 10%) *side chain similarity

Question 2

What do Beta-Lactams bind to?

Answer 2

▪ Bind to penicillin binding proteins (PBPs) which prevent the crosslinking of the cell wall components (peptidoglycans)

▪ PBPs are a family of enzymes needed for cell wall synthesis

▪ The cell wall is protective for the bacteria
- Cell contents are hyperosmolar and therefore withOUT the cell wall the cells swell and the bacterial cell membrane lyses (b/c of osmotic diff b/t inside/outside)

▪ Binding to a PBP in the septum of dividing bacteria prevent the division and result in long filamentous bacteria that die

Question 3

What are the Penicillins?

Answer 3

▪ Natural penicillins

▪ Penicillinase resistant penicillins

▪ Extended Spectrum Penicillins
- Aminopenicillins
- Antipseudomonal

Question 4

What are the names of the Natural Penicillins?

Answer 4

▪ Penicillin G, Penicillin VK

Question 5

What are the Natural Penicillins?

Answer 5

▪ Penicillin G-IV, IM

▪ Dosed in million units
- Eg. 4MU IV q4h

▪ Penicillin V Potassium - PO
- Dose in mg eg. 300mg PO q6h

▪ Adjust dosing in renal impairment

▪ Short half-life (〰30-60 minutes)

▪ Poor penetration across blood brain barrier-even with inflamed meninges

▪ Spectrum of Activity (narrow):
*- Mostly gram positive – ie. streptococci, enterococci, gram negative cocci and some anaerobes
- Staphylococci produce penicillinases and are resistant

Question 6

What are the names of the Penicillinase Resistant Penicillins?

Answer 6

▪ Cloxacillin, oxacillin, methicillin

Question 7

What are the Penicillinase Resistant Penicillins?

Answer 7

▪ Cloxacillin used clinically in Canada

▪ IV or PO

▪ Absorption decreased with food therefore separate out in time

▪ Hepatic metabolism – do not have to adjust for renal impairment

▪ Distributes widely in the body including bone, eyes and most body fluids

Spectrum of activity (narrow)
▪ Gram positives including staphylococcus (methicillin sensitive staphylococcus aureus-MSSA) and streptococci
▪ not enterococci, gram negatives and anaerobes

Question 8

What are the names of the Aminopenicillins?

Answer 8

▪ Amoxicillin-PO (and IV available as combination with clavulanic acid)

▪ Ampicillin-IV or PO

Question 9

What are the Aminopenicllins?

Answer 9

▪ Amoxicillin-PO (and IV available as combination with clavulanic acid)

▪ Ampicillin-IV or PO

▪ Half-life 1-2 hours

▪ Adjust in renal impairment
Spectrum of Activity:
- gram positives (not staphylococci) and some gram negatives
- Like penicillin but with better gram negative coverage
- When combined with beta-lactamase inhibitor (clavulanate, sulbactam) then broader coverage including staphylococci, most gram negative and anaerobes

Question 10

What are the names of the Antipseudomonal?

Answer 10

▪ Piperacillin-IV

Question 11

What are the Antipseudomonal?

Answer 11

▪ Piperacillin-IV

▪ No longer available alone- *just in combination with tazobactam (b/c too much resistant)

▪ Adjust dosing in renal impairment

▪ Short half-life approx. 1 hour

▪ Spectrum of Activity (broad): Developed to cover Pseudomonas Aeruginosa
- When combined with beta-lactamase inhibitor (tazobactam) then coverage includes most gram positive, most gram negative including pseudomonas and most anaerobes
- “big gun”

Question 12

What are the names of the Cephalosporins?

Answer 12

▪ Derived from the mold Acremonium

▪ 5 generations

▪ Generations 1-3 are available in Canada

Question 13

What are the Cephalosporins?

Answer 13

▪ Derived from the mold Acremonium

▪ 5 generations

▪ Generations 1-3 are available in Canada

▪ Similar mechanism of action to penicillins – bind to PBPs and inhibit cross linking of the peptidoglycans in the bacterial cell wall

▪ Bactericidal, time-dependent

*▪ Overall more stable against beta lactamases and therefore have broader spectrum of activity

Question 14

What are the names of the 1st Generation Cephalosporins?

Answer 14

▪ Cephalexin – PO

▪ Cefazolin – IV

▪ Others include: cefadroxil, cephalothin, cephirin and cephradrine (don’t know these)

Question 15

What are the 1st Generation Cephalosporins?

Answer 15

▪ Cephalexin – PO

▪ Cefazolin – IV

▪ Others include: cefadroxil, cephalothin, cephirin and cephradrine

▪ Distributes widely into most tissues and fluids – poor CSF penetration

▪ Short half-life – 30-80 minutes

▪ Renal excretion – adjust in renal impairment

Spectrum of activity:
- Good gram positive coverage both staphylococci and streptococci, not enterococci
- Some gram negative coverage (not pseudomonas) and some anaerobes

Question 16

What are the names of the 2nd Generation Cephalosporins?

Answer 16

▪ Cefuroxime, cefaclor, cefprozil – PO

▪ Cefuroxime, cefoxitin, cefotetan – IV

Question 17

What are the 2nd Generation Cephalosporins?

Answer 17

▪ Cefuroxime, cefaclor, cefprozil – PO

▪ Cefuroxime, cefoxitin, cefotetan – IV

▪ Renally cleared - adjust dosing in renal impairment

▪ Spectrum of activity
- In general cover what 1st generation covers with increased gram negative coverage (some respiratory organisms) and anaerobes including B. fragilis

Question 18

What are the names of the 3rd Generation Cephalosporins?

Answer 18

▪ Ceftazidime, ceftriaxone – IV

▪ Cefixime – PO

▪ Others include: cefoperazone, cefotaxime, ceftizoxime, cefpodoxime, cefdinir,cefditoren,ceftibuten

Question 19

What are the 3rd Generation Cephalosporins?

Answer 19

▪ Ceftazidime, ceftriaxone – IV

▪ Cefixime – PO

▪ Others include: cefoperazone, cefotaxime, ceftizoxime, cefpodoxime, cefdinir,cefditoren,ceftibuten

▪ Ceftriaxone does not need to be adjusted for renal impairment

▪ Distributes widely into most body tissues and fluids

Spectrum of Activity
- In general, better gram negative and anaerobic coverage and loses some of the gram positive coverage
- Ceftriaxone – has activity against most gram positive organisms (not MRSA or enterococcus)
- Ceftazidime - covers pseudomonas

Question 20

What are the names of the 4th and 5th Cephalosporins?

Answer 20

▪ Cefepime and ceftaroline

Question 21

What are the 4th and 5th Cephalosporins?

Answer 21

▪ Cefepime and ceftaroline

▪ Cefepime – gram positive, gram negative including pseudomonas, and anaerobes

▪ Ceftaroline – gram positive including MRSA, gram negatives and anaerobes

Question 22

What are the Carbapenems?

Answer 22

▪ Similar mechanism of action to penicillins – bind to PBPs and inhibit cross linking of the peptidoglycans in the bacterial cell wall

▪ Bactericidal, time-dependent

▪ Resistant to most beta lactamases (not carbapenemases or metallo- beta lactamases) and therefore have broad spectrum of activity

▪ Thought to have less cross allergenicity to other beta lactams

Question 23

What are the names of the Carbapenems?

Answer 23

▪ Meropenem, Ertapenem – IV

▪ Also Imipenem and Doripenem

Question 24

What are the Carbapenems?

Answer 24

▪ Meropenem, Ertapenem – IV

▪ Also Imipenem and Doripenem

▪ Penetrate body tissues and fluids well including CSF

▪ Bactericidal – time dependent

▪ Ertapenem – long half life 4 hours which allows for once daily dosing

▪ Spectrum of activity (broad) cover most gram positive, gram negative and anaerobes (ertapenem does not cover pseudomonas)

Question 25

What are the names of the Monobactams?

Answer 25

▪ Aztreonam IM, IV

Question 26

What are the Monobactams?

Answer 26

▪ Aztreonam IM, IV

▪ Distributes widely into body tissues and CSF

▪ Adjust dose in renal impairment

▪ Spectrum of Activity: aerobic gram negative rods (including pseudomonas)

Question 27

What are the adverse reactions of the Monobactams?

Answer 27

▪ Mostly gastrointestinal – nausea, vomiting

▪ Allergic reactions – rash, hives, anaphylaxis

Question 28

What are the names of the Glycopeptide?

Answer 28

▪ Vancomycin – IV, PO

Question 29

What are Glycopeptides?

Answer 29

▪ Vancomycin – IV, PO

▪ Inhibits cell wall synthesis through binding to d-alanine-d-alanine on the peptidoglycan terminus which prevents further elongation and cross-linking

▪ Distributes widely into tissue and fluids *except CSF

▪ PO vancomycin not absorbed from the GI tract – c.diff tx (have to give PO - severe diarrhea)

▪ Slowly bacteriocidal, AUC/MIC

▪ Spectrum of Activity (narrow): gram positives including MRSA and enterococci and clostridium difficile

Question 30

What is Vancomycin?

Answer 30

▪ Levels routinely drawn for IV formulation to ensure dosing is in target range and to prevent toxicity

▪ Weight based dosing adjusted for renal function

▪ Large molecule – v. poor absorption from GI tract

Question 31

What are the adverse effects of Vancomycin?

Answer 31

▪ Red man syndrome – infusion related reaction causing flushing (red at back of neck & top of shoulders)
- slow down rate

▪ Renal toxicity - if levels are really high

▪ Ototoxicity at very high levels

Question 32

What are the names of the Cyclic Lipopeptide?

Answer 32

▪ Daptomycin IV

Question 33

What are the Cyclic Lipopeptides?

Answer 33

▪ Daptomycin IV

▪ Binds to cell membrane which results in depolarization with potassium efflux

▪ Bacteriocidal

▪ Inactivated by pulmonary surfactant therefore cannot be used for pneumonia (*not for lung infections)

▪ Adjust dose for renal impairment

▪ Adverse reactions
▪ Rare cases of rhabdomyolysis, allergic pneumonitis

▪ Spectrum of Activity – similar to vancomycin