Infectious diseases: Pharmacology - Beta lactams

Question 1

Five types of beta lactams and examples

Answer 1

1. Penicillins (e.g. benzylpenicillin, ampicillin)
2. Cephalosporins (e.g. cefotaxime, cefaclor)
3. Monobactams (e.g. aztreonam)
4. Carbapenems (e.g. meropenem, ertapenem)
5. B-lactamase inhibitors (e.g. tazobactam, clavulanate)

Question 2

Mechanism of action of penicillins

Answer 2

Bind penicillin-binding proteins to prevent transpeptidation reaction essential to cross-linking and therefore stability of bacterial wall
This leads to cell lysis via unknown mechanisms

Bactericidal only when bacteria actively growing and synthesising cell wall

Question 3

Four mechanisms of resistance to beta lactams. Which of these is most common?

Answer 3

1. Inactivation by beta-lactamase (most common)
2. Modification of target PBPs
3. Decreased antibiotic penetration
4. Antibiotic efflux

Question 4

What is the mechanism of methicillin resistance in MRSA? What other examples of resistance share this mechanism?

Answer 4

Modification of target PBPs
Also occurs in pneumococci and enterococci resistance to penicillin

Question 5

What types of bacteria may develop resistance by decreasing penetration of antibiotic or via antibiotic efflux?

Answer 5

Gram negatives, as these are the only bacteria with an outer cell membrane

Question 6

Three classifications of penicillins and examples

Answer 6

1. Natural penicillins (e.g. benzylpenicillin - penicillin G, phenoxymethylpenicillin - penicillin V)
2. Antistaphylococcal (e.g. flucloxacillin, dicloxacillin, methicillin)
3. Extended spectrum (e.g. ampicillin/amoxicillin, piperacillin, ticarcillin)

Question 7

Describe the difference in antimicrobial coverage afford by natural, antistaphylococcal, and extended spectrum penicillins

Answer 7

Natural: Gram positives, GNCs, non-B-lactamase-producing anaerobes
Antistaphylococcal: staphylococci, streptococci
Extended spectrum: Gram positives, Gram negatives, antipseudomonal (except amoxicillin/ampicillin)

Question 8

What group of bacteria is not covered by natural penicillins?

Answer 8

GNRs

Question 9

What group of bacteria is not covered by antistaphylococcal penicillins?

Answer 9

Gram negatives, anaerobes, enterococci

Question 10

Which of the various classifications of penicillins are B-lactamase susceptible vs resistant?

Answer 10

B-lactamase susceptible: natural and extended spectrum penicillins
B-lactamase resistant: antistaphylococcal

Question 11

Describe the absorption of penicillins

Answer 11

Dicloxacillin, amoxicillin and ampicillin are acid-stable and well-absorbed orally (but with exception of amoxicillin are impaired by food)
Rest can be given IM or IV: IV preferred as IM causes pain and local irritation
Benzathine or procaine can be added to IM preparations to delay absorption and prolong duration of action

Question 12

Describe the distribution of penicillins

Answer 12

Widely distributed in body fluids and tissues with exception of eye, prostate and CNS
Highly polar so extracellular > intracellular concentrations

Question 13

Describe the excretion of penicillins

Answer 13

Natural penicillins rapidly excreted by kidneys (90% by tubular secretion; requires dose adjustment in renal failure)
Others less rapidly
Nafcillin primarily biliary excretion
Dicloxacillin both biliary and renal excretion (does not require dose adjustment)

Question 14

Nine microbial indications for natural penicillins

Answer 14

1. Streptococci
2. Staphylococci
3. Enterococci
4. Meningococci
5. Penicillin-susceptible pneumococci
6. Treponema pallidum (and other spirochetes)
7. Clostridium
8. Actinomyces
9. Others non-B-lactamase producing GPRs and anaerobes

Question 15

Two microbial indications for antistaphylococcal penicillins

Answer 15

1. B-lactamase-producing Staphylococci
2. Penicillin-susceptible streptococci and pneumococci

Question 16

Indications for extended spectrum penicillins

Answer 16

Gram negatives
Can be used in combination with B-lactamase inhibitors (e.g. tazobactam, clavulanate) to broaden coverage

Question 17

What % of staphyloccocal strains produce B-lactamase? What other two microbes are increasingly producing B-lactamase?

Answer 17

90%
Also produced increasingly by H. influenzae and N. gonorrhoae

Question 18

What is the major adverse effect seen with penicillins?

Answer 18

Hypersensitivity: anaphylaxis or serum sickness

Question 19

Two specific risks of ampicillin

Answer 19

1. Pseudomembranous colitis
2. Non-allergic rash (especially when given in setting of viral infection e.g. EBV)

Question 20

Specific risk of methicillin

Answer 20

Interstitial nephritis

Question 21

Specific risk of nafcillin

Answer 21

Neutropenia

Question 22

Describe the general difference in coverage offered by different generations of cephalosporins

Answer 22

First generation offers good Gram positive cover
Increasing Gram negative cover with second and third generation
Fourth generation covers both Gram positive and negative (including Pseudomonas)

Question 23

What is the difference in activity between penicillins and cephalosporins?

Answer 23

Cephalosporins less susceptible to B-lactamase

Question 24

Two organisms against which cephalosporins are not active

Answer 24

1. Enterococcus
2. Listeria monocytogenes

Question 25

Two examples of first generation cephalosporins

Answer 25

Cephalexin Cephazolin

Question 26

Three examples of second generation cephalosporins

Answer 26

Cefuroxime Cefaclor Cefotetan (actually a cephamycin)

Question 27

Three examples of third generation cephalosporins

Answer 27

Ceftriaxone Cefotaxime Ceftazidime

Question 28

One example of fourth generation cephalosporins

Answer 28

Cefepime

Question 29

One example of a cephamycin. What generation of cephalosporin does this fall under?

Answer 29

Cefotetan

Question 30

Coverage of first generation cephalosporins

Answer 30

GPC except MRSA Limited Gram negatives: E. coli, Klebsiella, Proteus Some anaerobic cocci

Question 31

Coverage of second generation cephalosporins

Answer 31

Extended Gram negative compared with first gen: Klebsiella, H. influenzae) Cefotetan offers anaerobe coverage Some Gram positives

Question 32

Coverage of third generation cephalosporins

Answer 32

Expanded Gram negative compared with first and second gen: Citrobacter, Serratia, B-lactamase-producing Haemophilus and Neisseria)

Question 33

Coverage of fourth generation cephalosporins

Answer 33

More resistant to enterobacter B-lactamase and some extended spectrum B-lactamase Pseudomonas cover

Question 34

Indications for first generation cephalosporins

Answer 34

Cephalexin: simple UTI or cellulitis (not multiorganism) Cephazolin: surgical prophylaxis

Question 35

Indications for second generation cephalosporins

Answer 35

Sinusitis, otitis, LRTI due to activity against B-lactamase-producing H. influenzae and M. catarrhalis Cefotetan: peritonitis, diverticulitis (mixed anaerobes) Cefuroxime: CAP

Question 36

Indications for third generation cephalosporins (specific for ceftazidime and ceftriaxone)

Answer 36

Ceftazidime: Pseudomonas Ceftriaxone: gonorrhoea (due to increasing penicillin resistance), meningitis where penicillin-resistant pneumococci is suspected, sepsis of unknown cause

Question 37

Indications for fourth generation cephalosporins

Answer 37

As for third gen but increased activity against penicillin-resistant streptococci and enterobacter

Question 38

Which cephalosporins cross the BBB?

Answer 38

Some third gen (e.g. ceftriaxone)

Question 39

What meningitis-causing organisms will not be covered by ceftriaxone and what other antibiotics should be considered instead?

Answer 39

Listeria monocytogenes (needs ampicillin or benzylpenicillin) Pseudomonas (needs aminoglycoside) Highly resistant pneumococcal strains (needs vancomycin)

Question 40

Four possible adverse effects of cephalosporins. Which of these are specific to cefotetan?

Answer 40

1. Hypersensitivity (5-10% cross-reactivity with penicillins) 2. Superinfection 3. Toxicity* 4. Disulfaram-like reaction (EtOH sensitivity)* * specific to cefotetan

Question 41

What is the mechanism of superinfection in the setting of cephalosporin use?

Answer 41

2nd/3rd gen cephalosporins have limited activity against Gram positives Leads to superinfection with e.g. MRSA, enterococcus

Question 42

What are the four features of cefotetan toxicity?

Answer 42

1. Local irritation 2. Renal toxicity 3. Hypoprothrombinaemia (increased bleeding risk)

Question 43

Three examples of beta lactamase inhibitors

Answer 43

Clavulanate Tazobactam Sulbactam

Question 44

Give four examples of bacteria which produce C class B-lactamases not easily inhibited by beta lactamase inhibitors

Answer 44

Enterobacter Citrobacter Serratia marscenens Pseudomonas

Question 45

Carbapenem coverage

Answer 45

Good activity against most GNRs including Pseudomonas (except for ertapenem) Resistant to most beta lactamases

Question 46

Does carbapenem dosing need to be renally adjusted?

Answer 46

Yes

Question 47

Indications for use of carbapenems

Answer 47

Multiresistant organisms including ESBL Mixed aerobic/anaerobic infections

Question 48

Which is more cross-reactive with penicillins: cephalosporins or carbapenems?

Answer 48

Cephalosporins (5-10%) > carbapenems (1%)