Infectious diseases: Pharmacology - Beta lactams Flashcards
Five types of beta lactams and examples
- Penicillins (e.g. benzylpenicillin, ampicillin)
- Cephalosporins (e.g. cefotaxime, cefaclor)
- Monobactams (e.g. aztreonam)
- Carbapenems (e.g. meropenem, ertapenem)
- B-lactamase inhibitors (e.g. tazobactam, clavulanate)
Mechanism of action of penicillins
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
Four mechanisms of resistance to beta lactams. Which of these is most common?
- Inactivation by beta-lactamase (most common)
- Modification of target PBPs
- Decreased antibiotic penetration
- Antibiotic efflux
What is the mechanism of methicillin resistance in MRSA? What other examples of resistance share this mechanism?
Modification of target PBPs
Also occurs in pneumococci and enterococci resistance to penicillin
What types of bacteria may develop resistance by decreasing penetration of antibiotic or via antibiotic efflux?
Gram negatives, as these are the only bacteria with an outer cell membrane
Three classifications of penicillins and examples
- Natural penicillins (e.g. benzylpenicillin - penicillin G, phenoxymethylpenicillin - penicillin V)
- Antistaphylococcal (e.g. flucloxacillin, dicloxacillin, methicillin)
- Extended spectrum (e.g. ampicillin/amoxicillin, piperacillin, ticarcillin)
Describe the difference in antimicrobial coverage afford by natural, antistaphylococcal, and extended spectrum penicillins
Natural: Gram positives, GNCs, non-B-lactamase-producing anaerobes
Antistaphylococcal: staphylococci, streptococci
Extended spectrum: Gram positives, Gram negatives, antipseudomonal (except amoxicillin/ampicillin)
What group of bacteria is not covered by natural penicillins?
GNRs
What group of bacteria is not covered by antistaphylococcal penicillins?
Gram negatives, anaerobes, enterococci
Which of the various classifications of penicillins are B-lactamase susceptible vs resistant?
B-lactamase susceptible: natural and extended spectrum penicillins
B-lactamase resistant: antistaphylococcal
Describe the absorption of penicillins
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
Describe the distribution of penicillins
Widely distributed in body fluids and tissues with exception of eye, prostate and CNS
Highly polar so extracellular > intracellular concentrations
Describe the excretion of penicillins
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)
Nine microbial indications for natural penicillins
- Streptococci
- Staphylococci
- Enterococci
- Meningococci
- Penicillin-susceptible pneumococci
- Treponema pallidum (and other spirochetes)
- Clostridium
- Actinomyces
- Others non-B-lactamase producing GPRs and anaerobes
Two microbial indications for antistaphylococcal penicillins
- B-lactamase-producing Staphylococci
- Penicillin-susceptible streptococci and pneumococci
Indications for extended spectrum penicillins
Gram negatives
Can be used in combination with B-lactamase inhibitors (e.g. tazobactam, clavulanate) to broaden coverage
What % of staphyloccocal strains produce B-lactamase? What other two microbes are increasingly producing B-lactamase?
90%
Also produced increasingly by H. influenzae and N. gonorrhoae
What is the major adverse effect seen with penicillins?
Hypersensitivity: anaphylaxis or serum sickness
Two specific risks of ampicillin
- Pseudomembranous colitis
- Non-allergic rash (especially when given in setting of viral infection e.g. EBV)
Specific risk of methicillin
Interstitial nephritis
Specific risk of nafcillin
Neutropenia
Describe the general difference in coverage offered by different generations of cephalosporins
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)
What is the difference in activity between penicillins and cephalosporins?
Cephalosporins less susceptible to B-lactamase
Two organisms against which cephalosporins are not active
- Enterococcus
- Listeria monocytogenes
Two examples of first generation cephalosporins
Cephalexin
Cephazolin
Three examples of second generation cephalosporins
Cefuroxime
Cefaclor
Cefotetan (actually a cephamycin)
Three examples of third generation cephalosporins
Ceftriaxone
Cefotaxime
Ceftazidime
One example of fourth generation cephalosporins
Cefepime
One example of a cephamycin. What generation of cephalosporin does this fall under?
Cefotetan
Coverage of first generation cephalosporins
GPC except MRSA
Limited Gram negatives: E. coli, Klebsiella, Proteus
Some anaerobic cocci
Coverage of second generation cephalosporins
Extended Gram negative compared with first gen: Klebsiella, H. influenzae)
Cefotetan offers anaerobe coverage
Some Gram positives
Coverage of third generation cephalosporins
Expanded Gram negative compared with first and second gen: Citrobacter, Serratia, B-lactamase-producing Haemophilus and Neisseria)
Coverage of fourth generation cephalosporins
More resistant to enterobacter B-lactamase and some extended spectrum B-lactamase
Pseudomonas cover
Indications for first generation cephalosporins
Cephalexin: simple UTI or cellulitis (not multiorganism)
Cephazolin: surgical prophylaxis
Indications for second generation cephalosporins
Sinusitis, otitis, LRTI due to activity against B-lactamase-producing H. influenzae and M. catarrhalis
Cefotetan: peritonitis, diverticulitis (mixed anaerobes)
Cefuroxime: CAP
Indications for third generation cephalosporins (specific for ceftazidime and ceftriaxone)
Ceftazidime: Pseudomonas
Ceftriaxone: gonorrhoea (due to increasing penicillin resistance), meningitis where penicillin-resistant pneumococci is suspected, sepsis of unknown cause
Indications for fourth generation cephalosporins
As for third gen but increased activity against penicillin-resistant streptococci and enterobacter
Which cephalosporins cross the BBB?
Some third gen (e.g. ceftriaxone)
What meningitis-causing organisms will not be covered by ceftriaxone and what other antibiotics should be considered instead?
Listeria monocytogenes (needs ampicillin or benzylpenicillin)
Pseudomonas (needs aminoglycoside)
Highly resistant pneumococcal strains (needs vancomycin)
Four possible adverse effects of cephalosporins. Which of these are specific to cefotetan?
- Hypersensitivity (5-10% cross-reactivity with penicillins)
- Superinfection
- Toxicity*
- Disulfaram-like reaction (EtOH sensitivity)*
- specific to cefotetan
What is the mechanism of superinfection in the setting of cephalosporin use?
2nd/3rd gen cephalosporins have limited activity against Gram positives
Leads to superinfection with e.g. MRSA, enterococcus
What are the four features of cefotetan toxicity?
- Local irritation
- Renal toxicity
- Hypoprothrombinaemia (increased bleeding risk)
Three examples of beta lactamase inhibitors
Clavulanate
Tazobactam
Sulbactam
Give four examples of bacteria which produce C class B-lactamases not easily inhibited by beta lactamase inhibitors
Enterobacter
Citrobacter
Serratia marscenens
Pseudomonas
Carbapenem coverage
Good activity against most GNRs including Pseudomonas (except for ertapenem)
Resistant to most beta lactamases
Does carbapenem dosing need to be renally adjusted?
Yes
Indications for use of carbapenems
Multiresistant organisms including ESBL
Mixed aerobic/anaerobic infections
Which is more cross-reactive with penicillins: cephalosporins or carbapenems?
Cephalosporins (5-10%) > carbapenems (1%)
