4. Antibiotics

Question 1

The Main Mechanisms of Antibiotic Action

Answer 1

1. Inhibition of bacterial cell wall synthesis.
2. Inhibition of bacterial protein synthesis
3. Inhibition of bacterial DNA synthesis
4. Inhibition of bacterial RNA synthesis
5. Inhibition of bacterial folate synthesis

Question 2

Inhibition of bacterial cell wall synthesis.

Answer 2

Bacteria have an inner plasma membrane
which is surrounded by a peptidoglycan wall

Gram-negative species also have an outer lipid bilayer.

Beta-lactams such as the penicillins and cephalosporins suppress peptidoglycan
synthesis and so destroy the integrity of the whole cell wall

Vancomycin and bacitracin also interfere with peptidoglycan wall formation, as do the carbapenems,

Question 3

Inhibition of bacterial protein synthesis

Answer 3

30S and 50S comprise the larger 70S ribosome

Eukaryotic cells have 80S ribosomes which are
unaffected by these antibiotics

Tetracyclines also inhibit reactions at the 30S unit.

Tobramycin binds to the 30S ribosome but also suppresses initiation of the larger
70S complex.

Aminoglycosides block reactions at the 30S and 50S subunits

The macrolide erythromycin affects the 50S subunit, as does clarithromycin

Protein synthesis is completed by a process of peptide elongation in a reaction
catalyzed by peptidyl transferase.

Drugs such as clindamycin and lincomycin are specific inhibitors of this enzyme.

Question 4

Inhibition of bacterial DNA synthesis

Answer 4

A class of enzymes known as the topoisomerases are required for bacterial DNA replication.

Drugs such as the fluoroquinolones (ciprofloxacin, levofloxacin)
inhibit the activity of topoisomerase II without affecting mammalian enzymes.

Metronidazole interferes with DNA synthesis via the direct action of toxic metabolites.

Question 5

Inhibition of bacterial RNA synthesis

Answer 5

Rifampicin, for example, blocks bacterial, but not
mammalian enzymes.

Question 6

Inhibition of bacterial folate synthesis

Answer 6

Sulfonamides compete with para-aminobenzoic acid (PABA) to inhibit
folate synthesis,

while trimethoprim blocks dihydrofolate reductase to achieve the same effect

Question 7

Classes of Antibiotics

Answer 7

1. Beta-Lactams. Penicillins, Cephalosporins
2. Sulfonamides
3. Tetracyclines
4. Glycopeptides
5. Carbapenems
6. (Fluoro)quinolones
7. Oxazolidinones
8. Macrolides
9. Aminoglycosides
10. Nitroimidazoles

Question 8

Beta-Lactams. Penicillins, Cephalosporins

Answer 8

(benzylpenicillin, amoxicillin, flucloxacillin,
piperacillin, cefuroxime, cephalexin).

beta-lactam ring essential for their mode of action, which is to suppress the
synthesis of peptidoglycan, a component of the bacterial cell wall

bactericidal.

Bacterial resistance is expressed mainly in the production of betalactamase
enzymes which rupture the beta-lactam ring; hence the addition of a
beta-lactamase inhibitor to co-amoxiclav (amoxicillin/clavulanic acid). They are
effective against gram-positive organisms but not against gram-negative bacteria,
most of which have an impermeable cell wall.

Question 9

Sulfonamides

Answer 9

A sulfonamide was the first commercially available
antibiotic (1932). They act by inhibiting bacterial synthesis of folate and are
broad-spectrum bacteriostatic agents

Question 10

Tetracyclines

Answer 10

oxytetracycline, doxycycline).

These inhibit bacterial protein synthesis and are bacteriostatic.

They are broad-spectrum antibiotics which are active
against both gram-positive and gram-negative species.

Question 11

Glycopeptides

Answer 11

vancomycin, teicoplanin).

These act by inhibiting cell wall synthesis and are bactericidal at higher blood concentrations.

Vancomycin is active against gram-positive organisms,
but it is a large molecule that is unable to penetrate the
outer lipid bilayer of gram-negatives.

Teicoplanin is also mainly active against gram positive species.

Question 12

Carbapenems

Answer 12

(imipenem, meropenem).

These are beta-lactams which inhibit bacterial cell wall synthesis

but which have a wider spectrum of activity than the
penicillins and cephalosporins,
being active against gram-positive but particularly
against gram-negative organisms.

They are also effective against anaerobes.

Question 13

(Fluoro)quinolones

Answer 13

(ciprofloxacin, levofloxacin).

These act by disrupting bacterial DNA replication and transcription. T

hey are broad-spectrum agents with particular
activity against gram-negative organisms.

They are generally less effective against
gram-positive species.

Fluoroquinolones are bactericidal, but the development of
resistance is rapid.

Question 14

Oxazolidinones

Answer 14

(linezolid).

These inhibit bacterial protein synthesis and are effective against gram-positive organisms.

They are bacteriostatic and are usually given as a third-line drug of last resort.

Question 15

Macrolides

Answer 15

(erythromycin, clarithromycin) These inhibit protein synthesis and are
bacteriostatic. They are commonly used in patients who are sensitive to penicillins
and have a similar, although slightly broader spectrum of antibacterial activity.

Question 16

Aminoglycosides

Answer 16

(gentamicin, tobramycin, neomycin). These inhibit protein synthesis
and are used mainly against gram-negative bacteria.

Whether they are bacteriostatic or bactericidal is dose-dependent.

Their duration of action is prolonged beyond the time when blood levels have fallen.

This is due to irreversible binding to the intracellular bacterial ribosome.

They are potentially nephrotoxic and
ototoxic and potentiate the effects of neuromuscular blocking drugs.

Question 17

Nitroimidazoles

Answer 17

Nitroimidazoles (metronidazole, tinidazole). Metronidazole is the commonest drug of
this class that is in clinical use in the UK. It undergoes reduction to produce toxic
metabolites that suppress bacterial DNA synthesis. This reduction takes place only in
anaerobic cells, and so the drug has no effect on aerobic organisms. Metronidazole is,
however, also active against protozoa such as Giardia lamblia and Entamoeba histolytica

Question 18

Antibiotic Prophylaxis

Risk factors for surgical site infection.

Answer 18

Assuming appropriate asepsis and infection control measures
these otherwise include

insertion of any metalwork, implant or
prosthesis;
prolonged surgery;
perioperative hypothermia;
difficult haemostasis; and the insertion of surgical drains.

Patients at greater risk include those at the extremes
of age, those who are immunocompromised
(for example receiving corticosteroids),
those with diabetes mellitus,
the obese (BMI >30 kg m–2) and smokers

Question 19

General principles

Answer 19

Narrow spectrum antibiotics should be selected,

targeted to the most likely pathogens for the surgical procedure

(and taking into account any local
patterns of antibiotic resistance that have been identified).

Clostridium difficile infection is a higher risk with
cephalosporins, fluoroquinolones (ciprofloxacin),
carbapenems (imipenem) and clindamycin.

The antibiotic should have a half-life long enough to extend the duration of the
operation after a single intravenous dose

This should be given as close to the time of
surgical incision as possible and no more than 1 hour before. Following arthroplasty,
antibiotics may be given for up to 24 hours

In long procedures such as revision
arthroplasty, a second intraoperative dose may also be necessary. If operative blood
loss is substantial (>1500 ml), additional doses should also be considered, on the
assumption that the effective blood concentration will be lowered as a result

Question 20

Antibiotic Resistance

Answer 20

Acquired resistance to antibiotics is usually achieved by
inhibition of the usual mode of action. The primary mechanisms include a simple
decrease in the permeability of the bacterial cell wall, enzymatic degradation (of
which beta-lactamase destruction of the active beta-lactam ring is the most obvious
example) and changes in the proteins whose synthesis is the antibiotic target.