29. Antibiotics Flashcards
What is ‘antimicrobial
stewardship’?
This refers to a coordinated programme
that promotes the appropriate prescribing and
use of antimicrobials
(including antibiotics)
order to reduce microbial resistance,
decrease the spread of infection
caused by multi-drugresistant organisms
and improve patient outcomes.
In 2014, NICE published a quality standard
for infection prevention and
control that included
antimicrobial stewardship.
What are the main principles of
good antibiotic prescribing?
In order to help prevent the development of bacterial resistance, it is important to prescribe antibiotics according to the principles of antimicrobial
stewardship, which include:
1
> Prescribe antibiotics only when clinically indicated.
2
> Collect specimens for culture (e.g. blood, urine)
prior to starting therapy.
3
> Prescribe antibiotics according to
local guidelines and seek microbiology
advice if needed.
4
> Choose correct class of antibiotic
that would be effective
against suspected organism.
5
> Use targeted, narrow-spectrum agents where possible.
6
> If broad-spectrum therapy commenced,
de-escalate as soon as possible
based on microbiology-sensitivity data.
7
> Ensure correct duration of treatment
(start and stop dates).
8 > Ensure correct dose (adjust for weight, renal function, liver function and if on renal replacement therapy).
9
> Switch intravenous agents
to oral preparation promptly.
10
> Source control where applicable
(e.g. drain collections).
11 > Ensure surgical prophylaxis compliance to reduce surgical site infection (ideally antibiotics should be a dministered 30 minutes prior to skin incision, they should be given before tourniquet is inflated and re-dose if 1500 mL blood loss or duration of surgery >4 hours).
What is concentration-dependent and time-dependent killing?
MIC
MBC
In order to answer this you need to understand a few pharmacokinetic concepts:
> Minimum inhibitory concentration (MIC) –
lowest concentration of
antibiotic required to
completely inhibit growth
of a particular bacterium
in vitro.
> Minimum bactericidal concentration (MBC) –
lowest concentration of
antibiotic required to
kill a particular bacterium in vitro
When evaluating antibiotic efficacy, there are three important
pharmacokinetic parameters:
1
• Peak serum level (Cmax)
2
• Trough serum level (Cmin)
3
• Area under the serum concentration–
time curve (AUC)
Integrating these pharmacokinetic parameters
with the MIC gives three
pharmacokinetic (PK)/pharmacodynamic (PD) indices that quantify the activity of an antibiotic:
1
• Peak/MIC ratio –
this is Cmax divided by the MIC.
2 • T > MIC (time above MIC) – this is the percentage of a dosage interval in which the serum level exceeds the MIC.
3 • 24-h AUC/MIC ratio – this is determined by dividing the 24-h AUC by the MIC.
> Concentration-dependent killing
What marker indiciates efficacy
e.g. aminoglycosides –
the ideal dosing regimen for
these antibiotics maximise concentration,
because the higher the concentration,
the more extensive and the faster
is the degree of killing.
Therefore, the 24-h AUC/MIC ratio
and the Peak/MIC ratio correlate
best with antibiotic efficacy.
> Time-dependent killing,
e.g. β-lactams – the ideal dosing regimen for these antibiotics maximise the duration of exposure. The T > MIC is the best predictor of antibiotic efficacy
How do antibiotics exert their effects?
bactstatic
Antibiotics are drugs used
to inhibit (bacteriostatic) or
kill (bacteriocidal) bacteria.
Bacteriostatic drugs require the aid
of host defences to clear tissues of the infecting microorganism.
If these defences are compromised (e.g. agranulocytosis) or impaired locally at the site of infection (e.g. cardiac vegetation in endocarditis),
the residual pathogen resumes growth
after stopping the bacteriostatic drug
and the infection relapses.
Their mode of
action can be classified as shown in Figure 29.1.
Which factors should be
considered when administering
gentamicin
> Aminoglycoside antibiotics
such as gentamicin are
used to treat urinary and biliary tract infections, endocarditis and
septicaemia.
> They work by binding irreversibly
to the 30 S subunit of the bacterial
ribosome and
inhibiting bacterial protein synthesis.
This leads to bacterial
cell death.
> These agents are administered intravenously
or intramuscularly, as they
are not absorbed enterally.
> At high plasma concentrations aminoglycosides
can cause ototoxicity
and nephrotoxicity.
> The dose of gentamicin is
3–5 mg/kg/day and can be given
in divided doses every eight hours.
Blood samples are taken 1 hour after the
administered dose
(‘peak’ plasma concentration) and/or
just before a dose
(‘trough’ plasma concentration).
‘Peak’ plasma gentamicin levels
should be 5–10 mg/L and
‘trough’ levels should be less than 2 mg/L.
> An alternative, once-daily regime is used
in some departments.
the full gentamicin dose is prescribed
as a single dose and the frequency
of administration is adjusted according to the ‘trough’ gentamicin levels using a nomogram, e.g. the Urban Craig nomogram.
In which patient groups should gentamicin be used with
caution?
> Gentamicin should be used with caution
during pregnancy as it can cross
the placenta and
cause fetal ototoxicity.
> Aminoglycosides are not metabolised, instead they are excreted unchanged by the kidneys, primarily by glomerular filtration. Therefore the dose and/or frequency of administration should be altered in renal failure.
Renal function should be quantified
using the creatinine clearance,
which can be estimated using the
Cockcroft and Gault formula.
> Aminoglycosides can potentiate the action of non-depolarising muscle relaxants or cause recurrence of the blockade produced by these agents.
They cause this effect by interfering with calcium entry into the presynaptic terminal of the motor axon, thereby preventing the release of acetylcholine from the presynaptic vesicles.
This drug interaction can
even cause a neostigmine-resistant block,
which can be antagonised by
the use of calcium salts.
Because of this effect on neurotransmission,
aminoglycosides are
contraindicated in patients
with myasthenia gravis.
Cockcroft and Gault formula to estimate creatinine clearance
140–Age (Years) x Weight (kg) (CrCl): = ×\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
72 x serum creatinine (μmol/L)
x
(0.85)
onlyif female)
Describe the structure of penicillin.
> The basic structure comprises a
thiazolidine ring nucleus
attached to a
β-lactam ring.
> The β-lactam ring has an
amino-acid side chain,
which varies between different types
penicillin and determines
their main antibacterial and
pharmacological properties.
> Other antimicrobial agents belonging the β-lactam group of antibiotics
include:
- Cephalosporins
- Monobactams
- Carbapenems.
Describe the mechanism of action
of penicillin.
> Penicillins are bactericidal antibiotics
that inhibit bacterial cell wall synthesis.
> The β-lactam ring binds to
bacterial cell wall proteins and
inhibits the formation of peptidoglycan
cross-links.
cross-links are essential for
maintaining bacterial cell
wall stability and
without them the wall is
weakened, resulting in
cytolysis and cell death
due to osmotic pressures.
> The resultant build-up of peptidoglycan
precursors stimulates the
bacterial release of enzymes,
which auto-digest the bacterial cell wall.
What is the spectrum of clinical
use? Penicllin
> Penicillins are active against most
Gram-positive organisms and some
Gram-negative cocci.
> They are not very effective against
Gram-negative bacilli.
> They can be divided into categories depending on their spectrum of action:
- Narrow spectrum, e.g. benzylpenicillin
- β-lactamase resistant, e.g. flucloxacillin
- Broad spectrum, e.g. ampicillin
- Anti-pseudomonal, e.g. piperacillin
What is the effect of probenecid
on penicillin?
Probenecid is a renal tubular blocking agent.
It inhibits the tubular
secretion of penicillin
and usually increases
penicillin plasma levels
(up to 2- to 4-fold
elevation in plasma concentrations
has been demonstrated).
How does resistance to penicillins
develop?
Inappropriate use of antibiotics
and poor prescribing play a
vital role in propagating antibiotic resistance.
There are several mechanisms by which
bacteria develop resistance to penicillins:
> Drug inactivation –
bacterial production of β-lactamase
leads to hydrolysis of the β-lactam ring.
> Alteration of penicillin binding proteins –
this prevents the antibiotics
from binding onto the bacterial cell wall.
> Alteration of bacterial cell wall permeability –
this prevents antibiotics
from penetrating the cell wall.
What are the major side effects
of the penicillins?
> Hypersensitivity due to an allergy
to the basic structure of the β-lactam
group of the antibiotics.
Therefore, up to 10% of patients
allergic to penicillin will suffer
cross-reactivity if given another
antibiotic containing a β-lactam group.
Hypersensitivity reactions occur in
10% of the population
while anaphylaxis occurs in
approximately 0.01%.
> Gastrointestinal disturbances.
> Encephalopathy in patients with renal failure.
> Rash, especially when ampicillin is
administered to patients with
infectious mononucleosis.
