Antibacterial Concepts & Antibiotic Stewardship

Question 1

What drug can be used for MRSA bacteraemia?

What is the recommended therapeutic blood level for this drug?

Answer 1

Teicoplanin

the recommmended therapeutic blood level is > 20 mg / L

Question 2

If someone has an MRSA bacteraemia and has therapeutic levels of teicoplanin below the recommended, what should be done if he is getting better?

Answer 2

• Continue the same dose of 400mg once daily
• increase the dose to 800mg daily
• give the same dose (400mg) but twice daily
• reduce the dose

each of these could be a reasonable option depending on the circumstances

Question 3

In general, what are the roles of antibiotics?

Answer 3

Bacterial infections are treated with antibiotics that inhibit bacterial growth

bacteriocidal antibiotics will kill bacteria, but most will just inhibit growth

the immune system can then intervene and macrophages will engulf the bacteria

Question 4

How can you test how susceptible to an antibiotic a bacteria is?

Answer 4

By determining the minimum amount of antibiotic that stops the bacteria from growing

this is the minimum inhibitory concentration (MIC)

Question 5

What is the MIC?

How can it be worked out?

Answer 5

Minimum inhibitory concentration:

• the minimum concentration of antibiotic which inhibits bacterial growth
• the same amount of culture medium and bacteria are placed in each test tube
• varying concentrations of antibiotics in doubling dilutions are placed in the test tubes
• these are left to grow overnight
• you can see which test tubes contain bacteria
• they may still be present - the bacteria are not killed but their growth has been inhibited

Question 6

Why are antibiotics given in different doses?

Answer 6

We dose antibiotics to try and ensure all patients get blood concentrations of antibiotic that are associated with increased survival

There is a % of time at which the blood level of antibiotic is above the MIC and is inhibiting growth

Question 7

How do MIC values vary within species?

Answer 7

There is intra-species variations in MIC values

e.g. e coli

different concentrations of antibiotic are needed to inhibit growth within a population of bacteria

Question 8

What are the following features on the blood antibiotic profile?

Answer 8

C max - the highest concentration of antibiotic that is achieved in the blood

AUC/MIC - the area under the curve divided by the MIC

T > MIC -

Question 9

Why does the MIC concentration need to be considered?

Answer 9

The MIC needs to be considered in relation to serum concentrations of antibiotic

Question 10

How can dosage vary depending on how different drugs are effective in different ways?

Answer 10

Some drugs are dosed infrequently but with higher doses

some drugs are dosed frequently but with lower doses

this depends on the time above the MIC

Question 11

What is meant by the pharmacodynamic target?

Answer 11

For all antibiotics there is a pharmacodynamic target that is associated with increased clinical cure

after the PD target has been acheived, there is no additional efficacy benefit

so antibiotics are dosed to the PD target, but not to exceed the PD target

you should give enough drug, not more and more drug

Question 12

What is meant by antibiotic pharmacokinetics?

Answer 12

There is a lot of variation between patients in how antibiotic is:

1. Distributed in the body
2. Cleared from the body

antibiotic treatment must consider human populations and the variation within it

Question 13

Why are multiple doses of antibiotics given during the day?

Answer 13

To keep the blood concentration of antibiotic above the MIC for as long as possible

or

continuous infusions of antibiotics are given where the concentration is kept just above the MIC

Question 14

What can be summarised about the MIC and antibiotic use?

Answer 14

• MIC is relatively important in relation to cure
• the antibiotic pharmacokinetics are relatively important to clinical cure
• MIC and PK values vary
• the PD target is fixed

Question 15

What information is used in simulations to predict optimal antibiotic doses?

Answer 15

• MIC value
• PK
• PD targets

these are used to help decide what is the best dose of an antibiotic for a population of patients

Question 16

How can the data for simulations be described?

Answer 16

The MIC and PK data can be described using probabilities

The PD target will be fixed

Question 17

What is the purpose of statistical simulations?

Answer 17

they can be used to determine the probability that, if treated with a certain antibiotic dose, for a certain infection, they will attain the desired pharmacodynamic target

this is the probability of target attainment

Question 18

How is the cure rate calculated?

What dose should be used?

Answer 18

1 - cure / probability of target attainment

with a dose of 2X - there may be a cure rate of 100%

if this dose of 2X has an acceptable toxicity profile, the antibiotic can be used to treat patients

Question 19

What is meant by the probability of target attainment?

Answer 19

Simulations can be used to determine what dose of antibiotic will be able to achieve a high PTA

if the recommended dose has an acceptable toxicity profile, the antibiotic can be used to treat patients

Question 20

Why are differences in different patients important to consider when prescribing antibiotics?

Answer 20

The same dose is given to people with the same condition and is usually sufficient

some patients may get too much antibiotic and have toxicity

some patients may get too little antibiotic

the dose needs to be changed to adapt to differences in different patients

Question 21

What is the difference in action of IV and oral antibiotics in the long term?

Answer 21

When the drug has reached systemic circulation, IV and PO antibiotics can be considered equal

someone who is very ill may be given their initial dose IV so the drug gets into the bloodstream immediately to have an effect

Question 22

What are the characteristics of oral antibiotics?

Answer 22

• Slower absorption
• antibiotic associated diarrhoea
• absorption may vary
• requires small bowel for absorption (cannot be used in small bowel resection)
• no intravenous (IV) access required, and no IV access side effects
• self administration
• cheaper

Question 23

What are the properties of intravenous antibiotics?

Answer 23

• Faster / instantaneous absorption
• antibiotic associated diarrhoea
• no bowel required for absorption
• absorption rate can be varied
• IV access is required and there may be side effects such as thrombophlebitis, thrombosis and infection
• medical staff required for administration
• more expensive

Question 24

In what types of infections have oral antibiotics been shown to be comparable to intravenous antibiotics?

Answer 24

• Bone and joint infections
• pyelonephritis
• empyema (lung abscess)
• febrile neutropenia in cancer patients

Question 25

When are intravenous antibiotics preferred to be used?

Answer 25

IV antibiotics are important to quickly and reliably achieve targeted serum antibiotic concentrations

some drugs are not available intravenously

some antibiotics are not well absorbed orally

Question 26

When is ciprofloxacin used?

What are the IV and PO disease and which is more effective?

Answer 26

It is used against E. coli in kidney infections

IV dose = 400mg 12 hourly

PO dose = 500mg 12 hourly with 80% oral bioavailability

Both IV and PO antibiotics have 400mg BD bio available

Both IV and PO administrations have the same PTA

Question 27

What is shown in these graphs about antibiotic durations?

Answer 27

Positive correlations:

• as durations increase, adverse events increase

Negative correlations:

• as durations increase, failure rates decrease
• but there are diminishing returns

Question 28

How are antibiotic durations chosen?

Answer 28

Antibiotic durations are chosen to try and maximise cure while minimising adverse effects

Question 29

What are the problems involved when looking at antibiotic durations?

Answer 29

To reduce antibiotic resistance, shorter courses of antibiotics tend to be given

this means there is an increased risk in some patients that the infection will come back, but they can be retreated

guidelines give recommended durations but there is no fixed answer as the duration needed depends on the patient

Question 30

What does the choice of antibiotic duration depend upon?

Answer 30

• Evidence
• clinical factors
• social factors
• costs
• resources available

Question 31

When are antibiotics started?

Answer 31

When the benefits or starting antibiotics are greater than the disadvantages

individual patient factors may mean antibiotics may or may not be started

Question 32

Under which conditions should antibiotics always / never be started?

Answer 32

There are times when antibiotics should always be started

e.g. Patients with sepsis

there are times when antibiotics should never be started

e.g. Patients with no evidence of infection such as auto-immune inflammation

Question 34

What factors should be considered when choosing not to start antibiotics in a patient with an infection?

Answer 34

It can be reasonable to not start antibiotics in a patient with an infection, but it must be done in the context of an overall management plan

e.g. A patient with a skin abscess may not be given antibiotics if there is a plan for surgical drainage of the abscess

Question 35

What are the benefits of early antibiotic therapy?

Answer 35

• Early treatment has a mortality and morbidity benefit
• narrow spectrum antibiotics can be given earlier, whereas if you wait and the patient becomes more ill, then broader spectrum antibiotics may be needed
• if clinically stable, an oral antibiotic may be administered and the response assessed
• prevention of infection metastases

Question 36

What are the disadvantages of early antibiotic therapy?

Answer 36

• May reduce time available to do cultures so there is reduced chance of giving targeted therapy and getting a diagnosis
• may reduce time to do investigations so patient may be “overtreated”
• may increase the chance of giving the wrong antibiotic or not enough antibiotic
• insufficient time to check allergies

Question 37

What are the 4 different strategies used when starting antibiotic therapy?

Answer 37

1. Start antibiotics early and look to stop / de-escalate early
2. Delay antibiotics with a plan for how / when to access / start antibiotics e.g. delayed prescription
3. Start with broad spectrum and aim to narrow
4. Start with narrow spectrum and have a plan for how / when to broaden

Question 38

What is meant by the therapeutic window?

Why do certain drugs need to be monitored?

Answer 38

Maintaining the concentration within the therapeutic window ensures a safe but sufficient dose is being given

gentamicin is nephrotoxic and ototoxic so patients must be monitored to ensure levels don’t enter the toxic range

monitoring for efficacy is also important as there needs to be high enough levels in order for the drug to be effective

Question 39

What is meant by surgical antibiotic prophylaxis?

Answer 39

Antibiotics are given at least an hour before surgery

this gives enough time for the antibiotics to reach high concentrations within the wounds

any time after an hour, and there is less benefit from the antibiotics

Question 40

What is meant by antibiotic stewardship?

Answer 40

A coherent set of actions which promote using antimicrobials responsibility

Question 41

What is meant by the 30% rule in antimicrobials prescribing?

Answer 41

• 30% of all hospitalised inpatients at any given time receive antibiotics
• over 30% of antibiotics are prescribed inappropriately in the community
• up to 30% of all surgical prophylaxis is inappropriate
• 30% of hospital pharmacy costs are due to antimicrobials use
• 10-30% of pharmacy costs can be saved by antimicrobial stewardship programs

Question 42

What are the factors that must be considered in antibiotic stewardship?

Answer 42

• Involves timely and optimal selection, dose and duration of an antimicrobial
• for the best clinical outcome for the treatment or prevention of infection
• minimal toxicity to the patient
• minimal impact on resistance and other adverse effects such as C. Difficile

Question 43

What % of patients have a penicllin allergy?

What types of antibiotics should not be used in people with this allergy?

Answer 43

10% of patients have a penicillin allergy

they may also cross-react to other beta-lactam antibiotics such as cephalosporins and carbapenems

Question 44

What are the 4 main limitations of antibiotics?

Answer 44

1. They will not treat non-infectious disease
   e. g. A lot of people naturally have E.coli in the urine which is asymptomatic
2. They will not treat contaminated samples
3. They may only be the supporting factor in some infections that require surgical intervention
4. They damage the microbiome

Question 45

Why can antibiotics not be used to treat infections that require surgical intervention?

Answer 45

Antibiotics need to get into the site of infection in order to be effective

they can only reach a site of infection if there is a vascular supply to this site

e.g. A large abscess of pus will not have a blood supply so the antibiotics wont actually clear the infection and surgery may be needed