Antibiotic Stewardship Flashcards
1
Q
What is the MIC?
A
Minimum inhibitory concentration - the minimum concentration of antibiotic which inhibits bacteria growth
2
Q
How is the MIC used in antibiotic testing?
A
- We test bacteria to see how susceptible they are to an antibiotic.
- To test how susceptible to an antibiotic a bacteria is we determine the minimum amount of antibiotic that stops the bacteria from growing - the minimum inhibitory concentration (MIC)
- To test:
- Grow set of culture in antibiotic concentration
- Standard culture media, with standard bacteria inoculum in a series of variable antibiotic concentrations
- View the test tubes to see the MIC
3
Q
What is the relationship between MIC and survival?
A
- More time blood antibiotic concentrations are above the MIC = higher chance of survival
We dose antibiotics to try and ensure all patients get blood concentrations of antibiotic that are associated with increased survival
4
Q
The MIC is variable in each case. What does the MIC depend on?
A
- The microorganism
- The affected human being
- The antibiotic itself
5
Q
How is the MIC determined?
A
- Grow set of culture in antibiotic concentration
- Standard culture media, with standard bacteria inoculum in a series of variable antibiotic concentrations
- View the test tubes to see the MIC
6
Q
How does MIC differ from MBC?
A
- MIC: the lowest concentration of an antibacterial agent necessary to inhibit visible growth
- MBC: the minimum concentration of an antibacterial agent that results in bacterial death
The closer the MIC is to the MBC, the more bactericidal the compound.
7
Q
Why is finding the MIC important?
A
will give dose necessary to give the patient increased survival
8
Q
Pharmacokinetics vs pharmacodynamics?
A
- Pharmacokinetics is the study of what t_he body does to the drug_
- Pharmacodynamics is the study of what the drug does to the body.
9
Q
What is:
- Cmax/MIC?
- AUC/MIC?
A
- Cmax is the maximum serum concentration that a drug achieves in a specified area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pharmacokinetics.
- Some drugs work best if Cmax is reached (e.g. drugs that are dosed once daily)
- Other drugs work best if kept above MIC for whole treatment course (e.g. drugs that are dosed regularly)
- AUC: area under the curve –> describes the variation of a drug concentration in blood plasma as a function of time.
10
Q
Define:
- MIC
- AUC
A
- MIC: (minimum inhibitory concentration) – The minimum concentration of antibiotic to inhibit the growth of an organism.
- AUC: (area under the curve) – The total exposure of an antibiotic to an organism
11
Q
There are 3 types of pharmacodynamic killing. What are these?
A
- Time-dependent killing (T>MIC)
- Concentration-dependent killing (Peak:MIC)
- AUC-dependent killing (AUC:MIC)
12
Q
Describe time-dependent killing (T>MIC)
A
Once the concentration of an antibiotic is above the MIC, there is not an increased rate of killing with increasing concentrations of antibiotic.
Prototypical antibiotics: B-lactams, clindamycin, linezolid, macrolides
13
Q
What is concentration-dependent killing (Peak:MIC)?
A
As the concentration of an antibiotic increases, its rate of killing increases.
Prototypical antibiotic: aminoglycosides
14
Q
What is AUC-dependent killing?
A
A combination of both T>MIC and Peak:MIC. The rate of bacterial killing is both related to the amount of time above the MIC and the total exposure of antibiotic to the organism.
Prototypical antibiotic: fluoroquinolones
15
Q
Look at the antibiotic concentration-efficacy relationships/graph.
where on this graph we should aim for?
A
Aiming for around 100 AUC:MIC - As we are talking about the action of a drug on an organism (bacteria) this is your pharmacodynamic target
16
Q
What is the pharmacodynamic target?
A
- For all antibiotics, there is a pharmacodynamics target (PD) that is associated with increased clinical cure
- After the PD target has been achieved, there is no additional efficacy benefit, so antibiotics are dosed to achieve the PD target, but not exceed it
- We should give enough drug, not more and more
- The PD target is fixed for each antibiotic
17
Q
What is the risk of giving a drug above the PD target?
A
Increased risk of antibiotic resistance and side effects
18
Q
What factors affect the movent (kinetics) and fate of the drug in the body?
A
- Release from the dosage form
- Absorption from the site of administration into the bloodstream
- Distribution to various parts of the body, including the site of action
- Rate of elimination from the body via metabolism or excretion of unchanged drug.
Antibiotic dosing must consider pharmacokinetic variation (variation in what the body does to the drug).
19
Q
Can these values vary:
- MIC values
- Pharmacokinetic values
- PD target
A
- Yes
- Yes
- Fixed
20
Q
The MIC, PK and PD target is used in statistical simulations to predict optimal antibiotic doses.
- How are these simulations carried out?
- What is the purpose?
A
- The MIC and PK data can be described using probabilities, the PD target will be fixed
- These statistical analyses (simulations) can be used to determine the probability that, if treated with a certain antibiotic dose, for a certain infection, a patient will attain the desired pharmacodynamic target –> this is called the probability of target attainment (PTA)__
- Simulations can be used to determine which dose will achieve a high PTA
- If the recommended dose has an acceptable toxicity profile, it can be used to treat patients
- HOWEVER, some patients will get too much/little
- Sometimes, increasing a dose to reach therapeutic levels is advised, but in some cases (e.g. if patient is at high risk of toxicity), maintaining a lower dose is better.
21
Q
What is the PTA?
A
Probability of Target Attainment: analysis compares plasma exposure of an antibiotic dosing regimen in a patient population against a target exposure associated with efficacy, expressed relative to the minimum inhibitory concentration (MIC) of the target pathogen to the antibiotic.
ie. determine the probability that, if treated with a certain antibiotic dose, for a certain infection, a patient will attain the desired pharmacodynamic target.
22
Q
Simulations example: what is the cure rate?
A
- For a drug dose of X- the cure rate would be 80%
- With a dose of 2X- maybe there will be cure rate of 100%, and this dose selected
- If the 2X dose has an acceptable toxicity profile, the antibiotic can be used to treat patients
Table explained:
- 1: MIC is 4mg/L but drug clearance is low so have high serum concs –> probability target attainment is high = cure
- 3: MIC is 4mg/L but drug clearance is HIGH so have low serum conc –> probability target attainment is low = death
- Would then want to double dose IF SAFE
23
Q
Know that antibiotic dosing is carried out for a population of patients
Most patients will get enough antibiotic
Some patients may get too much
Some patients may get too little.
What causes this?
A
Pharmacokinetic factors differ in each patient
24
Q
Clinical Case
- Mr Smith is a 70 year old man admitted with an MRSA bacteraemia following a pneumonia.
- He is being treated once daily with 400mg of an antibiotic called teicoplanin.
- After five days of antibiotics Mr Smith has improved. Blood levels of teicoplanin are collected and find his level of teicoplanin is 15mg/L. Below the recommended “therapeutic” blood levels of >20 mg/L.
- Mr Smith is much improved. What could be a reasonable thing to do with his teicoplanin?
- Continue the same dose
- Increase the dose to 800mg
- Give 400mg twice a day
- Reduce the dose
A
- Mr Smith is recommended to have Teicoplanin blood levels of >20 mg/L.
- Mr Smith has got much better –> it is possible his bacterial infection had a “lower MIC” than the average persons MIC.
- If the MIC is lower the amount of drug required may be lower, so 15mg/L might be enough for him.
- BUT all options may be reasonable, so:
- continue the same dose of drug if he is at risk of drug toxicity-and his infection is mild
- increase the dose, or dose frequency to achieve “therapeutic levels” in some more serious infections – to reduce the risk/probability of death
- If the microbiology lab gives you an MIC, you might be able to reduce the dose
As a doctor you will need to use your informed judgment to decide what to do.
25
Oral vs IV antibiotics:
* Rate of absorption?
* Side effects - antibiotic associated diarrhoea?
* Bowel required for absorption?
* IV access required?
* Ease of administration?
* Price?
* Efficacy?
* Absorption:
* Oral: slower absorption
* IV: faster/instantaneous absorption
* Side effects:
* BOTH have antibiotic associated diarrhoea
* Bowel required for absorption:
* Oral: requires small bowel for absorption
* IV: no bowel required
* IV access required?
* Oral: no (so no IV side effects)
* IV: yes (IV side effects e.g. Thrombophlebitis, thrombosis and infection)
* Ease of administration?
* Oral: Self-administration
* IV: Medical staff required for administration
* Price:
* Oral: cheaper
* IV: more expensive
* Efficacy:
* When the drug has reached the systemic circulation IV and PO antibiotics can be considered equal.
26
Oral antibiotics have ben shown to be comparable to intravenous antibiotics for a number of infections including:
* Bone and joint infection
* Pyelonephritis
* Empyema (lung abscess)
* Febrile neutropenia in cancer patients
When would IV antibiotics be needed?
* To quickly and reliably achieve targeted serum antibiotic concentrations
* Some drugs are only available intravenously
* Some antibiotics are not well absorbed orally
27
An oral or intravenous antibiotic example of **Ciprofloxacin:**
* IV dose=400mg 12 hourly
* PO dose=500mg 12 hourly
* Oral bioavailability =80%
Both IV and PO antibiotics have 400mg BD bioavailable-on average
28
As antibiotic duration increases, what is the effect on:
* adverse events?
* failure of treatment?
* As durations increase, adverse events increase e.g. antibiotic associated diarrhoea, C. difficile infection (bowel), risk of infection with IV antibiotics
* Failure rates decline (only true up to a certain point)
Antibiotic durations are chosen to try and maximise cure while minimising adverse events.
e.g. elderly patient you would consider a shorter antibiotic course
29
When should antibiotics be started?
* Antibiotics should be started when the **benefits of starting are greater than the disadvantages**.
* There are times when antibiotics should always be started e.g. patients with sepsis, and there are times when antibiotics should never be started e.g. patients with **no evidence of infection** e.g. auto-immune inflammation.
* In-between, individual patient factors may mean antibiotics may or may not be started.
* It can be reasonable not to start antibiotics in a patient with an infection, but this must be done within 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.
30
What are the benefits/disadvantages of early antibiotic therapy?
_Benefits:_
* Early treatment with mortality and morbidity benefit
* If clinically stable narrow spectrum antibiotics may be administered and the response assessed
* If clinically stable an oral antibiotic may be administered and the response assessed.
* Prevent infection metastases
_Disadvantages:_
* May reduce the time available to do cultures
* reduced chance of giving targeted therapy
* reduced chance of getting a diagnosis (the pathogen may give the diagnosis)
* May reduce time to do investigations i.e. overtreatment possible
* May increase the chance of giving the wrong antibiotic, or not enough antibiotic
* Insufficient time to check allergies
31
What is therapeutic drug monitoring? Which antibiotics are mostly subjected to TDM?
Therapeutic drug monitoring is the measurement of specific drugs at timed intervals in order to maintain a relatively constant concentration of the medication in the blood.
* vancomycin/teicoplanin (gylcopeptides)
* gentamicin (aminoglycosides)
32
What are ototoxic drugs?
Ototoxicity is the property of being toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, for example, as a side effect of a drug.
33
Some drugs have a very narrow therapeutic window. What does this mean?
* There is a very small concentration range where are you achieve that therapeutic window
* Above that window you run into toxicity very quickly
* Below that window you run into inefficacy problems very quickly
34
Why is TDM (therapeutic drug monitoring) used for vancomycin/teicoplanin and gentamycin?
* Both drugs are **ototoxic** and **nephrotoxic** drugs
* Need to be careful not to use too much
* These drugs have a narrow therapeutic window
35
What is the aim of surgical antibiotic prophylaxis? What are the downsides of this?
Antibiotic prophylaxis is effective for **preventing surgical site infections** in certain procedures.
However, the use of antibiotics for prophylaxis carries a risk of adverse effects (including Clostridium difficile-associated disease) and increased prevalence of antibiotic-resistant bacteria.
36
When should surgical antibiotic prophylaxis be given?
Prophylactic antibiotic administration should be initiated within one hour before the surgical incision, or within two hours if the patient is receiving vancomycin or fluoroquinolones.
37
What is antibiotic stewardship?
A coherent set of actions which promote using antimicrobials responsibly:
➤ is an inter-professional effort, across the continuum of care
➤ involves timely and optimal selection, dose and duration of an antimicrobial
➤ for the best clinical outcome for the treatment or prevention of infection
➤ with minimal toxicity to the patient
➤ and minimal impact on resistance and other ecological adverse events such as C. difficile
38
What is the 30% rule when prescribing antimicrobials?
➤ ~ 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 antimicrobial use
➤ 10-30% of pharmacy costs can be saved by antimicrobial stewardship programs
39
What does antibiotic stewardship involve?
* Clinical guidelines
* IV to PO switch
* Antibiotic restriction
* Microbiologist support
* Education
* Use of biomarkers
* Audit and feedback
40
Antibiotic interactions examples:
41
Antibiotic adverse reactions and effects examples:
42
Which 4 antibiotics should be AVOIDED in pregnancy? Why?
* **Quinolones e.g. ciprofloxacin**
* ****Arthropathy in animal studies
* **Trimethoprime (folate antagonist)**
* ****Teratogenic in 1st trimester
* **Aminoglycosides**
* ****Ototoxicity
* **Nitrofurantoin**
* ****Avoid at term-neonatal haemolysis
43
What is the most common drug allergy?
Pencillin - 10% of people report a penicillin allergy
44
What are beta lactam antibiotics? What are the 3 major classes of them?
Beta lactam antibiotics refers to antibiotics that have a Beta-lactam ring as part of its chemical structure:
1. Penicillins
2. Cephalosporins
3. Carbapemems
45
What may patients with a penicillin allergy also cross react to?
other beta-lactam antibiotics e.g. Cephalosporins e.g. cefuroxime
46
LTHT Algorithm for management of a patient with penicillin allergy
