MP321 week 4

Question 1

what patients are at risk of HAI

Answer 1

elderly
prolonged hospital admission (current or recent)
ICU/ HDU
invasive procedures
broad spectrum antibiotics
co-morbidity

Question 2

how do C.diff infections occur (CDI)

Answer 2

• patient, hospital environment and staff contaminated by spores
• C.diff spores ingested
• onset CDI usually after antibiotic therapy
• 4 Cs antibiotics
• spores ingested and produce toxins in the lower GIT which cause colitis
• symptoms vary from mild diarrhoea to severe bloody diarrhoea
• patients over 65 are at most risk

Question 3

antimicrobials and C.diff infection

Answer 3

-Broad spectrum antibiotics disrupt natural bowel flora allowing pathogenic organisms such as C. difficile to flourish

-Narrow spectrum antibiotics that cause little disruption to the bowel flora are less likely to cause CDI

-Antibiotics are a risk factor for CDI but some patients reported with CDI will not have been exposed to any antibiotics

Question 4

minimising the risk of C.diff when using antimicrobials

Answer 4

• minimise use of 4Cs antibiotics (try to use a narrower spectrum antibiotic) unless very severe infection
• balance between effectively treating current infection and not causing harm to both the patient and wider population (CDI, increased)

Question 5

prevention and management of CDI (c. diff infection)

Answer 5

prevention
- standard infection control precaution
- antimicrobial stewardship

management
- isolation of patient
medication review (antibiotics, PPIs, laxatives)(stop laxatives) (stop PPI unless absolutely necessary)

Question 6

key elements of antimicrobial stewardship

Answer 6

• prescribing guidance
• information about antibiotic use and antimicrobial resistance
• audit of clinical practice
• education of healthcare staff and patients/ public

Question 7

what does SAPG do?

Answer 7

aim is to improve use of antibiotics throughout all health and care settings in Scotland.

Question 8

what is SAPG

Answer 8

safeguarding antibiotics for Scotland

Question 9

obstacles to antimicrobial stewardship

Answer 9

Physician loss of autonomy
Resistance to being told what to do
fear of antagonising patients or more senior clinicians

Lack of resources – needs management buy in and support

Poor IT infrastructure
electronic prescribing.
electronic data capture -audit
antibiotic usage data.

Measuring its impact is difficult – outcome and process measures rather than clinical outcomes

Lack of evidence for some aspects of stewardship

Question 10

what does antimicrobial pharmacist do

Answer 10

Develops, reviews and implements policies and guidance

Evaluates antimicrobial use data

Audits compliance with policy and use of antibiotics

Provides education for medical, pharmacy and nursing staff

May have clinical role – Infectious Diseases ward, microbiology ward round

Question 11

pharmacist roles

Answer 11

pharmacists in all settings have a role in antimicrobial stewardships

Question 12

treatment for staph aureus and strep pyogenese skin and soft tissue infection

Answer 12

flucloxacillin - oral tablets 1g four times daily for 5 days

AND

phenoxymethyl penicillin- oral tablets 500mg four times daily for 5 days

if penicillin allergic
clarithromycin 500mg twice daily for 5 days

Question 13

chicken pox treatment

Answer 13

if less than 72 hours from sport appearing- can give aciclovir- 400mg 4 times daily for 5 days

could also give antihistamine for itching- chlorphenamine 2mg every 3-4 hours- drowsy

cooling lotion like calamine- remind patient not to rub as this could break the skin and lead to a secondary infection

Question 14

treatment for tonsillitis

Answer 14

phenoxymethyl penicillin - 500mg 4 times daily for 5 days

if penicillin allergic- clarithromycin 500mg twice daily for 5 days

Question 15

tetracycline dose for exacerbation of COPD infection

Answer 15

200mg for first dose then 100mg for next 5 days

Question 16

c.diff treatment

Answer 16

vancomycin capsules - 125mg four times daily for 10 days

metronidazole 400mg every 8 hours for 10 days - cannot drink ANY alcohol

Question 17

volume of distribution units

Answer 17

litres

Question 18

clearance units

Answer 18

litres / hour

Question 19

elimination rate constant units

Answer 19

K (/h)

Question 20

elimination half life units

Answer 20

hours

Question 21

b-lactam PK/PD relationships

Answer 21

• Glycopeptide antibiotics: vancomycin and teicoplanin
• Active against gram positive organisms, used in patients with
  – penicillin allergy
  – methicillin resistant Staphylococcus aureus (MRSA)
• PK/PD targets
  – traditionally regarded as “time-dependent”
  – AUC24/MIC ratio now accepted as more important for vancomycin
  – target AUC24 / MIC ratio >400 (AUC24 is the daily AUC)

Question 22

vancomycin PK/PD relationships

Answer 22

Glycopeptide antibiotics: vancomycin and teicoplanin
Active against gram positive organisms, used in patients with
penicillin allergy
methicillin resistant Staphylococcus aureus (MRSA)
PK/PD targets
traditionally regarded as “time-dependent”
AUC24/MIC ratio now accepted as more important for vancomycin
target AUC24 / MIC ratio >400 (AUC24 is the daily AUC)

Question 23

vancomycin toxicity

Answer 23

Vancomycin infusion reaction (flushing reaction)
Nephrotoxicity

Question 24

Vancomycin infusion reaction (flushing reaction)

Answer 24

4 – 47% of patients, varying severity, soon after the start or end of an infusion - related to the infusion rate
Caused by histamine release following degranulation of mast cells and basophils
Erythematous rash spreads across face, neck and upper torso with burning and severe pruritus – for images, see https://www.frontiersin.org/articles/10.3389/fpubh.2014.00217/full
Patient may be hypotensive, dizzy, agitated and experience headache, chills, fever, paraesthesia, chest pain, dyspnoea
To reduce risk, doses are administered by infusion at a rate not greater than 500 mg/h (i.e. a 1000 mg dose is infused over 2 hours)

Question 25

Nephrotoxicity

Answer 25

Mechanism unclear: oxidative stress, renal tubular ischaemia, acute tubulointerstitial damage Associated with high trough concentrations risk: low if <15 mg/L, medium >15 mg/L, high >20 mg/L Associated with long duration of therapy risk: low if <7 days, medium >7 days, high >14 days Can potentiate aminoglycoside toxicity

Question 26

Nephrotoxicity

Answer 26

Mechanism unclear: oxidative stress, renal tubular ischaemia, acute tubulointerstitial damage Associated with high trough concentrations risk: low if <15 mg/L, medium >15 mg/L, high >20 mg/L Associated with long duration of therapy risk: low if <7 days, medium >7 days, high >14 days Can potentiate aminoglycoside toxicity

Question 27

other less common vancomycin toxicity side effects

Answer 27

IgA mediated bullous dermatosis Neutropenia, especially with longterm use Thrombocytopenia Anaphylaxis Rare, associated with release of IgE

Question 28

Infectious Disease Society of America (IDSA) March 2020

Answer 28

“Efficacy is best related to AUC24/MIC ratio; the target AUC24 is ≥400 mg.h/L, assuming an MIC of ≤1 mg/L Troughs are not optimal surrogates for AUC­24 Aim for an AUC24 of 400–600 mg.h/L and steady state concentration during continuous infusion of 20–25 mg/L (equivalent to an AUC24 of 480-600 mg.h/L)” But trough concentrations are currently used for routine monitoring of vancomycin given by intermittent infusion

Question 29

Vancomycin – routes of administration

Answer 29

Oral administration is only used to treat C. difficile infections in the gut - there is no systemic absorption Intravenous administration is always used for systemic infections and there are two options Continuous infusion Intermittent infusion

Question 30

Design of vancomycin dosage regimens – targets for optimal efficacy and low toxicity

Answer 30

. Continuous infusion Mainly used in critically ill patients in intensive care units Cssaverage target 20 – 25 mg/L AUC24 target 480 – 600 mg.h/L 2. Intermittent infusion Easier to manage in general medical and surgical wards Trough target 10 – 20 mg/L AUC24 400 - 600 mg.h/L (assuming MIC <1 mg/L)

Question 31

for continuous infusions

Answer 31

start treatment with loading infusion (to achieve therapeutic concentrations quickly then start the continuous infusion at the end if the loading infusion after the infusion stops there is an exponential decline in the concentration

Question 32

intermittent infusion

Answer 32

loading infusion followed by the maintenance dosage regimen - want troughs between 10-20 mg/l

Question 33

clinical applications of PK

Answer 33

A patient is admitted to your ward with a suspected gram positive infection and it is decided to start vancomycin. As the clinical pharmacist You could be asked to recommend a loading and a maintenance dosage regimen (continuous or intermittent infusion) You would check if a prescribed dosage regimen is appropriate for a patient You could be asked to interpret measured vancomycin concentrations and to recommend a dose adjustment

Question 34

how continuous infusions are prescribed in clinical practice

Answer 34

Daily dose rate (mg/24 h) = 22.5 mg/L x CL (L/h) x 24 The approach used varies among different hospitals The daily dose is prescribed with the instruction to administer by infusion continuously over 24 hours, e.g. 2000 mg over 24 hours The daily dose is split in two and prescribed with the instruction to administer as two 12 hour infusions, e.g. 1000 mg twice daily, each infusion given over 12 hours - 24 hour infusions are difficult due to factors such as drug stability

Question 35

How intermittent infusions are used in clinical practice

Answer 35

Daily dose rate (mg/24 h) = 22.5 mg/L x CL (L/h) x 24 The daily dose is split into one (24 hourly), two (12 hourly) or three (8 hourly) equal doses Ideally, the dosage interval should be less than one elimination half-life Each dose must be administered at a maximum rate of 500 mg per hour, e.g. 1000 mg twice daily would be given as 1000 mg infused over 2 h every 12 hours

Question 36

Aminoglycosides PK/PD relationship

Answer 36

Efficacy: peak:MIC ratio, aim for a high peak, low trough Different targets: Gm–ve sepsis and synergistic use (Gm+ve) Administered by short IV infusion (30-60 minutes) or IV bolus

Question 37

penicillin PK/PD relationships

Answer 37

Efficacy: % time free concentrations >MIC (40-60% fT>MIC) Wide therapeutic range, ideal profile is flat

Question 38

vancomycin PK/PD relationships

Answer 38

Efficacy depends on: AUC24/MIC ratio >400 Target concentrations: trough 10 - 20 mg/L, Cssaverage 20 – 25 mg/L Loading infusion then intermittent IV infusion or continuous IV infusion

Question 39

metronidazole dose and counselling for c.diff infection

Answer 39

400mg every 8 hours for 10 days stop 4C antibiotic that caused infection cannot drink alcohol on this (causes abdominal pain and sickness)

Question 40

describe trimethoprim mode of action

Answer 40

blocks the reduction of dihydrofolate to tetrahydrofolate, the active form of folic acid, by susceptible organisms.

Question 41

UTI treatment, drug, dose, duration

Answer 41

trimethoprim 200mg twice daily for 3 days

Question 42

UTI treatment, drug, dose, duration- in pregnant woman

Answer 42

nitrofurantoin 100mg twice daily for 7 days

Question 43

UTI non drug advice

Answer 43

drink plenty fluids don't hold pee for too long pee after sex wipe front to back

Question 44

what advice must be given to everyone on antibiotics

Answer 44

FINISH THE COURSE !!!!

Question 45

what kind of drug is aciclovir

Answer 45

a nucleoside reverse transcriptase inhibitor

Question 46

how does aciclovir work (MOA)

Answer 46

-to make a strand of DNA we phosphorylate a nucleotide 3 times- the energy from these phosphates is then used by DNA polymerase to bind the nucleotide to the DNA strand - phosphorylation is done by kinase enzymes - when aciclovir enters a cell it is phosphorylated by viral kinases (once) then phosphorylated by host kinases the 2nd and 3rd time -now that it is phosphorylated it looks very like guanine (a real nucleotide) - viral DNA polymerase gets confused and adds aciclovir to the DNA chain - this causes chain termination - it does this because normally the next nucleotide in the chain would be joined on the OH group (however this is not present in aciclovir) - this prevents the virus replicating

Question 47

what kind of drugs make good topical applications

Answer 47

negative log P so struggles to diffuse passively- in absence of uptake mechanism the cream helps encapsulate the drug and delivery it through the skin

Question 48

It is recommended to reconstitute a 500 mg vial of flucloxacillin with 10 ml water for injection. If the vial has a displacement value of 0.4 mL for 500 mg, how should the product be prepared?

Answer 48

9.6ml should be added to achieve a 10ml volume of solution

Question 49

what is a normal adult body surface area? (range)

Answer 49

1.4-2 m^2

Question 50

treatment for severe community acquired pneumonia with risk of sepsis

Answer 50

IV amoxicillin 1g every 8 hours for 5 days should review daily and swap to oral when improving

Question 51

treatment for skin and soft tissue infection (cellulitis) in penicillin allergic patient

Answer 51

doxycycline 100mg twice daily for 5 days counselling ---- dairy interaction, sun interaction- photosensitivity

Question 52

doxycycline counselling

Answer 52

- dairy interaction - iron, magnesium, Gaviscon, stomach acid – avoid all – massive interaction - avoid the sun- photosensitivity, extremely severe

Question 53

treatment for skin and soft tissue infection (cellulitis) with no penicillin allergy

Answer 53

oral flucloxacillin 1g every 6 hours for 5 days

Question 54

normally how many half lives does it take to reach steady state concentration

Answer 54

5

Question 55

Gentamicin uses

Answer 55

Gram -ve sepsis: community or healthcare acquired, urinary tract, neutropenic, unknown source relatively narrow spectrum, less risk of C. difficile overgrowth sometimes used “synergistically” (low dose) with penicillins / vancomycin against Gram +ve organisms

Question 56

amikacin uses

Answer 56

Neutropenic sepsis, multi-resistant mycobacterial infections

Question 57

tobramycin uses

Answer 57

Exacerbations in patients with cystic fibrosis (Ps. aeruginosa)

Question 58

Aminoglycoside clinical pharmacokinetics

Answer 58

Absorption highly polar, water soluble => low oral bioavailability, administered IV (or topically in ear/eye drops)  Volume of distribution distributes into extracellular fluid 0.25 - 0.4 L/kg  by oedema, ascites, burns, malnutrition  by dehydration Elimination route 90-100% renal excretion via glomerular filtration clearance and dose requirements depend on renal function

Question 59

aminoglycosides - efficacy

Answer 59

Concentration-dependent kill rate higher peaks (Cmax) produce a faster kill, more effective against bacteria Energy dependent uptake into bacteria reduced after exposure to antibiotic: temporary resistance Post antibiotic effect prolonged suppression of bacterial growth even when antibiotic concentrations fall below detection limit

Question 60

ahminoglycosides - nephrotoxicity

Answer 60

Acute tubular necrosis: uptake into proximal renal tubule Saturable absorption into the kidney: risk lower with a large daily dose rather than lower doses given 8 or 12 hourly Increased risk in patients who are elderly, have renal or hepatic impairment Increased risk with other nephrotoxic agents: NSAIDs, diuretics, amphotericin, beta-lactams, vancomycin, cisplatin Toxicity generally related to drug exposure High trough concentrations Long duration of therapy, cumulative area under the curve (AUC)

Question 61

aminoglycosides - ototoxicity

Answer 61

Vestibular toxicity (esp. gentamicin, tobramycin) dizziness, vertigo, nystagmus, oscillopsia, tinnitus linked to duration of therapy -rare if <6 days Cochleotoxicity (esp. amikacin) hearing loss, tinnitus linked to genetic factors and age Monitoring patients on an aminoglycoside Question patient about dizziness and balance problems STOP if the patient raises concerns

Question 62

ideal amino glycoside concentration - time profile

Answer 62

high peak and low trough, close to 0 before next dose is administered

Question 63

How do I check that a prescribed gentamicin dosage regimen is safe?

Answer 63

Identify the type of infection (sepsis or endocarditis) to define the target peak and trough concentrations Identify the mode of administration (IV bolus or IV infusion) to determine the appropriate steady state equation (multiple doses) Predict the steady state peak and trough concentrations and adjust the dosage regimen, if necessary Measure concentration(s) and interpret the result(s) Sepsis measure a mid-dose concentration and plot on a nomogram use two concentrations to calculate individual CL and V Endocarditis usually measure peak and trough concentrations calculate individual CL and V Adjust the dosage regimen, if necessary

Question 64

where are most antibiotics used

Answer 64

primary care (~80%)

Question 65

the 5 Rs for antibiotics

Answer 65

right choice right dose right frequency right route right duration

Question 66

what is a normal duration for acute otitis media

Answer 66

4 days

Question 67

what is a normal duration for acute sore throat/ pharyngitis/ tonsillitis

Answer 67

1 week

Question 68

what is a normal duration for common cold

Answer 68

7- 10 days

Question 69

what is a normal duration for acute sinusitis

Answer 69

2 and a half weeks

Question 70

what is a normal duration for acute cough/ bronchitis

Answer 70

3 weeks

Question 71

are antibiotics required in upper respiratory tract infections

Answer 71

in sore throats 90% will resolve in 1 week without the use of antibiotics in acute otitis media 66% of children are better in 24 hours and antibiotics have no effect on symptoms

Question 72

when should antibiotics be used in upper respiratory tract infections

Answer 72

systemically very unwell (fever, chills, low bp, fast HR and breathing rate) symptoms and signs of serious complications like pneumonia and sepsis high risk of complications (over 65 with 2 of these symptoms or over 80 and one of these)- hospitalisation in the last year diabetic cardiac failure children under 2 with acute otitis media in both ears or children with discharge from the ear acute sore throat- using fever pain- a score of 4 or 5

Question 73

what can we do to prevent over use of antibiotics

Answer 73

educate the public- when people want antibiotics for something that does not require it- reassure them they are ok and will get better on their own educate healthcare staff- provide guidelines and policies to help staff make the right decision and b as specific as possible with the information known