S11: antimicrobials & anticoagulants

Question 1

Describe the three types of antibiotic resistance

Answer 1

Multi-drug resistant: non-susceptibility to at least one agent in three or more antimicrobial categories
Extensively-drug resistant: non-susceptibility to at least one agent in all but two or fewer antimicrobial categories
Pan-drug resistant: non-susceptibility to all agents in all antimicrobial categories

Question 2

Outline antimicrobial stewardship

Answer 2

Appropriate use of antimicrobials
Optical clinical outcomes
Minimize toxicity and other adverse events
Reduce the costs of healthcare for infections
Limit the selection for antimicrobial resistant strains

Question 3

List interventions for antimicrobial stewardship

Answer 3

Persuasive – education, consensus, audit
Restrictive – prior authorisation, automatic stop orders
Structural – computerised records, rapid lab tests, expert systems

Question 4

Describe the mechanism of action of beta-lactam antibiotics

Answer 4

Interfere with the synthesis of the bacterial cell wall peptidoglycan
Generally bactericidal
1) Antibiotic binds to penicillin-binding protein on bacteria
2) Inhibits the transpeptidation enzyme (links peptidoglycan chains to form rigid cell walls)
3) Disruption of bacterial cell wall structure

Question 5

List types of beta-lactam antibiotics

Answer 5

Penicillins
Cephalosporins
Carbapenems

Question 6

Describe co-amoxiclav and the role of clavulanic acid

Answer 6

Clavulanic acid = beta-lactamase inhibitor
Beta-lactamase = enzyme used by certain bacteria to break down beta-lactam antibiotic molecular structure
Clavulanic acid is commonly combined with amoxicillin to overcome these issue

Question 7

List indications for Penicillins

Answer 7

Bacterial meningitis
Bone and joint infections 
Skin and soft tissue infections 
Otitis media
Pneumonia 
UTIs
STIs

Question 8

List examples of cephalosporins

Answer 8

Cefalexin

Ceftriaxone

Question 9

List indications for cephalosporins

Answer 9

Septicaemia 
Pneumonia 
Meningitis 
Biliary tract infections 
UTIs (especially in pregnancy or in patients unresponsive to other drugs)
Sinusitis

Question 10

List antibacterials affecting bacterial protein synthesis

Answer 10

Tetracyclines
Macrolides
Nitrofurans

Question 11

Describe tetracyclines, giving examples

Answer 11

Following intake into susceptible organisms by active transport, tetracyclines act by inhibiting protein synthesis -> bind to bacterial ribosomes, preventing binding of tRNA to it, thus preventing the initiation of protein synthesis
Examples: doxycycline
Bacteriostatic

Question 12

List indications and warnings for tetracyclines

Answer 12

Respiratory tract infections
Acne
Chlamydia 
Lyme disease 
Warning: shouldn’t be given to children <12 years, pregnant & breastfeeding women -> causes staining of developing teeth

Question 13

Describe macrolides, giving examples

Answer 13

Inhibit bacterial protein synthesis by an effect on ribosomal translocation
Bactericidal/bacteriostatic
Examples: clarithromycin, azithromycin
Antimicrobial spectrum very similar to penicillin, also active against atypical respiratory pathogens

Question 14

Describe the mechanism of action of nitrofurans

Answer 14

Works by being reduced to multiple reactive intermediates by nitrofuran reductase inside the bacterial cell
These intermediates then attack ribosomal and DNA proteins within the bacteria, as well as inhibit the citric acid cycle

Question 15

Why is nitrofurantoin one of the first-line agents in treating UTIs?

Answer 15

Up to 50% of an oral dose nitrofurantoin is excreted in the urine in unchanged form
Allows nitrofurantoin to concentrate within urine, leading to more effective levels within the bladder than in other tissue compartments

Question 16

Describe quinolones, giving examples

Answer 16

Inhibit topoisomerase II, the enzyme that produces a negative supercoil in DNA & thus permits transcription or replication
Common examples: ciprofloxacin
Good cover of gram negative organisms, as well as atypical organisms & gram positives

Question 17

List indications and side effects of quinolones

Answer 17

Indications: complicated UTIs, pseudomonas aeruginosa, gonorrhoea
Side effects: tendinitis +/- rupture, aortic dissection, CNS effects

Question 18

List antibacterial agents that interfere with folate synthesis or action

Answer 18

Sulfonamides

Trimethoprim

Question 19

Describe trimethoprim

Answer 19

Folate antagonist: reversible inhibitor of dihydrofolate reductase, which is responsible for the production of tetrahydrofolic acid -> necessary for biosynthesis of bacterial nucleic acids & proteins
Binds with much stronger affinity to bacterial dihydrofolate reductase than human
Bacteriostatic/bactericidal
Indications: UTIs (careful when prescribing to reproductive age females)

Question 20

Describe metronidazole

Answer 20

Exact mechanism of action has not been established
It is thought anaerobes and protozoa metabolise metronidazole, making it active in blocking nucleic acid synthesis
Has disulfiram-like action, so patients must avoid using alcohol when on the antibiotic

Question 21

List types of antivirals

Answer 21

Aciclovir (DNA polymerase inhibitors)

Oseltamivir (neuraminidase inhibitors)

Question 22

Describe aciclovir

Answer 22

Predominately activated in infected cells, as the viral enzyme thymidine kinase is more effective at phosphorylating it, thus activating it
Fully phosphorylated form then inhibits viral DNA polymerase
Indications: herpes simplex virus (genital herpes, encephalitis), varicella zoster (chicken pox, shingles)

Question 23

Describe aciclovir in herpes simplex virus

Answer 23

NICE guidelines do not recommend routine prescribing of oral antivirals for healthy people with herpes labialis, more lenient when dealing with immunocompromised patients
Genital herpes: episodic antiviral treatment if attacks are infrequent (<6/year), suppressive antiviral treatment if attacks are more frequent (>6/year)/causing psychological distress/affecting the person’s social life

Question 24

Describe CYP450 enzymes

Answer 24

Present in most tissues of the body, but predominantly the liver
Essential for the metabolism of many medications and hormones
Most significant: CYP3A4 & CYP2D6

Question 25

Describe CYP450 inhibitors and inducers

Answer 25

Inhibitors block the metabolic activity of one or more CYP450 enzymes - Means the drugs usually broken down by the inhibited enzyme will be metabolised at a slower rate, essentially leading to an ‘overdose’ Inducers increase the enzyme synthesis of one or more CYP450 enzymes - Means more enzyme, therefore the drugs broken down by said enzyme break down quicker, leading to below therapeutic levels in the blood

Question 26

Give examples of CYP450 inhibitors & inducers

Answer 26

1) Warfarin metabolised by CYP2C9, metronidazole is a CYP2C9 inhibitor; inhibiting this enzyme will slow down the metabolism of warfarin, therefore allowing higher circulating conc. of warfarin to persist 2) Verapamil and simvastatin both metabolised by CYP3A4, macrolides inhibit CYP3A4; leads to overdosing of verapamil and simvastatin

Question 27

Describe enterohepatic circulation and relationship with oral antibiotics

Answer 27

Begins with drug absorption across the intestine into portal circulation, followed by uptake into hepatocytes Drug or conjugated metabolites are secreted into bile & returned to the intestine, where drug can be reabsorbed into circulation Oral antibiotics – can eliminate gut flora, thus lessen/prevent EHR -important interaction with oral contraceptives -> lower rates of EHR, lower blood concentrations of oestrogen/progesterone = increased risk of becoming pregnant

Question 28

Describe haemostasis and thrombosis

Answer 28

Limits bleeding following injury – adhesion and activation of platelets and fibrin formation Thrombosis: pathological haemostasis Venous and intracardiac thrombosis driven largely by coagulation cascade & fibrin, arterial thrombus mainly platelet rich

Question 29

Describe heparins

Answer 29

Produced naturally in mast cells and vascular endothelium Unfractionated heparins are large Low molecular weight heparins Inhibit coagulation in vitro and in vivo -> enhance antithrombin III activity

Question 30

Describe mechanism of action of unfractionated heparin

Answer 30

Typically i.v. bolus and infusion, s.c. for prophylaxis with low bioavailability Binding to antithrombin causing conformational change & increased activity of ATIII To catalyse inhibition of thrombin, heparin needs to simultaneously bind ATIII & IIa Xa inhibition only needs ATIII binding

Question 31

Describe low molecular weight heparins

Answer 31

Almost always s.c., bioavailability > 90%, longer half life More predictable dose response as dose not bind to endothelial cells, plasma proteins & macrophages Don’t inactivate thrombin, inhibition of Xa specifically by enhancing ATIII activity Fondaparinux – synthetic pentasaccharide selectively inhibits Xa by enhancing ATIII

Question 32

List examples of low molecular heparins

Answer 32

Dalteparin | Enoxaparin

Question 33

Describe pharmacokinetics of heparins

Answer 33

Large negatively charged molecules – poor GI absorption Given parenterally – i.v. or s.c. UFH – metabolism dose dependant, monitor with aPTT, used for moderate renal impairment and v. fine control LMWH – generally no monitoring, used in most situations

Question 34

List indications for heparins

Answer 34

Prevention of VTE During pregnancy used as do not cross the placenta – monitored with caution ACS – PCI and non PCI patients

Question 35

What are the adverse effects, warnings, contraindications and important drug interactions of heparins?

Answer 35

Adverse effects: bruising, bleeding, heparin induced thrombocytopenia, hyperkalaemia, osteoporosis Warnings, contraindications: clotting disorders, renal impairment Important drug interactions: other antithrombotic drugs, ACEi/ARB, amiloride, spironolactone

Question 36

Describe protamine sulphate

Answer 36

Forms inactive complex with heparin, given i.v. Dissociates heparin from ATIII, irreversible binding Much greater with UFH than LMWH, no effect on fondaparinux

Question 37

Describe vitamin K antagonists

Answer 37

Inhibit activation of vitamin K dependant clotting factors Inhibits conversion of vitamin K to active reduced form – competitive inhibition of VKOR Delay in onset of action as circulating active clotting factors present for several days -> must be cleared and replaced with non-carboxylated forms e.g. warfarin

Question 38

List indications for warfarin

Answer 38

VTE – PE, DVT & secondary prevention, superficial vein thrombosis Atrial fibrillation with high risk of stroke Heart valve replacement bioprosthetic & some mechanical Generally used in longer term anticoagulation compared to heparins

Question 39

Describe pharmacokinetics of warfarin

Answer 39

Good GI absorption & taken orally Functional CYP2C9 polymorphisms contribute to significant inter-individual variability Racemic mixture of two enantiomers – R & S which have different potency and metabolised differently Crosses the placenta – avoided in 1st (teratogenic) and 3rd (haemorrhage) trimesters Response affected by CYP2C9 and others, vitamin K intake & alcohol

Question 40

Describe warfarin adverse drug reactions and reversal

Answer 40

Bleeding – epistaxis and spontaneous retroperitoneal bleeding Most effective antidote is vitamin K Perioperative anticoagulation needs to be considered

Question 41

Outline warfarin drug-drug interactions

Answer 41

Majority potentiate anticoagulant action but some decrease effects - inhibition of hepatic metabolism especially CYP2C9: amiodarone, clopidogrel, intoxicating dose of alcohol - reduce vitamin K by eliminating gut bacteria involved in production: cephalosporin antibiotics - displacement of warfarin from plasma albumin: NSAIDs & drugs that decrease GI absorption of vitamin K (likely increase INR) - acceleration of warfarin metabolism: barbiturates, phenytoin, rifampicin, St Johns Wort (likely decrease INR)

Question 42

Describe warfarin use and INR

Answer 42

Monitoring required due to huge variation in patient response INR 2.5 – DVT, PE & AF INR 3.0-3.5 – recurrent DVT/PE in patients currently receiving anticoagulation

Question 43

Describe DOACs

Answer 43

Direct Xa: inhibit both free Xa and that bound with ATIII, do not directly effect thrombin – hepatic metabolism & excreted partly by kidneys Direct IIa: selective direct competitive thrombin inhibitor, both circulating and thrombin bound IIa Oral administration, standard dosing & little to no direct monitoring required

Question 44

List examples of DOACs

Answer 44

Direct Xa: apixaban, edoxaban & rivaroxaban | Direct IIa: dabigatran

Question 45

What are the adverse effects, warnings, contraindications and important drug interactions of DOACs?

Answer 45

Adverse effects: bleeding Warnings, contraindications: dabigatran contraindicated in low creatinine clearance (<30mL/min), others are at very low creatinine clearance (<15mL/min), avoid in pregnancy/breastfeeding Important drug interactions: [plasma] reduced by carbamazepine, phenytoin & barbiturates, [plasma] increased by macrolides Antidotes – andexanet and idarucizumab

Question 46

Which antihypertensive drug is least likely to exacerbate hyperkalaemia observed in some patients taking heparin?

Answer 46

Heparin has been showed to inhibit aldosterone action so spironolactone & ramipril would increase risk of hyperkalaemia Amlodipine