Antimicrobials Flashcards
What are anti-microbials?
Drugs which kills or inhibit growth of micro-organisms
What are antibiotics classifications? Give examples the drugs in each classification?
Based on what they target:
Bacterial cell wall and membrane
- penicillins
- cephalosporins
- carbapenems
- monobactams
- glycopeptides
- polymxins
Nucleic acid synthesis
- folate antagonists
- DNA gyrase i.e. Quinolones
- RNA polymerase i.e. Rifmycins
Protein synthesis -50s subunit: Macrolides Linomycins (Clindamycin) Oxozolidinones (linezolid) Chroamphenicol -30s subunit: Tetracyclines Aminoglycosides
What are the functional classification of antibiotics?
Bacteriostatic
-inhibit growth and replication = NON-LETHAL
E.g. Inhibitors of folate synthesis + quinolones
Bacteriacidal
-kill bacteria but can be bacteriostatic at lower doses
Eg penicillin + aminoglycosides
How do beta-lactam antibiotics work and which antibiotics come under this class?
INHIBITION OF CELL WALL SYNTHESIS
Beta-lactam antibiotics have beta-lactam ring which acts a structural mimic of D-Ala-D-Ala of penicillin binding protein (PBP) Acts to prevent the cross-linking of DD transpeptide proteins which are important for the formation of peptidogylcan cell wall
I.e bacteria unable to survive osmotic pressures
penicillins
Cephalosporins
Carbapenems
Monobactams
What are the 5 classes of penicillin? Give examples of types of penicillin.
Natural penicillins
Penicillinase-resistant penicillins (not really used clinically)
Aminopenicillins
Carboxypenicillins (not used clinically)
Acyl ureidopenicillins
Penicillin V
Amoxicillin
Flucloxacillin
Benzylpenicillin
What are the clinical features of penicillins?
Narrow spectrum
Excellent absorption
Safe in pregnancy
What are the clinical features of Cephalosporins? Give examples.
Broad spectrum
Safe in pregnancy
Cefuroxime
Ceftaxime
Ceftazidime
What are the clinical features of carbapenems? Give examples?
Broad spectrum
IV only
Safe in pregnancy
Meropenem
Ertapenem
Imipenem
What is the mechanism of action of glycopeptides?
Target gram +ve bacteria only, which are the bacteria without porins present in cell wall. Act to inhibit cell wall synthesis by binding to PBP
What are the clinical features of glycopeptides? Give examples.
Narrow spectrum
IV admin only
Safe in pregnancy
Vancomycin
Teicoplanin
Dalbavancin
What are the 3 types of antibiotics which causes inhibition of cell wall synthesis?
Beta-lactam antibiotics
Glycopeptides
Polymyxins (Colistin)
Which 2 antibiotics act by inhibiting folate synthesis? What is the mechanism of each?
Sulphonamides
-inhibits dihydropteroate sythetase (DPS) enzyme to inhibit conversion of PABA to folate
Trimethoprim
-inhibits dihydrofolate reductase to inhibit conversion of folate to tetrahydrofolate
THEREFORE both lead to inhibition of DNA production and are BACTERIOSTATIC
How are sulphonamides and trimethoprim used clinically?
Used in combination for synergistic effects
Broad spectrum
Why are sulphonamides and trimethoprim contraindicated in pregnancy?
Inhibition of folate means that foetus does not receive sufficient folate= leads to neural tube defects
What is the mechanism of Quinolones? What are their clinical features and give examples of types?
Inhibit DNA gyrase= important bacterial enzyme for correct topological formation of DNA
Can be broad or narrow spectrum and have excellent bioavailability
Eg: Ciprofloxacin Levofloxacin Ofloxacin Gatafloxacin
What is the mechanism of Rifamycins? What are the important considerations when using this drug?
How could you identify a patient on these drugs?
RNA polymerase inhibitor
Acts as potent liver enzyme inducer (CYP3A) which can lead to increased liver metabolism of other medications and therefore decrease the plasma concentration
Has low genetic barrier meaning it is vulnerable to genetic resistance being developed = SHOULD NOT BE USED ALONE
Orange urine/tears
What is the mechanism of Macrolides? Give examples of antibiotics in this class.
Targets 50s subunit to dysregulate protein production leading to bacteriostatic affect
Erythromycin
Azithromycin
Clarithromycin
What is the mechanism of Lincosamide (Clindamycin)? Which infections is it particularly effective against?
Targets 50s subunit and can have bacteriostatic or bacteriacidal effect depending on dose
Gram positive and anaerobic infections
What is the mechanism of Oxazolidinones (linezolid)? Which infections are they affective against?
Targets 50s subunit to have bacteriostatic effect
Gram positive infections
What is the mechanism for chloramphenicol? What infections is it useful in targeting?
Targets 50s subunit to have bacteriostatic effect
Topical infections such as ear or eye infections
CNS infections as is able to penetrate into CNS and cross BBB
What are the 2 antibiotic classes which target 30s subunit? What are their clinical features and indications?
Tetracyclines -broad spectrum bacteriostatic -contraindicated in preg, breast feeding and children -can cause teeth staining Eg -doxycycline -tetracycline -minocycline
Aminoglycerides -narrow spectrum= gram -ve infections -given IV Eg -Gentamycin -Amikacin -Tobramycin -Streptomycin
Which antibiotics are safe for use in pregnancy?
Penicillins
Cephalosporins
Clindamycin
Glycopeptides
Metronidazole
Which antibiotics are not safe for use in pregnancy and breasting feeding? Give a brief reason why
Carbapenams= Manufacturing warning
Macrolides=. Manufacturing warning
Quinolones= can affect skeletal development
Folate antagonist= neural tube defects
Tetracyclines= affect skeletal development
Aminoglycosides= auditory/vestibular nerve damage
What are the 3 methods of assessing in vitro antibiotic effectiveness?
Minimum inhibitory concentration (MIC)
-minimum in vitro concentration which can inhibit growth of bacteria
Minimum bactericidal concentration (MBC)
-minimum in vitro concentration of antibiotic which can kill bacteria
Detection of resistance mutations by PCR
-due to effecting bacteriostatic and bactericidal activity of ab
What does the “breaking point” refer to in terms of antibiotic effectiveness?
Point where certain concentration of antibiotic can no longer inhibit bacterial growth
What in vivo factors can affect the effectiveness of an antibiotic? How might present in a clinical setting?
Pharmackinetics
Pharmacodynamics
Foreign material
Source control
Host immune response
Patient might not be responding to an antibiotic despite it being the appropriate antibiotic for the bacterial infection they have
What does pharmacokinetics refer to in the context of antibiotics? What are the 4 components influencing pharmacokinetics?
Time course of antibiotics
- Absorption:
- Route of administration important ensure Ab reaching the site of infection
- bioavailability i.e. proportional drug absorbed into systemic circulation - Distribution:
- Volume of distribution i.e. serum [drug] relative to dose - Metabolism:
- CYP3A4 inducers (Rifampicin)
- CYP3A4 inhibitors (Ketoconazole) - Excretion:
- half-life
- renal excretion
- non-renal excretion i.e. Ceftriaxone = biliary and Azithromycin = gut
Which antibiotics have excellent bioavailability? What is the benefit of this?
Amoxicillin Linezolid Clindamycin Levofloxacin Ciprofloxacin Rifampicin Metronidazole
Means that lower dose of drug is required to achieve the same therapeutic effect meaning body will not be exposured to high doses
What is the significance of a small and large volume of distribution in context of antibiotics?
Small= drug is plasma bound i.e confined to circulation
-means lower dose required to reach certain plasma volume
Large= fat soluble i.e. drug more likely to be found on tissue
-means larger dose required to reach certain plasma volume
Which antiobitics can affect liver metabolism and what is the significance of this?
Rifampicin= CYP3A4 inducer
Ketoconazole/Clarithromycin= CYP3A4 inhibitor
Can lead to fatal drug interactions if patient on other medication which is relying on these metabolic pathways
How does pharmacokinetics lead to differences in how often different antibiotics need to be taken?
Some antibiotics able to stay w/i therpeutic range (above MIC) for longer meaning fewer doses required
What are the 3 different forms of killing dependent on pharmacodynamics of antibiotics? Give examples of antibiotics associated with each.
Concentration dependent killing (Cmax/MIC ratio)
I.e. peak drug concentration
Eg Aminoglycosides/Fluoroquinolones
Time dependent killing (AUC/MIC ratio)
I.e. time drug needs to spend above MIC
Eg Vancomycin/Azithromycin/fluoroquinolones/aminoglycerides/linezolid
Exposure dependent killing (AUC24/ratio)
Eg beta-lactams/vancomycin/macrolides/Clindamycin
What is the post-antibiotic effect? (PAE) What type of killing leads to greater PAE? Give an example of antibiotic with high PAE.
Time when bacterial growth is still inhibited when drug con < MIC
Concentration-dependent killing leads to greater PAE
GENTAMYCIN
-v high dose w/i 1 hour of taking which means only one dose needed a day because associated with very high PAE
What is the pharmacodynamic advantage of combining Co-amoxiclav and Gentamycin?
Gentamycin causes very high concentration in short among of time and has high PAE to continue to kill bacteria after peak
Co-amoxiclav requires regular doses to achieve MIC but then maintains steady killing action
THEREFORE:
Combined use can lead to more optimal treatment of infection
What are the 3 main AMR pathogens?
Methicillin-resistant staphylococcus aureus (MRSA)
Vancomycin resistance enterococci (VRE)
ESBL
What are the 3 main mechanisms of AMR? Give examples of resistance to specific antibiotics.
- Production of enzymes:
- beta-lactamase enzyme and beta-lactam molecule hydrolysis
- carbapenamase enzymes - Changes to target site/metabolic pathway:
- b-lactams= mutation in PBPs
- macrolides + lincosomides= methylation of rRNA
- Quinolones= DNA gyrase mutations
- Carbapenems= porin channel mutation
- folate antagonist= use of exogenous thymidine or thymidine - Efflux pumps
- Tetracyclines= actively pumping enzymes out of cell
What types of mutation are associated with AMR?
Natural resistance
Point mutations
Transformations by up taking DNA from other cells
Transduction= infection from bacteriophage
Conjugation= exchange of genetic material via plasmids or transposons
What are the two types of allergic reaction most commonly associated with antibiotic allergic reaction? What are the signs associated with each?
Type 1: Immediate, IgE mediated reaction Signs: -urticaria -angioedema= histamine mediated -anaphylaxis
Type 4:
Delayed hypersensitivity
Signs:
-multiple organs can be involved over number of weeks
-DRESS= drug rash with eosinophilia and systemic symptoms
-SJS= Steven-Johnson syndrome
-TEN= Toxic epidermal necrosis
What are the main ways which AMR has been accelerated?
Drug prescribing
Drug access
Veterinary use
Global travel
Environment
What are the 3 main mechanisms of action of antibiotics targetting aerobic bacteria? Give examples of the antibiotics in these classes.
1. Inhibition of cell wall synthesis With beta-lactam ring -penicillin -carbapenems -cephalosporins Without beta-lactam ring -vancomycin -teicoplanin
- Inhibition of folic acid metabolism (due to bacteria reliant on one production of folic acid)
- sulfamethoxazole= blocks PABA->DHFA
- trimethoprim = blocks DHFA->THFA
- co-trimoxazole= combo of 2 above - Inhibition of protein synthesis by targetting ribosomes
- macrolides I.e. erythromycin
- clindamycin
- tetracylines i.e. doxycyclines
- gentamicin
- chloramphenicol
What antibiotic is used to target anaerobic cells?
Metronidazole
I.e. only reduced to active form in anaerobic cells
What is a stepwise approach of treating someone with antibiotics and what is the reasoning for the additional antibiotics?
Amoxicillian
-covers streptococcus, listeria and enterococcus
Co-amoxiclav
-covers staphlococcus, haemophilus + ecoli
Tazocin
-covers pseudomonas
Meropenem
-covers ESBLs
Teicoplanin or vancomycin
-MRSA
Clarithromycin or doxycycline
-atypical bacteria
