Antibioitcs (Elizabeth Prentice) Flashcards
What are the 4 D’s of antibiotic prescribing
Drug
- right drug for right bug
Dose
- Adequate exposure of bug to antimicrobial
–> PK:PD index
–> MIC
–> Therapeutic Drug Monitoring
De-escalation
- Laboratory defined infection
Duration
- for the right amount of time
Which study illustrated the importance of early antibioitcs and the golden hour
Kumar et al 2006
Does the concept of bactericidal vs bacteristatic antibiotics have a clinical role
Often, bactericidal agents are preferred for severe infections
However,
It ignores the role of the host
There is no absolute distinction, for some antibiotics the action depends on the organism and concentration
Describe the mechanism of action of cell wall synthesis inhibitors
Inhibit enzymes that form cross-linking of peptidoglycan in the cell wall (these are called PBP or penicillin binding proteins)
Classify the commonly used Beta-lactams
Penicilins
1. Pencillin G / Pipericillin
2. Amoxicillin/Ampicillin
3. Cephalosporins
4. Carbapenems
5. Combinations (beta lactamase inactivator)
- Amoxicillin/Clavulanate
- Piperacillin/Tazobactam
Describe the coverage of penicillin
PENICILLIN
Anaerobes: yes
Gram positive:
- Streptococci
Gram negative:
- (weak activity against Gram - H.Ifluenzae)
Describe the coverage of cloxacillin and flucloxacillin
CLOXACILLIN
Anaerobes: No
Gram positive:
-nStrep. species and MSSA
No gram negative cover
Describe the coverage of amoxicillin vs augmentin
AMOXICILLIN
Anaerobes: yes
Gram positive:
- Ampicillin sensitive enterococci
- Streptococci
- (weak activity against staphylococcus)
Gram negative:
- weak
AUGMENTIN
Anaerobes: yes
Gram positive:
- Ampicillin sensitive enterococci
- Streptococci
- Staphylococci
Gram negative:
- Haemophilus Influenzae
- Many Enterobacteriacae
Non-fermentors (Pseudomonas aeruginosa)
- NO COVER
Describe the coverage of piperacillin vs piperacillin/tazobactam
The same as Augmentin BUT:
Pipericillin also covers non-fermentors (Pseudomonas aeruginosa)
AND
PipTaz has some activity against organisms with cephalosporniases (e.g. Amp-C enterobacteriacae)
Describe the coverage of first generation cephalosporins and give example
CEFAZOLIN / CEPHALEXIN / CEFADROXIL
Anaerobes: No
Gram positive
- Strep and Staph only
Gram negative
- weak
Describe the coverage of 2nd generation cephalosporins and give example
CEFUROXIME
Anaerobes: No
Gram positive
- Strep and Staph only
Gram negative
- better than gen 1
Pseudomonas
- None
Describe the coverage of third generation cephalosporins and give example
CEFTRIAXONE / CEFOTAXIME
Anaerobes: Minimal
Gram positive
- Broad
Gram negative
- Broad
Pseudomonas: No
How are 4th and 5th generation cephalosporins different to 3rd generation cephaolsporins
Give example of 4th generation cephalosporin
CEFEPIME (4th)
Has the same broad cover as 3rd gen and also covers pseudomonas
CEFTAROLINE / CEFTOBIPROLE
Have the same cover as 3rd gen and also covers MRSA and CNS. Do not cover pseudomonas
Describe the cover of carbapenems and note specific advantages and disadvantages of certain drugs
Anaerobes: Yes
Gram positive
- broad
- Does not cover Enterococci, MRSA, CoNS
Gram negative
- Broad
- Does not cover CREs
Pseudomonas: Yes
EXCEPTIONS
Ertapenem - does not cover pseudomonas
Imipenem + cilastatin does cover enterococci
What are the Glycopeptides, what is their mechanism of action and what is their specific importance?
Glycopeptides
- Vancomycin
- Teicoplanin
Mechanism
- Inhibits cell wall synthesis
Spectrum
- All Gram positive (including G+ anaerobes) and importantly including MRSA and enterococcus faecium
How is Vancomycin Resistant Enterococcus treated
Linezolid
Daptomycin
What is the mechanism of action and spectrum of activity of Aztreonam
Mechanism
- Cell wall synthesis inhibition
Spectrum
- Gram neagative
- Pseudomonas
Describe how protein synthesis inhibitors work and list the common classes of antimicrobials that work like this
Act on Ribosomes
Multiple different agents that disrupt the protein synthetic processes that occur during transcription and translation.
- Macrolides
- Aminoglycosides
- Lincosamides (clindamycin)
- Linezolid
Describe the spectrum of activity of Mcrolides
Similar to amoxicillin
Importantly it is also effective against atypical organisms such as:
- Mycoplasma pneumoniae
- Chlamydia trachomatis
- Legionella pneumophila
and
- Mycobacterium avium complex
Describe how nucleic acid (DNA) synthesis inhibitors work and list the common classes of antimicrobials that work like this
Inhibit DNA gyrase, the enzyme responsible for coiling of the DNA
The Fluoroquinolones
What are the important side effects of the fluoroquinolones
Connective tissue weakness
- Aortic dissection
- Achilles tendon rupture
Increased risk of antimicrobial resistance
Describe the spectrum of activity of ciprofloxacin. How does the spectrum of activity of Levofloxacin and Moxifloxacin differ from ciprofloxacin
CIPROFLOXACIN
Anaerobe: minimal
Gram positive
- minimal. Staph aureus only
Gram negative
- broad cover
Intracellular organisms
- Legionella pneumophila
- Chlamydia trachomatis
MOXIFLOXACIN
Covers what cipro covers but with a much bigger Gram positive cover.
No pseudomonas cover
LEVOFLOXACIN
Covers what cipro covers but with a much bigger Gram positive cover.
Covers Pseudomonas
How do antibiotics that inhibit metabolic pathways work
Many differnt metabolic pathways can be disrupted by different antimicrobials.
Example:
Cotrimoxazole - inhibits Folic acid synthesis (enzymes). Folic acid is needed for nucleic acid synthesis
How do inhibitors of cell membrane function work as antimicrobial agents. What is their spectrum of activity and give an example
They disrupt the phospholipid structure of the outer cell membrane of gram negative bacteria.
E.g. Colistin
Spectrum: Gram negative bacteria only including pseudomonas
E.g Daptomycin
Used for Vancomycin Resistant Enterobactericiae
When is colistin reserved for multiresistant organisms?
Toxic. Generally used topically. No need for systemic use as antimicrobial resistance expands
List the antibiotics classes by mechanism of action
- Cell wall synthesis inhibitors
- Protein synthesis inhibitors
- DNA synthesis inhibitors
- Metabolic pathway inhibitors
- Cell membrane function inhibitors
Describe the 3 mechanisms for antimicrobial resistance
Intrinsic Resistance
- Innately resistant (e.g. Vanco no effect on Gram neg as the outer cell membrane is impermeable to glycopeptides)
Acquired Resistance
- Induced resistance (preveiously susceptible) now resistant due to mutation or insertion fo genetic material into genome
Adaptive resistance
- Indiced by environmental stressors like sub-inhibitory levels of antibiotics.
List the ways that bacteria become resistant to antibiotics
- Target site alteration
- Change to structure of PBP (e.g. MRSA. Also VRE and VRSA) - Access to target site alteration (altered uptake or increased elimination of antimicrobial from the vicinity of the target site)
- efflux pumps and altered outer membrane permeability - porin repression (gram negatives). - Inactivating enzymes
- B lactamases (ESBL)
- Carbapenemases (CRE)
What is a biofilm
Secretion of biofilm by colony of bacteria prevents detection by host defenses - thick sticky matrix also prevents penetration by antibiotics.
What factors influence the choice of antibioitic
- Organism susceptibility
- Effect site concentration
- Collateral damage and side effects
- PKPD principles
Define the MIC
Minimum Inhibitory concentration (MIC) is lab defined construct that is the lowes concentration of antibiotic that inhibitis growth of a strain of bacteria.
Lab techniques
1. Microdilution
2. Disk diffusion
3. Gradient Test (gradient strips)
The best antibiotic for the bug will be effective at the lowest MIC.
However, the MIC must be compared against a breakpoint to describe whether the bacteria is resistant, Sensitive or Intermediate when the antibiotic is administered in usual doses.
What is the breakpoint
The breakpoint is a previously agreed upon concentration of antibiotic which defines whether a species of bacteria is susceptible or resistant to an antibiotic.
What is the Mutant Selection window
This is when the antibiotic concentration lies between the Minimum Inhibitory concentration (MIC) and the Mutant Prevention Concentration (MPC) there is a higher chance of the emergence of resistance
The area on the graph between these lines on a concentration time axis is called the mutant selection window
Summarise the penetration of Augmentin
CSF - Poor
Lung - Good
Soft Tissue - Good
Urinary tract - Fair
Summarise the penetration of Ceftriaxone
CSF - Good (in high dose)
Lung - Good
Soft Tissue - Good
Urinary tract - Good
Summarise the penetration of aminoglycosides
CSF - Poor
Lung - Poor (unless nebs)
Soft Tissue - Fair
Urinary tract - Good
Summarise the penetration of Bactrim
CSF - Good
Lung - Good
Soft Tissue - Good
Urinary tract - Good
Summarise the penetration of Ertapenem
CSF - Poor
Lung - Good
Soft Tissue - Good
Urinary tract - Good
Summarise the penetration of meropenem
CSF - Good (in high doses)
Lung - Good
Soft Tissue - Good
Urinary tract - Good
Summarise the penetration of Vancomycin
CSF - Poor
Lung - Fair
Soft Tissue - Poor
Urinary tract - Good
Define Therapeutic Drug monitoring
Measurement of specific drugs at designated time intervals to optimise individual dosing regimens and achieve required PK/PD targets.
However, TDM measures serum concentrations and may not reflect the concentration at the effect site.
Define and give examples of collateral damage during antimicrobial therapy
Unintended adverse effects on the ecology due to antibiotic use which manifests as the selecting out of, and development of colonization with, MDR pathogens.
E.g. Quinolones –> MRSA and resistant Pseudomonas
3rd gen cephalosporins –> C difficile, VRE, CRAB, ESBL Klebsiella
Summarise the pharmocokinetic and pharmocodynamic properties of commonly used antibiotics
- Time dependent (time above MIC) - should be 100% above MIC for effective killing
- Beta Lactams - Concentration dependent (Cmax/MIC)
- Aminoglycosides
- Metronidazole - Area under the concentration time curve (AUC 0-24h/MIC)
- Vancomycin
- Fluoroquinolones
When should the peak levels of aminoglycosides be measured
30 minutes after the FIRST dose of aminoglycoside (NOT after 3 days)
Why - must give an appropriate dose from the beginning. Its too late if this is only picked up 3 days later
How high above MIC do we aim to achieve for aminoglycosides which exhibit concentration dependent killing
10 - 12 above MIC
The minoglycoside concentration falls with time (one dose in 24 hours). why does it continue to have an antimicrobial effect?
They exhibit a POST-ANTIBIOTIC EFFECT which is seen because the antibiotic is taken up into the organism which continues to exert its effect even though the serum concentration has fallen.
Which antibiotics demonstrate a post antibiotic effect and what type PKPD mechanism of killing are these medications
Aminoglycosides
Metronidazole
Drug taken up by bacteria and continues to exert effect despite falling serum concentration.
What are the major problems with under dosing antibioitcs
- Inefficient killing
- Compromised clinical outcome
- Non-lethal selection pressure for multi-drug resistant organisms
Explain the impact of altered volume of distribution in septic patients
Lipophilic antibiotic drugs have intracellular accumulation and hepatic clearance so only maintenance dosing needs to be altered in hepatic dysfunction
- Fluoroquinolones
- Macrolides
Hydrophilic drugs is difficult in sepsis due to the increased volume of distribution and renal clearance. Additionally fluid administration and vasoplegia increase Vd. Therefore, more drug needs to be required to achive plasma (and therefore effect site) concentrations. This is only relevant for hydrophilic antibiotics.
Additionally hypoalbuminaemia mean higher free drug fraction which is filtered and removed at the kidneys
What is the dose of the following in sepsis
Amikacin
Cefepime
Ceftazidime
Cloxacillin
Ertapenem
Gentamicin
Imipenem
Meropenem
Piptaz
Amikacin: 25 - 30 mg/kg daily (NOT 1g)
Gentamicin: 7 - 9 mg/kg daily (Not 320 or 400)
Cefepime 2g 8h
Ceftazidime 2g 8h
Cloxacillin 2 g 6 hrly. 3g 6hrly in Staph bacteraemia
Ertapenem 1 g 12 hourly
Imipenem 1g 8hrly
Meropenem 1 - 2 g 8 hourly
Piptaz 4.5g 6 hourly
