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Pharmacology for Anaesthetists > Antibiotics > Flashcards

Antibiotics Flashcards

1
Q

What are the iatrogenic related factors that contribute toward the development of resistance to antimicrobial drugs

A
  1. Not indicated
  2. Wrong antibiotic (specific activity or effect site penetration)
  3. Inappropriate broad spectrum antibiotic
  4. Under dosing
  5. Too short or too long course of therapy
  6. Lack of knowledge of PK/PD optimal dosing strategy
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2
Q

Classify clinically common and relevant bacteria

A

NO WALL
- Myoplasma

FLEXIBLE THIN WALL

  • Treponema (Syphilis)
  • Borelia (Lyme)
  • Leptospira

RIGID THICK WALL
# Obligate intracellular
- Chlamydia
- Ricketsia

# Extracellular (Free-living)
1. Gram Positive 
----> Cocci (Strep and Staph)
----> Rods (BLANCC)
Bacillus (aerobic), Listeria, Actinomyces, Nocardia, Clostridium (anaerobic), Corynebacterium
  1. Gram Negative
    - —> Cocci (Neiserria)
    - —> Rods
    - ——-> Anaerobic (Bacteroides)
    - ——-> Aerobic (Pseudomonas)
    - ——-> Facultative
    - —————> Resp (Haemophilus, Bordatella, Legionella)
    - —————> Zoonotic (Yersinia (plague), Brucella)
    - —————> Enteric (CHEESSS VPK)
    - ——————————-> Campylobacter
    - ——————————-> Helicobacter
    - ——————————-> Escherichia
    - ——————————-> Enterobacter
    - ——————————-> Salmonella
    - ——————————-> Shigella
    - ——————————-> Serratia
    - ——————————-> Vibrio
    - ——————————-> Proteus
    - ——————————-> Klebsiella
  2. Acid Fast
    - -> Mycobacterium
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3
Q

Define and list the beta lactam antibiotics

A

Definition: These are antibiotics with a B-lactam ring in their chemical structure

Penicillins (and derivatives: e.g. amoxicillin / pipericillin)
Cephalosporins
Monobactams (Aztreonam)
Carbapenems

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4
Q

Describe the mechanism of action of beta lactam antibiotics. Which organisms are beta lactam antibiotics ineffective and why?

A

Bactericidal cell wall synthesis inhibitors

Penicillin binding proteins facilitate cross linking and structural integrity in the bacterial cell wall.

Bind to PGPs (penicillin binding proteins) preventing cross linking and weakening the peptidoglycan layer causing the cell to lyse due to osmotic pressure.

Ineffective against:

  1. M/O without cell wall –> mycoplasma
  2. Intracellular pathogens (Chlamydia, Brucella, Legionella)
  3. Impenetrable cell walls (mycobacterium)
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5
Q

List 4 intracellular pathogens inaccessible to beta lactams

A
  1. Chlamydia (obligate intracellular organisms)
  2. Ricketsia (obligate intracellular organisms)
  3. Legionella (Gram - facultative resp. rod)
  4. Brucella (Gram - facultative zoonotic rod)
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6
Q

What are the natural penicillins and why were penicillin derivatives developed?

A

Benzylpenicillin / Penicillin G

Phenoxymethylpenicillin / Penicillin V

–> Narrow spectrum and resistance is common

Agents developed with broader spectrum, increased bioavailability and stability

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7
Q

Compare the spectrum of antimicrobial activity of the penicillins

A

Pen G and Pen V - Gram + only

Cloxaxillin - Gram + with beta lactamase resistance

Amoxicillin - Gram + and Some Gram - (Klebs and Proteus)

Pipericillin - Gram + and some Gram - and Pseudomonas

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8
Q

Describe how the Gram + and Gram - coverage changes for cephalosporins with regard to the generation of the drug

A

With increasing generation there is increased Gram - cover and decreased Gram + cover

Except Generation 4 (Cefepime) which has good Gram + and Gram - coverage. No anaerobic coverage.

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9
Q

Classify the drugs and spectrum of activity of the cephalosporins

A

Generation | Name | Activity

1st | Cefazolin | G + and little G - (PEcK)

2nd | Cefuroxime | G+ less and G - more (HEPEcK)

3rd | Ceftriaxone | G + less less and G - more including nosocomial. No anaerobic

4th | Cefepime | G + like 1st gen and G - good. Antipseudomonas. No anaerobic.

5th | Ceftobiprole | Antipseudomonas and Vancomycin Resistant Enterococci (VRE)

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10
Q

Categorize and name common cephalosporings. USe parenthesis to demonstrate special characteristics for each drug

A

1st Gen
Cefazolin (G+)
Cefadroxil

2nd Gen
Cefuroxime (More G- and less G+ vs gen 1)
Cefoxitin (+ anaerobic cover)
Cefotetan (+ anaerobic cover)

3rd Gen
Ceftriaxone (Less G+. More G-. Nosocomial. Good CSF. No anaerobic. No pseudomonal.)

4th Gen
Cefepime (G+ good. G - good. Antipseudomonal. Resistant to B-lactamases. No anaerobic)

5th Gen
Ceftobiprole (Antipseudomonas and VRE)
Ceftaroline (MRSA but no VRE and no antipseudomonal)

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11
Q

What is a monobactam. Give and example and state spectrum of coverage

A

Monobactam is a beta lactam antibiotic. Example: Aztreonam. Spectrum: G - only

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12
Q

What type of antibiotics are the carbapenems describe the important characteristics of these drugs

A

Beta lactam antibiotics with a broad spectrum of activity (reserved for nosocomial pathogens and MDR pathogens)

Particularly effective against G - (G + slightly lower)
Anaerobic activity present

Antipseudomonal EXCEPT ertapenem

No activity against atypical organisms (Chlamydia, Legionella, Mycoplasma)

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13
Q

List and describe the ertapenems in common clinical use

A

Group 1 - Ertapenem:

  • Slightly reduced Gram - activity vs other carbapenems
  • No MRSA and No enterococcus
  • No atypical cover
  • Limited antipseudomonal
  • Half life 4 hours

Group 2 - Imipenem / Meropenem / Doripenem

  • Broad spectrum. Antipseudomonal.
  • No activity MRSA
  • No atypical cover
  • Half life 1 hour
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14
Q

What do carbapenems rely on for transport into the bacterial cell wall

A

Porins (outer membrane proteins).

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15
Q

What is cilastin and when is it used

A

Imipenem is deactivated in the kidneys by the enzyme dehydropeptidase 1 (DHP - 1).

To overcome this deactivation, it is administered with a DHP - 1 inhibitor –> cilastin

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16
Q

List the side-effects of Beta Lactams

A
  1. Neurotoxicity (seizures / spasms / hallucinations)

2. Hypersensitivity

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17
Q

Summarise ertapenem vs imipenem vs meropenem

A

Ertapenem - no antipseudomonal or enterococcus

Meropenem - more G - vs imipenem

Imipenem - more G + vs meropenem

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18
Q

Classify the cell wall synthesis antibacterial drugs

A

BETA LACTAMS

  1. Penicillins
  2. Cephalosporins
  3. Monobactams
  4. Carbapenems

GLYCOPEPTIDES
1. Glycopeptides (Vancomycin and Teicoplanin)

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19
Q

What are the Glycopeptide antibioitcs. List them and describe the mechanism of action

A

Vancomycin and Teicoplanin are cell wall synthesis inhibitors that bind to PGP in the peptidoglycan layer of the bacterial cell wall to bring about loss of structural integrity and hydrolysis.

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20
Q

Describe the spectrum of the glycopeptides

A

G+ (poor G - )

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21
Q

Describe resistance to the glycopeptides

A

Vancomycin Resistant Enterococci (VRE)
Vancomycin Intermediate Staph Aureus (VISA)
Glycopeptide Intermediate Staph Aureus (GISA)

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22
Q

Describe the side effects of the Glycopeptides

A

Ototoxicity and Nephrotoxicity

Nephrotoxicity of Vancomycin has been blown out of proportion.
BUT –> Vancomycin accumulates in renal failure and drug level monitoring is indicated.

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23
Q

What happens when vancomycin is infused rapidly

A

Histamine release –> ‘ red man syndrome’

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24
Q

Classify the antibiotics that inhibit protein synthesis

A

Aminoglycosides

  • Gentamicin
  • Amikacin
  • Streptomicin

Macrolides

  • Erythromycin
  • Azithromycin
  • Clarithromycin

Lincosamides
- Clindamycin

Tetracylcines
- Doxycycline

Oxazolidinones
- Linezolid

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25
Why are the aminoglycosides administered IV
Poorly absorbed from GIT
26
Are aminoglycosides used for treatment of pneumonia? Why?
No. Very poor tissue and lung penetration - so not good for pneumonia. However, nebulized aminoglycosides (in addition to targeted intravenous therapy ) is finding favour due to extremely high concentrations in the alveolar fluids that this delivery mode yields.
27
Describe the spectrum cover for aminoglycosides
Good Activity 1. Gram - 2. Staphylococci No activity 1. Streptococci 2. Anaerobes
28
What are the important side effects of aminoglycosides
Nephro and ototoxicity | Narrow therapeutic window (monitor peaks and troughs)
29
What is the mechanism of resistance to aminoglycoside antibioitcs
Aminoglycoside-modifying enzymes (AME) --> inactive the drug by modifying the structure of the aminoglycoside
30
What are the Macrolides and what is their mechanism of action
Bacteriostatic | Protein synthesis inhibitors - bind 50S ribosomal subunit --> cessation of bacterial protein synthesis
31
Make a table of the common bacteristatic and bacteriocidal antibiotics
Bactericidal 1. Beta - Lactams 2. Aminoglycosides 3. Glycopeptides 4. Fluoroquinolones 5. Nitroimidazoles (Metronidazole) Bacteriostatic 1. Macrolides 2. Clindamycin 3. Sulphamethaxazole/trimethoprim 4. Linezolid
32
Describe the special use with regard to each Macrolide
Erythromycin - Prokinetic (ICU enteral feeding) - Prokinetic dose 250 mg 6 hourly (vs. 500 mg 6 hourly) - Gram + action in penicillin allergic patients Azithromycin and Clarithromycin - Excellent activity against atypical organisms: Chlamydia, Legionella, Ricketsia, Brucella and have important role in the treatment of severe community acquired pneumonia.
33
What is the mechanism of action of Clindamycin and to what group of drugs does this belong
Clindamycin is a lincosamide antibiotic which acts as a protein synthesis inhibitor inhibiting the 50S ribosomal subunit of bacterial RNA inhibiting protein synthesis Similar spectrum of activity as erythromycin with better anaerobic cover. Excellent penetration into bone and soft tissue (received bad press as it was the first antimicrobial to cause pseudomembranous colitis)
34
What type of antibiotic is Linezolid and what is its mechanism of action
It is an Oxazolidinone and a protein synthesis inhibitor. Bacteriostatic. Good activity vs. MRSA and Enterococcus faecium.
35
List the antibiotics that inhibit bacterial nucleic acid synthesis
1. Quinolones - -> Ciprofloxacin, Moxifloxicin, Levofloxacin, Nalidixic acid 2. Rifamycins - -> Rifampicin
36
What is the mechanism of action of the Quinolones
Inhibit bacterial DNA replication by inhibiting DNA topoisomerase and GNA gyrase
37
Describe the spectrum of activity of the Quinolones
Gram + Gram - Some Anaerobes Antipseudomonas
38
What are the side effects of quinolones
1. Photosensitivity 2. Neurotoxicity 3. Tendinitis and tendon rupture (esp. elderly, pts with renal impairment, on corticosteroids) 4. Possibly increased risk of aortic dissection in patients with AAA. 5. Adverse effect on cartilage development
39
Why are quinolones not recommended in pregnancy or in children
They have an adverse effect on cartilage development
40
What is the mechanism of action of Rifampicin
Blocks synthesis of bacterial mRNA | Rx TB
41
What are the side effects of Rifampicin
Hepatic dysfunction | Skin Rashes
42
What is the mechanism of action of Sulfamethoxazole What is the mechanism of action of Trimethoprim What organisms does this combination drugs treat effectively
Both affect tetrahydrofolic acid metabolism and impair the synthesis of purines and pyrimidines Sulfamethoxazole - Bacteriostatic - Competes para-aminobenzoic acid (PABA) and enzyme involved in the catalysis of tetrahydrofolic acid (THFA) --> required for the synthesis of purines and pyramidines - May cause Steven-Johnson Syndrome Trimethopim - Prevents synthesis of THFA later in the pathway than sulfamethoxazole Organisms 1. Pneumocystis jerovecii 2. Nocardia
43
What type of antibiotic is Daptomycin. What is its mechanism of action and specific clinical use
Group: Antibiotics which depolarise the cell membrane --> Daptomycin is a lipopeptide MOA: Lipophilic tail of the molecule inserts into the bacterial cell membrane, causing rapid depolarisation and efflux of potassium ions. DNA, RNA and protein synthesis are arrested and the bacteria dies. Rx: MRSA, GISA, VRE and coagulase negative Staph
44
What is the penetration of Daptomycin
Excellent skin and soft tissue Does not penetrate BBB
45
What is MEtronidazole
Nitroimidazole Bacteriocidal Destroys bacterial DNA Also acts against parasites MOA: Must enter bacterial cell wall --> requires reduction by bacteria. Only possible in anaerobic bacteria. No aerobic cover
46
Classify antibiotic resistance
Intrinsic - Innate resistance despite dose given e.g. Vanco ineffective G- cell envelope Acquired (induced) - Developed resistance - -> Chromosomal mutations - -> Introduce new genetic material into bacterium Adaptive - Induced by env. stressor e,g, sub-inhibitory levels antibiotics.
47
Summarise the mechanisms of antibiotic resistance
1. Altered TARGET SITE e.g. altered cell wall in MRSA 2. Altered ACCESS to target site e.g. Gram -'ve altered porins or efflux pumps e.g. Gram -'ve lipopolysaccharide outer membrane permits AB access through pores only. If the pores change --> no access 3. DISABLING ENZYMES produced to antibiotic e.g. beta-lactamases and Aminoglycoside Modifying Enzymes (AME)
48
How do Beta-lactamases disable beta-lactam antibioitcs
The open the Beta-lactam ring --> unable to bind PBPs
49
List the beta-lactamase inhibitors and their mechanism
Clavulanate Tazobactam Sulbactam Avibactam "suicide inhibitors" --> nil antimicrobial activity but beta lactam ring present depleting beta lactamase so reduced available to disable active agent.
50
What are inducible B-lactamases
Essentially = cephalosporinases. In IBL-producing organisms beta-lactamases are suppressed until the presence of cephalosporins when rapid emergence of resistance to multiple beta lactams occurs.
51
What are extended spectrum beta lactamases, what organisms produce them and what antibioitcs should be used to treat these infections
Produced by enterobacteriacae --> confering resistance to all beta lactams except carbapenems. Carbapenems to treat OR 2nd Gen cephamycins (cefotetan and cefoxitin) are resistant to ESBLs
52
What are carbapenemases and what drug should be used to treat these infections
Resistant to all beta lactams including carbapenems. Carbapenem Resistant Enterobacteriales (CREs) Rx: Ceftazidine-avibactam
53
What are the effects of the secretion of a biofilm by a bacterial colony
1. Prevents detection by host's immune system 2. Thick/Sticky consistency retards antimicrobial penetration 3. Slower bacterial growth rate retarding bacteriostatic agents
54
What factors does choice of antibiotic depend
1. Organism susceptibility 2. Effect site concentration 3. Collateral and side effects 4. PK and PD profiles
55
Define minimum alveolar concentration
MIC - Lowest concentration of antibiotic (ug/mL) required that inhibits growth of a strain of bacteria
56
Can the MIC of one antibioitc be compared the MIC from another antibiotic?
No. The antibiotic breakpoint is used for this. The breakpoint is a previously agreed upon concentration of antibiotic which defines whether a species of bacteria is susceptible or resistant to the antibiotic i.e. where bacteria start to show resistance. If MIC < breakpoint then the bacterial isolate is reported as being susceptible/sensitive to the antibiotic The closer the MIC is to the breakpoint, the less susceptible the organism Breakpoints are updated and published annually
57
What does the term 'resistant' and 'intermediate' mean with regard to an organisms susceptibility to an agent?
'Resistant' implies that normally achievable serum drug levels are inadequate to inhibit bacterial growth. 'Intermediate' implies that organisms are likely to be inhibited only if maximally recommended doses are used to achieve serum concentrations. High enough concentrations (such as significant concentrations of gentamicin in the urine might be sufficient to treat LUTS deemed gentamicin resistant
58
Define Mutant Prevention Concentrations MPC
MPC is defined as the concentration of antibiotic the prevents the development of single step mutations. This means that above MPC microbes need to mutate more than once to develop resistance. dosing in the concentration window between MIC and MPC encourages mutations and selects for resistant organisms
59
What dosing range selects for resistant organisms and encourages mutations
Dosing between MIC and MPC = Mutant Selection Window MSW
60
Where does Augmentin penetrate poorly
CSF
61
Where does ceftriazone penetrate poorly
Penetrates well everywhere | CSF requires high dose for good penetration
62
Where do aminoglycosides penetrate poorly
CSF Lung Soft tissue
63
Where does cotrimoxazole penetrate poorly
Penetrates well everywhere
64
Where does ertapenem pentrate poorly
CSF
65
Where does MEropenem penetrate poorly
CSF requires high doses for good penetration
66
Where does imipenem penetrate poorly
Penetrates everywhere well
67
Where does vancomycin penetrate poorly
CSF, Lung and soft tissue
68
List the drugs with Good CSF penetration
Ceftriaxone (high dose) Meropenem (high dose) Imipenem Co-trimoxazole
69
List the drugs that penetrate the lung poorly
Aminoglycosides | Vancomycin
70
List the drugs that penetrate the soft tissue poorly
Aminoglycosides | Vancomycin
71
Define Therapeutic Drug monitoring
Measurement of specific drugs at designated drug intervals to optimise individual dosing regimens and achieve required PK/PD targets. Most TDM measures plasma concentration and does not measure conc. at effect site
72
What is collateral damage with regard to antibiotic prescribing
Unintended adverse effects on the ecology due to antibiotic use which causes the development of colonization with MDR pathogens Quinolones --> MRSA + Pseudomonas resistance Gen 3 ceph --> C. difficile infections / VREs / ESBL Klebs pneumoniae Also avoid nephrotoxic agents in renal failure etc
73
What are the three categories of antibiotics in terms of their pharmacokinetic - pharmacodynamic PKPD intractions
1. Time-dependent killing ( t > MIC) 2. Concentration dependent killing ( Cmax/MIC) 3. Combination of 1 and 2 expressed as AUC 0 -24 hr / MIC
74
Which antibiotics have time dependent based efficacy with regard to PKPD (t > MIC) and what does this mean
With these antibiotics we should aim to maximise the DURATION of EXPOSURE Exert their effects by the length of time that the plasma conc. is above MIC. TIME ABOVE MIC ! Dosing interval should lead to 100% of the time Conc > MIC 1. Penicilins 2. Cephalosporins 3. Carbapenems (Linezolid)
75
Which antibiotics have concentration dependent based efficacy with regard to PKPD (Cmax/MIC) and what does this mean
With these antibiotics we should aim to maximise the concentration of antibiotic 1. Aminoglycosides 2. Metronidazole (Fluoroquinolones)
76
Which antibiotics have concentration and time dependent based efficacy with regard to PKPD (Cmax/MIC) and what does this mean
With these antibiotics we should aim to maximise the amount of drug exposure These drugs exhibit a POST ANTIBIOTIC EFFECT (PAE) and are taken up into the organism so continue to be effective despite plasma conc falling below MIC 1. Vancomycin 2. Colistin 3. Azithromycin (Fluoroquinolones) (Linezolid)
77
When should peak level aminoglycosides be taken
30 minutes after the FIRST dose (underdosing is extremely common).
78
How doe concentration dependent antibiotics continue to exert their effect despite falling below MIC
Post Antibiotic Effect (PAE) --> antibiotic is taken up into the organism and continues to exert its effects from within, even though the serum concentration has fallen.
79
When should trough levels be taken for aminoglycosides and why
On day 3. Immediately before the dose is administered and relate to the toxicity of aminoglycosides (ototoxicity and nephrotoxicity) since the uptake of aminoglycosides in the ear and nephron is most pronounced with sustained levels.
80
How are trough levels minimized
By extended the dosing intervals --> usually once daily dose
81
How is a combination of concentration and time dependent killing expressed mathematically
AUC 0 - 24 hr / MIC
82
Why is subtherapeutic dosing bad
1. Ineffective killing 2. Worse clinical outcome 3. Non-lethal selection pressure - -> Proliferation of Multi-drug resistant strains - -> Selection of hypermutatable strains - -> Increased movement mobile genetic elements like plasmids
83
Which antimicrobials are hydrophilic and which are lipophilic> why is this relevant?
Hydrophilic (most) - Beta lactams / aminoglycosides / glycopeptides - Critically ill patients have increased Vd and renal clearance. Increased Vd and renal clearance (e.g. hyperdynamic CVS in sepsis) of hydrophilic agents results in subtherapeutic concentrations of the hydrophilic antibiotics. Reduced PB in critical illness helps initially but more free drug means more renal clearance in the long term. Lipophilic - Fluoroquinolones and macrolides - Fast intracellular accumulation and hepatic clearance SO only need maintenance dose adjusted in severe hepatic failure.
84
What is Augmented Renal Clearance and what PKPD interaction toes it predominantly affect and why
AUC --> urinary creatinine clearance exceeds 130 mL/min/1.73m^2 (Normal 88 - 125) Mechanism: Related to Inflammation / increased CO and RBF / ANP / Fluid resuscitation. AUC associated with subtherapeutic hydrophilic antimicrobials with time-dependent PKPD efficacy (does not affect conc. dependent)
85
What is the appropriate dosing for amikacin and gentamicin in the critically ill versus non-critically ill patient
Amikacin - 25 - 30 mg/kg (NOT 15 mg/kg) Gentamicin - 7 - 9 mg/kg (NOT 5 mg/kg)
86
What is a good principle with regard to dosing of antibiotics in AKI in the first 24 to 72 hours
Dose as normal (Vd increased) After 72 hours the dose reduction can be considered to prevent accumulation and toxicity
87
Which are the only antibiotics need dose adjustments for Child Pugh C
Metronidazole | Tigecycline
88
By what % must hepatic function reduce before drug clearance is affected
90% Hepatic flow often elevated in critical illness which may compensate for the reduction in liver enzyme activity in drugs which have a high extraction ratio.
89
When should IV antibiotics be preferred to PO
1. Meningitis 2. Osteomyelitis 3. Endocarditis 4. Septicaemia (Blood) Patients unable to swallow / absorb Haemodynamic unstable Initial therapy in severe infections If no PO forms available

Pharmacology for Anaesthetists (37 decks)

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