Antibiotics Flashcards
What are the iatrogenic related factors that contribute toward the development of resistance to antimicrobial drugs
- Not indicated
- Wrong antibiotic (specific activity or effect site penetration)
- Inappropriate broad spectrum antibiotic
- Under dosing
- Too short or too long course of therapy
- Lack of knowledge of PK/PD optimal dosing strategy
Classify clinically common and relevant bacteria
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
- 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 - Acid Fast
- -> Mycobacterium
Define and list the beta lactam antibiotics
Definition: These are antibiotics with a B-lactam ring in their chemical structure
Penicillins (and derivatives: e.g. amoxicillin / pipericillin)
Cephalosporins
Monobactams (Aztreonam)
Carbapenems
Describe the mechanism of action of beta lactam antibiotics. Which organisms are beta lactam antibiotics ineffective and why?
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:
- M/O without cell wall –> mycoplasma
- Intracellular pathogens (Chlamydia, Brucella, Legionella)
- Impenetrable cell walls (mycobacterium)
List 4 intracellular pathogens inaccessible to beta lactams
- Chlamydia (obligate intracellular organisms)
- Ricketsia (obligate intracellular organisms)
- Legionella (Gram - facultative resp. rod)
- Brucella (Gram - facultative zoonotic rod)
What are the natural penicillins and why were penicillin derivatives developed?
Benzylpenicillin / Penicillin G
Phenoxymethylpenicillin / Penicillin V
–> Narrow spectrum and resistance is common
Agents developed with broader spectrum, increased bioavailability and stability
Compare the spectrum of antimicrobial activity of the penicillins
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
Describe how the Gram + and Gram - coverage changes for cephalosporins with regard to the generation of the drug
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.
Classify the drugs and spectrum of activity of the cephalosporins
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)
Categorize and name common cephalosporings. USe parenthesis to demonstrate special characteristics for each drug
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)
What is a monobactam. Give and example and state spectrum of coverage
Monobactam is a beta lactam antibiotic. Example: Aztreonam. Spectrum: G - only
What type of antibiotics are the carbapenems describe the important characteristics of these drugs
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)
List and describe the ertapenems in common clinical use
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
What do carbapenems rely on for transport into the bacterial cell wall
Porins (outer membrane proteins).
What is cilastin and when is it used
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
List the side-effects of Beta Lactams
- Neurotoxicity (seizures / spasms / hallucinations)
2. Hypersensitivity
Summarise ertapenem vs imipenem vs meropenem
Ertapenem - no antipseudomonal or enterococcus
Meropenem - more G - vs imipenem
Imipenem - more G + vs meropenem
Classify the cell wall synthesis antibacterial drugs
BETA LACTAMS
- Penicillins
- Cephalosporins
- Monobactams
- Carbapenems
GLYCOPEPTIDES
1. Glycopeptides (Vancomycin and Teicoplanin)
What are the Glycopeptide antibioitcs. List them and describe the mechanism of action
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.
Describe the spectrum of the glycopeptides
G+ (poor G - )
Describe resistance to the glycopeptides
Vancomycin Resistant Enterococci (VRE)
Vancomycin Intermediate Staph Aureus (VISA)
Glycopeptide Intermediate Staph Aureus (GISA)
Describe the side effects of the Glycopeptides
Ototoxicity and Nephrotoxicity
Nephrotoxicity of Vancomycin has been blown out of proportion.
BUT –> Vancomycin accumulates in renal failure and drug level monitoring is indicated.
What happens when vancomycin is infused rapidly
Histamine release –> ‘ red man syndrome’
Classify the antibiotics that inhibit protein synthesis
Aminoglycosides
- Gentamicin
- Amikacin
- Streptomicin
Macrolides
- Erythromycin
- Azithromycin
- Clarithromycin
Lincosamides
- Clindamycin
Tetracylcines
- Doxycycline
Oxazolidinones
- Linezolid
Why are the aminoglycosides administered IV
Poorly absorbed from GIT
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.
Describe the spectrum cover for aminoglycosides
Good Activity
- Gram -
- Staphylococci
No activity
- Streptococci
- Anaerobes
What are the important side effects of aminoglycosides
Nephro and ototoxicity
Narrow therapeutic window (monitor peaks and troughs)
What is the mechanism of resistance to aminoglycoside antibioitcs
Aminoglycoside-modifying enzymes (AME) –> inactive the drug by modifying the structure of the aminoglycoside
What are the Macrolides and what is their mechanism of action
Bacteriostatic
Protein synthesis inhibitors - bind 50S ribosomal subunit –> cessation of bacterial protein synthesis
Make a table of the common bacteristatic and bacteriocidal antibiotics
Bactericidal
- Beta - Lactams
- Aminoglycosides
- Glycopeptides
- Fluoroquinolones
- Nitroimidazoles (Metronidazole)
Bacteriostatic
- Macrolides
- Clindamycin
- Sulphamethaxazole/trimethoprim
- Linezolid
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.
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)
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.
List the antibiotics that inhibit bacterial nucleic acid synthesis
- Quinolones
- -> Ciprofloxacin, Moxifloxicin, Levofloxacin, Nalidixic acid - Rifamycins
- -> Rifampicin
What is the mechanism of action of the Quinolones
Inhibit bacterial DNA replication by inhibiting DNA topoisomerase and GNA gyrase
Describe the spectrum of activity of the Quinolones
Gram +
Gram -
Some Anaerobes
Antipseudomonas
What are the side effects of quinolones
- Photosensitivity
- Neurotoxicity
- Tendinitis and tendon rupture (esp. elderly, pts with renal impairment, on corticosteroids)
- Possibly increased risk of aortic dissection in patients with AAA.
- Adverse effect on cartilage development
Why are quinolones not recommended in pregnancy or in children
They have an adverse effect on cartilage development
What is the mechanism of action of Rifampicin
Blocks synthesis of bacterial mRNA
Rx TB
What are the side effects of Rifampicin
Hepatic dysfunction
Skin Rashes
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
- Pneumocystis jerovecii
- Nocardia
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
What is the penetration of Daptomycin
Excellent skin and soft tissue
Does not penetrate BBB
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
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.
Summarise the mechanisms of antibiotic resistance
- Altered TARGET SITE e.g. altered cell wall in MRSA
- 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
- DISABLING ENZYMES produced to antibiotic e.g. beta-lactamases and Aminoglycoside Modifying Enzymes (AME)
How do Beta-lactamases disable beta-lactam antibioitcs
The open the Beta-lactam ring –> unable to bind PBPs
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.
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.
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
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
What are the effects of the secretion of a biofilm by a bacterial colony
- Prevents detection by host’s immune system
- Thick/Sticky consistency retards antimicrobial penetration
- Slower bacterial growth rate retarding bacteriostatic agents
What factors does choice of antibiotic depend
- Organism susceptibility
- Effect site concentration
- Collateral and side effects
- PK and PD profiles
Define minimum alveolar concentration
MIC - Lowest concentration of antibiotic (ug/mL) required that inhibits growth of a strain of bacteria
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
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
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
What dosing range selects for resistant organisms and encourages mutations
Dosing between MIC and MPC = Mutant Selection Window MSW
Where does Augmentin penetrate poorly
CSF
Where does ceftriazone penetrate poorly
Penetrates well everywhere
CSF requires high dose for good penetration
Where do aminoglycosides penetrate poorly
CSF
Lung
Soft tissue
Where does cotrimoxazole penetrate poorly
Penetrates well everywhere
Where does ertapenem pentrate poorly
CSF
Where does MEropenem penetrate poorly
CSF requires high doses for good penetration
Where does imipenem penetrate poorly
Penetrates everywhere well
Where does vancomycin penetrate poorly
CSF, Lung and soft tissue
List the drugs with Good CSF penetration
Ceftriaxone (high dose)
Meropenem (high dose)
Imipenem
Co-trimoxazole
List the drugs that penetrate the lung poorly
Aminoglycosides
Vancomycin
List the drugs that penetrate the soft tissue poorly
Aminoglycosides
Vancomycin
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
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
What are the three categories of antibiotics in terms of their pharmacokinetic - pharmacodynamic PKPD intractions
- Time-dependent killing ( t > MIC)
- Concentration dependent killing ( Cmax/MIC)
- Combination of 1 and 2 expressed as AUC 0 -24 hr / MIC
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
- Penicilins
- Cephalosporins
- Carbapenems
(Linezolid)
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
- Aminoglycosides
- Metronidazole
(Fluoroquinolones)
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
- Vancomycin
- Colistin
- Azithromycin
(Fluoroquinolones)
(Linezolid)
When should peak level aminoglycosides be taken
30 minutes after the FIRST dose (underdosing is extremely common).
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.
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.
How are trough levels minimized
By extended the dosing intervals –> usually once daily dose
How is a combination of concentration and time dependent killing expressed mathematically
AUC 0 - 24 hr / MIC
Why is subtherapeutic dosing bad
- Ineffective killing
- Worse clinical outcome
- Non-lethal selection pressure
- -> Proliferation of Multi-drug resistant strains
- -> Selection of hypermutatable strains
- -> Increased movement mobile genetic elements like plasmids
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.
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)
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)
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
Which are the only antibiotics need dose adjustments for Child Pugh C
Metronidazole
Tigecycline
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.
When should IV antibiotics be preferred to PO
- Meningitis
- Osteomyelitis
- Endocarditis
- Septicaemia (Blood)
Patients unable to swallow / absorb
Haemodynamic unstable
Initial therapy in severe infections
If no PO forms available
