Infectious Disease Pharmacology Flashcards
Give and example and describe the coverage of each of the following divisions of penicillins
- Narrow spectrum
- Narrow spectrum resistant to staph beta lactamase
- moderate spectrum
- broad spectrum resistant to staph beta lactamase
- antipseudomonal
Petkov blue
Give an example of each of 4 generations of cephalosporins
petkov blue
Give an example of each of the 4 beta lactam classes
Petkov blue
What class does Vancomycin belong to?
Glycopeptides
Petkov blue
What is the coverage of the class glycopeptides? Give an example of one
Gram + inc. MRSA
Vancomycin
Petkov blue
Macrolides coverage and example?
Gram + cocci, gram negative cocci and anaerobes
Erythromycin/clarithromycin
Petkov blue
Lincosamides have what coverage?
Gram positive aerobics, most anaerobes,MRSA
petkov blue
Lincosamides examples
CLindamycin, lincomycin
Petkov blue
Aminoglycoside coverage and example?
Gram - aerobes
Gentamicin
Petkov blue
Tetracycline coverage and example
Doxycycline
Gram +and gram -
Petkov blue
Quinolones cover what bacteria? Example?
Ciprofloxacin
Mostly gram -
Petkov blue
Metronidazole belongs to what class? Coverage (2)
Nitroimidazoles
Anaerobes and protozoa
petkov blue
Trimethoprim class
Pyramiding derivities
Petkov blue
Rifampicin coverage?
Gram + and mycobacteria
Petkov blue
Fusidic acid coverage?
Narrow spectrum Staph Aureus
Petkov blue
Mechanism of beta lactams?
Petkov blue
Vancomycin MOA
Glycopeptides inhibit glycol-peptide synthase
Prevents peptidoglycan-glycan formation in the bacterial cell wall
Petkov blue
Which antibiotics act by preventing protein synthesis?
Petkov blue
Chloramphenicol MOA
Petkov blue
Lincomycin MOA
Petkov blue
Which antibiotics act via 50s ribosomal subunit? How does this affect bacteria
Petkov blue
How do aminoglycosides work
Petkov blue
How do tetracyclines work
Petkov blue
WHich antibiotics act via 30s ribosomal subunit? How does this impact bacteria?
Petkov blue
How do quinolones work?
Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis
Petkov blue
How does ciprofloxacin work
Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis
Petkov blue
Which antibiotics act via inhibition of nucleic acid synthesis directly?
Quinolones, nitroimidazoles
Petkov blue
How does metronidazole work
Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis
Petkov blue
Which 2 classes act via inhibition of folic acid synthesis
Sulphonamides
Trimethoprim
Petkov blue
How do sulphonamides work?
Mimic folic acid by acting as false substrates
Petkov blue
How does trimethoprim work
Competitive inhibition of bacterial Di-hydro-folate reductase - inhibiting folic acid synthesis
Petkov blue
Name 3 bacteriocidal antibiotics
Petkov blue
Bacteriostatic antibiotics (4)
Lincosamides
Tetracycline
Sulphonamides
Macrolides at low plasma concentrationsPetkov blue
Petkov blue
How are fungi different from bacteria?
Bacteria have cell walls, membranes and are prokaryotes that rapidly replicate, asexually with DNA arranged in single circular chromosme in the cytoplasm. Bacterial ribosomes are structurally different from mammaliana nd non membran eassociated
Fungi are eukaryoytes ith nuclear material enclosed in a membrane, replicate slowlyt and have intracelular organelles . Most antifungals therefore target fungal cell membrane where erogsterol replaces cholesterol
What are the 4 classes of beta lactams?
Pencillins
Cephalosporins
Carbapenams
Monobactams
What two main classes of antibiotics attack the cell wall
Beta lactams
Glycopeptides
What differentiates pencillins and cephalosporins structurally
Both have acyl side chains connecting to a beta lactam ring, however the side chain may have different offshoots, and pencillins have a thiazolidine ring whereas cephalosporins have a dihydrothiazine ring
What is the significance of the acyl side chain in pencillins and cephalosporins?
Suscepatability to acid degredation in the stomach
Spectrum of acitivty
Which pencillins are produced naturally
Pencillin V and pencillin G
MOA of penicillins
Bacteriocidal, inhibit celll wall synthesis by prevenitng peptidoglycan cross linkage weakening cell walls - the beta lactam ring resembles the natural substrate D-ala-D-ala on the side chain of peptidoglycan where cross linkage occurs. Penicillins bind to several pencillin binding proteins in the cel wall that act as transpeptidase enzymes responsible for forming the cross links. Binding is irreversible due to acelyation of active serine site after cleavage of the beta lactam ring. Growth continues in the baceria but with reduced cross linkage of peptidoglycan until the cell wall weakens to the point at which it lyses
How do beta lactamases work?
hydrlyses the beta lactam ring
Which species have intrinsic resistance to beta lactams?
Gram negative are encoded in bacterial chromosomes and plasmids which may be disseminated leading to acquired resistance
Are beta lactams bacteriocidal?
Yes
However rarely does complete eradication occur, a significant number of beta lactam sesntiive cells known as persistors remain dormant until the antibiotic is removed.
Complete erradication required addition of synthergistic antibiotic e.g. gentamicin
Synergistic antibiotics have increased potency when cell wall damage has occured giving better intracellular access
How does a gram negative bacteria experience beta lactam induced peptidoglycan cross linkage effects?
The peptidoglycan layer to start with is thin, and although if weakened it weakens the cell wall the thicker lipopolysaccharide outer layer remains intact such that the cell doesn’t lyse generally. Internal hydrostatic pressure forces the bacteria to become spherical, in cells with high intracellular osmolality the pressure may be sufficient to lyse.
What is pencillin V
Phenoxymethypenicillin
What is pencillin G
Benzylpenicillin
How is flucloxacillin different to benzylpenicillin
reistsance to beta lactamase in staph
What is an extended spectrum aminopencillin?
Ampicillin, amoxicillin
What does pencillin intestinal absorption depend on?
whether it is susceptible to acid induced degradation in the stomach (hydrolysis) - if it is then it has reduced oral absorption
Amoxicillin vs ampicillin oral absorption? Why?
Amoxicllin has better oral absorption as it is less susceptable to acid induced degredation
Plasma half life of benzylpenicillin
30 minutes
Ampicillin plasma half lfie
2 hours
Tissue penetration in penicillins
Generally good, inflammation necessary for pencillins to pass into bone and through the BBB.
Pencillin excretion
Kidneys unchanged 60-90%
Mainly by renal tubular secretion
Bile 10%
20% metabolised
What agent blocks pencillin renal tubular secretion
Probenicid
Give an example of beta lactamase inhibitor
Tazobactam clavulinic acid
Do beta lactamases have intrinsic antimicrobial activity?
clavulanic acid does
Tazobactam does not
Side effects of penicillins
Mechanisms of resistance to pencillins come from (3)
Inactivation by lactamases
Altered permeability of porins in gram negative bacterial outer membrane
Altered pencillin binding proteins
Cephalosporins differ in structure to penicillins how?
Beta lactam ring is fused with a dihydrothiazine ring to produce cephem nucleus
Cephalosporins are more or less sensitive to beta lactamses?
Less
As generations of cephalosporins progress describe the changes in antimicrobial coverage
Gram positive cover is maintained, gram negative cover improved
MOA of cephalosporins
Bactericidal
Disrupt peptidoglycan cell wall integrity
Modified beta alctam ring is more stable making them less susceptable to beta lactamases
Distribution of cephalosporins
Widely
Readily cross placenta
Third generation cephalosporins penetrated the CSF especially if meningeal inflammation occurs (10% penetration)
Cephalosporin half lives
1-1.5 hours with exception of ceftriaxone which has a half life of 5.5-11 hours (R+D) (8hrs Smith)
Which cephalosporins are excreted unchanged in the urine?
Cepradine, cefuroxime, ceftazidime
Cefotaxime is metabolsied how?
Liver - 10% acitvity of metabolites compared to parent drug (desacetyl cefotaxime)
50% unchanged in urine
How are cephalosporins generally excreted
Urine unchanged, except for ceftriaxone which is 50% metaboised iin the liver
Renal excretion both filtration and tubular secretion
Probenicid increases peak concentration and plasma half life but to a lesser extent than penicillin
Side effects of cephalosporins?
Hypersensitivity
GI - C diff, especially third generation
Transient positive coombs test
LFT abnormalities
First generation cepahlosporins - examples + spectrum
Cefalexin, cefaclor, cefradine
Gram positive cocci
Second generation cephalosporins e.g. and spectrum
Cefuroxime, cefaclor, cefoxitin
Gram positive cocci
Cefuoxime also covers H influenzae
Third generation cephalosporins e.g. and spectrum
Cefotaxime, ceftazidime, Ceftriaxone
Broader spectrum, enahanced resistance to beta lactamse
Less potent against gram +
Pseudomonas sensitvie
Cross BBB
4th generation cephalosporins e.g. and spectrum vs 3rd gen
Cefepime, cefpirome
Enterobacter and pseudomonas
5th generation cephalosporins e.g. and activity
Ceftaroline, ceftobipole
MRSA, VRSA
Amoxicillin chemically is?
Aminopenicllin derivitve of ampicillin
(Scarth and smith)
Amoxicillin is available in what preparations?
Vials, sachets, capsules, suspension and syrup
Amoxicillin spectrum of acitvity
Bactericidal
- Some strains of haemophilus influenzae
- Some strains of E Coli
- Proteus, bordatellla pertussis, neiseria, salmonella, shigella
- Strep and Clostridium (not difficile)
Ineffective against
- Pseudomonas, klebsiella and pencillinase producing organisms
- 90%of Staph are resistance
What effect does adding clavulinic acid have to amoxicillin?
Reduces the MIC againt staph aureus, E Coli, H influenza and Klebsiella
AMoxicillin side effects
Allergy
GI
Intersisital nephritis
haemopoietic disturbances
Cholestatic jaundice late with clavulanic acid use
Amoxicillin pharmacokinetics
Absorption - rapidly absobed, 70-90% bioavailability
Distribution 20% protein bound in plasma, to labumin
Vd 0.3 - 0.4L/kg
Metabolism - 30% by liver
Excretion 250-350 ml/min
Eliminiation half life 60 minutes
40% renal elimination (20-35% unchanged)
Removed by haemodialysis
Clavulinic acid pharmacokinetics
Clavulinic acid 60% bioavailability (marked variability)
Clavulinic acid 20% protein bound Vd 0.2L/kg
Clavulanic acid 50-70% hepatically metabolised
Excretion 250-350ml/min
Elimination half life 60 minutes
Removed by haemodialysis
What preparations are cephalosporins available in?
1st and 2nd generation - oral and IV
3rd generation IV only
Cefuroxime bioavailability?
35-50%
Distribution of cephalosporins - % protein bound
- Cefradine
- Cefotaxime
- Cefuroxime
- Ceftazidime
Widely or narrowly distributed
Cefradine - 8-17%
Cefuroxime/cefotaxime 35-50%
Ceftazidime <10%
Ceftriaxone 95%
What % of ceftriaxone is excreted in bile?
40%
Cephalosporins vs dialysis
They are haemodialysed
Flucloxacillin chemical
Semisynthetic isoxazolyl penicillin
Flucloxacillin is acid stable or not?
Yes because it has good oral bioavailability
What is fluclox effective against?
Staph auerues
Beta haemolytic strep
Pneumococci
Flucloxacillin toxicity and side effects
GIT
CNS
Rashes
Glossitis
Jaundice in the critically ill
Pseudomembranous colits
Pharmacokinetics of flucloxacillin
Absorption - 50-70% orally absorbed
Distribution - 95% protein bound, Vd 6.8-9.4 L
Metabolism - 8-13% metabolised to active form 5 hydroxy-methyl-flucoxacilin
4% hdyrolused in liver to penicilloic acid which is inactvie, the rest is excreted uncahnged
Excretion - filtration and secretion, 35-75% of dose appear in the urine
Clearance 3ml/min/kg
Elimination half life 45 minutes
Fluclox vs haemodialsyis
Not dialysed
Interaction with administration of flucloxacillin - what is it incompatabile with
aminoglycosides cause precipitation
Out of the below agents what is Phenoxymethylpenicillin active against?
- Streptpcoccus
- Staphylococcus
- Oral anaerobes
- Enterococcus
- Bacillus
- Clostridium
- Listeria
- Trepnoma palladium
- E Coli
- Pseudomonas
- Bacteriodes
- Streptpcoccus - yes
- Staphylococcus - variable
- Oral anaerobes - yes
- Enterococcus - no
- Bacillus - yes
- Clostridium - yes
- Listeria - yes
- Trepnoma palladium - yes
- E Coli - variable
- Pseudomonas - variable
- Bacteriodes - variable
Give 2 penicllin binding proteins
Transpeptidase
Carboxypeptidase
Side effects of phenoxymethylpenicilin and BenPen
Hypernatraemia, hypokalaemia
Allergy
GIT
Haemolytic anaemia
Neuropathy/nephropathy
Phenoxymethylpenicillin and BenPen pharmacokinetics
A - 15-30% of oral dose of benpen , unstable under acid. 60% of oral phenoxymethylpenicillin
D - 60% protein bound, albumin. Vd 0.3 - 0.9 L/kg
Metbaolism - penicilloic acid which is inactive, further transformation
Excretion - 60-90% in urine, 25% unchanged, by active tubular secretion
Elimination half life 0.7 hours
Ben Pen is removed by haemodialysis
Piperacillin chemical preparation
semi synthetic penicillin
What spectrum does piperacillin cover
Gram negatives including - E coli, H influenzae, Klebsiella, neisseria, preoteus, shigella, serratia
Anaerobes including bacteriodes and clostridium
Gram postiive enterooccci stpah and streo
Pseudomonas
Indole positive proteus
Strep faecalis
Serratia
How does piperacillin sodium load and fluid load compare to other penicillins?
Lower sodium content
Serum potassium may decrease after administration
Toxicity and side effects of piperacllin
GIT
LFTs
Allergic reaction
Transient leucopenia
Transient neutorpenia
Piperacillin pharmacokinetics
Absorption - not acid stable, poor absorption, hydrolysed by acids
Distribution - 16% protein bound, Vd 0.32L/kg, hihg concentrations found in most tissues and body fluids
Metabolism - nil
Excretion - 20% in bile, remainder in urine by filtration and tubular secretion
Eliminatino half life 36 - 72 minutes
Dose reduction in renal impairement
30-50% removal by haemodialysis
Carbepenam spectrum of activity
Gram positive - not MRSA or enterococcus faecalis
Gram negative aerobic - not stenotrophomonas maltophilia
Anaerobic
ESBL
Do not cover MRSA or E faecalis
If used in isolation cause psuedomonas resisatnce
Imipenam - resistance to Beta lactamse, but only moderately effective against clostridium perfringens. Imipenam induces resisatnce to beta lactam agents in pseudomonas
How does imipenam compare to meropenam in preparation
IMipenam is metabolised by renal dehydropeptidsae I so is ocmbined with inhibitor cilastatin Meropenam is not metabolised in this way so not combined with cilastatin
MOA of carbopenams
Bind to penicillin binding proteins on the bacterial cytoplkasmic membrane blocking peptidoglycan synthesis and cell wall formation
Side effects and toxicity of carbopenams
Hypersiensitivity
Diarrhoea/vomiting
Pseudomomebranous colitis
positive coombs test
Can develop CNS side effects in those with pre-existing CNS disease
Pharmacokinetics of meropenam
Absorption - nil orally
Distribution - 12.5-20L
2% bound to plasma proteins
Metabolism - metabolised to inactive metabolite
Excretion - clearance equivalent to creatinine clearance, half life 60 minutes, 70% excreted unchanged in urine
Meropenam vs hepatic dysfunction?
Unaffected
Carbepenam effect on other drugs
Reduce sodium valproate levls
Which bacteria may have resistance to carbepenams?
Klebsiella pneumonia - CPE
What drug belongs to monobactams
aztreonam
What spectrum of acitivty does aztreonam have?
gram negative aeorbic e.g. enterobacter and speudomonas
Aztreonam methods of adminsitration?
nebulised
What are examples of glycopeptide antibiotics?
Vancomycin
Teicoplanin
Spectrum of acitivty of Glycopeptides
Aerobic and anaerobic gram positive - bacteriocidal (Staph, MRSA, enterococci, C difficile)
Bacteriostatic against enterococci and streptococci
All gram negatives are resistant
Due to large molecular weight and lack of penetratioun through gram negative cell membranes
MOA of glycopeptides
inhibit cell wall syntheiss
Large rigid structure binds to peptidoglycan precursers (peptidoglycan pentapeptide) hindering cross linkage and reduces cell wall rigidity - specifically binding to D-alanyl-D-alanine residues
no Competition between penicillins and glycopeptides for active activ peptide binding site
Vancomycin methods of administration
Oral
IV
Intrathecal
powder for reconstitution
Vancomycin pharmacokinetics
Absorption - no oral bioavailability
Distribution - 0.4-1L/kg, poor CNS penetration even with inflamed meninges, higher levels required for this. 50% protein bound. Widely distributed including in adpiose tissue. CSF level 7-30% of serum concentration in context of meningeal inflammation
Metabolism - very minimial hepatic metabolism
Excretion - 90% excreted unchanged in urine
Half life 6 hours
What factors into peak concentration vancomycin levels? What factors into trough levels?
Peak - dose
Trough - dose and interval
Teicoplanin vs vancomycin
similar acitvity
Longer duration of action
2-4x potency
Bone and CSF penetration more reliable (CNS penetration less reliable as per Smith)
Increased resistance to teicoplanin
Peck and Hill
Vancomycin side effects
Renal - nephrotoxicity 5-14%, usually seen with concurrent aminoglycosides, or with pre-existing renal impairmenet, usually resolves on withdrawal of vancomycin. Risk factors: dose >4g/day, trough levels >15, AUC >800/ 3% require dilaysis
Ototoxicity - discontinue if tinnitis occurs (1% and more seen with long duration and concurrent aminoglycosides
Phlebitis
Histamine release - if administered too rapidly, hypotension tachycardia and a widespread rash
Dose administration should not exceed 10mg/min
Haematological - neutropenia, thrombocytopenia 2% and reversible - more associated with prolonge duse
Teicoplanin side effects
Rash
Eosinophilia
Thrombocytopenia
Fever
What factor principally determines the level of bacteriocidal activity of teicoplanin if the bacteria is suceptable?
duration fo time where substance level is higher than the MIC
Teicoplanin vs haemodialysis
not dialysed
Teicoplanin toxicity
Cross hypersensitivtiy with vancomycin
Cutaneous reactions
LFTs increase
Infusion reactions
Cr increase
Teicoplanin kinetics
Absorption - nil oral absorption, IM absorption 90%
Distribution - mostly serum albumin bound, 90%
Vd 0.7-1.4L/kg
Distributed mainly in lungs, myocardium, bone
Metabolism - minimal 2 metabolites formed from hydroxylation representating 2-3% of adminsitered dose
Excretion - unchanged in urine 80%, 3% to faeces
Elimintation half life 100-170 hours
Low clearance at 10-4ml/kg/hr
Fluoroquinolones are notably actvie against?
Aerobic gram negative organisms - pseudomonas rapidly aquires resistance in monotherapy
legionella,. mycoplasma, ricketssia, chlamydia
Neisseria
Anaeorboes
Emerging resistance from E COli, shigella, neisseria gonorrhoea, acinetobacter and pseudomonas
How do ciprofloxacin and moxifloxacin compare in spectrum of activity
Moxifloaxacin has greater pneumococcal activity
MOA of fluoroquinolones?
Bactericidal
Block DNA replication by blocking topoisomerase enzymes and DNA gyrase essential for supercoiling, replication and separation of circular bacteria DNA
Pharmacokinetics of ciprofloxacin
Absorption - readily absorbed 80%, with first pass metabolism occuring
Distribution - widely, protein binding 30-40%, 2-3L/kg Vd, high CSF and tissue penetration
Metabolism - limited hepatic metabolism
Excretion - urine and faeces in unchanged form, active tubular secretion of ciprofloaxicin 500ml/min excretion, half life 3-7 hours
Side effects of fluoroquinolones
CNS - use with caution in epilepsy, especialy in coexistent use of NSAIDs; anxiety, insomnias and hallucinations
Tendon damage - rupture, especially with concurrent corticosteriods
CV - prolong QT
Haematological - haemolytic especially with G6PD
Photosensitivity
Allergy
Transient LFT elevations
Increased MRSA and C diff
Origin of fluoroquinolones
nalidixic acid - fluorinated
Preparations of ciprofloxacin
Oral - tablet and pwoder for suspension
IV
Eye drops
Eye ointment
Ciprofloxacin vs haemodialysis
25-30% removed
Ciprofloxacin vs haemodialysis
25-30% removed
Rifampicin is active against?
Gram positive bacteria
Limited gram negative - legionella, neisseria, H influenza
MOA of rifampicin
Bactercidal
Binds ot the beta subunit of DNA dependent RNA polymerase preventing DNA transcription into RNA
Antibiotics antagonised by rifampicin?
ciprofloxacin
Rifampicin kintetics
Absorption -
Distribution - very lipid soluble, penetrates CNS, abscesses and heart valves
Metabolism - liver mirosomes
Excretion - bile, active transport into bile can become saturated, additional drug then excreted uncahined in the urine imparting red colour
Rifampicin interactions primarily via?
CYP450 reducing plasma concentrations of anticonvulsants, OCP and warfarin
Metronidazole range of activity
obligate anaerobes and protozoe e.g. trichomaonas, clostridia, abcteriodes, trepnoma pallidum, campylobacter
Resisatnce in streptococci, lactobacilli
Metronidazole MOA
passive diffusion entry into cells
Metronidazole is reduced by pyruvate:ferridoxin oxidoreductase system in obligate anaeroboes and the nitro group of reduce metronidazole acts as an electron sink capturing electrons that would usually be transferred to hydrogen ions in the metabolic cycle as a result cytotoxic intermediates accumulate with free radicals inducing DNA strand breakage and cell death
Acts via a reactive intermediate which reacts with bacteria DNA so the resultant DNA complex can no longer function as an effective primer for DNA and RNA polymerases so all nucleic acid synthesis si thus blocked
Metronidazole pharmacokinetics
Absorption - almost 80-100% bioavailability orally, 75% rectally
Distribution - Widely distributed, CSF, cerebreal absecesses, prostate and pleural fluid
half life 8 hours
10% rpotein bound
Vd 0.75L/kg
Metabolism - completely in liver with active hydroxy metabolite eliminated slowl form the plasma (oxidation and glucuronidation)
Excretion - through kidney - 60% unchanged, does not accumulate in renal failure. Clearance is 1.22 ml/kg/min
Elimination half life is 6-10 hours
Metronidazole side effects
Nausea
Metallic taste
Not be consumed with alcohol as severe disulfiram like reaction
Prolonged use - peripheral neuropathy, leucopenia
What are the 3 sites involved in the formation of an elongating protein chain?
Aminoacyl site (A)
Peptidyl (P)
Exit (E)
Macrolide antibiotic spectrum of activity
Gram positive, some gram negative (esp azithro)
Anaerobes gram positive and negative
Obligate intracellular parasites -mycoplasma and legionella sensitive
Which is the parent macrolide
erythromycin
How is clarithromycin different to erythromycin in its pharmacodynamics
Less GI upset
Better coverage for streptococci, listeria and legionella
How is azithromycin different in its pharmacodynamics and kinetics to other members of its class
Better gram negative cover
e.g. moraxela catarrhalis, neisseria, H influenzae
Improved bioavailabiliy and longer half life than erythromycin
Macrolides are bacteriocidal or bacteriostatic?
Depends on plasma concentration
Macrolide MOA
Halt bacterial protein synthesis by binding to 50S ribosomal subunit after formation of the initiation complex - subsequent prevention of peptidyltransferase activity and or movement of tRNA from A to the P site prevents elongation of the peptide chain
Macrolide kinetics
Absorption - Orally or parenterally; erythromycin 10-60% absorption, clarithromycin 50%, azithromycin 37%
Distribution - CSF penetration poor, sputum and lung penetration good. Vd for erythromycin 0.34 - 1.22L/kg
Azithromycin 0.44 L/kg
12-50% azithromycinbound to plasma proteins
Metabolised - liver - erythromycin –> demethylation, clarithromycin –> 14-hydroxyclarithromycin, azithromycin via hepatic N and O demethylation to inactive metaboliutes
Excretion - Erythromycin and clarithromycin renally, erythromycin half life 1.6 hours, 2-15% unchanged in urine. CLarithromycin non linear, half life 5-6 hours, 33% excreted unchanged
Azithromycin - clearance 10ml/kg/min, 68 hour half life, 12% excreted uncahnged in urine but predominantly excreted in bile
Macrolide interactions
erythromycin and clarithromycin strong inhibitors of hepatic cytochrome CYP3A4 and p glycoprotein (the transport portein responsible for limiting enteral uptake of many drugs)
Simvastatin, warfarin, methylprednisone, phenytoin, ciclosporin, theophulline, sodium valproate, tacrolimus, midazolam, digoxin and carbamazepine levels are increased
macrolide side effecgts
GIT - common, prokinetic, avoid erythromycin in porphyria
CV - prolonged QT associated with erythromycin and clarithromycin
Ototoxicity has been reported
Heptic dysfunction
Allergy rare
Chemical structure of macrolides
Macrocyclic lactone ring to which deoxy sugars are attached
Does azithromycin dosing need to be adjusted in dialysis
No
In what patients should erythromycin not be given
prolonged QT
Porphyria
Digoxin toxicity
Caution if on warfarin, antiepileptics. immunosuppressants
Metronidazole chemically
synthetic imidazole derivitive
Metronidazole interactions
Increased anticoagulant effect of warfarin
Disulfuram reaction whe alcohol is consumed
Prolongs vecuronium
Metronidazole vs dialysis
removed by dialysis
Aminoglycoside coverage
Gram negative aerobes - E Coli, speudomonas, enterobacter, proteus, klebsiella, serratia
Staphylococcus
Strep limited
No anaerobic activity
What combination are aminoglycosides sometimes used in
With Vanc or Beta lactams it will be synergistic
Amikacin vs Gentamicin spectrum of activity
Amikacin has less resistance to enzyme inactivation
MOA of aminoglycosides
bactericidal - concentration dependent killing, post antibiotic effect
Block protein synthesis by irreversibly binding to bacterial 30S ribosome subunit - interfering with tRNA attachment and mRNA is either not transcribed or misread
Large polar molecules need active transport to gain entry into bacterial cells - passive diffusion into cell via porin channels, then oxygen dependent active transport into cytoplasm. Active transport enhanced by cell wall active drugs. Low pH and anaerobic conditions inhibit transport by reducing gradient.
Transport is inhibited by divalent cations calcium, magnesium, acidosis and low oxygen tension
What factors interfere with aminoglycoside penetration into a cell
Large polar molecules need active transport to gain entry into bacterial cells
Transport is inhibited by divalent cations calcium, magnesium, acidosis and low oxygen tension
Pharmacokinetics of Gentamicin
Absorption - No significantly absorbed when administrered orally as not lipid soluble, given parenterally only. NOT Inactivated in the GIT
Distribution - Low protein binding for other aminoglycosides (amikacin 20%), but 70-85% for gentamicin, distribute in extracellular fluid and penetrate cells, CSF and sputum poorly. Vd 0.14-0.7 L/kg for gentamicin. Hihg concentrations in the renal cortex
Metabolism - Not metabolised
Excretion - Excreted unchanged in urine by filtration, gentamicin clearance 1.18 - 1.32 ml/kg/min
Half life 2-3 hours with normal renal fucntion, 24-48 hours with severe renal impairment
Aminoglycoside side effects
Ototoxicity - vestibular and rarely auditory dysfunction occurs when significant amount accumulates in the inner ear perilymph - 1-5% receiving for >5 days. Effects permanent. Risk is increased in renal failure and with simultaneous furosemide use
Nephrotoxcity - 37% of ICU patients, reversible on discontinuing treatment. ATN as accumulates in renal cortex, manifests within a week of Tx, synergistic toxicity with cephalosporins
Both above are associated with high TROUGH concentrations
Muscle weakness - decrease prejunctional release of acetylcholine, reduce post junctional sensitivty to acetylcholine and increase non depolarisng muscle relaxant potency. i.e. avoid in myasthenia gravis
Chemical structure of aminoglycosides
aminocyclitol ring derivative bound to amino sugars
Gentamicin preparations
Liquid form for topical use
IV form
IM
Suitable for intrathecal or Intraventricular administrtion
Resistance to gentamicin acquired from - mechanisms of resistance
plasmid translocation
Transferase enzyme inactviating drug
Impaired entry into cell
Alteration or delation of 30S ribosomal subunit receptor protein
Aminoglycoside monitoring - what is the timing of a trough and a peak level
Trough - immediately prior
Peak -1 hour post
What effect does haemodialysis have on gentamicin and amikacin
Both removed - in both haemofiltration and dialysis
Effect of aminoglycosides on muscle paralysis
Proong non depolarising muscle relaxants by inhibiting pre synaptic acetylcholine release and stabilising the post synaptic membrane at the neuromuscular junction
Can be partially reversed by IV calcium
What is an example of a lincosamide
clindamycin
What is the antimicrobial coverage of clindamycin
Gram positive
Anaerobic
very little gram negative aerobic cover
Clindamycin MOA
inhibits bacterial protein synthesis through disruption of 50s ribosomal subunit
Bacteriostatic or bactercidial depending on concentration and organism
Resistance is inducible in gram postivie organisms - imparts resisatnce to macrolides also
Clindamycin side effects
Pseudomoembranous colitis and diarrhoea common
Fever
Rash
Eosinophilia
Give two examples of tetracyclines
,minoclycine, doxycycline
Tetracycline MOA
INhibiting attachment of tRNA amino acid complex to ribosome inhibiting codon-anticodon interaction
Binds to bacteria 30S ribosome preventing acces to amminoacyl transfer RNA (tRNA) to the mRNA-ribosome complex preventing elongation of polypeptide chain
Tetracyclines interactions
Chelated by milk, calcium and magnesium
Tetracycline contraindications
Avoid in renal and hepatic failure
Raised ICP
Increase muscle weakness in myasthenia gravis
Exacerbate SLE - photosensitivty
Deposited in growing teeth and bones so dont use in children
Prengant and lactating women should not receive
Fusidic acid active against
Staph auerues
MRSA
Staph epidermitis
Strep and pneumococci resistant
Some gram negatives are sensitive but most resistant
MOA of fusidic acid
Forms a complex with elongation factor and GTP blocking protein translocation and incorporation of amino acid residuals prevenitng protein syntheiss –> cell death
Fusidic acid kinetics
Well distirbuted, penetrates abscesses well
No active in CSF
Bone penetration si good
Excreted uncahnged in bile, but little active durg in faeces
Minimal renal excretion
Fusidic acid side effects
GIT
Otherwise well tolerated
Tetracycline chemical structure
napthacenecarboxamide deriviative
tetratcyline preparations
tablets
Syrup for IM injection
IV injection with ascorbic acid
Ointment
tetracycline spectrum of acitvity
Bacteriosttic
Active against gram positive and gram negative
- Clostridium
- Streptococcus
- Neisseria
- Brucella
- Vibrio
- H influenzae
- Yersinia pestis
- Ricketsiae
- Mycoplasma
- Chlamydia
- Leptospira
- Treponoma
Tetracycline pharmacokinetics
Absorption - incompletely absorbed, chelates with iron, calcium and aluminium. Theoretical bioavailability 77%
Distribution - widely, good tissue penetration,. 65% protein bound, Vd 0.75-1.37 L/kg
Metbaolism - 5% is metabolised to epitetracycline ootherwise unchanged
Excretion - 95% unchanined, 60% in urine via filtration and remainder inf aeces. Clearance 1.5 ml/min/kg
Half life 10-16 hours
Tetracyclines in ICU - beware
Raised ICP
Increased duration fo action of non depolarising muscle relaxants
Incompatible with many drugs pharmaceutically
What antimicrobial agents require no dose adjustment for renal replacement therapy?
Ciprofloxacin
Metronidazole
Azole antifungals
Penicillins apart from benzypenicillin (reduced by 30%)
Azithromycin
less commmon
- Rifampicin
Fusidic acid
What antimicrobial agents requrie dose decrease for renal replacement therapy?
aztreonam, acyclovir,zidovudine
What antimicorbial agents require more prolonged dosing intervals in the context of renal replacement therapy?
Cephalosporins, teicoplanin, macrolides erythromycin and clarithromycin
Both dose and dosing interval require altering for antimicrobial agents in the context of RRT?
Meropenam
Linezolid is what type of antibiotic and what chemical structure
Oxazolidinone
Linezolid spectrum of activity
Gram postiive organisms - enterococcus, streptococcus, staph, gram postiive anaerobes inclduign clostridium perfingens
Linezolid MOA
Inhibits bacterial protein synthesis by bidning to 50S binding subunit preventing initiation complex formation
Linezolid toxicity and side effects
Headache
LFTs
taste alteration
GIT
Fertility reversibly affected
Skina nd bleeding disorders
Phelbitis
pancreatitis
Linezolid Pharmacokinetics
Absorption - rapidly absorbed after oral administration and has oral bioavailabiltuy close to 100%
Distribution - drug is 31% protein bound, Vd 0.64L/kg
Metabolism - oxidised in liver to inactive carboxylic acid metbaolites
Excretion - 30% unchanged in urine, metabolites in urine and faeces
Eliminationhalf life 5 hours
Clearance 120ml/min
Linezolid interactions
Reversible non selective MAOI
Trimoprim sulfamethoxazole class
antifolate antibiotic
Bactrim pharmacodyanmics
Synergistic combinatino of folate antagonists blocking purine production and nucleaic acid synthesis
Trimethoprim in combination wit sulphonamides becomes bactercidal due to blockade of sequential steps in folate synthesis - sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid, trimtheoprim blocks production of tetrahydrofolic acid
Bactrim pharmacokinetics
Absorption - PO or IV
5:1 sulphamethoxazole:trimethoprime
Half life 8 hours
Renal clearance - 30-50% sulphonamide and 50-60% of trimethoprim excreted in urine within 24 hours
Bactrim spectrum of acitivty
Staph aureus
Haemophilus
Moraxella
Klebsiella
Pneumocytstis pneumonia
Bactrim side effects
GI
Fever, skin rashes - photosensivitiy, rarely SJS
Urinary tract disturbances - can precipitate
haematological - haemolytic or asplatic anaemia, thrombocytopenia (with diuretics)
Warfarin increases INR
CNS effects
Bactrim contraindications
Hypersensitivty
Blood dyscrasia
Marked renal or hepatic impairment
Megaloblastic bone marrow
What does this graph mean?
Concentration time curve describiong the relationship between antibiotic concentration and their killing power
Anitbiotic which kill over time are those which kill according to time spent over MIC
Antibiotics which kill be concentration kill according to the highest peak
What does this graph mean?
Concentration time curve describiong the relationship between antibiotic concentration and their killing power
Anitbiotic which kill over time are those which kill according to time spent over MIC
Antibiotics which kill be concentration kill according to the highest peak
Some kill by both
What are time or MIC dependent killing antibiotics?
Beta lactams
Carbepenams
Monobactams
Linezolid
Clindamycin
Macrolides
Concentration dependent killing antibiotics include?
Aminoglycosides
Metronidazole
Daptomycin
Fluoroquinolones
Combination of AUC and MIC dependent killing antibiotics are
Fluoroquinolones, azithromycin, tetracyclines, vancomycin, tigecycline, linezolid
Time dependent killing -pathophysiological mechanism for having this characteristic
- Those which kill bacteria most effectively at some specific event e.g. when about to divide
- Those which do not have much post antibiotic effect i.e. the kill characteristic only occurs when the drug concentration remains high
For what proportion of the duration of treatment does concentration need to be above MIC for drugs with concentration dependent kill characteristics to be functional?
Cephalosporins even with 40-50% of dosing interval above MIC killing efficacy close to maximal and cephalosporins have the hgihest requirement for time above MIC - beta lactams the next most frequency and carbepenams less (30% with early kill characterstics)
When might the proportion of the duration of treatment above MIC be greater than conventionally required?
Areas of poor penetration e.g osteomyelitis, CNS ifnection
Concentration dependent killing mechanism
Is a property of antibiotics which disable some sort of crucial steps in bacterial metabolism or protein synthesis - the higher the concentration reach the more synthetic enzyme molecules are inhibited e.g. aminoglycosides, metronidazole, daptomycin
What level above MIC does gentamicin need to reach to have ~90% of potential effect?
8-10x MIC at peak levels
AMinoglycoside killing is somewhat unique - describe why
Initially related to passive ionic binding of the drug to the bacterial lipopolysaccharide coat but later becomes more reliant on active uptake into the bacterial cell. Being exposed to aminoglycosides causes bacteria to downregulate this uptake and thus the first exposure to the drug increases subsequent MIC. The forst dose better be the bigger one as it will carry out the bulk of the killing. Once daily dosing allows enough time for this effect to dissapate somewhat between doses
Which drug mechanisms exaplin time and concentration dependent killing both being a factor?
Inhibits steps in DNA synthesis or replication, or components crucial for cellular division
Time is important because inhibited enzymes are most active durnig division and therefore time immersed in the drug is necessary to catch a large portion of the bacteria attempting this
Concentrationsi important to disable more of target cell components
Organisms intrinsically resistant to meropenam
Stenotrophomonas maltophila
Pseudomonas cepacia
Enterococcus faecium
MRSA
List of organisms intrinsiically resistant to glycopeptides
Lactobacillis casei
Pediococcus pentosaceus
Leuconostoc mesenteriods
What is the post antibiotic effect?
Persistent of effect long after serum concentration has fallen below MIC
Which antibiotics are seen to have a post antibiotic effect?
Inhibit some life sustaining enzyme or bind tightly to cell wall components
Usually concentration dependent kill characteristics
What drugs have a strong post antibiotic effect?
Aminoglycosides
Clindamycin
Macrolide antibiotics
Tetracyclines
Rifampicin
Quinupristin/dalfopristin
Examples of moderate post antibiotic effect
Carbapenems
Fluoroquinolones
Glycopeptides
Linezolid
Pharmacokinetics in critical illness are effected how
Factors which decrease the antibiotic peak dose:
- Poor gut absorption
- Increased volume of distribution - fluid overloaded
- Poor penetration to the site of action - ischaemic gut, oedamatous lung, poor tissue perfusion
Factors which increase the antibiotic peak dose:
- Decreased protein binding - increased fraction unbound
- Diminished clearance mechanisms
- Improved penetration into inflamed tissues (eg. meningitis)
Factors which increase the antibiotic half-life
- Decreased renal clearance
- Decreased hepatic clearance - blood flow diminished in shock and synthetic function may be poor if liver injury
- Decreased overall metabolism (eg. hypothermia)
Factors which decrease the antibiotic half-life
- Renal replacement therapy - e.g. fluconazole it totally removes
-Increased hepatic clearance, eg. enzymes induced by drug interactions; hyperdynamic circulation
- Increased glomerular filtration if hyperdynamic
- Hypermetabolic state
Factors in critical illness decreasing antibiotic peak dose
Factors which decrease the antibiotic peak dose:
- Poor gut absorption
- Increased volume of distribution - fluid overloaded
- Poor penetration to the site of action - ischaemic gut, oedamatous lung, poor tissue perfusion
Factors in critical illness increasing antibiotic peak dose
Factors which increase the antibiotic peak dose:
- Decreased protein binding - increased fraction unbound
- Diminished clearance mechanisms
- Improved penetration into inflamed tissues (eg. meningitis)
Factors in critical illness prolonging half life
- Decreased renal clearance
- Decreased hepatic clearance - blood flow diminished in shock and synthetic function may be poor if liver injury
- Decreased overall metabolism (eg. hypothermia)
Factors which decrease half life in critical illness
Factors which decrease the antibiotic half-life
- Renal replacement therapy - e.g. fluconazole it totally removes
-Increased hepatic clearance, eg. enzymes induced by drug interactions; hyperdynamic circulation
- Increased glomerular filtration if hyperdynamic
- Hypermetabolic state
How does pharmacodynamics differ inc ritical illness
Enhanced organ toxicity
Antibiotic toxicity will increase not only because clearance might be impaired, but because the organs themselves are likely damaged, and are therefore relatively defenceless. Toxicity may develop at drug levels which might otherwise be viewed as safe. Examples of this may include:
Increased nephrotoxicity from aminoglycosides, if the renal function is already impaired
Increased cardiotoxicity from bleomycin and vancomycin
Increased risk of QT prolongation and arrhythmia with fluoroquinolones in the context of cardiac ischaemia, profound hypothermia, or extreme electrolyte derangement
Increased bone marrow toxicity from linezolid, cotrimoxazole, gancyclovir, chloramphenicol, beta-lactams of all sorts…
With a disrupted blood-brain barrier, an increased risk of seizures from high-dose beta-lactams, due to enhanced penetration.
Worsening shock due to dapsone-induced methaemoglobinaemia and thus diminished oxygen-carrying capacity.
What is MIC
MIC is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation.
The results are usually reported as µg/mL.
WHy is MIC a good measure of antimicrobial susceptability
Easily performed
Frequently, an automated method is available
Simplicity and automation of the test enhances reproducibility
Rapid return of results
Why si MIC not an optimal measure of antimicrobial susceptability
Minor variations in methodology can result in large variations of the MIC.
For example, extended incubation will make the MIC appear higher
Lower inoculum concentrations will make the MIC appear lower
Interlaboratory variation in technique makes comparison problematic
MIC is inhibition of visible growth: the microorganisms weren’t necessarily killed!
MIC may not be related to in vivo efficacy, which is a complex parameter determined by numerous factors among which the MIC is only one. An antibiotic with a low MIC may have no effect if it does not penetrate into the infected tissue. An antibiotic with a high MIC will still be effective if it happens to be concentrated in the infected tissue (eg. gentamicin in urine).
Which aminoglycoside has the least antibiotic resisatnce?
Tobramycin is marginally more active than gentamicin against P. aeruginosa, but not against other aerobic Gram-negative bacteria. It is inactivated by a similar range of bacterial enzymes as gentamicin.
Amikacin is more resistant to bacterial enzymatic inactivation than gentamicin or tobramycin, so it should generally be reserved for treating infections resistant to other aminoglycosides.
Kanamycin, along with amikacin, has largely replaced streptomycin in the treatment of resistant mycobacterial infections, because of higher rates of susceptibility and better availability. However, kanamycin is inferior to other aminoglycosides against aerobic Gram-negative bacteria. Capreomycin has also been used for multidrug-resistant tuberculosis.
Wide spread use of carbepenams is linked to icnreasing prevalence of which infections?
However, widespread use of carbapenems is linked to an increasing prevalence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant Gram-negative bacteria and Clostridioides difficile (formerly known as Clostridium difficile). Furthermore, carbapenem resistance is emerging worldwide
Is meropenam active against extended spectrum beta lactamase enzymes?
Yes
Carbopenams vs enterocccus?
Imipenem has activity against Enterococcus faecalis, which meropenem lacks.
Imipenam is inactivated if given without an additional agent - what is it
Imipenem is formulated in combination with the renal dipeptidase enzyme inhibitor, cilastatin, to prevent inactivation.
Meropenam vs CNS pentration? side effect of same?
High-dose meropenem achieves adequate concentrations in the cerebrospinal fluid and has a lower incidence of seizures than imipenem.
Carbepenam spectrum of acitvity
Imipenem and meropenem have broad activity against Enterobacteriaceae (enteric Gram-negative bacilli), including isolates that produce extended-spectrum beta-lactamase enzymes (ESBLs), and Pseudomonas aeruginosa; this activity is comparable to that of aminoglycosides. They also have excellent activity against anaerobic Gram-negative bacteria (including Bacteroides fragilis), and many Gram-positive bacteria (including Nocardia species). Imipenem has activity against Enterococcus faecalis, which meropenem lacks.
What are carbepenams not active against?
Carbapenems are inactive against MRSA, VRE, Enterococcus faecium, Mycoplasma species, Chlamydia species and Stenotrophomonas maltophilia.
Narrow spectrum cephalosporin spectrum of acitivty
In terms of Gram-positive activity, they are active against streptococci and staphylococci, including beta-lactamase–producing (penicillin-resistant) staphylococci, but inactive against methicillin-resistant Staphylococcus aureus (MRSA), enterococci and Listeria monocytogenes. They are active against a narrow range of aerobic Gram-negative bacteria, including wild-type Escherichia coli and some Klebsiella species, but have no activity against anaerobic Gram-negative bacteria, including Bacteroides fragilis.
Why is cefuroxime used for respiratory infections and not cephalexin?
For oral treatment of respiratory tract infections, cefuroxime is preferred to cefalexin because of its superior activity against S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.
What is an enterobacteriaceae
Enteric gram negative bacilli
How do ceftriaxone and cefotaxime compare in their spectrum of acitvity to cephalexin
Activity against majority of community associated enterobacteriaceae
No active against pseudonomas
Less active against staphyloccci than cefazolin
Inactive against MRSA
Cefotax > ceftriaxone for staph but for both is dose depednent
Nil enteroccocus acitvity
Serratia, citrobacter and enterobacter have chromosomal resiatnce and ESBL inactive them
Why is ceftriaxone bad in neonates
Highly protein bound
Kicks bilirubin off albumin increasing the risk of kernicterus
What does ceftriaxone precipitate with
calcium
How is ceftazidime different to ceftriaxone
Extended spectrum including pseudomonal activity
Both inactivated by ESBL
How is cefepime different to ceftriaxone?
Extended spectrum including pseudomonal activity
Both inactivated by ESBL
Cefepime is bettyer for gram positive than ceftazidime
Ceftaroline is special why?
Acts against MRSA
Phenoxymethypenicillin absorption is blocked by?
Food
Phenoxymethypenicillin vs benpen
Less intrinsically active
Same spectrum
Absorption of flucloxacillin characteristics
Food impairs the absorption of of dicloxacillin and flucloxacillin. Ideally, they should be dosed at 6-hourly intervals, but for practical purposes (eg in children) four-times-daily dosing, evenly spaced during waking hours, is often used.
FLucloxacillin side effect
Cholestatic jaundice, more likely if old or polonged use . Can occur as long as 6 weeks after
Dicloxacillin side effects vs flucloxacillin
Less cholestatic jaundice - less irreversible hepatotoxicity
More interstitial nephriits
Why is amoxicillin used instead of Phenoxymethylpenicillin for strep pneumonia infections and respiratory infections
Orally - Longer half life so longer time above MIC and reduced faily dosing
Amoxicillin vs ampicillin
Same spectrum of acitivty, same pharmacodynamics
Orally has a better absorption, less affected by food
IV they are equivalent
Which organisms primarily contain the beta lactamase that tazobactam and clavulinic acid impair?
Staphylococcus aureus, Bacteroides fragilis and Haemophilus influenzae, and some of the beta-lactamase enzymes produced by Escherichia coli and Klebsiella species.
If treating pseudonomas with tazosin what specifically must be done?
6 hourly dosing
Daptomycin spectrum of acitivity
Daptomycin is only active against Gram-positive bacteria, including most strains of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). It has a similar spectrum of activity to the glycopeptides.
Which organ system does daptomycin have poor penentration into?
Lungs - inactvativated by pulmonary surfactant
Side effect daptomycin
Myopathy is an adverse effect of daptomycin. In patients treated with daptomycin, measure plasma creatine kinase concentration at least once weekly, or more frequently if the patient has renal impairment (creatinine clearance less than 30 mL/minute) or is receiving concomitant drugs associated with myopathy (eg statins).
Why is trimethoprim not used in neonates?
Avoid trimethoprim+sulfamethoxazole in neonates (up to 1 month old) because of the risk of kernicterus (precipitated by the displacement of bilirubin from albumin by sulfonamides).
How does trimethoprim affect the kidneys
Trimethoprim inhibits tubular secretion of creatinine, which can elevate serum creatinine without any true decrease in glomerular filtration rate. Trimethoprim also inhibits tubular excretion of potassium and can cause hyperkalaemia. Monitor serum potassium after 3 days of treatment with trimethoprim in patients at increased risk of hyperkalaemia (eg patients with renal impairment, patients who are taking a high dose of trimethoprim or other drugs that can cause hyperkalaemia).
Vancomycin vs C difficile
Oral vancomycin is used to treat Clostridioides difficile infection. In patients with severe disease, particularly in the presence of ileus, vancomycin can be given as a retention enema in addition to oral therapy. Intravenous vancomycin is not effective against C. difficile infection because of inadequate penetration of the drug into the lumen of the colon.
Linezolid spectrum of acitivty
Linezolid is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant enterococci (VRE), and penicillin-resistant strains of Streptococcus pneumoniae
Side effect linezolid
Bone marrow suppression and peripheral neuropathy can occur in patients taking linezolid for longer than 14 days, so haematological and neurological monitoring is required. A protocol for monitoring patients for linezolid toxicity has been proposed [Note 2].
Linezolid is a weak monoamine oxidase inhibitor, so it significantly interacts with some foods and drugs. Consult an appropriate resource on drug interactions if starting or stopping linezolid in patients taking other drugs.
Macrolide spectrum of acitivity
The macrolides, azithromycin, clarithromycin, erythromycin and roxithromycin, have a broad spectrum of activity, including activity against Gram-positive cocci, Corynebacterium species, Gram-negative cocci, and Legionella, Mycoplasma and Chlamydia species, as well as some Gram-positive and Gram-negative anaerobic bacteria. Erythromycin, azithromycin and clarithromycin are also active against Bordetella pertussis.
What is different about the spectrum of acitivty of clarithromycin to its other macrolides
Unlike other macrolides, clarithromycin has a microbiologically active metabolite. Clarithromycin is active against nontuberculous mycobacteria, including Mycobacterium avium complex (MAC), and is used in combination with other drugs for this indication. It is also used in combination with other drugs for eradication of Helicobacter pylori.
How is azithromycin different in its activity to erythrmoycin
Azithromycin is less active than erythromycin against Gram-positive bacteria, but has a broader range of Gram-negative activity (eg Salmonella species). Azithromycin is also active against nontuberculous mycobacteria (including MAC), Rickettsia species and some parasites (eg Toxoplasma gondii).
Metronidazole spectrum of acitvity
The nitroimidazoles, metronidazole and tinidazole [Note 3], have activity against almost all Gram-negative anaerobic bacteria (eg Bacteroides fragilis) and most Gram-positive anaerobic bacteria (eg Clostridium species, but not Cutibacterium acnes [formerly Propionibacterium acnes]). It is also active against protozoa, including Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Helicobacter pylori resistance to metronidazole is common in Australia (about 50% of H. pylori infections, reflecting high community exposure to nitroimidazole drugs).
Which bugs are resistant to quinolones?
Resistance to quinolones is now widespread, particularly in Enterobacteriaceae (enteric Gram-negative bacilli), Pseudomonas aeruginosa, Campylobacter species and Neisseria gonorrhoeae.
Ciprofloxacin spectrum of activity
Ciprofloxacin has a broad spectrum of activity, which includes activity against aerobic Gram-negative bacteria (including Haemophilus influenzae, Enterobacteriaceae [enteric Gram-negative bacilli], P. aeruginosa and Gram-negative cocci) and some aerobic Gram-positive cocci. It is also active against intracellular bacteria, including Legionella species and some mycobacteria. Ciprofloxacin has poor activity against anaerobic bacteria and streptococci.
Moxifloxacin spectrum of activity
Moxifloxacin, an extended-spectrum quinolone, has increased activity against Gram-positive aerobic bacteria (including staphylococci and streptococci) compared to ciprofloxacin. Susceptibility among strains of methicillin-resistant Staphylococcus aureus (MRSA) is variable. Moxifloxacin is active against many Gram-negative aerobic bacteria, but has poor activity against P. aeruginosa. Moxifloxacin has good activity against anaerobic bacteria and most atypical bacteria that cause pneumonia. It is also used for the management of some mycobacterial infections.
Norfloxacin spectrum indications
Multidrug resistant cystitis and acute ifnectious diarrhoea
Why are fluoroquinolones not used in children
adverse ffect in cartilage development based on animal studies - if required can be used
What is the theory behind using combination therapy in enndocarditis or enterococcal infections?
Synergistic action of cell wall active drugs and aminoglycosides
- Higher rates of cure
- Shorter duration
What are the 3 groups of patients in whom aminoglycosdies are contraindicated?
Toxicity previously - vestibular or auditory
Hypersensitivty (rare)
Myasthenia gravis
Why can aminoglycosides be used at dosing so much less frequent than their half life would suggest?
Post antibiotic effect
Do aminoglycosides cause C diff?
No
Which infections are aminoglycosides synergstic with cell wall active drugs?
Enterococcal
Streptococcal
Is nephrotoxicity from aminoglycosids reversible?
Generally yes
Over what duration can gentamicin be infused?
3-5 minutes slow IV injection safe
What weight should be used for gentamicin?
The appropriate aminoglycoside dosage is determined by the patient’s weight and kidney function. Adjusted body weight is used for children who are obese and adults who are obese class I (BMI 30 to 34.9 kg/m2). Expert advice is required for adults who are obese class II or III (BMI 35 kg/m2 or more).
Generally lean body weight is ideal due to dosage being dependent on renal clearance and Vd
Gentamicin dose for critically ill patients if their renal function is
- CrCl >60
- CrCl 40-60
- CrCl <40
> 60 = 7mg/kg 24 hourly
40-60 5mg/kg 36 hourly
<40 is 4mg/kg single dose
Gentamicin dosing for a patient who is 6’8 and 110kg - what factors to consider
NB4: If actual body weight (for patients who are not obese) or adjusted body weight (for patients who are obese) is greater than 100 kg, use a weight of 100 kg to calculate the dose.
In what situations is aminoglycoside plasma concentration monitoring required?
when treatment is expected to continue for >48 hours - if so commence from the first dose
How often does gentamicin concentration monitoring need to be performed?
48 hourly
How to monitor aminoglycoside drug concentrations
Once daily dosing - clinical efficiacy related to AUC< toxicity minimised by undetectable trough plasma concentration. MIC is required for AUC calculations
Timing of tetsing - 30 minutes after infusion completed, 6-8hrs after the dose
Nephrotoxicity risk in aminoglycoside use is found in which dosing regimen?
ANything >1 dose per day increases the risk
Prolonged Tx >5 days
WHat predicts aminoglycoside vestibular and auditory toxicity?
Not predicted by p;lasma concentration
Can occur early or weeks after
What symptoms are most commonly seen in aminoglycoside vestibular toxicity
Gait ataxia/imbalance
Oscillopsia - bouncing vision
Blurring vision with ehad movement
Hearing loss
Is there any benefit proven to 7mg/kg over 5mg/kg for gentamicin?
No
Pharmacologically it makes sense
7mg/kg may have benefit for pathogens with a high MIC e.g. pseudomonas
However there is no published study showing clinical advantage
How fast can you infuse vancomycin?
How long might a 1g dose take?
1.5g?
10mg/min
1g dose takes 1 hour
1.5g 90minutes
What type of reaction is red man syndrome?
Histmaine mediated non allergic reaction
Loading dose physiology for vancomycin?
Loading dose achieves therapeutic concentration more quickly b 12 hours - no evidence it improves clinical or microbiological outcomes
Vancomycin weight based dosing is based on which weight?
actual body weight
AUC for vancomycin dosing has what advantages?
Similar rates of clincial success
Reduced nephrotoxicity
Lower daily doses
Lower trough concentrations
Vancomycin nephrotoxicity is predicted by?
Higher daily doses realtive to kidney function
High trough concentration
Prolonged therapy
Co-committant nephrotoxins (Tazosin concurrent therapy 3-4x risk)
Vasopressors
Cefepime Vd
0.2L/kg
Cefepime clearance
85% renal unchanged
Clindamycin pharmacokinetics
Rapid absorption
90% bioavailable
Food does not affect absorption
Does not penetrate CSF but widely distributed
Oxidised by CYP3A4 wtih 10% unchanged in urine, 5% in faeces and the rest as metabolites
Bactrim pharmacokinetics
Absorption 100%- PO or IV
Vd 1.6L/kg + PPB 40% for trimethoprim, 0.3L/kg and 50% PPB for sulfamethoxazole.
Trimethorpim 30% metabolism in CYP450, some metabolites active. Sulfamethox 80% liver metabolism
Renal clearance - 30-50% sulphonamide and 50-60% of trimethoprim excreted in urine within 24 hours. Filtration + secretion
MOA of atrazoenam
The bactericidal action of aztreonam results from the inhibition of bacterial cell wall synthesis due to its binding to Penicillin Binding Protein 3 (PBP3). Aztreonam is resistant to hydrolysis by many beta-lactamases (i.e. penicillinases and cephalosporinases) produced by gram-negative and gram-positive pathogens
Aztreonam side effects
Generally well tolerated
Aztreonam pharmacokinetics
Nil absorption
50% protein bound
Minimally metabolised
