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