Infectious Disease Pharmacology Flashcards

1
Q

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

A

Petkov blue

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2
Q

Give an example of each of 4 generations of cephalosporins

A

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3
Q

Give an example of each of the 4 beta lactam classes

A

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4
Q

What class does Vancomycin belong to?

A

Glycopeptides
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5
Q

What is the coverage of the class glycopeptides? Give an example of one

A

Gram + inc. MRSA
Vancomycin

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6
Q

Macrolides coverage and example?

A

Gram + cocci, gram negative cocci and anaerobes
Erythromycin/clarithromycin

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7
Q

Lincosamides have what coverage?

A

Gram positive aerobics, most anaerobes,MRSA

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8
Q

Lincosamides examples

A

CLindamycin, lincomycin

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9
Q

Aminoglycoside coverage and example?

A

Gram - aerobes
Gentamicin

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10
Q

Tetracycline coverage and example

A

Doxycycline
Gram +and gram -

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11
Q

Quinolones cover what bacteria? Example?

A

Ciprofloxacin
Mostly gram -

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12
Q

Metronidazole belongs to what class? Coverage (2)

A

Nitroimidazoles
Anaerobes and protozoa

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13
Q

Trimethoprim class

A

Pyramiding derivities

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14
Q

Rifampicin coverage?

A

Gram + and mycobacteria

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15
Q

Fusidic acid coverage?

A

Narrow spectrum Staph Aureus

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16
Q

Mechanism of beta lactams?

A

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17
Q

Vancomycin MOA

A

Glycopeptides inhibit glycol-peptide synthase
Prevents peptidoglycan-glycan formation in the bacterial cell wall

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18
Q

Which antibiotics act by preventing protein synthesis?

A

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19
Q

Chloramphenicol MOA

A

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20
Q

Lincomycin MOA

A

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21
Q

Which antibiotics act via 50s ribosomal subunit? How does this affect bacteria

A

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22
Q

How do aminoglycosides work

A

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23
Q

How do tetracyclines work

A

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24
Q

WHich antibiotics act via 30s ribosomal subunit? How does this impact bacteria?

A

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25
How do quinolones work?
Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis Petkov blue
26
How does ciprofloxacin work
Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis Petkov blue
27
Which antibiotics act via inhibition of nucleic acid synthesis directly?
Quinolones, nitroimidazoles Petkov blue
28
How does metronidazole work
Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis Petkov blue
29
Which 2 classes act via inhibition of folic acid synthesis
Sulphonamides Trimethoprim Petkov blue
30
How do sulphonamides work?
Mimic folic acid by acting as false substrates Petkov blue
31
How does trimethoprim work
Competitive inhibition of bacterial Di-hydro-folate reductase - inhibiting folic acid synthesis Petkov blue
32
Name 3 bacteriocidal antibiotics
Petkov blue
33
Bacteriostatic antibiotics (4)
Lincosamides Tetracycline Sulphonamides Macrolides at low plasma concentrationsPetkov blue Petkov blue
34
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
35
What are the 4 classes of beta lactams?
Pencillins Cephalosporins Carbapenams Monobactams
36
What two main classes of antibiotics attack the cell wall
Beta lactams Glycopeptides
37
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
38
What is the significance of the acyl side chain in pencillins and cephalosporins?
Suscepatability to acid degredation in the stomach Spectrum of acitivty
39
Which pencillins are produced naturally
Pencillin V and pencillin G
40
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
41
How do beta lactamases work?
hydrlyses the beta lactam ring
42
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
43
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
44
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.
45
What is pencillin V
Phenoxymethypenicillin
46
What is pencillin G
Benzylpenicillin
47
How is flucloxacillin different to benzylpenicillin
reistsance to beta lactamase in staph
48
What is an extended spectrum aminopencillin?
Ampicillin, amoxicillin
49
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
50
Amoxicillin vs ampicillin oral absorption? Why?
Amoxicllin has better oral absorption as it is less susceptable to acid induced degredation
51
Plasma half life of benzylpenicillin
30 minutes
52
Ampicillin plasma half lfie
2 hours
53
Tissue penetration in penicillins
Generally good, inflammation necessary for pencillins to pass into bone and through the BBB.
54
Pencillin excretion
Kidneys unchanged 60-90% Mainly by renal tubular secretion Bile 10% 20% metabolised
55
What agent blocks pencillin renal tubular secretion
Probenicid
56
Give an example of beta lactamase inhibitor
Tazobactam clavulinic acid
57
Do beta lactamases have intrinsic antimicrobial activity?
clavulanic acid does Tazobactam does not
58
Side effects of penicillins
59
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
60
Cephalosporins differ in structure to penicillins how?
Beta lactam ring is fused with a dihydrothiazine ring to produce cephem nucleus
61
Cephalosporins are more or less sensitive to beta lactamses?
Less
62
As generations of cephalosporins progress describe the changes in antimicrobial coverage
Gram positive cover is maintained, gram negative cover improved
63
MOA of cephalosporins
Bactericidal Disrupt peptidoglycan cell wall integrity Modified beta alctam ring is more stable making them less susceptable to beta lactamases
64
Distribution of cephalosporins
Widely Readily cross placenta Third generation cephalosporins penetrated the CSF especially if meningeal inflammation occurs (10% penetration)
65
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)
66
Which cephalosporins are excreted unchanged in the urine?
Cepradine, cefuroxime, ceftazidime
67
Cefotaxime is metabolsied how?
Liver - 10% acitvity of metabolites compared to parent drug (desacetyl cefotaxime) 50% unchanged in urine
68
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
69
Side effects of cephalosporins?
Hypersensitivity GI - C diff, especially third generation Transient positive coombs test LFT abnormalities
70
First generation cepahlosporins - examples + spectrum
Cefalexin, cefaclor, cefradine Gram positive cocci
71
Second generation cephalosporins e.g. and spectrum
Cefuroxime, cefaclor, cefoxitin Gram positive cocci Cefuoxime also covers H influenzae
72
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
73
4th generation cephalosporins e.g. and spectrum vs 3rd gen
Cefepime, cefpirome Enterobacter and pseudomonas
74
5th generation cephalosporins e.g. and activity
Ceftaroline, ceftobipole MRSA, VRSA
75
Amoxicillin chemically is?
Aminopenicllin derivitve of ampicillin (Scarth and smith)
76
Amoxicillin is available in what preparations?
Vials, sachets, capsules, suspension and syrup
77
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
78
What effect does adding clavulinic acid have to amoxicillin?
Reduces the MIC againt staph aureus, E Coli, H influenza and Klebsiella
79
AMoxicillin side effects
Allergy GI Intersisital nephritis haemopoietic disturbances Cholestatic jaundice late with clavulanic acid use
80
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
81
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
82
What preparations are cephalosporins available in?
1st and 2nd generation - oral and IV 3rd generation IV only
83
Cefuroxime bioavailability?
35-50%
84
Distribution of cephalosporins - % protein bound - Cefradine - Cefotaxime - Cefuroxime - Ceftazidime Widely or narrowly distributed
Cefradine - 8-17% Cefuroxime/cefotaxime 35-50% Ceftazidime <10% Ceftriaxone 95%
85
What % of ceftriaxone is excreted in bile?
40%
86
Cephalosporins vs dialysis
They are haemodialysed
87
Flucloxacillin chemical
Semisynthetic isoxazolyl penicillin
88
Flucloxacillin is acid stable or not?
Yes because it has good oral bioavailability
89
What is fluclox effective against?
Staph auerues Beta haemolytic strep Pneumococci
90
Flucloxacillin toxicity and side effects
GIT CNS Rashes Glossitis Jaundice in the critically ill Pseudomembranous colits
91
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
92
Fluclox vs haemodialsyis
Not dialysed
93
Interaction with administration of flucloxacillin - what is it incompatabile with
aminoglycosides cause precipitation
94
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
95
Give 2 penicllin binding proteins
Transpeptidase Carboxypeptidase
96
Side effects of phenoxymethylpenicilin and BenPen
Hypernatraemia, hypokalaemia Allergy GIT Haemolytic anaemia Neuropathy/nephropathy
97
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
98
Piperacillin chemical preparation
semi synthetic penicillin
99
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
100
How does piperacillin sodium load and fluid load compare to other penicillins?
Lower sodium content Serum potassium may decrease after administration
101
Toxicity and side effects of piperacllin
GIT LFTs Allergic reaction Transient leucopenia Transient neutorpenia
102
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
103
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
104
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
105
MOA of carbopenams
Bind to penicillin binding proteins on the bacterial cytoplkasmic membrane blocking peptidoglycan synthesis and cell wall formation
106
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
107
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
108
Meropenam vs hepatic dysfunction?
Unaffected
109
Carbepenam effect on other drugs
Reduce sodium valproate levls
110
Which bacteria may have resistance to carbepenams?
Klebsiella pneumonia - CPE
111
What drug belongs to monobactams
aztreonam
112
What spectrum of acitivty does aztreonam have?
gram negative aeorbic e.g. enterobacter and speudomonas
113
Aztreonam methods of adminsitration?
nebulised
114
What are examples of glycopeptide antibiotics?
Vancomycin Teicoplanin
115
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
116
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
117
Vancomycin methods of administration
Oral IV Intrathecal powder for reconstitution
118
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
119
What factors into peak concentration vancomycin levels? What factors into trough levels?
Peak - dose Trough - dose and interval
120
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
121
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
122
Teicoplanin side effects
Rash Eosinophilia Thrombocytopenia Fever
123
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
124
Teicoplanin vs haemodialysis
not dialysed
125
Teicoplanin toxicity
Cross hypersensitivtiy with vancomycin Cutaneous reactions LFTs increase Infusion reactions Cr increase
126
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
127
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
128
How do ciprofloxacin and moxifloxacin compare in spectrum of activity
Moxifloaxacin has greater pneumococcal activity
129
MOA of fluoroquinolones?
Bactericidal Block DNA replication by blocking topoisomerase enzymes and DNA gyrase essential for supercoiling, replication and separation of circular bacteria DNA
130
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
131
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
132
Origin of fluoroquinolones
nalidixic acid - fluorinated
133
Preparations of ciprofloxacin
Oral - tablet and pwoder for suspension IV Eye drops Eye ointment
134
Ciprofloxacin vs haemodialysis
25-30% removed
135
Ciprofloxacin vs haemodialysis
25-30% removed
136
Rifampicin is active against?
Gram positive bacteria Limited gram negative - legionella, neisseria, H influenza
137
MOA of rifampicin
Bactercidal Binds ot the beta subunit of DNA dependent RNA polymerase preventing DNA transcription into RNA
138
Antibiotics antagonised by rifampicin?
ciprofloxacin
139
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
140
Rifampicin interactions primarily via?
CYP450 reducing plasma concentrations of anticonvulsants, OCP and warfarin
141
Metronidazole range of activity
obligate anaerobes and protozoe e.g. trichomaonas, clostridia, abcteriodes, trepnoma pallidum, campylobacter Resisatnce in streptococci, lactobacilli
142
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
143
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
144
Metronidazole side effects
Nausea Metallic taste Not be consumed with alcohol as severe disulfiram like reaction Prolonged use - peripheral neuropathy, leucopenia
145
What are the 3 sites involved in the formation of an elongating protein chain?
Aminoacyl site (A) Peptidyl (P) Exit (E)
146
Macrolide antibiotic spectrum of activity
Gram positive, some gram negative (esp azithro) Anaerobes gram positive and negative Obligate intracellular parasites -mycoplasma and legionella sensitive
147
Which is the parent macrolide
erythromycin
148
How is clarithromycin different to erythromycin in its pharmacodynamics
Less GI upset Better coverage for streptococci, listeria and legionella
149
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
150
Macrolides are bacteriocidal or bacteriostatic?
Depends on plasma concentration
151
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
152
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
153
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
154
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
155
Chemical structure of macrolides
Macrocyclic lactone ring to which deoxy sugars are attached
156
Does azithromycin dosing need to be adjusted in dialysis
No
157
In what patients should erythromycin not be given
prolonged QT Porphyria Digoxin toxicity Caution if on warfarin, antiepileptics. immunosuppressants
158
Metronidazole chemically
synthetic imidazole derivitive
159
Metronidazole interactions
Increased anticoagulant effect of warfarin Disulfuram reaction whe alcohol is consumed Prolongs vecuronium
160
Metronidazole vs dialysis
removed by dialysis
161
Aminoglycoside coverage
Gram negative aerobes - E Coli, speudomonas, enterobacter, proteus, klebsiella, serratia Staphylococcus Strep limited No anaerobic activity
162
What combination are aminoglycosides sometimes used in
With Vanc or Beta lactams it will be synergistic
163
Amikacin vs Gentamicin spectrum of activity
Amikacin has less resistance to enzyme inactivation
164
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
165
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
166
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
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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
168
Chemical structure of aminoglycosides
aminocyclitol ring derivative bound to amino sugars
169
Gentamicin preparations
Liquid form for topical use IV form IM Suitable for intrathecal or Intraventricular administrtion
170
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
171
Aminoglycoside monitoring - what is the timing of a trough and a peak level
Trough - immediately prior Peak -1 hour post
172
What effect does haemodialysis have on gentamicin and amikacin
Both removed - in both haemofiltration and dialysis
173
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
174
What is an example of a lincosamide
clindamycin
175
What is the antimicrobial coverage of clindamycin
Gram positive Anaerobic very little gram negative aerobic cover
176
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
177
Clindamycin side effects
Pseudomoembranous colitis and diarrhoea common Fever Rash Eosinophilia
178
Give two examples of tetracyclines
,minoclycine, doxycycline
179
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
180
Tetracyclines interactions
Chelated by milk, calcium and magnesium
181
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
182
Fusidic acid active against
Staph auerues MRSA Staph epidermitis Strep and pneumococci resistant Some gram negatives are sensitive but most resistant
183
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
184
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
185
Fusidic acid side effects
GIT Otherwise well tolerated
186
Tetracycline chemical structure
napthacenecarboxamide deriviative
187
tetratcyline preparations
tablets Syrup for IM injection IV injection with ascorbic acid Ointment
188
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
189
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
190
Tetracyclines in ICU - beware
Raised ICP Increased duration fo action of non depolarising muscle relaxants Incompatible with many drugs pharmaceutically
191
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
192
What antimicrobial agents requrie dose decrease for renal replacement therapy?
aztreonam, acyclovir,zidovudine
193
What antimicorbial agents require more prolonged dosing intervals in the context of renal replacement therapy?
Cephalosporins, teicoplanin, macrolides erythromycin and clarithromycin
194
Both dose and dosing interval require altering for antimicrobial agents in the context of RRT?
Meropenam
195
Linezolid is what type of antibiotic and what chemical structure
Oxazolidinone
196
Linezolid spectrum of activity
Gram postiive organisms - enterococcus, streptococcus, staph, gram postiive anaerobes inclduign clostridium perfingens
197
Linezolid MOA
Inhibits bacterial protein synthesis by bidning to 50S binding subunit preventing initiation complex formation
198
Linezolid toxicity and side effects
Headache LFTs taste alteration GIT Fertility reversibly affected Skina nd bleeding disorders Phelbitis pancreatitis
199
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
200
Linezolid interactions
Reversible non selective MAOI
201
Trimoprim sulfamethoxazole class
antifolate antibiotic
202
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
203
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
204
Bactrim spectrum of acitivty
Staph aureus Haemophilus Moraxella Klebsiella Pneumocytstis pneumonia
205
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
206
Bactrim contraindications
Hypersensitivty Blood dyscrasia Marked renal or hepatic impairment Megaloblastic bone marrow
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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
208
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
209
What are time or MIC dependent killing antibiotics?
Beta lactams Carbepenams Monobactams Linezolid Clindamycin Macrolides
210
Concentration dependent killing antibiotics include?
Aminoglycosides Metronidazole Daptomycin Fluoroquinolones
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Combination of AUC and MIC dependent killing antibiotics are
Fluoroquinolones, azithromycin, tetracyclines, vancomycin, tigecycline, linezolid
212
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
213
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)
214
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
215
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
216
What level above MIC does gentamicin need to reach to have ~90% of potential effect?
8-10x MIC at peak levels
217
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
218
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
219
Organisms intrinsically resistant to meropenam
Stenotrophomonas maltophila Pseudomonas cepacia Enterococcus faecium MRSA
220
List of organisms intrinsiically resistant to glycopeptides
Lactobacillis casei Pediococcus pentosaceus Leuconostoc mesenteriods
221
What is the post antibiotic effect?
Persistent of effect long after serum concentration has fallen below MIC
222
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
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What drugs have a strong post antibiotic effect?
Aminoglycosides Clindamycin Macrolide antibiotics Tetracyclines Rifampicin Quinupristin/dalfopristin
224
Examples of moderate post antibiotic effect
Carbapenems Fluoroquinolones Glycopeptides Linezolid
225
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
226
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
227
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)
228
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)
229
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
230
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.
231
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.
232
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
233
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).
234
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.
235
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
236
Is meropenam active against extended spectrum beta lactamase enzymes?
Yes
237
Carbopenams vs enterocccus?
Imipenem has activity against Enterococcus faecalis, which meropenem lacks.
238
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.
239
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.
240
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.
241
What are carbepenams not active against?
Carbapenems are inactive against MRSA, VRE, Enterococcus faecium, Mycoplasma species, Chlamydia species and Stenotrophomonas maltophilia.
242
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.
243
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.
244
What is an enterobacteriaceae
Enteric gram negative bacilli
245
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
246
Why is ceftriaxone bad in neonates
Highly protein bound Kicks bilirubin off albumin increasing the risk of kernicterus
247
What does ceftriaxone precipitate with
calcium
248
How is ceftazidime different to ceftriaxone
Extended spectrum including pseudomonal activity Both inactivated by ESBL
249
How is cefepime different to ceftriaxone?
Extended spectrum including pseudomonal activity Both inactivated by ESBL Cefepime is bettyer for gram positive than ceftazidime
250
Ceftaroline is special why?
Acts against MRSA
251
Phenoxymethypenicillin absorption is blocked by?
Food
252
Phenoxymethypenicillin vs benpen
Less intrinsically active Same spectrum
253
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.
254
FLucloxacillin side effect
Cholestatic jaundice, more likely if old or polonged use . Can occur as long as 6 weeks after
255
Dicloxacillin side effects vs flucloxacillin
Less cholestatic jaundice - less irreversible hepatotoxicity More interstitial nephriits
256
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
257
Amoxicillin vs ampicillin
Same spectrum of acitivty, same pharmacodynamics Orally has a better absorption, less affected by food IV they are equivalent
258
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.
259
If treating pseudonomas with tazosin what specifically must be done?
6 hourly dosing
260
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.
261
Which organ system does daptomycin have poor penentration into?
Lungs - inactvativated by pulmonary surfactant
262
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).
263
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).
264
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).
265
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.
266
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
267
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.
268
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.
269
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.
270
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).
271
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).
272
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.
273
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.
274
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.
275
Norfloxacin spectrum indications
Multidrug resistant cystitis and acute ifnectious diarrhoea
276
Why are fluoroquinolones not used in children
adverse ffect in cartilage development based on animal studies - if required can be used
277
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
278
What are the 3 groups of patients in whom aminoglycosdies are contraindicated?
Toxicity previously - vestibular or auditory Hypersensitivty (rare) Myasthenia gravis
279
Why can aminoglycosides be used at dosing so much less frequent than their half life would suggest?
Post antibiotic effect
280
Do aminoglycosides cause C diff?
No
281
Which infections are aminoglycosides synergstic with cell wall active drugs?
Enterococcal Streptococcal
282
Is nephrotoxicity from aminoglycosids reversible?
Generally yes
283
Over what duration can gentamicin be infused?
3-5 minutes slow IV injection safe
284
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
285
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
286
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.
287
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
288
How often does gentamicin concentration monitoring need to be performed?
48 hourly
289
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
290
Nephrotoxicity risk in aminoglycoside use is found in which dosing regimen?
ANything >1 dose per day increases the risk Prolonged Tx >5 days
291
WHat predicts aminoglycoside vestibular and auditory toxicity?
Not predicted by p;lasma concentration Can occur early or weeks after
292
What symptoms are most commonly seen in aminoglycoside vestibular toxicity
Gait ataxia/imbalance Oscillopsia - bouncing vision Blurring vision with ehad movement Hearing loss
293
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
294
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
295
What type of reaction is red man syndrome?
Histmaine mediated non allergic reaction
296
Loading dose physiology for vancomycin?
Loading dose achieves therapeutic concentration more quickly b 12 hours - no evidence it improves clinical or microbiological outcomes
297
Vancomycin weight based dosing is based on which weight?
actual body weight
298
AUC for vancomycin dosing has what advantages?
Similar rates of clincial success Reduced nephrotoxicity Lower daily doses Lower trough concentrations
299
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
300
Cefepime Vd
0.2L/kg
301
Cefepime clearance
85% renal unchanged
302
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
303
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
304
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
305
Aztreonam side effects
Generally well tolerated
306
Aztreonam pharmacokinetics
Nil absorption 50% protein bound Minimally metabolised
307