Antimicrobia Therapy Flashcards by ian rowley

What are the four main targets for Antimicrobials

Cell wall synthesis
Cell membrane permeability
Protein synthesis
Nucleic acid synthesis

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Characteristics of bacterial cell wall
Difference in gram pos and neg

Stops lysis in hypotonic environment
Made of n acetyl glucosamine, acetyl muramic acid and a polypeptide with multiple cross links
Several layers thick in gram neg
Hundereds of layers think in gram pos

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Why do antifungals cause severe side effects in high doses

Target sterols which are present in both fungal and human cell membranes

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How do antibiotics that effect protein synthesis avoid damaging human cells? How do they differ between bacteriostatic and bacteriosidal

Bacteria have different subunit size (50 and 30s vs human 60 and 40s)
Those that reversibly inhibit protein synthesis - static
Those that bind to 30s - cidal

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Examples of antibiotics effecting nucleic acid synthesis and how

Rifampicin - inhibits dna dependant rna polymerase
Quinolones - inhibit dna synthesis and disrupt coiling
Aciclovir - block active site of enzymes on dna stoping synthesis

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Mechanisms of aquisition of Antimicrobial resistance

Spontaneous mutation
Plasmid transfer
Chromosome transfer
Bacteriophages
Conjugation

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Mechanisms of Antimicrobial resistance

Enzymatic destruction - eg beta lactamase
Altered target site - eg mRNA altered penicillin binding proteins, VRE altered peptidoglycan wall
Protection of target site - quinolone resistance by protecting dna gyrase
Overproduction of target - sulphonamides and trimethoprim resistance
Bypass metabolic pathways - enterococci utilising folate from difference source resisting trimethoprim
Bind up abx
Decreased permeability - pseudomonas blocking abx Ingres though pores
Abx efflux - eg quinolone and macrolide resistance

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What is MRSA resistant to

Meticillin
Flucloxacillin
Cephalosporins

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Groups of beta lactam abx

Penicillins
Cephalosporins
Carbapenems
Monobactams,

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How do beta lactams work

Bind to penicillin binding proteins stopping cell wall synthesis
Osmotic lysis occurs
Additionally cause synergistic reaction with other classes of abx as increase permeability of cell thus other abx can enter more easily

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Proportion of people with penicillin allergy and anaphylaxis
Mortality of penicillin anaphylaxis

Allergy 1-10%
Anaphylaxis 0.05%
Mortality 10%!

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Side effect of penicillins in very high doses eg for meningitis

Convulsions

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Spectrum of benzylpenicillin
Route
Distribution

Mainly gram positive, anaerobes and certain gram negative cocci
Given parenterally
Widely distributed, only through bbb if inflamed

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Spectrum of amoxicillin
Uses

Similar to benzylpenicillin but with some more gram neg such as haemophius influenza and enterococci
LRTI and faecal strep infections

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Spectrum of flucloxacillin
Effect of beta lactamase
Distribution
Side effects

Unaffected by beta lactamase but narrower spectrum than benpen
Highly protein bound so limited distribution
Can cause cholestatic jaundice and hepatitis

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Half lives of benpen, Amos and fluclox

Benpen 30 mins
Amox 1 hr
Fluclox 45 mins

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Spectrum of pip taz vs amoxicillin
Side effects

Also cover apps pseudomonas
Due to Tazobactam also active agains beta lactamase producing organisms
Sodium overload

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Side effects of coamoxiclav

Choelostatic jaundice and hepatitis

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Examples of cephalosporins and generation

Cephalexin 2nd
Cefuroxime 2nd
Cefotaxime 3rd
Ceftriaxone 3rd
Cefixime 3rd
Ceftazidime 3rd
Cefpirome 4th
Ceftarline 5th

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Spectrum of cephalexin
Oral bioavailability
Excretion and t1/2

Gram positive cocci and some enterobacteria
Bioavailability nearly 100%
Excretion in urine, t1/2 50mins

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Spectrum of cefuroxime
Bioavailability
Excretion and half life

More active than cephalexin in enterobacteriaceae and h influenzae
Not absorbed orally, must be given iV
Excreted in urine with t1/2 80mins

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Spectrum of cefotaxime
Metabolism
T1/2

Large spectrum including many gram negative and against penicillin resistant strains
Limited effect on anaerobes, minimal effect on pseudomonas
Metabolised and renally excreted
80mins

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Which antibiotic must be added to cover listeria meningitis

Amoxicillin

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Differences between ceftriaxone and cefotaxime

Ceftriaxone has very similar spectrum but much longer t1/2 allowing for outpatient iV therapy

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Examples of carbapenems

Ertapenem Imipenem Meropenem

How do carbapenems differ in mechanism from other beta lactams Consequence

Specifically target pbp2 resulting in faster bacterial death and less endotoxin release

Why can carbapenems have a long dose interval despite relatively short t1/2

They continue to have a prolonged inhibition of bacterial growth even when concentration fallen beneath minimum inhibitory concentration

Adsverse effects of carbapenems

Neutropenia Neurotoxicity

Spectrum of imipenem Meropenem

Huge, nearly all gram neg and pos including anaerobes Poor intracellular penetration limits action agains intracellular infections Meropenem Is similar but more against gram neg and less against gram pos

Example of a monobactam abx Spectrum

Astreonam Gram neg aerobic

Cross sensitivity between penicillin and aztreonam for allergy Why

Little (but use with caution) Only has one beta lactam ring not 2

Example of glycopeptide abx How do they work Spectrum - why

Teicoplainin, vancomycin Prevent bacterial wall synthesis thus are slowly bacteriocidal Only effects gram positive, large and polar thus not able to penetrate outer membrane of gram neg

T1/2 of vancomycin

6-8hrs

When to monitor vancomycin;

Pre dose

Adverse effects of vancomycin

Hypersensitivity, nephrotoxicity, ototixicity, neutropenia, red man syndrome (histamine release on rapid infusion)

Symptoms and course of red man syndrome

Itching, causing, angioedema, hypotension, tachycardia NO bronchospasm Normally resolves within 1 hr of stoping vancomycin infusion

Half life of teicoplainin Why

47 hrs Heavily protien bound

Examples and mechanism of Aminoglycosides

Gentamicin, streptomycin, amikacin Bind to 30s sub unit inhibiting protein synthesis - causes cell membrane leaking and are bacteriocidal

Mechanisms of resistance to Aminoglycosides

Altered binding site Reduced uptake Aminoglycosides modifying enzymes

How can risk of ototoxicity and nephrotoxicity be reduced with Aminoglycosides

Monitor levels Slow iV injection

Is Aminoglycosides mediated nephro and otoxicity reversible

Nephro is reversible Oto is not

Tissue penetration of gentamicin

Poor

Oral bioavailability of gentamicin

Special bug treated with amikacin or streptomycin

Example and mechanism of macrolides

Clarithromycin, erythromycin Bind to 50s subunit inhibiting protein synthesis probably stopping translocation

Mechanism of resistance to macrolides

Altered binding site Drug inactivation Efflux of drug

Effect of renal and hepatic disease on erthyromycin

Renal little limpact (t1/2 from 1.5 to 5 hrs) Hepatic failure causes accumulation as it is mainly inactivated and excreted in bile

Side effects of ertythromycin

GI upset Hepatotoxicity Ototoxicity Cardiotoxicity Intrahepatic choleostasis

Examples and mechanism of tetracyclines

Doxycycline, tetracycline Bind to 30s and prevent binding of tRNA Prevents protein synthesis and is bacteriostatic

Methods of resistance to tetracyclines

Decreased cell entry Increased efflux Ribosomal protection Checmial modicaiton

Infections that are best treated with tetracyclines

Chlamydia Rickettsial Q fever Cholera Lymes disease Anthrax Plague

What dietary intake impairs tetracycline absorption

Best in fasted stated Impaired by ferrous ions

Side effects of tetracycline

GI Photosensitivity Dental discolouration in children Hepatotoxicity Nephrotoxicity Leukopenia Thrombocytopenia Bacterial and fungal superinfections Nephrotoxicity - aggregation if existing , nephritis, nephro genie diabetes insipidus

How does chloramphenicol work Spectrum

Binds to 50s subunit thus bacteriostatic At high concentrations bacteriocidal against h influenza and n meningitisis Broad spectrum including mycobacteria

Absorption and distribution of chloramphenicol

Well absorbed Widly distributed inc into CNS and eye

Adverse effects of chloramphenicol

Bone marrow suppression Grey baby syndrome - myocardial depression and circulatory collapse in prem neonates Optic neuritis Ototoxicity

How is chloramphenicol given

Usually topical eg into eye Rarely systemic (meningitis with proven severe penicillin allergy)

Mechanism of fusidic acid Spectrum

Inhibit bacterial cell protein synthesis Active vs most gram positive bacteria and gram neg cocci

Why is fusidic acid good for spots etc

Penetrates pus, abscesses and wound exudate well

Side effects of fusidic acid

Abnormal liver function Thrombophlebitis

Examples and mechanism of quinolones

Ciprofloxacin, levofloxacin, moxifloxacin Inhibit dna gyrase which causes supercoiling of dna

General spectrum of quinolones

Good vs most gram negative

Hepatic effects of Ciprofloxacin

Inhibits cyp450

Class of metronidazole Mechanism

Nitroimidazole Destroys dna, only do this when reduced by the very low redox values in anaerobic bacteria and Protozoa

Effect of metronidazole on other substances

Disulfarim like reaction with alcohol Potentiates warfarin Impairs phenytoin and lithium clearance Interferes with OCP and digoxin

How does rifampicin work Spectrum

Inhibit bacterial dna dependant rna polymerase stopping transcription Particularly against gram pos and mycobacteria Good intracellular penetration so active vs legionella and Q fever

Adverse effects of rifapicin

GI Hepatotoxicity Thrombocytopenia Renal failure Induces metabolism of ocp, anticoagulants, digoxin Red urine

Mechanism of trimethoprim

Inhibits dihydrofolate reductase thus inhibiting dna synthesis

Mechanism of sulphonamides

Inhibit folic acid synthesis at an earlier stage than trimethoprim

What is cotrimoxazole

Trimethoprim with a sulphonamide

Side effects of sulphonamides

Renal damage Rashes Bone marrow depression Yphypersisitivity and vasculitis

What are the antimycobacterials

Ethambutol, isoniazid, pyrazinamide