Antibiotics back to basics - zorgaanbod...¢  Antibiotics...

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Transcript of Antibiotics back to basics - zorgaanbod...¢  Antibiotics...

  • Antibiotics – back to basics

    Petra Schelstraete

    Kinderinfectieziekten UZ Gent

    LOK groep 01/12/2012

  • To be discussed

    • History

    • Basic principles of AB therapy and AB/host/infective organism interaction

    • AB classes + use

  • Antibiotics: Introduction

    • Antibiotics = a natural substance produced by a micro-organism to kill another

    • Anti-infectives/Anti-microbrial = any agent (natural or synthetic) that kills pathogens (microbes)

    • Antibiotics exploit the differences between bacterial and human cells: drug is more toxic to the infecting organism than to the host

  • Antibiotics: History

    • Alexander Fleming observed antibiosis against bacteria by a fungus of the genus Penicillium in 1928

    • Florey and Chain succeeded in purifying the first penicillin in 1942

    • Chain, Florey and Fleming: Nobel Prize in Medicine in 1945

  • Antibiotics: History

  • Bacteria

  • Gram-positieve kokken

    Staphylococcus aureus

    Staphylococcus epidermidis en andere coagulase-negatieve stafylokokken

    Staphylococcus saprophyticus

    Streptococcus pyogenes (groep A, β-hemolytisch) en groepen C en G

    Streptococcus agalactiae (groep B, β-hemolytisch)

    Streptococcus viridans

    Streptococcus bovis groep D

    Peptostreptococcus (anaërobe streptokok)

    Streptococcus pneumoniae (pneumokok)

    Enterococcus species groep D

    Gram-positieve staafjes

    Aërobe Bacillus anthracis

    Corynebacterium diphtheriae

    Listeria monocytogenes

    Anaërobe Clostridium difficile (pseudomembraneuze colitis)

    Clostridium perfringens (welchii)

    Clostridium tetani

    Gram-negatieve kokken

    Neisseria gonorrhoeae (gonokok)

    Neisseria meningitidis (meningokok)

    Moraxella catarrhalis

    Gram-negatieve staafjes

    Aërobe

    Enterobacteriën

    Citrobacter species

    Enterobacter species

    Escherichia coli

    Klebsiella pneumoniaeProteus mirabilis (indol- negatief)Providencia rettgeri, Morganella morganii, Proteus vulgaris en Providencia stuartii

    Salmonella Typhi en andere salmonellae

    Serratia species

    Shigella species

    Yersinia enterocolitica

    Andere Gram-negatieve staafjes

    Acinetobacter speciesBordetella pertussis (kinkhoest)Brucella (brucellose)Calymmatobacterium granulomatisFrancisella tularensis (tularemie)Gardnerella vaginalisHaemophilus ducreyi (ulcus molle)Haemophilus influenzaeLegionella pneumophilaPseudomonas aeruginosaVibrio cholerae

    Anaërobe

    Bacteroides fragilis en non-fragilis

    Fusobacteriën

    Prevotella

    Porphyromonas

  • AB effect: micro-organism and host

    • Micro-organism: – Bactericidal/bacteriostatic effect

    • Host : side effects – Diarrhea, dental staining

    – Toxic/related to dose: eg AG and nefrotoxicity

    – Toxic/not related to dose: eg hepatitis

    – Allergic: eg anaphylaxis in penicillin allergic patients

    – Effect on natural ecosystem : eg intestinal flora

  • AB effect: sensitive vs resistant organism

    • Resistance: the inability to kill or inhibit the organism with clinically achievable drug concentrations

    • Resistance may be innate (naturally resistant)

    • Resistance may be acquired - mutation - acquisition of foreign DNA

    • Resistance and MIC

  • Antimicrobial resistance: contributing factors

    • inadequate levels of antibiotics at the site of

    infection

    • too low dosage of AB

    • too short duration of treatment

    • overwhelming numbers of organisms

    • overuse / misuse of antibiotics

  • Famous resistant bugs

    • MRSA

    • VISA/VRSA

    • VRE

    • ESBL

  • AB effect: PK/PD

    • Pharmacokinetics: what the body does to the drug

    • Pharmacodynamics: what the drug does to the body.

  • GI Absorption

    Blood

    Renal

    excretion

    Pharmacokinetics

    Extracellular

    compartment

    of tissues

    Oral ingestion

  • Drug Pharmacokinetics in blood Se

    ru m

    A n

    ti b

    io ti

    c C

    o n

    ce n

    tr at

    io n

    0

    2

    4

    6

    8

    10

    0 1 2 3 4 5 6 7 8

    Time (hours)

    (m cg

    /m L)

    9 10 11 12

    Dose Dose

  • Effecten anti-infectieus middel: farmakokinetiek- farmacodynamiek

    • Relatie antibioticum tot MIC

    MIC

    conc

    tijd

    Piekconcentratie/MIC

    Duur concentratie boven MIC (time above MIC)

  • Concentratie-afhankelijke AB

    • Piekconc/MIC zo hoog mogelijk: volledige dagdosis in 1 gift (bv. aminoglycosiden)

    MIC

    conc

    tijd

  • Tijds afhankelijke AB

    • ‘time above MIC’ zo lang mogelijk: dagdosis opdelen in frequente giften (bv. betalactam AB)

    MIC

    conc

    tijd

  • Antibiotic groups

    • Beta lactam antibiotics

    – Penicillins

    – Cephaolsporins

    – Carbapenems

    – monobactams

    • Aminoglycosides

    • Macrolides/lincomycins

    • Sulfonamides

    • Fluoroquinolones

    • Glycopeptides

    • Tetracyclins

    • Oxazolidinones

    • Tuberculostatics

    • Urinary antiseptics

  • Classification of antibiotics • Chemical origin

    – Natural/semisynthetic/synthetic

    • Spectrum of activity – Broad vs narrow spectrum

    • Biological activity – Bactericidal/bacteriostatic

    • Pharmacodynamic properties – Time vs concentration dependent killing of bacteria

    • Mechanism of action

  • Mechanisms of action

  • AB that inhibit cell wall synthesis

    • Beta lactam antibiotics

    – Penicillins

    – Cephalosporins

    – Carbapenems

    – Monobactams

    • Glycopeptides

    BACTERICIDAL

  • Small spectrum penicillins

    – Beta lactamase (penicillinase) sensitive

    • peni V, peni G, benzathinepenicilline

    • Good activity to streptococci , no gram neg (only Neisseria), some anaerobic activity (peni G)

    • Tonsillitis, pneumonia, meningococcal meningitis

    – Beta lactamase (penicillinase) insensitive/antistaphylococcal penicillins

    • (Flu)(cl)oxacillin

    • Good gram pos activity

    • Infections of skin, bone

  • Broad spectrum penicillins (1)

    • Aminopenicillins

    – Amoxicillin, ampicillin

    • Gram pos (excl S. aur), some gram neg (beta lactamase neg), some anaerobic activity

    • Respiratory tract infections (ENT+Lung)

    – Amoxicillin + clavulanic acid

    • Good gram pos (incl S. aur) and gram neg and anaerobic activity

    • Respiratory infections, abdominal infections

  • Broad spectrum penicillins (2)

    • Carboxypenicillins

    – Temocillin

    – good gram neg activity (excl P. aeruginosa), no gram pos, no anaerobic activity

    • Acylureidopenicillins/antipseudomonas pencillins

    – Piperacilline+tazobactam

    – good gram pos and gram neg (incl P. aeruginosa) and anaerobic activity

    – Hospital infections lung, abdomen

  • Cephalosporins (1)

    • 1st generation – Mainly gram pos, some gram neg and anaerobic

    • 2nd generation – Weaker gram pos, better gram neg, some anaerob

    • 3rd generation – Excellent gram neg, some gram pos and anaerob

    • 4th generation – Excellent gram neg, good gram pos, some

    anaerob

  • Cephalosporins (2)

    • 1st generation: Cefadroxil, cefazoline

    – Tonsillitis, peri-operative prophylaxis

    • 2nd generation: Cefaclor, cefuroxime

    – Respiratory tract infections

    • 3rd generation: Cefotaxim, Ceftriaxone, Ceftazidim

    – Sepsis

    – Cave only ceftazidim active to P. aeruginosa

    • 4th generation: cefepime

    – severe hospital infections

  • carbapenems

    • Imipenem, meropenem

    • Good gram neg, gram pos and anaerobic activity

    • NO: MRSA, MRSE, S. maltophilia, B. cepacia

    • Life threatening polymicrobial infections

    • CAVE: imipenem and convulsions

    • CAVE: carbapenems and secondary yeast infections

  • monobactams

    • Aztreonam

    • Good gram neg (also P. aeruginosa), no gram pos,no anaerobic activity

  • glycopeptides

    • Vancomycin, teicoplanin

    • good gram pos, some anaerobe activity

    • Infections caused by MRSA, ampi R enterococcen, methi R CNS

    • Cave red man syndrome

  • Mechanisms of action

  • Inhib