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

rum

An

tib

ioti

c C

on

cen

trat

ion

0

2

4

6

8

10

0 1 2 3 4 5 6 7 8

Time (hours)

(mcg

/mL)

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

Inhibition of protein synthesis

• Macrolides, lincosamides

• Aminoglycosides

• Tetracyclins

• Fluoroquinolones

BACTERIOSTATIC (ML,LC)

BACTERICIDAL (AG, TC, FQ)

macrolides

• Azithromycin, clarithromycin, erythromycin, roxithromycin

• Gram pos and atypical organisms ( Mycoplasma

Chlamydia, Legionella), some gram neg and anaerobic activity

• Respiratory infections caused by atypical organisms and B. pertussis

lincomycins

• clindamycin

• Gram pos and anaerobic activity

• Bone infections

• CAVE: pseudomembranous colitis

aminoglycosides

• Amikacin, gentamycin, tobramycin

• Excellent gram neg, some gram pos (no streptococci), Mycobacteria

• Severe hospital infections: sepsis, endocarditis, pyelonephritis, pneumonia

• Synergistic action with beta lactam AB

• CAVE never monotherapy!

• Toxicity:

– Kidney: reversible

– Middle ear: irreversible

• ODD: less nefrotoxicity

fluoroquinolones

• Ciprofloxacin, (levofloxacin, norfloxacin, ofloxacin)

• Good gram neg and atypical, some gram pos and anaerobic activity

• Cystic fibrosis, urinary tract infection caused by P. aeruginosa

• Toxic effect on cartilago: not confirmed in human studies

Mechanisms of action

Inhibition of metabolic pathways

• Trimethoprim/Sulfomethoxazole

• Inhibition of folic acid synthesis

• Bacteriostatic, combination bactericidal

• gram neg and gram pos activity

• Urinary tract infections, Pneumocystis jiroveci, respiratory infections

sulfonamides

• Bacteriostatic/ combination bactericidal

• Inhibition of bacterial folic acid synthesis

Most appropriate AB therapy: THE CHOICE

• Micro-organisms must be sensitive

• AB must be able to reach site of infection

– PK/PD dynamics

• MIC/MBC

• Time dependent vs concentration dependent killing

• Minimal side effects

• Minimising risk of development of resistance

How to avoid/overcome AB resistance

• AB:

–Alter structure of AB (cephalosporins) –Add beta lactamase inhitor

• High dosage of AB “dead bugs dot not mutate”

• Restrictive use of AB –Guidelines – Switch to smaller spectrum AB according to

microbiological results • Hygienic measures to avoid transfer of

organisms

Bactericidal vs bacteriostatic

Beta lactamases

• Production of beta lactamase most important resistance mechanism to beta lactam antibiotics

• Beta lactamase production in both gram negative (e.g. E. coli, K. pneumoniae, P. mirabilis) and gram positive bacteria (S. aureus, B. fragilis)

• Can be overcome by addition of beta lactamase inhibitor to antibiotic (e.g. clavulanic acid, tazobactam)

What additional bugs do they cover?

• S. aureus

• H. influenzae

• Neisseria sp.

• Bacteroides fragilis

• E. coli and Klebsiella

• Not better for Pseudomonas or Enterobacter