Antibiotics: all you need to know

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Antibiotics all you need to know

• Anne Tonkin
• Clinical Pharmacologist

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Objectives

• Introduction to antibiotics
• brief history
• problem of resistance
• Principles of antibiotic use
• the antibiotic creed MINDME
• Antibiotic drug groups
• mechanisms of action
• spectrum of activity and common uses
• Putting it together what you need to know
• principles and information sources

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What are antibiotics?

• Drugs that inhibit growth of bacteria without
  affecting us
• attack prokaryotic cell processes
• do not affect eukaryotic cells
• human, fungal, parasitic
• do not affect viruses

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Differences between bacteria and us
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Them Us

• Prokaryotic cells
• small
• free-floating DNA
• no organelles
• 70S ribosomes for protein synthesis
• cell wall made of peptidoglycan

• Eukaryotic cells
• larger
• DNA enclosed within membrane-bound nucleus
• membrane-bound organelles with specific runctions
• 80S riboxomes for protein synthesis
• no cell wall

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Introduction to antibiotics

• Brief history
• 1495 mercury
• used to treat syphilis
• 1630 quinine (cinchona bark)
• used for malaria (South America) widely used
  from 1820
• 1889 concept of antibiosis
• 1910 arsenical compound for syphilis (Ehrlich)
• magic bullets
• 1929 penicillin discovered (Fleming)
• 1935 sulfonamides (Domagk)
• 1940 penicillin developed (Florey and Chain)
• used in millions during World War II and after
• 1940-1970 development of many new antibiotics
• new discoveries, synthetic developments of old
  molecules

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Impact

• Effective treatment of infectious diseases for
  first time
• Contribution to greatly increased life
  expectancyduring 20th century

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Development of penicillin

• Discovery
• chance observation by Fleming (1929)
• did not believe therapeutic agents were possible
• Development
• by Chain and Florey (early 1940s)
• large scale use in 1943 (World War II)

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The beginning Penicillin
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Penicillin action on E. coli
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1
2
4
5
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1 ordinary appearance 2-4 globular extrusions
emerge 5 rabbit-ear forms 6 Ghost form
For lecture only
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Sources of antibiotics

• 1940-1970
• most derived from bacteria
• 1970s onwards
• ongoing search for more natural products
• major effort in laboratories to adapt old ones
  synthesize new ones
• problem of antibioticresistance

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Testing for Susceptibility

• Tube dilution method
• Minimal inhibitory concentration (MIC)
• minimum concentration of drug required to inhibit
  the growth of the organism in the test tube
• Disk diffusion method
• Zone of inhibition (ZOI)
• larger the ZOI, the more sensitive the organism
  to the drug impregnated in the disk ZOI
  correlates with MIC

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Antibiotic Resistance

• Antibiotics apply selection pressure
• susceptible organisms removed from population,
  resistant organisms thrive
• Widespread use ofantibiotics
• selects for mutantswith resistance mechs
• leads to more resistance

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Mechanism of Selection for Resistance

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The Balance of Antibiotic Use

• Use when needed
• to save a life or limb or significant morbidity
• Avoid too much use
• that might promote development of resistance
• Currently, resistance is continuing to spread
• many bacteria contain plasmids
• carry genes conferring resistance to one or more
  antibiotics
• can be spread from one organism to another
• e.g. plasmids found in E. coli contain a gene
  called bla
• encodes an enzyme, ß-lactamase, that breaks down
  molecules with ß-lactam structure (penicillins,
  cephalosporins)

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Principles of Antibiotic Use
M Microbiology guides therapy wherever possible (tests or resistance patterns)
I Indications should be evidence-based only where benefit has been demonstrated
N Narrowest spectrum required choose based on likely organism
D Dosage appropriate to site and type of infection
M Minimise duration of therapy ideally less than 7 days
E Ensure monotherapy in most situations
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Implementing principles

• diagnosis
• of condition and most likely organism
• information
• about spectrum of activity of antibiotics
• about current local resistance patterns of most
  likely organisms
• implementation
• alternatives for patients who dont need
  antibiotics (information see NPS website)
• right drug at right dose for those who do

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Is an antibiotic needed?

• Most viral and minor bacterial diseases
• are self-limiting
• do not benefit from antibiotic use
• Unnecessary use
• exposure to ADRs (e.g, flucloxacillin)
• contributes to spread of resistance
• leads to unnecessary costs for no benefit

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Diagrammatic representation of the results of
treatment related to specific chemotherapy
Patients with normal immunity and uncomplicated
mild to moderate infections
Patients with serious life-threatening infections
from lecture by BC Yang
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Choice of antibiotic

• Consider
• spectrum of activity related to likely organism
• base on LOCAL data on likely organism and
  resistance patterns (e.g. use TGAntibiotics)
• safety including ADRs and interactions
• relative costs
• potential for selection of resistant organisms
• patient factors
• history of allergy and other ADRs
• elderly changes in PK, sensitivity to ADRs

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Antibiotic drug groups

• Major commonly used groups
• Beta-lactams
• penicillins, cephalosporins
• Macrolides
• erythromycin, roxithromycin, azithromycin
• Aminoglycosides
• gentamicin, tobramycin
• Sulfonamides
• Quinolones
• Tetracyclines

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Other antibiotic drug groups

• Less commonly used
• Antibacterial
• Lincosamides
• Linezolid
• Nitrofurantoin
• Polymyxins
• Rifamycins
• Antimycobacterial drugs
• Antifungal drugs
• Antiviral drugs

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Mechanisms of action

• Selective toxicity
• kill bacteria but leave host unharmed
• exploit differences between bacterial cells and
  host cells
• can be biochemical (e.g. structure of ribosome,
  need for metabolic pathways for folate synthesis)
  or morphological (e.g. presence of cell wall)
• Effects
• bacteriocidal kills bacteria
• bacteriostatic inhibits bacterial growth
• allows normal host defences to deal with infection

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Mechanisms of action
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Beta-lactams

• Large group
• includes penicillins, cephalosporins, carbapenems
  and monobactams
• Mechanism
• bacteriocidal interfere with cell wall
  biosynthesis
• Resistance mechanisms
• beta-lactamase (breaks down drug molecule)
• penicillins often combined with beta-lactamase
  inhibitor (clavulanic acid)

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Penicillins

• Spectrum of activity varies
• narrow mainly against GP organisms
• but inactivated by beta-lactamases
• Examples
• benzylpenicillin (pen G) parenteral only
• phenoxymethylpenicillin (pen V) orally active
• narrow with antistaph activity
• stable to beta-lactamasees
• dicloxacillin, flucloxacillin
• emergence of MRSA resistant to these drugs

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Penicillins

• Moderate spectrum
• GP (but beta-lactamase sensitive), and more
  activity against some GNs (e.g. E.coli)
• drugs of choice for enterococcal infections
• amoxycillin (oral or iv), ampicillin (iv)
• Broad spectrum
• penicillins with beta-lactamase inhibitor
• e.g. Augmentin amoxycillin clavulanic acid
• additional adverse effects and costs associated
  with clavulanic acid
• penicillins with antipseudomonal activity
• piperacillin and ticarcillin (need high doses)

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Cephalosporins

• Moderate spectrum
• some GP and some GN organisms
• GP strep and staph, incl beta-lactamase
  producing not enterococci
• GN most E.coli, Klebsiella not Enterobacter or
  Pseudomonas
• examples cephalexin, cephazolin
• Moderate spectrum with anti-Haemophilus
• cefuroxime, cefaclor

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Cephalosporins

• Broad spectrum (only in hospitals)
• most enteric GN rods, incl Pseudomonas
• less active against Staph, anaerobes
• no useful activity against enterococci or MRSA
• examples
• cefotaxime, ceftriaxone
• ceftazidime, cefepime

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Other beta-lactams

• Carbapenems (imipenem, meropenem)
• very broad-spectrum (GN, Pseudomonas, anaerobes,
  Staph)
• inactive against MRSA
• widespread use linked to resistant organisms
  (MSRA, VRE, multiresistant GN organisms)
• should be restricted to specific situations
• Monobactams (aztreonam)
• inactive against GP or anaerobes
• highly active against most GNs incl Pseudo

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Macrolides

• Mechanism
• inhibit protein synthesis (bacterial ribosomes
  different)
• Spectrum
• wide, incl GP and GN cocci, Legionella,
  Mycoplasma, Chlamydia, anaerobes
• not enteric GN rods
• Major indications
• community-acquired respiratory infections
• Examples
• erythromycin, clarithromycin (inhibit CYP450)
• azithromycin, roxithromycin (longer half-lives)
• ADRs mainly GI, QT prolongation

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Aminoglycosides

• Spectrum very variable, dep on location
• need to use local susceptibility patterns
• Mechanism
• inhibit protein synthesis
• rapidly bactericidal to GN organisms
• Examples
• gentamicin, tobramycin
• Major indication
• severe gram-negative sepsis
• only effective intravenously

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Aminoglycosides

• Toxicity
• all are nephrotoxic and ototoxic
• once daily administration
• effective, less likely to cause nephrotoxicity
• monitoring of blood levels is very important

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Sulfonamides trimethoprim

• Mechanism
• antimetabolites inhibit folate synthesis
• Sulfonamides
• on their own have very limited role
• with trimethoprim (cotrimoxazole)
• used for prophylaxis of PCP in HIV infection
• treatment of community-associated MRSA and other
  unusual infections
• Trimethoprim alone
• first line drug for uncomplicated UTI

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Quinolones

• Examples
• ciprofloxacin, moxifloxacin, norfloxacin
• Mechanism
• inhibit DNA synthesis/replication
• Spectrum and indications
• nor urinary and GI infections
• cipro wider spectrum against GN bacteria inc
  Haemophilus, enteric GNs, Pseudomonas, GN cocci,
  Legionella
• should be reserved as second-line
• cost and avoidance of resistance

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Tetracyclines

• Spectrum
• broad, includes GP and GN bacteria, Chlamydia,
  Mycoplasma etc
• Mechanism
• inhibit protein synthesis
• usually bacteriostatic
• Indications
• dermatology acne, other skin conditions
  (anti-inflammatory effects)
• Mycoplasma pneumonia, H.pylori

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Tetracyclines

• Adverse effects
• permanent staining of teeth contraindicated in
  early pregnancy, children up to age 12
• GI effects very common
• photosensitivity
• Example doxycyline
• often used when penicillins contraindicated

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Putting it all together What you need to know

• Know the basic principles (MINDME)
• Know when NOT to use antibiotics
• most community-presenting minor infections
• Know some drugs well
• penicillins, cephalosporins, aminoglycosides,
  trimethoprim
• Know where to get LOCAL information when you need
  it
• Therapeutic Guidelines
• hospital guidelines

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Prescribing in USA
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Principles of Antibiotic Use
M Microbiology guides therapy wherever possible (tests or resistance patterns)
I Indications should be evidence-based only where benefit has been demonstrated
N Narrowest spectrum required choose based on likely organism
D Dosage appropriate to site and type of infection
M Minimise duration of therapy ideally less than 7 days
E Ensure monotherapy in most situations