Antimicrobial Agents

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Antimicrobial Agents

• Martin Votava
• Olga Kroftová

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Overview

• If bacteria make it past our immune system and
  start reproducing inside our bodies, they cause
  disease.
• Certain bacteria produce chemicals that damage or
  disable parts of our bodies.
• Antibiotics work to kill bacteria.Antibiotics are
  specific to certain bacteria and disrupt their
  function.

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What is an Antibiotic?

• An antibiotic is a selective poison.
• It has been chosen so that it will kill the
  desired bacteria, but not the cells in your body.
  Each different type of antibiotic affects
  different bacteria in different ways.
• For example, an antibiotic might inhibit a
  bacteria's ability to turn glucose into energy,
  or the bacteria's ability to construct its cell
  wall. Therefore the bacteria dies instead of
  reproducing.

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Antibiotics

• Substances produced by various species
• of microorganisms bacteria, fungi,
  actinomycetes- to suppress the growth of other
  microorganisms and to destroy them.
• Today the term ATB extends to include synthetic
  antibacterial agents sulfonamides and quinolones.

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History

• The German chemist Paul Ehrlich developed the
  idea of selective toxicity that certain
  chemicals that would be toxic to some organisms,
  e.g., infectious bacteria, would be harmless to
  other organisms, e.g., humans.
• In 1928, Sir Alexander Fleming, a Scottish
  biologist, observed that Penicillium notatum, a
  common mold, had destroyed staphylococcus
  bacteria in culture.

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Sir Alexander Fleming
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Flemings Petri Dish
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Zone of Inhibition

• Around the fungal colony is a clear zone where no
  bacteria are growing
• Zone of inhibition due to the diffusion of a
  substance with antibiotic properties from the
  fungus

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History

• Penicillin was isolated in 1939, and in 1944
  Selman Waksman and Albert Schatz, American
  microbiologists, isolated streptomycin and a
  number of other antibiotics from Streptomyces
  griseus.

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Susceptibility vs. Resistanceof microorganisms
to Antimicrobial Agents

• Success of therapeutic outcome depends on
• Achieving concentration of ATB at the site of
  infection that is sufficient to inhibit
  bacterial growth.
• Host defenses maximally effective MI effect is
  sufficient bacteriostatic agents (slow protein
  synthesis, prevent bacterial division)
• Host defenses impaired- bactericidal agents
• Complete ATB-mediated killing is necessary

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Susceptibility vs. Resistance(cont.)

• Dose of drug has to be sufficient to produce
  effect inhibit or kill the microorganism
• However concentration of the drug must remain
  below those that are toxic to human cells
• If can be achieved microorganism susceptible to
  the ATB
• If effective concentration is higher than toxic-
  microorganism is resistant

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Susceptibility vs. Resistance(cont.)

• Limitation of in vitro tests
• In vitro sensitivity tests are based on
  non-toxic plasma concentrations cut off
• Do not reflect concentration at the site of
  infection
• E.g. G- aer.bacilli like Ps.aeruginosa inhibited
  by 2 4 ug/ml of gentamycin or tobramycin.
  Susceptible !?

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Antibiotic Susceptibility Testing
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Susceptibility vs. Resistance(cont.)

• Plasma concentration above 6-10 ug/ml may result
  in ototoxicity or nephrotoxicity
• Ration of toxic to therapeutic concentration is
  very low agents difficult to use.
• Concentration in certain compartments vitreous
  fluid or cerebrospinal fluid much lower than
  those in plasma.
• Therefore can be only marginally effective or
  ineffective even those in vitro test states
  sensitive.

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Susceptibility vs. Resistance(cont.)

• Therefore can be only marginally effective or
  ineffective even those in vitro test states
  sensitive.
• Conversely concentration of drug in urine may
  be much higher than in plasma , so resistant
  agents can be effective in infection limited to
  urine tract

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Resistance

• To be effective ATB must reach the target and
  bind to it.
• Resistance
• Failure to reach the target
• The drug is inactivated
• The target is altered

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Resistance (cont.)

• Bacteria produce enzymes at or within the cell
  surface inactivate drug
• Bacteria possess impermeable cell membrane
  prevent influx of drug.
• Transport mechanism for certain drug is energy
  dependent- not effective in anaerobic
  environment.
• ATB as organic acids penetration is pH
  dependent.

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Resistance (cont.)

• Acquired by mutation and passed vertically by
  selection to daughter cells.
• More commonly horizontal transfer of resistance
  determinant from donor cell, often another
  bacterial species, by transformation,
  transduction, or conjugation.
• Horizontal transfer can be rapidly disseminated
• By clonal spread or resistant strain itself
• Or genetic exchange between resistant and further
  susceptible strains.

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Resistance (cont.)

• Methicilin resistant strains of Staphylococcus
  aureus clonally derived from few ancestral
  strains with mecA gene
• Encodes low-affinity penicillin-binding protein
  that confers methicillin resistance.
• Staphylococcal beta-lactamase gene, which is
  plasmid encoded, presumambly transferred on
  numerous occasions. Because is widely distributed
  among unrelated strains, identified also in
  enterococci

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Selection of the ATB

• Requires clinical judgment, detailed knowledge of
  pharmacological and microbiological factors.
• Empirical therapy initial infecting organism
  not identified single broad spectrum agent
• Definitive therapy- microorganism identified a
  narrow spectrum low toxicity regiment to
  complete the course of treatment

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Empirical and Definite Therapy

• Knowledge of the most likely infecting
  microorganism and its susceptibility
• Gram stain
• Pending isolation and identification of the
  pathogen
• Specimen for culture from site of infection
  should be obtain before initiation of therapy
• Definite therapy

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Penicillins

• Penicillins contain a b-lactam ring which
  inhibits the formation of peptidoglycan
  crosslinks in bacterial cell walls (especially in
  Gram-possitive organisms)
• Penicillins are bactericidal but can act only on
  dividing cells
• They are not toxic to animal cells which have no
  cell wall

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Synthesis of Penicillin

• b-Lactams produced by fungi, some ascomycetes,
  and several actinomycete bacteria
• b-Lactams are synthesized from amino acids valine
  and cysteine

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b Lactam Basic Structure
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Penicillins (cont.) Clinical Pharmacokinetics

• Penicillins are poorly lipid soluble and do not
  cross the blood-brain barrier in appreciable
  concentrations unless it is inflamed (so they are
  effective in meningitis)
• They are actively excreted unchanged by the
  kidney, but the dose should be reduced in severe
  renal failure

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Penicillins (cont.)Resistance

• This is the result of production of b-lactamase
  in the bacteria which destroys the b-lactam ring
• It occurs in e.g. Staphylococcus aureus,
  Haemophilus influenzae and Neisseria gonorrhoea

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Penicillins (cont.)Examples

• There are now a wide variety of penicillins,
  which may be acid labile (i.e. broken down by the
  stomach acid and so inactive when given orally)
  or acid stable, or may be narrow or broad
  spectrum in action

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Penicillins (cont.)Examples

• Benzylpenicillin (Penicillin G) is acid labile
  and b-lactamase sensitive and is given only
  parenterally
• It is the most potent penicillin but has a
  relatively narrow spectrum covering
  Strepptococcus pyogenes, S. pneumoniae, Neisseria
  meningitis or N. gonorrhoeae, treponemes,
  Listeria, Actinomycetes, Clostridia

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Penicillins (cont.)Examples

• Phenoxymethylpenicillin (Penicillin V) is acid
  stable and is given orally for minor infections
• it is otherwise similar to benzylpenicillin

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Penicillins (cont.)Examples

• Ampicillin is less active than benzylpenicillin
  against Gram-possitive bacteria but has a wider
  spectrum including (in addition in those above)
  Strept. faecalis, Haemophilus influenza, and some
  E. coli, Klebsiella and Proteus strains
• It is acid stable, is given orally or
  parenterally, but is b-laclamase sensitive

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Penicillins (cont.)Examples

• Amoxycillin is similar but better absorbed orally
  
• It is sometimes combined with clavulanic acid,
  which is a b-lactam with little antibacterial
  effect but which binds strongly to b-lactamase
  and blocks the action of b-lactamase in this way
• It extends the spectrum of amoxycillin

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Penicillins (cont.)Examples

• Flucloxacillin is acid stable and is given orally
  or parenterally
• It is b-lactamase resistant
• It is used as a narrow spectrum drug for
  Staphylococcus aureus infections

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Penicillins (cont.)Examples

• Azlocillin is acid labile and is only used
  parenterally
• It is b-lactamase sensitive and has a broad
  spectrum, which includes Pseudomonas aeruginosa
  and Proteus species
• It is used intravenously for life-threatening
  infections,i.e. in immunocompromised patients
  together with an aminoglycoside

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Penicillins (cont.)Adverse effects

• Allergy (in 0.7 to 1.0 patients). Patient
  should be always asked about a history of
  previous exposure and adverse effects
• Superinfections(e.g.caused by Candida )
• Diarrhoea especially with ampicillin, less
  common with amoxycillin
• Rare haemolysis, nephritis

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Penicillins (cont.)Drug interactions

• The use of ampicillin (or other broad-spectrum
  antibiotics) may decrease the effectiveness of
  oral conraceptives by diminishing enterohepatic
  circulation

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Antistaphylococcus penicillins

• Oxacillin, cloxacillin
• Resistant against staphylococcus penicillinasis

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Cephalosporins

• They also owe their activity to b-lactam ring and
  are bactericidal.
• Good alternatives to penicillins when a broad
  -spectrum drug is required
• should not be used as first choice unless the
  organism is known to be sensitive

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Cephalosporins

• BACTERICIDAL- modify cell wall synthesis
• CLASSIFICATION- first generation are early
  compounds
• Second generation- resistant to ß-lactamases
• Third generation- resistant to ß-lactamases
  increased spectrum of activity
• Fourth generation- increased spectrum of activity
  
  
  

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Cephalosporins

• FIRST GENERATION- eg cefadroxil, cefalexin,
  Cefadrine - most active vs gram ve cocci. An
  alternative to penicillins for staph and strep
  infections useful in UTIs
• SECOND GENERATION- eg cefaclor and cefuroxime.
  Active vs enerobacteriaceae eg E. coli,
  Klebsiella spp,proteus spp. May be active vs H
  influenzae and N meningtidis

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Cephalosporins

• THIRD GENERATION- eg cefixime and other I.V.s
  cefotaxime,ceftriaxone,ceftazidine. Very broad
  spectrum of activity inc gram -ve rods, less
  activity vs gram ve organisms.
• FOURTH GENERATION- cefpirome better vs gram ve
  than 3rd generation. Also better vs gram -ve esp
  enterobacteriaceae pseudomonas aerugenosa. I.V.
  route only

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Cephalosporins (cont.)Adverse effects

• Allergy (10-20 of patients wit penicillin
  allergy are also allergic to cephalosporins)
• Nephritis and acute renal failure
• Superinfections
• Gastrointestinal upsets when given orally

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Aminoglycosides (bactericidal)streptomycin,
kanamycin, gentamicin, tobramycin, amikacin,
netilmicin, neomycin (topical)

• Mode of action - The aminoglycosides irreversibly
  bind to the 16S ribosomal RNA and freeze the 30S
  initiation complex (30S-mRNA-tRNA) so that no
  further initiation can occur. They also slow
  down protein synthesis that has already initiated
  and induce misreading of the mRNA. By binding to
  the 16 S r-RNA the aminoglycosides increase the
  affinity of the A site for t-RNA regardless of
  the anticodon specificity. May also destabilize
  bacterial membranes.
• Spectrum of Activity -Many gram-negative and some
  gram-positive bacteria
• Resistance - Common
• Synergy - The aminoglycosides synergize with
  ß-lactam antibiotics. The ß-lactams inhibit cell
  wall synthesis and thereby increase the
  permeability of the aminoglycosides.

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AminoglycosidesClinical pharmacokinetics

• These are poorly lipid soluble and, therefore,
  not absorbed orally
• Parenteral administration is required for
  systemic effect.
• They do not enter the CNS even when the meninges
  are inflamed.
• They are not metabolized.

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Aminoglycosides (cont.)Clinical pharmacokinetics

• They are excreted unchanged by the kidney (where
  high concentration may occur, perhaps causing
  toxic tubular demage) by glomerular filtration
  (no active secretion).
• Their clearance is markedly reduced in renal
  impairment and toxic concentrations are more
  likely.

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Aminoglycosides (cont.)Resistance

• Resistance results from bacterial enzymes which
  break down aminoglycosides or to their decreased
  transport into the cells.

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Aminoglycosides (cont.)Examples

• Gentamicin is the most commonly used, covering
  Gram-negative aerobes, e.g. Enteric organisms
  (E.coli, Klebsiella, S. faecalis, Pseudomonas and
  Proteus spp.)
• It is also used in antibiotic combination against
  Staphylococcus aureus.
• It is not active against aerobic Streptococci.

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Aminoglycosides (cont.)Examples

• In addition to treating known sensitive
  organisms, it is used often blindly with other
  antibiotics in severe infections of unknown
  cause.
• Streptomycin was formerly the mainstay of
  antituberculous therapy but is now rarely used in
  the developed world.

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Aminoglycosides (cont.)Examples

• Tobramycin used for pseudomonas and for some
  gentamicin-resistant organisms.
• Some aminoglycosides,e.g. Gentamicin, may also be
  applied topically for local effect, e.g. In ear
  and eye ointments.
• Neomycin is used orally for decontamination of GI
  tract.

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Aminoglycosides (cont.)Adverse effects

• Although effective, aminoglycosides are toxic,
  and this is plasma concentration related.
• It is essential to monitor plasma concentrations
  ( shortly before and after administration of a
  dose) to ensure adequate concentrations for
  bactericidal effects, while minimising adverse
  effects, every 2-3 days.

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Aminoglycosides (cont.)Adverse effects

• The main adverse effects are
  Nephrotoxicity Toxic to the 8th cranial
  nerve (ototoxic), especially the vestibular
  division.
• Other adverse effects are not dose related, and
  are relatively rare, e.g. Allergies,
  eosinophilia.

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Macrolides (bacteriostatic)erythromycin,
clarithromycin, azithromycin, spiramycin

• Mode of action - The macrolides inhibit
  translocation by binding to 50 S ribosomal
  subunit
• Spectrum of activity - Gram-positive bacteria,
  Mycoplasma, Legionella (intracellular bacterias)
• Resistance - Common

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Macrolides (cont.)Examples and clinical
pharmacokinetics

• Erythromycin is acid labile but is given as an
  enterically coated tablet
• Absorption is erratic and poor.
• It is excreted unchanged in bile and is
  reabsorbed lower down the gastrointestinal tract
  (enterohepatic circulation).
• It may be given orally or parenterally

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Macrolides (cont.)Examples and clinical
pharmacokinetics

• Macrolides are widely distributed in the body
  except to the brain and cerebrospinal fluid
• The spectrum includes Staphylococcus aureus,
  Streptococcuss pyogenes, S. pneumoniae,
  Mycoplasma pneumoniae and Chlamydia infections.

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Macrolides (cont.)Examples and clinical
pharmacokinetics

• Newer macrolides such as clarithromycin and
  azithromycin may have fewer adverse effects.

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Macrolides side effects

• Nauzea, vomitus
• Allergy
• Hepatitis, ototoxicity
• Interaction with cytochrome P450 3A4 (inhibition)

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Chloramphenicol, Lincomycin, Clindamycin
(bacteriostatic)

• Mode of action - These antimicrobials bind to the
  50S ribosome and inhibit peptidyl transferase
  activity.
• Spectrum of activity - Chloramphenicol - Broad
  range Lincomycin and clindamycin - Restricted
  range
• Resistance - Common
• Adverse effects - Chloramphenicol is toxic (bone
  marrow suppression) but is used in the treatment
  of bacterial meningitis.

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Clindamycin

• Clindamycin, although chemically distinct, is
  similar to erythromycin in mode of action and
  spectrum.
• It is rapidly absorbed and penetrates most
  tissues well, except CNS.
• It is particularly useful systematically for S.
  aureus (e.g.osteomyelitis as it penetrates bone
  well) and anaerobic infections.

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ClindamycinAdverse effects

• Diarrhoea is common.
• Superinfection with a strain of Clostridium
  difficile which causes serious inflammation of
  the large bowel (Pseudomembranous colitis)

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Chloramphenicol

• This inhibits bacterial protein synthesis.
• It is well absorbed and widely distributed ,
  including to the CNS.
• It is metabolized by glucoronidation in the
  liver.
• Although an effective broad-spectrum antibiotics,
  its uses are limitid by its serious toxicity.

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Chloramphenicol (cont.)

• The major indication is to treat bacterial
  meningitis caused by Haemophilus influenzae, or
  to Neisseria menigitidis or if organism is
  unknown.It is also specially used for Rikettsia
  (typhus).

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Chloramphenicol (cont.)Adverse effects

• A rare anemia, probably immunological in origin
  but often fatal
• Reversible bone marrow depression caused by its
  effect on protein synthesis in humans
• Liver enzyme inhibition

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Sulfonamides and trimethoprim

• Sulfonamides are rarely used alone today.
• Trimethoprim is not chemically related but is
  considered here because their modes of action are
  complementary.

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Sulfonamides, Sulfones (bacteriostatic)

• Mode of action - These antimicrobials are
  analogues of para-aminobenzoic acid and
  competitively inhibit formation of dihydropteroic
  acid.
• Spectrum of activity - Broad range activity
  against gram-positive and gram-negative bacteria
  used primarily in urinary tract and Nocardia
  infections.
• Resistance - Common
• Combination therapy - The sulfonamides are used
  in combination with trimethoprim this
  combination blocks two distinct steps in folic
  acid metabolism and prevents the emergence of
  resistant strains.

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Trimethoprim, Methotrexate, (bacteriostatic)

• Mode of action - These antimicrobials binds to
  dihydrofolate reductase and inhibit formation of
  tetrahydrofolic acid.
• Spectrum of activity - Broad range activity
  against gram-positive and gram-negative bacteria
  used primarily in urinary tract and Nocardia
  infections.
• Resistance - Common
• Combination therapy - These antimicrobials are
  used in combination with the sulfonamides this
  combination blocks two distinct steps in folic
  acid metabolism and prevents the emergence of
  resistant strains.

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Sulfonamides and trimethoprimMode of action

• Folate is metabolized by enzyme dihydrofolate
  reductase to the active tetrahydrofolic acid.
• Trimethoprim inhibits this enzyme in bacteria and
  to a lesser degree in animal s, as the animal
  enzyme is far less sensitive than that in
  bacteria.

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Sulfonamides and trimethoprimClinical
pharmacokinetics

• Most sulfonamides are well absorbed orally and
  they are widely distributed including to the CNS.
• Most are excreted by the kidney unchanged.
• They are effective against Gram-positive and many
  Gram-negative organism but are rarely used alone
  now.

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Sulfonamides and trimethoprimClinical
pharmacokinetics

• Trimethoprim is also well absorbed and excreted
  by the kidneys, with similar spectrum.
• Cotrimoxazole is widely used for urinary and
  upper respiratory tract infections but should not
  be the drug of choice because of its adverse
  effects.

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Sulfonamides and trimethoprimClinical
pharmacokinetics

• It is the drug of choice for the treatment and
  prevention of pneumonia caused by Pneumocystis
  carinii in immunosupressed patients.
• Trimethoprim is increasingly used alone for
  urinary tract and upper respiratory tract
  infections, as it is less toxic than the
  combination and equally effective.

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Sulfonamides and trimethoprimAdverse effects

• Gastrointestinal upsets
• Less common but more serious -sulfonamides
  allergy, rash, fever, agranulocytosis, renal
  toxicity -trimethoprim macrocytis anemia,
  thrombocytopenia -cotrimoxazole
  aplastic anemia

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Sulfonamides and trimethoprimDrug intereactions

• Sulfonamides can decrease metabolism of
  phenytoin, warfarin and some oral hypoglycaemics,
  increasing their effects.

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Quinolones (bactericidal)nalidixic acid,
ciprofloxacin, ofloxacin, norfloxacin,
levofloxacin, lomefloxacin, sparfloxacin

• Mode of action - These antimicrobials bind to the
  A subunit of DNA gyrase (topoisomerase) and
  prevent supercoiling of DNA, thereby inhibiting
  DNA synthesis.
• Spectrum of activity - Gram-positive cocci and
  urinary tract infections
• Resistance - Common for nalidixic acid
  developing for ciprofloxacin

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Quinolones

• The quinolones are effective but expensive
  antibiotics.
• With increased use, resistance to these drugs is
  becoming more common.
• They should in general be reverse drugs and not
  first-line treatment.

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Quinolones (cont.)Examples and clinical
pharmacokinetics

• Nalidixic acid, the first quinolone, is used as a
  urinary antiseptic and for lower urinary tract
  infections, as it has no systemic antibacterial
  effect.
• Ciprofloxacin is a fluoroquinolone with a broad
  spectrum against Gram-negative bacilli and
  Pseudomonas,

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Quinolones (cont.)Examples and clinical
pharmacokinetics

• It can be given orally or i.v. to treat a wide
  range of infections, including respiratory and
  urinary tract infections as well as more serious
  infections, such as peritonitis and Salmonella.
• Activity against anaerobic organism is poor and
  it should not be first choice for respiratory
  tract infections.

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Quinolones (cont.)Adverse effects

• Gastrointestinal upsets
• Fluoroquinolones may block the inhibitory
  neurotransmitter GABA, and this may cause
  confusion in the elderly and lower the fitting
  threshold.
• They are also contraindicated in epileptics.
• Allergy and anaphylaxis

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Quinolones (cont.)Adverse effects

• Possibly damage to growing cartilage not
  recommended for pregnant women and
  children Drug interaction
• Ciprofloxacin is a liver enzyme inhibitor and may
  cause life-threatening interaction with
  theophylline.

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Tetracyclines (bacteriostatic)tetracycline,
minocycline and doxycycline

• Mode of action - The tetracyclines reversibly
  bind to the 30S ribosome and inhibit binding of
  aminoacyl-t-RNA to the acceptor site on the 70S
  ribosome.
• Spectrum of activity - Broad spectrum Useful
  against intracellular bacteria
• Resistance - Common
• Adverse effects - Destruction of normal
  intestinal flora resulting in increased secondary
  infections staining and impairment of the
  structure of bone and teeth.

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Tetracyclines (cont.) Examples and clinical
pharmacokinetics

• Tetracycline, oxytetracycline have short
  half-lives.
• Doxycycline has a longer half-life and can be
  given once per day.
• These drugs are only portly absorbed.
• They bind avidly to heavy metal ions and so
  absorption is greatly reduced if taken with food,
  milk, antacids or iron tablets.

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Tetracyclines (cont.) Examples and clinical
pharmacokinetics

• They should be taken at least half an hour
  before food.
• Tetracyclines concentrate in bones and teeth.
• They are excreted mostly in urine, partly in
  bile.
• They are broad spectrum antibiotics, active
  against most bacteria except Proteus or
  Pseudomonas.

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Tetracyclines (cont.) Examples and clinical
pharmacokinetics

• Resistance is frequent.
• They are specially indicated for Mycoplasma,
  Rikettsia, Chlamydia and Brucella infections.
• Their most common use today is for acne, given
  either orally or topically.

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Tetracyclines (cont.) Adverse effects

• Gastrointestinal upsets
• Superinfection
• Discolouration and deformity in growing teeth and
  bones (contraindicated in pregnancy and in
  children lt 12 years)
• Renal impairment (should be also avoided in renal
  disease)

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Metronidazole

• Metronidazole binds to DNA and blocks
  replication. Pharmacokinetics
• It is well absorbed after oral or rectal
  administration and can be also given i.v.
• It is widely distributed in the body (including
  into abscess cavities)
• It is metabolized by the liver.

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Metronidazole (cont.)Uses

• Metronidazole is active against anaerobic
  organisms (e.g. Bacteroides, Clostridia), which
  are encountered particularly in abdominal
  surgery.
• It is also used against Trichomonas, Giardia and
  Entamoeba infections and can be used to treat
  pseudomembranous colitis.

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Metronidazole (cont.)Uses

• Increasingly, it is used as part of treatment of
  Helicobacter pyloris infestion of the stomach and
  duodenum associated with peptic ulcer disease.
• It is used also to treat a variety of dental
  infections, particularly dental abscess.

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Metronidazole (cont.)Adverse effects

• Nausea, anorexia and metallic taste
• Ataxia
• In patients, who drink alcohol, may occur
  unpleasant reactions. They should be advised not
  to drink alcohol during a treatment.
• Possibly teratogenic if taken in the first
  trimester of pregnancy

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Nitrofurantoin

• This is used as a urinary antiseptic and to treat
  Gram-negative infections in the lower urinary
  tract.
• It is taken orally and is well absorbed and is
  excreted unchanged in the urine.
• It only exerts its antimicrobial effect when it
  is concentrated in the urine and so has no
  systemic antibacterial effect.

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Nitrofurantoin (cont.)

• It is ineffective in renal failure because of
  failure to concentrate.
• Resistance develops relatively quickly.

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Nitrofurantoin (cont.)Adverse effects

• Gastrointestinal upsets
• Allergy
• Polyneuritis

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Fucidin

• Fucidin is active only against Staphylococcus
  aureus (by inhibiting bacterial protein
  synthesis) and is not affected b-lactamase.
• It is usually only used with flucloxacillin to
  reduce the development of resistance.
• It is well absorbed and widely distributed,
  including to bone

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Fucidin (cont.)

• It can be given orally or parenterally.
• It is metabolized in the liver. Adver
  se effects
• Gastrointestinal upsets
• Hepatitis and jaundice

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Vancomycin

• This interferes with bacterial cell wall
  formation and is not absorbed after oral
  administration and must be given parenterally.
• It is excreted by the kidney.
• It is used i.v. to treat serious or resistant
  Staph. aureus infections and for prophylaxis of
  endocarditis in penicillin-allergic people.

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Vancomycin (cont.)

• It is given orally to treat pseudomembranous
  colitis
• teicoplanin is similar but less toxic

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Vancomycin (cont.)Adverse effects

• Its toxicity is similar to aminoglycoside and
  likewise monitoring of plasma concentrations is
  essential.
• Nephrotoxicity
• Ototoxicity
• Allergy

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Antibiotics for leprosy

• Leprosy is caused by infection with Mycobacteria
  leprae.
• A mixture of drugs are used to treat leprosy,
  depending on the type and severity of the
  infection and the local resistance patterns.

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Antibiotics for leprosy

• Rifampicin is used and dapsone, which is related
  to the sulphoamides.
• Its adverse effects include haemolysis,
  gastrointestinal upsets and rashes.

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Chemotherapy for viruses
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Antiviral drugs

• Antiviral chemotherapy is still in its infancy.
• Viruses are more difficult targets than
  bacteria they are most vulnerable during
  reproduction, but all use host cell organelles
  and enzymes to do this, so that antiviral
  compounds are often as toxic to host cells as to
  virus.

104
Antiviral drugs (cont.)

• Viruses have assumed increasing importance in the
  setting of immunosuppression - both drug induced
  and AIDS.

105
Antiviral drugs (cont.)

• Current antiviral drugs are thought to work in
  one of the following ways - inhibition of
  viral uncoating shortly after penetration into
  the cell they are best for prophylaxis or very
  early in the disease course (e.g.amantadine) -
  interference with viral RNA synthesis and
  function (e.g. ribavirin)

106
Antiviral drugs (cont.)

• interference with DNA synthesis (e.g.
  cytarabine)
• inhibition of viral DNA polymerase (e.g.aciclovir
  and gancyclovir)
• inhibition of reverse transcriptase at
  retroviruses such as HIV (e.g.zidovudine)
• use of complex natural antiviral defences by
  employing interferon

107
AciclovirMode of action

• It is active against Herpes simplex and Herpes
  zoster.
• Aciclovir targets virus-infected cells quite
  specifically, and this explains the drugs
  relatively low toxicity.

108
Aciclovir (cont.)Clinical pharmacokinetics

• The drug is used topically, orally and i.v.
• Little drug is absorbed from topical
  formulations, and the bioavailability of the oral
  drug is low (about 20).
• It is widely distributed and crosses the
  blood-brain barrier.
• It is excreted in the urine and in lactating
  women in the breast milk.

109
Aciclovir (cont.)Therapeutic uses

• It is the drug of first choice for Herpes simplex
  and zoster infections, because of the great
  efficacy and lower toxicity than the
  alternatives.
• The drug has little activity against
  cytomegalovirus or Epstein-Barr virus.

110
Aciclovir (cont.)Therapeutic uses

• Herpes simplex infections of skin, mucous
  membranes and cornea
• Life-threatening Herpes simplex infections
  aciclovir i.v. reduces mortality
• Herpes zoster that is less sensitive to aciclovir
  than H. simplex .It is used for early topic or
  oral treatment of zoster aciclovir i.v. is used
  for life-threatening zoster infections as
  pneumonia

111
Aciclovir (cont.)Adverse effects

• Renal impairment mainly in high i.v. doses in
  dehydrated patients
• Local inflammation following extravascular
  administration
• Encephalopathy mainly in high i.v. doses

112
Zidovudine (AZT)Mode of action

• HIV virus is an RNA virus capable of including
  the synthesis of a DNA transcript of its genome,
  which can then become integrated into the host
  cells DNA, thereby allowing viral replication.
• Synthesis of the initial DNA transcript involves
  the enzyme reverse transcriptase.

113
Zidovudine (AZT) cont.Mode of action

• Zidovudine is a potent inhibitor of reverse
  transcriptase.
• It has relatively specific toxicity for the virus.

114
Zidovudine (AZT) cont.Clinical pharmacokinetics

• It is well absorbed from the gut but subject to
  first-pass metabolism
• Bioavailability is about 70
• The drug is widely distributed and crosses the
  blood-brain barrier
• Most of the drug is eliminated by hepatic
  metabolism, unchanged zidovudine accounting for
  about 10 of the dose

115
Zidovudine (AZT) cont.Clinical pharmacokinetics

• In patients with renal or liver impairment, the
  drug may accumulate, and doses are usually
  adjusted in these disease states

116
Zidovudine (AZT) cont.Therapeutic uses

• It is used to prolong life patients with AIDS and
  AIDS-related complex (ACR) it probably does not
  delay the onset of AIDS in HIV-positive patients
• The drug usually produces a rise in CD4 cell
  counts, but eventual deterioration is usual in
  spite of zidovudine
• In patients with late AIDS it is of little use.

117
Zidovudine (AZT) cont.Adverse effects

• Bone marrow toxicity
• Polymyositis
• Headache and insomnia

118
Zidovudine (AZT) cont.Drug interactions

• Paracetamol the risk of bone marrow suppression
  may increased
• Probenecid

119
Purine and pyrimidine analoguesMode of action

• These drugs are effective against DNA viruses
• The compounds structurally resemble purine and
  pyrimidine nucleosides
• The resulting DNA molecule is more easily
  fragmented, leading to transcription errors.
• They also inhibit viral DNA polymerase.

120
Purine and pyrimidine analoguesExamples and
clinical pharmacokinetics

• Idoxuridine it is not absorbed from the gut, and
  is used topically
• Vidarabine cannot be given orally because it is
  metabolized in the gut - it is usually given
  i.v. or topically

121
Purine and pyrimidine analoguesTherapeutic uses

• Idoxuridine may be used topically for Herpes
  simplex and zoster but is too toxic for systemic
  use and has largely been supplanted by aciclovir
• Vidarabine may be used for life-threatening
  systemic Herpes infections

122
Purine and pyrimidine analoguesAdverse effects

• Idoxuridine because it is used only topically,
  severe adverse effects are unusual
• Vidarabine anorexia, nausea, vomiting, diarroea
  and bone marrow suppression

123
Purine and pyrimidine analoguesDrug interactions

• The metabolism of vidarabine is inhibited by the
  xanthine oxidase inhibitor allopurinol, and
  toxicity may result

124
Ribavirin

• It is effective against a wide range of DNA and
  RNA viruses
• The drug may be given by aerosol inhalation,
  orally or i.v.
• Oral biavailabity is about 40
• It readily crosses the blood-brain barrier and
  has a very large volume of distribution, mainly
  because of cellular uptake.

125
Ribavirin (cont.)

• The drug is eliminated by both metabolism and
  renal excretion, with a terminal half-life of
  about 2 weeks

126
Ribavirin (cont.)Therapeutic uses

• Respiratory syncytial virus (RSV) infections
  bronchiolitis and pneumonia at young children
• Influenza A and B
• Lassa fever