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Antimicrobial Agents

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Title: Antimicrobial Agents


1
Antimicrobial Agents
  • Martin Votava
  • Olga Kroftová

2
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.

3
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.

4
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.

5
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.

6
Sir Alexander Fleming
7
Flemings Petri Dish
8
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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10
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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12
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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14
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

15
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 !?

16
Antibiotic Susceptibility Testing
17
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.

18
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

19
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

20
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.

21
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.

22
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

23
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

24
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

25
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

26
Synthesis of Penicillin
  • b-Lactams produced by fungi, some ascomycetes,
    and several actinomycete bacteria
  • b-Lactams are synthesized from amino acids valine
    and cysteine

27
b Lactam Basic Structure
28
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

29
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

30
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

31
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

32
Penicillins (cont.)Examples
  • Phenoxymethylpenicillin (Penicillin V) is acid
    stable and is given orally for minor infections
  • it is otherwise similar to benzylpenicillin

33
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

34
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

35
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

36
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

37
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

38
Penicillins (cont.)Drug interactions
  • The use of ampicillin (or other broad-spectrum
    antibiotics) may decrease the effectiveness of
    oral conraceptives by diminishing enterohepatic
    circulation

39
Antistaphylococcus penicillins
  • Oxacillin, cloxacillin
  • Resistant against staphylococcus penicillinasis

40
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

41
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



42
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

43
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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45
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

46
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.

47
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.

48
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.

49
Aminoglycosides (cont.)Resistance
  • Resistance results from bacterial enzymes which
    break down aminoglycosides or to their decreased
    transport into the cells.

50
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.

51
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.

52
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.

53
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.

54
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.

55
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

56
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

57
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.

58
Macrolides (cont.)Examples and clinical
pharmacokinetics
  • Newer macrolides such as clarithromycin and
    azithromycin may have fewer adverse effects.

59
Macrolides side effects
  • Nauzea, vomitus
  • Allergy
  • Hepatitis, ototoxicity
  • Interaction with cytochrome P450 3A4 (inhibition)

60
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.

61
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.

62
ClindamycinAdverse effects
  • Diarrhoea is common.
  • Superinfection with a strain of Clostridium
    difficile which causes serious inflammation of
    the large bowel (Pseudomembranous colitis)

63
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.

64
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).

65
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

66
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.

67
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.

68
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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70
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.

71
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.

72
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.

73
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.

74
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

75
Sulfonamides and trimethoprimDrug intereactions
  • Sulfonamides can decrease metabolism of
    phenytoin, warfarin and some oral hypoglycaemics,
    increasing their effects.

76
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

77
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.

78
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,

79
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.

80
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

81
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.

82
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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84
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.

85
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.

86
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.

87
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)

88
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.

89
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.

90
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.

91
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

92
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.

93
Nitrofurantoin (cont.)
  • It is ineffective in renal failure because of
    failure to concentrate.
  • Resistance develops relatively quickly.

94
Nitrofurantoin (cont.)Adverse effects
  • Gastrointestinal upsets
  • Allergy
  • Polyneuritis

95
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

96
Fucidin (cont.)
  • It can be given orally or parenterally.
  • It is metabolized in the liver. Adver
    se effects
  • Gastrointestinal upsets
  • Hepatitis and jaundice

97
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.

98
Vancomycin (cont.)
  • It is given orally to treat pseudomembranous
    colitis
  • teicoplanin is similar but less toxic

99
Vancomycin (cont.)Adverse effects
  • Its toxicity is similar to aminoglycoside and
    likewise monitoring of plasma concentrations is
    essential.
  • Nephrotoxicity
  • Ototoxicity
  • Allergy

100
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.

101
Antibiotics for leprosy
  • Rifampicin is used and dapsone, which is related
    to the sulphoamides.
  • Its adverse effects include haemolysis,
    gastrointestinal upsets and rashes.

102
Chemotherapy for viruses
103
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
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