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CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AND ANTIVIRAL AGENTS

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CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AND ANTIVIRAL AGENTS ANTIBACTERIAL DRUGS. Mechanisms of Action 1. Inhibition of bacterial cell wall synthesis or activation of ... – PowerPoint PPT presentation

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Title: CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AND ANTIVIRAL AGENTS


1
CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AND
ANTIVIRAL AGENTS
2
ANTIBACTERIAL DRUGS. Mechanisms of Action
  • 1. Inhibition of bacterial cell wall synthesis or
    activation of enzymes that disrupt bacterial cell
    walls (eg, penicillins, cephalosporins,
    vancomycin)
  • 2. Inhibition of protein synthesis by bacteria or
    production of abnormal bacterial proteins (eg,
    aminoglycosides, clindamycin, erythromycin,
    tetracyclines). These drugs bind irreversibly to
    bacterial ribosomes, intracellular structures
    that synthesize proteins. When antimicrobial
    drugs are bound to the ribosomes, bacteria cannot
    synthesize the proteins necessary for cell walls
    and other structures.
  • 3. Disruption of microbial cell membranes (eg,
    antifungals)
  • 4. Inhibition of organism reproduction by
    interfering with nucleic acid synthesis (eg,
    fluoroquinolones, rifampin, antiacquired
    immunodeficiency syndrome antivirals)
  • 5. Inhibition of cell metabolism and growth (eg,
    sulfonamides, trimethoprim)

3
Actions of antibacterial drugs on bacterial cells

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PenicillinsThe penicillins are classified as
BETA-lactam drugs because of their unique
four-membered lactam ring.They share features of
chemistry, mechanism of action, pharmacologic and
clinical effects, andimmunologic characteristics
with cephalosporins, monobactams, carbapenems,
and -lactamaseinhibitors, which also are -lactam
compounds.
  • Beta-Lactam Antibiotics

A penicillin culture
6
PENICILLINS Indications for Use
  • Clinical indications for use of penicillins
    include bacterial infections caused by
    susceptible microorganisms. As a class,
    penicillins usually are more effective in
    infections caused by gram-positive bacteria than
    those caused by gram-negative bacteria. However,
    their clinical uses vary significantly according
    to the subgroup or individual drug and microbial
    patterns of resistance. The drugs are often
    useful in skin/ soft tissue, respiratory,
    gastrointestinal, and genitourinary infections.
    However, the incidence of resistance among
    streptococci, staphylococci, and other
    microorganisms continues to grow.

7
Aminopenicillins
8
Piperacillin
9
Cephalosporins Cephamycins
  • Cephalosporins and cephamycins are similar to
    penicillins chemically, in mechanism of action,
    and in toxicity. Cephalosporins are more stable
    than penicillins to many bacterial ß-lactamases
    and therefore usually have a broader spectrum of
    activity. Cephalosporins are not active against
    enterococci and Listeria monocytogenes.

10
CephalosporinsIndications for Use
  • Cefepime is indicated for use in severe
    infections of the lower respiratory and urinary
    tracts, skin and soft tissue, female reproductive
    tract, and infebrile neutropenic clients. It may
    be used as monotherapy for all infections caused
    by susceptible organisms except P. aeruginosa a
    combination of drugs should be used for serious
    pseudomonal infections.

11
Monobactams
  • These are drugs with a monocyclic -lactam ring .
    They are relatively resistant to lactamases and
    active against gram-negative rods (including
    pseudomonas and serratia). They have no activity
    against gram-positive bacteria or anaerobes.
    Aztreonam is the only monobactam available in the
    USA. It resembles aminoglycosides in its spectrum
    of activity. Aztreonam is given intravenously
    every 8 hours in a dose of 12 g, providing peak
    serum levels of 100 g/mL. The half-life is 12
    hours and is greatly prolonged in renal failure.

12
Beta-Lactamase Inhibitors (Clavulanic Acid,
Sulbactam, Tazobactam)
  • These substances resemble beta-lactam molecules
    but themselves have very weak antibacterial
    action. They are potent inhibitors of many but
    not all bacterial lactamases and can protect
    hydrolyzable penicillins from inactivation by
    these enzymes.

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carbapenems
  • The carbapenems are structurally related to
    beta-lactam antibiotics. Ertapenem, imipenem, and
    meropenem are licensed for use in the USA.
    Imipenem has a wide spectrum with good activity
    against many gram-negative rods, it is
    administered together with an inhibitor of renal
    dehydropeptidase, cilastatin, for clinical use.
    Meropenem is not significantly degraded by
    renal dehydropeptidase and does not require an
    inhibitor.
  • Ertapenem is less active than meropenem or
    imipenem against Pseudomonas aeruginosa and
    acinetobacter species. It is not degraded by
    renal dehydropeptidase.

15
Chloramphenicol
  • Chloramphenicol is a potent inhibitor of
    microbial protein synthesis. It binds reversibly
    to the 50S subunit of the bacterial ribosome.

16
Chloramphenicol. Toxicity for Newborn Infants
  • Newborn infants lack an effective glucuronic
    acid conjugation mechanism for the degradation
    and detoxification of chloramphenicol.
    Consequently, when infants are given dosages
    above 50 mg/kg/d, the drug may accumulate,
    resulting in the gray baby syndrome, with
    vomiting, flaccidity, hypothermia, gray color,
    shock, and collapse.

17
TETRACYCLINES

18
Macrolides
  • Erythromycin
  • Clarithromycin (is derived from erythromycin)
  • Azithromycin (differs from erythromycin and
    clarithromycin mainly in pharmacokinetic
    properties). The drug is slowly released from
    tissues (tissue half-life of 24 days) to produce
    an elimination half-life approaching 3 days.
    These unique properties permit once-daily dosing
    and shortening of the duration of treatment in
    many cases. Ketolides (Telithromycin) is approved
    for clinical use. Many macrolide-resistant
    strains are susceptible to ketolides

19
Aminoglycosides
  • Streptomycin, neomycin, kanamycin, amikacin,
    gentamicin, tobramycin, sisomicin, netilmicin
  • The pharmacodynamic properties of
    aminoglycosides are
  • Concentration-dependent killing
  • Significant post-antibiotic effect

20
Lincosamides
  • Clindamycin is indicated for treatment of
    anaerobic infection caused by bacteroides and
    other anaerobes that often participate in mixed
    infections.
  • Clindamycin is now recommended rather than
    erythromycin for prophylaxis of endocarditis in
    patients with valvular heart disease who are
    undergoing certain dental procedures.
  • Clindamycin plus primaquine is an effective
    alternative to trimethoprim-sulfamethoxazole for
    moderate to moderately severe Pneumocystis
    jiroveci pneumonia in AIDS patients.
  • It is also used in combination with
    pyrimethamine for AIDS-related toxoplasmosis of
    the brain.

21
Oxazolidinones
  • Linezolid  is a member of the oxazolidinones, a
    new class of synthetic antimicrobials. It is
    active against gram-positive organisms including
    staphylococci, streptococci, enterococci,
    gram-positive anaerobic cocci, and gram-positive
    rods such as corynebacteria and Listeria
    monocytogenes.

22
Empirical blind therapy
  • Most antibiotic prescribing, especially in the
    community, is
  • empirical. Even in hospital practice,
    microbiological documentation
  • of the nature of an infection and the
    susceptibility
  • of the pathogen is generally not available for a
    day or two.
  • Initial choice of therapy relies on a clinical
    diagnosis and, in
  • turn, a presumptive microbiological diagnosis.
    Such blind
  • therapy is directed at the most likely
    pathogen(s) responsible
  • for a particular syndrome such as meningitis,
    urinary tract
  • infection or pneumonia.
  • Examples of blind therapy for these three
    conditions are ceftriaxone, trimethoprim and
    amoxicillin erythromycin, respectively. Initial
    therapy in the severely ill patient is often
    broad spectrum in order to cover the range of
    possible pathogens but should be targeted once
    microbiological information becomes available.

23
Sulfonamides
  • Sulfonamides are infrequently used as single
    agents.

24
Sulfonamides. Oral Nonabsorbable Agents
  • Sulfasalazine (salicylazosulfapyridine) is
    widely used in ulcerative colitis, enteritis, and
    other inflammatory bowel disease

25
Fluoroquinolones

26
Quinolones
27
Norfloxacin is the least active of the
fluoroquinolones against both gram-negative and
gram-positive organisms
  • Ciprofloxacin, enoxacin, lomefloxacin,
    evofloxacin, ofloxacin, and pefloxacin comprise a
    second group of similar agents possessing
    excellent gram-negative activity and moderate to
    good activity against grampositive bacteria.

28
  • Gatifloxacin, moxifloxacin, sparfloxacin, and
    rovafloxacin comprise a third group of
    fluoroquinolones with improved activity against
    gram-positive organisms, particularly
    S.pneumoniae and to some extent staphylococci.

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The fluoroquinolones side effects
  • Fluoroquinolones are approved for use only in
    people older than 18. They can affect the growth
    of bones, teeth, and cartilage in a child or
    fetus.

31
The fluoroquinolones side effects
  • Phototoxicity. Exposure to ultraviolet A rays
    from direct or indirect sunlight should be
    avoided during treatment and several days (5 days
    with sparfloxacin) after the use of the drug. The
    degree of phototoxic potential of
    fluoroquinolones is as follows lomefloxacin gt
    sparfloxacin gt ciprofloxacin gt norfloxacin
    ofloxacin levofloxacin gatifloxacin
    moxifloxacin.
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