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

4
(No Transcript)
5
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.

13
(No Transcript)
14
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.

29
(No Transcript)
30
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.