Title: CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AND ANTIVIRAL AGENTS
1CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AND
ANTIVIRAL AGENTS
2ANTIBACTERIAL 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)
3Actions of antibacterial drugs on bacterial cells
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5PenicillinsThe 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.
A penicillin culture
6PENICILLINS 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.
7Aminopenicillins
8Piperacillin
9Cephalosporins 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.
10CephalosporinsIndications 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.
11Monobactams
- 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.
12Beta-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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14carbapenems
- 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.
15Chloramphenicol
- Chloramphenicol is a potent inhibitor of
microbial protein synthesis. It binds reversibly
to the 50S subunit of the bacterial ribosome. -
16Chloramphenicol. 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.
17TETRACYCLINES
18Macrolides
- 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
19Aminoglycosides
- Streptomycin, neomycin, kanamycin, amikacin,
gentamicin, tobramycin, sisomicin, netilmicin - The pharmacodynamic properties of
aminoglycosides are - Concentration-dependent killing
- Significant post-antibiotic effect
-
20Lincosamides
- 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.
21Oxazolidinones
- 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. -
22Empirical 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.
23Sulfonamides
- Sulfonamides are infrequently used as single
agents.
24Sulfonamides. Oral Nonabsorbable Agents
- Sulfasalazine (salicylazosulfapyridine) is
widely used in ulcerative colitis, enteritis, and
other inflammatory bowel disease
25Fluoroquinolones
26Quinolones
27Norfloxacin 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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30The 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. -
31The 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.