Download 03_CLIN_PHARM_ANTIBACTERIAL

CLINICAL PHARMACOLOGY OF
ANTIBACTERIAL AND ANTIVIRAL AGENTS
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, anti–acquired
immunodeficiency syndrome antivirals)
5. Inhibition of cell metabolism and growth (eg, sulfonamides,
trimethoprim)
Actions of antibacterial drugs on bacterial cells
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Beta-Lactam Antibiotics
PENICILLINS
THE 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, AND
IMMUNOLOGIC CHARACTERISTICS WITH CEPHALOSPORINS,
MONOBACTAMS, CARBAPENEMS, AND -LACTAMASE
INHIBITORS, WHICH ALSO ARE -LACTAM COMPOUNDS.
A penicillin culture
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 gramnegative 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.
Aminopenicillins
Piperacillin
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
β-lactamases and therefore
usually have a broader spectrum
of activity. Cephalosporins are not
active against enterococci and
Listeria monocytogenes.
Cephalosporins
Indications 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.
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 1–2 g, providing peak serum
levels of 100 g/mL. The half-life is 1–2 hours and is greatly prolonged in
renal failure.
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.
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.
CHLORAMPHENICOL
Chloramphenicol is a potent inhibitor of microbial protein synthesis. It
binds reversibly to the 50S subunit of the bacterial ribosome.
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.
TETRACYCLINES
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 2–4 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
Aminoglycosides
Streptomycin, neomycin, kanamycin, amikacin, gentamicin,
tobramycin, sisomicin, netilmicin
The pharmacodynamic properties of aminoglycosides are:
 Concentration-dependent killing
 Significant post-antibiotic effect
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 trimethoprimsulfamethoxazole 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.
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.
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.
SULFONAMIDES
Sulfonamides are infrequently used as single
agents.
SULFONAMIDES. ORAL NONABSORBABLE
AGENTS
Sulfasalazine (salicylazosulfapyridine) is widely
used in ulcerative colitis, enteritis, and other
inflammatory bowel disease
Fluoroquinolones
Quinolones
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.
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.
The fluoroquinolones side effects
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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.
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 > sparfloxacin
> ciprofloxacin > norfloxacin = ofloxacin = levofloxacin =
gatifloxacin = moxifloxacin.