DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

membranes. The permeability of the bacterial membrane changes
immediately on contact with the drug. Sensitivity to polymyxin B
apparently is related to the phospholipid content of the cell
wall–membrane complex. The cell walls of certain resistant bacteria
may prevent access of the drug to the cell membrane. Polymyxin B
binds to the lipid A portion of endotoxin (the lipopolysaccharide of
the outer membrane of gram-negative bacteria) and inactivates this
molecule. Polymyxin B attenuates pathophysiological consequences
of the release of endotoxin in several experimental systems, but the
clinical utility of polymyxin B for this indication has not yet been
established.
Although resistance to polymyxins among normally susceptible
species is rare (likely owing to the minimal systemic use of this
agent for many years), emergence of resistance while on treatment
has been documented. Dosing regimens, including combination therapies,
able to suppress the emergence of resistance are currently
being studied.
Absorption, Distribution, and Excretion. Polymyxin B and colistin
are not absorbed when given orally and are poorly absorbed
from mucous membranes and the surfaces of large burns. They are
cleared renally, and modification of the dose is required in patients
with impaired renal function.
Therapeutic Uses and Dosage
Topical Uses. Polymyxin B sulfate is available for ophthalmic, otic,
and topical use in combination with a variety of other compounds.
Colistin is available as otic drops. Infections of the skin, mucous
membranes, eye, and ear due to polymyxin B–sensitive microorganisms
respond to local application of the antibiotic in solution or ointment.
External otitis, frequently due to Pseudomonas, may be cured
by the topical use of the drug. P. aeruginosa is a common cause of
infection of corneal ulcers; local application or subconjunctival
injection of polymyxin B often is curative. Polymyxin B, in combination
with neomycin (NEOSPORIN G.U. IRRIGANT), is administered
as a urinary bladder irrigant in conjunction with the use of indwelling
catheters.
Systemic Uses. Colistin is available as colistin sulfate for oral use
and as colistimethate sodium for parenteral administration. Due to
the emergence of multidrug-resistant gram-negative organisms
(especially Stenotrophomonas maltophilia, Acinetobacter spp.,
P. aeruginosa, and Klebsiella spp), there has been a resurgence in the
systemic use of polymyxins, despite their toxicity when administered
via this route. There are no prospective clinical trials of
polymyxin use for systemic infections; however, a number of studies
have described their use as salvage therapy for treatment of infections
caused by multidrug-resistant organisms (Linden et al., 2003;
San Gabriel et al., 2004). Because dosing of these agents varies by
drug (polymyxin B or colistin), by the particular commercial preparation,
and by the patient’s degree of renal dysfunction, expert consultation
is recommended before using these agents.
Untoward Effects. Polymyxin B applied to intact or denuded skin or
mucous membranes produces no systemic reactions because of its
almost complete lack of absorption from these sites. Hypersensitization
is uncommon with topical application. Polymyxins are nephrotoxic, and
administration with aminoglycosides or other nephrotoxins should be
avoided if possible. Polymyxins interfere with neurotransmission at the
neuromuscular junction, resulting in muscle weakness and apnea. Other
neurological reactions include paresthesias, vertigo, and slurred speech.
GLYCOPEPTIDES (VANCOMYCIN
AND TEICOPLANIN)
Vancomycin. Vancomycin is a tricyclic glycopeptide
antibiotic produced by Streptococcus orientalis.
Teicoplanin, a glycopeptide antibiotic produced by
Actinoplanes teichomyetius, is available in Europe
(Biavasco et al., 1997). A number of derivatives, the
lipoglycopeptides (including telavancin, oritavancin,
and dalbavancin), are in late-stage development.
H 2 N
CH 3
H 3 C
HO O
Teicoplanin. This agent is a mixture of six closely
related compounds: One compound has a terminal
hydrogen at the oxygen indicated by an asterisk; five
compounds have an R substituent of either a decanoic
acid [n-, 8-methyl-, 9-methyl, (Z)-4-] or of a nonanoic
acid [8-methyl]. Although not FDA approved for use in
the U.S., it is available in Europe. It is similar to vancomycin
in chemical structure, mechanism of action,
spectrum of activity, and route of elimination (i.e., primarily
renal).
HO NHR
HO
O
CH 2 OH
O*
Cl
Cl
CH 2 OH
O O
HO
O O H
HO
H 3 COCNH
O O O
H H
H H
O
N
N
N
N
N
H
HN H
H
H H
O
H O H
H
HOOC
HO
O
OH OH
CH 2 OH
O
O Cl
O
HO
H
Cl
H
O
H H H O
O
N
H
N
N
HN
H O
H 2 NC
HOOC H
O
HO
O
OH
OH
VANCOMYCIN
H
N
H O
OH
HO
O
CH 2 OH
O OH
OH
OH
TEICOPLANIN
H
OH
O
H
N
H
H 3 C
CH 3
O
HO
NHCH 3
H
NH 2
1539
CHAPTER 55
PROTEIN SYNTHESIS INHIBITORS AND MISCELLANEOUS ANTIBACTERIAL AGENTS