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INTRODUCTION
SUPPLEMENT ARTICLE
Vancomycin: A 50-Year Reassessment
Robert C. Moellering, Jr.
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
More than half a century ago, the compound now known as vancomycin was
isolated from a soil sample collected deep
in the interior jungle of Borneo. The isolation was performed by Dr. E. C. Kornfeld, an organic chemist at Eli Lilly, which
had begun a major program to discover
new antimicrobial agents with activity
against staphylococci [1]. Although it had
been only 15 years since the initial deployment of penicillin and the subsequent
discovery of macrolides and tetracyclines,
staphylococcal resistance to these compounds was already a major problem in
hospitals throughout the world.
The soil sample from Borneo contained
an organism (subsequently named “Streptomyces orientalis”) that yielded a compound in broth fermentation with a high
degree of bactericidal activity against
staphylococci. The initial compound was
labeled 05865, and early laboratory studies
showed that staphylococci failed to develop significant resistance to 05865 on
serial passage in culture media containing
the drug. Because of the growing menace
of drug-resistant staphylococci, the US
Food and Drug Administration essentially
“fast-tracked” approval of compound
05865, which was subsequently given the
generic name “vancomycin,” a term derived from the word “vanquish.” The orig-
Reprints or correspondence: Dr. Robert C. Moellering, Jr.,
Dept. of Medicine, Beth Israel Deaconess Medical Center,
110 Francis St., Ste. 6A, Boston, MA 02215 (rmoeller@
bidmc.harvard.edu).
Clinical Infectious Diseases 2006; 42:S3–4
2005 by the Infectious Diseases Society of America. All
rights reserved.
1058-4838/2006/4201S1-0002$15.00
inal preparations of vancomycin from fermentation broth contained a number of
impurities, and, because of the brown
color of the material, it was nicknamed
“Mississippi mud” by scientists at Eli Lilly
[1]. Despite its early promise, however, vancomycin was not widely used in the decade
following its discovery. The major reasonwas
that methicillin and, subsequently, other antistaphylococcal penicillins were discovered
and became the drugs of choice for treating
staphylococcal infections. Vancomycin was
relegated to a secondary role, in large part,
on the basis of results of early studies performed during the mid-1950s that showed
it to be ototoxic and nephrotoxic [1]. It is
very likely that whatever ototoxicity and nephrotoxicity resulted from the use of vancomycin were related to the presence of impurities in the earlier preparations; when
newer, purer preparations were retested in
the late 1970s, they produced no ototoxicity
and little nephrotoxicity in the animal models, unless given in combination with aminoglycosides [2, 3]. Because of the possible
toxicity of vancomycin, it was not heavily
marketed during the 1960s and 1970s and
was relegated to a secondary role in antibacterial chemotherapy.
However, the worldwide emergence of
methicillin-resistant staphylococci in the
1970s rekindled interest in vancomycin. It
was only at this juncture that the pharmacokinetics of the drug were determined, and the first of several nomograms
for dosage for patients with impaired renal
function was published [4]. It was also at
this point that the initial reevaluation of
vancomycin was published as a supple-
ment in Reviews of Infectious Diseases (the
predecessor to Clinical Infectious Diseases).
The supplement was entitled “Reassessments of Vancomycin—A Potentially Useful Antibiotic” [5] and reflected a cautious,
somewhat measured approach to the potential utility of vancomycin. That publication also marked the first quarter century of the existence of vancomycin as an
antimicrobial agent—a period during
which it was little more than a “slumbering non-giant.”
Things changed rapidly in the 1980s,
however, and the worldwide use of vancomycin accelerated. Another glycopeptide, teicoplanin, was also developed and
used widely during that time in most
countries, except the United States, where
it was never licensed. Because vancomycin
was no longer patented by that time, it
was not subjected to the intense marketing
typically associated with antimicrobial
agents. Nonetheless, the drug more than
“sold itself” because of a very real clinical
need. As predicted from earlier in vitro
studies, there was initially little emergence
of resistance to vancomycin or teicoplanin
among staphylococci and other gram-positive bacteria. However, the emergence of
vancomycin-resistant enterococci in the
middle of the 1980s served as a wake-up
call [6]. It took more than a decade until
significant resistance to vancomycin was
also discovered in staphylococci. These resistant isolates were initially termed “vancomycin-intermediate Staphylococcus aureus,” because the MICs of vancomycin for
these organisms were in the “intermediate” category of the arbitrarily assigned
Introduction: Vancomycin • CID 2006:42 (Suppl 1) • S3
vancomycin susceptibility breakpoints [7].
Nonetheless, these organisms were clinically resistant to vancomycin, and patients
infected with these organisms often experienced failure of therapy with vancomycin [8]. True high-level resistance to
vancomycin in S. aureus, which is due to
the acquisition of vanA genes, presumably
from enterococci, first occurred in 2002
in Michigan [9]. Although this event
served as a wake-up call that high-level
vancomycin resistance in S. aureus was
possible, to date, this has not become a
significant clinical problem, because only
5 isolates (all from the United States) have
been documented. Nonetheless, more
subtle hints of clinical failure of vancomycin have begun to emerge, and there is
growing evidence that vancomycin may
not be as effective against all strains of
staphylococci as it was 25 years ago [10].
At this point, the true significance of this
apparently diminished clinical activity of
vancomycin (and teicoplanin) remains to
be firmly defined, but it is of concern.
Thus, 50 years after its discovery, van-
S4 • CID 2006:42 (Suppl 1) • Moellering, Jr.
comycin remains an interesting and even
somewhat controversial agent. However,
we know a great deal more about the drug
than we did 25 years ago. It seems more
than reasonable at the half-century mark
to once again reassess the effectiveness and
utility of vancomycin. The articles in this
supplement deal with a number of important issues relating to the development,
pharmacodynamics, safety, and therapeutic efficacy of modern preparations of vancomycin and should serve to provide an
effective framework for determining its
appropriate clinical niche in the coming
years.
4.
5.
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8.
Acknowledgment
Potential conflicts of interest. R.C.M., Jr. has
served as a consultant to Pfizer, Cubist, and
Vircuron.
References
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3. Farber BF, Moellering RC Jr. Retrospective
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