SUPPLEMENT ARTICLE

Vancomycin: A History
Donald P. Levine
Department of Medicine, Wayne State University, Detroit, Michigan

Vancomycin became available for clinical use 150 years ago but was soon discarded in favor of other antibiotics
that were deemed to be more efficacious and less toxic. The advent of pseudomembranous enterocolitis,
coupled with the spread of methicillin-resistant Staphylococcus aureus, led to a resurgence in the use of
vancomycin. Almost immediately, concerns arose with regard to its therapeutic utility. In addition, resistance
to vancomycin developed, first in enterococci and later in staphylococci. Several types of resistance have now
been identified, each with a unique effect on infections treated with vancomycin. Recent studies have rekindled
interest in the best way to administer the antibiotic. The findings of future studies may result in a return to
measuring levels of vancomycin in serum, to assure a successful therapeutic outcome.

There is greater interest in vancomycin now, 50 years
after its discovery, than at any time in its history. Re-
cently published articles about vancomycin reflect par-
allel increases in both the use of vancomycin and our
knowledge about this interesting antibiotic (figure 1).
A historical review puts this into perspective. In the
1950s, with few options available to treat penicillin-
resistant staphylococcal infections, Eli Lilly and Com-
pany initiated a program aimed at discovering antibi-
otics with activity against these pathogens. In 1952, a
missionary in Borneo sent a sample of dirt to his friend
Dr. E. C. Kornfield, an organic chemist at Eli Lilly. An
organism isolated from that sample (Streptomyces or-
ientalis) produced a substance (“compound 05865”)
that was active against most gram-positive organisms,
including penicillin-resistant staphylococci [1]. Some
anaerobic organisms, including clostridia, were also
susceptible to compound 05865 [2], as was Neisseria
gonorrhoeae [3]. In vitro experiments were initiated to
determine whether the activity of compound 05865
would be preserved despite attempts to induce resis-
tance. After 20 serial passages of staphylococci from Eli
Lilly laboratories, resistance to penicillin increased
100,000-fold, compared with only a 4–8-fold increase
Reprints or correspondence: Dr. Donald P. Levine, Wayne State University, Dept.
of Medicine, 4201 St. Antoine, Ste. 5C, Detroit, MI 48201 (dlevine@med
.wayne.edu).
Clinical Infectious Diseases 2006; 42:S5–12
 2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4201S1-0003$15.00
in resistance to compound 05865 [4]. Isolates from
other laboratories were also tested, and the results were
similar [5, 6]. Subsequent animal experiments sug-
gested that compound 05865 might be safe and effective
in humans. However, before clinical trials were begun,
the compound, dubbed “Mississippi mud” because of
its brown color, needed to be purified. A switch from
picric acid precipitation to passage over an ion-ex-
change resin was an improvement, and the resulting
drug, which was named “vancomycin” (from the word
“vanquish”), was made available for clinical trials.
In studies of volunteers, vancomycin reached ther-
apeutic concentrations in various tissue compartments
and resulted in successful treatment of serious staph-
ylococcal infection in 8 of 9 patients, including 1 patient
with endocarditis. The sole therapeutic failure occurred
in a patient with empyema, in whom an adequate con-
centration could not be achieved in the empyema
pocket [2]. Six patients with endocarditis who had ex-
perienced prior therapy failure with other antibiotics
were also treated with vancomycin; 5 patients were
cured. The therapy failure occurred in a patient who
was admitted to the hospital with multiple complica-
tions, including shock and intractable heart failure, and
who died after receiving treatment for 5 days [7]. As
information about vancomycin spread, it was requested
for cases for which other drugs had failed. Emergency
shipments were made around the clock. Extra supplies
at one hospital were shipped to another, if needed.
Ultimately, reports of successful treatment were orga-
nized and submitted to the US Food and Drug Ad-

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 Figure 1. Number of English-language articles with “vancomycin” in the title published since 1955, according to a 2004 search of Medline
ministration, and, in 1958, in the absence of an effective al-
ternative, vancomycin was immediately approved [1]. Later
published studies confirmed the efficacy of the drug [8, 9].
However, methicillin, the first semisynthetic penicillin, was
also approved in 1958, followed shortly thereafter by cephal-
othin. Because of perceived toxicity, vancomycin became re-
served for patients with serious b-lactam allergies or patients
with infections caused by organisms that were resistant to the
newer agents.
TOXICITY
In the initial trials, little toxicity was observed in association
with vancomycin use. Venous irritation, chills, and rash were
reported but were considered to be infusion related. Ototoxicity
was observed, usually presenting as tinnitus, but was attributed
to elevated serum concentrations found in patients with renal
failure. These problems occurred more frequently in association
with the use of early preparations of vancomycin and were
considered to be the result of impurities in the compound.
Reports of ototoxicity described patients who were also re-
ceiving known ototoxic drugs. Traber and I [10] reported the
acute onset of tinnitus and documented hearing loss 7 days
after beginning therapy with vancomycin for a patient who was
receiving no other ototoxic drugs. His peak serum vancomycin
concentration was 49.2 mg/mL, and an audiogram revealed a
profound high-frequency sensorineural hearing loss that slowly
improved, despite continued treatment with vancomycin at a
lower dose [10]. Nevertheless, subsequent studies indicated that
vancomycin-induced ototoxicity was an infrequent occurrence
[11, 12]. Infusion-related chills seemed to be eliminated by use
of the purified commercial product, and skin rash, which was
described in early reports, has not been a persistent problem
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[7]. In a retrospective analysis of patients receiving vancomycin
between 1974 and 1981, auditory toxicity was not seen. Fever
and rash were uncommon (1%–3% of patients). Phlebitis af-
fected 13% of patients and necessitated discontinuation of ther-
apy for 2% of patients. Nephrotoxicity was infrequent (5% of
patients) and reversible, but it possibly was potentiated by con-
comitant aminoglycoside therapy. Neutropenia occurred in 2%
of patients but was rapidly reversible [13]. Thrombocytopenia
associated with the use of vancomycin has been studied [14,
15], as has the nephrotoxic potential of vancomycin [16–18].
Vancomycin rarely causes interstitial nephritis [16], and the
combination of vancomycin and aminoglycosides has been re-
ported to cause renal failure, especially in adults who are re-
ceiving prolonged therapy and whose trough serum vanco-
mycin concentrations are 110 mg/mL [17, 18]. Notably, the
combination does not appear to cause nephrotoxicity in chil-
dren [19, 20].
Rapid infusion of vancomycin has been associated with the
“red man,” or “red neck,” syndrome. This syndrome, which is
characterized by a combination of erythema, pruritis, hypo-
tension, and angioedema, is a histamine-like response to rapid
infusion, but was not a feature of early reports. Rybak et al.
[21] compared the incidence of red man syndrome in patients
taking either vancomycin or teicoplanin (a glycopeptide anti-
biotic with an antimicrobial spectrum similar to that of van-
comycin) with the incidence of red man syndrome in healthy
control subjects given vancomycin or placebo. For both patients
and control subjects, vancomycin infusions lasted 60 min and
were administered via infusion pumps with identical tubing.
Nine of 10 control subjects who received vancomycin experi-
enced symptoms, versus none of the patients who received
either vancomycin or teicoplanin (P ! .001) [21]. Interestingly,
 Figure 2. Use of vancomycin in the United States, France, Italy, Germany, the United Kingdom, and The Netherlands. Reprinted from Kirst et al.
[28] with permission from the American Society for Microbiology.
there was no difference in serum histamine levels between pa-
tients and control subjects, which could be explained only by
the hypothesis that infection blunts the effect of glycopeptides.
No matter how much toxicity is truly related to vancomycin,
many researchers were convinced that problems could be
avoided by careful monitoring of serum concentrations.
MONITORING
Measuring vancomycin levels in serum might be helpful to
prevent toxicity and to assure an adequate therapeutic drug
concentration. However, there are no definitive studies relating
serum concentrations of vancomycin to treatment outcome.
Indeed, the standard regimens of 500 mg of vancomycin every
6 h or 1 g of vancomycin every 12 h appear to have been
arbitrary. However, many clinicians preferred to know whether
the regimen they prescribed achieved an expected serum con-
centration, especially if dosage adjustments were necessitated
by renal failure. Thus, to assure a desired concentration without
actually measuring serum levels, several investigators con-
structed nomograms, several of which became popular [22, 23].
Other investigators compared individualized dosing based on
the actual serum concentration with dosing based on data from
nomograms and found the individualized method to be su-
perior [24, 25]. However, by 1994, without data to support either
a therapeutic or a toxic range, Cantu et al. [26] questioned the
value of monitoring serum concentrations of vancomycin. Moell-
ering [27] agreed but recommended monitoring of serum levels
in certain situations—for example, when patients receive van-
comycin/aminoglycoside combinations, when anephric patients
undergoing hemodialysis receive infrequent doses of vancomy-
cin, and when patients receive higher-than-usual doses of van-
comycin. With no clear consensus, many clinicians chose to dose
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according to nomogram data, whereas others measured serum
concentrations in every case. Currently, the issue is being recon-
sidered, as will be discussed later in this article.
CLINICAL USE
As noted above, shortly after being introduced, vancomycin
was eclipsed by antibiotics that were considered to be less toxic
and equally or more efficacious. Beginning in the early 1980s,
a dramatic increase in vancomycin use occurred, with a 1100-
fold increase occurring over the next 2 decades [28] (figure 2).
Two events were primarily responsible for this dramatic resur-
gence. The first was the advent of pseudomembranous enter-
ocolitis. Prior to its release, vancomycin was used to treat an
entity called “postoperative micrococcal colitis” [2]. The re-
sponse to vancomycin was excellent, and the presence of this
disease, also called “acute staphylococcal ileocolitis,” became
an indication for the use of vancomycin [29]. Although Clos-
tridium difficile is the primary agent of pseudomembranous
enterocolitis, Staphylococcus aureus is clearly an occasional cause
of the disorder [30]. Because vancomycin is active against both
pathogens and is poorly absorbed from the intestinal tract, it
became the drug of choice for treating pseudomembranous
enterocolitis [31]. However, widespread vancomycin use, es-
pecially via the oral route, was responsible, at least in part, for
the development of vancomycin-resistant enterococci (VRE)
(discussed below) [32]. With the recent interest in intracolonic
administration of vancomycin, VRE will likely remain a grow-
ing problem [33, 34].
The second event leading to increased vancomycin use was
the widespread appearance of resistant pathogens: first, meth-
icillin-resistant S. aureus (MRSA), and, then, penicillin-resistant
Streptococcus pneumoniae. Known for decades as a cause of
History of Vancomycin • CID 2006:42 (Suppl 1) • S7
 nosocomial infection [35], MRSA appeared suddenly in com-
munity isolates in Detroit and, later, throughout the world [36–
38]. With its predictable activity against MRSA, vancomycin
was the drug of choice, thus beginning a new era in the history
of the antibiotic.
In 1982, Sorrell et al. [39] described 19 patients with MRSA
infection, including 10 with bacteremia. Vancomycin was
equally as effective against MRSA as standard therapy was
against methicillin-susceptible S. aureus, but the results may
have been influenced by adjunctive therapy with aminoglyco-
sides, rifampin, or trimethoprim-sulfamethoxazole. In addi-
tion, although patients had peak and trough vancomycin levels,
which conformed to previously recommended ranges (18.0–
47.0 mg/mL and 4.8–12.9 mg/mL, respectively), tinnitus, rash,
neutropenia, and possible nephrotoxicity were observed. At the
same time, my colleagues and I described 24 patients with
infective endocarditis due to MRSA infection [40]. Most pa-
tients received other antibiotics in addition to vancomycin, so
the mean duration of bacteremia (9.2 days) must be interpreted
in that light. One patient, the index case patient, remained
bacteremic for 68 days without vancomycin therapy before un-
dergoing tricuspid valve excision. Prior to surgery, she was given
a variety of different regimens, and, each time, she appeared
to respond initially. Therapy with vancomycin would have been
started sooner, but the treating physician was reluctant to use
it because of concerns about toxicity.
With the increased use of vancomycin came data suggesting
that vancomycin might not be equivalent to b-lactams. For
example, some patients with septic thrombophlebitis had per-
sistent bacteremia, despite receiving treatment with heparin and
vancomycin. It was found that heparin causes vancomycin to
precipitate when administered through the same tubing, leading
to subtherapeutic concentrations of vancomycin [41]. Small
and Chambers [42] studied S. aureus isolates recovered from
patients who experienced failure of vancomycin therapy and
found that, compared with nafcillin, vancomycin resulted in
delayed bacterial eradication in vitro.
In an effort to address the question of the efficacy of van-
comycin, my colleagues and I studied patients with endocarditis
due to MRSA. We planned to compare vancomycin mono-
therapy with combination therapy involving vancomycin plus
either rifampin or gentamicin. However, clinicians were reluc-
tant to participate, fearing that the vancomycin-gentamicin
combination would prove to be too toxic. Thus, the final study
consisted of only 2 treatment arms: vancomycin monotherapy
or vancomycin plus rifampin [43]. Vancomycin monotherapy
resulted in prolonged bacteremia (9.0 days), which is consistent
with the results of our previous report but nearly 3 times as
long as the duration observed with nafcillin therapy [44]. Of
equal importance, 6 (14%) of 43 patients experienced therapy
failure; 3 died, and 3 required valve replacement or excision.
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Surprisingly, patients receiving vancomycin plus rifampin re-
mained bacteremic longer than did those receiving vancomycin
alone, although the data were not statistically significant. In
studies of coagulase-negative staphylococci, vancomycin and
rifampin are usually synergistic in vitro [45, 46]. The combi-
nation is less predictable against S. aureus, and antagonism has
been reported [47, 48]. Whether antagonism played a role in
our study is unknown. In a search for better alternatives, Mar-
kowitz et al. [49] found vancomycin to be superior to tri-
methoprim-sulfamethoxazole in treating patients infected with
either MRSA or methicillin-susceptible S. aureus, although the
main difference was in patients infected with methicillin-sus-
ceptible S. aureus.
The emergence of penicillin-resistant S. pneumoniae presented
new therapeutic challenges, especially for the treatment of men-
ingitis. Vancomycin was well-established therapy for shunt-re-
lated meningitis, but there always was concern about its pene-
tration across the blood-brain barrier. Because penicillin-resistant
S. pneumoniae may also be cephalosporin resistant, vancomycin
plus a third-generation cephalosporin is the standard initial em-
pirical regimen for known or suspected cases of pneumococcal
meningitis. Studies show variable penetration in adults, but re-
sults are favorable if high doses of vancomycin are used. However,
concomitant steroid therapy, which is also standard for acute
meningitis in adults, may prevent adequate vancomycin levels in
CSF. In pediatric patients, the combination of vancomycin plus
steroids does not appear to be harmful [50].
RESISTANCE AND ITS IMPACT
With the accelerated use of vancomycin that began in the 1980s,
it was inevitable that resistance would occur. VRE were reported
in Europe by 1986 and in the United States by 1987 [51]. Six
resistance patterns (designated “VanA” through “VanE,” and,
most recently, “VanG”) have been reported [52, 53]. VanA-type
strains are inducibly resistant to high levels of vancomycin (MIC,
⭓64 mg/mL) and teicoplanin (MIC, ⭓16 mg/mL). VanB-type
strains are also inducibly resistant to vancomycin (MIC, 4 to
11024 mg/mL) but retain susceptibility to teicoplanin [54]. VanC,
which is found in Enterococcus casseliflavus/Enterococcus flavescens
and Enterococcus gallinarum, is constitutive and confers low-level
resistance to vancomycin (MIC, 4–32 mg/mL) but not to tei-
coplanin [55]. VanD is also constitutive and has been found in
only a few isolates [55]. Like the Van A, VanB, and VanD types,
the VanE type appears to be acquired and also confers low-level
resistance to vancomycin only (MIC, 16 mg/mL), as does VanG
(MIC, 12–16 mg/mL). Multiple genes are responsible for these
different phenotypes, but they produce resistance by only one or
the other of 2 common pathways. The target for vancomycin is
the terminal d-alanyl-d-alanine of the growing peptidoglycan
chain. In vancomycin-resistant organisms, these peptidoglycan
intermediates are altered to either d-alanyl-d-lactate (VanA,
 VanB, and VanD) or d-alanyl-d-serine (VanC, VanE, and VanG).
These altered targets have reduced affinity for vancomycin, re-
sulting in much higher MICs.
Depardieu et al. [52] contributed much to the understanding
of resistance to vancomycin and helped to characterize the
clinical significance of each glycopeptide-resistant phenotype.
Using a strain of VanB-resistant Enterococcus faecalis, Aslangul
et al. [54] were able to prevent the emergence of resistance by
combining teicoplanin with gentamicin; monotherapy with ei-
ther vancomycin or teicoplanin induced resistance. Later ex-
periments with a VanB isolate proved that a 2-step mechanism
is required for the development of resistance to the combination
of teicoplanin and gentamicin [56]. VanE strains responded to
high doses of glycopeptides, whereas standard doses led to treat-
ment failure in the rabbit model of endocarditis. Notably, be-
cause such strains may be indistinguishable from other types
of resistant enterococci in clinical practice, Lafaurie et al. [57]
recommended the routine use of combination therapy with
gentamicin. Finally, Lefort et al. [58] found VanD strains to be
affected by a significant inoculum effect. Detection of such
strains is important, because standard doses of vancomycin or
teicoplanin might result in mutants with high-level glycopep-
tide resistance in infections with high bacterial density.
Perhaps the greatest concern about VRE is the potential for
resistance to spread from enterococci to other pathogens, in
particular to S. aureus. Enterococci possess several systems,
including plasmids and transposons, that enable the transfer
of genetic material to other bacteria. Although the transfer of
resistance from enterococci to S. aureus was demonstrated in
vitro in 1992 [59], some researchers questioned whether it
could occur in natural conditions. Intermediate resistance to
vancomycin had already been reported among staphylococci,
but it was not caused by transfer of genetic material from
enterococci. The first staphylococci with reduced susceptibility
to vancomycin were reported from Japan in 1997 [60, 61].
Additional strains soon appeared in the United States. The
MICs of these isolates range from 4 to 8 mg/mL; hence, they
are called “vancomycin-intermediate S. aureus” (VISA). These
strains produce an excess amount of non–cross-linked d-alanyl-
d-alanine, which captures vancomycin molecules, thus pre-
venting them from reaching the target site [62]. Infection with
VISA has been associated with treatment failure [63], but these
organisms are rare and, thus far, have not had a major clinical
impact [64]. More common are strains of MRSA that are “het-
eroresistant” to vancomycin (hVISA); such strains now account
for up to 26% of MRSA isolates in Japan [65]. The vancomycin
MIC of hVISA is within the susceptible range (⭐4 mg/mL), but
these strains contain subpopulations that exhibit reduced sus-
ceptibility. These organisms have additional importance, be-
cause they may be precursors to VISA [63, 66]. If so, the fact
that they are becoming widespread is of great concern.
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At present, there are no standardized methods to identify
hVISA, which makes reports of treatment failures difficult to
interpret [66]. Another problem is that routine clinical labo-
ratory techniques may be inadequate to detect staphylococci
with reduced susceptibility to vancomycin [67]. Nevertheless,
several published series indicate that vancomycin is ineffective
for the treatment of hVISA strains. Wong et al. [68] attributed
vancomycin therapy failure to heteroresistance in 4 patients
with bacteremia. Other investigators studied paired isolates re-
covered from a patient who experienced relapse of infection
after receiving vancomycin therapy for infective endocarditis.
The relapse isolate was identical to the initial isolate, as deter-
mined by PFGE, but resistant populations were identified. De-
spite MICs in the susceptible range (MIC, ⭐2 mg/mL), when
the relapse isolate was tested in the rabbit model of endocarditis,
vancomycin failed to reduce the organism count in vegetations
[69]. Charles et al. [70] compared 48 episodes of bacteremia
due to vancomycin-susceptible MRSA with 5 cases of bacter-
emia due to hVISA during a 12-month period. Patients infected
with hVISA were more likely to experience persistent fever and
bacteremia for 17 days (P ! .001). Although patients infected
with hVISA tended to have low trough serum vancomycin levels
during the first week of therapy, vancomycin therapy failed
even after dosage adjustments. Fridkin et al. [71] reported a
case-control analysis of infections due to S. aureus with reduced
susceptibility to vancomycin (SA-RVS). For that report, re-
duced susceptibility was defined as an MIC of ⭓4 mg/mL and
included isolates with MICs of 8–16 mg/mL, which are generally
referred to as VISA strains. Patients infected with SA-RVS had
a crude 6-month mortality rate of ∼80%, similar to patients
infected with VISA [71]. Patients infected with SA-RVS also
had a higher in-hospital mortality rate. Risk factors for SA-
RVS infection were antecedent vancomycin use and MRSA in-
fection in the preceding 2 or 3 months. In another study of
patients with serious infections due to SA-RVS, 76% experi-
enced glycopeptide therapy failure, and 40% died [72].
Currently, there is growing interest in another aspect of
staphylococcal function that affects therapeutic outcome. Ac-
cessory gene regulator group II polymorphism, which is dis-
cussed in more detail by Sakoulas et al. [73] and Stevens [74]
elsewhere in this supplement and which may also play an im-
portant role in vancomycin resistance, has recently been rec-
ognized as a risk factor for vancomycin therapy failure in MRSA
infection [75, 76].
The question regarding the transfer of resistance from en-
terococcus to S. aureus in nature was answered when the first
vancomycin-resistant S. aureus (VRSA; MIC, ⭓32 mg/mL) iso-
late was recovered from a patient in Michigan. The patient had
diabetes, peripheral vascular disease, renal failure, and chronic
infected foot ulcers that were treated intermittently with van-
comycin. In addition to VRSA, a VRE isolate was also recovered
History of Vancomycin • CID 2006:42 (Suppl 1) • S9
 from a foot lesion; this is a noteworthy fact because, by this
time, Enterococcus faecium had largely supplanted E. faecalis as
the predominant species found in hospital settings. It appears
that the staphylococcus acquired the VanA gene from the VRE
[77, 78]. A second VRSA strain was soon isolated from a patient
in Pennsylvania, who also had received intermittent courses of
vancomycin, but none during the 5 years prior to developing
VRSA infection [79]. She was colonized with VRE and MRSA,
both of which were isolated on multiple occasions. As in the
Michigan case, it appears that the MRSA acquired VanA from
the VRE, even though the patient was not being treated with
vancomycin at the time [80, 81]. In April 2004, a third VRSA
strain (vancomycin MIC, 64 mg/mL) was isolated from a pa-
tient in New York [82]. This strain was found to be vancomycin
susceptible, as determined by standard automated antimi-
crobial susceptibility testing. The observation that automated
techniques might misinterpret antibiotic susceptibility among
staphylococci prompted the Centers for Disease Control and
Prevention to publish new guidelines for laboratory testing of
S. aureus isolates [83].
As we advance further into the era of vancomycin resistance,
it is important to recall that failure of vancomycin therapy may
still occur in infections due to susceptible organisms. Fowler,
Jr. et al. [84] found vancomycin therapy to be an independent
risk factor for recurrent S. aureus bacteremia, and, in another
study, vancomycin treatment was cited as a potential reason
for increased mortality among patients with MRSA infection
[85]. Recent evidence suggests that outcomes might be deter-
mined by even slight differences in the MIC. In a recent study
by Fowler, Jr. et al. [76], patients with bacteremia due to MRSA
with an MIC of ⭐0.05 mg/mL had a 55.6% success rate, com-
pared with a 9.5% success rate among patients whose bacter-
emia was due to MRSA with an MIC of 1–2 mg/mL (P p .03).
Such a result might be avoided if there were reliable data in-
dicating what serum vancomycin level predicts therapeutic suc-
cess (i.e., the therapeutic concentration). Knowledge of the
therapeutic concentration and the MIC of the pathogen might
overcome the intrinsic deficiencies of the drug and improve its
utility. As an example, the serum vancomycin level was noted
to play a role in the treatment of pneumonia. Penetration of
vancomycin into lung tissue is poor [86], resulting in thera-
peutic failure in patients with pneumonia [87]. However, when
the serum concentration was maintained at a level sufficiently
above the MIC of the infecting organism, the outcome was
significantly improved. Moise et al. [88] showed that 78% of
the patients being treated for pneumonia who achieved an area
under the inhibition curve of 1345 survived, versus 24% of the
patients with an area under the inhibition curve of ⭐345. Fu-
ture studies must address whether specific therapeutic ranges
can be determined for different types of infections. A return
to monitoring serum levels, a practice almost abandoned long
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ago, might be required, but it might also extend the useful life
of this antibiotic. After 50 years, we are learning more about
vancomycin than ever before, and this knowledge may lead us
to a much more successful approach to patient care. Even after
50 years, there is still much to add to the history of vancomycin.
Acknowledgment
Potential conflict of interest. D.P.L. receives grant/research support
from Cubist, Nabi, and Wyeth and is a consultant for Cubist.
References
1. Anderson RCGR, Higgins HM Jr, Pettinga CD. Symposium: how a
drug is born. Cincinnati J Med 1961; 42:49–60.
2. Geraci JE, Heilman FR, Nichols DR, Ross GT, Wellman WE. Some
laboratory and clinical experiences with a new antibiotic, vancomycin.
Mayo Clin Proc 1956; 31:564–82.
3. Geraci JE, Wilson WR. Vancomycin therapy for infective endocarditis.
Rev Infect Dis 1981; 3(Suppl):S250–8.
4. McGuire JM, Wolfe RN, Ziegler DW. Vancomycin, a new antibiotic.
II. In vitro antibacterial studies. Antibiot Annu 1955; 3:612–8.
5. Griffith RS. Vancomycin: continued clinical studies. Antibiot Annu
1956–1957:118–22.
6. Griffith RS, Peck FB Jr. Vancomycin, a new antibiotic. III. Preliminary
clinical and laboratory studies. Antibiot Annu 1955; 3:619–22.
7. Geraci JE, Heilman FR, Nichols DR, Wellman WE. Antibiotic therapy
of bacterial endocarditis. VII. Vancomycin for acute micrococcal en-
docarditis: preliminary report. Mayo Clin Proc 1958; 33:172–81.
8. Geraci JE, Heilman FR. Vancomycin in the treatment of staphylococcal
endocarditis. Prog Neurobiol 1960; 35:316–26.
9. Kirby WM, Perry DM, Bauer AW. Treatment of staphylococcal sep-
ticemia with vancomycin: report of thirty-three cases. N Engl J Med
1960; 262:49–55.
10. Traber PG, Levine DP. Vancomycin ototoxicity in patient with normal
renal function. Ann Intern Med 1981; 95:458–60.
11. Brummett RE, Fox KE. Vancomycin- and erythromycin-induced hear-
ing loss in humans. Antimicrob Agents Chemother 1989; 33:791–6.
12. Brummett RE. Ototoxicity of vancomycin and analogues. Otolaryngol
Clin North Am 1993; 26:821–8.
13. Farber BF, Moellering RC Jr. Retrospective study of the toxicity of
preparations of vancomycin from 1974 to 1981. Antimicrob Agents
Chemother 1983; 23:138–41.
14. Marraffa J, Guharoy R, Duggan D, Rose F, Nazeer S. Vancomycin-
induced thrombocytopenia: a case proven with rechallenge. Pharma-
cotherapy 2003; 23:1195–8.
15. Zenon GJ, Cadle RM, Hamill RJ. Vancomycin-induced thrombocy-
topenia. Arch Intern Med 1991; 151:995–6.
16. Bergman MM, Glew RH, Ebert TH. Acute interstitial nephritis asso-
ciated with vancomycin therapy. Arch Intern Med 1988; 148:2139–40.
17. Cimino MA, Rotstein C, Slaughter RL, Emrich LJ. Relationship of
serum antibiotic concentrations to nephrotoxicity in cancer patients
receiving concurrent aminoglycoside and vancomycin therapy. Am J
Med 1987; 83:1091–7.
18. Rybak MJ, Albrecht LM, Boike SC, Chandrasekar PH. Nephrotoxicity
of vancomycin, alone and with an aminoglycoside. J Antimicrob Che-
mother 1990; 25:679–87.
19. Goren MP, Baker DK Jr, Shenep JL. Vancomycin does not enhance
amikacin-induced tubular nephrotoxicity in children. Pediatr Infect
Dis J 1989; 8:278–82.
20. Nahata MC. Lack of nephrotoxicity in pediatric patients receiving con-
current vancomycin and aminoglycoside therapy. Chemotherapy
1987; 33:302–4.
21. Rybak MJ, Bailey EM, Warbasse LH. Absence of “red man syndrome”
 in patients being treated with vancomycin or high-dose teicoplanin.
Antimicrob Agents Chemother 1992; 36:1204–7.
22. Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinetics
of vancomycin in patients with various degrees of renal function. An-
timicrob Agents Chemother 1984; 25:433–7.
23. Moellering RC Jr, Krogstad DJ, Greenblatt DJ. Vancomycin therapy in
patients with impaired renal function: a nomogram for dosage. Ann
Intern Med 1981; 94:343–6.
24. Rybak MJ, Boike SC. Monitoring vancomycin therapy. Drug Intell Clin
Pharm 1986; 20:757–61.
25. Rybak MJ, Boike SC. Individualized adjustment of vancomycin dosage:
comparison with two dosage nomograms. Drug Intell Clin Pharm
1986; 20:64–8.
26. Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin con-
centrations: reappraisal of their clinical value. Clin Infect Dis 1994; 18:
533–43.
27. Moellering RC Jr. Monitoring serum vancomycin levels: climbing the
mountain because it is there? Clin Infect Dis 1994; 18:544–6.
28. Kirst HA, Thompson DG, Nicas TI. Historical yearly usage of van-
comycin. Antimicrob Agents Chemother 1998; 42:1303–4.
29. Geraci JE. Vancomycin. Mayo Clin Proc 1977; 52:631–4.
30. Gravet A, Rondeau M, Harf-Monteil C, et al. Predominant Staphy-
lococcus aureus isolated from antibiotic-associated diarrhea is clinically
relevant and produces enterotoxin A and the bicomponent toxin LukE-
LukD. J Clin Microbiol 1999; 37:4012–9.
31. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile
colitis. JAMA 1993; 269:71–5.
32. Gerding DN. Is there a relationship between vancomycin-resistant en-
terococcal infection and Clostridium difficile infection? Clin Infect Dis
1997; 25(Suppl 2):S206–10.
33. Apisarnthanarak A, Khoury H, Reinus WR, Crippin JS, Mundy LM.
Severe Clostridium difficile colitis: the role of intracolonic vancomycin?
Am J Med 2002; 112:328–9.
34. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic van-
comycin for severe Clostridium difficile colitis: case series and review
of the literature. Clin Infect Dis 2002; 35:690–6.
35. Peacock JE Jr, Marsik FJ, Wenzel RP. Methicillin-resistant Staphylo-
coccus aureus: introduction and spread within a hospital. Ann Intern
Med 1980; 93:526–32.
36. Centers for Disease Control (CDC). Community-acquired methicillin-
resistant Staphylococcus aureus infections—Michigan. MMWR Morb
Mortal Wkly Rep 1981; 30:185–7.
37. Saravolatz LD, Pohlod DJ, Arking LM. Community-acquired methi-
cillin-resistant Staphylococcus aureus infections: a new source for nos-
ocomial outbreaks. Ann Intern Med 1982; 97:325–9.
38. Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E. Methicillin-
resistant Staphylococcus aureus: epidemiologic observations during a
community-acquired outbreak. Ann Intern Med 1982; 96:11–6.
39. Sorrell TC, Packham DR, Shanker S, Foldes M, Munro R. Vancomycin
therapy for methicillin-resistant Staphylococcus aureus. Ann Intern Med
1982; 97:344–50.
40. Levine DP, Cushing RD, Jui J, Brown WJ. Community-acquired meth-
icillin-resistant Staphylococcus aureus endocarditis in the Detroit Med-
ical Center. Ann Intern Med 1982; 97:330–8.
41. Barg NL, Supena RB, Fekety R. Persistent staphylococcal bacteremia
in an intravenous drug abuser. Antimicrob Agents Chemother 1986;
29:209–11.
42. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus en-
docarditis in intravenous drug users. Antimicrob Agents Chemother
1990; 34:1227–31.
43. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or
vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus
endocarditis. Ann Intern Med 1991; 115:674–80.
44. Korzeniowski O, Sande MA. Combination antimicrobial therapy for
Staphylococcus aureus endocarditis in patients addicted to parenteral
drugs and in nonaddicts: a prospective study. Ann Intern Med 1982;
97:496–503.
Downloaded from https://academic.oup.com/cid/article-abstract/42/Supplement_1/S5/275962
by guest
on 24 April 2018
45. Ein ME, Smith NJ, Aruffo JF, Heerema MS, Bradshaw MW, Williams
TW Jr. Susceptibility and synergy studies of methicillin-resistant Staph-
ylococcus epidermidis. Antimicrob Agents Chemother 1979; 16:655–9.
46. Lowy FD, Wexler MA, Steigbigel NH. Therapy of methicillin-resistant
Staphylococcus epidermidis experimental endocarditis. J Lab Clin Med
1982; 100:94–104.
47. Hackbarth CJ, Chambers HF, Sande MA. Serum bactericidal activity
of rifampin in combination with other antimicrobial agents against
Staphylococcus aureus. Antimicrob Agents Chemother 1986; 29:611–3.
48. Watanakunakorn C, Guerriero JC. Interaction between vancomycin
and rifampin against Staphylococcus aureus. Antimicrob Agents Che-
mother 1981; 19:1089–91.
49. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethox-
azole compared with vancomycin for the treatment of Staphylococcus
aureus infection. Ann Intern Med 1992; 117:390–8.
50. Ahmed A. A critical evaluation of vancomycin for treatment of bacterial
meningitis. Pediatr Infect Dis J 1997; 16:895–903.
51. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J
Med 2000; 342:710–21.
52. Depardieu F, Bonora MG, Reynolds PE, Courvalin P. The vanG gly-
copeptide resistance operon from Enterococcus faecalis revisited. Mol
Microbiol 2003; 50:931–48.
53. McKessar SJ, Berry AM, Bell JM, Turnidge JD, Paton JC. Genetic
characterization of vanG, a novel vancomycin resistance locus of En-
terococcus faecalis. Antimicrob Agents Chemother 2000; 44:3224–8.
54. Aslangul E, Baptista M, Fantin B, et al. Selection of glycopeptide-
resistant mutants of VanB-type Enterococcus faecalis BM4281 in vitro
and in experimental endocarditis. J Infect Dis 1997; 175:598–605.
55. Cetinkaya Y, Falk P, Mayhall CG. Vancomycin-resistant enterococci.
Clin Microbiol Rev 2000; 13:686–707.
56. Lefort A, Baptista M, Fantin B, et al. Two-step acquisition of resistance
to the teicoplanin-gentamicin combination by VanB-type Enterococcus
faecalis in vitro and in experimental endocarditis. Antimicrob Agents
Chemother 1999; 43:476–82.
57. Lafaurie M, Perichon B, Lefort A, Carbon C, Courvalin P, Fantin B.
Consequences of VanE-type resistance on efficacy of glycopeptides in
vitro and in experimental endocarditis due to Enterococcus faecalis.
Antimicrob Agents Chemother 2001; 45:2826–30.
58. Lefort A, Garry L, Depardieu F, Courvalin P, Fantin B. Influence of
VanD type resistance on activities of glycopeptides in vitro and in
experimental endocarditis due to Enterococcus faecium. Antimicrob
Agents Chemother 2003; 47:3515–8.
59. Noble WC, Virani Z, Cree RG. Co-transfer of vancomycin and other
resistance genes from Enterococcus faecalis NCTC 12201 to Staphylo-
coccus aureus. FEMS Microbiol Lett 1992; 72:195–8.
60. Centers for Disease Control and Prevention (CDC). Reduced suscep-
tibility of Staphylococcus aureus to vancomycin—Japan, 1996. MMWR
Morb Mortal Wkly Rep 1997; 46:624–6.
61. Hiramatsu K, Hanaki H, Ino T, Yabuta K, Oguri T, Tenover FC. Meth-
icillin-resistant Staphylococcus aureus clinical strain with reduced van-
comycin susceptibility. J Antimicrob Chemother 1997; 40:135–6.
62. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of
vancomycin resistance in a patient with methicillin-resistant Staphy-
lococcus aureus infection. N Engl J Med 1999; 340:517–23.
63. Fridkin SK. Vancomycin-intermediate and -resistant Staphylococcus au-
reus: what the infectious disease specialist needs to know. Clin Infect
Dis 2001; 32:108–15.
64. Tenover FC, Biddle JW, Lancaster MV. Increasing resistance to van-
comycin and other glycopeptides in Staphylococcus aureus. Emerg Infect
Dis 2001; 7:327–32.
65. Schwaber MJ, Wright SB, Carmeli Y, et al. Clinical implications of
varying degrees of vancomycin susceptibility in methicillin-resistant
Staphylococcus aureus bacteremia. Emerg Infect Dis 2003; 9:657–64.
66. Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resis-
tance to vancomycin: epidemiology, clinical significance, and critical
assessment of diagnostic methods. Antimicrob Agents Chemother
2003; 47:3040–5.
History of Vancomycin • CID 2006:42 (Suppl 1) • S11
 67. Tenover FC, Lancaster MV, Hill BC, et al. Characterization of staph-
ylococci with reduced susceptibilities to vancomycin and other gly-
copeptides. J Clin Microbiol 1998; 36:1020–7.
68. Wong SS, Ng TK, Yam WC, et al. Bacteremia due to Staphylococcus
aureus with reduced susceptibility to vancomycin. Diagn Microbiol
Infect Dis 2000; 36:261–8.
69. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treat-
ment failure associated with heterogeneous vancomycin-intermediate
Staphylococcus aureus in a patient with endocarditis and in the rabbit
model of endocarditis. Antimicrob Agents Chemother 2003; 47:1262–6.
70. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical
features associated with bacteremia due to heterogeneous vancomycin-
intermediate Staphylococcus aureus. Clin Infect Dis 2004; 38:448–51.
71. Fridkin SK, Hageman J, McDougal LK, et al. Epidemiological and
microbiological characterization of infections caused by Staphylococcus
aureus with reduced susceptibility to vancomycin, United States,
1997–2001. Clin Infect Dis 2003; 36:429–39.
72. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for
serious infections caused by methicillin-resistant Staphylococcus aureus
with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521–8.
73. Sakoulas G, Moellering RC Jr, Eliopoulos GM. Adaptation of methi-
cillin-resistant Staphylococcus aureus in the face of vancomycin therapy.
Clin Infect Dis 2006; 42(Suppl 1):S40–50 (in this supplement).
74. Stevens DL. The role of vancomycin in the treatment paradigm. Clin
Infect Dis 2006; 42(Suppl 1):S51–7 (in this supplement).
75. Moise-Broder PA, Sakoulas G, Eliopoulos GM, Schentag JJ, Forrest A,
Moellering RC Jr. Accessory gene regulator group II polymorphism in
methicillin-resistant Staphylococcus aureus is predictive of failure of
vancomycin therapy. Clin Infect Dis 2004; 38:1700–5.
76. Fowler VG Jr, Sakoulas G, McIntyre LM, et al. Persistent bacteremia
due to methicillin-resistant Staphylococcus aureus infection is associated
with agr dysfunction and low-level in vitro resistance to thrombin-
induced platelet microbicidal protein. J Infect Dis 2004; 190:1140–9.
77. Sievert DM, Boulton ML, Stolzman G, et al. Staphylococcus aureus
resistant to vancomycin—United States, 2002. MMWR Morb Mortal
Wkly Rep 2002; 51:565–7.
78. Chang S, Sievert DM, Hageman JC, et al. Infection with vancomycin-
S12 • CID 2006:42 (Suppl 1) • Levine
Downloaded from https://academic.oup.com/cid/article-abstract/42/Supplement_1/S5/275962
by guest
on 24 April 2018
resistant Staphylococcus aureus containing the vanA resistance gene. N
Engl J Med 2003; 348:1342–7.
79. Miller D, Urdaneta V, Weltman A. Vancomycin-resistant Staphylococcus
aureus—Pennsylvania, 2002. MMWR Morb Mortal Wkly Rep 2002;
51:902.
80. Whitener CJ, Park SY, Browne FA, et al. Vancomycin-resistant Staph-
ylococcus aureus in the absence of vancomycin exposure. Clin Infect
Dis 2004; 38:1049–55.
81. Tenover FC, Weigel LM, Appelbaum PC, et al. Vancomycin-resistant
Staphylococcus aureus isolate from a patient in Pennsylvania. Antimi-
crob Agents Chemother 2004; 48:275–80.
82. Kacica M, McDonald LC. Vancomycin-resistant Staphylococcus au-
reus—New York, 2004. MMWR Morb Mortal Wkly Rep 2004; 53:
322–3.
83. Centers for Disease Control and Prevention. Investigation and control
of vancomycin-intermediate and -resistant Staphylococcus aureus: a
guide for health departments and infection control personnel. Atlanta:
Centers for Disease Control and Prevention, 2004.
84. Fowler VG Jr, Kong LK, Corey GR, et al. Recurrent Staphylococcus
aureus bacteremia: pulsed-field gel electrophoresis findings in 29 pa-
tients. J Infect Dis 1999; 179:1157–61.
85. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer
AW, Carmeli Y. Comparison of mortality associated with methicillin-
resistant and methicillin-susceptible Staphylococcus aureus bacteremia:
a meta-analysis. Clin Infect Dis 2003; 36:53–9.
86. Cruciani M, Gatti G, Lazzarini L, et al. Penetration of vancomycin into
human lung tissue. J Antimicrob Chemother 1996; 38:865–9.
87. Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo JJ. Bac-
teremic pneumonia due to Staphylococcus aureus: a comparison of
disease caused by methicillin-resistant and methicillin-susceptible or-
ganisms. Clin Infect Dis 1999; 29:1171–7.
88. Moise PA, Forrest A, Bhavnani SM, Birmingham MC, Schentag JJ.
Area under the inhibitory curve and a pneumonia scoring system for
predicting outcomes of vancomycin therapy for respiratory infections
by Staphylococcus aureus. Am J Health Syst Pharm 2000; 57(Suppl 2):
S4–9.