Point: Vancomycin Is Not Obsolete for the Treatment of Infection Caused by Methicillin-Resistant Staphylococcus aureus
John F. Mohr
1
2
Barbara E. Murray
0
1
2
0
Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston
1
Received 21 March 2007; accepted 21 March 2007;
electronically published 4 May 2007. This is a modified version of a paper presented at the 44th Annual Meeting of the Infectious Diseases Society of America
,
Toronto
, Ontario,
Canada
,
12-15 October 2006. University of Texas Health Science, Center at Houston
, 6431 Fannin, MSB 2.112,
Houston, TX 77030
2
Department of Internal Medicine, Division of Infectious Diseases and Center for Emerging and Re-emerging Pathogens
Since the discovery, development, and US Food and Drug Administration approval of vancomycin in the 1950s, this agent has remained a mainstay for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, because of the development of new antistaphylococcal antibiotics and reports of vancomycin failures, the utility of vancomycin has recently been questioned. Although vancomycin did not undergo the strict US Food and Drug Administration approval process that is in place today to demonstrate efficacy, there is considerable information available that sheds light on the role vancomycin has in infectious diseases pharmacotherapy today. In addition, although we look to in vitro susceptibility testing to assess vancomycin activity against S. aureus, we have come to appreciate that resistance of S. aureus to vancomycin can be a continuousrather than a categoricalphenomenon. This has resulted in clinical microbiology laboratories having difficulty identifying S. aureus that may not respond to conventional doses of vancomycin. A better understanding is needed of the pharmacodynamic relationship between vancomycin and MRSA as relates to optimal dosing strategies, including consideration for loading doses, and development of rational categorical breakpoints for susceptibility based on clinical outcomes. By better understanding these critical issues, it may be possible to optimize the use of vancomycin, resulting in a cost-effective treatment option for many patients infected with MRSA.
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The bacterium Streptomyces orientalis (now classified
taxonomically as Amycolaptosis orientalis) was isolated
from a soil sample from Borneo in 1952. This organism
produced a fermentative by-product that was isolated
and initially referred to as compound 05865; it was
found to have in vitro activity against Staphylococcus
aureus, including strains that were resistant to
penicillina growing problem at that time. After extensive
efforts to create a purified product, it was ultimately
given the name vancomycin. Soon thereafter, the
drug was used for infections caused by
penicillinresistant S. aureus. The initial clinical experience with
vancomycin was positive, and this ultimately led to an
extensive emergency use program and collection of case
reports of patient outcomes. On the basis of these
open-label data, vancomycin received US Food and
Drug Administration (FDA) approval in 1958 and
became a treatment option for infections caused by
penicillin-resistant S. aureus. By the early 1960s, just a few years
after the introduction of methicillin to the market, vancomycin
was also recognized as a treatment for cases of
methicillinresistant S. aureus (MRSA) infection that were beginning to
appear [1].
On 10 October 1962, the Kefauver-Harris Amendments were
passed in response to the European thalidomide crisis. These
modifications to the Federal Food, Drug, and Cosmetic Act of
1938 added the requirement of efficacy and strengthened the
safety requirements for all new drugs that would undergo the
FDA approval process. These amendments contained a
grandfather clause for drugs marketed in the United States prior to
9 October 1962 and after 25 June 1938 that exempted them
from the efficacy requirements of the amended act. One of the
drugs exempted was vancomycin.
After the first case of MRSA infection was reported in 1961,
MRSA rates initially remained low until the late 1970s, followed
by a dramatic increase in resistance and, consequently, in the
use of vancomycin over the next 3 decades. Partly because of
limited therapeutic options, vancomycin became the drug of
choice to treat infections caused by MRSA, even without
efficacy data provided to the FDA. Although the increasing
prevalence of MRSA has been a catalyst for the development of new
antimicrobials, the development of these new agents has, in
turn, been a catalyst leading to uncertainties about vancomycin.
These factors have led some in recent years to question whether
vancomycin has become an obsolete antibiotic for the treatment
of infections caused by MRSA [2].
Although vancomycin did not undergo the approval process
after its discovery in the 1950s that it would go through today,
much information on the pharmacokinetics and
pharmacodynamics of vancomycin and the microbiology of S. aureus has
been published and continues to be g (...truncated)