**[Dealing with the problem of antibiotic resistance.]{.smallcaps}**

Antimicrobial agents differ in an important respect from all other
classes of pharmaceuticals. An inappropriately prescribed ß-blocker,
e.g., harms only the recipient and no harm accrues from an appropriately
prescribed ß-bocker. In contrast, every use of an antimicrobial, whether
appropriate or inappropriate, has a potential adverse public health
consequence. Each use affects the bacterial ecology, providing the
selective pressure that drives antimicrobial resistance. Antibiotics, as
a consequence of this inescapable Darwinian effect, are the only class
of therapeutics to have built-in obsolescence. ß-adrenergic receptors do
not evolve, do not replicate and do not spread; bacteria and antibiotic
resistance in bacteria do. The evolutionary capabilities of bacteria
make them a moving target for antibiotic therapy and the recent
evolution of *Staphylococcus aureus* provides an excellent illustration
of this problem, as well as of the difficulties in dealing with it.

The identification of *S. aureus* resistant to this new wonder drug was
reported shortly after this wonder drug was first used.
Penicillin-resistant *S. aureus* subsequently spread, first in hospitals
and eventually in the community, so that greater than 90% of isolates in
either setting are currently resistant to this antibiotic. The
introduction of methicillin two decades after the first patient received
penicillin injections was followed just a year later by a report of
staphylococcoal resistance to this semisynthetic penicillin, with
subsequent cycles of spread within hospitals, first in Europe, then in
the U.S. and the rest of the world. Approximately 60% of *S. aureus*
bloodstream isolates in U.S. intensive care units are currently
methicillin-resistant (MRSA). More recently, *S. aureus* in the
community have acquired distinctive methicillin-resistance genes as well
as virulence genes and have undergone remarkable spread among previously
healthy individuals, many of whom with nor characteristics previously
recognized as constituting a risk for MRSA infection. By 2004, 59% of
skin and skin structure infections in adults presenting to emergency
departments throughout the U.S. were caused by MRSA, almost all by this
novel community strain. These community-acquired MRSA (CA-MRSA), in
contrast to the hospital strains, while possibly more virulent, were
less resistant to a variety of non- ß-lactam antibiotics. This lesser
multidrug resistance is, however, proving to be short-lived, as these
community strains have become increasingly resistant to antibiotics of a
variety of classes -- a change once again illustrating the inevitable
evolution of antibiotic resistance.

Vancomycin, an antibiotic active against most MRSA, was first approved
by the U.S. FDA in 1958. It came into widespread use in the last 2-3
decades in response to the increasing numbers of hospital infections due
to methicillin-resistant staphylococci. In the middle-to-late 1980s,
however, reports of frequent failures of vancomycin therapy in patients
with serious staphylococcal infections began appearing in the medical
literature. In recent years the number of such reports has significantly
increased, an occurrence that is consistent with evidence of the
continued evolution of *S. aureus* in response to the selective pressure
of widespread vancomycin use.

The failure of therapy with vancomycin in patients infected with *S.
aureus* isolates with an minimal inhibitory concentration (MIC) of 4
mcg/ml, a level previously considered to indicate susceptibility to this
antibiotic, led the CLSI to recently reduce the susceptibility
breakpoint to 2 mcg/ml. At the same time, multiple centers throughout
the U.S. have reported a phenomenon that has been called "MIC creep", a
description of the progressive increase in the concentration of
vancomycin necessary to inhibit the in vitro growth of *S. aureus*. Most
centers reporting MIC creep have found that a large proportion of
isolates have an MIC at the 2 mcg/ml breakpoint. Nationally, 16% are
reported to have an MIC of 2 mcg/ml. Once again, the established
breakpoint appears to still be too high. Thus, although considered
susceptible by the CLSI standard, multiple reports now indicate a high
rate of failure of vancomycin therapy in patients infected with *S.
aureus* isolates with an MIC of 2 mcg/ml. This increasingly recognized
problem is magnified by the shortcomings in commonly used clinical
laboratory testing methods such that the clinician may not receive
accurate and complete reports of precise vancomycin MICs. Additional
factors, also not detected by the clinical laboratory, may contribute to
failure of vancomycin therapy, including poor bactericidal activity and
the presence of heteroresistance (hVISA - subpopulations with MICs in
the intermediate range of 4 -- 8 mcg/ml). All of these evolutionary and
technical factors have led to reduced confidence in the use of
vancomycin in the treatment of serious infections due to *S. aureus*.

Thus, the story of the evolutionary interaction of *S. aureus* vis á vis
vancomycin represents an excellent example of the inevitable
obsolescence of antibiotics while, at the same time, illustrating the
difficulties that relatively slow moving organizations have in
responding to this evolution. Thus, at a time when a great deal of
evidence exists that the vancomycin breakpoint for *S. aureus* should be
lowered below 2 mcg/ml, the CLSI has not acted (and the FDA is still
stuck at 4 mcg/ml). Furthermore, clinical laboratories have difficulty
in accurately determining the vancomycin MIC and do not even attempt to
identify problems such as heteroresistance, problems which leave both
the clinician and the patient in a difficult position. Attempts to
overcome some of the shortcomings of vancomycin vis-á-vis MRSA by
increasing the dose of this glycopeptide antibiotic administered have
yet to demonstrate improved outcomes, but have provided a signal
suggesting that the doses used may be associated with an increased risk
of nephrotoxicity and data from randomized clinical trials addressing
this and other issues are lacking. Many clinicians are unaware that a
potential problem even exists. Thus, an inadequate response is evident
at every step in the process.

Many of the steps necessary for effectively dealing with this problem
have been outlined by the Infectious Disease Society of America in their
statement submitted for the April 28 meeting. The following are three
important added considerations. Since the only long-term solution to the
problem of *S. aureus* infection, particularly those occurring in the
community, is the development of an effective vaccine, FDA and other
government agencies must provide incentives to development in this
arena. Vaccines are also needed for other target pathogens. Second,
there is needed continued emphasis on effective infection control
practices, free of political interference requiring measures that lack a
sound foundation in science (which implies funding for the development
of an accurate knowledge base dictating practice). Third, dealing with
the problem of antimicrobial resistance must be internationalized, since
it is a worldwide phenomenon and there are no fences that can be built
to uniformly prevent the importation of antimicrobial resistant
pathogens. The needed actions are multidisciplinary and complex. Their
implementation is critical and urgent.