Increasing Antibiotic Resistance among Methicillin-Resistant Staphylococcus aureus Strains
George Sakoulas
)
1
Robert C. Moellering
Jr.
0
0
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School
,
Boston, Massachussetts
1
Division of Infectious Diseases, Department of Medicine, Westchester Medical Center and New York Medical College
,
Valhalla
,
New York
Vancomycin use has increased dramatically worldwide since the mid-1980s, largely as a result of empirical and directed therapy against burgeoning methicillin-resistant Staphylococcus aureus (MRSA) infections. With limited choices, clinicians have traditionally relied on vancomycin alone in the management of serious MRSA infections and have enjoyed a significant period free of vancomycin resistance in S. aureus. Even now, 5 decades after its introduction, vancomycin resistance among S. aureus strains, as currently defined microbiologically, remains rare. Yet it is becoming clear that vancomycin is losing potency against S. aureus, including MRSA. Serious infections due to MRSA defined as susceptible in the laboratory are not responding well to vancomycin. This is demonstrated by increased mortality seen in patients with MRSA infection and markedly attenuated vancomycin efficacy caused by vancomycin heteroresistance in S. aureus. Therefore, it appears that our definition of vancomycin susceptibility requires further scrutiny as applied to serious MRSA infections, such as bacteremia and pneumonia.
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Historically, the development of antimicrobial
resistance in Staphylococcus aureus has been rapid.
Resistance to penicillin in S. aureus was noted only a year
after its introduction, and, in the early 1950s,
threequarters of S. aureus strains in large hospitals in many
countries had become penicillin resistant [1]. Currently,
90%95% of clinical S. aureus strains throughout the
world are resistant to penicillin. In 1959, the first
antistaphylococcal penicillinmethicillinwas
introduced. Within 2 years, the first methicillin-resistant S.
aureus (MRSA) strain emerged [2]. Currently, MRSA
accounts for 60% of clinical S. aureus strains isolated
from intensive care units in the United States [3, 4].
With the rapid emergence of community-associated
MRSA, an organism that now causes a majority of the
soft-tissue infections in patients presenting to
emergency rooms in many parts of the United States, it
appears that the antistaphylococcal b-lactams may soon
meet the same fate as penicillin with regard to their
ability to treat community-associated skin infections
[57].
This pattern has continued among the newer agents.
Linezolid was introduced clinically in the year 2000,
only to result in the first linezolid-resistant MRSA strain
being described in the literature a year later [8].
Daptomycin was introduced in 2003, and MRSA resistance
to it was first reported within 2 years [9].
What is interesting about vancomycin is that, unlike
any of the other antistaphylococcal antimicrobials,
resistance to this agent among S. aureus strains took
almost 40 years to be recognized, with the first
glycopeptide-intermediate S. aureus (GISA) isolate from a
pediatric patient in Japan described in 1996 [10].
Highlevel resistance mediated by the vanA gene complex
acquired from vancomycin-resistant enterococci (VRE)
emerged in Detroit, Michigan, in 2002 and so far has
been limited to the United States [11, 12]. The cases
for which the clinical details are reported are shown in
table 1. It is noteworthy that the vancomycin-resistant
phenotype has variable expression, with higher levels
of resistance seen in the Michigan strain compared with
8 8 4
in L 2 2 6
c m 1 1
y / 1 1 2
the subsequently found strain from Pennsylvania, perhaps
because of a more unstable phenotype or differences in metabolic
price (figure 1) [17].
Unlike b-lactam antibiotics, which bind to and interrupt the
activity of penicillin-binding proteins (enzymes involved in
cellwall synthesis), vancomycin binds with high affinity to the
DAla-D-Ala C-terminus of late peptidoglycan precursors and
prevents reactions of cell-wall synthesis using these precursors
in transglycosylase, transpeptidase, and D,D-carboxypeptidases
(figure 2) [17]. Resistance in VRE and vancomycin-resistant S.
aureus (VRSA) is due to the presence of operons that encode
enzymes that produce the low-affinity precursors
D-Ala-D-Lactate or D-Ala-D-Ser and also enzymes that eliminate the
competitive high-affinity peptidoglycan precursors normally
produced. In GISA strains, none of the operons mediating this
mechanism of resistance has been found. Instead, GISA has
altered its cellular physiology as a result of cumulative effects
of mutations and/or modulation of regulatory systems. This
altered physiology appears to change cell-wall metabolism in
such a way as to result in increased numbers of D-Ala-D-Ala
residues, which serve as dead-end binding sites for vancomycin.
This altered cell wall results in a reduced diffusion coefficient
of vancomycin, sequestration of vancomycin within the cell
wall by these false target (...truncated)