Perspectives on Daptomycin Resistance, with Emphasis on Resistance in Staphylococcus aureus
0
New York Medical College
,
Valhalla
,
New York
1
Received 22 January 2007; accepted 5 May 2007; electronically published 1 August 2007. England Medical Center
,
750 Washington St., Box 238, Boston, MA 02111
2
Division of Infectious Diseases, Westchester Medical Center
3
Division of Infectious Diseases, Tufts-New England Medical Center
,
Boston, Massachusetts
Methicillin-resistant Staphylococcus aureus infections are becoming more frequent and less easily treated by means of currently recommended agents. Vancomycin has been associated with decreased susceptibility in staphylococci and with treatment failures. Daptomycin is rapidly bactericidal; a dosage of 4 mg/kg daily is approved for treatment of skin and soft-tissue infections, and a dosage of 6 mg/kg daily is approved for treatment of patients with S. aureus bacteremia and right-sided endocarditis. Findings of in vitro studies suggest a correlation between the minimum inhibitory concentrations of daptomycin and vancomycin. Clinical failure was associated with increasing minimum inhibitory concentrations in case reports and in a randomized study of persons with S. aureus bacteremia and endocarditis. Patients who did not respond to therapy had deep-seated infections that required but could not be or were not managed with adjunctive surgical therapy. No definitive resistance mechanism has been identified, although genetic mutations have been described. Clinically, prior vancomycin therapy has not been associated with failure of daptomycin therapy. Although clinical practitioners must monitor for daptomycin resistance, the available data support the use of daptomycin in the treatment of methicillin-resistant S. aureus bacteremia and endocarditis.
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understand that the emergence of VISA and VRSA represent
the tip of the iceberg of a more microbiologically subtle
evolution, highlighted by vancomycin treatment failure in serious
MRSA infections, that has occurred in staphylococci under
vancomycin selection pressure.
Daptomycin is a cyclic lipopeptide in a class of antibiotics
derived from the fermentation of Streptomyces roseosporus. The
mechanism of daptomycin action is unique: the drug kills
bacteria in a concentration-dependent manner by binding
preferentially to gram-positive bacterial membranes, inserting into
the membrane, and causing rapid membrane depolarization
and bacterial cell death due to disruption of critical metabolic
functions, such as protein, DNA, and RNA synthesis. Unlike
antimicrobial agents active at the cell wall, agents that kill by
means of membrane depolarization fail to lyse cells [1215].
In vitro studies demonstrated that daptomycin had bactericidal
activity equal to or greater than that of vancomycin, linezolid,
and quinupristin-dalfopristin [16]. In vivo, daptomycin was
effective in models of endocarditis [17]. Use of daptomycin
was approved in the United States and Europe at a dosage of
4 mg/kg daily for treatment of skin and soft-tissue infections
and was approved in the United States at a dosage of 6 mg/kg
daily for treatment of S. aureus bacteremia and right-side
infective endocarditis [18]. Clinical studies showed that
daptomycin for the treatment of pneumonia failed, and it was shown
that daptomycin is inactivated by surfactant [19].
Other options for treating S. aureus infections include
antistaphylococcal penicillins and cefazolin (for MSSA),
trimethoprim-sulfamethoxazole, clindamycin, linezolid,
quinupristindalfopristin, tetracyclines, and tigecycline. Although many
clinicians routinely use these agents for the management of
soft-tissue infection, many drugs developed earlier are not
approved by the US Food and Drug Administration for this
purpose. Only vancomycin and linezolid are recommended for the
treatment of MRSA pneumonia. Several investigational agents,
including dalvabancin, televancin, and PBP-2atargeted
b-lactams (e.g., ceftobiprole), will likely become available in the near
future for treatment of soft-tissue infection. The role of
combination therapy, with the intent of potentiating the regimen
or reducing the likelihood of resistance, remains debatable, with
fewer clinical data than in vitro data.
Failure of vancomycin to treat glycopeptide-susceptible
MRSA; concern for the development of staphylococcal
resistance to daptomycin, linezolid, and other gram-positive agents;
the increased cost of the newer antibiotics; and the surge in
the rate of methicillin resistance among community-acquired
S. aureus strains have all come together to create a situation in
which there are fewer clinical data than microbiological
observations. In this review, we summarize the interface of
available clinical and microbiological data on daptomycin resistance
and provide perspective for clinicians who treat patients with
MRSA infection.
EMERGENCE OF VANCOMYCIN RESISTANCE
IN S. AUREUS
Although vancomycin was introduced in 1958, its use was not
significant until the mid-1980s, when the prevalence of
methicillin resistance a (...truncated)