Evolution of a Vancomycin-Intermediate
 Staphylococcus aureus
 Strain In Vivo: Multiple Changes in the Antibiotic Resistance Phenotypes of a Single Lineage of Methicillin-Resistant
 S
 .
 aureus
 under the Impact of Antibiotics Administered for Chemotherapy

Sieradzki, Krzysztof; Łęski, Tomasz A.; Dick, James D.; Borio, Luciana; Tomasz, Alexander

doi:10.1128/jcm.41.4.1687-1693.2003

Cited by 126 publications

(113 citation statements)

References 18 publications

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“…Previously, a concomitant rise in the level of vancomycin resistance with decreased ␤-lactam resistance has been reported in some clinical vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) strains. In VISA strains, the mechanism remains undefined, with some strains showing excision of SCCmec carrying mecA, while in others mecA is retained (31,32). In contrast, in VRSA strains, the loss of ␤-lactam resistance seems to be associated with the inability of PBP 2a to utilize the UDP-N-acetylmuramic acid-depsipeptide (D-Ala-D-Lac) cell wall precursor produced in VRSA for transpeptidation, leaving PBP 2 to be essential for the synthesis of the abnormally structured cell wall (33).…”

Section: Discussionmentioning

confidence: 99%

Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus

Renzoni

Kelley

Rosato

et al. 2017

Antimicrob Agents Chemother

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Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most difficult to treat in clinical settings due to the resistance of MRSA to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. The decreased susceptibility to DAP (DAP resistance [DAP r ]) reported in MRSA is frequently accompanied by a paradoxical decrease in ␤-lactam resistance, a process known as the "seesaw effect." Despite the observed discordance in resistance phenotypes, the combination of DAP and ␤-lactams has been proven to be clinically effective for the prevention and treatment of infections due to DAP r MRSA strains. However, the mechanisms underlying the interactions between DAP and ␤-lactams are largely unknown. In the study described here, we studied the role of mprF with DAP-induced mutations in ␤-lactam sensitization and its involvement in the effective killing by the DAP-oxacillin (OXA) combination. DAP-OXA-mediated effects resulted in cell wall perturbations, including changes in peptidoglycan insertion, penicillin-binding protein 2 (PBP 2) delocalization, and reduced membrane amounts of PBP 2a, despite the increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications that result in impairment of PrsA location and chaperone functions, both of which are essential for PBP 2a maturation, the key determinant of ␤-lactam resistance. These observations provide for the first time evidence that synergistic effects between DAP and ␤-lactams involve PrsA posttranscriptional regulation of CM-associated PBP 2a.KEYWORDS MRSA, daptomycin, seesaw effect, ␤-lactams, PrsA, ␤-lactams S taphylococcus aureus has a proclivity for developing multidrug resistance (e.g., methicillin-resistant S. aureus [MRSA]), and infections with this pathogen result in enhanced attributable mortality (1). Since its FDA approval in 2003, the cyclic anionic lipopeptide antibiotic daptomycin (DAP), produced by Streptomyces roseosporus (2), has become the clinical mainstay of anti-MRSA therapy due to its potent staphylocidal

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Section: Discussionmentioning

confidence: 99%

Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus

Renzoni

Kelley

Rosato

et al. 2017

Antimicrob Agents Chemother

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“…For example, population analysis of isolates acquired from S. aureus infections has revealed subpopulations that have reduced susceptibility to vancomycin [8,9]. Isolates that were recovered after administration of further vancomycin therapy were increasingly dominated by the mutants.…”

Section: Potential Applicationsmentioning

confidence: 99%

“…These changes in window position relative to therapeutic drug concentrations should cause each successive mutation to be more readily fixed in the population as a result of the decreased time that mutant growth is restricted and of the diminished killing of mutant cells. The same principles should apply to the acquisition of nontarget mutations, such as those involved in drug efflux, and to the gradual loss of susceptibility observed when vancomycinintermediate S. aureus subpopulations are enriched in patients [8,9]. Thus, the window hypothesis provides a clear rationale for avoiding antimicrobial doses that place drug concentrations inside the window.…”

Section: Stepwise Accumulation Of Drug-resistance Mutationsmentioning

confidence: 99%

“…From the perspective of most patients, using the selection window to guide dosing constitutes a form of altruism: an individual accepts an increased risk of adverse toxic effects in exchange for slower acquisition of drug resistance within the community. However, as drug-resistant mutant subpopulations grow, the selection window will become increasingly important for all patients, because drug-resistance can be acquired during therapy [7][8][9]. Herein, we review recent tests and refinements of the window hypothesis.…”

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confidence: 99%

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Mutant Selection Window Hypothesis Updated

Drlica¹,

Zhao²

2007

Clinical Infectious Diseases

347

338

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The mutant selection window hypothesis postulates that, for each antimicrobial-pathogen combination, an antimicrobial concentration range exists in which selective amplification of single-step, drug-resistant mutants occurs. This hypothesis suggests an antimutant dosing strategy that is keyed to the upper boundary of the selection window: the mutant prevention concentration. Correlations are described between the mutant prevention concentration-a static parameter that is measured with agar plates-and fluctuating drug concentrations that restrict mutant amplification in vitro and in animals. When drug resistance is acquired stepwise, the mutant selection window increases, making the suppression of each successive mutant increasingly more difficult. For agents that kill drug-resistant mutants in a drug concentration-dependent manner, the use of the area under the 24-h time-drug concentration curve value divided by the value of the mutant prevention concentration is suggested as an index for designing antimutant dosing regimens. The need for such regimens is emphasized by a clinical example in which acquisition of drug resistance occurs concurrently with eradication of susceptible bacterial cells. These data support using the mutant selection window to optimize antimicrobial dosing regimens.Antimicrobial resistance is a complex problem that is likely to require attention at many levels [1]. Issues concerning dosing are addressed by the mutant selection window hypothesis [2,3]. This hypothesis maintains that drug-resistant mutant subpopulations present prior to initiation of antimicrobial treatment are enriched and amplified during therapy when antimicrobial concentrations fall within a specific range (the mutant selection window). The upper boundary of the mutant selection window is the MIC of the least drugsusceptible mutant subpopulation, a value called the mutant prevention concentration (MPC) [4]. The lower boundary of the mutant selection window is the lowest concentration that exerts selective pressure, often approximated by the minimal concentration that inhibits colony formation by 99% (MIC 99 ). Two principles emerge from the hypothesis. First, traditional dos-

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“…From the 1990's to the present, however, the emergence of resistance to vancomycin also occurred in a significant proportion. [1][2][3] First among these organisms were Enterococcus faecium and Enterococcus faecalis. 4 Subsequently, vancomycin (glycopeptide)-resistant enterococci (VRE) became a major hospital-acquired pathogen.…”

Section: Infections Caused By Gram-posi-tive Cocci An Outline Of Thementioning

confidence: 99%

Novel pharmaceutical molecules against emerging resistant gram-positive cocci

Manfredi¹,

Sabbatani²

2010

Braz J Infect Dis

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Introduction: methicillin-and also vancomycin (glycopeptide)-resistant Gram-positive organisms have emerged as an increasingly problematic cause of hospital-acquired infections, also spreading into the community. Vancomycin (glycopeptide) resistance has emerged primarily among Enterococci, but the MIC values of vancomycin for the entire Staphylococcus species are also increasing worldwide. Material and Methods: the aim of our review is to evaluate the efficacy and tolerability of newer antibiotics with activity against methicillin-resistant and glycopeptide-resistant Gram-positive cocci, on the ground of our experience at a tertiary care metropolitan Hospital, and the most recent literature evidences in this field. Results: Quinupristin-dalfopristin, linezolid, daptomycin, and tigecycline show an excellent in vitro activity, comparable to the activity of vancomycin and teicoplanin for methicillin-resistant staphylococci, and superior to the one that vancomycin for vancomycin-resistant isolates. Dalbavancin, televancin, and oritavancin are new lipoglycopeptide agents with excellent activity against Gram-positive cocci, and have superior pharmacodynamics properties compared to vancomycin. We review the bacterial spectrum, clinical indications and practical use, pharmacologic properties, and expected adverse events and contraindications associated with each of these novel antimicrobial agents, compared with the present standard of care. Discussion: linezolid activity is substantially comparable to that of vancomycin in patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, although its penetration into the respiratory tract is exceptionally elevated. Tigecycline has activity against both Enterococus species and MRSA; it is also active against a broad spectrum of Enterobacteriaceae and anaerobes, which allows for use intraabdominal, diabetic foot and surgical infections. Daptomycin has a rapid bactericidal activity for Staphylococcus aureus and it is approved in severe complications, such as bacteremia and right-sided endocarditis. It cannot be used to treat pneumonia and respiratory diseases, due to its inactivation in the presence of pulmonary surfactant.

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Evolution of a Vancomycin-Intermediate Staphylococcus aureus Strain In Vivo: Multiple Changes in the Antibiotic Resistance Phenotypes of a Single Lineage of Methicillin-Resistant S . aureus under the Impact of Antibiotics Administered for Chemotherapy

Cited by 126 publications

References 18 publications

Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus

Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus

Mutant Selection Window Hypothesis Updated

Novel pharmaceutical molecules against emerging resistant gram-positive cocci

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