Characterization of a Daptomycin-Nonsusceptible Vancomycin-Intermediate
            <i>Staphylococcus aureus</i>
            Strain in a Patient with Endocarditis

Julian, Kathleen G.; Kosowska-Shick, Klaudia; Whitener, Cynthia; Roos, Martin; Labischinski, Harald; Rubio, Aileen; Parent, Leslie J.; Ednie, Lois M.; Koeth, Laura; Bogdanovich, Tatiana; Appelbaum, Peter C.

doi:10.1128/aac.00559-07

Cited by 113 publications

(120 citation statements)

References 22 publications

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“…Decreased susceptibility to DAP in S. aureus has been reported to lead to clinical failures in patients with MRSA deep-site infections, such as endocarditis and abscesses (28)(29)(30). Previously, we identified two major factors that mutually cooperate in the acquisition of DAP resistance; one is related to the cell membrane (mrpF mutations), and the second affects cell wall factors (VraSR) (6).…”

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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“…As described above, in many cases, the hVISA or VISA phenotype is detected after a prolonged period of infection, which is associated with a failure of glycopeptide therapy (121,151,213,313,316,326,337,340,348,376). The testing of later clinical isolates from patients who have failed glycopeptide treatment appears more likely to yield a positive result for hVISA or VISA.…”

Section: Practical Approach To Hvisa and Visa Detectionmentioning

confidence: 98%

“…For many patients, the hVISA or VISA phenotype was detected in bacterial isolates only after a prolonged period of infection associated with the failure of glycopeptide therapy (48,121,124,151,213,313,316,326,337,340,376). In many of these cases, a detailed analysis of the earlier clinical isolate failed to detect any vancomycin heteroresistance, and the phenotype appears to have emerged from a vancomycin-susceptible strain during therapy.…”

Section: Global Epidemiology and Associated Features Of Hvisa And Visamentioning

confidence: 99%

“…For example, 6 laboratory-derived VISA strains demonstrated a stable phenotype after 20 passages on nonselective medium (250). Many of the earlier studies of the features of VISA were performed with laboratory-derived strains after stepwise selection on glycopeptide-containing medium (62,215,250,315,319,320,322); however, more recent studies have utilized clinical isolates (32,56,121,151,314,318), and in many cases, the phenotypic features have been similar. The ability to induce the selection of VISA from vancomycin-susceptible parent isolates varies between strains in terms of both the level of resistance attained and the rate at which resistance develops (58,250,267).…”

Section: Phenotypic Features and Mechanisms Of Resistancementioning

confidence: 99%

“…Other common features include an increased level of production of abnormal muropeptides (319); an overexpression of PBP2 and PBP2Ј (108,215), although reduced levels of expression of PBP2Ј were found in a laboratory-derived mutant due to the inactivation of mecA (322); reduced PBP4 expression levels (319); increased levels of D-Ala-D-Ala residues; and reduced levels of peptidoglycan cross-linking in most isolates studied ( Fig. 1) (151,215,250,318,320). For some VISA isolates a small increase in peptidoglycan cross-linking was found (30,32,267).…”

Section: Cell Wall Changesmentioning

confidence: 99%

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Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

et al. 2010

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SUMMARY The emergence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) over the past decade has provided a challenge to diagnostic microbiologists to detect these strains, clinicians treating patients with infections due to these strains, and researchers attempting to understand the resistance mechanisms. Recent data show that these strains have been detected globally and in many cases are associated with glycopeptide treatment failure; however, more rigorous clinical studies are required to clearly define the contribution of hVISA to glycopeptide treatment outcomes. It is now becoming clear that sequential point mutations in key global regulatory genes contribute to the hVISA and VISA phenotypes, which are associated predominately with cell wall thickening and restricted vancomycin access to its site of activity in the division septum; however, the phenotypic features of these strains can vary because the mutations leading to resistance can vary. Interestingly, changes in the staphylococcal surface and expression of agr are likely to impact host-pathogen interactions in hVISA and VISA infections. Given the subtleties of vancomycin susceptibility testing against S. aureus, it is imperative that diagnostic laboratories use well-standardized methods and have a framework for detecting reduced vancomycin susceptibility in S. aureus.

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Antibacterial Drugs

Chan¹,

Cross²,

He³

et al. 2013

Drug Discovery

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Characterization of a Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus Strain in a Patient with Endocarditis

Cited by 113 publications

References 22 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

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

Antibacterial Drugs

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