Characterization of Methicillin-Resistant Staphylococcus aureus Strains Recovered from a Phase IV Clinical Trial for Linezolid versus Vancomycin for Treatment of Nosocomial Pneumonia

Mendes, Rodrigo E.; Deshpande, Lalitagauri M.; Smyth, Davida S.; Shopsin, Bo; Farrell, David J.; Jones, Ronald N.

doi:10.1128/jcm.02024-12

Cited by 31 publications

(31 citation statements)

References 52 publications

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“…Our goal was to determine bacterial and epithelial responses that follow early interactions between the alveolar wall and USA300, with an eye to understanding the time course of bacterial stabilization and subsequent epithelial injury. We also addressed the puzzling feature of this pathology that although USA300 might be antibiotic sensitive in vitro (22,23), antibiotics tend to be ineffective in containing lung injury (23)(24)(25), possibly because of host factors.…”

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confidence: 99%

Disruption of staphylococcal aggregation protects against lethal lung injury

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Islam

Parker

et al. 2018

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Disruption of staphylococcal aggregation protects against lethal lung injury

Hook

Islam

Parker

et al. 2018

Journal of Clinical Investigation

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“…These broad selection criteria were intentionally applied to provide maximum strain variability, and the results indicate the ability of the system to correctly identify S. aureus and MRSA among diverse collections of organisms. However, several studies have documented the overwhelming presence of USA300 (CC8) and USA100 (CC5) carrying SCCmec types IV and II, respectively, in the United States (22,(25)(26)(27), while the MRSA population in Europe, Latin America, and Asia-Pacific countries seem to be more heterogeneous (22,25,28). Therefore, validation prior to clinical use in regions other than the United States seems prudent.…”

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confidence: 99%

“…Isolates showing discrepant results regarding bacterial identification or the methicillin (oxacillin) status between the BD Max StaphSR and phenotypic assays were repeated. Remaining discrepant results on repeat testing were evaluated further by using matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) and in-house PCR assays for detection of nuc and/or mecA/C (21) and epidemiology typing (i.e., multilocus sequence typing [MLST], spa and SCCmec typing) (22).…”

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confidence: 99%

Performance of BD Max StaphSR for Screening of Methicillin-Resistant Staphylococcus aureus Isolates among a Contemporary and Diverse Collection from 146 Institutions Located in Nine U.S. Census Regions: Prevalence of mecA Dropout Mutants

et al. 2016

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This study determined the performance of BD Max StaphSR and the rate of methicillin-resistant Staphylococcus aureus (MRSA) with an unrecognized staphylococcal cassette chromosome mec (SCCmec) right-extremity junction (MREJ) region among 907 methicillin-resistant S. aureus (MRSA) and 900 methicillin-susceptible S. aureus (MSSA) isolates. The rate of mecA/mecC dropout mutants was also evaluated. Only three MRSA isolates (99.7% sensitivity; 904/907) were classified as MSSA by the BD Max StaphSR assay, due to negative results for MREJ. Eight MSSA isolates (99.1% sensitivity; 892/900) were assigned as MRSA. However, six of these MSSA isolates had the mecA gene confirmed by PCR and sequencing (99.8% sensitivity; 898/900). Overall, 7.1% (64/900) of MSSA isolates showed results compatible with a mecA dropout genotype. Several studies have reported a decline in the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) and invasive infections in US and European hospitals (1-6). However, the incidence of community-onset (CO) MRSA infection has varied according to geographic region (7-10). Despite variability in the occurrence of CO-MRSA and HA-MRSA invasive diseases, S. aureus persists as the most common organism responsible for human infections, and methicillin resistance remains the most commonly identified resistance in medical institutions (11). Therefore, proper infection control practices and antimicrobial stewardship strategies play important roles in controlling MRSA infections (12, 13).Screening for MRSA carriers has become an important tool for early detection and to help prevent MRSA spread (14). Early generations of molecular assays targeting the mecA gene may provide false-positive results due to the copresence of methicillin-resistant staphylococci other than S. aureus (i.e., coagulase-negative staphylococci [CoNS]) (15). Performance evaluations of second-generation assays targeting the staphylococcal cassette chromosome mec (SCCmec)-orfX right-extremity junction (MREJ) region reported the presence of S. aureus carrying a genetic element that lacked the mecA (so-called dropout) mutant, again resulting in false-positive reports (16). Newer approaches targeting both mec and MREJ region sequences have been developed to minimize the likelihood of false-positive results, thus minimizing unnecessary isolation precautions (17). However, a false-positive reaction can still occur in the presence of mixed populations of methicillinresistant CoNS and a dropout S. aureus mutant.This study aimed to (i) determine the relative percentage rate of mecA/mecC dropout mutants among methicillin-susceptible S. aureus (MSSA) isolates collected from U.S. hospitals and (ii) determine the relative percentage rate of MRSA with unrecognized MREJ region sequences. A total of 907 MRSA and 900 MSSA isolates were included (at least 100 MRSA and 100 MSSA from each U.S. Census region). Isolates were collected from 146 U.S. hospitals during the 2013 SENTRY Antimicrobial Surveillance Program (see Table S1 in the s...

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“…Five isolates each were typed as clonal complex 5 (CC5) or CC45. We focused on these CCs because CC5 is a leading cause of hospital-acquired methicillin-resistant S. aureus (MRSA) associated with complicated infections (15)(16)(17), whereas CC45 is a predominant colonizer of healthy individuals, and is also found in bloodstream infections associated with suboptimal clinical outcomes in Europe (Berlin-IV) and the United States (USA600) (18,19). By strategically selecting samples from opposite ends of a continuum of clinical readouts and clonotypes (PB/RB and CC5/45, respectively), we postulated that this would provide the best opportunity to test linkage between FnBPs and differential therapeutic outcomes in non-CDI S. aureus bacteremia.…”

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Endovascular Infections Caused by Methicillin-Resistant Staphylococcus aureus Are Linked to Clonal Complex-Specific Alterations in Binding and Invasion Domains of Fibronectin-Binding Protein A as Well as the Occurrence of fnbB

et al. 2015

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e Endovascular infections caused by Staphylococcus aureus involve interactions with fibronectin present as extracellular matrix or surface ligand on host cells. We examined the expression, structure, and binding activity of the two major S. aureus fibronectinbinding proteins (FnBPA, FnBPB) in 10 distinct, methicillin-resistant clinical isolates from patients with either persistent or resolving bacteremia. The persistent bacteremia isolates (n ‫؍‬ 5) formed significantly stronger bonds with immobilized fibronectin as determined by dynamic binding measurements performed with atomic force microscopy. Several notable differences were also observed when the results were grouped by clonal complex 5 (CC5) strains (n ‫؍‬ 5) versus CC45 strains (n ‫؍‬ 5). Fibronectinbinding receptors on CC5 formed stronger bonds with immobilized fibronectin (P < 0.001). The fnbA gene was expressed at higher levels in CC45, whereas fnbB was found in only CC5 isolates. The fnbB gene was not sequenced because all CC45 isolates lacked this gene. Instead, comparisons were made for fnbA, which was present in all 10 isolates. Sequencing of fnbA revealed discrete differences within high-affinity, fibronectin-binding repeats (FnBRs) of FnBPA that included (i) 5-amino-acid polymorphisms in FnBR-9, FnBR-10, and FnBR-11 involving charged or polar side chains, (ii) an extra, 38-amino-acid repeat inserted between FnBR-9 and FnBR-10 exclusively seen in CC45 isolates, and (iii) CC5 isolates had the SVDFEED epitope in FnBR-11 (a sequence shown to be essential for fibronectin binding), while this sequence was replaced in all CC45 isolates with GIDFVED (a motif known to favor host cell invasion at the cost of reduced fibronectin binding). These complementary sequence and binding data suggest that differences in fnbA and fnbB, particularly polymorphisms and duplications in FnBPA, give S. aureus two distinct advantages in human endovascular infections: (i) FnBPs similar to that of CC5 enhance ligand binding and foster initiation of disease, and (ii) CC45-like FnBPs promote cell invasion, a key attribute in persistent endovascular infections.

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Characterization of Methicillin-Resistant Staphylococcus aureus Strains Recovered from a Phase IV Clinical Trial for Linezolid versus Vancomycin for Treatment of Nosocomial Pneumonia

Cited by 31 publications

References 52 publications

Disruption of staphylococcal aggregation protects against lethal lung injury

Disruption of staphylococcal aggregation protects against lethal lung injury

Performance of BD Max StaphSR for Screening of Methicillin-Resistant Staphylococcus aureus Isolates among a Contemporary and Diverse Collection from 146 Institutions Located in Nine U.S. Census Regions: Prevalence of mecA Dropout Mutants

Endovascular Infections Caused by Methicillin-Resistant Staphylococcus aureus Are Linked to Clonal Complex-Specific Alterations in Binding and Invasion Domains of Fibronectin-Binding Protein A as Well as the Occurrence of fnbB

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