scholarly journals Linezolid Attenuates Lethal Lung Damage during Postinfluenza Methicillin-Resistant Staphylococcus aureus Pneumonia

2019 ◽  
Vol 87 (10) ◽  
Author(s):  
Atul K. Verma ◽  
Christopher Bauer ◽  
Vijaya Kumar Yajjala ◽  
Shruti Bansal ◽  
Keer Sun
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Effect ◽  
Critical Role ◽  
Lung Damage ◽  
Alpha Toxin ◽  
Methicillin Resistant ◽  
Content Type ◽  
Linezolid Therapy ◽  
Staphylococcus Aureus Pneumonia ◽  
The Impact

ABSTRACT Postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) infection can quickly develop into severe, necrotizing pneumonia, causing over 50% mortality despite antibiotic treatments. In this study, we investigated the efficacy of antibiotic therapies and the impact of S. aureus alpha-toxin in a model of lethal influenza virus and MRSA coinfection. We demonstrate that antibiotics primarily attenuate alpha-toxin-induced acute lethality, even though both alpha-toxin-dependent and -independent mechanisms significantly contribute to animal mortality after coinfection. Furthermore, we found that the protein synthesis-suppressing antibiotic linezolid has an advantageous therapeutic effect on alpha-toxin-induced lung damage, as measured by protein leak and lactate dehydrogenase (LDH) activity. Importantly, using a Panton-Valentine leucocidin (PVL)-negative MRSA isolate from patient sputum, we show that linezolid therapy significantly improves animal survival from postinfluenza MRSA pneumonia compared with vancomycin treatment. Rather than improved viral or bacterial control, this advantageous therapeutic effect is associated with a significantly attenuated proinflammatory cytokine response and acute lung damage in linezolid-treated mice. Together, our findings not only establish a critical role of alpha-toxin in the extreme mortality of secondary MRSA pneumonia after influenza but also provide support for the possibility that linezolid could be a more effective treatment than vancomycin to improve disease outcomes.

scholarly journals Emergence of Linezolid-Resistant Mutants in a Susceptible-Cell Population of Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (5) ◽  
pp. 2466-2468 ◽  
Author(s):  
Yurika Ikeda-Dantsuji ◽  
Hideaki Hanaki ◽  
Taiji Nakae ◽  
Yoshio Takesue ◽  
Kazunori Tomono ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Population ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Rrna Genes ◽  
Chloramphenicol Resistance ◽  
Methicillin Resistant ◽  
Content Type ◽  
Susceptible Cell ◽  
Linezolid Therapy ◽  
Resistant Mutants

ABSTRACTMethicillin-resistantStaphylococcus aureuswith a MIC of linezolid of 4 μg/ml, isolated from a patient who had undergone unsuccessful linezolid therapy, yielded linezolid-resistant mutants in blood agar at 48 h of incubation. The resistant clones showed a MIC of linezolid ranging from 8 to 64 μg/ml and accumulated the T2500A mutation(s) of the rRNA genes. Emergence of these resistant clones appears to be facilitated by a cryptic mutation or mutations associated with chloramphenicol resistance.

scholarly journals Nasal Methicillin-Resistant Staphylococcus aureus (MRSA) PCR Testing Reduces the Duration of MRSA-Targeted Therapy in Patients with Suspected MRSA Pneumonia

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Nidhu Baby ◽  
Andrew C. Faust ◽  
Terri Smith ◽  
Lyndsay A. Sheperd ◽  
Laura Knoll ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Targeted Therapy ◽  
Length Of Hospital Stay ◽  
Serum Levels ◽  
Methicillin Resistant ◽  
Content Type ◽  
Before And After ◽  
Health Care Associated Pneumonia ◽  
The Impact ◽  
Suspected Pneumonia

ABSTRACT The objective of this study was to evaluate the impact of pharmacist-ordered methicillin-resistant Staphylococcus aureus (MRSA) PCR testing on the duration of empirical MRSA-targeted antibiotic therapy in patients with suspected pneumonia. This is a retrospective analysis of patients who received vancomycin or linezolid for suspected pneumonia before and after the implementation of a pharmacist-driven protocol for nasal MRSA PCR testing. Patients were included if they were adults of >18 years of age and initiated on vancomycin or linezolid for suspected MRSA pneumonia. The primary endpoint was the duration of vancomycin or linezolid therapy. After screening 368 patients, 57 patients met inclusion criteria (27 pre-PCR and 30 post-PCR). Baseline characteristics were similar between the two groups, with the majority of patients classified as having health care-associated pneumonia (68.4%). The use of the nasal MRSA PCR test reduced the mean duration of MRSA-targeted therapy by 46.6 h (74.0 ± 48.9 h versus 27.4 ± 18.7 h; 95% confidence interval [CI], 27.3 to 65.8 h; P < 0.0001). Fewer patients in the post-PCR group required vancomycin serum levels and dose adjustment (48.1% versus 16.7%; P = 0.02). There were no significant differences between the pre- and post-PCR groups regarding days to clinical improvement (1.78 ± 2.52 versus 2.27 ± 3.34; P = 0.54), length of hospital stay (11.04 ± 9.5 versus 8.2 ± 7.8; P = 0.22), or hospital mortality (14.8% versus 6.7%; P = 0.41). The use of nasal MRSA PCR testing in patients with suspected MRSA pneumonia reduced the duration of empirical MRSA-targeted therapy by approximately 2 days without increasing adverse clinical outcomes.

scholarly journals Impact of the Novel Prophage ϕSA169 on Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Liang Li ◽  
Genzhu Wang ◽  
Yi Li ◽  
Patrice Francois ◽  
Arnold S. Bayer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Hot Spot ◽  
Critical Role ◽  
Bacteriophage Therapy ◽  
Methicillin Resistant ◽  
Content Type ◽  
Antimicrobial Resistance Genes

ABSTRACT Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections are life-threatening syndromes with few therapeutic options. The potential impact of bacteriophages on the persistent outcome has not been well studied. In this study, we investigated the role of a novel prophage (ϕSA169) in MRSA persistence by using a lysogen-free clinically resolving bacteremia (RB) isolate and comparing it to a derivative which was obtained by infecting the RB strain with ϕSA169, which has been lysogenized in a clinical persistent MRSA bacteremia (PB) isolate. Similar to the PB isolate, the ϕSA169-lysogenized RB strain exhibited well-defined in vitro and in vivo phenotypic and genotypic signatures related to the persistent outcome, including earlier activation of global regulators (i.e., sigB, sarA, agr RNAIII, and sae); higher expression of a critical purine biosynthesis gene, purF; and higher growth rates accompanied by lower ATP levels and vancomycin (VAN) susceptibility and stronger δ-hemolysin and biofilm formation versus its isogenic parental RB isolate. Notably, the contribution of ϕSA169 in persistent outcome with VAN treatment was confirmed in an experimental infective endocarditis model. Taken together, these results indicate the critical role of the prophage ϕSA169 in persistent MRSA endovascular infections. Further studies are needed to identify the mechanisms of ϕSA169 in mediating the persistence, as well as establishing the scope of impact, of this prophage in other PB strains. IMPORTANCE Bacteriophages are viruses that invade the bacterial host, disrupt bacterial metabolism, and cause the bacterium to lyse. Because of its remarkable antibacterial activity and unique advantages over antibiotics, for instance, bacteriophage is specific for one species of bacteria and resistance to phage is less common than resistance to antibiotics. Indeed, bacteriophage therapy for treating infections due to multidrug-resistant pathogens in humans has become a research hot spot. However, it is also worth considering that bacteriophages are transferable and could cotransfer host chromosomal genes, e.g., virulence and antimicrobial resistance genes, while lysogenizing and integrating into the bacterial chromosome (prophage), thus playing a role in bacterial evolution and virulence. In the current study, we identified a novel prophage, ϕSA169, from a clinical persistent MRSA bacteremia isolate, and we determined that ϕSA169 mediated well-defined in vitro and in vivo phenotypic and genotypic signatures related to the persistent outcome, which may represent a unique and important persistent mechanism(s).

scholarly journals Fate of Mutation Rate Depends onagrLocus Expression during Oxacillin-Mediated Heterogeneous-Homogeneous Selection in Methicillin-Resistant Staphylococcus aureus Clinical Strains

2011 ◽  
Vol 55 (7) ◽  
pp. 3176-3186 ◽  
Author(s):  
Konrad B. Plata ◽  
Roberto R. Rosato ◽  
Adriana E. Rosato
Keyword(s):  
Staphylococcus Aureus ◽  
Mutation Rate ◽  
Selection Process ◽  
Critical Role ◽  
Ectopic Expression ◽  
Regulatory System ◽  
Methicillin Resistant ◽  
Content Type ◽  
Heterogeneous Expression ◽  
Mrsa Strains

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) strains are characterized by a heterogeneous expression of resistance. We have previously shown in clinical oxacillin-susceptible,mecA-positive MRSA strains that selection from a very heterogeneous (HeR) to highly homogeneous (HoR) resistant phenotype was mediated by acquisition of mutations through an oxacillin-induced SOS response. In the present study, we used a spotted DNA microarray to evaluate differential gene expression during HeR-HoR selection and found increased expression of theagrtwo-component regulatory system. We hypothesized that increased expression ofagrrepresents a mechanistically relevant component of this process. We demonstrated that inactivation ofagrduring the HeR-HoR selection process results in a significant increase in mutation rate; these effects were reversed by complementing theagrmutant. Furthermore, we found that extemporal ectopic expression ofagrand, more specifically, RNAII inagr-null mutant HeR cells suppressed mutation frequency and the capacity of these cells to undergo the HeR-HoR selection. These findings sustain the concept that increased expression ofagrduring HeR-HoR selection plays a critical role in regulating the β-lactam-induced increased mutation rate in very heterogeneous MRSA strains. Moreover, they indicate that a temporally controlled increase inagrexpression is required to tightly modulate SOS-mediated mutation rates, which then allows for full expression of oxacillin homogeneous resistance in very heterogeneous clinical MRSA strains.

scholarly journals β-Lactams Enhance Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus Bacteremia Compared to Vancomycin Alone

2013 ◽  
Vol 58 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Thomas J. Dilworth ◽  
Omar Ibrahim ◽  
Pamela Hall ◽  
Jora Sliwinski ◽  
Carla Walraven ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Synergistic Activity ◽  
Methicillin Resistant ◽  
Content Type ◽  
Staphylococcus Aureus Bacteremia ◽  
High Incidence ◽  
The Difference ◽  
Initiation Of Therapy ◽  
The Impact

ABSTRACTVancomycin (VAN) is often used to treat methicillin-resistantStaphylococcus aureus(MRSA) bacteremia despite a high incidence of microbiological failure. Recentin vitroanalyses of β-lactams in combination with VAN demonstrated synergistic activity against MRSA. The goal of this study was to examine the impact of combination therapy with VAN and a β-lactam (Combo) on the microbiological eradication of MRSA bacteremia compared to VAN alone. This was a retrospective cohort study of patients with MRSA bacteremia who received Combo therapy or VAN alone. Microbiological eradication of MRSA, defined as a negative blood culture obtained after initiation of therapy, was used to evaluate the efficacy of each regimen. A total of 80 patients were included: 50 patients in the Combo group and 30 patients in the VAN-alone group. Microbiological eradication was achieved in 48 patients (96%) in the Combo group compared to 24 patients (80%) in the VAN-alone group (P= 0.021). In a multivariable model, the Combo treatment had a higher likelihood of achieving microbiological eradication (adjusted odds ratio, 11.24; 95% confidence interval, 1.7 to 144.3;P= 0.01). In patients with infective endocarditis (n= 22), 11/11 (100%) who received Combo therapy achieved microbiological eradication compared to 9/11 (81.8%) treated with VAN alone, but the difference was not statistically significant (P= 0.20). Patients with MRSA bacteremia who received Combo therapy were more likely to experience microbiological eradication of MRSA than patients who received VAN alone.

scholarly journals Impact of Antibiotic Treatment on the Burden of Nasal Staphylococcus aureus among Hospitalized Patients

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Anubhav Kanwar ◽  
Jennifer L. Cadnum ◽  
Annette L. Jencson ◽  
Curtis J. Donskey
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Treatment ◽  
Inhibitory Activity ◽  
Hospitalized Patients ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Regimens ◽  
Systemic Antibiotics ◽  
The Impact

ABSTRACT We examined the impact of systemic antibiotics on the burden of nasal Staphylococcus aureus in hospitalized patients. Of 1,482 patients, 237 (16%) had nasal methicillin-susceptible S. aureus (MSSA) and 92 (6%) had nasal methicillin-resistant S. aureus (MRSA) on admission. Treatment regimens that included agents with inhibitory activity against MRSA or MSSA significantly reduced the burden of carriage, whereas regimens lacking anti-MRSA activity, including fluoroquinolones, promoted MRSA overgrowth.

scholarly journals Role of the Stringent Stress Response in the Antibiotic Resistance Phenotype of Methicillin-Resistant Staphylococcus aureus

2016 ◽  
Vol 60 (4) ◽  
pp. 2311-2317 ◽  
Author(s):  
Sandra Aedo ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Stress Response ◽  
Phenotypic Expression ◽  
Beta Lactam ◽  
Resistance Level ◽  
Methicillin Resistant ◽  
Content Type ◽  
Resistance Phenotype ◽  
Oxacillin Resistance ◽  
The Impact

ABSTRACTResistance to beta-lactam antibiotics in methicillin-resistantStaphylococcus aureus(MRSA) requires the presence of an acquired genetic determinant,mecAormecC, which encode penicillin-binding protein PBP2A or PBP2A′, respectively. Although all MRSA strains share a mechanism of resistance, the phenotypic expression of beta-lactam resistance shows considerable strain-to-strain variation. The stringent stress response, a stress response that results from nutrient limitation, was shown to play a key role in determining the resistance level of an MRSA strain. In the present study, we validated the impact of the stringent stress response on transcription and translation ofmecAin the MRSA clinical isolate strain N315, which also carries known regulatory genes (mecI/mecR1/mecR2andblaI/blaR1) formecAtranscription. We showed that the impact of the stringent stress response on the resistance level may be restricted to beta-lactam resistance based on a “foreign” determinant such asmecA, as opposed to resistance based on mutations in the nativeS. aureusdeterminantpbpB(encoding PBP2). Our observations demonstrate that high-level resistance mediated by the stringent stress response follows the current model of beta-lactam resistance in which the native PBP2 protein is also essential for expression of the resistance phenotype. We also show that theStaphylococcus sciuri pbpDgene (also calledmecAI), the putative evolutionary precursor ofmecA, confers oxacillin resistance in anS. aureusstrain, generating a heterogeneous phenotype that can be converted to high and homogenous resistance by induction of the stringent stress response in the bacteria.

scholarly journals Convergent Adaptation in the Dominant Global Hospital Clone ST239 of Methicillin-Resistant Staphylococcus aureus

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Sarah L. Baines ◽  
Kathryn E. Holt ◽  
Mark B. Schultz ◽  
Torsten Seemann ◽  
Brian O. Howden ◽  
...  
Keyword(s):  
Health Care ◽  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Health Care Environment ◽  
Methicillin Resistant ◽  
Content Type ◽  
Public Health Burden ◽  
Evolutionary Response ◽  
The Impact

ABSTRACTInfections caused by highly successful clones of hospital-associated methicillin-resistantStaphylococcus aureus(HA-MRSA) are a major public health burden. The globally dominant sequence type 239 (ST239) HA-MRSA clone has persisted in the health care setting for decades, but the basis of its success has not been identified. Taking a collection of 123 ST239 isolates spanning 32 years, we have used population-based functional genomics to investigate the evolution of this highly persistent and successful clone. Phylogenetic reconstruction and population modeling uncovered a previously unrecognized distinct clade of ST239 that was introduced into Australia from Asia and has perpetuated the epidemic in this region. Functional analysis demonstrated attenuated virulence and enhanced resistance to last-line antimicrobials, the result of two different phenomena, adaptive evolution within the original Australian ST239 clade and the introduction of a new clade displaying shifts in both phenotypes. The genetic diversity between the clades allowed us to employ genome-wide association testing and identify mutations in other essential regulatory systems, includingwalKR, that significantly associate with and may explain these key phenotypes. The phenotypic convergence of two independently evolving ST239 clades highlights the very strong selective pressures acting on HA-MRSA, showing that hospital environments have favored the accumulation of mutations in essential MRSA genes that increase resistance to antimicrobials, attenuate virulence, and promote persistence in the health care environment. Combinations of comparative genomics and careful phenotypic measurements of longitudinal collections of clinical isolates are giving us the knowledge to intelligently address the impact of current and future antibiotic usage policies and practices on hospital pathogens globally.IMPORTANCEMethicillin-resistantStaphylococcus aureus(MRSA) is responsible for innumerable drug-resistant health care-associated infections globally. This study, the first to investigate the evolutionary response of hospital-associated MRSA (HA-MRSA) over many decades, demonstrates how MRSA can persist in a region through the reintroduction of a previously unrecognized distinct clade. This study also demonstrates the crucial adaptive responses of HA-MRSA to the highly selective environment of the health care system, the evolution of MRSA isolates to even higher levels of antibiotic resistance at the cost of attenuated virulence. However,in vivopersistence is maintained, resulting in a clone of HA-MRSA able to resist almost all antimicrobial agents and still cause invasive disease in the heavily compromised hosts found in modern health care settings.

scholarly journals The Increased Accumulation of Staphylococcus aureus Virulence Factors Is Maximized in a purR Mutant by the Increased Production of SarA and Decreased Production of Extracellular Proteases

2021 ◽  
Vol 89 (4) ◽  
Author(s):  
Duah Alkam ◽  
Piroon Jenjaroenpun ◽  
Aura M. Ramirez ◽  
Karen E. Beenken ◽  
Horace J. Spencer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Binding Proteins ◽  
Protease Production ◽  
Alpha Toxin ◽  
Extracellular Proteases ◽  
Content Type ◽  
Enhanced Production ◽  
Fibronectin Binding ◽  
The Impact

ABSTRACT Mutation of purR was previously shown to enhance the virulence of Staphylococcus aureus in a murine sepsis model, and this cannot be fully explained by increased expression of genes within the purine biosynthesis pathway. Rather, the increased production of specific S. aureus virulence factors, including alpha toxin and the fibronectin-binding proteins, was shown to play an important role. Mutation of purR was also shown previously to result in increased abundance of SarA. Here, we demonstrate by transposon sequencing that mutation of purR in the USA300 strain LAC increases fitness in a biofilm while mutation of sarA has the opposite effect. Therefore, we assessed the impact of sarA on reported purR-associated phenotypes by characterizing isogenic purR, sarA, and sarA/purR mutants. The results confirmed that mutation of purR results in increased abundance of alpha toxin, protein A, the fibronectin-binding proteins, and SarA, decreased production of extracellular proteases, an increased capacity to form a biofilm, and increased virulence in an osteomyelitis model. Mutation of sarA had the opposite effects on all of these phenotypes and, other than bacterial burdens in the bone, all of the phenotypes of sarA/purR mutants were comparable to those of sarA mutants. Limiting the production of extracellular proteases reversed all of the phenotypes of sarA mutants and most of those of sarA/purR mutants. We conclude that a critical component defining the virulence of a purR mutant is the enhanced production of SarA, which limits protease production to an extent that promotes the accumulation of critical S. aureus virulence factors.

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