scholarly journals MEDI4893* Promotes Survival and Extends the Antibiotic Treatment Window in a Staphylococcus aureus Immunocompromised Pneumonia Model

2015 ◽  
Vol 59 (8) ◽  
pp. 4526-4532 ◽  
Author(s):  
L. Hua ◽  
T. S. Cohen ◽  
Y. Shi ◽  
V. Datta ◽  
J. J. Hilliard ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Treatment ◽  
Adjunctive Therapy ◽  
Survival Rates ◽  
Passive Immunization ◽  
Bacterial Overgrowth ◽  
Content Type ◽  
Increased Risk ◽  
Immunocompromised Mice ◽  
Treatment Window

ABSTRACTImmunocompromised individuals are at increased risk ofStaphylococcus aureuspneumonia. Neutralization of alpha-toxin (AT) with the monoclonal antibody (MAb) MEDI4893* protects normal mice fromS. aureuspneumonia; however, the effects of the MAb in immunocompromised mice have not been reported. In this study, passive immunization with MEDI4893* increased survival rates and reduced bacterial numbers in the lungs in an immunocompromised murineS. aureuspneumonia model. Lungs from infected mice exhibited alveolar epithelial damage, protein leakage, and bacterial overgrowth, whereas lungs from mice passively immunized with MEDI4893* retained a healthy architecture, with an intact epithelial barrier. Adjunctive therapy or prophylaxis with a subtherapeutic MEDI4893* dose combined with subtherapeutic doses of vancomycin or linezolid improved survival rates, compared with the monotherapies. Furthermore, coadministration of MEDI4893* with vancomycin or linezolid extended the antibiotic treatment window. These data suggest that MAb-mediated neutralization of AT holds promise in strategies for prevention and adjunctive therapy among immunocompromised patients.

scholarly journals Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

2014 ◽  
Vol 83 (1) ◽  
pp. 339-345 ◽  
Author(s):  
Bao Zhong Zhang ◽  
Yan Hong Hua ◽  
Bin Yu ◽  
Candy Choi Yi Lau ◽  
Jian Piao Cai ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Survival Rates ◽  
Passive Immunization ◽  
Health Concern ◽  
Drug Resistant ◽  
Public Health Concern ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains

Staphylococcus aureusis a common pathogen found in the community and in hospitals. Most notably, methicillin-resistantS. aureusis resistant to many antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments, such as immunotherapeutic approaches. To date, most clinical trials of vaccines or of passive immunization againstS. aureushave ended in failure. In this study, we investigated two ESAT-6-like proteins secreted byS. aureus,S. aureusEsxA (SaEsxA) and SaEsxB, as possible targets for a vaccine. Mice vaccinated with these purified proteins elicited high titers of anti-SaEsxA and anti-SaEsxB antibodies, but these antibodies could not preventS. aureusinfection. On the other hand, recombinant SaEsxA (rSaEsxA) and rSaEsxB could induce Th1- and Th17-biased immune responses in mice. Mice immunized with rSaEsxA and rSaEsxB had significantly improved survival rates when challenged withS. aureuscompared with the controls. These findings indicate that SaEsxA and SaEsxB are two promising Th1 and Th17 candidate antigens which could be developed into multivalent and serotype-independent vaccines againstS. aureusinfection.

scholarly journals Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Vien T. M. Le ◽  
Hoan N. Le ◽  
Marcos Gabriel Pinheiro ◽  
Kenneth J. Hahn ◽  
Mary L. Dinh ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Production ◽  
Protective Efficacy ◽  
Survival Rates ◽  
Rabbit Model ◽  
Rank Test ◽  
Necrotizing Pneumonia ◽  
Time Curve ◽  
Content Type

ABSTRACT The protective efficacy of tedizolid phosphate, a novel oxazolidinone that potently inhibits bacterial protein synthesis, was compared to those of linezolid, vancomycin, and saline in a rabbit model of Staphylococcus aureus necrotizing pneumonia. Tedizolid phosphate was administered to rabbits at 6 mg/kg of body weight intravenously twice daily, which yielded values of the 24-h area under the concentration-time curve approximating those found in humans. The overall survival rate was 83% for rabbits treated with 6 mg/kg tedizolid phosphate twice daily and 83% for those treated with 50 mg/kg linezolid thrice daily (P = 0.66 by the log-rank test versus the results obtained with tedizolid phosphate). These survival rates were significantly greater than the survival rates of 17% for rabbits treated with 30 mg/kg vancomycin twice daily (P = 0.003) and 17% for rabbits treated with saline (P = 0.002). The bacterial count in the lungs of rabbits treated with tedizolid phosphate was significantly decreased compared to that in the lungs of rabbits treated with saline, although it was not significantly different from that in the lungs of rabbits treated with vancomycin or linezolid. The in vivo bacterial production of alpha-toxin and Panton-Valentine leukocidin, two key S. aureus-secreted toxins that play critical roles in the pathogenesis of necrotizing pneumonia, in the lungs of rabbits treated with tedizolid phosphate and linezolid was significantly inhibited compared to that in the lungs of rabbits treated with vancomycin or saline. Taken together, these results indicate that tedizolid phosphate is superior to vancomycin for the treatment of S. aureus necrotizing pneumonia because it inhibits the bacterial production of lung-damaging toxins at the site of infection.

scholarly journals Improved Protection in a Rabbit Model of Community-Associated Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia upon Neutralization of Leukocidins in Addition to Alpha-Hemolysin

2016 ◽  
Vol 60 (10) ◽  
pp. 6333-6340 ◽  
Author(s):  
Binh An Diep ◽  
Vien T. M. Le ◽  
Zehra C. Visram ◽  
Harald Rouha ◽  
Lukas Stulik ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Human Monoclonal Antibody ◽  
Rabbit Model ◽  
Passive Immunization ◽  
Severe Pneumonia ◽  
Phagocytic Cells ◽  
Methicillin Resistant ◽  
Content Type ◽  
Alpha Hemolysin ◽  
Full Protection

ABSTRACTCommunity-associated methicillin-resistantStaphylococcus aureus(CA-MRSA), especially the USA300 pulsotype, is a frequent cause of skin and soft tissue infections and severe pneumonia. Despite appropriate antibiotic treatment, complications are common and pneumonia is associated with high mortality.S. aureusstrains express multiple cytotoxins, including alpha-hemolysin (Hla) and up to five bicomponent leukocidins that specifically target phagocytic cells for lysis. CA-MRSA USA300 strains carry the genes for all six cytotoxins. Species specificity of the leukocidins greatly contributes to the ambiguity regarding their role inS. aureuspathogenesis. We performed a comparative analysis of the leukocidin susceptibility of human, rabbit, and mouse polymorphonuclear leukocytes (PMNs) to assess the translational value of mouse and rabbitS. aureusmodels. We found that mouse PMNs were largely resistant to LukSF-PV, HlgAB, and HlgCB and susceptible only to LukED, whereas rabbit and human PMNs were highly sensitive to all these cytotoxins. In the rabbit pneumonia model with a USA300 CA-MRSA strain, passive immunization with a previously identified human monoclonal antibody (MAb), Hla-F#5, which cross-neutralizes Hla, LukSF-PV, HlgAB, HlgCB, and LukED, provided full protection, whereas an Hla-specific MAb was only partially protective. In the mouse USA300 CA-MRSA pneumonia model, both types of antibodies demonstrated full protection, suggesting that Hla, but not leukocidin(s), is the principal virulence determinant in mice. As the rabbit recapitulates the high susceptibility to leukocidins characteristic of humans, this species represents a valuable model for assessing novel, cytotoxin-targeting anti-S. aureustherapeutic approaches.

scholarly journals Role of Antibodies in Protection Elicited by Active Vaccination with Genetically Inactivated Alpha Hemolysin in a Mouse Model of Staphylococcus aureus Skin and Soft Tissue Infections

2014 ◽  
Vol 21 (5) ◽  
pp. 622-627 ◽  
Author(s):  
Christopher P. Mocca ◽  
Rebecca A. Brady ◽  
Drusilla L. Burns
Keyword(s):  
Staphylococcus Aureus ◽  
Soft Tissue ◽  
Murine Model ◽  
Bacterial Colonization ◽  
Passive Immunization ◽  
The United States ◽  
Soft Tissue Infections ◽  
Content Type ◽  
Alpha Hemolysin ◽  
Active Vaccination

ABSTRACTDue to the emergence of highly virulent community-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) infections,S. aureushas become a major threat to public health. A majority of CA-MRSA skin and soft tissue infections in the United States are caused byS. aureusUSA300 strains that are known to produce high levels of alpha hemolysin (Hla). Therefore, vaccines that contain inactivated forms of this toxin are currently being developed. In this study, we sought to determine the immune mechanisms of protection for this antigen using a vaccine composed of a genetically inactivated form of Hla (HlaH35L). Using a murine model of skin and soft tissue infections (SSTI), we found that BALB/c mice were protected by vaccination with HlaH35L; however, Jh mice, which are deficient in mature B lymphocytes and lack IgM and IgG in their serum, were not protected. Passive immunization with anti-HlaH35L antibodies conferred protection against bacterial colonization. Moreover, we found a positive correlation between the total antibody concentration induced by active vaccination and reduced bacterial levels. Animals that developed detectable neutralizing antibody titers after active vaccination were significantly protected from infection. These data demonstrate that antibodies to Hla represent the major mechanism of protection afforded by active vaccination with inactivated Hla in this murine model of SSTI, and in this disease model, antibody levels correlate with protection. These results provide important information for the future development and evaluation ofS. aureusvaccines.

scholarly journals Clearance of Staphylococcus aureus Nasal Carriage Is T Cell Dependent and Mediated through Interleukin-17A Expression and Neutrophil Influx

2013 ◽  
Vol 81 (6) ◽  
pp. 2070-2075 ◽  
Author(s):  
Nathan K. Archer ◽  
Janette M. Harro ◽  
Mark E. Shirtliff
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Neutrophil Migration ◽  
Nasal Carriage ◽  
Causal Connection ◽  
Content Type ◽  
Neutrophil Influx ◽  
Increased Risk

ABSTRACTThe anterior nares of humans are the major reservoir forStaphylococcus aureuscolonization. Approximately 20% of the healthy human population is persistently and 80% is intermittently colonized withS. aureusin the nasal cavity. Previous studies have shown a strong causal connection betweenS. aureusnasal carriage and increased risk of nosocomial infection, as well as increased carriage due to immune dysfunction. However, the immune responses that permit persistence or mediate clearance ofS. aureuson the nasal mucosa are fundamentally undefined. In this study, we developed a carriage model in C57BL/6J mice and showed that clearance begins 14 days postinoculation. In contrast, SCID mice that have a deficient adaptive immune response are unable to eliminateS. aureuseven after 28 days postinoculation. Furthermore, decolonization was found to be T cell mediated but B cell independent by evaluating carriage clearance in T-cell receptor β/δ (TCR-β/δ) knockout (KO) and IgH-μ KO mice, respectively. Upregulation of the cytokines interleukin 1β (IL-1β), KC (also termed CXC ligand 1 [CXCL1]), and IL-17A occurred following inoculation with intranasalS. aureus. IL-17A production was crucial for clearance, since IL-17A-deficient mice were unable to effectively eliminateS. aureuscarriage. Subsequently, cell differential counts were evaluated from nasal lavage fluid obtained from wild-type and IL-17A-deficient colonized mice. These counts displayed IL-17A-dependent neutrophil migration. Antibody-mediated depletion of neutrophils in colonized mice caused reduced clearance compared to that in isotype-treated controls. Our data suggest that the Th17-associated immune response is required for nasal decolonization. This response is T cell dependent and mediated via IL-17A production and neutrophil influx. Th17-associated immune responses may be targeted for strategies to mitigate distal infections originating from persistentS. aureuscarriage in humans.

scholarly journals Genome Sequence of a Staphylococcus aureus Strain Isolated from a Dairy Cow That Was Nonresponsive to Antibiotic Treatment

2020 ◽  
Vol 9 (20) ◽  
Author(s):  
John D. Lippolis ◽  
Ellie J. Putz ◽  
Hao Ma ◽  
David P. Alt ◽  
Eduardo Casas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dairy Cattle ◽  
Antibiotic Treatment ◽  
Genome Sequence ◽  
Dairy Cow ◽  
Aureus Strain ◽  
Chronic Case ◽  
Content Type

Staphylococcus aureus can cause mastitis in dairy cattle. We report the genome sequence of a Staphylococcus aureus strain isolated from a dairy cow with a chronic case of mastitis. The infection with this strain of Staphylococcus aureus was not cleared from the animal with antibiotic treatment.

scholarly journals Clearance of Staphylococcus aureus from In Vivo Models of Chronic Infection by Immunization Requires Both Planktonic and Biofilm Antigens

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Janette M. Harro ◽  
Yvonne Achermann ◽  
Jeffrey A. Freiberg ◽  
Devon L. Allison ◽  
Kristen J. Brao ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protective Efficacy ◽  
Passive Immunization ◽  
Quadrivalent Vaccine ◽  
Bacterial Populations ◽  
In Vivo Models ◽  
Content Type ◽  
Pentavalent Vaccine ◽  
And Control

ABSTRACT Staphylococcus aureus is a causative agent of chronic biofilm-associated infections that are recalcitrant to resolution by the immune system or antibiotics. To combat these infections, an antistaphylococcal, biofilm-specific quadrivalent vaccine against an osteomyelitis model in rabbits has previously been developed and shown to be effective at eliminating biofilm-embedded bacterial populations. However, the addition of antibiotics was required to eradicate remaining planktonic populations. In this study, a planktonic upregulated antigen was combined with the quadrivalent vaccine to remove the need for antibiotic therapy. Immunization with this pentavalent vaccine followed by intraperitoneal challenge of BALB/c mice with S. aureus resulted in 16.7% and 91.7% mortality in pentavalent vaccine and control groups, respectively (P < 0.001). Complete bacterial elimination was found in 66.7% of the pentavalent cohort, while only 8.3% of the control animals cleared the infection (P < 0.05). Further protective efficacy was observed in immunized rabbits following intramedullary challenge with S. aureus, where 62.5% of the pentavalent cohort completely cleared the infection, versus none of the control animals (P < 0.05). Passive immunization of BALB/c mice with serum IgG against the vaccine antigens prior to intraperitoneal challenge with S. aureus prevented mortality in 100% of mice and eliminated bacteria in 33.3% of the challenged mice. These results demonstrate that targeting both the planktonic and biofilm stages with the pentavalent vaccine or the IgG elicited by immunization can effectively protect against S. aureus infection.

scholarly journals Role of Phenol-Soluble Modulins in Formation of Staphylococcus aureus Biofilms in Synovial Fluid

2015 ◽  
Vol 83 (7) ◽  
pp. 2966-2975 ◽  
Author(s):  
Sana S. Dastgheyb ◽  
Amer E. Villaruz ◽  
Katherine Y. Le ◽  
Vee Y. Tan ◽  
Anthony C. Duong ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Synovial Fluid ◽  
Antibiotic Treatment ◽  
Joint Infection ◽  
Regulatory System ◽  
Surface Proteins ◽  
Host Matrix ◽  
Content Type ◽  
Prosthetic Joint ◽  
Prosthetic Joint Infections

Staphylococcus aureusis a leading cause of prosthetic joint infections, which, as we recently showed, proceed with the involvement of biofilm-like clusters that cause recalcitrance to antibiotic treatment. Here we analyzed why these clusters grow extraordinarily large, reaching macroscopically visible extensions (>1 mm). We found that while specificS. aureussurface proteins are a prerequisite for agglomeration in synovial fluid, low activity of the Agr regulatory system and subsequent low production of the phenol-soluble modulin (PSM) surfactant peptides cause agglomerates to grow to exceptional dimensions. Our results indicate that PSMs function by disrupting interactions of biofilm matrix molecules, such as the polysaccharide intercellular adhesin (PIA), with the bacterial cell surface. Together, our findings support a two-step model of staphylococcal prosthetic joint infection: As we previously reported, interaction ofS. aureussurface proteins with host matrix proteins such as fibrin initiates agglomeration; our present results show that, thereafter, the bacterial agglomerates grow to extremely large sizes owing to the lack of PSM expression under the specific conditions present in joints. Our findings provide a mechanistic explanation for the reported extreme resistance of joint infection to antibiotic treatment, lend support to the notions that Agr functionality and PSM production play a major role in defining different forms ofS. aureusinfection, and have important implications for antistaphylococcal therapeutic strategies.

scholarly journals Modulation of Staphylococcus aureus Biofilm Matrix by Subinhibitory Concentrations of Clindamycin

2016 ◽  
Vol 60 (10) ◽  
pp. 5957-5967 ◽  
Author(s):  
Katrin Schilcher ◽  
Federica Andreoni ◽  
Vanina Dengler Haunreiter ◽  
Kati Seidl ◽  
Barbara Hasse ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Treatment ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Extracellular Dna ◽  
Content Type ◽  
Transcriptional Stress ◽  
Sigma Factor B ◽  
Subinhibitory Concentrations ◽  
Biofilm Matrix

ABSTRACTStaphylococcus aureusbiofilms are extremely difficult to treat. They provide a protected niche for the bacteria, rendering them highly recalcitrant toward host defenses as well as antibiotic treatment. Bacteria within a biofilm are shielded from the immune system by the formation of an extracellular polymeric matrix, composed of polysaccharides, extracellular DNA (eDNA), and proteins. Many antibiotics do not readily penetrate biofilms, resulting in the presence of subinhibitory concentrations of antibiotics. Here, we show that subinhibitory concentrations of clindamycin triggered a transcriptional stress response inS. aureusvia the alternative sigma factor B (σB) and upregulated the expression of the major biofilm-associated genesatlA,lrgA,agrA, thepsmgenes,fnbA, andfnbB. Our data suggest that subinhibitory concentrations of clindamycin alter the ability ofS. aureusto form biofilms and shift the composition of the biofilm matrix toward higher eDNA content. An understanding of the molecular mechanisms underlying biofilm assembly and dispersal in response to subinhibitory concentrations of clinically relevant antibiotics such as clindamycin is critical to further optimize antibiotic treatment strategies of biofilm-associatedS. aureusinfections.

scholarly journals Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Binh An Diep ◽  
Jamese J. Hilliard ◽  
Vien T. M. Le ◽  
Christine Tkaczyk ◽  
Hoan N. Le ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Passive Immunization ◽  
Adjunctive Treatment ◽  
Alpha Toxin ◽  
Necrotizing Pneumonia ◽  
Promising Candidate ◽  
Content Type ◽  
Serious Bacterial Infections ◽  
Mrsa Strains

ABSTRACT The role broad-spectrum antibiotics play in the spread of antimicrobial resistance, coupled with their effect on the healthy microbiome, has led to advances in pathogen-specific approaches for the prevention or treatment of serious bacterial infections. One approach in clinical testing is passive immunization with a monoclonal antibody (MAb) targeting alpha toxin for the prevention or treatment of Staphylococcus aureus pneumonia. Passive immunization with the human anti-alpha toxin MAb, MEDI4893*, has been shown to improve disease outcome in murine S. aureus pneumonia models. The species specificity of some S. aureus toxins necessitates testing anti-S. aureus therapeutics in alternate species. We developed a necrotizing pneumonia model in ferrets and utilized an existing rabbit pneumonia model to characterize MEDI4893* protective activity in species other than mice. MEDI4893* prophylaxis reduced disease severity in ferret and rabbit pneumonia models against both community-associated methicillin-resistant S. aureus (MRSA) and hospital-associated MRSA strains. In addition, adjunctive treatment of MEDI4893* with either vancomycin or linezolid provided enhanced protection in rabbits relative to the antibiotics alone. These results confirm that MEDI4893 is a promising candidate for immunotherapy against S. aureus pneumonia.

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