Efficacy of a Multimechanistic Monoclonal Antibody Combination against Staphylococcus aureus Surgical Site Infections in Mice.
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SUBMITTER: Ortines RV
PROVIDER: S-EPMC6658795 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant bacterium responsible for serious nosocomial and community-acquired infections worldwide. Since few antibiotics are effective for treating MRSA infections, the development of new therapies is of great importance. Previous studies demonstrated that PBP2a is a target that generates protective antibodies against MRSA. A murine monoclonal antibody (MAb) that recognizes PBP2a from MRSA strains was previously isolated and characterized. In this report, we evaluated the biodistribution of this MAb in blood and tissues, as well as the extent of protection conferred using prophylactic and therapeutic assays compared to vancomycin treatment. Biodistribution was evaluated 12-96 h after MAb administration. It predominantly remained in the serum, but it was also detectable in the kidneys, lungs, and spleen at low concentrations (about 4.5% in the kidneys, 1.9% in the lungs, and 0.7% the spleen) at all observed timepoints. Prophylactic studies in a murine model demonstrated a significant bacterial load reduction in the kidneys of the groups treated with either with IgG (greater than 3 logs) or F(ab')2 (98%) when compared to that of the control groups (untreated). Mice were challenged with a lethal dose, and the survival rate was higher in the treated mice. Treatment with the MAb resulted in a bacterial load reduction in the kidneys similar to that of mice treated with vancomycin, and a MAb/vancomycin combination therapy was also effective. These results demonstrate that an anti-PBP2a MAb may be a promising therapeutic for treating MRSA infections.
| S-EPMC6880988 | biostudies-literature
Project description:Staphylococcus aureus can cause devastating and life-threatening infections. With the increase in multidrug resistant strains, novel therapies are needed. Limited success with active and passive immunization strategies have been attributed to S. aureus immune evasion. Here, we report on a monoclonal antibody, 514G3, that circumvents a key S. aureus evasion mechanism by targeting the cell wall moiety Protein A (SpA). SpA tightly binds most subclasses of immunoglobulins via their Fc region, neutralizing effector function. The organism can thus shield itself with a protective coat of serum antibodies and render humoral immunity ineffective. The present antibody reactivity was derived from an individual with natural anti-SpA antibody titers. The monoclonal antibody is of an IgG3 subclass, which differs critically from other immunoglobulin subclasses since its Fc is not bound by SpA. Moreover, it targets a unique epitope on SpA that allows it to bind in the presence of serum antibodies. Consequently, the antibody opsonizes S. aureus and maintains effector function to enable natural immune mediated clearance. The data presented here provide evidence that 514G3 antibody is able to successfully rescue mice from S. aureus mediated bacteremia.
| S-EPMC5783355 | biostudies-literature
Project description:BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) has become a major health threat in the United States. Staphylococcal enterotoxin B (SEB) is a potent superantigen that contributes to its virulence. High mortality and frequent failure of therapy despite available antibiotics have stimulated research efforts to develop adjunctive therapies.MethodsTreatment benefits of SEB-specific monoclonal antibody (mAb) 20B1 were investigated in mice in sepsis, superficial skin, and deep-tissue infection models.ResultsMice challenged with a SEB-producing MRSA strain developed fatal sepsis, extensive tissue skin infection, and abscess-forming deep-seeded thigh muscle infection. Animals preimmunized against SEB or treated passively with mAb 20B1 exhibited enhanced survival in the sepsis model, whereas decrease of bacterial burden was observed in the superficial skin and deep-tissue models. mAb 20B1 bound to SEB in the infected tissue and decreased abscess formation and proinflammatory cytokine levels, lymphocyte proliferation, and neutrophil recruitment.ConclusionsmAb 20B1, an SEB-neutralizing mAb, is effective against MRSA infection. mAb 20B1 protects against lethal sepsis and reduces skin tissue invasion and deep-abscess formation. The mAb penetrates well into the abscess and binds to SEB. It affects the outcome of S. aureus infection by modulating the host's proinflammatory immune response.
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Project description:Epidemic methicillin-resistant Staphylococcus aureus (MRSA) imposes an increasing impact on public health. Due to multi-antibiotics resistance in MRSA strains, there is an urgent need to develop novel therapeutics such as effective monoclonal antibodies (mAbs) against MRSA infections. Staphylococcus aureus surface protein A (SasA), a large surface-located protein (~240 kDa), is one of MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) and a potential target for immunotherapeutic approaches against S. aureus infections. In the present study, we analyzed the sequence of SasA with bioinformatics tools and generated a protective monoclonal antibody (2H7) targeting the conserved domain of SasA. 2H7 was shown to recognize wild-type S. aureus and promote opsonophagocytic killing of S. aureus. In both sepsis and peritoneal infection models, prophylactic administration of 2H7 improved the survival of BALB/c mice challenged by S. aureus strain USA300 and ST239 (prevalent MRSA clones in North America and Asian countries, respectively) and enhanced bacterial clearance in kidneys. Additionally, 2H7 prophylaxis prevented the formation of intraperitoneal abscess in a murine model of peritoneal infection and therapeutic administration of 2H7 showed protective efficacy in a murine sepsis model. Our results presented here provide supporting evidences that an anti-SasA mAb might be a potential component in an antibody-based immunotherapeutic treatment of MRSA infections.
| S-EPMC4771200 | biostudies-literature
Project description:Staphylococcus aureus causes a wide range of infectious diseases. Treatment of these infections has become increasingly difficult due to the widespread emergence of antibiotic-resistant strains; therefore, it is essential to explore effective alternatives to antibiotics. A secreted protein of S. aureus, known as eLtaS, is an extracellular protein released from the bacterial membrane protein, LtaS. However, the role of eLtaS in S. aureus pathogenesis remains largely unknown. Here we show eLtaS dramatically aggravates S. aureus infection by binding to C3b and then inhibiting the phagocytosis of C3b-deposited S. aureus. Furthermore, we developed a monoclonal antibody against eLtaS, MAE4, which neutralizes the activity of eLtaS and blocks staphylococcal evasion of phagocytosis. Consequently, MAE4 is capable of protecting mice from lethal S. aureus infection. Our findings reveal that targeting of eLtaS by MAE4 is a potential therapeutic strategy for the treatment of infectious diseases caused by S. aureus.
| S-EPMC4657049 | biostudies-literature
Project description:Staphylococcus aureus is a major pathogenic bacterium that causes a variety of clinical infections. The emergence of multi-drug resistant mechanisms requires novel strategies to mitigate S. aureus infection. Alpha-hemolysin (Hla) is a key virulence factor that is believed to play a significant role in the pathogenesis of S. aureus infections. In this study, we screened a naïve human Fab library for identification of monoclonal antibodies targeting Hla by phage display technology. We found that the monoclonal antibody YG1 blocked the Hla-mediated lysis of rabbit red blood cells and inhibited Hla binding to A549 cells in a concentration-dependent manner. YG1 also provided protection against acute peritoneal infection, bacteremia, and pneumonia in murine models. We further characterized its epitope using different Hla variants and found that the amino acids N209 and F210 of Hla were functionally and structurally important for YG1 binding. Overall, these results indicated that targeting Hla with YG1 could serve as a promising protective strategy against S. aureus infection.
| S-EPMC8319846 | biostudies-literature
Project description:BACKGROUND:Surgical site infections (SSIs) are among the most common hospital acquired infections. While the incidence of SSI in certain indicator procedures is the subject of ongoing surveillance efforts in hospitals and health care systems around the world, SSI rates vary markedly within surgical categories and are poorly represented by routinely monitored indicator procedures (eg, mastectomy or hernia surgery). Therefore, relying on indicator procedures to estimate the burden of SSI is imprecise and introduces bias as hospitals may take special precautions to achieve lower SSI rates. The most common cause of SSI is Staphylococcus aureus (S. aureus), as recently confirmed by a Europe-wide point-prevalence study conducted by the European Centre for Disease Prevention and Control (ECDC). OBJECTIVE:The primary objective of this study is to determine the overall and procedure-specific incidence of S. aureus SSI in Europe. Secondary objectives are the overall and procedure-specific outcomes as well as the economic burden of S. aureus SSI in Europe. Explorative objectives are to characterize the composition of the surgical patient population and to estimate the number of patients at risk for S. aureus SSI. METHODS:A retrospective, multinational, multicenter cohort study (Staphylococcus aureus Surgical Site Infection Multinational Epidemiology in Europe [SALT] study) with a nested case-control part will be conducted. The study will include all surgical procedures at a participating center in order to prevent selection bias and strengthen the understanding of SSI risk by determining the incidence for all common surgical procedures. Data will be assessed in the cohort population, including 150,000 adult patients who underwent any surgical procedure in 2016, and the case-control population. We will match patients establishing S. aureus SSI 1:1 with controls from the same center. Data on demographics, surgery, and microbiology will be exported from electronic files. More detailed data will be captured from the case-control population. The SALT study will include 13 major or academic surgical centers in Europe, comprising 3 in France, 4 in Germany, 2 in Italy, 3 in Spain, and 1 in the United Kingdom. Sites were selected using a feasibility questionnaire. RESULTS:The SALT study is currently recruiting patients. The aim is to complete recruitment in February 2018 and to close the database in September 2018. The final results are expected by the end of 2018. CONCLUSIONS:Results of the SALT study will help to better understand the precise risk of certain procedures. They will also provide insight into the overall and procedure-specific incidence and outcome as well as the economic burden of S. aureus SSI in Europe. Findings of the study may help guide the design of clinical trials for S. aureus vaccines. TRIAL REGISTRATION:ClinicalTrials.gov NCT03353532; https://clinicaltrials.gov/ct2/show/NCT03353532 (Archived by WebCite at http://www.webcitation.org/6xAK3gVmO).
| S-EPMC5869375 | biostudies-literature
Project description:BackgroundSufficient details have not been specified for the epidemiological characteristics of Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA) among surgical site infections (SSIs) in mainland China. This systematic review aimed to estimate proportions of S. aureus and MRSA in SSIs through available published studies.MethodsPubMed, Embase and four Chinese electronic databases were searched to identify relevant primary studies published between 2007 and 2012. Meta-analysis was conducted on the basis of logit-transformed metric for proportions of S. aureus and MRSA, followed by pre-defined subgroup meta-analysis. Random-effects meta-regression was also conducted to explore the impact of possible factors on S. aureus proportions.Results106 studies were included, of which 38 studies involved MRSA. S. aureus accounted for 19.1% (95%CI 17.2-21.0%; I(2) = 84.1%) of all isolates in SSIs, which was roughly parallel to 18.5% in the United States (US) (P-value = 0.57) but significantly exceeded those calculated through the surveillance system in China (P-value<0.001). In subgroup analysis, S. aureus in patients with thoracic surgery (41.1%, 95%CI 26.3-57.7%; I(2) = 74.4%) was more common than in those with gynecologic surgery (20.1%, 95%CI 15.6-25.6%; I(2) = 33.0%) or abdominal surgery (13.8%, 95%CI 10.3-18.4%; I(2) = 70.0%). Similar results were found in meta-regression. MRSA accounted for 41.3% (95%CI 36.5-46.3%; I(2) = 64.6%) of S. aureus, significantly lower than that in the US (P-value = 0.001). MRSA was sensitive to vancomycin (522/522) and linezolid (93/94), while 79.9% (95%CI 67.4-88.4%; I(2) = 0%) and 92.0% (95%CI 80.2-97.0%; I(2) = 0%) of MRSA was resistant to clindamycin and erythromycin respectively.ConclusionThe overall proportion of S. aureus among SSIs in China was similar to that in the US but seemed higher than those reported through the Chinese national surveillance system. Proportions of S. aureus SSIs may vary with different surgery types. Commonly seen in SSIs, MRSA tended to be highly sensitive to vancomycin and linezolid but mostly resistant to clindamycin and erythromycin.
| S-EPMC4300093 | biostudies-literature
Project description:BackgroundThe prevalence of Methicillin resistant Staphylococcus aureus (MRSA) is progressively increasing globally with significant regional variation. Understanding the Staphylococcus aureus lineages is crucial in controlling nosocomial infections. Recent studies on S. aureus in Uganda have revealed an escalating burden of MRSA. However, the S. aureus genotypes circulating among patients are not known. Here, we report S. aureus lineages circulating in patients with surgical site infections (SSI) at Mulago National hospital, Kampala, Uganda.MethodsA cross-sectional study involving 314 patients with SSI at Mulago National Hospital was conducted from September 2011 to April 2012. Pus swabs from the patients' SSI were processed using standard microbiological procedures. Methicillin sensitive Staphylococcus aureus (MSSA) and MRSA were identified using phenotypic tests and confirmed by PCR-detection of the nuc and mecA genes, respectively. SCCmec genotypes were determined among MRSA isolates using multiplex PCR. Furthermore, to determine lineages, spa sequence based-genotyping was performed on all S. aureus isolates.ResultsOf the 314 patients with SSI, S. aureus accounted for 20.4% (64/314), of which 37.5% (24/64) were MRSA. The predominant SCCmec types were type V (33.3%, 8/24) and type I (16.7%, 4/24). The predominant spa lineages were t645 (17.2%, 11/64) and t4353 (15.6%, 10/64), and these were found to be clonally circulating in all the surgical wards. On the other hand, lineages t064, t355, and t4609 were confined to the obstetrics and gynecology wards. A new spa type (t10277) was identified from MSSA isolate. On multivariate logistic regression analysis, cancer and inducible clindamycin resistance remained as independent predictors of MRSA-SSI.ConclusionSCCmec types I and V are the most prevalent MRSA mecA types from the patients' SSI. The predominant spa lineages (t645 and t4353) are clonally circulating in all the surgical wards, calling for strengthening of infection control practices at Mulago National Hospital.
| S-EPMC3688721 | biostudies-literature
Project description:Staphylococcus aureus (S. aureus) is a common cause of surgical site infections (SSIs) globally. Data on the occurrence of methicillin-susceptible S. aureus (MSSA) as well as methicillin-resistant S. aureus (MRSA) among patients with surgical site infections (SSIs) in sub-Saharan African are scarce. We characterized S. aureus from SSIs in Ghana using molecular methods and antimicrobial susceptibility testing (AST). Wound swabs or aspirate samples were collected from subjects with SSIs. S. aureus was identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS); AST was performed by Kirby-Bauer disk diffusion, and results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guideline. Detection of spa, mecA, and pvl genes was performed by polymerase chain reaction (PCR). Whole-genome sequencing (WGS) was done using the Illumina MiSeq platform. Samples were collected from 112 subjects, with 13 S. aureus isolates recovered. Of these, 92% were sensitive to co-trimoxazole, 77% to clindamycin, and 54% to erythromycin. Multi-drug resistance was detected in 5 (38%) isolates. The four mecA gene-positive MRSA isolates detected belonged to ST152 (n = 3) and ST5 (n = 1). In total, 62% of the isolates were positive for the Panton-Valentine leukocidin (pvl) toxin gene. This study reports, for the first time, a pvl-positive ST152-t355 MRSA clone from SSIs in Ghana. The occurrence of multi-drug-resistant S. aureus epidemic clones suggests that continuous surveillance is required to monitor the spread and resistance trends of S. aureus in hospital settings in the country.
| S-EPMC7918159 | biostudies-literature