Dataset Information

Bactericidal fully human single-chain fragment variable antibodies protect mice against methicillin-resistant Staphylococcus aureus bacteraemia.

ABSTRACT:

Objectives

The increasing prevalence of antibiotic-resistant Staphylococcus aureus, besides the inadequate numbers of effective antibiotics, emphasises the need to find new therapeutic agents against this lethal pathogen.

Methods

In this study, to obtain antibody fragments against S. aureus, a human single-chain fragment variable (scFv) library was enriched against living methicillin-resistant S. aureus (MRSA) cells, grown in three different conditions, that is human peripheral blood mononuclear cells with plasma, whole blood and biofilm. The antibacterial activity of scFvs was evaluated by the growth inhibition assay in vitro. Furthermore, the therapeutic efficacy of anti-S. aureus scFvs was appraised in a mouse model of bacteraemia.

Results

Three scFv antibodies, that is MEH63, MEH158 and MEH183, with unique sequences, were found, which exhibited significant binding to S. aureus and reduced the viability of S. aureus in in vitro inhibition assays. Based on the results, MEH63, MEH158 and MEH183, in addition to their combination, could prolong the survival rate, reduce the bacterial burden in the blood and prevent inflammation and tissue destruction in the kidneys and spleen of mice with MRSA bacteraemia compared with the vehicle group (treated with normal saline).

Conclusion

The combination therapy with anti-S. aureus scFvs and conventional antibiotics might shed light on the treatment of patients with S. aureus infections.

SUBMITTER: Soltanmohammadi B

PROVIDER: S-EPMC8240403 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Bactericidal fully human single-chain fragment variable antibodies protect mice against methicillin-resistant <i>Staphylococcus</i> <i>aureus</i> bacteraemia.

Soltanmohammadi Behnoush B Piri-Gavgani Somayeh S Basardeh Eilnaz E Ghanei Mostafa M Azizi Masoumeh M Khaksar Zabihollah Z Sharifzadeh Zahra Z Badmasti Farzad F Soezi Mahdieh M Fateh Abolfazl A Azimi Parisa P Siadat Seyed Davar SD Shooraj Fahimeh F Bouzari Saeid S Omrani Mir Davood MD Rahimi-Jamnani Fatemeh F

Clinical & translational immunology 20210629 7

<h4>Objectives</h4>The increasing prevalence of antibiotic-resistant <i>Staphylococcus aureus</i>, besides the inadequate numbers of effective antibiotics, emphasises the need to find new therapeutic agents against this lethal pathogen.<h4>Methods</h4>In this study, to obtain antibody fragments against <i>S. aureus</i>, a human single-chain fragment variable (scFv) library was enriched against living methicillin-resistant <i>S. aureus</i> (MRSA) cells, grown in three different conditions, that i ...[more]

PMID: 34221401

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Project description:BackgroundClinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAMERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%).ObjectiveThe aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial.MethodsAmong participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output).ResultsOf the 266 participants included, age (p = 0.04), randomisation to combination therapy (p = 0.002), vancomycin area under the concentration-time curve (p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam (p < 0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration-time curve with acute kidney injury also persisted in the multivariable model.ConclusionsFor participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration-time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.