Cold atmospheric plasma and plasma-antibiotic combinations against ESKAPE pathogens: a systematic review of preclinical evidence
Abstract
IntroductionAntimicrobial resistance among ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) is a growing global threat, compounded by biofilm-associated tolerance. Cold atmospheric plasma (CAP) generates reactive oxygen and nitrogen species (RONS) that disrupt bacteria and biofilms independently of conventional resistance mechanisms. This review synthesized evidence on CAP effectiveness against ESKAPE pathogens, including antibiotic synergy and mechanisms.MethodsPubMed, Scopus, and Embase were searched from inception to 31 July 2026 following PRISMA 2020 and Cochrane Rapid Reviews guidance. Primary experimental studies comparing CAP with antibiotics, CAP–antibiotic combinations, or untreated controls in planktonic or biofilm ESKAPE pathogens were eligible. Two reviewers independently screened and extracted data. Risk of bias was assessed using QUIN and SYRCLE. Findings were synthesized narratively.ResultsOf 495 records, 25 studies met eligibility criteria (22 in vitro, 3 with in vivo animal components). S. aureus (n = 10), P. aeruginosa (n = 8) and both studied together (n = 4) predominated; other pathogens were under-represented, while Enterobacter spp. were absent. CAP achieved approximately 1–9 log10 CFU reductions, with biofilms generally requiring longer exposures. Eight studies evaluated CAP–antibiotic combinations, all reporting potentiation, in one P. aeruginosa biofilm study, sublethal CAP pretreatment reduced the MIC/MBEC of gentamicin and ciprofloxacin by up to 512-fold and tobramycin by 256-fold; magnitudes in the remaining seven studies were more modest. Mechanistic evidence implicated RONS-mediated membrane disruption, lipid peroxidation, protein oxidation, and oxidative stress responses; one study identified host NOX2 activation. No resistance emerged in the single formal study.ConclusionCAP demonstrates promising antimicrobial and antibiofilm activity against ESKAPE pathogens, particularly as an antibiotic potentiator. Heterogeneity in devices, gases, and exposure protocols precluded meta-analysis. Standardized reporting, formal synergy testing, studies of under-represented pathogens, and clinical trials are needed.Systematic review registrationhttps://osf.io/jcb8t.
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BibTeX
@article{vinitha2026cold,
title = {{Cold atmospheric plasma and plasma-antibiotic combinations against ESKAPE pathogens: a systematic review of preclinical evidence}},
author = {Ganesan Vinitha and Kokila Manickam and Debdeep Dasgupta},
journal = {Frontiers in Microbiology},
year = {2026},
month = nov,
doi = {10.3389/fmicb.2026.1984043},
url = {https://www.frontiersin.org/articles/10.3389/fmicb.2026.1984043},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cold atmospheric plasma and plasma-antibiotic combinations against ESKAPE pathogens: a systematic review of preclinical evidence
AU - Ganesan Vinitha
AU - Kokila Manickam
AU - Debdeep Dasgupta
PY - 2026
DA - 2026/11/09
JO - Frontiers in Microbiology
DO - 10.3389/fmicb.2026.1984043
UR - https://www.frontiersin.org/articles/10.3389/fmicb.2026.1984043
AB - IntroductionAntimicrobial resistance among ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) is a growing global threat, compounded by biofilm-associated tolerance. Cold atmospheric plasma (CAP) generates reactive oxygen and nitrogen species (RONS) that disrupt bacteria and biofilms independently of conventional resistance mechanisms. This review synthesized evidence on CAP effectiveness against ESKAPE pathogens, including antibiotic synergy and mechanisms.MethodsPubMed, Scopus, and Embase were searched from inception to 31 July 2026 following PRISMA 2020 and Cochrane Rapid Reviews guidance. Primary experimental studies comparing CAP with antibiotics, CAP–antibiotic combinations, or untreated controls in planktonic or biofilm ESKAPE pathogens were eligible. Two reviewers independently screened and extracted data. Risk of bias was assessed using QUIN and SYRCLE. Findings were synthesized narratively.ResultsOf 495 records, 25 studies met eligibility criteria (22 in vitro, 3 with in vivo animal components). S. aureus (n = 10), P. aeruginosa (n = 8) and both studied together (n = 4) predominated; other pathogens were under-represented, while Enterobacter spp. were absent. CAP achieved approximately 1–9 log10 CFU reductions, with biofilms generally requiring longer exposures. Eight studies evaluated CAP–antibiotic combinations, all reporting potentiation, in one P. aeruginosa biofilm study, sublethal CAP pretreatment reduced the MIC/MBEC of gentamicin and ciprofloxacin by up to 512-fold and tobramycin by 256-fold; magnitudes in the remaining seven studies were more modest. Mechanistic evidence implicated RONS-mediated membrane disruption, lipid peroxidation, protein oxidation, and oxidative stress responses; one study identified host NOX2 activation. No resistance emerged in the single formal study.ConclusionCAP demonstrates promising antimicrobial and antibiofilm activity against ESKAPE pathogens, particularly as an antibiotic potentiator. Heterogeneity in devices, gases, and exposure protocols precluded meta-analysis. Standardized reporting, formal synergy testing, studies of under-represented pathogens, and clinical trials are needed.Systematic review registrationhttps://osf.io/jcb8t.
SN - 1664-302X
ER -