Author: admin

New research from the University of Minnesota Medical School is providing important insights into how COVID-19 persists in cancer patients even long after testing positive. The findings were recently published in iScience.

During a peak of COVID-19 in 2020, there was concern around cancer patients who had contracted COVID-19 and developed severe inflammatory reactions that looked similar to autoimmune conditions. To better understand this phenomenon, researchers studied three cancer patients who had undergone transplant therapies and were hospitalized with severe COVID-19 infections.

The research team discovered that even up to six weeks after a patient’s last positive nasal swab test, the virus was still present in the lining of their gut. The persistence of the virus appeared to trigger increased inflammation and damage to tissue. The researchers also identified a specific inflammatory marker, called SERPINA1, that was consistently linked to tissue inflammation in these cases. 

COVID-19 can persist in gastrointestinal tissue, and this may be associated with inflammation and poor patient outcomes during the process of transplantation. Prior to treatments and clinical decisions, one may consider measuring GI tissue markers, such as SERPINA1. This may be especially important when considering the use of anti-cancer transplantation therapies.”

Justin Hwang, Ph.D., assistant professor with the University of Minnesota Medical School and a Masonic Cancer Center researcher

“We learned that the virus that causes COVID-19 infection lasted longer in the intestines than we would have predicted. More research is needed to determine whether there is a link to Long COVID or other similar complications in this at-risk population,” added Emil Lou, MD, Ph.D., FACP, a physician-scientist and gastrointestinal oncologist with the Masonic Cancer Center, and professor with tenure with the University of Minnesota Medical School and M Health Fairview. 

Further research will aim to study larger groups that have been infected with COVID-19. The researchers also recommend caution around patients with high levels of SERPINA1, who may need close monitoring as some cancer treatments could increase inflammation. 

This study was supported by Mrs. Hinda Litman and the Litman Family Fund for Cancer Research, the American Cancer Society, a University of Minnesota Data Science Initiative (DSI) Seed Grant, Friends and family of Gayle Huntington, the Mu Sigma Chapter of the Phi Gamma Delta Fraternity, University of Minnesota (FIJI), Dick and Lynnae Koats, Ms. Patricia Johnson and the Love Like Laurie Legacy. 

Introduction

Staphylococcus aureus, a ubiquitous pathogen colonizing human skin, nasal passages, and mucosal surfaces, is implicated in infections ranging from mild cutaneous conditions to life-threatening systemic diseases.^1,2 Its public health significance stems from its versatile pathogenicity and escalating antibiotic resistance, exacerbated by the widespread misuse of antimicrobials, particularly in nosocomial settings. Since the emergence of methicillin-resistant Staphylococcus aureus (MRSA) in the UK in 1961, it has evolved into a global health crisis, contributing to over 100,000 deaths in 2019 alone.³ Vancomycin has long been the “last line of defense” in the treatment of MRSA infections.⁴ However, the emergence of heterogeneous and vancomycin-Intermediate Staphylococcus aureus (hVISA and VISA) strains in recent decades has significantly compromised vancomycin’s clinical utility.^5,6

VISA strains exhibit reduced susceptibility to vancomycin without meeting the threshold for full resistance, while hVISA populations consist predominantly of vancomycin-susceptible Staphylococcus aureus with a subpopulation displaying intermediate resistance.⁷ The presence of vancomycin heterogeneity and intermediate resistance strains suggests that these infections may require higher doses of the drug or extended treatment durations for effective therapy.⁶

The resistance mechanisms of VISA are predominantly linked to structural and functional alterations in the bacterial cell wall.^8,9 Vancomycin exerts its bactericidal activity by binding to cell wall precursor molecules (D-Ala-D-Ala termini of lipid II), thereby inhibiting peptidoglycan biosynthesis. VISA strains exhibit a characteristically thickened cell wall, a phenotype attributed to dysregulation of the peptidoglycan biosynthesis pathway and elevated cross-linking density between peptidoglycan polymers. This thickened cell wall architecture serves as a primary resistance mechanism by impeding vancomycin diffusion to its intracellular targets. Genomic analyses further reveal that VISA resistance correlates with mutations in key regulatory loci, eg, walKR, rpoB, vraSR, graRS and mprF. These genetic modifications are hypothesized to alter membrane charge and permeability, reducing drug influx while enhancing efflux pump activity.^8,9

The global emergence of antibiotic-resistant pathogens, particularly VISA and vancomycin-resistant Staphylococcus aureus (VRSA), has intensified the demand for novel antimicrobial therapies. Conventional antibiotics, such as daptomycin, are becoming increasingly ineffective due to escalating resistance, necessitating innovative therapeutic approaches. At the same time, the diagnostic difficulty of hVISA—where routine MIC testing in labs fails to detect it and hospital labs do not perform population analysis—exacerbates the challenges in treating patients with hVISA. Current clinical management of hVISA and VISA infections often relies on vancomycin dose escalation or combination therapy with β-lactams or daptomycin.⁶ However, these strategies demonstrate limited efficacy and carry risks of nephrotoxicity and other adverse effects. Consequently, research efforts are increasingly focused on developing targeted antimicrobial agents and alternative treatment modalities. Promising avenues include new antibiotics, antimicrobial peptides, synthetic agents, natural derivatives as well as drug delivery system. Such advancements not only address the urgent clinical need for VISA management but also contribute to mitigating the broader antimicrobial resistance crisis.

Monotherapy

The clinical management of hVISA and VISA infections is challenged by high rates of vancomycin treatment failure, compounded by limited therapeutic alternatives.⁹ Current options include daptomycin, linezolid, ceftaroline, trimethoprim/sulfamethoxazole, tigecycline, and quinupristin/dalfopristin, though only daptomycin and linezolid have been studied extensively.⁶

Daptomycin, an FDA-approved lipopeptide for Staphylococcus aureus bloodstream infections and right-sided endocarditis including methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA,^10,11 shows reduced utility against hVISA/VISA strains. Notably, its use has been associated with the increase in the minimum inhibitory concentration (MIC) of vancomycin and emerging daptomycin nonsusceptibility in vitro.⁶ Genomic studies reveal that mutations in yycH (a cell wall stress response regulator), mprF (phosphatidylglycerol lysyltransferase), and dltA (D-alanylation pathway) confer cross-resistance to daptomycin in hVISA/VISA strains, complicating its clinical efficacy.^12,13

Linezolid, an oxazolidinone inhibiting ribosomal protein synthesis, remains controversial for hVISA/VISA management. While observational studies report clinical success with linezolid monotherapy or combination regimens,^14,15 in vitro susceptibility testing often fails to correlate with these outcomes.¹⁶ We hypothesize that this may be related to some factors, eg immune modulation, and intracellular activity. This discrepancy underscores the need for robust clinical trials to clarify linezolid’s role and optimize dosing strategies. Furthermore, prolonged linezolid use carries risks of myelosuppression and mitochondrial toxicity, necessitating careful risk-benefit evaluation.

Collectively, these limitations highlight the urgent need for standardized susceptibility testing, pharmacokinetic/pharmacodynamic optimization, and novel therapeutics targeting hVISA/VISA-specific resistance mechanisms.

Combination Therapy

The therapeutic potential of antibiotic combinations against hVISA/VISA infections lies in their ability to generate synergistic antibacterial effects, offering enhanced clinical efficacy compared to monotherapy (Table 1). This approach has emerged as a viable strategy for managing these challenging infections, with investigated combinations spanning glycopeptides, β-lactams, quinolones, oxazolidinones, lipopeptides, phosphonic acid derivatives, and phenothiazines. Vancomycin exhibits synergistic antibacterial activity when combined with β-lactam antibiotics, quinolones, aminoglycosides, rifamycins, sulfonamides, and oxazolidinones.

β-Lactam Combinations

Vancomycin demonstrated synergistic activity when combined with β-lactams including nafcillin,³¹ oxacillin,³² cloxacillin,¹⁹ piperacillin-tazobactam,²⁴ cefazolin, cefoxitin, ceftazidime,^30,31 cefmetazole, cefotaxime, cefepime,^19,27 ceftobiprole,²⁰ cefixime, imipenem, and meropenem.³⁴ This synergy stems from β-lactam-mediated inhibition of penicillin-binding proteins (PBPs), which alters peptidoglycan cross-linking and modifies cell wall architecture.³⁴ This alteration in the bacterial cell surface structure facilitates the binding of VAN to its specific target sites.³⁷ These structural changes facilitate vancomycin binding to its molecular targets through the “seesaw effect” – a phenomenon where β-lactam-induced cell wall stress increases bacterial susceptibility to glycopeptides by modulating PBP expression and peptidoglycan biosynthesis.^22,38 Notably, Aritaka et al²⁴ reported that only ampicillin, oxacillin, imipenem, and cefmetazole showed synergy with vancomycin, while cephalothin, penicillin G, and piperacillin did not, contradicting other studies.^27,32,34 This discrepancy may reflect concentration-dependent effects, as sub-MIC β-lactam levels can paradoxically induce antagonism.^18,39 We hypothesize that other factors, such as differences in testing media, strain genetics, or endpoints, could also explain this phenomenon.

Non-β-Lactam Synergy

Vancomycin combinations with ciprofloxacin, gentamicin, and trimethoprim/sulfamethoxazole exhibited anti-VISA/hVISA synergy,²⁶ though conflicting data exist for gentamicin.⁴⁰ Teicoplanin demonstrated enhanced efficacy when paired with cefazolin, cefmetazole, cefotaxime, cefepime,²⁷ or rifampicin.²⁹ However, oxazolidinones like tedizolid showed superior anti-GISA activity compared to glycopeptides.²⁹ Promising alternatives include: ampicillin-sulbactam with trovafloxacin¹⁷ or arbekacin;⁴¹ ciprofloxacin-rifampicin combinations;³⁶ linezolid paired with imipenem¹⁴ or rifampicin;²³ fosfomycin combined with imipenem, ceftriaxone, or linezolid;^25,35 daptomycin synergized with nafcillin²¹ or cephalosporins,³³ enhanced by sulbactam in triple therapy;³³ thioridazine-dicloxacillin targeting VraSR-mediated cell wall metabolism.²⁸

Experimental-Clinical Disconnects

While existing studies demonstrate promising evidence for combination therapies targeting hVISA and VISA, substantial inconsistencies and methodological limitations persist across these investigations. These discrepancies likely stem from heterogeneous experimental designs, divergent methodologies, and strain-specific variations, underscoring the necessity for standardized approaches to develop reliable therapeutic paradigms.

First, discrepancies in antimicrobial synergy emerge across different susceptibility testing modalities. Alejandro et al¹⁹ reported in vitro synergy between glycopeptides (vancomycin/teicoplanin) and β-lactams (cloxacillin/cefotaxime) against VISA strains, yet failed to replicate this synergy in murine infection models – a critical limitation for clinical translation. Subsequent susceptibility testing revealed synergistic interactions between vancomycin-cefotaxime/imipenem/meropenem combinations against vancomycin-susceptible Staphylococcus aureus (VSSA), VISA, and hVISA strains. However, time-kill assays demonstrated vancomycin-meropenem synergy exclusively in VISA strains, with no significant interaction observed against VSSA.³⁴ This dichotomy between in vitro susceptibility data and in vivo efficacy suggests complex pharmacokinetic-pharmacodynamic interactions and host-pathogen dynamics that current experimental models may inadequately replicate.

Second, antimicrobial concentration profoundly influences combination therapy outcomes. In a VISA endocarditis rat model, very-low-dose ceftobiprole (0.25 mg/kg) combined with standard vancomycin dosing achieved superior bacterial clearance compared to low-dose ceftobiprole (5 mg/kg) combinations.²⁰ This dose–response relationship was corroborated in vitro, where 0.5 µg/mL imipenem enhanced vancomycin efficacy more significantly than 0.125 µg/mL concentrations.³⁶ Similarly, quinolone-rifampicin combinations exhibited concentration-dependent synergy, with higher quinolone concentrations improving bactericidal activity.³⁶ These findings emphasize the critical need for optimized dosing regimens that consider MIC variations among vancomycin-nonsusceptible strains.

Third, substantial inter-strain variability in therapeutic responses necessitates precision medicine approaches. Clinical isolates demonstrate heterogeneous susceptibility profiles to both monotherapy and combination regimens, mandating strain-specific antimicrobial selection and dose adjustment.²⁰ This phenotypic diversity likely originates from differential expression of resistance mechanisms across genetic lineages.

The mechanistic basis for antimicrobial synergy remains incompletely characterized. Following Hiramatsu’s seminal 1997 reported on hVISA emergence in Japanese hospitals,⁴² subsequent research has implicated multiple-resistance pathways: 1) altered cell wall architecture (thickening/structural remodeling), 2) modified membrane surface charge distribution, 3) differential penicillin-binding protein expression/activity, and 4) genetic mutations affecting membrane phospholipid biosynthesis.^33,43–45 Notably, vancomycin exposure in resistant strains induces cell wall precursor accumulation through impaired autolytic activity, creating a paradoxical bacteriostatic effect that may potentiate β-lactam efficacy.

Despite current limitations, combination therapies retain significant clinical potential for vancomycin-nonsusceptible Staphylococcus aureus infections. Future research priorities should include: 1) development of pharmacokinetic models to optimize dosing regimens; 2) large-scale clinical trials validating experimental findings. Such efforts will facilitate the creation of targeted, evidence-based treatment algorithms for these challenging infections.

Novel Antimicrobial Agents

Given the limitations of traditional antibiotics, novel antimicrobial agents offer a promising frontier for combating hVISA and VISA. These encompass new antibiotics, antimicrobial peptides (AMPs), synthetic agents, natural derivatives, and other (Table 2).

Table 2 Details About the Novel Antimicrobial Agents

New Antibiotics

Studies reveal that optimized glycopeptides (eg, LY333328, oritavancin, YV4465)^40,51–53 achieve dose-dependent bactericidal effects in vitro by improving pharmacokinetic parameters (eg, AUC/MIC ratios) and enhancing target binding. Oritavancin retains bacteriostatic activity (2–3 log reduction) against certain VISA strains even at high inoculum densities (10⁷ CFU/mL), while YV4465 reduces bacterial load by ~2 log₁₀ CFU/g in murine infection models. Fluoroquinolones (levonadifloxacin and BMS-284756),^48,49 oxazolidinones (tedizolid and AZD2563),^56,57 and fluoroketolides (CEM-101)⁴⁷ exhibit enhanced potency against multidrug-resistant strains (including hVISA, DNS, and linezolid-resistant isolates), with MIC₉₀ values 2–16 times lower than conventional agents, and remain effective against strains carrying the cfr resistance gene. Dalbavancin shows bactericidal curves comparable to MSSA against hVISA and DNS isolates, suggesting its capacity to penetrate biofilms and suppress resistance mutations.⁵⁵ Notably, while apramycin shows no existing resistance mechanisms, its attenuated activity under high inoculum conditions highlights the need to optimize dosing strategies or combination therapies.⁴⁶ The novel carbapenem ME1036⁵⁰ demonstrated superior in vivo efficacy (>3 log reduction) against VISA in immunocompromised murine models, while the β-lactam RWJ-54428⁵⁴ exhibited potent broad-spectrum activity (MIC₉₀ ≤2 mg/L) against glycopeptide-intermediate Staphylococcus aureus, aligning with its MRSA-targeting profile. Collectively, these antibiotics address VISA/hVISA infections through enhanced target specificity, prolonged half-lives, and evasion of resistance pathways, offering transformative options for complex infections such as endocarditis. However, they are currently in preclinical studies.

Antimicrobial Peptides (AMPs)

The semisynthetic lantibiotic NVB333 exhibits potent in vivo activity in murine thigh and bronchoalveolar infection models against MRSA and VISA, achieving >3-log CFU reductions despite modest MICs, with efficacy driven by high plasma exposure (AUC/MIC = 138) and lung penetration.⁵⁸ NAI-107, another lantibiotic, shows dose-proportional bactericidal effects in immunocompromised models, reducing MRSA and GISA loads by 3-log in rat endocarditis and granuloma pouch infections, sustained by trough plasma levels exceeding its MBC.⁵⁹ The cationic peptide omiganan inhibits VISA, hVISA, and VRSA at MIC₉₀ ≤32 μg/mL, unaffected by vancomycin resistance mechanisms,⁶¹ while melittin (Mel)-loaded non-ionic surfactant vesicles (NISVs) disrupt membrane integrity in VISA, MRSA, and clinical isolates, enhancing dermal penetration and bacterial clearance in porcine skin models.⁶⁰ Engineered lantibiotics like nisin V outperform parental nisin against hVISA and hypervirulent pathogens, with broad-spectrum activity validated in food systems.⁶² Additionally, synthetic amphiphilic dipeptides (eg, Trp-His(1-Bn)-NHBn) target fungal and bacterial membranes via charge-hydrophobicity interplay, though direct VISA data are pending.⁹⁴ Collectively, these peptides leverage membrane disruption, resistance evasion, and optimized pharmacokinetics to address VISA/hVISA infections across systemic, topical, and complex biofilm-associated contexts.

Synthetic Agents

Pyridyl disulfides exhibited high susceptibility against VISA/VRSA via 7–9 carbon alkyl chains, synergized with vancomycin, and disrupted biofilms.⁶³ Alpha-amyrin (AM) reduced biofilm biomass in clinical VISA isolates but increased metabolic activity, suggesting non-bactericidal effects.⁶⁴ Aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide derivatives showed MICs of 0.5–8 μg/mL against VISA, comparable to linezolid.⁶⁵ Benzo-heptacyclic derivatives 48 and 51 inhibited staphyloxanthin biosynthesis by targeting CrtN, sensitized VISA strain Mu50 to hydrogen peroxide, and displayed efficacy comparable to linezolid in vivo.⁶⁶ 8-Hydroxycycloberberine derivative 15a achieved MIC of 0.25–0.5 μg/mL against VISA by suppressing topoisomerase IV.⁶⁷ Glycosylated lipo-vancomycin analogs exhibited 128–1024-fold enhanced activity against VISA compared to vancomycin, with optimized pharmacokinetics.⁶⁸ Retapamulin demonstrated MIC₉₀ of 0.12 μg/mL against VISA/VRSA and remained active against 94% of mupirocin-resistant isolates.⁷⁰ Benzothiazole compound 7a exhibited in vivo efficacy in a VISA murine infection model.⁷¹ Chroman/coumaran derivatives 69 and 105 potently inhibited virulence factors in VISA strain Mu50.⁷² 1,4-Benzodioxane-derived inhibitor 47 showed anti-VISA activity comparable to linezolid in vivo.⁷³ Bis-indole derivatives displayed MIC of 1–4 mg/L against VISA and inhibited the NorA efflux pump.⁷⁴ Eremomycin aminoalkylamides 4a,b outperformed vancomycin against glycopeptide-resistant strains (including VISA).⁷⁵ 3-Substituted indoles inhibited VISA growth via nucleophilic addition mechanisms (MIC: 8–16 mg/L).⁷⁶ Myricetin combined with vancomycin/oxacillin reversed VISA resistance.⁷⁷ 9,10-Dihydroacridine derivatives disrupted VISA cell division by promoting FtsZ polymerization.⁶⁹ Thieno[2,3-d]pyrimidinediones achieved MIC of 2–16 mg/L against VISA/VRSA with low cytotoxicity.⁷⁸ These diverse synthetic agents, operating through distinct mechanisms, expand therapeutic strategies against multidrug-resistant staphylococcal infections.

Natural Derivatives

Recent advancements highlight the potential of naturally derived antimicrobial compounds as promising candidates against these multidrug-resistant strains, with several demonstrating efficacy in both in vitro and in vivo models. Plant-derived antimicrobial agents, such as Achyrofuran (a 2,2′-biphenol compound targeting membrane integrity),⁷⁹ Galangin (a flavonoid inhibiting peptidoglycan biosynthesis),⁸¹ Anisochilus carnosus acetone extract (Acace, disrupting cell division),⁸⁵ exemplify diverse antibacterial mechanisms. Similarly, pterostilbene,⁸⁴ soybean glycinin basic subunit,⁸³ synergistic combinations like sodium new houttuyfonate with berberine chloride⁸⁸ and Valencia Orange Oil (CPV),⁸² further underscore the versatility of phytochemicals in compromising bacterial survival through membrane permeabilization or metabolic interference. Meanwhile, microbially derived compounds, including bioactive metabolites from cyanobacteria⁸⁰ and Pseudomonas aeruginosa,⁸⁷ exhibit multifaceted antibacterial mechanisms, such as membrane destabilization, induction of oxidative stress, and metabolic inhibition. Semi-synthetic derivatives, such as the quercetin–pivaloxymethyl conjugate (Q-POM),⁸⁶ not only exhibit intrinsic antibacterial activity but also enhance the potency of conventional antibiotics (eg, vancomycin, ceftolozane-tazobactam), suppress biofilm formation, and delay resistance evolution. While many natural products show promising in vitro activity with low cytotoxicity, their clinical translation hinges on rigorous preclinical validation. Comprehensive studies are imperative to elucidate molecular mechanisms, optimize pharmacokinetic profiles, and evaluate long-term toxicity. Moreover, synergistic combination therapies—integrating natural compounds with existing antimicrobials—could amplify efficacy, reduce therapeutic doses, and circumvent resistance mechanisms. This strategy may prove pivotal in addressing multidrug-resistant infections and shaping the future of antimicrobial drug development.

Other

The “reverse antibiotic” nybomycin selectively targets quinolone-resistant VISA strains (eg, Mu50) by reverting gyrA mutations, restoring susceptibility to quinolones while exhibiting negligible resistance development (<1 × 10⁻¹¹/generation).⁹⁰ The cytotoxic nucleoside analog gemcitabine and its derivative CP-4126 inhibit VISA, MRSA, and MSSA (MIC 0.06–4.22 mg/L) via bactericidal synergy with gentamicin, with resistance linked to mutations in nucleoside kinase gene SadAK.⁹¹ Telomycin, a phage-resistant Streptomyces-derived metabolite, exhibits potent activity against MRSA-VISA and Listeria monocytogenes, with antibacterial efficacy doubled in phage-resistant strains.⁸⁹ Targeting RNA degradation, a novel RnpA inhibitor suppresses mRNA/rRNA turnover in MRSA, VISA, and VRSA, demonstrating efficacy in systemic mouse infections and biofilm disruption.⁹³ Lastly, the folate synthesis inhibitor iclaprim suppresses Panton-Valentine leukocidin (PVL) and alpha-hemolysin (AH) toxin production in VISA and MRSA at sub-MIC levels, outperforming trimethoprim and vancomycin in toxin suppression while concentrating at infection sites.⁹² Collectively, these agents exploit resistance reversal (nybomycin), RNA catabolism (RnpA inhibitor), toxin modulation (iclaprim), and novel biosynthesis pathways (telomycin), offering multifaceted strategies to combat VISA/hVISA infections.

Drug Delivery System

In addition to the discovery of novel antimicrobial agents, improvements in drug delivery systems represent another direction. In recent years, drug delivery systems have shown great potential in treating hVISA and VISA. Copper(I) oxide nanoparticles (Cu2O-NPs), as a novel antimicrobial agent, significantly inhibited the growth of Staphylococcus aureus and effectively combated biofilm formation by disrupting bacterial cell membranes and causing leakage of cellular components, all while showing no cytotoxicity.⁹⁵ This makes them a promising candidate as an anti-biofilm agent in medical devices. Similarly, nanoemulsion systems, such as those containing cinnamon and clove oils, demonstrated high antimicrobial activity, particularly in nanoemulsions with Tween 20, which exhibited significant anti-biofilm effects (66–76%) and rapid bacterial membrane disruption, making them a powerful tool against VISA.⁹⁶ Additionally, vancomycin-loaded nanoliposomes enhanced drug stability and penetration, effectively lowering the MIC for resistant strains and preventing the development of vancomycin resistance, offering a new strategy to boost vancomycin efficacy.⁹⁷ Furthermore, magnetic nanocomposites (Fe3O4@SiO2@CS-NISIN) functionalized with nisin show excellent local antibacterial effects, effectively inhibiting hVISA and VISA growth and providing strong support for novel antimicrobial materials.⁹⁸ Finally, melittin (Mel)-loaded nonionic surfactant vesicles (NiSV) target bacterial membranes, disrupting membrane integrity and demonstrating significant antimicrobial activity against MRSA and VISA.⁶⁰ These systems significantly enhance therapeutic efficacy through several synergistic mechanisms, including improved drug bioavailability, spatiotemporally controlled release via pH/enzyme-responsive drug delivery, enhanced penetration of biofilm physical barriers, and multi-target antimicrobial actions such as membrane disruption, reactive oxygen species (ROS) generation, and metabolic interference. Together, these advancements lay a critical foundation for the development of next-generation intelligent antimicrobial agents, demonstrating substantial translational potential in addressing medical device-associated infections and persistent skin infections.

Conclusions

hVISA and VISA present significant clinical challenges. The emergence of these pathogens underscores the formidable obstacles facing conventional antibacterial therapies. This review consolidates all reported treatment strategies for hVISA and VISA since their identification, encompassing monotherapy, combination therapy, the development of novel antibacterial agents, and advanced drug delivery systems (Figure 1). While these interventions often demonstrate efficacy in vitro or in animal models, their clinical reliability remains unproven. Future research should prioritize: 1) elucidating the synergistic mechanisms of combination therapies and establishing standardized concentration-effect models; 2) designing highly selective drugs targeting specific hVISA/VISA molecular targets (eg, CrtN, FtsZ); 3) optimizing delivery systems for precise antibacterial action and resistance mitigation; 4) leveraging multi-omics approaches to inform personalized treatment regimens; and 5) accelerating the clinical translation of natural products and synthetic compounds. Furthermore, interdisciplinary efforts—such as AI-driven drug design and microbiome modulation—should be intensified to counter evolving resistance. These strategies offer a promising pathway to surmount current therapeutic limitations and deliver safer, more enduring solutions for multidrug-resistant Staphylococcus infections.

Acknowledgments

Figure was created in https://BioRender.com and we have provided proof of the BioRender license to publish Figure 1.

Author Contributions

All authors made a significant contribution to the work reported, whether in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas, took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.

Funding

This study was financially supported by Municipal Financial Subsidy of Nanshan District Medical Key Discipline Construction.

Disclosure

The authors declared no potential conflicts of interest in this work.

References

1. Gherardi G. Staphylococcus aureus infection: pathogenesis and antimicrobial resistance. Int J Mol Sci. 2023;24(9):8182. doi:10.3390/ijms24098182

2. Turner NA, Sharma-Kuinkel BK, Maskarinec SA, et al. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nat Rev Microbiol. 2019;17(4):203–218. doi:10.1038/s41579-018-0147-4

3. Murray CJL, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629–655. doi:10.1016/S0140-6736(21)02724-0

4. Cheng X, Ma J, Su J. An overview of analytical methodologies for determination of vancomycin in human plasma. Molecules. 2022;27(21):7319–7336. doi:10.3390/molecules27217319

5. Cheng X, Ma L, Wang Y, Sun W, Su J. Prevalence and molecular characteristics of heterogeneous vancomycin intermediate Staphylococcus aureus in a tertiary care center of northern China. Diagn Microbiol Infect Dis. 2024;108(3):116180. doi:10.1016/j.diagmicrobio.2024.116180

6. Gomes DM, Ward KE, LaPlante KL. Clinical implications of vancomycin heteroresistant and intermediately susceptible S taphylococcus aureus. Pharmacotherapy. 2015;35(4):424–432. doi:10.1002/phar.1577

7. Keikha M. Global distribution of heterogeneous vancomycin-intermediate Staphylococcus aureus strains (1997–2021): a systematic review and meta-analysis. J Global Antimicrob Resist. 2024;31(1):11–21. doi:10.1016/j.jgar.2024.02.002

8. Gardete S, Tomasz A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest. 2014;124(7):2836–2840. doi:10.1172/JCI68834

9. Howden BP, Davies JK, Johnson PDR, Stinear TP, Grayson ML. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev. 2010;23(1):99–139. doi:10.1128/CMR.00042-09

10. Waring R. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. n Engl J Med. 2006;355(7):653–665. doi:10.1056/NEJMoa053783

11. Sakoulas G, Golan Y, Lamp KC, Friedrich LV, Russo R. Daptomycin in the treatment of bacteremia. Am J Med. 2007;120(10):S21–S27. doi:10.1016/j.amjmed.2007.07.012

12. Chen CJ, Huang YC, Chiu CH. Multiple pathways of cross-resistance to glycopeptides and daptomycin in persistent MRSA bacteraemia. J Antimicrob Chemother. 2015;70(11):2965–2972. doi:10.1093/jac/dkv225

13. Mwangi MM, Wu SW, Zhou Y, et al. Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing. Proc Natl Acad Sci USA. 2007;104(22):9451–9456. doi:10.1073/pnas.0609839104

14. Ribes S, Pachón-Ibáñez ME, Domínguez MA, et al. In vitro and in vivo activities of linezolid alone and combined with vancomycin and imipenem against Staphylococcus aureus with reduced susceptibility to glycopeptides. Eur J Clin Microbiol Infect Dis. 2010;29(11):1361–1367. doi:10.1007/s10096-010-1007-y

15. Tenover FC, Sinner SW, Segal RE, et al. Characterisation of a Staphylococcus aureus strain with progressive loss of susceptibility to vancomycin and daptomycin during therapy. Int J Antimicrob Agents. 2009;33(6):564–568. doi:10.1016/j.ijantimicag.2008.12.010

16. Leonard SN, Szeto YG, Zolotarev M, Grigoryan IV. Comparative in vitro activity of telavancin, vancomycin and linezolid against heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA). Int J Antimicrob Agents. 2011;37(6):558–561. doi:10.1016/j.ijantimicag.2011.02.007

17. Aeschlimann JR, Hershberger E, Rybak MJ. Activities of trovafloxacin and ampicillin-sulbactam alone or in combination versus three strains of vancomycin- intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model. Antimicrob Agents Chemother. 2000;44(5):1153–1158. doi:10.1128/AAC.44.5.1153-1158.2000

18. Aritaka N, Hanaki H, Cui L, Hiramatsu K. Combination effect of vancomycin and ␤-Lactams against a Staphylococcus aureus Strain, Mu3, with heterogeneous resistance to vancomycin. Antimicrob Agents Chemother. 2001;45(4):1292–12944. doi:10.1128/AAC.45.4.1292-1294.2001

19. Domenech A, Ribes S, Cabellos C, et al. Experimental study on the efficacy of combinations of glycopeptides and β-lactams against Staphylococcus aureus with reduced susceptibility to glycopeptides. J Antimicrob Chemother. 2005;56(4):709–716. doi:10.1093/jac/dki294

20. Entenza JM, Veloso TR, Vouillamoz J, Giddey M, Majcherczyk P, Moreillon P. In vivo synergism of ceftobiprole and vancomycin against experimental endocarditis due to vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2011;55(9):3977–3984. doi:10.1128/AAC.00402-11

21. Leonard SN, Rolek KM. Evaluation of the combination of daptomycin and nafcillin against vancomycin-intermediate Staphylococcus aureus. J Antimicrob Chemother. 2013;68(3):644–647. doi:10.1093/jac/dks453

22. Werth BJ, Vidaillac C, Murray KP, et al. Novel combinations of vancomycin plus ceftaroline or oxacillin against methicillin-resistant Vancomycin-Intermediate Staphylococcus aureus (VISA) and Heterogeneous VISA. Antimicrob Agents Chemother. 2013;57(5):2376–2379. doi:10.1128/AAC.02354-12

23. Cabellos C, Garrigós C, Taberner F, Force E, Pachón-Ibañez ME. Experimental study of the efficacy of linezolid alone and in combinations against experimental meningitis due to Staphylococcus aureus strains with decreased susceptibility to beta-lactams and glycopeptides. J Infect Chemother. 2014;20(9):563–568. doi:10.1016/j.jiac.2014.05.008

24. Dilworth TJ, Leonard SN, Vilay AM, Mercier RC. Vancomycin and piperacillin-tazobactam against methicillin-resistant staphylococcus aureus and vancomycin-intermediate Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model. Clin Ther. 2014;36(10):1334–1344. doi:10.1016/j.clinthera.2014.06.027

25. Del Río A, García-de-la-mària C, Entenza JM, et al. Fosfomycin plus β-lactams as synergistic bactericidal combinations for experimental endocarditis due to methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2016;60(1):478–486. doi:10.1128/AAC.02139-15

26. Kang YR, Chung DR, Kim J, et al. In vitro synergistic effects of various combinations of vancomycin and non-beta-lactams against Staphylococcus aureus with reduced susceptibility to vancomycin. Diagn Microbiol Infect Dis. 2016;86(3):293–299. doi:10.1016/j.diagmicrobio.2016.08.009

27. Lai CC, Chen CC, Chuang YC, Tang HJ. Combination of cephalosporins with vancomycin or teicoplanin enhances antibacterial effect of glycopeptides against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA. Sci Rep. 2017;7(1):41758. doi:10.1038/srep41758

28. Rasmussen KS, Poulsen MØ, Jacobsen K, et al. Combination of thioridazine and dicloxacillin as a possible treatment strategy of staphylococci. New Microbiol. 2017;40(2):146–147.

29. Betts JW, Abdul Momin HF, Phee LM, Wareham DW. Comparative activity of tedizolid and glycopeptide combination therapies for the treatment of Staphylococcus aureus infections: an in vitro and in vivo evaluation against strains with reduced susceptibility to glycopeptides. J Med Microbiol. 2018;67(2):265–271. doi:10.1099/jmm.0.000671

30. Singh NB, Yim J, Jahanbakhsh S, Sakoulas G, Rybak MJ. Impact of cefazolin co-administration with vancomycin to reduce development of vancomycin-intermediate Staphylococcus aureus. Diagn Microbiol Infect Dis. 2018;91(4):363–370. doi:10.1016/j.diagmicrobio.2018.03.020

31. Tran N, Rybak MJ. β-lactam combinations with vancomycin show synergistic activity against vancomycin-susceptible Staphylococcus aureus, Vancomycin-Intermediate S. aureus (VISA), and heterogeneous VISA. Antimicrob Agents Chemother. 2018;62(6):e00157–18. doi:10.1128/AAC.00157-18

32. Bakthavatchalam YD, Ralph R, Veeraraghavan B, Babu P, Munusamy E. Evidence from an in vitro study: is oxacillin plus vancomycin a better choice for heteroresistant Vancomycin-Intermediate Staphylococcus aureus? Infect Dis Ther. 2019;8(1):51–62. doi:10.1007/s40121-018-0224-z

33. Lai CC, Chen CC, Lu YC, et al. The potential role of sulbactam and cephalosporins plus daptomycin against daptomycin-nonsusceptible VISA and H-VISA isolates: an in vitro study. Antibiotics. 2019;8(4):184. doi:10.3390/antibiotics8040184

34. SrIsrattakarn A, ChaIyapoke C, Booncharoen S, et al. Synergistic effect of vancomycin combined with cefotaxime, imipenem, or meropenem against Staphylococcus aureus with reduced susceptibility to vancomycin. Turk J Med Sci. 2021;51(4):2150–2158. doi:10.3906/sag-1910-166

35. Saravolatz LD, Pawlak J. In vitro activity of fosfomycin alone and in combination against Staphylococcus aureus with reduced susceptibility or resistance to methicillin, vancomycin, daptomycin or linezolid. J Antimicrob Chemother. 2023;78(1):238–241. doi:10.1093/jac/dkac380

36. Kang YR, Chung DR, Ko JH, et al. Comparing the synergistic and antagonistic interactions of ciprofloxacin and levofloxacin combined with Rifampin against drug-resistant Staphylococcus aureus: a time–kill assay. Antibiotics. 2023;12(4):711. doi:10.3390/antibiotics12040711

37. Doern CD. When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. J Clin Microbiol. 2014;52(12):4124–4128. doi:10.1128/JCM.01121-14

38. Jousselin A, Manzano C, Biette A, et al. The staphylococcus aureus chaperone PrsA is a new auxiliary factor of oxacillin resistance affecting penicillin-binding protein 2A. Antimicrob Agents Chemother. 2016;60(3):1656–1666. doi:10.1128/AAC.02333-15

39. Jacqueline C, Amador G, Batard E, et al. Comparison of ceftaroline fosamil, daptomycin and tigecycline in an experimental rabbit endocarditis model caused by methicillin-susceptible, methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus. J Antimicrob Chemother. 2011;66(4):863–866. doi:10.1093/jac/dkr019

40. Aeschlimann JR, Allen GP, Hershberger E, Rybak MJ. Activities of LY333328 and vancomycin administered alone or in combination with gentamicin against three strains of vancomycin-intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model. Antimicrob Agents Chemother. 2000;44(11):2991–2998. doi:10.1128/AAC.44.11.2991-2998.2000

41. Hiramatsu K. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother. 1997;40(1):135–136. doi:10.1093/jac/40.1.135

42. Keiichi H, Aritaka N, Hanaki H, et al. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet. 1997;350(9092):1670–1673. doi:10.1016/S0140-6736(97)07324-8

43. Mishra NN, Bayer AS. Correlation of cell membrane lipid profiles with daptomycin resistance in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2013;57(2):1082–1085. doi:10.1128/AAC.02182-12

44. Pillai SK, Wennersten C, Venkataraman L, Eliopoulos GM, Moellering RC, Karchmer AW. Development of reduced vancomycin susceptibility in methicillin‐susceptible Staphylococcus aureus. Clin Infect Dis. 2009;49(8):1169–1174. doi:10.1086/605636

45. Moreira B, Boyle-Vavra S, deJonge BL, Daum RS. Increased production of penicillin-binding protein 2, increased detection of other penicillin-binding proteins, and decreased coagulase activity associated with glycopeptide resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1997;41(8):1788–1793. doi:10.1128/AAC.41.8.1788

46. Truelson KA, Brennan-Krohn T, Smith KP, Kirby JE. Evaluation of apramycin activity against methicillin-resistant, methicillin-sensitive, and vancomycin-intermediate Staphylococcus aureus clinical isolates. Diagn Microbiol Infect Dis. 2018;92(2):168–171. doi:10.1016/j.diagmicrobio.2018.05.018

47. Jones R, Sader H, Biedenbach D. Antimicrobial characterization of CEM-101: activity against Staphylococci, β-Haemolytic and Viridans Group Streptococci; 2009.

48. Schmitz FJ. Increased in vitro activity of the novel des-fluoro(6) quinolone BMS-284756 against genetically defined clinical isolates of Staphylococcus aureus. J Antimicrob Chemother. 2002;49(2):283–287. doi:10.1093/jac/49.2.283

49. Bakthavatchalam YD, Shankar A, Muniyasamy R, et al. Levonadifloxacin, a recently approved benzoquinolizine fluoroquinolone, exhibits potent in vitro activity against contemporary Staphylococcus aureus isolates and Bengal Bay clone isolates collected from a large Indian tertiary care hospital. J Antimicrob Chemother. 2020:dkaa142. doi:10.1093/jac/dkaa142

50. Yanagihara K, Ohnishi Y, Morinaga Y, et al. Efficacy of ME1036 against meticillin-resistant Staphylococcus aureus and vancomycin-insensitive S. aureus in a model of haematogenous pulmonary infection. Int J Antimicrob Agents. 2008;32(5):401–404. doi:10.1016/j.ijantimicag.2008.04.030

51. Bouza E, Burillo A. Oritavancin: a novel lipoglycopeptide active against Gram-positive pathogens including multiresistant strains. Int J Antimicrob Agents. 2010;36(5):401–407. doi:10.1016/j.ijantimicag.2010.06.048

52. Arhin FF, Sarmiento I, Parr TR, Moeck G. Activity of oritavancin and comparators in vitro against standard and high inocula of Staphylococcus aureus. Int J Antimicrob Agents. 2012;39(2):159–162. doi:10.1016/j.ijantimicag.2011.09.017

53. Yarlagadda V, Konai MM, Paramanandham K, Nimita VC, Shome BR, Haldar J. In vivo efficacy and pharmacological properties of a novel glycopeptide (YV4465) against vancomycin-intermediate Staphylococcus aureus. Int J Antimicrob Agents. 2015;46(4):446–450. doi:10.1016/j.ijantimicag.2015.05.014

54. Swenson JM. In vitro activity of a new cephalosporin, RWJ-54428, against streptococci, enterococci and staphylococci, including glycopeptide-intermediate Staphylococcus aureus. J Antimicrob Chemother. 2002;49(5):845–850. doi:10.1093/jac/dkf020

55. Bongiorno D, Lazzaro LM, Stefani S, Campanile F. In vitro activity of dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus isolates. Antibiotics. 2020;9(12):865. doi:10.3390/antibiotics9120865

56. Howe RA, Wootton M, Noel AR, Bowker KE, Walsh TR, MacGowan AP. Activity of AZD2563, a novel oxazolidinone, against Staphylococcus aureus strains with reduced susceptibility to vancomycin or linezolid. Antimicrob Agents Chemother. 2003;47(11):3651–3652. doi:10.1128/AAC.47.11.3651-3652.2003

57. Barber KE, Smith JR, Raut A, Rybak MJ. Evaluation of tedizolid against Staphylococcus aureus and enterococci with reduced susceptibility to vancomycin, daptomycin or linezolid. J Antimicrob Chemother. 2016;71(1):152–155. doi:10.1093/jac/dkv302

58. Boakes S, Weiss WJ, Vinson M, Wadman S, Dawson MJ. Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models. J Antibiot. 2016;69(12):850–857. doi:10.1038/ja.2016.47

59. Jabés D, Brunati C, Candiani G, Riva S, Romanó G, Donadio S. Efficacy of the new lantibiotic NAI-107 in experimental infections induced by multidrug-resistant gram-positive pathogens. Antimicrob Agents Chemother. 2011;55(4):1671–1676. doi:10.1128/AAC.01288-10

60. Sangboonruang S, Semakul N, Obeid MA, et al. Potentiality of melittin-loaded niosomal vesicles against vancomycin-intermediate Staphylococcus aureus and Staphylococcal skin infection. IJN. 2021;16:7639–7661. doi:10.2147/IJN.S325901

61. Fritsche TR, Rhomberg PR, Sader HS, Jones RN. In vitro activity of omiganan pentahydrochloride tested against vancomycin-tolerant, -intermediate, and -resistant Staphylococcus aureus. Diagn Microbiol Infect Dis. 2008;60(4):399–403. doi:10.1016/j.diagmicrobio.2007.11.004

62. Field D, Quigley L, O’Connor PM, et al. Studies with bioengineered Nisin peptides highlight the broad‐spectrum potency of Nisin V. Microb Biotechnol. 2010;3(4):473–486. doi:10.1111/j.1751-7915.2010.00184.x

63. Sheppard JG, McAleer JP, Saralkar P, Geldenhuys WJ, Long TE. Allicin-inspired pyridyl disulfides as antimicrobial agents for multidrug-resistant Staphylococcus aureus. Eur J Med Chem. 2018;143:1185–1195. doi:10.1016/j.ejmech.2017.10.018

64. Chung PY, Loh PLN, Neoh HM, Ramli R. Alpha-amyrin as an anti-biofilm agent against methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. Heliyon. 2023;9(7):e17892. doi:10.1016/j.heliyon.2023.e17892

65. Yu W, Yang L, Xie J, et al. Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents: synthesis and bioactivity. Acta Pharmacol Sin. 2008;29(2):267–277. doi:10.1111/j.1745-7254.2008.00720.x

66. Li B, Ni S, Chen F, et al. Discovery of potent benzocycloalkane derived diapophytoene desaturase inhibitors with an enhanced safety profile for the treatment of MRSA, VISA, and LRSA infections. ACS Infect Dis. 2018;4(3):208–217. doi:10.1021/acsinfecdis.7b00259

67. Yang YS, Wei W, Hu XX, et al. Evolution and antibacterial evaluation of 8-hydroxy-cycloberberine derivatives as a novel family of antibacterial agents against MRSA. Molecules. 2019;24(5):984. doi:10.3390/molecules24050984

68. Guan D, Chen F, Xiong L, et al. Extra sugar on vancomycin: new analogues for combating multidrug-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. J Med Chem. 2018;61(1):286–304. doi:10.1021/acs.jmedchem.7b01345

69. Chen CC, Zhang YQ, Zhong DX, et al. The study of 9,10-dihydroacridine derivatives as a new and effective molecular scaffold for antibacterial agent development. Biochem Biophys Res Commun. 2021;546:40–45. doi:10.1016/j.bbrc.2021.01.096

70. Saravolatz LD, Pawlak J, Saravolatz SN, Johnson LB. in vitro activity of retapamulin against Staphylococcus aureus resistant to various antimicrobial agents. Antimicrob Agents Chemother. 2013;57(9):4547–4550. doi:10.1128/AAC.00282-13

71. Durcik M, Cotman AE, Toplak Ž, et al. New dual inhibitors of bacterial topoisomerases with broad-spectrum antibacterial activity and in vivo efficacy against vancomycin-intermediate Staphylococcus aureus. J Med Chem. 2023;66(6):3968–3994. doi:10.1021/acs.jmedchem.2c01905

72. Ni S, Wei H, Li B, et al. Novel inhibitors of staphyloxanthin virulence factor in comparison with linezolid and vancomycin versus methicillin-resistant, linezolid-resistant, and vancomycin-intermediate Staphylococcus aureus infections in vivo. J Med Chem. 2017;60(19):8145–8159. doi:10.1021/acs.jmedchem.7b00949

73. Ni S, Li B, Chen F, et al. Novel staphyloxanthin inhibitors with improved potency against multidrug resistant Staphylococcus aureus. ACS Med Chem Lett. 2018;9(3):233–237. doi:10.1021/acsmedchemlett.7b00501

74. Caspar Y, Jeanty M, Blu J, et al. Novel synthetic bis-indolic derivatives with antistaphylococcal activity, including against MRSA and VISA strains. J Antimicrob Chemother. 2015;70(6):1727–1737. doi:10.1093/jac/dkv015

75. Moiseenko EI, Grammatikova NE, Shchekotikhin AE. Synthesis and antibacterial activity of aminoalkylamides of eremomycin. MHC. 2020;13(3):298–304. doi:10.6060/mhc200812s

76. Burchak ON, Pihive EL, Maigre L, et al. Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine derivatives as new antibacterial agents. Bioorg Med Chem. 2011;19(10):3204–3215. doi:10.1016/j.bmc.2011.03.060

77. Pinto HB, Brust FR, Macedo AJ, Trentin DS. The antivirulence compound myricetin possesses remarkable synergistic effect with antibacterials upon multidrug resistant Staphylococcus aureus. Microb Pathogenesis. 2020;149:104571. doi:10.1016/j.micpath.2020.104571

78. Dewal MB, Wani AS, Vidaillac C, Oupický D, Rybak MJ, Firestine SM. Thieno[2,3-d] pyrimidinedione derivatives as antibacterial agents. Eur J Med Chem. 2012;51:145–153. doi:10.1016/j.ejmech.2012.02.035

79. Casero C, Estévez-Braun A, Ravelo ÁG, Demo M, Méndez-álvarez S, Machín F. Achyrofuran is an antibacterial agent capable of killing methicillin-resistant vancomycin-intermediate Staphylococcus aureus in the nanomolar range. Phytomedicine. 2013;20(2):133–138. doi:10.1016/j.phymed.2012.11.003

80. Bhateja P, Mathur T, Pandya M, Fatma T, Rattan A. Activity of blue green microalgae extracts against in vitro generated Staphylococcus aureus with reduced susceptibility to vancomycin. Fitoterapia. 2006;77(3):233–235. doi:10.1016/j.fitote.2006.01.009

81. Ouyang J, Sun F, Feng W, Xie Y, Ren L, Chen Y. Antimicrobial activity of galangin and its effects on murein hydrolases of vancomycin-intermediate Staphylococcus aureus (VISA) strain Mu50. Chemotherapy. 2018;63(1):20–28. doi:10.1159/000481658

82. Muthaiyan A, Biswas D, Crandall PG, Wilkinson BJ, Ricke SC. Application of orange essential oil as an antistaphylococcal agent in a dressing model. BMC Complement Altern Med. 2012;12(1):125. doi:10.1186/1472-6882-12-125

83. Osman A, El-Didamony G, Sitohy M, Khalifa M, Enan G. Soybean glycinin basic subunit inhibits methicillin resistant-vancomycin intermediate Staphylococcus aureus (MRSA-VISA) in vitro; 2016:17–26.

84. Yang SC, Tseng CH, Wang PW, et al. Pterostilbene, a methoxylated resveratrol derivative, efficiently eradicates planktonic, biofilm, and intracellular MRSA by topical application. Front Microbiol. 2017;8:1103. doi:10.3389/fmicb.2017.01103

85. Kannian P, Mohana S, Rohini MV, Punithavalli B, Gunasekaran P. Identification and evaluation of Anisochilus carnosus (L. fil.) Wall. as a novel candidate with therapeutic potential against multi-drug resistant Staphylococcus aureus. J Herbal Med. 2020;23:100369. doi:10.1016/j.hermed.2020.100369

86. Kim MK, Lee TG, Jung M, Park KH, Chong Y. In vitro synergism and anti-biofilm activity of quercetin–pivaloxymethyl conjugate against Staphylococcus aureus and Enterococcus species. Chem Pharm Bull. 2018;66(11):1019–1022. doi:10.1248/cpb.c18-00380

87. Xu LQ, Zeng JW, Jiang CH, et al. Isolation and determination of four potential antimicrobial components from Pseudomonas aeruginosa extracts. Int J Med Sci. 2017;14(13):1368–1374. doi:10.7150/ijms.18896

88. Li X, Wang P, Hu X, et al. The combined antibacterial effects of sodium new houttuyfonate and berberine chloride against growing and persistent methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. BMC Microbiol. 2020;20(1):317. doi:10.1186/s12866-020-02003-2

89. Abdelaziz R, Abd El-Hamid MI, El-Wafaei N, et al. Phage-resistant Streptomyces abietis and its telomycin bioactive metabolite as a possible alternative to antibiotics. Microb Pathogenesis. 2024;194:106822. doi:10.1016/j.micpath.2024.106822

90. Hiramatsu K, Igarashi M, Morimoto Y, Baba T, Umekita M, Akamatsu Y. Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature. Int J Antimicrob Agents. 2012;39(6):478–485. doi:10.1016/j.ijantimicag.2012.02.007

91. Jordheim LP, Ben Larbi S, Fendrich O, et al. Gemcitabine is active against clinical multiresistant Staphylococcus aureus strains and is synergistic with gentamicin. Int J Antimicrob Agents. 2012;39(5):444–447. doi:10.1016/j.ijantimicag.2012.01.019

92. Bryant AE, Gomi S, Katahira E, Huang DB, Stevens DL. The effects of iclaprim on exotoxin production in methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. J Med Microbiol. 2019;68(3):456–466. doi:10.1099/jmm.0.000929

93. Olson PD, Kuechenmeister LJ, Anderson KL, et al. Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. PLoS Pathog. 2011;7(2):e1001287. doi:10.1371/journal.ppat.1001287

94. Sharma K, Aaghaz S, Maurya IK, et al. Antifungal evaluation and mechanistic investigations of membrane active short synthetic peptides-based amphiphiles. Bioorg Chem. 2022;127:106002. doi:10.1016/j.bioorg.2022.106002

95. Singh A, Ahmed A, Prasad KN, et al. Antibiofilm and membrane-damaging potential of cuprous oxide nanoparticles against Staphylococcus aureus with reduced susceptibility to vancomycin. Antimicrob Agents Chemother. 2015;59(11):6882–6890. doi:10.1128/AAC.01440-15

96. Franklyne JS, Andrew Ebenazer L, Mukherjee A, Natarajan C. Cinnamon and clove oil nanoemulsions: novel therapeutic options against vancomycin intermediate susceptible Staphylococcus aureus. Appl Nanosci. 2019;9(7):1405–1415.

97. Ahmed E, Hassan M, Shamma R, Makky A, Hassan D. Controlling the evolution of selective vancomycin resistance through successful ophthalmic eye-drop preparation of vancomycin-loaded nanoliposomes using the active-loading method. Pharmaceutics. 2023;15(6):1636. doi:10.3390/pharmaceutics15061636

98. Nasaj M, Farmany A, Shokoohizadeh L, et al. Development of chitosan‐assisted Fe₃ O₄ @SiO₂ magnetic nanostructures functionalized with nisin as a topical combating system against vancomycin‐intermediate Staphylococcus aureus (VISA) skin wound infection in mice. J Nanomater. 2022;2022(1):2914210. doi:10.1155/2022/2914210

People with chronic insomnia may experience faster declines in memory and thinking skills as they age-along with brain changes that can be seen on imaging scans-than people who do not have chronic insomnia, according to a study published in the September 10, 2025, issue of Neurology^®, the medical journal of the American Academy of Neurology.

The study found that people with chronic insomnia-trouble sleeping at least three days a week for three months or more-had a 40% higher risk of developing mild cognitive impairment or dementia than those without insomnia, which is the equivalent of 3.5 additional years of aging. The study does not prove that insomnia causes brain aging, it only shows an association.

Insomnia doesn’t just affect how you feel the next day-it may also impact your brain health over time. We saw faster decline in thinking skills and changes in the brain that suggest chronic insomnia could be an early warning sign or even a contributor to future cognitive problems.”

Diego Z. Carvalho, MD, study author of the Mayo Clinic in Rochester, Minnesota, and member of the American Academy of Neurology

The study tracked a group of cognitively healthy older adults-2,750 people with an average age of 70-for an average of 5.6 years. Of participants, 16% had chronic insomnia.

At the start of the study, participants were asked whether they had been sleeping more or less than usual during the past two weeks. They also took yearly thinking and memory tests, and some had brain scans to look for white matter hyperintensities-areas where small vessel disease may have damaged brain tissue-and for amyloid plaques, a protein that can build up and is linked to Alzheimer’s disease.

During the study, 14% of the people with chronic insomnia developed mild cognitive impairment or dementia, compared to 10% of those who did not have insomnia.

After accounting for factors like age, high blood pressure, use of sleep medications and a diagnosis of sleep apnea, they found that people with insomnia were 40% more likely to develop mild cognitive impairment or dementia than those without insomnia. They also had faster declines on tests measuring different thinking skills.

Among those with insomnia, researchers determined the type: those getting less sleep than usual in the past two weeks; or those getting more sleep than usual in the past two weeks.

People who reported getting less sleep than usual were more likely to have lower cognitive test scores at the beginning of the study, comparable to being four years older. They also had more white matter hyperintensities and amyloid plaques. For amyloid, the effect was similar to what is seen in people with the APOE ε4 gene, a known genetic risk factor.

People who reported getting more sleep than usual, on the other hand, were more likely to have fewer white matter hyperintensities at the start of the study.

Some groups were especially vulnerable. Participants who carry the APOE ε4 gene-linked to higher Alzheimer’s risk-showed steeper declines in memory and thinking skills.

“Our results suggest that insomnia may affect the brain in different ways, involving not only amyloid plaques, but also small vessels supplying blood to the brain,” Carvalho said. “This reinforces the importance of treating chronic insomnia-not just to improve sleep quality but potentially to protect brain health as we age. Our results also add to a growing body of evidence that sleep isn’t just about rest-it’s also about brain resilience.”

A limitation of the study was that insomnia diagnoses came from medical records, which do not capture undiagnosed cases or reflect how severe symptoms are.

The study was supported by the National Institutes of Health, GHR Foundation, Mayo Foundation for Medical Education and Research, and a grant from Sleep Number Corporation to the Mayo Clinic.