The 2014 Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections recommend antimicrobial therapy for cellulitis based on the suspected pathogen and severity of infection; vancomycin or another agent active against both MRSA and streptococci is recommended when MRSA risk factors or severe nonpurulent infection are present. The guidelines do not describe an anti-inflammatory effect of vancomycin or recommend selecting antibiotics for anti-inflammatory properties. They note that cutaneous inflammation and systemic features may initially worsen after antimicrobial therapy, possibly from sudden pathogen destruction and release of enzymes that increase local inflammation. When specifically addressing anti-inflammatory treatment of cellulitis, the guidelines discuss adjunctive NSAIDs or systemic corticosteroids, which may hasten clinical improvement when combined with antimicrobial therapy; systemic corticosteroids may be considered in nondiabetic adults (weak recommendation, moderate-quality evidence). For documented group A streptococcal necrotizing fasciitis, however, penicillin plus clindamycin is recommended, with clindamycin described as suppressing streptococcal toxin and cytokine production. [1]
A 2008 review examined the immunomodulatory properties of antibiotics across infectious and inflammatory conditions. Anti-inflammatory effects were best established for macrolides in chronic inflammatory pulmonary disorders, while immunomodulatory effects were also reported with several other antibiotic classes and conditions. In experimental bacterial meningitis and sepsis, nonbacteriolytic antibiotics, including rifampicin, clindamycin, aminoglycosides, and daptomycin, were associated with less release of proinflammatory bacterial components and reduced inflammatory responses compared with bacteriolytic β-lactams. Clindamycin was associated with reduced morbidity and mortality compared with ceftriaxone in a murine S. aureus sepsis model, while retrospective data in children with deep-tissue S. pyogenes infections found more favorable outcomes with initial protein-synthesis inhibitor therapy, primarily clindamycin, compared with cell wall-inhibiting antibiotics alone. Fluoroquinolones and tetracyclines also demonstrated immunomodulatory effects in experimental models. The authors noted that, outside established macrolide applications, clinical evidence remains limited and randomized clinical studies are needed before these immunomodulatory properties can be applied in clinical practice. [2]
A 2018 systematic review assessed the immunomodulatory effects of azithromycin, clarithromycin, erythromycin, and roxithromycin in 45 human studies involving 1,834 participants. Macrolides were most frequently associated with reductions in neutrophil counts and function and inflammatory mediators including IL-8, TNF-α, IL-1β, IL-6, neutrophil elastase, and MMP-9. Outside of COPD, azithromycin and roxithromycin reduced inflammatory cytokines in periodontitis; clarithromycin and roxithromycin reduced inflammatory cell counts and mediators in chronic rhinosinusitis and bronchiectasis; azithromycin, clarithromycin, and roxithromycin demonstrated immunomodulatory effects in asthma; erythromycin reduced neutrophilic inflammation and inflammatory mediators in diffuse panbronchiolitis; and azithromycin and clarithromycin reduced neutrophils and inflammatory mediators in cystic fibrosis. The authors concluded that substantial evidence supports macrolide immunomodulatory effects, particularly inhibition of neutrophilic inflammation and macrophage activation, although studies were heterogeneous and some observed anti-inflammatory effects could reflect antimicrobial activity against pathogens contributing to inflammation. [3]
A 2025 review examined the non-antimicrobial properties of antibiotics, noting that antibiotics can exert host effects that modulate immune responses and inflammatory cytokine production and may influence the clinical course of infection independently of their primary antibacterial activity. Macrolides have particularly well-described immunomodulatory effects, including modulation of neutrophil function and reductions in inflammatory signaling and cytokine production. In severe sepsis caused by pneumonia, macrolide use was associated with lower 30- and 90-day mortality despite macrolide-resistant organisms; however, in a randomized study of pulmonary and nonpulmonary sepsis, clarithromycin did not reduce 28-day mortality but reduced sepsis recurrence, which was attributed to immune modulation and increased activated monocytes. Other antibiotics with reported anti-inflammatory or immunomodulatory effects included fluoroquinolones, which can decrease inflammatory cytokines and T-cell activation; rifampicin, which can suppress T-cell activity and modulate neutrophil responses; dapsone, which may reduce reactive oxygen species, prostaglandins, IL-8, and complement activity; and tetracyclines, which can reduce proinflammatory cytokines, neutrophil migration, lymphocyte proliferation, and matrix metalloproteinases. The authors noted growing interest in these non-antimicrobial effects as a means of limiting inflammation and host tissue damage, while emphasizing the potential consequences of antibiotic use, including antimicrobial resistance and microbiome disruption. [4]
A 2024 narrative review evaluated the immunomodulatory effects of antibiotics in sepsis, with most evidence derived from preclinical studies and relatively few human clinical trials. Macrolides had the most extensively studied effects, including suppression of TNF, IL-1, IL-6, and IL-8; clinical studies in community-acquired pneumonia reported changes in inflammatory mediators and favorable outcomes with macrolide-containing regimens, while studies in sepsis and septic shock showed mixed clinical results. Tigecycline, clindamycin, trimethoprim/sulfamethoxazole, and linezolid suppressed cytokine production from S. aureus toxin-stimulated immune cells in a concentration-dependent manner, whereas vancomycin did not demonstrate this effect; separate experimental data found that vancomycin increased LPS-stimulated IL-10 but also upregulated Toll-like receptor expression and exhibited predominantly pro-inflammatory effects under sepsis-like conditions. In contrast, daptomycin downregulated Toll-like receptor transcription and reduced macrophage TNF release and iNOS accumulation compared with vancomycin or oxacillin, while quinolones and fosfomycin also demonstrated anti-inflammatory effects in preclinical models. The authors emphasized that clinical evidence for these immunomodulatory effects remains limited. [5]
A 2017 review evaluated the effects of antibiotics on Staphylococcus aureus virulence factor expression and host immune responses, incorporating in vitro, animal, and available clinical evidence. Clindamycin and linezolid consistently suppressed several staphylococcal toxins, including α-toxin, TSST-1, and PVL, and protein-synthesis inhibitors were also associated with variable suppression of proinflammatory cytokine responses following staphylococcal stimulation. In contrast, β-lactams generally increased exotoxin production at subinhibitory concentrations and were associated with greater IL-8 and MCP-1 release than protein-synthesis inhibitors in an endothelial-cell model. Vancomycin generally had limited or no effect on α-toxin, TSST-1, and PVL production and showed inconsistent effects on toxin-stimulated cytokine production; in a macrophage model, daptomycin reduced TNF release and nitric oxide synthase accumulation compared with vancomycin or oxacillin. Although in vivo data supported toxin suppression with clindamycin and linezolid in toxin-associated staphylococcal disease, the authors stated that whether antibiotic effects on toxin production or immunomodulation improve treatment outcomes remained to be determined. [6]
A 2019 review compared in vitro, in vivo animal model, and limited human clinical data addressing linezolid’s (LZD) immunomodulatory effects beyond its established bacteriostatic activity against Gram-positive pathogens. In vitro investigations utilized human polymorphonuclear neutrophils (PMNs), peripheral blood mononuclear cells (PBMCs), whole blood, and airway epithelial cells stimulated with bacterial toxins or endotoxins to evaluate LZD’s influence on phagocytosis, cytokine production, and gene expression. Results consistently demonstrated that while LZD did not impair baseline phagocytic functions, it significantly suppressed phagocytosis activated by endotoxins and reduced production and mRNA expression of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and IFN-γ, in a concentration-dependent manner. LZD further inhibited overexpression of MUC5AC mucin induced by MRSA supernatant in airway epithelial cells via MAPK pathway modulation, highlighting its potential role in mitigating mucin-related airway obstruction during respiratory infections. In vivo studies primarily employing murine and rabbit models of MRSA pneumonia, post-influenza bacterial pneumonia, sepsis, and ventilator-associated pneumonia detailed LZD’s immunomodulatory capacity alongside its antimicrobial efficacy. LZD administration resulted in significant reductions in pulmonary and systemic pro-inflammatory cytokines (e.g., TNF-α, IL-6, MIP-2), decreased neutrophilic infiltration, attenuated lung tissue damage, and improved survival compared to controls or vancomycin-treated groups, despite comparable bacterial clearance. Notably, LZD’s early administration blunted cytokine storms and diminished bacterial toxin production, including Panton-Valentine leucocidin, correlating with improved histopathological outcomes. In sepsis and endotoxemia models, LZD reduced leukocyte adhesion and improved intestinal microcirculation. However, human clinical evidence remained sparse, with retrospective and randomized trials suggesting faster defervescence and cytokine modulation but limited data on broader immunological impacts. [7]
A 2012 in vitro study (see Table 1) investigated the concentration-dependent effects of seven anti-staphylococcal antibiotics (vancomycin, trimethoprim/sulfamethoxazole, tigecycline, daptomycin, linezolid, clindamycin, and azithromycin) on cytokine production from human peripheral blood mononuclear cells (PBMCs) stimulated with Staphylococcus aureus toxins. PBMCs isolated from ten healthy volunteers were cultured in complete RPMI 1640 medium and exposed to purified staphylococcal toxins representing key virulence factors: toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin A (SEA), α-toxin, and Panton–Valentine leucocidin (PVL) at 100 ng/mL. Antibiotics were introduced at clinically relevant free serum peak concentrations (Cmax) ranging from 0.5 to 100 mg/L, and cytokine responses including interleukin-1β (IL-1β), IL-6, IL-8, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were measured by ELISA after 24 hours of incubation. Cell viability was confirmed by flow cytometry to exclude cytotoxic artifact. Controls included unstimulated PBMCs, toxin-only stimulation, and phytohemagglutinin as a positive mitogen control. The results demonstrated that all four toxins significantly induced proinflammatory cytokine production, with PVL eliciting the highest TNF-α and IL-8 levels and superantigens TSST-1 and SEA preferentially stimulating IL-6, IFN-γ, and IL-1β. At approximate serum Cmax concentrations, tigecycline consistently reduced IL-6 levels by 52%–57% and IFN-γ by 43%–53% versus toxin controls (p≤ 0.05), identifying it as the most potent inhibitor of these cytokines. Linezolid also showed significant inhibition of TNF-α (12%–35%) and IL-8 (25%–42%) production (p≤ 0.02), whereas trimethoprim/sulfamethoxazole paradoxically increased TNF-α and IL-8 production (p= 0.002). Clindamycin, daptomycin, vancomycin, and azithromycin demonstrated variable and generally non-significant effects at these concentrations. Importantly, increasing antibiotic concentrations from 5 to 100 mg/L revealed concentration-dependent cytokine modulation, with tigecycline, clindamycin, and trimethoprim/sulfamethoxazole showing the most pronounced inhibitory effects at concentrations exceeding 25 mg/L, including near-complete suppression (>90%) of TNF-α, IL-8, IL-6, and IFN-γ at 50–100 mg/L. These findings suggest that antibiotics with high tissue penetration and protein synthesis inhibition capabilities tend to suppress toxin-induced proinflammatory cytokine production by human immune cells, which may contribute to their therapeutic benefit in severe S. aureus infections characterized by toxin-mediated inflammation. [8]
A 2013 experimental investigation (see Table 2) explored the thrombo-inflammatory response induced by MRSA and the modulatory effects of timely antibiotic administration using novel human whole blood and murine infection models. Utilizing an isolate of MRSA from a clinical bloodstream infection, the study inoculated human whole blood samples and purified monocytes with live bacteria, assessing thrombin generation kinetics, microparticle (MP) formation, and cytokine synthesis. Thrombin generation assays revealed that MRSA significantly accelerated initiation phases while increasing the rate of thrombin formation in both time- and concentration-dependent manners, without affecting total thrombin quantity. Mechanistic interrogation demonstrated that this hypercoagulability was largely dependent on tissue factor (TF) activity and was attenuated by CD14+ monocyte-derived TF-positive MPs, as evidenced by antibody blockade and high-speed centrifugation to deplete MPs. Flow cytometry characterized MPs as predominantly phosphatidylserine positive with contributions from monocyte, platelet, and red blood cell origins, whereas neutrophil-derived MPs were minimal. MRSA exposure also induced robust synthesis of pro-inflammatory cytokines including IL-6, IL-8, MCP-1, TNF-α, and IL-1β, with temporal patterns indicating early MCP-1 elevation preceding maximal cytokine levels at 24 hours. The effects of antibiotics commonly employed against MRSA, linezolid and vancomycin, were assessed with respect to timing of administration. When applied at five times the minimum inhibitory concentration at the onset of bacterial inoculation, both agents normalized thrombin generation parameters and markedly suppressed cytokine production. In contrast, delayed administration (≥9–12 hours post-inoculation) failed to reverse the prothrombotic and proinflammatory changes. Control experiments using toxin stimuli such as lipopolysaccharide and alpha-toxin confirmed that the antibiotics’ immunomodulatory effects were primarily bacterium-directed rather than acting directly on immune cells. In vivo corroboration came from a C57BL/6 mouse model of MRSA peritoneal infection, where early vancomycin treatment decreased bacterial load, MCP-1 cytokine levels, and plasma thrombin-antithrombin complexes, whereas late treatment did not. [9]
A 2002 investigation (see Table 3) examined the immunomodulatory effects of several commonly used antimicrobial agents (β-lactams, quinolones, gentamicin, vancomycin, and metronidazole) on cytokine production by human peripheral blood mononuclear cells (PBMNC). Using in vitro cultures of isolated PBMNC and whole blood obtained from healthy donors, cytokine responses to endotoxin stimulation (lipopolysaccharide at 100 ng/mL) were measured in the presence or absence of therapeutically relevant antibiotic concentrations. The study utilized enzyme-linked immunosorbent assays (ELISAs) to quantify TNF-α and IL-6 in culture supernatants, while cytotoxicity was assessed by MTT and trypan blue exclusion assays. Antibiotics were tested over a wide range of concentrations reflective of therapeutic dosing, and the experimental design incorporated both isolated immune cells and whole blood to mimic distinct physiological environments. Results demonstrated that quinolones (ciprofloxacin, ofloxacin) and vancomycin significantly inhibited endotoxin-induced TNF-α production by isolated PBMNC, with inhibition rates approximately 25–50%, while gentamicin and metronidazole also showed notable reductions in TNF-α release without evidence of cytotoxicity. Only ofloxacin exerted a significant suppressive effect on endotoxin-induced IL-6 production in PBMNC cultures. Conversely, β-lactams tested (penicillin G, azlocillin, cefotaxime, cefazolin) did not significantly affect cytokine production under the same conditions. When these antimicrobial agents were tested in whole blood assays, none demonstrated a significant impact on endotoxin-induced TNF-α or IL-6 release, even at supratherapeutic concentrations, suggesting that the immunomodulatory effects observed in isolated cells may be attenuated or absent in the complex milieu of whole blood. These findings imply that antibiotics can differentially modulate mononuclear cell inflammatory responses ex vivo. [10]