The association and causal role of infectious agents in chronic inflammatory diseases have major implications for public health, treatment, and prevention. Pharmacological treatment of combined infectious and inflammatory diseases requires the administration of multiple drugs, including antibiotics and anti-inflammatory drugs. However, this can cause adverse effects, and therefore, dual-action drugs need to be developed. Anti-inflammatory drugs that have already shown antimicrobial properties appear to be promising candidates. NSAIDs, namely aceclofenac, diclofenac, and ibuprofen, were tested in clinical trials with patients diagnosed with uncomplicated urinary tract infections (UTIs) and cellulitis. The administration of ibuprofen, a drug tested in the highest number of studies, resulted in symptom resolution in patients with UTIs. Additionally, ibuprofen caused a high survival rate in mice infected with Pseudomonas aeruginosa and demonstrated potent in vitro antibacterial effects against Bacillus cereus, Escherichia coli, and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) (MIC 0.625-2.5 mg/L). For most anti-inflammatory drugs, only data showing their in vitro and in vivo antimicrobial effects are available. Among these, auranofin caused a high survival rate in mice infected with Enterococcus faecium, S. aureus, and Clostridioides difficile. It also produced a strong in vitro growth-inhibitory effect against Streptococcus agalactiae, S. pneumoniae, S. aureus, S. epidermidis, Bacillus subtilis, C. difficile, E. faecalis, E. faecium, and Mycobacterium tuberculosis (MIC 0.0015-5 mg/L). Similarly, aspirin caused a high survival rate in M. tuberculosis-infected mice and strong to moderate in vitro activity against E. coli, B. cereus, P. aeruginosa, Enterobacter aerogenes, Klebsiella pneumoniae and Salmonella choleraesuis (MIC 1.2-5 mg/L). Moreover, topical application of celecoxib resulted in a high reduction in MRSA burden in mice. However, it only caused moderate in vitro effects against S. epidermidis, S. aureus and Bacillus subitilis (MIC 16-64 mg/L). These data suggest that certain non-steroidal anti-inflammatory drugs (NSAIDs) are promising drug candidates for the development of dual-action drugs for the potential treatment of combined infectious and inflammatory diseases such as tuberculosis, musculoskeletal infections and UTIs. Nevertheless, future clinical trials must be conducted to ascertain the antibacterial effect of these NSAIDs before their practical use.

• Keywords
• bacterial infection, cellulitis, cystitis, dual-action drugs, inflammation, osteomyelitis, septic arthritis, single-drug therapy,
• Publication type
• Journal Article MeSH
• Review MeSH

Musculoskeletal infections (MIs) are among the most difficult-to-treat staphylococcal diseases due to antibiotic resistance. This has encouraged the development of innovative strategies, such as combination therapy, to combat MI. The aim of this study was to investigate the in vitro antistaphylococcal activity of anti-inflammatory drugs and the combined antimicrobial effect of celecoxib and oxacillin. The minimum inhibitory concentrations (MICs) of 17 anti-inflammatory drugs against standard strains and clinical isolates of S. aureus, including methicillin-resistant strains (MRSAs), were determined using the broth microdilution method. The fractional inhibitory concentration indices (FICIs) were evaluated using checkerboard assays. Celecoxib produced the most potent antistaphylococcal effect against all tested strains (MICs ranging from 32 to 64 mg/L), followed by that of diacerein against MRSA3 and MRSA ATCC 33592 (MIC 64 mg/L). Several synergistic effects were observed against the tested S. aureus strains, including MRSA (FICI ranging from 0.087 to 0.471). The strongest synergistic interaction (FICI 0.087) was against MRSA ATCC 33592 at a celecoxib concentration of 2 mg/L, with a 19-fold oxacillin MIC reduction (from 512 to 26.888 mg/L). This is the first report on the combined antistaphylococcal effect of celecoxib and oxacillin. These findings suggest celecoxib and its combination with oxacillin as perspective agents for research focused on the development of novel therapies for MI caused by S. aureus. This study further indicates that celecoxib could resensitize certain MRSA strains, in some cases, to be susceptible to β-lactams (e.g., oxacillin) that were not previously tested. It is essential to mention that the in vitro concentrations of anti-inflammatory drugs are higher than those typically obtained in patients. Therefore, an alternative option for its administration could be the use of a drug delivery system for the controlled slow release from an implant at the infection site.

• Keywords
• antibacterial activity, antistaphylococcal synergistic effect, methicillin-resistant S. aureus, musculoskeletal infections, non-steroidal anti-inflammatory drugs,
• MeSH
• Anti-Bacterial Agents * pharmacology   MeSH
• Anti-Inflammatory Agents * pharmacology   MeSH
• Celecoxib * pharmacology   MeSH
• Humans MeSH
• Methicillin-Resistant Staphylococcus aureus * drug effects   MeSH
• Microbial Sensitivity Tests * MeSH
• Oxacillin * pharmacology   MeSH
• Staphylococcal Infections drug therapy   microbiology   MeSH
• Staphylococcus aureus * drug effects   MeSH
• Drug Synergism * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents * MeSH
• Anti-Inflammatory Agents * MeSH
• Celecoxib * MeSH
• Oxacillin * MeSH

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

• Keywords
• SYSADOA, celecoxib, diacerein, non-inferiority trial, osteoarthritis,
• MeSH
• Anthraquinones therapeutic use   MeSH
• Anti-Inflammatory Agents, Non-Steroidal therapeutic use   MeSH
• Arthralgia drug therapy   MeSH
• Osteoarthritis, Knee drug therapy   MeSH
• Celecoxib therapeutic use   MeSH
• Double-Blind Method MeSH
• Middle Aged MeSH
• Humans MeSH
• Pain Measurement MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Equivalence Trial MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Anthraquinones MeSH
• Anti-Inflammatory Agents, Non-Steroidal MeSH
• Celecoxib MeSH
• diacerein MeSH Browser