مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
When the Air We Breathe Fuels Resistance: Environmental and Therapeutic Modulators of Drug-Resistant Pulmonary Co-Infection — Synergistic Impact of Secondhand Smoke, Levofloxacin, and Nitric Oxide
When the Air We Breathe Fuels Resistance: Environmental and Therapeutic Modulators of Drug-Resistant Pulmonary Co-Infection — Synergistic Impact of Secondhand Smoke, Levofloxacin, and Nitric Oxide
Introduction: Antimicrobial resistance (AMR) and environmental pollutants are converging threats to global respiratory health. Co-infection with pan-drug-resistant (PDR) Acinetobacter baumannii and Streptococcus pneumoniae significantly increases mortality and treatment failure, particularly in urban populations. Secondhand smoke (SHS) exposure further impairs host immunity, disrupts lung barrier integrity, and increases infection susceptibility, yet its role in modulating therapeutic response remains underexplored. In parallel, nitric oxide (NO) has emerged as a promising adjunct to antibiotics such as levofloxacin, but its efficacy across different pathogen contexts and environmental exposures is not fully understood. Against this backdrop, the present study seeks to evaluate the synergistic effects of SHS exposure and NO inhalation on the pathogenesis, treatment response, and microbial dynamics of co-infection with PDR A. baumannii and S. pneumoniae under levofloxacin therapy. Specifically, it aims to identify pathogen-specific and environment-driven predictors of treatment failure and therapeutic potentiation.
Methods: C57BL/6 mice will be exposed to secondhand smoke (SHS) and subsequently infected intranasally with standardized inocula of either PDR A. baumannii (1 × 10⁷ CFU), S. pneumoniae (1 × 10⁶ CFU), or both pathogens in combination. Four treatment arms will be established: no treatment, levofloxacin administered intraperitoneally at 100 mg/kg/day, inhaled nitric oxide (NO) delivered at 160 ppm for one hour per day via a whole-body exposure chamber, and combined therapy with both levofloxacin and NO. The primary outcome measures will include survival, clinical scoring, weight loss, and bacterial burden in lung and spleen tissues (CFU counts). Secondary outcome measures will encompass lung and bronchoalveolar lavage fluid (BALF) analyses for cytokine levels (IL-6, IL-1β, TNF-α, CXCL1, IFN-γ) and oxidative stress markers (myeloperoxidase [MPO] and glutathione [GSH]). Additional assessments will include pharmacokinetic profiling of levofloxacin using LC-MS/MS, lung microbiota characterization through 16S rRNA sequencing, and structural evaluation via histopathology and micro-computed tomography (micro-CT). Finally, predictive modeling with receiver operating characteristic (ROC) curves and correlation matrices will be applied to evaluate therapeutic responses across the different infection groups.
Expected Results
We hypothesize that SHS exposure will worsen clinical outcomes by increasing pathogen virulence and host inflammation, while inhaled NO will restore levofloxacin efficacy via anti-inflammatory and antimicrobial synergy. Pathogen-specific responses are anticipated, offering mechanistic insight into host-environment-drug interactions. Combined SHS exposure and co-infection are expected to synergistically impair therapy outcomes, while NO may offset these effects in a dose- and pathogen-dependent manner.
Results: We hypothesize that SHS exposure will worsen clinical outcomes by increasing pathogen virulence and host inflammation, while inhaled NO will restore levofloxacin efficacy via anti-inflammatory and antimicrobial synergy. Pathogen-specific responses are anticipated, offering mechanistic insight into host-environment-drug interactions. Combined SHS exposure and co-infection are expected to synergistically impair therapy outcomes, while NO may offset these effects in a dose- and pathogen-dependent manner.
Conclusion: This study introduces a novel, clinically relevant murine model simulating SHS-linked drug-resistant co-infections and therapeutic modulation. By integrating environmental exposure, pathogen specificity, and drug synergy, we aim to reveal actionable biomarkers and treatment strategies for managing AMR in high-risk urban populations. These findings may support the incorporation of nitric oxide as a resistance-breaking adjuvant in personalized pulmonary infection therapy.