Chronic bronchial infection (CBI) [1] leads to persistent airway inflammation and impaired mucociliary clearance, increasing the risk of symptom worsening, recurrent exacerbations, reduced quality of life, and mortality [2,3]. These adverse outcomes may occur across different underlying lung diseases, with non-cystic fibrosis bronchiectasis (NCFB) being one of the most common conditions predisposing to CBI [1]. Inhaled antibiotics (IAs) deliver high drug concentrations directly to the site of infection while minimizing systemic exposure, thereby reducing toxicity, adverse effects, and the risk of antimicrobial resistance [4]. These therapies can reduce bacterial load, promote pathogen eradication, and have been associated with decreased exacerbation frequency [5,6].

Current clinical guidelines for the management of bronchiectasis provide clear recommendations for the use of IAs in patients with chronic Pseudomonas aeruginosa infection and frequent exacerbations [7,8]. In contrast, for CBI caused by other potentially pathogenic microorganisms (PPMs), guidelines advocate a more cautious and individualized approach. In these cases, IA therapy is generally restricted to selected patients with a high disease burden who remain symptomatic despite optimized standard therapy, including long-term macrolides. This cautious positioning reflects the more limited and heterogeneous evidence supporting IA therapy in these populations.

At present, several IAs are recommended by clinical guidelines [7,8] and are commonly used in routine clinical practice for patients with NCFB and chronic P. aeruginosa infection. Among these, colistimethate sodium and tobramycin are the most widely prescribed, supported by the strongest evidence base and longest clinical experience [9,10]. Tobramycin is typically administered in cyclic regimens with alternating on- and off-treatment periods, whereas colistimethate sodium is commonly prescribed as continuous therapy in real-world practice. Other IAs, such as gentamicin, are frequently used off-label, most often as continuous therapy, particularly in patients who are intolerant of or have failed first-line options. Aztreonam lysine has been evaluated in randomized clinical trials in NCFB [11]; however, clinical benefits were inconsistent, and its use in routine clinical practice remains limited. When more than one IA is required, agents are generally administered in alternating treatment cycles rather than concomitantly. Although nebulized levofloxacin has demonstrated efficacy and safety in randomized controlled trials in cystic fibrosis [12–14], it is not currently approved as first-line therapy for CBI not associated with CF, and no randomized controlled trials have evaluated its use in this setting. Consequently, in routine clinical practice, nebulized levofloxacin is typically prescribed as a second- or third-line option, and the available evidence to date is largely derived from observational and real-world studies, including the present analysis.

Given its favorable pharmacokinetic profile and broad-spectrum activity against P. aeruginosa, Staphylococcus aureus, Stenotrophomonas maltophilia, Haemophilus influenzae, and other pathogens implicated in CBI [15,16], nebulized levofloxacin may represent a valuable option for patients with NCFB and other chronic structural lung diseases, particularly those with frequent exacerbations and limited therapeutic alternatives [15]. To provide real-world evidence, we conducted a subanalysis of the INBREATHING registry, a multicenter retrospective cohort study including consecutive adult patients with non-CF chronic bronchial infection who initiated inhaled antibiotic therapy across 22 Spanish centers between January 2018 and June 2025. Registry details have been published previously [17]. CBI was defined according to national guideline criteria based on sputum microbiology [8]. Treatment selection and sequencing were based on routine clinical practice without a predefined protocol.

The present analysis focused on patients receiving nebulized levofloxacin and explored associations between its use and clinical outcomes, with descriptive comparisons within the broader cohort of patients treated with other inhaled antibiotics. Given the observational design, analyses were considered exploratory, and no causal inference was intended. For the present analysis, inclusion required complete data for the predefined primary outcomes, defined a priori as the number of exacerbations and hospitalizations during the year prior to IA initiation and at 6 months of follow-up. Other variables, including lung function and microbiological data, were analyzed when available but were not inclusion criteria. Among 395 patients with CBI included in the registry, 108 received nebulized levofloxacin, of whom 81 met the data completeness criteria and were included. After excluding these patients, 287 individuals treated with other inhaled antibiotics were identified as potential comparators; 285 fulfilled the same criteria and were included, whereas 2 were excluded due to insufficient follow-up or missing outcome data.

Demographic characteristics, comorbidities, lung function, microbiological data, and adverse events were collected at IA initiation, with follow-up assessments at 6 months and, when available, at 12 months. Microbiological follow-up was not protocolized and reflected routine clinical practice at each participating center. Sputum production and purulence, as well as their improvement over time, were assessed based on routine clinical evaluation and were not measured using standardized scoring systems. Posttreatment microbiological outcomes were assessed according to national guideline criteria [8], including resistance development, defined as a change in antimicrobial susceptibility category reported in routine antibiograms.

Exacerbations and hospitalizations during the year preceding IA initiation and at 6 and 12 months of follow-up were analyzed using paired statistical tests according to data type. The number of exacerbations and hospitalizations was compared using the Wilcoxon signed-rank test, whereas the presence or absence of at least one event was compared using the McNemar test. Between-group comparisons were performed using the Student t test or the Mann–Whitney U test for continuous variables, as appropriate, and the chi-square test or Fisher's exact test for categorical variables, depending on expected cell counts. Given the exploratory nature of this real-world analysis, no formal correction for multiple testing was applied.

Baseline characteristics, follow-up outcomes, and group comparisons are summarized in Table 1. During the study period, patients could have received up to 3 IAs; however, data from only 1 IA course per patient were included. Levofloxacin was predominantly used as a second-line (40.7%) or third-line (37.0%) IA, whereas in the comparison group, the most recent antibiotic available was selected, corresponding to first-line treatment in 71.9%. Among the 285 patients in the comparison group, the most frequently used IAs were colistimethate (67.7%), tobramycin (14.4%), and gentamicin (8.8%); 6 patients received a combination of agents. Patients treated with levofloxacin were younger (68 [61–75] vs 73 [64–80] years; P<.001) and more often female (66.7% vs 51.2%; P=.019). The most common underlying respiratory diseases were bronchiectasis (79% vs 100%) and chronic obstructive pulmonary disease (COPD) (24.7% vs 33.0%). P. aeruginosa was the predominant pathogen in both groups (72.8% vs 80%).

In the before–after analysis, patients treated with levofloxacin showed a significant reduction in exacerbations at 6 months compared with the year before IA initiation (median [IQR,] 2 [1–3] vs 0 [0–1]; P<.001), which was maintained at 12 months among the 57 patients completing follow-up (0 [0–1]; P<.001). Hospitalizations also decreased significantly at 6 months (0 [0–1] vs 0 [0–0]; P=.001), although the difference was not significant at 12 months (P=.3). The combined outcome (exacerbations plus hospitalizations) was significantly reduced at both 6 months (2 [1–3] vs 0 [0–1]; P<.001) and 12 months (0 [0–2]; P<.001). Compared with other IAs, reductions in exacerbations and hospitalizations were similar at both time points (Fig. 1), suggesting comparable clinical outcomes. In sensitivity analyses restricted to first-line IA use (levofloxacin n=18; others n=205), results were directionally consistent with the primary analysis; however, statistical power was limited due to the small number of patients receiving first-line levofloxacin (data not shown).

Figure 1.

Exacerbations and hospitalizations reduction between patients treated with nebulized levofloxacin and those treated with other IA.

No statistically significant differences were observed in spirometry before and after treatment, although data were available for only 61 and 166 patients, respectively (data not shown). Both groups reported similar improvements in symptoms such as sputum production and purulence (Table 1). Intolerance and overall adverse event rates were comparable (19.8% vs 20.4%). Microorganism eradication occurred more frequently in the comparison group (15.1% vs 43.2%). Among patients receiving levofloxacin, 23.0% achieved negative posttreatment cultures, 67.6% maintained the same microorganism, and 9.5% presented a different one. Resistance development was less frequent with levofloxacin (10.9% vs 24.7%; P=.046).

To our knowledge, this is the first study to report real-world outcomes of nebulized levofloxacin in non-CF CBI. In this large, multicenter registry, treatment with nebulized levofloxacin was associated with a significant reduction in exacerbations and symptomatic improvement, with a safety and tolerability profile comparable to that of other IAs. Moreover, a lower rate of antimicrobial resistance was observed, suggesting a potentially favorable resistance profile. These findings support the potential role of inhaled levofloxacin as an effective and well-tolerated therapeutic option for patients with CBI due to P. aeruginosa or other pathogens in clinical practice. Given the retrospective observational design, these findings should be interpreted as associative and hypothesis-generating rather than as evidence of comparative effectiveness.

Most available evidence on inhaled levofloxacin derives from CF studies. The phase III randomized trials MPEX-207 [13] and MPEX-209 [14] confirmed its efficacy and safety in this population. In MPEX-207 [13], levofloxacin significantly reduced sputum P. aeruginosa density and prolonged time to first exacerbation versus placebo. In MPEX-209 [14], it was noninferior to tobramycin in improving FEV1, with fewer hospitalizations and better quality-of-life scores. The proportion of patients with ≥4-fold increases in P. aeruginosa minimum inhibitory concentrations (MICs) was similar between levofloxacin and tobramycin (21% vs 17%), consistent with our observation of a lower posttreatment resistance rate in the levofloxacin group (10.9% vs 24.7%; P=.046). Our findings are also consistent with the real-world study by Schwarz et al. [18], which included 86 CF patients treated with inhaled levofloxacin and reported improvements in FEV1 (+2.27% predicted; P=.0027) and reductions in annual exacerbation rate (3.23±1.39 vs 2.71±1.58; P=.0024). Although lung function data were incomplete in our cohort, the observed reduction in exacerbations and favorable safety profile reinforce the consistency of clinical benefit across populations.

The broad-spectrum activity and favorable pharmacodynamic properties of levofloxacin likely contribute to these outcomes. In vitro data from King et al. [19] demonstrated that levofloxacin exhibited the strongest bactericidal and antibiofilm activity among several IAs (levofloxacin, ciprofloxacin, tobramycin, amikacin, and aztreonam), particularly against P. aeruginosa, Burkholderia cepacia, S. maltophilia, Achromobacter xylosoxidans, and S. aureus. In our cohort, the main pathogens were P. aeruginosa, H. influenzae, Escherichia coli, S. aureus, and S. maltophilia, suggesting that its broader antibacterial spectrum, enhanced biofilm penetration, and bactericidal effect through inhibition of DNA gyrase and topoisomerase IV – key enzymes involved in bacterial DNA replication – may contribute to the observed clinical benefits and lower frequency of resistance. However, fluoroquinolones are well known to promote antimicrobial resistance when used systemically [20], and this finding should therefore be interpreted cautiously. Importantly, microbiological follow-up in this study was relatively short, with most patients evaluated at 6 months and fewer reaching 12 months. Consequently, these results should be considered exploratory, and longer-term microbiological surveillance will be required to better characterize the ecological impact and resistance risk associated with prolonged use of inhaled levofloxacin.

In addition, its short administration time may contribute to improved treatment adherence and overall patient convenience. The safety profile of levofloxacin in our study was consistent with previous trials [21], with most adverse events being mild and respiratory in nature (mainly cough or dyspnea) and with discontinuation rates similar to those of other IAs. No severe systemic or renal adverse events were reported, supporting its safety in clinical practice.

It is important to acknowledge the limitations of this study. First, the retrospective design inherently limits causal inference and may be affected by information bias in the recording of clinical outcomes. Second, data completeness varied across centers, resulting in missing values for some variables, particularly lung function, which could not be consistently analyzed. Microbiological follow-up was not standardized, and the frequency of posttreatment cultures depended on local clinical practice, which may have influenced the assessment of bacterial eradication and resistance. In addition, treatment allocation and the line of IA therapy were determined by routine clinical judgment rather than by protocol, leading to differences in baseline characteristics between groups and raising the possibility of confounding by indication. As no multivariable adjustment was performed, comparisons between IAs should be interpreted as descriptive rather than causal. Treatment adherence and duration were not measured objectively, and residual confounding cannot be excluded. Nevertheless, the multicenter design of the INBREATHING registry and the inclusion of a large, unselected real-world cohort enhance the external validity and clinical relevance of our findings. Finally, cost-effectiveness analyses were beyond the scope of this study and would require a specifically designed prospective evaluation.

From a clinical perspective, these results suggest that nebulized levofloxacin is a safe and effective therapeutic option for patients with CBI and chronic structural lung diseases, especially NCFB, particularly those with frequent exacerbations and prior treatment with other IAs. Its broad antibacterial activity and favorable resistance profile make it a valuable component of antibiotic rotation strategies for the long-term management of chronic infection.

In conclusion, this multicenter real-world analysis suggests that nebulized levofloxacin use was associated with fewer exacerbations during follow-up and maintenance of microbiological stability in patients with CBI. Safety outcomes were comparable to those observed with other IAs, and a lower frequency of resistance was observed during follow-up in this cohort. Given the retrospective design, these findings should be interpreted as associative and hypothesis-generating rather than as evidence of causal or comparative effectiveness. Prospective controlled studies are warranted to confirm these observations and to better define the role of nebulized levofloxacin within the therapeutic algorithm for CBI.