Abstract

1. Background

Bronchiectasis is a structural respiratory disease characterized by permanently dilated bronchi. The pathogenesis consists of chronic bronchial infection, neutrophil-mediated inflammation, structural lung disease, and impaired mucociliary clearance. This pathology relapses and remits during the course of the disease, leading to increased bacterial load and recurrent exacerbations [1]. As the frequency of exacerbations increases, there is an associated reduction in the forced expiratory volume in 1 s, an increased severity of lung disease on computed tomography (CT), and an increase in chronic infection with Pseudomonas aeruginosa and Haemophilus influenza [2]. In addition, more severe and frequent exacerbations are associated with a worse quality of life, more hospital admissions, higher mortality, and increased economic burdens [3].

In a recent consensus, experienced clinicians proposed a working definition of an exacerbation of bronchiectasis for use in clinical research [4]. Most therapeutic interventions focus on reducing exacerbations to improve short- and long-term outcomes, so it is recommended practice to initiate oral or intravenous antibiotic treatment based on knowledge of the likely causative organism. Existing guidelines predominantly recommend empirical antibiotic choices based on whether P. aeruginosa is being targeted [5].

To date, the optimal duration of antibiotic treatment for exacerbations of bronchiectasis has not been systematically studied. The practice of 14 days’ therapy for infective exacerbations was extrapolated from the treatment approach used for cystic fibrosis (CF), without any definitive evidence for the approach in non-CF bronchiectasis populations. In the guidelines on non-CF bronchiectasis by the European Respiratory Society [6], the authors systematically reviewed the literature comparing short (<14 days) and long (14–21 days) treatment durations. They reported only one small study in which the outcomes were similar at 7 and 14 days [7].

We hypothesized that clinical and microbiological characteristics exist that can be associated with the optimal duration of antibiotic treatment during an exacerbation. In this study, we specifically aimed to identify the factors associated with long-course antibiotic treatment for exacerbations of bronchiectasis.

2. Materials and Methods

3. Results

3.1. Participants

Of the 283 exacerbated patients attended by the participating hospitals with exacerbations of bronchiectasis during the study period, 92 (33%) were excluded from the analysis because they did not receive antibiotic treatment, or the duration of the antibiotic treatment was not recorded. The population therefore comprised 191 patients with bronchiectasis exacerbations, of which most were women (57%; n = 108) and elderly (median age, 72 (63, 79) years). Participants were divided in the short-course group (69%; n = 132) and the long-course group (31%; n = 59) based on their antibiotic treatment duration, as decided by the attending physician (Figure 1).

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Figure 1

Chart for study enrollment.

3.4. Factors Associated with Longer Courses of Antibiotic Treatment

Univariate logistic regression analyses were performed for the main characteristics of patients at baseline and during an acute exacerbation. Several variables were significantly associated with longer courses of antibiotic treatment (Table 4). However, when all significant variables were put into the multivariable model, only three factors remained as independent associated with longer antibiotic treatment. These were the use of LTOT (OR 2.51 (95% CI 1.02 to 6.22)), the presence of a moderate to severe exacerbation (OR 3.31 (95% CI 1.26 to 8.65)), and an etiology of P. aeruginosa confirmed by microbiological isolation (OR 2.89 (95% CI 1.43 to 5.82)). The AUC was 0.73 (95% CI 0.65 to 0.80) for this final model predicting longer antibiotic treatment duration (Figure 2). Internal validation by bootstrapping with 1000 samples demonstrated robust results. All three variables remained significant after bootstrapping, with small 95% CIs around the original coefficients.

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Figure 2

Area under the receiver-operator characteristic curve for the multivariable model.

Table 4

Univariate and multivariable logistic regression analyses in predicting long-course antibiotic treatment.

Variable	Univariate			Multivariable a,b,c
	OR	95% CI	p-Value	OR	95% CI	p-Value
LTOT	3.75	1.60–8.78	0.002	2.51	1.02–6.22	0.046
FACED score			0.033	–	–	–
Mild 0–2	1.00	–	–	–	–	–
Moderate 3–4	1.60	0.78–3.27	0.20	–	–	–
Severe 5–7	2.93	1.30–6.58	0.009	–	–	–
Site of treatment: Hospital ward/Intensive Care Unit/Intermediate Care Unit	2.68	1.21–5.96	0.015	–	–	–
Moderate to severe exacerbation	4.12	1.64–10.35	0.003	3.31	1.26–8.65	0.015
Pseudomonas aeruginosa	3.76	1.94–7.29	<0.001	2.89	1.43–5.80	0.003
MRSA	6.02	1.13–31.98	0.035	–	–	–

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Abbreviations: CI, confidence interval; i.v., intravenous; LC, long-course; LTOT, Long-Term Oxygen Therapy; MRSA, Methicillin-resistant Staphylococcus aureus; MV, mechanical ventilation; OR, odds ratio. Data are shown as estimated ORs (95% CIs) of the explanatory variables in the LC group. The OR represents the odds that LC antibiotic treatment will occur, given exposure to the explanatory variable, compared to the odds of the outcome occurring in the absence of that exposure. p-values are based on the null hypothesis that all ORs relating to an explanatory variable equal unity (i.e., no effect). ^a Adjusted for center. ^b Hosmer–Lemeshow goodness-of-fit test, p = 0.35 ^c Probability of LC antibiotic treatment = Exp (β)/(1 + Exp (β)), where β = −2.543 + 0.528 (for Valencia center) + 0.922 (for LTOT) + 1.196 (for moderate to severe exacerbation) + 1.061 (for P. aeruginosa microbiology). In the presence of all these risks factors, the probability of LC antibiotic treatment was 76.2%, while in the absence of all these risk factors, the probability of LC antibiotic treatment was 7.3%.

4. Discussion

To the best of our knowledge, this is the first analysis of baseline patient, clinical, and microbiological characteristic associated with longer courses of antibiotic therapy for exacerbations of bronchiectasis. The main findings of the study are as follows. First, we showed that longer courses of antibiotic treatment were provided to patients treated with LTOT and who had a more severe disease at baseline. Second, we showed that moderate to severe bronchiectasis exacerbations lasting more days, and for which P. aeruginosa is isolated also tend to receive longer antibiotic courses. Third, we also showed that LTOT, moderate to severe exacerbations, and microbiological isolation of P. aeruginosa were associated with the need for longer courses of antibiotic treatment. These three aspects could help us to detect those patients with an exacerbation who require a longer course of antibiotic treatment.

The optimal duration of either oral or intravenous antibiotic therapy has not been studied for non-CF bronchiectasis, with current practice extrapolated from that used for CF. In the absence of any direct data comparing long and short courses, 14 days of treatment continues to be recommended in guidelines [2,15,16]. Some authors [17,18] have demonstrated a favorable impact with 14 days of intravenous antibiotic therapy for exacerbations, with improvements shown in sputum bacterial volume, markers of inflammation, the incremental walk test, and the St. George’s Respiratory Questionnaire. However, spirometry results remained unchanged. Collaco et al. [19] also observed that patients with CF who received longer courses of intravenous antibiotics tended to have worse lung function and they demonstrated that the greatest improvement in lung function may occur within the first week of therapy, indicating that courses lasting 14–21 days may provide no additional benefit.

Consistent with the recent guideline of the British Thoracic Society [20], we observed that patients treated with longer courses of antibiotics presented with more markers of severe disease than patients treated with shorter-term therapy. When we assessed the two main severity scores, the FACED score was milder in the short-course group and more severe in the long-course group. In the supplementary analysis, we showed that a moderate and a severe FACED score were independent factors associated with longer antibiotic treatment for patients with a bronchiectasis exacerbation without a diagnosis of community-acquired pneumonia. By contrast, no differences were found for the BSI score. FACED is an easy-to-use system that incorporates five dichotomized parameters to classify severity according to its 5-year prognosis [11]. Rosales et al. [21] demonstrated that severity stratified by FACED and BSI scores can show relevant differences in patient distribution.

Concerning the microbiological results, we showed that prior chronic colonization with P. aeruginosa or etiologic isolation during a bronchiectasis exacerbation influenced the need for prolonged antibiotic treatment. Recently, Crisafulli et al. [22] also demonstrated that P. aeruginosa affected the length of hospitalization during exacerbations of COPD. We could explain the longer exacerbation and hospitalization durations of our patients in the long-course group by P. aeruginosa isolation in 31.4% of cases. It was also possible to explain the initial use of three or more antibiotics in 15 patients from the long-course group by the isolation of multidrug resistant P. aeruginosa in 15.2%.

Univariate analysis of the main characteristics at baseline and during exacerbations revealed several variables that were significantly associated with longer courses of antibiotic treatment. However, the multivariate analysis only confirmed that LTOT, the presence of a moderate to severe exacerbation, and the microbiological isolation of P. aeruginosa during an exacerbation were significant associated with longer treatment durations. In recent study, Sundh et al. [23] concluded that LTOT prescribed for 24 h each day did not decrease hospital admissions compared therapy for just 15–16 hin patients with oxygen-dependent COPD. Together with our finding, this could indicate that LTOT usage is associated with considerable healthcare costs. On the other hand, we can say that LTOT is a clinical factor that reflect disease severity. Previous studies have shown that P. aeruginosa isolation in bronchiectasis patients was associated with accelerated loss of lung function and increased daily sputum production [24], as well as a poorer quality of life, regardless of whether it is a cause or consequence of functional deterioration [25]. The findings of our study also suggest that longer antibiotic treatment during exacerbations is appropriate for patients with P. aeruginosa infection (with and without diagnosis of community-acquired pneumonia), consistent with the latest recommendations of the British Thoracic Society [20].

Finally, when we repeated all regression analyses after excluding patients with a diagnosis of community-acquired pneumonia, we found that the presence of arrhythmia as comorbidity at baseline appear a factor negatively associated with long-term therapy. A potential explanation is that attending physicians tended to shorten the course of antibiotic therapies to avoid cardiac complications in patients with a baseline arrhythmic comorbidity, or it could simply be a random response without any clinical significance. Future studies addressing the impact of vascular disease on bronchiectasis exacerbations are desirable.

The strengths of our study are the prospective inclusion of consecutive patients in two centers, the inclusion of clinically relevant variables, and the long-term follow-up. The study provides important preliminary evidence on which recommendations for decisions about antibiotic treatment durations for exacerbations of bronchiectasis can be based. However, the study also has somemain limitations. First, there is a significant imbalance between patients treated with longer coursesas compared to shorter courses. Second, the microbiological study was performed during an exacerbation and we did not establish whether the identified microorganisms were responsible for prior chronic bronchial infection. Third, we could not perform a complete microbiological study in all cases, despite almost all patients providing at least one respiratory sample. Fourth, the present study was not powered to detect differences in mortality rates because this was not a study goal. Nevertheless, based on the 1-year follow-up results, we speculate that duration of antibiotic treatment does not affect the mortality rate.

5. Conclusions

In conclusion, LTOT use, the presence of a moderate to severe exacerbation, and microbiological isolation of P. aeruginosa each are associated with the need for a longer course of antibiotic therapy during bronchiectasis exacerbations. Patients receiving longer courses of treatment also tend to have more severe disease, colonization with P. aeruginosa, and a history of worse outcomes in terms of previous hospitalizations. Accordingly, decisions about the duration of antibiotic therapy should be guided by complete clinical and microbiological assessments of patients when they present with an acute exacerbation. Our study is really the reflection of clinical practice and if on the one hand it has a potential bias in the process of treatment decision-making, on the other it provides insights into a subset of exacerbated patients who could benefit from longer antibiotic treatment. However, more evidence is still needed to support clinic decision-making. Studies are currently underway to determine the optimal length of treatment in CF, and similar studies are needed for patients with non-CF bronchiectasis.

Abbreviations

Supplementary Materials

The Supplementary Materials are available online at https://www.mdpi.com/2077-0383/8/11/1950/s1.

Author Contributions

A.T. is the guarantor of the paper; G.S. and R.A. designed the study; G.S., R.A., V.A.-S., and P.O. contributed to the clinical and laboratory work for the study; A.T., G.S., R.A., A.G., and M.P.F.B. drafted the article and revised it critically for important intellectual content; A.T., G.S., R.A., V.A.-S., R.M. and R.M. contributed to final approval of the version to be published; all authors read and approved the final manuscript.

Funding

None declared.

Conflicts of Interest

None declared.

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