Risk factors for multidrug-resistant pathogens in bronchiectasis exacerbations

Multidrug-resistant (MDR) pathogens are a worldwide health threat with clinical negative consequences if inadequately recognized and treated. Non-cystic fibrosis bronchiectasis (BE) is a chronic structural lung condition that facilitates chronic colonization by microorganisms and courses with frequent exacerbations and recurrent infections. [1, 2] This means that patients receive numerous courses with broad-spectrum antibiotics, making them more likely to acquire MDR pathogens.

The main pathogens involved in chronic colonization and acute exacerbations are Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas aeruginosa, and, to a lesser extent, Enterobacteriaceae. The incidence and spread of MDR microorganisms among BE patients is worrisome because the antibiotic arsenal is scarce and the most threatening potential MDR pathogens in respiratory patients include P. aeruginosa and extended-spectrum betalactamase (ESBL) Enterobacteriaceae. These pathogens are difficult to treat because they require different antibiotic regimens to those usually recommended in guidelines.

To our knowledge, no prospective studies have been aimed at identifying independent risk factors for MDR pathogens in BE exacerbations. [3, 4] We hypothesized that MDR exacerbations depend on patient characteristics, including usual treatments and prior health contacts, and that knowledge of these factors may be useful for reducing inappropriate antibiotic treatment.

The aim of our study was to investigate risk factors associated with isolation of multi-drug resistant microorganisms in bronchiectasis exacerbations and their clinical impact on outcome.

We conducted a prospective and observational study of adult patients with bronchiectasis attended in the specialized clinic of two tertiary care university hospitals during the period 2011–2015. In our specific specialized clinic, patients are referred from primary care, other hospitals, other specialties or any other medical facilities. We confirmed the diagnosis of bronchiectasis by computerized tomography scan of lungs along with compatible symptoms and aetiology of bronchiectasis had been investigated according to Spanish guidelines [5] previous to study recruitment. Local committees approved the study and patients gave written informed consent (Biomedical research ethics committee Hospital La Fe 2011/0342).

Patients were enrolled in the study when they presented the first exacerbation (after signing the informed consent) and required new antibiotic treatment or hospital admission and no subsequent exacerbations for every patient were included. Exclusion criteria were: a) severe immunosuppression, such as in solid-organ or bone-marrow transplantation or HIV/AIDS, or receiving chemotherapy or other immunosuppressive drugs (≥20 mg prednisone-equivalent per day for 2 weeks or more); b) active tuberculosis; c) cystic fibrosis (CF); d) pulmonary interstitial disease and e) hospitalization in the preceding 21 days.

The most notable findings of our study are the following: 1. MDR pathogens are frequently (20.1%) isolated in BE exacerbations, with a higher proportion among hospitalized patients (24.5%); 2. The principal MDR microorganisms were Pseudomonas (46%), MRSA and ESBL+ Enterobacteriaceae; 3. Independent MDR risk factors were prior MDR isolation, hospitalization in the previous year and chronic renal disease.

Due to the structural changes in permanently dilated airways, bronchiectasis courses with recurrent infections and exacerbations. Pathogens involved depend on several aspects: lung function, advanced phase of the disease and patient comorbidities. [1, 2, 12] However, little is known regarding frequency and factors associated with isolation MDR at exacerbations [13].

We found that in 20% of exacerbations MDR pathogens were isolated and the most frequent were Pseudomonas, MRSA and ESBL+ Enterobacteriaceae. We evaluated resistance using conventional methods usually performed in daily routine and we don’t perform automated methods or clonal analysis of resistance. [14] The percentage and spectrum of MDR is more similar to nosocomial than to community-acquired infections, in line with the current approach to those problematic pathogens based on host characteristics and prior treatments, [3, 13, 14] and slightly higher than that reported by McDonnell et al. [15] In fact, MDR exacerbations occurred in elderly patients with a higher proportion of comorbid conditions, indicating associations with more debilitating diseases, requiring more contacts with health resources. Our results showed that the use of prior inhaled antibiotics and long-term oxygen therapy was greater in patients with MDR pathogens. Interestingly, no differences were found with regard to the use of bronchodilators or inhaled corticosteroids. Metersky et al. [16] have reported that, in health-care associated pneumonia, inhaled corticosteroids were associated with Pseudomonas etiology, although they found no association with resistance.

The spectrum of microorganisms identified, [17] whether treated as outpatients or in hospital, was similar except for the fact that MDR was barely encountered in outpatients. [18] The fact that MDR exacerbations were more frequently admitted is clinically relevant because exacerbations that require hospitalization have been reported to be associated with an increase in 1-year mortality. [19]

In our study, we found three independent MDR risk factors: renal disease, prior MDR isolation and hospitalization in the previous year. Chronic renal disease is a recognized MDR risk factor, as reported in pneumonia studies. [3] Shindo et al., [20] identified 6 independent MDR risk factors, regardless of whether the patient has health-care associated or community-acquired pneumonia, suggesting that risk factors relied more on host factors than on the setting of infection. Prior hospitalization is a fairly widely recognized independent MDR risk factor and specifically for MRSA, [21] and for Enterobacteriacea mainly related to exposure to III/IV generation of cephalosporins or broad-spectrum penicillins. [22]

Prior MDR isolation was independently associated with a higher risk of MDR exacerbation. In our cohort, approximately 50% of patients had chronic Pseudomonas infection, [23] reflecting the most severe patients seen in a specific BE clinic. Prior MDR colonization is a recognized risk factor for MRSA [24, 25] and for Pseudomonas [26] in COPD patients. We found that 40% of patients with MDR exacerbations had prior isolation with the same microorganism.

The proportion of MDR exacerbations was higher among those patients with higher FACED and BSI scores, as expected in more advanced BE disease, with more proportion of exacerbations and hospitalizations. Almost 80% of MDR exacerbations occurred in patients with higher punctuations in prognostic scales such as FACED or BSI whereas MDR in mild scales were lower 6.2% and 40.6% respectively. However, after entering in the model other independent factors, these scales are not remaining independently associated with multi-drug resistance.

With regard antimicrobial susceptibility, MDR exacerbations received less appropriate treatment than non-MDR, thus also requiring more changes in antibiotic regimens although without statistical differences. In fact, the choice of initial treatment was microbiological suitable in 75% of cases, probably because physicians took into consideration prior MDR colonization, [27] a policy that is supported by our findings. Currently, factors considered in the antibiotic selection include extent of the disease, severity, local resistance patterns, and prior culture results. [28] A practical conclusion is that extended-spectrum antibiotics against MDR could be withdrawn in patients with no risk factors and indicated if 2 or more risk factors are present. Where 1 risk factor is present, an extended-spectrum antibiotic may be indicated until MDR pathogens have been ruled out; a microbiological work-up should therefore be implemented. [29] Nevertheless, these recommendations need to be validated in different populations or BE subsets [30] and knowledge of local resistance rates and colonization rates should be considered. This policy may contribute to containing broad-spectrum coverage for MDR in unnecessary episodes and this strategy may contribute to curbing the future emergence of resistant microorganisms in this population.

Patients with MDR exacerbations required more hospitalizations and greater use of antibiotics although without longer hospital stay. In general, MDR infections have been associated with a higher number of days of hospitalization, [31] with higher antibiotic requirements, more hospitalization, [32] more use of health resources, with the attendant higher costs, and may eventually have a negative impact on prognosis. [33] Nevertheless, we consider that one-year follow-up could be insufficient for evaluating the potential clinical impact of MDR exacerbations and probably for that aim more subsequent exacerbations should be assessed.

Our findings have identified three independent risk factors - hospitalization in the previous year, chronic renal disease, and prior multidrug-resistant isolation- for identification multidrug-resistant pathogens in BE exacerbations. This information may be useful for clinicians in guiding initial antibiotic therapy in exacerbations of BE. A further validation in different BE cohorts including distinct phenotypes and larger follow-up periods should be performed. MDR risk prediction in BE exacerbations is a new field that requires validation for clinical decision-making in selecting initial appropriate antibiotics and for safely avoiding anti-MDR coverage.