Pharmacotherapy for lower respiratory tract infections

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Liapikou Adamantia† & Antonio Torres †

Sotiria Hospital, 6th Respiratory Department, Athens, Greece




Pharmacotherapy of LRTIs




Expert opinion

Introduction: Bacterial infections play an important role as etiological agents in acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and exacerbations of non-cystic fibrosis (CF) bronchiectasis. In acute bronchitis and asthma exacerbations their role is less well defined than with patients with COPD. The clinical features, causative pathogens and therapies of common acute respiratory tract infections are detailed in this review. Areas covered: This article covers medical literature published in any language from 2000 to 2014, on ‘lower respiratory tract infections’, identified using PubMed, MEDLINE and The search terms used were ‘COPD exacerbations’, ‘bronchiectasis’, ‘macrolides’ and ‘inhaled antibiotics’. Expert opinion: Given that almost half of AECOPD are caused by bacteria, administration of antibacterial agents is recommended for patients with severe exacerbations or severe underlying COPD. Chronic prophylactic use of macrolides seems to be of benefit, particularly in patients with bronchiectasis and chronic mucous hypersecretion. In an effort to manage chronic airway infection non-CF bronchiectasis due to drug-resistant pathogens, aerosolized antibiotics may be of value, and the data from recent studies are examined to demonstrate the potential value of this therapy, which is often used as an adjunctive measure to systemic antimicrobial therapy. Keywords: acute bronchitis, inhaled antibiotics, macrolides, non-cystic fibrosis bronchiectasis Expert Opin. Pharmacother. [Early Online]



The Global Burden of Disease Study found that respiratory tract infections today remain one of the top 10 causes of morbidity and mortality in adults and children worldwide, and various risk factors propagate them [1]. Lower respiratory tract infections (LRTIs) can be divided into those that affect the airways, giving rise to bronchitis, and those that give rise to pulmonary parenchymal inflammation in the form of pneumonia. The management of pneumonia will be beyond the scope of this review. LRTIs consisting of acute bronchitis, acute exacerbations of chronic obstructive pulmonary disease (AECOPD), bronchiectasis and asthma can range in severity from a mild short-lived episode in an otherwise healthy person to a severe lifethreatening illness. About 90% of antimicrobial consumption occurs in community respiratory infections, which remain the leading cause of antibiotic prescription. Antibiotic treatment for AECOPD and non-cystic fibrosis (CF) bronchiectasis is mainly empirical, based on the severity of the acute illness and the history of the pulmonary disease (number of exacerbations, microbial colonization), leading to first- or second-line antibiotic choices, according to published guidelines and resistance patterns. Maintenance treatment with low-dose macrolides such as erythromycin and azithromycin provides clinical benefit in several chronic neutrophilic airway diseases,

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L. Adamantia & A. Torres

Article highlights. .


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Respiratory viruses appear to be the most common cause of acute bronchitis; antimicrobial agents should not be prescribed in acute bronchitis. In AECOPD and in exacerbations of bronchiectasis, an assessment of severity of the exacerbation and the disease and decision about whether to treat the patient in the community or in hospital are required. Long-term treatment with macrolides can be considered in patients with severe COPD and frequent exacerbations or hospital admissions, despite optimal pharmacologic and non-pharmacologic treatment. In non-CF bronchiectasis prolonged antibiotic therapy (oral or nebulized) recommended in any of the following situations: three or more recurrent exacerbations per year or chronic colonization by Pseudomonas species, especially resistant species.

This box summarizes key points contained in the article.

including CF, diffuse panbronchiolitis, non-CF bronchiectasis and exacerbation-prone COPD. This article reviews the key components of the antimicrobial treatment of airway disease (acute bronchitis, COPD, non-CF bronchiectasis, asthma), both acute and chronic, with an emphasis on those recent studies that are likely to change practice in the next few years. 2.

Pharmacotherapy of LRTIs

Acute bronchitis Acute bronchitis is inflammation of the large conducting airways which affects adults and children without underlying pulmonary disease. The European Respiratory Society (ERS) defines acute bronchitis as an acute illness with cough, productive or not, associated with symptoms or clinical signs of LRTI (sputum production, wheeze, dyspnea, chest discomfort). Clinical features of acute bronchitis include headache, myalgias and malaise [2]. It is one of the most common diagnoses made by primary care clinicians and emergency department physicians. The disorder affects ~ 5% of adults annually, with a higher incidence observed during the winter and fall than in the summer and spring [3]. 2.1

Microbiology Respiratory viruses appear to be the most common cause of acute bronchitis; however, the organism responsible is rarely identified in clinical practice because viral cultures and serological assays are not routinely performed. Those isolated in acute bronchitis (from the most to the least common in large series) include influenza A and B viruses, parainfluenza virus, respiratory syncytial virus (RSV), coronavirus, adenovirus and rhinovirus (RV). Human metapneumovirus has also been identified as a causative agent [4]. The yield of specific pathogens varies according to several factors, including the presence 2.1.1


or absence of an epidemic, the season of the year and the influenza vaccination status of the population. Bacterial etiologies include Haemophilus influenzae, Streptococcus pneumoniae and Branhamella catarrhalis. B. catarrhalis bronchitis is associated with impaired host defenses and is commonly seen in cigarette smokers [5]. Mycoplasma pneumoniae, Chlamydophila pneumoniae and Bordetella pertussis are rare etiological agents; they are isolated in 5 -- 10% of cultures of the acute bronchitis in adults [6] and up to 20% of patients present with more prolonged duration of cough. Some data have suggested that B. pertussis may underlie 13 -- 32% of cases of cough lasting ‡ 6 days, although in recent prospective studies, B. pertussis comprised only 1 -- 6% of cases of acute bronchitis [7,8]. Treatment The treatment of acute bronchitis is broken down into two categories: symptom management and antimicrobial therapy. 2.1.2

1) Supportive therapy with analgesia, antipyretics, adequate hydration and assistance with expectoration of viscid secretions may be required. Cough suppressants, expectorants, antihistamines, inhaled corticosteroids and bronchodilators should not be prescribed in acute LRTI in primary care. Antitussive agents are only occasionally useful, and there is no routine role for inhaled bronchodilators or mucolytic agents [9,10]. 2) Antimicrobial agents should not be prescribed in acute bronchitis in otherwise normal persons in the absence of bacterial infection [10]. But in clinical practice, as indicated in a recent study from the USA [11], 91% of patients diagnosed with acute bronchitis were treated with antibiotics. In a study of > 3000 adults with LRTI, Butler et al. [12] observed that patients with purulent sputum were prescribed antibiotics 3.2 times more frequently, but that this was of no benefit in terms of symptomatic improvement, regardless of sputum color. In a randomized clinical trial, based on the GRACE study data [13], including 16 networks in 12 different European countries, with 2061 patients > 18 years old assigned to either amoxicillin 1 g or placebo taken thrice daily, neither duration of symptoms rated ‘moderately bad’ or worse nor mean symptom severity differed significantly between groups. Although antibiotics are not recommended, they may be considered in some situations: i) in patients > 65 years of age with comorbidities such as heart failure, renal failure, hepatic failure, diabetes mellitus, serious neurological disorders; ii) in immunocompromised patients; and iii) when a specific pathogen is suspected [10]. Where pertussis is suspected, both the ACCP guidelines and guidelines of the Centers for Disease Control and Prevention recommend macrolides as first-line therapy for B. pertussis [9]. From a Cochrane review including 11 trials, short-term antibiotics (azithromycin for 3 -- 5 days or clarithromycin or

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Pharmacotherapy for LRTIs

erythromycin for 7 days) were as effective as long-term (erythromycin for 10 -- 14 days) antibiotics in eradicating B. pertussis from the nasopharynx but had fewer side effects. The best regimen was azithromycin in a 3-day course of 10 mg/kg/day [14]. Anti-influenza agents such as the neuraminidase inhibitors (including oseltamivir and zanamivir) decrease the duration of symptoms by ~ 1 day and result in an earlier return to normal activity (by 0.5 day) among patients with infections caused by susceptible viruses. Antimicrobial therapy may be more beneficial when a treatable pathogen is identified than when a treatable pathogen is not identified. Acute exacerbations of COPD The chronic and progressive course of COPD is often aggravated by AECOPD, which is the most frequent cause of hospital admissions and death among patients with COPD. AECOPD is defined as an acute change in the baseline clinical status of the patient beyond the daily variability, which presents with increased dyspnea, increased volume of purulent sputum or any combination of these symptoms, and which requires a therapeutic change [15]. Approximately 70% of exacerbations of COPD (ECOPD) are caused by respiratory infections including bacteria (40 -60%), viruses (about 30%) and atypical bacteria (5 -- 10%) [16,17]. The most common viruses detected in airway secretions in exacerbation are RV, influenza, RSV, parainfluenza and adenovirus. Viral infections may facilitate subsequent bacterial infection or increases in the numbers of bacteria already colonizing the lower airways. Although viral infection may be self-limiting, secondary bacterial infection may prolong exacerbations [18]. It has been shown that up to 25% of patients with COPD in the stable phase present bacterial colonization, mainly attributable to H. influenzae, S. pneumoniae and Moraxella catarrhalis. The increased risk of colonization has being associated with a lower forced expiratory volume in the first second of expiration (FEV1) percentage and the persistence of smoking [19]. At present, pathogens clearly implicated in COPD exacerbations are nontypeable H. influenzae, S. pneumoniae, M. catarrhalis and Pseudomonas aeruginosa. Nontypeable Haemophilus influenza is the most common pathogen and its role is well investigated and the acquisition of new strains of pathogenic bacterial species to which the patient is susceptible has been linked to AECOPD [20]. It has also been observed that the severity of lung function, measured by FEV1, has an impact on the microbiology of exacerbation. In patients with mild disease, S. pneumoniae predominates, whereas those with greater impairment of lung function show a higher proportion of H. influenzae and P. aeruginosa as lung function deteriorates [20,21]. In patients with increased airway obstruction and frequent exacerbations, the microbiology of the exacerbations is often more complex, with a predominance of Enterobacteriaceae and P. aeruginosa [22]. 2.2

Moreover, patients with COPD are exposed to frequent antibiotic courses and they are more likely to be infected with antibiotic-resistant pathogens, making empiric antibiotic choices challenging. In a study of hospitalized patients with COPD with community acquired pneumonia, more infections attributable to P. aeruginosa were observed [23]. Therapy of AECOPD Treatment with appropriate antibiotics significantly decreases the bacterial burden (and frequently eradicates sensitive organisms) and reduces clinical failure and the risk of progression to more severe infections, such as pneumonia. The European Guidelines on LRTI [10] recommend antibiotics in ECOPD in patients with all three of the following symptoms: increased dyspnea, sputum volume and sputum purulence. In addition, antibiotics should be considered for exacerbations in patients with severe COPD and in patients who require invasive or noninvasive ventilation [24]. The study by Anthonisen et al. [25] is the most important study showing the beneficial effect of antibiotic treatment in AECOPD. The authors grouped patients by clinical symptoms: increased dyspnea, increased volume and increased purulence of sputum. Class I included patients who met all three criteria, class II included patients with only two of the criteria and class III included patients with just one of the criteria. Recent studies have shown a clear relationship between sputum purulence and the presence of bacteria [16,26]. A systematic review of the very few available randomized placebo-controlled studies has shown that antibiotics reduce the risk of short-term mortality by 77%, treatment failure by 53% and sputum purulence by 44% in hospitalized patients with AECOPD [27]. Additionally, in a retrospective cohort study of hospitalized AECOPD patients involving 84,621 patients, it was found that early antibiotic administration (first 2 days) was associated with improved outcomes [28]. The selection of antibiotics in AECOPD exacerbations is based on: i) the probability of bacterial etiology of the exacerbation; ii) the severity of the underlying disease (FEV1 and > exacerbations/year); iii) the presence of comorbidities (especially cardiac disease); iv) the presence of risk factors of relapse; and v) the pattern of antibiotic resistance. Recent antibiotic use (within the previous 3 months), as well as recent hospitalization and the use of oral corticosteroids (> 10 mg of prednisone daily in the previous 2 weeks) places the patient in a high-risk group for harboring antibiotic-resistant pathogens. Table 1 shows the classification of AECOPD into groups and the recommended therapy. The first group of patients (group A) presents with > 2 Anthonisen criteria, but generally has only mild-to-moderate impairment of lung function (FEV1 > 50% of predicted value), no comorbidities and < 3 exacerbations/year. The combination of amoxicillin--clavulanic acid is appropriate for this group, and in high doses (875/125 mg/sample) it is 2.2.1

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L. Adamantia & A. Torres

Table 1. Therapy of AECOPD. Group A B

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Oral treatment


Mild COPD without comorbidity Moderate-to-severe COPD without risk factors of P. aeruginosa

Amoxicillin--clavulanic acid Amoxicillin--clavulanic acid

Macrolide; levofloxacin; moxifloxacin Levofloxacin; moxifloxacin



Moderate-to-severe COPD with risk factors of P. aeruginosa

Parenteral treatment

Amoxicillin--clavulanic acid, second- or thirdgeneration cephalosporin, levofloxacin, moxifloxacin Ciprofloxacin or b-lactam with P. aeruginosa activity +/- aminoglycosides

*Levofloxacin 750 mg/24 h or 500 mg twice daily. COPD: Chronic obstructive pulmonary disease.

appropriate to obtain efficacy for strains of pneumococcus resistant to penicillin. The second group of patients (group B) is characterized by the presence of additional risk factors of treatment failure, which include moderate-to-severe lung function impairment (FEV1 > 35 to < 50% of the predicted value) and/or significant comorbidity (e.g., cardiac disease, diabetes, hepatic/renal insufficiency) and/or frequent exacerbations (> 3 year). They can be treated with oral amoxicillin--clavulanic acid (with high doses of amoxicillin) and non-antipseudomonal thirdgeneration cephalosporins such as ceftriaxone or cefotaxime. Quinolones should be considered as first-line treatment (levofloxacin and moxifloxacin), as they are active against Gram (-) bacilli other than P. aeruginosa. The third group of patients (group C) included patients with moderate or severe exacerbated COPD (FEV1 < 50%) with risk factors of P. aeruginosa. The treatment of these patients includes the administration of fluoroquinolones (ciprofloxacin or a high dose of levofloxacin). An aminoglycoside (tobramycin or amikacin) may also be added in the first 3 -- 5 days. The moxifloxacin in acute exacerbations of chronic bronchitis trial (MAESTRAL) compared the use of moxifloxacin (400 mg/day for 5 days) versus amoxicillin--clavulanate (875/125 mg twice daily [b.i.d.] for 7 days) in outpatient AECOPD, demonstrating the noninferiority of moxifloxacin to amoxicillin--clavulanate in the treatment of AECOPD [29]. The standard duration of antibiotic administration in AECOPD was used to be 10 days. Clinical studies have demonstrated comparable, and in some cases, superior efficacy for short-course, 5-day fluoroquinolone therapy compared with standard therapy in AECOPD, as measured by both clinical and bacteriological outcomes [30]. Long-term antibiotic therapy in stable COPD The frequency of current use of long-term antibiotics for the prevention of AECOPD in clinical practice is unknown [31]. A number of studies have evaluated whether long-term antibiotic (especially macrolide) treatment decreases the risk of AECOPD, with conflicting results. In the past decade, six 2.3


studies showing the use of continuous long-term antibiotics in patients with COPD [32-35] and one employing intermittent/pulsed treatment have been published [36]. However, these studies were limited by small patient numbers, use of low doses of narrow spectrum antibiotics and inadequate efficacy measurements. Macrolides administered at low doses, mainly for their immunomodulatory and anti-inflammatory activities rather than bactericidal/bacteriostatic effects, in stable patients with severe COPD have been shown to significantly reduce the number of exacerbations [33,37]. The immunomodulatory effects of macrolides include reduced sputum and antimicrobial peptide production, inhibition of biofilm formation and reduced production of different virulent factors, although antiviral effects have recently been reported. The difference should be made with the anti-infective approach used in treating chronic colonization with bacteria such as P. aeruginosa, which, in some instances, can be long-term. Seemungal et al. [35], in a randomized DPBC study of 109 patients, administered erythromycin 250 mg b.i.d. to patients with moderate COPD (80% of patients on inhaled corticosteroids) over 12 months. They found that erythromycin treatment was associated with a significant reduction in exacerbations compared with placebo but had no significant impact on FEV1, sputum inflammatory markers, serum inflammatory markers or bacterial flora. In a randomized study by Alberts et al. [32], involving 1577 patients, treatment with azithromycin (250 mg/day) for 1 year lowered the risk of an exacerbation by 27% and improved quality of life (QoL) by 2.8 points on the St George’s respiratory questionnaire. But long-term therapy with antibiotics, particularly with macrolides, is associated with significant side effects and the risk of developing bacterial resistance [32,38] not only affecting the treated patients but also adversely affecting community macrolide resistance. Another antibiotic studied in the treatment of stable COPD is moxifloxacin, due to its antibacterial effectiveness. The use of quinolones during periods of stability has been shown to eradicate bacteria in sputum in most patients with severe COPD and frequent exacerbations. In the study by

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Pharmacotherapy for LRTIs

Sethi et al. [36], moxifloxacin was given once daily for 5 days, and the treatment was repeated every 8 weeks for a total of six courses. Pulsed therapy with moxifloxacin reduced the odds of an exacerbation by 25% in the primary population for efficacy analysis (per protocol population, as prespecified in the protocol) in patients with moderate-to-severe COPD, whereas a post hoc analysis found this reduction to be 45% in patients with purulent or mucopurulent sputum at baseline. The recent Spanish guidelines for COPD [37] suggest that long-term treatment with macrolides can be considered in patients with severe COPD and frequent exacerbations or hospital admissions, despite optimal pharmacologic and non-pharmacologic treatment, and always with accurate clinical and bacteriological control in reference centers. Some questions remain unanswered in this regard: it is not clear which is the best antibiotic, whether it is better to use the same drug or rotate different antibiotics, which is the best dose for macrolides, and, once started, what the duration of treatment should be. And, of course, we have to define the right regimen in terms of avoiding the emergence of resistance. Inhaled antibiotics Inhaled antibiotics are likely to have a future role in the longterm management of patients with COPD, because this route of administration has the ability to target drug delivery directly to the respiratory tract, reducing systemic exposure and maximizing pharmacodynamic parameters. To date, there has been only one study [39] investigating the use of inhaled antibiotics in patients with severe COPD colonized with P. aeruginosa. Two-week treatment with inhaled tobramycin nebulizer solution (TNS) resulted in a substantial reduction from baseline of proinflammatory chemotactic mediators and also led to a 42% decrease in the incidence of exacerbations, when compared to the 6-month period prior to initiating TNS therapy. Ongoing and future trials using inhaled powder formulation of antibiotics (quinolones) will provide information as to whether inhaled antibiotics are a useful therapeutic option in the prevention of AECOPD.

increasing frequency, and cultures for these germs should be obtained annually and whenever there is unexplained clinical deterioration. In a study of 100 patients with steady-state bronchiectasis, the presence of P. aeruginosa in the sputum was associated with a lower FEV1:FVC ratio (60 vs 72% in the absence of a pathogenic microorganism) and higher volume of daily sputum production [40]. Approximately 30% of patients are chronically colonized with and exacerbate because of P. aeruginosa; thus, identifying this pathogen is important in directing therapy for future exacerbations [41]. Treatment Antibiotic therapy, elimination of secretions and the treatment of associated bronchospasm form the basis of the approach to managing exacerbations. Antibiotic therapy is generally indicated when the patient has an acute exacerbation of symptoms characterized by an increase in cough, change in quantity or quality of sputum, dyspnea, fever and malaise. Ideally, a sputum culture should be submitted to the microbiology laboratory before initiation of antibiotic therapy.


Exacerbations of non-CF bronchiectasis Patients with non-CF bronchiectasis are commonly infected with microorganisms that contribute to the chronic cycle of infection and inflammation that may ultimately lead to progressive airway and lung parenchymal dysfunction in patients with features suggestive of bronchiectasis, an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnea, and/or cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management [10]. 2.3.2

Microbiology The microorganisms that most often colonize bronchiectasis are nontypeable H. influenzae and P. aeruginosa. M. catarrhalis is also seen, as well as S. pneumoniae and Staphylococcus aureus. Nontuberculous mycobacteria are isolated with

Inhaled antibiotics Empiric therapy can be chosen based on the patient’s prior culture history and the potential risk of P. aeruginosa infection. The antibiotic should be changed in accordance with the microorganism isolated from sputum collected during the exacerbation, based on an antibiogram [10]. Antibiotics that penetrate respiratory secretions well should be used at high doses. Mild exacerbations can be treated orally on an outpatient basis, whereas intravenous delivery is required for severe exacerbations, chronic bronchial infection by microorganisms resistant to oral antibiotics and whenever there is no response to oral antibiotic therapy [42]. Patients with milder disease (FEV1 > 60% predicted) and relatively low volume of daily sputum production (< 20 ml/ day) can be started on a nonpseudomonal antibiotic; those with more severe disease should be empirically treated with an antipseudomonal agent pending culture results (Table 2). Particularly: 2.3.3

1) If there is no previous bacteriology, first-line treatment is amoxicillin/clavulanic 2 g twice day [10]. Alternatives are moxifloxacin 400 mg/day or levofloxacin 750 mg/day. 2) High-dose oral regimens (e.g., amoxicillin 1 g three times a day) may be needed in patients with severe bronchiectasis chronically colonized with H. influenzae. 3) Ciprofloxacin (750 mg/ 12 h) or levofloxacin (750 mg/ 24 h) should be used in patients colonized with P. aeruginosa with cautious use in the elderly [40,42] or an antipseudomonal b-lactam by intravenous route. The antibiotics should be administered until the sputum is no longer purulent or for at least 10 days. In cases of Pseudomonas infection, intake should continue for 14 -- 21 days.

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L. Adamantia & A. Torres

Table 2. Therapy of exacerbations of non-CF bronchiectasis [42].

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First-line treatment


Mild exacerbation

Amoxicillin--clavulanic acid: 875/125 mg every 8 h, oral

Pseudomonas species Severe exacerbation Pseudomonas species

Ciprofloxacin: 750 mg/12 h, oral Amoxicillin--clavulanic acid: 1 -- 2 g/8 h, i.v. Ceftazidime: 2 g/8 h, i.v. + tobramycin: 5 --10 mg/kg/24 h, i.v. or amikacin: 15 -- 20 mg/kg/24 h, i.v.

Amoxicillin: 1 -- 2 g/8 h, oral; ciprofloxacin: 750 mg/12 h, oral; or azithromycin: 500 mg/24 h, oral Levofloxacin : 750 mg/24 h, oral Ceftriaxone: 2 g/24 h, i.v. Imipenem: 1 g/8 h; piperacillin-tazobactam: 4 g/8 h; aztreonam: 2 g/8 h; cefepime: 2 g/8 h; meropenem: 2 g/8 h; or ciprofloxacin : 400 mg/12 h, i.v. + amikacin: 15 -- 20 mg/kg/24 h, i.v.

CF: Cystic fibrosis; i.v.: Intravenous.


Combination antibiotics

Combination antibiotics should be used for infections due to strains of P. aeruginosa that are resistant to one or more antipseudomonal antibiotic (including ciprofloxacin) or if the clinician suspects that the patient will require many subsequent antibiotic courses to reduce the development of drug resistance. Intravenous aminoglycosides should only be used with appropriate and robust dosing and with monitoring systems in place that have been agreed with local microbiologists and pharmacists [42]. Inhaled antibiotics Inhaled antibiotics are a useful tool in the management of chronic infection with P. aeruginosa in the setting of CF. The theoretical advantages include the high concentration of antibiotic delivered into the airway and reduced systemic absorption and systemic side effects. Bilton et al. [43] evaluated the role of inhaled antibiotic therapy (tobramycin) in addition to oral ciprofloxacin in acute exacerbations of bronchiectasis due to P. aeruginosa; that trial showed improved microbiological outcomes with combination therapy but no additional clinical benefit. Further studies are needed to answer the efficacy of a combined systemic and nebulized treatment strategy. 2.3.5

Chronic bronchial infection in non-CF bronchiectasis patients


The use of long-term antibiotics in non-CF bronchiectasis remains the subject of debate. There is insufficient evidence to recommend the use of intermittent long-term macrolide therapy and nebulized antibiotics (tobramycin) in non-CF bronchiectasis, in general [10], according to the ERS/ECCMID in 2011. On the contrary, BTS and SEPAR guidelines on non-CF bronchiectasis recommend prolonged antibiotic therapy (oral or nebulized) in any of the following situations: three or more recurrent exacerbations per year or chronic 6

colonization by Pseudomonas species, especially resistant species [40,42]. Long-term nebulized antibiotics Long-term nebulized antibiotics should be considered if the patient is chronically colonized with P. aeruginosa. The choice of antibiotic should be guided by the antibiotic sensitivity results. Available antibiotics are sodium colistimethate and tobramycin without an adjuvant. Given that tobramycin alone is administered intermittently, in 28-day periods followed by 28 days off-treatment, 28 days of another antibiotic, oral or inhaled, might be required for patients with difficult-to-control bronchial infection during off-treatment periods [42]. Murray et al. [44] conducted a 1-year randomized placebocontrolled study assessing the efficacy of nebulized gentamicin compared to placebo in a number of sputum, objective, subjective and exacerbations parameters. They reported substantial improvements in sputum bacterial density, with eradication of P. aeruginosa in over 30% and eradication of other pathogens in over 90%, together with reduced sputum purulence, fewer exacerbations and delay in first exacerbation, improved exercise capacity and improvement in subjective parameters of cough and QoL. Tobramycin for inhalation 300 mg (TOBI) was evaluated carefully in non-CF bronchiectasis in the study by Barker et al. [45] and demonstrated impressive microbial efficacy in a 4-week randomized placebo-controlled study of TOBI with a 4.5 log10 CFU/ml reduction in P. aeruginosa density compared to placebo (twice the level of log10 CFU/ml reduction seen in CF). The recent development of dry-powder antibiotic preparations administered by a portable device has broadened our view of antibiotic administration. In the most recent proofof-concept multicenter study [46], adults who were culture positive for predefined potential respiratory pathogens (including both P. aeruginosa and H. influenzae) were randomized to ciprofloxacin dry powder for inhalation (DPI)

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Pharmacotherapy for LRTIs

32.5 mg or placebo administered b.i.d. for 28 days. Subjects on ciprofloxacin DPI showed a significant reduction (p < 0.001) in total sputum bacterial load at the end of treatment (-3.62 log10 CFU/ml) compared with placebo. Further studies are needed to address the optimal antibiotic choice and doses required. Long-term systemic antibiotic treatment The effectiveness of long-term macrolide therapy in CF has provided the rationale for using these agents in patients with bronchiectasis not caused by CF [47]. The use of macrolides, especially azithromycin, appears to decrease the frequency and intensity of exacerbations and to diminish sputum volume in patients with non-CF idiopathic bronchiectasis and may thus represent an effective treatment option. According to BTS guidelines patients having with three or more exacerbations per year requiring antibiotic therapy or patients with fewer exacerbations that are causing significant morbidity should be considered for long-term antibiotics. The drug for which the most experience has accumulated is azithromycin, which is taken in weight-adjusted dosages of 250 -- 500 mg, 3 days per week, for periods ranging from 3 to 6 months [42]. In the past year, three randomized controlled trials (RCTs) have shown that macrolide treatment significantly prevents exacerbations in patients with non-CF bronchiectasis [48-50]. In the largest recently published randomized, double-blind trial, 141 adult patients with a diagnosis of bronchiectasis and at least one pulmonary exacerbation in the previous year, were assigned to receive azithromycin 500 mg three times per week or placebo for 6 months [48]. The rate of event-based exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group during the 6-month treatment period (p < 0.0001). Conversely, pre-bronchodilator FEV1 and the St George’s Respiratory Questionnaire total score, both coprimary end points, showed no significant differences between the azithromycin and placebo groups. Aside from these documented beneficial effects, it is important to recognize the risk of developing macrolide resistance among respiratory pathogens of uncertain clinical significance. One particular area of concern regarding resistance is the empirical use of macrolides in patients with bronchiectasis, who may be infected with Mycobacterium avium-intracellulare. Therefore, in these patients, careful evaluation and investigation for the possible presence of such infections should be undertaken before initiating treatment with macrolides.

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Infectious exacerbations of asthma Asthma is characterized by persistent airway inflammation that produces airway hyperresponsiveness and recurrent episodes of airway obstruction. Acute exacerbations (AEs) are the main cause of morbidity, mortality and healthcare costs associated with asthma. 2.4

Microbiology Respiratory virus infections account for at least 80% of asthma exacerbations. With the development of polymerase chain reaction (PCR) technology, the detection of an expanded number of respiratory viruses has become possible, and the methods have a high degree of sensitivity and specificity but are not necessarily quantitative [51]. Viruses such as human RVs, RSV, seasonal influenza A viruses, metapneumoviruses, coronaviruses and bocaviruses may all trigger AE in adults and children. Among respiratory viruses, RVs are by far the most common, accounting for ~ 60% of all AE in all ages. Novel potential antiviral therapies that target the virus or boost host response to the virus are under investigation [52]. Sinusitis is an important trigger of asthma exacerbations with S. pneumoniae and H. influenzae accounting for 76% of positive cultures in sinusitis. About 75% of asthmatics experiencing exacerbations had positive cultures for M. catarrhalis on pharyngeal swabs [53]. Adults with stable asthma have been shown to have a greater incidence of S. pneumoniae, and asthma has been shown to be a risk factor for invasive Str. pneumoniae infections (IPI) in both adults and children [54,55]. It appears that asthma is associated with an abnormal innate and/or acquired immune response to pneumococci, which makes the association reported in epidemiological studies biologically plausible. The risk of invasive pneumococcal disease, defined as isolation of S. pneumoniae from a normally sterile site, was increased in those with asthma (adjusted odds ratio = 2.4) compared with controls, even after adjustment of other risk factors for pneumococcal disease [55]. Together, these studies show the importance of asthma in the risk of IPI, and combined with the other studies, they strongly advocate the need for antipneumococcal vaccination for individuals with asthma. Atypical bacteria M. pneumoniae and C. pneumoniae are also common respiratory pathogens associated with AEs in both adults and children [56]. A comprehensive evaluation of the role of both Chlamydophila and Mycoplasma infections in chronic asthma was reported by Johnston and Martin [57]. The authors concluded that, although many studies investigating the association between asthma and these pathogens have been uncontrolled and have provided conflicting evidence, there are biological mechanisms that may account for such a link, and that there may be a role for antibacterial therapy in the management of asthma. 2.4.1

Therapy Mycoplasma pneumoniae and C. pneumoniae may be associated with asthma chronicity and although several studies support the use of macrolide antibiotics for the treatment of atypical pathogens in patients with asthma exacerbations [58], asthmatic patients may benefit from prolonged treatment with these antibiotics. In cell-based assays, azithromycin, but not the closely related erythromycin or telithromycin, was shown to have antiviral activity to RV by inducing IFN and IFN-stimulated 2.4.2

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genes [59]. In a DBRC study of 278 adults with asthma exacerbation, Johnston et al. [60] provided evidence that telithromycin (at a dose of 800 mg/day for 10 days) led to an improvement in symptoms, unrelated to bacteriologic status. Antibiotic therapy in AE should be administered in exacerbations of infectious origin based, first, on clinical criteria: fever, elevated white blood cells count, high level of C-reactive protein and purulent sputum. Second, a sputum culture should be obtained before the beginning of the antibiotic treatment. The antibiotics of first choice are macrolides (clarithromycin and azithromycin). Long-term antibiotic therapy The role of neutrophilic airway inflammation becomes more prominent in severe asthma, and the optimal primary end point of prophylactic antimicrobial treatment in longer-term studies of severe asthma should be the effect on asthma exacerbations (expressed as the rate of exacerbations, the total number of exacerbations or the time to the first exacerbation). Although several short-term studies of macrolides in mildto-moderate asthma have failed to improve lung function, the azithromycin in severe asthma trial (AZISAST) azithromycin (250 mg three times a week for 6 months) -- has demonstrated a significant reduction in the rate of exacerbations in patients with exacerbation-prone non-eosinophilic severe asthma [61]. The Simpson study, however, documented improvements in QoL and symptoms and provided evidence of modulation in IL-8 levels and neutrophil accumulation and activation in the airways of patients with refractory asthma [62]. A Cochrane review [63] concluded that there is insufficient documented evidence to either support or refute the use of macrolides in the treatment of asthma. It appears, however, that certain subgroups of patients with asthma may benefit from long-term macrolide treatment, especially those with neutrophilic inflammation that does not respond to regular guideline-directed treatment. These results need to be confirmed in larger long-term RCTs in well phenotyped patients with severe asthma (one such RCT is currently ongoing in Australia). 2.5



Antimicrobial therapy of LRTI (acute bronchitis, AECOPD, exacerbations of non-CF bronchiectasis) is based mainly on clinical observations. The etiology of infective AECOPD still relies on clinical empiricism and efforts to access the efficacy of new therapies in the treatment and prevention of COPD exacerbations have been hampered by the lack of broad evidence. The advent of more sensitive molecular detection methods, as well as the development of experimental infection models, has progressed the understanding of respiratory virus infection in the course of COPD and asthma. Few trials support the use of prophylactic macrolide treatment in selective COPD patients but more do so in patients with non-CF bronchiectasis colonized with P. aeruginosa, with caution regarding their 8

impact on the emergence of macrolide resistance. Data suggest that inhaled antibiotics will reduce bacterial burden and the rate of exacerbations. In the next few years, it is likely that novel agents will represent optimal treatment options for LRTIs. 4.

Expert opinion

Antibiotics are commonly used in the management of respiratory infections such as acute bronchitis, non-CF bronchiectasis, COPD and asthma. Substantial progress is being made in the development of new individual pathogen-specific rapid diagnostic tests, such as nucleic acid amplification diagnostic tests, which help to rapidly distinguish bacterial from viral infection. Multiplex PCR testing of nasopharyngeal swabs or aspirates is being developed to diagnose infections resulting from B. pertussis, M. pneumoniae or C. pneumoniae with clinically useful sensitivity and specificity [64]. Not all rapid tests are widely available and their routine use is not cost-effective. Although there are issues of interpretation, sensitivity and specificity that need to be resolved, some hospitals use them for specific cases or infections in immunocompromised patients. Acute infection Antibiotic therapy of acute respiratory infections such as acute bronchitis, AECOPD, exacerbations of non-CF bronchiectasis and asthma exacerbations is mainly empirical. In acute bronchitis, since the etiological agent is most frequently a virus, efforts must be focused on the limitation of antibiotic prescription in primary care. In AECOPD and in exacerbations of bronchiectasis, an assessment of severity of the exacerbation and decision about whether to treat the patient in the community or in hospital are required. The choice of antibiotic is usually empirical and based on the likely microbial agent (according to the severity of the disease) and on knowledge of previous sputum cultures in an individual. In patients with bronchiectasis and chronically colonized with P. aeruginosa, the addition of TNS (300 mg b.i.d.) to high-dose oral ciprofloxacin (750 mg b.i.d.) for 14 days led to a greater reduction in microbial load at day 14 but with no clinical benefit [41]. 4.1

Chronic infection Antibiotics, particularly those of the macrolide and quinolone groups, show potentially beneficial immunomodulatory effects on host inflammatory responses. Low-dose long-term use of antibiotics, particularly macrolides, appears to perpetuate airway colonization, by reducing microbial load and bacterial products in the airway, clearance of bacteria should be enhanced and allow the airway an opportunity to heal [41]. Studies conducted over the past decade have indicated that treatment with long-term or intermittent antibiotics in COPD may have a beneficial effect by reducing the frequency of exacerbations and hospitalizations or by extending time to 4.2

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Pharmacotherapy for LRTIs

next exacerbation [37]. Long-term treatment with macrolides can be considered in patients with severe COPD and frequent exacerbations or hospital admissions, despite optimal pharmacologic and non-pharmacologic treatment [37]. Continuous antibiotics (macrolides) in bronchiectasis improved symptoms but had no effect on lung function or mortality. In practice, the prescription of long-term antibiotics should be considered for patients exacerbating at least three times a year and with P. aeruginosa colonization and in patients with fewer exacerbations but with greater morbidity. Nebulized antibiotics (tobramycin) showed improvements in sputum bacterial density with over eradication of P. aeruginosa in over 30%, reduced sputum purulence, fewer exacerbations and delay to first exacerbations and improvement in QoL. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.






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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Little P, Stuart B, Moore M, et al. Amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomized, placebo-controlled trial. Lancet Infect Dis 2013;13:123-9 A placebo-controlled study comparing the benefits and harms of amoxicillin (1 g three times daily for 7 days) for acute LRTI with those of placebo both overall and in patients aged $ 60 years. They concluded that when pneumonia is not suspected clinically, amoxicillin provides little benefit for acute LRTI in primary care and causes slight harms.

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Declaration of interest




As there is a high risk of resistance with continuous use of quinolone antibiotics in patients colonized with P. aeruginosa, this class of drug should be avoided. In asthma, the long-term antibiotics are still very unclear and more studies are needed.

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Anzueto A, Miravitlles M. Short-course fluoroquinolone therapy in exacerbations of chronic bronchitis and COPD. Respir Med 2010;104:1396-403


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Alberts RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-98 A randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD. Among 1142 patients with COPD, azithromycin taken 250 mg/day for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved the quality of life but caused hearing decrements in a small percentage of subjects.



Pomares X, Monto´n C, Espasa M, et al. Long-term azithromycin therapy in patients with severe COPD and repeated exacerbations. Int J Chron Obstruct Pulmon Dis 2011;6:449-56


He Z-Y, Ou L-M, Zhang J-Q, et al. Effect of 6 months of erythromycin treatment on inflammatory cells in

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Seemungal TA, Wilkinson TM, Hurst JR, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;178:1139-47 A randomized, double-blind, placebocontrolled study of erythromycin administered at 250 mg twice daily (b. i.d.) to 109 patients with COPD over 12 months. Macrolide therapy was associated with a significant reduction in exacerbations and shorter duration of exacerbations compared with placebo. Sethi S, Jones PW, Theron MS, PULSE Study Group. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Respir Res 2010;11:10 Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg/day orally (n = 573) or placebo (n = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. This therapy reduced the odds of exacerbation by 20% in the intent-to-treat population, by 25% among the per-protocol population (PP) and by 45% in PP patients with purulent/mucopurulent sputum at baseline. Miravitlles M, Soler-Catalun˜a JJ, Calle M, et al. Spanish COPD guidelines (GesEPOC). Pharmacological treatment of stable COPD. Arch Bronconeumol 2012;48:247-57 Spanish COPD guidelines for the management of stable COPD.


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Pharmacotherapy for LRTIs

significant reductions in total bacterial load compared with placebo in subjects with non-CF bronchiectasis.

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Pasteur MC, Bilton D, Hill AT; British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010;65(Suppl 1):i1-58.Review Guidelines of British Thoracic Society for non-cystic fibrosis (CF) bronchiectasis. Vendrell M, de Gracia J, Olveira C, et al. Diagnosis and treatment of bronchiectasis. Recommendations of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). Arch Bronconeumol 2008;44(11):629-40 Guidelines of SEPAR for nonCF bronchiectasis. Bilton D, Henig N, Morrissey B, et al. Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest 2006;130:1503-10 A double-blind, randomized, active comparator, parallel-design study, conducted at 17 study centers, compared 2 weeks of therapy with ciprofloxacin with either an inhaled tobramycin solution or placebo in 53 adults with known P. aeruginosa infection who were having AE of bronchiectasis. The addition of inhaled tobramycin achieved greater microbiological response but no statistically significant difference in clinical efficacy at days 14 or 21. Murray MP, Govan JR, Doherty CJ, et al. A randomized controlled trial of nebulised gentamycin in non cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011;183:491-9 Barker AF, Couch L, Fiel SB, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000;162:481-5 Wilson R, Welte T, Polverino E, et al. Ciprofloxacin DPI in non-cystic fibrosis bronchiectasis: a phase II randomized study. Eur Respir J 2013;41:1107-15 A Phase II, randomized, double-blind, multicenter study proved that ciprofloxacin dry powder for inhalation 32.5 mg b.i.d. for 28 days was well tolerated and achieved





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pathogenesis? Am J Respir Crit Care Med 2005;172:1078-89 This article reviews the evidence for an association between atypical bacterial respiratory pathogens and the pathogenesis of asthma and discusses the biological mechanisms that could account for such a link.


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Liapikou Adamantia†1 MD PhD & Antonio Torres2 † Author for correspondence 1 Consultant in Respiratory Medicine, Sotiria Hospital, 6th Respiratory Department, Mesogion 152, 11527, Athens, Greece Tel: +30 2107763458; E-mail: [email protected] 2 Professor of Pulmonology, Director of ICU, University of Barcelona, Institut Clinic del To´rax, Institut d’investigacions Biome`diques August Pi i Sunyer, Hospital Clinic, Department of Pneumology, Ciber de Enfermedades Respiratorias, Villarroel 170, 08036, Barcelona, Spain


Expert Opin. Pharmacother. (2014) 15(16)

Pharmacotherapy for lower respiratory tract infections.

Bacterial infections play an important role as etiological agents in acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and exacer...
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