The use of moxifloxacin for acute exacerbations of chronic obstructive pulmonary disease and chronic bronchitis

10.1586/ERS.12.50 481ISSN 1747-6348© 2012 Expert Reviews Ltdwww.expert-reviews.com

Drug Profile

Chronic obstructive pulmonary disease (COPD) is most commonly caused by cigarette smoking, although in parts of the world fossil fuel smoke inhalation makes a major contribution. The prev-alence of COPD varies across the world with an estimated overall prevalence of 11.8% for men and 8.5% for women [1]. COPD is likely to be the third most common cause of death worldwide by the year 2020 only surpassed by cardio vascular and cerebrovascular diseases, and is the fifth lead-ing cause of disability-adjusted life years lost. In the USA, it is estimated that 11.8 million adults have COPD and it accounted for 8 million out-patient visits, 1.5 million emergency department visits, 726,000 hospitalizations and 119,000 deaths in 2000. Prevalence increases with age, and was highest in women aged 65–74 years (10.4%) and 75–84 years (9.7%), and men aged 75–84 years (11.2%). In 2007, 60,000 men and nearly 65,000 women died from COPD, with death rates of 65.3 out of 100,000 for men and 46.8 out of 100,000 for women [1–5].

Age- and sex-standardized admission rates for COPD vary substantially across European coun-tries, while admission rates to hospital correlate with estimates of COPD prevalence [6]. Acute exacerbations of COPD (AECOPD) account for

a large proportion of the impact, both in terms of quality of life, and the economic burden to the healthcare system of this chronic disease [7,8]. In the UK, COPD exacerbations are the most common cause of emergency hospital admission in the winter months [9]. They lead to substantial morbidity and mortality, a marked reduction in quality of life and a poor prognosis [10–12], plac-ing a substantial burden on both patients and the healthcare systems [12,13].

One of the most commonly used definitions of an AECOPD was developed by Anthonisen et al. in 1987 and consists of a triad of respiratory symptoms: increased dyspnea, sputum volume and sputum purulence [14]. The definition often includes the length of time the symptoms have persisted. The current American Thoracic Society/European Respiratory Society consensus statement states: “an exacerbation of COPD is an event in the natural course of disease characterized by a change in the patient’s baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management” [9,15]. Exacerbations can also be classified by levels, with level 1 requiring outpatient treatment, level 2 requiring hospitalization and level 3 requiring intensive care [15].

Robert Wilson* and Aislinn Macklin-DohertyRoyal Brompton Hospital, London, UK*Author for correspondence: Tel.: +44 207 351 8337 Fax: +44 207 351 8338 [email protected]

Chronic obstructive pulmonary disease is a common condition which causes considerable morbidity and mortality. It is a heterogenous disorder in which the majority of patients have chronic bronchitis. Bacterial infections are a major cause of acute exacerbations of both conditions which have a major impact on healthcare resources, quality of life and disease progression. Antibiotics are used to treat exacerbations involving purulent sputum production, together with increased breathlessness and/or sputum volume. Moxifloxacin is a quinolone antibiotic and is one of the treatment options. This article discusses pathophysiology of these diseases, moxifloxacin clinical studies and appropriate use of moxifloxacin.

The use of moxifloxacin for acute exacerbations of chronic obstructive pulmonary disease and chronic bronchitisExpert Rev. Respir. Med. 6(5), 481–492 (2012)

Keywords: antibiotic • bacterial infection • chronic bronchitis • chronic obstructive pulmonary disease • exacerbation • moxifloxacin • quinolone

Expert Review of Respiratory Medicine

2012

6

5

481

492

© 2012 Expert Reviews Ltd

10.1586/ERS.12.50

1747-6348

1747-6356

Use of moxifloxacin for acute exacerbations

Wilson & Macklin-Doherty

Expert Rev. Respir. Med.

Drug Profile

For reprint orders, please contact [email protected]

Expert Rev. Respir. Med. 6(5), (2012)482

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COPD is a heterogeneous condition in terms of severity and the fact that it encompasses several pathologies (chronic bron-chitis, airflow obstruction, bronchiolitis and emphysema), which usually coexist. Bacterial and viral infections are associated with AECOPD [16,17]. Mucus hypersecretion, the hallmark of chronic bronchitis, identifies a subgroup of young adults at risk of devel-oping COPD independently of smoking habits [18]. Bacteria have marked affinity for mucus, and as mucociliary clearance is impaired in COPD, this makes bacterial infection more likely [19]. Bacteria inhaled or aspirated from the nasopharynx utilize excessive mucus that is poorly cleared as the first step when they infect the mucosa. This is the likely reason that mucus hyper-secretion is associated with COPD mortality from an infectious cause [20]. Bacterial infection attracts a neutrophilic inflamma-tory response that causes sputum to become purulent during an exacerbation. Studies have shown that higher levels of neutrophils are associated with higher bacterial load and thus purulence is a good predictor of the presence of bacterial infection [17,21–23]. Soler et al. performed bronchoscopies on patients admitted with an exacerbation of COPD to directly investigate the presence or absence of bacterial airway infection [24]. Purulent sputum, forced expiratory volume in 1 s (FEV

1) <50% of predicted, ≥4 exacerba-

tions in the last year and previous hospitalizations due to COPD were associated with the presence of pathogenic bacteria ≥102 colony-forming units/ml, which is accepted as a significant level.

There are several possible causes of an AECOPD. These include air pollution, allergic responses and patients forgetting to take their medication. However, evidence of an infectious cause was found in 78% of patients hospitalized because of an exacerba-tion. Thirty percent had bacterial infection, 23% viral, and 25% viral and bacterial coinfection [16]. In this study, patients with infectious exacerbations had longer hospitalizations and greater impairment of lung function. These data indicate that infection is the major driver of more severe COPD exacerbations and that management needs to be focused on preventing and treating infection and its consequences.

The most common bacterial species involved in AECOPD are nontypeable Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis [19]. Bacteria colonize the airways of COPD patients in the stable state, and while their concentration in lower airway is higher during AECOPD, it is unlikely that change in bacterial load alone is the most important mechanism for exacerbations [25]. Neutrophilic airway and systemic inflam-mation are more pronounced with well-defined bacterial exacer-bations than nondefined exacerbations [26]. Some patients are more susceptible to exacerbations than others, which has been called the frequent exacerbator phenotype [27]. Self-reported pres-ence of purulent sputum, history of frequent exacerbations and hospitalization in patients with FEV

1 <50% were found in one

study to predict the presence of bacterial infection [28].Lower airway bacterial colonization by the same species in sta-

ble COPD is an important and often unrecognized contributing factor to the clinical incidence of acute exacerbations which high-lights the significance of interplay between bacterial infection and colonization. Some COPD patients are persistently colonized with

H. influenzae and molecular studies of the presence of bacterial DNA suggest sputum cultures may underestimate the frequency with which this occurs [29]. This is a dynamic process in which host defenses may be compromised to the point of being unable to eradicate certain strains of bacteria but allow their colonization, these strains may therefore be carried for variable periods of time. When a new strain arrives, these bacteria may then overtake the growth of other strains and the chances of an exacerbation occur-ring are increased, because the new strain which is not recognized by the immune system has a better chance of escaping the host defenses and proliferating in the airway (Figure 1) [30]. However, if an exacerbation does not occur, development of an adaptive immune response may limit proliferation of the pathogen, or regulatory mechanisms dampen the inflammation, despite the pathogen persisting. Three studies, two using sputum and the third lavage, have shown that bacterial colonization by potential pathogens, when the patients’ condition is stable, is associated with chronic inflammation [31–33]. In one study, colonization was also associated with higher concentrations of fibrinogen in plasma and poorer health status, which suggests a systemic, as well as local, inflammatory response [33]. Several studies have shown that bacterial persistence in the airway has adverse clinical consequences. White et al. showed that resolution of bronchial inflammation following antibiotic treatment of an exacerbation is dependent on bacterial eradication [34]. Antibody responses occur to bacteria colonizing the airway in the stable state, which shows that the body is reacting to the potential pathogen causing chronic inflammation [32]. ‘Pulsed’ moxifloxacin treatment given to patients at regular intervals during stable COPD significantly reduced the exacerbation frequency, particularly for a group of patients who produce purulent sputum when stable [35].

Antibiotic treatment of acute exacerbations is almost always empirical because the results of sputum culture and antibiotic sensitivities are delayed for 48 h, so in everyday practice they are often not performed. The aim of antibiotic treatment is to sterilize the airway leading to a resolution of the inflammatory response. The success or failure of treatment will depend upon many factors: the extent of infection and the virulence of the strain; sensitivity of the strain to the antibiotic chosen; potency of the antibiotic; pharmacokinetics of the antibiotic; whether bacterial infection is the only factor provoking the exacerbation; the presence of viral and bacterial coinfection [17]; the severity of the patients lung disease and therefore the efficacy of their local host defenses; the number of recent acute exacerbations; concurrent use of steroids [18] and comorbid illness, for example, heart failure or poorly controlled diabetes [36]. Failure to eradicate the bacterial infection will lead to bacterial colonization, persistent inflammation and therefore relapse of the same infection, or a future exacerbation is more likely. However, some patients acquire bacterial strains leading to colonization and this does not necessarily cause an exacerbation. The determinants of whether an exacerbation occurs are poorly understood but innate immunity, molecular differences between pathogenic strains [27], the severity of the airways disease and current smoking habit have all been shown to influence whether colonization is present or not [30].


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Drug Profile

In one study comparing the quinolone antibiotic moxifloxacin with the macro-lide antibiotic clarithromycin, there was superior bacteriological eradication of the most common pathogens seen in AECOPD in patients treated with the quinolone (77 vs 62%) due to persistence of H. influenzae in the clarithromycin-treated patients [37]. However, the pri-mary end point of the study, which was whether the patient had sufficiently recov-ered shortly after the course of antibiotic not to require more antibiotic treatment, showed no difference between moxifloxa-cin and clarithromycin (89 vs 88% recov-ery, respectively). An analysis of paired sputum samples in the study showed that the explanation for this result was that many patients with persistent H. influen-zae, who had been treated with clarithro-mycin, recovered clinically as judged by the criteria used in this trial. However, another study using moxifloxacin has suggested that persis-tent bacterial infection after antibiotic treatment may lead to incomplete recovery from the exacerbation, possibly due to the inflammatory response persisting, and this in turn can lead to a shorter time until the next exacerbation [38]. These results therefore suggest that moxifloxacin could be more effective at reducing frequency of exacerbations due to its superior effect on bacteriological eradication.

Further studies are needed to clarify the importance of bac-terial eradication after antibiotic therapy for AECOPD exac-erbation and its relationship to recovery and reducing chronic airway inflammation. Future studies need to incorporate careful bacteriology and more sensitive measures of patient responses to treatment. Patient-reported outcome measures may prove useful in this regard [39], and studies need to be longer than the standard design to capture the consequences of bacterial persistence when it occurs. Another consideration is the speed of action of an anti-biotic in killing bacteria, which will differ for bacteriocidal versus bacteriostatic antibiotics. One study has suggested that rapid killing by moxifloxacin speeds up the rate of recovery [40], but how early the antibiotic is given after the onset of exacerbation, and therefore the time the infection has to become established, could also be important.

Guidelines for antibiotic treatment of AECOPD have been produced by many national/international societies and national health agencies. They are intended to promote the choice of antibiotic to minimize the risk of treatment failure, while containing the development and spread of antibacterial resist-ance. Therefore, equal emphasis is placed on which patients suffering an exacerbation need not be given an antibiotic. Most guidelines attempt to be evidence based. However, they are constrained in this regard because few antibiotics have been tested against a placebo treatment group, and most active

comparator-controlled clinical trials are only powered to show equivalence not superiority of one antibiotic over another [36].

Broadly speaking, three guideline approaches have been taken, although the differences are more to do with emphasis rather than any difference of opinion. In the first view, COPD is seen as an inflammatory disorder in which for the most part bacteria are passengers taking advantage of a favorable environment in the air-way during an exacerbation. First-line treatment is with systemic corticosteroids and in most cases the host defenses alone will clear the bacteria once the inflammation has reduced. Clinical features and investigations are used to determine the severity of the exac-erbation and those patients needing an antibiotic. The second approach taken by the majority of guidelines is based on the study by Anthonisen et al. described earlier [14]. Type 3 patients (one cardinal symptom) should not be given an antibiotic, whereas type 1 and 2 patients should be. Some guidelines place greater emphasis on sputum purulence because of the evidence that this is a signal of bacterial infection, for example, type 2 patients (two cardinal symptoms) without sputum purulence do not need an antibiotic. The third approach is to use characteristics that define patients at risk of greater morbidity and mortality [41]. This is a rational approach as these patients have more severe disease and thus more frequent exacerbations. Therefore, they have received more antibiotics in the past and as a consequence are at higher risk of carrying resistant strains. They also have less respiratory reserve if antibiotic failure leads to clinical deterioration.

The use of patient stratification by clinical criteria as a basis for selecting an antibiotic has been incorporated into very few clinical studies to date. Martinez et al. divided patients on the basis of FEV

1, the number of exacerbations in the last year, comorbidity

and sputum production [42]. They showed that regardless of therapy, the group with the more severe disease, that they termed ‘complicated’, demonstrated lower clinical and microbiological

Sterile mucosa

Infection by new bacterialstrain Pathogen virulence

versus lung hostdefences Elimination of infecting

bacteria

Viral infection

Airway and systemicinflammation

Increase in respiratory and systemic symptoms

Strain-specific immune response and antibiotics

Bacterial persistence/colonization

Figure 1. The role of bacteria in acute exacerbations of chronic obstructive pulmonary disease and chronic bronchitis.



Drug Profile

success than uncomplicated patients without those features. Uncomplicated patients were randomized to receive either short-course levofloxacin or azithromycin, and complicated patients received standard-course levofloxacin or amoxicillin/clavulanate. However, there were no differences in the antibiotic comparisons within each group so the benefits or otherwise of the stratification for guiding antibiotic treatment remain unproven.

Choice of antibiotic is usually argued on a number of factors including suspected etiology, clinical features and local patterns of antibacterial resistance. A number of studies have shown that the bacteria most commonly isolated vary with the severity of airflow obstruction. H. influenzae is the most common patho-gen isolated overall in patients with COPD. S. pneumoniae and other Gram-positive cocci are pathogens more greatly associated with milder forms of COPD (i.e., with mild airflow obstruction) whereas Pseudomonas aeruginosa and other Gram-negative bacilli are more commonly isolated in patients with more severe COPD, but are very rare in mild cases [36]. The GOLD guidelines use need for hospitalization to choose between older agents, including amoxicillin for the out-patient setting, or amoxicillin/clavula-nate, which protects amoxicillin against b-lactamases produced by H. influenzae and M. catarrhalis [101]. They also recommend consideration of treatment of Gram-negative organisms such as P. aeruginosa in patients with more severe GOLD stage 3 or 4 dis-ease. This approach also draws attention to two other factors: cost and tolerability, as newer agents are likely to be more costly than generic comparators; and some antibiotics are less well tolerated because of side effects, for example, gastrointestinal.

French guidelines are interesting in that they refer to pharmaco-kinetics of antibiotics and their ability to penetrate bronchial tissue and mucus (quinolones, macrolides, ketolides are better; b-lactams are worse); and propensity of the antibiotic to induce resistance [43]. These are potentially very important factors but there is no evidence that they influence clinical outcome of AECOPD. Development of antibiotic resistance in a community is best avoided by not prescribing antibiotics to otherwise well patients with a viral illness or an exacerbation of mild COPD; using short courses of treatment such as the 5-day course recom-mended for moxifloxacin; using correct dosages; and antibiotic diversity. A general principle should be not to use the same anti-biotic on every occasion, and to try to vary the antibiotic class when managing patients with frequent exacerbations. Although the benefits of cycling antibiotics are unproven in terms of overall resistance development, in an individual patient a recent antibiotic course makes a resistant strain more likely [36].

Overview of the marketMost guidelines have an alternative recommendation if first-line treatment fails. Usually, the second-line antibiotics are those that are active against strains resistant to first-line older agents. First-line agents recommended for the treatment of acute exacerbations of chronic bronchitis or AECOPD are: trimethoprim–sulphameth-oxazole, amoxicillin, ampicillin, tetracycline (including doxycy-cline), trimethoprim and macrolides. Second-line agents include b-lactam/b-lactamase inhibitors (e.g., amoxicillin/clavulanate),

ketolides (e.g., azithromycin and telithromycin), quinolo-nes (e.g., moxifloxacin and levofloxacin) and second- or third- generation cephalosporins. Ciprofloxacin or high-dose levofloxacin are the only oral anti biotics active against P. aeruginosa [36]. In a meta-analysis of randomized controlled trials first-line thera-pies (amoxicillin, ampicillin, trimethoprin–sulphamethoxazole and doxycycline) are associated with a lower treatment success compared with second-line antibiotics (macrolides/ketolides were included together in this analysis, amoxicillin–clavulanate, second - and third-generation cephalosporins and quinolones) [44]. Given the emerging resistance patterns of common pathogens to older first-line antibiotics used in AECOPD, the huge impact on clinical outcomes as well as the burden on the healthcare system with fre-quent antibiotic use, there is an ever increasing need to identify the most effective antimicrobial therapy in these patient populations. In more severe disease where Gram-negative pathogens are thought to play a greater role in adverse events, the use of second-line and more potent agents (e.g., quinolones) may be more appropriately used in the first instance and is already recommended by some [27].

Moxifloxacin (quinolone) gave better cure rates and a longer time to next exacerbation when compared with a basket of first-line comparators (amoxicillin, cefuroxime and clarithromycin) [38].

Introduction to the drugMoxifloxacin is a third generation fluoroquinolone antibiotic with potent activity against the major respiratory pathogens implicated in AECOPD. It was originally developed with the intention of cre-ating a new antimicrobial drug with a potent and wide spectrum of activity against both Gram-negative organisms (e.g., P. aer-uginosa), an effect well achieved by the older second-generation ciprofloxacin and ofloxacin, as well as against Gram-positive bac-teria (e.g., S. pneumoniae) against which these older quinolones are less effective [45]. It has a ten times-higher activity against Gram-positive bacteria such as S. pneumoniae than ciprofloxacin an older quinolone antibiotic, but is still active against Gram-negative bacteria with the notable exception of P. aeruginosa [46]. Dosing is 400 mg per day for all approved indications, although these indications vary across countries. Both oral and intrave-nous formulations are in use. Treatment duration is 5–21 days according to indication and severity, but in AECOPD, a 5–10-day course is recommended. Only the oral formulation is approved for AECOPD in Europe, the intravenous formulation being used for community-acquired pneumonia. Of the newer-generation quino-lones, it is currently used on the largest scale clinically through-out Europe, having been approved by every member state of the EU [45,102].

Chemistry & mode of actionMoxifloxacin is a fluoroquinolone and is a derivative of nalidixic acid [45]. Fluoroquinolones directly inhibit bacterial DNA synthesis by targeting DNA gyrase and topoisomerase IV [47]. Unlike ciprofloxacin and levofloxacin, which primarily target the ParC subunit of topoisomerase IV in Gram-positive bacteria, moxifloxacin primarily targets the GyrA subunit of DNA gyrase as an initial lethal event leading to the formation



Drug Profile

of drug–topoisomerase–DNA complexes which lead to several types of irreversible cell damage. This is thought to be attributable to the presence of a free substituent at position C-8 as shown in Figure 2. It thereby retains high bacteriocidal activity against S. pneumoniae strains bearing mutations, usually amino acid substitutions, in topoisomerase IV associated with resistance to older fluoroquinolones [48]. Quinolones also demonstrate an attractive feature of rapid bactericidal activity which may arise via a two-step process involving bacteriostatic formation of cleaved complexes with subsequent release of DNA breaks which results in chromosome fragmentation and bacterial cell death [47].

Moxifloxacin has concentration-dependent bactericidal activ-ity against both Gram-positive and Gram-negative bacteria and also demonstrates antianaerobic activity [45]. Quinolone anti-biotics including moxifloxacin penetrate well into both epithe-lial cells and phagocytes as well as secretions, so moxifloxacin’s efficacy in vivo could be associated with both extracellular and intracellular bacterial killing.

Pharmacokinetics/pharmacodynamics & metabolismMoxifloxacin has a superior pharmacokinetic/pharmaco dynamic profile against major respiratory tract pathogens and this mini-mizes the selection of resistant strains, which is particularly important for S. pneumoniae [49].

In a multiple dose study, linear pharmacokinetics of moxi-floxacin are seen between 50 and 800 mg [50]. The peak serum concentration of moxifloxacin (C

max) is achieved after a single

dose and importantly, at 400 mg the mean trough concentration exceeds the MIC required for key respiratory pathogens (>90% S. pneumoniae) for over 24 h [51]. C

max is achieved quickly in a

mean of 1.49 h [51] and median of 1.5 h [50]. In once-daily dosing of 400 mg, steady state C

max achieved at day 10 was 4.5 mg/l and

AUC was 48 mg·h/l [50]. Moxifloxacin is excreted by both the liver and kidney so it does not accumulate markedly and its metabolites do not exhibit any significant antimicrobial activity [50,51].

Moxifloxacin is rapidly and almost completely absorbed with an absolute bioavailability of 91% and has an elimination half-life of approximately 12 h [51]. Data demonstrate comparable AUCs and elimination times in both plasma and saliva which supports other evidence of good absorption, distribution and shows that a high level of systemic exposure to drug is achieved with sustained terminal half-life, maintaining a high level of drug exposure at sites of infection [50].

Concentration in epithelial lining fluid, bacterial tissue and alveolar macrophages exceeds MIC of common respiratory pathogens for up to 24 h postdose [52].

Flouroquinolones exhibit a concentration-dependent killing effect on many of these pathogens and the 24-h AUC/MIC ratio correlates best with both clinical and microbiological outcomes [46,53]. It has been demonstrated that a 24-h AUC/MIC ratio of >125 yields the best efficacy against common respiratory patho-gens and moxifloxacin compares favorably to other newer fluoro-quinolones in that it has the highest AUC/MIC against S. pneu-moniae [53,54]. Thus, moxifloxacin eradicates S. pneumoniae faster

in vitro than levofloxacin in animal models. No metabolic inter-actions with other drugs undergoing Phase I biotransformation involving cytochrome P450 have been observed [55].

ResistanceNew subpopulations of quinolone-resistant bacteria continue to emerge which has prompted investigation into novel measures to prevent it. Investigators have developed a method to optimize antimicrobial dosing to reduce resistance patterns based on the ‘mutant selection window’ [49]. A selection of drug-resistant mutants occur within this window at antibiotic concentrations above the MIC and below the mutant prevention concentration, which is the concentration at which growth of the least-susceptible next-step mutant strain is prevented [46,49].

It has been proposed that this window may provide the key target antibiotic concentrations to achieve minimal selection and amplification of such mutants. Potential future applica-tions suggest it may also be possible to narrow this window by manipulating compound design [56].

This has shown particular relevance to moxifloxacin which has demonstrated lower potential to select for resistant strains because it exceeds the MIC

90 for approximately 30 h [57] and

in vitro resistance to moxifloxacin develops slowly because it occurs at two separate target site mutations (both DNA gyrase and topoisomerase IV) against which moxifloxacin has high intrinsic activity and it occurs via a multiple stepwise manner. The likelihood of bacteria acquiring such mutations is therefore infrequent and this, combined with the bactericidal properties of moxifloxacin and high levels of sustained drug exposure, confer lower levels of resistance [47,58,59].

Although cross-resistance has been observed between moxif loxacin and other f luoroquinolones in Gram-negative bacteria, some Gram-positive bacteria resistant to other fluoroquinolones may still be susceptible to moxifloxacin as it inhibits both topoisomerases II (DNA gyrase) and IV. While resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, and macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin, other resistance mechanisms such as permeation barriers and drug efflux may do so. However, moxifloxacin was found to be a poor

N

OH

OO

O

H3C

N

HN

H

H

†HCl

C7

C8

F

Figure 2. Moxifloxacin. Highlighted are bulky bicyclic fused ring at C7 and free substituent methoxyl group at C8, which may confer advantageous properties in avoiding drug-resistant mutant selection. †Moxifloxacin is marketed as the hydrochloride structural compound.



Drug Profile

substrate for energy-dependent active efflux in S. pneumoniae which is attributed to the presence of a bulky bicyclic fused ring at C7 [47,48]. Thus, its chemical structure seems to confer multiple advantageous properties in avoiding drug-resistant mutant selection, particularly in S. pneumoniae (Figure 2). This is emphasized by the fact that moxifloxacin-resistant pneumococci have been rarely identified in many surveys around the world [60].

Clinical efficacyRandomized double-blind clinical studiesMost early antibiotic comparator trials are equivalence studies performed as part of the registration of a new antibiotic [61–63] and included patients with chronic bronchitis when the presence or absence of COPD is often not clear. The design of AECOPD trials has evolved over time, particularly with respect to patient selection and clinical end points. Patients enrolled in more recent trials have all three Anthonisen type 1 symptoms and significant COPD. Moxifloxacin trials have been particularly innovative in this regard. A Cochrane review was completed recently, and was compromised by the small number of placebo-controlled trials available for analysis [64]. A significant benefit for antibiotics ver-sus placebo was found for mortality (relative risk ratio: 0.23), but this result was heavily influenced by a single study (ofloxacin vs placebo) in patients with very severe exacerbations requiring ventilator support [65]. The need for antibiotics to be given to all patients in this setting is now proven. Antibiotics also influenced treatment failure (relative risk ratio: 0.47) and the number of patients needed to treat to avoid failure was three. Antibiotics influenced resolution of sputum purulence but did not influence recovery of peak flow nor gas exchange.

The MOSAIC study was a large, multicenter, double-blind trial in which enrolled patients were middle aged or older, had a heavy smoking history, a history of frequent exacerbations, significant comorbidity, and in many cases, severe COPD [38]. Patients were randomized to receive moxifloxacin (400 mg once daily for 5 days) or one of the older agents; amoxicillin, cefuro-xime or clarithro mycin (standard dosages for 7 days) as selected by the enrolling doctor. Patients were assessed in a stable phase to measure their health status so that following treatment of an exacerbation judgment could be made about their full or partial recovery. When patients had an Anthonisen type 1 exacerbation, they were randomized to one of the treatment groups. In terms of symptomatic improvement (sufficient that further antibiotic treatment was not required) shortly after the end of treatment, which was the primary end point of the study, the two groups were equivalent. However, moxi floxacin resulted in superior bac-teriological eradication, and possibly as a result of this in a better clinical cure rate, as assessed by a return to baseline health status. Moxifloxacin was associated with fewer requirements for addi-tional antibiotics (7.6% in the moxifloxacin arm compared with 14.1% in the comparator arm; p = 0.006) in the weeks following the exacerbation (fewer cases of rapid relapse), and an extended time to the next exacerbation (mean of 133 days in the moxi-floxacin arm vs mean of 118 days in the comparator). There was therefore an extension of 15 days to next exacerbation (p = 0.03)

and the benefit of moxifloxacin over comparator antibiotics was significant for 5 months after the initial exacerbation.

In contrast to this, the study by Lode et al. compared levofloxacin with clarithromycin and did not show a longer exacerbation-free interval on use of a quinolone versus a macrolide [66]. Levofloxacin was associated with a higher bacteriological eradication rate in patients with COPD but no significant difference in exacerbation-free interval when compared with clarithromycin (101 days for levofloxacin vs 95 days for clarithromycin). A reason for the dif-ference in outcome compared with the MOSAIC study could be the characteristics of the patients studied. Approximately, 75% of the patients recruited for the Lode et al. study only had moderate airflow obstruction and would therefore be less prone to frequent exacerbations, and in contrast to the MOSAIC study, Lode et al. included nonsmokers and patients having type 2 exacerbations.

The MOSAIC study database was interrogated to identify those patient characteristics that influence short (failure to return to baseline health status after acute treatment) and long-term outcomes [67]. Frequent exacerbations (≥4 in the past year), low FEV

1 (<50% predicted), randomization to comparator antibiotic

(cefuroxime, amoxicillin and clarithromycin), and wheeze during the acute episode were risk factors for both adverse outcomes; whereas comorbid cardiopulmonary disease was a risk factor for clinical failure at the end of treatment, and older age (>65 years) was a risk factor for shorter time to next exacerbation. The supe-riority of moxifloxacin with respect to rapid relapse was largely accounted for by patients with frequent exacerbations and age >65 years. These findings of the post hoc analysis of the MOSAIC study are similar to other published studies [68], and describe a more vulnerable patient in whom the choice of antibiotic may be more important. Other risk factors for poor outcome that have been described include low body mass index, current smoking habit, alcohol consumption and duration of chronic bronchitis. Not all of the characteristics are amenable to antibiotic treat-ment. For example, a wheezy patient will not do well, even if the bacterial infection is eradicated, unless that aspect of their management is dealt with.

The MAESTRAL study enrolled at risk COPD patients aged ≥60 years, ≥20 pack per year smoking history, FEV

1 ≤60%

predicted and ≥2 previous exacerbations in the last year [69]. Moxifloxacin was compared with amoxicillin–clavulanic acid, two antibiotics recommended for at risk AECOPD patients in guidelines. A novel end point of clinical failure up to 8 weeks post-therapy was chosen to capture early relapses following an exacerbation. This was partly based on the results of the MOSAIC study, and partly on other studies that have identified a vulnerable period following an AECOPD during which the COPD patient is likely to relapse if the initial exacerbation has not fully resolved [27]. Moxifloxacin was noninferior to amoxicillin–clavulanic acid in the study overall, but achieved superiority in those patients with bacteriologically proven exacerbation. The overall eradication rate of bacterial infection at the end of therapy was higher with moxifloxacin than with amoxicillin–clavulanic acid, mainly explained by a better efficacy against H. influenzae. There was a clear correlation between bacteriological eradication, at the



Drug Profile

end of therapy and clinical cure at 8 weeks post-therapy, which emphasizes the importance of completely clearing the infection to enable bronchial inflammation to resolve (Figure 1).

Randomized open label studiesIn addition to support the efficacy of moxifloxacin in AECOPD, these studies have suggested that treatment with the quinolone gave faster symptom relief and return to normal activities [70,71], and had lower relapse rates which translated into cost savings [72]. A systematic analysis and meta-analysis of published studies con-cluded that the clinical success rate achieved with moxifloxacin tended to be higher than that obtained using standard first-line antibiotics [73].

Postmarketing observational studiesThese have confirmed the efficacy and good tolerability of moxi-floxacin in AECOPD, with 96.3% of patients being cured or improved as judged by physician assessment after moxifloxacin treatment. Symptom relief occurred in almost 70% of patients by day 3. Adverse reactions were reported in only 2.3% of patients. Most patients (92.1%) considered moxifloxacin to be beneficial [74]. Moxifloxacin significantly reduced time to recovery from AECOPD in patients with moderate-to-severe disease compared with comparators [75,76]. Patients’ symptoms improved after a mean of 3.4 days allowing a return to normal daily activities after 5.4 days and full recovery taking 6.5 days with moxifloxacin therapy [77].

Safety & tolerabilityThe safety profile of the quinolone family has gathered some attention due to the occurrence of rare but severe side effects which has led to the withdrawal or restriction of use of some of the more potent class members (e.g., trovafloxacin and tema floxacin). These unusual events are thought to be attributable to the struc-ture of the individual agents rather than a class-related effect [78]. Indeed, moxifloxacin has a similar incidence of adverse effects as comparators [77,79], and data show that using moxifloxacin in its accepted indications and following guidelines is not associated with an excessive incidence of drug-related adverse reactions [80]. The most common adverse effects involve the GI tract (nausea and diarrhea) and these are usually mild and do not cause discon-tinuation of therapy. Moxifloxacin is a well-tolerated drug, even among elderly populations [79,81]. Moxifloxacin causes a reproduc-ible mean QTc prolongation of 4–7 ms and is contraindicated in patients with pre-existing pro-arrhythmic conditions and it should not be given with other drugs that cause QTc prolongation [78,82]. A review of published trials, meta-analyses, postmarketing surveillance studies, spontaneous reports, and case reports was published in 2009 [83]. This showed that tendon rupture was infrequent (<0.4%), even in elderly COPD patients and those on corticosteroids; phototoxicity and CNS adverse events were less common than with other fluoroquinolones; severe cardiac toxicity was not reported from large cohort studies, or pharmaco vigilance reports; hepatotoxicity was similar to that of other fluoroquinolo-nes but less than that for amoxicillin–clavulanic acid and teli-thromycin; severe reactions such as Stevens–Johnson syndrome

are extremely rare with moxifloxacin. It has been suggested that fluoroquinolones with higher anti-anaerobic activity (e.g., gati-floxacin and moxifloxacin) may be associated with a higher risk of Clostridium difficile-associated disease. However rates reported in the Phase II/III studies have been very similar to comparators [83]. Prevention of C. difficile-associated disease is best achieved through infection control measures.

As a result of the attention focused on the safety of moxi-floxacin, the limited populations at higher risk of more signifi-cant adverse events are now well characterized and included in safety warnings with prescribing information. This should reduce current low adverse event rates even lower [79,102].

Regulatory affairsMoxifloxacin oral tablets are registered in 123 countries world-wide. Moxifloxacin intravenous solution is registered in 108 coun-tries. In the EU, moxifloxacin is approved for acute exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired pneumonia, uncomplicated pelvic inflammatory disease, complicated skin and skin structure infections and complicated intra-abdominal infections [102].

ConclusionA treatment algorithm is set out in Figure 3 which identifies the group of patients for which moxifloxacin is an appropriate anti-biotic choice for AECOPD. Antibiotics are recommended for patients with type 1 or type 2 Anthonisen exacerbations, or with a severe exacerbation that requires mechanical intervention. Where patients are not infected with P. aeruginosa, and have risk factors for poor outcome, amoxicillin–clavulanic acid is recommended, moxifloxacin and levofloxacin are alternatives. Where patients are infected with P. aeruginosa, ciprofloxacin (with levofloxacin recommended as an alternative) is recommended [84].

Expert commentaryIn the past, most antibiotic studies have been conducted as part of registration trials for new antibiotics. These equivalence studies have provided no help in providing an evidence base for anti-biotic prescription in AECOPD. There is an urgent need for more studies to inform appropriate antibiotic therapy for AECOPD exacerbations. Key questions that remain unanswered are as follows:

• The consequences (if any) of not prescribing antibiotics to COPD patients who have bacterial infection but relatively intact host defences. These patients may clear the superficial mucosal infection themselves, particularly if inflammation causing the AECOPD is treated with a short course of predni-solone. However, bacterial persistence could lead to incomplete recovery or early relapse (Figure 1);

• The importance of antibiotic resistance. This is proven in community-acquired pneumonia, but the data for AECOPD are less clear. It seems likely that antibiotic resistance will make bacterial persistence more likely with incomplete resolution of the exacerbation;



Drug Profile

• Should antibiotic prescription be modified in patients who have risk factors for poor outcome? There is a strong logical argument for this approach, but little evidence from clinical trials;

• Exacerbation frequency is likely to be increased by bacterial persistence after an exacerbation and lower airway bacterial colonization in the stable state. An important finding of the MAESTRAL study was that clinical efficacy at 8 weeks post-therapy correlated with bacteriologic efficacy at end of test. As well as antibiotic choice, other parameters such as prompt start of treatment, choice of dosage and length of course may also influence the outcome. The relative importance of these different factors requires further investigation [69].

Patient selection and design of the trial will both be important in the future, and the studies must be sufficiently powered to either show superiority of one comparator over another, or have a placebo arm. New end points should replace the present defi-nition of antibiotic failure, which is the doctor’s decision about requirement for further antibiotic therapy, because this has not differentiated between antibiotics despite significant differences in the success of antibiotic in eradicating bacteria. Patient-reported outcome measures and longer-term follow-up to capture relapses after treatment maybe the most promising end points. The MAESTRAL study which had an end point of 8 weeks post therapy, demonstrated that assessment at a time period of 4 weeks or greater was a reliable parameter in assessing more long-term

efficacy of antibiotic treatment in terms of reduced clinical relapse.

The MOSAIC study enrolled a homo-geneous population of patients with signifi-cant COPD and stratified at random ization for the use of corticosteroids, which were anticipated to lessen the difference between comparator antibiotic therapy by reducing airway inflammation independent of bac-terial eradication or persistence [38]. Based on this, the MAESTRAL study stratified patients according to steroid use and dem-onstrated that clinical failure rates were higher in steroid-treated patients than non-steroid-treated patients regardless of antibi-otic therapy [69]. Further analysis has shown that between-group differences could still be confounded by under lying factors related to medical history (e.g., comorbid cardiopulmonary disease), the severity of the disease (e.g., FEV

1), and the use of con-

comitant medication (long-acting broncho-dilators) [67]. The analysis suggests that future clinical trials of antibiotic therapy at COPD exacerbation should systemati-cally take these factors into account either a priori (at random ization) or a posteriori (statistical analysis) in order to increase the

sensitivity of the studies to detect differences between antibiotic regimens.

Moxifloxacin has several properties that make it a good choice for at-risk patients: excellent activity against the most common pathogens – H. influenzae, S. pneumoniae and M. catarrhalis; favorable pharmaco kinetics with good penetration into the bron-chial mucosa and secretions; safe and well tolerated; once-daily dosage; and in most cases a short 5-day course.

Five-year viewThe authors are not aware of any new antibiotic currently in devel-opment targeting AECOPD as an indication. The only urgent need for a new antibiotic in this indication is an alternative to ciprofloxacin in patients with P. aeruginosa infection. P. aerugi-nosa is more commonly being isolated in AECOPD, usually from patients with more severe disease, and the infection often becomes chronic. Such patients often have associated bronchiectasis if a high resolution CT scan is performed. Ciprofloxacin resistance develops with repeated prescription. The authors have some expe-rience using a prolonged course of azithromycin, which may be acting to reduce bacterial virulence factor production or as an anti-inflammatory agent, to reduce the frequency of prescription of ciprofloxacin.

Attention will therefore continue to focus on which patients do not need an antibiotic for AECOPD, and the most appropriate anti-biotic choice, dosage and length of course when one is prescribed. A number of antibiotics that have been available for many years as oral

COPD exacerbation

Sputumpurulent

Sputum mucoid

Anthonisen type 1 or 2

Anthonisentype 3

No antibiotic

Risk factors forpoor outcome

No antibiotic

Yes No

FEV1 <35%, frequent antibiotics and associated bronchiectasis

High risk of antibioticresistance

Low risk of antibioticresistance

Risk ofPseudomonas aeruginosa

Amoxicillin/clavulanateMoxi�oxacinLevo�oxacin

First-line antibiotics (e.g., amoxicillin and

doxycycline) Cipro�oxacin

Figure 3. Algorithm showing which patients with an acute exacerbation of chronic obstructive pulmonary disease and chronic bronchitis should receive antibiotic therapy. Anthonisen types: type 1: all three cardinal symptoms of increased breathlessness, increased sputum volume, purulent sputum. Type 2: two of these symptoms. Type 3: one of these symptoms. COPD: Chronic obstructive pulmonary disease; FEV1: Forced expiratory volume in 1 s.



Drug Profile

and/or intravenous formulations are being developed for delivery by the inhaled route: ciprofloxacin, levofloxacin, tobramycin, amika-cin, aztreonam and colomycin. Some of these have been available in the nebulized form previously, but are now being developed as formulations in more convenient hand-held devices. The primary target for these formulations will be as antibiotic prophylaxis in patients with cystic fibrosis and bronchiectasis who suffer from chronic bronchial suppuration. However, amikacin is being tar-geted at ventilator-associated pneumonia and the authors think it is inevitable that AECOPD will also be considered. There is also a group of patients who are frequent exacerbators who may

benefit from being managed in the same way as a patient with bronchiectasis.

Financial & competing interests disclosureR Wilson has received honoraria for giving lectures, attending advisory boards and providing expert testimony for Bayer plc. A Macklin-Doherty has nothing to disclose. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Bacteria are frequent causes of acute exacerbations of chronic obstructive pulmonary disease (AECOPD); approximately half of exacerbations involve bacterial infection.

• AECOPDs are common and associated with disease progression, impaired quality of life, most common acute medical admission to hospital, and cause time lost from work.

• In most cases, AECOPDs are airway mucosal infections that may be cleared by the host inflammatory responses; in these circumstances antibiotic treatment shortens the exacerbation and by limiting damage caused by the inflammatory response may make relapse less likely. An algorithm can be used to decide who needs an antibiotic and which antibiotic to choose.

• Nontypeable Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and in severe chronic obstructive pulmonary disease Pseudomonas aeruginosa, are the most common pathogens.

• In AECOPD cases with well-identified risk factors such as more severe airflow obstruction, older age, more frequent exacerbations, comorbid illness, low BMI, airway infections have more serious consequences. These may include bronchopneumonia and respiratory failure, or worsening of the comorbid condition.

• Moxifloxacin is a quinolone antibiotic with excellent activity against the main bacterial pathogens except P. aeruginosa. Moxifloxacin is safe and well tolerated. Clinical trials have shown superior outcome against older first-line antibiotics, and against amoxicillin–clavulanic acid in patients with positive bacterial sputum cultures.

• More research is required to confirm that the choice of antibiotic is critical in patients with risk factors for poor outcome, both in terms of recovery from AECOPD and in reducing early relapse.

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The use of moxifloxacin for acute exacerbations of chronic obstructive pulmonary disease and chronic bronchitis