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Respiratory Medicine: COPD Update (2007) 2, 124–132

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1745-0454/$ - sdoi:10.1016/j.r

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REVIEW

Antibiotic therapy and prophylaxis in COPD

Francesco Blasi�, Paolo Tarsia, Maria Pappalettera, Matteo Saporiti,Stefano Aliberti

Institute of Respiratory Diseases, University of Milan, Ospedale Maggiore IRCCS Fondazione Policlinico,Mangiagalli e Regina Elena, Milan, Italy

KEYWORDSCOPD;Exacerbations;Antibiotics;Prophylaxis

ee front matter & 2006medu.2006.10.002

ing author. Tel.: +39 02ess: francesco.blasi@un

Summary Bacteria are held responsible for a significant proportion of chronicobstructive pulmonary disease (COPD) exacerbations although demonstration ofappreciable beneficial effects following antibiotic treatment has been difficult toobtain. Recent evidence suggests that antimicrobial treatment is not indicated in allCOPD patients with exacerbations and that adequate patient stratification isessential. Among the factors associated with greatest benefit following antibiotictherapy are sputum purulence, patient severity, and presence of comorbidities. It isnow recognized that exacerbation microbiology varies with baseline disease severity,with Gram-negative bacteria and Pseudomonas aeruginosa more commonlyencountered in more severely compromised patients. Antibiotic selection must takeinto consideration patient characteristics and probable etiologic agents. A significantnumber of COPD patients have persistent airway bacterial colonization outsideexacerbation episodes. Recently, prophylactic antibiotic use in these patients hasrecently received renewed attention.& 2006 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125Bacteria in COPD exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125Patient stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Potential pathogens involved in COPD exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Antibiotic resistance issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Antibiotic selection in COPD exacerbation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Airway bacterial colonization and antibiotic prophylaxis in COPD . . . . . . . . . . . . . . . . . . . . . . . 129

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Elsevier Ltd. All rights reserved.

50320621; fax: +39 02 503920628.imi.it (F. Blasi).

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Exacerbations and prophylaxis 125

Introduction

Chronic obstructive pulmonary disease (COPD) ischaracterized by a progressive decline in respira-tory function, exercise capacity, and health status.COPD is punctuated by periodic exacerbationsassociated with substantial morbidity, respiratoryfailure requiring mechanical ventilation in somepatients, and is the primary cause of death for thisdisease.1 Exacerbations are associated with sub-stantial treatment failures, relapses requiringhospitalization, and increased 1 year mortality.2

Therefore, treatment strategies are required toidentify when and for whom different therapeuticapproaches (including antibiotic therapy) should beimplemented in order to contain morbidity andmortality associated with exacerbations.

Bacteria in COPD exacerbations

Bronchoscopic sampling of the distal airway usingprotected brush specimens, in exacerbated andstable phase COPD patients, has shown that at least50% of patients may have bacteria in high concen-trations in their lower airways during exacerba-tions,3 and that bacterial yield may rise to 70% insevere exacerbations requiring mechanical ventila-tion.4

Exclusive reliance on invasive and non-invasiveculture techniques analyzing bronchial secretionsmay underestimate the presence of bacteria, asthese may proliferate within the epithelial celllayer and submucosa with little shedding into thelumen.5 Bandi et al.6 cultured Hemophilus influen-zae in only 7% of secretions from exacerbated COPDpatients but demonstrated intracellular H. influen-zae in bronchial biopsies from 87% of patients withexacerbations.

Sethi et al.7 used molecular typing to identifynew strains within a bacterial species in sputumisolates collected during an exacerbation and atstable phase. Acquisition of a strain with which thepatients had not previously been infected wasassociated with a more than two-fold increasedrisk of presenting with an exacerbation. Thisincreased risk was seen for H. influenzae, Strepto-coccus pneumoniae, and Moraxella catarrhalisstrains. A subsequent study by the same group8

demonstrated a strain-specific immune response inexacerbated patients with evidence of new H.influenzae strain acquisition. These new strainspresent an antigenic structure unknown to thehost, leading to an immune and inflammatoryresponse that clinically translates into an acuteexacerbation.9 A recent study specifically analyzing

M. catarrhalis in COPD exacerbations, identifiedthis bacterium in 10.2% of acute episodes.10 Similarto what happens with H. influenzae, acquisition ofa new bacterial strain was associated with strain-specific immunity towards M. catarrhalis.

Exacerbations are known to be associated withincreased airway inflammation.11 The presence ofbacteria in airway secretions during exacerbationsis associated with higher levels of IL8 (a neutrophilchemoattractant) in sputum and IL6 (a marker ofsystemic inflammation) in the blood.12 H. influen-zae outer membrane protein P6 seems to be amajor bacterial determinant of airway inflamma-tion (stimulating production of IL8, TNFa, and IL10)during infection with this bacteria.13 Furthermore,H. influenzae strains associated with an exacerba-tion caused more airway neutrophil recruitment,adherence and activation compared to strains thatcaused asymptomatic carriage.14 Irrespective ofthe bacterium involved, microbial eradication isassociated with a resolution of airway inflamma-tion, whereas continued bacterial presence isassociated with lesser inflammation reduction.15

Taken together, all these findings support theimportance of bacteria as a cause of exacerbations.An often quoted meta-analysis on randomizedplacebo-controlled antibiotic trials in COPD exacer-bations observed a mean increase of 10.75 L/min inpeak expiratory flow readings. The clinical signifi-cance of this finding has been questioned. A morerecent literature appraisal, based on much thesame studies as the former, supports the use ofantibiotics in COPD exacerbations, particularly inmore severe patients.16 Lastly, a very recentCochrane analysis17 concludes that good qualityrandomized-controlled trials of antibiotic treat-ment for COPD exacerbations has shown evidenceof clinical benefit. Particularly in exacerbationswith increased cough and sputum purulence,antibiotic therapy, regardless of drug choice,significantly decreased short-term mortality, treat-ment failure and sputum purulence. This effect wasgreatest in patients with severe exacerbations,with lack of benefit found for community-basedstudies.

Regrettably, in most older antibiotic efficacystudies on patients with exacerbations, a precisedefinition of COPD was often absent, with enrol-ment of young, non-obstructed never-smokers, andproblems of antibiotic resistance had not yetarisen. In addition, many studies offered unsatis-factory definitions of exacerbation, high populationseverity heterogeneity, and lacked stratification forsteroid use. It has been argued that the recentlyintroduced new brands of antibiotics are expensiveand usually not appropriate. However, reduction in

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failure and relapse rates associated with neweragents would considerably reduce the overall costsof COPD exacerbations.

Suggested novel end points in clinical trialsare the need for repeated courses of antibioticsfor the exacerbation as a surrogate marker ofrelapse, and the time free from exacerbation atlong-term follow-up. Studies should be aimed atdemonstrating superiority of novel agents ratherthan equivalence compared to traditional thera-peutic options.

Patient stratification

It is now clear that not all COPD patients presentingwith an exacerbation need to be treated withantibiotics. Therefore, efforts are currently beingmade to identify patients who would most likelybenefit from antimicrobial therapy. Anthonisen etal.18 in the 1980s identified three cardinal symp-toms: increase in dyspnea; increase in sputumvolume; and increase in sputum purulence. Pre-sence of all three symptoms (Type I exacerbation)was associated with beneficial effects followingantimicrobial treatment. A Type II exacerbation isdefined as the presence of two cardinal symptoms,whereas a Type III exacerbation presents only onecardinal symptom. Among the symptoms of anexacerbation, a clear relationship has emergedbetween the presence of sputum purulence andairway bacterial load.

Stockley et al.19 devised a sputum color chart todistinguish between purulent and mucoid COPDexacerbations. The presence of green purulentsputum was 94.4% sensitive and 77.0% specific forthe yield of a high bacterial load, indicating asubset of patients that would most likely benefitfrom antibiotic therapy. Similarly, a further studyusing a quali-quantitative colorimetric scale allow-ing both color distinction and color degree ofintensity on sputum samples from exacerbatedCOPD patients found an association betweensputum purulence and bacterial identification.20

Patient baseline severity must also be consideredas antibiotics have not been proven to be beneficialin ambulatory patients with mild symptoms (simplechronic bronchitis).21 Conversely, antibiotics have agreater beneficial effect in patients with moresevere disease,22 which translates into a survivaladvantage in those sufficiently severe to requiremechanical ventilation.23

Putting together all the above information,patient stratification systems have been devisedin order to direct antibiotic treatment in exacer-bations of COPD. The most recent joint European

Respiratory Society/European Society for ClinicalMicrobiology and Infectious Diseases (ERS/ESCMID)guideline24 identifies three different groups. GroupA includes patients not requiring hospitalization(mild COPD). Group B includes patients that areadmitted to hospital (moderate–severe COPD)without risk factors for Pseudomonas aeruginosainfection. Finally, Group C comprises patientsadmitted to hospital (moderate–severe COPD) withrisk factors for P. aeruginosa.

In Group A outpatients, an antibiotic should begiven during exacerbations of COPD in the presenceof a Type I exacerbation presenting with all three ofthe cardinal symptoms: increased dyspnea; in-creased sputum volume; and increased sputumpurulence. In addition, antibiotics should be con-sidered for exacerbations in patients with severeunderlying COPD, irrespective of exacerbationintensity.

In patients with Group B or C exacerbationsrequiring hospitalization antibiotics should begiven to the following: (1) patients with a Type IAnthonisen exacerbation; (2) patients with a Type IIAnthonisen exacerbation when increased purulenceof sputum is one of the two cardinal symptoms; and(3) patients with a severe exacerbation that re-quires invasive or non-invasive mechanical ventila-tion. Antibiotics are generally not recommended inAnthonisen Type II exacerbations without purulenceor in Type III patients (see Fig. 1).

Potential pathogens involved in COPDexacerbations

It is now accepted that airway microbiologychanges during the different stages of severity ofthe disease. Studies in patients with mild exacer-bations,25 which do not require hospital admission,have shown that the predominant microorganismsare H. influenzae, S. pneumoniae and M. catar-rhalis. In contrast, in patients requiring mechanicalventilation (mean FEV1 o30%)4 the role of theabove agents is less important and other patho-gens, such as enteric Gram-negative bacilli and P.aeruginosa may be more frequent. Identified riskfactors for P. aeruginosa infection include: (1)recent hospitalization; (2) frequent administrationof antibiotics (four courses in the last year); (3)very severe COPD (FEV1 o 30%); and (4) isolation ofP. aeruginosa during a previous exacerbation orcolonization during a stable period.26,27 Other obser-vations support the concept that COPD severity (asexpressed by FEV1 impairment) is an importantdeterminant of the type of pathogen associa-ted with an exacerbation26,27 (see Table 1).

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Figure 1 An algorithm for indications for antimicrobial treatment of acute COPD exacerbations based on severity ofexacerbation.

Exacerbations and prophylaxis 127

During the 1990s a number of studies addressedthe possible involvement of atypical pathogens(Chlamydia pneumoniae, Mycoplasma pneumoniae,and Legionella pneumophila) as a cause of COPDexacerbations. Based on current evidence, Legio-nella infection does not appear to be a significantissue in this setting. Conversely, most studies showthat C. pneumoniae is found in between 4% and 20%of exacerbations,28,29 with M. pneumoniae beingless frequent. Viruses and atypical organisms maybe involved in exacerbations by causing a primaryinfection that worsens lower airway inflammation,enhancing bacterial proliferation, leading to sec-ondary bacterial involvement in these episodes.

Antibiotic resistance issues

Penicillin-resistant S. pneumoniae strains have beenisolated in most countries world-wide, with impor-tant regional variations. Penicillin-resistant strainrates above 40% have been described in theUS, France, Spain, Hungary, and Japan amongothers.30,31 In parallel, resistance to erythromycinis observed in 1–42% of S. pneumoniae isolates whennational data of European countries are considered.Factors associated with increased risk of infectionswith drug-resistant pneumococci include previousantibiotic treatment with a b-lactam, age over 65years, presence of comorbidity, and use of systemicsteroids.32

The number of macrolide-resistant S. pneumo-niae strains is on the rise. Results from theAlexander Project indicate that in 1996 and 1997the global rate of pneumococcal macrolide resis-tance was 16.5–21.9%31; by 1998–2000, the resis-tance rate had increased to 24.6%.33

Although penicillin resistance among pneumo-coccal strains has taken several decades todevelop, the prevalence of S. pneumoniae resis-

tance to the newer fluoroquinolones has rapidlybecome substantial in some countries.34 Outsidethese limited areas, the worldwide prevalence isstill o2%.

b-lactamases account for most of the resistanceto b-lactams in H. influenzae and M. catarrhalis.35

The proportion of b-lactamase positive H. influen-zae varies from 2% to 22% in Europe,36 and 30–40%in North America. Since the late 1990s, over 90% ofM. catarrhalis strains produce b-lactamases in mostcountries of the world.37 There are no clinical cluesthat can predict the presence of b-lactamase-producing bacteria during exacerbations, exceptthat patients with these organisms tend to havehad more previous courses of antibiotics.

The true role of antimicrobial resistance inclinical practice is debated. Data indicate thatappropriate doses of b-lactams should achieveadequate drug concentrations to treat pneumococ-cal strains thought to be non-susceptible. Similarly,the extremely high tissue concentrations reachedby newer macrolides might effectively inhibitresistant S. pneumoniae strains. However, in-creased risk of death or treatment failures havebeen reported for infections with high-level peni-cillin-resistant and macrolide-resistant bacteremicpneumococci.38 Wide geographic variations areobserved in resistance rates, therefore, makingknowledge of local microbiological conditions im-perative in guiding treatment.

Antibiotic selection in COPD exacerbation

In patients with mild COPD exacerbations, gener-ally not requiring hospitalization, an antibioticshould be considered only in presence of all threeof the Anthonisen criteria (Type I exacerbation).Common pathogens in this group are H. influenzae,S. pneumoniae, and M. catarrhalis. The ERS/ESCMID

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Table 1 Stratifying antibiotic treatment by comorbidities and pathogens (based on Woodhead et al.24).

F. Blasi et al.128

guideline24 suggests the use of amoxicillin, ampicillinor a tetracycline, although use of these drugs may bea concern in countries with high levels of antibioticresistances of S. pneumoniae and b-lactamase-producing H. influenzae, due to high relapse rate.Alternatively, high-dose amoxicillin–clavulanate isactive against both S. pneumoniae and H. influenzae.Although rates of macrolide-resistant S. pneumoniaecan be high, and most H. influenzae strains areresistant to clarithromycin, newer macrolides (clar-ithromycin, azithromycin) have shown good activitywhen compared to other antibiotics in clinical trials.39

Telithromycin is a ketolide derived from macrolidesthat is effective against S. pneumoniae strainsresistant to penicillins and macrolides, and is moreeffective than azithromycin against H. influenzae.Clinical experience with this drug is still limited. Inmild COPD exacerbation patients requiring antimicro-bial therapy, oral treatment is generally sufficient.

In acute phase COPD requiring hospitalization butpresenting no risk factors for P. aeruginosa (GroupB), antibiotic treatment is indicated in Type Iexacerbations, Type II exacerbations (providedsputum purulence is present), and in severedisease. In addition to pathogens present in mildCOPD patients, other Gram-negative microrganismssuch as Enterobacteriaceae must be kept in mind,as well as drug resistant bacteria. Amoxicillin–

clavulanate is a suitable first choice drug, althoughthe new quinolones must be considered (Table 2).Levofloxacin and moxifloxacin are more active thanciprofloxacin against most S. pneumoniae strainsand achieve high concentrations in bronchialsecretions. In addition, they are active againstGram-negative bacilli other than P. aeruginosa.Treatment with medications directed at resistantorganisms, such as a fluoroquinolones or amoxicil-lin–clavulanate should perform better than amox-icillin or other traditional first-line agents. There isincreasing evidence suggesting that the enhanced

bacterial eradication associated with fluoroquino-lones leads to faster symptom resolution andresults in more prolonged disease-free intervalscompared to cephalosporins and extended spec-trum macrolides. The oral route is preferred, but insome situations the parenteral route has to beused. Non-antipseudomonal third-generation ce-phalosporins, such as ceftriaxone and cefotaxime,are also antibiotics with good activity against themajority of microorganisms.

In hospitalized exacerbated moderate–severeCOPD patients with risk factors for P. aeruginosa,the most active orally administered antipseudomo-nal antibiotic is ciprofloxacin. This antibiotic is alsoactive against H. influenzae, M. catarrhalis, otherGram-negative bacilli, and atypical pathogens. Amajor limitation with ciprofloxacin is its poor acti-vity against S. pneumoniae, although this pathogenmay be more uncommon in severely compromisedpatients compared to those with milder disease.Another concern is the increasing rate of resist-ance to P. aeruginosa observed in some Europeancountries. High dosages of ciprofloxacin are re-commended to achieve higher serum and bronchialconcentrations.40 The activity of levofloxacinagainst P. aeruginosa has recently been approvedby the US Food and Drug Administration (750mgonce daily), although clinical experience is limited.

In moderate–severe patients, oral antibioticadministration may be considered if the patient isable to eat. If this is not the case, the i.v. route hasto be used. Switching to oral treatment may beconsidered when there is clinical stabilization 3–5days after admission. In the most severely illpatients (particularly when admitted to an ICU),i.v. administration of antibiotics is mandatory.In this category of patients, particularly whenP. aeruginosa is suspected, combinations of anti-biotics are advisable (see Table 2). Antipseudomo-nal b-lactams include ceftazidime, cefepime,

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Table 2 Proposed antibiotic choices in patients with COPD exacerbations based on patient stratification (basedon Woodhead et al.24).

Oral treatment Alternative Parenteral treatment

Group AMild COPDAntibiotic therapy may notbe required

AmoxicillinTetracycline

Macrolidea Amoxicillin-clavualanate

–

LevofloxacinMoxifloxacin

Group BModerate–severe COPDwithout risk factors for P.aeruginosa

Amoxicillin-clavulanate

Levofloxacinb

MoxifloxacinbAmoxicillin Amoxicillin-clavulanate2nd or 3rd generationcephalosporinc

LevofloxacinMoxifloxacin

Group CModerate or severe COPDwith risk factors for P.aeruginosa

Ciprofloxacin Ciprofloxacin or betalactamd

with P. aeruginosa activity7aminoglycosidese

In countries with high incidence of penicillin-resistant Streptococcus pneumoniae, high doses of amoxicillin or amoxicillin-clavulanate are suggested.

aErythromycin, clarithromycin, roxithromycin or azithromycin. Telithromycin may be an alternative for consideration in thecommunity or in hospitals for COPD exacerbation or CAP. However, clinical experience with this antibiotic is currently toolimited to make specific recommendations. Oral cephalosporins are generally not recommended due to poor pharmacokinetics.

bLevofloxacin and moxifloxacin show better coverage towards S. pneumoniae than Ciprofloxacin.cCeftriaxone or cefotaxime.dCefepime, piperacillin–tazobactam, or a carbapenem.eThere are no data on the benefit of combination therapy for P. aeruginosa treatment in COPD exacerbations.

Exacerbations and prophylaxis 129

piperacillin/tazobactam, or a carbapenem (imipe-nem/cilastatin or meropenem). A fluoroquinoloneor one of the above antipseudomonal b-lactamsmay be used in combination with an aminoglyco-side.

Although there are no definitive data on thesubject, antibiotic treatment in exacerbated COPDpatients should be maintained for an average of7–10 days. Shorter courses (5 days) of newerfluoroquinolones have been as effective as 10 daysof treatment with b-lactams in some trials.41–43

Up to 10–20% of patients with moderate–severeexacerbations do not respond to initial antibiotictreatment and may require a change in thetherapy.44 Some failures may be related to patho-gens not covered by the empirical regimen. P.aeruginosa, Staphylococcus aureus (includingmethicillin-resistant strains), acinetobacter andother non-fermenters are the most frequent causesof failure. Aspergillus spp. have been morecommonly described in recent years, particularlyin patients with prolonged systemic steroid treat-ment. Alternatively, high-level antibiotic resistanceto common pathogens (such as S. pneumoniae)must also be considered.

Airway bacterial colonization and antibioticprophylaxis in COPD

The lower airways of healthy non-smoking adultsare usually a sterile environment. Conversely,presence of bacteria in the lower airways may beintermittently detectable in most COPD patients atsome time in the course of the disease. In roughly25–40% of COPD patients, bacteria are persistentlypresent in the lower airways.3,45 This condition hasbeen termed ‘‘colonization’’, under the impressionthat it somewhat resembled commensal coloniza-tion of the oropharynx. The presence of coloniza-tion was felt to be a marker of disease severity withbacterial presence being caused by long-termairway inflammation and derangement of defencemechanisms. However, in recent years is has beenincreasingly recognized that chronic bacterialcolonization in COPD is by no means a passiveprocess. A bronchoscopic study in stable COPDpatients indicates that the presence of bacteria isassociated with increased neutrophil counts andlevels of pro-inflammatory cytokines in airwaylining fluid.46 Later studies confirmed that stableCOPD patients with positive sputum cultures

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present elevated levels of IL8, leukotriene B4,neutrophil elastase, and TNF-a compared to non-colonized patients.47,48 Inflammatory cytokine le-vels were also increased in nasal wash,48 as wereplasma fibrinogen levels,47 suggesting inflammatoryspill out beyond the lower airways. In addition, a12-month longitudinal study on COPD patientsfound an association between increasing bacterialload and accelerated decline in FEV1, suggestingthat bacterial colonization may contribute todisease progression.49

H. influenzae is the most commonly identifiedbacterial pathogen identified in chronically colo-nized COPD patients. A recent study suggests thatcolonization with this bacterium may be morecommon than previously thought.50 Molecular typ-ing techniques were applied on COPD patientscolonized with H. influenzae that showed pro-longed periods of negative culture growth. Thesetyping methods identified that the strains preced-ing and following the episodes of negative cultureswere identical. The results suggest that traditionalculture may underestimate the true incidence ofrespiratory tract H. influenzae colonization inCOPD. In contrast to the prolonged carriage of H.influenzae, M. catarrhalis appears to be clearedmore quickly from the airways.10

The results of the above findings suggest thatantibiotic therapy in colonized patients may exertimportant therapeutic effects, possibly affectingthe natural history of the disease. This has offerednew impetus to the prophylactic use of antimicro-bials to reduce the frequency and severity of COPDexacerbations and therefore affect the decline inlung function associated with exacerbations. Pro-phylactic use of antibiotics, particularly duringwinter months, was common in some countriesroughly 30 years ago, but was largely abandoneddue to lack of scientific validation. Recently, aCochrane review analyzed nine clinical trials invol-ving 1055 patients, randomized to prophylacticantibiotic treatment.51 Most of these studies wereconducted in the late 1950s and early 1960s, andused agents such as tetracyclines, penicillin,sulfaphenazole, and co-trimoxazole. The likelihoodof having an exacerbation during the course of thestudy was decreased with treatment. The averagenumber of patients needed to treat to preventan exacerbation was 14. Prophylactic antibioticswere associated with a small but not statisticallysignificant reduction in exacerbations, and in thenumber of disability days. There was a smallincrease in adverse events with antibiotics. Theauthors conclude that prophylactic antibioticsdo not have a place in routine treatment beca-use of concerns about the development of anti-

biotic resistance and the possibility of adverseevents.

Clearly, more recent large-scale trials areneeded to determine the impact of more modernantibiotics as prophylactic measures in COPDpatients in the current era of antibiotic resistance.Currently, a large multicenter prospective rando-mized trial is underway, comparing 5-day courses ofmoxifloxacin every 2 months with placebo in COPDpatients.52

Conclusions

Over recent years, introduction of more sophisti-cated microbiological techniques have furnishedfurther evidence for the role of bacteria as a causeof COPD exacerbations. Better definition of patientsubgroups should help identify subjects who maytruly benefit from antimicrobial therapy. Futurestudies should be based on a specific approach toCOPD that takes into account its unique character-istics. This would give rise to highly informativedata that could be translated into solid antibiotictreatment recommendations in future guidelines onthe antibiotic management of COPD exacerbations.A further area that requires investigation is thepotential utility of antibiotic treatment outsideexacerbations to reduce the burden of chronicairway bacterial colonization.

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