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Respiratory Medicine (2005) 99, 663–669

KEYWORDChronic obpulmonary23-valentcoccal cappolysacchacine;Acute exacAzithromy

0954-6111/$ - sdoi:10.1016/j.r

�CorrespondiHospital, Via de

E-mail addr

Treatment of acute exacerbation of severe-to-verysevere COPD with azithromycin in patientsvaccinated against Streptococcus pneumoniae

Mario Cazzola�, Antonello Salzillo, Carlo De Giglio, Amedeo Piccolo,Clara Califano, Paolo Noschese

Department of Pneumology, Unit of Pneumology and Allergology, A. Cardarelli Hospital, Naples, Italy

Received 1 November 2004

Sstructivedisease;pneumo-sularride vac-

erbation;cin

ee front matter & 2004med.2004.11.007

ng author. Departmentl Parco Margherita 24,ess: mcazzola@qubisoft

Summary Sixty-five consecutive eligible adult patients, who were treated asoutpatients for stable severe-to-very severe COPD, were enrolled in the study. All ofthem received 23-valent pneumococcal capsular polysaccharide vaccine intramus-cularly. Patients were seen monthly, as well as whenever they had symptomssuggestive of an exacerbation, at our outpatient clinic. Eighteen out of 65 patientssuffered from acute exacerbation (AECOPD). Three of these patients presented twoepisodes of AECOPD. Patients with an acute exacerbation of COPD receivedazithromycin 500mg/day once daily for 3 days and a short course of oralprednisolone 25mg/die. In 16 cases, a single species was isolated, while in theremaining 5 cases at least two species were recovered. Clinical cure or improvementat the end of therapy (3–5 days post-therapy) was reported in 17 episodes of AECOPDwith no relapse at the late post-therapy (10–14 days after the completion oftreatment). Bacteriologic eradication or presumptive eradication rates at the end oftherapy were 86% (24 out of 28 isolates). Azithromycin eradicated all isolates ofHaemophilus influenzae, Moraxella catarrhalis, H. parainfluenzae, Klebsiellapneumoniae, and Klebsiella spp. isolated at baseline. Eradication of Sta aureusoccurred in 1 of 3 isolates whereas azithromycin was unable to eradicatePseudomonas aeruginosa isolates. Our data seem to indicate that pneumococcalvaccination reduces the possibility that an AECOPD is caused by Streptococcuspneumoniae. This finding allows the use of antibiotics such as azithromycin, which,otherwise, should be avoided because of resistances.& 2004 Elsevier Ltd. All rights reserved.

Elsevier Ltd. All rights reserved.

of Respiratory Clinical Pharmacology, Division of Pneumology and Allergology, A. Cardarelli80121 Napoli, Italy. Tel./fax: +39 81 404188..it (M. Cazzola).

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M. Cazzola et al.664

Introduction

Resistance to macrolides in strains of Streptococcuspneumoniae varies markedly in different parts ofthe world. This variability is illustrated in the rangeof macrolide resistance in Europe, where over 40%of isolates from France and Italy were resistant, incontrast to less than 10% of isolates from Germany,The Netherlands, the Czech Republic and Poland.1

Poor activity of macrolides in vitro is hypotheticallyreflected in a poor clinical response. There are nowseveral reports of failure when using a macrolide totreat a pneumococcal infection caused by a macro-lide-resistant strain.2–7 Recently, Lonks et al.7 used amatched case-controlled study to investigatewhether breakthrough bacteraemia (defined aspneumococcal bacteraemia occurring in patientsreceiving macrolide therapy) was linked with thesusceptibility of the isolate to macrolides. In 136control patients infected with erythromycin-suscep-tible pneumococci, there was no evidence of break-through bacteraemia, but it occurred in 24% (18/76)of patients infected with strains of reduced suscept-ibility to erythromycin, including intermediate andresistant cases.7 However, the mortality rate tendedto be lower among case patients taking macrolidesthan among patients not taking a macrolide (0%versus 18%; P ¼ 0:06), which is an intriguing finding.7

The estimated increased prevalence of macrolideand multidrug resistant pneumococci worldwidemight reduce the efficacy of macrolides to treatpneumococcal lower respiratory tract infections.8

The problem of resistance is heightened by thedifficulty in choice among commonly used groups ofantibiotics, since resistance to erythromycin isprevalent among penicillin-resistant strains9 andresistance to ciprofloxacin is prevalent amongpenicillin-non-susceptible and erythromycin-resis-tant strains.9,10

Antibiotic resistance has presented a new clinicalchallenge especially for the treatment of pneumo-coccal lower respiratory tract infections. It has alsorevived interest in the prevention of pneumococcalinfections by vaccination, raising the question ofwhether more extensive use of the present vaccinewould be an effective means for the prevention andcontrol of antibiotic-resistant pneumococcal dis-ease. Today, 23-valent pneumococcal polysacchar-ide vaccines, covering the 23 most important of the90 pneumococcal serotypes, are available through-out the world and used to a variable extent in high-risk groups and the elderly.

S. pneumoniae is a pathogen commonly asso-ciated with acute bacterial exacerbations ofobstructive pulmonary disease (AECOPD). Amongpatients with AECOPD, it is estimated to be

responsible for 15–25%.11 Despite reports of macro-lide-resistant S. pneumoniae, advanced-generationmacrolides, azithromycin and clarithromycin arestill commonly used in the empirical treatment ofAECOPD.12 In fact, as evidenced by the study ofDestache et al.13 these macrolide agents provide abroader spectrum of activity than did the oldergeneric agents and improve outcomes in patientswith AECB of bacterial origin.

Because the choice of initial therapy in thetreatment of community-acquired respiratory in-fections is empirical (i.e. made without the benefitof knowing the pathogen and its antibiotic suscept-ibility) due to the fact that office-based physicianscan rarely, if ever, obtain sputum samples withwhich to identify causal pathogens,14 and in view ofthe increasing prevalence of macrolide-resistantpneumococci, we evaluated the clinical and bac-teriologic outcomes associated with using a stan-dard 3-day course of oral azithromycin for theoutpatient treatment of those patients withAECOPD who had received 23-valent pneumococcalpolysaccharide vaccine.

Patients and methods

Sixty-five consecutive eligible adult patients, whowere treated as outpatients for stable severe-to-verysevere COPD in accordance with American ThoracicSociety/European Respiratory Society criteria,15

were enrolled in the study. Table 1 shows thebaseline demographics and characteristics of theenrolled patients. All patients were treated withsalmeterol/fluticasone 50=250mg combination bidand continued to take the possible usual therapiesfor concomitant co-pathologies. All of them received23-valent pneumococcal capsular polysaccharidevaccine 0.5mL (25mg each capsular type) intramus-cularly. We excluded from the study immunocom-promised people with presumed poor response to thevaccine (such as patients with myeloma or otheractive malignant disease, renal dialysis, hypogam-maglobulinaemia, anatomical or functional asplenia,or HIV-1 infection).16 Written informed consent wasobtained before patient enrolment.

The inclusion period was from September 1 toDecember 31, 2003. The follow-up period ended onJuly 31, 2004. Patients were seen monthly, as wellas whenever they had symptoms suggestive of anexacerbation, at our outpatient clinic.

At each of these visits, clinical information andsputum, when present, and serum samples wereobtained. Patients were questioned about thestatus of their chronic respiratory symptoms

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Table 1 Baseline demographics and characteris-tics of the enrolled patients.

Variable Number (%)of patients

SexMale 51 (78)Female 14 (22)

Age (years) 62.4712.8FEV1p50% of normal 42 (65)430% of normal 23 (35)

Co-existing cardiopulmonarydiseaseYes 31 (48)No 34 (52)

Exacerbations in previous yearX3 18 (28)o3 47 (72)

SmokingYes 53 (81)No 12 (19)

Treatment of AECOPD 665

(dyspnea, cough, sputum production, viscosity, andpurulence), and the responses were graded as 1 (atthe usual level), 2 (somewhat worse than usual), or3 (much worse than usual) according to the methodof Sethi et al.17 A minor worsening of two or moresymptoms or a major worsening of one or moresymptoms prompted a clinical assessment of thecause.17 If the patient had fever (a temperaturethat exceeded 38.0 1C), appeared ill, or had signs ofconsolidation on examination of the lungs, a chestfilm was obtained to rule out pneumonia. If othercauses of the worsening of symptoms, such aspneumonia, upper respiratory infection, and con-gestive heart failure, were ruled out, the patientwas considered to be having an AECOPD. Allpatients produced a sputum specimen. Thosespecimens that contained 425 neutrophils andp10 epithelial cells per low-power (100� ) micro-scopical field were submitted for culture. Thedetermination of whether the patient had stabledisease or an exacerbation was made before theresults of sputum cultures were available.

All patients with an AECOPD received azithromy-cin 500mg/day once daily for 3 days and a shortcourse of oral prednisolone 25mg/die.

To compare the efficacy of the antibiotic treat-ment, clinical and bacteriological responses wereassessed 3–5 (post-therapy) and 10–14 (late post-therapy) days after the completion of treatment.Clinical (symptomatic) response was assessed bythe investigators as follows: cure: an elimination of

signs and symptoms and no recurrence at thefollow-up visits; improvement: a significant, butincomplete, resolution of signs or symptoms;relapse: worsening of signs and symptoms followingan initial improvement; failure: no improvement.Patients were designated as unappreciable if theycould not be assigned to a category and weredisqualified for efficacy analysis.

Patients were classified as bacteriologicallyappraisable if they had a positive culture of apre-therapy sputum specimen with a respiratorypathogen. The following organisms were consid-ered potential pathogens: Haemophilus influenzae,Klebsiella pneumoniae, S. pneumoniae, Klebsiellaspp., Moraxella catarrhalis, Staphylococcus aur-eus, H. parainfluenzae and Pseudomonas aerugino-sa. At post-therapy, bacteriological response wasbased on microbiological culture data as follows:eradication: pathogen eliminated; persistence:culture positive for original pathogen; colonization:culture positive for a new pathogen without thesigns of infection; superinfection: culture positivefor a new pathogen during therapy (requiredsymptomatic response). At late post therapy visit,it was based as follows: eradication: pathogeneliminated; relapse: recurrence of the same patho-gen with or without the development of resistance(required a positive follow-up culture preceded byat least one negative culture); colonization: cul-ture positive for a new pathogen without the signsof infection; eradication with reinfection: culturepositive for a new pathogen after treatment(required symptomatic response of failure orrelapse). If no follow-up sputum specimen wasproduced for culture, the following definitionswere assigned: presumed microbiological persis-tence: no follow-up culture obtained with asymptomatic response of relapse or failure; pre-sumptive eradication: implied absence of appro-priate material for culture, or culture not clinicallyindicated (required symptomatic response of cureor improvement); indeterminate: could not beevaluated (bacteriological response could not bedefined or categorized), or new antibiotic startedfor a condition other than the study indicationbefore appropriate material for culture was ob-tained, or no pathogen isolated from the pre-therapy culture.

Results

Eighteen out of 65 patients suffered from AECOPD.Three of these patients presented two episodes ofAECOPD.

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Table 4 Bacteriological results in isolates ofpatients with acute exacerbation of COPD.

Bacteriological response Number (%)of isolates

Post-therapyIsolate number 28 (1 0 0)Eradication or presumptive

eradication24 (86)

Persistence or presumedpersistence

4 (14)

Colonization 0 (0)Superinfection 0 (0)Indeterminate 0 (0)

Late post-therapyIsolate number 24 (1 0 0)Eradication or presumptive

eradication24 (1 0 0)

Relapse 0 (0)Colonization 0 (0)Eradication with reinfection 0 (0)Indeterminate 0 (0)

M. Cazzola et al.666

In 16 cases, a single species was isolated, while inthe remaining 5 cases at least two species wererecovered, with a total of 28 bacterial isolatesobtained at baseline (Table 2). The species isolatedwere H. influenzae (9 isolates), M. catarrhalis(5 isolates), H. parainfluenzae (5 isolates), K.pneumoniae (3 isolates), S. aureus (3 isolates), P.aeruginosa (2 isolates), Klebsiella spp. (1 isolates).No S. pneumoniae strain was isolated from thesputum of our patients.

Clinical cure or improvement at the end oftherapy (3–5 days post-therapy) was reported in17 out of 21 episodes of AECOPD, with no relapse atthe late post-therapy (10–14 days after thecompletion of treatment) (Table 3).

Bacteriologic eradication or presumptive eradi-cation rates at post-therapy were 86% (24 out of 28isolates) (Table 4). Azithromycin eradicated allisolates of H. influenzae, M. catarrhalis, H. para-influenzae, K. pneumoniae, and Klebsiella spp.isolated at baseline. Eradication of S. aureusoccurred in 1 of 3 isolates whereas azithromycinwas unable to eradicate P. aeruginosa isolates. At

Table 2 Pathogens isolated prior to treatment(n ¼ 28) in 21 episodes of acute exacerbation ofCOPD.

H. influenzae 9M. catarrhalis 5S. aureus 3H. parainfluenzae 5K. pneumoniae 3P. aeruginosa 2Klebsiella spp 1

Table 3 Clinical responses in patients with acuteexacerbation of COPD.

Clinical response Number (%) of patients

Post-therapyPatient number 21 (1 0 0)Cure 11 (52)Improvement 6 (29)Relapse 0 (0)Failure 4 (19)Unappreciable 0 (0)

Late post-therapyPatient number 17 (1 0 0)Cure 17 (1 0 0)Improvement 0 (0)Relapse 0 (0)Failure 0 (0)Unappreciable 0 (0)

the late post-therapy, neither relapse nor reinfec-tion was observed.

Discussion

Recent documentation has shown that airwaycolonization with S. pneumoniae, specifically whenpresent as a monoculture, increases the risk of afirst COPD exacerbation.18 Also Sethi et al.17

showed a significant increase in exacerbationswhen S. pneumoniae was isolated. It is clear,therefore, that the dilemma facing the clinicianwho must initiate therapy before cultureresults are available is that treatment of AECOPDmust cover S. pneumoniae, which is becomingincreasingly resistant to ß-lactam and macrolideantibacterials.1 The situation is compounded bycross-resistance within and between classes ofantibacterial agents, which further limits treat-ment options.

The ultimate tool of modern medicine forcombating infectious diseases may be the vaccine.COPD patients are able to mount a significantimmune response to pneumococcal infection. Theymay therefore benefit from pneumococcal vaccina-tion.18 The modern pneumococcal vaccine wasintroduced in 1977, and expanded from 14 to 23-valent in 1983 to include between 75% and 90% ofall pathogenic strains associated with bacterae-mia.19 The polysaccharide vaccine has not onlybeen shown to be highly effective, but also safe,

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Treatment of AECOPD 667

and cost effective.16,20 A retrospective study,which involved 1898 patients with chronic lungdisease documented that receipt of pneumococcalvaccine, as defined by administrative data, wasassociated with significant reductions in the risk ofhospitalization for pneumonia and influenza.21

Nonetheless, it has been suggested that the overallefficacy of the vaccine is possibly reduced in elderlypatients with COPD.22 Leech et al.23 did notobserve significantly difference in the rates ofdeath, hospital admissions and emergency visitsand the mean length of hospital over a 2-yearperiod between a group of patients who receivedthe 14-valent pneumococcal vaccine and anothertreated with saline placebo. However, David etal.24 who assessed the importance of S. pneumo-niae and immunologic response to 14-valent pneu-mococcal vaccine in a randomized (saline placeboor vaccine) double-blind study involving patientswith COPD, documented that although pneumoniaoccurred frequently in these patients, non-pneu-mococcal causes predominated and isolates fromsputum were predominantly non-vaccine types.Recently, Bogaert et al.18 have shown that pneu-mococcal colonization in COPD patients is fre-quently caused by vaccine serotype strains.However, mathematical modelling and animal datasuggest that serotype replacement may occur afterthe initiation of routine vaccination pro-grammes,25–27 which may question the overalleffectiveness of pneumococcal vaccination.

In the present study, only 18 out of 65 patientsvaccinated against S. pneumoniae suffered from anAECOPD, but none of them had an episode causedby S. pneumoniae. This a surprising finding con-sidering the amount of acute exacerbations thatpatients suffered from in the previous year. Wecannot define the exact value of 23-valent pneu-mococcal polysaccharide vaccine because this wasnot a placebo controlled study. We must stress,however, that all patients were under regulartreatment with salmeterol/fluticasone combina-tion, and it is well known that this treatmentreduces the number of AECOPD episodes.28 It hasbeen suggested that fluticasone propionate andsalmeterol could augment antibiotic treatment bymaintaining epithelial integrity and reducing thenumber of sites available for bacterial adher-ence.29 Bacteria adherent to mucus are clearedvia the mucociliary system, which would beenhanced by the preservation of ciliated cells.Salmeterol and fluticasone when administeredtogether at low concentrations, exhibit a synergis-tic effect with respect to the preservation ofciliated cells, showing a trend toward reduceddamage and a significant preservation of the

number of ciliated cells compared to either agentalone at the same concentrations.29 It seemsimportant to highlight that the use of salmeterol/fluticasone combination for treating COPDpatients was permitted in Italy only after the firstmonths of 2003 and, for this reason, 48 patientsreceived it for the first time only after theenrolment in the study. However, other factorscould justify this finding. For example, the periodof observation varied between 7 and 10.5 months,that was always less than 1 year. One way of partlyovercomes the lack of the placebo arm is to refer tothe same period the year before and list thenumber of exacerbations during that period but,unfortunately, we only asked for the number ofexacerbations that patients had suffered in theprevious year. We must also highlight that betweenJune and August 2003 there was a heat wavethat has influenced the levels of pollution;consequently, it can partially justify the numberof AECOPD suffered from our patients in theprevious year.

We did not measure the antibody response ofpatients to vaccine, and this is a bias of our study,considering that it has been documented that themajority of individuals respond to the vaccinationswith a marked increase in antibody levels, butthere are individuals who do not respond, demon-strating the individual variability in the response tovaccination with these antigens.30 The smallstudied sample and the lack of a placebo arm areother two important biases, but this was a single-centre, non-sponsored study that wished to repeatwhat happens in the real daily life.

In any case, our data seem to indicate thatpneumococcal vaccination reduces the possibilitythat an AECOPD is caused by S. pneumoniae. Thisfinding was not really unexpected, but we musthighlight that all the enrolled patients weresuffering from severe-to-very severe COPD and ithas been documented that in patients withFEV1o50%, S. pneumoniae is isolated with lessfrequency than H. influenzae, Enterobacteriaceaeand Pseudomonas species.31,32 All our patientswere immunocompetent and a recent meta-analy-sis has documented unambiguously the high effi-cacy of pneumococcal polysaccharide vaccine inreducing definite pneumococcal pneumonia by 71%in immunocompetent adults.33 This finding allowsthe use of antibiotics such as azithromycin, which,otherwise, should be avoided because of resis-tances. In effect, as a result of the in vitro reports,many prescribers are changing their choice ofantibiotics for pneumococcal, as well as forcommunity-acquired respiratory tract infections ingeneral, away from macrolides.

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M. Cazzola et al.668

Although, according to our data, we considerpneumococcal vaccination an important therapeu-tic action in COPD patients, we cannot omit tohighlight that we have treated our patients withazithromycin when they were suffering from anacute exacerbation. The activity of this azalideagainst common respiratory pathogens remainssatisfying, although its reduced in vitro activityagainst macrolide-resistant S. pneumoniae.34 Ourdata seem to indicate that azithromycin is a goodchoice for treating acute exacerbations in COPDpatients vaccinated against S. pneumoniae. Thesmall sample of treated patients and the reducednumber of AECOPD that these patients havesuffered from, however, do not allow us to drawsolid conclusions. In any case, despite increasingconcerns over macrolide resistance and a higherincidence of Gram-negative pathogens, a standard5-day course of oral azithromycin was clinically andbacteriologically equivalent to a 7-day course oforal levofloxacin in the treatment of patients withacute bacterial exacerbations of chronic bronchitisthat were not vaccinated against S. pneumoniae.35

This result is not surprising because, althoughazithromycin is mainly located intracellularly, theclinically achievable concentration of this macro-lide in epithelial lining fluid (ELF), which has beensuggested to be more predictive of the potentialantimicrobial effects of azithromycin against ex-tracellular pathogens associated with lower re-spiratory tract infections,36 exceed the MIC90s ofthe common respiratory pathogens included macro-lide-susceptible S. pneumoniae but not macrolide-resistant S. pneumoniae.37 It has been calculatedthat for an MIC of 0.5 mg/mL�1, after administra-tion of azithromycin 500mg on day 1 and 250mgdaily for the next 4 days to a 70 kg subject,AUC0�24/MIC, which has been suggested to be themost predictive pharmacodynamic parameter forthe efficacy of azithromycin, is 57.5 for ELF.38 Aplasma AUC0–24/MIC ratio of at least 10 (non-neutropenic host) and 25–30 (neutropenic host)have been suggested for the in vivo bacteriologicresponse of the common respiratory pathogens.37

It must be highlight that because of high tissuebioavailability, azithromycin has better in vivoefficacy than comparative agents, despite a similaror higher MIC. In particular, the reason for thedisparity between the rates of in vitro resistanceand clinical failures has been hypothesized to bedue to high concentrations of the drug within theWBCs (peak intracellular azithromycin concentra-tions within phagocytic cells reach at least 80mg/Land these concentrations are still 20–40mg/L 12days later) that bacteria are exposed to onphagocytosis, both in the blood and at the infection

site.39 As it is the phagocytes that take up and clearthe bacteria from the infection site or the blood,Amsden40 has suggested that azithromycin’s phar-macokinetics should enable the drug to be effectivein an infection, even with resistant pneumococci,as long as the MICs do not rise much above16–32mg/L. These values could be used as thebreakpoint, whether the dynamics of azithromycinare dependent on maximizing the AUC above theMIC or the time above MIC. It is likely that bychoosing clinical MIC breakpoints of 4–8mg/L forazithromycin rather than the present standardbreakpoints of X2mg/L, the clinician can make achoice that will optimize the pharmacodynamics ofthe drug against the isolated pathogen and result inthe best possible clinical outcome.

Considering the high level of macrolide-resis-tance in S. pneumoniae in Italy, we believe theresults of the present study suggest an interestingtherapeutic possibility that, in any case, must beexplored with a larger, better designed trial. Inparticular, a study must be designed that willcompare the impact of azithromycin and a classicmacrolide, such as clarithromycin or roxithromycin,in the treatment of acute exacerbations in COPDpatients vaccinated against S. pneumoniae in orderto confirm the advantage of this azalide over theother macrolides.

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