Effect of long term treatment with azithromycin on
disease parameters in cystic fibrosis: a randomised trial
J Wolter, S Seeney, S Bell, S Bowler, P Masel, J McCormack
Background: Relentless chronic pulmonary inflammation is the major contributor to morbidity and
mortality in patients with cystic fibrosis (CF). While immunomodulating therapies such as prednisolone
and ibuprofen may be beneficial, their use is limited by side effects. Macrolides have immunomodula-
tory properties and long term use dramatically improves prognosis in diffuse panbronchiolitis, a condi-
tion with features in common with the lung disease of CF.
Methods: To determine if azithromycin (AZM) improves clinical parameters and reduces inflammation
in patients with CF, a 3 month prospective randomised double blind, placebo controlled study of AZM
(250 mg/day) was undertaken in adults with CF. Monthly assessment included lung function, weight,
and quality of life (QOL). Blood and sputum collection assessed systemic inflammation and changes in
bacterial flora. Respiratory exacerbations were treated according to the policy of the CF Unit.
Results: Sixty patients were recruited (29 men) of mean (SD) age 27.9 (6.5) years and initial forced
expiratory volume in 1 second (FEV1) 56.6 (22.3)% predicted. FEV1% and forced vital capacity (FVC)%
predicted were maintained in the AZM group while in the placebo group there was a mean (SE)
decline of –3.62 (1.78)% (p=0.047) and –5.73 (1.66)% (p=0.001), respectively. Fewer courses of
intravenous antibiotics were used in patients on AZM (0.37 v 1.13, p=0.016). Median C reactive pro-
tein (CRP) levels declined in the AZM group from 10 to 5.4 mg/ml but remained constant in the pla-
cebo group (p<0.001). QOL improved over time in patients on AZM and remained unchanged in
those on placebo (p=0.035).
Conclusion: AZM in adults with CF significantly improved QOL, reduced CRP levels and the number
of respiratory exacerbations, and reduced the rate of decline in lung function. Long term AZM may
have a significant impact on morbidity and mortality in patients with CF. Further studies are required to
define frequency of dosing and duration of benefit.
nomodulatory agents such as prednisolone and ibuprofen
have been shown to be beneficial, but prescribing is limited
because of concern regarding long term efficacy and side
Macrolide antibiotics display immunomodulatory proper-
ties and are well tolerated. Long term, low dose erythromycin
was efficacious in improving symptoms of chronic suppurative
respiratory disease in patients with diffuse panbronchiolitis
(DPB).2–4Cystic fibrosis has several features in common with
DPB; both conditions are characterised by chronic bacterial
colonisation and a marked neutrophil infiltrate within the
airways.2The first suggestion that long term macrolide
therapy may also be beneficial in CF was a small study
demonstrating significant improvement in lung function in
seven paediatric patients who took azithromycin (AZM) daily
for several months.5We report the results of the first long term
prospective randomised, double blind, placebo controlled trial
of oral AZM in adult patients with CF on clinical,bacteriologi-
cal, and inflammatory parameters.
hronic bronchial sepsis and an exuberant host inflam-
matory response results in bronchiectasis and, ulti-
mately,respiratory failure in cystic fibrosis (CF).Immu-
Sixty adult patients (29 men) of mean age 27.9 years (range
18–44) with CF and with clinically stable disease were
recruited from a total population of 129 patients at two adult
CF centres. Enrolment required a period of clinical stability
defined as no change in symptoms or medication, no
admission to hospital, and no intravenous antibiotic therapy
for at least 2 weeks prior to enrolment.Patients were excluded
if they had known allergies to macrolides,known or suspected
intolerance to sputum induction, severe liver disease, or on
personal request. During the study usual treatment was
unchanged and monitored by the clinic physician and
included physiotherapy, oral and/or inhaled antibiotics, bron-
chodilators, pancreatic and vitamin supplements.
Placebo and AZM were concealed in identical capsules. Medi-
cation was randomised prior to commencement of the study
by the hospital pharmacy independently of trial staff.
Randomisation was in blocks of 10 (5 placebo/5 AZM) and
patients were automatically dispensed the next allocated
treatment (containing either AZM 250 mg or placebo daily for
3 months). Unblinding occurred after statistical analysis.
Informed consent was obtained from all subjects and the
trial was approved by the ethics committees of the Mater
Adult Hospital and The Prince Charles Hospital.
Patients were assessed every month by lung function
measured by spirometry, weight, and quality of life (QOL)
survey. QOL was assessed using the Chronic Respiratory Dis-
ease Questionnaire (CRDQ)6 7at entry and at monthly
intervals. This questionnaire has been used in previous
research studies7and has also been investigated for its
adaptation for use in CF.8Scores are obtained for the domains
of fatigue, mastery, emotion, dyspnoea, and total quality of
life. In addition, blood was collected each month for measure-
ment of C reactive protein (CRP), erythrocyte sedimentation
rate (ESR), and sputum for microbiological analysis.
Work attributable to the
University Department of
Medicine, Mater Adult
Hospital and The Adult
Cystic Fibrosis Unit, The
Prince Charles Hospital,
See end of article for
Ms S Seeney, University
Department of Medicine,
Mater Adult Hospital,
South Brisbane, Australia
Revised version received
2 October 2001
Accepted for publication
17 October 2001
To determine whether clinical improvement was due to the
treatment of organisms susceptible to azithromycin, serologi-
cal evidence of infection (in the absence of available molecu-
lar techniques at that time) with Legionella pneumophila, Myco-
plasma pneumoniae, and Chlamydia pneumoniae at baseline and
study completion was sought.
Sputum was cultured for Pseudomonas aeruginosa, Burkholde-
ria cepacia,other typical pathogens such as Staphylococcus aureus
and Haemophilus influenzae, and atypical mycobacteria. Spu-
tum was plated onto 5% horse blood, MacConkey and senal
agar with colistin, nalidixic acid, (37°C, 5% CO2), and also
chocolate agar with bacitracin (anaerobic at 37°C) plus man-
nitol salt and Pseudocepacia agar with ticarcillin and
polymixin B (37°C, 0% CO2).
Quantitative bacterial counts of P aeruginosa were per-
formed by serial dilutions of sputum with phosphate buffered
saline. Colony counts were performed in duplicate on blood
agar and were expressed logarithmically after incubation for
48 hours at 37°C, 5% CO2.
An acute respiratory exacerbation was defined as increased
cough, sputum, and/or dyspnoea, and/or reduced forced
expiratory volume in 1 second (FEV1) and a decision to treat
with intravenous antibiotics (either inpatient or outpatient)
by the usual treating CF physician. AZM was continued
throughout these periods.
Statistical analysis and sample size
The primary study outcome was change in FEV1% predicted
and was based on improvements in FEV1reported in the open
label study by Jaffe.5A sample size of eight per group was
required to detect a difference of 10% between drug and pla-
cebo groups with 90% power and 5% statistical significance.
However, allowing for a potentially wide range of responses
and anticipating loss to follow up, a sample size of 30 per
group was considered optimal.
The analysis was blinded.An intention to treat analysis was
performed. At the bivariate level of analysis, Fisher’s exact
tests were used to test the association between independent
categorical variables. McNemar’s test was used where cat-
egorical outcomes were compared over two time points (base-
line and 3 months). Frequency distributions of all continuous
variables were examined for outlying values and to determine
whether or not they were approximately normal. The latter
assumption was also formally tested with Kolmogorov-
Smirnov tests for normality. Where the assumption could not
be met, data were summarised in terms of medians rather
than means and logarithmically transformed for analysis.
Group means or log means were compared over time and by
treatment group using repeated measures analysis of variance
(ANOVA) models utilising a generalised estimating equations
approach to accommodate the partially complete time series
data (that is, all available data at each follow up point were
utilised in the analyses). Trends over time were considered as
categorical contrasts of each time point against baseline and,
where these suggested appropriate,as linear contrasts.Models
were adjusted for baseline FEV1% predicted as a covariate
since this was determined to be substantially different
between the two treatment groups.Statistical significance was
quoted based on the conventional p<0.05 level (two tailed).
Analyses were performed using SUDAAN version 7.5.
The design of the trial is shown in fig 1.
There were no significant differences between the two
groups with respect to age, number of doses missed, or
number of adverse events experienced during the trial. How-
ever, the placebo group contained more men and was also on
average, taller, heavier, and had better lung function than
those randomised to receive AZM (table 1). The chance differ-
ences observed between the two groups were not anticipated
and there were no obvious reasons for these differences.
? ? ??
? ? ??
? ? ??
? ? ??
? ? ??
? ? ??
? ? ??
(AZM) and placebo arms
Baseline characteristics of azithromycin
Placebo (n=30) AZM (n=30)
FVC (% pred)
Values are mean (SD). BMI = body mass index; FEV1= forced
expiratory volume in 1 second; FVC = forced vital capacity.
Mean (SD) change in FEV1and FVC % predicted over time and by treatment group
Change in FEV1% predicted*Change in FVC % predicted*
Month 1Month 2Month 3 Month 1Month 2Month 3
Mean (SE) excess
effect of AZM over
3.62 (1.78)%5.73 (1.66)%
*All changes are from baseline FEV1% predicted and adjusted for baseline FEV1% predicted levels in each case.
Clinical response to azithromycin in CF213
Unless otherwise stated, these differences were accounted for
in the analyses of treatment group differences over time by
adjusting for sex, body mass index (BMI), and FEV1%
There was a significant overall difference in change in FEV1
(p=0.047) and FVC (p=0.001) % predicted between the AZM
and placebo groups. Over the 3 months of the study the mean
FEV1% predicted was 3.62% (95% confidence interval (CI)
–7.13 to –0.13%) less and the mean FVC % predicted was
5.73% (95% CI –8.98% to –2.47%) less in the placebo group
than in the AZM group (table 2). The AZM group maintained
lung function over time while the placebo group experienced
deterioration in FEV1and FVC % predicted.The p value for the
difference between AZM and placebo and the stated difference
The AZM group had significantly fewer total days of intra-
venous antibiotic treatment for acute respiratory exacerba-
tions (p=0.009), fewer days at home receiving intravenous
antibiotics (p=0.037), and fewer courses of intravenous anti-
biotics during the study (p=0.016).The number of days spent
in hospital for antibiotic treatment of acute respiratory
exacerbations was lower in the AZM group (p=0.056,table 3).
Treatment had a significant effect on the time trend of CRP
measurements (p<0.001). Median CRP values declined
steadily over time on AZM but remained relatively constant in
the placebo group (fig 2). At baseline, CRP was significantly
negatively correlated with FEV1% predicted (p<0.001) and
BMI (p=0.048). In patients who received AZM the reduction
in CRP over time was strongly related to baseline CRP
(p<0.001). Patients who received AZM with a CRP level of
>10 µg/ml at baseline had significantly poorer lung function
than patients receiving AZM with a normal CRP level at base-
line (mean (SD) FEV1 42 (16)% predicted v 60 (15)%
No statistically significant differences in ESR or BMI were
detected over time,either overall or between treatment groups
(p>0.10 in all cases).
One patient was excluded from the end point analysis after
commencing long term prednisone on the same day as the
study. Fifteen patients (25%, nine placebo) did not complete
the 3 months of treatment, three because of adverse events
and the remainder because of non-compliance or personal
request. Of the 15 patients who did not complete treatment,
four stopped their medication before completing 1 month of
treatment, a further five stopped before 2 months, and the
remaining six stopped their medication before completing 3
months.Nineteen patients (31.7%,12 placebo) reported miss-
ing doses of medication throughout the treatment period.
Thirty one patients (16 placebo) used maintenance antibiotics
(oral and/or nebulised) either continuously or intermittently
during the study.
Quality of life
There were significant improvements in all dyspnoea scores
over time overall in both groups (p=0.042, table 4). Improve-
ments in dyspnoea, emotional, mastery and total scores were
significantly higher for those receiving AZM compared with
placebo. Improved fatigue scores were seen only in the AZM
There were 16 adverse events in 15 patients (seven on
placebo). Of the three patients who discontinued treatment
due to adverse events,urticarial reaction in a patient receiving
AZM was considered “likely” to be related to the study drug,
while neutropenia in a patient in the AZM group and “swell-
ing” in a patient in the placebo group were considered “possi-
bly” related to the study drug. A further two events were con-
sidered “possibly” related to the study drug (rash in each of
placebo and AZM groups
Acute exacerbations of respiratory disease: antibiotics and admissions in
PlaceboAZM p value
Number of courses of IV treatment
Total days IV treatment
Total days home IV treattment
Total hospital days
1.1 (0.5, 0–7)
7.1 (1, 0–44)
2.1 (0, 0–14)
5.2 (0, 0–36)
0.4 (0, 0–2)
2.0 (0, 0–17)
0.2 (0, 0–5)
2.1 (0, 0–15)
Values are mean (median, range).
on C reactive protein (CRP) levels
Effect of treatment group
214Wolter, Seeney, Bell, et al
the AZM and placebo groups). All events resolved without
Fifty seven patients had sputum analysis at baseline. A
mucoid strain of P aeruginosa was isolated from 83.3% of sub-
jects and a non-mucoid strain from 66.6%. S aureus was
isolated from 41.3% of patients tested at baseline, B cepacia
from four patients, and H influenzae from one patient. No
mycobacteria were isolated during the course of the study.
77% of the S aureus isolates from the AZM group and 69.2%
from the placebo group were sensitive to erythromycin.
There was no significant difference in organisms isolated or
bacterial counts between the two groups at baseline,nor in the
type or quantity of microorganisms at the final assessment
(p>0.095 in all cases). The presence of B cepacia, S aureus,
mucoid and non-mucoid forms of P aeruginosa was not influ-
enced by sex, but the presence of S aureus was significantly
correlated with reduced dyspnoea scores (p=0.021).
There was no evidence to suggest that clinical improvement
was due to treatment of bacteria susceptible to macrolide
therapy. Twenty nine patients underwent serological tests
before and after treatment and a further 22 patients had
incomplete testing (only initial titres performed). Only one
patient (in the placebo group) had a fourfold rise in chlamy-
dia and mycoplasma titres.
This is the first prospective randomised, double blind, placebo
controlled trial of oral AZM in CF. Treatment with AZM
significantly reduced the rate of decline in FEV1and FVC %
predicted over time compared with placebo. AZM treatment
was associated with significantly fewer acute respiratory
exacerbations requiring intravenous antibiotics and signifi-
cantly improved QOL scores compared with placebo. There
was evidence of reduced host systemic inflammation with a
decline in CRP levels over time in subjects receiving AZM.
Randomisation was moderately successful with the excep-
tion of sex, lung function, and weight, biasing the results in
favour of a reduced effect of AZM. The imbalance was consid-
ered to be of clinical significance and adjustments were made
in the modelling. Stratification for disease severity within the
groups was not performed. While it may be argued that those
with a more severe phenotype may have had a greater scope
for improvement, it is important to note that all parameters
were adjusted for baseline values in the statistical analysis,
reducing the chance of any observed difference being the
result of reversion to the mean.
The natural history of CF is one of persistent pulmonary
inflammation as a consequence of chronic bacterial infection,
resulting in intermittent exacerbations of pulmonary symp-
toms and with temporary clinical improvement after treat-
ment. More severe disease is generally associated with more
frequent exacerbations requiring intravenous treatment.
Although randomisation produced two clinically dissimilar
groups, all patients were stable before enrolment. Despite evi-
dence that the group randomised to receive AZM had more
severe disease than the placebo group, they required
significantly fewer courses of intravenous antibiotics and
fewer days of intravenous treatment during the study period.
Furthermore, patients in the AZM group had higher baseline
CRP levels and treatment was associated with significant
reductions in CRP despite fewer courses of systemic antibiot-
ics. This finding provides strong evidence that the small but
significant differences in lung function between the two
over time in the AZM group represent real benefit to patients
receiving AZM and supports a systemic anti-inflammatory
The small changes in lung function seen in this study con-
trast with those reported by Jaffe et al5who reported an
increase of 11% in FEV1% predicted after treatment with
AZM. The mean age of patients in their study was 12.1 years
and the mean duration of AZM treatment was 6 months com-
pared with a mean age of 27.9 years and maximum treatment
duration of 3 months in our study. Although changes in lung
function were small, the differences from placebo were statis-
tically significant. Treatment of an older group with poten-
tially more advanced and permanent lung disease may limit
any benefit achievable with anti-inflammatory therapy.
Patients in this study generally had more severe disease than
in the study of Jaffe et al5which is likely to be responsible for
the smaller FEV1response to treatment. We have demon-
strated maintenance rather than improvements in lung func-
tion in a group with severe disease. Over the 3 months of the
study the placebo group experienced a change in FEV1% pre-
dicted of –0.91%, which equates to a drop of approximately
3–4% over 12 months.These changes are similar to changes in
FEV1reported by Ramsey et al9in a study to determine the
effect of inhaled tobramycin in CF. Over a 20 week treatment
period they reported a fall in FEV1% predicted of 2.64% in
their adult placebo group which equates to a change of
approximately 6–7% over a 12 month period. Maximum ben-
efits of such treatment may be achieved in subjects without
enough to allow stratification of results based on disease
severity are necessary to assess maximum achievable benefits
from early onset of treatment.
At the time of this trial there was no validated disease-
specific questionnaire available for the measurement of QOL
in CF. The QOL questionnaire used for this study was the
CRDQ, developed for use in patients with chronic obstructive
pulmonary disease (COPD) who share many clinical features
in common with CF patients on a day to day basis. This ques-
tionnaire has been used in a previous clinical trial with adult
CF patients7and has also been validated for its adaptation for
use in CF.8
Mean (SD) QOL scores over time: baseline and final assessment (month 3)
nQOL scoren QOL scorep value*
*Interaction of treatment effect and time. **Minimum and maximum score possible for each domain.
Clinical response to azithromycin in CF 215
There was no evidence that AZM influenced the microbio- Download full-text
logical profile of sputum after 3 months of treatment.
Improvement was not related to a bacterial effect on
organisms sensitive to AZM.However,in the absence of acces-
sible molecular techniques, serological testing was performed
to determine whether clinical improvement was due to the
treatment of susceptible organisms. Serological testing may
have been inadequate to rule out an acute infection. In
HIV/AIDS patients weekly treatment with AZM has been used
for long periods and has not been associated with develop-
ment of resistance.10
AZM was chosen over other macrolides such as erythromy-
cin because of a superior gastrointestinal side effect profile
and ease of administration.It was well tolerated but,despite a
once daily regimen, adherence with treatment was moderate
with almost one third of patients reporting missed doses at
the range of previously published studies of adherence in
chronic diseases, including CF, which quote ranges of
non-adherence from 15% to 50% for most areas of
Although relatively costly, long term treatment with AZM
may result in direct cost reductions associated with reduced
number of acute respiratory exacerbations requiring intra-
venous antibiotic therapy as well as reduced indirect costs
associated with improved QOL.Although the outcomes of this
study are promising, the choice of macrolide, dose, dose inter-
val, duration of effect, and impact of long term treatment on
disease progression and the microbiological environment of
the lung are unknown.Macrolides including AZM accumulate
intracellularly,13but concentration/effect ratios are poorly
defined both for the treatment of infection and inflammation.
Reports of reduced adhesion of bacteria to epithelial cells after
twice weekly AZM suggest that less frequent dosing than was
used in this trial may be possible.14
The mechanism by which macrolides downregulate the
host inflammatory response is unclear but is almost certainly
multifactorial. Suppression of interleukin (IL)-8 secretion
maybe important4 15 16
transcription.17 18Other effects include suppression of tumour
necrosis factor (TNF)-α synthesis and modulation of IL-1 and
GM-CSF productionby lipopolysaccharide
monocytes.15 19Macrolides also interfere with neutrophil
function.20 21In addition to effects on the host immune
response, macrolides inhibit alginate production, protease
activity, flagellin expression, and bacterial motility of P
aeruginosa.22–24AZM reduces adherence of P aeruginosa to
epithelial cells,14opening the possibility of a preventative role
for these agents.
In summary,we have shown that long term oral AZM treat-
ment is associated with improvements in several key disease
indicators in CF. Treatment with AZM was associated with a
significantly reduced rate of decline in lung function over a 3
month period.It significantly improved CRP levels as a marker
of systemic inflammation, QOL, and reduced the number of
acute respiratory exacerbations compared with placebo. We
conclude that macrolides may have a role in the long term
management of patients with CF.
This project was supported by The John P Kelly Mater Research Foun-
dation and The Mater Hospital Private Practice Fund. Azithromycin
and placebo capsules were donated by Pfizer.
J Wolter, S Seeney, J McCormack, University Department of Medicine
and Department of Infectious Disease, Mater Adult Hospital, Brisbane,
S Bell, P Masel, The Adult Cystic Fibrosis Unit, The Prince Charles
Hospital, Brisbane, Australia
S Bowler, Department of Respiratory Medicine, Mater Adult Hospital,
1 Oermann CM, Sockrider MM, Konstan, MW. The use of
anti-inflammatory medications in cystic fibrosis. Chest 1999;115:1053.
2 Ichikawa Y, Ninomiya H, Koga H, et al. Erythromycin reduces
neutrophils and neutrophil-derived elastolytic-like activity in the lower
respiratory tract of bronchiolitis patients. Am Rev Respir Dis
3 Kobayashi H., Takeda H., Sakayori S, et al. Study on azithromycin in
treatment of diffuse panbronchiolitis (abstract). Kansenshogaku Zasshi
4 Mukae H., Kadota J, Ashitani J, et al. Elevated levels of soluble adhesion
molecules in serum of patients with diffuse panbronchiolitis. Chest
5 Jaffe A, Francis J, Rosenthal M, et al. Long-term azithromycin may
improve lung function in children with cystic fibrosis. Lancet
6 Guyatt GH, Berman LB, Townsend M, et al. A measure of quality of life
for clinical trials in chronic lung disease. Thorax 1987;42:773–8.
7 Wolter JM, Bowler SD, McCormack JG. Home intravenous therapy in
cystic fibrosis: a prospective randomised trial examining clinical, quality
of life and cost aspects. Eur Respir J 1997;10:896–900.
8 Bradley J, Dempster M, Wallace E, et al. The adaptations of a quality of
life questionnaire for routine use in clinical practice: the chronic
respiratory disease questionnaire in cystic fibrosis. Qual Life Res
9 Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of
inhaled tobramycin in patients with cystic fibrosis. N Engl J Med
10 Oldfield EC, Fessel WJ, Dunne MW, et al. Once weekly azithromycin
therapy for prevention of Mycobacterium avium complex infection in
patients with AIDS: a randomised, double-blind, placebo-controlled
multicenter trial. Clin Infect Dis 1998;26:611–9.
11 Conway SP, Pond MN, Hamnett T, et al. Compliance with treatment in
adult patients with cystic fibrosis. Thorax 1996;51:29–33.
12 Abbott J, Dodd M, Bilton D, et al. Treatment compliance in adults with
cystic fibrosis. Thorax 1994;49:115–20.
13 Carbon C. Clinical relevance of intracellular and extracellular
concentrations of macrolides. Infection 1995;23(Suppl 1):10–14.
14 Fisher JJ, Baumon U, Gudowius P, et al. Azithromycin reduces epithelial
adherence of P aeruginosa in patients with cystic fibrosis (abstract).
Pediatr Pulmonol 1999;Suppl 19:265.
15 Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin modulates IL-8
expression in normal and inflamed human bronchial epithelial cells. Am J
Respir Crit Care Med 1997;156:266–71.
16 Khan AA, Slifer TR, Araujo FG, et al. Effect of clarithromycin and
azithromycin on production of cytokines by human monocytes. Int J
Antimicrob Agents 1999;11:121–32.
17 Desaki M, Takizawa H, Ohtosh T, et al. Erythromycin suppresses nuclear
factor-kappa B and activator protein-1 activation in human bronchial
epithelial cells. Biochem Biophys Res Commun 2000;267:124–8.
18 Abe S, Nakomura H, Inove S, et al. Interleukin-8 gene repression by
clarithromycin is mediated by the activator protein-1 binding site in
human bronchial epithelial cells. Am J Respir Cell Mol Biol
19 Morikawa K, Watabe H, Araake M, et al. Modulatory effect of
antibiotics on cytokine production by human monocytes in vitro. J
Antimicrob Agents Chemother 1996;40:1366–70.
20 Sugihara E. Effect of macrolide antibiotics on neutrophil function in
human peripheral blood (abstract). Kansenshogaku Zasshi
21 Villagrasa V, Berto L, Cortijo J, et al. Effects of erythromycin on
chemoattractant-activated human polymorphonuclear leukocytes. Gen
22 Molinari G, Guzman CA, Pesce A, et al. Inhibition of Pseudomonas
aeruginosa virulence factors by subinhibitory concentrations of
azithromycin and other macrolide antibiotics. J Antimicrob Chemother
23 Howe RA, Spencer RC. Macrolides for the treatment of Pseudomonas
aeruginosa infections? J Antimicrob Chemother 1997;40:153–5.
24 Kawamura SK, Iinuma Y, Hasegawa T, et al. Effect of subinhibitory
concentrations of macrolides on expression of flagellin in Pseudomonas
aeruginosa and Proteus mirabilis. Antimicrob Agents Chemother
216Wolter, Seeney, Bell, et al