Download Azithromycin Therapy in Hospitalized Infants with Acute Bronchiolitis

Azithromycin Therapy in Hospitalized Infants with Acute Bronchiolitis
is Not Associated with Better Clinical Outcomes: A Randomized,
Double-Blinded, and Placebo-Controlled Clinical Trial
Leonardo A. Pinto, MD, PhD1, Paulo M. Pitrez, MD, PhD1, Fernanda Luisi, PhD1, Patricia Piccoli de Mello, MD2,
Moises Gerhardt, MD2, Roberta Ferlini, MD2, Daniel Cardoso Barbosa, MD2, Ivana Daros, MD2, Marcus H. Jones, MD, PhD1,
Renato T. Stein, MD, PhD1, and Paulo J. Marostica, MD, PhD1,2
Objective To test the hypothesis that azithromycin reduces the length of hospitalization and oxygen requirement
in infants with acute viral bronchiolitis (AB).
Study design We performed a randomized, double-blinded, placebo-controlled trial in southern Brazil, from 2009
to 2011. Infants (<12 months of age) hospitalized with AB were recruited in 2 hospitals. Patients were randomized to
receive either azithromycin or placebo, administered orally, for 7 days. At enrollment, clinical data were recorded
and nasopharyngeal samples were collected for viral identification through immunofluorescence. Main outcomes
were duration of oxygen requirement and length of hospitalization.
Results One hundred eighty-four patients were included in the study (azithromycin 88 subjects, placebo 96 subjects). Baseline clinical characteristics and viral identification were not different between the groups studied. A virus
was detected in 112 (63%) patients, and of those, 92% were positive for respiratory syncytial virus. The use of azithromycin did not reduce the median number of days of either hospitalization (P = .28) or oxygen requirement (P = .47).
Conclusions Azithromycin did not improve major clinical outcomes in a large sample of hospitalized infants
with AB, even when restricting the findings to those with positive respiratory syncytial virus samples. Azithromycin
therapy should not be given for AB because it provides no benefit and overuse increases overall antibiotic resistance. (J Pediatr 2012;-:---).
See related article, p A
cute viral bronchiolitis (AB) is the most common lower respiratory tract illness among infants. It is characterized by
acute inflammation, edema, and increased mucus production after an acute viral infection. The management of AB
has been, for the past decades, almost exclusively supportive, with oxygen supplementation, adequate hydration, and
ventilatory support for severe cases.1 Despite the extensive research to find effective therapies, clinical trials did not show interventions with relevant clinical impact on AB.1
Macrolides have a well-established antibacterial effect,2 covering a wide spectrum of agents, including intracellular pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae. In the past years, an additional anti-inflammatory property
has been associated with macrolide use3-5; more recently, 1 experimental study has linked macrolides with a specific antiviral
effect6 against rhinovirus.
Recent clinical trials have reported that some macrolides had a beneficial effect in the treatment of inflammatory lung diseases, such as cystic fibrosis and asthma.4,7 Macrolides seem to inhibit interleukin (IL)-6 and IL-8 production and to reduce
overall neutrophilic inflammation.8 Because AB is characterized by a strong neutrophilic airway response,9,10 some small trials
have used this rationale to test the efficacy of macrolides in this illness. In 1 study of hospitalized infants with moderate to severe
AB, clarithromycin significantly reduced length of stay in hospital (LOS).11 Contrarily, in another trial, azithromycin was not
effective for respiratory syncytial virus (RSV) infection in young infants.12 These
contrasting findings may be related to differences in methodology and small sam~o Lucas
From the Department of Pediatrics, Hospital Sa
ple sizes.
and Institute of Biomedical Research, Pontifıcia
lica do Rio Grande do Sul; and
Universidade Cato
In the present study, we tested the hypothesis that a 7-day course of azithroDepartment of Pediatrics, Hospital de Clınicas de Porto
mycin reduces the LOS and oxygen requirement in a large recruited population
Alegre, Universidade Federal do Rio Grande do Sul,
Porto Alegre, Brazil
of infants with AB.
1
2
AB
IL
LOS
RSV
Acute viral bronchiolitis
Interleukin
Length of stay in hospital
Respiratory syncytial virus
~o de Amparo a Pesquisa do Estado
Funded by Fundaça
do Rio Grande do Sul, which did not participate in the
collection, analysis, or interpretation of data, nor in the
writing or the decision to submit the manuscript. The
authors declare no conflicts of interest.
Trial registered with Brazilian Clinical Trials Registry:
RBR-257ZBC.
0022-3476/$ - see front matter. Copyright ª 2012 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.05.053
1
THE JOURNAL OF PEDIATRICS
Methods
This study is a randomized, double-blinded, placebo-controlled trial. Infants with a clinical diagnosis of AB were recruited from the pediatric emergency departments or
hospital wards of 2 large, tertiary hospitals, in Porto Alegre,
Brazil. Patients were randomized to receive either azithromycin or placebo, administered orally, once daily, for 7 days.
Clinical data were recorded and nasopharyngeal samples
for viral identification were collected at enrollment. All subjects were followed until discharge.
A diagnosis of AB was confirmed if children were: (1) aged
12 months or younger and admitted with a clinical diagnosis
of AB (prodromal viral symptoms, with a first episode of
wheezing/crackles, and tachypnea); and (2) recruited within
48 hours of hospitalization and had a maximum of 72 hours
of a history of lower respiratory tract clinical manifestations
(wheeze and/or respiratory distress). Main exclusion criteria
were: (1) any contraindication for oral macrolide therapy; (2)
prescription of macrolide therapy by the attending physician
due to clinical and radiologic features consistent with a diagnosis of Chlamydia sp or Bordetella pertussis respiratory infection; (3) having a chronic cardiopulmonary disorder,
congenital or acquired immunodeficiency, or neuromuscular
disease; and (4) history of prematurity or other neonatal
complications.
Infants were randomized (simple/unrestricted randomization) to receive either a daily oral dose of azithromycin (10
mg/kg/d) or an equivalent volume of placebo for 7 days.
Medication was administered within 72 hours of initial clinical symptoms and a blinded study team member supervised
this intervention.
A standardized form was used to collect clinical information of the patients included in the trial. All infants were
managed according to protocols routinely used by the pediatric staff in both hospitals. Infants enrolled in the study
could receive additional therapies (other than macrolides)
prescribed by the attending pediatricians, and these were recorded for the analysis. Assessment of clinical data included
signs of severity at admission (respiratory rate and accessory
muscle use), use of medications (bronchodilator, corticosteroids, and antibiotic therapy), site of admission, LOS, measurements of oxyhemoglobin saturation, and levels of
oxygen requirement (and number of days of use).
Viral Identification
A nasopharyngeal sample for respiratory viruses was collected from each patient at enrollment. Direct immunofluorescence (Respiratory Virus Panel; Biotrin, Dublin, Ireland)
was used to detect adenovirus, parainfluenza (1, 2, and 3), influenza (A and B), and RSV.
Outcome Measures
Primary outcomes were: (1) LOS for AB; and (2) duration of
supplemental oxygen required. Patients’ discharge was decided when infants showed oxyhemoglobin saturation con2
Vol. -, No. -
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sistently at $94% saturation in room air and oral feeding
was established for at least 6 hours. Other variables analyzed
were: (1) antibiotic use; (2) bronchodilators use; and (3) admission to the pediatric intensive care unit. We also analyzed
clinical outcomes in the following subgroups: (1) age of #3
months; (2) identification of respiratory viruses; and (3) positive for RSV.
Statistical Analyses
To detect a reduction in LOS of 1 day (SD 2 days), based on
data from the study of Tahan et al,11 allowing for a 2-sided
5% significance level and a power of 80%, a sample size of
63 patients per group would be required (http://www.stat.
ubc.ca/rollin/stats/ssize). Considering that analysis based
on age and viral identification was a secondary aim, the researchers aimed to enroll between 180 and 200 infants. The
authors have considered that benefits of <1 day (24 hours)
of LOS would not be relevant to have an impact on clinical
practice.
The primary outcomes (LOS and duration of supplemental oxygen requirement) were compared between groups by
use of Mann-Whitney tests, considering that outcome variables failed in the tests for normality. Kaplan-Meier curves
were used to assess the effect of azithromycin on LOS.
The protocol has been approved by the Human Research
Ethics Committees of both participating institutions, and
the study was registered in the Brazilian Clinical Trials Registry (No. RBR-257ZBC), which is a joint project of the Brazilian Ministry of Health and the Pan-American Health
Organization (http://www.ec.gov.br).
Results
During the study period, 189 infants were evaluated for eligibility in the clinical trial (109 from Hospital S~ao Lucas/Pontifıcia Universidade Cat
olica do Rio Grande do Sul, and 80
from Hospital de Clınicas de Porto Alegre, Universidade Federal do Rio Grande do Sul). Four patients were excluded and
1 patient was lost through follow-up (Figure 1). Baseline
characteristics of the studied patients are shown in Table I.
There were no differences in baseline characteristics
between the intervention and the control groups, except for
respiratory rate, which was higher in the placebo group.
From the 184 patients included, 176 nasal samples were
collected for viral etiology tests, before randomization. Of
the total samples collected, 64.4% (112 of 176) were positive
for at least 1 virus. Of these, RSV was the most common (n =
104, 92.8%), followed by influenza and parainfluenza. The
proportion of infants positive for respiratory viruses or specifically for RSV infection did not differ between the groups
studied.
LOS (primary outcome) was not different between placebo
and treated groups, nor was the time of oxygen supplementation. Kaplan-Meier curves for probability of discharge
from hospital showed no significant difference between the
groups (Figure 2). Subgroup analysis for age and specific
Pinto et al
- 2012
ORIGINAL ARTICLES
Figure 1. Flow diagram of patient enrollment and exclusion in
the double-center clinical trial of azithromycin versus placebo
for the treatment of AB.
viral diagnosis showed no significant differences (Table II).
There was no beneficial effect by treatment group in
patients who had RSV infection or among infants with AB
who were stratified by age (with a cut-off at 3 months of
age) (Table II). Results for other secondary outcomes, such
as antibiotic or bronchodilator prescriptions, also did not
show significant differences between placebo and active
groups.
Discussion
The present study demonstrated that treatment with azithromycin for 7 days did not alter the clinical course of AB. Importantly, our clinical trial used adequate methodology and
power to answer the question of whether infants with a first
virally triggered episode of wheezing benefit from the use of
macrolide therapy at the time of the acute event. This finding
is important considering that there is an international trend
in the past years for overuse of these drugs in the treatment
of AB.13
Table I. Demographic and clinical characteristics of
patients randomized to treatment with azithromycin or
placebo (N = 184)
Age, mo, mean (SD)
Birth weight, kg, mean (SD)
Current weight, kg, mean (SD)
Respiratory rate, /min, mean (SD)
Sex (boys), n (%)
Retractions, n (%)
Family history of asthma, n (%)
Antibiotic therapy, n (%)
Steroid therapy, n (%)
Bronchodilator therapy, n (%)
Azithromycin
(n = 88)
Placebo
(n = 96)
P
3.08 (2.23)
3.13 (0.40)
5.63 (1.71)
46.8 (8.98)
56 (63.6)
74 (84.1)
14 (15.9)
4 (4.5)
4 (4.5)
18 (20.5)
3.12 (2.29)
3.24 (0.51)
5.75 (1.72)
51 (12.97)
55 (57.9)
81 (84.4)
11 (11.5)
6 (6.3)
7 (7.3)
21 (21.8)
.90
.12
.63
.01
.43
.44
.39
.59
.40
.76
Given the immunomodulatory properties of macrolides,
several studies have confirmed an anti-inflammatory effect
in some chronic pulmonary diseases.4 A few clinical trials
have shown benefits in the administration of macrolides in
patients with cystic fibrosis.14,15 In other respiratory diseases,
the benefits are controversial and routine use has not been indicated.4 Systematic reviews are inconclusive regarding the
benefits of macrolides in exacerbations of asthma.16 Further
randomized controlled studies are needed to assess the benefits of macrolides in different disorders associated with lung
inflammation. In AB, there would be 2 main rationales for
justifying clinical investigations of macrolide therapies. The
main assumption is based on the concept that airway inflammation in viral AB is predominantly neutrophilic9,10 and that
these cells would likely be a main target for the immunomodulatory effect of macrolides. Some studies with murine
models have demonstrated anti-inflammatory (in vivo) and
antiviral effects (in vitro) of macrolides in animals infected
with parainfluenza and rhinovirus.6,17
Two previous studies have tested macrolides in AB. Tahan et al11 have shown that in hospitalized infants with
moderate to severe AB, a 3-week intervention with clarithromycin significantly reduced LOS and oxygen requirement. However, only 21 patients were included in the
study. This study also presented a relevant mistake in the
statistical analysis of the main outcome (LOS), which was
discussed previously in a letter to the editor.18 In contrast,
a study by Kneyber et al12 showed that infants and young
children with RSV lower respiratory tract disease did not
benefit from routine treatment with macrolides. The authors estimated an appropriate study with a sample size of
100 patients, but the trial was interrupted when only 71 patients were included; thus, a type II error cannot be ruled
out.12 Therefore, in our study, we believe that we have answered this question more properly, with a negative result
regarding the effect of macrolides in AB with the inclusion
of a proper sample size. It also is possible that differences
in bioavailability, pharmacokinetic properties, or intrinsic
immunomodulatory effects between azithromycin and clarithromycin may explain different results. Although clinical
trials have shown the same antimicrobial efficacy,19,20 one
study that investigated pharmacokinetics of these drugs
showed that clarithromycin has higher concentrations in epithelial lung and alveolar cells.21
Recent studies showed that viral respiratory infections
in infants induce different cytokine inflammatory responses.22,23 However, when we analyzed the subgroup of
104 subjects who had RSV-positive AB, we did not observe
any significant difference between the active and the placebo
groups for the main outcomes (ie, LOS and days in use of
supplemental oxygen). Interestingly, Laham et al22 suggested
that different viruses might cause disease via different mechanisms or share a common mechanism that is distinct from
immune activation. Our study was designed with a clinical
practical purpose: to evaluate whether macrolide treatment
in AB could have any significant clinical impact, regardless
of the viral etiology.
Azithromycin Therapy in Hospitalized Infants with Acute Bronchiolitis is Not Associated with Better Clinical Outcomes:
A Randomized, Double-Blinded, and Placebo-Controlled Clinical Trial
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Figure 2. Kaplan-Meier curve showing the probability of
discharge in patients randomized to treatment with
azithromycin or placebo.
Our results also support previous suggestions that antibiotics are of no benefit among young infants hospitalized with
AB.24 Nevertheless, antibiotics, especially macrolides, are still
often prescribed.25 Behrendt et al25 found that 25% of hospiTable II. Primary outcome measurements in patients
randomized to treatment with azithromycin or placebo
(N = 184)*
All subjects
LOO2
LOS†
By age
<3 mo (n = 107)
LOO2
LOS
>3 mo (n = 77)
LOO2
LOS
By virus detection
Positive for virus (n = 112)
LOO2
LOS
Negative for virus (n = 64)
LOO2
LOS
By RSV detection
Positive for RSV (n = 104)
LOO2
LOS
Negative for RSV (n = 72)
LOO2
LOS
Azithromycin
Placebo
Sig.
n = 88
4.00 (2.00-6.00)
5.00 (3.00-7.00)
n = 96
4.00 (3.00-6.00)
5.00 (3.00-7.00)
.47
.29
n = 51
4.00 (3.00-7.00)
6.00 (4.00-7.00)
n = 37
3.00 (2.00-5.00)
3.00 (3.00-6.00)
n = 56
4.00 (3.00-8.00)
5.00 (3.00-9.00)
n = 40
4.00 (2.00-6.00)
5.00 (3.00-6.00)
n = 52
4.00 (3.00-7.00)
5.00 (3.00-7.00)
n = 30
3.00 (2.00-5.00)
4.50 (2.75-7.00)
n = 60
5.00 (3.00-7.00)
5.00 (4.00-8.75)
n = 34
3.00 (2.00-5.00)
4.00 (3.00-7.00)
n = 47
4.00 (3.00-8.00)
5.00 (3.00-7.00)
n = 36
3.00 (2.00-5.00)
4.00 (3.00-7.00)
n = 57
5.00 (3.00-7.00)
5.00 (4.00-8.50)
n = 36
3.00 (2.00-5.00)
4.50 (3.00-6.75)
.10
.67
.19
.19
.44
.41
.93
.66
.48
.55
.64
.70
LOO2, length of oxygen requirement (in days); Sig., significance level.
*Mean/SD and median/interquartile are both shown for a clear presentation of the variables.
Variables were not normally distrbuted and Mann-Whitney test was used for comparison.
†LOS is given in days.
4
Vol. -, No. talized RSV patients are treated with parenteral antibiotics,
even though a secondary or concurrent bacterial infection
seldom occurs in hospitalized infants with AB. The international guidelines for the management of AB have advised
against the routine use of antibiotics in hospitalized RSV patients. Kozyrskyj et al26 documented that dispensing rates for
macrolides in children with wheezing increased 15-fold between 1996 and 2000. This is consistent with reported increases in the use of these antibiotics across Canada and
the United States, after their introduction on the market in
the 1990s.27 A facilitating factor for this overprescription in
many countries is that macrolides are well tolerated, safe,
and easy to use in the pediatric age group. Other studies of
antibiotic utilization also have reported significant macrolide
use in patients with exacerbations of wheezing.28 Chlamydia
sp and Mycoplasma pneumoniae have been identified in children with acute episodes of wheezing,29 but neither the role
of these organisms in precipitating wheezing in AB nor an effect of treatment is known. Infection by atypical bacteria
probably is less common (10% of cases) in infants with
AB.30,31 Hence, in AB, atypical bacterial infection should
not be a frequent clinical indication for the prescription of
macrolides.
Considering the published data indicating overuse of
macrolides among preschool-aged children26 and the perception that this finding is not restricted to a few geographic
areas but is worldwide, the results of our study reinforce
that health professionals should be concerned with both
the inadequate indication in infants with AB and inducing
increased antimicrobial resistance in young children. This
problem of overprescription might be even more relevant
in developing countries, as is the case for the population
we have studied.
Some limitations of our study should be acknowledged
here. First, it is known that the treatment of infants with
AB varies depending on hospital protocols and, lately, it depends on a subjective decision by the attending pediatrician,
as occurred in this study. However, the percentage of patients
in whom bronchodilators or antibiotics were prescribed was
similar in the azithromycin and the placebo group, thus reducing the possible confounding factor by treatment differences. Second, inflammatory markers such as ILs or cellular
counts in the respiratory secretions were not measured, but
even a positive association between inflammatory markers
and macrolide use would not be clinically relevant based in
our negative findings. Last, we did not test our samples for
other respiratory infections, such as Chlamydia sp, M pneumoniae, Bordetella pertussis, and rhinovirus. In AB, rhinovirus is commonly detected.32,33 Hence, we cannot rule out
that in our study a beneficial effect of macrolides could be
found in cases of AB caused solely by rhinovirus. A recent
publication has shown that co-detection of viruses with B
pertussis was present in 8.5% of <6-month-old infants with
bronchiolitis.34 Depending on the frequency of B pertussis
or atypical bacteria, different responses to macrolides may
be observed in subgroups of infants with AB, which was
not the main objective of our study. n
Pinto et al
- 2012
ORIGINAL ARTICLES
The authors thank the students and residents who contributed with patient selection/inclusion: A.V. Azevedo, A.T. Ribeiro, A.W. Wiemann,
B.F. de Conto, B.Z. Munhoz, E.M. Morais, G.A. Bergmann, L.C. Marostica, L.S. Valiati, L.F. Spinelli, L.O. Sussela, M.R. Nunes, R. Regert,
S.L. Lardi, T.D. Gandolfi, A.D. Daudt, J.Z. Sanvitto, F. Kliemann, L.
Refosco, J. Peres, A. Reinstein, G. Gomes, K. Corezola, D. Pires, and A.
Pearson.
Submitted for publication Feb 2, 2012; last revision received Apr 22, 2012;
accepted May 23, 2012.
Reprint requests: Leonardo A. Pinto, MD, Department of Pediatrics, Institute of
~o Lucas da PUCRS, Av Ipiranga 6690/2
Biomedical Research, Hospital Sa
andar, 90610-000 Porto Alegre, Brazil. E-mail: [email protected]
References
1. Zorc JJ, Hall CB. Bronchiolitis: recent evidence on diagnosis and management. Pediatrics 2010;125:342-9.
2. Lakos AK, Pangercic A, Gasparic M, Kukuruzovic MM, Kovacic D,
Barsic B. Safety and effectiveness of azithromycin in the treatment
of respiratory infections in children. Curr Med Res Opin 2012;28:
155-62.
3. Kanoh S, Rubin BK. Mechanisms of action and clinical application of
macrolides as immunomodulatory medications. Clin Microbiol Rev
2010;23:590-615.
4. Friedlander AL, Albert RK. Chronic macrolide therapy in inflammatory
airways diseases. Chest 2010;138:1202-12.
5. Pinto LA, Camozzato C, Avozani M, Machado DC, Jones MH, Stein RT,
et al. Effect of clarithromycin on the cell profile of bronchoalveolar lavage fluid in mice with neutrophil-predominant lung disease. Rev
Hosp Clin Fac Med Sao Paulo 2004;59:99-103.
6. Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J 2010;36:646-54.
7. Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin
Immunol 2006;117:1233-6.
8. Desaki M, Takizawa H, Ohtoshi T, Kasama T, Kobayashi K, Sunazuka T,
et al. Erythromycin suppresses nuclear factor-kappaB and activator
protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun 2000;267:124-8.
9. Everard ML, Swarbrick A, Wrightham M, McIntyre J, Dunkley C,
James PD, et al. Analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection. Arch Dis Child 1994;
71:428-32.
10. Pitrez PM, Pinto LA, Machado DC, Tsukazan MT, Jones MH, Stein RT.
Upper airway cellular pattern in infants with acute bronchiolitis: neutrophils or eosinophils?. J Pediatr (Rio J) 2003;79:443-8.
11. Tahan F, Ozcan A, Koc N. Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial. Eur Respir J 2007;29:91-7.
12. Kneyber MC, van Woensel JB, Uijtendaal E, Uiterwaal CS, Kimpen JL.
Azithromycin does not improve disease course in hospitalized infants
with respiratory syncytial virus (RSV) lower respiratory tract disease:
a randomized equivalence trial. Pediatr Pulmonol 2008;43:142-9.
13. Hinnerskov M, Therkildsen JM, Cordoba G, Bjerrum L. Macrolide overuse for treatment of respiratory tract infections in general practice. Dan
Med Bull 2011;58:A4356.
14. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled
crossover trial. Lancet 2002;360:978-84.
15. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long
term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002;57:212-6.
16. Richeldi L, Ferrara G, Fabbri LM, Gibson PG. Macrolides for chronic
asthma. Cochrane Database Syst Rev 2002;1:CD002997.
17. Beigelman A, Mikols CL, Gunsten SP, Cannon CL, Brody SL, Walter MJ.
Azithromycin attenuates airway inflammation in a mouse model of viral
bronchiolitis. Respir Res 2010;11:90.
18. Korppi M. Macrolide resistance in Streptococcus pyogenes: a marker of
an overuse of macrolides. Pediatr Pulmonol 2009;44:1246-7. author reply 8-9.
19. Rouse MS, Steckelberg JM, Brandt CM, Patel R, Miro JM, Wilson WR.
Efficacy of azithromycin or clarithromycin for prophylaxis of viridans
group streptococcus experimental endocarditis. Antimicrob Agents
Chemother 1997;41:1673-6.
20. O’Doherty B, Muller O. Randomized, multicentre study of the efficacy
and tolerance of azithromycin versus clarithromycin in the treatment
of adults with mild to moderate community-acquired pneumonia. Azithromycin Study Group. Eur J Clin Microbiol Infect Dis 1998;17:828-33.
21. Patel KB, Xuan D, Tessier PR, Russomanno JH, Quintiliani R,
Nightingale CH. Comparison of bronchopulmonary pharmacokinetics
of clarithromycin and azithromycin. Antimicrob Agents Chemother
1996;40:2375-9.
22. Laham FR, Israele V, Casellas JM, Garcia AM, Lac Prugent CM,
Hoffman SJ, et al. Differential production of inflammatory cytokines
in primary infection with human metapneumovirus and with other
common respiratory viruses of infancy. J Infect Dis 2004;189:2047-56.
23. Melendi GA, Laham FR, Monsalvo AC, Casellas JM, Israele V,
Polack NR, et al. Cytokine profiles in the respiratory tract during primary infection with human metapneumovirus, respiratory syncytial virus, or influenza virus in infants. Pediatrics 2007;120:e410-5.
24. Friis B, Andersen P, Brenoe E, Hornsleth A, Jensen A, Knudsen FU, et al.
Antibiotic treatment of pneumonia and bronchiolitis. A prospective
randomised study. Arch Dis Child 1984;59:1038-45.
25. Behrendt CE, Decker MD, Burch DJ, Watson PH. International variation in the management of infants hospitalized with respiratory syncytial
virus. International RSV Study Group. Eur J Pediatr 1998;157:215-20.
26. Kozyrskyj AL, Dahl ME, Ungar WJ, Becker AB, Law BJ. Antibiotic treatment of wheezing in children with asthma: what is the practice? Pediatrics 2006;117:e1104-10.
27. Hyde TB, Gay K, Stephens DS, Vugia DJ, Pass M, Johnson S, et al. Macrolide resistance among invasive Streptococcus pneumoniae isolates.
JAMA 2001;286:1857-62.
28. Akkerman AE, Kuyvenhoven MM, van der Wouden JC, Verheij TJ. Prescribing antibiotics for respiratory tract infections by GPs: management
and prescriber characteristics. Br J Gen Pract 2005;55:114-8.
29. Esposito S, Blasi F, Arosio C, Fioravanti L, Fagetti L, Droghetti R, et al.
Importance of acute Mycoplasma pneumoniae and Chlamydia pneumoniae infections in children with wheezing. Eur Respir J 2000;16:1142-6.
30. Pientong C, Ekalaksananan T, Teeratakulpisarn J, Tanuwattanachai S,
Kongyingyoes B, Limwattananon C. Atypical bacterial pathogen infection in children with acute bronchiolitis in northeast Thailand. J Microbiol Immunol Infect 2011;44:95-100.
31. Bezerra PG, Britto MC, Correia JB, Duarte Mdo C, Fonceca AM, Rose K,
et al. Viral and atypical bacterial detection in acute respiratory infection
in children under five years. PLoS One 2011;6:e18928.
32. Papadopoulos NG, Moustaki M, Tsolia M, Bossios A, Astra E,
Prezerakou A, et al. Association of rhinovirus infection with increased
disease severity in acute bronchiolitis. Am J Respir Crit Care Med
2002;165:1285-9.
33. Pitrez PM, Stein RT, Stuermer L, Macedo IS, Schmitt VM, Jones MH,
et al. Rhinovirus and acute bronchiolitis in young infants. J Pediatr
(Rio J) 2005;81:417-20.
34. Nuolivirta K, Koponen P, He Q, Halkosalo A, Korppi M, Vesikari T,
et al. Bordetella pertussis infection is common in nonvaccinated infants
admitted for bronchiolitis. Pediatr Infect Dis J 2010;29:1013-5.
Azithromycin Therapy in Hospitalized Infants with Acute Bronchiolitis is Not Associated with Better Clinical Outcomes:
A Randomized, Double-Blinded, and Placebo-Controlled Clinical Trial
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