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WO2008031437A2 - Traitement de l'asthme, de l'eczéma et / ou d'allergies à l'aide d'antibiotiques - Google Patents

Traitement de l'asthme, de l'eczéma et / ou d'allergies à l'aide d'antibiotiques Download PDF

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Publication number
WO2008031437A2
WO2008031437A2 PCT/DK2007/050125 DK2007050125W WO2008031437A2 WO 2008031437 A2 WO2008031437 A2 WO 2008031437A2 DK 2007050125 W DK2007050125 W DK 2007050125W WO 2008031437 A2 WO2008031437 A2 WO 2008031437A2
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Prior art keywords
asthma
allergy
eczema
treatment
use according
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WO2008031437A3 (fr
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Hans Bisgaard
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REGION HOVEDSTADEN V/GENTOFTE HOSPITAL
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REGION HOVEDSTADEN V/GENTOFTE HOSPITAL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G01N2800/122—Chronic or obstructive airway disorders, e.g. asthma COPD
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • the present invention relates to a treatment of asthma, eczema and/or allergy in individuals, in particular treatment of infants, for reducing the risk of acquiring asthma, eczema and/or allergy at a later stage in life.
  • Persistent wheeze represents a major chronic disorder in young children being the main cause of hospitalization, medication use and other healthcare resource utilizations and burdens their quality of life.
  • It reflects a common clinical phenotype with heterogeneous etiologies such as post-bronchiolitic, virus-associated or atopy- related wheeze; as well as proper asthma. Such phenotype has also been separated on a temporal pattern into transient early onset, late onset or persistent pattern.
  • Biopsies from infants with persistent wheeze and reversible airflow obstruction revealed neither thickening of the reticular basal membrane nor eosinophilic inflammation even in the presence of atopy.
  • Broncho-alveolar-lavage in young children with severe persistent wheeze showed increased lymphocytes and epithelial cells, but in contrast to findings in adult asthmatics, macrophages and neutrophils were up-regulated, while eosinophils and mast-cells were less predominant.(5;6) .
  • the present invention is based on the finding of a correlation between bacterial colonization in the airways and later development of asthma, eczema and/or allergy.
  • the present invention relates to the treatment of asthma, eczema and/or allergy in an individual, in particular prevention or reduction of asthma, eczema and/or allergy, by administering an effective amount of an antibiotic in order to reduce or eradicate pathogenic bacterial growth in the airways thereby inhibiting pathogenic bacteria in stimulating asthma, eczema and/or allergy through various routes.
  • the individual is an infant.
  • the present invention also includes treatment of pregnant women to prevent their infants from being colonized with bacteria during birth.
  • the bacterial colonization is asymptomatic in the sense that the bacteria do not cause a clinically detectable infection.
  • the invention relates to the use of an antibiotic for the preparation of a composition for treatment of asthma, eczema and/or allergy in an individual, or for the preparation of a composition for the administration to a pregnant woman for the treatment of asthma, eczema and/or allergy in her infant to be born.
  • the invention relates to a method for diagnosing a risk for acquiring asthma, eczema and/or allergy in an individual, said method comprising
  • a Examining a sample from the respiratory tract of the individual, b. Evaluating whether colonization with pathogenic bacteria is present in the respiratory tract, and c. Diagnosing the risk based on the presence or absence of pathogenic bacteria in the respiratory tract.
  • Figure 1 Flow chart of subjects included into the analyses of the primary outcome wheeze.
  • Figure 2 First whez episode as observed during the first 4 years of life.
  • the cumulated risk is indicated for neonates with (•) and without (— ) early colonization with S. pneumoniae, M. catarrhalis and H. influenzae.
  • Figure 3 Persistent wheeze. Development during the first 4 years of life.
  • the cumulated risk is indicated for neonates with (•) and without (— ) early colonization with S. pneumoniae, M. catarrhalis and H. influenzae.
  • Figure 4 Acute severe exacerbation of wheeze. Development during the first 4 years of life. The cumulated risk is indicated for neonates with (•) and without (— ) early colonization with S. pneumoniae, M. catarrhalis and H. influenzae.
  • Figure 5 Hospitalization for acute severe exacerbation of wheeze during the first 4 years of life. The cumulated risk is indicated for neonates with (•) and without (— ) early colonization with S. pneumoniae, M. catarrhalis and H. influenzae.
  • Eosinophils in blood relative mean increase (95%CI) during the first 4 years of life for neonates with and without early colonization with S. pneumoniae, M. catarrhalis and H. influenzae.
  • allergy refers to any type of disease related to allergy, such as the most common allergic conditions that include hay fever (allergic rhinitis), asthma, allergic eyes (allergic conjunctivitis), allergic eczema, hives (urticaria), and allergic shock (also called anaphylaxis and anaphylactic shock).
  • allergic conditions include hay fever (allergic rhinitis), asthma, allergic eyes (allergic conjunctivitis), allergic eczema, hives (urticaria), and allergic shock (also called anaphylaxis and anaphylactic shock).
  • Antibiotics An antibiotic is a chemical substance that kills or slows the growth of microorganisms, in particular bacteria, and cures infections.
  • Asthma is a chronic inflammatory pulmonary disorder that is characterized by reversible obstruction of the airways resulting in chest tightness, coughing and wheezing.
  • Atopic dermatitis Atopic dermatitis, commonly referred to as eczema, is a chronic skin disorder categorized by scaly and itching rashes. People with eczema often have a family history of allergic conditions like asthma, hay fever, or eczema.
  • Broad spectrum antibiotic An antibiotic having a wide range of activity against both gram-positive and gram-negative organisms.
  • Delay of asthma, eczema and/or allergy By the term is meant that onset of asthma, eczema and/or allergy is delayed to a later stage in life.
  • the typical onset of asthma in untreated population is an age of 2-3 years. When the onset is delayed it is normally delayed by at least Vz year, more preferably at least 1 year.
  • Eczema is an itching dermatitis often with vesicles. Atopic dermatitis is the most common form of eczema.
  • Infant A child in the earliest period of life, preferably before 1 year, more preferably before 6 months, more preferably before 3 months.
  • Inhibition of asthma, eczema and/or allergy By the term is meant that the infant does not acquire asthma, eczema and/or allergy at a later stage in life.
  • Pathogenic bacteria Bacteria causing disease or capable of causing disease.
  • Prevention of asthma, eczema and/or allergy By the term is meant that the infant has a reduced risk of acquiring asthma, eczema and/or allergy at a later stage in life.
  • Reduction of asthma, eczema and/or allergy By the term is meant that the infant has a reduced risk of acquiring asthma, eczema and/or allergy at a later stage in life.
  • Respiratory tract The term respiratory tract is used in it's conventional meaning, i.e. mouth and nose, airways and lungs.
  • the present invention relates to the use of an antibiotic for the preparation of a composition for the administration of an antibiotic for the treatment of asthma, eczema and/or allergy in an individual, in particular in an infant.
  • the treatment is preferably prevention of asthma, eczema and/or allergy or reduction of asthma, eczema and/or allergy.
  • the treatment is delay of asthma, eczema and/or allergy symptoms.
  • the present inventors have shown a correlation between airway colonization with pathogenic bacteria in asymptomatic neonates and later development of severe persistent lung symptoms and asthma.
  • Reduction or eradication of the pathogenic bacteria by administration of antibiotics reduces the risk of acquiring asthma, eczema and/or allergy at a later stage in life, thereby preventing asthma, eczema and/or allergy or reducing asthma, eczema and/or allergy or delaying asthma, eczema and/or allergy.
  • the invention also relates to treatment of older children as well as adults in order to prevent symptoms or reduce symptoms or asthma, eczema and/or allergy.
  • the pathogenic bacteria colonizing the airways may be any pathogenic bacteria, in particular pathogenic bacteria normally infecting the airways.
  • the pathogenic bacteria typically found to colonize the airways of the infants are selected from the group consisting of Streptococcus pneumoniae (S. p.), Haemophilus influenze (H. L), Moraxella catarrhalis (M.c), and Staphylococcus aureus.
  • selected antibiotics according to the present invention preferably have the ability to inhibit or reduce the growth of the pathogenic bacteria colonizing the airways, whereby the antibiotics can be used in infants to protect against asthma, eczema and/or allergy onset in children or later in life.
  • the antibiotics may be administered in any suitable form as described more detailed below. Without being bound by theory it is believed that the infants are colonized with bacteria received from the mother, in particular bacteria colonizing the genital tract of the mother. Thus, in another aspect the invention relates to treatment of the mother during pregnancy in order to reduce the bacteria load in the mother. Therefore, the present invention also relates to the treatment of asthma, eczema and/or allergy in infants by administering to a pregnant woman a sufficient amount of an antibiotic.
  • the antibiotics used according to the present invention may be any antibiotics useful for reducing or eradicating pathogenic bacterial growth in the airways. Such antibiotics are known to the person skilled in the art.
  • the antibiotic should be useful for reducing or eradicating one or more of the group consisting of Streptococcus pneumoniae (S. p.), Haemophilus influenze (H. i.), Moraxella catarrhalis (M.c), and Staphylococcus aureus, more preferably eradicating one or more of the group consisting of Streptococcus pneumoniae (S. p.), Haemophilus influenze (H.i.), and Moraxella catarrhalis (M.c).
  • the antibiotic may be any antibiotic selected from the group of Beta- Lactams, Aminoglycosides, Quinolones, Glycopeptides, and Macrolides.
  • Beta Lactams are divided into four subdivisions:
  • Penicillins examples are penicillin, amoxicillin, cloxacillin
  • Cephalosporins examples are cefazolin, cefuroxime, cefotaxime, ceftazidime, cefepime, cefpirome
  • Aminoglycosides examples are gentamicin, amikacin, tobramycin, netilmicin Quinolones: Examples are ciprofloxacin, ofloxacin, gatifloxacin, moxifloxacin
  • Glycopeptides examples are vancomycin, teicoplanin
  • Macrolides examples are erythromycin, azithromycin, clarithromycin
  • an antibiotic selected from an antibiotic having a broad spectre, such as ampicillin is administered.
  • an antibiotic selected from an antibiotic having a broad spectre is administered.
  • the effective treatment is as short as possible, preferably less than one week, more preferably at the most 3 days, such as a treatment that is effective after one dosage only.
  • the antibiotic is a macrolide, such as azithromycin.
  • azithromycin may be effective in a dosing regime of few days, such as 3 days or a single dosage.
  • Azithromycin is commercially available under the trade name Zithromax.
  • the composition is administered to an infant to prevent or reduce asthma, eczema and/or allergy at a later stage in life.
  • the composition is administered after diagnosis of a pathogenic colonization in the airways.
  • the composition is administered prophylactically to infants without bacterial analysis. In particular in the latter case it may be relevant to administer a broad spectrum antibiotic. It is furthermore found that an early treatment is most effective in prevention of asthma, eczema and/or allergy.
  • the composition is administered to an infant younger than 3 months, more preferably administered to the infant younger than 2 months.
  • the daily dosage typically depends on the age of the infant as well as the weight of the infant as known to the person skilled in the art.
  • the antibiotic may be administered in any suitable form known to be effective against infections, such as the forms commercially available for other indications.
  • the daily dosage may be divided into two or more dosages administered two or more times per day.
  • the composition is administered to a pregnant woman in the last part of the pregnancy, preferably shortly before the expected time of birth, such as in the last month of pregnancy in order to avoid the infant being colonized with pathogenic bacteria during birth, thereby preventing or reducing asthma, eczema and/or allergy at a later stage in life of the infant to be born.
  • the composition is administered after diagnosis of a pathogenic colonization in the genital tract.
  • the composition is administered prophylactically without bacterial analysis.
  • composition prepared according to the invention may be administered by any suitable route to the mother, including orally or locally to the genital tract.
  • the daily dosage may be divided into two or more dosages administered two or more times per day.
  • antibiotic for administration to the individual
  • the antibiotic may be administered in any suitable form for any suitable type of administration, yet the antibiotic is typically administered for systemic treatment, such as an oral administration form.
  • oral formulations may be selected from the group of tablets, capsules, powders, granules, solutions, syrups or suspensions.
  • a solution or a suspension that may be administered with the food or directly injected into the mouth of the infant.
  • the formulation comprises azithromycin, such as azithromycin tablets, azithromycin capsules, optionally film-coated and azithromycin powder for oral suspension
  • the formulation for administration to a pregnant woman may be in any form suitable for administration, such as orally for systemic use (see above), and/or locally to the genital tract.
  • the formulation suitable for vaginal administration may be presented as pessaries, tampons, suppositories, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the formulation comprises azithromycin, such as azithromycin tablets, azithromycin capsules, optionally film-coated and azithromycin powder for oral suspension
  • the invention further relates to a method for diagnosing a risk for acquiring asthma, eczema and/or allergy in an individual, said method comprising
  • a Examining a sample from the respiratory tract of the individual, b. Evaluating whether colonization with pathogenic bacteria is present in the respiratory tract, and c. Diagnosing the risk based on the presence or absence of pathogenic bacteria in the respiratory tract.
  • the present inventors have found a correlation between colonization of the respiratory tract with pathogenic bacteria and later development of asthma, eczema and/or allergy, thus a risk for acquiring asthma, eczema and/or allergy is high if a presence of one or more types of pathogenic bacteria are found in the sample from the respiratory tract, preferably the lower respiratory tract.
  • pathogenic bacteria selected from the group consisting of Streptococcus pneumoniae (S. p.), Haemophilus influenze (H. i.), and Moraxella catarrhalis (M. c.) is present.
  • S. p. Streptococcus pneumoniae
  • H. i. Haemophilus influenze
  • M. c. Moraxella catarrhalis
  • the sample from the respiratory tract may be any suitable sample, such as nasal secretion, secretion from pharynx, trachea or bronchial secretion, for example secretion obtained from suction of secretion from the respiratory tract.
  • the sample may be diagnosed using a rapid diagnostic tool, such as a dipstick or another point-of-care device.
  • a rapid diagnostic tool such as a dipstick or another point-of-care device.
  • Any suitable method, either indirect or direct for detecting the pathogenic bacteria may be used, such as a method described US patent Nos. 6,967,084, 7,045,342, 7,091 ,049.
  • Airway bacteria were investigated in the asymptomatic infant at 1 and 12 months of age. Hypopharyngeal aspirates were performed by the doctor in the COPSAC Clinical Research Unit (CRU) in the sedated 1 -month-old infant after lung function test(9) under aseptic conditions with a soft suction catheter passed through the nose into hypopharynx. Aspiration was done intermittently assuring not to apply suction while passing through the oro- and nasopharynx. Hypopharyngeal sampling was repeated in the 12 month old awake infant. Samples were transported to the microbiology laboratories within 2 hours from collection and included in the microbiology routine. Material representative for lower airways was cultured and standard laboratory techniques applied for identification of S. pneumoniae, H. influenzae, M. catarrhalis, S. pyogenes and S. aureus, chosen prior to the study.(10) The CRU personel were unaware of the outcome of the culture.
  • CRU COPSAC Clinical Research Unit
  • Wheeze was translated to the parents as wheeze or whistling sounds, breathlessness or persistent troublesome cough severely affecting the wellbeing of the infant, and was recorded as the composite dichotomized scores (yes/no) as previously described in details(1 1 ).
  • the symptom description was supported by a dedicated book on early childhood wheeze with integrated dairy cards (see www.cj32sac.com).
  • the CRU doctor reviewed symptom definition and the diary entries with the parents at the 6-monthly clinical sessions.
  • the infants were given a full physical examination and parents were interviewed by the doctors at the CRU (authors) using structured questions and standardized response categories focusing on the child's lung symptoms, diagnoses, medication, healthcare utilization, lifestyle and home environment. Symptoms from airways or the skin were diagnosed and treated by the CRU doctor rather than by other health care providers.
  • Whez episodes were defined as three consecutive days of wheeze, at which point the parents were requested to bring the child to the CRU for examination.
  • Persistent wheeze was defined as five such episodes within 6 months or daily symptoms for four weeks. Differential diagnoses were excluded at that point by chest X-rays and sweat tests. Acute severe exacerbation of whez symptoms was diagnosed by the CRU doctors or from hospitalization for such symptoms.
  • Blood eosinophil concentration (10 9 /L) was measured by standard methods.
  • Total level of immunoglobulin E was determined by ImmunoCAPTM (Pharmacia Diagnostics AB, Uppsala, Sweden) in serum(16); detection limit 2 kU/L.
  • Persistent wheeze defined the threshold for daily treatment with 400 microgram of inhaled budesonide pMDI with a spacer for 3 months increasing to 6 and 12 months at subsequent relapses. Montelukast 4 mg daily was added to children with recurrent wheeze despite budesonide maintenance treatment. Acute severe exacerbation of wheeze was treated with budesonide 1600 ⁇ g daily for 2 weeks or oral prednisolone 1 -2 mg/kg daily for 3 days. No other treatment was allowed for whez symptoms.
  • the primary outcomes were the indicators of recurrent wheeze: whez episodes; persistent wheeze; acute severe exacerbations and acute hospitalization for wheeze.
  • the secondary outcomes were lung function; blood eosinophils; total-lgE and specific IgE.
  • Age accumulated risks of first whez episode; diagnosis of persistent wheeze; acute severe whez exacerbation and hospitalization stratified on colonization of bacteria were estimated by the Kaplan-Meier estimator. Change in risk due to bacterial colonization was quantified as hazard ratios obtained by Cox regression. Confounder adjusted hazard ratios were calculated for the sub-cohort of children with full records of the confounders in question. The effect of bacterial colonization on the logarithmic lung function and logarithmic total IgE at four years of age was assessed by ANOVA methods. The event specific allergy at age 4 years was modelled by logistic regression. Logarithmic measurements of blood eosinophils at ages 6 months, 18 months, and 4 years were modelled by a mixed linear model including a random effect for each child.
  • S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus or S. pyogenes were colonized with S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus or S. pyogenes in 30 (9%), 28 (9%), 27 (8%), 196 (61%) and 1 (0%) cases respectively.
  • Prevalence of S.p or M.c or H.i. was 66/321 (21%). Multiple strains were found in 49 infants (2 strains), 15 (3 strains) and 2 (4 strains).
  • S. aureus colonization comprised 73 different Fag-patterns within the 170 colonies, the most common pattern repeating in 14%.
  • the hazard ratio being 1.92 (1.43;2.57) for a first wheeze; 2.46 (1 .44;4.18) for development of persistent wheeze; 2.73 (1.49; 5.00) for acute severe exacerbation and 3.87 (1.87;8.02) for acute hospitalization.
  • Table 1 Hazard Ratio (presence/absence of bacterium strain) for primary outcomes whez episode, persistent wheeze, exacerbation and hospitalization with and without adjustment for the possible confounders listed in table 2.

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Abstract

La présente invention concerne le traitement de l'asthme, de l'eczéma et / ou d'allergies chez des patients, en particulier le traitement d'enfants en bas âge en vue de réduire le risque d'apparition d'asthme, d'eczéma et / ou d'allergies plus tard dans la vie, par l'administration d'une quantité efficace d'un antibiotique afin de réduire ou de supprimer la croissance bactérienne pathogène dans les voies respiratoires, ce qui empêche ainsi les bactéries pathogènes de favoriser l'asthme, l'eczéma et / ou des allergies par diverses voies. Le patient est en particulier un enfant en bas âge. De plus, la présente invention concerne également le traitement des femmes enceintes afin d'éviter aux nourrissons d'être colonisés par des bactéries lors de l'accouchement.
PCT/DK2007/050125 2006-09-13 2007-09-13 Traitement de l'asthme, de l'eczéma et / ou d'allergies à l'aide d'antibiotiques Ceased WO2008031437A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102670639A (zh) * 2012-06-05 2012-09-19 金小晶 阿奇霉素的新用途

Non-Patent Citations (6)

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Title
BENN CHRISTINE STABELL ET AL: "Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood" JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 110, no. 1, July 2002 (2002-07), pages 72-77, XP002471023 ISSN: 0091-6749 *
BLASI F ET AL: "POTENTIAL ROLE OF ANTIBIOTICS IN THE TREATMENT OF ASTHMA" FOREST PATHOLOGY, BLACKWELL WISS.- VERLAG, BERLIN, DE, vol. 3, no. 3, September 2004 (2004-09), pages 237-242, XP009064079 ISSN: 1437-4781 *
GAINOV IAIN C ET AL: "Do macrolides have a role in the long term treatment of asthma." PEDIATRIC RESEARCH, vol. 53, no. 4 Part 2, April 2003 (2003-04), page 575A, XP009096680 & ANNUAL MEETING OF THE PEDIATRIC ACADEMIC SOCIETIES; SEATTLE, WA, USA; MAY 03-06, 2003 ISSN: 0031-3998 *
LEHMANN H S ET AL: "Staphylococcal enterotoxin-B-mediated stimulation of interleukin-13 production as a potential aetiologic factor in eczema in infants." INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY DEC 2004, vol. 135, no. 4, December 2004 (2004-12), pages 306-312, XP009096566 ISSN: 1018-2438 *
PENDERS J ET AL: "Clostridium difficile and E. coli colonization in early life are associated with an increased risk of allergy" EUROPEAN JOURNAL OF EPIDEMIOLOGY, vol. 21, no. Suppl. S, July 2006 (2006-07), page 86, XP002471024 & 2ND EUROPEAN CONGRESS OF EPIDEMIOLOGY; UTRECHT, NETHERLANDS; JUNE 28 JULY 01, 2006 ISSN: 0393-2990 *
SNYDER R D ET AL: "Prophylactic antibiotics in asthmatic children." ANNALS OF ALLERGY JUL 1970, vol. 28, no. 7, July 1970 (1970-07), pages 307-312, XP009096578 ISSN: 0003-4738 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102670639A (zh) * 2012-06-05 2012-09-19 金小晶 阿奇霉素的新用途

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