Francesca Santamaria Dipartimento di Scienze Mediche Traslazionali

Novità nella Terapia delle Malattie Respiratorie

Novembre 2014

Novità nella Terapia delle Malattie Respiratorie

• Wheezing

prescolare

• Tosse

• Infezioni

• Wheezing

prescolare

Wheezingepisodico

virale

Wheezing da fattori multipli

Mantenimento consigliato sempre un trial terapeutico, sospendere se inefficace

Antileucotrienico, oppure CSI, oppure

CSI + antileucotrienico

CSI (es. beclometasone equivalente 400 μg/die per 3 mesi)se sintomi persistenti:

CSI + antileucotrienico

Wheezing in età prescolare: terapia

© 2013 PROGETTO LIBRA • www.ginasma.it Brand Eur Respir J. 2014

OR for long-term ICS and/or leukotriene modifiers prescription

7.1

2.2 2.7

8.5

Frequent wheeze ED visits Personal allergy Day-care diseases attendance

8 –

7 –

6 –

5 –

4 –

3 –

2 –

1 –

0

Terapia di mantenimento nel wheezing prescolare:in base a cosa decidere?

What drives prescribing of asthma medication to preschool wheezing children? Montella, Pediatr Pulmonol 2013

376 pts (32.8 mo) with wheezing (54% frequent wheeze: ≥ 4 episodes/yr)

77% 23%

ED visi

ts

Hospit

al ad

miss

ions

Previo

us b

ronc

hioliti

s

Noctu

rnal

arou

sals

0%

50%

100%

Not treated Treated

Frequenza e severità dei

sintomi sono i principali

determinanti nella decisione dei pediatri di libera scelta di trattare o non

trattare a lungo termine

p < 0.05

p = NS

23% 77%

What drives prescribing of asthma medication to preschool wheezing children? Montella, Pediatr Pulmonol 2013

Eur Respir J. 2014

Novità nella Terapia delle Malattie Respiratorie

• Tosse

Duration of symptoms of respiratory tract infections in children: systematic review. Thompson, BMJ. 2013

Days

Resolution of acute cough

in 50% of ch. at 10 days

10%: cough at 25 days

50

%

10

Starting point for treatment of cough: Medical History

Acute (< 3 wks)

Recurrent acute (≥ 2/yr; 7-14 days) Chronic (> 8 wks)

Prolonged acute (subacute; 3-8 wks)

Marais, ADC 2005

ACUTE and SUB-ACUTE

CHRONIC

RECURRENT

Therapy for cough should be directed at the aetiology and specific treatments used

where possible Chung, Pulm Pharmacol Ther 2002

ACUTE COUGH

Foreign Body urgent rigid bronchoscopy

HOW TO TREAT?

EZIOLOGIA

specifica se ne è chiaramente identificabile la causa (ad es. se associata a caratteristiche suggestive di una patologia polmonare o sistemica)

non specifica quando è isolata, senza evidenza di altri sintomi respiratori ed associata a rx- torace nella norma Shields, Thorax 2008

Respiratory tract infection Non Specific Cough.

Honey, Dextromethorphan (DM), and No Treatment on Nocturnal Cough for Coughing children and Their Parents. Paul, Arch Pediatr Adolesc Med 2007

Honey may be preferable for cough and sleep difficulty in URTI

105 ch. with URTI & night cough

Honey DM No therapy

Cough frequencyFirst nightSecond night

p<0.001

-1. 9 -1.4- 0.9

Scor

e

Over-The-Counter (OTC) drugs

Decongestionants Expectorans

Antihistamines AntitussivesDextromethorphan Codeine

Non drugs (honey)

Treating cough and cold: Guidance for caregivers of children and youth. Goldman, Paediatr Child Health 2011

Fluid intake Mainstay of therapy Humidified air, Echinacea, Zinc, Vitamin C Frequently used, not recommended Non steroidal anti-inflammatory drugs Not significantly reduce symptom score/duration may affect discomfort caused by the viral illness Antihistamines No clinically significant effect Honey Pasteurized honey safe in > 1 yr Demulcent/antioxidant/antimicrobial effects/increases cytokines

2010

Azione

antiossidante

antiinfiammatoria

anestetica

antinfettiva

Mucolitici

• Controindicazione in età < 2 aa (aumento di tosse/muco, dispnea, vomito)*

• Per età > 2 aa, l'uso di un mucolitico è possibile, ma non va continuato in caso di persistenza o peggioramento dei sintomi.

• Alcune significative misure in grado di dar sollievo: Far dormire in posizione supina, con la testa sollevata Far bere il bambino frequentemente Tenere fresca la stanza Non fumare in casa, anche al di fuori della camera

•Acetilcisteina, carbocisteina, ambroxolo, bromexina,

sobrerolo, neltenexina, erdosteina, telmesteina *

•Farmaci uso rettale con derivati terpenici (es, canfora, timo, terpineolo, mentolo, olii di aghi di pino, eucalipto e trementina): NO < 30 mesi e se epilessia/conv. febbrili)

Novembre 2010

Mucolitici per uso orale/rettale

Upper Airway Cough Syndrome (UACS) in Children

• Includes various types of rhinosinus diseases that induce cough (allergic/nonallergic rhinosinusitis; tonsillar hypertrophy)

• Antihistamines/ nasal steroids + allergen avoidance(= allergic rhinitis)

• Resolution can take up to 2- 4 wks of therapy Goldsobel, J Pediatr 2010

PROLONGED ACUTE (SUBACUTE) COUGH3-8 wks

Chest 2006 Thorax 2008

CHRONIC COUGH

Chronic sinus disease?Protracted Bacterial

Bronchitis?

•SPECIFIC COUGH

Protracted Bacterial Bronchitisin which patients?

Preschool healthy children with significant viral LRT infections

• H. influenzae

• S. pneumoniae

• M. catarrhalis

• P. aeruginosa

Priftis, Chest 2013

Chronic wet cough ≥ 4 wks in the absence of other diagnoses

Persistent symptoms + intermittent exacerbations

Impairment of host defenses and impaired mucociliary clearance

CILIA CHANGES RECOVERY AFTER MANY WEEKS

CHEST IMAGING

• Normal lung (30%) • Bronchial wall thickening (48%)• Increased bronchial markings (20%)• Consolidation (14%)

Narang, PLoS One. 2014

Chronic SinusitisOral antibiotic therapy Scadding, CEA 2007

Protracted Bacterial Bronchitis (PBB)

Oral antibiotic therapy + Chest physiotherapy Priftis, Chest 2013

Kompare, J Pediatr 2012

CHRONIC COUGH

• Infezioni

Novità nella Terapia delle Malattie Respiratorie

1. Clinicians should not administer salbutamol2. Clinicians should not administer epinephrine3. Nebulized hypertonic saline should not be administered in the ED4. Clinicians may administer nebulized hyper. saline (3%) in hospital5. Clinicians should not administer systemic steroids in any setting6. Clinicians may choose not to administer O2 if SaO2 > 90%7. Clinicians may choose not to use continuous pulse oximetry8. Clinicians should not use chest physiotherapy9. Clinicians should not administer antibacterial medications to infants

and children unless there is a concomitant bacterial infection, or a strong suspicion of one

10. Clinicians should administer nasogastric or intravenous fluids for infants who cannot maintain hydration orally

Pediatrics. 2014 Nov

Not receiving therapy

Receiving therapy0

0.5

1

1.5

Strepto Staphylo Veillonella Rothia

Changes in gastric and lung microflora with acid suppression. Rosen, JAMA Pediatr. 2014 Oct

5yr prospective study of 99 pts 1-18 yrs (cough at least 3 times/wk for at least 1 month broncho/gastroscopy; 48% acid suppressed)

p < 0.05

Gastric bacterial concentrations, log10

CFU/ml

Bacillus; Dermabacter; Lactobacillus; Peptostreptococcus; Capnocytophaga;Propionibacterium

Positive correlations between proximal nonacid reflux & lung bacterial concentrations (r 0.5!)

Lu

ng

Gastric flora can influence lung flora through nonacid GER in acid-suppressed patients

Acid suppression may need to be limited in patients at risk for infections

Oral Amoxicillin: 1° choice: effective, tolerated, cheap Alternatives: co-amoxiclav, cefaclor, macrolides

Macrolides: -add if no response to 1st line therapy after 48 h

(see severity assessment)

-use if Mycoplasma/Chlamydia is suspected

Pediatric CAP: which antibiotic should be used?

Thorax 2011, CID 2011

Parenteral therapy Preferred: intravenous azithromycin(10 mg/kg on days 1 and 2 of therapy;transition to oral therapy if possible)

Alternatives: intravenous erythromycin lactobionate(20 mg/kg/d every 6 hours)

Oral therapy (step-down therapyor mild infection)

Preferred: azithromycin (10 mg/kg on day 1, followed by 5 mg/kg/d once daily on days 2–5)

Alternatives: clarithromycin(15 mg/kg/d in 2 doses) or oral erythromycin (40 mg/kg/d in 4 doses);

INPATIENTS Management of Atypical Bacteria

Macrolides at least x 14 days (azithro 5 days)

OUTPATIENTS

CID 2011

Erythromycin interacts with motilin receptors, induces strong gastric and pyloric bulb contractions infantile hypertrophic

pyloric stenosis (3 to 12 wks old infants: 1-2 %o births)

5 giorni di terapia per un bambino di 15 Kg: claritromicina ~ € 16 azitromicina ~ € 22 eritromicina ~ € 10

PEARLS

Use of macrolides in mother and child and risk ofinfantile hypertrophic pyloric stenosis. Lund BMJ 2014.

Erythromycin is associated with hypertrophic pyloric stenosis risk, but no certainty about other macrolides (pertussis !!!!!)

A comparative clinical study of macrolide-sensitive and macrolide-resistant Mycoplasma p. in pediatric patients.

Matsubara J Infect Chemother 2009.

68% macrolide-sensitive

32%

macrolide-resistant

Efficacy of macrolide therapy 91.5% for macrolide sensitive 22.7% for macrolide resistance (p < 0.01)

In children increasing prevalenceof macrolide-resistant M. pneumoniae

More prolonged fever (> 48 hr) and cough

Macrolide sensitive

Macrolideresistent

Fever days 1.5 4.0

Cough days 7.0 11.4

Frequency of the A2063G mutation in 23S rRNA gene [significantly >> in children (61.3%) than adults (13.3%)]

Yoo, Antimicrob Agents Chemother. 2012

The resistance

30 ch. with Mycoplasma (PCR + serology)

70% resistant (fever)After minocycline,

fever disappeared (48 h)

Antibiotic Management of Atypical Bacteria

Mycoplasma (DNA copies)

KawaiRespirology. 2012

Clinical Relevance of Mycoplasma macrolide resistance Cardinale, J Clin Microbiology 2013

Levofloxacin in macrolide resistant M. pneumoniae

Oral therapy (step-down therapyor mild infection)

INPATIENTS Management of Atypical BacteriaPreferred: intravenous azithromycin(10 mg/kg on days 1 and 2 of therapy;transition to oral therapy if possible)

Alternatives: intravenous erythromycin lactobionate(20 mg/kg/d every 6 hours) or levofloxacin(16-20 mg/kg/d every 12 hours; maximum dailydose, 750 mg)

OUTPATIENTS

Parenteral therapy

Preferred: azithromycin (10 mg/kg on day 1, followed by 5 mg/kg/d once daily on days 2–5)

Alternatives: clarithromycin(15 mg/kg/d in 2 doses) or oral erythromycin (40 mg/kg/d in 4 doses);for children >7 yrs old, doxycycline(2–4 mg/kg/day in 2 doses; for adolescents with skeletal maturity, levofloxacin (500 mg) or moxifloxacin (400 mg)/dCID 2011

WARNING

Bacteria acquire macrolide resistance very fast if used indiscriminately (especially the second-generation agents)

Lancet 2007 Eur Respir J 2010

S. pneumoniae resistance to macrolides

Italy 34% (range, 25-50%)

Southern Italy >70%www.ecdc.europa.eu (2012)

Resistenza S. pneumoniae ai macrolidi in Campania (2012)

TUTTI I MATERIALI: 61.7% SANGUE e LIQUOR: 63% RESPIRATORI: 61.7%

AR-ISS: sorveglianza antibiotico-resistenza in Italia Rapporto del triennio 2006-2008

Gram-negativi : ↑↑ resistenza E. coli: fluorochinoloni K. pneumoniae: Italia: 36%!! cefalosporine III^ gen. (37%) fluorochinoloni

Can Resistance to AntibioticsBe Minimized?

Recommendations

1. Limit the spectrum of activity of antimicrobials to that required to treat the identified pathogen.

2. Use the proper dosage of antibiotics to achieve a minimal concentration to decrease risk of resistance.

3. Treat for the shortest effective duration to minimize exposure of both pathogens and normal microbiota to antimicrobials.

4. Limit exposure to any antibiotic.

Sinusitis and Pneumonia Hospitalization After Introduction of PCV. Lindstrand, Pediatrics. 2014 Nov 10

PCV7PCV13 PCV13PCV7

PCV7 and PCV13 prevent

pneumonia at preschool age

If discovery of new antibiotics continues to falter while resistance to drugs continues to spread, society’s medicine chest will soon lack effective treatments for many infections. Nathan, Sci Transl Med. 2012

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