Les infections sévères à pneumocoque Pourquoi ? Comment ? Quel traitement? Muriel Le Bourgeois Service de Pneumologie et Allergologie Pédiatriques Hôpital Necker Enfants Malades

Streptococcus pneumoniae Est un des pathogènes les plus virulents Mortalité 0,3/100 000/an 0-15ans (0,89/100000/an nourrisson), IDF Ovetchkine P, Cohen R, Gaudelus J.Arch Pediatr. 2001 Est devenu la principale bactérie responsable Des infections communautaires de l’enfant Des bactériémies Des pneumonies bactériémiques du nourrisson et de l’enfant, des pleuropneumopathies Des méningites du nourrisson

Etude prospective française 2001-2003 From January 2001 through December 2003, a total of 1084 children with bacterial meningitis were enrolled in a prospective French nationwide survey. The most frequent pathogens found in children older than 28 days were Neisseria meningitis (55.3%) and Streptococcus pneumoniae (33.4%). S. pneumoniae was the most frequent pathogen found among infants aged 2-12 months (49.5%), whereas N. meningitidis was the most frequent pathogen among children >12 months old (69.7%). Approximately one-half of S. pneumoniae isolates had diminished susceptibility to penicillin. The case-fatality rates were 7.6% for children with N. meningitidis meningitis and 10.8% for children with S. pneumoniae infection. Etude prospective française 2001-2003 S. pneumoniae de sensibilité diminuée dans 50% des cas Mortalité due à S. pneumoniae plus importante Bingen, E. Clin Infect Dis. 2005

Augmentation du nombre de pleurésies purulentes Byington, Clin Infect Dis, 2002 Etude épidémiologique dans l’Utah de 1993 à 1999 540 pneumopathies communautaires 153 Pleurésies Purulentes : 28,3% 13 % en 1994 à 41 % en 1997 1cas/100000  5 cas/100000 10 20 30 40 50 60 70 80 90 1993- 1994 1995- 1996 1997- 1998 1999- 2000 2001- 2002 Schultz, Pediatrics 2004 Hospitalisation à Houston pour Pleurésie Purulente

Pleurésies purulentes S. pneumoniae 72% dont Sérotype 1: 50% An Epidemiological Investigation of a Sustained High Rate of Pediatric Parapneumonic Empyema: Risk Factors and Microbiological Associations Carrie L. Byington,1 LaShonda Y. Spencer,1,2 Timothy A. Johnson,4 Andrew T. Pavia,1,2 Daniel Allen,5 Edward O. Mason,6 Sheldon Kaplan,6 Karen C. Carroll,3 Judy A. Daly,5 John C. Christenson,1 and Matthew H. Samore2 Departments of 1Pediatrics, 2Medicine, and 3Pathology, and 4School of Medicine, University of Utah, and 5Clinical Microbiology Laboratories, Primary Children's Medical Center, Salt Lake City, Utah; and 6Department of Pediatrics and Microbiology, Baylor College of Medicine, Houston, Texas Received 9 July 2001; revised 5 September 2001; electronically published 3 January 2002. We investigated the increasing incidence of pediatric empyema during the 1990s at Primary Children's Medical Center in Salt Lake City. Of 540 children hospitalized with community-acquired bacterial pneumonia (CAP) who were discharged from 1 July 1993 through 1 July 1999, 153 (28.3%) had empyema. The annual population incidence of empyema increased during the study period from 1 to 5 cases per 100,000 population aged <19 years. Streptococcus pneumoniae was identified as the most common cause of CAP with or without empyema; serotype 1 accounted for 50% of the cases of pneumococcal empyema. Patients with empyema were more likely to be >3 years old, to have &ges;7 days of fever, to have varicella, and to have received antibiotics and ibuprofen before admission to the hospital, compared with patients without empyema (P < .0001 for each factor). The increasing incidence of empyema was associated with infection due to S. pneumoniae serotype 1, outpatient treatment with certain antibiotics, ibuprofen use, and varicella. Pleurésies purulentes S. pneumoniae 72% dont Sérotype 1: 50% Byington, CL, Clin Infect Dis. 2002

Ramphul, Pediatric Pulmonol, 2006 1997-2003 75 Pleurésies purulentes 15 (20 %) pneumopathie excavée S. Pneumoniae 13/15 Sérotypes variés Pas de résistance Cavitatory lung disease complicating empyema in children. Ramphul N, Eastham KM, Freeman R, Eltringham G, Kearns AM, Leeming JP, Hasan A, Hamilton LJ, Spencer DA. Department of Respiratory Paediatrics, Freeman Hospital, Newcastle upon Tyne, NE 7 7DN, United Kingdom. OBJECTIVE: The incidence of empyema has increased dramatically in children in the UK over the last decade. Streptococcus pneumoniae (S. pneumoniae) serotype 1 is the dominant serotype. We have observed more pneumatocoele and bronchopleural fistulae formation over this time. AIM: Our aim was to determine the number of children who developed cavitatory disease as a complication of empyema at a tertiary referral centre and whether there was any association with S. pneumoniae serotype 1. METHOD: We reviewed 75 cases presenting with empyema or parapneumonic effusion between February 1997 and July 2003. Bacterial culture and pneumococcal antigen detection were supplemented by real-time polymerase chain reaction (PCR) to detect pneumococcal DNA. RESULTS: Cavitatory disease was present in 15 cases. Three children developed bronchopleural fistulae. S. pneumoniae was detected in 13 of 15 cases (4 cases serotype 1, 3 serotype 3, 2 serotype 14, and 2 serotype 9V; serotype assay was not performed in two cases). Staphylococcus aureus (S. aureus) was isolated in one case. No organism was isolated in the final case but an Antistreptolysin-O titre was >800 U/ml on two occasions suggestive of group A streptococcal infection. CONCLUSION: Twenty percentage of cases of empyema in our series were complicated by cavitatory lung disease. It is an important complication of childhood empyema associated classically with S. aureus, but these data suggest that S. pneumoniae now appears to be the main cause. There does not seem to be an association with any particular serotype. Ramphul, Pediatric Pulmonol, 2006

Pleurésies purulentes Necker-Enfants Malades 1997-2004

Pleurésies purulentes Necker-Enfants Malades 1997-2004

Causes de cette augmentation Augmentation de fréquence des pleurésies purulentes à S. pneumoniae souvent sévères +++ Causes de cette augmentation Plusieurs hypothèses Infection virale ? Virulence bactérienne ? Causes médicamenteuses ?

Pleurésies purulentes Necker-Enfants Malades 1997-2004

Facteur viral Transmission accrue des souches bactériennes lors des épidémies virales (gouttelettes de Pflügge) Augmentation de l’adhésion des souches bactériennnes pathogènes lors d’une infection virale favorisant le portage nasopharyngé Coopération non spécifique virus-bactérie pouvant augmenter le potentiel invasif de S. pneumoniae

Facteur bactérien Pathogénicité des souches de S. pneumoniae Cependant sérotypes variables suivant les séries Résistances des souches?

Tan, et al. Pediatrics 2002 Byington, CL, Clin Infect Dis. 2002 The frequency of children who are hospitalized with pneumococcal pneumonia complicated by necrosis, empyema/complicated parapneumonic effusion, and lung abscess seems to be increasing. The factors that contribute to this increase are unclear; therefore, the objective of this study was to describe and compare the relative frequency, clinical characteristics, and outcome of hospitalized children with complicated pneumonia with those of children with uncomplicated pneumonia caused by Streptococcus pneumoniae in the era of antibiotic resistance. METHODS: A multicenter, retrospective study of 8 children's hospitals in the United States was undertaken. A total of 368 children who were hospitalized with pneumococcal pneumonia identified from patients enrolled in the US Pediatric Multicenter Pneumococcal Surveillance Study over the period from September 1, 1993, to January 31, 2000 were studied. Demographic and clinical variables, antibiotic susceptibility, pneumococcal serotypes, antimicrobial therapy, and clinical outcome in hospitalized children with complicated versus uncomplicated pneumococcal pneumonia were measured. RESULTS: A total of 368 patients with pneumococcal pneumonia were identified. Of the 368 isolates, 47 (12.8%) were intermediate and 37 (10.1%) were resistant to penicillin; 18 (5%) were intermediate to ceftriaxone, and 9 (2.5%) were resistant to ceftriaxone. A total of 133 patients met the criteria for complicated pneumonia and had a chest tube placed; 56 of these patients subsequently underwent decortication. The proportion of hospitalized patients with complicated pneumococcal pneumonia increased progressively over the study period from 22.6% in 1994 to 53% in 1999. Patients with complicated disease were older (median age: 45 vs 27 months) and significantly more likely to be of white race and have chest pain on presentation compared with patients with uncomplicated disease. Patients who had complicated disease and underwent decortication were more likely to have pleural fluid lactate dehydrogenase levels of >7500 IU/L compared with those patients who had chest tube placement alone. Fifty-three percent of children who were > or =61 months of age and were hospitalized had complicated pneumonia. This group of children accounted overall for 42% of the patients with complicated pneumonia, 48.2% of the patients who subsequently underwent decortication, and 44% of the patients who had received a course of antibiotics before diagnosis. Pneumococcal serotypes 1, 6, 14, and 19 were the most prevalent serotypes causing disease, with serotype 1 causing 24.4% of the complicated cases versus 3.6% of the uncomplicated cases. Ninety-eight percent of the patients in both groups recovered from their pneumonia. Antibiotic resistance was not found to be more prevalent in those patients with complicated disease. CONCLUSIONS: The relative frequency of complicated disease in hospitalized children with pneumococcal pneumonia is increasing. Patients with complicated pneumococcal disease were older and significantly more likely to be of white race compared with those patients with uncomplicated disease. Pneumococcal serotype 1 caused significantly more disease in patients with complicated versus uncomplicated pneumonia. Patients with complicated disease were not more likely to be infected with an antibiotic-resistant isolate. Tan, et al. Pediatrics 2002

Facteur médicamenteux Anti-inflammatoires non stéroïdiens Action inhibitrice sur l’adhérence des PN, de la phagocytose, de la bactéricidie in vitro Fasciites nécrosantes au cours de varicelles Etude de Byington ( Clin Infect Dis. 2002 ) Prise d’AINS dans les jours précédant une pleurésie purulente : OR 4, IC 95% (2.5-6.5) p<0,001 mais étude rétrospective Actions inhibitrices : - de l’adhérence des leucocytes - de la phagocytose - de la bactéricidie (in vitro) - de certains inhibiteurs de la cyclo-oxygénase

Evolution de l’usage des antibiotiques en France en fonction de l’âge, depuis 2001 Reduction of antibiotic use in the community reduces the rate of colonization with penicillin G-nonsusceptible Streptococcus pneumoniae. Guillemot D, Varon E, Bernede C, Weber P, Henriet L, Simon S, Laurent C, Lecoeur H, Carbon C. Centre de Resource en Biostatistiques, Epidemiologie et Pharmacoepidemiologie, Institut Pasteur, Unit 657, INSERM, France. guillemo@pasteur.fr BACKGROUND: There is a lack of evidence documenting the impact of optimized antibiotic use on the rates of colonization with penicillin G-nonsusceptible Streptococcus pneumoniae (PNSP) in children. This study evaluates the effect of community-based intervention strategies on the prevalence of pnsp colonization. METHODS: A controlled, population-based pharmacoepidemiological trial was conducted from January through May 2000. Three French geographic areas were selected on the basis of demographic similarities. Two intervention strategies were implemented: (1) reduced antibiotic use, which was achieved by not prescribing antibiotics for presumed viral respiratory tract infections (the prescription-reduction group); and (2) better adaptation of dose and duration (the dose/duration group). A control group received no intervention. The target population was children aged 3-6 years who were attending kindergarten. Oropharyngeal pneumococcus colonization and antibiotic use were monitored throughout the 5-month study. RESULTS: The prescription-reduction, dose/duration, and control groups included 601, 483, and 405 children, respectively. The interventions induced significantly larger decreases in antibiotic use in the prescription-reduction group (-18.8%) and dose/duration group (-17.1%) than in the control group (-3.8%), and the rates of PNSP colonization were initially similar for the 3 groups (52.5%, 55.1%, and 50.0%, respectively). At the end of the 5-month study, the rates of PNSP colonization were 34.5% for the prescription-reduction group (P=.05) and 44.3% for the dose/duration group (P=.8), compared with 46.2% for the control group. CONCLUSIONS: Intensive educational strategies aimed at optimizing antibiotic use can significantly reduce the rate of PNSP colonization in areas with high resistance rates.

PHRC Promoteur : AP-HP / DRRC Ile de France / URC Necker Cochin Etude P2M : Analyse des facteurs associés au risque de pleurésies purulentes chez l’enfant Etude multicentrique (15 centres) prospective de type cas/témoins - 110 cas et 220 témoins PHRC Promoteur : AP-HP / DRRC Ile de France / URC Necker Cochin Investigateur Coordinateur Dr Le Bourgeois Service de Pneumologie et Allergologie Pédiatriques Hôpital Necker Enfants Malades Coordination bactériologique et virologique Bactériologie Dr Ferroni Virologie Dr Leruez-Ville Hôpital Necker-Enfants Malades CNR des Pneumocoques Dr Varon HEGP Coordination, Méthodologie, Gestion et Analyse CeRBEP, IP / U657, INSERM Méthodologie Dr Guillemot Chef de projet, Épidémiologie Christine Toneatti Statistique Claire Bernède Moniteurs d’étude épidémiologiques Caroline Douay, Jean-Romain Richard Pr Bellon, CHU Lyon Dr Brémont, CHU Toulouse Dr David, CHU Nantes Pr Delacourt, CHIC Créteil Dr Derelle, CHRU Nancy Dr Deschildre, CHRU Lille Pr Dubus, CHU Marseille Dr Epaud, CHU Trousseau, Paris Dr Fayon, CHRU Bordeaux Dr Houdouin, CHU Robert Debré, Paris Pr Labbé, CHU Clermont-Ferrand Dr Langlet, CHRU Strasbourg Pr Marguet, CHRU Rouen Dr Sardet, CHG Lens Comité de pilotage : Dr Le Bourgeois, Dr Ferroni, Dr Leruez-Ville, Dr Varon, Dr Guillemot, C. Toneatti Comité scientifique : Pr Abenhaim, Pr Bégaud, Pr Nassif, Pr Scheinmann, Pr Thalabard, un représentant du département des maladies infectieuses de l’INVS, un représentant du département de pharmacovigilance de l’AFSSAPS

Objectifs de l’Etude P2M Objectif principal Evaluer chez l'enfant de 3 mois à 15 ans après une infection virale, l’association entre la survenue de pleurésie purulente et l’exposition aux AINS avant le début de la symptomatologie pleuro-pulmonaire. Objectifs secondaires Analyse microbiologique approfondie pour l’ensemble des enfants hospitalisés pour pleurésie purulente Recherche de co-infection virale Caractérisation des bactéries isolées dans le liquide Analyse comparative entre les cas et les témoins : de la présence au niveau des sécrétions nasales de virus de la diversité clonale et sensibilité aux antibiotiques des souches de S. pneumoniae chez les cas et chez les témoins en situation de colonisation nasopharyngée.

Questions thérapeutiques Indication Ponctions répétées Drainage Thoracoscopie (VAT) Fibrinolytiques Traitement antibiotique Quelle association ?

Méta analyse chez l’enfant Pas de vraie méta-analyse (biais institutionnel, variables mesurées) 44 études rétrospectives (1369 enfants) 2 4 6 8 10 12 14 16 18 20 Drain Thoracotomie Fibrinolyse VAT * VAT précoce ou Thoracotomie : Durée d’hospitalisation plus courte (p=0.003) Délai d’apyrexie un peu plus rapide que drain ou fibrinolyse (3.5 si VAT vs 10 si drain) (mais p=0.055) Pas de différence de durée de drainage entre les 4 traitements 25 % des enfants n’ayant eu qu’un drainage ont eu secondairement une chirurgie Robert B, J Ped Surg 2004

Très peu d’études randomisées chez l’enfant Therapy of Parapneumonic Effusions in Children: Video-Assisted Thoracoscopic Surgery Versus Conventional Thoracostomy Drainage Kurt, B. Pediatrics ,2006 Durée du drainage moins long, pas d’utilisation de fibrinolytiques dans le groupe VATS Faible effectif : VATS n=10 versus drainage n=8…. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Sonnappa S, Am J Respir Crit Care Med. 2006 VATS n=30 versus drainage + fibirinolytique n=30 Absence de différence, coût moindre pour le groupe fibrinolytique

Prise en charge de l’épanchement chez l’enfant : Ponctions itératives Une seule étude prospective randomisée 67 pleurésies purulentes Analyse du liquide: pH<7.2, Glycopleurie<40 g/l,PNN>1000/mm3 32 enfants : drainage / 35 enfants : ponctions répétées (1 à 4) Pas de différence pour Durée de la fièvre 6.2 vs 6.5 Durée hospitalisation 22 vs 24 j Volume drainage 35 vs 30 ml/kg Ponctions itératives aussi efficaces que le drainage s’il n’existe pas de déviation médiastinale importante Shoseyov, Chest, 2002

Antibiothérapie IV pendant 15 jours Prise en charge des pleuropneupopathies aiguës (NEM 2006) Pleuropneumopatie aiguë purulente TOUJOURS Rx Pulmonaire, Echo pleurale, Ponction pleurale O2dépendance Signes de lutte Polypnée Déviation médiastinale Rx Tolérance Bonne Moyenne Epanchement important et PAS de pneumopathie importante Epanchement  important ET pneumopathie importante AB seuls AB Drainage chir AB Discuter Drain Ponctions itératives (?) Antibiothérapie IV pendant 15 jours - C3G (cefotaxime ou ceftriaxone) + Rifampicine ou vancomycine autre association si allergie selon antibiogramme Relais par une antibiothérapie orale Surveillance

Evolution chez l’enfant Bonne évolution à long terme : fonctions respiratoires normales Même si épaississement pleural important initial Satish Arch Dis Child 2003 Cependant formes plus graves Evaluation prospective

Prévention Vaccin PREVENAR heptavalent Sérotypes 4, 6B, 9V, 14, 18C, 19F, 23F BEH 2006 : la vaccination par le vaccin heptavalent conjugué pneumococcique est recommandée à partir de l’âge de 2 mois pour tous les enfants (3 injections). Le rappel a lieu entre l’âge de 12 et 15 mois Pour les enfants à risque âgés de 24 à 59 mois , la vaccination pneumococcique est recommandée selon le schéma suivant : 2 doses de vaccin conjugué à 2 mois d’intervalle suivies d’une dose de vaccin polyosidique 23 au moins deux mois après la deuxième dose de vaccin conjugué.

Effect of Introduction of the Pneumococcal Conjugate Vaccine on Drug-Resistant Streptococcus pneumoniae Kyaw, MH et al.for Active Bacterial Core Surveillance of the Emerging Infections Program Network - NEJM,2006 1996-2004 : Incidence annuelle des infections invasives à pneumocoques Pénicilline-sensibles et résistants chez les enfants < 2ans Pénicilline-résistants chez les malades > 2ans Definition classique de l’infection invasive pneumocoque présent dans sites normalement stérile : LCR, sang, liquide pleural

Number of episodes of bacteremia caused by Streptococcus pneumoniae and by other respiratory pathogens per 10,000 emergency department visits, by year. ♦, S. pneumoniae; square;, other respiratory pathogens. *Emergence of vaccine-related pneumococcal serotypes as a cause of bacteremia. Steenhoff AP, Clinical Infectious Diseases 2006;42:907-914

Impact de la vaccination sur les pleurésies purulentes à S. pneumoniae ? Schultz Pediatrics 2004 Diminution de fréquence post vaccinale Fletcher and South West of England Invasive Community Acquired Infection Study Group, Pediatr Infect Dis, 2006 18/27 pleurésies purulentes à S. pneumoniae dues au sérotype 1 Byington, Pediatr Infect Dis, 2006 Significativement plus de cas de pleurésie purulente/an dans la période de 54 mois post-PCV-7 / 56 mois pré -PCV-7. Le Sérotype 1 reste le plus fréquent et les sérotypes 3 et 19A émergent. Tableaux cliniques moins graves

Conclusion Les infections invasives à S. pneumoniae sont fréquentes chez l’enfantavec une augmentation de fréquence des formes compliquées. Importance d’évaluer les facteurs de risque Devenir après la généralisation de la vaccination antipneumococcique et l’apparition du futur vaccin nonavalent?

Relais par une antibiothérapie orale Antibiothérapie IV pendant 15 jours C3G + Rifampicine ou Vancomycine autre association si allergie selon antibiogramme Mauvaise diffusion dans la plèvre Relais par une antibiothérapie orale Céfotaxime Clindamycine Rifampicine Vancomycine Fosfomycine IV Posologie 25 8 15 10 100 mg/kg/dose mg/kg/dose mg/kg/dose mg/kg/dose mg/kg/dose toutes les toutes les toutes les toutes les toutes les 6 h 8 h 12 h 6 h 12 h CMI 50 1 0.006 0.06 0.25 64 (mg/l) T>CMI 80% 100% 100% 100% 20% QI au pic 28 28 106 100 2 QI en <1 4 6 12 <1 résiduel Paramètres Pc/Pd sériques des différents antibiotiques proposés pour S. pneumoniae