treatmentanddiagnosisofcommunity-acquired

1、Treatment and Diagnosis of Community-acquired Pneumonia (CAP) in Children 兒童社區(qū)感染肺炎的診斷和治療,吳秉昇醫(yī)師臺(tái)北慈濟(jì)醫(yī)院小兒科,1,,,Diarrhoea 14%,,,,,2,Pneumonia,,AIDS 2%,Black RE et al. Lancet. 2010;375(9730):1969–1987.Note: Causes that

2、 led to less than 1% of deaths were not presented,Leading Cause of Death in Children < 5 Years Old,,,,,,,,,,,,,,,,Preterm birthcomplications 12%,Birth asphyxia 9%,Sepsis 6%,Other 5%,Congenitalabnormalities 3%,Tetan

3、us 1%,Measles 1%,Injury 3%,Malaria 8%,Pertussis 2%,Meningitis 2%,Other infections9%,Other non-communicablediseases 4%,Neonatal deaths 41%,,,14%,4%,},Diarrhoea 1%,,Pneumonia Mortality: A Global Burden,,SymptomsFever

4、CoughPurulent sputumPleuritic chest painShortness of breathLoss of appetite, fatigue, muscle aches,How to Diagnose Pneumonia - Symptoms,Lancet Infect Dis 2015; 15: 439-50,Meta-analysis of clinical predictors of pneu

5、monia in children: Not one clinical feature was sufficient to diagnose pneumonia definitivelyFeatures with the highest pooled positive likelihood ratios:respiratory rate higher than 50 breaths per min, grunting, chest

6、 indrawing, and nasal flaring,Etiology of Community-Acquired Pneumonia in Hospitalized Children,4,Pediatrics 2004;113:701–707,Common bacterial and viral etiologies of CAP in children,Virus Respiratory syncytial virus

7、Influenza A and BAdenovirus Parainfluenza viruses 1, 2, 3Human Metapneumovirus (2001),BacteriaS. pneumoniaeH. Influenzae type bNontypeable H. InfluenzaeS. aureusM. catarrhalisM. tuberculosis,5,Bacteria (atypi

8、cal)M. pneumoniaeC. pneumoniaeC. trachomatis,N Engl J Med, Vol. 346, No. 6, February 7, 2002,Etiology of Community-acquired Pneumonia in Hospitalized Children in Northern Taiwan,Methods: From August 2001 to July 2002,

9、 children admitted with radiologically confirmed CAPResults: A total of 209 children, ages ranged from 7 months to 16 yearsAt least 1 etiologic agent in 85.6% of all casesTypical bacterial pathogens in 88 cases (42.1%

10、); 86 S. pneumoniae (41.1%), Mycoplasma pneumoniae in 77 cases (36.8%), Chlamydia species in 24 cases (11.5%), viral etiology in 86 cases (41.1%) and mixed viral–bacterial infections in 69 cases (33%)Conclusion: S. pneu

11、moniae, Mycoplasma pneumoniae and viruses were equally common etiologic agents of childhood CAP in Taiwan. Frequent coinfection increased the difficulty of both predicting the responsible organisms and choosing empiric

12、antibiotics.,The Pediatric Infectious Disease Journal ? Volume 31, Number 11, November 2012,Etiology of CAP is age-dependent,7,Pediatrics 2004;113:701–707,,Birth,3 m,5 years,18 years,1 year,,,,,,8,化膿性細(xì)菌性肺炎的特徵,一開始病情輕微的呼吸道

13、感染，突然出現(xiàn)呼吸狀況急遽惡化體溫正常時(shí)精神活力極差呼吸急促 (呼吸速率11月以下嬰兒 > 60/min，1-4歲 > 40/min，5歲以上 > 30/min)血氧飽和度≤ 92%、發(fā)紺敗血癥徵候，例如意識(shí)障礙、出血傾向、低血壓呼吸窘迫徵候，包括鼻翼搧動(dòng)(nasal flaring)、呼嚕聲(grunting)、胸壁凹陷 (chest wall retrac

14、tion)等肺部實(shí)質(zhì)化 (consolidation)、空洞形成 (cavity formation),兒童社區(qū)肺炎處置建議 / 臺(tái)灣兒科醫(yī)學(xué)會(huì)Acta Paediatr Taiwan. 2007 Jul-Aug;48(4):167-80. Review.,非典型肺炎的特徵,活力正常且無化膿性細(xì)菌性肺炎的特徵結(jié)膜炎、中耳炎、皮疹與哮鳴聲 (wheezing)較常見,兒童社區(qū)肺炎處置建議 /

15、臺(tái)灣兒科醫(yī)學(xué)會(huì)Acta Paediatr Taiwan. 2007 Jul-Aug;48(4):167-80. Review.,When Does a Child or Infant With CAP Require Hospitalization?,Moderate to severe CAPInfants less than 3–6 months of age with suspected bacterial CAP

16、Caused by a pathogen with increased virulence, such as CA-MRSAConcern about careful observation at home or who are unable to comply with therapy or unable to be followed up,11,Clin Infect Dis. 2011 Oct;53(7):617-30.,12

17、,Pediatrics 2004;113:701–707,13,Rhedin S, et al. Thorax 2015;70:847–853.,*p<0.05, **p<0.01 and ***p<0.001.,A total of 121 cases, of which 93 cases met the WHO criteria for radiological pneumonia, and 240 control

18、s were included in the study. Viruses were detected in 81% of the cases (n=98) and 56% of the controls (n=134).,,,,臺(tái)灣抗藥性肺炎鏈球菌比率逐年上升,,Hseuh PR. Clin Microbiol Infect 2005;11:925,14,分離自各年齡層的侵襲性肺炎鏈球菌對各類抗生素具有感受性比例 (2008-2012

19、),疫情報(bào)導(dǎo)第29 卷 第19 期 p. 284-300,,Penicillin55%,Cefotaxime69%,Vancomycin100%,Levofloxacin94.7%,Amoxicillin79.9%,侵襲性肺炎鏈球菌感染癥疫情週報(bào) 2016 年第 41 週（2016/10/09－2016/10/15）,2015年全年齡發(fā)生率為每10萬人口2.23人，主要集中在未滿5歲的嬰幼兒及65歲以上的老年人，累積發(fā)生率

20、以75歲以上老人最高（每10萬人口9.81人），其次為2~4歲幼兒（每10萬人口8.8人）。全年皆有病例，但發(fā)病高峰為冬季與春季,)Invasive pneumococcal Disease,國內(nèi)常見肺炎鏈球菌血清型別及佔(zhàn)檢出菌株數(shù)百分比,2012-2013 年間血清型15（不包含15B) 檢出率增加,疫情報(bào)導(dǎo)第30 卷 第22 期 p. 451-463,,,Epidemiology of CAP in children- Atypi

21、cal Bacteria,Increasing in importance 20-30% of all pneumonias are atypical pathogens!Mycoplasma pneumoniaeChlamydia pneumoniae,18,Chlamydia pneumoniae,The prevalence of Chlamydia-associated acute respiratory infecti

22、ons : <1.5%Like CAP caused by Mycoplasma pneumoniae typically affects young adultsChlamydia pneumoniae has been recently identi?ed as an agent of asthma exacerbation and has been associated with its severity,19,Cl

23、in Infect Dis. 2014 Apr;58:1198-9.Clin Infect Dis 2007;44:568-76.,Mycoplasma pneumoniae,Smallest self-replicating organism, capable of cell-free existenceSpidle-shaped cells (1-2 μ m), cell volume < 5% of typi

24、cal bacillusNo ability to synthesize peptidoglycan cell walls (pleomorphism)P1 adhesin: responsible for interaction with host cells,,,Epidemiology,Causing 10-30 % community-acquired pneumonia in childrenTrans

25、mission: by aerosols (close personal contact), spread gradually among family members within a householdIncubation period: 1-3 weeks Greatest proportion in the summer in temperate climates Cyclic epidemics every 3-5 ye

26、ars Reinfection: two P1 adhesin subtypes / incomplete immunity,Clinical manifestation,May manifest in upper and lower respiratory tract *Children ages less than 5 years: Wheezing and coryza*School-aged children 5-1

27、5 years of age: BronchopneumoniaClinical presentation is often similar to C. pneumoniae and respiratory viruses May be present in the respiratory tract concomitantly with other pathogens, somehow intensify subsequent

28、 infections,Mycoplasma pneumoniae: Incidence by age,,Rate/1000/yr,Age,Foy et al. Am J Epidemiol 1973;97;93-102,23,Focal reticulonodular opacification (perihilar),Focal reticulonodular opacification (perihilar and periph

29、eral),Mycoplasma pneumoniae pneumonia,Groundglass consolidation(Pseudoconsolidation),Atelectasis,Mycoplasma pneumoniae pneumonia,Dense homogeneous consolidation and pleural effusion,Mycoplasma pneumoniae pneumonia,M. pn

30、eumoniae and adenovirus co-infection,100/5/28,100/5/30,100/6/1,Extra-pulmonary symptoms of Mycoplasma pneumoniae,Skin – Rash Joint – pains (arthralgia) or inflammation (arthritis)Blood – hemolytic anemiaHeart – inflam

31、mation of heart muscle (carditis)Kidney – inflammation of kidney tissue (nephritis)Nerves – spinal cord demyelination,28,A 8-year-old boyMycoplasma pneumoniae pneumonia with rashes pneumonia with rashes,Fever for 7 da

32、ysBreath sound clear,29,Taiwan Guideline of pneumonia Management 臺(tái)灣肺炎診治指引,30,兒童社區(qū)肺炎處置建議 / 臺(tái)灣兒科醫(yī)學(xué)會(huì)Acta Paediatr Taiwan. 2007 Jul-Aug;48(4):167-80. Review.,Taiwan Guideline of pneumonia Management 臺(tái)灣肺炎診治指引,3

33、1,兒童社區(qū)肺炎處置建議 / 臺(tái)灣兒科醫(yī)學(xué)會(huì)Acta Paediatr Taiwan. 2007 Jul-Aug;48(4):167-80. Review.,Antibiotics for Atypical Pathogens,ErythromycinTetracyclineAdverse reactions: Teeth & bone: not recommended for children up to 8

34、 yrGI irritation, fatty liver etc. New macrolides: Less GI side effect, less drug interaction, longer half-lifeClarithromycin (Klaricid®): bid, 7-10 daysAzithromycin (Zithromax®): qd, 3-5 days,32,After usin

35、g tetracycline repeatedly….,33,,34,Macrolides block growth of nascent peptide chain by stimulating dissociation of the peptidyl-tRNA from the ribosome,Macrolides Inhibit Protein Synthesis(50S Robosomal Subunit),Clarithr

36、omycin可穿過血管肺泡屏障在 ELF 濃度比 Azithromycin 高 40 倍,36,濃度越高代表治療效率越好,Antimicrob Agents Chemother. 2008;52(1):24-36.,,肺泡巨噬細(xì)胞,肺泡上皮細(xì)胞表面液體(ELF),微血管壁,肺泡上皮細(xì)胞,間隙,,,比較Clarithromycin, Azithromycin, Ciprofloxacin和Cefuroxime (Single-do

37、se Study),37,Antimicrob Agents Chemother. 1996 Jul;40(7):1617-22.,,Alveolar cell (AC) 肺泡細(xì)胞 Ciprofloxacin: quinolone antibiotics抑制DNA合成Cefuroxime: cephalosporin antibiotic抑制細(xì)胞壁合成,,,,Clarithromycin組織濃度高，抑菌效果好,37,The ONLY

38、 Macrolide with an ACTIVE metabolite,14-OH Clarithromycin = an active metaboliteRoutine susceptibility testing underestimates Clari activity. It does not account for in vivo synergy with its metabolite,14-OH clarithromy

39、cin, as evidenced by the following MIC90.5,6 Against H. influenzae, 14-OH clarithromycin is twice as active as the parent compound in vitro:514-OH metabolite provides in vitro activity (92%)/synergisti

40、c activity (8%) against H influenzae.7,38,Infection 1992 May-Jun;20(3):164-7.,,Patel KB, et al. ICMAS No. 407. Lisbon. 1996.,Multiple Dose Plasma Concentrations of Clarithromycin and Azithromycin Compared to Pathog

41、ens,39,Half life (hrs)Clarithromycin 6Azithromycin 68,Potential of Various Macrolide Antibiotics to Induce Resistant Mutant Selection Window Hypothesis,?,40,MIC: Minimal inhibitory concentrationMP

42、C: Mutant prevention concentration,Clin Infect DIs. 2007 Mar 1;44(5):681-8.,,Azithromycin Use versus Macrolide Resistance (S. pneumoniae),,QUE,NFLD,ON,NB,Azithromycin use (% of macrolides),Macrolide resistance (%),,,,,

43、,,,,,,,,,,,,,,,,,,,,,,,,,0,5,10,15,20,25,0,10,20,30,40,50,60,BC,NS,MB,SK,AB,R=0.9659p<0.0001,Strong correlation between azithromycin use and macrolide resistance,,,,,Davidson RJ, Chan CCK, Doern G, Zhanel GG. Present

44、ed at 13th ECCMID. 2003.Clin Microbiol Infect. 2003;9:240–1,41,Mechanism of MLr strain,Macrolide – binding to domain V of 23S rRNA at positions 2063 and 2064Mutation at A2063 or A2064 – highest resistance Lower l

45、evel of antibiotic resistance –A2067 and C2617,J Infect Chemother (2010) 16:78-86,Worldwide macrolide-resistant M. pneumoniae (MRMP) rates,Taiwan MRMP incidence(2011) 12.3% CGMH(2010-2011) 23% NTUH,,Pediatr P

46、ulmonol. 2013;48(9):904-11J Infect Chemother 2013;19(4):782-6Front Microbiol 2016; 7:329,44,Community-acquired pneumonia 仍是兒童常見且重要的疾病 Severity & AgeIncidence of invasive pneumococcal disease: decreased Atypical

47、pathogens cause as much as 20-30% of all CAPCo-infection was usualAtypical pneumonia is under-tested, under-diagnosed and under-treatedMacrolide resistant Mycoplasma pneumoniae emergenceNew macrolide is indicated as