Антибиотики для внебольничной пневмонии у детей

[Intervention Review] Antibiotics for community-acquired pneumonia in children Sushil K Kabra1, Rakesh Lodha2, Ravindra M Pandey3 1Pediatric Pulmonology Division, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, India. 2Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, India. 3Department of Biostatistics, All India Institute of Medical Sciences, Ansari Nagar, India Contact address: Sushil K Kabra, Pediatric Pulmonology Division, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, , India.

Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 3, Review content assessed as up-to-date: 17 September Citation: Kabra SK, LodhaR, PandeyRM.Antibiotics for community- acquired pneumonia in children.CochraneDatabase of Systematic Reviews 2010, Issue 3. Art. No.: CD DOI: / CD pub3. Copyright © 2010 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

Фон Пневмония, вызванная бактериальными патогенами является ведущей причиной смертности среди детей в странах с низким уровнем дохода. Раннее назначение антибиотиков улучшает результаты. Цели Чтобы определить эффективные антибиотики для внебольничной пневмонией (ВП) у детей путем сравнения различных антибиотиков. стратегия поиска Мы провели поиск в Кокрановском центральном регистре контролируемых испытаний (CENTRAL) (Cochrane Library 2009, выпуск 2), который содержит Специализированный Зарегистрироваться Cochrane острых респираторных инфекций Группы; MEDLINE (с 1966 по сентябрь 2009 года); и EMBASE (1990 для Сентябрь 2009 г.). критерии отбора Рандомизированные контролируемые исследования (РКИ) у детей обоего пола, сравнивая по крайней мере, два антибиотика для CAP в больнице или амбулатории (амбулаторные) настройки. Сбор и анализ данных Два автора независимо извлекали данные из полных статей отдельных исследований.

Main results There were 27 studies, which enroled 11,928 children, comparing multiple antibiotics. None compared antibiotic with placebo. For ambulatory treatment of non-severe CAP, amoxycillin compared with co-trimoxazole had similar failure rates (OR 0.92; 95% CI 0.58 to 1.47) and cure rates (OR 1.12; 95% CI 0.61 to 2.03). (Three studies involved 3952 children). In children hospitalised with severe CAP, oral amoxycillin compared with injectable penicillin or ampicillin had similar failure rates (OR 0.95; 95% CI 0.78 to 1.15). (Three studies involved 3942 children). Relapse rates were similar in the two groups (OR 1.28; 95% CI 0.34 to 4.82). In very severe CAP, death rates were higher in children receiving chloramphenicol compared to those receiving penicillin/ampicillin plus gentamycin (OR 1.25; 95% CI 0.76 to 2.07). (One study involved 1116 children).

Authors conclusions There were many studies with different methodologies investigating multiple antibiotics. For treatment of ambulatory patients with CAP, amoxycillin is an alternative to co-trimoxazole.With limited data on other antibiotics, co-amoxyclavulanic acid and cefpodoxime may be alternative second-line drugs. For severe pneumonia without hypoxia, oral amoxycillin may be an alternative to injectable penicillin in hospitalised children; however, for ambulatory treatment of such patients with oral antibiotics, more studies in community settings are required. For children hospitalised with severe and very severe CAP, penicillin/ampicillin plus gentamycin is superior to chloramphenicol. The other alternative drugs for such patients are ceftrioxone, levofloxacin, co-amoxyclavulanic acid and cefuroxime. Until more studies are available, these can be used as a second-line therapy. There is a need for more studies with larger patient populations and similar methodologies to compare newer antibiotics.

P L A I N L A N G U A G E S U M M A R Y Different antibiotics for community-acquired pneumonia in children younger than 18 years of age in both hospital and ambulatory (outpatient) settings Pneumonia is the leading cause ofmortality in children under five years of age.Most cases of community-acquired pneumonia (CAP) in low-income countries are caused by bacteria. This systematic review identified 27 randomised controlled trials, enroling children, comparing antibiotics for treatment of CAP in children; most were single studies only. We found that for outpatient treatment of pneumonia, amoxycillin is an alternative treatment to co-trimoxazole. Oral amoxycillin in hospitalised children with severe pneumonia without hypoxia (decreased level of oxygen)may be effective.However, for outpatient treatment,more studies in community settings are required. For very severe pneumonia, a combination of penicillin or ampicillin and gentamycin is more effective than chloramphenicol alone.

B A C K Р O U N D Пневмония является главной и единственной причиной ofmortality у детей в возрасте менее пяти лет, по оценкам заболеваемости 0,29 и 0,05 эпизодов в ребенка в год в странах с низким уровнем доходов и стран с высоким уровнем дохода соответственно. По оценкам, в общей сложности около 156 млн новый эпизоды происходят каждый год, и большинство из них происходят в Индии ( ), Китай (21 млн), Пакистан (10 млн) и Бангладеш, Индонезия и Нигерия (шесть миллионов каждый) (Rudan 2008). Пневмония несет ответственность за примерно twomillion смертей ежегодно у детей ниже пяти лет и это происходит в основном в африканских и Регионы Юго-Восточной Азии. Пневмония способствует о одной пятой (19%) всех случаев смерти детей в возрасте до пяти лет, из whichmore чем 70% состоится в Африке к югу от Сахары и Юго- Восточная Азия (Rudan 2008). Для снижения младенческой и под-пять ребенка смертности, важно, чтобы снизить смертность от пневмонии путем соответствующего вмешательства в виде антибиотиков. Выбор из первого ряда антибиотиков для эмпирической терапии пневмонии является решающее значение для офисной практике, а также здравоохранения.

Пневмония определяется как инфекции паренхимы легких (альвеол) микробными агентами. Трудно определить возбудителя в большинстве случаев пневмонии. Методы, используемые для идентификации из этиологическим агентов включают культуру крови, легких прокол, носоглотки стремление и иммунные анализы крови и анализы мочи. Легких пункция инвазивная процедура, связанная со значительной заболеваемостью и, следовательно, не может быть выполнена регулярно в большинстве случаев. Выход из крови слишком низкий (5% до 15% для бактериальных патогенов), которые будут полагаться (MacCracken 2000).There несколько исследований, что документ этиологию пневмонии детей в возрасте до пяти лет из стран с низким уровнем дохода. Большинство исследований проводится посев крови для бактериальной этиологии

от пневмонии. Некоторые исследования, проведенные назофарингеальных и идентификации атипичных организмов. Обзор 14 исследований с участием 1096 аспираты легких, принятые fromhospitalised дети до в назначении антибиотиков сообщил бактериальных патогенов в 62% случаев (Берман 1990). В 27% больных, общее бактериальные патогены Были выявлены Пневмококк (S. пневмонии) и гемофильной инфекции (H. гриппа) (Берман 1990). Исследования с использованием назофарингеальных для идентификации вирусные агенты показывают, что около 40% от пневмонии у детей Be-

низкие пять лет вызвана вирусных агентов, с самых распространенных вирусный возбудитель быть респираторно-синцитиальный вирус (Майтрейи 2000). У грудных детей в возрасте до трех месяцев, частыми возбудителями включают С. пневмонии, H. гриппа, грамотрицательные палочки и Staphylo- кокк (WHOYISG 1999). Болезнетворные микроорганизмы отличаются в странах с высоким уровнем доходов и включают более вирусных и атипичных организмов (Gendrel 1997; Ishiwada 1993; Numazaki 2004; Wubbel 1999). Таким образом, схемы лечения могут быть различными в highincome и страны с низкими доходами.

Описание вмешательства Администрация соответствующими антибиотиками на ранней стадии пневмонии улучшает исход заболевания, особенно при Возбудитель бактериального. Всемирная организация здравоохранения (ВОЗ) разработала руководящие принципы для ранней диагностики и оценки от тяжести пневмонии на основе клинических признаков (WHOYISG 1999) и предполагает введение ко-тримоксазол в качестве первой линии препарата. Обычно используемые антибиотики для внебольничная пневмония (CAP) включают ко-тримоксазол, Амоксициллин, устные цефалоспорины и макролид препараты. Несмотря на свидетельства подняться бактериальной резистентности к ко-тримоксазолу (IBIS 1999; Тимофей 1993),

исследования, проведенные в тот же период времени показал хороший клинический эффективность устного ко-тримоксазола при нетяжелой пневмонии (Awasthi 2008; Расмуссен 1997; Straus 1998). Тем не менее, В одном исследовании сообщалось удвоение клинических отказов с котримоксазолу лечение, по сравнению с обработкой амоксициллина в тяжелой и рентгенологически подтвержденной пневмонии (Straus 1998). Мета-анализ всех испытаний на пневмонию основе подход случай-менеджмент предложил byWHO (идентификационный от пневмонии на клинические симптомы / признаки и администрации эмпирические антимикробные агенты) нашел снижение смертности а также пневмонии, связанных смертности (Sazawal 2003). Для удовлетворения Цель общественного здравоохранения по сокращению детской смертности от пневмонии, эмпирическое назначение антибиотиков полагаются в большинстве случаи. Это необходимо ввиду неспособности наиболее часто доступные лабораторные тесты для выявления причинных патогенов.

Почему это важно сделать этот отзыв Эмпирические назначение антибиотиков является основой лечения пневмонии у детей. Администрация TheMost необходимости антибиотик в качестве первой линии медицины может улучшить исход пневмонии. Есть несколько антибиотики, предписанные для лечения пневмония, поэтому важно знать, какие лучше всего работают в пневмония у детей. Последний обзор всех имеющихся рандомизированных контролируемых исследований (РКИ) на антибиотики, используемые для пневмонии у детей был опубликован в 2006 году (Kabra 2006). С тех пор, несколько новых исследования (Асгар 2008; Аткинсон 2007; Аурангзеб 2003; Bansal 2006; Брэдли 2007; Эспозито 2005; Hasali 2005; Hazir 2008; Lee2008; Лу 2006) были опубликованы. Поэтому важно, чтобы обновить информацию, включив все новые клинические испытания.

О Б Е К Т И В Е С Для определения эффективных антибиотиков лекарственной терапии для Внебольничная пневмонией (ВП) у детей путем сравнения различных антибиотиков.

М Е Т О Д S Критерии рассмотрения исследования для данного обзора Виды исследований Рандомизированные контролируемые исследования (РКИ), сравнивающих антибиотики для внебольничная пневмония (CAP) у детей. Мы рассмотрели только те исследования, используя определение случая пневмонии (как дается Всемирной организации здравоохранения (ВОЗ)) или radiologically- подтвердил пневмония в данном обзоре.

Types of participants We included children under 18 years of age with CAP treated in a hospital or community setting. We excluded studies describing pneumonia post-hospitalisation in immunocompromised patients (for example, following surgical procedures). Types of interventions We compared any intervention with antibiotics (administered by intravenous route, intramuscular route, or orally) with another antibiotic for the treatment of CAP.

Types of outcome measures Primary outcomes Clinical cure. Definition of clinical cure is symptomatic and clinical recovery by the end of treatment. Treatment failure rates. Definition of treatment failure is the presence of any of the following: development of chest indrawing, convulsions, drowsiness or inability to drink at any time, respiratory rate above the age-specific cut-off point on completion of treatment, or oxygen saturation of less than 90% (measured by pulse oximetry) after completion of the treatment. Loss to follow up or withdrawal from the study at any time after recruitment was taken as failure in the analysis.

Secondary outcomes The clinically relevant outcome measures were as follows. Relapse rate: defined as children declared cured, but developing recurrence of disease at follow up in a defined period. Hospitalisation rate (in outpatient studies only). Defined as need for hospitalisation in children who were getting treatment on an ambulatory (outpatient) basis. Length of hospital stay: duration of total hospital stay (from day of admission to discharge) in days. Need for change in antibiotics: children required change in antibiotics from the primary regimen. Additional interventions used: any additional intervention in the form of mechanical ventilation, steroids, vaso-pressure agents, etc. Mortality rate.

Search methods for identification of studies We retrieved studies through a search strategy which included cross-referencing.We checked the cross-references of all the studies by hand. Electronic searches We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2), which contains the Acute Respiratory Infections Groups Specialised Register, MEDLINE (1966 to September 2009) and EMBASE (1990 to September 2009). There were no language or publication restrictions. We combined theMEDLINE search with theCochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2008). See Appendix 1 for the EMBASE search strategy.

MEDLINE (OVID) 1 exp PNEUMONIA/ 2 pneumonia 3 or/1-2 4 exp Anti-Bacterial Agents/ 5 antibiotic$ 6 or/4-5 7 exp CHILD/ 8 exp INFANT/ 9 (children or infant$ or pediatric or paediatric) 10 or/ and 6 and 10

Searching other resources We also searched bibliographies of selected articles to identify any additional trials not recovered by the electronic searches. Data collection and analysis Selection of studies Two review authors (SKK, RL) independently selected potentially relevant studies based on their title and abstract. The complete texts of these studies were retrieved electronically or by contacting the trial authors. Two review authors (SKK, RL) independently reviewed the results for inclusion.

Data extraction and management All the relevant studies were masked for authors names and institutions, the location of the study, reference lists and any other potential identifiers. The papers were then given a serial number by a person who was not involved in the review. Two review authors (SKK, RL) independently reviewed the results for inclusion in the analysis. Differences about study quality were resolved through discussion. We recorded data on a pre-structured data extraction form. We assessed publication bias using the Cochrane Collaborations Risk of bias tool. Before combining the studies for each of the outcome variables, we carried out assessment of heterogeneity with Breslows test of homogeneity using the Review Manager (RevMan) software (version 5.0) (RevMan 2008).

We performed sensitivity analysis to check the importance of each study in order to see the effect of inclusion and exclusion criteria. We computed both the effect size and summary measures with 95% confidence intervals (CI) using RevMan software. For all the outcome variables, we used a random-effects model to combine the study results. We collected data on the primary outcome (cure rate/failure rate) and secondary outcomes (relapse rate, rate of hospitalisation and complications, need for change in antibiotics, need for additional interventions and mortality). When available, we also recorded additional data on potential confounders such as underlying disease, prior antibiotic therapy and nutritional status. We did multiple analyses, firstly on studies comparing the same antibiotics. We also attempted to perform indirect comparisons of various drugs when studies with direct comparisons were not available. For example, we compared antibiotics A and C when a comparison of antibiotics A and B was available and likewise a separate comparison between antibiotics B and C. We only did this type of comparison if the inclusion and exclusion criteria of these studies, the dose and duration of the common intervention (antibiotic B), baseline characteristics and the outcomes assessed were similar (Bucher 1997). Antibiotics

Assessment of risk of bias in included studies We assessed risk of bias in all included studies using the Cochrane Collaborations Risk of bias tool (Higgins 2008): 1. Sequence generation: assessed as yes, no or unclear Yes: when the study described the method used to generate the allocation sequence in sufficient detail. No: sequence not generated. Unclear: when it was not described or incompletely described. 2. Allocation concealment: assessed as yes, no or unclear Yes: when the study described the method used to conceal the allocation sequence in sufficient detail. No: described details where allocation concealment was not done. Unclear: when it was not described or incompletely described. 3. Blinding of participants, personnel and outcome assessors: assessed as yes, no or unclear Yes: when it was a double-blind study. No: when it was an unblinded study. Unclear: not clearly described. 4. Incomplete outcome data: assessed as yes, unclear Yes: describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. Unclear: either not described or incompletely described.

5. Free of selective outcome reporting: assessed as yes, no or unclear Yes: results of study free of selective reporting. Details of all the patients enrolled in the study are included in the paper. No: details of all the enrolled patients not given in the paper. Unclear: details of all the enrolled patients incompletely described. 6. Other sources of bias Among the other sources of potential bias considered was funding agencies and their role in the study.We recorded funding agencies as governmental agencies, universities and research organisations or pharmaceutical companies.We considered studies supported by pharmaceutical companies to be unclear unless the study defined the role of the pharmaceutical companies. We also considered studies notmentioning the source of funding as unclear under this heading.

Assessment of heterogeneity For each of the outcome variables, we carried out assessment of heterogeneity with Breslows test of homogeneity using RevMan software (as described in data extraction and analysis section). Assessment of reporting biases Before combining the study resultswe checked for publication bias by using a funnel plot. For each of the outcome variables (cure rate, failure rate, relapse rate, rate of hospitalisation, the complications needed for change in antibiotics and mortality rate) we used a two-by-two table for each study and performed Breslows test of homogeneity to determine variation in study results.

R E S U L T S Description of studies See:Characteristics of included studies;Characteristics of excluded studies. Results of the search Two review authors (SKK, RL) screened the article titles. Fortyfour studies were short-listed as potential randomised controlled trials to be included and we attempted to collect the full-text articles; we obtained the full text for 43. These papers were blinded by a third person who was not involved in the review. Two review authors (SKK, RL) independently extracted data by using a predesigned data extraction form; the extracted data matched completely.

Included studies We identified 27 studies for inclusion, with the following comparisons. Azithromycin with erythromycin: four studies (Harris 1998; Kogan 2003; Roord 1996; Wubbel 1999), involving 457 children aged two months to 16 years. Clarithromycin with erythromycin: one study (Block 1995), involving 357 children below 15 years of age with clinical or radiographically diagnosed pneumonia treated on an ambulatory basis. Co-trimoxazole with amoxycillin: two studies (CATCHUP 2002; Straus 1998), involving 2066 children aged two months to 59 months. Co-trimoxazole with procaine penicillin: two studies (Keeley 1990; Sidal 1994), involving 723 children aged three months to 12 years. Chloramphenicol with penicillin and gentamycin together: one study (Duke 2002), involving 1116 children aged one month to five years. Single-dose benzathine penicillin with procaine penicillin: two studies (Camargos 1997; Sidal 1994), involving 176 children between two and 12 years of age in one study (Sidal 1994) and 105 children aged between three months to 14 years in the other similar study (Camargos 1997). Amoxycillin with procaine penicillin: one study (Tsarouhas 1998), involving 170 children aged six months to 18 years. Ampicillin with chloramphenicol plus penicillin: one study (Deivanayagam 1996), involving 115 children aged five months to four years. Co-trimoxazole with single-dose procaine penicillin followed by oral ampicillin: one study (Campbell 1988), involving 134 children aged below five years.

Penicillin with amoxycillin: two studies (Addo-Yobo 2004; Atkinson 2007), involving 1905 children aged three months to 59 months. Co-trimoxazole with chloramphenicol: one study (Mulholland 1995), involving 111 children aged under five years. Cefpodoxime with co-amoxyclavulanic acid: one study (Klein 1995), involving 348 children aged three months to 11.5 years. Azithromycin with amoxycillin: one study (Kogan 2003), involving 47 children aged one month to 14 years. Amoxycillin with co-amoxyclavulanic acid: one study (Jibril 1989), involving 100 children aged two months to 12 years. Chloramphenicol in addition to penicillin with ceftriaxone: one study (Cetinkaya 2004), involving 97 children aged between two to 24 months admitted to hospital with severe pneumonia. Levofloxacin and comparator (co-amoxyclavulanic acid or ceftriaxone): one study (Bradley 2007) involving 709 children aged 0.5 to 16 years of age with community-acquired pneumonia treated in hospital or ambulatory care.

Parenteral ampicillin followed by oral amoxycillin with home-based oral amoxycillin: one study (Hazir 2008) involving 2037 children between three months to 59 months of age with WHO-defined severe pneumonia. Chloramphenicol with ampicillin and gentamycin: one study (Asghar 2008), involving 958 children between two to 59 months with very severe pneumonia. Penicillin and gentamicin with co-amoxyclavulanic acid (Bansal 2006), involving 71 children with severe and very severe pneumonia between two months to 59 months of age. Co-amoxyclavulanic acid with cefuroxime or clarithromycin: one study (Aurangzeb 2003), involving 126 children between two to 72 months of age.

Excluded studies We excluded a total of 17 studies. Four studies were carried out in adult patients (Bonvehi 2003; Fogarty 2002; Higuera 1996; van Zyl 2002). Three studies included children with severe infections or sepsis (Haffejee 1984; Mouallem 1976; Vuori- Holopaine 2000).

One study did not provide separate data for children (Sanchez 1998). Two studies were not RCTs (Agostoni 1988; Paupe 1992). Three studies only compared the duration of antibiotic use (Hasali 2005; Petola 2001; Ruhrmann 1982); of these, one study (Hasali 2005) also did not report the outcome in the form of cure or failure rates. One studied only sequential antibiotic use (Al-Eiden 1999). One compared azithromycin with symptomatic treatment for recurrent respiratory tract infection only (Esposito 2005). Full text article could not be obtained for one study (Lu 2006). One study (Lee 2008) was excluded because the outcome was not in the form of cure or failure rates.

Risk of bias in included studies Details of sequence generation were described in 16 studies (Addo-Yobo 2004; Asghar 2008; Atkinson 2007; Awasthi 2008; Bansal 2006;Camargos 1997;CATCHUP 2002;Cetinkaya 2004; Deivanayagam 1996; Duke 2002;Hazir 2008; Jibril 1989; Keeley 1990; Mulholland 1995; Roord 1996; Shann 1985), were not clear in nine studies (Aurangzeb 2003; Block 1995; Bradley 2007; Campbell 1988;Harris 1998; Klein 1995; Straus 1998; Tsarouhas 1998;Wubbel 1999) and sequence was not generated in two studies (Kogan 2003; Sidal 1994).

Allocation Allocation concealment was adequate in 16 studies (Addo-Yobo 2004; Asghar 2008; Atkinson 2007; Awasthi 2008; Bansal 2006; Camargos 1997; CATCHUP 2002; Cetinkaya 2004; Deivanayagam 1996; Duke 2002; Harris 1998; Hazir 2008; Keeley 1990; Mulholland 1995; Shann 1985; Tsarouhas 1998), it was unclear in eight studies (Aurangzeb 2003; Block 1995; Bradley 2007; Campbell 1988; Jibril 1989; Klein 1995; Straus 1998;Wubbel 1999) and no concealment was done in three studies (Kogan 2003; Roord 1996; Sidal 1994) (see Table 1).

Methods,Randomised, non-blinded controlled clinical trial ParticipantsChildren between 3 to 72 months of age, admitted in the hospital with communityacquired pneumonia InterventionsThe patients were randomly allotted to 1 of the 3 groups Group 1 was given amoxicillin 75 mg/kg/d IV in 3 divided doses, Group 2 was given cefuroxime 75 mg/kg/d IV in 3 divided doses and Group 3 was given clarithromycin 15 mg/kg/d IV divided into 2 divided doses Outcomes1. Improvement defined as slower respiratory rate (either back to normal for the age of the child), or more than 5 as compared to the previous day evaluation without retractions. The same defined as still breathing fast as before as or higher than that with no chest in drawing or danger signs 2. Worse was defined as development of severe pneumonia or very severe disease 3. Cure was defined as return of respiratory rate to age specific normal range

Notes- Risk of bias ItemAuthors judgementDescription

Allocation concealment?UnclearNot mentioned Blinding? All outcomes No Incomplete outcome data addressed? All outcomes Yes Free of selective reporting?UnclearThere are discrepancies in the number of patients in different study arms Free of other bias?UnclearSource of funding not mentioned

Analysis Comparison 10 Cefpodoxime versus co-amoxyclavulanic acid, Outcome 1 Cure rate (response rate) at end of treatment. Review: Antibiotics for community-acquired pneumonia in children Comparison: 10 Cefpodoxime versus co-amoxyclavulanic acid Outcome: 1 Cure rate (response rate) at end of treatment Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio n/N n/N M-H,Random,95% CI M-H,Random,95% CI Klein /188 87/ % 0.69 [ 0.18, 2.60 ] Total (95% CI) % 0.69 [ 0.18, 2.60 ] Total events: 179 (Treatment), 87 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.56 (P = 0.58) Favours treatment Favours control Analysis

Analysis Comparison 10 Cefpodoxime versus co-amoxyclavulanic acid, Outcome 2 Mean age (months). Review: Antibiotics for community-acquired pneumonia in children Comparison: 10 Cefpodoxime versus co- amoxyclavulanic acid Outcome: 2 Mean age (months)