Trial of Amoxicillin Compared With Placebo for Pneumonia in Children Aged 2-59 Months
Condition: Acute Respiratory Infections; Pneumonia
MeSH terms: Pneumonia; Respiratory Tract Infections
Study type: Interventional

Summary: 
      Many children with "non-severe pneumonia" (cough and fast breathing) have neither clinical
      pneumonia as assessed by physicians nor pneumonia on chest radiographs. Inappropriate use of
      antibiotics for these cases is leading to resistant strains of bacteria in the community.
      Evidence shows that almost 50% of antibiotic prescription is unnecessary.As over half of
      antibiotic prescription for ARI are not necessary since most of these infections are viral
      and do not respond to antibiotic therapy which will be source of resistance in the community.

      To address this issue the investigators conducted this randomized, double blind placebo
      controlled clinical trial of oral Amoxicillin versus placebo in children with non-severe
      pneumonia taking into account all the necessary safety precautions for their well being.

      The study hypothesis was that the clinical outcome of children 2 to 59 months of age with
      cough and fast breathing (WHO defined non-severe pneumonia) with or without wheezing is
      equivalent, whether they are treated with amoxicillin or placebo.
    

Detailed description: 
      Pneumonia is one of the major cause of childhood morbidity and mortality in developing
      countries. Burden of acute respiratory infections (ARI) is high with an estimated 5-7
      episodes in under 5 population every year resulting in 2 million deaths. However, most of
      these are due to severe bacterial pneumonia.

      In order to reduce pneumonia related deaths in communities where qualified personnel and
      diagnostic facilities are often not available WHO developed management guidelines based on
      simple clinical signs followed by empirical treatment. All children with cough and fast
      breathing are classified into management categories: Children with fast breathing only are
      classified as having non-severe pneumonia requiring oral antibiotic at home, children who
      have lower chest indrawing and /or general danger signs (GDS) are classified as severe
      pneumonia, and very severe pneumonia respectively. Both these groups require referral to a
      hospital and injectible antibiotic therapy. These guidelines have shown to effectively reduce
      ARI related mortality by 34% (?) in communities where they have been successfully
      implemented.

      However, there are certain concerns regarding these guidelines. It is felt that using the
      sign of fast breathing alone for prescribing antibiotic may not be the most judicious thing
      from a public health perspective as it may lead to the spread of antibiotic resistance. Fast
      breathing could be due to many other causes not related to pneumonia.

      There are many factors affecting the respiratory rate I children. Children with fever will
      have elevated respiratory rates in any case. Although WHO guidelines recommend that
      respiratory rate must be counted when child is afebrile, calm and preferably sleeping. In
      real life such practice is not always possible.

      Another issue is the children with cough and fast breathing who have wheezing. In many
      developing countries wheeze is commonly associated with fast and difficult breathing. Data
      from the developed countries shows that wheeze is more common in viral than bacterial
      infections. Likewise, data from the developing countries has shown that viruses, especially
      respiratory syncytial virus (RSV), are isolated more frequently than bacteria from children
      with episodes of acute lower respiratory tract infections. A randomized trial of infants with
      bronchiolitis and pneumonia found no difference in clinical outcome in children with
      antibiotics compared with placebo(ref?). Wheeze has long been unaddressed and is one of the
      major cause for overuse of antibiotics. Evidence shows that three cycles of inhaled
      bronchodilator was found to be associated with a significant decrease in respiratory rate
      leading to revised classification of "no pneumonia" in these children. It has convincingly
      shown that majority of these children continue to do well when sent home without an
      antibiotic.

      Though fast breathing is an important indicator for clinical diagnosis of pneumonia it cannot
      distinguish viral from bacterial pathogens Controversy still exists concerning the relative
      importance of viral and bacterial pathogens so a reliable distinction between bacterial and
      viral infection has yet to be established and this issue has raised a lot of questions for
      the programme managers, senior researchers and technical experts, which still need to be
      answered.

      Many children with "non-severe pneumonia" (cough and fast breathing) have neither clinical
      pneumonia as assessed by physicians nor pneumonia on chest radiographs. Inappropriate use of
      antibiotics for these cases is leading to resistant strains of bacteria in the community.
      Evidence shows that almost 50% of antibiotic prescription is unnecessary. As over half of
      antibiotic prescription for ARI are not necessary since most of these infections are viral
      and do not respond to antibiotic therapy which will be source of resistance in the community.
      When resistant bacteria become common, we may begin to see treatment failures in the children
      with severe pneumonia who really require an effective antibiotic. It is imperative to have
      the knowledge of likely cause and pattern of pneumonia which could be utilized to better
      understand the model of antibiotic resistance.

      For the above stated reasons, there is a need to further elaborate the role of antibiotics in
      children with cough and fast breathing. To address this issue we conducted this randomized,
      double blind placebo controlled clinical trial of oral Amoxicillin versus placebo in children
      with non-severe pneumonia taking into account all the necessary safety precautions for their
      well being. The primary objective was to determine whether children aged 2 to 59 months with
      cough and fast breathing, with or without wheezing, but no evidence of WHO defined severe
      illness, have equivalent clinical failure at 72 hours of therapy when treated with
      Amoxicillin compared to placebo.
    

Intervention name(s): Amoxicillin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Oral Amoxicillin 15 mg/kg/dose 8 hourly; The placebo was similar in colour, consistency and volume as oral amoxicillin
Other intervention name(s): Amoxycillin
Intervention MeSH terms: Amoxicillin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: ARI; LRTI