RCT of Efficacy of Amoxicillin Over Ampicillin on Severe Pneumonia
Condition: Treatment Failure; Lethargy; Altered Mental Status; Convulsion, Non-Epileptic; Hypoxia; Feeding; Difficult, Newborn
MeSH terms: Pneumonia; Seizures; Lethargy; Hypoxia
Study type: Interventional

Summary: 
      Burden: Pneumonia remains the leading infectious cause of death accounting for 920,000
      children under five around the world. This means a loss of over 2,500 child lives every day,
      or over 100 every hour. Since 2000, the number of child deaths caused by pneumonia has
      decreased by 47 percent. The tremendous progress made is due in part to the rapid roll-out of
      vaccines, better nutrition, and improved care-seeking and treatment for symptoms. However,
      pneumonia hasn't declined as quickly as other diseases such as malaria (58%), HIV/AIDS (61%),
      and measles (85%).

      Knowledge gap: The Lancet Series on Childhood Pneumonia and Diarrhea has reported that case
      management is one of the three most effective interventions to reduce pneumonia deaths in
      children. It is also noted that the cost-effectiveness of these interventions in the national
      health system needs urgent assessment. It was suggested to find out means to reduce hospital
      stay without compromising the quality of care.

      Relevance: The main purpose of the study is to compare the efficacy of two doses of
      parenteral Amoxicillin plus single-dose Gentamicin compared to four doses of parenteral
      Ampicillin plus single-dose Gentamicin. After 72 hours of treatment injectable Amoxicillin or
      injection Ampicillin will be switched to or replaced by oral Amoxicillin and will be
      discharged with an advice to attend to Ambulatory Care Unit (ACU) to receive a once-daily
      dose of injection Gentamicin for a total of 5 days. It is anticipated that this modified
      therapy will reduce the hospitalization stay of children with severe pneumonia and would
      therefore be relevant in countries with the resource-poor settings. By reducing the
      hospitalization period, this therapy has the potentials to reduce hospital-acquired
      infection.

      Hypothesis (if any): Rate of treatment failure with two doses of injectable Amoxicillin plus
      single-dose Gentamicin will be no more than that of four doses of injectable Ampicillin plus
      single-dose Gentamicin in the management of children between 2 months to 59 months
      hospitalized for WHO classified severe pneumonia.
    

Detailed description: 
      Severe pneumonia is a serious infection in children which requires timely intervention.
      Management of severe pneumonia is done by appropriate antibiotics and supportive care. WHO
      recommendation is to use injection ampicillin four times a day for 3-5 days and injection
      gentamicin once a day for 3-5 days in children with severe pneumonia. In the study, the
      investigators want to compare the response of injection ampicillin with another similar and
      equally effective antibiotic (amoxicillin). The reason for choosing amoxicillin is that the
      dose is two times a day and it is cost-effective and reduces chances of nosocomial infection.
      The response of the drugs will be compared by the time difference of clinical improvement of
      the patients or time difference of disappearance of the sign and symptoms on admission. The
      investigators are interested to compare the recovery time from the illness as well as
      treatment failure in both groups. In that way, the investigators will be able to develop a
      better treatment for pneumonia in children in low-cost settings.

      The study will be an open-label, randomized, controlled intervention in children between two
      months to 59 months admitted to Dhaka Hospital of icddr,b. Investigators will use sealed
      envelopes to randomly assign the children to either treatment arm. In the first arm children
      will receive 2 daily doses of parenteral Amoxicillin and a single daily dose of parenteral
      Gentamicin; and in 2nd arm, children will receive 4 daily doses of parenteral Ampicillin and
      a single daily dose of parenteral Gentamicin. After 72 hours of treatment, injection
      Amoxicillin and injection Ampicillin will be replaced with oral Amoxicillin but injection
      gentamicin will be continued for a total of 5 days in one daily dose. During this time
      participants will be suggested to discharge from the hospital and attain to the Ambulatory
      care unit for getting a once-daily dose of injection of Gentamicin. Both the treatment arm
      will continue for 5 days.

      During the study period, participants in both study arms will also receive standardized
      hospital management for other co-morbidities-such as diarrhea, malnutrition, and any other
      complications. Hypoxia will be managed by B-CPAP through a nasal cannula.

      Any participants will be declared "Treatment failure" who show the persistence of danger
      signs after 48 hours or develop new danger signs within 24 hours of initiation of antibiotic
      treatment. If a participant needs mechanical ventilation, dies at any time during a hospital
      stay, or left the hospital against medical advice will be also declared as a treatment
      failure.

      Participants from either study group who develops the features of "treatment failure" should
      be rescued with the second-line antibiotic regimen, which is injection ceftriaxone and
      injection levofloxacin.

      Monitoring of the children with severe pneumonia The following parameters should be routinely
      monitored in every child with severe pneumonia. Special attention should be given to
      participants receiving I/V fluid therapy and those with SAM. Such as: Heart rate, respiratory
      rate, temperature, respiratory pattern including chest recession, lower chest wall indrawing,
      use of accessory muscles, the establishment of oral feeding, liver size, oxygen saturation
      level, chest auscultation: (rales, rhonchi, bilateral basal crepitation, pleural rub), fluid
      and calorie intake.

      Participants on oxygen therapy should have at least 3-4 hourly observations of all the above
      parameters and participants without getting oxygen should be observed at least 2 hourly by
      the study nurses. All the patients should be evaluated by the physicians at least 12 hourly.

      Signs of Improvement:

      In absence of complications, within 2 days of initiation of treatment, there should be signs
      of improvement i ) breathing rate within normal limit; ii) absence of the lower chest wall
      in-drawing; iii) less to no fever; iv) improved ability to eat and drink, and v) better
      oxygen saturation without assistance.

      Discharge criteria

        -  Respiratory distress has resolved

        -  Oxygen saturation > 90%

        -  Feeding well

        -  Able to take oral medication or have completed a course of parenteral antibiotics

        -  The parents understand the signs of pneumonia, risk factors, and when to return

      The study objective is to compare the efficacy of two doses of injectable Amoxicillin plus
      single-dose injectable Gentamicin compared to four doses of injectable Ampicillin plus
      single-dose injectable Gentamicin in the management of participants hospitalized with WHO
      pneumonia.

      Secondary objectives are to compare time to resolution of danger signs of pneumonia, length
      of hospital stay, mortality rate, rate of complication requiring mechanical ventilation, and
      rate of multiorgan or renal or cardiac failure between the two treatment groups.

      Children more than 2 months to less than 59 months will be enrolled in the study, if
      participants have a history of cough or difficulty in breathing and WHO classified severe
      pneumonia plus at least two of the following:

      i) Central cyanosis or oxygen saturation <90% on pulse oxymetry ii) Severe respiratory
      distress (e.g. grunting, very severe chest indrawing) iii) Signs of pneumonia with a general
      danger sign: inability to breastfeed or drink; lethargy or reduced level of consciousness;
      convulsion iv) In addition, some or all of the other signs of pneumonia may be present, such
      as:

        -  Signs of pneumonia [age specific fast breathing( Annex 1)]

        -  Chest indrawing: lower chest wall indrawing

        -  Chest auscultation signs: (any one)

             1. Decreased breath sounds

             2. Bronchial breath sounds

             3. Crackles

             4. Abnormal vocal resonance (decreased over a pleural effusion or empyema, increased
                over lobar consolidation)

             5. Pleural rub

      Participants with a life-threatening condition that required immediately assisted ventilation
      or referring to an outside hospital (such as septic shock, cardiac arrest, apnea, respiratory
      failure, etc.) will be excluded from the study. Children with uncorrected cyanotic CHD,
      hypercapnia (PCO2 > 60mm of Hg), status asthmaticus and upper-airway obstruction, preterm
      baby (but not ex-preterm), and those for who inform consent can't be secured from their
      parents/ care-givers. Caregivers presented with any drug container of antibiotics or
      prescription showing getting antibiotics will be excluded.

      Sample size calculation:

      [For two-sample comparison of proportion (non-inferiority)]

      Null hypothesis: p2-p1≤ δ (inferior), where: pi (entered in command) is the overall
      proportion of participants expect to experience the outcome of the treatments are
      non-inferior, and delta is the smallest change in proportions between groups (p2 - p1) which
      would still be clinically important.

      Assumptions:

      power = 0.8; alpha = 0.025 (one-sided); pi = 0.50; delta = 0.16 Estimated required sample
      size (per group) = 154,

      Total sample is 308

      This study will be conducted at the Dhaka Hospital of icddr,b, Dhaka, Bangladesh. This
      hospital is located in Dhaka city, the capital of Bangladesh. It provides care and treatment
      to around 110,000 diarrheal patients with or without associated complications and with or
      without other health problems each year. The vast majority of the patients come from poor
      socio-economic backgrounds from urban and peri-urban Dhaka, the capital city of Bangladesh.

      Patients attending this hospital are first assessed by an experienced triage nurse, which
      includes assessment of the type of diarrhea and degree of dehydration, and presence of other
      health problems including ALRI/ pneumonia, severe malnutrition, impaired mental status
      (convulsion), and sepsis. The non-diarrhoeal patients have been redirected to other
      appropriate hospitals in the city. Based on an assessment of diarrhoeal patients, those with
      uncomplicated illness without signs of dehydration are referred to the Out-Patient Department
      (OPD) for 4-5 hours of observation, maintenance of hydration using ORS solution, and for
      provision of health education to the mothers/caregivers. Those with some and severe
      dehydration but without any associated health problems are admitted to Short Stay Ward (SSW)
      for correction of dehydration and maintenance of hydration using ORS and/or intravenous
      fluids, provision of antimicrobial therapy as appropriate, with an average stay of 24 hours.
      Those with associated complications of diarrhea and/or associated health problems are
      referred to a physician for assessing the need for admission to either the Longer Stay Ward
      (LSW) or Acute Respiratory Ward (ARI) or to the Intensive Care Word (ICU) depending on the
      clinical severity. The usual associated conditions include difficult respiration, cyanosis,
      apnoea, hypothermia or hyperthermia, marked lethargy or comatose condition, poor peripheral
      perfusion not attributable to severe dehydration. Participants hospitalized in SSW are
      assessed by hospital clinicians for possible admission to LSW and further workup and
      management. After admission to the LSW/ARI/SCU, the attending physician will obtain medical
      history, performs a thorough clinical examination, makes a problem list including
      differential diagnoses for each of them, arranges for required laboratory workups, and
      develops the treatment plan following standard guidelines of the hospital. Investigators will
      also perform bedside procedures such as sampling blood, performing lumbar punctures, etc.
      Oxygen saturation is determined by pulse oximeter when necessary, and blood glucose estimated
      by bedside Gluco Check machine in nearly all patients admitted to the LSW/ARI /SCU.
    

Intervention name(s): Amoxicillin
Intervention type(s): Drug
Intervention description(s): Twice daily doses of injectable amoxicillin
Other intervention name(s): no other intervention
Intervention MeSH terms: Amoxicillin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Investigators have completed the enrollment of 308 participants by the study endline. All the Serious adverse events have been reported appropriately to the Ethical Review Committee and the Data Safety and Monitoring Board (DSMB)
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: RCT; severe pneumonia; amoxicillin; under five