Efficacy of Oral Amoxicillin versus Parenteral Ceftriaxone in Treatment of Uncomplicated Community Acquired Pneumonia (CAP): A Prospective, Single Blinded, Parallel Design, Randomized Controlled Trial

Abstract

Aim: Community acquired Pneumonia (CAP) is one of the major causes of under-five morbidity and mortality in most of the tropical countries. Management of CAP with an appropriate antibiotic will help reduce the growing antibiotic resistance. The aim of the study was to compare the efficacy of oral amoxicillin with parenteral ceftriaxone in uncomplicated CAP in children aged 6 months to 12 years. Methods: This was a prospective, single blinded, parallel design, randomized control trial. One hundred children with uncomplicated CAP, aged 6 months to 12 years, admitted in pediatric wards at a tertiary care centre were included in the study. The enrolled patients were randomized in two groups in the ratio of 1:1. Group I received oral amoxicillin and group II received intravenous ceftriaxone for 7 days. Number of days for defervescence, day of settlement of respiratory distress, day of subsidence of cough, duration of hospital stay, step-up to higher antibiotics, adverse drug reactions were compared in both the groups. Results: Time to deferervescence of fever in Group I was 3.7±0.9 days as compared to 3.66±0.8 days in group II (p=0.81). Settlement of respiratory distress occurred in 3.22±0.85 days in group I as compared to 3±0.67 days in group II (p=0.19). Subsidence of cough occurred in 11.68±0.92 days in group I as compared to 11.14±1.06 days in group II (p=0.74). Duration of hospital stay was 6.02±1.11 days in group I as compared to 7.24±1.18 days in group II (p<0.0001). Step-up to a higher antibiotic was required in 2 (4%) children on oral amoxicillin and 1 (2%) child on IV. ceftriaxone (p=1.00). Two children from oral amoxicillin group had diarrhea without any signs of dehydration on day 2 of treatment, which subsided in 2 days after giving probiotics and oral rehydration solution. This did not require discontinuation of amoxicillin. No side effects were observed from IV ceftriaxone group. Conclusion: Use of oral amoxicillin for uncomplicated CAP in children has a similar outcome as compared to parenteral cephalosporins. It reduces the duration of hospital stay and thus the cost of treatment. More importantly, it prevents the unnecessary use of a higher-class antibiotic, thereby helping to reduce antibiotic resistance. Introduction Pneumnia remains the single largest infectious cause of death in children worldwide.1 Globally, more than 800,000 children die of pneumonia annually before their fifth birthday.2 Incidence of pneumonia in low and middle-income countries (LMIC) is ten times that of high-income countries (HIC), which is attributable to a low birth weight, malnutrition, vitamin A deficiency, lack of breastfeeding, passive smoking, poor socioeconomic status, large family size, overcrowding and pollution in these countries.3 Nevertheless, community acquired pneumonia (CAP) incurs huge costs either directly for treatment or through loss of working hours by guardians of diseased children.4 CAP is an infection of lung parenchyma in a previously healthy patient who acquired the infection in the community and has no history of hospitalization in the 2 weeks preceding manifestation.5,6 The most common causes of uncomplicated CAP are Hemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, certain gram-negative rods, certain viruses and atypical organisms.6,7,8 The clinical diagnosis of CAP is made using the new World Health Organization (WHO) criteria5 which primarily includes two categories ARTICLE HISTORy Received 30 December 2020 Accepted 4 March 2021 KEyWORDS Community acquired pneumonia, amoxicillin, cephalosporin, randomized control trial, uncomplicated pneumonia 2 PEDIATRIC ONCALL JOURNAL (JANUARy-MARCH 2021) 18(1): 1-6 of pneumonia: 1) pneumonia with fast breathing and/ or chest indrawing, which requires home therapy with oral amoxicillin, and 2) severe pneumonia defined as pneumonia with any general danger sign (including inability to drink/feed, persistent vomiting, convulsions, lethargy or unconsciousness, stridor in a calm child or severe malnutrition). Uncomplicated CAP is defined as CAP in which there are no signs of other complications such as pleural effusion, cavitation or abscess from admission to discharge.9 A microbial culture takes significant amount of time. This could potentially delay initiation of treatment. Without microbiological culture, we cannot accurately predict the causative agent. This justifies the role of empirical treatment with higher antibiotics in CAP.10 The current management guidelines focus more on diagnostic sensitivity than specificity, leading to abuse of higher antibiotics.11,12 WHO recommends first line treatment with twice daily amoxicillin given for 7 days, for pneumonia with rapid breathing (age appropriate measure) with or without chest indrawing but no danger signs, in children under 5 years of age.5 While there is no standard recommendation of IV ceftriaxone for 7 days for an uncomplicated CAP, it is being used rampantly in clinical settings for the treatment of uncomplicated CAP.13,14,15,16 Also, many studies from LMICs suggest the use of ceftriaxone for severe pneumonia.17,18,19,20,21,22 However, some studies suggest that the use of narrow-spectrum antibiotics against CAP is as useful as broad-spectrum antibiotics.22 If proven equally efficacious, the use of lower generation antibiotics with high therapeutic indices, like penicillin or amoxicillin must definitely be made a priority. In addition to contributing to drug resistance, adverse reactions to cephalosporins must also be considered while prescribing these antibiotics.22 Additionally, in LMI countries, use of narrow spectrum antibiotics will also be a cost-effective alternative for treating CAP. The objective of our study was to assess the efficacy of oral amoxicillin versus parenteral cephalosporin in uncomplicated CAP among children 6 months to 12 years of age. Methods & Materials This study was a prospective, single blinded, parallel design, randomized control trial in a tertiary care hospital of a metropolitan city in Western India conducted over a period of 18 months from January 2018 to August 2019. Children admitted in the pediatric wards were enrolled for the study. Patients were blinded regarding the drug administered throughout the study. One hundred children between 6 months to 12 years of age, diagnosed with uncomplicated CAP (presenting with fast breathing or chest indrawing but no danger signs) were enrolled.5,9 Children admitted in Pediatric Intensive Care Unit (PICU), those with underlying immunodeficiency disorders (acquired or congenital), with other co-existing infections (for example: dengue, malaria, measles etc.) or with underlying co-morbidities like cystic fibrosis, sickle cell disease, disorders of cilia etc., children with underlying anatomical disorders of the lung like pulmonary sequestration, tracheo-esophageal fistula, congenital cystic adenoid malformation or any other co-existing acute or chronic disorders were excluded from the study. After obtaining approval from the Institutional Ethics Committee (IEC), a written informed consent was taken from the caretakers. The study was registered with the Clinical Trials Registry – India (CTRI) [CTRI/2019/07/020174]. Children presenting with clinical features of CAP viz. tachypnea, respiratory distress, fever, were evaluated using the WHO criteria for clinical diagnosis of pneumonia.5 A chest X-ray was done for all and cases having radiological evidence of lobar and/or bronchopneumonia were enrolled. Chief complaints, co-morbidities, family & socioeconomic history, birth history, and immunization history of the patients were recorded. Physical examination along with baseline investigations like complete blood count, blood culture, sputum for gram stain and culture sensitivity, arterial blood gases (ABG) done on the day of admission were recorded. The enrolled patients were divided in two groups in the ratio of 1:1. Group I received oral amoxicillin and Group II received intravenous ceftriaxone. Randomization to Group I or II was done by numbering the subjects serially and dividing them into odd and even numbers with odd numbers being included in Group I and even numbers in Group II. After randomization, patients in group I treatment were given oral amoxicillin at 100mg/kg/day in three divided doses for 7 days. Patients in group II were given intravenous (IV) ceftriaxone at 75mg/kg/day in two divided doses for 7 days. In order to blind the patients from the drug which they were taking, normal saline (NS) intravenously was given and multivitamin syrup orally to all the patients. In this way, all patients were on medications given with both the routes, which made it possible to give the patients drug according to their groups and without revealing the drug. The effectiveness of the two antibiotics were evaluated based on the following parameters: number of days to defervescence of fever (defined as complete abatement of fever for ≥24 hours), days to settlement of respiratory distress, days to subsidence of cough, the duration of hospital-stay, step-up to higher antibiotics, and any significant adverse reactions requiring change of drug. Children from both groups received supplemental oxygen. They were monitored for tachypnea, respiratory distress, fever, cough, oxygen saturations (SpO2) and development of complications. For Group I, children were discharged after the respiratory distress had settled and the children were afebrile for 24 hours. The remaining course of antibiotic was completed at home. Appropriate responses were recorded from these patients’ caretakers at the time of discharge on completion of the hospital course. For Group II, children were discharged after 7 days of completion of intravenous antibiotic therapy, provided they were afebrile and respiratory distress had settled. Step-up to higher antibiotics i.e. failure of response, was considered under following circumstances: no improvement and/or