Kimberly Treier 11 April 2016

3-Day versus 5-Day Antibiotic Therapy for Community-Acquired Pneumonia

Current guidelines, such Infectious Diseases Society of America/America Thoracic Society1, recommend treatment of community acquired pneumonia with antibiotic therapy for a minimum duration of 5. However, concerns for cost, compliance and antibiotic resistance prompt the question of efficacy of shorter antibiotic therapy in this disease management. Minimal data evaluating this question exists at this time, however, a few studies published conflicting results as to the effectiveness of shorter therapy in children younger than the age of 5. One additional study suggests this may be an alternative option in adults requiring hospitalized for pneumonia.

Previous studies of outpatient pediatric patients suggest a shorter course of antibiotic therapy may be comparable to more traditional recommendations.

A randomized, double-blind, placebo-controlled trial2 of 2000 children aged 2-59 months with WHO-defined non-severe pneumonia in the outpatient setting of seven Pakistani hospitals assessed the efficacy of 15 mg/kg oral amoxicillin every 8 hours for three days (n=1000) versus five days (n=1000). Participants receiving antibiotic for only three days received placebo in the same manner for the following two days . Children with chronic illnesses, asthma or previous antibiotic use within the preceding 48 hours were included and baseline characteristics were similar between the two groups. Treatment failure, the primary outcome, occurred in 21% of the three-day treatment group compared to 20% of the five-day group via intention-to-treat analysis and no significant differences were identified. Of those cured by day 14 of follow-up, disease relapse, the secondary outcome, occurred in 12/803 (1.5%) of children in the 3-day treatment group compared to 13/811 (1.6%) of the five-day group. Characteristics significantly associated with treatment failure (p<0.0001) included age 2-11 months (OR 1.61, 95% CI 1.27-2.04), vomiting (OR 1.56, 95% CI 1.14-2.13, p 0.004), illness duration of ≥ 3 days, respiration rate above age-specific criteria (OR 1.81, 95% CI 1.43-2.27), and non-adherence in the five-day group (OR 3.96, 95% CI 2.12-7.39). Though not statistically significant, more participants in the five-day group reported side effects (8% versus 7%) at the first follow-up (day 3) (OR 0.94, 95% CI 0.66-1.33, p=0.698). Thus, these results suggest three days of amoxicillin therapy in children aged 2-59 months with WHO-defined non-serious pneumonia is just as effective as five days of therapy.

After publication of the aforementioned trial, another study published similar findings. This randomized, double blind, placebo controlled trial3 of 2188 children aged 2-59 months with non-severe pneumonia in the outpatient setting of seven Indian hospitals evaluated the efficacy of amoxicillin 31-54 mg/day for three days followed by two more days of therapy (n=1093) or placebo (n=1095). Children with severe pneumonia, other conditions requiring antibiotics, chronic diseases and a penicillin allergy were excluded. Baseline characteristics were similar between the two groups. The proportion of children recovering after three days compared to five

days of antibiotic therapy, the primary outcome, was 980/1095 (89.5%) and 983/1093 (89.9%), respectively, in the intention-to-treat analysis. The proportion of relapse within the next 6-14 days, one of the secondary outcomes, was 58/1095 (5.3%) in the three-day treatment group and 48/1093 (4.4%) in the five-day group. Characteristics significantly associated with treatment failure included non-adherence at day 5 (OR 11.57, 95% CI 7.4-18.0), excess respiratory rate of >10 breaths/minute (OR 2.89, 95% CI 1.83-4.55) and nasopharyngeal swab positive for respiratory syncytial virus (OR 1.95, 95% CI 1.0-3.8). Adverse effects occurred similarly between the two groups. Thus, results from this study support the hypothesis that three days of amoxicillin treatment in children aged 2-59 months with non-severe pneumonia is as effective as five days of treatment. A more recent study of outpatient pediatric patients presents data supports traditional recommendations for antibiotic duration but shorter therapy may be less effective. A randomized, double-blind placebo-controlled trial4 of 140 children aged 6-59 months with community-acquired alveolar pneumonia (CAAP) treated at a regional hospital in Israel evaluated the efficacy of amoxicillin 80 mg/kg/day for three, five or ten days. Children receiving antibiotics within the previous 14 days, impaired immunity, more than one pneumonia episode within the past year, chronic illness and/or presence of another condition requiring antibiotic therapy were excluded. More children aged <24 months (58.3%) and males (75%) were included in the three-day group. Baseline presentation characteristics did not differ with statistical significance. Treatment for three (n=12) versus ten (n=13) days were compared (Stage I) and five (n=56) versus ten (n=59) days (Stage II) were compared. Stage I was discontinued due to four treatment failures all occurring in the three-day group. Absence of treatment failure within 30 days, the primary outcome, occurred among all participants in the five-day and ten-day treatment groups in Stage II. These results suggest five and ten days of amoxicillin therapy are comparable, whereas, three days of treatment may be associated with an unacceptable failure rate. A study suggests shorter antibiotic therapy may be non-inferior to conventional recommendations in adult patients admitted for pneumonia.

A randomized, double blind, placebo-controlled non-inferiority trial5 of 119 adults with mild to moderate-severe pneumonia admitted to hospitals in the Netherlands evaluated the efficacy of three-day intravenous amoxicillin treatment followed by oral amoxicillin 750 mg (n=63) or placebo (n=56) three times daily for a total of eight days. Only individuals with radiologic evidence of pneumonia, no confounding co-infections and clinical improvement after the initial intravenous therapy were included. Characteristics at baseline and during follow-up occurring more in the three-day treatment group include underlying disease (70% vs 64%), diabetes mellitus (16% vs 11%), smoker (55% vs 27%), pleural effusion (13% vs 3.2%) and detected pathogen at study entry (59% vs 49%). Those occurring more in the eight-day treatment group include more than one pneumonia episode per year (18% vs 14%) and median community acquired pneumonia score (39 vs 18). Cure

rate, the primary outcome measure, did not differ between the two groups at Day10 in both the intention-to-treat and per protocol analyses and differed only marginally on Day 28 (secondary outcome measure). Four treatment failures occurred in both the three-day and eight-day treatment groups (7% and 6%, respectively) and mild adverse events occurred in six (11%) patients in the three-day and thirteen (21%) patients in the eight-day groups. Additionally, the estimated length of stay differed by one day (7.9 vs 8.9 days) favoring shorter treatment. Though some differences exist between the two treatment groups, such as comorbidities, episode characteristics and frequency of pneumonia, these results suggest that treatment of mild to moderate-severe pneumonia in hospitalized individuals with three days of amoxicillin is not inferior to eight days of treatment. References 1 Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clinical Infectious Diseases 2007; 44:S27-72 2 Pakistan Multicentre Amoxicillin Short Course Therapy (MASCOT) Pneumonia Study Group. Clinical Efficacy of 3 Days Versus 5 Days of Oral Amoxicillin for Treatment of Childhood Pneumonia: A Multicentre Double-Blind Trial. Lancet 2002;360:835-841 3 Agarwal G, Awasthi S, Kabra SK, et al. Three Day Versus Five Day Treatment With Amoxicillin For Non-Severe Pneumoia In Young Children: A Multicenter Randomised Controlled Trial. BMJ 2004;328:791-4 4 Greenberg D, Givon0Lavi N, Sadaka Y, et al. Short-Course Antibiotic Treatment for Community-Acquired Alveolar Pneumonia in Ambulatory Children: A Double-Blind, Randomized, Placebo-Controlled Trial. The Pediatric Infectious Disease Journal 2014;33(2):136-142 5 el Moussaoui R, de Borgie CA, van den Broek P, et al. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomized, double blind study. BMJ 2006;332:1355