A study today in the New England Journal of Medicine shows that a shorter regimen of antibiotics in young African children diagnosed with severe pneumonia may be sufficient.
The double-blinded, randomized controlled trial, conducted in 3,000 children under the age of 5 in Malawi who had severe pneumonia but were not infected with HIV, found that 3 days of twice-daily treatments with amoxicillin was non-inferior to the 5-day regimen recommended by the World Health Organization (WHO).
The authors of the study say further research is needed to see whether the results can be duplicated in other low-resource settings and pediatric populations, but they suggest the findings could allow for shorter, simplified antibiotic treatments for children with severe pneumonia in low-resource countries.
In another randomized controlled trial involving young pneumonia patients published in the same journal, researchers in Pakistan found that, when compared with 3 days of amoxicillin, the frequency of treatment failure in children under 5 with non-severe pneumonia was higher in children who received a placebo.
Three days' treatment 'not substantively worse'
For the study in Malawi, a team of researchers from Malawi and the United States recruited children ages 2 to 59 months from a malaria-endemic region of the country who met the WHO criteria for chest-indwelling pneumonia—which indicates a more severe illness—and did not have HIV.
While the WHO recommends 5 days of oral amoxicillin for such children, concerns about global antibiotic resistance, and a paucity of data on the proper duration of treatment for pneumonia, have heightened the need for more research on the subject.
The researchers randomly assigned the children in a 1:1 ratio to receive amoxicillin twice daily for either 3 or 5 days, then evaluated them on days 2, 4, 6, and 14. A non-inferiority design was chosen based on the hypothesis that 3 days of amoxicillin would not be more beneficial than 5 days with respect to the primary outcome of treatment failure by day 6, but would be only slightly less beneficial. The non-inferiority margin for the 3-day regimen was if the incidence of treatment failure was 1.5 times that of the 5-day group. Secondary outcomes included treatment failure by day 6 or relapse by day 14.
Altogether, 1,497 children were assigned to the 3-day amoxicillin group and 1,503 children to the 5-day group. Among children with day 6 data available, treatment failure occurred in 5.9% of the children in the 3-day arm (85 of 1,442 children) and 5.2% of the 5-day group (75 of 1,456). The adjusted difference between the two groups (0.7 percentage points; 95% confidence interval [CI], –0.9 to 2.4) met the criterion for non-inferiority.
Among children with day 14 data available, 12.5% of the 3-day group (176 of 1,411) had treatment failure by day 6 or relapse by day 14, compared with 10.8% (154 of 1,429) of the 5-day group (adjusted difference, 1.7 percentage points; 95% CI, –0.7 to 4.1). The incidence of treatment failure was consistent across prespecified subgroups. The percentage of children with serious adverse events was similar in the two groups (9.8% in the 3-day group and 8.8% in the 5-day group).
"The results of this trial suggest that a 3-day regimen of amoxicillin is not substantively worse than a 5-day regimen for the treatment of chest-indrawing pneumonia among HIV-uninfected children," the authors wrote. "Keeping in mind the benefits to both patients and the health care system of a shorter course of antibiotic therapy and the fact that the WHO already recommends 3 days of amoxicillin for treatment of fast-breathing pneumonia, it appears that a 3-day regimen of amoxicillin in children with chest-indrawing pneumonia might be sufficient."
The authors also note that, because poor adherence to antibiotic treatment has been linked to treatment failure in pneumonia patients, a shorter regimen might improve adherence and outcomes while also minimizing adverse events, costs, and the emergence of antibiotic resistance.
Antibiotics may not be warranted in all cases
For the study in Pakistan, researchers from Pakistan, Sweden, and the United States recruited children ages 2 to 59 months who met the WHO criteria for non-severe pneumonia with tachypnea—a condition where breathing is fast and shallow.
The WHO recommends 3 days of amoxicillin for children who have mild pneumonia with tachypnea and live in areas with a low prevalence of HIV and malaria, but based on recent trial data indicating that pneumococcal vaccines may be reducing the incidence of bacterial pneumonia, the researchers theorized that treatment with a placebo may be non-inferior.
A total of 4,002 children underwent randomization, with 2,003 receiving amoxicillin twice daily for 3 days and 1,999 receiving placebo. The primary outcome of the trial was treatment failure during the 3-day course of amoxicillin or placebo, with a non-inferiority margin of 1.75 percentage points. Secondary outcomes included relapse between days 4 and 14.
In the per-protocol population, which included all children who received five of six doses, the incidence of treatment failure was 4.9% among placebo recipients (95 of 1,927 children) and 2.6% among amoxicillin recipients (51 of 1,929). The between-group difference (2.3 percentage points; 95% CI, 0.9 to 3.7) was above the non-inferiority margin.
Results were similar in the intention-to-treat analysis (between-group difference, 2.3 percentage points; 95% CI, 0.9 to 3.6). Relapse occurred in 2.2% of children in the placebo group (40) and 3.1% (58) in the amoxicillin group (mean difference, 0.9 percentage points; 95% CI, –2.1 to 0.3). Results were consistent across sub-groups.
The number of children with pneumonia and tachypnea needed to be treated in order to prevent one treatment failure was 44 (95% CI, 31 to 80).
The authors of the study say the findings indicate that current WHO recommendations are valid, but argue that the relatively high number needed to treat, and the presence of high-risk subgroups, need to be considered.
"This number is high enough to suggest that antibiotics may not be warranted for a large number of children, yet there are subgroups with a clinical phenotype severe enough to warrant antibiotic therapy," they wrote. "Identifying these subgroups for targeted treatment can limit unnecessary antibiotic use."
They add that more targeted treatment could limit antibiotic expenditures and reduce antibiotic resistance in a part of the world where it's becoming rampant.
"Resistance to beta-lactam antibiotics is at epidemic levels in parts of Asia, and stewardship of antibiotic prescription is the only sure means of preventing further extension of resistance to cephalosporin and carbapenem," they said.
Not enough data to change practice
In an editorial that accompanies the two studies, infectious disease experts from Australia say that although the two trials are important, they don't provide enough evidence to change current clinical practice. Furthermore, the studies highlight how little is known about appropriate antibiotic prescribing for the various types of early childhood pneumonia, which remains the leading cause of death in children younger than 5 in low-income settings.
"Additional data from randomized, controlled trials or from meta-analyses that use individual patient data from several large randomized, controlled trials with smaller relative margins conducted in various settings would be required for the current results to change practice," they wrote.
"These important trials…have contributed to our current knowledge, yet many gaps remain in our understanding of the appropriate management of pneumonia and deserve greater attention."
