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Abstract & Commentary
Source: Schrag S, et al. Effect of short-course, high-dose amoxicillin therapy on resistant pneumococcal carriage. JAMA 2001;286:49-56.
Streptococcus pneumoniae bacteria commonly colonize the nasopharynx of asymptomatic children. However, invasive pneumococcal infections, such as otitis media (OM), sinusitis, meningitis, pneumonia, and bacteremia, result in significant morbidity and mortality worldwide. The growing prevalence of penicillin and multi-drug resistant strains of the pneumococcus have raised considerable alarm in the medical community.
Because antibiotic use and overuse has been cited as one of the chief causes of emerging resistance, some have suggested that changes in antibiotic prescribing practices may reduce the spread of resistant organisms. In this study, the authors sought to determine whether a short-course, high-dose antibiotic regimen would beneficially impact nasopharyngeal carriage rates of resistant pneumococcus in children being treated for respiratory tract infections.
The authors conducted a prospective, single-center trial in 795 children ages 6-59 months who required antibiotic therapy for acute respiratory tract infections, OM, pneumonia, or sinusitis. Subjects were randomized to receive amoxicillin at a standard dose regimen (40 mg/kg/d divided bid) for 10 days, or a new high-dose, short-course regimen (90 mg/kg/d divided bid) for five days. Investigators measured pneumococcal nasopharyngeal carriage rates at days 0, five, 10, and 28 for both susceptible and drug-resistant strains. They also measured patient compliance with the regimens (defined as completing 80-120% of the medication by volume), as well as adverse reaction rates.
At baseline, pneumococcal carriage rates were 76% and 73% for the short-course/high-dose and standard regimen groups, respectively. As would be expected with antibiotic therapy, overall carriage rates declined on days five, 10, and 28 for both groups. Investigators found significantly lower rates of penicillin-resistant pneumoccoccus carriage with the short-course/high-dose therapy than the standard regimen (24% vs 32%, RR = 0.77, P = 0.03). There was a similar trend in resistance to trimethoprim-sulfamethoxasole (17% vs 23%, respectively, RR = 0.77, P = 0.08). Adherence to therapy was significantly better with the short-course/high-dose regimen (82% vs 74%, P = 0.02) and there was no difference in adverse event rates.
Based on their findings, the authors conclude that the short-course/high-dose amoxicillin therapy may be promising as an intervention to decrease the impact of antibiotic use on the emergence and spread of drug-resistant pneumococcus.
Comment by Theodore C. Chan, MD, FACEP
This same short-course, high-dose amoxicillin therapy recently has been approved by the FDA. This regimen has been recommended by a number of groups for the treatment of acute OM in regions where pneumococcal drug resistance is high.1 There are a number of theoretical advantages to this new regimen. First, the increased antibiotic concentrations from the higher dose can overcome penicillin resistance (which, unlike macrolide resistance, is not absolute). Second, the shorter course may reduce overall antibiotic exposure and selective pressure that can facilitate the emergence of resistant strains. While a number of studies suggest the shorter regimen has equal clinical efficacy, this is one of the first studies to suggest benefit in terms of reducing drug-resistance. This study found other benefits to the shorter therapy as well, including that patient compliance was improved with no increase in adverse effects.
It is important to note, however, that this study was performed at a single institution in the Dominican Republic. There may be important differences in both the pediatric population and pneumococcal strains in this developing country. For example, over one-third of the pneumococcal strains at baseline were drug-resistant in this study. Recent work in the U.S. suggests the prevalence of drug-resistant pneumococcus approaches 25% but varies greatly by region.2
Finally, it is interesting to note that while both antibiotic regimens reduced overall pneumococcal carriage rates, the greatest impact was seen in drug-susceptible strains. In fact, for both regimens the actual ratio of drug-resistance to susceptible carriage increased by day 28, suggesting that despite therapy modifications, antibiotic use in general will continue to contribute to the emerging resistance problem.
(Dr. Chan, Associate Clinical Professor of Medicine, Emergency Medicine, University of California, San Diego, is on the editorial board of Emergency Medicine Alert.)
1. Dowell SF, et al. Acute otitis media: Management and surveillance in an era of pneumococcal resisitance: A report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999;18:1.
2. Whitney CG, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000;343:1917.