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Abstract & Commentary
Synopsis: Short-course, high-dose antibiotic therapy was associated with lower rates of subsequent carriage of resistant pneumococci than was longer-course, lower-dose therapy.
Source: Schrag SJ, et al. JAMA. 2001;286:49-56.
From the Dr. Robert Reid Cabral public hospital in santo Domingo, Dominican Republic, comes a study of 795 children (aged 6-59 months) who received amoxicillin for a respiratory infection in order to test the hypothesis that short-course, high-dose therapy reduces the risk of post-treatment resistant pneumococcal carriage. To this end, patients were randomized to receive either 90 mg/kg/d for 5 days or 40 mg/kg/d for 10 days, each with twice-daily dosing. Nasopharyngeal cultures for Streptococcus pneumoniae (SP) were collected at baseline, 5 days, 10 days, and 28 days. The clinical response to therapy was not evaluated.
Compliance with the briefer regimen was higher with rates of 82% compared with 74% (P = 0.02). At the initial visit, 73% of the kids were found to have SP while 26% had penicillin nonsusceptible S pneumonia (PNSP). The rate of PNSP carriage was found to correlate with recent receipt of antibiotics, the presence of 3 or more children in the household, and attendance at school or day care. By day 5 of therapy, the isolation rate of SP had dropped to 25% and that of PNSP to 20%. By day 10, the recovery rate went up to 31% for SP and 21% for PNSP.
On day 28 following the initiation of therapy, the rate of SP carriage went back up to about 52% for both regimens, but, however, the rate of isolation of PNSP rose to only 24% in the short-course group compared with 32% in the 10-day course group. The differences were significant at the P = 0.03 level with a relative risk of 0.77 and 95% confidence intervals of 0.60-0.97. The incidence of adverse effects was low and similar in intensity. Thus, high-dose short-course therapy appears to be associated with a lesser effect on carriage of antibiotic resistance than is low-dose, long-course therapy.
Comment by Alan d. Tice, MD, FACP
This study shows what kind of clinical studies can be done in developing countries with good investigators and a little help from the CDC. This collaboration provided methodology and microbiology along with excellent ready access to a large number of compliant patients.
The concept of trying to shorten the course of therapy is an important one, especially with the growing problem of antimicrobial resistance. How to limit this resistance is particularly important with the pathogen studied. It makes sense that shorter courses of intense therapy would be less likely to encourage the development and spread of resistant strains, but little has been done to prove it.
With the rising concerns about antimicrobial resistance, a new look at duration of therapy is in order. It is not easy, however, to shorten courses of therapy in the United States where any failure may end up in court if the textbook recommendations are not followed.
Short-course therapy is an important consideration for a number of infections and has been proven effective in careful studies of uncomplicated cystitis, gonorrhea, and chlamydia. It may also be possible to provide parenteral therapy as an alternative to oral antibiotics and achieve results with a single dose compared to a week’s worth of oral antibiotics, as has been demonstrated with ceftriaxone therapy of otitis media. Opportunities for single-dose intramuscular or intravenous therapy also appear possible with streptococcal pharyngitis.
The results of this investigation confirm the benefit of shorter, higher-dose courses of therapy in reducing PNSP carriage relative to that of lower-dose, shorter duration therapy, but also raise a number of additional questions. Of particular interest is why it is that the sensitive strep are not eliminated after 5 or even 10 days of therapy? Why does the difference in PNSP carriage between short and long course therapies not appear before 28 days of therapy? The apparent protective effect of siblings is interesting but may well relate to a reservoir of relatively susceptible strains in the home.
Should we really be telling patients to stop antibiotics when they are afebrile, they feel better, rather than to continue them for some often arbitrarily chosen duration? Most short-course therapies entail high doses of antibiotics and/or only the most potent drugs. Shortening the course of intravenous antibiotic therapy in the hospital is actively being studied. Should we not look at outpatient and oral regimens as well? At any rate, the results discussed here provide fodder to the argument: "Hit em hard, and then get out."