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Reproduced by permission from the American Academy of Pediatrics
Reprint requests to (H.M.F.) Department of Family Medicine, University of Connecticut Health Center, Farmington, CT 06030-3960.
Outline
ABSTRACT. Objective. An orally administered antimicrobial regimen for the treatment of group A [small beta, Greek]-hemolytic streptococcal (GABHS) pharyngitis given once rather than multiple times each day would be more convenient and might result in improved patient compliance. The purpose of this study was to evaluate the effectiveness of once-daily amoxicillin in the treatment of GABHS pharyngitis.
Patients. Children presenting to a private pediatric office with GABHS pharyngitis.
Design. Patients were randomly assigned to receive orally either amoxicillin (750 mg once daily) or penicillin V (250 mg three times a day) for 10 days. Compliance was monitored by urine antimicrobial activity.
Outcomes. Outcomes were measured by impact on the clinical course, eradication of GABHS within 18 to 24 hours, and bacteriologic treatment failure rate as determined by follow-up throat cultures 4 to 6 and 14 to 21 days after completing therapy. GABHS isolates were serotyped to distinguish bacteriologic treatment failures (same serotype as initial throat culture) from new acquisitions (different serotypes).
Results. During the 16 months of this study, 152 children between 4 and 18 years of age (mean, 9.9 years) were enrolled; 79 children were randomly assigned to receive once-daily amoxicillin and 73 were assigned to receive penicillin V three times a day. The children in the two treatment groups were comparable with respect to age, duration of illness before initiation of therapy, compliance, and signs and symptoms at presentation. There was no significant difference in the clinical or bacteriologic responses of the patients in the two treatment groups at the 18- to 24-hour follow-up visit. Bacteriologic treatment failures occurred in 4 (5%) of the 79 patients in the amoxicillin group and in 8 (11%) of the 73 patients in the penicillin V group.
Conclusions. These data demonstrate that once-daily amoxicillin therapy is as effective as penicillin V therapy given three times a day for the treatment of GABHS pharyngitis, and if confirmed by additional investigations, once-daily amoxicillin therapy could become an alternative regimen for the treatment of this disease. Pediatrics 1999;103:47-51.
KEY WORDS. group A streptococcal, pharyngitis, treatment, amoxicillin, Streptococcus pyogenes, streptococcal infections.
ABBREVIATION. GABHS, group A [small beta, Greek]-hemolytic streptococcus.
An orally administered antimicrobial regimen for the treatment of group A [small beta, Greek]-hemolytic streptococcal (GABHS) pharyngitis that could be given once rather than several times each day would be convenient, especially for children who are attending school. A single daily dose might also result in improved patient compliance. Four antimicrobials are currently approved by the United States Food and Drug Administration for once-daily therapy for GABHS pharyngitis: cefadroxil, cefixime, ceftibuten, and azithromycin. (1-5) Unfortunately, these agents all have a broad spectrum of antimicrobial activity and are relatively expensive. Penicillin is the treatment of choice for GABHS pharyngitis; however, in two earlier studies, orally administered penicillin G and penicillin V given once daily were both ineffective in the treatment of this disease. (6,7) Pharmacokinetic data and clinical experience suggested that orally administered amoxicillin given once daily might be effective in the treatment of GABHS pharyngitis, (8-14) as did a recent investigation by Shvartzman and co-workers. (15) Therefore, we initiated a prospective, randomized, controlled investigation to compare two treatment regimens for GABHS pharyngitis: 750 mg of amoxicillin given orally once daily and the conventional regimen of 250 mg of penicillin V given orally three times daily. Outcomes were measured by the eradication of GABHS from the upper respiratory tract 18 to 24 hours after beginning therapy, the impact on the clinical course, and the bacteriologic treatment failure rate. (1)
PATIENTS AND METHODS
During the winter to spring of 1996 to 1997, consecutive patients between 3 and 18 years of age seen in a private pediatric office in Danbury, Connecticut (M.F.R.) with clinical findings suggestive of GABHS pharyngitis were enrolled in the investigation after written, informed consent had been obtained. Patients with a history of hypersensitivity to penicillin or amoxicillin and patients who had received antimicrobial therapy within the previous week were excluded.All study patients were evaluated as previously described for the presence of three objective signs (fever; tonsillar exudate; and tender, enlarged cervical lymph nodes) and one subjective symptom (sore throat) before and 18 to 24 hours after the initiation of antimicrobial therapy. (16) Two rayon-tipped swabs (Culturette II; Marion Scientific, Kansas City, MO) were then simultaneously and vigorously rubbed over each patient's posterior pharynx and tonsils (or tonsillar fossae). One swab was used to perform a rapid antigen detection test for GABHS (Q-test; Becton Dickinson, Cockeysville, MD) and the other swab was transported by overnight courier to the Clinical Microbiology Laboratory at the University of Connecticut Health Center where it was streaked onto a blood agar plate, incubated anaerobically overnight at 37[degree sign]C, and then examined for the presence of [small beta, Greek]-hemolytic streptococci. All [small beta, Greek]-hemolytic streptococci were confirmed as group A with the Streptex test (Murex Biotech Ltd, Kent, England).
At the initial visit, patients were randomly assigned (using a table of random numbers) to receive either 250 mg of penicillin V (250 mg/5 mL of suspension) orally three times daily for 10 days or 750 mg of amoxicillin (250 mg/5 mL of suspension) orally once a day for 10 days. All patients were asked to return in 18 to 24 hours for a follow-up visit at which time they were reevaluated by the same physician who had performed the initial assessment and who was unaware of which treatment regimen had been received. At this follow-up visit, a second throat culture was obtained. Patients returned for additional follow-up visits 4 to 6 and 14 to 21 days after completing the assigned antimicrobial therapy, or if any signs or symptoms suggestive of GABHS pharyngitis recurred. At each of these follow-up visits a repeat throat culture was obtained. All follow-up throat cultures were processed in the same laboratory at the University of Connecticut Health Center as the initial culture. Any patient who had received the experimental amoxicillin regimen and had a positive throat culture at the 18- to 24-hour, the 4- to 6-day, or the 14- to 21-day follow-up visit was given a 10-day course of penicillin V administered three times daily (conventional therapy). In addition, patients who had received the conventional penicillin regimen and had signs or symptoms of pharyngitis with a positive throat culture at the 4- to 6-day or the 14- to 21-day follow-up visit were given another 10-day course of the penicillin V regimen.
For patients with positive follow-up throat cultures, pretreatment and posttreatment GABHS isolates were characterized by M typing and T agglutination patterns and by serum opacity reactions according to established methods. (17) Bacteriologic treatment failures were defined as the presence of the same serotype of GABHS on either follow-up culture (4 to 6 days or 14 to 21 days after completing therapy) as on the initial throat culture, regardless of the clinical status of the patient. Patients with a different serotype of GABHS on the follow-up than on the initial throat culture were considered to have newly acquired GABHS rather than a treatment failure.
Compliance was determined by having a parent dip a strip of filter paper into the patient's urine on the seventh day of antimicrobial therapy. The strip was allowed to air-dry and was then mailed in a preaddressed envelope to the University of Connecticut Health Center where it was assayed for antimicrobial activity using a modification of the technique of Markowitz and Gordis. (18)
Data were analyzed using Student's t test and [chi squared] analysis.
RESULTS
GABHS were isolated from 161 patients who were randomly assigned to treatment groups as follows: 84 received 750 mg of amoxicillin once daily and 77 received 250 mg of penicillin V three times daily for 10 days. Six patients (2 in the amoxicillin group and 4 in the penicillin V group) were not included in the analyses because they had failed to return for their follow-up visits and 3 patients (all in the amoxicillin group) because they had prematurely discontinued their therapy. One patient discontinued the amoxicillin prematurely because of urticaria, 1 because of abdominal pain, and 1 because he was switched to erythromycin therapy after being diagnosed with Mycoplasma pneumoniae pneumonia. The remaining 152 patients (79 amoxicillin and 73 penicillin V) ranged in age from 4 to 18 years (mean age, 9.9 years). The patients in the amoxicillin and penicillin V treatment groups were similar with respect to age (mean, 9.0 years and 11.4 years, respectively), sex (65% and 62% males, respectively), duration of illness before treatment (mean, 1.2 days and 1.4 days, respectively), and clinical findings at the time of the initial visit (**). Approximately 85% of the patients in both treatment groups returned their filter paper strips and [tilde operator]80% of these patients in both treatment groups were determined to be compliant.
Figure 1. Specific signs and symptoms before and after 18 to 24 hours of therapy.
All 152 patients returned for the 18- to 24-hour follow-up evaluation. At this time the clinical responses of the patients in the two treatment groups were comparable-[tilde operator]90% of patients in both treatment groups were afebrile and clinically improved (**). At this time, 1 (1%) of the 73 patients in the penicillin V group and none of the 79 patients in the amoxicillin group had a positive throat culture for GABHS.
All 152 patients returned for follow-up visits 4 to 6
days and/or 14 to 21 days after completing therapy. Overall, 28 (18%) of the
152 patients had GABHS isolated on the follow-up throat culture obtained at
one of these visits as shown in **. Of the 79 patients in the once-daily amoxicillin
group, 13 (16%) had GABHS isolated on one of these follow-up throat cultures:
4 (5%) had strains identical to the strains isolated on their initial throat
cultures and were considered to have bacteriologic treatment failures, whereas
9 (11%) had different strains of GABHS and were considered to have new acquisitions.
Of the 4 patients with bacteriologic treatment failures, 1 had signs or symptoms
suggestive of GABHS pharyngitis at the time of their positive follow-up throat
culture. Of the 73 patients in the three times daily penicillin V group, 15
(21%) had GABHS isolated on one of these follow-up throat cultures: 8 (11%)
had strains identical to the strains isolated on their initial throat cultures
and were considered to have bacteriologic treatment failures, whereas 7 (10%)
had different strains of GABHS and were considered to have new acquisitions.
Of the 8 patients with bacteriologic treatment failures, 1 had signs or symptoms
suggestive of GABHS pharyngitis at the time of their positive follow-up throat
culture. There was no significant difference between the amoxicillin and penicillin
V treatment groups in the number of patients with positive follow-up throat
cultures or in the number of patients with bacteriologic treatment failures.
The number of patients with symptomatic treatment failures was too small to
analyze statistically. There was no relationship between either the ages of
the patients or compliance and the bacteriologic outcomes. All the patients
with treatment failures who received a subsequent 10-day course of penicillin
V remained well during the several months follow-up observation and repeat
cultures were not performed or treatment given again during this period.
Table 1. Bacteriologic Response to Antibiotic Therapy
Both the amoxicillin and penicillin therapies were well tolerated. Among the 79 patients who completed the amoxicillin therapy, 2 patients developed macular rashes, 3 patients developed diarrhea, and 3 patients complained of abdominal pain. Among the 73 patients who completed the penicillin therapy, 1 patient developed urticaria after his last dose, 2 patients developed diarrhea, and 1 patient developed abdominal pain. The side effects from either penicillin or amoxicillin resolved within 24 hours of stopping the antibiotics.
DISCUSSION
Amoxicillin given three times daily for 10 days has been shown to be just as effective as penicillin V given three times daily for 10 days in the treatment of GABHS pharyngitis. (13,14) A single high-dose of amoxicillin with probenicid has been used to treat gonococcal urethritis. (10,11) Clinical data suggest that orally administered amoxicillin might be effective in the treatment of GABHS when given as a single daily dose of 750 mg. (15) The absorption of amoxicillin is unaffected by the ingestion of food (8,9) and its serum half-life in children is 1.1 to 1.8 hours. (8) In contrast, the absorptions of both penicillin G and penicillin V are reduced by the ingestion of food and these agents have serum half-lives in children of 0.95 to 1.2 hours and 0.76 to 0.99 hours, respectively. (19) In addition, the peak serum levels in children after a 125-mg orally administered dose of penicillin V and amoxicillin are 1.74 [micro sign]g/mL and 3.86 [micro sign]g/mL, respectively. The minimal inhibitory concentrations of penicillin V and amoxicillin for GABHS are comparable. (9,13,20)In the present study, we have demonstrated that 750 mg of amoxicillin suspension given once-daily for 10 days is as effective as 250 mg of penicillin V suspension given three times daily for 10 days. These two antimicrobial regimens were comparable in their abilities to eradicate GABHS from the upper respiratory tract, in their impacts on the clinical course of the disease, and in their bacteriologic treatment failure rates. The clinical responses, eradication rates at 18 to 24 hours, and the bacteriologic treatment failure rates for the patients in both treatment groups in this study were comparable to those reported in earlier investigations. (2,7,16) The compliance rates for the patients in our study who received once-daily amoxicillin and three times daily penicillin V were comparable. It has been shown, however, that the fewer doses per day a patient is requested to take, the better their compliance. (21)
The power of this study to demonstrate a statistically significant difference in the effectiveness of the two antimicrobial regimens is limited by the sample size. For example, the [small beta, Greek] error in the comparison of bacteriologic treatment failure rates for once-daily amoxicillin and three-times-daily penicillin V is >0.70. To be able to show a statistically significant difference between a 5% and 11% bacteriologic treatment failure rate with a two-tailed [small alpha, Greek] of 0.05, one would need to enroll 353 participants in each of the treatment groups.
One potential problem with using amoxicillin to treat suspected GABHS pharyngitis is if the patient has infectious mononucleosis, the amoxicillin may produce a morbilliform rash that could be misinterpreted as an allergic reaction. This did not occur in our study; however, if it does occur, the rash is self-limited and resolves when the amoxicillin is discontinued. (22) The risk of this rash occurring can be reduced by administering amoxicillin only to those patients who have either a positive rapid antigen detection test or throat culture. In addition, infectious mononucleosis can be suspected (and amoxicillin avoided) if splenomegaly is present.
Previous attempts have been made to treat GABHS pharyngitis with a single daily dose of orally administered penicillin. Breese et al (6) gave 50 children a single dose of 800 000 units buffered penicillin G each day for 10 days and compared the outcomes of these patients with those of patients who received standard therapy. Serotyping of isolates was not performed, and, therefore, bacteriologic treatment failures could not be distinguished from new acquisitions. They found that 42% of patients had positive follow-up throat cultures during the 2 months after completion of once-daily penicillin therapy. In contrast, 14% to 15% of the children with GABHS pharyngitis who had been given the same total daily dose of penicillin G in either two or four divided doses had positive follow-up throat cultures. The authors concluded that a single dose of 800 000 units buffered penicillin G orally each day for 10 days was inadequate for the treatment of GABHS pharyngitis.
In 1989, we reported that a single daily dose of penicillin V (750 mg) for 10 days was comparable to 250 mg of penicillin V three times daily for 10 days in its ability to eradicate GABHS from the upper respiratory tract in 18 to 24 hours and in its impact on the clinical course of the disease. However, a bacteriologic treatment failure occurred in 6 (8%) of the 76 patients in the three-times-daily group and in 16 (22%) of the 74 patients in the once-daily group (P < .05). (7) In a preliminary investigation in which patients received 1500 mg of penicillin V once-daily for 10 days, we observed a 20% bacteriologic treatment failure rate, suggesting that a doubling of the single daily dose of penicillin V would not have been effective. (7)
In the only previous investigation of once-daily amoxicillin in the treatment of GABHS pharyngitis, Shvartzman et al (15) compared a group of 82 patients who received 250 mg of penicillin V given three or four times daily for 10 days with a group of 75 patients who received a once-daily dose of amoxicillin (50 mg/kg for children not to exceed the adult dose and 750 mg for adults) for 10 days. There was no difference observed in the clinical responses of the patients in the two treatment groups or in the proportion of patients in the two treatment groups with positive throat cultures 24 to 48 hours after initiating antimicrobial therapy. However, the patients receiving once-daily amoxicillin had significantly fewer bacteriologic treatment failures 4 to 11 days after completing antimicrobial therapy than the patients receiving three-times-daily penicillin (0% and 6.1%, respectively; P < .05).
Recently, investigators have demonstrated that once-daily azithromycin as well as once-daily regimens of several cephalosporins (eg, cefadroxil, cefixime, ceftibuten, cefpodoxime, cefprozil) are comparable with penicillin V administered three to four times daily in the treatment of GABHS pharyngitis (1-5,23,24). However, the cost of these agents, even as a single daily dose, as well as their broader spectra of antimicrobial activity, have precluded their widespread adoption as standard therapy for GABHS pharyngitis.
The results of this and one earlier investigation demonstrate that once-daily amoxicillin therapy is effective in the treatment of GABHS pharyngitis. Once-daily amoxicillin therapy is well-tolerated by patients and convenient for parents. Amoxicillin is less expensive and has a narrower spectrum of antimicrobial activity than the presently approved once-daily antimicrobial regimens for the treatment of GABHS pharyngitis. If confirmed by additional investigations, once-daily amoxicillin therapy could become an alternative regimen for the treatment of GABHS pharyngitis.
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