only 2030% of patients with group a beta hemolytic streptococcus ( gabhs ) pharyngitis presents with classical symptoms of the disease .
reliance on clinical judgment alone has a poor predictive value and results in 80% to 95% overestimation of disease [ 2 , 3 ] .
diagnostic strategies for acute gabhs pharyngitis are thus based on epidemiological factors , signs , and symptoms , as well as the result of throat cultures ( tcs ) .
several studies have shown that the use of throat culture leads to more judicious use of antibiotics [ 57 ] .
physicians prescribe antibiotics for acute pharyngitis as they are concerned that patients with this complaint may be suffering from gabhs infection that if left untreated might develop suppurative complications , such as , tonsillar abscess or nonsuppurative complications , such as , rheumatic fever [ 6 , 8 ] . antibiotics , however ; confer only minor symptomatic benefits for gabhs sore throat .
they shorten the duration of symptoms by merely half a day on average [ 8 , 9 ] .  
more recent studies have shown that antibiotic use only reduced the incidence of rheumatic fever by a mere 0.5 cases per 100,000 .
the importance of preventing rheumatic fever has lessened as the incidence of rheumatic fever and rheumatic heart disease has declined significantly in the last 20 years , from a mean annual incidence of 13.4 per 100,000 to 5 per 100,000 .
prevalence has decreased as well from 5.7 per 1,000 in the eighties to 0.5 per 1,000 in 2000 [ 8 , 10 , 11 ] .  
this failure probably stems from the fact that about 20% of children with gabhs is infected with bacteria which contain m protein , a virulence factor located on the surface of the bacterial wall that confers resistance to commonly used antibiotics .
newer beta - lactamase - resistant antibiotics did not prevent this treatment failure [ 13 , 14 ] .  
review of the literature from 1945 to 1999 , which includes 10,484 cases of gabhs sore throat , found that antibiotic treatment reduced the occurrence of acute otitis media , a common complication of this disease , by a mere 25% , compared to the placebo group and sinusitis by only 50% .
rheumatic fever , a nonsuppurative complication , was reduced by less than 33% , compared to placebo [ 8 , 10 , 11 , 15 ] .  
in addition to the uncertainly in the scientific literature , parents seem to be uncertain regarding the benefits of antibiotic treatment for acute gabhs pharyngitis and tend to stop treatment earlier than prescribed . in a pilot study
, we randomly followed 75 children with gabhs pharyngitis for 6 months and have found that more than 75% of them did not complete ten days of antibiotics .
this finding led us to conduct a multisite , prospective cohort observational study , the results of which are reported here .
the goal of this study was to determine whether noncompliance with antibiotic treatment affects short - term or long - term complications .
two central , primarily rural , and agricultural regions of the largest health maintenance organization ( hmo ) in israel , comprising approximately one million patients . using a standard protocol
, we located from our computerized data base 107,840 patients , aged 6 months to 18 years , who were examined by their primary care physician for upper respiratory tract infection , tonsillitis , pharyngitis , sore throat , tonsillopharyngitis , neck pain , cervical lymphadenopathy , pta , rpa , from january 1 , 1999 until december 31 , 2000 .
we then accessed the charts of 78,473 of these children who were diagnosed with infected throat or one of the differential variants , excluding all children diagnosed as having viral upper respiratory infections .
47,000 of these patients were formally diagnosed with acute pharyngitis or acute tonsillitis and received a prescription for antibiotics , indicating that their physician suspected bacterial disease . in the index visit , 35,000 of these children had at least four out of five symptoms in the modified centor criteria used for this study and nadir modified breese epidemiological and clinical score card ( ecsc ) that has 91% sensitivity and 98% specificity when the score was above 15 ( score between 4 and 36 ) for the diagnosis of gabhs [ 1719 ] .
colonies yielding beta - hemolysis were grouped for surface carbohydrate assessment by using a latex bead agglutination test ( figure 1 ) . of the 6336 children ( with positive cultures with 4 or more centor criteria and 15 or higher ecsc ) , 4,775 parents consented to enroll their children to the study ( figure 1 ) . excluded from the study were children who were diagnosed as gabhs chronic carriers or who had suffered from post - gabhs complications ; had any chronic illness , such as , renal or hepatic impairment ; had bleeding disorder ; had congenital or acquired immunodeficiency or suffered from malignancy .  
initial patient / parent contact was made by one of the authors ( m. sarrell ) within 3 to 5 days of the initial positive throat culture . at that time , initial information regarding the illness and whether a prescription for antibiotics was given by the primary care physician .  
the attending physicians of the two thousand study patients were contacted by email within 48 hours of the enrollment by one author ( m. sarrell ) .
the physicians were requested to inform the authors of any additional cultures taken during therapy , and to request that they obtain two additional throat cultures and engage in improve adherence strategies by providing information , counseling , reminders , reinforcement , and if needed personal attention or supervision .
while repeated cultures are not routinely recommended for asymptomatic patients who have completed a course of antimicrobial therapy , in light of the poor compliance with treatment in the pilot study , performance of such follow - up cultures was considered important for the purposes of the study .
the first follow - up culture was performed within 10 to 14 days of the initial positive culture regardless of treatment status .
the purpose of this culture was verification of antibiotics treatment failure or persistence of gabhs in the oropharynx of the untreated patients .
the second additional throat culture was taken between days 21 and 30 after the initial positive culture , regardless of treatment status , to ascertain the presence of residual gabhs or recurrences . treating physicians
were also requested to obtain blood for liver enzymes , renal function tests , and urine analysis from all the participants and to perform annual follow - up evaluation thereafter .  
a second patient / parent contact was made by our study coordinator within 10 to 14 days of initiation of antibiotic treatment .
she collected information about demographic characteristics , past medical history , febrile status , need for repeat throat culture during the treatment period ( that was not part of the study protocol ) , and type of medication prescribed . during this contact she obtained information about the number of days of actual treatment , omission compliance and complications , the patients / parents perceived as deriving from the treatment ( or lack thereof ) .
the computerized charts of the participants were searched within 2 to 4 weeks of the second patient / parent contact for additional information , including demographic characteristics , medical and environmental history , initial clinical data , such as , in - office fever evaluation , results of the physical examination , additional culture taken , type of antibiotics used , and disposition of prescription received .
a second search of the computerized medical charts was performed by our research assistant between 30 and 90 days of initiation of medical treatment , to ascertain that the 2 requested throat cultures were obtained . relapse or recurrence of clinical or bacterial pharyngitis ,
suppurative or nonsuppurative complication , or even whether the participants complained of any sore throat within 30 days of completion of treatment were also evaluated . in order to assure that all possible short - term complications that occurred within 90 days of the index case were obtained ,
an additional comprehensive search of the hmo database was done within 120 days of the second computer search .
we ascertained that findings that were either not available on the original computerized chart or were seen by other than their primary care physician , ( e.g. , emergency departments , patients that relocated ) , were not overlooked .
the charts of the participants were then reviewed by one of the authors on a yearly basis , from january 2000 to january 2010 , noting possible late nonsuppurative complications of gabhs infection .
no patients were lost to followup , even if they had changed physicians , due to our ability to track them through the centralized database to their new physician or another hmo .
the children that were enlisted to the army ( and thus not members of any hmo during their military service ) were contacted either through their former attending physician or the military physician .  
minor treatment failure was defined as any clinical or bacterial recurrence of pharyngitis during the short - term follow - up period and its correlation to compliance with treatment .  
major treatment failure was defined as retropharyngeal or peritonsillar abscess or long - term complications , such as rheumatic fever .  
suppurative complications were chosen as a model , because the nonsuppurative complications ( rheumatic heart disease , arthritis , carditis ) have been practically eradicated in our region .
this cohort study was designed to analyze rare events ( according to the cioms classification 110 events per 10,000 children years ) .
the annual incidence of peritonsillar abscess ( pta ) in our region is 24 cases per 100,000 and the incidence of retropharyngeal abscess ( rpa ) is 57 cases per 100,000 .  
power calculations suggested 6,500 to 7,000 person - years of intervention would be needed to detect a 22% difference in pta and rpa between the fully treated ( ft ) and partially treated ( pt ) arms of the study population .
furthermore , one - sided alpha of 0.025 , a statistical power of 95% , and the pta / rpa incidence given above showed that approximately 19,000 children - years would be needed to show the noninferiority of ft versus pt . since the primary outcome of interest is the pta / rpa hazard ratio between ft and pt .
the null hypothesis to be tested is hr pta / rpa > 2 ( i.e. , the pta / rpa hazard ratio for ft versus pt is higher or equal to 2 ) .
the pta / rpa hazard ratio was calculated for ft versus pt .   for purposes of analysis ,
participants were divided into four subgroups based on length of treatment : 1st subgroup ( untreated ) , those who did not receive any treatment , 2nd subgroup ( partially treated ) , children that received antibiotics for 1 to 3 days , 3rd subgroup ( mostly - treated ) , children treated for 4 to 6 days , and 4th subgroup ( fully - treated ) children treated between 7 to 10 days .
data are presented as proportions ( with 99% confidence intervals [ cis ] ) , means ( with sds ) , or medians ( with interquartile ranges ) , using pearson  tests , student 's tests , or fisher exact test .
comparisons of length of treatment according to time and treatment were assessed using the repeated measures and analysis of variance and the paired t test .
a 2-tailed p value of.05 was used to determine the statistical significance of differences observed between groups and to calculate confidence intervals around differences in sample means and odds ratios .
we used the mcnamara test to measure the changes between the groups and their subgroups regard to the length of antibiotic treatment .
over half of their children ( 1023 , 51% ) were between the ages of 6 months and 6.9 years , and over half 1,039 ( 52% ) were female .
the majority of children ( 1,821 , 91% ) were prescribed penicillin or amoxicillin , allergic or intolerant to penicillin were treated with cephalosporin 25 ( 1.5% ) , erythromycin 109 ( 5.5% ) , and azithromycin 45 ( 2.5% ) , all medication were prescribed twice daily for 10 days , except azithromycin once daily for 5 days .
no statistical correlation was found between the type of antibiotics , the children received , or the demographic characteristics and the complications found in the later medical examinations .
only 196 children ( 9.8% ) actually completed 10 days of antibiotic treatment . despite having received a prescription from their physician , two hundred and thirteen participants ( 11% )
did not start taking any treatment whatsoever , including those who did not even purchase antibiotics .
as shown in table 1 a no statistical correlation was found concerning length frequency and duration , palatability , number of daily dose of treatment , but a statistically significant difference was found between all the subgroups concerning the length of antibiotics treatment ( p   <
the majority of children ( 1192 , 59.6% ) had 3 days or less of fever , defined as any rectal temperature less than 38.5c or oral temperature less than 37.8c .
the majority of children ( 1591 , 80% ) received medication for four to six days at the most ( partially treated subgroup ) .
as illustrated in table 1 , the association between the duration of fever and the number of days of treatment was statistically significant ( p < .0001 ) .  
of the 306 ( 15.3% ) children with clinically diagnosed recurrent tonsillopharyngitis , only 236 ( 12.3% ) had positive gabhs findings on the throat culture taken within 10 to 14 days after conclusion of the primary infection .
an additional thirty - four ( 1.7% ) had a positive second study culture ( taken 2130 days after the index positive gabhs culture ) .
of note is the fact that the majority ( 156 , 66% ) of the positive study culture at 1014 days were found among the subgroup treated for 7 to 10 days .
no such positive results were found in the subgroup treated for 1 up to 3 days .
furthermore , no positive gabhs throat cultures were found on the second study culture in the untreated group .
the majority ( 26 , 76% ) of positive gabhs cultures were in the mostly treated subgroups .
as illustrated in table 2 , these findings were both statistically significant ( p  <  .0001 ) ( table 2 ) .  
cervical lymphadenitis , acute otitis media , and impetigo were the only suppurative complications noted .
110 ( 5.5% ) children developed cervical lymphadenitis , most ( 52 , 47% ) among the 6 to 7 days treatment subgroup and 33 ( 33% ) among the 4 to 5 days treatment subgroup , a significant difference among the treatment subgroups ( p < .0001 ) .
additionally , no children developed nonsuppurative complications during 10 years of followup nor did any of the children develop iga nephropathy during the follow - up period .
furthermore , they were no association between the five modified centor criteria and development of complication , even when stratified by type of antibiotics or the season of the year . altogether , 304 ( 15% )
new onset cases of acute otitis media ( aom ) were diagnosed within 30 days of the initial diagnosis .
however , only 31 ( 10% ) of those were in the untreated subgroup , as compared to 141 ( 46% ) in the 7 to 10 days treatment subgroup , 98 ( 38% ) in the 4 to 6 days treatment subgroup and 98 ( 33% ) in the 1 to 3 days subgroup , a statistically significant difference among the all treatment subgroups ( p  <  .0001 ) .   attempting to elucidate the possible causes for the differences between the recurrence of gabhs and the length of antibiotic treatment or clinical score on enrolment or illness severity , a multivariate stepwise logistic analysis was performed .
the duration of fever was the most significant predictor for such recurrence , age under 6 years being less significant , while treatment for 7 to 10 days had no significant influence on the recurrence of gabhs .  
of note is that the contribution of the duration of fever was apparent even after controlling for the concomitant influence of age , gender , medical history , single- or two - parent home , type of antibiotics or the season of the year , and concomitant illnesses , such as , conjunctivitis , otitis media , upper respiratory infection , gastroenteritis , or lymphadenitis , which may have otherwise explained the influence of the length of treatment in relation to those illnesses ( table 3 ) .
this study found a very poor parent / child compliance to antibiotic treatment prescribed for symptomatic , culture - positive gabhs tonsillopharyngitis .
11% of children did not start taking any treatment at all , and only 10% completed a full course of treatment .
the reason for this low rate of compliance is unclear , but it coincides with other reported studies [ 14 , 16 ] . we speculate that a large proportion of lack of compliance is the parent 's sensation that antibiotics are potentially dangerous   and overprescribed [ 18 , 19 ] . despite this poor compliance , in our study as in others , there was a very low rate of suppurative complications .
furthermore , despite the poor compliance , we found no increase in the incidence of acute rheumatic fever , the most dreaded complication of gabhs , in our patients .
in fact , since the year 2000 , the incidence of rf in our region has declined from 2.2 per 100,000 to 0.2 per 100,000 in 2008 , according to the epidemiological department of the israeli ministry of health .
this is in concordance with other developed countries , including , the united states , where the original recommendation for 10 days of antibiotic treatment of gabhs originated . in that country ,
currently there are only 10 cases of rf per 100,000 patients with gabhs pharyngitis , and only 1 case per 10,000 patients with acute rheumatic fever develop rheumatic heart disease [ 2022 ] .
in fact , concomitant with the increased use of antibiotics , recurrence of gabhs in the usa rose from 9% and 10.7% in the years 1975 to 1979 , respectively , to 25.9% and 37.5% in the years 1995 to 1996 , despite the decline in acute rheumatic fever .
14% of patients in our study had a recurrent infection , proven by a gabhs - positive throat cultures .
this percentage is similar to other studies which found that penicillin failed to eradicate gabhs from the throat in approximately 13% to 26% of the patients evaluated [ 23 , 24 ] .
the majority of recurrences in our study were in the younger group ( mean age of 10.2 years , and 60% of them younger than 9.9 years ) .
this is consistent with other published studies where such recurrences were more frequent among children aged 1 to 8 years than among children aged between 13 and 19 years [ 24 , 25 ] .   historically ,
prescribing 10 days of oral penicillin began in the 1950s , substituting the intramuscular injections of long - acting parenteral penicillin , based on surrogate markers of eradication of gabhs from the tonsillopharynx . however , no study has conclusively proven that this practice unequivocally prevents acute rheumatic fever [ 26 , 27 ] . even though orally prescribed penicillin appeared to be equally effective for clinical and laboratory resolution of signs and symptoms , it is difficult to administer and expensive , considering the staggering financial burden of approximately 140 office visits per annum per 1,000 children younger than 15 years [ 28 , 29 ] . substituting azithromycin or cephalosporins for penicillin was found to produce better bacteriological and clinical results and also required a shorter course of treatment [ 30 , 31 ] .   
our results may not apply to adults , sick people , or chronic gabhs carriers .
it does not address the optimal length of treatment required to achieve appropriate eradication of the microbe or whether complete eradication is required at all .
the method of pill / doses counts is not a good measure of adherence , but due to it simplicity and empiric nature it was found adequate for this study .
we were unable to assess the true variation of the incidence of acute rheumatic fever , due to the fact that this disease has been practically eradicated from our population .
our data suggest that the large majority of parents / patients stop administering antibiotics to their children who suffer from gabhs prior to the completion of the recommended course .
a more judicious use of antibiotics would promote and improve compliance , cut costs , and prove more convenient to parents and children alike .
 
 background . 
 uncertainty exists concerning the necessity of 10-day antibiotic treatment of group a beta hemolytic streptococcus ( gabhs ) pharyngitis . objective . to assess the incidence of gabhs recurrence and suppurative and nonsuppurative complications in relation to compliance 
 . methods . 
 ( design ) . prospective cohort observational study . 
 ( subjects ) . 
 2,000 children aged 6 months to 18 years with sore throat and positive gabhs culture . 
 ( main outcome measures ) . 
 recurrence of symptomatic culture positive gabhs pharyngitis , incidence of suppurative , and long - term , regional , nonsuppurative complications of gabhs pharyngitis , over a ten year period . results . 
 213 ( 11% ) of the children received no treatment . 
 most children received antibiotics for only 46 days ( in correlation with the duration of fever , which in most cases lasted up to 3 days ) . 
 three hundred and six ( 15.3% ) children had clinically diagnosed recurrent tonsillopharyngitis ; 236 ( 12.3% ) had positive gabhs findings within 10 to 14 days and thirty - four ( 1.7% ) within 2130 days after the index positive gabhs culture . 
 the remaining 1.3% had no positive culture despite the clinical findings . 
 almost all recurrences [ 236 ( 11.6% ) ] occurred within 14 days and 156 ( 7.6% ) in the fully treated group . 
 the presence of fever during the first 3 days of the disease was the most significant predictor for recurrence . 
 other predictors were the age younger than 6 years and the presence of cervical lymphadenitis . 
 no increase in the incidence of nonsuppurative or suppurative complications was noted during the 10-year follow - up period , compared to the past incidence of those complications in israel . 
 conclusions . 
 our data suggests that the majority of children discontinue antibiotics for gabhs tonsillopharyngitis a day or two after the fever subsides . 
 the incidence of complications in our study was not affected by this poor compliance . 
1. Introduction
2. Methods
3. Results
4. Discussion
5. Conclusion 