A placebo-controlled trial of antimicrobial treatment for acute otitis media

A Placebo-Controlled Trial of Antimicrobial Treatment for Acute Otitis Media Paula A. Tähtinen, M.D., Miia K. Laine, M.D., Pentti Huovinen, M.D., Ph.D., Jari Jalava, Ph.D., Olli Ruuskanen, M.D., Ph.D., and Aino Ruohola, M.D., Ph.D.
From the Department of Pediatrics, The efficacy of antimicrobial treatment in children with acute otitis media remains Turku University Hospital (P.A.T., M.K.L., controversial.
O.R., A.R.), the Division of Health Protec-tion, National Institute for Health and Wel- fare (P.H., J.J.), and the Department of Medical Microbiology and Immunology, In this randomized, double-blind trial, children 6 to 35 months of age with acute University of Turku (P.H.) — all in Turku, otitis media, diagnosed with the use of strict criteria, received amoxicillin–clavula- Finland. Address reprint requests to Dr. Ruohola at the Department of Pediatrics, nate (161 children) or placebo (158 children) for 7 days. The primary outcome was Turku University Hospital, PL 52 FIN- the time to treatment failure from the first dose until the end-of-treatment visit on 20521, Turku, Finland, or at aino.ruohola@ day 8. The definition of treatment failure was based on the overall condition of the child (including adverse events) and otoscopic signs of acute otitis media.
N Engl J Med 2011;364:116-26.
Copyright 2011 Massachusetts Medical Society. RESULTS
Treatment failure occurred in 18.6% of the children who received amoxicillin–
clavulanate, as compared with 44.9% of the children who received placebo (P<0.001). The difference between the groups was already apparent at the first scheduled visit (day 3), at which time 13.7% of the children who received amoxicillin–clavulanate, as compared with 25.3% of those who received placebo, had treatment failure. Over- all, amoxicillin–clavulanate reduced the progression to treatment failure by 62% (hazard ratio, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001) and the need for rescue treatment by 81% (6.8% vs. 33.5%; hazard ratio, 0.19; 95% CI, 0.10 to 0.36; P<0.001). Analgesic or antipyretic agents were given to 84.2% and 85.9% of the children in the amoxicillin–clavulanate and placebo groups, respectively. Adverse events were significantly more common in the amoxicillin–clavulanate group than in the placebo group. A total of 47.8% of the children in the amoxicillin–clavulanate group had diarrhea, as compared with 26.6% in the placebo group (P<0.001); 8.7% and 3.2% of the children in the respective groups had eczema (P = 0.04).
CONCLUSIONS
Children with acute otitis media benefit from antimicrobial treatment as compared
with placebo, although they have more side effects. Future studies should identify patients who may derive the greatest benefit, in order to minimize unnecessary antimicrobial treatment and the development of bacterial resistance. (Funded by the Foundation for Paediatric Research and others; ClinicalTrials.gov number, n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. Antimicrobial Treatment of Acute Otitis Media A cute otitis media is the most com- following acute inflammatory signs in the tym- mon bacterial infection during early child- panic membrane had to be present: distinct ery- hood.1 Antimicrobial agents have been the thematous patches or streaks or increased vascu- Comment on
primary treatment for this infection since the larity over full, bulging, or yellow tympanic this article at
1950s, when the first studies showed that anti- membrane. Third, the child had to have acute microbial therapy improved the outcome.2,3 Nev- symptoms, such as fever, ear pain, or respiratory ertheless, there is no consensus regarding the symptoms. A parent of each child provided written optimal management of acute otitis media.1 Be- informed consent. The protocol, which is available cause the treatment of acute otitis media is a ma- at NEJM.org, was approved by the ethics commit- jor reason for the use of antimicrobial agents in the tee of the Hospital District of Southwest Finland. outpatient setting, experts have called for these The authors vouch for the accuracy and com- agents to be used judiciously.4,5 Several guidelines pleteness of the reported data and the fidelity of for the management of acute otitis media recom- this report to the study protocol.
mend an observation period before antimicrobial therapy is even considered.6-10 These recommen- Study Design
dations are based largely on meta-analyses that This was a randomized, double-blind, placebo-con- concluded that for 1 child to have relief of symp- trolled study that was initiated by the investigators toms, 7 to 17 children must be treated with anti- and was conducted independently of any commer- microbial agents.11-15 However, some experts have cial entities. Our objective was to study the effi- suggested that the original studies included in the cacy of antimicrobial treatment with respect to the meta-analyses had important limitations, such as resolution of symptoms and signs of acute otitis biases in patient selection, varying diagnostic cri- media. The hypothesis was that amoxicillin–clavu- teria, and suboptimal spectrum or dosage of an- lanate would reduce the risk of treatment failure.
At the enrollment visit (day 1), the patient's We conducted a randomized, double-blind, symptoms, medical history, and demographic and placebo-controlled study of the efficacy of anti- clinical characteristics were recorded, a nasopha- microbial therapy in the age group with the high- ryngeal sample was obtained, and a clinical ex- est incidence of acute otitis media. Our aim was amination was performed that included thorough to assess the efficacy of antimicrobial treatment otoscopic and tympanometric examinations. De- for acute otitis media when strict diagnostic cri- tails of nasopharyngeal sampling, bacterial cultur- teria are used and the antimicrobial coverage and ing, analyses of resistance of the bacteria to anti- dosage of the active treatment are adequate.
microbial agents, and otoscopic examinations are provided in the Supplementary Appendix.
Eligible patients were randomly assigned to re- ceive amoxicillin–clavulanate (40 mg of amoxicil- Patients and Diagnostic Criteria
lin per kilogram of body weight per day plus Children 6 to 35 months of age with acute symp- 5.7 mg of clavulanate per kilogram per day, divid- toms were eligible for our diagnostic screening. A ed into two daily doses) or placebo for 7 days. The list of the exclusion criteria, along with descrip- placebo was similar to the active treatment in tions and explanations, is provided in the Supple- appearance and taste. (For a description of the mentary Appendix, available with the full text of study drugs, the randomization procedure, and the this article at NEJM.org. Children in whom acute procedure for concealment of study assignments, otitis media was diagnosed per protocol were eli- see the Supplementary Appendix.) Parents were gible for inclusion in the study. Three overall crite- given a diary and were asked to record symptoms, Videos showing
ria were required for the diagnosis of acute otitis doses of study drugs and any other medications, otoscopic signs of
media (see videos 1, 2, and 3). First, middle-ear absenteeism of the child from day care and of acute otitis media
fluid had to be detected by means of pneumatic the parent from work, and adverse events. Fever are available at
otoscopic examination that showed at least two was defined as a body temperature of 38°C or of the following tympanic-membrane findings: higher. We encouraged the use of analgesic and bulging position, decreased or absent mobility, antipyretic agents and allowed the use of anal- abnormal color or opacity not due to scarring, or gesic ear drops and decongestant nose drops or air–fluid interfaces. Second, at least one of the sprays.
n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. The first visit after the enrollment visit was The secondary outcomes, which were assessed scheduled for 2 days after the initiation of the by the study physician, were the time to the ini- study drug (day 3). The end-of-treatment visit was tiation of rescue treatment and the development scheduled for the day after the last dose of study of contralateral acute otitis media. Data on the drug was administered (i.e., on day 8). At that use of analgesic or antipyretic agents, absentee- visit, diaries and used and unused study-drug cap- ism of the child from day care and of the parent sules were returned, and adherence to the study from work, and the resolution of each symptom drug was estimated. Parents were told to contact were based on recordings in the diary. The treat- a study physician whenever they thought that their ment result, as of the end-of-treatment visit, was child's condition had not improved satisfactorily based on the parents' assessment of the child's or had worsened; an additional visit was arranged overall condition as reported to the study physi- on any day of the week. Whenever possible, the cian and on the otoscopic signs. Adverse events same study physician examined the patient at were ascertained from entries by the parents in consecutive visits. At each visit, the study physi- the diary and from reports by the study physicians cian first asked the parents for their assessment after they questioned the parents.
of their child's overall condition, which was re- corded as healthy, better, no improvement, or Statistical Analysis
worse. The child was then examined by the phy- We estimated that with 260 patients, the study sician. At any visit, the physician could switch from would have 90% power to detect an absolute re- the study drug to rescue treatment if the child's duction of 15 percentage points in the rate of overall condition or otoscopic signs warranted the treatment failure in the amoxicillin–clavulanate change (see the Supplementary Appendix). Parents group as compared with the placebo group, as- were encouraged to keep their children in the suming a 25% rate of treatment failure in the study for follow-up assessments even if they had placebo group, with a type I error of 0.05. We discontinued the study drug.
planned to enroll 320 patients to account for a possible 20% rate of withdrawal from the study.
The Kaplan–Meier method was used to analyze The primary outcome was the time to treatment time-to-event data with the use of the log-rank failure, which was a composite outcome consist- test; hazard ratios and confidence intervals were ing of six independent components: no improve- calculated on the basis of a Cox regression model. ment in overall condition by the first scheduled Categorical outcomes were compared with the use visit (day 3) (i.e., unless parents thought that their of the chi-square test. Student's t-test was used to child's overall condition was improving, the case compare means. Absolute percentage-point differ- was categorized as treatment failure), a worsening ences in rates and 95% confidence intervals are of the child's overall condition at any time, no provided.
improvement in otoscopic signs by the end-of- All analyses were performed on data from the treatment visit on day 8 (see videos 4 through 8), intention-to-treat population. All reported P val- perforation of the tympanic membrane at any ues are two-sided and have not been adjusted for time, severe infection (e.g., mastoiditis or pneu- multiple testing. All analyses were performed with monia) necessitating systemic open-label antimi- the use of SPSS software, version 16.0.
crobial treatment at any time, and any other rea- son for stopping the study drug (e.g., an adverse event or nonadherence to the study drug) at any time. The time of treatment failure was the study Study Patients
day on which the study physician confirmed any The intention-to-treat population comprised 319 one of the components for the first time. Several patients — 161 in the amoxicillin–clavulanate components could be confirmed concurrently, but group and 158 in the placebo group (Fig. 1 and this was not a requirement. The first two compo- Table 1). The rate of adherence to the study drug nents were based on the parents' assessment of was approximately 94% as assessed according their child's overall condition, including adverse to diary entries and approximately 99% as as- events (healthy, better, no improvement, or worse) sessed according to the amount of returned study as reported to the study physician; the other four drugs, with no significant differences between components were assessed by the study physician. the groups.
n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. Antimicrobial Treatment of Acute Otitis Media 6500 Children were in age-specific population 1062 Had parents who contacted us by telephone 316 Were excluded 124 Did not meet inclusion criteria 76 Met exclusion criteria48 Declined to participate68 Had other reasons 746 Participated in enrollment visits 424 Were excluded 387 Did not meet inclusion criteria (no acute otitis media) 26 Met exclusion criteria 8 Declined to participate3 Were unable to attend follow-up 322 Underwent randomization 162 Were assigned to receive amoxicillin–clavulanate 160 Were assigned to receive placebo 161 Received amoxicillin–clavulanate 159 Received placebo 1 Did not receive amoxicillin–clavulanate and 1 Did not receive placebo and did not come to any did not come to any follow-up visits 1 Withdrew on day 1 161 Were included in the analysis (1 was included 158 Were included in the analysis (1 was included until withdrawn by parent on day 3) until withdrawn by parent on day 3) Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients.
A detailed list of the reasons for exclusion of patients before randomization is provided in Figure 1 in the Supple-
mentary Appendix.
nate group and 25.3% in the placebo group had Treatment failure occurred in 30 of the 161 chil- treatment failure. The separation between the dren (18.6%) who received amoxicillin–clavulanate curves continued to widen during the subsequent and in 71 of the 158 children (44.9%) who received follow-up and peaked at the end-of-treatment visit placebo (P<0.001). The Kaplan–Meier analysis on day 8. Overall, amoxicillin–clavulanate reduced showed that a separation between the curves for the risk of treatment failure by 62% (hazard ratio, the two groups was already apparent at the first 0.38; 95% confidence interval [CI], 0.25 to 0.59; scheduled visit, on day 3 (Fig. 2A). At that time, P<0.001). To avoid treatment failure in 1 child, 13.7% of the children in the amoxicillin–clavula- 3.8 children (95% CI, 2.7 to 6.2) needed to be n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. Table 1. Selected Baseline Characteristics of the Intention-to-Treat Population.
Amoxicillin–Clavulanate Placebo Group
Group (N = 161)
Previous episodes of acute otitis media — no.
Time since previous episode of acute otitis media — mo* ≥1 dose of pneumococcal conjugate vaccine — no. (%) ≥1 dose of influenza vaccine — no. (%) ≥1 dose of Haemophilus influenzae type b vaccine — no. (%) Symptoms — no. (%) Highest measured temperature within the previous 24 hr <38°C: no fever Reported by parents Reported by child Respiratory symptoms Otoscopic signs at enrollment — no./total no. (%) Bilateral acute otitis media† Full or bulging tympanic membrane Pathogenic bacteria in nasopharyngeal sample — no./total no. (%) H. influenzae S. pyogenes * Data were missing for three patients in the amoxicillin–clavulanate group and two patients in the placebo group.
† Data were missing for two patients in the amoxicillin–clavulanate group and two patients in the placebo group, in whom an adequate view of the contralateral tympanic membrane was not possible owing to thick cerumen.
‡ All strains were susceptible to amoxicillin–clavulanate.
§ Strains with intermediate susceptibility to penicillin were detected in 18 samples in the amoxicillin-clavulanate group and 21 samples in the placebo group. In the amoxicillin–clavulanate group, one strain of S. pneumoniae was fully resis- tant to penicillin.
treated with amoxicillin–clavulanate. Each of termination of treatment failure was based on the six components of the primary outcome oc- overall condition in 27 children in the amoxicillin– curred less often in the amoxicillin–clavulanate clavulanate group and 48 in the placebo group; on group than in the placebo group (Fig. 3). The de- overall condition and otoscopic signs in 0 and n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. Antimicrobial Treatment of Acute Otitis Media 6 children in the two groups, respectively; on otoscopic signs in 2 and 15 children, respective- A Time to Treatment Failure
ly; and on any reason to stop the study drug in 1 and 2 children, respectively (Table 2 in the Sup- P<0.001 by log-rank test plementary Appendix). In a subgroup analysis, the treatment effect was similar in children with unilateral acute otitis media and in those with bilateral acute otitis media (Table 3 in the Sup- Secondary Outcomes
Rescue treatment was initiated in 11 of the 30
Patients with Treatment Failure (%)
children in the amoxicillin–clavulanate group (36.7%) and in 53 of the 71 children in the pla- Study Day
cebo group (74.6%) who had treatment failure No. at Risk
(P<0.001). The need for rescue treatment was de- creased by 81% with amoxicillin–clavulanate as compared with placebo (hazard ratio, 0.19; 95% B Time to Rescue Treatment
CI, 0.10 to 0.36; P<0.001) (Fig. 2B). Thus, rescue treatment was required in the case of 6.8% and P<0.001 by log-rank test 33.5% of all the children in the amoxicillin–clavu- lanate group and placebo group, respectively (Fig. 3, and Table 2 in the Supplementary Appendix).
Contralateral acute otitis media developed in 13 of the 159 children in the amoxicillin–clavu- lanate group (8.2%) and 29 of the 156 children in the placebo group (18.6%) for whom data were Patients Needing Rescue
available (P = 0.007) (Fig. 3). There was no signifi- cant between-group difference in the use of an- algesic or antipyretic agents (Fig. 3). Among the Study Day
children who received analgesic or antipyretic No. at Risk
agents, the mean duration of treatment was 3.6 days and 3.4 days in the amoxicillin–clavulanate and placebo groups, respectively (P = 0.45). Absen- Figure 2. Kaplan–Meier Curves for the Time to Treatment Failure
teeism from day care was reported for 107 of 672 and Rescue Treatment.
follow-up days (15.9%) among day-care attendees Kaplan–Meier curves are shown for the time to treatment failure (Panel A) in the amoxicillin–clavulanate group and for 144 and the time to rescue treatment (Panel B). The time to treatment failure, of 568 follow-up days (25.4%) among day-care which was the primary composite outcome, consisted of six independent attendees in the placebo group (a reduction of 9.4 components: no improvement in overall condition by the first scheduled percentage points with amoxicillin–clavulanate; visit (day 3); a worsening of the child's overall condition at any time; no im-provement in otoscopic signs by the end-of-treatment visit (day 8); perfora- 95% CI, −13.9 to −4.9; P<0.001). Parents of day- tion of the tympanic membrane at any time; severe infection necessitating care attendees in the amoxicillin–clavulanate open-label systemic antimicrobial treatment at any time; and any other rea- group missed significantly fewer workdays than son for stopping the study drug at any time. Only the first event in an indi- did parents of day-care attendees in the placebo vidual patient was included in the analysis of the primary outcome.
group (81 days [12.1%] vs. 101 days [17.8%], a reduction of 5.7 percentage points; 95% CI, −9.7 not improved or had worsened in 11 children to −1.8; P = 0.005).
(6.8%) in the amoxicillin–clavulanate group, as At the end-of-treatment visit, there was a sig- compared with 47 children (29.7%) in the placebo nificantly better treatment result with respect to group (22.9 percentage points less with amoxi- both overall condition and otoscopic signs with cillin–clavulanate; 95% CI, −31.4 to −14.4). Oto- amoxi cillin–clavulanate than with placebo (P<0.001 scopic signs had not improved or had worsened for both outcomes) (Fig. 4). Overall condition had in 8 children (5.0%) and 60 children (38.0%) in n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. Absolute Percentage-Point Difference (95% CI)
Primary Outcome
Treatment failure
−26.3 (−36.5 to −16.1) No improvement in overall condition by day 3 −6.5 (−13.2 to 0.3) Worsening of overall condition at any time −10.9 (−18.7 to −3.2) No improvement in otoscopic signs by day 8 −9.5 (−14.4 to −4.6) Perforation of tympanic membrane at any time −2.5 (−5.5 to 0.4) Severe infection at any time −1.3 (−3.0 to 0.5) Any reason to stop the study drug at any time −0.7 (−3.4 to 2.1) −26.7 (−35.5 to −17.9) Contralateral acute otitis media −10.4 (−17.9 to −2.9) Use of analgesic or antipyretic agents −1.7 (−9.6 to 6.2) −40 −30 −20 −10 Figure 3. Absolute Differences between the Amoxicillin–Clavulanate and Placebo Groups in Cumulative Rates of Primary and Secondary
Outcomes.
In the analysis of the primary outcome, a patient was counted only once, on the study day on which any one of the six independent com-
ponents of treatment failure was first confirmed. In a separate, secondary analysis of the cumulative incidence of each component of the
primary outcome, a patient could be included in more than one component category if the components were confirmed by the study
physician at the same time. For the secondary outcome of contralateral acute otitis media, data were missing for two children in each
group; for the outcome of use of analgesic or antipyretic agents, data were missing for three children in the amoxicillin–clavulanate
group and two children in the placebo group.
the amoxicillin–clavulanate and placebo groups, reported by parents, ear pain as reported by the respectively (a decrease of 33.0 percentage points children, ear rubbing, restless sleep, or excessive with amoxicillin–clavulanate; 95% CI, −42.0 to crying (Fig. 2 in the Supplementary Appendix).
−24.0). In 1 child (0.6%) in the amoxicillin–clavu- After the end of the study-treatment period, lanate group and 10 children (6.3%) in the pla- children who had received amoxicillin–clavulanate cebo group, both overall condition and oto- had less pathogenic bacteria in the nasopharynx scopic signs had worsened (a decrease of 5.7 than did children who had received placebo (Ta- percentage points with amoxicillin–clavulanate; ble 4 in the Supplementary Appendix). However, 95% CI, −9.7 to −1.7), whereas 13 children antimicrobial resistance was identified from the (8.1%) in the amoxicillin–clavulanate group and nasopharyngeal samples of one child in the amox- 4 (2.5%) in the placebo group were completely icillin–clavulanate group. On study days 1 and 8, healthy with respect to overall condition and we detected an isolate of Streptococcus pneumoniae otoscopic signs (an increase of 5.5 percentage that first showed intermediate resistance and later points with amoxicillin–clavulanate; 95% CI, 0.6 showed full resistance to penicillin.
Treatment with amoxicillin–clavulanate signifi- Adverse Events
cantly accelerated the resolution of fever, poor An adverse event occurred in 85 children (52.8%) appetite, decreased activity, and irritability. The in the amoxicillin–clavulanate group and in 57 effect of treatment on the resolution of fever was children (36.1%) in the placebo group (an increase already seen 6 hours after the first dose had been of 16.7 percentage points with amoxicillin–clavu- administered, and the effect on the resolution of lanate; 95% CI, 5.8 to 27.6; P = 0.003) (Table 2). the symptoms of poor appetite, decreased activ- There were no cases of mastoiditis. Two children in ity, and irritability was seen on the second study the placebo group had severe infection — one had day. There was no significant effect of amoxicil- pneumococcal bacteremia and the other had radio- lin–clavulanate on the resolution of ear pain as graphically confirmed pneumonia. The most com- n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. Antimicrobial Treatment of Acute Otitis Media A Overall Condition at End of Treatment
B Otoscopic Signs at End of Treatment
Completely resolved No. of Patients
No. of Patients
Figure 4. Child's Overall Condition and Otoscopic Signs at the End of Treatment.
The child's overall condition at the end-of-treatment visit (day 8), as compared with the first visit, was assessed by
the parents (Panel A). Otoscopic signs at the end-of-treatment visit (day 8), as compared with the first visit, were as-
sessed by a study physician (Panel B). In the case of children who either received rescue treatment (49 children) or
discontinued the study (2 children) before the end-of-treatment visit, the treatment result was carried forward from
that time to the end-of-treatment visit on day 8.
mon adverse event was diarrhea, which affected 77 Nonetheless, amoxicillin–clavulanate significant- children (47.8%) in the amoxicillin–clavulanate ly reduced two components — worsening of the group and 42 (26.6%) in the placebo group (an in- child's overall condition and lack of improvement crease of 21.2 percentage points with amoxicillin– in otoscopic signs — as well as the combined oc- clavulanate; 95% CI, 10.6 to 31.9). No watery or currence of perforations of the tympanic mem- bloody diarrhea was reported, and diarrhea did brane and severe infections.
not result in discontinuation of the study drug. Antimicrobial treatment had a more beneficial Eczema was significantly more common in the effect on acute otitis media in our study than in amoxicillin–clavulanate group than in the placebo previous randomized, double-blind, placebo-con- group. Children with severe infections and perfora- trolled studies.21-30 Previous studies have shown tions of the tympanic membrane were given rescue that the higher the failure rate is in the placebo treatment. All other adverse events resolved spon- group, the more antimicrobial treatment is shown taneously by the end-of-treatment visit (day 8), ex- to be superior. In a study by Kaleida et al.,26 cept in three children with diarrhea in each group failure rates in the placebo group were 8% and in one child in the placebo group in whom ex- among patients who were not severely ill and anthema developed on day 8 and lasted for 4 days. 24% among those who were severely ill, and the respective absolute differences in failure rates between the antimicrobial-therapy group and the placebo group were 4 percentage points and 12 Our study shows that amoxicillin–clavulanate is percentage points, respectively. In the placebo superior to placebo for the treatment of acute oti- group in our study, the failure rate was even tis media. The primary outcome, the time to higher — 44.9%, with a 26-percentage-point dif- treatment failure, incorporated six independent ference between the groups. The number needed components, including acute symptoms and oto- to treat for 1 child to benefit from antimicrobial scopic signs that are required for the diagnosis of therapy, as calculated on the basis of the results acute otitis media. Moreover, our composite out- of our study, is 3.8, as compared with 7 to 17 on come measured the net effect of the treatment, the basis of the meta-analyses.11-15,31,32 A marked because the assessment of the child's overall con- difference between the amoxicillin–clavulanate dition included adverse events. This study was not group and the placebo group was also seen in powered to assess the effect of treatment on each the need for rescue treatment. Rescue treatment component of the composite primary outcome. was initiated in the children receiving antimi- n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. or otoscopic signs. In addition, we used an ac- Table 2. Adverse Events.
tive treatment with adequate dosage and antimi- crobial coverage.
Clavulanate Group Placebo Group
The resolution of several symptoms was accel- erated with amoxicillin–clavulanate therapy, as compared with placebo. This was an unexpected Any adverse event finding, since most patients in both groups re- ceived analgesic or antipyretic agents, and it has been emphasized that symptoms often resolve spontaneously.33,34 Furthermore, although bac- teria can virtually always be found in the middle Pneumococcal bacteremia ear during an episode of acute otitis media,35,36 Radiographically confirmed the symptoms are not specific to acute otitis media but instead resemble those that are man- Complications of otitis media ifested during viral-type respiratory infections.37 Since we analyzed the treatment effect on symp- toms with a time-to-event approach, as suggested by some experts,38,39 we were able to observe that the effect of amoxicillin–clavulanate became apparent early. The earliest treatment effect was seen with respect to the resolution of fever. The rapid resolution of fever during the first day of antimicrobial treatment is well documented in the case of childhood pneumonia.40,41 In the current study, the effect of the treatment on other symp- toms was seen on the second study day. From the Non-itchy exanthema third study day onward, rescue treatment was initiated significantly more often in children in Diaper dermatitis the placebo group than in those in the amoxicil- * There were no cases of severe watery or bloody diarrhea.
lin–clavulanate group. As highlighted by Mygind † There were no cases of severe vomiting.
et al., assessment of the treatment effect on symp- toms should take into account the need for rescue crobial therapy in our study approximately as treatment for the most symptomatic patients.22 often as in previous studies.21,24,26-30 In contrast, Despite the tendency for symptoms to resolve a third of the children in the placebo group in spontaneously, which was also seen in our study, our study needed rescue treatment, as compared our results challenge the view that antimicrobial with an average of 12% in other studies. Our treatment of acute otitis media should be with- decision to provide rescue treatment for children held to see whether symptoms will resolve with- who had improvement in overall condition but no out such treatment.
improvement in otoscopic signs can be criticized. Since no symptom is specific to acute otitis Nonetheless, these children still had clinically media in children of preverbal age, it is also manifest acute otitis media after a 1-week obser- important to examine the treatment effect on vation period. Even when these children were ex- the site of the infection itself — namely, the cluded from the analysis, children in the placebo middle ear. At the end of treatment, otoscopic group needed rescue treatment significantly more signs had not improved or had worsened in often than did those in the amoxicillin–clavula- 5.0% and 38.0% of children in the amoxicillin– nate group. The greater beneficial effect of anti- clavulanate and placebo groups, respectively. microbial therapy in our study than in previous Whether these children were at risk for the per- studies results primarily from methodologic dif- sistent presence of fluid in the middle ear is a ferences. Only children who met stringent diag- question for further research. The results of this nostic criteria for acute otitis media were in- study are consistent with the results of our previ- cluded in our study, and we did not exclude ous study of acute otitis media with tympanos- patients according to the severity of symptoms tomy-tube otorrhea, which showed that antimi- n engl j med 364;2 nejm.org january 13, 2011 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on January 19, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. Antimicrobial Treatment of Acute Otitis Media crobial treatment rapidly ameliorated the infection cillin–clavulanate — is beneficial. Antimicrobial in the middle ear.42 treatment reduces the risk of treatment failure by From a different perspective, our results can improving both overall condition and otoscopic also be interpreted as showing that half the chil- signs.
dren in the placebo group did not have treatment Supported by the Fellowship Award of the European Society failure and two thirds did not need rescue treat- for Paediatric Infectious Diseases (to Dr. Ruohola) and by grants ment. These findings suggest that not all pa- from the Foundation for Paediatric Research; Research Funds from Specified Government Transfers; the Jenny and Antti Wi- tients with acute otitis media need antimicrobial huri Foundation; the Paulo Foundation; the Maud Kuistila Me- treatment. It will be important in the future to morial Foundation; the Emil Aaltonen Foundation; the Finnish characterize patients who do not need antimicro- Cultural Foundation, Varsinais-Suomi Regional Fund; the Turku University Hospital Research Foundation; and the Finnish–Nor- bial treatment. The identification of prognostic wegian Medical Foundation.
markers, together with the use of stringent diag- Disclosure forms provided by the authors are available with nostic criteria, could reduce the use of antimi- the full text of this article at NEJM.org.
We thank all the families who participated in this study and crobial agents in the treatment of acute otitis the staff at the health center of Turku and at the pediatric infec- media.14,43 Reduced use of antimicrobial agents tious disease ward at Turku University Hospital for their com- may limit the development of resistant bacteria mitment to the study; Raakel Luoto, M.D., Ph.D., and Elina Lah ti, M.D., Ph.D., for their help with data collection; study nurses and increase the chances that the subsequent use Sari Rajamäki, R.N., Maarit Rosenblad, R.N., and Kaisa Erk- of antimicrobial agents, when truly indicated, kilä, R.N., for their assistance in the study clinic; Laura Lind- would be beneficial.
holm, M.Sc., for her assistance with bacterial analyses; Maria Ruohola and Ulla Torkko for assistance with data handling; In conclusion, our study provides evidence that Tero Vahlberg, M.Sc., for his assistance with statistical analy- in children 6 to 35 months of age, the treatment ses; Cris Patricoski, M.D., for his advice regarding video otos- of acute otitis media with an antimicrobial agent copy equipment; and Tuomo Puhakka, M.D., Ph.D., for assess- ing digital images and videos of tympanic-membrane findings that gives adequate coverage — such as amoxi- in the study patients.
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Source: https://tracs.unc.edu/docs/bios_seminars/pastyear/Schwartz-NEJM_Article.pdf