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Original Studies

Delayed Versus Immediate Antimicrobial Treatment for Acute Otitis Media

Tähtinen, Paula A. MD; Laine, Miia K. MD; Ruuskanen, Olli MD, PhD; Ruohola, Aino MD, PhD

Author Information
The Pediatric Infectious Disease Journal: December 2012 - Volume 31 - Issue 12 - p 1227-1232
doi: 10.1097/INF.0b013e318266af2c

Abstract

Acute otitis media is the most common bacterial infection during early childhood.1 Several guidelines suggest initial observation for the management of acute otitis media with the option of delayed initiation of antimicrobial treatment if the child’s condition does not improve.2–7 Such watchful waiting has been regarded to be justified, as it reduces the use of antimicrobials,8–10 and several meta-analyses have highlighted the high tendency of spontaneous recovery from acute otitis media.11–17

Previous studies comparing delayed versus immediate initiation of antimicrobial treatment have focused on measuring reduction in antimicrobial use and parental satisfaction.8–10 Their conclusion was that watchful waiting may be an acceptable alternative to immediate antimicrobial treatment for some children. However, none of the previous studies analyzed the watchful waiting group participants who received antimicrobial treatment as a separate group to find out whether delayed initiation of antimicrobial treatment might worsen the treatment result. Instead, they compared the whole immediate antimicrobial treatment group with the whole watchful waiting group. Because two thirds of children in the watchful waiting groups did not receive antimicrobial treatment, the majority of children in these groups actually belonged to no antimicrobial treatment group instead of delayed antimicrobial treatment group.8–10

Our aim was to study whether delayed, as compared with immediate, initiation of antimicrobial treatment worsens the recovery from acute otitis media and whether the preceding watchful waiting period is associated with consequences. We used strict diagnostic criteria and antimicrobial agents with optimal dosage and coverage.

MATERIALS AND METHODS

Study Population

Children 6–35 months of age with acute symptoms were eligible for diagnostic screening. At the enrollment visit (day 1), the child’s symptoms and baseline characteristics were recorded, and a clinical examination, including thorough pneumatic otoscopic and tympanometric examinations, was performed. Three overall criteria were required for the diagnosis of acute otitis media. First, middle-ear fluid had to be detected by means of pneumatic otoscopic examination that showed at least 2 of the following tympanic membrane findings: bulging position, decreased or absent mobility, abnormal color or opacity not due to scarring or air-fluid interfaces. Second, at least 1 of the following acute inflammatory signs in the tympanic membrane had to be present: distinct erythematous patches or streaks or increased vascularity on a full, bulging or yellow tympanic membrane. Third, the child had to have acute symptoms (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/B285).

The study protocol was approved by the Ethics Committee of the Hospital District of Southwest Finland. Written informed consent was obtained from parents of all children before any study procedure was done. All visits were free of charge, and no compensation for participation was given.

Study Design

This was a prospective follow-up study. The study population consisted of children participating in the randomized, double-blind, placebo-controlled trial of the efficacy of antimicrobial treatment for acute otitis media (www.clinicaltrials.gov, identifier NCT00299455).18 We conducted the study at the primary care level and recruited the patients between March 2006 and December 2008 (excluding June and July each year).

At the enrollment visit, children with acute otitis media were randomized to receive either immediate antimicrobial treatment, amoxicillin-clavulanate (40/5.7 mg/kg/day, divided into 2 daily doses), or a placebo. The amoxicillin dose was based on the Finnish acute otitis media treatment guidelines. Details concerning the randomization procedure have been described previously.18 Parents were given a diary to record symptoms, doses of study drugs and any other medications, absenteeism of the child from day care and of the parent from work and adverse events. Fever was defined as a body temperature of 38°C or higher. We strongly encouraged the use of analgesic/antipyretic agents.

During the follow-up, families could contact and visit the study clinic 7 days a week from 8 AM to 8 PM if they felt their child’s overall condition was not improving or was worsening. All children had the first scheduled follow-up visit 48–72 hours after study entry. At all visits, the study physician first asked parents for their assessment of their child’s overall condition, which was recorded as healthy, better, no improvement or worse. Subsequently, a clinical examination, including pneumatic otoscopy examination, was performed. If the child’s overall condition had not improved satisfactorily or had worsened, delayed antimicrobial treatment could be initiated after individual consideration together with parents. Those children who managed well, continued with the study drug. For some children, delayed antimicrobial treatment was initiated more than 72 hours after study entry. These children had managed well during the first 72 hours, but their overall condition had subsequently worsened. The second scheduled visit was 1 day after the last dose of antimicrobial treatment. After this visit, all children had a visit on study day 16 (± 3 days).

The delayed antimicrobial treatment group consisted of placebo recipients to whom open antimicrobial treatment was initiated after watchful waiting period. Delayed antimicrobial treatment was amoxicillin-clavulanate (40/5.7 mg/kg/day, divided into 2 daily doses), for 7 days (see Fig., Supplemental Digital Content 2, https://links.lww.com/INF/B286). Delayed antimicrobial treatment was initiated after individual consideration, as in daily practice. Although the initial study drug was discontinued, the allocation of each participant was kept blinded until the completion of the whole trial.

The immediate antimicrobial treatment group consisted of children who were randomized to immediately receive amoxicillin-clavulanate (40/5.7 mg/kg/day, divided into 2 daily doses) for 7 days. Because the allocation was kept blinded, these children could also receive delayed antimicrobial treatment (see Fig., Supplemental Digital Content 2, https://links.lww.com/INF/B286). In the analyses, they remained in the immediate antimicrobial treatment group.

Outcomes

Our main outcome was improvement during antimicrobial treatment, that is, from the day when antimicrobial treatment (study drug or delayed antimicrobial treatment) was initiated to the day after the last dose of antimicrobial treatment. Clinical condition was defined as improved if both the child’s overall condition, as assessed by parents, and otoscopic signs, as assessed by the study physician, had improved during antimicrobial treatment. Clinical condition was not improved if the child’s overall condition and/or otoscopic signs had not improved at all or had worsened during antimicrobial treatment.

Other outcomes were assessed between study days 1 and 16: severe infections, time to be completely asymptomatic, time to completely normal otoscopic examination, time to resolution of individual symptoms, absenteeism from day care, parental absenteeism from work, analgesic/antipyretic agents use and adverse events. Time to be completely asymptomatic was defined as the first day after which all symptoms were absent. Time to completely normal otoscopic examination was defined as the day when the study physician observed that all otoscopic signs of otitis media were resolved including complete resolution of middle ear fluid. Individual symptoms were defined as resolved when they had not been present and marked in the symptom diary for 2 consecutive days. Data on the resolution of each symptom, absenteeism of the child from day care and of the parent from work and the use of analgesic/antipyretic agents, were based on diary entries.

Statistical Analysis

For categoric outcomes, absolute percentage-point differences in rates and 95% confidence intervals (CIs) were calculated. The main outcome was also compared by the Fischer exact test. Categoric outcomes were further analyzed by a logistic regression model including those baseline characteristics in which the absolute difference between the 2 groups was clinically meaningful, namely, exceeded 10% (ie, day-care attendance, parental smoking, bilateral acute otitis media and moderate/marked bulging of the tympanic membrane). The unadjusted and adjusted odds ratios and 95% CIs are provided.

Time-to-event data were analyzed using the Kaplan-Meier method with the log-rank test. Because of the high tendency of spontaneous resolution of symptoms, analyses included those patients who had the symptom recorded in the diary at least once during the first 48 hours. If the symptom was not resolved by day 16, data were censored on day 16, at the last follow-up visit, or, if the diary was missing, on the study day with last diary recordings available, whichever was the earliest. If another open antimicrobial treatment was initiated due to a new episode of acute otitis media, data were censored from that day forward. Means were compared by Student t test. All reported P values are 2-sided and were not adjusted for multiple testing. All analyses were performed with the use of SPSS software, version 16.0 (SPSS Inc., Chicago, IL).

RESULTS

Study Patients

The delayed antimicrobial treatment group comprised 53 children and the immediate antimicrobial treatment group 161 children (see Fig., Supplemental Digital Content 2, https://links.lww.com/INF/B286). Median watchful waiting period before the initiation of delayed antimicrobial treatment was 48 hours. Days for the initiation of delayed antimicrobial treatment as well as the prescribed agents are presented in Figure, Supplemental Digital Content 2, https://links.lww.com/INF/B286. Baseline characteristics are shown in Table, Supplemental Digital Content 1, https://links.lww.com/INF/B285.

Improvement During Antimicrobial Treatment

Improvement during antimicrobial treatment was observed in 48 of the 53 children (91%) in the delayed antimicrobial treatment group and in 155 of the 161 children (96%) in the immediate antimicrobial treatment group (P = 0.15; Table 1). The unadjusted odds ratio for improvement during antimicrobial treatment was 0.37 (95% CI: 0.11–1.27; P = 0.12) for the delayed antimicrobial treatment group, as compared with the immediate antimicrobial treatment group. Adjusted for baseline characteristics (day-care attendance, parental smoking, bilateral acute otitis media and moderate/marked bulging of the tympanic membrane), the odds ratio for improvement during antimicrobial treatment was 0.28 (95% CI: 0.08–1.05; P = 0.06) for the delayed antimicrobial treatment group, as compared with the immediate antimicrobial treatment group.

TABLE 1
TABLE 1:
Cumulative Rates of Patient-related Outcomes and Absolute Differences Between the Delayed and Immediate Antimicrobial Treatment Groups

Severe Infections

During the watchful waiting period, 1 child in the delayed antimicrobial treatment group developed blood-culture–verified pneumococcal bacteremia and another radiographically confirmed pneumonia (see Fig., Supplemental Digital Content 2, https://links.lww.com/INF/B286). At study entry, both children were afebrile, had good overall condition and unilateral acute otitis media.

Completely Asymptomatic

The Kaplan-Meier curves showed a tendency for children in the delayed antimicrobial treatment group to become asymptomatic later (days 1–8; P = 0.02 by log-rank test; Fig. 1A). However, from day 9 onward (when all children had received at least 1 dose of antimicrobial treatment) the curves approached each other, and the difference between the 2 groups was not statistically significant for the whole follow-up period (days 1–16; P = 0.18 by log-rank test). Altogether, 35 (66%) children in the delayed antimicrobial treatment group and 115 (71%) children in the immediate antimicrobial treatment group were completely asymptomatic by study day 16.

FIGURE 1
FIGURE 1:
Time to be completely asymptomatic and time to completely normal otoscopic examination from study day 1. The cumulative incidence curves are shown for the time to be completely asymptomatic (A) and the time to completely normal otoscopic examination (B). On x-axis, 1 denotes time of the first dose of study drug (immediate antimicrobial treatment or placebo).

Completely Normal Otoscopic Examination

The delayed initiation of antimicrobial treatment was associated with prolonged time to completely normal otoscopic examination (P = 0.04 by log-rank test; Fig. 1B). By study day 16, the otoscopic examination was completely normal in 19 (36%) and 81 (50%) children in the delayed and immediate antimicrobial treatment groups, respectively.

Resolution of Individual Symptoms

Delayed, as compared with immediate, initiation of antimicrobial treatment was associated with prolonged resolution of fever (median time to resolution 48 and 6 hours, respectively, P < 0.001 by log-rank test), ear pain as reported by parents (60 versus 24 hours, P = 0.04), poor appetite (84 versus 36 hours, P = 0.02) and decreased activity (60 versus 24 hours, P = 0.002; Fig. 2). In addition, ear pain as reported by children appeared to last longer in the delayed as compared with the immediate antimicrobial treatment group (60 versus 18 hours, P = 0.15), but the difference did not reach statistical significance because only a few children could express themselves verbally. No significant differences were found for ear rubbing (36 versus 48 hours, P = 0.43), irritability (60 versus 36 hours, P = 0.62), restless sleep (60 versus 36 hours, P = 0.09) or excessive crying (60 versus 48 hours, P = 0.45; Fig. 2). All the differences between the groups appeared to be due to the watchful waiting period, because when comparing the resolution of symptoms during antimicrobial treatment (ie, from the initiation day of antimicrobial treatment to 1 day after the last dose of antimicrobial treatment), there were no statistically significant differences between the groups (data not shown).

FIGURE 2
FIGURE 2:
Resolution of individual symptoms from study day 1. Kaplan-Meier curves show the resolution of individual symptoms. Symptoms were recorded in diary every 6 hours (day 1), 12 hours (days 2–7) and 24 hours (days 8–16). On x-axis, 1 denotes time of the first dose of study drug (immediate antimicrobial treatment or placebo).

Absenteeism From Day Care and Work

Absenteeism from day care and parental absenteeism from work tended to be more common among day-care attendees in the delayed antimicrobial treatment group as compared with the immediate antimicrobial treatment group (Table 1). Among day-care attendees, the mean number of days of absenteeism from day care was 3.3 and 1.8 in the delayed and immediate antimicrobial treatment groups, respectively (P < 0.001). Due to the watchful waiting period, parents of day-care attendees in the delayed antimicrobial treatment group missed more work days than parents whose child received antimicrobial treatment immediately (mean number of days 2.1 versus 1.2, P = 0.03).

Analgesic/Antipyretic Agents

In both groups, approximately 90% of children used oral analgesic/antipyretic agents (Table 1). The mean number of days of usage was 5.2 and 4.0 in the delayed and immediate antimicrobial treatment groups, respectively (P = 0.01). The mean number of doses used was 1.9 doses per day in both groups.

Adverse Events

Adverse events between study days 1 and 16 were equally common in the delayed, as compared with the immediate, antimicrobial treatment groups. Diarrhea occurred in 23 (43%) and 81 (50%), vomiting in 11 (21%) and 25 (16%) and rash in 8 (15%) and 19 (12%) of the 53 and 161 children in the delayed and immediate antimicrobial treatment groups, respectively. No watery or bloody diarrhea occurred, and diarrhea did not result in cessation of study drug in any case.

DISCUSSION

Our results indicate that delayed, as compared with immediate, initiation of antimicrobial treatment does not worsen the recovery from acute otitis media, because improvement during antimicrobial treatment was similar in both groups. It is notable that, although the overall condition of children in the delayed antimicrobial treatment group might have worsened during the watchful waiting period, virtually all children recovered well after the initiation of antimicrobial treatment. Thus, the watchful waiting period does not seem to worsen the benefits of antimicrobial treatment for the management of acute otitis media. This is important information for practicing physicians who have been advised by guidelines to use the watchful waiting approach. This approach, together with adequate symptomatic medication, seems to be an acceptable alternative for the management of acute otitis media. However, as previously pointed out, delaying times should be adjusted according to the length and the severity of prior symptoms.19

Unfortunately, the watchful waiting period may cause consequences for the child, family and society. In our study, 2 of 53 children in the delayed antimicrobial treatment group developed severe infections. Similarly, in other acute otitis media studies, severe infections have mainly developed in children not receiving antimicrobials.20–23 The fact that the resolution of middle ear fluid occurred later in the delayed than in the immediate antimicrobial treatment group is important for children with recurrent episodes of otitis media and thus at risk of developing prolonged otitis media with effusion during the intervals. Immediate antimicrobial treatment might result in resolution of middle ear fluid between the episodes that would change their diagnosis from chronic otitis media with effusion to recurrent acute otitis media, and thus, improve prognosis and reduce tympanostomy tube insertions. Of previous studies, only McCormick et al9 evaluated the treatment result on the site of the infection itself, namely, the middle ear. Their results are in line with ours: watchful waiting prolongs the recovery of infection in the middle ear. In addition, Little et al8 and McCormick et al9 reported that symptoms lasted longer in the watchful waiting group, as compared with the immediate antimicrobial treatment group. We got similar results: delayed initiation of antimicrobial treatment seems to be associated with prolonged resolution of symptoms. In particular, the consequences of prolonged fever should not be dismissed. Prolongation of fever by 2 days is significant for the family, as fever causes anxiety and parental absenteeism from work. In our study, parents of children in the delayed antimicrobial treatment group missed an average of 1 work day more than parents of children in the immediate antimicrobial treatment group. This difference may seem small, but when multiplied with the 9 million annual episodes of acute otitis media diagnosed in the United States,15,24 it could be discussed that the difference in the absenteeism might actually be the most important economic consequence related to the delayed initiation of antimicrobial treatment. According to the Occupational Employment Statistics for 2010, the mean wage for an 8-hour work day in the United States is $170.25 Therefore, costs of 1-day absence from work would exceed 1.5 billion dollars in the United States every year. Our results, together with the Cochrane authors, emphasize the need to identify those children whose antimicrobial treatment should not be delayed.16

This study has obvious limitations. First, this was a subanalysis of our randomized, placebo-controlled trial of antimicrobial treatment for acute otitis media. Therefore, our results can show only associations, not causal effects. It is also possible that our sample size was underpowered to detect differences between the 2 groups. However, this subanalysis was preplanned and as a result, both study groups received equal antimicrobial treatment with optimal antimicrobial coverage. Second, this subanalysis was not blinded for the delayed antimicrobial treatment agent because delayed antimicrobial treatment was provided openly. This may have resulted in ascertainment biases by parents and study personnel. On the other hand, when the initiation of delayed antimicrobial treatment was considered, parents and study personnel did not know whether the child had received antimicrobial treatment or placebo because the allocation of each participant was kept blinded until the completion of the whole trial. The placebo was similar to the active treatment in appearance and taste. Third, although our study groups had similar symptoms at baseline, the delayed antimicrobial treatment group may have been more ill than the immediate antimicrobial treatment group when the antimicrobial treatment was initiated. This is logical because the reason for delayed antimicrobial treatment after watchful waiting period is nonimprovement or worsening of overall condition. In effect, our study groups represent well the 2 alternatives in daily practice: antimicrobials can be provided either immediately to all children regardless of illness severity or alternatively after watchful waiting period to children whose condition does not improve. It is to be noted that, in our study, the access to delayed antimicrobial treatment was as easy as by providing safety-net antimicrobial prescription because parents could contact and visit our study clinic from dawn to dusk on any day. Finally, our results cannot be generalized to older children because most of the children were less than 2 years of age. On the other hand, our study patients represent the age group with the highest incidence of acute otitis media, and in several countries, watchful waiting is suggested for this age group also.2,4–7

As the rationale behind the watchful waiting approach has been the priority of reducing the use of antimicrobials, it could be asked whether the reduction might be achieved the other way round. Currently, the recommended duration of antimicrobial treatment for acute otitis media is 10 days in the United States.3 We recently showed that treatment response is evident within 5 days of the initiation of antimicrobial treatment.18 If immediate antimicrobial treatment is reserved for strict diagnoses of acute otitis media and the treatment is ceased when the response is evident, the use of antimicrobials would be substantially reduced. Furthermore, this would save all parties from dilemmas related to watchful waiting.

The importance of this study is that the results are directly applicable in clinical decision making. Our results provide new information regarding the delayed initiation of antimicrobial treatment for acute otitis media because we investigated only those children who had received antimicrobials whereas the previous studies had investigated the watchful waiting group as such, thus grouping together children receiving delayed antimicrobials and those recovering well without antimicrobials.8–10 It appears that, although a reduction in the use of antimicrobials is an important goal, it should not be achieved at the expense of the child and family. Acute otitis media is a common infection that interferes with the family’s daily routine. Our results highlight the importance of making treatment decisions individually. Practicing physicians should take into account the severity of symptoms and otoscopic signs, history of otitis media and the overall situation of the family when considering whether a delay in antimicrobial treatment is in the best interest of the child.

ACKNOWLEDGMENTS

The authors thank all the families who participated in this study and the staff at the health center of Turku for their commitment to the study; Raakel Luoto, MD, PhD, and Elina Lahti, MD, PhD, for their contribution to data collection; study nurses Sari Rajamäki, RN, Maarit Rosenblad, RN, and Kaisa Erkkilä, RN, for their assistance in the study clinic; Maria Ruohola and Ulla Torkko for assistance with data handling, and Tero Vahlberg, MSc, for his assistance with statistical analyses.

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Keywords:

otitis media; treatment; watchful waiting; infant; child/preschool

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