Clinical Review & Education
From The JAMA Network
Antibiotics for Acute Otitis Media Yes or No Michael E. Pichichero, MD
JAMA PEDIATRICS Effect of Antimicrobial Treatment of Acute Otitis Media on the Daily Disappearance of Middle Ear Effusion: A Placebo-Controlled Trial Terhi Tapiainen, MD, PhD; Tiia Kujala, MD; Marjo Renko, MD; Petri Koivunen, MD; Tero Kontiokari, MD, PhD; Aila Kristo, MD, PhD; Tytti Pokka, MSc; Olli-Pekka Alho, MD; Matti Uhari, MD, PhD IMPORTANCE Antimicrobial treatment reduces the symptoms
of acute otitis media (AOM). The effect of antimicrobial treatment on the duration of middle ear effusion (MEE) and concomitant hearing impairment is not known. OBJECTIVE To determine whether the antimicrobial treatment
of AOM reduces the duration of MEE. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled trial involved a total of 84 children with AOM between 6 months and 15 years of age. Participants were recruited from September 14, 1999, to January 4, 2000; October 10, 2005, to December 16, 2005; and September 22, 2009, to June 4, 2012, from among children attending an AOM prevention trial and children visiting local outpatient clinics in Oulu, Finland. INTERVENTIONS Children were randomly allocated to receive either 40 mg/kg of amoxicillin-clavulanate or a placebo mixture per day for 7 days.
Patients, their families, and their physicians may have different perspectives about the risks and benefits of treatment options for children’s middle ear infections.1 For instance, patients and their family members may favor aggressive use of antibiotics to treat otitis media, hoping to alleviate pain and discomfort as quickly as possible. In contrast, pediatricians and other physicians must remain cognizant of public health issues related to the overuse of antibiotics. There is no doubt antibiotics have been overused since their introduction decades ago. Nevertheless, the allure of antibiotics is powerful because they can save lives, cure illness, and hasten recovery from common maladies like middle ear infections. The pendulum of medical opinion often swings back and forth until sufficient evidence accumulates to establish widespread acceptance of a management approach for a specific illness. This has certainly been the case for the use of antibiotics for 294
MAIN OUTCOMES AND MEASURES The primary outcome measure was the time to the disappearance of MEE as defined by a normal tympanogram finding (A curve) from both ears on 2 consecutive measurement days. Parents performed daily tympanometry at home. The study physician performed tympanometry and otoscopy at study entry, after 3 and 7 days, and then weekly until both ears were healthy. The main secondary outcome measures were the time to normal otoscopy findings and the proportion of children without persistent MEE at 14 days and 2 months. RESULTS Middle ear effusion disappeared 2.0 weeks (13.7 days) earlier (P = .02) in the antimicrobial group (mean time, 2.7 weeks; 95% CI, 1.7-3.7) than in the placebo group (4.7 weeks; 95% CI, 3.6-5.7). Normal otoscopy findings were observed 1.4 weeks sooner in the antimicrobial group than in the placebo group (P = .02). On day 14, 69% of children in the antimicrobial group and 38% in the placebo group had normal tympanometry findings (number needed to treat, 3.2; 95% CI, 2.0-10.5). On day 60, 2 children (5%) in the antimicrobial group and 10 children (24%) in the placebo group had persistent MEE (P = .01). CONCLUSIONS AND RELEVANCE Antimicrobial treatment effectively reduced the duration of MEE and possible concomitant hearing impairment in children with AOM. Antimicrobial treatment also reduced the risk for persistent MEE.
JAMA Pediatr. 2014;168(7):635-641. doi:10.1001/jamapediatrics.2013.5311.
the treatment of acute otitis media (AOM). Recent recommendations by the American Academy of Pediatrics advocate watchful waiting as an alternative to antibiotic prescription for AOM in selected patients.2 However, this approach could be challenged by publication of a randomized clinical trial in the July 2014 issue of JAMA Pediatrics.3 In a randomized, double-blind, placebo-controlled, parallelgroup trial of 84 children aged between 6 months and 15 years, Tapiainen et al3 assessed the time to disappearance of middle ear fluid (MEF) from behind the tympanic membrane in children who received antibiotic (n = 42) or placebo (n = 42). The primary outcome evaluated was the time to disappearance of the fluid based on daily tympanometer readings accomplished by the parents at home and time to normal otoscopy as determined by the investigators. As measured by patient-administered tympanometry,
JAMA January 20, 2015 Volume 313, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/23/2015
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From The JAMA Network Clinical Review & Education
children treated with antibiotic had earlier resolution of MEF (2.7 weeks [95% CI, 1.7-3.7] of MEF for the antibiotic group vs 4.7 weeks [95% CI, 3.6-5.7] for the placebo group; P = .02). These findings were confirmed by physician-performed otoscopy in which normal otoscopy findings were found about 10 days sooner in the antibiotic group compared with the placebo group (P = .02). The statistically significant differences in duration of persistent MEF were sustained throughout the follow-up time frame of 2 months. Children who received antibiotic also experienced a shorter duration of earache. These benefits are experienced if antibiotics are given to 3 children in order to benefit 1 child. These benefits were offset, in part, by a 12% diarrhea rate in children treated with antibiotic (n = 5), compared with none of the placebo group children experiencing diarrhea. The study published in JAMA Pediatrics3 is consistent with others finding the beneficial effects of antibiotics in children with AOM.4,5 Less immediate benefits of treated AOM relate to children with MEF experiencing some hearing loss, potentially not acquiring language skills very well while the fluid is present, and generally feeling quite uncomfortable when they have MEF. Adults experience discomfort related to MEF when airplane cabins are pressurized or depressurized. When this occurs, infants often cry and adults wince. The study by Tapiainen et al3 is limited because the population studied was not completely representative of the usual pediatric patients who present with AOM. There were a disproportionate number of children older than the age at which AOM typically occurs and relatively few children in the peak AOM age group of 6 to 24 months. This study has an issue with generalizability because only about 20% of the enrolled patients were in the typical age range for AOM. Daily tympanometry readings taken by parents at home must have been challenging and likely required ARTICLE INFORMATION Author Affiliation: Rochester General Hospital Research Institute, Rochester, New York. Corresponding Author: Michael E. Pichichero, MD, Rochester General Hospital Research Institute, 1425 Portland Ave, Rochester, NY 14621 (michael [email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Pichichero ME. Changing the treatment paradigm for acute otitis media in children. JAMA. 1998;279(21):1748-1750.
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highly motivated parents. Tympanometry measurement is difficult in younger children, even in experienced professional hands. Second, tympanometry measures the movement of the tympanic membrane in response to positive and negative pressure after a seal with the external ear canal is established. Decreased movement of the tympanic membrane occurs from middle ear effusion or because the membrane is stiff, often from prior infections. Therefore, tympanometry has limited sensitivity and specificity compared with pneumatic otoscopy and tympanocentesis.6 Consequently, Tapiainen et al3 could not be certain that the tympanometer measurements reflected middle ear effusion and associated temporary hearing impairment. Complimentary readings using acoustic reflectometry would have been beneficial.6 Tapiainen et al3 acknowledged that the findings contradicted several randomized clinical trials and 2 meta-analyses that found no effect of antibiotic treatment on the duration of MEF persistence. One explanation for the differences might be that the randomized trials included patients whose diagnosis of AOM was uncertain.7 Inclusion of children without AOM in clinical trials, as likely occurred in many previous studies, diluted and masked the true effects of antibiotic treatment on faster resolution of MEF. The study by Tapiainen et al3 and 2 others4,5 that had stringent diagnostic criteria (and all clinicians making the diagnosis were highly skilled) show beneficial effects of antibiotic treatment of AOM for children and their parents. These findings supported a recent US Food and Drug Administration panel’s decision that the evidence in favor of the beneficial effects of antibiotics on AOM is clear and that further trials are not needed.8 Although the benefits of antibiotics in AOM are clear, those benefits rely on an accurate diagnosis of the disease. Indiscriminant use of antibiotics for children who do not have AOM could be harmful from a public health perspective.
2. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media [published correction appears in Pediatrics. 2014;133(2):346]. Pediatrics. 2013;131(3):e964-e999. 3. Tapiainen T, Kujala T, Renko M, et al. Effect of antimicrobial treatment of acute otitis media on the daily disappearance of middle ear effusion: a placebo-controlled trial. JAMA Pediatr. 2014;168 (7):635-641. 4. Hoberman A, Paradise JL, Rockette HE, et al. Treatment of acute otitis media in children under 2 years of age. N Engl J Med. 2011;364(2):105-115. 5. Tähtinen PA, Laine MK, Huovinen P, Jalava J, Ruuskanen O, Ruohola A. A placebo-controlled trial of antimicrobial treatment for acute otitis media. N Engl J Med. 2011;364(2):116-126.
6. Puhakka T, Pulkkinen J, Silvennoinen H, Heikkinen T. Comparison of spectral gradient acoustic reflectometry and tympanometry for detection of middle-ear effusion in children. Pediatr Infect Dis J. 2014;33(8):e183-e186. 7. Pichichero ME, Casey JR. Comparison of study designs for acute otitis media trials. Int J Pediatr Otorhinolaryngol. 2008;72(6):737-750. 8. Issues in the design of clinical trials for systemic antibacterial drugs for the treatment of acute otitis media. Workshop sponsored by the Food and Drug Administration; Silver Spring, MD; September 7, 2011.
(Reprinted) JAMA January 20, 2015 Volume 313, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/23/2015
295
From The JAMA Network
Antibiotics for Acute Otitis Media Yes or No Michael E. Pichichero, MD
JAMA PEDIATRICS Effect of Antimicrobial Treatment of Acute Otitis Media on the Daily Disappearance of Middle Ear Effusion: A Placebo-Controlled Trial Terhi Tapiainen, MD, PhD; Tiia Kujala, MD; Marjo Renko, MD; Petri Koivunen, MD; Tero Kontiokari, MD, PhD; Aila Kristo, MD, PhD; Tytti Pokka, MSc; Olli-Pekka Alho, MD; Matti Uhari, MD, PhD IMPORTANCE Antimicrobial treatment reduces the symptoms
of acute otitis media (AOM). The effect of antimicrobial treatment on the duration of middle ear effusion (MEE) and concomitant hearing impairment is not known. OBJECTIVE To determine whether the antimicrobial treatment
of AOM reduces the duration of MEE. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled trial involved a total of 84 children with AOM between 6 months and 15 years of age. Participants were recruited from September 14, 1999, to January 4, 2000; October 10, 2005, to December 16, 2005; and September 22, 2009, to June 4, 2012, from among children attending an AOM prevention trial and children visiting local outpatient clinics in Oulu, Finland. INTERVENTIONS Children were randomly allocated to receive either 40 mg/kg of amoxicillin-clavulanate or a placebo mixture per day for 7 days.
Patients, their families, and their physicians may have different perspectives about the risks and benefits of treatment options for children’s middle ear infections.1 For instance, patients and their family members may favor aggressive use of antibiotics to treat otitis media, hoping to alleviate pain and discomfort as quickly as possible. In contrast, pediatricians and other physicians must remain cognizant of public health issues related to the overuse of antibiotics. There is no doubt antibiotics have been overused since their introduction decades ago. Nevertheless, the allure of antibiotics is powerful because they can save lives, cure illness, and hasten recovery from common maladies like middle ear infections. The pendulum of medical opinion often swings back and forth until sufficient evidence accumulates to establish widespread acceptance of a management approach for a specific illness. This has certainly been the case for the use of antibiotics for 294
MAIN OUTCOMES AND MEASURES The primary outcome measure was the time to the disappearance of MEE as defined by a normal tympanogram finding (A curve) from both ears on 2 consecutive measurement days. Parents performed daily tympanometry at home. The study physician performed tympanometry and otoscopy at study entry, after 3 and 7 days, and then weekly until both ears were healthy. The main secondary outcome measures were the time to normal otoscopy findings and the proportion of children without persistent MEE at 14 days and 2 months. RESULTS Middle ear effusion disappeared 2.0 weeks (13.7 days) earlier (P = .02) in the antimicrobial group (mean time, 2.7 weeks; 95% CI, 1.7-3.7) than in the placebo group (4.7 weeks; 95% CI, 3.6-5.7). Normal otoscopy findings were observed 1.4 weeks sooner in the antimicrobial group than in the placebo group (P = .02). On day 14, 69% of children in the antimicrobial group and 38% in the placebo group had normal tympanometry findings (number needed to treat, 3.2; 95% CI, 2.0-10.5). On day 60, 2 children (5%) in the antimicrobial group and 10 children (24%) in the placebo group had persistent MEE (P = .01). CONCLUSIONS AND RELEVANCE Antimicrobial treatment effectively reduced the duration of MEE and possible concomitant hearing impairment in children with AOM. Antimicrobial treatment also reduced the risk for persistent MEE.
JAMA Pediatr. 2014;168(7):635-641. doi:10.1001/jamapediatrics.2013.5311.
the treatment of acute otitis media (AOM). Recent recommendations by the American Academy of Pediatrics advocate watchful waiting as an alternative to antibiotic prescription for AOM in selected patients.2 However, this approach could be challenged by publication of a randomized clinical trial in the July 2014 issue of JAMA Pediatrics.3 In a randomized, double-blind, placebo-controlled, parallelgroup trial of 84 children aged between 6 months and 15 years, Tapiainen et al3 assessed the time to disappearance of middle ear fluid (MEF) from behind the tympanic membrane in children who received antibiotic (n = 42) or placebo (n = 42). The primary outcome evaluated was the time to disappearance of the fluid based on daily tympanometer readings accomplished by the parents at home and time to normal otoscopy as determined by the investigators. As measured by patient-administered tympanometry,
JAMA January 20, 2015 Volume 313, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/23/2015
jama.com
From The JAMA Network Clinical Review & Education
children treated with antibiotic had earlier resolution of MEF (2.7 weeks [95% CI, 1.7-3.7] of MEF for the antibiotic group vs 4.7 weeks [95% CI, 3.6-5.7] for the placebo group; P = .02). These findings were confirmed by physician-performed otoscopy in which normal otoscopy findings were found about 10 days sooner in the antibiotic group compared with the placebo group (P = .02). The statistically significant differences in duration of persistent MEF were sustained throughout the follow-up time frame of 2 months. Children who received antibiotic also experienced a shorter duration of earache. These benefits are experienced if antibiotics are given to 3 children in order to benefit 1 child. These benefits were offset, in part, by a 12% diarrhea rate in children treated with antibiotic (n = 5), compared with none of the placebo group children experiencing diarrhea. The study published in JAMA Pediatrics3 is consistent with others finding the beneficial effects of antibiotics in children with AOM.4,5 Less immediate benefits of treated AOM relate to children with MEF experiencing some hearing loss, potentially not acquiring language skills very well while the fluid is present, and generally feeling quite uncomfortable when they have MEF. Adults experience discomfort related to MEF when airplane cabins are pressurized or depressurized. When this occurs, infants often cry and adults wince. The study by Tapiainen et al3 is limited because the population studied was not completely representative of the usual pediatric patients who present with AOM. There were a disproportionate number of children older than the age at which AOM typically occurs and relatively few children in the peak AOM age group of 6 to 24 months. This study has an issue with generalizability because only about 20% of the enrolled patients were in the typical age range for AOM. Daily tympanometry readings taken by parents at home must have been challenging and likely required ARTICLE INFORMATION Author Affiliation: Rochester General Hospital Research Institute, Rochester, New York. Corresponding Author: Michael E. Pichichero, MD, Rochester General Hospital Research Institute, 1425 Portland Ave, Rochester, NY 14621 (michael [email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Pichichero ME. Changing the treatment paradigm for acute otitis media in children. JAMA. 1998;279(21):1748-1750.
jama.com
highly motivated parents. Tympanometry measurement is difficult in younger children, even in experienced professional hands. Second, tympanometry measures the movement of the tympanic membrane in response to positive and negative pressure after a seal with the external ear canal is established. Decreased movement of the tympanic membrane occurs from middle ear effusion or because the membrane is stiff, often from prior infections. Therefore, tympanometry has limited sensitivity and specificity compared with pneumatic otoscopy and tympanocentesis.6 Consequently, Tapiainen et al3 could not be certain that the tympanometer measurements reflected middle ear effusion and associated temporary hearing impairment. Complimentary readings using acoustic reflectometry would have been beneficial.6 Tapiainen et al3 acknowledged that the findings contradicted several randomized clinical trials and 2 meta-analyses that found no effect of antibiotic treatment on the duration of MEF persistence. One explanation for the differences might be that the randomized trials included patients whose diagnosis of AOM was uncertain.7 Inclusion of children without AOM in clinical trials, as likely occurred in many previous studies, diluted and masked the true effects of antibiotic treatment on faster resolution of MEF. The study by Tapiainen et al3 and 2 others4,5 that had stringent diagnostic criteria (and all clinicians making the diagnosis were highly skilled) show beneficial effects of antibiotic treatment of AOM for children and their parents. These findings supported a recent US Food and Drug Administration panel’s decision that the evidence in favor of the beneficial effects of antibiotics on AOM is clear and that further trials are not needed.8 Although the benefits of antibiotics in AOM are clear, those benefits rely on an accurate diagnosis of the disease. Indiscriminant use of antibiotics for children who do not have AOM could be harmful from a public health perspective.
2. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media [published correction appears in Pediatrics. 2014;133(2):346]. Pediatrics. 2013;131(3):e964-e999. 3. Tapiainen T, Kujala T, Renko M, et al. Effect of antimicrobial treatment of acute otitis media on the daily disappearance of middle ear effusion: a placebo-controlled trial. JAMA Pediatr. 2014;168 (7):635-641. 4. Hoberman A, Paradise JL, Rockette HE, et al. Treatment of acute otitis media in children under 2 years of age. N Engl J Med. 2011;364(2):105-115. 5. Tähtinen PA, Laine MK, Huovinen P, Jalava J, Ruuskanen O, Ruohola A. A placebo-controlled trial of antimicrobial treatment for acute otitis media. N Engl J Med. 2011;364(2):116-126.
6. Puhakka T, Pulkkinen J, Silvennoinen H, Heikkinen T. Comparison of spectral gradient acoustic reflectometry and tympanometry for detection of middle-ear effusion in children. Pediatr Infect Dis J. 2014;33(8):e183-e186. 7. Pichichero ME, Casey JR. Comparison of study designs for acute otitis media trials. Int J Pediatr Otorhinolaryngol. 2008;72(6):737-750. 8. Issues in the design of clinical trials for systemic antibacterial drugs for the treatment of acute otitis media. Workshop sponsored by the Food and Drug Administration; Silver Spring, MD; September 7, 2011.
(Reprinted) JAMA January 20, 2015 Volume 313, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/23/2015
295
