Children's Ears & Antibiotics: Gold Mine for Pharmaceutical Companies, Land Mine for Children
This report was first released in June 1994, and was updated in August 1994 to reflect the information published in the final version of the Agency for Health Care Policy and Research Guidelines, "Otitis Media with Effusion in Young Children." August 1994, Revised Edition.
Why This Matters
Although two government investigations have found Dr. Bluestone’s evidence to be unduly representative of drug companies’ interests and unbalanced in determining the efficacy of antibiotics in treating ear infections, a branch of the Department of Health and Human Services released federal guidelines supporting Bluestone’s research. The guidelines were not only used by HMO’s and insurance companies for years to determine appropriate treatment, but also by pediatricians. The scope of this problem is considerable: in 1990, 24.5 million patients saw their doctor primarily for ear infections, and drugs were ordered 29 million times. While some experts believe that there is virtually nothing to gain from prescribing antibiotics, there is much to lose. The widespread use of antibiotic treatment has added to the creation of antibiotic resistant organisms. Additionally, this case reflects the bigger issue of mixing public and private funds for medical research without appropriate disclosure.
In 1994, when POGO released this report, we were successful in persuading the federal government to change its policies from recommending the use of antibiotics to also recommending “watchful waiting” as a reasonable alternative. In 2004, the federal government finally reversed its position, the government is finally discouraging the use of antibiotics for treatment of childrens ear infections - but not before the pharmaceutical industry made $4 billion from producing and selling these drugs.
Table of Contents
The Otitis Media Research Center Studies
Reevaluation of the Studies
Background on Otitis Media
The Agency for Health Care Policy and Research Guidelines
The Risks to Children
International Responses to Treating Otitis Media
Acute Otitis Media in the United States
"The Cantekin Affair"
Public Policy Impact
The federal government has just approved treatment for a common childhood illness which is not justified by the evidence, but will benefit pharmaceutical companies and will increase the risk of developing antibiotic-resistant bacteria. The research used to justify the use of
antibiotic therapy to treat fluid in children's middle ears, or otitis media with effusion (OME) was funded both by pharmaceutical companies as well as by the federal government. That research had already been found by two government investigations to represent unduly drug companies' interests and to be slanted in its conclusions that antibiotics were effective in resolving OME.
The current emphasis on antibiotic therapy has an enormous impact, as otitis media (including both OME and acute otitis media -- AOM) is the most common diagnosis by physicians for children under fifteen; middle ear fluid is the principal diagnosis between 20% - 35% of the time; and according to the Centers for Disease Control antibiotics are prescribed for fluid in the middle ear 99% of the time. This case is illustrative of the growing problem caused by the general overuse of antibiotics -- the creation of so-called antibiotic-resistant "superbugs."
This report details our evidence that the conclusions drawn from the studies evaluating the efficacy of antibiotics on pediatric OME did not reflect the data. The late Rep. Ted Weiss conducted an investigation into these studies, and found that there was an "apparent bias" in the research. In 1990, as a result of the Congressional hearings, the Public Health Service performed an inquiry into the research that resulted in a five-year probation for the Primary Investigator of the research. Dr. John Bailar, the Scholar-in-Residence at the National Academy of Sciences' Institute of Medicine and editorial board member of the New England Journal of Medicine, is writing a paper in which he reports that his statistical review of the data concludes that the antibiotics were no more effective than placebos. He writes, "This remarkable trend . . . seems to demolish the conclusion that antibiotics (of the mixed types in the studies summarized in these meta-analyses) improve the outcome." In fact, the FDA has never approved the use of antibiotics for this purpose. Despite these very credible and damning condemnations of the research, parents and pediatricians have not been adequately alerted to the significant evidence that suggests against prescribing antibiotics for OME.
The Department of Health and Human Services assembled a Guideline Panel that has just issued guidelines for the treatment of OME. The prescription of antibiotics for this purpose has been approved by the Guidelines Panel, and sent to all pediatricians, HMO's and insurance companies, despite the fact they acknowledge their evidence is "limited and inconsistent". Of the eight groups of studies used by the panel to assess the efficacy of antibiotic treatment, six were based on the very study that had been discredited by the Public Health Service's Office of Scientific Integrity. However, the guidelines continue to accept the use of antibiotics as a legitimate option for treatment.
In a phone interview, Dr. Larry Culpepper, a member of the Guideline Panel, said "(T)he Guideline Panel did not find evidence supporting effectiveness of antibiotics in changing outcomes beyond one month. Not treating with antibiotics (watchful waiting) remains a very viable option."
Scholars in the field, such as the President of the American Society of Pediatric Otolaryngology, are warning of the recent emergence of antibiotic-resistant bacteria of the variety that are associated with OME -- hemophilus influenzae and streptococcal pneumonia due to the overuse of antibiotics in the treatment of OME. To make matters worse, the Centers for Disease Control has found that among children under two years old, the incidence of both OME and AOM increased 224% between 1976 and 1990.
Dr. Charles Bluestone, founder and Director of the University of Pittsburgh's Otitis Media Research Center (OMRC), considered an authoritative source on the treatment of pediatric otitis media, has received more than $20 million of federal research grant money to pursue his work. Currently, nearly half of all the money the federal government spends researching otitis media in children is spent at OMRC. At the time of this research, according to a Congressional investigation and a Public Health Service review, Bluestone was also receiving $3.5 million in research funding from the pharmaceutical industry between 1980 and 1989, and did not disclose most of this private funding as the government requires. More significantly, he personally received over $262,000 in speaking fees over five years, in addition to approximately $25,000 a year in travel expenses from the drug companies that produce the antibiotics he was evaluating.(Appendix A and B)1
In 1986, Bluestone sent the New England Journal of Medicine (NEJM) the results of his research on the success of Amoxicillin (a penicillin derivative), the most commonly prescribed antibiotic, in treating fluid in the middle ear, also known as otitis media with effusion (OME). He wrote in the abstract that "The results of this study lend support to the use of antimicrobial (antibiotic) treatment for infants and children with otitis media with effusion." (parenthetical phrase added) In the February 19, 1987 published version of his study, the NEJM qualified his conclusion to say, ". . . amoxicillin treatment increases to some extent the likelihood of resolution."2 However, this work and others from the OMRC are often cited as the source for the current frequent use of antibiotics.(Appendix C)3
In 1988, the House Committee on Government Operations held hearings on the impact of mixing industry money with federal medical research. The Chairman of the subcommittee on Human Resources, the late Representative Ted Weiss (D-NY), concluded in this case that the University of Pittsburgh:
". . . also failed to examine apparent bias in the conclusions of Dr. Bluestone's published research. The NIH grantees reported that the drug was completely ineffective for treating hearing loss and that more than half the ear infections that were 'cured' at 2 weeks had recurred within 6 weeks. However, these findings were not mentioned in the conclusions of the published article or in later claims by the researchers that the drug was effective. This was a serious omission, since the recurrence of these ear infections is a major problem, and since hearing loss is the primary danger of this type of ear infection."(Appendix A)4
Dr. Diana Zuckerman, a trained epidemiologist, directed Rep. Weiss' investigation and arranged for an independent statistical analysis of one of Bluestones' studies. The trial data was analyzed four different ways, and all showed that in the trial, neither Amoxicillin nor the other antibiotics were any more effective than placebos.
The controversy surrounding this research grew to the point that in 1990 the Public Health Service Office of Scientific Integrity (OSI) conducted an investigation into the allegations surrounding Bluestone's research. The report concluded:
"It seemed evident to the OSI panel that these data do not provide support for the long-term effectiveness of any of the antibiotic drugs, relative to placebos, through a period of 16 weeks (p. 16). . . . In general, the results unfortunately suggest that only a small minority will have any long-term benefits from treatment. This issue should have been given more careful attention in the treatment studies concluded at the OMRC (p. 17) . . . The later, more specific recommendations regarding each of these treatment possibilities appear to be based more upon the investigators' viewpoints rather than on data collected during the study (p. 24) . . . the panel felt that the issues raised by differing placebo cure rates and differing antibiotic efficacy rates had not been dealt with and presented as objectively as possible (p. 33) . . . the coincidence of the large pharmaceutical company honoraria to Dr. Bluestone and the less-than-objective reporting of the efficacy of pharmacological treatments present the appearance of conflict of interest." (p. 35) (Appendix D)5
As a result of this report, Dr. Bluestone was placed on probation by the acting Director of the National Institutes of Health.
Currently, Dr. John Bailar, the Scholar-in-Residence at the National Academy of Sciences' Institute of Medicine and editorial board member of the New England Journal of Medicine, is completing a paper for which he performed a statistical analysis of the University of Pittsburgh research. He has concluded that the data did not support the assertion that antibiotics were any more effective than placebo in treating otitis media with effusion. Dr. Bailar wrote, "This remarkable trend . . . seems to demolish the conclusion that antibiotics (of the mixed types in the studies summarized in these meta-analyses) improve the outcome."
Perhaps the most common affliction children face is "otitis media," commonly referred to as ear infections. There are two types: acute otitis media (AOM) occurs when the patient experiences pain and the ear drum is red; and otitis media with effusion (OME) occurs when there is fluid in the middle ear, which may involve hearing loss, fullness of the ear, discomfort, loss of balance, or no symptoms at all. Estimates of the percentage of appointments with doctors for earaches that result in a diagnosis of OME range from 20% - 35%. According to the Centers for Disease Control, in 1991, doctors prescribed or gave antibiotics 99% of the times they diagnosed a patient with OME. [ While this statistic is technically accurate, it is based on the International Classification of Diseases (ICD). It is believed that some doctors may mistakenly use the ICD code for OME when classifying a patient with AOM.]
In 1990, according to the Center for Disease Control, AOM and OME were the primary reason for 19.7 million appointments with doctors for children under 15 years old, and 24.5 million visits for patients of all ages. As a result of those appointments, drugs were prescribed or ordered 29 million times. In 1990, Amoxicillin was prescribed ten million times or 34% of the times drugs were prescribed for AOM and OME.6
According to the American Society for Microbiology, 42% of all antibiotics prescribed to children are to those diagnosed with AOM and OME.
There has been a significant increase in the number of incidents of AOM and OME between 1975 and 1990. For those children under two years old, frequency of doctor's visits due to AOM and OME has increased 224%; for children between two and five, it has increased 130%; and for children between six and ten years old, 78.5%. (There is a common argument made in the otolaryngology community that the increase in the number of children going to day care accounts for this increase. It would seem, however, that this dramatic jump would apply more to the two-to-five age group, rather than to the children under two, who are less likely to be in a day care center.)7
Treatment for both AOM and OME is typically a steady stream of antibiotics. Usually a child will begin on Amoxicillin, and advance to the more expensive "boutique" antibiotics, including Ceclor, Suprax and Augmentin. Amoxicillin has been on the market for approximately 20 years and is now available as a generic. The total annual medical treatment (not including surgical treatment) for AOM and OME has been estimated to be approximately two billion dollars. (Berman, Roark and Luckey, Pediatrics, 1994) Dr. Stuart Levy, Professor at Tufts University School of Medicine, wrote in his 1992 book, The Antibiotic Paradox:
"More and more parents of young children suffering from ear infections are finding that the prior successes of the penicillin drugs in treating this illness may not be repeated. They must now rely on other more costly drugs to which they may have a toxic reaction." (p. 205)
Despite the abundance of evidence, reliance on a constant flow of antibiotics to children with OME continues to be the current practice in the United States. To make matters worse, an arm of the Department of Health and Human Services just released the report of their Guidelines Panel supporting the use of antibiotics for OME, despite the fact that, in their own words, their evidence is "limited and inconsistent." The evidence they used to support this conclusion had already been found by two government investigations to unduly represent drug companies' interests and not balanced in its conclusions that antibiotics were effective in resolving OME.
The Health and Human Services Agency for Health Care Policy and Research (AHCPR) assembled an Otitis Media Guideline Panel, which determined recommendations to be sent to all pediatricians in the country regarding the appropriate treatment of OME. The Panel was co-chaired by Dr. Sylvan Stool, of the University of Pittsburgh's OMRC (and co-author with Bluestone of the textbook, Pediatric Otolaryngology). When the AHCPR became aware of the appearance of conflict-of-interest, they took several steps to try to distance the panel members who were associated with the OMRC from the discussions on the use of antibiotics. The report is a presentation and comparison of four options for the treatment of OME -- observation, antibiotic therapy, antibiotics and steroids, and surgical intervention. The research used to support the option of antibiotic therapy was based in large part on the discredited work from the OMRC.
Since the Project on Government Oversight circulated the October 1993 "Parent Guide" draft version of this report, the Agency for Health Care Policy contacted us and acknowledged that their language supports the option of antibiotics, although their data for this is "limited and inconsistent." While they subsequently reworked their description of the benefits and harms of antibiotics, they remain firm in giving legitimacy to the use of antibiotics for OME.
In the draft, the option of "observation" is described as follows: "in about 60% of children, otitis media with effusion goes away without treatment within 3 months." In comparison, they assert that antibiotics "may increase chance and speed of otitis media with effusion going away" and "may decrease chance of a future attack of acute otitis media." Based on this information, what parent would choose not to give their child antibiotics?8
In the final version of the "Parent Guide," the option of "observation" is described as follows: "in about 60% of children, middle ear fluid goes away without treatment within 3 months; in 85 percent it goes away within 6 months." In comparison, they assert that antibiotics "may increase chance (by about 14 percent) and speed of middle ear fluid going away" and "may decrease chance of middle ear infection." While this final version gives the parent more information, it clearly remains supportive of antibiotic treatment.9
The Guideline Panel acknowledged that the evidence on which they based this position came from research conducted by Bluestone at OMRC, and they felt it was necessary to describe this data as "limited and inconsistent", and that they "failed to find compelling evidence for or against" this treatment. These caveats are not included in the Parent Guide, or the Quick Reference Guide for Clinicians, but are buried in their longer Clinical Practice Guideline. Table 5 of the Clinical Practice Guideline reveals that of the eight meta-analyses (groups of studies) used by the panel to assess the efficacy of antibiotic treatment, six relied on the very study that had been discredited by the Public Health Service's Office of Scientific Integrity.10
The October draft was used as a reference for an American Academy of Family Physicians (AAFP) pamphlet on earaches. The AAFP pamphlet does not even suggest, let alone encourage, the option of "observation" or "watchful waiting" as a method of treating fluid in the middle ear. This brochure has just been sent out to family physicians around the country to give to parents who want to learn more about their children's "earaches." At the end of the brochure, the reader is directed to contact AHCPR for a copy of the guidelines for more information.11
In a phone interview, Dr. Larry Culpepper, a member of the Guideline Panel, agreed that a concerted effort is needed to educate the public. He said, "The Guideline Panel did not find evidence supporting effectiveness of antibiotics in changing outcomes beyond one month. Not treating with antibiotics (watchful waiting) remains a very viable option." The Guidelines report did not take this position on the effectiveness of antibiotics.
These Guidelines are the basis upon which all pediatricians treat their patients for otitis media with effusion, and are used by HMO's and insurance companies for their definitions of appropriate treatment.
Dr. Robert Ruben, President of the American Society of Pediatric Otolaryngology, believes that there is virtually nothing to gain from prescribing antibiotics for OME. Furthermore, he stated that the excessive use of antibiotics is creating a significant medical phenomena -- antibiotic resistant bacteria. Dr. Ruben wrote in a 1993 paper:
"Both of the most common of the bacteria associated with OME, hemophilus influenzae and streptococcal pneumonia, have acquired significant antibiotic resistance. . . . It would appear that the wide spread use of antibiotics for OME has added to the creation of antibiotic resistant organisms throughout the world. Development of these resistant organisms is increased when the antibiotic is given over a prolonged period of time. . . The creation of antibiotic resistant organisms is now a medical social problem that needs to be addressed and regulated."12
Dr. Ruben delivered a paper in May of this year in which he concludes:
"Overall, the effectiveness of antibiotics for all of the types of morbidities associated with OME is marginal or to equal that of placebo. The sequelae resultant from the use of antibiotics is substantial both to the patient and to society. Analysis of the data indicates that antibiotics are an ineffective and a dangerous form of care for OME." ("Effectiveness and Sequelae of Interventions for Otitis Media with Effusion," Ruben, May 16, 1994)
There has been additional research completed in the United States that suggests that the younger population is becoming more and more immune to the effects of antibiotics because of the overuse of this medical treatment. The result is that children are contracting illnesses that would normally be cured through the administration of an antibiotic. Because these children have already ingested significant amounts of a number of antibiotics, they have developed a resistance to these drugs, and do not respond to antibiotic treatment. In The Antibiotic Paradox, Dr. Levy wrote:
"Another now common community resistance problem has developed with Hemophilus influenzae, the cause of ear infections in infants. . . . The first appearance of ampicillin-resistant strains was totally unexpected (ampicillin is the first generation of amoxicillin). They were discovered in the early 1970s when two infants in Bethesda, Maryland failed to respond to ampicillin. They both died before the problem of resistance was diagnosed. The event sparked international concern. . . . Today, less than twenty years later, ampicillin-resistant and multiresistant Hemophilus influenzae is a problem throughout the world." (pp. 133-134)
A 1992 study of patients in Buffalo, New York researched antibiotic resistance in children previously treated with ampicillin. They discovered that 46% of children with hemophilus influenzae bacteria in their middle ear had become immune to ampicillin, and 100% with M catarrhalis bacteria were immune. (Faden et al, Ann Otol Rhinol Laryngol, 1992)
It is particularly interesting to compare the pro-antibiotic culture in the United States to that of Scandinavia and other countries in Northern Europe, where antibiotics are rarely -- if ever -- administered for OME. In fact, even in cases of acute otitis media antibiotics are very rarely administered in these countries. Instead, they rely on pain-killers, and have not "medicalized" the problem the way doctors and parents have in the United States. Of particular interest is that antibiotic resistant hemophilus influenzae bacteria develops in only three to five percent of children in Northern Europe -- a dramatic comparison to the United States.
Even as long ago as 1974, research emanating from Scandinavia indicated that it is the overuse of antibiotics that might in fact cause repeated episodes of acute otitis media:
". . . frequency of recurrence of otitis media in the first month after recovery is low as compared with that in those 'routinely' treated with antibiotics from any of the first seven days of disease; in those treated with antibiotics, risk of recurrence is high, especially when treatment was begun from the first day of disease." (Diamant and Diamant, Arch Otolaryngology, 1974)
In a study of over 4,800 children in The Netherlands, it was found that over 90% of children with acute otitis media were cured within a few days through a treatment of nose drops and pain-killers. The study concluded, ". . . treatment of acute otitis media in children can be limited to nose drops and analgesics alone for the first three to four days. An antibiotic, preferably a penicillin, can be given in the severe cases (still ill after three to four days with persistent high temperature or severe pain, or both) and to patients who do not clinically appear to be ill but still have discharge of the ear after two weeks." (F.L. van Buchem et al, British Medical Journal, 1985)
A more recent study of the antibiotic treatment of acute otitis media in over 3600 children in nine countries (Australia, Belgium, Canada, Great Britain, Israel, The Netherlands, New Zealand, Switzerland and the United States) also suggests that the repeated use of antibiotics hindered a patient's ability to heal:
"Patients who did not take antibiotics had a higher rate of recovery than those who did; the rate of recovery did not differ between different types of antibiotic. . . Antibiotic treatment did not improve the rate of recovery of patients in this study." (Froom, Culpepper et al, British Medical Journal 1990)
In 1991, Bluestone himself published a paper on the efficacy of Amoxicillin for treating acute otitis media, reporting the results of research conducted between 1981-1985. His paper states that, "It is concluded that children with acute otitis media should routinely be treated with amoxicillin (or an equivalent antimicrobial drug)." This conclusion was reached even though his data showed that Amoxicillin was successful in treating AOM 96% of the time, while children without antibiotics were cured 92.5% of the time. (Kaleida, Casselbrant, Rockette, Paradise, Bluestone et al., Pediatrics 1991)
Dr. Kenneth Grundfast and Cynthia J. Carney, both members of the AHCPR Guideline Panel, wrote in their book, Ear Infections in Your Child, "Studies have shown that, in many instances, acute symptoms of otitis media subside without treatment in 24 to 72 hours in 70 to 80 percent of children."
Despite this, children are nearly certain to be prescribed antibiotics in the United States when diagnosed with acute otitis media. This practice is used as a preventive measure to ensure that the few children who should ultimately receive antibiotics do not fall between the cracks and develop such serious complications as mastoiditis or meningitis.
Dr. Erdem Cantekin, Director of Research at the OMRC and a member of Bluestone's research team, took exception with Bluestone's conclusions in the New England Journal of Medicine's article on antibiotics and OME, as well as Bluestone's many speeches supporting the use of antibiotics. Cantekin's analysis of the data concluded that there was no evidence that Amoxicillin was any more effective than placebos.
A 1990 Congressional report about the "Cantekin Affair", by the late Rep. Ted Weiss (D-NY), found Cantekin's case to be valid. The report concluded that none of the several investigations into the matter had objectively and thoroughly reviewed the allegations. In two sub-headings of their report, the Weiss committee wrote, "The University of Pittsburgh Medical School's misconduct investigation erroneously dismissed the charges against Dr. Bluestone" and further that "Despite conclusive evidence of wrongdoing, NIH has defended Dr. Bluestone's failure to disclose non-federal research funds on his NIH grant applications."
As Dr. Bluestone is the founder of the OMRC, and has been very successful at bringing in both federal and private research funding at the University of Pittsburgh facility, it should not be surprising the University staunchly denied any of the accusations against Bluestone or his research. And, in fact, the University of Pittsburgh filed misconduct charges against Cantekin for submitting his dissenting paper based on the same research to the New England Journal of Medicine (NEJM). The University went so far as to move his office out of the medical complex.
Finally, in 1991, the Journal of the American Medical Association (JAMA) published Cantekin's dissenting paper -- after writing an unprecedented five-page editorial discussing the controversy. JAMA's editor criticized the University of Pittsburgh's attack on Cantekin, and wrote:
"So after all these years and all these inquiries, so costly in time, money, and emotions, the public have yet to see the counter view. Looking back, surely publication of this dissenting view would have been very greatly to the benefit of all parties. We are now publishing it so that our readers can decide for themselves." (Appendix J)13
The Cantekin et al. analysis concluded, "Amoxicillin with and without decongestant-antihistamine combination is not effective for the treatment of persistent asymptomatic middle-ear effusions in infants and children." (Appendix J)14
Cantekin has written a critique of the AHCPR Guidelines Panel report, and recommends that, "(T)he Guidelines Panel should be reformulated to represent the world expertise on this subject, and not merely the view -- prevalent only in the United States -- that drug treatment followed by surgical intervention is the answer to otitis media."
In addition to the obvious significance of challenging the current practice of treating fluid in the middle ear in children with antibiotics, this case represents a much bigger issue for federal scientific research. It is common practice in medical research to mingle federal and corporate research money. It is even common for scientists to receive honoraria or consulting fees from the companies whose product they are evaluating for the government. A July 1992 Department of Health and Human Services Inspector General report concluded:
"We found that gifts and offers of value related to studies, speaking engagements, and program attendance are used by pharmaceutical companies to promote their drugs. We also found that promotional practices involving items of value appear to affect physicians' prescribing decisions."("Prescription Drug Promotion Involving Payments and Gifts: Physicians' Perspectives", p.i)
In the Bluestone case, the controversy only arose because of questions regarding his reporting of these sources of research funding, honoraria and travel expenses. The assumption that science researchers display such integrity that money will not have any impact on their science, goes contrary to the laws of human nature. It is unfair and unrealistic to place such temptations in such a competitive, high-stakes arena. Tax dollars spent on medical research should be pure and unadulterated by corporate funding.
The Project On Government Oversight believes that this case is not only significant on its own merit, but should open the door to a public discussion and review of the assumptions that lie behind the mixing of public and private funds for medical research today.
Appendix A - "Are Scientific Misconduct and Conflicts of Interest Hazardous to Our Health?" Report of the U.S. House of Representatives Committee on Government Operations, September 10, 1990.
Appendix B - Public Health Service, "Review of Allegations Involving the Otitis Media Research Center, Children's Hospital of Pittsburgh", June 1, 1989.
Appendix C - Abstracts From Selected Bluestone Articles
Appendix D - Public Health Service Office of Scientific Integrity, "Inquiry Report Covering Clinical Trials for Otitis Media Conducted at the Children's Hospital of Pittsburgh", December, 1990.
Appendix E - Center for Disease Control, Advance Data, "Office Visits for Otitis Media: United States 1975-90" By Susan M. Schappert, M.A. September 8, 1992.
Appendix F - Parent Guide Draft, Otitis Media Guideline Project of the Agency for Health Care Policy and Research, October 22, 1993.
Appendix G - "Middle Ear Fluid in Young Children," Otitis Media With Effusion Parent Guide, U.S. Department of Health and Human Services Agency for Health Care Policy and Research, July 1994.
Appendix H - "Otitis Media With Effusion in Young Children," Clinical Practice Guideline, Number 12, U.S. Department of Health and Human Services Agency for Health Care Policy and Research, p.48.
Appendix I - Sequelae of Surgical and Medical Interventions for Otitis Media with Effusion, by Robert J. Ruben, M.D., F.A.C.S., F.A.A.P., Presented at: Second Extraordinary International Symposium on Recent Advances in Otitis Media, In Oita, Japan, March 31st - April 3, 1993.
Appendix J - Editorial: "The Cantekin Affair," Abstract: "Antimicrobial Therapy for Otitis Media with Effusion," Cantekin et al., Journal of the American Medical Association, December 18, 1991.
1. "Are Scientific Misconduct and Conflicts of Interest Hazardous to Our Health?" Report of the U.S. House of Representatives Committee on Government Operations, September 10, 1990. Public Health Service, "Review of Allegations Involving the Otitis Media Research Center, Children's Hospital of Pittsburgh," June 1, 1989.
2. "Efficacy of Amoxicillin with and without Decongestant-Antihistamine for Otitis Media with Effusion in Children," Ellen Mandel, Howard E. Rockette, Charles D. Bluestone, et al., New England Journal of Medicine, February 19, 1987.
3. "Comparative Efficacy of Erythromycin-sulfisoxazole, Cefaclor, Amoxicillin or Effusion in Children," Ellen Mandel, Howard E. Rockette, Jack L. Paradise, Charles D. Bluestone et al., The Pediatric Infectious Disease Journal, Volume 10, Number 12, December 1991.
5. Public Health Service, Office of Scientific Integrity, "Inquiry Report Covering Clinical Trials for Otitis Media Conducted at the Children's Hospital of Pittsburgh," December, 1990.
6. Center for Disease Control, Advance Data, "Office Visits for Otitis Media: United States 1975-90."
12. Sequelae of Surgical and Medical Interventions for Otitis Media with Effusion, Robert J. Ruben, Presented at: Second Extraordinary International Symposium on Recent Advances in Otitis Media, In Oita, Japan, March 31 - April 3, 1993.
13. Earaches in Children: A Painful Problem for Many Children.