Wilkins L, Lewis RA, Klein R, Rosemberg E. Suppression of adrenal andro-gen secretion by cortisone in a case of conandro-genital adrenal hyperplasia.Bull Johns Hopkins Hosp.1950;86:249 –252
Wilkins L, Lewis RA, Klein R, Gardner L, Crigler JF, Rosemberg E, Migeon CJ. Treatment of congenital adrenal hyperplasia with cortisone.J Clin Endocrinol.1951;11:1–25
REVIEW ARTICLES AND MONOGRAPHS WHICH INCLUDE CITATIONS NOT LISTED ABOVE
Donahoue PA, Parker K, Migeon CJ. Congenital adrenal hyperplasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds.The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill, 1995: 2929 –2966
Grumbach MM, Conte FA. Disorders of sex differentiation. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds.Williams’ Textbook of Endo-crinology. 9th ed. Philadelphia, PA: WB Saunders; 1998:1303–1425
Lee PA, Plotnick LP, Kowarski AA, Migeon CJ, eds.Congenital Adrenal Hyperplasia. Baltimore, MD: University Park Press; 1977:1–532 Miller WL. Genetics, diagnosis and management of 21-hydroxylase
defi-ciency.J Clin Endocrinol Metab.1994;78:241–246
Miller WL. Pathophysiology, genetics, and treatment of hyperandrogenism.
Pediatr Clin North Am.1997;44:375–395
Morel Y, Miller WL. Clinical and molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.Adv Hum Genet.1991;20:1–68 New MI, ed. Congenital adrenal hyperplasia.Ann NY Acad Sci.1985;458:
1–287
New MI. Congenital adrenal hyperplasia. In: DeGroot LJ, Besser M, Burger HG, et al, eds. Endocrinology. 3rd ed, vol 2. Philadelphia, PA: WB Saunders; 1995:1813–1835
White PC, New MI. Genetic basis of endocrine disease 2: congenital adrenal hyperplasia due to 21-hydroxylase deficiency.J Clin Endocrinol Metab.
1992;74:6 –11
COMMENTARY
The Rational Use of Antimicrobials in Acute Otitis Media: A Bacteriologic
Investigation of Otitis Media in Infancy
, by E. A. Mortimer Jr, and R. L.
Watterson Jr,
Pediatrics
, 1956;17:359 –366;
Otitis Media in the Practice of
Pediatrics: Bacteriological and Clinical Observations
, by J. D. Coffey Jr,
Pediatrics
, 1966;38:25–32;
Acute Otitis Media: Treatment Results in
Relation to Bacterial Etiology
, by B. W. Nilson, et al,
Pediatrics
, 1969;43:
351–358;
The “In Vivo Sensitivity Test”—Bacteriology of Middle Ear
Exudate During Antimicrobial Therapy in Otitis Media
, by V. M. Howie
and J. H. Ploussard,
Pediatrics
, 1969;44:940 –944; and
Otitis Media:
A Clinical and Bacteriological Correlation
, by V. M. Howie, et al,
Pediatrics
, 1970;45:29 –35
Comments by Jack L. Paradise, MD
T
he most common reason for antimicrobial use in United States children is treatment of otitis media.1 Of 44.5 million office-basedprescrip-tions for antimicrobials in 1986 for children younger than than 10 years of age, 42% were for otitis media,2
and of the estimated 20 million visits in 1990 for otitis media by children younger than 14 years of age, antimicrobials were prescribed at.80%.3,4In a recent
prospective study, antimicrobial treatment of otitis media accounted for .90% of all antimicrobial use during the first 2 years of life.5
Foundations for rational use of antimicrobials for acute otitis media (AOM) were first laid down in the United States in a series of five reports6 –10inPediatrics
over a 14-year period beginning in 1956. Each of the reports concerned the bacteriology of AOM as deter-mined from aspiration and culture of middle ear exudate. Taken as a group, these reports in my judg-ment constitute the most important contribution of an otolaryngologic nature to appear in the 50-year history of Pediatrics. Today, when otitis media con-stitutes the most common reason for office visits by children,3it seems remarkable that during the 8 years
of publication of Pediatrics before 1956, only two reports in any way involving otitis media were pub-lished: one, a case report describing chronic suppu-rative otitis media as one element of what came to be termed the Wiskott–Aldrich syndrome,11 and the
other, a brief discussion of the diagnosis and man-agement of secretory otitis media (otitis media with effusion [OME]).12
An additional bit of historical perspective is nec-essary as preface to a discussion of the five selected reports. Early in the 20th century, the organisms implicated most commonly in AOM were the group Ab-hemolytic streptococcus (Streptococcus pyogenes) From the Department of Pediatrics, University of Pittsburgh School of
Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Received for publication Mar 19, 1998; accepted Mar 19, 1998.
Address correspondence to: Jack L. Paradise, MD, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583.
and the pneumococcus (Streptococcus pneumoniae); other frequently encountered organisms considered pathogenic included staphylococci, other varieties of streptococci,Haemophilus influenzae, and coliform ba-cilli.13,14 Treatment consisted primarily of measures
to relieve pain, and in cases that seemed severe, myringotomy.13By the late 1930s, sulfanilamide had
been shown to be effective in treating streptococcal AOM—in one study,15 reducing the proportion of
cases requiring mastoidectomy from 69% to 8%— and sulfapyridine had shown promise in treating pneumococcal AOM.14 Nonetheless, in the
discus-sion of the treatment of AOM in a standard pediatric textbook of the time, almost two pages were devoted to myringotomy but only a single paragraph to sul-fonamide therapy.14Sulfonamides remained the only
antimicrobial drugs available for treating AOM until the mid-1940s, when penicillin first became avail-able. By the time volume 1 of Pediatrics was published in 1948, antibacterial therapy with sulfon-amides or penicillin had become, among pediatri-cians, the predominant mode of treating AOM. A standard pediatric textbook of that time stated that such therapy had “reduced materially the incidence of suppurative otitis media and also of mastoiditis,” and it also noted “a growing tendency toward con-servatism” regarding the use of myringotomy.16
However, only in connection with myringotomy was bacterial culture of middle ear contents mentioned.
In 1956, in “A Bacteriologic Investigation of Otitis Media in Infancy,”6 Edward Mortimer and Reich
Watterson at Cleveland City Hospital reported find-ings of the first study in the United States to use tympanocentesis for diagnostic purposes in children with AOM. Previous such studies had been under-taken only in Scandinavia.17–20Mortimer and
Watter-son found, as did the the Scandinavian investigators, that in children younger than 2 years of age, the most commonly recovered pathogen was S pneumoniae, and the next most common, nontypeable H influen-zae. They considered staphylococci, diphtheroids, and other miscellaneous organisms recovered from the aspirates to be contaminants because they were cultured also from the surface of the tympanic mem-brane before aspiration. Not infrequently as well, cultures of middle ear exudate were sterile. Clini-cally, Mortimer and Watterson pointed out that the relative severity of the otitis, as judged by the ap-pearance of the eardrum, did not correlate well with the presence or absence of organisms on culture. They also noted that “it was unusual to find an organism in the middle ear that was not also present in the nose and/or the throat.” Their report included a figure showing the type of otoscope and the aspi-ration equipment they used.
Ten years later, in “Otitis Media in the Practice of Pediatrics: Bacteriological and Clinical Observa-tions,”7John Coffey reported findings gathered over
a 1-year period in his private pediatric practice in Natchez, MS. Coffey collected middle ear specimens by tympanocentesis from 267 infants and children with purulent otitis media, and found that in addi-tion to S pneumoniae and H influenzae, Moraxella ca-tarrhalis(then calledNeisseria catarrhalis) appeared to
be the cause of a substantial number of cases. Rela-tively few cases were attributable toS pyogenes. Cof-fey made a number of important observations in-cluding 1) that a majority of the children had apparently been free of ear pain; 2) that a number of children—primarily those in whomH influenzaewas cultured from the middle ear— had associated con-junctival discharge; 3) that those with bullous myr-ingitis, an entity thought previously to be attribut-able to viral infection, in fact had positive cultures for
S pneumoniaeand/orH influenzae; 4) that none of the children from whose aspiratesM catarrhaliswas iso-lated were acutely ill or febrile; and 5) that of the children whose cultures showed no growth, most had a history of recurrent otitis media, many had received antimicrobial treatment, and many had vis-cid middle ear effusions characteristic of OME. In instances of relapse or recurrence of otitis media, Coffey often found middle ear pathogens other than those recovered originally. Finally, he gently re-minded readers that “the number of cases found varies directly with the diligence with which they are sought.” The observation that M catarrhalis was a middle ear pathogen had been made previously in Finland by Gro¨nroos,21 but Coffey appears to have
been the first anywhere to report the presence of the organisms intracellularly in middle ear exudate.
The connection between initial bacteriologic find-ings in AOM and the outcome of specific treatments was first made in 1969 by Bjorn Nilson and col-leagues at Johns Hopkins, in “Acute Otitis Media: Treatment Results in Relation to Bacterial Etiology.”8
In a double-blind, randomized trial, they assigned 306 children younger than 3 years of age with AOM to receive either penicillin V, penicillin V plus a sulfonamide, or ampicillin. Clinical response was correlated with the type of organism isolated from the initial middle ear aspirate. Patients with otitis generally, irrespective of culture results, and patients with pneumococcal otitis fared equally well with each of the three regimens. However, patients in whom the infecting organism wasH influenzaefared better with either the penicillin-sulfa combination or ampicillin than with penicillin V alone. Correspond-ingly, most patients receiving ampicillin achieved bacteriostatic serum levels for the strains ofH influ-enzaeinitially isolated, whereas most patients receiv-ing penicillin V did not. This report by Nilson and colleagues appears to have offered the first reported evidence of the superiority of one antimicrobial over another in treating otitis media caused by a specific pathogen.
Later in 1969 came the next development in the use of information derived from tympanocentesis to ra-tionalize antimicrobial therapy for otitis media. In “The ‘In Vivo Sensitivity Test’—Bacteriology of Mid-dle Ear Exudate During Antimicrobial Therapy in Otitis Media,”9Virgil Howie and John Ploussard
re-ported data derived from initial and repeat tympa-nocentesis in patients with otitis media in their pri-vate practices in Huntsville, AL. Starting from the premise that “the ultimate test of the efficacy of antibiotic therapy is its ability to eradicate the organ-ism at the site of infection,” Howie and Ploussard
undertook to evaluate response to treatment accord-ingly. In the course of 858 episodes treated on an individual basis with a variety of antimicrobials, they performed a total of 1233 tympanocenteses and cul-tures. In 271 of the episodes, they were able not only to perform initial tympanocentesis and culture, but also to repeat the procedure 1 to 12 days after insti-tuting antimicrobial therapy. Importantly, they per-formed the repeat tympanocenteses whenever feasi-ble, without regard to patients’ degree of clinical improvement. They found that both S pneumoniae
and H influenzae were eradicated most effectively from middle ear exudate by ampicillin or by sulfon-amides combined with either penicillin V or eryth-romycin. Sulfonamides alone and tetracycline were both relatively ineffective in eradicating S pneu-moniae, whereas penicillin and erythromycin were both relatively ineffective in eradicatingH influenzae.
Clinical outcomes, as distinct from bacteriologic out-comes, were not reported by Howie and Ploussard. Accordingly, they were careful to qualify their infer-ences about the effectiveness of therapy by prefacing the inferences with phrases such as “using only our data presented . . . ” and “ . . . by the ‘In Vivo Sensi-tivity Test . . . ,’” and they cautioned that “the effec-tiveness of a drug in sterilizing the middle ear may not mean that it is the best drug for the patient.”
Finally, in 1970, in “Otitis Media: A Clinical and Bacteriological Correlation,”10Howie and Ploussard,
together with Richard Lester, provided additional clinical details about the same 858 episodes in rela-tion to the initial bacteriologic findings. In contrast to previous reports suggesting thatH influenzaecaused AOM in children older than 3 years of age only infrequently, Howie and colleagues found no corre-lation between patient age and the type of infecting organism. Notably, however, although symptoms were variable and inconsistent, the cases in their series attributable toS pneumoniaewere significantly more often associated with severe pain and with high fever than were the cases attributable to H influenzae. Correspondingly, most of the cases attrib-utable toH influenzaewere associated with little or no fever and with mild or no pain.
Among the noteworthy aspects of these studies that collectively have contributed so much to our understanding of AOM, perhaps the most notewor-thy is the fact that major elements of the work were contributed by pediatric practitioners. These individ-uals recognized the need for new knowledge; they brought to bear keen clinical skills to make important observations; and they had the initiative and the courage, and took the time in the course of their practices, to perform the necessary investigative pro-cedures and to record, analyze, and report their find-ings. This is not to depreciate the contributions of those working in academic settings, but rather to acknowledge not only the practitioners’ contribu-tions to our understanding, but also the exceptional effort required to overcome the obstacles to research inherent in pediatric practice.
A timely lesson to be derived from these studies is that tympanocentesis is a procedure well within the purview of everyday pediatric practice. As clinicians
treating children with AOM, we currently confront a major problem of antimicrobial resistance, particu-larly on the part of S pneumoniae.22 In especially
re-fractory cases, there is no reasonable substitute for diagnostic tympanocentesis (or myringotomy) to en-able identification of the offending organism (if any) and determination of its antimicrobial sensitivities, so that treatment can be directed accordingly. Incis-ing the tympanic membrane in children with AOM to relieve pressure and accomplish drainage became a lost art for most pediatricians trained after the advent of the antimicrobial era, and few currently practicing primary care clinicians perform the proce-dure. Even fewer, in my experience, feel comfortable undertaking diagnostic tympanocentesis. That is a limitation that cries out for remedying. If treatment is to be rationalized maximally, pediatricians must in-corporate tympanocentesis into their armamentar-ium. To do so, they will need at minimum to acquire a surgical head for their otoscopes, no different from the type pictured 42 years ago in the report by Mor-timer and Watterson6and pictured again in another
report in Pediatrics 25 years later.23 A more recent
report had as its goal improving general familiarity with a convenient tympanocentesis apparatus and with appropriate technique for performing the pro-cedure.24
An unanswered research question involving tym-panocentesis concerns the optimal design for com-parative trials of antimicrobials in treating AOM. Most experts would agree that children entering such trials should undergo initial tympanocentesis and aspiration of middle ear contents so that the infecting organism(s) can be identified. Experts do not agree, however, on whether such trials should be designed to measure primarily clinical outcomes or whether, instead, they should focus primarily on bacteriologic outcomes as determined by the results of repeat tympanocentesis 3 to 5 days after therapy has been instituted, much as originally described by Howie and Ploussard.9 Marchant and colleagues
have called attention to three interrelated factors that argue for a primary focus on bacteriologic outcomes: 1) the well known fact that some patients with AOM fail to improve clinically despite treatment with an antimicrobial effective against the infecting organ-ism, whereas others improve despite treatment with an ineffective antimicrobial; 2) limited correlations between clinical efficacy (measured by the presence or absence of symptoms as noted at a visit 3 to 6 days after the onset of therapy) and bacteriologic efficacy (measured at the same visit by tympanocentesis and culture in the comparative trials of antimicrobials that they conducted); and 3) in the same trials, greater differences between drugs in bacteriologic efficacy than in clinical efficacy. Accordingly, March-ant and colleagues concluded that between-drug dif-ferences can be demonstrated more readily with bac-teriologic than with clinical outcome measures, and therefore that tests of differences between bacterio-logic outcomes would require smaller sample sizes than would tests of differences between clinical out-comes.25
validity of its evidential basis depends on a number of assumptions including 1) that symptomatic re-sponse at 3 to 6 days is a consistently valid indicator of concurrent middle ear status and also a valid predictor of middle ear status that is obtained at the termination of therapy or at any given point there-after; 2) that in any individual episode of AOM treated with a given antimicrobial drug, symptom-atic status on each of days 3 to 6 is invariably the same (My clinical experience would suggest other-wise); 3) that in any such episode, middle ear bacte-riologic status on each of days 3 to 6 also is invariably the same; 4) that the time between the repeat tym-panocentesis and the most recent preceding dose of antimicrobial has no influence on the culture results; 5) that the recovery of anybacterial pathogens from middle ear exudate, irrespective of their concentra-tion, is indicative of inadequate antibacterial efficacy; 6) that whatever the antimicrobial drug used, therate
of bacterial killing is a consistent indicator of even-tual antibacterial efficacy; and 7) that performing tympanocentesis twice within 6 days does not affect clinical outcomes favorably, and, therefore, does not obscure differences in such outcomes that might oth-erwise have been observable. None of these assump-tions has, to my knowledge, been tested.
Currently, some experts favor a trial design that would involve relatively small numbers of subjects and would require both initial and repeat tympano-centesis routinely. Others, however, favor a design that would involve, in combination with in vitro studies of efficacy of the drugs in question, some-what larger numbers of subjects, stratification by initial clinical severity, outcome measures that in-clude otoscopic findings as well as symptomatic re-sponse, and repeat tympanocentesis only in subjects with clinically defined treatment failure (M. L. Co-hen, MD, personal communication, July 1997; letter to FDA).
Even if it becomes established that early bacte-riologic response is, in fact, a more sensitive index of antibacterial efficacy than either early or later clinical response, one might then reasonably ask whether it is preferable, in the interest of restrict-ing sample size, to subject all projected patients in a trial to a second tympanocentesis on day 3 to day 5, even though by then most will have become asymptomatic, or whether it would be preferable to enroll a larger number of subjects, all of whom would undergo initial tympanocentesis but few of whom would undergo repeat tympanocentesis be-cause few would have an unfavorable clinical course. The issue involves both practical and eth-ical considerations.
Plainly, the reports over the past half-century in
Pediatrics involving tympanocentesis have laid
cru-cial groundwork not only for rational antimicrobial treatment of AOM, but also for continuing efforts by otitis media researchers in this complex era of evolv-ing antimicrobial resistance.
REFERENCES
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2. Nelson WL, Kuritsky JN, Kennedy DL, Lao CS. Outpatient pediatric antibiotic use in the US: trends and therapy for otitis media, 1977–1986. American Society for Microbiology Program and Abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 4 –7, 1987; Washington, DC
3. Schappert SM. Office Visits for Otitis Media: United States, 1975–90. Hyattsville, MD: National Center for Health Statistics; Vital and Health Statistics; No 214; 1992
4. Nelson CR.Drug Utilization in Office Practice, National Ambulatory Med-ical Care Survey, 1990. Hyattsville, MD: National Center for Health Statistics; Vital and Health Statistics; No 232; 1993
5. Paradise JL, Rockette HE, Colborn DK, et al. Otitis media in 2253 Pittsburgh-area infants: prevalence and risk factors during the first two years of life.Pediatrics. 1997;99:318 –333
6. Mortimer EA Jr, Watterson RL Jr. A bacteriologic investigation of otitis media in infancy.Pediatrics. 1956;17:359 –366
7. Coffey JD Jr. Otitis media in the practice of pediatrics: bacteriological and clinical observations.Pediatrics. 1966;38:25–32
8. Nilson BW, Poland RL, Thompson RS, Morehead D, Baghdassarian A, Carver DH. Acute otitis media: treatment results in relation to bacterial etiology.Pediatrics. 1969;43:351–358
9. Howie VM, Ploussard JH. The “in vivo sensitivity test”— bacteriology of middle ear exudate during antimicrobial therapy in otitis media.
Pediatrics. 1969;44:940 –944
10. Howie VM, Ploussard JH, Lester RL Jr. Otitis media: a clinical and bacteriological correlation.Pediatrics. 1970;45:29 –35
11. Aldrich RA, Steinberg AG, Campbell DC. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczema-toid dermatitis and bloody diarrhea.Pediatrics. 1954;13:133–139 12. Samuels SS. Secretory otitis media in children. Pediatrics. 1955;15:
334 –336
13. Politzer A.A Textbook of the Diseases of the Ear, 5th ed. Philadelphia, PA: Lea & Febiger; 1909:722
14. Holt LE Jr, McIntosh R.Holt’s Diseases of Infancy and Childhood.New York, NY: D Appleton–Century Company; 1940:382–396
15. Fisher GE. Sulfanilamide in the treatment of otitis media.JAMA. 1939; 112:2271
16. Nelson WE. The Ear. In: Nelson WE, ed.Mitchell–Nelson Textbook of Pediatrics,5th ed. Philadelphia, PA: WB Saunders Company, 1950: 937–942
17. Nielsen JC.Studies of the Aetiology of Acute Otitis Media. Copenhagen: Munksgaard; 1945
18. Bjuggren G, Tunevall G. The Pfeiffer bacillus in otitis in children.Acta Otolaryngol (Stockh). 1950;38:130 –146
19. Bjuggren G, Tunevall G. Otitis in childhood: a clinical and sero-bacteriological study with special reference to the significance of Hae-mophilus influenzaein relapses.Acta Otolaryngol (Stockh). 1952;42:311–328 20. Lahikainen EA. Clinico-bacteriologic studies on acute otitis media: as-piration of tympanum as a diagnostic and therapeutic method.Acta Otolaryngol (Stockh). 1953;(suppl 107):1– 82
21. Gro¨nroos JA, Kortekangas AE, Ojala L, Vuori M. The aetiology of acute middle ear infection.Acta Otolaryngol (Stockh). 1964;:58:149 –158 22. Paradise JL. Managing otitis media: a time for change.Pediatrics.1995;
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1998;102;221
Pediatrics
Jack L. Paradise
35
−
, 1970;45:29
Pediatrics
V. M. Howie, et al,
, by
Otitis Media: A Clinical and Bacteriological Correlation
944; and
−
1969;44:940
,
Pediatrics
, by V. M. Howie and J. H. Ploussard,
Therapy in Otitis Media
Bacteriology of Middle Ear Exudate During Antimicrobial
−−
Sensitivity Test''
The ''In Vivo
358;
−
, 1969;43:351
Pediatrics
, by B. W. Nilson, et al,
Etiology
Acute Otitis Media: Treatment Results in Relation to Bacterial
32;
−
1966;38:25
,
Pediatrics
, by J. D. Coffey Jr,
Pediatrics: Bacteriological and Clinical Observations
Otitis Media in the Practice of
366;
−
, 1956;17:359
Pediatrics
Watterson Jr,
, by E. A. Mortimer Jr, and R. L.
Investigation of Otitis Media in Infancy
The Rational Use of Antimicrobials in Acute Otitis Media: A Bacteriologic
Services
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1998;102;221
Pediatrics
Jack L. Paradise
35
−
, 1970;45:29
Pediatrics
V. M. Howie, et al,
, by
Otitis Media: A Clinical and Bacteriological Correlation
944; and
−
1969;44:940
,
Pediatrics
, by V. M. Howie and J. H. Ploussard,
Therapy in Otitis Media
Bacteriology of Middle Ear Exudate During Antimicrobial
−−
Sensitivity Test''
The ''In Vivo
358;
−
, 1969;43:351
Pediatrics
, by B. W. Nilson, et al,
Etiology
Acute Otitis Media: Treatment Results in Relation to Bacterial
32;
−
1966;38:25
,
Pediatrics
, by J. D. Coffey Jr,
Pediatrics: Bacteriological and Clinical Observations
Otitis Media in the Practice of
366;
−
, 1956;17:359
Pediatrics
Watterson Jr,
, by E. A. Mortimer Jr, and R. L.
Investigation of Otitis Media in Infancy
The Rational Use of Antimicrobials in Acute Otitis Media: A Bacteriologic
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