DISEASE MANAGEMENT

Paediatr Drugs 1999 Jan-Mar; 1 (1): 31-50 1174-5878/99/0001-0031/$10.00/0 © Adis International Limited. All rights reserved.

Management of Acute Otitis Media in the 1990s The Decade of Resistant Pneumococcus Stan L. Block Kentucky Pediatric Research, Incorporated, Bardstown, Kentucky, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . 1. Overview . . . . . . . . . . . . . . . . . . . . . . . 1.1 Epidemiology of Acute Otitis Media (AOM) . 1.2 Managed-Care and Tympanostomy Tubes . 1.3 Antibiotic Overprescribing . . . . . . . . . . . 2. Diagnosing AOM . . . . . . . . . . . . . . . . . . . 3. Basis of Antibiotic Selection for AOM . . . . . . . 3.1 Bacteriology of AOM . . . . . . . . . . . . . . 3.2 Age and Bacteriology . . . . . . . . . . . . . 3.3 Other Pathogens of AOM . . . . . . . . . . . 3.4 First-Line Therapy . . . . . . . . . . . . . . . . 3.5 Selecting Second-Line Antibiotic Therapy . . 3.6 Adverse Effects . . . . . . . . . . . . . . . . . 3.7 Palatability Issues . . . . . . . . . . . . . . . . 3.8 Dosage Regimens . . . . . . . . . . . . . . . 4. Antibiotic Therapy for AOM in the 1990s . . . . . 4.1 Refractory AOM . . . . . . . . . . . . . . . . 4.2 Short Course Therapy . . . . . . . . . . . . . 4.3 Patients with Otorrhoea . . . . . . . . . . . . 4.4 Additional Considerations for AOM . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . .

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Acute otitis media (AOM) has become increasingly difficult to treat in the 1990s, the decade of drug-resistant pneumococcus. Throughout the world, drugresistant strains of this pathogen are being recovered from 20 to 50% of cases of initial untreated AOM, and from 45 to 90% of refractory AOM. Almost as alarming is that β-lactamase–producing strains of Haemophilus influenzae are currently being isolated in 40 to 50% of cases of AOM in the US. Clinicians can no longer expect ‘Pollyanna-like’ high rates of clinical resolution for this disease. It is now imperative that they become aware of the regional prevalence of these drug-resistant bacteria and, just as importantly, their patterns of antibacterial resistance. Although some authors would hold that any antibacterial, or even placebo, should be adequate for most cases of AOM, clinical practice appears to suggest

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Block

otherwise. Amoxicillin, still the first-line therapeutic choice for initial nonrefractory AOM, will often fail. The real dilemma begins when clinicians search for clinical data to select an antibacterial for therapeutic failures – few data are available. Thus, to give optimal treatment to a child who has failed antibacterial therapy – the true actual indication for all second-line antibacterials – they must instead become familiar with the following in vivo and in vitro data: 1. ‘In vivo sensitivity data’: otherwise known as bacteriological efficacy, in which repeat tympanocentesis is performed in mid-therapy. This reveals the bacterial ‘Achilles heel’ or weakness for the individual antibacterial agents. 2. Clinical efficacy data: analysis of rates of clinical resolution after therapy in comparative trials which use a single tympanocentesis initially and a ‘gold standard’ comparator antibacterial. 3. ‘Bug to drug’ data: comparison of reported middle ear concentrations for each individual antibacterial agent relative to the respective minimum inhibitory concentrations of isolates, particularly drug-resistant pneumococcus and H. influenzae (if possible, obtained from the paediatric respiratory tract). The selection of an antibacterial agent for AOM in any particular case should not be merely a random process. It involves awareness of the pathogens most likely to be observed: with co-infections; after failure with a particular antibacterial (the bacterial ‘Achilles heel’ of the drug); and at different points in time, whether initially or after therapeutic failures (e.g. first-line versus fourth-line failure).

1. Overview Acute otitis media (AOM) is the most common bacterial infection afflicting children in developed countries. It accounted for 24.5 million office visits in the US in 1990.[1] The greater Boston longitudinal prospective study,[2] conducted in the late 1970s, showed that in this mostly White, metropolitan population, 62% of children experienced their first episode of AOM by the end of the first year of life and 83% had had an episode by the third year. Over the past 2 decades, the burden of AOM appears to be increasing.[3] We recently, retrospectively, evaluated 251 mostly White consecutive birth cohorts from rural Kentucky, born between 1989 and 1990, for the incidence of AOM.[3] The first episode of AOM was documented in 44% of children by 6 months of age, 86% by 24 months and 94% by 36 months. In the first year of life, 28 and 8% had experienced more than 3 episodes or more than 6 episodes, respectively, of AOM. AOM also accounted for 25% © Adis International Limited. All rights reserved.

of total office visits annually during the first 3 years of life. Ventilatory tubes were inserted in 2% of patients during the first year and 4% in the second year, a rate comparable with that of a similar group of patients in the Pittsburgh area.[4] The total annual cost of treating children with otitis media in the US exceeds $US3.5 billion.[5] In 1991, the tangible and indirect costs per episode of AOM were around $US400. The cost of managing AOM has been further escalating, secondary to increasing numbers of children who are: • enrolled in daycare centres[1] and • enrolled in managed-care plans.[6] 1.1 Epidemiology of Acute Otitis Media (AOM)

The increasing numbers of children being placed in daycare has had a profound effect on the incidence of both early onset and refractory AOM.[7] Children in daycare are less often breastfed, more often exposed to respiratory infections, more often Paediatr Drugs 1999 Jan-Mar; 1 (1)

Acute Otitis Media in the 1990s

infected or colonised in the nasopharynx with resistant bacteria, receive more antibiotics, fail therapy more commonly, and more easily spread both disease and resistant pathogens.[7-10] Furthermore, the placement of tympanostomy tubes was 7-fold higher among children enrolled in daycare vs those in homecare (21 vs 3%).[8] Other well documented risk factors for the development of AOM include: younger age (6 to 18 months old), the early onset of AOM, male gender, a family history of AOM, White race, bottle-feeding, smoking household, anatomical abnormalities (e.g. cleft palate) and certain ethnic groups (Alaskan and Native American).[7] In the only study in the US that has examined risk factors for penicillin-resistant Streptococcus pneumoniae (PRSP) in culture-proved AOM, Block and colleagues[11] identified daycare attendance as a major risk factor, along with the otitis-prone condition (more than 3 AOM episodes in 6 months), higher numbers of previously prescribed antibiotics and age of less than 24 months. Furthermore, a major risk factor for the development of more ominous invasive infections with PRSP appears to be previous antibiotic exposure, which is also directly related to daycare attendance.[1] 1.2 Managed-Care and Tympanostomy Tubes

Within some genres of managed-care plans, recent data suggest that ‘gatekeeper’ physicians may find powerful economic incentives to quickly insert tympanostomy tubes in young children, apparently after only a few episodes of AOM. The average overall cost of tube insertion in the US is about $US2400. Among 67 995 children from the Cincinnati area enrolled in managed-care who were followed during the 12 months from July 1993 to June 1994, tympanostomy tubes were inserted in 43% of boys and 28% of girls with AOM by 1 year of age, and in 30% of all children during the second 12 months of life.[12] On the other hand, the annual placement of tympanostomy tubes in a private care population in the greater Pittsburgh area, where 2253 children were followed from © Adis International Limited. All rights reserved.

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birth to age 2 during a similar interval, was only 1.8% by 1 year of age and 4.2% by the second year of life.[4] These rates as similar to the rural Kentucky experience (see section 1.1). 1.3 Antibiotic Overprescribing

A recent review of the Kentucky Medicaid database revealed that 60% of patients diagnosed with the common cold were treated with antibiotics.[13] Physicians and mid-level providers may often overprescribe antibiotics to avoid the potent economic and social pressure by parents for an antibiotic prescription. Both sides perceive that the antibiotic prescription is ‘safer’, enables the child to resume daycare faster and prevents the incidence (nearly a quarter of patients) of secondary AOM that is observed within 1 week of an untreated upper respiratory tract infection.[14] Clinicians, whether enrolled in managed-care plans or not, may overdiagnose or less carefully diagnose AOM because of time constraints necessary for proper cleaning of the ear canal and examination of the tympanic membrane (TM), and in an attempt to reduce subsequent office visits. For a superlative summary of ‘judicious antibiotic usage’ which all clinicians should incorporate into practice, the reader is referred to the entire January 1998 supplement of Pediatrics.[1] 2. Diagnosing AOM The accurate diagnosis of AOM is based strictly upon the careful visualisation of the TM by using pneumatic otoscopy. The symptoms of AOM are often nonspecific and notoriously unreliable for diagnosing AOM in practice. Frequently, children who present with ‘earache’ have normal TMs, and conversely, many present asymptomatically with bulging purulent TMs, especially following therapy. Fever is present in only 23% of patients with AOM[15] and is more often reflective of the underlying viral infection, rather than a predictor of AOM severity. To accurately diagnose AOM, physicians should use a relatively fresh, bright halogen light source, either wall mounted or with a fully functioning Paediatr Drugs 1999 Jan-Mar; 1 (1)

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battery. It is also incumbent upon the clinician examining the TMs of younger infants and children with smaller ear canals, to use the original speculums (not the disposables) which: (i) allow the fullest possible light source and a seal to be obtained; (ii) are longer [35mm (1.375in) long] and more tapered; and (iii) provide a 3mm speculum size – the optimal size for most children 4 to 30 months old.[16] Disposable speculums are inadequately tapered, too narrow in diameter and too short to obtain an adequate visualisation of the TM or to gain access around the bend of the ear canal in young children. For the cleaning of the external canal, the author recommends using a wire loop cerumen curette (Storz Instruments, Inc.). Both the curette and nondisposable speculums can easily be cleaned with an alcohol pad after each examination. The clinician should employ a gentle approach, especially with younger children who require careful positioning on the caregiver’s lap and who must usually be firmly restrained during the otoscopic examination. Uncooperativeness markedly impedes the necessary quick but thorough examination of younger children, and many of these patients will require a multitude of visits over the ensuing years. Essential signs of AOM include any or all of the following TM findings: • erythema or significant injection (not just pinkness or the blush of crying) • purulent effusion/air fluid level • white, yellow or pale-green discoloured opacification not from tympanosclerosis • a full or bulging TM. Mobility of the TM is usually decreased, but is sometimes normal in early AOM. Alteration of the light reflex is especially unreliable. Otorrhoea from a spontaneous perforation or draining pressure equalising (PE) tube is pathognomic for AOM. Middle ear effusion (MEE) or decreased mobility without inflammatory changes of the TM is not AOM, but merely otitis media with effusion (OME), which does not require antibiotics, at least not for 3 months. Other ancillary TM findings of OME include orange or straw-coloured effusion, dullness or retraction. © Adis International Limited. All rights reserved.

Block

As for the conundrum of whether or not to treat AOM, the reader is referred to the cogent and persuasive article by Paradise.[17] 3. Basis of Antibiotic Selection for AOM 3.1 Bacteriology of AOM

Practitioners treating AOM must be cognisant of the marked changes in the microbiological resistance rates that have occurred since the mid-1990s. Consequently, they should carefully evaluate data reporting pathogens and rates of resistance in AOM as to their current relevance, particularly if the data were obtained before 1993 or were not obtained from paediatric patients. In the late 1980s, before the onslaught of PRSP, Marchant et al.[18] evaluated pathogens from 448 children with AOM. Among the 332 pathogens isolated from MEE in 293 patients, the most common pathogen was S. pneumoniae (44%), followed by nontypeable Haemophilus influenzae (33%) and Moraxella (or Branhamella) catarrhalis (20%). No PRSP were isolated and β-lactamase–producing strains accounted for <20% of H. influenzae recovered. The practitioner should also be aware that nontypeable H. influenzae is not the serotype included in the HiB (serotype B) vaccine, a vaccine which will not diminish the number of episodes of AOM in developed countries. In addition, 2 or 3 pathogens have been recovered in 7 to 11% of patients undergoing tympanocentesis, which further complicates antibiotic choices for AOM and reduces therapeutic response.[11,18] Antibiotic resistance among pathogens of AOM is mediated by 2 primary mechanisms: the production of β-lactamase enzymes or alteration of penicillin-binding proteins of the cell wall. The Gram-negative organisms H. influenzae and M. catarrhalis excrete β-lactamase enzymes outside the cell wall where they can hydrolyse βlactam antibiotics before they attack their target – the cell wall itself. The proportion of β-lactamase– producing H. influenzae from paediatric patients with AOM in the US has nearly tripled from rates of 15 to 20% in the 1980s to currently reported Paediatr Drugs 1999 Jan-Mar; 1 (1)

Acute Otitis Media in the 1990s

rates of 45 to 55%.[19-21] Since the late 1980s, M. catarrhalis strains recovered from AOM in the US have nearly uniformly produced β-lactamase, albeit in a less potent form than that produced by H. influenzae. During the 1990s, the proportion of PRSP isolates recovered from children in the US has increased almost exponentially compared with rates from the 1980s, when PRSP accounted for <5% of recovered strains.[22] On the other hand, recovery of PRSP has ranged from 20 to 45% of strains recovered from the respiratory tract (predominantly intermediately penicillin-resistant strains) in parts of Europe since the 1980s.[23,24] S. pneumoniae acquires resistance to β-lactam antibiotics as a result of alteration of penicillin-binding proteins in the cell wall, which subsequently reduces the antibiotic binding affinity. Resistance to many other antibiotics (sulpha drugs, tetracyclines, etc.) may be acquired by induction of genes to produce degrading enzymes and antibiotic efflux pumps.[25] Primary mechanisms for increasing rates of PRSP include antibiotic pressure with induction and selection of hardier strains of the penicillin-resistant pathogen, and geographic transmigration of strains.[26] The degree of resistance for S. pneumoniae is classified according to its minimum inhibitory concentrations (MICs) for penicillin, as follows: resistant (or highly resistant) ≥2.0 mg/L, intermediately resistant 0.1 to 1.0 mg/L and susceptible <0.1 mg/L. The series of S. pneumoniae isolates described by Doern et al.[27] highlights the nearly 2-fold higher rate of recovery of PRSP from the upper respiratory tract of children (AOM 42%) compared with PRSP isolates predominantly recovered from either adults (sputum 25%) or patients of all ages with invasive disease (bacteraemia 22% and meningitis 17%). Pichichero and colleagues[19] have further corroborated this alarmingly high rate, reporting a 46% rate of PRSP from children with AOM during the period from 1994 to 1995. Even more worrying was their observation that 33% of 93 S. pneumoniae strains recovered, mostly from nonrefractory AOM, were highly resistant. As with AOM, nasopharyngeal colonisation with PRSP © Adis International Limited. All rights reserved.

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has recently been reported to be as high as 41% among all attendees at daycare centres in both rural Nebraska and Kentucky during Winter.[9,10] One area in the southeast US has reported an unusually high rate of PRSP (41%) from invasive disease among White children less than 6 years old.[28] However, Kaplan et al.[29] have documented an annual rate of 23% for strains of PRSP in a recent series of invasive disease isolates from 6 sites in the US. A multinational antimicrobial trial[30] observed that, although rates of PRSP from AOM were higher in Eastern Europe or Israel than in the US (34.6 vs 21%), strains were less likely to be highly resistant outside the US (7 vs 11%). However, this difference may be primarily related to the lower mean age of the US children (2.5 vs 4.0 years) included in the study. 3.2 Age and Bacteriology

Both Carlin et al.[31] and Hoberman et al.[32] observed that children younger than 18 to 24 months of age accounted for either all of, or a significantly higher rate of, AOM failures in their respective series. This may be related to the differential incidence of resistant pathogens recovered from AOM among age groups. Children younger than 7 months tended to have a much higher frequency of both PRSP and β-lactamase–producing Gramnegative organisms (27 and 27%, respectively) than those older than 48 months (11 and 12%, respectively).[33] Nearly three-quarters of the pathogens recovered from children older than 48 months were susceptible to first-line antibiotics, such as amoxicillin. Although S. pyogenes is rarely observed in younger children, it appears to play a significant role in AOM in older children, with reported rates of 9 to 13% in Eastern Europe/Israel[30] and the US,[33] respectively. 3.3 Other Pathogens of AOM

Although viruses and atypical ‘bacteria’ may commonly be pathogenic for AOM, it is uncommon for them to be the sole cultured pathogens (6 to 10%) from paediatric patients with AOM; Paediatr Drugs 1999 Jan-Mar; 1 (1)

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Block

Table I. Factors for selection of antimicrobials to treat acute otitis media (after Pichichero[42]) Antibiotic class

Generic name of antibiotic

Total dosage (mg/kg/day)

Frequency/ day

Palatability

Cost

Adverse effects

Aminopenicillins

Amoxicillin-clavulanic acid high dose

45/6.4 80-90/6.4

×2 ×2 (or ×3)

Acceptable

High

GI 10-15%

Amoxicillin high dose

40 60-80

×2 (or ×3) ×2 (or ×3)

Good

Low

Occasional GI

Cefaclor

30-40

×2 (or ×3)

Excellent

High

Serum sickness–like reactions in 1-3.4%

Second-generation cephalosporins

Third-generation cephalosporins

Cefuroxime axetil

30

×2

Poor

Very high

Occasional GI

Cefprozil

30

×2

Good

High

Occasional GI

Loracarbef

30

×2

Excellent

Very high

Occasional GI

Cefixime

8

×1

Excellent

High

Occasional GI

Ceftibuten

9

×1

Good

High

Occasional GI

Cefpodoxime proxetil

10

×2 or ×1

Acceptable

High

Occasional GI

Cefdinir

14

×1 or ×2

? Acceptable High

Occasional GI

Sulpha combinations

Cotrimoxazole (trimethoprimsulfamethoxazole)

8/40

×2

Brand = good Moderate generic = Low poor

Occasional dermatological, extremely rare Stevens-Johnson syndrome

First-generation macrolide

Erythromycin-sulfisoxazole

50/160

×4

Acceptable

Moderate

Gastritis 10%, occasional dermatological

Second-generation macrolide

Clarithromycin

15

Fair to poor

Moderate (bodyweight <15kg) High (>15kg)

Gastritis 5%

Third-generation macrolide

Azithromycin

10 first day ×1 5 next 4 days (only 5 days total)

Good

Moderate

Infrequent GI

GI = gastrointestinal.

more commonly, they are copathogens with bacteria.[34-36] The marked variation in rates of positive bacterial growth among isolates from tympanocentesis, which range from 65 to 91%, is more likely to be dependent on the culture technique used.[20,37] Growth is enhanced by rapid plating and incubation of the ear aspirates rather than allowing them to grow at room temperature, and by using blood and chocolate agar plates rather than transport media. Two recent studies[38,39] have demonstrated that polymerase chain reaction (PCR)– based assay systems can detect bacterial DNA in 48% and messenger RNA in 31% of MEEs with sterile cultures. As for atypical pathogens, Klein and Teele[40] noted in the 1970s that Mycoplasma pneumoniae was recovered from only 1 of 771 MEE samples © Adis International Limited. All rights reserved.

from patients with AOM. Both clinical data[20] and personal clinical experience with tympanocentesis show that bullous myringitis is not caused by M. pneumoniae, even when MEE are tested with more sensitive PCR assays for that pathogen (0 of 50 patients). In contrast, Block et al.[41] have isolated Chlamydia pneumoniae from a small but significant percentage (8% of 101 children) with AOM. Five of the children with this pathogen were very young (8 to 17 months old) and 3 had refractory AOM. C. pneumoniae was the sole pathogen isolated in only 2 of these children and, as with viruses, was usually associated with another typical bacterial pathogen. C. trachomatis appears to be an uncommon pathogen in OME and even rarer in AOM among younger children.[41] Paediatr Drugs 1999 Jan-Mar; 1 (1)

Acute Otitis Media in the 1990s

3.4 First-Line Therapy

Practitioners have available to them a dizzying armamentarium of antibiotic choices for the treatment of AOM, including a newer, very broad spectrum oral cephalosporin recently approved (cefdinir) and possibly another one currently undergoing clinical trials (cefditoren) [see table I]. Despite the increasing numbers of resistant pathogens being recovered from children with AOM in the 1990s, most experts still recommend narrow spectrum amoxicillin as standard first-line therapy. The drug is inexpensive, modestly efficacious, palatable and well tolerated. However, because of the increasing numbers of PRSP and compliance problems with thrice daily administration, the author is now recommending amoxicillin in dosages of 60 to 80 mg/kg/day administered twice daily for children aged 4 to 36 months with moderately severe to severe AOM. Other second-line antibiotics may be selected initially for the child who is allergic to penicillin (except for amoxicillin-clavulanic acid), or who is a recent amoxicillin or other second-line antibiotic failure within the last 30 days. 3.4.1 Post-Therapy Follow-Up

Follow-up at end of therapy is usually not necessary in most healthy children over the age of 15 months (see table II), because nearly all parents are able to accurately discern after therapy whether an older child’s AOM has resolved.[43] Nonetheless, for younger or otitis-prone children whose symptoms resolve after therapy, clinicians may want to consider, at minimum, a later recheck for OME at 1 to 3 months by direct observation, spectral-gradient acoustic reflectometer[44] or tympanometry. Monthly or weekly readings by the caregivers with a home acoustic reflectometer (e.g. EarCheck™ , MDI Instruments, Woburn, MA, USA) may be a cost-effective means of monitoring for OME or new onset AOM.[44] 3.4.2 Bacteriology of Therapeutic Failures

During the 1980s, H. influenzae accounted for the majority (46 to 62%) of pathogens recovered from bacteriological failures.[22,45] Currently, it ap© Adis International Limited. All rights reserved.

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pears that S. pneumoniae, and in particular PRSP, may account for the majority of pathogens recovered from antibiotic failures in the 1990s. The highest risk for PRSP with AOM occurs in patients who have been recently treated or who have failed antibiotics (refractory AOM) compared with those with nonrefractory AOM (44 versus 9%), particularly for highly PRSP strains (30 versus 2%) [fig. 1].[11] Barry et al.[46] similarly reported that 43% of 70 French children failing antibiotic therapy were infected with PRSP. Even higher rates (80 and 91%) have been reported among recently treated children with AOM in France and Spain, respectively.[47] Data from the 1980s suggested that most AOM recurrences are caused by a different bacterial pathogen.[45,48] In the decade of PRSP, the author perceives that patients initially infected with that organism who fail therapy or whose disease recurs within 2 weeks continue to be infected with the original organism. Other possible causes for antibiotic failure are listed in table III. 3.5 Selecting Second-Line Antibiotic Therapy

Unfortunately, of the recent comparative clinical trials for AOM in the US, there are only sparse Table II. Recommendations for follow-up after an episode of acute otitis media (AOM)a At the end of therapy (10-14 days) All children younger than 15mo experiencing ≥2 episodes of AOM Otitis-prone children older than 15mo during the winter Any AOM associated with otorrhoea Recent antibiotic failures At 24-48h More systemically ill-appearing children treated as outpatients Persistent severe symptoms: earache or fever (not due to obvious viral infection) Immunocompromised children a

Most children younger than 24 months in the US will be receiving periodic checkups, which subsequently will enable routine assessment for otitis media with effusion at 3-month intervals. Use of the home acoustic reflectometer could also improve monitoring for persistent silent effusions.

Paediatr Drugs 1999 Jan-Mar; 1 (1)

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Block

No antibiotic treatment within past 3 days Penicillin-susceptible S. pneumoniae‡ (39%) Intermediately penicillin-resistant Streptoccccus pneumoniae† (7%) Penicillin-resistant S. pneumoniae* (2%)

S. pyogenes (7%) Haemophilus influenzae (−) [21%] Moraxella catarrhalis (+) [11%] H. influenzae (+) (12%) Treatment within past 3 days Penicillin-susceptible S. pneumoniae‡ (37%) Intermediately penicillin-resistant S. pneumoniae† (14%)

Moraxella catarrhalis (+) [3%] H. influenzae (+) [8%] Penicillin-resistant S. pneumoniae* (30%)

H. influenzae (−) [8%]

Fig. 1. Pathogens collected from children with acute otitis media from rural Kentucky (1992-1994) who either had not received antibiotics for at least 3 days (n = 220) or were treated within the past 3 days (n = 63) [from Block et al., [3] with permission]. MIC = minimum inhibitory concentration; + = β-lactamase–producing; – = non–β-lactamase–producing; * MIC ≥ 2.0 mg/L; † MIC > 0.1-1.0 mg/L; ‡ = MIC < 0.1 mg/L.

data available regarding therapy of either refractory AOM or antibiotic failures – the actual targeted population for these broader spectrum antibiotics.[11,19,50] In the past, clinicians have been accustomed to reports of optimistically high cure rates for most antibiotics used to treat AOM, which Marchant et al.[18] have called the ‘Pollyanna phenomenon’, after the ‘blindly optimistic heroine’ of the novel by the same name. Basically, nontympanocentesis comparative clinical trials rarely reveal any differences in clinical outcomes, probably because of: • overdiagnosis and use of less experienced or nonvalidated investigators in these trials • inclusion of cases of mild to moderate AOM • inclusion of much less difficult to treat, first-line patients only © Adis International Limited. All rights reserved.

• use of overly broad criteria (symptoms only, rather than TM examination) for satisfactory outcome • inherently high rates of natural spontaneous resolution for infections caused by Haemophilus organisms, as opposed to PRSP this decade. When treating refractory AOM (third- or fourthline antibiotic failures) in the 1990s, practitioners should expect efficacy rates in the range of 50 to 60%, even with the more efficacious oral antibiotic choices.[20] Furthermore, minimal data are available regarding the treatment of AOM caused by PRSP. Most clinical trials evaluating antibiotic efficacy in these patients have treated fewer than 20 to 30 patients in an unblinded and noncomparative fashion. Only 3 antibiotics (cefuroxime, cefprozil and amoxicillinPaediatr Drugs 1999 Jan-Mar; 1 (1)

Acute Otitis Media in the 1990s

clavulanic acid) have demonstrated a modest degree of efficacy (60 to 70%) in the treatment of AOM caused by PRSP, but with only a very small series of patients in noncomparative clinical trials.[19,30,46] As a result of the paucity of available data regarding refractory AOM and second-line therapy, practitioners should resort to evaluating 3 surrogate markers: (i) in vivo ‘sensitivity test’: bacteriological efficacy mid-therapy; (ii) in vivo clinical efficacy after therapy; and (iii) in vitro predicted efficacy, which compares either antibiotic MEE concentrations or serum concentrations against pathogen MIC50-90 values (antibiotic concentrations at which 50 to 90% of pathogens are inhibited). It is improbable that much new information will be added to the first 2 sets of data [(i) and (ii)] for already approved drugs, thus only the last set of data [(iii)] will enable clinicians to predict efficacy if major shifts in resistance patterns continue to occur. Thus, familiarity with pharmacodynamic parameters, regional susceptibility patterns and other factors as listed in table IV are essential for optimal management strategies.

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AOM who are treated with placebo. Thus, nontreatment of AOM would potentially place a young child at risk for invasive pneumococcal disease, a clinical and medicolegal conundrum. Note, however, that these data are not a definitive benchmark of antibiotic efficacy because 63% of antibiotictreated patients in these types of trials experienced clinical resolution at the end of therapy despite the apparent lack of bacteriological response in midtherapy.[18] In Vivo Clinical Efficacy After Therapy

Surprisingly, a single drug has been used as a standard comparator (amoxicillin-clavulanic acid) in all US Food and Drug Administration (FDA) clinical tympanocentesis trials for AOM in the US during the 1990s. These data comparing new antibiotics against this ‘gold standard’ antibiotic often reveal some of the potential pathogen weaknesses of many newer antibiotics that have recently been approved. These data are published in the PhysiTable III. Causes of treatment failure in acute otitis media (AOM) Microbiological/pharmacodynamic factors

3.5.1 Tympanocentesis Trials

Highly resistant pathogen (MIC >> MEE concentration)

In Vivo ‘Sensitivity Test’

Inadequate MEE concentration of an antibiotic for a usually susceptible pathogen

Howie evaluated the efficacy rates of many older antibiotics in the late 1980s, before the emergence of high rates of β-lactamase–producing H. influenzae and PRSP.[52] Nonetheless, for particular pathogens, his data reveal distinct ‘Achilles heels’ of certain older antibiotics used to treat AOM (see table V). Howie performed an initial pre-therapy tympanocentesis and repeated the procedure 2 to 7 days into therapy to document microbiological efficacy for AOM. His results showed that, with certain exceptions, second-generation cephalosporins and clarithromycin appear to have an ‘Achilles heel’ for H. influenzae (few strains were β-lactamase–producing), whereas certain thirdgeneration cephalosporins appear to have an ‘Achilles heel’ for S. pneumoniae (even before the decade of PRSP). Furthermore, he clearly showed that pneumococcus persists in 81% of patients with © Adis International Limited. All rights reserved.

Protection by a copathogen viral[35] β-lactamase–producing organism[49]

Chlamydia pneumoniae[20] Inadequate spectrum of empiric antimicrobial coverage (e.g. cotrimoxazole (trimethoprim-sulfamethoxazole) for Streptococcus pyogenes, cefixime for S. pneumoniae) Host factors Nonadherence: parental vs child Reduced absorption: gastroenteritis or antibiotic-induced increased motility Poor eustachian tube function: anatomical or functional (infancy, otitis prone) Environmental factors Daycare environment with secondary reinfection by viral URTI or AOM bacterial pathogen Smoking household MEE = middle ear effusion; MIC = minimum inhibitory concentration; URTI = upper respiratory tract infection; >> = much greater than.

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Table IV. Factors to consider when selecting an effective antibiotic for therapeutic failures (adapted from Harrison[51]) Likelihood of different pathogens (PRSP, Haemophilus influenzae) by each age group in the particular community in antibiotic failures Current susceptibility patterns of bacterial isolates from paediatric AOM Pharmacokinetics (dosage intervals) Pharmacodynamics: in vitro predicted efficacy (MEE or serum concentrations vs bacterial MICs)

In vivo efficacy data (tympanocentesis trials) Adverse effects, palatability, costs AOM = acute otitis media; MEE = middle ear effusion; MICs = minimum inhibitory concentrations; PRSP = penicillin-resistant Streptococcus pneumoniae.

cian’s Desk Reference (PDR)[53] and provide unbiased, objective, readily available information based upon more stringent, standardised criteria than other information which is sometimes published. All patients in these trials have undergone tympanocentesis, indicative of culture-proven, severe and real ‘AOM’. Any antibiotic displaying a trend towards a lower efficacy rate, either overall or for a specific pathogen compared with amoxicillin-clavulanic acid, is highlighted in the US AOM efficacy data in the PDR. The absence of a disclaimer in the PDR regarding efficacy for AOM suggests that the following newer agents appear to be drugs showing efficacy equivalent to amoxicillin-clavulanic acid for first-line patients: cefpodoxime (twice daily only), cefuroxime and the newest cephalosporin, cefdinir.[54] Azithromycin for 5 days was equivalent to amoxicillin-clavulanic acid at 1 month after therapy because of the prolonged half-life (76 hours) of the former drug. Neither of the 2 single dose ceftriaxone trials reported in the PDR were conducted in tympanocentesis patients. Even in these easier-to-treat patients, single dose ceftriaxone was statistically less effective than amoxicillin-clavulanic acid, and merely as effective as a less-than-optimal, narrow spectrum second-line agent – cotrimoxazole (tri© Adis International Limited. All rights reserved.

methoprim plus sulphamethoxazole) – a drug demonstrating poor efficacy in persistent AOM (75% failure rate).[50] Thus, analysing these easy-to-find tympanocentesis data for many of the newer antibiotics of the 1990s may help practitioners reduce some of the statistical ‘Pollyanna phenomenon’ and ‘background noise’ touted in many nontympanocentesis trials. It may also help to uncover some of the ‘Achilles heels’ of particular antibiotics. In Vitro Data Predicting In Vivo Efficacy Based on Pharmacodynamics

Craig and Andes[55] have presented an insightful approach for predicting β-lactam and sulpha antibiotic efficacy by comparing pharmacokinetic and pharmacodynamic data. Their pharmacodynamic model shows that serum concentrations of an antibiotic must remain above the pathogen MIC 90 value for more than 40 to 50% of the dosage interval in order to achieve 90% or more efficacy for a particular pathogen, as corroborated by both animal and human models of infection. Limitations of these data include: the lack of distinction between β-lactamase–positive or –negative H. influenzae; the fact that most of the isolates were obtained from adults prior to 1993; and the lack of applicability to the 2 newer macrolides because of their extremely high tissue penetration and the prolonged half-life of azithromycin. In addition, the model may not apply to short course β-lactam therapy or single dose ceftriaxone. Table V. In vivo sensitivity test – acute otitis media efficacy midtherapy: bacteriological failure rates by drug (adapted from Klein,[52] with permission)

Streptococcus pneumoniae (%) Placebo 81 Amoxicillin 6 Cefaclor 18 Cefixime 26 Cefpodoxime 17 Cefprozil 8 Clarithromycin 0 Cotrimoxazole (trimethoprim- 12 sulfamethoxazole)

Drug

Haemophilus influenzae (%) 52 21 33 6 5 57 80 25

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The central question regarding antibiotic efficacy for AOM revolves around the issue: ‘Does enough drug to kill the bug get to the infected site?’[56] In other words, does the peak MEE concentration from AOM exceed the MIC50-90 values for more resistant (and recently reported paediatric AOM) pathogens, particularly PRSP and βlactamase–positive H. influenzae? As table VI shows, only a handful of antibiotics used to treat AOM achieve high concentrations in MEE.[42] For MEE concentrations, clinicians need only remember the 2 new macrolides (≈9 mg/L), azithromycin and clarithromycin; 2 newer cephalosporins (≈4 mg/L), ceftibuten and loracarbef; and high dose amoxicillin (≈6 mg/L) with or without clavulanic acid. All other antibiotics, except for the sulpha components, have MEE concentrations ranging between 0.5 and 2.0 mg/L. The macrolides concentrate primarily in the intracellular compartment of the infected site or in the leucocytes, whereas the β-lactams concentrate in the extracellular compartment. The benefit of aggregating in either respective compartment is still theoretical and unproven. To predict antibiotic efficacy, mean peak MEE concentration data have been applied to recent, problematic paediatric AOM isolates which are most likely to be encountered after failure with a course of antibiotic(s) as shown in table VII. When either serum or MEE concentration data are analysed, trends in the in vitro data tend to corroborate in vivo tympanocentesis data regarding specific pathogen coverage for each antibiotic. Using these in vitro data for intermediate PRSP, amoxicillin-clavulanic acid, cefprozil, cefuroxime, cefpodoxime, amoxicillin, clarithromycin and azithromycin would be antibiotic choices expected to perform reasonably well. (Only the first 3 antibiotics have some sparse corroborative in vivo data.) Clindamycin, although not approved for AOM and tested in a limited number of cases of PRSP,[11] would also be expected to perform well. For highly resistant PRSP, only the aminopenicillins and clindamycin, which have limited in vivo efficacy data, and the 2 new macrolides (high MEE © Adis International Limited. All rights reserved.

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Table VI. Antibiotic drugs with high middle ear effusion (MEE) penetration in acute otitis media Drug

Time after initial Peak MEE dose (h) concentration (mg/L)

Amoxicillina

1.5-4.0

4.0-6.2

Azithromycin

24

8.6

48

9.4

Ceftibuten

4.0

4.0

Clarithromycinb

64.0

8.3

14-hydroxy-clarithromycin

64.0

2.9

total clarithromycinc

64.0

11.2

Loracarbef

2.0

2.0-3.9

Most other oral antibioticsd

1.5-4.0

0.5-2.0

a

15-45 mg/kg/dose.

b

Dose administered 4h after the fifth dose.

c

MEE concentration of clarithromycin plus 14-hydroxyclarithromycin.

d

Many MEE concentrations of older antibiotics were obtained in children with chronic otitis media with effusion undergoing tympanostomy tube placement.

concentrations relative to MIC50 values) which have no efficacy data, may be potential selections. Furthermore, as suggested by unbiased PDR tympanocentesis data, new second-generation cephalosporins and clarithromycin in general appear to be less efficacious for β-lactamase–producing H. influenzae (except for cefuroxime). Two thirdgeneration cephalosporins (cefixime is nearly equivalent to ceftibuten) are less efficacious for penicillin-susceptible (or -resistant) S. pneumoniae. Ceftriaxone has the best susceptibility and pharmacodynamic profile; however, it is a parenterallyadministered drug and currently lacks any published peer reviewed data regarding single dose therapy either in tympanocentesis-documented AOM or in patients with persistent AOM. Studies are under way in Europe for the latter indication using intramuscular doses of ceftriaxine 50 mg/kg for 3 days. Cefdinir, which is expected to be available in 1999, has a bacteriological susceptibility profile similar to that of cefpodoxime and an efficacy similar to that of amoxicillin-clavulanic acid in tympanocentesis trials. It can be administered Paediatr Drugs 1999 Jan-Mar; 1 (1)

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Table VII. The likelihood of an antibiotic middle ear effusion (MEE) concentration exceeding MIC50 or MIC90 values for a particular pathogen in paediatric patients with acute otitis media (AOM) (MIC50 or MIC90 values from rural Kentucky children from 1992 to 1995)

Amoxicillinc

4.0-6.3

Amoxicillin-clavulanic acidc

4.0-6.3

Penicillin-resistant Streptococcus pneumoniae highly resistanta intermediately (n = 33) resistantb (n = 43) ++ +++ ++ +++

Azithromycin

8.6

++

+++

++

+++

Cefaclor

0.47-7.0

–

–

+

+

++

Cefixime

0.35-2.86

–

–

+++

+++

+++

Cefpodoxime

0.49-0.87

–

++

+++

+++

+

Cefprozil

2.0

–

++

+

++

++

Cefuroxime

0.61

+

++

++

++

++

Clarithromycin

7.4 (11.2)d

++

+++

+

+

+++

Clindamycin

3.6

+++

+++

–

–

–

Cotrimoxazole (trimethoprimsulfamethoxazole)e

1.39-2.0

+

++

+

++

++

Erythromycin

0.5

+

+++

–

–

+++

Antibiotic

a

Mean peak MEE concentration (mg/L)

Haemophilus influenzae positive (n = 60)

negative (n = 74)

Moraxella catarrhalis positive (n = 40)

–

++

–

+++

+++

+++ +++

Penicillin MIC ≥ 2.0 mg/L.

b

Penicillin MIC = 0.1 to 1.0 mg/L.

c

Amoxicillin-clavulanic acid in a ratio of 2 : 1; peak MEE concentration is presumed to be the same as amoxicillin in the equivalent dose. Higher range reported used a dosage of 45 mg/kg/dose.

d

Total clarithromycin = clarithromycin plus 14-hydroxy-clarithromycin.

e

Trimethoprim plus sulfamethoxazole in a ratio of 19 : 1.

MIC = minimum inhibitory concentration; + = coverage of 10-50% of organisms; ++ = coverage of 50-90% of organisms; +++ = coverage of >90% of organisms; – = <10% coverage.

either once or twice daily and apparently has no palatability problems.[54] 3.6 Adverse Effects

The antibiotics used to treat patients with AOM are extremely well tolerated but occasionally produce minimal to moderate adverse effects, with exceedingly rare serious adverse effects encountered. The most common adverse reactions observed with oral antibiotics are either dermatological or gastrointestinal in nature (table I).[57] The highest proportion of significant dermatological reactions are observed with 3 antibiotics: cefaclor, cotrimoxazole and erythromycin-sulfisoxazole (sulfafurazole). The author advocates avoiding the use of cefaclor in children because of the 1.5 to 3.4% incidence of serum sickness–like reactions that have been reported.[58,59] © Adis International Limited. All rights reserved.

The 2 combination sulpha drugs used for AOM (cotrimoxazole and erythromycin-sulfisoxazole) may cause generalised maculopapular and urticarial rashes in a small but significant number of children. Any antibiotic, but in particular cotrimoxazole, can rarely cause a severe and life-threatening Stevens-Johnson syndrome.[60] Most currently available oral antimicrobials cause gastrointestinal distress with moderate diarrhoea, vomiting or gastritis symptoms in approximately 5 to 10% of children. Ceftriaxone has the highest potential for anaphylaxis, and requires patient monitoring for at least 30 minutes after injection. Diarrhoea has been most frequently observed in children treated with amoxicillin-clavulanic acid. However, with the new twice daily formulation, the rate of diarrhoea has been reduced by half to about 9%, comparable with most other β-lactam Paediatr Drugs 1999 Jan-Mar; 1 (1)

Acute Otitis Media in the 1990s

antibiotics.[30] In addition, gastrointestinal intolerance may be further reduced by the ingestion of food or milk before administration; yogurt has no effect (personal unpublished data). The rates of diarrhoea also appear to be slightly worse in children younger than 12 months of age and clinicians may want to warn these families. Gastritis seems to occur most frequently with erythromycinsulfisoxazole (10%) and clarithromycin (5%). 3.7 Palatability Issues

The taste of some liquid formulations of antibiotics may be problematic for children, as shown in table I. If the antibiotic does not get beyond the mouth of a child, therapy is doomed. Clarithromycin and the 2 ester-based antibiotics, cefuroxime axetil and cefpodoxime proxetil, seem to be particularly troublesome. Cefuroxime axetil is especially unpleasant tasting for children and most practitioners avoid its liquid formulation. However, this antibiotic is not only FDA approved for children 3 months and older, but has a broad spectrum of coverage. If the child is younger than 6 months and drinks from a bottle, the taste issue may be surmounted by mixing the antibiotic with milk in the bottle. The taste or aftertaste of clarithromycin may be problematic after the initial doses, but it frequently can be circumvented by administering pre- and postdose liquid ‘chasers’ (such as chocolate milk or fruit punch, for example). Practitioners should also write ‘no refrigeration’ on each prescription for clarithromycin, whereas they should always write ‘refrigerate’ on prescriptions for cefpodoxime proxetil. Generic liquid formulations of erythromycin-sulfisoxazole and cotrimoxazole can also be troublesome. 3.8 Dosage Regimens

The dosage regimens are displayed in table I and will probably have a significant influence on patient adherence. Patient adherence to antimicrobial regimens diminishes rapidly with increased frequency of dosage (once daily 80%, twice daily 69% and 3 times daily 38%).[61] Only the newer © Adis International Limited. All rights reserved.

43

third-generation cephalosporins and azithromycin are approved for a single daily dosage regimen. All other antimicrobial agents used to treat AOM can be administered twice daily, except for erythromycinsulfisoxazole. In addition, azithromycin is prescribed for 5 days rather than the customary 10 days, and cefpodoxime as recently been approved for 5 day therapy. 4. Antibiotic Therapy for AOM in the 1990s Although high dose amoxicillin 60 to 80 mg/kg/day is not considered standard therapy for AOM, many experts have suggested that it may improve pathogen coverage, particularly for intermediate PRSP. Canafax and colleagues[35] and Lister et al.[62] have recommended doubling the standard dose of amoxicillin to 75 mg/kg/day divided 3 times daily or 70 to 90 mg/kg/day divided twice daily, respectively. However, in vitro data for amoxicillin-clavulanic acid also suggests that twice daily administration improves the area under the plasma concentration-time curve (AUC), time above MICs and peak plasma drug concentration (Cmax) of the amoxicillin component compared with thrice daily dosage.[63] In the author’s clinical experience over 5 years, no increase in adverse effects, such as diarrhoea or gastritis, are observed with routine use of higher doses of the amoxicillin component (60 to 80 mg/kg/day twice daily) alone or in combination with clavulanic acid. (This formulation will be available in 1999 as a 90mg amoxicillin/6.4mg clavulanic acid formulation in the US.) 4.1 Refractory AOM

Despite the emphasis of managed-care on using the least expensive antimicrobials for children with penicillin allergies or for second-line therapy after amoxicillin failure, in the decade of PRSP, the author does not advocate the following drugs: cotrimoxazole, erythromycin-sulfisoxazole or cefaclor, as being cost-effective second-line therapy. Cotrimoxazole does not cover Group A streptococcus, a pathogen which may be recovered in up Paediatr Drugs 1999 Jan-Mar; 1 (1)

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Amoxicillin 60-80 mg/kg/day

First-line

Success

4-36mo, severe AOM

Failure

Second-line

Azithromycin

± Cefuroxime

Cefpodoxime

Clarithromycin

Cefprozil, loracarbef

Amoxicillin/clavulanic acid

Success

Cefdinir

Failure

Third-line

Failure

Failure

Failure

Cefpodoxime

Azithromycin

High dose amoxicillin/clavulanic acid

Clarithromycin

Success

Cefdinir

Failure

Failure ± Tympanocentesis

Fourth-line

Clindamycin 20-30 mg/kg/day divided tid High dose amoxicillin/clavulanic acida Ceftriaxone 50 mg/kg/day for 3-5 days

Fig. 2. An algorithm for the antibiotic management of acute otitis media (AOM) in the 1990s, the decade of penicillin-resistant Streptococcus pneumoniae (PRSP). a Amoxicillin 40 mg/kg/day plus amoxicillin/clavulanic acid 45/6.4 mg/kg/day or the new formu-

lation amoxicillin/clavulanic acid 90/6.4 mg/kg/day.

to 15% of older children with AOM,[33] has weak coverage of both penicillin-susceptible and penicillinresistant pneumococcus, and may fail in up to 75% of cases of persistent AOM.[50] Also, nearly a quarter of strains of β-lactamase–positive H. influenzae in the US have recently been reported as resistant to cotrimoxazole in vitro.[64] Erythromycin-sulfisoxazole causes gastritis in approximately 10% of children, requires administration at least 3 times daily (which hampers compliance), achieves meagre MEE concentrations of the erythromycin component (0.2 to 0.5 mg/L), and creates palatability problems in up to 10% of children. This antibiotic provides weaker coverage of AOM pathogens, especially when analysed by each respective component of the compound. Susceptibility testing of 87 recent strains of Haemophilus isolates from paediatric acute conjunctivitis showed resistance to both erythromycin (MIC50 and MIC90 values 8 and 16 mg/L, respectively) and © Adis International Limited. All rights reserved.

sulpha drugs (128 and 256 mg/L, respectively) [personal data, 1997-98]. Pneumococcal isolates from the same series also showed profound resistance to sulpha drugs (MIC50 and MIC90 values of 32 and >256 mg/L, respectively). Furthermore, 2 other marcolides, clarithromycin and azithromycin, are priced similarly to erythromycin-sulfisoxazole for the younger and older patient, respectively. Although second-generation cephalosporins may be selected as second-line therapy (fig. 2), the author does not advocate their use for third-line therapy because of reduced in vitro coverage and in vivo efficacy for PRSP (except cefprozil) and β-lactamase–positive H. influenzae. Cefuroxime is an exception for resistance to both pathogens; however, very poor palatability precludes its routine use. After a child fails second-line therapy with a macrolide, practitioners should consider selecting one of the broad spectrum β-lactams, such as Paediatr Drugs 1999 Jan-Mar; 1 (1)

Acute Otitis Media in the 1990s

amoxicillin-clavulanic acid, cefpodoxime (twice daily) or cefdinir; and similarly, after a child fails second-line therapy with a β-lactam, they should consider either of the 2 new macrolides, clarithromycin or azithromycin.[26,42] Tympanocentesis should be considered as a possible adjunctive intervention for fourth-line therapy in children who have refractory AOM[65] (fig. 2). This procedure both drains the chronic abscess and allows for identification of the causative organism in order to specifically target therapy with the most active antimicrobial possible. However, only a handful of practitioners in the US, and throughout the rest of the world, perform tympanocentesis in the office; thus, teaching centres may want to reconsider instituting routine teaching of this procedure during training (table VIII). Current data show that PRSP may account for 44% and penicillin-susceptible S. pneumoniae another 25% of the pathogens in refractory AOM in the US; in France and Spain, PRSP may account for as many as 80 to 90% of the pathogens. Thus, for refractory AOM, clinicians should consider using oral clindamycin, amoxicillin combined with amoxicillin-clavulanic acid, or parenteral ceftriaxone (fig. 2).[11,65] The combined amoxicillin and amoxicillin-clavulanic acid (available in 1999) should primarily be considered if the patient has not previously been treated with standard doses of amoxicillin-clavulanic acid. Although clavulanic acid possesses no activity against PRSP, animal data suggest a positive synergistic effect for PRSP when it is combined with amoxicillin,[66] and it provides important additional coverage for the not uncommonly isolated β-lactamase–producing copathogens. In addition, although it is untested for AOM or PRSP, practitioners might consider empirically using a higher dose of azithromycin 12 mg/kg/day if it has not been prescribed for the current episode of refractory AOM. This dosage has been approved for streptococcal pharyngitis and may notably further increase the high antibiotic concentrations (≈9 mg/L) already achieved in MEE.[20] © Adis International Limited. All rights reserved.

45

Before selecting clindamycin as sole therapy, clinicians should ensure: (i) previous coverage of H. influenzae, because clindamycin does not cover that organism; and (ii) that strains of PRSP have been documented as susceptible to clindamycin in their region (43% clindamycin resistance has been reported in Spain).[47] Some authors[64] have advocated coadministration of clindamycin with another antibiotic possessing good Gram-negative coverage. This combination is particularly worrisome to this author in light of the propensity of clindamycin to cause antibiotic-induced colitis, albeit primarily reported in adults. Although sulfisoxazole has been advocated as an adjunctive antibiotic, most H. influenzae strains (the intended target) are currently resistant (see discussion in section 4.1). All prescriptions for clindamycin should include both an oral explanation and written notation on the prescription to discontinue the medication if severe diarrhoea or blood in the stool develops. For the treatment of refractory AOM ceftriaxone is an excellent choice, but, in the author’s opinion, should be administered at a dose of 50 mg/kg/day for a minimum of 3 to 5 days, and not as a single dose.[11] Despite the remarkably high peak MEE concentrations (35 and 19 mg/L at 24 and 48 hours, respectively) obtained with a single dose of ceftriaxone in patients with OME,[67] this single dose may be inadequate to alleviate or cure the signs and symptoms of AOM caused by PRSP after 72 to 96 hours, particularly in younger children.[11] No data are available for the use of single dose ceftriaxone for AOM failure. Ceftriaxone remains the simplest effective parenteral antibiotic for many serious infections in paediatric patients, and may actually facilitate Table VIII. Potential indications for tympanocentesis in children with bulging acute otitis media (AOM) Acute severe and unremitting otalgia, before or during therapy Refractory AOM unresponsive to multiple courses of antibiotics Febrile, possibly septic, hospitalised children with or without another source Suppurative complications: mastoiditis, meningitis, labyrinthitis

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Block

more cost-effective home-based parenteral therapy. Thus, theoretically, in order to limit any worsening of resistance of PRSP to this drug, the routine use of single dose parenteral ceftriaxone for AOM should be limited only to those children with concomitant significant gastroenteritis or poor oral intake, suspected bacteraemia (fever with leucocytosis) or more severe associated illness, or those with compliance problems (the obstreperous toddler and the itinerant or noncompliant family). It should not be used as an empirical ‘routine antipyretic’ for any febrile child in the office or emergency room. Single dose ceftriaxone has demonstrated efficacy comparable only with that of amoxicillin and cotrimoxazole[68,69] for first-line therapy, and then only in nontympanocentesis patients. Finally, some patients will fail even the most valiant attempts to eradicate their infection (or effusion), or will be such high risk candidates for significant otological problems such as those described in table IX, that they will require insertion of tympanostomy tubes. 4.2 Short Course Therapy

The standard duration of therapy for AOM empirically consists of 10 days with β-lactams, sulpha drugs or macrolides, and 3 or 5 days with azithromycin, in Europe or in the US, respectively. Although many other oral β-lactam drugs have been tested, only cefpodoxime has been approved for mild to moderate AOM as a 5 day therapy within the US. none has been approved yet for short course therapy in the US. Nonetheless, some authors are currently challenging the conventional wisdom of 10-day therapy with β-lactams for certain populations. They are now advocating 5- to 7-day therapy for uncomplicated AOM, but exclusively in children older than 4 to 5 years, who have less resistant pathogens and better eustachian tube function.[20,70] Children younger than 2 years in general seem to experience more failures with either 5- or 10-day therapy.[1,30] Clinicians must remember that because symptoms and infection in older patients tend to resolve © Adis International Limited. All rights reserved.

Table IX. When to refer for tympanostomy tube insertion Refractory AOM after 4 sequential courses of different efficacious antimicrobial agents Chronic OME: persisting for more than 3-4mo 6 or 7 recurrent episodes of AOM within a year, only if intervals of documented normal tympanic membranes ≥4 monthly episodes of AOM during the summer/autumn in healthy infants <12-18mo children at high risk for hearing loss or language delay (infants <6mo with recurrent AOM, history of prior hearing loss) children with severe eustachian tube dysfunction; e.g. Down’s syndrome, cleft palate, immunocompromised Retraction pockets, or hypertrophic white sclerosis possibly consistent with cholesteatoma AOM = acute otitis media; OME = otitis media with effusion.

much more quickly, families often discontinue treatment as soon as the symptoms have resolved and then hoard the leftover 5 days’ worth of pills to partially treat (1 to 2 days at a time) several more upper respiratory tract infections over the ensuing months. Therefore, for all patients younger than 13 years, the author staunchly advocates using liquid formulations, which also admonish caregivers to discard the suspension after 10 to 14 days (with the exception of cotrimoxazole). 4.3 Patients with Otorrhoea

The child who presents with a spontaneous perforation of the TM and obvious otorrhoea, without other mitigating factors, should be treated in the same manner as any other child with AOM. However, follow-up, regardless of age, must always be recommended at the end of therapy to ensure that the perforation has resolved and that a cholesteatoma has not formed. The child with a history of ventilating tubes who subsequently develops otorrhoea presents a different therapeutic dilemma. Block and cohorts[71] have shown that in these children, who tend to be younger (average age 24 months), oral antimicrobials should be selected as with the child with refractory AOM. The antibiotic should have coverage of PRSP because it accounts for half of pathogens recovered (53% PRSP of 42 pathogens, 1992-1997) within 24 hours of onset in this condition. However, the practitioner needs Paediatr Drugs 1999 Jan-Mar; 1 (1)

Acute Otitis Media in the 1990s

to be fully aware of the significant potential for β-lactamase–producing H. influenzae when selecting either high dose amoxicillin or clindamycin monotherapy. The author also advocates the instillation of topical ofloxacin aural drops with aural ‘pumping’ of the tragus 2 to 4 times daily for the first 3 or 4 days in those children with ventilating tubes. (Remember: antibiotic-steroid combination otic drops are extremely painful if they happen to reach the middle ear space.) If no improvement occurs within 48 hours, institute aural ‘toileting’ and suctioning daily and consider parenteral ceftriaxone for 3 to 5 days. 4.4 Additional Considerations for AOM

In the author’s opinion, the use of antimicrobial prophylaxis for recurrent AOM should probably be abandoned in the era of PRSP, as suggested by more recent data in the mid-1990s. The most current in vivo data (1993 to 1994) from Roark and Berman[72] found that prophylaxis with amoxicillin was no more effective than placebo in preventing recurrent AOM episodes in otitis-prone patients. Brook and Gober[73] and Guillemot et al.[74] observed that children treated with amoxicillin prophylaxis or low daily doses of an oral β-lactam, respectively, had higher rates of resistant organisms isolated in the nasopharynx after therapy. In vitro data suggest that subtherapeutic doses of antimicrobials induce and select out more resistant pathogens.[75] Because most strains of H. influenzae and S. pneumoniae are markedly resistant to sulpha drugs (see previous data in section 4.1), antimicrobial prophylaxis with sulfisoxazole may be nothing more than a risk for dermatological hypersensitivity. If antimicrobial prophylaxis for recurrent AOM is implemented, it should be limited to a shorter duration (2 to 4 weeks), used only in those patients with >4 episodes of recurrent AOM within a 6-month interval and patients should receive alternate amoxicillin with sulfisoxazole monthly if therapy is deemed necessary for longer than 1 month. In the long run, intermittent treatment of each recurrent episode of AOM and then © Adis International Limited. All rights reserved.

47

the insertion of PE tubes in failures as suggested in table IX may be the preferred therapy, rather than prophylaxis. As recommended in the American Academy of Pediatrics 1997 Redbook,[65] the available polysaccharide pneumococcal vaccine may be considered for children older than 24 months of age and prone to otitis who are attending daycare and still experiencing frequent episodes of AOM. The development of a multivalent protein-conjugate pneumococcal vaccine containing the most prevalent PRSP serotypes would be particularly beneficial to protect infants from the age of 9 to 24 months when they become at highest risk for AOM and, in particular, for PRSP. Either the available injectable or the newly developed cold-adapted nasal influenza vaccines (when available) should also be administered to children prone to otitis to protect against flu-induced episodes of AOM during the winter season.[76,77] 5. Conclusions AOM has become increasingly difficult to treat in the 1990s because of the high rates of PRSP and β-lactamase–producing H. influenzae being recovered from children with AOM. Clinicians can no longer expect ‘Pollyanna-like’ high rates of resolution with standard antibiotic therapy. Predicting the most effective antimicrobial therapy requires: (a) awareness of efficacy rates reported from unbiased sources using tympanocentesis; and (b) in vitro pharmacodynamic principles of antibiotic penetration at the site of infection compared with MIC50 and MIC90 values from key MEE pathogens. Treatment of refractory AOM often fails with standard therapy. Thus, clinicians must become fully aware of respiratory tract bacteriology from paediatric patients in their region and their antimicrobial susceptibility patterns. They should also become familiar with how to use either nonstandard doses of routine antibiotics or some nonstandard antibiotics for AOM. Antimicrobial prophylaxis currently appears to have more risks than benefits. Both newer broad spectrum antibiotics Paediatr Drugs 1999 Jan-Mar; 1 (1)

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and new protein-conjugate vaccines are desperately needed to battle PRSP and resistant nontypeable H. influenzae infections in children. References 1. Dowell SF, Marcy MS, Phillips WR, et al. Otitis media: principles for judicious use of antimicrobial agents. Pediatrics 1998; 101: S165-71 2. Teele DW, Klein JO, Rosner B, et al. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 1989; 160: 83-93 3. Block S, Hedrick J, Harrison CJ, et al. Increasing incidence of acute otitis media in the 1990s during the first 3 years of life. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1998 Sep 25-27; San Diego 4. Paradise JL, Rockette HE, Colborn DK, et al. Otitis media in 2253 Pittsburgh area infants: relevance and risk factors during the first two years of life. Pediatrics 1997; 99: 318-33 5. Wandstrat TL, Kaplan B. Pharmacoeconomic impact of factors affecting compliance with antibiotic regimens in the treatment of acute otitis media. Pediatr Infect Dis J 1997; 16 (2 Suppl.): S27-9 6. Chartrand SA, Klein JO, McCracken GH, et al. Treating otitis media in an age of antimicrobial resistance [monograph]. Fair Lawn (NJ): MPE Communications, Dec 1997 7. Klein JO. Current issues in upper respiratory tract infections in infants and children: rationale for antibacterial therapy. Pediatr Infect Dis J 1994; 13: S5-8 8. Boken DJ, Chartrand SA, Goering RV, et al. Colonization with penicillin-resistant Streptococcus pneumoniae in a child-care center. Pediatr Infect Dis J 1995; 14: 879-84 9. Duchin JS, Breiman RF, Diamond A, et al. High prevalence of multidrug-resistant Streptococcus pneumoniae among children in a rural Kentucky community. Pediatr Infect Dis J 1995; 14: 745-50 10. Wald ER, Dashefsy B, Byers C, et al. Frequency and severity of infections in day care. J Pediatr 1988; 112: 540-6 11. Block SL, Harrison CJ, Hedrick JA, et al. Penicillin-resistant Streptococcus pneumoniae in acute otitis media: risk factors, susceptibility patterns, and antimicrobial management. Pediatr Infect Dis J 1995; 14: 751-9 12. Myer III CM, France A. Ventilation tube placement in a managed care population. Arch Otolaryngol Head Neck Surg 1997; 123: 226-8 13. Manous II AG, Hueston WJ, Clark JR. Antibiotics and upper respiratory infection: do some folks think there is a cure for the common cold? J Fam Pract 1996; 42: 357-61 14. Heikkinen T, Ruuskanen O. Temporal development of acute otitis media during upper respiratory tract infection. Pediatr Infect Dis J 1994; 13: 659-60 15. Schwartz RH, Rodriguez JR, Brook I, et al. The febrile response in acute otitis media. JAMA 1981; 245: 2057-8 16. Block SL. Dispose of the disposables [letter]. Pediatr Inf Dis J 1998; 12: 1179-80 17. Paradise JL. Managing otitis media: time for a change [letter]. Pediatrics 1995 Oct; 96: 712-5 18. Marchant CD, Carlin SA, Johnson CE, et al. Measuring the comparative efficacy of antibacterial agents for acute otitis media: the ‘Pollyanna phenomenon’. J Pediatr 1992; 120: 72-7

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19. Pichichero ME, Mclinn S, Aronovitz G, et al. Cefprozil treatment of persistent and recurrent acute otitis media. Pediatr Infect Dis J 1997; 16: 471-8 20. Block SL. Causative pathogens, antibiotic resistance and therapeutic considerations in acute otitis media. Pediatr Infect Dis J 1997; 16: 449-56 21. Doern GV, Brueggemann AB, Pierce G, et al. Antibiotic resistance among clinical isolates in the United States in 1994 and 1995 and detection of B-lactamase–positive strains resistant to amoxicillin-clavulanate: results of a national multicenter surveillance study. Antimicrob Agents Chemother 1997; 41: 292-7 22. Jorgensen JH, Doern GV, Maher LA, et al. Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother 1990; 34: 2075-80 23. Baquero F, Martinez-Beltran J, Loza E. A review of antibiotic resistance patterns of Streptococcus pneumoniae in Europe. J Antimicrob Chemother 1991; 28 Suppl. C: 31-8 24. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3: 171-96 25. Neu HC. Otitis media: antibiotic resistance of causative pathogens and treatment alternatives. Pediatr Infect Dis J 1995; 14: S51-6 26. Friedland IR, McCracken GH. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994; 6: 377-82 27. Doern GV, Brueggeman A, Holley HP, et al. Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996; 40: 1208-13 28. Hofmann J, Cetron MS, Farley MM. The prevalence of drugresistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995; 333: 481-6 29. Kaplan SL, Mason EO, Barson WJ, et al. Three year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics 1998; 102: 538-45 30. Hoberman A, Paradise JL, Block S, et al. Efficacy of amoxicillin/clavulanate for acute otitis media: relation to Streptococcus pneumoniae susceptibility. Pediatr Infect Dis J 1996; 15 Suppl.: 955-62 31. Carlin SA, Marchant CD, Shurin PA, et al. Host factors and early therapeutic response in acute otitis media. J Pediatr 1991; 118: 178-83 32. Hoberman A, Paradise JL, Burch DJ, et al. Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin) for treatment of acute otitis media in children. Pediatr Infect Dis J 1997; 16: 463-70 33. Block SL, Hedrick JA, Smith RA., et al. Pathogens of acute otitis media (AOM) in a pediatric population: ≤7 months vs. ≥48 months. Presented at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1996 Sep 15-18; New Orleans 34. Chonmaitree T, Owen MJ, Patel JA, et al. Effect of viral respiratory tract infection on outcome of acute otitis media. J Pediatr 1992; 120: 856-62 35. Canafax DM, Yuan Z, Chonmaitree T, et al. Amoxicillin middle ear fluid penetration and pharmacokinetics in children with acute otitis media. Pediatr Infect Dis J 1998; 17: 149-56

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36. Ruuskanen O, Heikkinen T. Otitis media etiology and diagnosis. Pediatr Infect Dis J 1994; 13: S23-6 37. Del Baccaro MA, Mendelman PM, Inglis AF, et al. Bacteriology of acute otitis media: a new perspective. J Pediatr 1992; 120: 81-4 38. Post JC, Preston RA, Aul JJ, et al. Molecular analysis of bacterial pathogens in otitis media with effusion. JAMA 1995; 273: 1598-604 39. Rayner MG, Zhang Y, Gorry MC, et al. Evidence of bacterial metabolic activity in culture-negative otitis media with effusion. JAMA 1998; 279: 296-9 40. Klein JO, Teele DW. Isolations of viruses and mycoplasmas from middle ear effusions: a review. Ann Otorhinolaryngol 1976; 85 Suppl. 25: 140-4 41. Block S, Hammerschlag MB, Hedrick J, et al. Chlamydia pneumoniae in acute otitis media. Pediatr Infect Dis J 1997; 16: 858-62 42. Pichichero ME. Assessing the treatment of alternatives for acute otitis media. Arch Fam Pract. In press 43. Hathaway TJ, Katz HP, Dershewitz RA, et al. Acute otitis media: who needs posttreatment follow-up? Pediatrics 1994; 94: 143-7 44. Block SL, Mandel E, McLinn S, et al. Spectral gradient acoustic reflectometry for the detection of middle ear effusion by pediatricians and parents. Pediatr Inf Dis J 1998; 17: 559-63 45. Schwartz RH, Rodriguez WJ, Khan WN. Persistent purulent otitis media. Clin Pediatr 1981; 20: 445-7 46. Barry B, Gehanno P, Blumen M, et al. Clinical outcome of acute otitis media caused by pneumococci with decreased susceptibility to penicillin. Scand J Infect Dis 1994; 26: 446-52 47. Del Castillo F, Baquero-Artigao F, Garcia-Perrea A. Influence of recent antibiotic therapy on antimicrobial resistance of Streptococcus pneumoniae in children with acute otitis media in Spain. Pediatr Infect Dis J 1998; 17: 94-7 48. Barenkamp SJ, Shurin PA, Marchant CD, et al. Do children with recurrent Haemophilus influenzae otitis media become infected with a new organism or reacquire the original strain? J Pediatr 1984; 105: 533-7 49. Brook I, Yocum P. Bacteriology and beta-lactamase activity in ear aspirates of acute otitis media that failed amoxicillin therapy. Pediatr Infect Dis J 1995 Sep; 14 (9): 805-8 50. Pichichero ME, Pichichero CL. Persistent acute otitis media I: causative pathogens. Pediatr Infect Dis J 1995; 14: 178-83 51. Harrison CJ. Rational selection of antimicrobials for paediatric upper respiratory infections. Paediatr Infect Dis J 1995; 14 (7 Suppl.): S121-9 52. Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J 1993; 12: 973-5 53. Physicians’ Desk Reference. 52nd ed. Montvale (NJ): Medical Economics Data Production Company, 1999 54. McCarty JM, Block SL, Hedrick JA, et al. Comparative safety and efficacy of cefdinir versus amoxicillin/clavulanate for treatment of acute suppurative otitis media in children. Pediatr Infect Dis J. In press 55. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics pf antibiotics in otitis media. Pediatr Infect Dis J 1996 Mar; 15 (43): 255-9 56. Block SL. Strategies for dealing with amoxicillin failures in acute otitis media. Arch Fam Pract. In press

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57. McCarty J, Hedrick JA, Block SL, et al. Serum sickness– like reactions to amoxicillin, cefaclor, cephalexin, and trimethoprim-sulfamethoxazole. J Infect Dis 1988; 158: 474-7 58. Platt R, Dreis MW, Kennedy DL, et al. Serum sickness–like reactions to amoxicillin, cefaclor, cephalexin and trimethoprim-sulfamethoxazole. J Infect Dis 1988; 158: 474-7 59. Levine LR. Quantitative comparison of adverse reactions to cefaclor vs. amoxicillin in a surveillance study. Pediatr Infect Dis J 1985; 4 (4): 358-61 60. Ginsburg CM. Stevens-Johnson syndrome in children. Pediatr Infect Dis J 1982; 1: 155-8 61. Sclar DA, Tartaglione TA, Fine MJ. Overview of issues related to medical compliance with implications for the outpatient management of infectious diseases. Infect Agents Dis 1994; 3: 266-73 62. Lister PD, Pong A, Chartrand SA, et al. Rationale behind highdose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies. Antimicrob Agents Chemother 1997; 41: 1926-32 63. Reed MR. Clinical pharmacokinetics of amoxicillin and clavulanate. Pediatr Infect Dis J 1996; 15: 949-54 64. Chartrand SA. Antibiotic resistance in pediatric respiratory tract pathogens. Semin Pediatr Infect Dis 1998 Oct; 9 (4): 292-300 65. American Academy of Pediatrics. Pneumococcal infections. In: Peter G, editor. 1997 Red Rook: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village (IL): American Academy of Pediatrics, 1997: 416 66. Bottenfield G, Hoberman A, Burch DJ, et al. A new formulation of amoxicillin-clavulanate for the treatment of drug-resistant Streptococcus pneumoniae. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1998 Sep 27-28; San Diego 67. Gudnason T, Gudbrandsson F, Barsanti F, et al. Penetration of ceftriaxone into the middle ear fluid of children. Pediatr Infect Dis J 1998; 17: 258-60 68. Green SM, Rothrock SG. Single-dose intramuscular ceftriaxone for acute otitis media in children. Pediatrics 1993; 91: 23-30 69. Barnett ED, Teele DW, Klein JO, et al. Comparison of ceftriaxone and trimethoprim-sulfamethoxazole for acute otitis media: Greater Boston Otitis Media Study Group. Pediatrics 1997; 99: 23-8 70. Paradise JL. Short-course antimicrobial treatment for acute otitis media: not best for infants and young children. JAMA 1997; 278: 1640-2 71. Block SL, Hedrick JA, Smith RA, et al. Culture of spontaneously draining acute otitis media (AOM): a practical epidemiologic technique for assessing community-wide resistance in pediatric AOM. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1997 Sep 28Oct 1; Toronto 72. Roark B, Berman S. Continuous twice daily or once daily amoxicillin prophylaxis compared with placebo for children with recurrent acute otitis media. Pediatr Infect Dis J 1997; 16: 376-81 73. Brook I, Gober AE. Prophylaxis with amoxicillin or sulfisoxazole for otitis media: effect on the recovery of penicillin-resistant bacteria from children. Clin Infect Dis 1996; 22: 143-5

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74. Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of β-lactam. JAMA 1998; 279: 365-70 75. Negri MC, Morosini MI, Loza E, et al. In vitro selective antibiotic concentrations of β-lactams for penicillin-resistant Streptococcus pneumoniae populations. Antimicrob Agents Chemother 1994; 38: 122-5 76. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med 1998; 20: 1405-12

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77. Clements DA, Langdon L, Bland C, et al. Influenza A vaccine decreases the incidence of acute otitis media in 6- to 30month old children in day care. Arch Pediatr Adolesc Med 1995; 149: 1113-7

Correspondence and reprints: Stan L. Block, MD, Kentucky Pediatric Research, Incorporated, 201 South 5th Street, Bardstown, KY 40004, USA.

Paediatr Drugs 1999 Jan-Mar; 1 (1)