P&T News: March 1995, Vol. 15, No. 9

Antibiotic Treatment of Otitis Media

Mark K. Sorenson, R.Ph., and Douglas E. Morgan, R.Ph.
Peer Review Status: Internally Peer Reviewed by Jody R. Murph, M.D., Associate Professor, Department of Pediatrics, and Richard J. Smith, M.D., Professor, Department of Otolaryngology

Pathophysiology
The term otitis media is used to describe inflammation of the mucoperiosteal lining of the middle ear. Patients may present to clinicians with otitis media of two common types:

• Acute otitis media - fluid in the middle ear accompanied by signs or symptoms of ear infection (bulging eardrum usually accompanied by pain; or perforated eardrum, often with drainage of purulent material).
  
• Otitis media with effusion - fluid in the middle ear without signs or symptoms of ear infection.

Serious complications of otitis media are infrequent due to prompt diagnosis and treatment, but may occur when there is extension of inflammation and infection beyond the mucoperiosteal lining of the middle ear.4 These complications may include mastoiditis, meningitis, epidural abscess, or osteomyelitis of the temporal bone.

Numerous investigators have studied the etiologic pathogens associated with otitis media in children. Most studies have concentrated on bacterial pathogens in children between 1 month and 6 years of age. Bacteria may be isolated from middle ear fluid in about two-thirds of patients with acute otitis media and in one-third to one-half of specimens obtained at the time of myringotomy or tympanostomy tube placement in patients with middle ear effusions.5 The most common bacterial pathogens recovered from the middle ear of patients with acute otitis media are Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. In otitis media with effusion these organisms, plus Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, are prevalent. 10 Sterile cultures are noted following needle tympanocentesis in about one third of patients with acute otitis media; this may reflect limitations of bacterial culture methods, but may also be related to the etiologic role of certain viruses in the development of otitis media. 10

Colonization of the nasopharynx with pathogenic bacteria is thought to be the initial event in the pathogenesis of acute otitis media.11 Concomitant viral infection may induce respiratory epithelial injury, leading to eustachian tube inflammation and obstruction, causing impairment of middle ear drainage.l2 Acute otitis media develops when there is reflux, aspiration, or insufflation of nasopharyngeal bacteria through the eustachian tube into the middle ear. The frequent occurrence of otitis media in otherwise healthy children is in part a reflection of the fact that the eustachian tube of the young child is shorter, wider, straighter, and more horizontal than that of the older child. Therefore, organisms from the nasopharynx are able to reach the middle ear more readily than they do in older individuals. The mucosa of the eustachian tube becomes hyperemic and edematous, resulting in its obstruction.

Risk factors associated with the development of otitis media have included day care attendance, parental smoking, presence of wood-burning stoves, bottle feeding in a supine position, and not being breast fed. 13

Treatment
The optimal management of acute otitis media is unclear as evidenced by the diverse conclusions expressed in recent review articles.l4-20 It is generally agreed that antibiotic therapy improves the clinical course of acute otitis media. Early use of antibiotics may improve and accelerate acute symptomatic relief 2l and may decrease the incidence of delayed suppurative complications such as mastoiditis. A recent meta-analysis of children (n= 5400, 33 clinical trials) receiving antibiotics for acute otitis media found that antimicrobial drugs have a modest, but significant impact (p less than 0.05) on the primary control of acute otitis media when compared to placebo or no drug.2l Meta-analysis of antibiotic therapy directed exclusively to otitis media with effusion revealed a similar modest, but significant, benefit of antibiotic therapy. 1 Treatment with antibiotics usually provides control of infections prior to tympanic membrane rupture or development of severe complications such as mastoiditis. In the pre-antibiotic era, many cases of acute otitis media healed spontaneously. However, this resolution frequently required myringotomy or followed spontaneous perforation of the tympanic membrane. Serious intracranial complications developed in about 3% of cases in the pre-antibiotic era, whereas the incidence of intracranial complications has fallen to about 0.15% following the introduction of antibiotics.22

Appropriate antibiotic selection for acute otitis media is based in part on knowledge of the likely pathogens and the susceptibility to antibiotics of any organism isolated from a patient. Many experts continue to recommend amoxicillin for the initial empiric treatment of all episodes,l4-l7 though some limit this to situations where betalactamase-producing organisms are not expected.l8 Others suggest initial treatment with a beta-lactamase-stable drug because of presumed cost effectiveness or an increased prevalence of amoxicillin-resistant organisms.l9,20 However, therapy should not be based only on the theoretical advantage of an extended antibacterial spectrum of a given drug. Although an extended spectrum antibiotic may in some series demonstrate improved bacteriologic outcomes, it is not clear that acute or delayed clinical outcomes associated with these expensive drugs are superior to those associated with narrower-spectrum antibiotics21 such as amoxicillin or trimethoprim-sulfamethoxazole (Bactrim(R), Septra(R)).

Antibiotic selection should also be based upon knowledge of the antibiotic concentration that can be achieved at the site of the infection and results of controlled studies of antibiotic therapy in which efficacy has been based on both the clinical results obtained and eradication of pathogens isolated from the middle ear.22 The concentrations of various penicillins within the middle ear after oral administration have been assessed. Oral penicillins G and V achieve concentrations within the middle ear sufficient to inhibit most strains of S. pneumoniae. Concentrations of oral penicillin, however, exceed the minimum inhibitory concentration (MIC) of H. influenzae in only about 50% of cases; therefore, oral penicillin G or V is not recommended as therapy for acute otitis media. Administration of ampicillin or amoxicillin at doses typically used for otitis media achieves middle ear concentrations that exceed the MIC of the usual gram-positive organisms and equal or exceed the MIC for most strains of H. influenzae. In a comparative study of amoxicillin, cefaclor (Ceclor (R)), erythromycin-sulfisoxazole (Pediazole (R)), and trimethoprim-sulfamethoxazole, amoxicillin had the highest ratio of mean peak concentration in middle ear fluid to MIC for common pathogens of otitis media (excluding ampicillin-resistant H. influenzae).23 Trimethoprim-sulfamethoxazole had the highest ratio of mean peak concentration in middle ear fluid to MIC for ampicillin-resistant H. influenzae.

Drug Use Evaluation Initiative Results
The Drug Use Evaluation (DUE) program recently completed a review of antibiotic treatment choices in UIHC patients with a diagnosis of otitis media or middle ear effusion. Children 12 years of age or younger were evaluated. A random 7% sample of 1544 patients (identified during the six-month period 10/1/93 to 3/31/94) was selected for review. Of the 113 patients (545 cases) reviewed, 86 patients (504 cases) were managed by the Department of Pediatrics, while 27 patients (41 cases) were followed by Otolaryngology. Nearly all patients (103 of 113) were outpatients seen in the clinics.

The choice of antibiotic prescribed in the 545 cases is summarized in Table 1. Amoxicillin was chosen most frequently, followed closely by trimethoprim-sulfamethoxazole, while cefixime (Suprax (R)) and amoxicillin-clavulanate (Augmentin (R)) were the third and fourth most frequently chosen antibiotics. When different antibiotics were selected for subsequent episodes in the same patient, the most common antibiotic sequence was found to be amoxicillin, followed by trimethoprim-sulfamethoxazole, then amoxicillin-clavulanate or cefixime. [Note: Cefpodoxime (Vantin (R)), lorcarbacef (Lorabid (R)), cefprozil (Cefzil (R)), and cefaclor were not UIHC formulary antibiotics during this period.] Otolaryngology physicians saw more complicated, chronic cases and tended to prescribe broader spectrum antibiotics. Myringotomy and tube placement were more frequent in patients followed by Otolaryngology than in those followed by Pediatrics (93% versus 29%, respectively). Outcome assessment is difficult to evaluate with the retrospective study design employed, although resolution appeared to have been documented in 235 of 545 cases (43%). Infection failed to resolve in 114 cases (21%), while middle ear effusion with no infection was noted for 128 cases (23 %). Case outcome was unknown in 68 cases (12%), primarily due to failure to return for follow-up visits.

Table 1. Antibiotics Selected for Otitis Media/Middle Ear Effusion: Results of Drug Use Evaluation
Antibiotic Selected by Prescriber	Otitis Media (n=457 cases)a	Middle Ear Effusion (n=88 cases)a
Amoxicillin (Amoxil[R])	159 (35%)	21 (24%)
Trimethoprim-Sulfamethoxazole (Bactrim[R], Septa[R])	137 (30%)	22 (25%)
Cefixime (Suprax[R])b,c	64 (14%)	10 (11%)
Amoxicillin/clavulanate (Augmentin[R])	53 (12%)	21 (24%)
Erythromycin-Sulfisoxazole (Pediazole[R])	19 (4%)
Cefpodoxime (Vantin[R])b	10 (2%)
Cefaclor (Ceclor[R])c	9 (2%)	1 (1%)
Lorcarbacef (Lorabid[R])c	3 (less than 1%)
Cefprozil (Cefzil[R])c	2 (less than 1%)
Sulfisoxazole (Gantrisin[R])	2 (less than 1%)	14 (16%)
Miscellaneous Agents	4 (less than 1%)
__________ a Some cases were treated with multiple courses of antibiotics b Cefpodoxime replaced cefixime as the formulary broad-spectrum cephalosporin in July 1994 c Non-stocked agent at UIHC

Prophylaxis was used in 43 of 86 Pediatric patients (50%), and in 10 of 27 Otolaryngology patients (37%). Amoxicillin or trimethoprim-sulfamethoxazole was used in 48 of the 113 patients. Sulfisoxazole (Gantrisin(R)), cefixime, or amoxicillin-clavulanate use was split evenly among 30 patients. Erythromycin-sulfisoxazole and cefpodoxime were each used for prophylaxis in 2 patients. Otolaryngology physicians prescribed fewer courses of prophylactic antibiotics, but more of these patients also had tubes placed.

Adverse effects attributed to antibiotics were identified or reported in 30 of 113 patients (27%). The most frequent adverse reaction described was diarrhea, found in 12 patients (11%). Skin rash or hives (urticaria) was described in 9 patients (8%). Candida infection, oral thrush, or diaper rash was reported in 7 patients (6%). Neutropenia was attributed to trimethoprim-sulfamethoxazole in one patient.

The review suggested that antibiotic prescribing is generally consistent with literature supported guidelines in the Pediatric and Otolaryngology outpatient clinics at UIHC. Initial therapy consists of amoxicillin and trimethoprim-sulfamethoxazole, while antibiotics with broader antimicrobial activity (e.g., cefpodoxime, amoxicillin-clavulanate) are reserved for refractory cases.

Recommendations
Initial therapy of acute otitis media should consist of amoxicillin due to its activity against most of the usual pathogens and its superior penetration into middle ear fluid. Ampicillin also possesses these characteristics for the treatment of otitis media; however, its use has been associated with a greater incidence of loose stools and it is dosed more frequently. Therefore, the use of ampicillin has fallen into disfavor. In children who are penicillin allergic or who are suspected of being infected with a beta lactamase producing organism, trimethoprimsulfamethoxazole administered twice daily is recommended. Amoxicillin and trimethoprim sulfamethoxazole have safety and clinical efficacy comparable to more expensive alternatives in the initial therapy of otitis media. Antibiotic dosing and cost information are summarized in Table 2.

Table 2. Antibiotics Commonly Used at UIHC For The Treatment of Otitis Media
Antibiotic Oral Solution (Concentration per 5 ml)	Daily Dose	Typical Dose[a]
Amoxicillin 250 mg/5ml	20 to 40 mg/kg	125 mg TID
Trimethoprim-Sulfamethoxazole (Bactrim[R], Septra[R])[c] 40 mg/5ml (trimethoprim)	8 to 10 mg/kg (trimethoprim)	50 mg BID
Amoxicillin-Clavulanate (Augmentin[R])[d] 250 mg/5ml (amoxicillin)	20 to 40 mg/kg (amoxicillin)	125 mg TID
Cefpodoxime proxetil (Vantin[R]) 100 mg/5ml	10 mg/kg	60 mg BID
Erythromycin-Sulfisoxazole (Pediazole[R])[e] 200 mg/5ml (erythromycin)	50 mg/kg (erythromycin)	150 mg TID or QID
NOTE: This table includes only drugs stocked at UIHC.
[a] Typical daily dose for an 18-month-old toddler weighing 12 kg. [b] UIHC acquisition cost for specified 10-day course of therapy for a 12 kg. child. [c] Trimethoprim-sulfamethoxazole, 40 mg/5 ml trimethoprim, 200 mg/5 ml sulfamethoxazole. [d] Amoxicillin-clavulanate, 250 mg/5 ml amoxicillin, 62.5 mg/5 ml clavulanic acid. [e] Erythromycin ethylsuccinate-sulfisoxazole, 200 mg/5 ml erythromycin activity, 600 mg/5 ml sulfisoxazole.

In children refractory to therapy, the use of antibiotics with broader antimicrobial activity (e.g., amoxicillin-clavulanate, erythromycin-sulfisoxazole, and the cephalosporins) should be considered. Therapy decisions with these drugs should be guided by knowledge of the drug's side effect profile, anticipated compliance of the patient with the antibiotic dosing frequency, and cost of the drug under consideration.

References

1. Managing otitis media with effusion in young children. AHCPR Publication No. 94-0623. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. July 1994.

2. National Disease and Therapeutics Index. Plymouth

Meeting Pennsylvania (19462-1048):1MS America, 1992.

3. Pediatr Infect Dis J 1989;8:S114.

4. Otolaryngol ClinNorthAm 1994;27:431-41.

5. PediatrInJectDis J 1982;1:98-103.

6. Pediatrics 1979; 63:915-9.

7. Latyngoscone 1982;92:273-7.

8. JPediatr 1978;93:739-43.

9. Ann Stow Rhinol Larvneol 1970;79:358-70.

10. Scand J lnfect Dis 1994;93(Suppl):20-32.

11. Anna Rev Med 1978;29:285-306.

12. Laryngoscope 1977;87:493-507.

13. Otolaryngol Clin North Am 1991;24:775-86.

14. J Pediatr 1991;119:495-500.

15. Clin Infest Dis 1992;14(suppl 2):S 197-203.

16. J Pediatr Health Care 1990;4:297-303.

17. Ala Mod 1991;60:24-30.

18. Pediatr Infect Dis J 1987;6:985-8.

19. Pediatr Infect Dis J 1988;7:23-6.

20. Pediatr Infect Dis J 1989;8:806. [Letter].

21. J Pediatr 1994; 124:355-67.

22. Textbook of Pediatric infectious diseases. Philadelphia: Saunders; 1992:174-89.

23. J lnfect Dis 1982;145:815-21.

As noted in Table 1, in the first year of life, three doses each of diphtheria, tetanus, and pertussis (DTP) vaccine, Haemophilus influenzae type b (Hib) vaccine, and oral poliovirus (OPV) are recommended at 2, 4, and 6 months, though the third OPV dose may be given through age 18 months, and a third dose of Hib is not required for children who received Haemophilus b conjugate vaccine (Meningococcal Protein Conjugate--(PRP-OMP).

For hepatitis B vaccine, the first dose is recommended at birth but can be given up to age 2 months; the second is recommended at 2 months but can be given at 1 to 4 months if at least one month has elapsed since the first dose; and the third dose is recommended at age 6 to 18 months.

Vaccines recommended at 12 to 15 months can be administered simultaneously during one visit or during two separate visits. The second mumps, measles, and rubella (MMR) dose may be given at entry to kindergarten or middle school. Tetanus and diphtheria (Td) is recommended at age 11 to 12 years, but may be given through age 14 to 16 years. When Td is given at 11 to 12 years, health care providers can use the opportunity to ensure that the child has received a second dose of MMR.

TABLE 1. Recommended childhood immunization schedule[1]-United States, January 1995
Vaccine	Birth	2 Mos.	4 Mos.	6 Mos.	12+ Mos.	15 Mos.	18 Mos.	4-6 Yrs.	11-12 Yrs.	14-16 Yrs.
Hepatitis B	HB-1
		HB-2		HB-3
Diphtheria, Tetanus, Pertussis[4]		DTP	DTP	DTP	DTP or DTaP at 15 months or more			DTP or DTaP	Td
H. influenzae type b[5]		Hib	Hib	Hib	Hib
Poliovirus		OPV	OPV	OPV				OPV
Measles, Mumps, Rubella[6]					MMR			MMR here or...	MMR here
[1] Recommended vaccines are listed under the routinely recommended ages. Shaded bars indicate range of acceptable ages for vaccination. [2] Vaccines recommended in the second year of life (i.e., 12 to 15 months of age) may be given at either one or two visits. [3] Infants born to hepatitis B surface antigen (HBsAg)-negative mothers should receive the second dose of hepatitis B vaccine between 1 and 4 months of age, provided at least 1 month has elapsed since receipt of the first dose. The third dose is recommended between 6 and 18 months of age. Infants bron to HBsAG-positive mothers should receive immunoprophylaxis for hepatitis B with 0.5 ml hepatitis B immune globulin (HBIG) within 12 hours of birth, and the appropriate dose of either vaccine (Recombivax HB[R] or Engerix-B[R]) at a separate site. In these infants, the second dose of vaccine is recommended at 1 month of age and the third dose at 6 months of age. All pregnant women should be screened for HBsAg during an early prenatal visit. [4] The fourth dose of diphtheria and tetanus toxoids and pertussis vaccine (DTP) may be administered as early as 12 months of age, provided at least 6 months have elapsed since the third dose of DTP. Combined DTP-Hib products may be used when these two vaccines are administered simultaneously. Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) is licensed for use for the fourth and/or fifth dose of DTP in children aged 15 months or older and may be preferred for these doses in children in this age group. [5] Three H. influenzae type b conjugate vaccines are available for use in infants: 1) oligosaccharide conjugate Hib vaccine (HbOC) (HibTITER[R]); 2) polyribosylribitol phosphate-tetanus toxoid conjugate (PRP-T) (ActHIB[R], OmniHIB[R]); and 3) Haemophilus b conjugate vaccine (Meningococcal Protein Conjugate) (PRP-OMP) (PedvaxHIB[R]). Children who have received PRP-OMP at a2 and 4 months of age do not require a dose at 6 months of age. After the primary infant Hib conjugate vaccine series is completed, any licensed Hib conjugate vaccine may be used as a booster dose at age 12 to 15 months. [6] The second dose of measles-mumps-rubella (MMR) vaccine should be administered EITHER at 4 to 6 years of age OR at 11 to 12 years of age. _______ Adapted from MMWR. 1995;43:960 and MMWR, 1995;44:174-5.

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