Antibiotic concentrations at the infection site: implications for AOM

January 2002

The literature contains numerous studies and review articles on the use of antibiotics for the treatment of acute otitis media (AOM); treatment recommendations for using specific antibiotics often differs among experts. Clinicians may choose from 16 antibiotics when treating a specific patient. While these antibiotics represent several different drug classes, many are from the same class, and differences among them are not always readily apparent.

The patient-specific evaluation of choosing an antibiotic can include several factors – patient allergy status, adverse effect profile, compliance factors (taste of suspensions, number of doses/day), cost and the clinician’s preferences (and biases). Other important factors include national and local bacterial sensitivity data and the pharmacologic and pharmacokinetic characteristics of each antibiotic. These latter factors, which may not be given as much conscious thought when choosing an antibiotic, will be the focus of this month’s column. As well, an appreciation of these factors is inherent in an understanding of the literature.

Antibiotic pharmacology

Essential to the effective use of antibiotics for AOM is an appreciation for their pharmacology. Antibiotics used for AOM treatment can be grouped into three classes: ß-lactams (penicillins and cephalosporins and a carbacephem), macrolides and miscellaneous (trimethoprim-sulfamethoxazole [TMP-SMX]).

Eleven of the 16 antibiotics used are ß-lactams, which bind to penicillin-binding proteins (PBP) to inhibit bacterial cell wall synthesis. This function is concentration independent – increasing concentration of the antibiotic at the site of infection beyond a certain point (the minimum inhibitory concentration [MIC] of the targeted bacterial pathogen) provides no additional benefit. What is most important is the time the antibiotic concentration is maintained above the pathogen’s MIC, for bacterial growth resumes once infected tissue antibiotic concentrations fall below the MIC.

Studies have shown that effective bacterial killing occurs when the free antibiotic concentration exceeds the MIC for 40%-50% of the dosing interval. Maximal killing occurs when antibiotic concentration exceeds the MIC for 60%-70% of the dosing interval. This principle also applies to the macrolide antibiotics. The site of infection for AOM is obviously the middle ear, and information on concentrations of antibiotics in middle ear fluid (MEF) is valuable. The concentration of antibiotics in MEF is not identical to blood concentrations; in general, 20%-50% of AOM antibiotic blood concentrations reach MEF. Quantifying antibiotic MEF concentrations can be difficult, for several factors may affect them – type of fluid obtained (suppurative [AOM] vs. serous or mucoid [chronic infections]), and timing of fluid sampling after antibiotic administration (when does the peak level occur?) It has been estimated that MEF:MIC ratios of approximately 3-6 are necessary for bacterial eradication. This has been shown in animal studies and in limited human studies. While some of these data – time above MIC – are known for some antibiotics, this information is not complete.

Bacterial surveillance

Also important to effective AOM treatment are bacterial sensitivity patterns. Clinicians should be aware of increasing bacterial resistance concerns, and resistance of Streptococcus pneumoniae is of paramount importance to pediatricians. Antibiotic activity toward Streptococcus pneumoniae is affected by alterations in the PBPs. As these alterations occur, the MIC of the organism increases. Current standards (breakpoints) for activity of penicillin toward S. pneumoniae are susceptible (<0.06 µg/ml), intermediate resistance (0.12-1.0 µg/ml), and resistant (>2.0 µg/ml). Breakpoints for amoxicillin differ: susceptible (<2.0 µg/ml), intermediate resistance (4.0 µg/ml), and resistant (>8.0 µg/ml).

Breakpoints also exist for other antibiotics used in AOM treatment. Thus, as MICs increase to S. pneumoniae, concentrations of antibiotics in MEF must also increase, to allow for similar time above MIC and MEF:MIC values. This is the basis for recent recommendations for increased antibiotic (eg, amoxicillin) dosages in the treatment of AOM, especially when resistant S. pneumoniae is known or suspected to be responsible. Antibiotics most likely to be effective have relatively low MICs to S. pneumoniae and/or achieve relatively high concentrations in MEF. Bacterial surveillance data then, both nationally and locally, assume significant importance.

Although S. pneumoniae is the major pathogen responsible for AOM in children, Haemophilus influenzae and Moraxella catarrhalis cannot be ignored. These organisms display resistance to many of the antibiotics used for AOM treatment mainly by production of ß-lactamase enzymes, enzymes that destroy the antibiotic’s basic structure (ß-lactam ring). Increasing concentrations of antibiotics sensitive to the various ß-lactamase enzymes are no more effective. Instead, another antibiotic containing ß-lactamase inhibitors should be used (eg, amoxicillin-clavulanate [Augmentin, GlaxoSmithKline] vs. amoxicillin).

Published bacterial surveillance studies of isolates from numerous centers located throughout the country are useful for determining trends in antibiotic activity and comparisons of activity among antibiotics. MIC₉₀ values (the MIC at which the growth was inhibited in 90% of organisms) are frequently given. One recent study (Doern) evaluated 1,531 isolates of S. pneumoniae from the 1999-2000 season from 33 U.S. medical centers. A rate of 34.2% nonsusceptibility toward penicillin was found, with a rate of full resistance of 21.5%. MICs to various ß-lactam antibiotics increased as well. Antimicrobial resistance was highest among MEF and sinus samples and among young children (0-5 years).

Resistance to amoxicillin (using the new amoxicillin breakpoints described above) was 6.3%. Resistance rates to other antibiotics were also determined: macrolides 26%, TMP-SMX 35.9%, and clindamycin 9.2%. Oral cephalosporins most active were cefpodoxime (Vantin, Pharmacia), cefuroxime axetil (Ceftin, Lifecycle Ventures), and cefdinir (Omnicef, Abbott). Ceftriaxone (Rocephin, Roche) also displayed good activity. Cefaclor, lorcarbef (Lorabid, Monarch), a carbacephem, and cefixime (Suprax, Wyeth Lederle) displayed relatively low activity.

Another study (Thornsberry) evaluated resistance rates among 1,276 isolates of S. pneumoniae and 1,476 isolates of H. influenzae and M. catarrhalis, from 51 medical centers during the 1996-1997 season. Twenty-six percent of S. pneumoniae isolates were nonsusceptible to penicillin (19% fully resistant). As with the previous study, respiratory and ear isolates, and isolates from young children (0-2 years) were most likely to display nonsusceptibility. Rates of nonsusceptibility varied by geographic region (low of 25% in Pacific region to high of 56% in East South Central region). ß-lactamase production was 35% for H. influenzae and 93% for M. catarrhalis. The most active oral cephalosporins toward S. pneumoniae were cefpodoxime and cefuroxime. Ceftriaxone displayed even greater activity (lower MIC₉₀). Several oral cephalosporins displayed relatively low activity toward S. pneumoniae: cefaclor, cefixime, ceftibutin (Cedax, Biovail), and lorcarbef. Twenty-six percent of S. pneumoniae isolates displayed resistance to macrolide antibiotics.

Middle ear fluid levels

Various studies have measured antibiotic MEF concentrations; however, these studies have been limited by low patient numbers or use of samples from chronic ear infections (antibiotic concentrations can differ in fluid from acutely infected ears). Additionally, it has been difficult to accurately determine peak concentrations and elimination half-lives in MEF, as multiple samples would be necessary, and this is difficult to perform in children. Nonetheless, available MEF antibiotic concentration data are valuable.

An in vitro pharmacokinetic model was used by Lister in 1997 to evaluate the use of antibacterial effects of increased amoxicillin doses on S. pneumoniae. Pneumococci cultures were exposed to amoxicillin concentrations of 3 µg/ml-9 µg/ml every 12 hours (with a simulated elimination half-life of 1.6 hours). It was determined that peak concentrations of 6 µg/ml-9 µg/ml would be needed in MEF to eliminate penicillin-nonsusceptible strains. Other studies have shown amoxicillin at doses of 13 mg/kg/dose-15 mg/kg/dose (40 mg/kg/day-45 mg/kg/day) to produce MEF concentrations of 1 µg/ml-6 µg/ml.

MEF concentrations have been measured for many of the antibiotics used in the therapy of AOM. Concomitant plasma levels have usually been additionally measured, and in general, approximately 20%-50% of plasma antibiotic concentrations are attained in MEF. A 1998 study (Canafax) evaluated MEF penetration and pharmacokinetics of amoxicillin (25 mg/kg per dose) in 30 children with AOM. A wide range of MEF values were found, with an estimated mean peak of 9.5 µg/ml. An MEF concentration of >2.0 µg/ml was attained in 60% of children. It was estimated that MEF levels were maintained above 1.0 µg/ml (MIC for intermediate-resistant S. pneumoniae) for 30%-40% of the dosing interval (BID dosing), which would likely yield a bacteriologic cure rate of 70%-75%. The researchers concluded that 75 mg/kg/day-90 mg/kg/day dosing should be used clinically.

Recently Dagan and colleagues published the results of a study (unblinded, open label) evaluating the use of amoxicillin-clavulanate extra strength (Augmentin ES-600, GlaxoSmithKline) dosed at 90 mg/kg/day to evaluate its bacteriologic and clinical efficacy in the treatment of AOM in 521 children. Tympanocentesis was performed on children with the first dose and repeated on day 4-6 for children infected with S. pneumoniae. Forty-six percent of S. pneumoniae organisms were nonsusceptible to penicillin and 8% were nonsusceptible to amoxicillin. MEF amoxicillin concentrations were not measured. Ninety-eight percent of all S. pneumoniae pathogens were eradicated; 91% of penicillin-nonsusceptible pathogens were eradicated (MICs 2 µg/ml-4 µg/ml), compared with 100% eradication for penicillin-susceptible pathogens (P<0.05). Children infected with penicillin-nonsusceptible S. pneumoniae were more likely to be younger and have received a recent course (<3 months) of antibiotics, which should not be surprising to pediatric clinicians.

Antibiotics available

Numerous antibiotics are available to treat AOM. Without large, well-done clinical trials (which are rare) to document superior efficacy of one antibiotic over another, clinicians are left with a variety of information to use when choosing an antibiotic. Having an appreciation for antibiotic pharmacology, antibacterial activity, and dosing principles is helpful when attempting to rationally choose an antibiotic most likely to be effective for a specific patient. The value of assessing a patient at risk for infection by penicillin-nonsusceptible S. pneumoniae is frequently mentioned in the literature and is supported by studies, such as several discussed here.

Children younger than 2 years who attend day care, and who have recently (within the preceding 3 months) been treated with an antibiotic are most at risk. Using an antibiotic that is relatively active toward nonsusceptible S. pneumoniae for these patients is rational. Amoxicillin continues to deserve preference as a first-line antibiotic, in part due to its excellent activity toward S. pneumoniae. Increasing the dose to 90 mg/kg/day increases activity toward nonsusceptible S. pneumoniae. Other antibiotics, as discussed above, have been shown by in vitro data to have good activity toward S. pneumoniae and other AOM pathogens. It is most important for clinicians to use information and data currently available when assessing which antibiotic is most likely to be effective for a particular patient.

For more information:

• Dagan R. Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media. Pediatr Infect Dis J. 2001;20:829-37.
• Lister PD. Rationale behind high-dose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies. Antimicrob Agents Chemother. 1997;41:1926-32.
• Thornsberry C. Survey of susceptibilities of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates to 26 antimicrobial agents: a prospective US study. Antimicrob Agents Chemother. 1999;43:2612-23.
• Doern GV. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother. 2001;45:1721-9.
• Canafax DM. Amoxicillin middle ear fluid penetration and pharmacokinetics in children with acute otitis media. Pediatr Infect Dis J. 1998;17:149-56.
• Craig WA. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J. 1996;15:255-9.