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Tips for using amoxicillin for AOM treatment
Antimicrobial resistance has forced many pediatricians to reconsider their therapeutic regimen for acute otitis media.
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Amoxicillin is generally accepted as the initial antibiotic of choice for most infants and children diagnosed with acute otitis media (AOM). Reasoning for using amoxicillin includes its good antimicrobial activity toward the bacterial pathogens commonly responsible for AOM, a low adverse effect profile, good tolerability and low cost.
Dosing of amoxicillin for AOM has traditionally begun at 40-45 mg/kg/day in 2-3 divided doses, and this is the dose that is found in the product’s labeling. However, higher doses are now more commonly recommended, as higher doses are more likely to provide enhanced effectiveness for AOM resulting from nonsusceptible Streptococcus pneumoniae.
Microbiology
S pneumoniae is the most common bacterial pathogen producing AOM in the pediatric population. While amoxicillin has excellent antimicrobial activity toward S pneumoniae, this is changing, as S pneumoniae is displaying increasing antimicrobial resistance. Antimicrobial susceptibility and resistance by S pneumoniae is usually defined and discussed in the context of activity by penicillin. By definition, a S pneumoniae isolate with a minimum inhibitory concentration (MIC) < 0.06 µg/ml or less is considered to be susceptible. Nonsusceptible isolates are defined as intermediate nonsusceptible (0.12-1 µg/ml) or resistant (> 2 µg/ml). Until 2000, the MIC interpretive standards for penicillin and amoxicillin were similar. Current interpretive standards of amoxicillin for S pneumoniae include MIC values < 2 µg/ml or less as susceptible, 4 µg/ml as intermediate nonsusceptible, and > 8 µg/ml or higher as resistant.
Amoxicillin’s activity toward S pneumoniae results from its binding to bacterial enzymes that function to maintain the integrity of the cell wall, and are referred to as penicillin-binding proteins (PBP). As these PBP gradually mutate, amoxicillin begins to lose its effectiveness toward disrupting the bacterial cell wall, and the concentration of amoxicillin necessary to kill S pneumoniae increases, resulting in higher MIC values. The most relevant pharmacologic consideration for amoxicillin relating to activity toward S pneumoniae is the time that concentrations at the site of infection exceed the MIC. For amoxicillin and other ß-lactam antibiotics, a drug concentration maintained above the pathogen MIC for at least 40% of the dosing interval correlates with good clinical efficacy. Thus, as resistance increases, MICs rise, and a dosage necessary to maintain a concentration above the MIC also rises.
Some data are available which have measured and correlated plasma and middle ear fluid (MEF) amoxicillin concentrations with projected activity toward S pneumoniae. Amoxicillin concentrations in MEF achieve approximately 20% to 50% of plasma concentrations. Although data of MEF amoxicillin concentrations over time are limited, pharmacodynamic and pharmacokinetic studies indicate that a peak MEF-to-pathogen MIC ratio of approximately 3 to 6 correlates with a bacterial eradication rate of 80% to 85%. Studies measuring MEF amoxicillin from 40-45 mg/kg/day dosing have reported concentrations of 1-6 µg/ml. Several studies have measured MEF amoxicillin concentrations after larger doses, and a single amoxicillin dose of 45 mg/kg has been reported to produce MEF concentrations of 6-8 µg/ml, which should be effective toward many nonsusceptible penicillin-intermediate and some penicillin-resistant strains. One in vitro study predicted that a MEF concentration of 6-9 µg/ml would be necessary to eradicate penicillin nonsusceptible S pneumoniae strains. It is likely that doses of 75-90 mg/kg/day are necessary to achieve such MEF concentrations.
Clinical studies
The most useful controlled clinical studies of AOM are those that evaluate clinical and bacteriologic outcome data. The new amoxicillin-clavulanate dosage form (14:1 ratio of amoxicillin to clavulanate) has been evaluated at a dosage of 90 mg/kg/day, divided twice daily, in an open label manner, using both clinical and bacteriologic outcome data, ie, a double-tap study (Dagan). Of 521 children enrolled, S pneumoniae was isolated from 159 children. Of these isolates, 28% displayed intermediate nonsusceptibility toward penicillin and 28% were resistant to penicillin. Nearly all isolates (92%) were susceptible to amoxicillin. Bacterial eradication rates for penicillin nonsusceptible pathogens were high – 100% for S pneumoniae isolates susceptible or intermediate nonsusceptible, and 91% for penicillin-resistant isolates. Bacteriologic eradication for all pathogens in this study was 96%. This compares to a bacteriologic eradication rate of 83% in a similar study evaluating amoxicillin at a dosage of 45 mg/kg/day.
Other studies have investigated the eradication rates of S pneumoniae from the nasopharynx from amoxicillin therapy in children with AOM. Several studies have compared eradication rates of amoxicillin at 45 mg/kg/day and 90 mg/kg/day dosages, and have found that the higher dose more effectively eradicates nasopharyngeal S pneumoniae. While this information is useful, it is important to consider that the positive predictive value of nasopharyngeal cultures for the presence of S pneumoniae in the middle ear is only 22% to 45%.
In a recent study, Garbutt sought to estimate the local prevalence of penicillin nonsusceptible S pneumoniae in children younger than 7 who presented with acute upper respiratory tract infection (AOM, cough, acute sinusitis, pharyngitis, nonspecific upper respiratory infection). Nasopharyngeal swabs were taken from these children who were recruited from seven community pediatric offices. Of 212 children enrolled, 40% had S pneumoniae isolates. Of these isolates, 48% were nonsusceptible to penicillin. Susceptibility to amoxicillin was not tested directly. S pneumoniae isolates with a penicillin MIC of 2 µg/ml or less were considered to be susceptible to amoxicillin at a dosage of 40-45 mg/kg/day, as the breakpoint for susceptibility to amoxicillin has recently been increased to 2 µg/ml or less. Thus, only 7% of S pneumoniae isolates were considered to be nonsusceptible to amoxicillin, and the authors concluded that the probability of infection with S pneumoniae nonsusceptible to amoxicillin is low. However, this assumption may not be appropriate, even though the interpretive standards of S pneumoniae susceptibility to amoxicillin have recently been changed. While different interpretive standards now exist for penicillin and amoxicillin to evaluate susceptibility of S pneumoniae, most published clinical studies have evaluated S pneumoniae susceptibility to penicillin, and it is in this context that dosing recommendations have been made.
Clinical implications
Although data describing the local prevalence rate of S pneumoniae penicillin or amoxicillin nonsusceptibility may be helpful, these data are commonly not available, and when available, they must be interpreted carefully.
Antibiotic susceptibilities can vary by numerous factors, including patient age, body site of culture, or invasiveness of specific isolates. No guidelines have been developed which translate these factors into clinical decision strategies. However, there are data that have assessed the risk of infection with S pneumoniae isolates that are more likely to display nonsusceptibility to penicillin. These risk factors include day care attendance, recent (with three months) use of an antibiotic and age 2 or younger. It is this reasoning that forms the basis for the Drug-resistant S pneumoniae Therapeutic Working Group’s recommendation to increase amoxicillin dosing to 80-90 mg/kg/day for specific children with AOM. The recently published guidelines on AOM by the AAP (Diagnosis and Management of Acute Otitis Media, 2004) list 90 mg mg/kg/day as the starting dose when amoxicillin is prescribed. It is interesting to note that this dose is described as an “option,” implying that “carefully preformed studies have shown little clear advantage to one approach over another.”
Although data relating larger doses of amoxicillin, as compared with standard dosages, to improved clinical outcomes are not complete, some good data exist which suggest that higher doses are more likely to be beneficial for some children with AOM. This includes children more likely to be infected with a S pneumoniae pathogen displaying nonsusceptibility toward penicillin.
Younger children (2 years of age or younger), children who are regularly exposed to other children, such as through day care, and children who have recently received an antibiotic are more likely to be infected with a nonsusceptible pathogen. Higher amoxicillin doses will more likely achieve MEF concentrations necessary to provide activity toward these nonsusceptible pathogens, and some data do exist from controlled trials that document the efficacy of higher amoxicillin doses. Lower amoxicillin doses may still be appropriate for children at lower risk of infection by a nonsusceptible pathogen (eg, a 4-year-old child who does not attend day care and who has not recently received an antibiotic).
One may also consider the implications of commonly prescribing higher amoxicillin doses. As amoxicillin is relatively inexpensive, cost is not likely to be an important consideration. While drug adverse effects generally increase with dose, clinical studies evaluating higher doses of amoxicillin or amoxicillin-clavulanate have not reported significant increases in gastrointestinal adverse effects. When prescribing high-dose amoxicillin-clavulanate, it is important that clinicians use the newer formulation (600 mg/5 ml), as this dosage form reduces the ratio of clavulanate to amoxicillin, thus reducing risk of gastrointestinal irritation.
For more information:
- Craig WA. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J. 1996;15(10):255-259.
- Dowell SF. Acute otitis media: management and surveillance in an era of pneumococcal resistance-a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J. 1999;18(1):1-9.
- Seikel K. Middle ear fluid concentrations of amoxicillin after large dosages in children with acute otitis media. Pediatr Infect Dis J. 1997;16(10):710-711.
- Dagan R. Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media. Pediatr Infect Dis J. 2001;20:829-837
- Garbutt J. Developing community-specific recommendations for first-line treatment of acute otitis media: is high-dose amoxicillin necessary? Pediatrics. 2004;114:342-347.
- Brook I. Eradication of Streptococcus pneumoniae in the naspharyngeal flora of children with acute otitis media after amoxicillin-clavulanate therapy. Antimicrobial Agents and Chemotherapy. 2004;48:1419-1421.
- Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.