February 1996
BOSTON—Despite increasing prevalence of middle ear pathogens resistant to amoxicillin, this agent remains the drug of choice for empiric therapy of acute otitis media (AOM) in the majority of cases, according to otitis media experts.
The principal reason is that the number of amoxicillin-related AOM treatment failures does not justify abandoning the agent as first-line empiric therapy for AOM, according to Jerome O. Klein, MD, of Boston City Hospital, where he is Chief of the Division of Pediatric Infectious Diseases. Many AOM cases resolve without antibiotic therapy, including 20% of cases due to Streptococcus pneumoniae and 50% of cases due to Haemophilus influenzae. In addition, 28% of AOM cases occur in the absence of a bacterial pathogen, said Klein, who is Professor of Pediatrics at Boston University.
He and a colleague, Elizabeth D. Barnett, MD, also of Boston City Hospital, reported in Pediatric Clinics of North America that fewer than 10% of AOM cases in otherwise healthy children can be expected to fail amoxicillin therapy because the causative pathogen is resistant to the drug. Treatment failure usually does not have severe clinical consequences, however, so pediatricians can delay therapy with broader spectrum antibiotics, such as oral cephalosporins and macrolides, Klein observed.
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Some researchers have questioned the use of amoxicillin as empiric AOM therapy for select patients. Those researchers include William J. Rodriguez, MD, PhD, of Children's National Medical Center, Washington, D.C. He and colleagues studied 151 children diagnosed with AOM at a pediatric clinic in northern Virginia and found that 54% of pathogens isolated from middle ear fluid were resistant to penicillin or ampicillin. Penicillin-resistant Streptococcus pneumoniae made up about 8% of the pathogens.
Rodriguez and colleagues analyzed 159 samples of middle ear fluid and recovered 165 isolates, of which 61 (37%) were Streptococcus pneumoniae, 45 (27%) were Haemophilus influenzae, and 41 (25%) were Moraxella catarrhalis. Of the 61 S pneumoniae isolates, 13 (21%) were resistant to penicillin. Eleven isolates had intermediate resistance to penicillin, defined as having a minimal inhibitory concentration (MIC) for penicillin of 0.1 µg/mL to 1 µg/mL. Two isolates had a penicillin MIC between 1 µg/mL and 2 µg/mL.
Forty of the 41 M catarrhalis strains (98%) and 28 of the 45 H influenzae strains (62%) were resistant to ampicillin. The investigators also recovered six group A Streptococcus isolates—all of which were susceptible to penicillin—and four Staphylococcus aureus isolates, all of which were resistant to amoxicillin. Samples from five children provided no pathogens and samples from three children contained bacteria of uncertain significance. Rodriguez and colleagues published their findings recently in the Pediatric Infectious Diseases Journal.
Because most primary care physicians do not perform tympanocentesis, Rodriguez is concerned about the continued empiric use of amoxicillin, at least in places with a high prevalence of drug-resistant organisms, he said.
Rodriguez and colleagues suggested that infants and preschool children who attend day care or who appear to be ill or in great pain within 12 hours of an office evaluation be treated with antibiotics of proven efficacy against H influenzae and intermediately resistant S pneumoniae.
In an interview with Infectious Diseases in Children, Rodriguez explained that pediatricians do not necessarily have to avoid amoxicillin as empiric therapy. Instead, they could modify how they use it. For example, in communities that have a high prevalence of penicillin-resistant middle ear pathogens or in patients with AOM accompanied by severe illness, pediatricians might do well to use the standard dosage of amoxicillin—40 mg/kg/day—together with a fixed-dose combination of amoxicillin/clavulanate (Augmentin). This strategy raises the amoxicillin dosage to 80 mg/kg/day of amoxicillin and provides clavulanate to block beta-lactamase if it is present. By combining amoxicillin with Augmentin, pediatricians avoid having to raise the dosage of clavulanate, which can increase problems with diarrhea, Rodriguez said.
Other treatment options for patients at risk for resistant pathogens include some of the second and third-generation cephalosporins and some of the newer macrolides, such as clarithromycin, Rodriguez said.
Klein, too, believes that amoxicillin may not be the best empiric agent in all circumstances. Sometimes, pediatricians should consider using drugs that are more effective than amoxicillin for treating penicillin-resistant S pneumoniae. In Klein's opinion, such alternative agents may be appropriate initial therapy for immunocompromised children, such as those with HIV disease, children who have severe symptoms and invasive illness, such as mastoiditis and bacteremia, and children known to have been exposed to penicillin-resistant S pneumoniae, especially children hospitalized lately and children who recently received antibiotics.
Michael D. Poole, MD, Associate Professor of Otolaryngology and Pediatrics at the University of Florida, Gainesville, agrees that agents other than amoxicillin may be appropriate initial therapy for patients who are at higher risk of infection with drug-resistant organisms. These patients include young children in group day care who have had extensive exposure to antibiotics and young children whose AOM is accompanied by severe symptomatic illness, he said.
Amoxicillin remains appropriate first-line therapy for uncomplicated otitis media, particularly for children who do not attend day care and do not have recurrent infections, Poole said. Under some circumstances, such as when parents prefer a more convenient dosing regimen than that of standard amoxicillin therapy (3 times a day), Poole might prescribe an agent that a child would take less frequently, he said.
Responding to an increasing prevalence of S pneumoniae resistant to penicillin and multiple drugs, pediatricians recently have begun turning to clindamycin as second-line therapy, Poole said. "It is highly active against S pneumoniae and other gram-positive bacteria, but is not active against gram-negative bacteria, he said. "It is probably the most consistently active oral agent against pneumococci now," Poole said, adding that a few resistant strains have been reported.
He sometimes opts for this agent when treating culture confirmed AOM cases due to multidrug-resistant pneumococci and treating patients with AOM whose amoxicillin treatment has failed and who are at high risk for drug-resistant pneumococci.
For some patients, pediatricians may want to use clindamycin in combination with an agent that covers gram-negative bacteria, such as a sulfa drug, he said. Those patients include children who are allergic to beta-lactam antibiotics, whose therapy with macrolides has failed, or who are markedly symptomatic and are at high risk for infection with drug-resistant organisms.
In most places, failure of empiric AOM treatment frequently may be related to infection with highly penicillin resistant S pneumoniae (HPRSP). For example, a study of children from rural Kentucky showed that HPRSP caused 19 of 63 cases (30%) of AOM treated with antibiotics within 3 days of when investigators obtained a culture sample of middle ear fluid.
Some children may be more at risk than others for AOM due to HPRSP. The Kentucky study, by Stan L. Block, MD, of Bardstown, Ky., and colleagues, found that of 23 HPRSP isolates recovered, 19 (83%) were from children younger than 25 months and 20 (87%) were from children who were prone to otitis media (3 or more AOM episodes within the previous 4 months).
The findings have not swayed Block from his use of amoxicillin as first-line therapy, but he has changed the way he prescribes the drug. Even among children with non-refractory AOM, investigators observed amoxicillin resistance in 32% of 220 isolates. Thus, Block frequently prescribes relatively high doses of amoxicillin to 80 mg/kg/day—as first-line empiric therapy for patients 3 months to 36 months old. This may improve coverage for both S pneumoniae and many gram-negative organisms, he said. For older patients with AOM who are less likely to be infected with HPRSP, Block relies on the standard dose of 40 mg/kg/day, and he frequently limits amoxicillin therapy to 5 to 7 days to reduce the flow of antibiotics into the community.
For more information, see:
- Barnett ED, Klein JO. The problem of resistant bacteria for the management of acute otitis media. Pediatr Clin North Am. 1995;42:509-17.
- 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;14:751-59.
- Rodriguez WJ, Schwartz RH, Thorne MM. Increasing incidence of penicillin and ampicillin-resistant middle ear pathogens. Pediatr Infect Dis J. 1995;14:1075-78.
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