a SLACK Incorporated newspaper
February 1999
ATLANTA - Despite the growth of resistant organisms, amoxicillin re mains the first-line treatment for acute otitis media (AOM), according to a panel of experts in the management of otitis and resistant organisms.
However, the panel, which issued its report in the Pediatric Infectious Disease Journal said that higher doses of 80 to 90 mg/kg/day might be necessary to achieve effective middle ear fluid concentrations of the drug in certain patients. Amoxicillin-clavulanate (Augmentin, SmithKline Beecham), cefuroxime axetil (Ceftin, Glaxo Wellcome) and intramuscular ceftriaxone (Ro chephin, Roche) are effective alternatives for patients with clinically defined treatment failures after three days of therapy, the panel added.
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"What is new [about the recommendations] is that in areas where there is a concern for increased resistance, the dose of amoxicillin is recommended to be doubled. I don't know of any large group that has promoted that, but it seems that based on the pharmacokinetics that you get higher concentrations of antibiotic activity by increasing the dose of amoxicillin, which would encompass additional strains of pneumococci that are moderately or even highly resistant," said Jerome O. Klein, MD, a member of the panel.
The steady rise of drug-resistant Streptococcus pneumoniae (DRSP) prompted the Centers for Disease Control and Prevention (CDC) to convene a working group to establish guidelines about treating AOM, meningitis and pneumonia in an era of drug resistance.
"AOM was selected as the initial target since it is the number one reason to use antibiotics in infancy and young children, and the most common causative organism is the pneumococci. Resistant pneumococci are more common in AOM than in other respiratory infections," said Ron Dagan, MD, another panel member. Nearly 30 million doctor visits each year are due to otitis media (OM).
Most physicians treat OM empirically based on the patient's symptoms, without obtaining information about the specific bacteria causing the infection. Three bacteria are responsible for most cases of otitis: S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. S pneumoniae is responsible for about 50% of all cases of OM, H. influenzae is implicated in 20% to 30% and M. catarrhalis accounts for 10% to 15% of cases. The panel said that of the three, S. pneumoniae is the least likely to resolve spontaneously.
Therefore, an agent that is effective against S. pneumoniae should be the most important consideration when choosing AOM therapy, the panel agreed. Although there is no DRSP infection surveillance in most communities, penicillin resistance has been detected in all places were surveillance data are available. In addition, research shows penicillin-resistant S. pneumoniae is more prevalent in children than adults. This means that physicians must consider the possibility of resistant organisms when treating otitis.
"Amoxicillin is the best oral antimicrobial agent in clinical use for treating DRSP. It is highly effective against pneumococci and displays the best pharmacodynamic profile (longest time above MIC90) against DRSP of any of the commonly available oral agents," the panel wrote in the guidelines. Amoxicillin given in standard doses of 40 mg/kg/day to 45 mg/kg/day achieves peak middle ear fluid concentrations of 1 µg/mL to 6 µg/mL, which should eradicate penicillin-susceptible strep in most cases.
Higher doses of 70 mg/kg/day to 90 mg/kg/day can be expected to achieve concentrations that may eliminate penicillin-nonsusceptible strains. In creasing the doses in clinical treatment failures appears to be a reasonable approach for high-risk patients, the panel said, although the Food and Drug Administration has not ap proved amoxicillin in higher doses, and no controlled trial has compared these higher doses with standard doses of amoxicillin.
However, Klein said that George McCracken and his colleagues identified concentrations of drugs in the middle ear that could be achieved by higher doses, so it was proven that one could get more drug to the site of infection. Klein is a member of the Infectious Diseases in Children editorial advisory board.
Patients at higher risk for DRSP are those who have recently taken antimicrobials, attend day care and are younger than 2 years.
Although there are 16 agents currently indicated for AOM treatment, only three are appropriate alternatives to amoxicillin in clinically proven treatment failures: amoxicillin-clavulanate, cefuroxime axetil and intramuscular ceftriaxone. The other agents good evidence for efficacy in the DRSP era," the panel said.
Some physicians may be surprised about the recommendation to use ceftriaxone because they fear it will lose its effectiveness against more severe infections. "That's a recurring theme that you hear, but it looks like that is not the case," said Klein, professor of pediatrics at Boston University School of Medicine.
"Ceftriaxone as an IM shot does give you high concentrations in the blood and the middle ear and so it should be of benefit in a child whom you are concerned may have more than just OM: a child with high fever who has not responded to antibiotics, where there is a concern for associated sepsis or disease outside of the middle ear. We've used ceftriaxone in those circumstances," Klein said.
"Rocephin is indeed a `big gun,'"said Dagan, director of the pediatric infectious disease unit, Soroka University Medical Center, Beer-Sheva, Israel. But, he added, in failures and with penicillin- resistant S. pneumoniae, one shot only of IM ceftriaxone may not be enough. "This is important because the one shot was licensed and is heavily publicized, so that pediatricians have to know that they need maybe three days and not one for these cases," he explained.
"We all have to remember that the treatment of AOM is empirical, and it needs to cover at least S. pneumoniae, H. influenzae and, in some regions, also M. catarrhalis. In many regions now, S. pneumoniae are becoming resistant to many antibiotics, but mainly to various b-lactams and trimethoprim-sulfamethoxazole (TMP-SMX). In cases with clinically defined treatment failure after three days of therapy, the chance of finding antibiotic-resistant S. pneumoniae are great in regions where antibiotic-resistant S. pneumoniae are prevalent (and unfortunately, the United States is one of those regions).
"In these cases, many drugs such as most oral cephalosporins and regular doses of amoxicillin are not useful. Several other drugs may be considered, including some of the more recent macrolides/azalides. However, if we provide those drugs as second liners, we have to also cover H. influenzae," he explained. And there is some "hint" that these drugs are not useful against H. influenzae, added Dagan, who is also a member of the editorial advisory board of Infectious Diseases in Children.
That was why the panel picked those three alternatives, Dagan said. "If we know that H. influenzae is not present, we may think of clindamycin (since in the United States most of the drug resistant S. pneumoniae are still susceptible to clindamycin), but in some regions of the world, most of macrolide-resistant S. pneumoniae are also clindamycin resistant.
"So, as you see, we have to use the `big guns' now days, but the recommendation of the group (and of course my own, too) is to give ceftriaxone to cases of failure on other drugs, or when an oral drug is not feasible, but NOT as a primary treatment!" Dagan emphasized.
Another key point of the recommendation, said Klein, is how to treat children who are allergic to amoxicillin. In the past, these children were treated with TMP-SMX. "The resistance rate for trimethoprim-sulfa is running ahead of the resistant rates for amoxicillin," said Klein, "so trimethoprim-sulfa is no longer to be the alternative of choice [for children with allergies]. A macrolide, such as erythromycin-sulfa, azithromycin (Zithromax, Pfizer), or clarythromycin (Biaxin, Abbott) should be used in those circumstances."
If after three days of therapy, there is a lack of clinical improvement, such as pain, fever and tympanic membrane findings of redness, bulging or otorrhea, that child can be considered a treatment failure. Children with signs or symptoms that are not specific to AOM, such as persisting middle ear effusion, coryza, cough or other indications of viral infection should not be considered treatment failures, the panel said.
If assessment is done 10 days or later, physicians should carefully distinguish between persisting middle ear effusion and true clinical failures.
Tympanocentesis is recommended in treatment failures to determine the causative organism. If the alternative agent is chosen empirically, it should not only be effective against DRSP but also effective against b-lactamase producers.
Klein said the new recommendations should give pediatricians some ammunition when they talk to parents about appropriate treatment for AOM, since they encounter parents who push them to prescribe broad-spectrum antibiotics.
Dagan said the recommendations should provide a guide for pediatricians who have become confused about which actions they should take. "The recommendations mean first, not to treat at all when treatment is not needed, and not to always blame otitis for every fever. Second, in cases of failures, always try to have cultures by tympanocentesis before you treat," Dagan said. "Otherwise, use high-dose amoxicillin or amoxicillin-clavulanate for failures. If this does not work or is not feasible, only then use ceftriaxone."
Because resistance patterns change often, the panel said that recommendations for treating AOM should be updated regularly. The panel is working on recommendations for treating meningitis caused by DRSP.
For more information:
- 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;18:1-9.
- Barnett ED, Klein JO. The problem of resistant bacteria for the management of acute otitis media. Pedaitr Clin North Am. 1995;42:509-17.
- Dagan R, Abramson O, Leibovitz E., et. al. Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pedatr Infect Dis J. 1996;15:980-5.
- Ginsburg CM, McCracken GH Jr., Nelson JD. Pharmacology of oral antibiotics used for treatment of otitis media and tonsillopharyngitis in infants and children. Ann Otol Rhinol Laryngol. Suppl 1981;90:37-43.
- Leibovitz E. et al The bacteriologic efficacy of one-day vs. three-day intramuscular ceftriaxone in the treatment of non-responsive acute otitis media. Abstract M-039. Presented at the 38th ICAAC. Sept. 24-27, 1998 San Diego.
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