Does Acetaminophen Interfere in the Antibiotic Treatment of Acute Otitis Media Caused by a Penicillin-Resistant Pneumococcus Strain? A Gerbil Model

Abstract

The possible interference of acetaminophen, combined with antibiotics, in the treatment of acute otitis media (AOM) caused by a penicillin-resistant (minimal inhibitory concentration [MIC], 2 g/mL), amoxicillin/clavulanic acid-and erythromycin-sensitive pneumococcus was evaluated in a gerbil model. Animals were challenged with 5 ϫ 10 6 bacteria in each ear through transbullar instillation. Acetaminophen was administered s.c. at 50 mg/kg 30 min before each antibiotic dose. Amoxicillin/clavulanic acid and erythromycin (2.5 and 10 mg/ kg) were administered s.c. at 2, 10, and 18 h after inoculation. Samples were obtained from the middle ear (ME) on day 2 after inoculation for bacterial count. The overall results showed no difference between animals that received acetaminophen, with or without antibiotics, and those that did not receive acetaminophen. The antibiotic concentrations in the ME were practically identical in both groups of animals, so acetaminophen did not interfere with the pharmacokinetics of antibiotics in the ME. However, both antibiotics significantly reduced the number of culture-positive and the bacterial concentration in ME samples when compared with antibiotic-untreated animals. Both antibiotics, whether combined with acetaminophen or not, lowered the number of AOM to Ͻ25%, but Ͼ75% of animals presented otitis media with effusion, and no differences were shown between groups. A high rate of bacterial eradication from the ME correlated with antibiotic serum concentrations being over the MIC of the infecting organism for only Ͼ15% of the dose interval and with an ME concentration exceeding the MIC by a factor of 1.7. In this experimental model, acetaminophen had neither a synergistic nor an antagonistic effect on the antibiotics tested. Abbreviations AOM, acute otitis media BHIE, brain-heart infusion broth enriched with 5% horse serum C 15 min, concentration at 15 min after antibiotic administration CFU, colony-forming units MBC, minimal bactericidal concentration ME, middle ear MEF, middle ear fluid without washing MEWF, middle ear washing fluid MIC, minimal inhibitory concentration MIC 50 , minimal concentration inhibiting 50% of the strains tested MIC 90 , minimal concentration inhibiting 90% of the strains tested OME, otitis media with effusion Acute otitis media (AOM) is one of the most frequently diagnosed infectious diseases of childhood, and the number of office visits for this pathology is increasing in many countries (1). One of the most common approaches to treating AOM in children is to administer an antibiotic to eradicate the pathogen, as well as an anti-inflammatory or analgesic drug such as acetaminophen (2, 3). Anti-inflammatory activity is mainly exerted through the inhibition of COX-1 and COX-2 isoenzymes that catalyze the rate-limiting step of prostaglandin synthesis (4). Recent data suggest that the little antiinflammatory activity of acetaminophen is due to its activity against COX-3 (that shows Ͻ20% activity of COX-1 and COX-2 and is present at approximately 25% of the level ...

Impact of Ibuprofen Therapy in the Outcome of Experimental Pneumococcal Acute Otitis Media Treated With Amoxicillin or Erythromycin

“…In summary, ibuprofen seems to be useful combined with antibiotics for the treatment of an experimental pneumococcal AOM, an effect not observed using acetaminophen (6). Early therapy clearly correlated with improved effectiveness; therefore, if antibiotics are indicated, they should be administered, combined with ibuprofen, as early as possible.…”

“…In contrast, ibuprofen inhibits both COX-1 and COX-2 having more potent analgesic and anti-inflammatory effects (5). We previously demonstrated using an experimental AOM model caused by Streptococcus pneumoniae that acetaminophen combined with amoxicillin/clavulanic acid or erythromycin had neither a synergistic nor an antagonistic effect on the antipneumococcal activity (6). Therefore, use of acetaminophen to alleviate ear pain and decrease body temperature (3) may be advocated alone or combined with an antibiotic in the management of AOM.…”

Gaps in antibiotic development: the postmarketing task

“…In the postmarketing phase, animal models have been used to study pharmacodynamic prediction of efficacy in systemic infections caused by strains with decreased susceptibility using humanized models [34], the relationship of pharmacodynamic parameter values with tissue injury [35], the effects of treatment delay on pharmacodynamics [35], the significance of local (as middle ear fluid) vs. serum pharmacodynamic parameters in local infections (otitis media) [36], pharmacodynamics in mixed local infections (S. pneumoniae þ H. influenzae) [37], the effect of the disease (acute otitis media vs. otitis media with effusion) on pharmacodynamics in middle ear fluid [38], or the effect of concomitant medications as analgesics on the relationship between pharmacodynamic parameters and eradication [39,40].…”