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 μg/mL), amoxicillin/clavulanic acid– and erythromycin-sensitive pneumococcus was evaluated in a gerbil model. Animals were challenged with ∼5 × 106 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 <25%, but >75% 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 >15% 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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- AOM:
-
acute otitis media
- BHIE:
-
brain-heart infusion broth enriched with 5% horse serum
- C15 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
- MIC50:
-
minimal concentration inhibiting 50% of the strains tested
- MIC90:
-
minimal concentration inhibiting 90% of the strains tested
- OME:
-
otitis media with effusion
REFERENCES
Schappert SM 1992 Office visit for otitis media: United States, 1975–90. Adv Data 8: 1–19
Hoberman A, Paradise JL, Reynolds EA, Urkin J 1997 Efficacy of Auralgan for treating ear pain in children with acute otitis media. Arch Pediatr Adolesc Med 151: 675–678
Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J 2001 Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 322: 336–342
Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL 2002 COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 99: 13926–13931
Byington CL, Spencer LY, Johnson TA, Pavia AT, Allen D, Mason EO, Kaplan S, Carroll KC, Daly JA, Christenson JC, Samore MH 2002 An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations. Clin Infect Dis 34: 434–440
Klein OG 2000 Otitis externa, otitis media, and mastoiditis. In: Mandell GL, Bennett JE, Dolin R (eds) Principles and Practice of Infectious Diseases. Churchill Livingstone, Philadelphia, pp 669–675.
del Castillo F, Baquero-Artigao F, Garcia-Perea A 1998 Influence of recent antibiotic therapy on antimicrobial resistance of Streptococcus pneumoniae in children with acute otitis media in Spain. Pediatr Infect Dis J 17: 94–97
Takata GS, Chan LS, Shekelle P, Morton SC, Mason W, Marcy SM 2001 Evidence assessment of management of acute otitis media: I. The role of antibiotics in treatment of uncomplicated acute otitis media. Pediatrics 108: 239–247
Roger G, Carles P, Pangon B, Thien HV, Polonovski JM, Begue P, Garabedian EN 1998 Management of acute otitis media caused by resistant pneumococci in infants. Pediatr Infect Dis J 17: 631–638
Teele DW, Klein JO, Rosner B 1989 Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 160: 83–94
Kawana M, Kawana C, Giebink GS 1992 Penicillin treatment accelerates middle ear inflammation in experimental pneumococcal otitis media. Infect Immun 60: 1908–1912
National Committee for Clinical Laboratory Standards 1992 Methods for Determining Bactericidal Activity of Antimicrobial Agents, Document M26-T. Villanova, PA, National Committee for Clinical Laboratory Standards
National Committee for Clinical Laboratory Standards 1997 Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Fourth Edition: Approved Standard M7-A4. Villanova, Pa, National Committee for Clinical Laboratory Standards
European C 1986 Journal officiel des communautés européennes. Luxembourg, Office des publications officielles des communautés européennes
Cenjor C, Ponte C, Parra A, Nieto E, Garcia-Calvo G, Gimenez MJ, Aguilar L, Soriano F 1998 In vivo efficacies of amoxicillin and cefuroxime against penicillin-resistant Streptococcus pneumoniae in a gerbil model of acute otitis media. Antimicrob Agents Chemother 42: 1361–1364
Jacobs MR, Dagan R, Appelbaum PC, Burch DJ 1998 Prevalence of antimicrobial-resistant pathogens in middle ear fluid: multinational study of 917 children with acute otitis media. Antimicrob Agents Chemother 42: 589–595
Perez-Trallero E, Fernandez-Mazarrasa C, Garcia-Rey C, Bouza E, Aguilar L, Garcia-de-Lomas J, Baquero F 2001 Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenes isolates and their ecological relationships: results of a 1-year (1998–1999) multicenter surveillance study in Spain. Antimicrob Agents Chemother 45: 3334–3340
Ginsburg CM, McCracken GH, Nelson JD 1981 Pharmacology of oral antibiotics used for treatment of otitis media and tonsillopharyngitis in infants and children. Ann Otol Rhinol Laryngol Suppl 90: 37–43
Canafax DM, Yuan Z, Chonmaitree T, Deka K, Russlie HQ, Giebink GS 1998 Amoxicillin middle ear fluid penetration and pharmacokinetics in children with acute otitis media. Pediatr Infect Dis J 17: 149–156
Seikel K, Shelton S, McCracken GH 1997 Middle ear fluid concentrations of amoxicillin after large dosages in children with acute otitis media. Pediatr Infect Dis J 16: 710–711
Craig WA, Andes D 1996 Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J 15: 255–259
Parra A, Ponte C, Cenjor C, Garcia-Calvo G, Gimenez MJ, Aguilar L, Soriano F 2002 Optimal dose of amoxicillin in treatment of otitis media caused by a penicillin-resistant pneumococcus strain in the gerbil model. Antimicrob Agents Chemother 46: 859–862
Soriano F, Parra A, Cenjor C, Nieto E, Garcia-Calvo G, Gimenez MJ, Aguilar L, Ponte C 2000 Role of Streptococcus pneumoniae and Haemophilus influenzae in the development of acute otitis media and otitis media with effusion in a gerbil model. J Infect Dis 181: 646–652
Ponte C, Cenjor C, Parra A, Nieto E, Garcia-Calvo G, Gimenez MJ, Aguilar L, Soriano F 1999 Antimicrobial treatment of an experimental otitis media caused by a beta-lactamase positive isolate of Haemophilus influenzae. J Antimicrob Chemother 44: 85–90
Labro MT 1998 Anti-inflammatory activity of macrolides: a new therapeutic potential?. J Antimicrob Chemother 41( suppl B): 37–46
Schultz MJ, Speelman P, Zaat S, van Deventer SJ, van der Poll T 1998 Erythromycin inhibits tumor necrosis factor alpha and interleukin 6 production induced by heat-killed Streptococcus pneumoniae in whole blood. Antimicrob Agents Chemother 42: 1605–1609
Cundell D, Masure HR, Tuomanen EI 1995 The molecular basis of pneumococcal infection: a hypothesis. Clin Infect Dis 21 ( suppl 3): S204–S211
Tuomanen E, Rich R, Zak O 1987 Induction of pulmonary inflammation by components of the pneumococcal cell surface. Am Rev Respir Dis 135: 869–874
van Langevelde P, van Dissel JT, Ravensbergen E, Appelmelk BJ, Schrijver IA, Groeneveld PH 1998 Antibiotic-induced release of lipoteichoic acid and peptidoglycan from Staphylococcus aureus: quantitative measurements and biological reactivities. Antimicrob Agents Chemother 42: 3073–3078
Alper CM, Doyle WJ, Seroky JT, Bluestone CD 1996 Efficacy of clarithromycin treatment of acute otitis media caused by infection with penicillin-susceptible, -intermediate, and -resistant Streptococcus pneumoniae in the chinchilla. Antimicrob Agents Chemother 40: 1889–1892
Carbon C 1990 [Antibiotics and anti-inflammatory agents: drug interactions]. Pathol Biol (Paris) 38: 255–260
Dellamonica P, Garraffo R, Etesse-Carsenti H, Bernard E, Mondain V 1993 Pharmacokinetic and bacteriological study of cefadroxil-salicylate and josamycin-salicylate drug regimens. Int J Clin Pharmacol Res 13: 11–20
Tuomanen E, Hengstler B, Rich R, Bray MA, Zak O, Tomasz A 1987 Nonsteroidal anti-inflammatory agents in the therapy for experimental pneumococcal meningitis. J Infect Dis 155: 985–990
Carsenti-Etesse H, Farinotti R, Durant J, Roger PM, De Salvador F, Bernard E, Rouveix B, Dellamonica P 1998 Pharmacokinetic parameters and killing rates in serum of volunteers receiving amoxicillin, cefadroxil or cefixime alone or associated with niflumic acid or paracetamol. Eur J Drug Metab Pharmocokinet 23: 357–366
Botting RM 2000 Mechanism of action of acetaminophen: is there a cyclooxygenase 3?. Clin Infect Dis 31 ( suppl 5): S202–S210
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by a grant from Fondo de Investigaciones Sanitarias (FIS 99/111) and SmithKline Beecham S.A., Madrid, Spain.
Rights and permissions
About this article
Cite this article
Ponte, C., Parra, A., Cenjor, C. et al. Does Acetaminophen Interfere in the Antibiotic Treatment of Acute Otitis Media Caused by a Penicillin-Resistant Pneumococcus Strain? A Gerbil Model. Pediatr Res 54, 913–918 (2003). https://doi.org/10.1203/01.PDR.0000090931.94785.DA
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000090931.94785.DA
