Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media

Abstract

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocoldefined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (P ϭ 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (P ϭ 0.04) and of AOM treatment failure were 12% and 16% (P ϭ 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit ␤-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.) KEYWORDS acute otitis media, amoxicillin-clavulanate, antimicrobial treatment N ext to the common cold, acute otitis media (AOM) is the most frequently diagnosed illness in children in the United States (1) and the most commonly cited indication for antimicrobial treatment (2). Findings of two recent placebo-controlled trials support routine antimicrobial treatment of AOM in very young children. In those trials, affected children under 3 years of age who received antimicrobial treatment for 7 or 10 days experienced more-favorable outcomes than those who received placebo (3, 4). In both studies, amoxicillin-clavulanate was used as the active treatment-albeit in different dosing regimens-because it had been previously shown to have the highest rates of eradication of AOM pathogens, with high resultant rates of clinical cure. The efficacy of A/C is attributable in part to inactivation, by the clavulanate

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“…In the majority of studies, subjects were admitted to the pediatric ( n = 9) or neonatal ward ( n = 4). One study was performed on the pediatric intensive care [ 24 ], in one study, patients received home-based treatment [ 25 ]. In the remaining three studies, the setting was unknown.…”

“…2.5 mg/kg 2. 5 mg/kg Oral Not with food Blood T = 15, 30, 45 min, 1, 2, 4, 8 h Hober-man et al [ 25 ] Amoxicillin/clavulanic acid (28:1) 1. 1.6 mg/kg 2.…”

SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs

“…These data may have implications regarding the clinical observation that amoxicillin/clavulanate therapy results in significantly increased incidence of antibiotic-associated diarrhea (AAD) compared to treatment with amoxicillin alone [18]. Clavulanate was assumed to be the causative agent as it increases intestinal motility in children [18], and amoxicillin/clavulanate formulations containing lower clavulanate ratios reduced AAD rates [18,25]. However, data from the current canine study revealed that amoxicillin/clavulanate causes more alterations in gut microbiota composition than amoxicillin alone, suggesting that microbiome damage is a mechanism responsible for AAD.…”

Acute Otitis Media in Childhood - Use of Guidelines for Diagnosis and Treatment in Emergency Rooms

“…Nevertheless, several studies have recommended shorter courses for children, particularly for infants under two years of age, with 5-7 day courses being recommended. [42][43][44][45][46][47] The prescription of analgesics was shown to be practically routine, with 97.1% of doctors prescribing analgesics in addition to antibiotics for the management of otalgia and other symptoms. This concern with treating pain is in agreement with the AAP recommendations.…”