Children with acute otitis media (AOM) are routinely and successfully treated with antimicrobials, with data showing that the combination of amoxicillin-clavulanate (A/C) to treat AOM in children aged younger than 3 years is associated with more favorable outcomes than placebo.1,2
Although effective, antimicrobial treatment is associated with the unwanted adverse effect of diarrhea that studies show can affect between 25% to 48% of children.1,2 Children who experience this common adverse effect may have to wait to return to daycare until it resolves, which in turn may delay parents’ return to work.3
Finding a way to maintain the efficacy of antimicrobial treatment while reducing this unwanted adverse effect was the objective of recent study by Hoberman and colleagues.3 Based on evidence showing that the clavulanate component of the routinely administered antimicrobial treatment is responsible for diarrhea, the investigators examined the efficacy and safety of a novel formulation of the antimicrobial in which the total effective dose of clavulanate is reduced.
The open-label study found that reducing the total dose of clavulanate was associated with the desired reduction in diarrhea and diaper dermatitis without appearing to compromise efficacy; however, the lead author of the study, Alejandro Hoberman, MD, chief, Division of General Academic Pediatrics, professor of Pediatrics and Clinical and Translational Science, Children’s Hospital of Pittsburgh of UPMC, Pennsylvania, emphasized that these findings will have to be properly studied in a larger clinical trial.
In this open-label study, children with AOM aged 6 to 23 months were treated with a reduced clavulanate A/C formulation comprised of amoxicillin-clavulanate with 600 mg amoxicillin and 21.5 mg clavulanate 5mL.
All children enrolled in the study had AOM diagnosed using stringent criteria that included an onset of symptoms within the preceding 48 hours; a total score of ≥2 on the Acute Otitis Media-Severity of Symptoms (AOM-SOS) scale; middle-ear effusion; and moderate or marked bulging of the tympanic membrane (TM) or slight bulging of the TM with otalgia or marked TM erythema.
The primary outcome of the study was the proportion of children developing diarrhea, which was defined as the occurrence of ≥3 watery stools on 1 day or ≥2 watery stools on 2 consecutive days. The study also included secondary outcomes that included the proportion of children experiencing diaper dermatitis that required an antifungal cream and the proportion of children whose symptomatic response was considered satisfactory.
The study included 2 phases. In Phase I, 40 children were treated with the new formulation administered at a dosing regimen of 90/3.2 (A/C) mg/kg/day in 2 divided doses for 10 days and compared with 401 historical controls administered the standard treatment of 90/6.4 (A/C) mg/kg/day.
Because there were no differences in outcomes seen between the 2 treatment regimens, the investigators added 72 children in a Phase II part of the study that compared the same reduced-clavulanate formulation to standard therapy but with a different dosing regimen: 80/2.85 (A/C) mg/kg/day divided into 2 doses for 10 days.
The study found that the dosing regimen delivered in Phase II suggests a potential for an improved safety profile over standard therapy, without compromising efficacy.
Children treated with the dosing regimen of 80/2.85 (A/C) mg/kg/day divided into 2 doses over 10 days had similar rates of diarrhea compared with historical controls (17% vs 26%, respectively; P=0.10). In addition, these children had lower rates of diaper dermatitis compared with historical controls (21% vs 33%, respectively; P=0.04).
The study also found that parental satisfaction was significantly (albeit marginally) higher among children who received the novel formulation compared with the standard formulation. On a scale from 1 to 5, parental satisfaction with the novel formulation was 4.75 compared with a parent satisfaction of 4.47 for the standard formulation (P=0.02).
“Further clinical research is warranted on this novel formulation/dosage regimen,” says Hoberman, who announced that he and his colleagues will be conducting a Phase III randomized clinical trial to further assess the new formulation’s safety and efficacy in children aged younger than 24 months diagnosed with AOM using stringent criteria.
Importantly, Hoberman says that clinicians should know that the novel formulation and reduced dosing regimen used in Phase II did not appear to reduce the clinical efficacy of the novel formulation. Furthermore, the study showed that levels of amoxicillin and clavulanate achieved in plasma should be sufficient to eradicate Streptococcus pneumoniae and Haemophilus influenzae.
“It is important to note that a 55% reduction in the clavulanate concentration resulted in a reduction of only 33% in the maximum serum concentration and a reduction of only 5% in the area under the concentration curve,” Hoberman points out. “The increased exposure to clavulanate may result from increased absorption or reduced excretion of clavulanate in young children compared [with] older children.”
1. Hoberman A, Paradise JL, Rockette HE, et al. Treatment of acute otitis media in children under 2 years of age. N Engl J Med. 2011;364(2):105-115.
2. Tahtinen PA, Laine MK, Huovinen P, Jalava J, Ruuskanen O, Ruohola A. A placebo-controlled trial of antimicrobial treatment for acute otitis media. N Engl J Med. 2011;364(2):116-126.
3. Hoberman A, Paradise JL, Rockette HE, et al. Reduced-concentrate clavulanate for young children with acute otitis media. Antimicrob Agents Chemother. Accepted manuscript posted online April 24, 2017. Available at: http://aac.asm.org/content/early/2017/04/18/AAC.00238-17. Accessed June 6, 2017.