Inpharma 1410 - 25 Oct 2003
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Gatifloxacin matches amoxicillin/clavulanate in paediatric otitis media – Pamela Hunter – Results from two phase III studies presented at the 43rd Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) [Chicago, US; September 2003] showed that a new paediatric oral suspension of the fluoroquinolone, gatifloxacin was as effective as a conventional paediatric amoxicillin/clavulanate formulation and a new high-dose amoxicillin/clavulanate formulation in treating acute otitis media in children. Fluoroquinolones are not normally used in children other than for life-threatening infections due to arthrotoxic effects seen in juvenile animals, but the significance of extrapolating such studies to humans has been questioned. The studies involved > 700 children aged between 6 months and 7 years who had recurrent acute otitis media or had failed treatment for acute otitis media. There were no significant differences in the efficacies of gatifloxacin and amoxicillin/clavulanate in the two studies. However, in the first study, gatifloxacin was more effective than high-dose amoxicillin/clavulanate in children over 2 years of age, and those who had bilateral infection or severe infections. In the second study, gatifloxacin was more effective than amoxicillin/clavulanate in younger patients, those with bilateral disease and patients with moderate or severe infections. Importantly, treatment with gatifloxacin did not result in arthrotoxicity up to one year following treatment in either study. Gatifloxacin is a new 6-methoxy-fluoroquinolone with an excellent spectrum of activity that includes the majority of bacterial pathogens causing upper and lower respiratory tract infections. The incidence of resistance to penicillins and macrolides among many of the major respiratory pathogens has increased dramatically in the last decade and fluoroquinolones offer an alternative therapy. These agents have not been recommended for use in children, other than for life-threatening infections, as they have been shown to cause arthropathy and arthrotoxicity in juvenile animals. However, the correlation between such animal studies and arthrotoxicity in humans has not been proven; thus, gatifloxacin has been evaluated in phase III studies involving young children with otitis media. Results from a study comparing a paediatric oral suspension of gatifloxacin with a new high-dose formulation of amoxicillin/ clavulanate and another comparing gatifloxacin with a conventional formulation of amoxicillin/ clavulanate were presented at the 43rd ICAAC.
Comparison with high-dose amoxicillin/ clavulanate Gatifloxacin was compared with high-dose amoxicillin/ clavulanate in a randomised, investigatorblinded, multicentre study involving 354 children aged between 6 months and 7 years.1 The patients had recurrent otitis media or had failed treatment for acute otitis media with another antibacterial agent; acute otitis media was diagnosed according to the investigators’ criteria [see table 1].*
assigned study medication. Patients received either gatifloxacin 10 mg/kg once daily (n = 176), or amoxicillin 90 mg/kg plus clavulanate 6.4 mg/kg twice daily, for up to 10 days; the maximum allowed doses of gatifloxacin and amoxicillin/ clavulanate were 600mg and 3600mg/256 mg, respectively. The primary endpoint was the clinical response rate at the test of cure (TOC) visit 3–10 days after the initiation of treatment. Other endpoints included the time to resolution of signs and symptoms, and the bacteriological response rate. Table 2. Clinical cure rates at the test of cure assessment Population or subcategory a
Clinically evaluable Microbiologically evaluableb Severity of Infection: moderate severe Type of infection: bilateral unilateral Age of patient: < 2 years ≥ 2 years
Gatifloxacin
Amoxicillin/ Clavulanate
Cured/total
Cured/total
105/124 (85%) 24/30 (80%)
92/117 (79%) 27/35 (77%)
47/56 (84%) 58/68 (85%)
43/51 (84%) 47/64 (73%)
57/67 (85%) 48/57 (84%)
52/68 (76%) 40/49 (83%)
49/62 (79%) 56/62 (90%)
45/58 (78%) 47/59 (80%)
Clinically evaluable: patients who had received ≥ 3 days of the study drug and no other antibacterial agent. b Microbiologically evaluable: patients who were clinically evaluable and had ≥ 1 pathogen isolated from the middle ear fluid prior to treatment. a
Table 1. Criteria for diagnosis of acute otitis media Middle ear effusiona Decreased or absent tympanic mobility Yellow, white or erythematous
Acute inflammationb Ear pain within 24 hours
Marked erythema of tympanic membrane Discolouration of tympanic Bulging or fullness of tympanic membrane membrane Opacification of tympanic membrane a b
Patients were required to have ≥ 2 of these symptoms Patients were required to have ≥ 1 of these symptoms
Of the 354 patients who were enrolled and randomised, 349 received at least one dose of their
Where possible, middle ear fluid was obtained by tympanocentesis prior to treatment. In some cases, especially if treatment was not successful, repeat tympanocentesis was performed during or after treatment for further evaluation. The middle ear fluid was successfully used to isolate and identify pathogens in 37/176 (21%) patients in the gatifloxacin group and 38/173 (22%) in the amoxicillin/clavulanate group. In the majority of patients only one pathogen was isolated, but more than one species was isolated from three gatifloxacin-treated patients and four amoxicillin/ clavulanate recipients. The majority of the isolates were Haemophilus influenzae (n = 33) or Streptococcus pneumoniae (28).
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Inpharma 25 Oct 2003 No. 1410
Single Article
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Gatifloxacin matches amoxicillin/clavulanate – There were 124 clinically evaluable patients in the gatifloxacin group and 117 in the amoxicillin/clavulanate group; 30 gatifloxacin recipients and 35 patients in the amoxicillin/clavulanate group were microbiologically evaluable.** Gatifloxacin was at least as effective as amoxicillin/ clavulanate, with the greatest differences between the treatments observed in patients with severe and/or bilateral infections, and those who were aged ≥ 2 years [see table 2, previous page]. High bacteriological eradication rates were reported in the gatifloxacin and amoxicillin/clavulanate groups (81% vs 82%), although the numbers of patients from whom pathogens had been isolated were small as tympanocentesis was optional. The extent to which nasopharyngeal colonisation was reduced was greater among gatifloxacin, compared with amoxicillin/clavulanate, recipients.
Equal to conventional amoxicillin/clavulanate The second study enrolled 419 patients, 413 of whom received at least one dose of study medication.2,3 The diagnosis of acute otitis media and sampling of middle ear fluid was similar to the other study, but the children enrolled were randomised in a 2:1 ratio to receive gatifloxacin and amoxicillin/clavulanate, respectively. Patients received gatifloxacin 10 mg/kg once daily (n = 277), or amoxicillin 45 mg/kg plus clavulanate 6.4 mg/kg twice daily, for up to 10 days; the maximum allowed doses of gatifloxacin and amoxicillin/clavulanate were 600mg and 1800mg/256mg, respectively. Table 3. Clinical cure rates at the test of cure assessment Population or subcategory Clinically evaluablea Microbiologically evaluableb Severity of Infection: moderate severe Type of infection: bilateral unilateral Age of patient: < 2 years ≥ 2 years Diagnosis: recurrent otitis media (ROM) otitis media treatment failure (OMTF) ROM and OMTF
Gatifloxacin
Amoxicillin/ Clavulanate
Cured/total
Cured/total
222/246 (90%) 97/110 (88%)
102/121 (84%) 46/54 (85%)
78/87 (90%) 139/153 (91%)
32/40 (80%) 69/80 (86%)
113/128 (88%) 109/118 (92%)
49/54 (91%) 53/67 (79%)
81/88 (92%) 141/158 (89%)
36/45 (80%) 66/76 (87%)
67/75 (89%)
35/43 (81%)
140/154 (91%)
62/63 (85%)
15/17 (88%)
5/5 (100%)
Clinically evaluable: patients who had received ≥ 3 days of the study drug and no other antibacterial agent. b Microbiologically evaluable: patients who were clinically evaluable and had ≥ 1 pathogen isolated from the middle ear fluid prior to treatment. a
As in the previous study, the majority of the isolates
Inpharma 25 Oct 2003 No. 1410
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were H. influenzae (39 gatifloxacin and 15 amoxicillin/ clavulanate) and S. pneumoniae (40 gatifloxacin and 20 amoxicillin/clavulanate). There were also 36 isolates of Staphylococcus aureus (21 gatifloxacin and 15 amoxicillin/clavulanate). Gatifloxacin was at least as effective as amoxicillin/ clavulanate at the end of treatment (TOC assessment), and showed superiority to amoxicillin/ clavulanate in patients with moderate and severe infection and in those aged < 2 years [see table 3]. The bacteriological eradication rates among the microbiologically evaluable patients were 89% (108/122) in the gatifloxacin group and 87% (52/60) in the amoxicillin/ clavulanate group. The numbers of β-lactam- resistant pathogens were not high enough to see any significant difference between the groups.
No indications of arthrotoxicity Gatifloxacin was well tolerated in both studies, with low incidences of drug-related adverse events; the most common adverse events among gatifloxacin and amoxicillin/clavulanate recipients were diarrhoea and vomiting. No serious adverse events were reported among gatifloxacin recipients in either study. Importantly, no signs of arthrotoxicity were observed among the 453 gatifloxacin recipients in follow-up assessments conducted for 12 months after treatment.
Gatifloxacin a valuable treatment option These two studies indicate that the fluoroquinolone gatifloxacin is a safe alternative to amoxicillin/ clavulanate in the treatment of acute otitis media in children. The clinical efficacy in both studies was at least equivalent to that of the comparator, even in the study where the high-dose formulation of amoxicillin/ clavulanate was used. There were insufficient numbers of β -lactam-resistant bacteria to indicate whether gatifloxacin would have any advantage over amoxicillin/ clavulanate, but bacteriological eradication rates were equal to the β -lactam combination. "When considered as second line treatment for acute otitis media, gatifloxacin . . . represents an important treatment option with a favorable risk benefit profile," concluded the researchers. * Recurrent infection was classified as at least three episodes of acute otitis media in the previous 6 months or at least four episodes in the previous 12 months. Those who had failed therapy had received at least 48 hours’ treatment with another antibacterial or had infection within 14 days of previous therapy ** Clinically evaluable patients were those who had received ≥ 3 days of the study drug and had not received any other antibacterial agent. Microbiologically evaluable patients were those who were clinically evaluable and had one or more pathogens isolated from the middle ear fluid prior to treatment. 1. Sher L, et al. Gatifloxacin vs. high-dose amoxicillin/clavulanate for recurrent otitis media and acute otitis media treatment failures. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy : 299 (plus poster) abstr. G-1850, 14 Sep 2003. 2. Saez-Llorens X, et al. Gatifloxacin vs. amoxicillin/clavulanate for the treatment of recurrent otitis media and acute otitis media treatment failures. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy : 299 (plus poster) abstr. G-1849, 14 Sep 2003. 3. Arguedas A, et al. Microbiologic response in recurrent otitis media and acute otitis media treatment failures, gatifloxacin vs. amoxicillin/clavulanate. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy : 298 (plus poster) abstr. G-1848, 14 Sep 2003. 800969144
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