Fluoroquinolone antibiotics, including levofloxacin, are used to treat adults with respiratory tract infections caused by bacteria that commonly cause otitis media in children. The emergence of drug resistance in these respiratory pathogens, especially Streptococcus pneumoniae , and the recognition that drug-resistant pathogens can be important causes of recurrent and persistent otitis media in children has raised the concern that there may be few alternatives to standard antibiotic therapies for treatment of this disease.1–3
Fluoroquinolones have demonstrated reliable activity against the 3 leading causes of acute otitis media (AOM) in infants and children: S. pneumoniae (including pencillin-resistant isolates), Haemophilus influenzae , and Moraxella catarrhalis. However, fluoroquinolones have been used sparingly in children because these drugs have been shown to cause lesions in the cartilage of juvenile animals.4 persistent otitis media.5,6 7,8
More recently, an open-label, noncomparator trial assessed the eradication of bacteria from the middle ear fluid of levofloxacin-treated children 6 months to 5 years of age with, or at high risk for, recurrent or persistent AOM.9 H. influenzae and 84% (31 of 37) for S. pneumoniae ] of patients after 4–6 days of therapy and the clinical cure rate 2–5 days after completing levofloxacin therapy was 82.6% (119 of 144). These findings were consistent with those published for children with recurrent and persistent disease who were treated with high-dose amoxicillin/clavulanate or gatifloxacin,7
The primary aim of this study was to demonstrate noninferiority of levofloxacin compared with amoxicillin/clavulanate in the clinical response (cure) at the end of therapy (2–5 days after last dose) in children (<5 years) who had recurrent and/or persistent AOM.
METHODS
Design.
This was a randomized (1:1, levofloxacin:comparator), evaluator-blinded, active-comparator, noninferiority, multicenter study conducted at 66 centers in 6 countries (Argentina, Brazil, Chile, Costa Rica, Panama, and United States) from October 2002 to May 2005. Tympanocentesis was not performed as a protocol-defined procedure and therefore the microbiology of these infections was not defined. Study protocol was approved by the Ethics Committee or Institutional Review Board for each center. Informed consent was obtained from parents or guardians and patients capable of understanding the nature of the study, depending on the institutional policies. A Data Safety Monitoring Committee monitored for any potential safety risks in children participating in this trial. An interactive voice response system was used to randomize subjects in a 1:1 ratio (levofloxacin: amoxicillin/clavulanate). Randomization was generated using randomly permuted blocks and was stratified by center.
Patients.
Outpatient children aged 6 months to <5 years of age, who had recurrent and/or persistent AOM, were eligible. Recurrent disease was defined as ≥3 episodes of AOM in the 6 months before enrollment or ≥4 episodes over the year before enrollment. Persistent disease was defined as evidence of AOM that was unchanged or worsened after ≥3 days of treatment with an antimicrobial regimen used to treat AOM. Children with persistent disease after receiving amoxicillin/clavulanate that provided ≥90 mg/kg/d of amoxicillin were not eligible for enrollment because they would have had a 50% chance of being assigned a regimen similar to the one that was failing. Clinical signs and symptoms of AOM were defined as: (1) either middle ear effusion evidenced by ≥2 of the following: decreased or absence of tympanic membrane mobility by pneumatic otoscopy; yellow or white discoloration of the tympanic membrane; opacification of the tympanic membrane; and (2) ≥1 of the following indicators of acute inflammation: ear pain within 24 hours, including unaccustomed tugging or rubbing of ear; marked redness of the tympanic membrane; distinct fullness or bulging of the tympanic membrane; or acute purulent otorrhea (<48 hours duration) not caused by otitis externa.
Children were not eligible to participate if they had a tympanostomy tube in the affected ear, required systemic antibacterials other than study drug, or used corticosteroids chronically [prednisone (or equivalent) ≥2 mg/kg or ≥20 mg/d for ≥14 days]. Other exclusion criteria included: serious bacterial infection that may have interfered with assessment of clinical response; history of previous hypersensitivity or serious adverse reaction against any quinolone or beta lactam antibiotic; history or presence of musculoskeletal signs or symptoms that in the opinion of the investigator may have confounded future safety evaluation of musculoskeletal complaints.
Study Procedure.
Screening of patients began within 24 hours before first dose of study drug and included review of medical history, assessment of clinical signs and symptoms of AOM, physical examination (including musculoskeletal examination with evaluation of joints and height), vital signs, and clinical laboratory tests (including serum chemistry, hematology, and urinalysis). A blinded evaluator performed the assessment of signs and symptoms of AOM and identified type of AOM infection (recurrent and/or persistent ) and extent of disease (bilateral or unilateral). Blood specimens for culture and antibiotic susceptibility testing of isolated pathogens were collected from patients considered by the investigator to be at risk for bacteremia.
Eligible patients were randomized and received either levofloxacin oral suspension 10 mg/kg twice daily for 10 days (maximum daily dose of 500 mg) or amoxicillin/clavulanic acid (14:1 ratio) oral suspension containing 45 mg amoxicillin/kg twice daily for 10 days (maximum daily dose of 3600 mg amoxicillin).
Children were evaluated 4–6 days into therapy (visit 2), 2–5 days after completing therapy (visit 3), and 10–17 days after last dose of study drug (visit 4). These assessments were conducted by the same evaluator who remained blinded to study drug assignment throughout the treatment and assessment periods. At visit 2, patients were assessed for clinical signs and symptoms of AOM. At visit 3, the investigator determined clinical response to therapy by comparing patient's clinical signs and symptoms at this visit to admission. At visit 4, the investigator determined clinical response to therapy by comparing the patient's clinical signs and symptoms to those observed at admission and visit 3.
Safety evaluations (adverse events, physical examination, vital signs, clinical laboratory tests, height, history) were performed during the study. Any patient presenting with arthralgia or clinical evidence of arthropathy was evaluated within 72 hours of presentation. A follow-up telephone contact was performed 25–35 days after last dose of study drug for adverse events assessment.
Efficacy Evaluation.
Clinical response was categorized as cured, improved, failure, or unable to evaluate. Response definitions at visit 3 were: (1) Cured: resolution of signs and symptoms associated with AOM, excluding evidence by examination or tympanometry of clinically important middle ear effusion; (2) Improved: incomplete resolution of signs and symptoms associated with AOM but no need for further antimicrobial therapy; (3) Failure: persistent signs and symptoms of AOM (after patient on study therapy ≥72 hours) that indicated need for alternative antimicrobial therapy; and (4) Unable to evaluate: because of administration of nonstudy antimicrobial, insufficient course of therapy (<72 hours) or patient not returning for evaluations.
The primary efficacy end point was clinical cure (cured versus not cured) at visit 3 based on resolution as defined above, excluding the presence of middle ear effusion. Secondary efficacy end points included clinical cure rate at visit 4, and clinical success (cured and improved categories) at visits 3 and 4.
Safety Evaluation.
Children who received ≥1 dose of study medication and provided safety information were included in the safety analysis. Safety was evaluated by monitoring possible treatment-related adverse events and changes from baseline in clinical laboratory values, vital signs, and physical examination. The investigator recorded severity of adverse event (mild, moderate, or marked), action taken (none, dose reduced, drug stopped temporarily, drug stopped permanently), and relationship of adverse event to study drug (not related, doubtful, possible, probable, very likely). Musculoskeletal adverse events were recorded and evaluated throughout the study, including events reported by patient, parent, or from musculoskeletal evaluations by the investigator or specialist. Any musculoskeletal or serious adverse abnormalities persisting at the end of study were followed until resolution. As previously described,9,10
Statistical Methods.
Sample size was calculated to determine whether levofloxacin is noninferior to amoxicillin/clavulanic therapy. With a cure rate of 80% in each treatment arm and estimated clinical evaluability rate of 80%, approximately 1650 patients (825 per group) were to be enrolled to assure 660 clinically evaluable patients in each treatment group and noninferiority margin of 10% in the difference in cure rates between groups to be detected with >95% power. The hypothesis of therapeutic noninferiority between levofloxacin and comparator regimens was operationally tested using a 2-sided 95% confidence interval (CI) for the difference in clinical cure rates between the 2 treatment groups (comparator minus levofloxacin). To establish noninferiority of levofloxacin compared with standard therapy, it was stipulated that the upper bound of the 2-sided 95% CI around the difference in cure rates between groups remains below the noninferiority margin of 10%.
Efficacy analyses were performed on clinical cure rate at visit 3, with additional analyses by 2 age groups (≤2 years, >2 years). The prespecified clinically evaluable analysis set was the primary population and included all children who meet the following: randomized; confirmed diagnosis of otitis media; took study medication for ≥72 hours when a clinical failure or otherwise for ≥8 days; no concomitant systemic antimicrobial; clinical evaluation performed within prespecified window of time; not lost to follow-up; no significant protocol violation with an impact on clinical evaluation.
RESULTS
Patients.
Of the 1678 children screened for participation in this trial, 1650 were randomized (827 levofloxacin, 823 comparator) (Fig. 1 ). Two patients randomized to amoxicillin/clavulanate incorrectly received levofloxacin, and 1 patient randomized to levofloxacin incorrectly received amoxicillin/clavulanate. These 3 patients were placed in their randomized treatment group for efficacy analyses, and in the actual study-drug treatment group for safety analyses. None of these 3 patients had a serious adverse event or adverse event leading to treatment discontinuation. The most frequent reason for being excluded from the clinically evaluable population at visit 3 in both treatment arms (91 of 827, 11% in the levofloxacin arm and 75 of 823, 9% in the amoxicillin/clavulanate arm) was inappropriate clinical evaluation which was caused by failure to be evaluated between study days 2 and 5. The second most frequent cause of exclusion in both treatment arms from the clinically evaluable population was insufficient course of therapy which was primarily caused by children being given study drug for a duration of <8 days for subjects who were not a clinical failure, or <72 hours for subjects who failed therapy.
FIGURE 1.:
Patient flow through the study and reasons for exclusion from the clinically evaluable analysis set.
There were no clinically relevant differences between treatment groups in any demographic or baseline characteristic (Table 1 ). Children ranged in age from 6 months to 5.3 years of age, with a higher percentage of males (57%) and children ≤24 months of age (59%). A similar percentage had bilateral (52%) and unilateral (48%) AOM at study entry. Seventy-five percent of children had recurrent disease, 12% had persistent disease, and 13% had both recurrent and persistent disease.
TABLE 1:
Average duration of therapy was 10.2 days for the levofloxacin and amoxicillin/clavulanate groups; 89% levofloxacin-treated and 91% comparator-treated children received 8–12 days of therapy. There were no differences between treatment groups in use of prestudy systemic antimicrobial therapy (15% levofloxacin-treated and 12% comparator-treated). The most commonly used systemic prestudy antimicrobial, amoxicillin, was used by 8% of levofloxacin-treated children and 7% in comparator. Only 4 (1%) levofloxacin-treated and 1 (<1%) comparator-treated children received systemic antibacterials during study-drug therapy.
Clinical Response.
For the primary efficacy analysis, clinical cure rate was 72.4% in levofloxacin group and 69.9% in comparator group (Table 2 ). For both age groups, upper limits of CIs were less than the noninferiority margin of 10% indicating that levofloxacin treatment was noninferior to comparator overall and in younger and older children. Clinical failures at 4–6 days into therapy occurred in 0.3% levofloxacin-treated and 1.0% of comparator-treated patients. Persistence of middle ear effusion at visit 3 occurred in 16% and 20% of children in levofloxacin and comparator groups, respectively. Clinical cure rate at visit 4 was 74.9% and 73.9% in levofloxacin and comparator groups, respectively; levofloxacin was noninferior to comparator overall and in both younger and older children (Table 2 ).
TABLE 2:
Overall clinical success (cured or improved) rate at visit 3 in levofloxacin (94.0%) was greater than comparator (90.8%) because the 95% CI around the difference (−6.02% to −0.29%) excluded zero (Table 3 ). Clinical success rate at visit 4 in levofloxacin (83.6%) was noninferior to comparator (80.4%) for entire population studied. Similarly, clinical success rate in levofloxacin was noninferior to comparator for each age group at both visits. Consistent with the view that infants with recurrent or persistent AOM are more difficult to treat than children >24 months of age, clinical cure and clinical success rates were lower for younger (≤24 months) compared with older (>24 months) children at visits 3 and 4.
TABLE 3:
Safety.
Of the 1607 children evaluable for safety, 448 (56%) levofloxacin-treated and 475 (59%) comparator-treated children experienced 1 or more adverse events up to visit 4. Adverse events occurring in ≥5% of children are summarized in Table 4 . Diarrhea was the most frequent adverse event. Most adverse events were mild or moderate in severity (97% levofloxacin; 96% comparator). Fifty-one children had 69 adverse events of marked severity; marked severe events in most of these patients (55%) were considered doubtfully related or not related to study drug. Adverse events leading to treatment discontinuation occurred in 31 (4%) levofloxacin-treated and 22 (3%) comparator-treated patients, with most adverse events involving gastrointestinal system (3% and 2%, respectively). There were no differences in treatment-emergent markedly abnormal laboratory values between treatment groups.
TABLE 4:
Forty-two patients experienced musculoskeletal adverse events, with similar frequency in levofloxacin (23 of 797; 3%) and comparator (19 of 810; 2%) groups (Table 5 ). The most frequent musculoskeletal adverse events were arthralgia [12 (2%) levofloxacin and 6 (1%) comparator] and myalgia [11 (1%) levofloxacin and 7 (1%) comparator]. The Data Safety Monitoring Committee identified disorders (arthralgia, arthritis, tendinopathy, or gait abnormality) in 12 (2%) levofloxacin-treated and 5 (<1%) comparator-treated children. Disorders characterized as arthralgia, arthritis, or gait abnormality occurred in 10, 2, and 1 levofloxacin-treated and in 5, 0, and 0 comparator-treated children, respectively. Differences between treatment groups were not statistically significant for disorders combined or for disorders individually. However, evaluation of a larger experience that included this trial and 2 other prospective clinical trials9,11
TABLE 5:
Serious adverse events were reported in 10 (1%) children in levofloxacin and 13 (2%) children in comparator group. Most serious events were gastrointestinal disorders (4 levofloxacin; 5 comparator) or respiratory (3 levofloxacin; 5 comparator). The investigator considered relationship to study therapy as possible or probable in 2 levofloxacin-treated (gastroenteritis, dehydration; diarrhea, vomiting) and 1 comparator-treated patient (otitis media).
DISCUSSION
Consistent with findings of an open-label, noncomparative trial that demonstrated rapid eradication of S. pneumoniae and H. influenzae from middle ear infection in levofloxacin-treated children,9 persistent AOM. Although this large trial did not provide information regarding the microbiology of middle ear infection in these children, this study did focus on children at high risk for bacterial infection and therefore children considered to require antibiotic therapy. In these infants and children, levofloxacin therapy was associated with a clinical cure rate that was noninferior to high-dose amoxicillin/clavulanate based on protocol-defined criteria of noninferiority. Furthermore, rate of clinical success (cured and improved) 2–5 days after completing therapy was greater in levofloxacin-treated children (94.0%) than children treated with high-dose amoxicillin/clavulanate (90.8%) in the clinically evaluable population analysis. Although this difference was small (3.2%), the 95% CI of this difference excluded zero and therefore these findings suggest that differences may exist between treatment arms regarding the likelihood of cure or improvement in children at the end of therapy. High-dose amoxicillin/clavulanate has been considered an effective therapy for treatment of children with this condition. Results of this trial suggest that levofloxacin is comparable with this therapy and that levofloxacin could be effective in treating infants and children with recurrent or persistent AOM.
Results of this large trial are consistent with the analysis of a collection of trials completed with gatifloxacin,7 7
Levofloxacin was well tolerated by children with recurrent and/or persistent AOM. The most common treatment-emergent adverse events, serious adverse events, and treatment-limiting events were diarrhea and vomiting and these occurred in similar incidences in amoxicillin/clavulanate-treated children. Although the low incidence of musculoskeletal adverse events did not appear to be different between treatment groups, there was a trend of an increased incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, or gait abnormality) in levofloxacin-treated children compared with amoxicillin/clavulanate-treated children. As recently reported,10
As a therapy for infants and children with recurrent or persistent middle ear infection, consideration of fluoroquinolones, and levofloxacin specifically, is driven by the concern that β-lactams, macrolides, and trimethoprim/sulfamethoxazole have, or may become, increasingly inactive against the leading bacterial causes of this disease. Surveillance of isolates from the respiratory tract of children12 13 persistent otitis media in children. In the presence of this activity, it is logical to consider fluoroquinolones as alternative therapies for children identified as having infections especially difficult-to-treat or failing first-line regimens. Like the pooled analysis of gatifloxacin therapy,7 14 persistent AOM.
CONCLUSIONS
Levofloxacin therapy in children with recurrent or persistent AOM was effective. The results support previous reports that levofloxacin therapy is associated with high rates of microbiologic eradication of bacteria that are leading causes of this disease.
ACKNOWLEDGMENTS
This article is dedicated to the memory of Joseph J. Stavola, MD, in recognition of his contribution to this trial and his life's work as a pediatrician, student, and teacher. The authors thank all of the investigators, their study teams, and patients and their parents/guardians for participating in the study. The authors also acknowledge Bradford Challis, PhD, and Susan Glasser, PhD, of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., for their contribution to the preparation of the article.
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