ORIGINAL STUDIES

Comparative Study of Levofloxacin in the Treatment of Children With Community-Acquired Pneumonia John S. Bradley, MD,* Adriano Arguedas, MD,† Jeffrey L. Blumer, PhD, MD,‡ Xavier Sa´ez-Llorens, MD,§ Rama Melkote, MSc, MPH,储 and Gary J. Noel, MD储 Background: Levofloxacin has established efficacy and safety in the treatment of community-acquired pneumonia (CAP) in adults, and its use as an alternative therapy for children with CAP has been proposed. Objective: Assess the clinical efficacy and safety of levofloxacin compared with standard of care antibiotic therapy in the treatment of CAP in children aged 6 months to 16 years. Methods: In an open-label, multicenter, noninferiority trial, children with CAP were randomized 3:1 to receive levofloxacin or comparator antimicrobial therapy (0.5 to ⬍5 years: amoxicillin/clavulanate or ceftriaxone; ⱖ5 years: clarithromycin or ceftriaxone with clarithromycin or erythromycin lactobinate) for 10 days. The primary outcome was cure rates at the test-of-cure visit (10 –17 days after completing treatment) as determined by symptoms, physical examination, and chest radiography. Results: Seven hundred and thirty-eight children were enrolled and 539 (405 levofloxacin-treated, 134 comparator-treated) were clinically evaluable at test-of-cure visit. Clinical cure rates were 94.3% (382 of 405) in levofloxacin-treated and 94.0% (126 of 134) in comparator-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (⬍5 years, 92.2% versus 90.8%; ⱖ5 years, 96.5% versus 97.1%; respectively) and for children categorized as being at higher risk for severe disease. Mycoplasma pneumoniae was the most frequently identified cause of pneumonia (230 children). Levofloxacin was as well tolerated as comparators, with similar type and incidence of adverse events. Conclusions: Levofloxacin was as well tolerated and effective as standard-of-care antibiotics for the treatment of CAP in infants and children. Key Words: levofloxacin, pneumonia, community-acquired pneumonia, standard-of-care antibiotic (Pediatr Infect Dis J 2007;26: 868 – 878)

Accepted for publication May 3, 2007. From the *Children’s Hospital and Health Center, San Diego, CA; †Instituto de Atencio´n Pedia´trica, Neeman-ICIC, Universidad de Ciencias Me´dicas, San Jose´, Costa Rica; ‡Case Western Reserve University, Rainbow Babies Hospital and Children’s Hospital, Cleveland, OH; §Hospital del Nin˜o, Ciudad de Panama´, Panama´; and 㛳Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ. Address for correspondence: Gary J. Noel, MD, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 920 Route 202 South, Raritan, NJ 08869. E-mail: [email protected]. Copyright © 2007 by Lippincott Williams & Wilkins ISSN: 0891-3668/07/2610-0868 DOI: 10.1097/INF.0b013e3180cbd2c7

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B

acterial pneumonia is an important cause of morbidity and mortality in children.1 The emergence of drug resistance among bacteria that commonly cause these infections, especially Streptococcus pneumoniae, has raised concern about the need for alternative antibiotics to treat children with pneumonia. In adults, fluoroquinolones, including levofloxacin, have been established as effective therapy for patients with bacterial pneumonia. Levofloxacin’s broad spectrum of activity includes the leading bacterial and atypical pneumonia pathogen causes of community-acquired pneumonia (CAP), including penicillin- and macrolide-resistant pneumococci. Recent assessment of levofloxacin activity against pneumococci underscores that levofloxacin remains active against these bacteria and thus potentially a valuable alternative therapy to treat children with CAP, as antibiotic resistance in pneumococci becomes more prevalent. Fluoroquinolones, including levofloxacin, have not been used extensively to treat children because of concerns about the safety of these agents in this population, and levofloxacin is not approved for use in children. The basis for this concern is the observation that juvenile laboratory animals given single or multiple large doses of these agents develop lesions in cartilage, typically in weight-bearing joints. However, published, retrospectively reviewed experience over the past 15 years on the use of fluoroquinolones to treat children for a variety of serious infectious diseases suggests that the adverse events associated with fluoroquinolones in children are similar to those reported in adults.2 Consensus statements and opinions expressed by experts in the field of pediatric infectious diseases suggest that fluoroquinolones have been used safely and effectively to treat specific infections in children and may be considered as alternative therapy in serious infectious diseases.3 Levofloxacin may be an adequate option for empiric therapy in the treatment of CAP in children, given (1) the broad spectrum of activity of levofloxacin against both bacterial and atypical pathogens causing CAP, (2) its established efficacy in the treatment of CAP in adults, (3) the safety profile of levofloxacin in adults, and (4) studies that suggest that fluoroquinolones can be used safely in children. The pharmacokinetics of levofloxacin have been studied in children 0.5–17 years old and established that levofloxacin is cleared more rapidly in young children than it is in adolescents.4 Based on these pharmacokinetics and the pharmacodynamic, targets that have been shown to be associated with positive clinical outcomes in adults with pneumonia treated with levofloxacin,5 it was possible to rationally design dose regimens for levofloxacin use in children. The aim of the

The Pediatric Infectious Disease Journal • Volume 26, Number 10, October 2007

The Pediatric Infectious Disease Journal • Volume 26, Number 10, October 2007

present study was to assess the clinical efficacy and safety of levofloxacin compared with “standard of care” antibiotic therapy in the treatment of CAP in infants and children (0.5–16 years).

METHODS Design. This was a randomized (3:1, levofloxacin:comparator), open-label, active-comparator, noninferiority, multicenter study conducted at 43 centers in 7 countries (Argentina, Brazil, Chile, Costa Rica, Mexico, Panama, and United States) from August 2002 to June 2004. The study protocol was approved by the Ethics Committee or Institutional Review Board for each center. Informed consent was obtained from parents or guardians of the patient and informed assent was obtained from patients ⬎6 years old. A Data Safety Monitoring Committee (DSMC) was established to monitor for any potential safety risks in children participating in this trial. Patients. Male and female children 0.5–16 years old with a clinical diagnosis of CAP in a hospital or outpatient setting were eligible to participate in the study. A diagnosis of CAP was defined as radiographic evidence of pulmonary infiltrate consistent with acute infection requiring antibiotic therapy, and the presence of 2 or more of the indications of pneumonia: fever (rectal or oral temperature ⱖ38°C for children ⬎2 years, or ⱖ38.3°C for children 0.5 to ⱕ2 years), shortness of breath, cough, chest pain, abnormal white blood cell count (⬎15,000/␮L or ⬍5000/␮L), or physical signs of pneumonia on examination (eg, rales on auscultation, dullness to percussion, egophony). Children were not eligible to participate if they received systemic antibiotics for more than 24 hours immediately before enrollment, required a systemic antibiotic other than the study drugs, or had a suspected infection with microorganisms known to be resistant to the study drugs. Other exclusion criteria included hospitalization or residence in a long-term care facility for 14 or more days before the onset of symptoms; infection acquired in a hospital (⬎48 hours after hospital admission and ⬍7 days after hospital discharge); signs and symptoms of a bacterial infection of the central nervous system; history or presence of arthropathy or periarticular disease or any other musculoskeletal signs or symptoms that in the opinion of the investigator may have confounded a future safety evaluation of musculoskeletal complaints. Study Procedure. Eligible children were randomized to receive either levofloxacin or a comparator antibiotic. The target duration for receiving study drug was 10 days. Levofloxacin and comparators were given either orally or by intravenous (iv) administration. The randomization was stratified by age group and country to ensure balance between treatment groups. The patients were randomized in a 3:1 levofloxacin:comparator ratio within 14 strata in the study (1 for the 2 age groups within each country). The antibiotics, dosages, and dosing regimens differed by age group because of age-specific differences in the microbiologic etiology of pneumonia and drug clearance, as well as the requirement that comparators be FDA-approved for the treatment of CAP. © 2007 Lippincott Williams & Wilkins

Study of Levofloxacin

Patients were allowed to switch between oral and iv therapy options within treatment arms. For Group I (ⱖ6 months to ⬍5 years), levofloxacin was administered (a) 10 mg/kg/dose as oral suspension bid (up to 500 mg/d) or (b) 10 mg/kg/dose iv q 12 hours (up to 500 mg/d). The comparator administration was (a) amoxicillin and clavulanic acid (7:1) oral suspension bid, with dose determined by calculating amoxicillin 22.5 mg/kg/dose (up to 875 mg/d), or (b) ceftriaxone 25 mg/kg/dose iv q 12 hours (up to 4 g/d). For Group II (ⱖ5 to 16 years), levofloxacin was administered (a) as 10 mg/kg/dose as oral suspension qd (up to 500 mg/d), (b) as one 250 mg tablet qd (for children weighing 22.5–27.5 kg) or 2 250 mg tablets qd (for children weighing ⬎45.5 kg), or (c) 10 mg/kg/dose iv q 24 hours (up to 500 mg/d). The comparator administration was (a) clarithromycin 7.5 mg/kg/dose as oral suspension (or as a 250 mg tablet) bid (up to 250 mg bid), clarithromycin 250 mg oral tablet bid, or (b) ceftriaxone 25 mg/kg/dose iv q 12 hours (up to 4 g/d), with either erythromycin lactobionate 10 mg/kg/dose iv q 6 hours (up to 4 g/24 hours) or clarithromycin 7.5 mg/kg/dose as oral suspension (or as a 250 mg tablet) bid (up to 250 mg bid). Children were evaluated at 3–5 days into therapy at the on-therapy visit (OTV), 1–3 days after completing therapy at the post-therapy visit (PTV), and at the test-of-cure visit (TOCV) that occurred 10 –17 days after the last dose of study drug. At TOCV the investigator determined the clinical response to therapy by comparing the patient’s clinical signs and symptoms and findings of the chest roentgenogram at this visit to those observed at admission. An observer blinded to study drug assignment read the chest roentgenogram. Any patient presenting with arthralgia or clinical evidence of arthropathy from day 1 through the final visit was evaluated within 72 hours of presentation by an investigator trained in evaluation of joint pathology or in consultation with a specialist (rheumatologist or orthopedic surgeon). A follow-up telephone contact was also performed 25–35 days after the last dose of study drug for adverse events assessment. Efficacy Evaluation. Clinical symptoms of CAP were assessed by the investigator as present or absent at screening, OTV, PTV, and TOCV. The primary endpoint was the clinical cure rate (cured versus not cured) at TOCV based on resolution of the clinical signs and symptoms of pneumonia and radiologic findings reported at admission, with additional analyses by age group, prestudy antimicrobial usage, and risk for severe disease. Clinical response was categorized as cured, improved, clinical failure, relapse 关at TOCV only兴, or unable to evaluate. The response definitions at TOCV were as follows: (1) cured: resolution of signs and symptoms associated with active infection along with an improvement or lack of progression of abnormal findings of chest roentgenogram; (2) improved: continued incomplete resolution of signs and symptoms with no deterioration or relapse after PTV and no requirement for additional antimicrobial therapy; (3) clinical relapse: resolution or improvement of signs and symptoms at PTV evaluation with reappearance or deterioration of signs and symptoms of infection at TOCV; (4) failure: patient was considered a clinical failure at PTV, response was carried forward to

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TOCV; and (5) unable to evaluate: unable to determine response because patient was not evaluated after PTV. Risk assessment for severe disease was based on a “pediatric modification” of the Fine criteria that have been validated in adults as a tool for measuring severity of pneumonia.6 This modification included addition of trisomy 21 to clinical conditions associated with risk as well as criteria related to vital signs that were defined by age categories (Fig. 2). Criteria for abnormalities of vital signs by age were adapted from published values.7 This modified assessment tool has not been validated for use in children but was used in this trial to explore its potential for identifying those children at highest risk for severe disease. A patient was evaluable for clinical efficacy unless categorized into 1 of the following: not evaluable for safety; no confirmed clinical diagnosis of CAP; did not take the study drug for at least 5 days (except if patient took study drug for greater than 48 hours but for fewer than 5 days because patient judged a clinical failure by the investigator); took an effective, nonstudy drug systemic antimicrobial between study enrollment and TOCV culture (except if patient took an effective systemic antimicrobial therapy because patient had been judged a clinical failure by the investigator); TOCV clinical evaluation not completed 7–21 days after the last dose of study drug (except if patient discontinued because of clinical failure or was considered a clinical failure upon the completion of therapy and TOCV evaluation was obtained before 7 days after therapy); lost to follow-up but relayed safety information (no TOCV evaluation); or protocol violations that warranted exclusion from analysis. Patients who received the incorrect study drug dose or incorrect study drug were excluded from all efficacy analyses at all visits. Microbiologic response was determined at PTV and TOCV. The microbiologically evaluable analysis set included all the children who were evaluable for microbiologic efficacy. Microbiologic response to treatment was evaluated in terms of both pathogen and infection eradication rates and was based on the fate of the original pathogen(s). Sputum was obtained from co-operative children and these specimens were considered to be reflective of lower respiratory disease if microscopic analysis of a Gram-stained specimen demonstrated inflammatory cells (⬎25 PMN/hpf) and few (⬍5 cell/hpf) epithelial cells. In some young children, respiratory specimens were obtained by suctioning secretions from the trachea, using a sterile catheter passed through the nasopharynx. These specimens were not considered to reflect lower respiratory tract disease and because interpretation of isolates recovered by this technique as specimens causing pneumonia can be difficult, if not impossible, microbiologic diagnosis of these children was identified separate from those children in whom sputum was obtained. Sputum samples were sent to the local laboratories for culture of pathogens. Susceptibility to levofloxacin and the comparators was initially evaluated at the local microbiology laboratories using disk zones, and then all pathogens isolated were preserved and sent to a central laboratory (Covance Central Laboratory Services, Indianapolis IN) for minimum inhibitory concentration (MIC) testing using a broth microdilution technique. The disk zone results were used in the analyses only when MIC results were

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unavailable. All susceptibility testing was performed in accordance with Clinical and Laboratory Standards Institute (CLSI) methods. Organisms with a MIC of ⱕ2 ␮g/mL were considered susceptible to levofloxacin; organisms with a MIC of 4 ␮g/mL were considered to have intermediate susceptibility to levofloxacin; and organisms with a MIC ⱖ8 ␮g/mL were considered resistant to levofloxacin. Microbiologic response definitions were as follows: (1) eradicated: absence of the admission pathogen at evaluation; (2) presumed eradicated: presumed absence of admission pathogen as a result of substantial improvement of infection so that no material for culture was available; (3) persisted: presence of the admission pathogen in the culture; (4) presumed persisted: presumed presence of the admission pathogen for children with clinical failure for whom no culture was taken or for whom the culture was taken while the patient was receiving study antibiotics; (5) persisted with acquisition of resistance: presence of admission pathogen in the culture with documented acquisition of resistance; (6) microbiologic relapse 关at TOCV only兴: reappearance of an organism identical to that isolated at admission; and (7) unknown: no culture results available because of patient being lost to follow-up. Diagnosis of infection caused by Chlamydophila pneumoniae or M. pneumoniae was made on the basis of the serologic criteria in children with compatible clinical and radiologic findings. Serum was tested for acute and convalescent antibody titer, and the criteria were 1 or more of the following: (a) single microimmunofluorescence IgM titer ⱖ1:32 for C. pneumoniae or single IgM ELISA titer ⱖ1:16 for M. pneumoniae, or a 4-fold increase or decrease in IgM titer between the acute and convalescent serology; or (b) single microimmunofluorescence IgG titer ⬎1:512 for C. pneumoniae or single IgG ELISA titer ⱖ1:128 for M. pneumoniae, or a 4-fold increase in IgG titer between the acute and the convalescent serology. Safety Evaluation. Parents and study personnel were not blinded to study drug assignment. Some investigators chose to remain blinded to study drug, but this was not required per protocol. Children who received at least 1 dose of study medication and provided safety information were included in the safety analysis. Safety was evaluated by monitoring treatment-emergent adverse events and changes from baseline in clinical laboratory values, vital sign measurements, and weight and physical examination findings. The investigator recorded the severity of an adverse event (mild, moderate, or marked), action taken (none, dose reduced, drug stopped temporarily, drug stopped permanently), and relationship of an adverse event to the study drug (not related, doubtful, possible, probable, very likely). Musculoskeletal adverse events were recorded and evaluated throughout the study, including events reported by the patient and/or parent or from musculoskeletal evaluations by the investigator or specialist from the time of first study related procedure through the final visit. Patients were instructed to be evaluated by the investigator within 72 hours of onset of symptoms or signs of a musculoskeletal disorder. A DSMC reviewed the musculoskeletal and serious adverse event safety data on an ongoing basis. Any musculoskeletal or serious adverse ab© 2007 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal • Volume 26, Number 10, October 2007

TABLE 1. Demographic and Baseline Characteristics for Patients in the Modified Intent-to-Treat Analysis Set Characteristic Age (yr) Mean (SD) Range ⱖ0.5 to ⬍5 ⱖ5 to 16 Gender Male Female Race White Black Other* Initial hospital status Inpatient Outpatient Risk for severe disease† N High risk Low risk Country Argentina Brazil Chile Costa Rica Mexico Panama United States

Levofloxacin (N ⫽ 529)

Comparator (N ⫽ 180)

Total (N ⫽ 709)

5.52 (4.01) 0.5–16.7 264 (50) 265 (50)

5.47 (4.12) 0.5–16.1 92 (51) 88 (49)

5.50 (4.04) 0.5–16.7 356 (50) 353 (50)

266 (50) 263 (50)

92 (51) 88 (49)

358 (50) 351 (50)

265 (50) 53 (10) 211 (40)

96 (53) 19 (11) 65 (36)

361 (51) 72 (10) 276 (39)

277 (52) 252 (48)

98 (54) 82 (46)

375 (53) 334 (47)

518 266 (51) 252 (49)

175 89 (51) 86 (49)

693 355 (51) 338 (49)

26 (5) 76 (14) 11 (2) 146 (28) 117 (22) 52 (10) 101 (19)

9 (5) 26 (14) 4 (2) 50 (28) 40 (22) 17 (9) 34 (19)

35 (5) 102 (14) 15 (2) 196 (28) 157 (22) 69 (10) 135 (19)

Study of Levofloxacin

least 1 dose of study drug, and had a confirmed diagnosis of CAP. Clinical and microbiologic responses were summarized by age group at PTV and TOCV.

RESULTS

*Mostly Hispanic. † Risk for severe disease at baseline based on age, concomitant severe disease, altered mental status, abnormal age-adjusted vital signs.

normalities persisting at the end of the study were followed until resolution. Statistical Methods. The sample size was calculated to determine whether levofloxacin is noninferior to standard of care therapy. With a cure rate of 90% in each treatment arm, and an estimated clinical evaluability rate of 78%, approximately 650 total children (487 levofloxacin, 163 standard of care therapy) were to be enrolled in the study to achieve 380 clinically evaluable levofloxacin children and 127 clinically evaluable comparator children and allow up to 10% difference in cure rates between groups to be detected with 90% power. A 2-sided 95% confidence interval (CI) for the difference in clinical cure rates between the 2 treatment groups (comparator minus levofloxacin) was performed to assess therapeutic noninferiority between levofloxacin and comparator regimens. To establish noninferiority of levofloxacin compared with standard therapy, it was stipulated that the upper bound of the 95% CI around the difference in cure rates between groups remain below a noninferiority margin of 10%. The efficacy analyses were performed on the clinical cure rate at TOCV, with additional analyses by the 2 age groups (⬍5 years, ⱖ5 years) and risk for severe disease (low versus high). The clinically evaluable analysis set was the primary population and included all children who were randomized, had a confirmed diagnosis of CAP, and were evaluable for clinical efficacy according to predetermined criteria (see Efficacy evaluation). Additional analysis was performed on the modified intent-to-treat (MITT) population, which included all children who were randomized, took at © 2007 Lippincott Williams & Wilkins

Patients. There were 738 children enrolled in the study, of whom 728 were randomized: 546 to the levofloxacin group and 182 to the comparator group. The demographics and baseline characteristics of the 709 children who received at least 1 dose of the study drug and had a confirmed diagnosis of CAP (MITT population) are shown in Table 1. There were no clinically relevant differences between treatment groups in any demographic or baseline characteristic. Children ranged in age from 0.5 to 16.7 years, and an equal percentage of children (50%) were male and female as randomized to each age group (⬍5 years, ⱖ5 years). There were no differences between treatment groups in the incidence of prestudy systemic antimicrobial therapy use: 142 (27%) levofloxacin-treated children and 51 (28%) comparator-treated. The most commonly used systemic prestudy antimicrobials, ampicillin and ceftriaxone sodium, were used by 6% of children in both treatment groups. Only 4 (1%) levofloxacin-treated children and 1 (1%) comparator-treated patient received systemic antibacterials during study drug therapy, and these children were excluded from the efficacy analysis (Fig. 1). Most children completed at least 10 days of their assigned treatment (85% in the levofloxacin group and 83% in the comparator group). The average durations of therapy for the levofloxacin and comparator groups were 10.5 and 10.4 days, respectively. All but 8% of levofloxacin-treated and 9% of comparator-treated children received between 7 and 14 days of therapy. The flow of children through the study at each visit and reasons for exclusion from efficacy analysis is shown in Figure 1. At TOCV, 539 (74%) children were clinically evaluable; primary reasons for clinical nonevaluability included insufficient or incorrect course of therapy, or inappropriate clinical evaluation. In this study designed to assess the clinical efficacy of levofloxacin, most of the children (64%) were not microbiologically evaluable at TOCV as they did not have a proven microbiologic infection at admission. Clinical Response. Clinical cure rates at TOCV are summarized for the clinically evaluable children and MITT population by age group and risk for severe disease (Table 2). The cure rates for children in the levofloxacin and comparator groups were similar in both the clinical evaluable and MITT populations. For the primary endpoint of clinical cure rate in the clinically evaluable population, the rate in the levofloxacin group (94.3%) was similar to that in the comparator group (94.0%). Subgroup analyses of children younger and older than 5 years and children at high and low risk for severe infection (Table 2) also demonstrated that cure rates were similar for levofloxacin-treated and comparator-treated children. An estimate of severity of pneumonia was made using a modification of a scoring system that has not been validated in children (Fig. 2). The rate of hospitalization was higher in children assessed to be at high risk for severe infection compared with those assessed as low risk patients (65%

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FIGURE 1. Flow diagram of patient progress through the study and reasons for exclusion from clinical analysis.

versus 31%, respectively). There was a trend for children at “low risk” (levofloxacin, 96.1%; comparator, 95.3%) for severe disease to have higher cure rates at TOCV compared with children at “high risk” (levofloxacin, 92.3%; comparator, 92.5%). The cure rates for levofloxacin- and comparatortreated children by risk strata were also similar and met criteria for demonstrating noninferiority between levofloxacin and comparator groups. Children who were failing or assessed to be slowly responding to systemic antibiotics at the point that they were being considered for entry into the trial were excluded from the trial.

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Therefore, levofloxacin and comparator regimens were not assessed as therapy for children who were deteriorating after receiving first-line treatments. However, brief (⬍24 hours) treatment with systemic antimicrobials before enrolment in the study was allowed. The potential for this brief treatment to influence the outcomes in this trial was assessed by evaluating children who received this therapy and those who received no therapy before study entry. In children who took prestudy antimicrobials, the clinical cure rate at TOCV for the clinically evaluable children was 95.6% in the levofloxacin group and 93.1% in the comparator group. In children who did not receive any antimi© 2007 Lippincott Williams & Wilkins

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Study of Levofloxacin

TABLE 2. Clinical Cure Rate for Patients at the Test-of-Cure Visit by Age and Risk for Severe Disease at Baseline Levofloxacin

Comparator

Baseline Characteristic Clinical evaluable population All patients Age group ⱖ0.5 to ⬍5 yr ⱖ5 to 16 yr Risk for severe disease Low risk High risk Modified intent-to-treat population All patients Age group ⱖ0.5 to ⬍5 yr ⱖ5 to 16 yr Risk for severe disease Low risk High risk

Treatment Difference

N

Cured (%)*

N

Cured (%)*

Difference†

95% CI‡

405

382 (94.3)

134

126 (94.0)

⫺0.3

(⫺4.9, 4.3)

205 200

189 (92.2) 193 (96.5)

65 69

59 (90.8) 67 (97.1)

⫺1.4 0.6

(⫺9.4, 6.5) (⫺4.1, 5.3)

203 194

195 (96.1) 179 (92.3)

64 67

61 (95.3) 62 (92.5)

⫺0.7 0.3

(⫺6.6, 5.1) (⫺7.1, 7.6)

503

439 (87.3)

170

145 (85.3)

⫺2.0

(⫺8.1, 4.1)

247 256

211 (85.4) 228 (89.1)

87 83

71 (81.6) 74 (89.2)

⫺3.8 0.1

(⫺13.1, 5.4) (⫺7.6, 7.8)

250 242

210 (84.0) 221 (91.3)

85 77

74 (87.1) 61 (87.0)

3.1 ⫺4.3

(⫺5.4, 11.5) (⫺12.6, 4.0)

*Cured indicates cured response category only. † Difference in % clinical cure rates (comparator minus levofloxacin). ‡ Two-sided 95% confidence interval (CI) around the difference in the % clinical cure rates using normal approximation to binomial probability without continuity correction. Upper confidence limit of ⬍10 indicates that levofloxacin is non-inferior to comparator, defined as ⬍10% difference. Numbers in parenthesis represent percentages.

crobials immediately before the first dose of study drug, the clinical cure rate was 94.0% in the levofloxacin group and 94.3% in the comparator group. In an analysis of the success rate (cured or improved) at the PTV, children in the levofloxacin-treated and comparatortreated groups also had similar clinical success rates (92.7% versus 93.9%) in the clinically evaluable population. Four children were considered clinical failures at both PTV and TOCV (0.7% 关3 children兴 in levofloxacin and 0.7% 关1 child兴 in the comparator group). Pathogens were not identified at screening for any of these children. Cure of pneumonia required improvement or lack of progression of radiographic abnormalities as well as resolution of clinical findings supporting the diagnosis of pneumonia. Resolution of these specific abnormalities was analyzed by treatment group. Resolution of abnormal chest radiograph findings were comparable at the TOCV in the levofloxacin-treated (70%; 276 of 392) and comparatortreated (65%; 84 of 129) groups. As evident by the rate of resolution of symptoms at the PTV, cough tended to be the slowest symptom to resolve. The percent of children noted to have resolution of cough was lower (72% levofloxacin; 66% comparator) than the percent with resolution for other symptoms (fever, shortness of breath, chest pain, abnormal WBC 关all ⱖ88%兴) at the PTV. Microbiologic Response. The microorganisms commonly considered important respiratory pathogens in children and identified as causing pneumonia in this trial in children who were clinically evaluable at TOCV are shown in Table 3. The majority of identified infections were caused by M. pneumoniae in children older and younger than 5 years. S. pneumoniae was the second most frequently identified cause of pneumonia in this trial and was identified in blood in 11 children and in sputum in 10 children (Table 4). Eight infants had pneumococci isolated only from nasopharyngeal (n ⫽ 5) © 2007 Lippincott Williams & Wilkins

or oropharyngeal aspiration of respiratory tract secretions. Although these children are identified as having S. pneumoniae isolated from a specimen obtained upon admission to the study, it is not clear that the cause of these children’s pneumonia was pneumococci. One child in the comparator group had pneumococci isolated from both blood and a nasopharyngeal aspirate, and therefore was considered to have documented pneumococcal infection. In addition, 2 levofloxacin-treated children who underwent thoracentesis (1 and 4 days after starting therapy) had S. pneumoniae isolated from pleural fluid. Both were assessed to be clinical cured at the TOCV. Because neither child had S. pneumoniae isolated from blood or sputum upon admission, they were not included in analysis of outcome for patients with pneumococcal pneumonia diagnosis on admission. Microbiologic eradication or presumed eradication at the TOCV occurred in 96.5% (138 of 143) levofloxacintreated and 95.7% (45 of 47) comparator-treated children (difference, 0.8%; 95% CI: ⫺7.3–5.7%). These eradication rates were largely reflective of clinical outcome because most of the children assessed at the TOCV with an identified pathogen were considered to be infected with M. pneumoniae and successful eradication of this pathogen was based on clinical improvement. Outcome of children identified as having S. pneumoniae isolated on admission cultures is shown in Table 4. Of the 17 levofloxacin-treated children clinically evaluated at TOCV, including 5 with bacteremia, all but 2 were assessed to be clinical cures, and all but 1 were assessed to have microbiologic eradication. A 6-month-old boy with entry nasopharyngeal cultures positive for pneumococcus and a chest roentgenogram demonstrating a right upper lobe and left lower lobe infiltrate was diagnosed as having bronchiolitis several days after completing levofloxacin therapy. He was categorized as having a relapse of a lower respiratory

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FIGURE 2. Depiction of the algorithm used for risk assessment for severe disease.

tract infection. Although no respiratory secretions were obtained for culture at the time relapse with bronchiolitis, the child was presumed to have microbiologic persistence of a pneumococcal infection by the physician caring for the boy. A 1.2-year-old girl who had pneumococci isolated from an oral pharyngeal aspirate, had a right middle lobe infiltrate on x-ray examination or on admission. She was assessed to have clinical improvement, not cure, and presumed microbiologic eradication at the TOCV. No infiltrates were evident on chest roentgenogram at the TOCV. In addition, 5 levofloxacintreated children were identified as having S. pneumoniae isolated from a specimen obtained upon admission, but were not clinically evaluated at the TOCV. A 1-year-old diagnosed with pneumococcal pneumonia by sputum culture was assessed as cured at the PTV. A 9.6-year-old (positive sputum

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culture) and an 1.2 years old with pneumonia and pneumococcal bacteremia were not evaluated at the PTV. Two children who had pneumococci isolated from nasopharyngeal isolates were assessed as improved at the PTV. Of the 5 comparator-treated children identified as being infected with S. pneumoniae and clinically evaluated at TOCV, 4 were assessed to be clinical cures and to have microbiologic eradication; 1 child (6 month old with pneumonia and pneumococcal bacteremia) was assessed as improved with microbiologic eradication. One comparator-treated 6-year-old child with pneumonia and pneumococcal bacteremia was not evaluable at either the PTV or TOCV. The levofloxacin MICs of all Haemophilus influenzae isolates were ⱕ0.03 ␮g/mL (range, 0.015– 0.03 ␮g/mL). The levofloxacin MICs for all S. pneumoniae isolates were ⱕ2 ␮g/mL (range, 0.5–2 ␮g/mL). © 2007 Lippincott Williams & Wilkins

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Study of Levofloxacin

TABLE 3. Number and Cure Rate at the Test-of-Cure-Visit of Clinically Evaluable Children With Important Lower Respiratory Microorganisms Isolated From Specimens Obtained at Enrollment Levofloxacin Age Group Pathogen

Comparator

Source of Specimen

Age, ⱖ0.5 to ⬍5 yr Mycoplasma pneumoniae Chlamydophila pneumoniae Streptococcus pneumoniae Moraxella catarrhalis Haemophilus influenzae Age, ⱖ5 to 16 yr Mycoplasma pneumoniae Chlamydophila pneumoniae Streptococcus pneumoniae Streptococcus pyogenes Klebsiella pneumoniae Haemophilus spp Haemophilus influenzae

N*

% Cured

N*

% Cured

Serology Serology Blood Sputum Other Sputum Sputum

66 1 2 0 5† 2 3

89 100 100 — 60 0 67

18 3 2‡ 0 1‡ 0 1

83 67 50 — 0 — 100

Serology Serology Blood Sputum Sputum Sputum Sputum Sputum

63 2 3 4 2 1 1 0

100 100 100 100 100 100 100 —

21 1 1 1 0 0 0 2

95 100 100 100 — — — 100

*Includes children clinically evaluable at the test-of-cure visit as per protocol. † Sputum was collected from infants through nasopharyngeal (2) or oropharyngeal (3) aspiration; see Table 4 for details. ‡ Includes 1 infant who had a blood taken for culture and a sputum collected through nasopharyngeal aspiration.

TABLE 4. Clinical and Microbiologic Responses of Children With Streptococcus pneumoniae Isolated From Specimens Upon Admission to the Trial Clinical Response Source of Specimen at Admission Treatment group: Levofloxacin Evaluated at test-of-cure visit Sputum Sputum Sputum Sputum Sputum Sputum Sputum Blood culture† Blood culture† Blood culture Blood culture† Blood culture† NP aspirate‡ NP aspirate‡ OP aspirate§ OP aspirate§ OP aspirate§ Not evaluated at test-of-cure visit Sputum Sputum Blood culture† NP aspirate‡ NP aspirate‡ Treatment group: Comparator Evaluated at test-of-cure visit Sputum Blood culture† Blood culture† Blood culture† Blood culture NP aspirate‡ Not evaluated at test-of-cure visit Blood culture†

Microbiologic Response (Eradication)

Age (yr) Post-Therapy

Test-of-Cure

Post-Therapy

Test-of-Cure

2.2 5.0 7.0 9.1 10.0 10.6 14.1 1.0 4.4 5.0 7.1 7.4 0.5 0.6 0.9 1.2 1.2

UTE Cured Cured Cured Improved Cured Cured Cured Cured Cured Cured Cured Improved Improved Cured Improved Improved

Cured* Cured* Cured Cured Cured Cured Cured* Cured Cured Cured Cured Cured Clinical relapse Cured Cured Improved Cured

Unknown Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Documented Presumed Presumed Presumed Presumed Presumed

Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed Presumed persistence Presumed Presumed Presumed Presumed

9.6 11.4 1.2 0.7 1.0

UTE Cured UTE Improved Improved

UTE UTE UTE UTE UTE

Unknown Presumed Documented Presumed Presumed

Unknown Unknown Unknown Unknown Unknown

13.6 1.1 1.7 11.8 0.5

Cured Cured Cured Cured Improved

Cured Cured* Cured Cured Improved

Presumed Presumed Presumed Presumed Presumed

Presumed Presumed Presumed Presumed Presumed

UTE

UTE

Unknown

Unknown

6.0

*Investigator designated as cured but not evaluable per protocol because of inappropriate dosing: received half of prescribed dose (2 children in levofloxacin) or incorrect frequency (1 child in each group). † Repeat blood culture performed at the On-Therapy Visit. ‡ The sputum culture in this infant was collected through nasopharyngeal aspiration with a sterile catheter. Direct observation with a laryngoscope was not employed. § The sputum culture in this infant was collected via suction. After thoracic percussion, the examiner waited until the child coughed, and took a suction sample. UTE indicates unable to evaluate.

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TABLE 5. Adverse Events Occurring in ⱖ5% of Patients up to the Test-of-Cure Visit for the Safety Analysis Set Adverse Event Diarrhea Vomiting Abdominal pain Upper respiratory tract infection Rhinitis Bronchospasm Fever

Levofloxacin (N ⫽ 533) n (%)

Comparator (N ⫽ 179) n (%)

Total (N ⫽ 712) n (%)

37 (7) 34 (6) 24 (5) 26 (5)

19 (11) 15 (8) 12 (7) 9 (5)

56 (8) 49 (7) 36 (5) 35 (5)

19 (4) 16 (3) 12 (2)

10 (6) 10 (6) 11 (6)

29 (4) 26 (4) 23 (3)

Safety. Of the 712 children evaluable for safety, 275 (52%) levofloxacin-treated children and 94 (53%) comparatortreated children experienced 1 or more adverse events up to TOCV. A summary of adverse events occurring in at least 5% of children in a treatment group up to TOCV is summarized in Table 5. Diarrhea was the most frequent adverse event. Most adverse events were mild or moderate in severity. Seventeen children had 23 adverse events of marked severity. Most of the severe events were considered doubtfully related or not related to study drug. Twenty-five children experienced musculoskeletal adverse events. The overall frequency of these events was comparable in the levofloxacin (19 of 533; 4%) and comparator groups (6 of 179; 3%). The most frequent musculoskeletal adverse events reported were arthralgia and myalgia. Arthralgia was reported in 9 (2%) levofloxacin-treated children and 1 (1%) comparator-treated child. Myalgia was reported in 10 (2%) levofloxacin-treated and 4 (2%) comparator-treated children. To be more precise in assessing events that could correlate with the cartilage toxicity observed in juvenile laboratory animals, events were characterized by the DSMC to be 1 of 4 disorders (arthralgia, arthritis, tendinopathy, or gait abnormality). These disorders were identified in 10 (2%) levofloxacin-treated and 2 (1%) comparator-treated children. Disorders characterized as arthralgia, tendinopathy, or arthritis occurred in 9, 1, and 1 levofloxacin-treated children, and in 1, 1, and 0 comparator-treated children, respectively. Differences between treatment groups were not statistically significant for any of the disorders. Serious adverse events were reported in 33 (6%) children in the levofloxacin group and 8 (4%) children in the comparator group. Most of the serious events were respiratory disorders (13 关2%兴 levofloxacin and 4 关2%兴 comparator, with asthma and pneumonia accounting for most in both groups), or condition aggravated (9 关2%兴 levofloxacin and 2 关1%兴 comparator). The investigator considered the relationship to study therapy as doubtfully related or not related to study drug in 31 children (6%) in the levofloxacin group, and in 7 children (4%) in the comparator group. The relationship to study therapy was assessed as possible in 1 comparatortreated patient (hepatomegaly), and probable or very likely in 3 levofloxacin-treated patients (hepatitis, rash, aggravated pneumonia). The patient with hepatitis had elevated liver

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function tests and hepatomegaly at baseline, and the persistence of this baseline elevation and of hepatomegaly was the basis for the physician caring for the child to assess the relationship of drug as being possible. Two serious adverse events in levofloxacin-treated children resulted in fatal outcomes. One death occurred after 3 days of levofloxacin treatment during a bronchoscopy procedure being done to rule out tuberculosis, and 1 death occurred 3 weeks after completion of levofloxacin treatment when the patient developed severe bronchospasm; neither death was considered related to levofloxacin by the investigator. Adverse events leading to treatment discontinuation occurred in 12 (2%) levofloxacin-treated and 2 (1%) comparator-treated children. No single type of treatment-limiting adverse event occurred in more than 1% of children. In the levofloxacin group, the most frequent category of adverse events that were treatment-limiting involved the gastrointestinal system (1%). There were no differences in the incidence of treatment-emergent markedly abnormal laboratory values between the treatment groups. Given the potential effects of levofloxacin on the musculoskeletal system, abnormal alkaline phosphatase values in 2 children were considered to be clinically relevant. Two children in the levofloxacin group (1.7-year-old girl and 2.3-year-old girl) were noted to have increases in alkaline phosphatase; as the increases did not seem to be caused by either liver or bone disease, these events were possibly the result of transient hyperphosphatemia in infants.

DISCUSSION The results of this large trial demonstrate that levofloxacin is not inferior to standard-of-care therapy for the treatment of infants and children diagnosed as having CAP. Levofloxacin given at a dose of 10 mg/kg twice-a-day for children younger than 5 years and once-a-day for children older than 5 years for 10 days was tolerated as well as comparators and appeared to result in clinical cure rates that were similar to FDA-approved therapies for pneumonia in children. These findings were consistent in hospitalized and nonhospitalized children, and the results of this trial are consistent with those of clinical trials assessing the efficacy of levofloxacin in adults.8 Clinical cure in levofloxacin-treated children exceeded 90% at TOCV. These rates are comparable to those measured in the comparator group and to rates reported in adult trials of CAP. Furthermore, these rates are similar to those reported in a smaller trial (n ⫽ 296) that compared the efficacy of amoxicillin/clavulanate, azithromycin, and erythromycin as treatment of children with pneumonia.9 In this trial, the cure rates in children younger than 5 years were 89.5% for amoxicillin/clavulanate and 86.5% for azithromycin based on the FDA’s analysis of the intent-to-treat population. Corresponding rates in children older than 5 years were 95.6% and 92.9% for azithromycin and erythromycin, respectively. The results of this trial are based largely on clinical findings, as are the results of nearly all large comparative clinical trials involving children with CAP. A viral cause of © 2007 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal • Volume 26, Number 10, October 2007

pneumonia was not assessed in most of the children enrolled. The paucity of bacteria isolates (eg, S. pneumoniae, H. influenzae, S. aureus) obtained in this trial is not unexpected, given the difficulty in establishing an accurate bacterial etiology of CAP in children and infants without more invasive techniques. The reliance on sputum and blood cultures is likely to have resulted in an underestimation of the number of children in this trial who had these bacterial infections, whereas the inclusion of nasopharyngeal and oropharyngeal cultures may result in an overestimation. Recent work suggests that performance of DNA amplification on specimens may be more sensitive in detecting bacterial causes of pneumonia than reliance on blood or sputum culture in children; given the clinical presentation of children enrolled in the trial, it is possible that more episodes of documented bacterial infection would have been identified if these methods had been used.10 The clinical trial experience reported here reflects a difficulty in establishing a microbiologic diagnosis of CAP in children that is similar to the experience in clinical practice. Given the potential for inappropriate use of antibiotics in children with viral lower respiratory tract infection as well as the potential for this use to impact on antibacterial drug resistance among respiratory bacterial pathogens, it is critical to consider microbiologic diagnosis in making decisions to use antibiotics in treating children with CAP, especially in children with mild disease. The results of serologic testing in this trial underscored the importance of mycoplasma as a cause of CAP in children. Increasingly in recent years, M. pneumoniae has been recognized as a frequent cause of CAP in infants and young children. Mycoplasma are widely considered to be a leading, if not the most important, cause of CAP in children ⬎5-yearold.10,11 Although mycoplasma are also widely considered to be a less important cause of CAP in children younger than 5 years, most experiences have suggested these pathogens are important cause of CAP even in this younger age group.12,13 It has been suggested that most of these infections will eventually resolve without complication. However, M. pneumoniae has been documented to cause bronchopneumonia, parapneumonic effusions and necrotizing pneumonitis.14 Symptomatic infections are most often treated in children with macrolides.15,16 Of note, children younger than 5 years in the comparator group received amoxicillin/clavulanate orally or ceftriaxone parenterally, neither of which is felt to provide adequate therapy for mycoplasma. Because rates of cure between comparator-treated children (83% of 18 documented mycoplasma infections) and levofloxacin-treated children (89% of 66 documented mycoplasma infections) were not statistically different, one can question the actual clinical benefit provided by antibiotic therapy that has no in vitro activity against mycoplasma. These infections may have high rate of spontaneous resolution, especially in young children. Criteria for identification of children at risk for severe pneumonia or who are most likely to benefit from hospitalization have not been defined. In this trial, an attempt to modify established criteria currently used in adults for use in children was made and these criteria were used in analysis of cure rates. Nearly 50% of children enrolled in the trial met our criteria for high risk of severe infection based on a newly © 2007 Lippincott Williams & Wilkins

Study of Levofloxacin

created modification of the Fine criteria. Analyses of cure rates based on the risk for severe infection suggest that children meeting criteria of low risk trended to have higher cure rates and to be less frequently hospitalized, and may also have higher rates of spontaneous resolution of infection. Although this observation does not establish the modified criteria as a valid method for identification of risk, it suggests that this, or a similar modification of criteria, could prove valuable in characterizing children enrolled in CAP trials. The safety profile defined in children in this study is similar to that defined in clinical trials involving adults and to that reported for other nonfluoroquinolone antibiotics in pediatric CAP trials. The low-rate (2%) of treatment-limiting adverse events indicates that levofloxacin is well tolerated by infants and children. Adverse event rates related to the musculoskeletal system are consistent with the rate and type of events expected to occur in otherwise healthy children. None of the observed events was considered to indicate toxicity associated with the lesions in cartilage. This occurred despite the potential for over-reporting of joint disorders by unblinded parents and investigators. The majority of patients in this study subsequently enrolled in a companion study that had the objective of specifically assessing the incidence of set of 4 musculoskeletal disorders (defined as arthralgia, arthritis, tendinopathy and gait abnormality) that occur after initiating levofloxacin or nonfluoroquinolone therapy for acute infectious diseases in children. The results of this long-term companion study, which also included the experience of children who had participated in trials assessing levofloxacin as a treatment for acute otitis media,17 were recently reported and indicated that the incidence of having 1 or more of these 4 musculoskeletal disorders within approximately 60 days of starting therapy was higher in levofloxacin-treated children compared with those treated with nonfluoroquinolone agents.18 Abnormalities demonstrating lesions in cartilage were not demonstrated in the 5 levofloxacin-treated children who underwent MRI or CT evaluation of their disorder. No long-term joint abnormality or growth impairment associated with study drug exposure was evident based on the observation that the disorders identified had all resolved and that there were no differences between treatment groups based on analyses of growth curves constructed over the year after treatment. Because the children evaluated in this long-term study had participated in open-label trials, both parents and investigators may have been aware of study drug assignments. Nonetheless, it is anticipated that the final results of this large, long-term surveillance trial as well as the analyses of data collected prospectively on overall safety of levofloxacin as part of trials involving children with pneumonia and otitis media will be important in establishing the risk of using levofloxacin in children. The results of this study demonstrate the effectiveness of levofloxacin in terms of its noninferiority in relation to standard-of-care therapy (amoxicillin/clavulanate, ceftriaxone, clarithromycin, erythromycin lactobionate) for the treatment of CAP in infants and children. Levofloxacin administered 10 mg/kg/d as a single dose in children ⱖ5 years and 20

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mg/kg/d in 2 divided doses in children ⬍5years of age (up to 500 mg/d) for 10 days was well tolerated.

2005, and the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), December 2005. REFERENCES

ACKNOWLEDGMENTS The authors thank the following investigators, their study teams, and patients for participating in the study: Argentina: Victor Israele, MD, Buenos Aires; Abel Jasovich, MD, Buenos Aires; Brazil: Paulo Carvalho, MD, Porto Alegre, RS; Clo´vis Cunha, MD, Curitiba, PR; Ana Maria Magni, MD, Sa˜o Paolo, SP; Nelson Rosario, MD, Curitiba, PR; Cla´udio Schvartsman, MD, Sa˜o Paulo, SP; Chile: Elena Santolaya DePablo, Santiago; Costa Rica: Elias JimenezFonseca, MD, San Jose; Iris Perez-Quiros, MD, San Jose; Mexico: Alejandro Flores-Nun˜ez, MD, Puebla PueblaAtlixco; Felipe Jesu´s Oliveros-Lozano, MD, ISSEMYM, Edo Me´xico; Pedro Antonio Martinez-Arce, MD, Jalisco; Isidro Zavala, MD, Zapopan Jalisco; Panama: Eduardo OrtegaBarria, MD, Xavier Saez-Llorens, MD, Javier Nieto Guevara, MD, Rau´l Esquivel, MD, Ciudad de Panama´; United States: Antonio Arrieta, MD, Orange County, CA; Basim Asmar, MD, Detroit, MI; Parvin Azimi, MD, Oakland, CA; Jeffrey Blumer, MD, PhD, Cleveland, OH; John Bradley, MD, San Diego, CA; Blake Bulloch, MD, Phoenix, AZ; Barton Comstock, MD, Berrien Springs, MI; Blaise Congeni, MD, Akron, OH; Bishara Freij, MD, Royal Oak, MI; James Hedrick, MD, Bardstown, KY; Eduardo Hernandez, MD, Slidell, LA; Keith Kappel, MD, Metairie, LA; Leonard Krilov, MD, Mineola, NY; Arden Levy, MD, Spartanburg, SC; Natalie Neu, MD, New York, NY; Steven Parrillo, D.O., Philadelphia, PA; Teri Lynn Perryman, MD, Seguin, TX; Thomas Rand, MD, PhD, Boise, ID; Mobeen Rathore, MD, Jacksonville, FL; Robert Reid, MD, Hollywood, FL; Jose Romero, MD, Omaha, NE; Russell Steele, MD, New Orleans, LA; Raymon Tidman, MD, Blue Ridge, GA; Clarence Nelson Uy, MD, Chiefland, FL; Ellen Wald, MD, Pittsburgh, PA; Mark Ward, MD, Houston, TX; Wignes Warren, MD, West Covina, CA. We also acknowledge Partha Bagchi, PhD, Bradford Challis, PhD, and Susan Glasser, PhD, of Johnson & Johnson Pharmaceutical Research and Development, L.L.C., for their contribution to the preparation of the manuscript. This study was supported by Johnson and Johnson Pharmaceutical Research and Development, L.L.C., and is registered at ClinicalTrials.gov corresponding to NCT00034736. Posters were presented at the Annual Meeting of the Infectious Diseases Society of America (IDSA), October

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1. Langley JM, Bradley JS. Defining pneumonia in critically ill infants and children. Pediatr Crit Care Med. 2005;6:S9 –S13. 2. Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone arthropathy in animals versus children. Clin Infect Dis. 1997;25:1196 –1204. 3. Committee on Infectious Diseases. The use of systemic fluoroquinolones. Pediatrics. 2006;118:1287–1292. 4. Chien S, Wells TG, Blumer JL, et al. Levofloxacin pharmacokinetics in children. J Clin Pharmacol. 2005;45:153–160. 5. Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA. 1998;279: 125–129. 6. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J of Med. 1997;336:243–250. 7. Robertson J, Shilkofski N, eds. The Harriet Lane Handbook: A Manual for Pediatric House Officers. 17th ed. Philadelphia, PA: Mosby; 2005. 8. Andrews J, Nadjm B, Gant V, Shetty N. Community-acquired pneumonia. Curr Opin Pulm Med. 2003;9:175–180. 9. Summary basis for approval: Zithromax for pediatric use, NDA 50 –710: supplemental. Application for inclusion of Community Acquired Pediatric Pneumonia Claim S-001, December 6, 1996. 10. Michelow IC, Olsen K, Lozano J, et al. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics. 2004;113:701–707. 11. Korppi M, Heiskanen-Kosma T, Kleemola M. Incidence of communityacquired pneumonia in children caused by Mycoplasma pneumoniae: serological results of a prospective, population-based study in primary health care. Respirology. 2004;9:109 –114. 12. Esposito S, Bosis S, Cavagna R, et al. Characteristics of Streptococcus pneumoniae and atypical bacterial infections in children 2–5 years of age with community-acquired pneumonia. Clin Infect Dis. 2002;35:1345– 1352. 13. Tsolia MN, Psarras S, Bossios A, et al. Etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin Infect Dis. 2004;39:681– 686. 14. Wang RS, Wang SY, Hsieh KS, et al. Necrotizing pneumonitis caused by Mycoplasma pneumoniae in pediatric patients: report of five cases and review of literature 关see comment兴. Pediatr Infect Dis J. 2004;23:564 –567. 15. Pickering LK, Baker CJ, Long SS, McMillan JA. Red Book: 2006 Report of the Committee on Infectious Diseases. 27 ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006. 16. Bradley JS. 2006 –2007 Nelson’s Pocket Book of Pediatric Antimicrobial Therapy. 16th ed. Miami, FL: AWWE Medical Publishers; 2006. 17. Arguedas A, Dagan R, Pichichero M, et al. An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute otitis media. Pediatr Infect Dis J. 2006;25:1102–1109. 18. Noel GJ, Bradley JS, Balis D, Melkote R. Increased incidence of musculoskeletal disorders (MSDs) in children within one-year of levofloxacin therapy: a large (n ⫽ 2223), comparative, prospective trial experience. Poster presented at: Annual Meeting of the Infectious Diseases Society of America; October 2006; Toronto, Canada.

© 2007 Lippincott Williams & Wilkins