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Sheldon L. Kaplan, MD 642 Chief, Infectious Diseases Linezolid Versus Vancomycin in the Treatment of Resistant Gram-Positive Infections in Children Texas Children’s Hospital Baylor College of Medicine Sheldon L. Kaplan,1 Barbara Edge-Padbury,2 Sharon Naberhuis-Stehouwer,2 Jon B. Bruss,2 and the Linezolid Pediatric Study Group Houston, TX 77030 Phone: (832) 824-4330 1 Fax: (832) 825-4347 Texas Children’s Hospital, Baylor College of Medicine, Houston, TX; 2Pharmacia Corp., Kalamazoo, MI E-mail: SLKaplan@ TexasChildrensHospital.org • Between-group differences in secondary efficacy variables, safety, and baseline • Patients in both treatment groups were similar in baseline demographic • Clinical cure rates in patients with infections due to selected pathogens were similar ABSTRACT METHODS demographics were assessed using an F test or chi-square test; paired t tests were characteristics (Table 2). in the linezolid and vancomycin groups (Table 3). TABLE 4. Drug-Related Adverse Events Reported in >1% of Patients in Either used to assess within-treatment group differences from baseline. Treatment Group – The median age of patients was 1.5 years and 1.8 years in the linezolid and BACKGROUND: Increasing numbers of resistant gram-positive infections STUDY DESIGN Linezolid Vancomycin • All statistical tests were two-sided, with p-values ≤0.05 considered statistically significant. vancomycin groups, respectively. (RGPI) causing empiric treatment failures among children are a concern. • Phase III, randomized, open-label, comparator-controlled, multinational, multicenter TABLE 3. Clinical Cure Rates and MIC Ranges for Infections Due to Selected Adverse event, n (%) (n=213) (n=99) p-Value Linezolid (LZD) is active against susceptible and resistant strains of study conducted from February 2001 to December 2001 – Among patients ≤90 days old, a greater proportion of pre-term infants were Pathogens (ME patients)* randomized to linezolid (26/43, 60%) versus vancomycin (8/18; 44%). Diarrhea 8 (3.8) 6 (6.1) 0.3601 Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus Linezolid Linezolid Vancomycin Vancomycin • 59 investigator sites in the United States and Latin America RESULTS Vomiting 4 (1.9) 1 (1.0) 0.5699 pneumoniae, and Enterococcus faecium. • CSSSI was the most common baseline diagnosis, with cellulitis, skin abscess, and Pathogen n/N (%) MIC Range† n/N (%) MIC Range† PATIENTS infected surgical incision the most frequent types of CSSSI; no significant differences Thrombocytopenia 4 (1.9) 0 (0) 0.1700 OBJECTIVE: To assess clinical efficacy and safety of intravenous (IV)/oral LZD All S aureus 37/39 (95) 2-4 24/26 (92) ≤0.5-2 • Hospitalized male or female patients from birth to age 12 years, including BASELINE CHARACTERISTICS AND TREATMENT between treatment groups were noted for the distribution of skin infection type, Loose stools 4 (1.9) 0 (0) 0.1700 and IV vancomycin (VAN) for known/suspected RGPI in children (0-12 years). • A total of 316 patients received ≥1 dose (intent to treat [ITT]) of linezolid (n=215) or preterm neonates degree of involvement, or lesion area. MRSA 16/17 (94) 2 9/10 (90) ≤0.5-2 Rash 3 (1.4) 7 (7.1) 0.0082 METHODS: Eligible hospitalized or chronic care facility patients (pts) with vancomycin (n=101) (Table 1). known/suspected nosocomial pneumonia (NP), complicated skin/skin • Presence of known/suspected NP or pneumonia due to penicillin-resistant • The mean total treatment durations were similar between the linezolid (11.3 ± 5.0 S epidermidis‡ 23/29 (79) 0.5-2 11/13 (85) 1-2 Nausea 3 (1.4) 0 (0) 0.2354 structure infections (CSSSI), bacteremia, or other infections were randomized S pneumoniae, CSSSI, bacteremia (catheter-related or unknown source), or other days) and vancomycin (12.2 ± 6.4 days) groups; 53% of patients who received Anemia 3 (1.4) 1 (1.0) 0.7710 TABLE 1. Populations for Analysis*† linezolid switched to oral therapy, compared with 31% of the vancomycin-treated Other coagulase- in a 2:1 fashion to receive IV LZD 10 mg/kg q8h with the option to switch to infections due to a resistant gram-positive bacterial pathogen as determined by Linezolid Vancomycin patients. negative staphylococci 14/15 (93) 0.5-2 3/4 (75) ≤0.5-1 Eosinophilia 3 (1.4) 0 (0) 0.2354 LZD suspension 10 mg/kg q8h or IV VAN 10-15 mg/kg q6-24h per dosing laboratory findings (Gram’s stain or culture results) or clinical signs and symptoms of active infection; specific criteria for each type of infection also had to be fulfilled. Population n (%) n (%) S pneumoniae 3/3 (100) 1-2 1/1 (100) ≤0.5 Oral monilia 2 (0.9) 4 (4.0) 0.0634 recommendations with the option to switch to an appropriate oral agent for CLINICAL OUTCOME 10-28 d. Clinical response was evaluated at end of treatment and follow-up Patients randomized to treatment 219 (100.0) 102 (100.0) Fever 1 (0.5) 3 (3.0) 0.0613 • No prior treatment with a potentially effective antibiotic for >24 hours within 48 • Clinical cure rates at the test-of-cure follow-up visit were 79.1% (155/196) versus E faecalis 7/10 (70) 1-2 3/4 (75) 1-2 (test of cure). hours of study entry, unless the treatment failed ITT patients 215 (98.2) 101 (99.0) 74.1% (63/85) (p=0.359; 95% CI: -6.0, 15.9) and 89.3% (134/150) versus Red man syndrome 0 (0) 10 (10.1) <0.0001 E faecium 5/5 (100) 1-4 – – Pruritus 0 (0) 2 (2.0) 0.0374 RESULTS: 215 pts received LZD and 101 pts received VAN. Clinical cure rates CE patients 151 (68.9) 73 (71.6) 84.5% (60/71) (p=0.306; 95% CI: -4.9, 14.6) for the linezolid versus vancomycin • Other exclusion criteria: a known/suspected pre-existing pulmonary condition were 79% vs 74% (p=0.359) and 89% vs 85% (p=0.306) for LZD vs VAN in ME patients 93 (42.5) 46 (45.1) groups in the ITT and CE groups, respectively (Figure 1). VRE 1/1 (100) 4 – – (ie, tuberculosis or sequestration); need for concomitant systemic antibiotic therapy; intent-to-treat (ITT) and clinically evaluable (CE) pts, respectively. Cure rates decubitus or ischemic ulcers, necrotizing fasciitis, gas gangrene, or burns on >20% ITT = intent to treat; CE = clinically evaluable; ME = microbiologically evaluable. • Clinical cure rates were similar by age category, race, and baseline infection ME = microbiologically evaluable; MIC = minimum inhibitory concentration; MRSA = methicillin-resistant were similar by age, sex, race, and infection diagnosis. Microbiologic success of the total body surface; a device infected with S aureus or Enterococcus species * ITT patients were those who received ≥1 dose of study medication; CE patients were ITT patients who diagnosis in the ITT population. Staphylococcus aureus; VRE = vancomycin-resistant enterococci. rates were 88% vs 87% (p=0.855) for LZD vs VAN in microbiologically that could not be removed; pneumonia or bacteremia due to penicillin-susceptible had received ≥80% of the prescribed study medication, had a follow-up assessment and did not * ME patient population: linezolid, n=93; vancomycin, n=46. CONCLUSIONS receive other effective antibiotics (except for lack of efficacy); ME patients were CE patients with a • Clinical cure rates were comparable by baseline diagnosis between treatment evaluable (ME) pts. Pathogen eradication rates in the ME group were high for S pneumoniae (MIC <2 µg/mL); and endocarditis, skeletal infections, and central confirmed gram-positive pathogen isolated at baseline that was not resistant to study medications. † All isolates were susceptible to both linezolid and vancomycin (except VRE) according to National Committee LZD vs VAN, respectively, for methicillin-sensitive S aureus (95% vs 94%; nervous system infections † Patients were randomized to receive linezolid and vancomycin in a 2:1 ratio. groups in the CE population (Figure 2). for Clinical Laboratory Standards criteria. • Linezolid was as effective as vancomycin in the treatment of known or p=0.816), methicillin-resistant (MR) S aureus (88% vs 90%; p=0.888), and MR ‡ Considered a pathogen for bacteremic and neonatal infections. suspected resistant gram-positive infections in children from birth to 12 S epidermidis (81% vs 91%; p=0.470). Significantly more VAN-treated pts TREATMENT years of age. had drug-related adverse events vs LZD-treated patients (34% vs 19%, • Patients were randomized in a 2:1 ratio to receive either: TABLE 2. Baseline Demographic and Clinical Characteristics: ITT* FIGURE 1. Clinical cure rates at follow-up for linezolid and vancomycin • Clinical cure rates among CE patients with catheter-related bacteremia due to • Linezolid and vancomycin demonstrated comparable rates of clinical respectively; p=0.0026), with anaphylaxis [red man syndrome] (LZD, 0% vs – IV linezolid 10 mg/kg every 8 hours, with the option to switch to oral linezolid Linezolid Vancomycin among intent-to-treat, clinically evaluable, and microbiologically evaluable coagulase-negative staphylococci were similar in the linezolid and vancomycin success for the treatment of CSSSI, NP, and bacteremia. VAN, 10%; p<0.0001) and rash (LZD, 1.4% vs VAN, 7.1%; p=0.0082) the suspension 10 mg/kg every 8 hours after 3 days of IV therapy, or (n=215) (n=101) patients.* groups (82% [18/22] and 75% [6/8], respectively; p=0.680; 95% CI: -27.2, 40.9). most frequently reported VAN-related events. – IV vancomycin 10 to 15 mg/kg every 6 to 24 hours per dosing recommendations, Characteristic n (%) n (%) • Microbiologic eradication rates for linezolid and vancomycin were with the option to switch to an appropriate oral agent after at least 3 days of Age category, n (%) • Clinical cure rates among CE patients with CSSSI due to S aureus were similar in comparable for S aureus, including MRSA, and coagulase-negative CONCLUSIONS: IV/oral LZD was better tolerated and as effective as VAN in the linezolid and vancomycin groups (93% [27/29] vs 95% [18/19], respectively; staphylococci. IV therapy 0-90 days 43 (20.0) 20 (19.8) treating RGPI in children. p=0.819; 95% CI: -15.3, 12.0). 91 days - <1 year 34 (15.8) 16 (15.8) • Linezolid was better tolerated than vancomycin, with lower incidences of • Patients with infections known to be caused by VRE were treated with linezolid from 1-4 years 88 (40.9) 42 (41.6) the outset; those randomized to vancomycin who had VRE subsequently isolated MICROBIOLOGIC OUTCOME drug-related adverse events and adverse events leading to discontinuation 5-11 years 50 (23.3) 23 (22.8) were switched to linezolid and allowed to remain in the study. • Linezolid was microbiologically as effective as vancomycin in patients with S aureus, of therapy. Age, y including MRSA, and coagulase-negative staphylococci, including methicillin- INTRODUCTION • Total duration of therapy was 10-28 days, depending on infection type. Mean ± SD 2.91 ± 3.16 2.94 ± 3.13 • Linezolid is an effective and well-tolerated empiric antibiotic therapy for resistant Staphylococcus epidermidis (MRSE). known or suspected resistant gram-positive infections in children. Median 1.50 1.80 • Gram-positive pathogens are a major cause of nosocomial pneumonia (NP), EFFICACY AND SAFETY ASSESSMENTS Race, n (%) • Microbiologic success rates were not statistically different between treatments for community-acquired pneumonia requiring hospitalization, complicated skin and • The primary efficacy variable was patient clinical outcome, and secondary efficacy White 93 (43.5) 38 (37.6) any pathogen category. skin structure infections (CSSSI), and bacteremia in children.1 variables were patient microbiologic outcome, individual pathogen eradication Black 26 (12.1) 23 (22.8) rates, clinical signs and symptoms of infection, body temperature, white blood cell • Pathogen eradication rates in the ME group were high for linezolid and vancomycin • Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Asian/Pacific Islander 4 (1.9) 2 (2.0) REFERENCES (WBC) count, lesion size and degree of involvement (CSSSI only), and chest for methicillin-susceptible S aureus (95% vs 94%, respectively; p=0.816), MRSA enterococci (VRE) are important nosocomial pathogens, and MRSA is becoming a Mixed/multiracial 91 (42.5) 38 (37.6) 1. Richards MJ, Edwards JR, Culver DH, Gaynes RP, and the National Nosocomial radiograph findings (NP only). (88% vs 90%, respectively; p=0.888), and MRSE (81% vs 91%, respectively, very important pathogen in pediatric infections acquired in the community.2,3 Sex, n (%) Infections Surveillance System. Nosocomial infections in pediatric intensive care p=0.470). Antibiotic-resistant Streptococcus pneumoniae may account for the majority of • Safety/tolerability variables included adverse events, laboratory assays, vital signs, Male 117 (54.4) 59 (58.4) units in the United States. Pediatrics 1999;103:1-7. pneumococcal isolates in some areas of the world. Few options are available to and concomitant medications. Female 98 (45.6) 42 (41.6) FIGURE 2. Clinical cure rates at follow-up by baseline diagnosis in TOLERABILITY 2. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin- treat serious infection due to these antibiotic-resistant pathogens in children. Geographic region, n (%) clinically evaluable patients.* • Significantly more vancomycin-treated patients had drug-related adverse events • Clinical efficacy and/or safety/tolerability assessments were performed on Days 3, resistant Staphylococcus aureus in children with no identified predisposing risk. • Linezolid, an oxazolidinone, has a wide spectrum of activity with demonstrated in North America 95 (44.2) 46 (45.5) compared with those who received linezolid (34% vs 19%, respectively; 10, 17, and 24 during treatment, at the end of treatment, and at the test-of-cure visit JAMA 1998;279:593-598. vitro and in vivo antibacterial activity against staphylococci, streptococci, and Latin America 120 (55.8) 55 (54.5) p=0.0026); red man syndrome (10% vs 0%; p<0.0001) and rash (7% vs 1%; (12-28 days after treatment completion). p=0.0082) were the most frequently reported vancomycin-related events (Table 4). 3. Fergie JE, Purcell K. Community-acquired methicillin-resistant Staphylococcus aureus enterococci, including resistant strains. Underlying and past medical conditions, n (%) Congenital heart disease 33 (15.3) 10 (9.9) infections in South Texas children. Pediatr Infect Dis J 2001;20:860-863. EVALUABILITY CRITERIA • The incidence of drug-related adverse events leading to discontinuation was • Pharmacokinetic evaluation in pediatric patients suggested that linezolid 10 mg/kg Short gut syndrome 10 (4.7) 5 (5.0) • Clinically evaluable (CE) patients fulfilled entry criteria, received ≥80% of prescribed significantly higher in the vancomycin group (6.1%) than in the linezolid group 4. Kearns GL, Abdel-Rahman SM, Blumer JL, et al. Single dose pharmacokinetics given two or three times daily, depending on age, is an appropriate regimen for Renal insufficiency 13 (6.0) 6 (5.9) study medication, had a follow-up assessment, and did not receive other antibiotics (0.9%; p=0.0077). of linezolid in infants and children. Pediatr Infect Dis J 2000;19:1178-1184. use in pediatric patients.4 Linezolid has 100% oral bioavailability, and thus the Malignancy 18 (8.4) 9 (8.9) effective against gram-positive pathogens (except for lack of efficacy). switch from intravenous (IV) to oral administration is very convenient. Prosthetic device 20 (9.3) 6 (5.9) 5. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B, and the Linezolid • Microbiologically evaluable (ME) patients were CE patients who had a baseline Baseline diagnosis, n (%) MRSA Study Group. Linezolid versus vancomycin for the treatment of methicillin- • In large clinical trials, linezolid was found to be as effective and safe as vancomycin pathogen isolated that was not resistant to study medications. Nosocomial pneumonia 23 (10.7) 16 (15.8) resistant Staphylococcus aureus infections. Clin Infect Dis 2002;34:1481-1490. for the treatment of serious MRSA infections in adults,5 and a study conducted in pediatric patients suggests that linezolid is well tolerated and effective in those Complicated SSSI 80 (37.2) 40 (39.6) STATISTICAL ANALYSIS Catheter-related bacteremia 48 (22.3) 13 (12.9) 6. Kaplan SL, Patterson L, Edwards KM, et al. Linezolid for the treatment of community- hospitalized with community-acquired pneumonia.6 • Comparability of treatments was assessed using 95% confidence intervals (CI) for the acquired pneumonia in hospitalized children. Pediatr Infect Dis J 2001;20:488-494. Bacteremia of unknown source 33 (15.3) 19 (18.8) • The objective of this study was to assess comparative clinical efficacy, safety, and difference in clinical cure rates and the chi-square test for homogeneity of proportions for Other infection 31 (14.4) 13 (12.9) tolerability of IV/oral linezolid and IV vancomycin for known or suspected resistant the distribution of clinical cures and failures between treatment groups. Similar analyses ITT = intent to treat; SSSI = skin and skin structure infection; SD = standard deviation. ACKNOWLEDGMENTS gram-positive infections in children from birth to 12 years of age. were performed for microbiologic success rates and pathogen eradication rates. * Patients were randomized to receive linezolid and vancomycin in a 2:1 ratio. The authors wish to acknowledge the investigators in the Linezolid Pediatric Study Group.
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