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					                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Sheldon L. Kaplan, MD

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    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@

                                                                                                                                                                                             • 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
  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.