Empiric Treatment With Linezolid Versus Vancomycin for Known/Suspected Resistant Gram-Positive Infections in Neonates Jaime G. Deville, 1 Barbara Edge-Padbury, 2 Sharon Naberhuis-Stehouwer, 2 Jon B. Bruss, 2 and the Linezolid Pediatric Study Group 1 UCLA School of Medicine, Los Angeles, CA; 2 Pharmacia Corp., Kalamazoo, MI 644 ABSTRACT BACKGROUND: Morbidity and mortality in neonates with gram-positive infections (GPI) caused by susceptible and resistant strains of Staphylococcus aureus, coagulase- negative staphylococci, and enterococci are increasing problems. Linezolid (LZD), a new oxazolidinone, is active against these pathogens. OBJECTIVE: To compare the clinical efficacy/safety of intravenous (IV) LZD 10 mg/kg q8h with IV vancomycin (VAN) 10-15 mg/kg q6-24h (per dosing recommendations) in neonates (0-90 days). METHODS: Hospitalized patients (pts) with known/suspected nosocomial pneumonia (NP), complicated skin/skin structure infections (CSSSI), bacteremia, or other infections were eligible. Test-of-cure clinical response was evaluated at follow-up. RESULTS: 63 neonates randomized 2:1 (LZD, n=43; VAN, n=20) were evaluated. Baseline characteristics in the intent-to-treat (ITT) treatment groups were similar except LZD -treated neonatal pts were significantly younger (LZD 25.7 ± 19.2 d vs VAN 40.3 ± 28.3 d; p=0.020); however, no significant differences were noted in gestational age or post-conceptional age. Mean Apgar scores indicated moderate deficits (at 1 min: 6.1 ± 2.4 vs 5.6 ± 3.3; p=0.548; at 5 min: 7.9 ± 1.3 vs 7.6 ± 1.8; p=0.422) for LZD vs VAN, respectively. Clinical cure rates at follow-up in the LZD group were higher, but not significantly different for LZD vs VAN (78% vs 61%; p=0.196), respectively. Corresponding rates in clinically evaluable (CE) pts were 84% vs 77% (p=0.553) and microbiologic success rates in microbiologically evaluable pts were 77% vs 82% (p=0.741) for LZD vs VAN, respectively. Pathogen eradication rates were as follows: methicillin-resistant S aureus (67% vs 50%), S epidermidis (85% vs 100%), S hemolyticus (100%, LZD only), S hominis (100%, LZD only), and Enterococcus faecalis (60% vs 0%) in the LZD and VAN groups, respectively. Modified Division of AIDS (DAIDS) shift criteria results for hematology and chemistry assays were similar between treatments. LZD-treated neonates had fewer drug-related adverse events than VAN-treated neonates (LZD, 12% vs VAN, 32%; p=0.058). CONCLUSIONS: LZD was well tolerated and as effective as VAN in the treatment of resistant GPI. METHODS STUDY DESIGN • This was a phase III, randomized, open-label, comparator-controlled, multinational, multicenter study conducted from February 2001 to December 2001 at 59 investigator sites in the United States and Latin America. • A subset analysis of results in neonates (birth to ≤ 90 days of age) is reported here. PATIENTS • The overall study enrolled hospitalized male or female patients from birth to 12 years of age; neonates from birth to ≤90 days of age were included in this analysis. • Patients were required to have a diagnosis of known/suspected NP, CSSSI, bacteremia, or other infections due to a resistant gram-positive bacterial pathogen as determined by laboratory findings (Gram’s stain or culture results) or clinical signs and symptoms of active infection. • Patients who received >24 hours prior treatment with an antibiotic potentially effective against gram- positive infections within 48 hours of study entry were excluded, unless the prior treatment failed. • Other exclusion criteria included a known/suspected pre-existing pulmonary condition (ie, tuberculosis or sequestration); need for concomitant systemic antibiotic therapy; decubitus or ischemic ulcers, necrotizing fascitis, gas gangrene, or burns on >20% of the total body surface; a device infected with Staphylococcus aureus or Enterococcus species that could not be removed; pneumonia or bacteremia due to penicillin-susceptible Streptococcus pneumoniae (MIC <2 μg/mL); and endocarditis, skeletal infections, and central nervous system infections. TREATMENT • Patients were randomized in a 2:1 ratio to receive IV linezolid 10 mg/kg every 8 hours or IV vancomycin 10 to 15 mg/kg per dosing recommendations. • Patients randomized to vancomycin who had vancomycin-resistant Enterococcus (VRE) subsequently isolated were switched to linezolid and allowed to remain in the study. • Total duration of therapy was 10-28 days, depending on infection type. EFFICACY AND SAFETY ASSESSMENTS • The primary efficacy variable was patient clinical outcome, and secondary efficacy variables were patient microbiologic outcome, individual pathogen eradication rates, clinical signs and symptoms of infection, body temperature, white blood cell (WBC) count, lesion size and degree of involvement (CSSSI only), and chest radiograph findings (NP only). • Safety/tolerability variables included adverse events, laboratory assays, vital signs, and concomitant medications. • Clinical efficacy and/or safety/tolerability assessments were performed on Days 3, 10, 17, and 24 during treatment, at the end of treatment, and at the test-of-cure visit (12-28 days after treatment completion). EVALUABILITY CRITERIA • Clinically evaluable (CE) patients fulfilled entry criteria, received ≥80% of prescribed study medication, had a follow-up assessment, and did not receive other antibiotics effective against gram-positive pathogens (except for lack of efficacy). • Microbiologically evaluable (ME) patients were CE patients who had a baseline pathogen isolated that was not resistant to study medications. STATISTICAL ANALYSES • Comparability of the treatments was assessed using 95% confidence intervals (CI) for the difference in clinical cure rates and the chi-square test for homogeneity of proportions for the distribution of clinical cures and failures between treatment groups. Similar analyses were performed for microbiologic success rates and pathogen eradication rates. • Between-group differences in secondary efficacy variables, safety, and baseline demographics were assessed using an F test or chi-square test; paired t tests were used to assess within-treatment group differences from baseline. • All statistical tests were two-sided, with p-values ≤ 0.05 considered statistically significant. RESULTS BASELINE CHARACTERISTICS AND TREATMENT • A total of 63 neonates received linezolid (n=43) or vancomycin (n=20) and were included in the intent-to-treat (ITT) analysis (Table 1). INTRODUCTION • Gram-positive pathogens are becoming increasingly prevalent in the United States. In children, gram-positive pathogens are a major cause of nosocomial pneumonia (NP), complicated skin and skin structure infections (CSSSI), bacteremia, and sepsis. 1 • A recent survey of neonatal intensive care units found that infections acquired in these units were most commonly due to coagulase-negative staphylococci and enterococci. 2 • Linezolid, an oxazolidinone, has a broad spectrum of in vitro and in vivo activity against antibiotic-susceptible and -resistant gram-positive bacteria, and it lacks cross-resistance with current antimicrobial therapies due to a unique mechanism of action for inhibiting bacterial protein synthesis. 3,4 • A phase II, open-label study found that linezolid was effective (92.4% cure rate) and well tolerated in children who were hospitalized with community-acquired pneumonia. 5 • The objective of this subset analysis was to assess outcome in neonates ≤ 90 days old. This study compared the clinical efficacy, safety, and tolerability of linezolid and vancomycin for the treatment of known or suspected resistant gram-positive infections in hospitalized pediatric patients from birth to 12 years of age. Percentage of Patients With Clinical Cure Clinically Evaluable 77.5 61.1 84.4 76.9 (n=40) (n=18) (n=32) (n=13) 0 20 40 60 80 100 Vancomycin Linezolid 10 30 50 70 90 Intent To Treat FIGURE. Clinical cure rates for linezolid and vancomycin among intent-to-treat and clinically evaluable neonatal patients at follow-up. Jaime G. Deville, MD UCLA School of Medicine 10833 Le Conte Ave 22-442 MDCC Los Angeles, CA 90095-1752 Phone: (310) 825-9660 Fax: (310) 825-9175 E-mail: JDeville@mednet.ucla.edu CONCLUSIONS • In neonates, linezolid was as effective as vancomycin in treating known or suspected resistant gram-positive infections, including those due to MRSA and MRSE. • Fewer drug-related adverse events in neonates were reported with linezolid therapy (11.6%) compared with vancomycin therapy (31.6%). REFERENCES 1. Richards MJ, Edwards JR, Culver DH, Gaynes RP, and the National Nosocomial Infections Surveillance System. Nosocomial infections in pediatric intensive care units in the United States. Pediatrics 1999;103:1-7. 2. Sohn AH, Garret DO, Sinkowitz-Cochran RL, et al. Prevalence of nosocomial infections in neonatal intensive care unit patients: results from the first national point-prevalence survey. J Pediatr 2001;139:821-827. 3. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother 1998;42:3251-3255. 4. Zurenko GE, Yagi BH, Schaadt RD, et al. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob Agents Chemother 1996;40:839-845. 5. Kaplan SL, Patterson L, Edwards KM, et al. Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Pediatr Infect Dis J 2001;20:488-494. TABLE 1. Baseline Demographic and Clinical Characteristics of Neonates: ITT* Population Linezolid † Vancomycin † Characteristic (n=43) (n=20) p-Value Age, days Mean ± SD 25.7 ± 19.2 40.3 ± 28.3 0.020 Median 18 36 Gestational age, wk Mean ± SD 32.4 ± 5.1 33.4 ± 5.3 0.514 Median 32 35 Post-conceptional age, wk Mean ± SD 36.0 ± 6.1 38.6 ± 7.3 0.174 Median 35 38 Race, n (%) White 18 (41.9) 3 (15.0) 0.077 Black 5 (11.6) 5 (25.0) Asian/Pacific Islander 0 1 (5.0) Mixed/multiracial ‡ 20 (46.5) 11 (55.0) Sex, n (%) Male 24 (55.8) 12 (60.0) 0.755 Female 19 (44.2) 8 (40.0) Apgar score, 1 min Mean ± SD 6.1 ± 2.4 5.6 ± 3.3 0.548 Median 7 7 Apgar score, 5 min Mean ± SD 7.9 ± 1.3 7.6 ± 1.8 0.422 Median 8 8 Baseline diagnosis, n (%) Nosocomial pneumonia 7 (16.3) 3 (15.0) 0.173 Complicated SSSI 6 (14.0) 6 (30.0) Catheter-related bacteremia 11 (25.6) 2 (10.0) Bacteremia of unknown source 14 (32.6) 9 (45.0) Other infection 5 (11.6) 0 ITT = intent to treat; SD = standard deviation; SSSI = skin and skin structure infection. * ITT population included those patients who received ≥1 dose of study medication. † Patients were randomized to receive linezolid and vancomycin in a 2:1 ratio. ‡ Included patients of Latin American origin. TABLE 2. Clinical Cure Rates in Neonates: Overall and by Baseline Diagnosis ITT Population CE Population Linezolid Vancomycin Linezolid Vancomycin n/N (%) n/N (%) n/N (%) n/N (%) Overall 31/40 (77.5) 11/18 (61.1) 27/32 (84.4) 10/13 (76.9) Nosocomial pneumonia 2/5 (40.0) 2/2 (100.0) 2/3 (66.7) 1/1 (100.0) Complicated SSSI 5/5 (100.0) 2/5 (40.0) 4/4 (100.0) 2/3 (66.7) Catheter-related bacteremia 9/11 (81.8) 2/2 (100.0) 9/10 (90.0) 2/2 (100.0) Bacteremia unknown source 11/14 (78.6) 5/9 (55.6) 8/10 (80.0) 5/7 (71.4) Other infections 4/5 (80.0) – 4/5 (80.0) – ITT = intent to treat; CE = clinically evaluable; SSSI = skin and skin structure infection. TABLE 3. Summary of Pathogen Eradication Rates * for ME Neonatal Patients Linezolid Vancomycin Pathogen n/N (%) n/N (%) Staphylococcus aureus 2/3 (67) 3/5 (60) MRSA 2/3 (67) 1/2 (50) Enterococcus faecalis 3/5 (60) 0/1 (0) Enterococcus faecium 1/1 (100) – Enterococcus durans 1/1 (100) – All coagulase-negative staphylococci 15/17 (88) 6/6 (100) Staphylococcus epidermidis 11/13 (85) 6/6 (100) MRSE 11/13 (85) 6/6 (100) Staphylococcus hominis 6/6 (100) – Staphylococcus hemolyticus 3/3 (100) – ME = microbiologically evaluable; MRSA = methicillin-resistant S aureus; MRSE = methicillin-resistant S epidermidis. *Patients could have had ≥1 organism. • An analysis of baseline characteristics for each ITT group indicated that infants in the linezolid group were significantly younger than those in the vancomycin group (25.7 ± 19.2 days vs 40.3 ± 28.3 days, respectively; p=0.020). However, there were no differences in gestational age at delivery or post-conceptional age, suggesting that the relative maturity of infants in each group was comparable (Table 1). • The 1-minute and 5-minute Apgar scores were similar in the linezolid and vancomycin groups (1 min: 6.1 ± 2.4 vs 5.6 ± 3.3, respectively; p=0.5483 and 5 min: 7.9 ± 1.3 vs 7.6 ± 1.8, respectively; p=0.422) (Table 1). • The most common baseline diagnosis for both treatment groups was bacteremia of unknown source (32.6% for linezolid vs 45.0% for vancomycin) (Table 1). • The mean total treatment durations were similar between linezolid (11.5 ± 4.3 days) and vancomycin (10.3 ± 7.2 days). • The most common pathogens isolated at baseline were S aureus (including methicillin- resistant S aureus [MRSA]), coagulase-negative staphylococci (including methicillin-resistant Staphylococcus epidermidis [MRSE]), and Enterococcus species. CLINICAL OUTCOME • For the ITT population, clinical cure rates at the test-of-cure, follow-up visit were numerically higher with linezolid treatment (77.5%; 31/40) compared with vancomycin (61.1%; 11/18), but the differences were not statistically significant (95% CI: -9.6, 42.4; p=0.196) (Figure; Table 2). • Clinical cure rates for linezolid and vancomycin in CE patients were 84.4% (27/32) and 76.9% (10/13), respectively (95% CI: -18.7, 33.6; p=0.553) (Figure; Table 2). MICROBIOLOGIC OUTCOME • In the ME population, microbiologic success rates were 76.9% and 81.8% for the linezolid and vancomycin groups, respectively (95% CI: -32.9, 23.1; p=0.741). • Pathogen eradication rates in linezolid-treated infants were 88% for coagulase-negative staphylococci, 67% for MRSA, and 60% for Enterococcus faecalis; linezolid was microbiologically as effective as vancomycin against MRSA (67% vs 50%, respectively) and MRSE (85% vs 100%, respectively) (Table 3). TOLERABILITY • The percentages of patients with study-emergent adverse events were similar: 76.7% for linezolid-treated patients compared to 73.7% for vancomycin-treated patients (p=0.795). • Of the adverse events reported at rates that were statistically different (p≤0.05) between treatment groups, all occurred more frequently in the vancomycin group, including patent ductus arteriosus, tachycardia, oral monilia, rash, skin erosion, and laboratory test abnormality (guaiac-positive stool, bandemia, and hypereticulocytosis). • Drug-related adverse events occurred in 11.6% of linezolid-treated infants and 31.6% of vancomycin-treated infants (p=0.058). The only statistically significant difference between treatment groups was for oral monilia, which was reported by 10.5% (2/19) of patients in the vancomycin group and no patients in the linezolid group (p=0.031). • Analyses of categorical shifts in hematology or chemistry values assessed using modified AIDS Clinical Trials Group (ACTG) grading criteria revealed similar changes from baseline in the linezolid and vancomycin groups. In patients 8-90 days old (no ACTG criteria available for patients 0-7 days old), clinically significant shifts (3-4 grades) occurred in: – hemoglobin in 2/40 linezolid-treated patients and 0/16 vancomycin-treated patients, – neutrophil counts in 1/40 linezolid-treated patients and 0/15 vancomycin-treated patients, and – platelet counts in 4/40 linezolid-treated patients and 1/15 vancomycin-treated patients.