Safety and pharmacokinetics of SPR206 in subjects with varying degrees of renal impairment.

SPR206 is a novel polymyxin derivative with potent in vitro activity against susceptible and multidrug-resistant strains of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter species. SPR206 is eliminated renally. The safety, tolerability, and pharmacokinetics (PK) of SPR206 were evaluated in healthy subjects with normal renal function (Cohort 1) and subjects with varying degrees of renal impairment (RI) (Cohorts 2-4) or end-stage renal disease (ESRD) on hemodialysis (HD) (Cohort 5). Subjects in Cohorts 1-4 received a 100-mg intravenous (IV) dose of SPR206. Subjects in Cohort 5 received a 100-mg IV dose within 2 h after HD on day 1 and 1 h before HD on day 5. Safety and PK analyses included 37 subjects. Mostly mild but no serious treatment-related adverse events were reported. Systemic exposure to SPR206 increased as renal function decreased, with mean area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last) values 39% to 239% greater in subjects with RI vs healthy subjects. Mean plasma clearance (CL) of SPR206 decreased with decreasing renal function (29% to 76% lower vs healthy subjects). In subjects with ESRD, AUC0-last decreased by 51%, and CL increased by 92% for dialyzed vs nondialyzed conditions. SPR206 was excreted in urine within 12 h in healthy subjects and subjects with mild RI (Cohort 2) but was prolonged in those with moderate and severe RI (Cohorts 3 and 4, respectively). In summary, SPR206 was generally safe and well tolerated, and the PK of SPR206 was well characterized in subjects with RI.

Pharmacokinetics of SPR206 in Plasma, Pulmonary Epithelial Lining Fluid, and Alveolar Macrophages following Intravenous Administration to Healthy Adult Subjects.

SPR206 is a next-generation polymyxin being developed for the treatment of multidrug-resistant (MDR) Gram-negative infections. This Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206's safety and pharmacokinetics in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AM) in healthy volunteers. Subjects received a 100 mg intravenous (IV) dose of SPR206 infused over 1 h every 8 h for 3 consecutive doses. Each subject underwent 1 bronchoscopy with BAL at 2, 3, 4, 6, or 8 h after the start of the third IV infusion. SPR206 concentrations in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Thirty-four subjects completed the study and 30 completed bronchoscopies. Mean SPR206 peak concentrations (Cmax) in plasma, ELF, and AM were 4395.0, 735.5, and 860.6 ng/mL, respectively. Mean area under the concentration-time curve (AUC0-8) for SPR206 in plasma, ELF, and AM was 20120.7, 4859.8, and 6026.4 ng*h/mL, respectively. The mean ELF to unbound plasma concentration ratio was 0.264, and mean AM to unbound plasma concentration ratio was 0.328. Mean SPR206 concentrations in ELF achieved lung exposures above the MIC for target Gram-negative pathogens for the entire 8-h dosing interval. Overall, SPR206 was well tolerated; 22 subjects (64.7%) reported at least 1 treatment-emergent adverse event (TEAE). Of the 40 reported TEAEs, 34 (85.0%) were reported as mild in severity. The most frequent TEAEs were oral paresthesia (10 subjects [29.4%]) and nausea (2 subjects [5.9%]). This study demonstrates pulmonary penetration of SPR206 and supports further development of SPR206 for the treatment of patients with serious infections caused by MDR Gram-negative pathogens.

Telavancin in the Treatment of Concurrent Staphylococcus aureus Bacteremia: A Retrospective Analysis of ATLAS and ATTAIN Studies.

INTRODUCTION: Concurrent Staphylococcus aureus bacteremia (SAB) worsens outcomes and increases mortality in patients with complicated skin and skin structure infections (cSSSI), hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia (HABP/VABP). These challenges highlight the need for alternative treatments. Telavancin (TLV), a bactericidal lipoglycopeptide with high in vitro potency, effectively treats patients with cSSSI and HABP/VABP caused by Gram-positive pathogens, particularly S. aureus. METHODS: This retrospective analysis evaluated patients from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections and Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia studies with baseline, concurrent SAB. Differences in the clinical cure rates at test-of-cure and safety outcomes were compared for TLV vs vancomycin (VAN) treatment groups. RESULTS: A total of 105 patients, 32 cSSSI and 73 HABP/VABP, had baseline, concurrent SAB. The clinical cure rates for all-treated SAB patients in the cSSSI (TLV 57.1% and VAN 54.5%) and HABP/VABP (TLV 54.3% and VAN 47.2%) groups were comparable. For both types of infections, the safety profile of TLV and VAN showed similar incidences of adverse events (AEs), serious AEs, or AEs leading to discontinuation. One VAN-treated patient died in the cSSSI group, and there were 13 deaths in each treatment arm of the HABP/VABP group. CONCLUSION: This retrospective analysis demonstrated that TLV is clinically comparable in both efficacy and safety to VAN, and, therefore, may be an appropriate therapeutic option for the treatment of patients with HABP/VABP or cSSSI and concurrent SAB. Given the limited sample size in this subgroup, the interpretation of these results is limited. FUNDING: Theravance Biopharma Antibiotics, Inc.

Source control review in clinical trials of anti-infective agents in complicated intra-abdominal infections.

In clinical trials of complicated intra-abdominal infections, assessment of adequacy of the initial surgical approach to the management of the infection is of considerable importance in determining outcome. Antibiotic therapy would not be expected to adequately treat the infection if the surgical procedure was inadequate with respect to source control. Inclusion of such cases in an efficacy analysis of a particular therapeutic antibiotic may confound the results. We analyzed the source control review process used in double-blind clinical trials of antibiotics in complicated intra-abdominal infections identified through systematic review. We searched MEDLINE (PubMed) and ClinicalTrials.gov databases to identify relevant articles reporting results from double-blind clinical trials that used a source control review process. Eight prospective, randomized, double-blind, multicenter, clinical trials of 5 anti-infective agents in complicated intra-abdominal infections used a source control review process. We provide recommendations for an independent, adjudicated source control review process applicable to future clinical trials.

Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects.

ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects (6 active and 2 placebo) who received 15 mg/kg for 5 days. Safety was assessed from adverse event (AE) reporting, standard clinical laboratory procedures, and testing for renal, cochlear, and vestibular function. ACHN-490 exhibited linear and dose-proportional PK, with agreement between the studies for PK parameters assessed. The 15-mg/kg dose did not accumulate with repeated dosing over 5 days. Mean steady-state (±standard deviation) area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C(max)), half-life (t(1/2)), clearance, and volume of distribution at steady state (V(ss)) for the 15-mg/kg, day 5 dose were 239 ± 45 h·mg/liter, 113 ± 17 mg/liter, 3 ± 0.3 h, 1.1 ± 0.1 ml/min/kg, and 0.24 ± 0.04 liters/kg, respectively. AEs were mild to moderate and rapidly resolved. No evidence of nephrotoxicity or ototoxicity was observed.

A double-blind, placebo-controlled trial of oral human immunoglobulin for gastrointestinal dysfunction in children with autistic disorder.

Controversy exists regarding the extent and possible causal relationship between gastrointestinal symptoms and autism. A randomized, double-blind, placebo-controlled, parallel groups, dose-ranging study of oral, human immunoglobulin (IGOH 140, 420, or 840 mg/day) was utilized with 125 children (ages 2-17 years) with autism and persistent GI symptoms. Endpoint analysis revealed no significant differences across treatment groups on a modified global improvement scale (validated in irritable bowel syndrome studies), number of daily bowel movements, days of constipation, or severity of problem behaviors. IGOH was well-tolerated; there were no serious adverse events. This study demonstrates the importance of conducting rigorous trials in children with autism and casts doubt on one GI mechanism presumed to exert etiological and/or symptomatic effects in this population.

The economics of pediatric formulation development for off-patent drugs.

BACKGROUND: Many drugs currently used in children have never been adequately studied in rigorous scientific trials. Although these medications can still be prescribed in the pediatric setting, they are considered "off-label" because they are not specifically approved for use in children. The role of the Economics Working Group (EWG) within the Pediatric Formulation Initiative (PFI) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is to identify economic barriers and to propose possible mechanisms to create cost-effective and appropriately formulated products for off-patent pediatric drugs and to ensure their distribution and availability. OBJECTIVE: The purpose of this article was to briefly outline the EWG's considerations and recommendations on these topics. METHODS: Information for this article was gathered from the proceedings of a PFI workshop sponsored by the NICHD, held December 6 and 7, 2005, in Bethesda, Maryland. Other information was based on: the authors' unpublished and published research as well as personal communication with members of the EWG; a comprehensive search of Web sites, publications, and publicly accessible databases of the European Medicines Agency, the US Food and Drug Administration, the Agency for Healthcare Research and Quality, and the NICHD; and the databases and publications available from the Louis Lasagna Library of the Tufts Center for the Study of Drug Development (Boston, Massachusetts). RESULTS: The US Congress has attempted to remedy the lack of incentives to develop pediatric drugs by passing 2 key pieces of legislation. After >10 years, this US pediatric initiative has stimulated a great deal of pediatric drug research, and similar initiatives have been emulated in Europe and proposed in Japan. Although the initiative is generally considered successful in the United States, an incentive gap exists that still hinders pediatric drug development. It results from a series of factors, including: (1) a relatively small market size (<10% of the overall pharmaceutical market); (2) a predominance of off-patent drug use in the pediatric setting (perhaps as much as 70%); (3) no pediatric incentives for generic drug manufacturers; (4) fewer chronic illnesses in children than in adults; (5) a higher proportion of uninsured (mostly Medicaid recipients) and underinsured (many young families) patients; and (6) higher per-patient costs as well as greater complexity of drug development. By understanding these barriers, more appropriate incentives can be generated by government, where these incentives are not inherently present in the market. CONCLUSIONS: The lack of child-friendly formulations leaves 40% of the world's population at increased risk for avoidable adverse events, suboptimal dosing, noncompliance, and lack of access to new medicines. Incentive programs are the surest and least expensive means to overcome the tendency of "big pharma" to overlook the pediatric market as too small, and of start-up and specialty companies to consider it too problematic. Given the relatively lengthy period required to build product development infrastructure, these several decades-when market growth potential, demographics, and public health considerations are aligned in favor of pediatric formulation needs-are a critical time frame for creating a private and public sector environment to support this effort.

Impact of ontogeny on linezolid disposition in neonates and infants.

The impact of age on linezolid disposition during the first few months of life has not been previously investigated. We characterized linezolid pharmacokinetics after a single, 10.0-mg/kg intravenous dose in 42 infants stratified as follows: group 1 (n = 9), gestational age <34 weeks and postnatal age <8 days; group 2 (n = 7), gestational age <34 weeks and postnatal age 8 days to 12 weeks; group 3 (n = 11), gestational age >or=34 weeks and postnatal age <8 days; and group 4 (n = 15), gestational age >or=34 weeks and postnatal age 8 days to 12 weeks. Linezolid was quantitated by a validated HPLC-triple-quadrupole mass spectrometer method from repeated blood samples (n = 7, 0.3 mL each) obtained over a 12-hour period. Pharmacokinetic parameters were determined by standard model-dependent techniques. The values (mean +/- SD) for total body clearance (CL) (0.25 +/- 0.12 L x h(-1) x kg(-1)), apparent volume of distribution (VD(ss)) (0.75 +/- 0.19 L/kg), and elimination half-life (t(1/2)) (2.8 +/- 2.1 hours) from the entire study cohort were similar to values reported previously for children and adolescents. Examination of the linezolid pharmacokinetics as a function of age revealed that CL increased rapidly during the first week of life and as a function of postnatal age. Age stratification revealed lower values for CL in those infants aged less than 8 days (group 1, 0.12 +/- 0.06 L x h(-1) x kg(-1); group 3, 0.23 +/- 0.12 L x h(-1) x kg(-1)) as compared with those aged 8 days to 12 weeks (group 2, 0.31 +/- 0.07 L x h(-1) x kg(-1); group 4, 0.31 +/- 0.10 L x h(-1) x kg(-1)). In contrast to the results for CL, gestational age served to be the most useful predictor of VD(ss). Evaluation of the pharmacokinetic data would appear to support the use of linezolid dosing regimens currently approved for infants and young children in neonates with postnatal age greater than 7 days.

Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates.

BACKGROUND: Gram-positive infections caused by susceptible and resistant strains of Staphylococcus aureus, coagulase-negative staphylococci and enterococci are increasing problems in neonates. Linezolid, a new oxazolidinone, is active against these pathogens and has recently been approved by the Food and Drug Administration for treating Gram-positive infections in pediatric patients. OBJECTIVE: To compare the clinical efficacy and safety of intravenous and oral linezolid with vancomycin (10 to 15 mg/kg every 6 to 24 h) in neonates (age 0 to 90 days). METHODS: Hospitalized infants with known or suspected hospital-acquired pneumonia, complicated skin or skin structure infections, bacteremia or other infections (e.g. pyelonephritis, abdominal abscess) were eligible. Test-of-cure clinical response was evaluated at follow-up. RESULTS: Sixty-three neonates, randomized 2:1 to linezolid (n = 43) or vancomycin (n = 20) were included in the intent-to-treat group. Clinical cure rates at follow-up in the intent-to-treat group were higher, but not significantly different, for linezolid vs. vancomycin (78% vs. 61%; P = 0.196). Corresponding cure rates in clinically evaluable patients were 84% vs. 77% (P = 0.553) for linezolid and vancomycin, respectively. Pathogen eradication rates were as follows in the linezolid and vancomycin groups, respectively: S. aureus (67% vs. 60%; P = 0.850); coagulase-negative staphylococci (88% vs. 100%; P = 0.379); and enterococci (71% vs. 0%; P = 0.168). Results for hematology and chemistry assays were similar between treatment groups. Fewer linezolid-treated neonates had drug-related adverse events than vancomycin-treated neonates (12% vs. 32%; P = 0.058). CONCLUSIONS: Linezolid is well-tolerated and as effective as vancomycin in the treatment of resistant Gram-positive infections in neonates.

Linezolid for the treatment of children with bacteremia or nosocomial pneumonia caused by resistant gram-positive bacterial pathogens.

BACKGROUND: Nosocomial infections, particularly hospital-acquired pneumonia (HAP) and bacteremia, are an increasing concern in pediatric hospitals and pediatric intensive care units. Gram-positive pathogens are a leading cause of these infections in children. Linezolid is well-tolerated and as effective as vancomycin in the treatment of these infections in adults. OBJECTIVE: To evaluate the clinical effectiveness and safety of iv/oral linezolid and iv vancomycin in children with resistant Gram-positive HAP or bacteremia. METHODS: Hospitalized children <12 years of age were randomized 2:1 to linezolid or vancomycin. Patients received linezolid 10 mg/kg iv every 8 h with the option to change treatment to oral linezolid suspension 10 mg/kg every 8 h or iv vancomycin 10 to 15 mg/kg every 6 to 24 h. Clinical response was evaluated at follow-up. Results from an analysis of patients with HAP or bacteremia are presented. RESULTS: Thirty-nine patients (linezolid, 23; vancomycin, 16) with HAP and 113 patients with bacteremia (linezolid, 81; vancomycin, 32) were included in the intent-to-treat group. Clinical cure rates for clinically evaluable patients with HAP did not differ between treatment groups (linezolid, 90.0% and vancomycin, 100%; P = 0.305). No significant difference was seen in clinical cure rates in the clinically evaluable population between the linezolid and vancomycin groups for patients with catheter-related bacteremia (84.8 and 80.0%, respectively; P = 0.716) or patients with bacteremia of unknown source (79.2 and 69.2%, respectively; P = 0.501). In this subset fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19.4% vs. 28.3%; P = 0.230). Similar percentages of patients with laboratory abnormalities, including selected hematologic parameters, were seen in both treatment groups. CONCLUSIONS: Intravenous/oral linezolid was well-tolerated and as effective as vancomycin in treating children with resistant Gram-positive HAP or bacteremia.

Linezolid for the treatment of complicated skin and skin structure infections in children.

BACKGROUND: Gram-positive pathogens are a major cause of complicated skin and skin structure infections (CSSSIs) in children. Many pathogens are developing decreased susceptibility to currently used antibiotics, increasing the need for new therapies. Linezolid is well-tolerated and effective in the treatment of these infections in adults. OBJECTIVE: To evaluate the clinical efficacy and safety of iv/oral linezolid and iv vancomycin in children with Gram-positive CSSSIs. METHODS: Hospitalized children <12 years of age were randomized (2:1 ratio) to receive either linezolid 10 mg/kg iv every 8 h (with the option to change treatment to oral linezolid suspension 10 mg/kg every 8 h) or iv vancomycin 10 to 15 mg/kg every 6 to 24 h (according to age). Clinical response, tolerance and safety were evaluated at follow-up. The results of a subset analysis of patients with CSSSIs are presented here. RESULTS: One hundred twenty intent-to-treat patients (linezolid 80, vancomycin 40) with CSSSI were included in this analysis. Clinical cure rates for clinically evaluable patients with CSSSI did not differ between treatment groups (linezolid, 93.2% vs. vancomycin, 90.0%; P = 0.594). Significantly fewer linezolid-treated patients experienced drug-related adverse events than did vancomycin-treated patients (23% vs. 48%; P = 0.006). The percentages of patients with laboratory abnormalities, including selected hematologic parameters, were generally low and similar between the treatment groups. CONCLUSIONS: Linezolid given iv or orally was well-tolerated and safe. It was as effective as vancomycin in treating children with Gram-positive CSSSIs.

Linezolid for the treatment of methicillin-resistant Staphylococcus aureus infections in children.

BACKGROUND: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly prevalent. Linezolid is effective and well-tolerated in the treatment of adults with MRSA infections. OBJECTIVE: To evaluate the clinical efficacy and safety of iv/oral linezolid in children with MRSA infections. METHODS: Data were obtained from two independent clinical trials. In an outpatient trial children (5 to 17 years of age) with uncomplicated skin and skin structure infections (SSSIs) were treated with linezolid or cefadroxil. In an inpatient trial hospitalized children (0 to 11 years of age) with pneumonia, bacteremia or complicated SSSI caused by resistant Gram-positive pathogens were administered iv linezolid with the option to switch to oral suspension (patients >90 days of age) or iv vancomycin. A subset of patients with MRSA infections from the two clinical trials is analyzed herein. RESULTS: In the outpatient trial children with skin infections caused by MRSA were treated with linezolid (15 patients) and cefadroxil (10 patients). In the microbiologically evaluable population, the clinical cure rate was 92.3% in the linezolid group and 85.7% in the cefadroxil group (P = 0.64). The pathogen eradication rate for MRSA was 92.3 and 85.7% in the linezolid and cefadroxil groups, respectively (P = 0.64). There were very few adverse events or drug-related adverse events and no serious adverse events in the outpatient trial. In the inpatient trial 20 children treated with linezolid and 14 treated with vancomycin had infections caused by MRSA. In the microbiologically evaluable population, the clinical cure rate was 94.1% in the linezolid group and 90.0% in the vancomycin group (P = 0.69). Pathogen eradication rates were 88.2 and 90.0% for the linezolid and vancomycin groups, respectively (P = 0.89). Susceptibility patterns of the MRSA isolates showed distinct patterns between the outpatient and inpatient trials. In the inpatient trial fewer patients in the linezolid group had drug-related adverse events than did those in the vancomycin group (20% vs. 43%; P = 0.15). CONCLUSIONS: Intravenous/oral linezolid is effective and well-tolerated in children with MRSA infections.

Hematologic effects of linezolid in young children.

BACKGROUND: Linezolid is an effective and well-tolerated antibiotic for the treatment of Gram-positive infections, including hospital and community-acquired pneumonia and complicated and uncomplicated skin and skin structure infections. In adults linezolid treatment for >/=2 weeks has been associated with reversible hematopoietic suppression, primarily thrombocytopenia. OBJECTIVE: To evaluate the occurrence of hematologic effects in children with Gram-positive infections in an open label study of linezolid vs. vancomycin. METHODS: Detailed analyses of hematologic data, including reported hematologic adverse events, complete blood counts, reticulocyte index (RI) and iron studies (serum iron and transferrin saturation), were conducted in both groups at baseline and during and after treatment with the use of an intent-to-treat analysis. RESULTS: Three hundred sixteen patients (median age, 1.65 yr) randomized 2:1 to linezolid (n = 215) or vancomycin (n = 101) were treated. Total treatment durations were similar in the vancomycin group (12.2 +/- 6.4 days; median, 11.0 days) and the linezolid group (11.3 +/- 5.0 days; median, 11.0 days) (P = 0.20). No significant differences were noted in drug-related hematologic events, such as thrombocytopenia (linezolid, 1.9% vs. vancomycin, 0%; P = 0.170), anemia (linezolid, 1.4% vs. vancomycin, 1.0%; P = 0.771) or neutropenia (linezolid, 0% vs. vancomycin, 0%). Hemoglobin values also were similar between treatment groups when assessed by shifts from baseline to lowest recorded value. Frequency of occurrence of any substantially abnormal value for hemoglobin (15.7% vs. 12.4%), platelets (12.9% vs. 13.4%) and neutrophils (5.9% vs. 4.3%) were similar in the linezolid and vancomycin groups. No clinically relevant changes in RI or iron studies were noted between treatment groups, and parallel increases in RI occurred with both linezolid and vancomycin. CONCLUSIONS: No significant differences in hematologic profiles between linezolid and vancomycin occurred in this pediatric population.

Safety and tolerability of linezolid in children.

BACKGROUND: Linezolid, an oxazolidinone, is effective in the treatment of adults and children with community-acquired and nosocomial pneumonia and uncomplicated and complicated skin and skin structure infections (SSSIs), including infections caused by Gram-positive resistant pathogens. Because of the increasing use of linezolid, it is important to review the common adverse events (AEs) associated with its use in children with the use of data from clinical trials. OBJECTIVE: The safety and tolerability of linezolid in pediatric patients with Gram-positive infections were determined in four pediatric clinical studies. Study I included pediatric patients with community-acquired pneumonia; Study II included otitis media; Study III included SSSIs; and Study IV included complicated SSSIs, nosocomial pneumonia and bacteremia. METHODS: Studies I and II had no comparator arm. Study III was randomized and compared linezolid with cefadroxil. Study IV also was randomized and compared linezolid with vancomycin. Patients <12 years of age received linezolid 10 mg/kg; patients age 12 years and older received 600 mg (intravenous/oral). Dosing frequency (two to three times daily) varied depending on age and clinical diagnosis. The primary safety endpoints were AEs, drug-related AEs, serious AEs and selected laboratory tests. RESULTS: In the 4 studies 958 patients were included in the intent-to-treat analysis. In the linezolid vs. cefadroxil study (Study III), the most common AEs in patients treated with linezolid were diarrhea (7.8%), headache (6.5%) and upper respiratory tract infection (3.7%). In the linezolid vs. vancomycin study (Study IV), the most common AEs in the linezolid group were fever (14.1%), diarrhea (10.8%) and vomiting (9.4%). The most common drug-related AEs for linezolid in all 4 studies were diarrhea, vomiting, loose stools and nausea. None of these common AEs or drug-related AEs occurred more frequently in patients treated with linezolid than in those in the comparator group. CONCLUSIONS: Linezolid was safe and well-tolerated in pediatric patients with community-acquired pneumonia, otitis media, SSSIs and infections caused by Gram-positive resistant pathogens.

Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.

BACKGROUND: Pediatric infections caused by resistant Gram-positive infections are an increasing concern with limited treatment options. Linezolid, a new oxazolidinone, is active against staphylococci, streptococci and enterococci. OBJECTIVE: To assess clinical efficacy and safety of linezolid vs.vancomycin in antibiotic-resistant Gram-positive infections in children. DESIGN Hospitalized children (birth to 12 years of age) with nosocomial pneumonia, complicated skin/skin structure infections, catheter-related bacteremia, bacteremia of unknown source or other infections caused by Gram-positive bacteria were randomized 2:1 to receive linezolid intravenously followed by oral linezolid or vancomycin and then by an appropriate oral agent. Treatment duration was 10 to 28 days. RESULTS: There were 321 patients enrolled (linezolid 219, vancomycin 102). Clinical cure rates were 79% vs.74% (P = 0.36) and 89% vs.85% (P = 0.31) for linezolid and vancomycin in intent-to-treat and clinically evaluable patients, respectively. Cure rates were similar by age and infection diagnosis. Pathogen eradication rates in microbiologically evaluable patients were high for linezolid and vancomycin, respectively, for methicillin-susceptible S. aureus (95% vs.94%; P = 0.82), methicillin-resistant S. aureus (88% vs.90%; P = 0.89) and methicillin-resistant coagulase-negative staphylococci (85% vs.83%, P = 0.87). In clinically evaluable patients, linezolid-treated patients required significantly fewer days of intravenous therapy compared with vancomycin-treated patients (8.0 +/- 4.8; 10.9 +/- 5.8 days, respectively; P < 0.001). In addition significantly fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19% vs.34%, respectively; P = 0.003). Hematologic events were uncommon and similar between treatment groups. CONCLUSIONS: Linezolid was well-tolerated and as effective as vancomycin in treating serious Gram-positive infections in children.

A severity score for complicated skin and soft tissue infections derived from phase III studies of linezolid.

BACKGROUND: Severity scoring systems are useful for assessing patient risk and predicting prognosis. METHODS: We developed a scoring system using data from a phase III study comparing antibiotics in hospitalized patients with complicated skin and soft tissue infections (study A), and used logistic regression analysis to identify factors contributing to treatment failure. We tested this system using data from a similar study (study B). RESULTS: In study A (n = 682), cure rates were lower in patients with at least 1 comorbid condition (P <0.05) and in the highest risk class (P = 0.05); elevated blood urea nitrogen, hyponatremia, anemia, lesion size, and surgical wound infection were independent predictors of failure (P <0.05). In study B (n = 166), findings were similar and significant for risk class (P <0.05). In the combined analysis (n = 848), cure rates were higher for linezolid than for the comparator in all patients (85% versus 77%; P <0.01) and in subanalyses by comorbid conditions, median score, and risk class (P <0.05). CONCLUSIONS: We developed and validated a scoring system in which baseline variables predicted outcome. Patients with higher severity scores generally had poorer outcomes regardless of treatment group. Our finding that linezolid was an independent predictor of cure merits further evaluation.

Quantitative priming with inactivated pertussis toxoid vaccine in the aerosol challenge model.

Serum antibodies to pertussis toxin (PT) have been shown to be protective against severe pertussis disease, although a specific level of anti-PT antibody that correlates with protection has not been demonstrated. Current animal models such as the intracerebral challenge model have significant limitations in correlating protection to a specific level of anti-PT antibody. This study examines the protective effects of priming with tetranitromethane-inactivated pertussis toxoid (PTx) vaccine in the aerosol challenge model and whether a measurable response to a priming dose of PTx is enough to initiate a protective secondary response when challenged with infection. The correlation of priming with markers of illness such as leukocytosis, weight loss, bacterial proliferation, and mortality after established infection with Bordetella pertussis was explored. BALB/c mice were immunized with PTx vaccine on day 6 of life and then challenged with B. pertussis using the aerosol challenge model. Data were analyzed according to the primary immunologic response, differentiating responders (anti-PT immunoglobulin G [IgG] > or =1 microg/ml) from nonresponders (anti-PT IgG <1 microg/ml). Mice that showed evidence of priming on the day of aerosol challenge were able to mount a secondary response to the challenge with a > or =2-fold rise in anti-PT IgG antibody by day 7 and a > or =10-fold rise by day 14 post-aerosol challenge. These primed mice were significantly better protected against leukocytosis, weight loss, and proliferation of B. pertussis in the lungs following aerosol challenge than the nonprimed group. This protection correlated with levels of anti-PT antibody in serum present on the day of aerosol challenge.

Hematologic effects of linezolid: summary of clinical experience.

Linezolid has been associated with reversible myelosuppression. Clinical trial data were evaluated for anemia, thrombocytopenia, and neutropenia. Thrombocytopenia and a slight increased risk for anemia were evident at > or =2 weeks of linezolid treatment. Hematologic abnormalities were consistent with mild, reversible, duration-dependent myelosuppression. Appropriate monitoring is warranted with linezolid use.