Background SPR206 is a novel intravenously (IV)-administered next-generation polymyxin being developed for the treatment of multi-drug resistant (MDR) Gram-negative (GN) infections. A Phase 1 bronchoalveolar lavage (BAL) study was... more
Background SPR206 is a novel intravenously (IV)-administered next-generation polymyxin being developed for the treatment of multi-drug resistant (MDR) Gram-negative (GN) infections. A Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206 safety and PK in plasma and pulmonary matrices (ELF and AM) in healthy volunteers. Methods Subjects received 100 mg SPR206 administered intravenously over 1 h q8h for 3 consecutive doses. Blood samples were collected pre-dose (second and third dose) and at 2, 3, 4, 6, and 8 h after the start of the last dose. Each subject underwent one standardized bronchoscopy with BAL at 2, 3, 4, 6 or 8 hours after the start of the third IV infusion. Concentrations of SPR206 in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Plasma, ELF, and AM PK parameters were determined by noncompartmental analysis. SPR206 AUC0–8 in ELF and AM were calculated using the mean concentration values at the BAL sampling times. SPR206...
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Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug being developed for the treatment of serious bacterial infections. The active moiety, tebipenem, has broad-spectrum activity against... more
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug being developed for the treatment of serious bacterial infections. The active moiety, tebipenem, has broad-spectrum activity against commonEnterobacteralespathogens, including extended-spectrum-β-lactamase (ESBL)-producing multidrug-resistant strains.
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Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales . This study evaluated the safety, tolerability, and... more
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales . This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg).
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ABSTRACTPertussis in infants is often severe, resulting in prolonged hospitalization. Treatment is limited to supportive care. Antibiotics do not significantly alter the course of the disease unless administered during the catarrhal... more
ABSTRACTPertussis in infants is often severe, resulting in prolonged hospitalization. Treatment is limited to supportive care. Antibiotics do not significantly alter the course of the disease unless administered during the catarrhal phase. Therapies directed at pertussis toxin, a major virulence factor ofBordetella pertussis, may be beneficial. This study uses the aerosol challenge model to further examine the protective effects of P-IGIV, a new intravenous immunoglobulin product, which has high levels of pertussis toxin antibodies. P-IGIV was prepared as a 4% immunoglobulin G (IgG) solution from the pooled donor plasma from donors immunized with inactivated pertussis toxoid. The IgG pertussis toxin antibody concentration in P-IGIV is >7-fold higher than conventional intravenous immunoglobulin products. In the aerosol challenge model, P-IGIV-treated mice exhibited a dose-dependent decrease in mortality when monitored for 28 days postchallenge. P-IGIV in doses of 2,800, 1,400, and...
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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... more
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. 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. A total of 105 patients, 32 cSSSI and 73 HABP/VABP, had baseline, concurrent SAB. The clinical cure ra...
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Pertussis in infants is often severe, resulting in complications and prolonged hospitalization. Treatment is limited to supportive care. Antibiotics do not significantly alter the course of the disease. Therapies directed at pertussis... more
Pertussis in infants is often severe, resulting in complications and prolonged hospitalization. Treatment is limited to supportive care. Antibiotics do not significantly alter the course of the disease. Therapies directed at pertussis toxin, a major virulence factor of Bordetella pertussis, might be beneficial. This study examines the safety and pharmacology of intravenous pertussis immunoglobulin (P-IGIV), which has high levels of pertussis toxin antibodies. P-IGIV was prepared as a 4% IgG solution from the pooled plasma from donors immunized with inactivated pertussis toxoid. The IgG pertussis toxin antibody concentration of 733 microg/ml is >7-fold higher than contained in conventional intravenous immunoglobulin products. Children with presumptive pertussis were allocated to one of three treatment doses of P-IGIV. Twenty-six of 30 enrolled children had confirmed pertussis. There were no adverse events associated with P-IGIV except one patient who had transient hypotension that responded to an infusion rate decrease. P-IGIV doses of 1500, 750 and 250 mg/kg achieved > or =4-fold, 3-fold and >2-fold rises in peak geometric mean titers of pertussis toxin IgG antibodies, respectively. P-IGIV exhibited a half-life of 38.4 days and a volume of distribution of 87.8 ml/kg. All three treatment groups showed declines in lymphocytosis (P < 0.05) and paroxysmal coughing by the third day after P-IGIV infusion compared with preinfusion values. P-IGIV is safe and achieves high pertussis toxin antibody titers in infants. This study provides data for a prospective, controlled trial of P-IGIV.
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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. To evaluate the clinical efficacy and... more
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. To evaluate the clinical efficacy and safety of iv/oral linezolid in children with MRSA infections. 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. 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). Intravenous/oral linezolid is effective and well-tolerated in children with MRSA infections.
Research Interests: Adolescent, Medicine, Vancomycin, Population, Humans, and 15 moreChild, Internal Medicine, Female, Male, Staphylococcus aureus, Outpatients, Methicillin Resistance, Linezolid, Methicillin Resistant Staphylococcus Aureus, Oxazolidinones, Acetamides, Child preschool, Adverse effect, Paediatrics and reproductive medicine, and Staphylococcal infections
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... more
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. To evaluate the occurrence of hematologic effects in children with Gram-positive infections in an open label study of linezolid vs. vancomycin. 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. 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. No significant differences in hematologic profiles between linezolid and vancomycin occurred in this pediatric population.
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ABSTRACTThis randomized, double-blind, multicenter trial compared the efficacy and safety of linezolid, an oxazolidinone, with those of oxacillin-dicloxacillin in patients with complicated skin and soft tissue infections. A total of 826... more
ABSTRACTThis randomized, double-blind, multicenter trial compared the efficacy and safety of linezolid, an oxazolidinone, with those of oxacillin-dicloxacillin in patients with complicated skin and soft tissue infections. A total of 826 hospitalized adult patients were randomized to receive linezolid (600 mg intravenously [i.v.]) every 12 h or oxacillin (2 g i.v.) every 6 h; following sufficient clinical improvement, patients were switched to the respective oral agents (linezolid [600 mg orally] every 12 h or dicloxacillin [500 mg orally] every 6 hours). Primary efficacy variables were clinical cure rates in both the intent-to-treat (ITT) population and clinically evaluable (CE) patients and microbiological success rate in microbiologically evaluable (ME) patients. Safety and tolerability were evaluated in the ITT population. Demographics and baseline characteristics were similar across treatment groups in the 819 ITT patients. In the ITT population, the clinical cure rates were 69....
Research Interests: Microbiology, Patient Safety, Medical Microbiology, Medicine, Population, and 15 moreHumans, Female, Male, Middle Aged, Adverse Event, Antimicrobial agents, Linezolid, Oxazolidinones, Confidence Interval, Clinical evaluation, Acetamides, Dicloxacillin, Adverse effect, Pharmacology and pharmaceutical sciences, and Penicillins
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 ≥2 weeks of... more
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 ≥2 weeks of linezolid treatment. Hematologic abnormalities were consistent with mild, reversible, duration-dependent myelosuppression. Appropriate monitoring is warranted with linezolid use.
Research Interests: Microbiology, Medical Microbiology, Medicine, Humans, Internal Medicine, and 14 moreAnemia, Thrombocytopenia, Boston, Retrospective Studies, Antimicrobial agents, Harvard Medical School, Linezolid, Massachusetts General Hospital, Hemoglobins, Oxazolidinones, Acetamides, Clinical Trials as Topic, neutropenia, and Pharmacology and pharmaceutical sciences
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... more
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. D...
Research Interests: Immunology, Clinical Trial, Medicine, Aerosols, Biological Sciences, and 15 moreMice, Weight Loss, Female, Animals, Animal Model, Antibody, Adverse Drug Reaction, Age Factors, Pertussis Vaccine, Protective Antigen, Whooping Cough, Bordetella Pertussis, immunoglobulin G, Medical and Health Sciences, and leukocytosis
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... more
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.
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Study ObjectiveTelavancin and vancomycin are both approved for treatment of hospital‐acquired and ventilator‐associated bacterial pneumonias caused by Staphylococcus aureus, and both agents can cause renal dysfunction. The objective of... more
Study ObjectiveTelavancin and vancomycin are both approved for treatment of hospital‐acquired and ventilator‐associated bacterial pneumonias caused by Staphylococcus aureus, and both agents can cause renal dysfunction. The objective of this study was to assess renal function changes by performing renal shift table analyses of telavancin‐ and vancomycin‐treated patients in phase III trials.DesignRetrospective, descriptive analysis of data from the safety population from the Assessment of Telavancin for Treatment of Hospital‐Acquired Pneumonia (ATTAIN) trials.PatientsA total of 1503 adults with hospital‐acquired or ventilator‐associated bacterial pneumonia primarily caused by gram‐positive pathogens and who received telavancin (n = 751) or vancomycin (n = 752).Measurements and Main ResultsDecline or improvement in creatinine clearance (CrCl) across seven defined categories (≤30, >30–40, >40–50, >50–60, >60–70, >70–80, and >80 ml/min) was classified as negative or pos...
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Carbapenem-resistant Acinetobacter baumannii and Enterobacterales are identified as urgent threats, and multidrug-resistant (MDR) Pseudomonas aeruginosa and extended-spectrum beta-lactamase (ESBL)-producing pathogens are identified as... more
Carbapenem-resistant Acinetobacter baumannii and Enterobacterales are identified as urgent threats, and multidrug-resistant (MDR) Pseudomonas aeruginosa and extended-spectrum beta-lactamase (ESBL)-producing pathogens are identified as serious threats by the Centers for Disease Control and Prevention (CDC). SPR206 is a novel polymyxin derivative with potent in vitro and in vivo activity against A. baumannii , P. aeruginosa , and multiple clinically important species of Enterobacterales , including multidrug- and extensively drug-resistant strains.