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1.
Antimicrob Agents Chemother ; 66(1): e0144121, 2022 01 18.
Article in English | MEDLINE | ID: mdl-34807760

ABSTRACT

In this first-in-human study, PLG0206, a novel engineered cationic antimicrobial peptide, was evaluated for safety, tolerability, and pharmacokinetics (PK) when intravenously (i.v.) administered as a single dose to healthy subjects. Six cohorts of 8 subjects each received escalating single i.v. infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, or 1 mg/kg dose or placebo over 1 to 4 h. Subjects were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). Serial pharmacokinetic samples were taken prior to infusion and up to 48 h postinfusion. Safety and tolerability were assessed throughout the study. The demographic characteristics of subjects were comparable between those treated with PLG0206 and placebo and between dose groups. The incidence of treatment-emergent adverse events (TEAE) related to PLG0206 was low, and most events were mild in severity and were similar between the PLG0206 treatment and placebo groups. The most common adverse events reported for PLG0206 were infusion-related reactions, which were mitigated with increasing infusion time and volume. There were no severe adverse events (SAEs), life-threatening events, or deaths throughout the study. i.v. PLG0206 exhibited linear pharmacokinetics over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t1/2) ranged from 7.37 to 19.97 h. Following a single i.v. infusion to healthy subjects, PLG0206 was safe and well tolerated and exhibited linear PK at doses ranging from 0.05 to 1 mg/kg. These findings support the ongoing development of i.v. PLG0206 as an antimicrobial agent.


Subject(s)
Peptides , Dose-Response Relationship, Drug , Double-Blind Method , Healthy Volunteers , Humans , Peptides/adverse effects
2.
N Engl J Med ; 380(8): 729-740, 2019 02 21.
Article in English | MEDLINE | ID: mdl-30786187

ABSTRACT

BACKGROUND: The increasing multidrug resistance among gram-negative uropathogens necessitates new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae. METHODS: We randomly assigned 609 patients with complicated urinary tract infections (UTIs), including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with optional oral step-down therapy after at least 4 days of intravenous therapy, for a total of 7 to 10 days of therapy. The primary objective was to show the noninferiority of plazomicin to meropenem in the treatment of complicated UTIs, including acute pyelonephritis, with a noninferiority margin of 15 percentage points. The primary end points were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified intention-to-treat population. RESULTS: Plazomicin was noninferior to meropenem with respect to the primary efficacy end points. At day 5, composite cure was observed in 88.0% of the patients (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (difference, -3.4 percentage points; 95% confidence interval [CI], -10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191 patients) and 70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). At the test-of-cure visit, a higher percentage of patients in the plazomicin group than in the meropenem group were found to have microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8% vs. 68.6%) and Enterobacteriaceae that produce extended-spectrum ß-lactamases (82.4% vs. 75.0%). At late follow-up (24 to 32 days after initiation of therapy), fewer patients in the plazomicin group than in the meropenem group had microbiologic recurrence (3.7% vs. 8.1%) or clinical relapse (1.6% vs. 7.1%). Increases in serum creatinine levels of 0.5 mg or more per deciliter (≥40 µmol per liter) above baseline occurred in 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group. CONCLUSIONS: Once-daily plazomicin was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains. (Funded by Achaogen and the Biomedical Advanced Research and Development Authority; EPIC ClinicalTrials.gov number, NCT02486627.).


Subject(s)
Anti-Bacterial Agents/administration & dosage , Enterobacteriaceae Infections/drug therapy , Meropenem/administration & dosage , Sisomicin/analogs & derivatives , Urinary Tract Infections/drug therapy , Administration, Intravenous , Administration, Oral , Adult , Aged , Anti-Bacterial Agents/adverse effects , Drug Administration Schedule , Drug Resistance, Multiple, Bacterial , Enterobacteriaceae/drug effects , Female , Humans , Male , Meropenem/adverse effects , Microbial Sensitivity Tests , Middle Aged , Patient Acuity , Sisomicin/administration & dosage , Sisomicin/adverse effects , Urinary Tract Infections/microbiology
4.
Clin Infect Dis ; 60(10): 1462-71, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25670823

ABSTRACT

BACKGROUND: Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. METHODS: ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4-14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24-32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated. RESULTS: Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, -4.2%; 95% confidence interval [CI], -8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, -1.0%; 95% CI, -4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea. CONCLUSIONS: Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens. CLINICAL TRIALS REGISTRATION: NCT01445665 and NCT01445678.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Bacterial Infections/drug therapy , Cephalosporins/administration & dosage , Drug Resistance, Multiple, Bacterial , Intraabdominal Infections/drug therapy , Metronidazole/administration & dosage , Penicillanic Acid/analogs & derivatives , Adolescent , Adult , Aged , Aged, 80 and over , Bacterial Infections/microbiology , Double-Blind Method , Drug Therapy, Combination/methods , Female , Humans , Intraabdominal Infections/microbiology , Male , Middle Aged , Penicillanic Acid/administration & dosage , Prospective Studies , Tazobactam , Treatment Outcome , Young Adult
5.
Antimicrob Agents Chemother ; 58(9): 5350-7, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24982069

ABSTRACT

Ceftolozane-tazobactam (TOL-TAZ) is a novel antibacterial with activity against Pseudomonas aeruginosa and other common Gram-negative pathogens, including extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, that are associated with complicated intra-abdominal infections (cIAIs). This prospective, double-blind, randomized, multicenter, phase II trial assessed patient clinical and microbiological responses to and the safety of TOL-TAZ plus metronidazole compared with those of meropenem. Hospitalized adults with cIAIs that required surgical intervention were randomized (2:1) to receive intravenous (i.v.) TOL-TAZ (1.5 g [containing 1,000 mg TOL and 500 mg TAZ] every 8 h [q8h]) with or without i.v. metronidazole (500 mg q8h) or i.v. meropenem (1 g q8h) for 4 to 7 days. The primary endpoint was the clinical response at the test-of-cure visit in the microbiologically modified intent-to-treat (mMITT) and microbiologically evaluable (ME) populations. Secondary measures included the patients' microbiological response and safety. In total, 82 patients received TOL-TAZ (90.2% with metronidazole), and 39 received meropenem. For the mMITT population, clinical cure was seen in 83.6% of the patients (51/61; 95% confidence interval [CI], 71.9 to 91.8) who received TOL-TAZ and 96.0% of the patients (24/25; 95% CI, 79.6 to 99.9) who received meropenem (difference, -12.4%; 95% CI, -34.9% to 11.1%); in the ME population, clinical cure was seen in 88.7% and 95.8% of the patients (difference, -7.1%; 95% CI, -30.7% to 16.9%) who received TOL-TAZ and meropenem, respectively. TOL-TAZ demonstrated microbiological success against Escherichia coli (89.5%), Klebsiella pneumoniae (100%), and P. aeruginosa (100%). The adverse event rates were similar in the groups (50.0% with TOL-TAZ and 48.8% with meropenem). TOL-TAZ in combination with metronidazole was well tolerated and resulted in clinical and microbiological success rates supportive of further clinical development in patients with cIAIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01147640.).


Subject(s)
Cephalosporins/therapeutic use , Intraabdominal Infections/drug therapy , Metronidazole/therapeutic use , Penicillanic Acid/analogs & derivatives , Thienamycins/therapeutic use , Cephalosporins/adverse effects , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Infusions, Intravenous , Male , Meropenem , Metronidazole/administration & dosage , Metronidazole/adverse effects , Middle Aged , Penicillanic Acid/adverse effects , Penicillanic Acid/therapeutic use , Tazobactam , Thienamycins/administration & dosage , Thienamycins/adverse effects , Treatment Outcome
7.
Lancet Infect Dis ; 13(3): 269-75, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23332713

ABSTRACT

To bring new antibacterial drugs to the market is challenging because discovery of new agents is difficult, two large trials per indication are needed in accordance with traditional regulatory requirements, and the economic reward is limited if the use of new antibiotics is constrained. These challenges have resulted in an alarmingly thin antibiotic pipeline, despite the rapid and continued growth in the need for new drugs. Approaches that balance the quantity of data needed for registration with the unmet medical need would encourage work in this area. Therefore, a tiered regulatory framework that allows either disease-based or pathogen-based label indications is proposed, with label wording that promotes the most appropriate use of new agents. Such a framework is within the bounds of present regulatory approaches, is amenable to international harmonisation, and would be a welcome step towards the facilitation of a robust and sustainable discovery and development infrastructure.


Subject(s)
Anti-Bacterial Agents , Drug Approval/legislation & jurisprudence , Drug Evaluation , Anti-Bacterial Agents/pharmacology , Clinical Trials as Topic , Drug Resistance, Bacterial , Humans , Needs Assessment , United States
8.
Antimicrob Agents Chemother ; 56(6): 3086-91, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22450972

ABSTRACT

The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a ß-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Cephalosporins/adverse effects , Cephalosporins/pharmacology , Penicillanic Acid/analogs & derivatives , Administration, Oral , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Cephalosporins/administration & dosage , Dose-Response Relationship, Drug , Female , Half-Life , Humans , Male , Middle Aged , Penicillanic Acid/administration & dosage , Penicillanic Acid/adverse effects , Penicillanic Acid/pharmacokinetics , Tazobactam , Young Adult
9.
Antimicrob Agents Chemother ; 54(8): 3427-31, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20457817

ABSTRACT

CXA-101 is a novel, broad-spectrum cephalosporin with excellent antipseudomonal activity. A Phase 1 study was performed to determine the safety, tolerability, and pharmacokinetics of CXA-101 after single- and multiple-dose intravenous administration over 1 h to healthy male and female subjects. In part 1 of the study, five cohorts of eight subjects each (six receiving CXA-101 and two receiving a placebo) received single ascending doses of 250, 500, 1,000, 1,500, and 2,000 mg. In part 2, cohorts 1 and 2 received 500 mg and 1,000 mg, respectively, every 8 h, and cohort 3 received 1,500 mg every 12 h; each cohort received dosing for 10 days. Standard safety and tolerability assessments were performed. Blood and urine pharmacokinetic samples were assayed by a validated bioanalytical method and analyzed using standard noncompartmental methodology. All 64 subjects completed dosing; none withdrew from the study. Drug-related systemic adverse events were infrequent and mild. Mild, non-treatment-limiting infusion site events occurred during multiple-dose administration. No clinically significant laboratory or electrocardiographic finding or dose-limiting toxicity was observed. CXA-101 exhibited dose-linear pharmacokinetics; the mean plasma half-life was approximately 2.3 h. More than 90% of the administered dose was eliminated unchanged through renal excretion. In summary, CXA-101 administered as a 1-hour infusion was generally safe and well tolerated in single doses up to 2,000 mg and in multiple doses up to 3 g daily over 10 days. The favorable safety and predictable pharmacokinetic profile of CXA-101 support its continuing clinical development for the treatment of serious bacterial infections.


Subject(s)
Anti-Bacterial Agents , Cephalosporins , Adult , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacokinetics , Cephalosporins/administration & dosage , Cephalosporins/adverse effects , Cephalosporins/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Treatment Outcome
10.
Antimicrob Agents Chemother ; 54(5): 2119-24, 2010 May.
Article in English | MEDLINE | ID: mdl-20211892

ABSTRACT

The worldwide increase in fluoroquinolone-resistant and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae pathogens has led to doripenem and other carbapenems assuming a greater role in the treatment of serious infections. We analyzed data from 6 phase 3 multinational doripenem clinical trials on ciprofloxacin-resistant Enterobacteriaceae isolates consisting of all genera (CIPRE) and ESBL-producing Enterobacteriaceae isolates consisting of Escherichia coli, Klebsiella spp., and Proteus spp. with ceftazidime MICs of >or=2 microg/ml (ESBLE) for prevalence by geographic region and disease type, in vitro activities of doripenem and comparator agents, and clinical or microbiologic outcomes in doripenem- and comparator-treated patients across disease types (complicated intra-abdominal infection [cIAI], complicated urinary tract infection [cUTI], and nosocomial pneumonia [NP]). Of 1,830 baseline Enterobacteriaceae isolates, 88 (4.8%) were ESBLE and 238 (13.0%) were CIPRE. The incidence of ESBLE was greatest in Europe (7.8%); that of CIPRE was higher in South America (15.9%) and Europe (14.4%). ESBLE incidence was highest in NP (12.9%) cases; that of CIPRE was higher in cUTI (18.3%) and NP (14.9%) cases. Against ESBLE and CIPRE, carbapenems appeared more active than other antibiotic classes. Among carbapenems, doripenem and meropenem were most potent. Doripenem had low MIC(90)s for CIPRE (0.5 microg/ml) and ESBLE (0.25 microg/ml). Doripenem and comparators were highly clinically effective in infections caused by Enterobacteriaceae, irrespective of their ESBL statuses. The overall cure rates were the same for doripenem (82%; 564/685) and the comparators (82%; 535/652) and similar for ESBLE (73% [16/22] versus 72% [21/29]) and CIPRE (68% [47/69] versus 52% [33/64]). These findings indicate that doripenem is an important therapeutic option for treating serious infections caused by ESBLE and CIPRE.


Subject(s)
Carbapenems/therapeutic use , Ciprofloxacin/therapeutic use , Clinical Trials, Phase III as Topic/statistics & numerical data , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae/drug effects , beta-Lactam Resistance , Anti-Bacterial Agents/therapeutic use , Doripenem , Enterobacteriaceae Infections/epidemiology , Global Health , Microbial Sensitivity Tests , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/therapeutic use , Piperacillin/therapeutic use , Piperacillin, Tazobactam Drug Combination , Prevalence
11.
Drug Saf ; 32(9): 709-16, 2009.
Article in English | MEDLINE | ID: mdl-19670912

ABSTRACT

The seizure-inducing potential of carbapenems has been debated since the introduction of imipenem/cilastatin over 20 years ago. Doripenem is a new carbapenem, recently approved in the US for the treatment of adults with complicated urinary tract infections (cUTI) or complicated intra-abdominal infections (cIAI), and additionally in the EU for nosocomial pneumonia, including ventilator-associated pneumonia. Here, the seizure-inducing potential of doripenem is evaluated, using data from in vitro and in vivo animal studies, doripenem clinical trials and doripenem postmarketing reports of seizures. Animal studies indicate that doripenem has low binding affinity for GABA receptors and does not induce seizures at doses greater than seizure-inducing doses of imipenem or meropenem. In clinical studies of cUTI or cIAI, no seizures were reported in the 1332 patients treated with doripenem (500-mg infusion every 8 hours). In two studies, patients with nosocomial pneumonia were treated with doripenem 500 mg (1- or 4-hour infusion every 8 hours), and the incidence of seizures was lower for doripenem (1.2% [6/485]) than imipenem (3.8% [10/263]) or piperacillin/tazobactam (2.7% [6/221]). For patients with seizure-predisposing conditions, seizures occurred during treatment for 3/193 (1.5%) in doripenem, 1/66 (1.5%) in piperacillin/tazobactam and 6/116 (5.2%) in the imipenem group. The review of data from both clinical trials and postmarketing surveillance supports the low seizure-inducing potential of doripenem. The seizure potential of doripenem should be evaluated further in patients at increased risk for seizure.


Subject(s)
Anti-Bacterial Agents/adverse effects , Carbapenems/adverse effects , Seizures/chemically induced , Animals , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/complications , Bacterial Infections/drug therapy , Carbapenems/therapeutic use , Doripenem , Humans , Product Surveillance, Postmarketing , Randomized Controlled Trials as Topic , Seizures/epidemiology , Seizures/physiopathology , Young Adult
12.
Clin Ther ; 30(5): 868-83, 2008 May.
Article in English | MEDLINE | ID: mdl-18555934

ABSTRACT

BACKGROUND: Complicated intra-abdominal infections (cIAIs) require surgical intervention and empiric antibacterial therapy. Doripenem, a broad-spectrum carbapenem, provides coverage of key gram-negative and -positive aerobes and anaerobes encountered in cIAI. OBJECTIVE: This study was designed to compare the efficacy and safety profile of doripenem and meropenem in hospitalized adult patients with cIAI. METHODS: In this prospective, multicenter, doubleblind, noninferiority study, hospitalized adults with cIAI were randomly assigned to receive doripenem 500 mg IV q8h or meropenem 1 g IV q8h. After a minimum of 9 doses and adequate clinical improvement (relative to before the start of IV study drug, decreased body temperature and white blood cell count, improved or absent signs and symptoms of cIAI, and return of normal bowel function), patients could be switched to oral amoxicillin/clavulanate. Antibacterial therapy (IV plus subsequent oral) was given for a total of 5 to 14 days. The coprimary efficacy end points were the clinical cure rate (complete resolution or significant improvement of signs or symptoms of the index infection) in patients microbiologically evaluable (>or=1 baseline pathogen isolated from an intra-abdominal culture that was susceptible to both IV study drug therapies) at the test-of-cure (TOC) visit (21-60 days after the completion of study drug therapy) and the clinical cure rate in the microbiological modified intent-to-treat (mMITT) population (a bacterial pathogen identified at baseline, regardless of its susceptibility to the study drug). Noninferiority was concluded if the lower limit of the 2-sided 95% CI for the difference (doripenem minus meropenem) in the proportion of patients classified as clinical cures was >or=-15%. RESULTS: A total of 476 patients were enrolled. The microbiologically evaluable population (319 patients) was 62.7% male and 67.7% white, with a mean age and weight of 46.7 years and 77.2 kg, respectively. In this population, doripenem and meropenem were associated with clinical cure rates at the TOC visit of 85.9% and 85.3%, respectively. The corresponding treatment difference was 0.6% (95% CI, -7.7% to 9.0%); this difference was not statistically significant. Similarly, in the mMITT population (385 patients), the clinical cure rates were 77.9% and 78.9%, respectively, and the corresponding 1.0% treatment difference was not statistically significant (95% CI, -9.7% to 7.7%). Clinical cure rates were not significantly different between the 2 treatment arms in key subgroups (eg, age, sex, race, baseline Acute Physiology and Chronic Health Evaluation II score, primary infection site). Microbiological eradication rates for common pathogens isolated at study entry were not significantly different between the 2 treatment groups. Doripenem was well tolerated in the population studied. In the intent-to-treat population (471 patients), 83.0% and 78.0% of patients experienced >or=1 adverse event (AE) and 13.2% and 14.0% experienced >or=1 serious AE in the doripenem and meropenem treatment arms, respectively. In the doripenem and meropenem treatment arms, AEs resulted in study drug discontinuation in 5.1% and 2.1% of patients and death in 2.1% and 3.0% of patients, respectively. CONCLUSIONS: The present study found that doripenem (500 mg q8h) was effective in the treatment of cIAI, was therapeutically noninferior to meropenem (1 g q8h), with a safety profile not significantly different from that of meropenem in this selected population of patients with cIAI.


Subject(s)
Abdominal Abscess/drug therapy , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Carbapenems/therapeutic use , Thienamycins/therapeutic use , Abdominal Abscess/microbiology , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Bacterial Infections/microbiology , Carbapenems/administration & dosage , Carbapenems/adverse effects , Doripenem , Double-Blind Method , Female , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Humans , Injections, Intravenous , Male , Meropenem , Middle Aged , Prospective Studies , Thienamycins/administration & dosage , Thienamycins/adverse effects
13.
Curr Med Res Opin ; 24(7): 2113-26, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18549664

ABSTRACT

OBJECTIVE: Doripenem is a new carbapenem that has broad-spectrum activity against bacterial pathogens commonly responsible for nosocomial pneumonia (NP). It has several advantages over currently available carbapenems and other classes of drugs used in this indication. This prospective, randomized, open-label, multicenter study was designed to establish whether doripenem was noninferior to piperacillin/tazobactam in NP. METHODS: Adults (n=448) with signs and symptoms of NP, including non-ventilated patients and those ventilated for <5 days, were stratified by ventilation mode, illness severity (Acute Physiology and Chronic Health Evaluation II score), and geographic region and then randomly allocated to treatment with doripenem 500 mg every 8 h by a 1-h intravenous (IV) infusion or piperacillin/tazobactam 4.5 g every 6 h by 30-min IV infusion. After receiving IV study drug for at least 72 h, eligible patients could be switched to oral levofloxacin 750 mg once daily. Antibiotic therapy was continued for a total of 7-14 days. The primary endpoint was the clinical cure rate, assessed 7-14 days after treatment completion, in clinically evaluable patients and in the clinical modified intent-to-treat population (cMITT). TRIAL REGISTRATION: ClinicalTrials.gov, NCT00211003. RESULTS: Doripenem was noninferior to piperacillin/tazobactam. Clinical cure rates in clinically evaluable patients (n=253) were 81.3% in the doripenem arm and 79.8% in the piperacillin/tazobactam arm (between-treatment difference: 1.5%; 95% confidence interval [CI], -9.1 to 12.1%) and in the cMITT population 69.5% and 64.1%, respectively, (between-treatment difference: 5.4%; 95% CI, -4.1 to 14.8%). Baseline resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa to piperacillin/tazobactam was 44% and 26.9%, respectively; a doripenem minimum inhibitory concentration (MIC) >8 mug/mL occurred in 0% and 7.7%, respectively. Favorable microbiological outcome rates against Gram-negative pathogens were numerically higher with doripenem than with piperacillin/tazobactam, but the difference was not statistically significant. Both study drugs were generally well tolerated, as only 16.1% and 17.6% of patients receiving doripenem and piperacillin/tazobactam, respectively, had a drug-related adverse event. Study limitations included the open-label design, the low rate of monotherapy (adjunctive use of aminoglycoside was required when P. aeruginosa was suspected), and the exclusion of the most critically ill and immunocompromized patients. CONCLUSIONS: Doripenem was clinically and microbiologically effective in patents with NP, including those with early-onset ventilator-associated pneumonia, and was therapeutically noninferior to piperacillin/tazobactam.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Carbapenems/therapeutic use , Cross Infection/drug therapy , Penicillanic Acid/analogs & derivatives , Piperacillin/therapeutic use , Pneumonia, Bacterial/drug therapy , Adult , Aged , Aged, 80 and over , Bacteria/drug effects , Bacteria/isolation & purification , Cross Infection/microbiology , Doripenem , Female , Humans , Male , Middle Aged , Penicillanic Acid/therapeutic use , Prospective Studies , Tazobactam , Treatment Outcome
14.
Clin Ther ; 30(4): 717-33, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18498921

ABSTRACT

BACKGROUND: Ventilator-associated pneumonia (VAP) is a common nosocomial infection that is associated with prolonged length of stay (LOS) and significant mortality. OBJECTIVE: The aim of this study was to compare resource utilization with doripenem, an investigational carbapenem, versus imipenem from a hospital perspective among patients with VAP. METHODS: This analysis was based on data from a Phase III, randomized, open-label, noninferiority study that compared clinical cure of VAP with doripenem 500 mg q8h i.v. (4-hour infusion) with imipenem 500 mg q6h (30-minute infusion) or 1000 mg q8h i.v. (1-hour infusion). Total hospital LOS, intensive care unit (ICU) LOS, and time on mechanical ventilation for doripenem and imipenem were compared in a clinical modified intent-to-treat population. P values were determined using the generalized Wilcoxon test, which compared treatments in a time-to-event analysis, censoring patients at the late follow-up visit (28-35 days after the end of i.v. therapy). RESULTS: Patients in the doripenem and imipenem groups had similar baseline clinical characteristics. Median hospital LOS was significantly shorter with doripenem versus imipenem (22 vs 27 days; P=0.010); median time on mechanical ventilation was significantly shorter for doripenem (7 vs 10 days; P=0.034); median ICU LOSs were similar between the 2 groups (12 vs 13 days). Clinical cure and mortality rates were similar. CONCLUSIONS: Of the 3 primary end points in this analysis, hospital LOS and time on mechanical ventilation were significantly shorter with doripenem compared with imipenem; no statistical significance was observed in ICU LOS. These findings suggest that doripenem use may be associated with an economic and clinical benefit to patients and hospitals.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Carbapenems/therapeutic use , Hospital Costs/statistics & numerical data , Imipenem/therapeutic use , Pneumonia, Ventilator-Associated/drug therapy , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/economics , Carbapenems/administration & dosage , Carbapenems/economics , Costs and Cost Analysis , Doripenem , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Imipenem/administration & dosage , Imipenem/economics , Infusions, Intravenous , Length of Stay , Male , Middle Aged , Pneumonia, Ventilator-Associated/economics , Pneumonia, Ventilator-Associated/epidemiology , Survival Rate/trends , Treatment Outcome
15.
Crit Care Med ; 36(4): 1089-96, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18379232

ABSTRACT

OBJECTIVE: Doripenem is an investigational carbapenem with broad-spectrum activity against gram-negative and gram-positive pathogens, including multidrug-resistant strains, commonly responsible for ventilator-associated pneumonia (VAP). This large, phase III study compared doripenem with imipenem for the treatment of ventilator-associated pneumonia. DESIGN: Prospective, multicenter, parallel randomized, active-controlled, open-label study. SETTING: Intensive care units. PATIENTS: Adults (N = 531) who met clinical and radiologic criteria for ventilator-associated pneumonia. INTERVENTIONS: Patients were stratified by duration of mechanical ventilation (< 5 vs. > or = 5 days), severity of illness (Acute Physiology and Chronic Health Evaluation II score < or = 15 vs. > 15), and geographic region and then randomly assigned to doripenem 500 mg every 8 hrs via a 4-hr intravenous infusion or imipenem 500 mg every 6 hrs or 1000 mg every 8 hrs via 30- or 60-min intravenous infusions, respectively, for 7-14 days. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end points were the clinical cure rates in the clinical modified intent-to-treat (cMITT) and clinically evaluable populations. Doripenem was noninferior to imipenem (lower boundary of 95% confidence interval around the difference between treatments > or = -20%). Clinical cure rates were 68.3% (doripenem) and 64.2% (imipenem) in the clinically evaluable and 59.0% (doripenem) and 57.8% (imipenem) in the cMITT populations. In patients with Pseudomonas aeruginosa, clinical cure was 80.0% (doripenem) and 42.9% (imipenem) (p not significant); microbiological cure was 65.0% (doripenem) and 37.5% (imipenem). Only 18% (5 of 28) of P. aeruginosa isolates had minimum inhibitory concentration > or = 8 microg/mL at baseline or following therapy in the doripenem arm compared with 64% (16 of 25) in the imipenem treatment group (p = .001). Clinical cure rate was higher with doripenem than imipenem at higher Acute Physiology and Chronic Health Evaluation II scores and older ages. Doripenem was generally well tolerated. CONCLUSIONS: In this large, phase III study of patients with ventilator-associated pneumonia, a 4-hr intravenous infusion of doripenem was clinically efficacious and therapeutically noninferior to imipenem.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Carbapenems/therapeutic use , Imipenem/therapeutic use , Pneumonia, Ventilator-Associated/drug therapy , APACHE , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Carbapenems/administration & dosage , Carbapenems/adverse effects , Doripenem , Female , Hospital Mortality , Humans , Imipenem/administration & dosage , Imipenem/adverse effects , Infusions, Intravenous , Male , Microbial Sensitivity Tests , Middle Aged , Pneumonia, Ventilator-Associated/classification , Pneumonia, Ventilator-Associated/microbiology , Treatment Outcome
16.
Diagn Microbiol Infect Dis ; 58(4): 491-4, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17509789

ABSTRACT

The impact of different antimicrobial regimens for intra-abdominal infections on the frequency of bowel colonization with vancomycin-resistant enterococci (VRE) was examined in 2 randomized open-label trials of intra-abdominal infection comparing piperacillin-tazobactam or ceftriaxone/metronidazole with ertapenem. In these short-term studies, overall rates of bowel colonization with VRE were generally comparable after treatment with piperacillin-tazobactam, ceftriaxone/metronidazole, or ertapenem.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Enterococcus/drug effects , Enterococcus/growth & development , Gram-Positive Bacterial Infections/microbiology , Intestines/microbiology , Vancomycin Resistance , beta-Lactams/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Enterococcus/isolation & purification , Ertapenem , Female , Humans , Male , Middle Aged
17.
Surg Infect (Larchmt) ; 6(4): 439-48, 2005.
Article in English | MEDLINE | ID: mdl-16433608

ABSTRACT

BACKGROUND: The Study for Monitoring Antimicrobial Resistance Trends (SMART) was begun in 2002 to monitor international drug-resistance patterns among aerobic and facultative gram-negative bacilli isolated from patients with intra-abdominal infections. METHODS: In 2002, 40 medical centers from 17 countries collected consecutive non-duplicate isolates from intra-abdominal infections for susceptibility testing against 12 antimicrobial agents using the broth microdilution methods recommended by the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards). RESULTS: A total of 3,134 aerobic and facultative gram-negative bacilli were isolated. Enterobacteriaceae accounted for 82% of the total and were most consistently susceptible to amikacin and the carbapenems. Escherichia coli (45%) and Klebsiella spp. (17%) were the most common species. The susceptibility rates of these organisms to the 12 antimicrobial agents differed among geographic regions, with isolates from the Asia/Pacific and Latin American regions usually having the highest rates of resistance. Ampicillin/sulbactam was the agent least frequently active against E. coli (56% susceptible) and Klebsiella spp. (73% susceptible). Extended-spectrum beta-lactamases (ESBLs) were detected phenotypically in 7% of E. coli, 13% of Klebsiella spp., and 18% of Enterobacter spp. Producers of ESBL overall had a more antibiotic-resistant profile than non-producers but were usually susceptible to carbapenems. CONCLUSIONS: Antimicrobial resistance rates among gram-negative bacilli isolated from intra-abdominal infections differed among geographic regions. The carbapenems were consistently active in vitro against Enterobacteriaceae worldwide, including ESBL producers.


Subject(s)
Abdomen/microbiology , Bacteria, Aerobic/drug effects , Drug Resistance, Bacterial , Enterobacteriaceae/drug effects , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/microbiology , Anti-Bacterial Agents/pharmacology , Enterobacteriaceae/enzymology , Gram-Negative Bacteria/enzymology , Humans , Microbial Sensitivity Tests/methods , beta-Lactamases/metabolism
18.
Pulm Pharmacol Ther ; 17(4): 199-203, 2004.
Article in English | MEDLINE | ID: mdl-15219264

ABSTRACT

This report describes a post-hoc analysis of two large studies of typical community-acquired pneumonia (CAP) in hospitalized patients, focusing on demographics, disease characteristics, and outcome in patients with and without chronic obstructive pulmonary disease (COPD). In both studies, ertapenem 1 g IV daily was compared with ceftriaxone 1 g IV daily as initial antimicrobial therapy. Clinically improving patients could be switched to oral antibiotic therapy after 3 days. Of the 857 patients treated in both studies, 264 (31%) had COPD. The proportions of patients who were male, were >/=65 years of age, had a Pneumonia Severity Index of IV/V, or had Haemophilus influenzae isolated in a baseline culture were higher in patients with COPD. Streptococcus pneumoniae was the most common pathogen both in patients with and without COPD. Clinical response rates in assessable patients 7-14 days after completion of therapy for the combined treatment groups were 90% (187/208) for patients with COPD and 93% (424/456) for those without COPD (odds ratio 0.7 [95% CI, 0.4-1.2], P = 0.17). Of assessable COPD patients, 109/121 (90%) treated with ertapenem and 78/87 (90%) treated with ceftriaxone achieved a favorable clinical response (odds ratio 1.0 [95% CI, 0.6-1.8], P = 0.94). The outcome in patients with or without COPD was similar regardless of therapy. In patients with COPD as well as in the overall study population, the efficacy of ertapenem as initial antimicrobial monotherapy for patients with serious typical community-acquired pneumonia was comparable to that of ceftriaxone.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Lactams/therapeutic use , Pneumonia, Bacterial/drug therapy , Pulmonary Disease, Chronic Obstructive/drug therapy , Adult , Aged , Aged, 80 and over , Ceftriaxone/therapeutic use , Community-Acquired Infections/complications , Community-Acquired Infections/drug therapy , Drug Therapy, Combination , Enterobacteriaceae , Ertapenem , Female , Haemophilus influenzae , Hospitalization , Humans , Injections, Intravenous , Male , Middle Aged , Pneumonia, Bacterial/complications , Pulmonary Disease, Chronic Obstructive/complications , Randomized Controlled Trials as Topic , Streptococcus pneumoniae , Treatment Outcome , beta-Lactams
19.
J Antimicrob Chemother ; 53 Suppl 2: ii59-66, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15150184

ABSTRACT

The efficacy and safety of ertapenem, 1 g once a day, for the treatment of community-acquired pneumonia (CAP) requiring parenteral therapy were compared with those of ceftriaxone, 1 g once a day, in 866 hospitalized adults randomized in two prospective, double-blind, multicentre studies. Patients were stratified according to Pneumonia Severity Index (< or = 3 or >3) or age (< or = 65 or >65 years). After > or = 3 days of parenteral antimicrobial therapy, patients who had clinically improved could be switched to oral co-amoxiclav. The median durations of parenteral, oral and total therapy in the 658 clinically evaluable patients, of whom 88% were switched to oral therapy, were 4, 7 and 12 days, respectively, in both treatment groups. The most common pathogen was Streptococcus pneumoniae, of which 79% (143/181) were penicillin susceptible and 3.3% (6/181; three in each treatment group) were penicillin resistant. Cure rates for the two treatments were equivalent: 91.9% for ertapenem and 92.0% for ceftriaxone (95% confidence interval for the difference, adjusted for strata: -4.5 to 4.4). Cure rates in the different severity and age strata and bacterial eradication rates for both treatment groups were also similar. The most common drug-related adverse events in both treatment groups were diarrhoea and mild-to-moderate elevations in aminotransferase levels. The results of these studies demonstrate that ertapenem, 1 g once a day, was highly effective therapy for CAP in hospitalized adults with moderate-to-severe disease.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Ceftriaxone/therapeutic use , Lactams/therapeutic use , Adolescent , Adult , Aged , Anti-Bacterial Agents/adverse effects , Ceftriaxone/adverse effects , Child , Child, Preschool , Community-Acquired Infections/drug therapy , Community-Acquired Infections/microbiology , Double-Blind Method , Ertapenem , Female , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/isolation & purification , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/isolation & purification , Humans , Lactams/adverse effects , Male , Middle Aged , Pneumonia, Bacterial/drug therapy , Pneumonia, Bacterial/microbiology , Treatment Outcome , beta-Lactams
20.
J Antimicrob Chemother ; 53 Suppl 2: ii75-81, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15150186

ABSTRACT

Ertapenem is a Group 1 carbapenem that was licensed in the USA in November 2001 and in Europe in April 2002. Its safety profile has been assessed in 240 healthy volunteers participating in 12 clinical pharmacology studies and in 2046 patients enrolled in five Phase IIa and eight Phase IIb/III clinical trials. The most common drug-related adverse events (AEs) reported in trials comparing ertapenem and piperacillin-tazobactam and in trials comparing ertapenem and ceftriaxone were: diarrhoea (ertapenem versus piperacillin-tazobactam 5.0% versus 7.0%; ertapenem versus ceftriaxone 5.6% versus 5.9%); infused vein complications (ertapenem versus piperacillin-tazobactam 4.5% versus 7.9%; ertapenem versus ceftriaxone 3.2% versus 4.6%); nausea (ertapenem versus piperacillin-tazobactam 2.5% versus 3.4%; ertapenem versus ceftriaxone 3.4% versus 3.3%); and elevations in alanine aminotransferase levels (ertapenem versus piperacillin-tazobactam 8.8% versus 7.3%; ertapenem versus ceftriaxone 8.3% versus 6.9%). Most ertapenem-related AEs were reported as mild-to-moderate in intensity. Ertapenem was not associated with prolongation of the QTc interval. Local reactions of moderate-to-severe intensity at the infusion site were infrequent and occurred with similar frequency in the ertapenem and comparator treatment groups. No overall differences in safety were observed between elderly (aged > or = 65 years and > or = 75 years) and younger patients. Ertapenem, 1 g once a day given by intravenous infusion or intramuscular injection, was generally well tolerated and had overall safety and tolerability profiles similar to those of piperacillin-tazobactam and ceftriaxone.


Subject(s)
Anti-Bacterial Agents/adverse effects , Bacterial Infections/drug therapy , Clinical Trials as Topic , Community-Acquired Infections/drug therapy , Lactams/adverse effects , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Bacteria, Aerobic/drug effects , Bacteria, Anaerobic/drug effects , Bacterial Infections/microbiology , Ceftriaxone/administration & dosage , Ceftriaxone/adverse effects , Ceftriaxone/therapeutic use , Community-Acquired Infections/microbiology , Ertapenem , Female , Humans , Lactams/administration & dosage , Lactams/therapeutic use , Male , Middle Aged , Penicillanic Acid/administration & dosage , Penicillanic Acid/adverse effects , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/therapeutic use , Piperacillin/administration & dosage , Piperacillin/adverse effects , Piperacillin/therapeutic use , Piperacillin, Tazobactam Drug Combination , Randomized Controlled Trials as Topic , beta-Lactams
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