RESUMEN
BACKGROUND AND OBJECTIVE: Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). METHODS: Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cleff) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. RESULTS: HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (ß = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (ß = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cleff for each antibiotic (meropenem ß = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (ß = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (ß = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cleff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (ß = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (ß = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. CONCLUSION: MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.
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Antibacterianos , Terapia de Reemplazo Renal Continuo , Estudios Cruzados , Meropenem , Diálisis Renal , Choque Séptico , Humanos , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Choque Séptico/terapia , Choque Séptico/tratamiento farmacológico , Choque Séptico/sangre , Proyectos Piloto , Terapia de Reemplazo Renal Continuo/métodos , Diálisis Renal/métodos , Meropenem/uso terapéutico , Meropenem/administración & dosificación , Meropenem/farmacocinética , Tazobactam/uso terapéutico , Tazobactam/farmacocinética , Piperacilina/farmacocinética , Piperacilina/uso terapéutico , Piperacilina/administración & dosificación , Hemodiafiltración/métodosRESUMEN
BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia. OBJECTIVES: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam. METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens. RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies. CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.
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Antibacterianos , Cefalosporinas , Combinación de Medicamentos , Bacterias Gramnegativas , Inhibidores de beta-Lactamasas , beta-Lactamas , Humanos , Inhibidores de beta-Lactamasas/farmacocinética , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/farmacología , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapéutico , beta-Lactamas/farmacología , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapéutico , Cefalosporinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Tazobactam/farmacocinética , Tazobactam/uso terapéutico , Tazobactam/farmacología , Neumonía Bacteriana/tratamiento farmacológico , Compuestos de Azabiciclo/farmacocinética , Compuestos de Azabiciclo/uso terapéutico , Compuestos de Azabiciclo/farmacología , Carbapenémicos/farmacocinética , Carbapenémicos/uso terapéutico , Carbapenémicos/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Ceftazidima/farmacocinética , Ceftazidima/uso terapéutico , Cefiderocol , Meropenem/farmacocinética , Meropenem/uso terapéutico , Meropenem/farmacología , Imipenem/farmacocinética , Imipenem/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Combinación Cilastatina e Imipenem/farmacocinética , Combinación Cilastatina e Imipenem/uso terapéutico , Ácidos Borónicos , Compuestos Heterocíclicos con 1 AnilloRESUMEN
OBJECTIVES: To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MICâ≥â4 mg/L). METHODS: An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h. RESULTS: Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5-4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin. CONCLUSIONS: The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint.
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Fosfomicina , Infecciones por Pseudomonas , Humanos , Pseudomonas aeruginosa , Tobramicina/farmacología , Tobramicina/uso terapéutico , Fosfomicina/farmacología , Fosfomicina/uso terapéutico , Antibacterianos/uso terapéutico , Cefalosporinas/uso terapéutico , Tazobactam/farmacocinética , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiologíaRESUMEN
Ceftolozane-tazobactam (C/T) recommended dosing in patients undergoing renal replacement therapies (RRT) is lacking evidence. The objective of this study was to evaluate the clinical outcomes of C/T dosing in patients on RRT. MATERIALS AND METHODS: A retrospective descriptive study conducted at our institution between May 1, 2017, and March 15, 2022. The primary endpoint was to determine the clinical cure for patients who received C/T for documented infection while on RRT. The secondary endpoints were the microbiologic cure, 30-day infection recurrence, and 30-day crude mortality. RESULTS: Of the 27 patients who met the inclusion criteria, 17 (63%) were males, median age was 69 (62 - 82) years, and weight 67 (57 - 79) kg. The majority of patients had pneumonia 19 (70.4%) followed by bacteremia 5 (18.5%). Multidrug resistant Pseudomonas spp. was the causative organism of infection in 22 subjects (81.5%). Clinical cure was achieved in 17 subjects (63%). Of the 14 subjects who had their culture repeated, 10 (71.4%) patients had microbiologic cure vs. 4 (28.5%) patients who had a microbiologic failure (p = 0.327). 30-day infection recurrence occurred in 6 (35.3%) patients of the clinical cure group and 2 (20%) patients in the clinical failure group (p = 0.362), while mortality occurred in 5 (29.4%) subjects vs. 7 (70%) in both groups, respectively (p = 0.049). The most frequently used doses of C/T were 1.5 g IV q8h while undergoing continuous venovenous hemodiafiltration and 0.75 g IV q8h while undergoing hemodialysis (p = 0.209). The median duration of therapy was 9 (4.5 - 13) days in the clinically cured group vs. 5 (3.75 - 5.5) days in those who had clinical failure (p = 0.038). There was no adverse event reported using these doses during the study period. CONCLUSION: The used doses of C/T in this study were higher than those approved by the U.S. FDA, while clinical success is uncertain. Larger outcomes and pharmacokinetics studies are needed to establish effective dosing and therapy duration.
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Bacteriemia , Terapia de Reemplazo Renal Continuo , Masculino , Humanos , Anciano , Femenino , Antibacterianos/uso terapéutico , Estudios Retrospectivos , Tazobactam/farmacocinética , Tazobactam/uso terapéutico , Bacteriemia/tratamiento farmacológicoRESUMEN
Probability of target attainment (PTA) analyses were conducted to support the recommended ceftolozane/tazobactam dosing regimens, adjusted for renal function, in patients with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Previously published population pharmacokinetic models describing the disposition of ceftolozane and tazobactam in plasma and epithelial lining fluid (ELF) in patients with HABP/VABP were used to simulate ceftolozane and tazobactam concentration-time profiles in plasma and ELF over the course of 14 days. The simulations were conducted for patients with normal renal function and for patients receiving adjusted doses for mild, moderate, and severe renal impairment. PTA was calculated using established pharmacokinetic/pharmacodynamic targets for ceftolozane and tazobactam. Across renal function groups, plasma PTA was 100% for ceftolozane and >99% for tazobactam; ELF PTA was >99% for ceftolozane and >87% for tazobactam. These results provided support for the currently recommended ceftolozane/tazobactam dosing regimens for HABP/VABP, which were efficacious and well tolerated in the Ceftolozane-Tazobactam Versus Meropenem for Treatment of Nosocomial Pneumonia (ASPECT-NP) trial.
Asunto(s)
Neumonía Bacteriana , Neumonía Asociada al Ventilador , Humanos , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Bacterias , Cefalosporinas , Hospitales , Pruebas de Sensibilidad Microbiana , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Asociada al Ventilador/tratamiento farmacológico , Tazobactam/farmacocinética , Tazobactam/uso terapéutico , Ventiladores MecánicosRESUMEN
OBJECTIVES: To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen for critically ill adult patients. METHODS: Population PK models for piperacillin/tazobactam were developed using a non-linear mixed effect modelling approach. The percentage of time within 24â h for which the free concentration exceeded the MIC at a steady-state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function were explored using Monte-Carlo simulation. RESULTS: A total of 226 plasma samples from 38 patients were used to develop a population PK model. Piperacillin/tazobactam PK was best described by two-compartment models, in which estimated glomerular filtration rate (eGFR), calculated using CKD-EPI equation based on cystatin C level, was a significant covariate for total clearance of each piperacillin and tazobactam. ECMO use decreased the central volume of distribution of both piperacillin and tazobactam in critically ill patients. Patients with Escherichia coli or Klebsiella pneumoniae infection, but not those with Pseudomonas aeruginosa infection, exhibited a PK/pharmacodynamic target attainment >90% when the target is 50%fT>MIC, as a result of applying the currently recommended dosage regimen. Prolonged or continuous infusion of 16â g/day was required when the treatment goal was 100%fT>MIC or 100%fT>4×MIC, and patients had an eGFR of 130-170â mL/min/1.73â m2. CONCLUSIONS: ECMO use decreases piperacillin/tazobactam exposure. Prolonged or continuous infusion can achieve the treatment target in critically ill patients, particularly when MIC is above 8â mg/L or when patients have an eGFR of 130-170â mL/min/1.73â m2.
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Enfermedad Crítica , Oxigenación por Membrana Extracorpórea , Adulto , Antibacterianos/farmacología , Enfermedad Crítica/terapia , Humanos , Pruebas de Sensibilidad Microbiana , Ácido Penicilánico/farmacocinética , Piperacilina/farmacocinética , Combinación Piperacilina y Tazobactam/farmacocinética , República de Corea , Tazobactam/farmacocinéticaRESUMEN
The pharmacokinetics of ceftolozane-tazobactam (TOL-TAZ) and ceftazidime-avibactam (CEF-AVI) is influenced by renal function. Application of recommended dosages in patients with renal impairment requires the use of fractions of the full dose, as only one dosage is available for both antibiotics. The objective of this study was to evaluate the adequacy of alternative dosage regimens based on the full dose. We performed pharmacokinetic/pharmacodynamic (PK/PD) simulations of recommended and alternative dosage regimens in patients with various degrees of renal impairment by using the Pmetrics program. Alternative regimens included longer dosage interval and prolonged infusions of the full dose for both drugs. Probabilities of target attainment (PTA) were assessed considering PK/PD targets defined for cephalosporins and beta-lactamase inhibitors as well as MIC breakpoints. The risk of overexposure was also assessed. Results showed that alternative dosage regimens based on a full dose of TOL-TAZ and CEF-AVI administered every 12 or 24 h were associated with PTA similar to that of recommended dosages, especially when administered as prolonged infusion. The alternative dosage regimens were not associated with overexposure in most cases. In addition, those regimens could reduce dosing errors, drug cost, and nurse labor. Clinical investigation ovf those alternative dosage regimens would be required before implementation.
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Ceftazidima , Cefalosporinas , Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacocinética , Compuestos de Azabiciclo/uso terapéutico , Ceftazidima/farmacocinética , Ceftazidima/uso terapéutico , Cefalosporinas/farmacocinética , Análisis Costo-Beneficio , Combinación de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Tazobactam/farmacocinética , Tazobactam/uso terapéuticoRESUMEN
Critical illness and extracorporeal circulation, such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), may alter the pharmacokinetics of piperacillin-tazobactam. We aimed to develop a population pharmacokinetic model of piperacillin-tazobactam in critically ill patients during ECMO or CRRT and investigate the optimal dosage regimen needed to achieve ≥90% of patients attaining the piperacillin pharmacodynamic target of 100% of dosage time above MIC of 16 mg/L. This prospective observational study included 26 ECMO patients, of which 13 patients received continuous venovenous hemodiafiltration (CVVHDF). A population pharmacokinetic model was developed using nonlinear mixed-effects models, and Monte Carlo simulations were performed to evaluate creatinine clearance (CrCL) and infusion method in relation to the probability of target attainment (PTA) in four patient groups according to combination of ECMO and CVVHDF. A total of 244 plasma samples were collected. In a two-compartment model, clearance decreased during ECMO and CVVHDF contributed to an increase in the volume of distribution. The range of PTA reduction as CrCL increased was greater in the order of intermittent bolus, extended infusion, and continuous infusion method. Continuous infusion should be considered in critically ill patients with CrCL of ≥60 mL/min, and at least 12, 16, and 20 g/day was required for CrCL of <40, 40 to 60, and 60 to 90 mL/min, respectively, regardless of ECMO or CVVHDF. In patients with CrCL of ≥90 mL/min, even a continuous infusion of 24 g/day was insufficient to achieve adequate PTA. Therefore, further research on permissible high continuous infusion dose focused on the risk of toxicity is required. (This trial has been registered at ClinicalTrials.gov under registration no. NCT02581280, December 1, 2014.) IMPORTANCE To the best of our knowledge, this is the first large prospective pharmacokinetic/pharmacodynamic (PK/PD) study of piperacillin-tazobactam in ECMO patients. We used piperacillin-tazobactam plasma concentration data from four different cases (concomitant use of ECMO and CVVHDF, receiving ECMO only, weaned from ECMO and receiving CVVHDF, and weaned from ECMO and not receiving CVVHDF) to provide preliminary insights into the incremental effects of critical illness, ECMO, and CVVHDF on PK. Our analysis revealed that volume of distribution increased in patients on CVVHDF and clearance decreased during ECMO and as creatinine clearance was reduced. When targeting 100% fT>MIC (16 mg/L, clinical breakpoint for Pseudomonas aeruginosa), continuous infusions would have achieved the highest percentage of target attainment compared to intermittent bolus or extended infusion if the total daily dose was the same. Continuous infusion should be considered in critically ill patients with creatinine clearance of ≥60 mL/min, regardless of ECMO or CVVHDF.
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Antibacterianos/farmacocinética , Enfermedad Crítica/terapia , Infección Hospitalaria/tratamiento farmacológico , Oxigenación por Membrana Extracorpórea/efectos adversos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Piperacilina/farmacocinética , Terapia de Reemplazo Renal/efectos adversos , Tazobactam/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Terapia Combinada , Creatinina/sangre , Infección Hospitalaria/sangre , Infección Hospitalaria/etiología , Infección Hospitalaria/microbiología , Femenino , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/fisiología , Infecciones por Bacterias Gramnegativas/sangre , Infecciones por Bacterias Gramnegativas/etiología , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Masculino , Persona de Mediana Edad , Piperacilina/uso terapéutico , Estudios Prospectivos , Tazobactam/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. METHODS: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. RESULTS: A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [- 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; - 2.6 [- 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; - 2.1 [- 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [- 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [- 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [- 8.7 to 19.0]). CONCLUSIONS: C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.
Asunto(s)
Cefalosporinas , Neumonía Bacteriana , Neumonía Asociada al Ventilador , Insuficiencia Renal , Tazobactam , Adulto , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapéutico , Método Doble Ciego , Humanos , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Asociada al Ventilador/tratamiento farmacológico , Probabilidad , Insuficiencia Renal/complicaciones , Tazobactam/farmacocinética , Tazobactam/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection. METHODS: ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 µg/mL for ceftolozane and time that the unbound concentration exceeded the 1 µg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated. RESULTS: Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (Vss) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and Vss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate. CONCLUSIONS: In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. CLINICALTRIALS. GOV IDENTIFIER: NCT02387372.
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Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Insuficiencia Renal/patología , Tazobactam/farmacocinética , Tazobactam/uso terapéutico , Adulto , Antibacterianos/efectos adversos , Cefalosporinas/efectos adversos , Enfermedad Crítica , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Prospectivos , Pseudomonas aeruginosa/efectos de los fármacos , Tazobactam/efectos adversos , Adulto JovenRESUMEN
Ceftolozane/tazobactam (C/T) is a combination of a novel cephalosporin with tazobactam, recently approved for the treatment of hospital-acquired and ventilator-associated pneumonia. The plasma pharmacokinetics (PK) of a 3-g dose of C/T (2 g ceftolozane and 1 g tazobactam) administered via a 1-hour infusion every 8 hours in adult patients with nosocomial pneumonia (NP) were evaluated in a phase 3 study (ASPECT-NP; NCT02070757). The present work describes the development of population PK models for ceftolozane and tazobactam in plasma and pulmonary epithelial lining fluid (ELF). The concentration-time profiles of both agents were well characterized by 2-compartment models with zero-order input and first-order elimination. Consistent with the elimination pathway, renal function estimated by creatinine clearance significantly affected the clearance of ceftolozane and tazobactam. The central volumes of distribution for both agents and the peripheral volume of distribution for tazobactam were approximately 2-fold higher in patients with pneumonia compared with healthy participants. A hypothetical link model was developed to describe ceftolozane and tazobactam disposition in ELF in healthy participants and patients with pneumonia. Influx (from plasma to the ELF compartment) and elimination (from the ELF compartment) rate constants were approximately 97% lower for ceftolozane and 52% lower for tazobactam in patients with pneumonia versus healthy participants. These population PK models adequately described the plasma and ELF concentrations of ceftolozane and tazobactam, thus providing a foundation for further modeling and simulation, including the probability of target attainment assessments to support dose recommendations of C/T in adult patients with NP.
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Antibacterianos/farmacocinética , Líquido del Lavado Bronquioalveolar/química , Cefalosporinas/farmacocinética , Plasma/química , Neumonía Asociada al Ventilador/tratamiento farmacológico , Tazobactam/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Peso Corporal , Cefalosporinas/uso terapéutico , Creatinina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tazobactam/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVE: New treatments are needed for multidrug-resistant (MDR) gram-negative infections in neonates. Ceftolozane/tazobactam is a ß-lactam/ß-lactamase inhibitor combination that has broad-spectrum activity against most common gram-negative bacteria, including MDR strains. We evaluated pharmacokinetics (PK) and safety of ceftolozane/tazobactam in term and premature neonates and young infants. STUDY DESIGN: This is a subgroup analysis of a phase 1, noncomparative, open-label, multicenter study that characterized the PK, safety, and tolerability of a single intravenous (IV) dose of ceftolozane/tazobactam in pediatric patients with proven/suspected gram-negative infection or receiving perioperative prophylaxis. RESULTS: Seven patients were enrolled in Group A (birth [7 days postnatal] to < 3 months, > 32 weeks gestation) and six patients were enrolled in Group B (birth [7 days postnatal] to < 3 months, ≤ 32 weeks gestation). PK profiles in neonates and young infants were generally comparable to those of older children receiving a single IV dose of ceftolozane/tazobactam. No serious adverse events (AEs), treatment-related AEs, severe AEs, or clinically significant laboratory abnormalities were reported. CONCLUSION: Among term and premature neonates and young infants, PK was comparable to older children and ceftolozane/tazobactam was generally well tolerated. An adaptable and flexible study design is necessary for enrollment in neonatal PK trials.
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Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Tazobactam/farmacocinética , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Cefalosporinas/efectos adversos , Cefalosporinas/uso terapéutico , Niño , Ensayos Clínicos como Asunto/métodos , Farmacorresistencia Bacteriana Múltiple , Femenino , Infecciones por Bacterias Gramnegativas/prevención & control , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Inyecciones Intravenosas , Masculino , Cuidados Preoperatorios , Tazobactam/efectos adversos , Tazobactam/uso terapéuticoRESUMEN
The purpose of this work was to develop and validate a single sensitive, selective and rapid bioanalytical method to determine ceftolozane and tazobactam concentrations in human plasma and urine and to use this method to analyze samples from a human clinical study. Human plasma and urine samples were prepared by protein precipitation using a solution of acetonitrile, water and formic acid. Following protein precipitation, samples were analyzed by liquid chromatography tandem mass spectrometry. Chromatographic resolution was achieved on a Kinetex PFP column using a gradient elution, a flow rate of 0.4 mL/min, and a total run time of 5 min. Positive electrospray ionization was employed and analytes were quantitated using multi-reaction monitoring mode. Method validation was conducted in accordance with Unites States Food and Drug Administration's regulatory guidelines for bioanalytical method validation. Calibration curves were determined to linear over the range of 0.1 to 40 µg/mL for ceftolozane and 0.05 to 20 µg/mL for tazobactam. The method was determined to be accurate (-6.24 to 12.53 percent relative error), precise (less than 13.28 percent standard deviation) and sensitive in both human plasma and urine. Ceftolozane and tazobactam were determined to be stable across a battery of stability studies including autosampler, benchtop, freeze/thaw and long-term stability. This validated method successfully applied to human clinical samples to determine the concentration versus time profiles of the intravenously administered combination of Zerbaxa (ceftolozane-tazobactam) in burn patients.
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Cefalosporinas , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Tazobactam , Cefalosporinas/administración & dosificación , Cefalosporinas/sangre , Cefalosporinas/farmacocinética , Cefalosporinas/orina , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Tazobactam/administración & dosificación , Tazobactam/sangre , Tazobactam/farmacocinética , Tazobactam/orinaRESUMEN
BACKGROUND: The antipseudomonal cephalosporin/ß-lactamase inhibitor combination ceftolozane/tazobactam could be a potential treatment option for cystic fibrosis (CF) pulmonary exacerbations. The pharmacokinetics (PK) of ceftolozane/tazobactam in children with CF merits further evaluation. METHODS: This is a retrospective subgroup analysis of a phase 1, noncomparative trial that characterized PK, safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients. This analysis compares ceftolozane and tazobactam plasma PK parameters, estimated from a population PK model, between patients with and without CF enrolled in that trial. Individual attainment of PK/pharmacodynamic (PD) targets of ceftolozane and tazobactam (free ceftolozane concentration >4 µg/mL for >30% and free tazobactam concentration >1 µg/mL for 20% of the dosing interval) in patients with and without CF were evaluated. RESULTS: The study enrolled 18 patients aged greater than or equal to 2 to less than 18 years old, which included 9 with CF. Weight-normalized ceftolozane PK parameters were similar between patients with CF (clearance: 0.16 L/h/kg, half-life: 1.54 hours, volume of distribution: 0.26 L/kg) and without CF (clearance: 0.15 L/h/kg, half-life: 1.62 hours, volume of distribution: 0.26 L/kg), as were most weight-normalized tazobactam PK parameters. Weight-normalized tazobactam clearance was higher in patients with CF (0.73 L/h/kg) than patients without CF (0.42 L/h/kg). All patients achieved the prespecified PK/PD targets for ceftolozane and tazobactam. CONCLUSIONS: This retrospective analysis demonstrated generally similar weight-normalized plasma PK parameters for ceftolozane and tazobactam among children with and without CF; thus, projected doses for treatment of pediatric hospital-acquired/ventilator-associated pneumonia, which are higher than the pediatric complicated urinary tract infection/intra-abdominal infection doses, may be appropriate for treatment of CF pulmonary exacerbation.
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Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Fibrosis Quística/sangre , Infecciones por Bacterias Gramnegativas/sangre , Tazobactam/farmacocinética , Administración Intravenosa , Adolescente , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Cefalosporinas/sangre , Cefalosporinas/uso terapéutico , Niño , Preescolar , Fibrosis Quística/tratamiento farmacológico , Femenino , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Masculino , Tazobactam/sangre , Tazobactam/uso terapéuticoRESUMEN
Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. Colistin has been the only treatment available for these infections for many years, but its results are suboptimal. Ceftolozane-tazobactam (C/T) is a newly available therapeutic option that has shown good antipseudomonal activity, even against a number of XDR P. aeruginosa strains. However, data about combinations containing C/T are scarce. The aim of this study was to analyze the activity of C/T and colistin alone and in combination against a collection of XDR P. aeruginosa strains containing 24 representative clinical isolates from a multicentre Spanish study. Twenty-four time-kill experiments performed over 24 h were conducted in duplicate to determine the effects of colistin and C/T alone and combined. An in vitro pharmacodynamic chemostat model then was used to validate this combination against three selected XDR P. aeruginosa ST175 isolates with different susceptibility levels to C/T. Static time-kill assays demonstrated superior synergistic or additive effect for C/T plus colistin against 21 of the 24 isolates studied. In the in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model, the C/T regimen of 2/1 g every 8 h with a steady-state concentration of 2 mg/liter colistin effectively suppressed the bacterial growth at 24 h. Additive or synergistic interactions were observed for C/T plus colistin against XDR P. aeruginosa strains and particularly against C/T-resistant strains. C/T plus colistin may be a useful treatment for XDR P. aeruginosa infections, including those caused by high risk-clones resistant to C/T.
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Antibacterianos/farmacología , Cefalosporinas/farmacología , Colistina/farmacología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/efectos de los fármacos , Tazobactam/farmacología , Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Colistina/farmacocinética , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Biológicos , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/crecimiento & desarrollo , Tazobactam/farmacocinética , Resistencia betalactámica/efectos de los fármacosRESUMEN
OBJECTIVES: To determine the oxygenator impact on alterations of ceftolozane/tazobactam in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation circuit including the Quadrox-i oxygenator (Maquet, Wayne, NJ). DESIGN: A 1/4-inch and 3/8-inch, simulated closed-loop extracorporeal membrane oxygenation circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of ceftolozane/tazobactam was administered into the circuits and serial preoxygenator and postoxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, and 24-hour time points. Ceftolozane/tazobactam was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation SETTING:: A free-standing extracorporeal membrane oxygenation circuit. PATIENTS: None. INTERVENTIONS: Single-dose administration of ceftolozane/tazobactam into closed-loop extracorporeal membrane oxygenation circuits prepared with and without an oxygenator in series with serial preoxygenator, postoxygenator, and reference samples obtained for concentration determination over a 24-hour study period. MEASUREMENTS AND MAIN RESULTS: For the 1/4-inch circuit, there was approximately 92% ceftolozane and 22-25% tazobactam loss with the oxygenator in series and 19-30% ceftolozane and 31-34% tazobactam loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was approximately 85% ceftolozane and 29% tazobactam loss with the oxygenator in series and 25-27% ceftolozane and 23-26% tazobactam loss without an oxygenator in series at 24 hours. The reference ceftolozane and tazobactam concentrations remained relatively constant during the entire study period demonstrating the drug loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation. CONCLUSIONS: This ex vivo investigation demonstrated substantial ceftolozane loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and significant ceftolozane loss in the absence of an oxygenator. Tazobactam loss was similar regardless of the presence of an oxygenator. Further evaluations with multiple dose in vitro and in vivo investigations are needed before specific drug dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation.
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Antibacterianos/administración & dosificación , Cefalosporinas/administración & dosificación , Oxigenación por Membrana Extracorpórea/instrumentación , Oxigenación por Membrana Extracorpórea/métodos , Oxigenadores de Membrana , Tazobactam/administración & dosificación , Adolescente , Adulto , Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Niño , Preescolar , Diseño de Equipo , Humanos , Lactante , Recién Nacido , Tasa de Depuración Metabólica , Tazobactam/farmacocinética , Adulto JovenRESUMEN
The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 µg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level ß-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 µg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against ß-lactamase-producing Gram-negative bacteria.
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Enfermedad Crítica , Tazobactam/sangre , Tazobactam/farmacocinética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/sangre , Combinación Piperacilina y Tazobactam/farmacocinética , Estudios Prospectivos , Inhibidores de beta-Lactamasas/sangre , Inhibidores de beta-Lactamasas/farmacocinéticaRESUMEN
The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modeling and dosing simulations were performed using Pmetrics. A four-compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratios for ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30, respectively. Model-estimated CVVHDF clearance rates were 2.7 ± 0.8 and 3.0 ± 0.6 liters/h, respectively. Residual non-CVVHDF clearance rates were 0.6 ± 0.5 and 3.3 ± 0.9 liters/h, respectively. In the initial 24 h, doses as low as 0.75 g every 8 h enabled cumulative fractional response of ≥85% for empirical coverage against Pseudomonas aeruginosa, considering a 40% fT>MIC (percentage of time the free drug concentration was above the MIC) target. For 100% fT>MIC, doses of at least 1.5 g every 8 h were required. The median (interquartile range) steady-state trough ceftolozane concentrations for simulated regimens of 1.5 g and 3.0 g every 8 h were 28 (21 to 42) and 56 (42 to 84) mg/liter, respectively. The corresponding tazobactam concentrations were 6.1 (5.5 to 6.7) and 12.1 (11.0 to 13.4) mg/liter, respectively. We suggest a front-loaded regimen with a single 3.0-g loading dose followed by 0.75 g every 8 h for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.
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Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapéutico , Hemodiafiltración/métodos , Tazobactam/farmacocinética , Tazobactam/uso terapéutico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/microbiología , Antibacterianos/administración & dosificación , Cefalosporinas/administración & dosificación , Intervalos de Confianza , Terapia de Reemplazo Renal Continuo , Enfermedad Crítica , Humanos , Pruebas de Sensibilidad Microbiana , Estudios Prospectivos , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/patogenicidad , Tazobactam/administración & dosificaciónRESUMEN
Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.