INTRODUCTION: In order to compare the clinical efficacy and safety of prolonged versus intermittent antipseudomonal beta-lactam antibiotic infusion for the treatment of severe acute infections in adult patients, a meta-analysis of randomized controlled trials (RCTs) was performed.
METHODS: We systematically searched MEDLINE and Cochrane Library databases until December 2022. The outcomes were all-cause mortality, clinical success, microbiological eradication and adverse events. The pooled risk ratios (RR) were estimated by the fixed or random effect methods according to heterogeneity statistics. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the certainty of evidence for each outcome.
RESULTS: Twenty eligible RCTs with 2081 participants were included in the meta-analysis. The risk of all-cause mortality was significantly lower in the prolonged infusion group than in the intermittent infusion group (RR 0.77, 95% confidence interval [CI] 0.63-0.95, p = 0.01, I2 = 0%; moderate certainty). Treatment with prolonged infusion showed significant benefit in clinical success (RR 1.09, 95% CI 1.02-1.17, p = 0.008, I2 = 19%; moderate certainty). There were no significant differences in microbiological eradication (RR 1.12, 95% CI 0.99-1.28, p = 0.07, I2 = 49%; low certainty), any adverse events (RR 0.96, 95% CI 0.86-1.08, p = 0.50, I2 = 27%; moderate certainty) and serious adverse events (RR 0.99, 95%CI 0.70-1.39 p = 0.95, I2 = 0%; low certainty).
CONCLUSIONS: Prolonged antipseudomonal beta-lactam infusion probably decreases all-cause mortality. Additionally, it probably increases clinical success in adults with severe acute infections. This infusion strategy may result in little to no difference in microbiological eradication and is probably not associated with a rise in any adverse events.The evidence suggests that prolonged infusion may not increase serious adverse events.
Background: β-lactams remain the cornerstone of the empirical therapy to treat various bacterial infections. This systematic review aimed to analyze the data describing the dosing regimen of β-lactams. Methods: Systematic scientific and grey literature was performed in accordance with Preferred Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The studies were retrieved and screened on the basis of pre-defined exclusion and inclusion criteria. The cohort studies, randomized controlled trials (RCT) and case reports that reported the dosing schedule of β-lactams are included in this study. Results: A total of 52 studies met the inclusion criteria, of which 40 were cohort studies, 2 were case reports and 10 were RCTs. The majority of the studies (34/52) studied the pharmacokinetic (PK) parameters of a drug. A total of 20 studies proposed dosing schedule in pediatrics while 32 studies proposed dosing regimen among adults. Piperacillin (12/52) and Meropenem (11/52) were the most commonly used β-lactams used in hospitalized patients. As per available evidence, continuous infusion is considered as the most appropriate mode of administration to optimize the safety and efficacy of the treatment and improve the clinical outcomes. Conclusion: Appropriate antibiotic therapy is challenging due to pathophysiological changes among different age groups. The optimization of pharmacokinetic/pharmacodynamic parameters is useful to support alternative dosing regimens such as an increase in dosing interval, continuous infusion, and increased bolus doses.
PURPOSE: Antibiotics are frequently used in patients receiving intermittent or continuous renal replacement therapy (RRT). RRT may alter the pharmacokinetics (PK), as well as the ability to achieve PK/pharmacodynamic (PD) targets. Therapeutic drug monitoring (TDM) could help evaluatedrug exposure and guide antibiotic dosage adjustment. The present review describes recent TDM data on antibiotic exposure and PK/PD target attainment in patients receiving intermittent or continuous RRT, proposing practical guidelines for performing TDM.
METHODS: Studies on antibiotic TDM performed in patients receiving intermittent or continuous RRT published between 2000 and 2020 were searched and assessed. The authors focused on studies that reported data on PK/PD target attainment. TDM recommendations were based on clinically relevant PK/PD relationships and previously published guidelines.
RESULTS: In total, 2383 reports were retrieved. After excluding non-relevant publications, 139 articles were selected. Overall, 107 studies reported PK/PD target attainment for 24 agents. Data were available for various intermittent and continuous RRT techniques. The study design, TDM practice, and definition of PK/PD targets were inconsistent across studies. Drug exposure and target attainment rates were highly variable. TDM appears necessary to control drug exposure in patients receiving intermittent and continuous RRT techniques, especially for antibiotics with narrow therapeutic margins and in critically ill patients. Practical recommendations can provide insights on relevant PK/PD targets, sampling, and timing of TDM for various antibiotic classes.
CONCLUSION: Highly variable antibiotic exposure and target attainment have been reported in patients receiving intermittent or continuous RRT. TDM for aminoglycosides, beta-lactams, glycopeptides, linezolid, and colistin is recommended in patients receiving RRT and suggested for daptomycin, fluoroquinolones, and tigecycline in critically ill patients on RRT.
OBJECTIVE: The impact on outcome of five interventions was reviewed in order to investigate the state-of-art for management of Enterobacteriaceae bloodstream infection (E-BSI).
METHODS: We searched for randomized controlled trials (RCTs) and observational studies, published from January 2008 to March 2019 on PUBMED, EMBASE and COCHRANE library. Populations consisted of patients with E-BSI.
INTERVENTIONS: i. performance of imaging to assess BSI source and/or complications; ii. follow-up blood culture (FU-BC); iii. use of loading dose followed by extended/continuous infusion (E/CI) of beta-lactams; iv. duration of treatment (short vs. long-term); and v. infectious disease (ID) consultation. Patients without intervention were considered as controls. The main outcome was 30-day mortality. RoB 2.0 and ROBINS-I tools were used for bias assessment.
RESULTS: No study was eligible for intervention i, iii and v. For FU-BC, one observational study including 901 patients with E-BSI was considered. Intervention consisted of repeating BCs within 2-7 days after index BCs. All-cause 30-day mortality was observed in 35 out of 247 patients (14.2%) in the intervention group vs. 96 out of 654 patients (14.7%) in the control group. For short treatment duration, two RCTs and six observational studies were included comprising 4473 patients with E-BSI. All-cause mortality was similar in short and long treatment groups (OR 1.10, 95% CI 0.83-1.84).
CONCLUSIONS: Out of the assessed interventions, only short treatment duration in non-immunocompromised patients with E-BSI is supported by current data. Studies investigating the use of systematic imaging, follow-up BCs, E/CI beta-lactams and ID consultation in patients with E-BSI are needed.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by frequent exacerbations.
PURPOSE: To evaluate the comparative effectiveness and adverse events (AEs) of pharmacologic interventions for adults with exacerbation of COPD.
DATA SOURCES: English-language searches of several bibliographic sources from database inception to 2 January 2019.
STUDY SELECTION: 68 randomized controlled trials that enrolled adults with exacerbation of COPD treated in out- or inpatient settings other than intensive care and compared pharmacologic therapies with placebo, "usual care," or other pharmacologic interventions.
DATA EXTRACTION: Two reviewers independently extracted data and rated study quality and strength of evidence (SOE).
DATA SYNTHESIS: Compared with placebo or management without antibiotics, antibiotics given for 3 to 14 days were associated with increased exacerbation resolution at the end of the intervention (odds ratio [OR], 2.03 [95% CI, 1.47 to 2.80]; moderate SOE) and less treatment failure at the end of the intervention (OR, 0.54 [CI, 0.34 to 0.86]; moderate SOE), independent of severity of exacerbations in out- and inpatients. Compared with placebo in out- and inpatients, systemic corticosteroids given for 9 to 56 days were associated with less treatment failure at the end of the intervention (OR, 0.01 [CI, 0.00 to 0.13]; low SOE) but also with a higher number of total and endocrine-related AEs. Compared with placebo or usual care in inpatients, other pharmacologic interventions (aminophyllines, magnesium sulfate, anti-inflammatory agents, inhaled corticosteroids, and short-acting bronchodilators) had insufficient evidence, showing either no or inconclusive effects (with the exception of the mucolytic erdosteine) or improvement only in lung function.
LIMITATION: Scant evidence for many interventions; several studies had unclear or high risk of bias and inadequate reporting of AEs.
CONCLUSION: Antibiotics and systemic corticosteroids reduce treatment failure in adults with mild to severe exacerbation of COPD.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018111609).
BACKGROUND: Critically ill patients display altered pharmacokinetics and pharmacodynamics and are more likely to be infected with more resistant pathogens. Beta-lactam antibiotics exhibit time-dependent pharmacodynamics; therefore, it is postulated that continuous infusion (CI) may optimize these parameters.
OBJECTIVE: To perform a systematic review and meta-analysis of the available literature comparing CI versus intermittent bolus (IB) of beta-lactam antibiotics in critically ill adult patients with respiratory infections to determine if clinical benefits exist.
METHODS: PubMed, EMBASE, and Web of Science were searched. Thirteen randomized controlled trials were included in the meta-analyses of clinical cure and/or mortality. Four retrospective studies reporting clinical cure and/or mortality, and 11 studies that reported pharmacokinetic/pharmacodynamic parameters were included in the systematic review.
RESULTS: The majority of patients in both groups maintained the percentage of time the free drug concentration exceeded the minimum inhibitory concentration (%fT > MIC) targets throughout the treatment, with differences favoring CI being more prevalent when the MIC of the offending pathogen increased. CI of beta-lactam antibiotics in critically ill adult patients with respiratory infections significantly improved clinical cure rates when compared to IB (risk ratio [RR] 1.177; 95% CI 1.065-1.300). No significant differences in mortality rates were seen when patients were treated with either dosing modality (RR 0.845; 95% CI 0.644-1.108).
CONCLUSIONS: CI of beta-lactam antibiotics is associated with better cure rates and higher %fT > MIC when administered to critically ill patients with respiratory infections, but may be most beneficial in severely ill patients with more resistant Gram-negative bacterial infections.
RATIONALE: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis.
OBJECTIVES: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics.
METHODS: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis.
MEASUREMENTS AND MAIN RESULTS: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure.
CONCLUSIONS: Compared with intermittent dosing, administration of β-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality.
OBJETIVO: Revisar sistemáticamente la eficacia y seguridad de la infusión intravenosa prolongada o continua (EI / CI) frente a la infusión intravenosa de corto plazo (ITS) de imipenem / meropenem en pacientes adultos con infección pulmonar grave. Métodos: Se electrónicamente buscaron las bases de datos incluidas en PubMed, EMBASE, The Cochrane Library (Número 6, 2015) y el CBM desde su inicio hasta junio de 2015, para recoger los ensayos controlados aleatorios (ECA) sobre EI / CI frente a las ITS de imipenem / meropenem de infección severa . Dos revisores de forma independiente la literatura, extrajeron los datos y evaluaron el riesgo de sesgo de los estudios incluidos. A continuación, el meta-análisis se realizó mediante el programa informático RevMan 5.2. RESULTADOS: Se incluyeron un total de 6 ECA con 442 pacientes. Los resultados del meta-análisis mostraron que, en comparación con el grupo de infecciones de transmisión sexual, la EI / CI puede mejorar significativamente la tasa microbiológica éxito (IC RR = 1,16, 95%: 1,02 a 1,32; P = 0,02), sin aumentar reacción adversa a un medicamento (RR = 0,99, IC 95% 0,65 a la 1,52; P = 0,97). No hubo diferencias significativas en la tasa efectiva clínica (RR = 1,12, IC del 95%: 0,97 a 1,28; p = 0,13), la tasa de supervivencia (RR = 1,03; IC del 95%: 0,92 a 1,16; P = 0,62) y estancias hospitalarias (MD = -0.43, IC del 95% -1.29 a la 0,42; P = 0,32) entre los dos grupos. CONCLUSIONES: No hay diferencia significativa en el efecto clínico entre la IE / IC e ITS para la infección pulmonar grave. Mientras, las infecciones causadas por bacterias gram-negativas con alta MIC podría beneficiarse más de EI / CI. Debido a la limitada cantidad y la calidad de los estudios incluidos, todavía tienen que ser verificados por estudios más alta calidad de la conclusión anterior.
La infusión continua de vancomicina (CIV) y la infusión intermitente de vancomicina (IIV) son dos estrategias de administración importantes en el ámbito clínico. Sin embargo, los artículos previos que comparan la eficacia y seguridad del CIV frente IIV mostraron resultados inconsistentes. Por lo tanto, se llevó a cabo un meta-análisis para comparar la eficacia y seguridad del CIV y IIV. PubMed, Cochrane Library y Web of Science hasta junio el año 2015 se realizaron búsquedas utilizando las palabras clave 'vancomicina "," intravenosa "," parenteral "," continua "," intermitente "," discontinua "," infusión "," administración "y 'dosificación'. Once estudios fueron incluidos en el meta-análisis. Tampoco se observó heterogeneidad ni sesgo de publicación. Los pacientes tratados con CIV tuvieron una incidencia significativamente menor de nefrotoxicidad en comparación con los pacientes que recibieron IIV [riesgo relativo (RR) = 0,61, 95% intervalo de confianza (IC) desde 0,47 hasta 0,80; P <0,001]. No se detectó ninguna diferencia significativa en el fracaso del tratamiento entre los dos grupos. La mortalidad entre los pacientes que recibieron CIV y pacientes que reciben IIV fue similar (RR = 1,15, IC del 95%: 0,85 a 1,54; p = 0,365). Esta meta-análisis mostró que tenía CIV seguridad superior en comparación con IIV, mientras que la eficacia clínica no fue significativamente diferente. Se necesita un ensayo adicional multicéntrico, aleatorizado y controlado para confirmar estos resultados.
In order to compare the clinical efficacy and safety of prolonged versus intermittent antipseudomonal beta-lactam antibiotic infusion for the treatment of severe acute infections in adult patients, a meta-analysis of randomized controlled trials (RCTs) was performed.
METHODS:
We systematically searched MEDLINE and Cochrane Library databases until December 2022. The outcomes were all-cause mortality, clinical success, microbiological eradication and adverse events. The pooled risk ratios (RR) were estimated by the fixed or random effect methods according to heterogeneity statistics. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the certainty of evidence for each outcome.
RESULTS:
Twenty eligible RCTs with 2081 participants were included in the meta-analysis. The risk of all-cause mortality was significantly lower in the prolonged infusion group than in the intermittent infusion group (RR 0.77, 95% confidence interval [CI] 0.63-0.95, p = 0.01, I2 = 0%; moderate certainty). Treatment with prolonged infusion showed significant benefit in clinical success (RR 1.09, 95% CI 1.02-1.17, p = 0.008, I2 = 19%; moderate certainty). There were no significant differences in microbiological eradication (RR 1.12, 95% CI 0.99-1.28, p = 0.07, I2 = 49%; low certainty), any adverse events (RR 0.96, 95% CI 0.86-1.08, p = 0.50, I2 = 27%; moderate certainty) and serious adverse events (RR 0.99, 95%CI 0.70-1.39 p = 0.95, I2 = 0%; low certainty).
CONCLUSIONS:
Prolonged antipseudomonal beta-lactam infusion probably decreases all-cause mortality. Additionally, it probably increases clinical success in adults with severe acute infections. This infusion strategy may result in little to no difference in microbiological eradication and is probably not associated with a rise in any adverse events.The evidence suggests that prolonged infusion may not increase serious adverse events.