Análisis farmacocinético/farmacodinámico del tratamiento antimicrobiano en pacientes críticos con neumonía de adquisición hospitalaria y neumonía asociada a ventilación mecánica

Introducció: Són necessaris els estudis farmacocinètics/farmacodinàmics (PK/PD) dels antibiòtics utilitzats en el tractament de la pneumònia nosocomial (NN) en pacients crítics per dur a terme règims de dosificació eficaços i segurs. Justificació Científica Es desconeix la farmacocinètica pulmonar del meropenem quan s'administra en perfusió continua (PC) i la seguretat i grau d'absorció sistémica de la colistina nebulitzada administrada a dosis altes. Hipòtesis i Objetius Hipòtesis de treball En pacients crítics amb pneumònia nosocomial: · L'utilització de PC de meropenem permet assolir un objectiu PK/PD òptim al pulmó en comparació amb altres règims de dosificació. · L'utilització de colistina nebulitzada adminstrada a altes dosis es un tractament segur donada la baixa absorció sistèmica. Objetius Avaluar el comportament PK/PD dels antibiòtics meropenem intravenós i colistina nebulitzada utilitzats pel tractament de la NN en pacients crítics per proposar règims de dosificació eficaços i segurs. Disseny de l'estudi Estudi 1: Assaig clínic unicèntric, obert i aleatoritzat amb grups paral·lels en pacients crítics amb NN. Els pacients van ser assignats a un dels dos grups d'estudi (Grup 1: PC intravenosa d'1 g/8h de meropenem o Grup 2: PC intravenosa de 2 g/8h de meropenem). Es va dur a terme la determinació de les concentracions intrapulmonars de meropenem mitjançant la seva medició en el líquid de revestiment epitelial pulmonar (ELF) un cop assolit l'estat estacionari. EudraCT: 2016-002796-10 Estudi 2: Estudi farmacocinètic, retrospectiu i unicèntric per la determinació dels nivells plasmàtics de colistina després de l'administració de dosis altes de colistimetat de sodi (3 MUI/8h i 5 MUI/8h) per via nebulitzada. Resultats Estudi 1: Les medianes (RIQ) de concentració (AUC0-24h) de meropenem a plasma i ELF van ser de 287,6 (190,2) i 84,1 (78,8) mg h/L al Grup 1 (1g/8h) vs 448,1 (231,8) i 163,0 (201,8) mg h/L al Grup 2 (2g/8h), respectivament. La taxa de penetració va ser aproximadament del 30% i comparable entre els dos grups. A la simulació de Montecarlo únicament la major dosis aprovada per fitxa tècnica (2g/8h) en PC va assolir una taxa de probabilitat d'èxit de tractament (PTA) òptima pels aïllaments amb CMI de fins a 2 mg/L. Estudi 2: Es van incloure un total de 27 pacients (15 pacients al grup de 3 MUI/8h i 12 pacients al grup de 5 MUI/8h). Les concentracions de colistina al plasma van ser indetectables (<0,1 mg/L) en 8 pacients (53.3%) al grup de 3 MUI/8h i en 7 pacients (58.3%) al grup de 5 MUI/8h. Les concentracions medianes (RIQ) de colistina quantificable a plasma abans de la nebulització i a les 1, 4 i 8 h van ser 0,17 (0,12-0,33), 0,20 (0,11-0,24), 0,17 (0,12-0,23) i 0,17 (0,11-0,32) mg/L, respectivament, al grup de 3 MUI/8 h i 0,20 (0,11-0,35), 0,24 (0,12-0,44), 0,24 (0,10-0,49) i 0,23 (0,11-0,44) mg/L, respectivament, al grup de 5 MUI/8 h, sense diferències entre els grups en cap dels moments mesurats. Es va observar fracàs renal durant el tractament en tres pacients a cada grup, probablement no relacionada amb el tractament amb colistina. El tractament amb colistimetat de sodi nebulitzat va ser ben tolerat, sense episodis de brancoespasme ni signes clínics de neurotoxicitat. Conclusions En pacients crítics amb diagnòstic de NN i funció renal normal: · L'administració de meropenem en PC permet assolir concentracions intrapulmonars adequades per tractar microorganismes amb CMI de fins a 2 mg/L, sent necessària l'utilització de la dosis màxima autoritzada de meropenem en PC (2g/8h) per assolir una PTA major del 90% per a microorganismes amb CMI de fins a 2 mg/L. · S'observa una mínima exposició sistèmica de colistina formada a plasma després de l'administració de dosis altes de colistimetat de sodi per via nebulitzada. Així mateix, s'observa una bona tolerància i abscència de toxicitat sistèmica al fàrmac.Introducción: Son necesarios estudios farmacocinéticos/farmacodinámicos (PK/PD) de los antibióticos empleados en el tratamiento de la neumonía nosocomial (NN) en pacientes críticos que permitan el diseño de regímenes de dosificación eficaces y seguros. Justificación Científica Se desconoce la farmacocinética pulmonar de meropenem cuando se administra en perfusión continua (PC) y la seguridad y grado de absorción sistémica de colistina nebulizada cuando se utiliza a altas dosis. Hipótesis y Objetivos Hipótesis de trabajo En pacientes críticos con NN: · El empleo de PC de meropenem permite alcanzar un objetivo PK/PD óptimo en pulmón frente a otros regímenes de dosificación. · El empleo de colistina nebulizada a altas dosis es un tratamiento seguro dada su escasa absorción sistémica. Objetivos Evaluar el comportamiento PK/PD de los antibióticos meropenem intravenoso y colistina nebulizada empleados para el tratamiento de la NN en pacientes críticos para proponer regímenes de dosificación eficaces y seguros. Diseño del estudio Estudio 1: Ensayo clínico unicéntrico, abierto, aleatorizado de grupos paralelos en pacientes críticos con NN. Los pacientes serán asignados a uno de los dos grupos de estudio [Grupo 1 (PC intravenosa de 1 g/8h meropenem) o Grupo 2 (PC intravenosa de 2 g/8h de meropenem)]. Se llevará a cabo la determinación de las concentraciones intrapulmonares de meropenem mediante su medición en líquido de revestimiento epitelial pulmonar (ELF) una vez alcanzado el estado estacionario. EudraCT: 2016-002796-10 Estudio 2: Estudio farmacocinético, retrospectivo y unicéntrico para la evaluación de los niveles plasmáticos de colistina tras la administración de dosis altas de CMS (3 MUI/8h y 5 MUI/8h) por vía nebulizada. Resultados Estudio 1: La mediana (RIQ) de concentraciones (AUC0-24h) de meropenem en plasma y ELF fueron 287.6 (190.2) y 84.1 (78.8) mg h/L en el grupo de 1g/8h vs 448.1 (231.8) y 163.0 (201.8) mg h/L en el grupo de 2 g/8 h respectivamente. La tasa de penetración fue aproximadamente del 30% y comparable entre ambos grupos. En la simulación de Montecarlo únicamente la mayor dosis aprobada (2g/8h) en PC permitió alcanzar un PTA óptimo para los aislamientos con CMI de hasta 2 mg/L. Estudio 2: Se incluyeron un total de 27 pacientes (15 pacientes en el grupo de 3 MUI/8h y 12 pacientes en grupo de 5 MUI/8h). Las concentraciones de colistina en plasma fueron indetectables (<0.1 mg/L) en 8 (53.3%) pacientes en el grupo de 3 MUI/8h y en 7 pacientes (58.3%) en el grupo de 5 MUI/8h. Las concentraciones medianas (RIQ) de colistina cuantificable en plasma antes de la nebulización y a las 1, 4 y 8 h fueron 0.17 (0.12-0.33), 0.20 (0.11-0.24), 0.17 (0.12-0.23) y 0.17 (0.11-0.32) mg/L, respectivamente en el grupo de 3 MUI/8 h y 0.20 (0.11-0.35), 0.24 (0.12-0.44), 0.24 (0.10-0.49) y 0.23 (0.11-0.44) mg/L, respectivamente en el grupo de 5 MUI/8 h, sin diferencias entre los grupos en ningún momento medido. Se observó fracaso renal durante el tratamiento en tres pacientes en cada grupo, probablemente no relacionado con el tratamiento con CMS. El tratamiento con CMS nebulizado fue bien tolerado, sin episodios de broncoespasmo ni signos de neurotoxicidad. Conclusiones En pacientes críticos con diagnóstico de NN y función renal normal: · La administración de meropenem en PC permite alcanzar concentraciones intrapulmonares adecuadas para tratar microorganismos con CMI de hasta 2 mg/L, siendo necesario el empleo de la dosis máxima autorizada de meropenem en PC (2g/8h) para alcanzar una PTA mayor del 90% para microorganismos con CMI de hasta 2 mg/L. · Se observa una mínima exposición sistémica de colistina formada en plasma tras administración de dosis altas de CMS por vía nebulizada,observándose una buena tolerabilidad y ausencia de toxicidad sistémica.Introduction: Pharmacokinetic/pharmacodynamic (PK/PD) studies are needed to allow the design of safe and effective dosage regimens of antibiotics for the treatment of nosocomial pneumonia (NN) in critically ill patients. Scientific justification Little is known about the intrapulmonary pharmacokinetics of meropenem when administered by continuous infusion (CI) and the safety of high doses of nebulized colistin. Hypothesis and objectives Hypothesis In critically ill patients with NN: · The use of meropenem by CI achieved an optimal intrapulmonary PK/PD target compared to other dosage systems. · The use of high-dose nebulized colistin is a safe given its low systemic absorption. Objectives To evaluate the PK/PD of meropenem administered intravenous by CI and high doses nebulized colistin in critically ill patients with NN and to propose effective and safe dosage regimens. Study design Study 1: Single-center, open-label, randomized clinical trial in critically ill patients with NN. Patients will be assigned to Group 1 (intravenous CI 1 g/8h meropenem) or Group 2 (intravenous CI 2 g/8h meropenem). Meropenem concentrations in plasma and epithelial lining fluid (ELF) will be assessed at steady state. EudraCT: 2016-002796-10 Study 2: Pharmacokinetic, retrospective, single-center study for the evaluation of plasma levels of colistin after the administration of high doses of nebulized CMS (3 MIU/8h and 5 MIU/8h). Results Study 1: The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC ≤ 2 mg/L. Study 2: Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12-0.33), 0.20 (0.11-0.24), 0.17 (0.12 0.23) and 0.17 (0.11- 0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11 0.35), 0.24 (0.12-0.44), 0.24 (0.10-0.49) and 0.23 (0.11-0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated, and no bronchospasms or neurotoxicity events were observed. Conclusions In critically ill patients with NN and normal renal function: · Meropenem administered by CI allows reaching adequate intrapulmonary concentrations to treat microorganisms with MIC of up to 2mg/L. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L). · After the administration of high dose colistin by nebulization, systemic exposure was minimal, and the treatment was well tolerated

Clinical, microbiological and treatment characteristics of severe postoperative respiratory infections: An observational cohort study

Respiratory infections are frequent and life-threatening complications of surgery. This study aimed to evaluate the clinical, microbiological and treatment characteristics of severe postoperative pneumonia (POP) and tracheobronchitis (POT) in a large series of patients. This single-center, prospective observational cohort study included patients with POP or POT requiring intensive care unit admission in the past 10 years. We recorded demographic, clinical, microbiological and therapeutic data. A total of 207 patients were included, and 152 (73%) were men. The mean (SD) age was 70 (13) years and the mean (SD) ARISCAT score was 46 (19). Ventilator-associated pneumonia was reported in 21 patients (10%), hospital-acquired pneumonia was reported in 132 (64%) and tracheobronchitis was reported in 54 (26%). The mean (SD) number of days from surgery to POP/POT diagnosis was 6 (4). The mean (SD) SOFA score was 5 (3). Respiratory microbiological sampling was performed in 201 patients (97%). A total of 177 organisms were cultured in 130 (63%) patients, with a high proportion of Gram-negative and multi-drug resistant (MDR) bacteria (20%). The most common empirical antibiotic therapy was a triple-drug regimen covering MDR Gram-negative bacteria and MRSA. In conclusion, surgical patients are a high-risk population with a high proportion of early onset severe POP/POT and nosocomial bacteria isolation

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

Background: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. Methods: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. Results: The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. Conclusions: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected

Antimicrobial Lessons From a Large Observational Cohort on Intra-abdominal Infections in Intensive Care Units

evere intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by disease-specific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed.Severe intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by diseasespecific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed

Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis

Purpose: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. Methods: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (&lt; 2 h), 'urgent' (2-6 h), and 'delayed' (&gt; 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). Results: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value &gt; 12, p &lt; 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (&lt; 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). Conclusion: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome