Colistin plasma concentrations are not associated with better clinical outcomes in patients with pneumonia caused by extremely drug-resistant Pseudomonas aeruginosa.

IMPORTANCE: In some cases, colistin is the only treatment option for infections caused by the very drug-resistant Pseudomonas aeruginosa. However, in the past decade, there have been questions concerning its pharmacokinetics and concentration at the site of infection. In this scenario, its use in a difficult-to-treat infection like pneumonia is currently debatable. This is a clinical pharmacokinetic study of colistin in patients with multidrug-resistant P. aeruginosa pneumonia. Our findings demonstrate that colistin exposure is associated with worse clinical outcomes rather than better clinical outcomes, implying that other therapeutic options should be explored in this clinical setting.

A retrospective case-control study to evaluate the use of beta-lactam desensitization in the management of penicillin-allergic patients: a potential strategy for Antimicrobial Stewardship Programs.

Introduction: Penicillin allergy labels (PAL) are common in the hospital setting and are associated with worse clinical outcomes. Desensitization can be a useful strategy for allergic patients when alternative options are suboptimal or not available. The aim was to compare clinical outcomes of patients with PAL managed with antibiotic desensitization vs. those who received alternative non-beta-lactam antibiotic treatments. Methods: A retrospective 3:1 case-control study was performed between 2015-2022. Cases were adult PAL patients with infection who required antibiotic desensitization; controls were PAL patients with infection managed with an alternative antibiotic treatment. Cases and controls were adjusted for age, sex, infection source, and critical or non-critical medical services. Results: Fifty-six patients were included: 14 in the desensitization group, 42 in the control group. Compared to the control group, desensitized PAL patients had more comorbidities, with a higher Charlson index (7.4 vs. 5; p = 0.00) and more infections caused by multidrug-resistant (MDR) pathogens (57.1% vs. 28.6%; p = 0.05). Thirty-day mortality was 14.3% in the desensitized group, 28.6% in the control group (p = 0.24). Clinical cure occurred in 71.4% cases and 54.8% controls (p = 0.22). Four control patients selected for MDR strains after alternative treatment; selection of MDR strains did not occur in desensitized patients. Five controls had antibiotic-related adverse events, including Clostridioides difficile or nephrotoxicity. No antibiotic-related adverse events were found in the study group. In multivariate analysis, no differences between groups were observed for main variables. Conclusion: Desensitization was not associated with worse clinical outcomes, despite more severe patients in this group. Our study suggests that antibiotic desensitization may be a useful Antimicrobial Stewardship tool for the management of selected PAL patients.

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.

Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.

BACKGROUND: Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For ß-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). OBJECTIVES: To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. METHODS: Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. RESULTS: Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. CONCLUSIONS: The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

Antibiotic desensitization as a potential tool in antimicrobial stewardship programs: retrospective data analysis and systematic literature review.

OBJECTIVES: Antibiotic allergy labels (AAL) are related to worse therapeutic results. Strategies to improve the management of these patients, such as the implementation of antibiotic desensitization, are essential for Antimicrobial Stewardship Programs (ASP). The aim of our study is to evaluate the efficacy and safety of antibiotic desensitization procedures for the management of patients with AAL. METHODS: A retrospective study from 2015 to 2022 was performed to describe all antibiotic desensitization conducted in our institution, within the framework of ASP. A systematic literature review using electronic databases, such as PubMed, was also done to identify studies describing antibiotic desensitization between 2000 and 2022. RESULTS: Sixteen antibiotic desensitization protocols were carried out in our institution. In fourteen cases, the desensitization was successfully completed, and the antibiotic could be used to treat the infection. In the systematic review, twenty-two studies were included, with a total of 202 desensitization episodes . In 97% of them, the desensitization was completed successfully. No desensitization-related mortality was observed neither in our cohort nor in literature review. CONCLUSIONS: Antibiotic desensitization strategies should be considered a safe and effective tool that can be included in ASP for patients with a high risk of or confirmed allergy to penicillin.

Therapeutic Drug Monitoring and Prolonged Infusions of Ceftolozane/Tazobactam for MDR/XDR Pseudomonas aeruginosa Infections: An Observational Study.

BACKGROUND AND OBJECTIVE: Prolonged infusion of ceftolozane/tazobactam (C/T) is a strategy used to increase achievement of pharmacokinetic/pharmacodynamic targets for the treatment of multi- or extensively drug-resistant MDR/XDR Gram-negative microorganisms. The objective of this study was to describe our therapeutic drug monitoring (TDM) experience of C/T administered by prolonged infusion or intermittent infusion to patients with MDR/XDR Pseudomonas aeruginosa infections. Our outcomes of interest were pharmacokinetic/pharmacodynamic target achievement and clinical cure. METHODS: Patients with MDR/XDR P. aeruginosa infections treated with C/T were enrolled between February 2018 and February 2020. Blood samples were obtained as part of a TDM program. The pharmacokinetic/pharmacodynamic therapeutic target of C/T was defined as 100% of the duration of the dosing interval that free concentrations are above the minimum inhibitory concentration (MIC) (100 %ƒT ≥ MIC) of the causative pathogen. Dose changes were performed according to TDM results. RESULTS: Forty patients were included: 13 (32.5%) with a proven MDR and 27 (67.5%) with a XDR P. aeruginosa infection. C/T was administered by prolonged infusion in 32 (80%) patients and by intermittent infusion in 8 (20%) patients. Lower doses were administered in the prolonged infusion compared to the intermittent infusion group [3 (9.4%) vs. 5 (62.5%] patients received a dose of 9 g/day (ceftolozane 2 g + tazobactam 1 g, every 8 h; p = 0.004). All patients achieved the pharmacokinetic/pharmacodynamic target and C/T concentrations exceeded 10 × MIC in > 50% of patients in both groups. TDM-recommended dose reductions occurred in 19 (47.5%) patients, being 16 (84.2%) in the prolonged infusion group. A high proportion of patients achieved clinical cure (82.5%). CONCLUSIONS: The administration of C/T by prolonged infusion with TDM-guided dosing allowed the achievement of a pharmacokinetic/pharmacodynamic target even at lower doses. C/T showed a high efficacy for treating MDR/XDR P. aeruginosa infections.

Early procalcitonin to predict mortality in critically ill COVID-19 patients: a multicentric cohort study.

BACKGROUND: High levels of procalcitonin (PCT) have been associated with a higher risk of mortality in COVID-19 patients. We explored the prognostic role of early PCT assessment in critically ill COVID-19 patients and whether PCT predictive performance would be influenced by immunosuppression. METHODS: Retrospective multicentric analysis of prospective collected data in COVID-19 patients consecutively admitted to 36 intensive care units (ICUs) in Spain and Andorra from March to June 2020. Adult (>18 years) patients with confirmed COVID-19 and available PCT values (<72 hours from ICU admission) were included. Patients were considered as "no immunosuppression" (NI), "chronic immunosuppression" (CI) and "acute immunosuppression" (AIT if only tocilizumab; AIS if only steroids, AITS if both). The primary outcome was the ability of PCT to predict ICU mortality. RESULTS: Of the 1079 eligible patients, 777 patients were included in the analysis. Mortality occurred in 227 (28%) patients. In the NI group 144 (19%) patients were included, 67 (9%) in the CI group, 66 (8%) in the AIT group, 262 (34%) in the AIS group and 238 (31%) in the AITS group; PCT was significantly higher in non-survivors when compared with survivors (0.64 [0.17-1.44] vs. 0.23 [0.11-0.60] ng/mL; P<0.01); however, in the multivariable analysis, PCT values was not independently associated with ICU mortality. PCT values and ICU mortality were significantly higher in patients in the NI and CI groups. CONCLUSIONS: PCT values are not independent predictors of ICU mortality in COVID-19 patients. Acute immunosuppression significantly reduced PCT values, although not influencing its predictive value.

Pharmacokinetics and Pharmacodynamics of Meropenem by Extended or Continuous Infusion in Low Body Weight Critically Ill Patients.

Background: Pathophysiological changes such as extreme body weights in critically ill patients with severe infections may alter the pharmacokinetics (PK) of antimicrobials, leading to treatment failure or toxicity. There are almost no PK data on meropenem in critically ill patients with low body weight (LwBW) and therefore information is lacking on the most appropriate dosing regimens, especially when administered by extended infusion. Objectives: To assess if the current administered doses of meropenem could lead to supratherapeutic concentrations in LwBW patients and to identify the factors independently associated with overexposure. Methods: A matched case-control 1:1 study of surgical critically ill patients treated with meropenem administered by extended or continuous infusion and undergoing therapeutic drug monitoring was conducted. Cases (patients with LwBW (body mass index (BMI) < 18.5 kg/m2)) were matched with normal body weight controls (NBW) (patients with BMI ≥ 18.5 kg/m2 and ≤30 kg/m2)) by age, gender, baseline renal function and severity status (APACHE II score). A 100% fT > MIC was considered an optimal pharmacokinetic/pharmacodynamic (PK/PD) target and 100% fT > 10 × MIC as supratherapeutic exposure. Results: Thirty-six patients (18 cases and 18 controls) were included (median (range) age, 57.5 (26-75) years; 20 (55.6% male)). Meropenem was administered by 6 h (extended) or 8 h (continuous) infusion at a median (range) daily dose of 5 (1-6) g/day. Similar median meropenem trough plasma concentrations (Cmin,ss), measured pre-dose on day three to four of treatment) were observed in the two groups (19.9 (22.2) mg/L vs 22.4 (25.8) mg/L, p > 0.999). No differences in the proportion of patients with an optimal or a supratherapeutic PKPD target between cases and controls were observed. A baseline estimated glomerular filtration rate (eGFR) < 90 mL/min was the only factor independently associated with a supratherapeutic PK/PD target. Conclusions: LwBW seems not to be a risk factor for achieving a supratherapeutic PK/PD target in critically ill patients receiving meropenem at standard doses by extended or continuous infusion.

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. TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.

Is 1 mg/kg of sugammadex sufficient to reverse moderate neuromuscular block? A randomized clinical trial / ¿Es suficiente 1mg/kg de sugammadex para revertir el bloqueo neuromuscular moderado? Ensayo clínico aleatorizado

Abstract Background: Sugammadex has made it possible to reverse any type of rocuronium-induced block quickly and safely. The most frequent neuromuscular blockade is the moderate one where doses smaller than those recommended by the industry could get a full reversal. Objective: We aimed to evaluate the effectiveness of half the industry recommended dose of sugammadex to reverse a moderate neuromuscular block. Methods: Unicenter phase IV clinical trial that included 34 patients undergoing laparoscopic cholecystectomy. Intravenous general anesthesia was induced, with acceleromyographic monitoring of the neuromuscular block. After the intervention, the block was reversed with all or half the dose of sugammadex recommended for moderate blocks, using a blinded syringe. Results: Patient characteristics of the 2 groups were similar. Mean time to recovery was 3.6± 1.7minutes for the study group and 3.1 ± 1.7minutes for the control group (P=0.42). Reversal of the block was complete with a single dose of sugammadex in all patients. There was an important linear correlation between depth of block and time to recovery. Conclusion: Intraoperative monitoring is essential to allow us to individualize the dose of the neuromuscular blocking agent. To reverse a moderate block under neuromuscular monitoring, a dose of 1 mg/kg is sufficient in most cases and is equally safe and effective.

Resumen Introducción: El sugammadex permite revertir cualquier tipo de bloqueo inducido por rocuronio de forma rápida y segura. El bloqueo neuromuscular más frecuente es el moderado, en el cual dosis inferiores a las recomendadas por la industria podrían revertirlo completamente. Objetivo: Evaluar la efectividad de la mitad de la dosis de sugammadex recomendada por la industria para revertir un bloqueo neuromuscular moderado. Métodos: Ensayo clínico de fase IV en un unico centro que incluyó a 34 pacientes intervenidos de colecistectomía laparoscópica. Se realizó anestesia general intravenosa con monitoreo aceleromiográfico del bloqueo neuromuscular. Tras la intervención, el bloqueo se revirtió con la totalidad o con la mitad de la dosis de sugammadex recomendada para bloqueos moderados, utilizando una jeringa ciega. Resultados: Las características de los pacientes de los dos grupos fueron similares. La media de tiempo de recuperación fue de 3,6 ± 1,7 minutos para el grupo de estudio y de 3,1 ± 1,7 minutos para el grupo de control (p = 0,42). La reversión del bloqueo se completó con una dosis única de sugammadex en todos los pacientes. Hubo una correlación lineal importante entre la profundidad del bloqueo y el tiempo de recuperación. Conclusión: El monitoreo transquirúrgico es esencial para individualizar la dosis del agente de bloqueo neuromuscular. Para revertir un bloqueo moderado bajo monitoreo neuromuscular, una dosis de 1mg/kg es suficiente e igualmente segura y efectiva.

Systemic pharmacokinetics and safety of high doses of nebulized colistimethate sodium in critically ill patients with hospital-acquired and ventilator-associated pneumonia.

OBJECTIVES: To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded. RESULTS: 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 this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.