Background The question of an optimal strategy and outcomes in COVID-19 tracheostomy has not been answered yet. The critical focus in our case study is to evaluate the outcomes of tracheostomy on intubated COVID-19 patients. Methods A multicentric prospective observational study of 1890 COVID-19 patients undergoing tracheostomy across 120 hospitals was conducted over 7 weeks in Spain (March 28 to May 15, 2020). Data were collected with an innovative approach: instant messaging via WhatsApp. Outcome measurements: complications, achieved weaning and decannulation and survival. Results We performed 1,461 surgical (81.3%) and 429 percutaneous tracheostomies. Median timing of tracheostomy was 12 days (4-42 days) since orotracheal intubation. A close follow-up of 1616/1890 (85.5%) patients at the cutoff time of 1-month follow-up showed that in 842 (52.1%) patients, weaning was achieved, while 391 (24.2%) were still under mechanical ventilation and 383 (23.7%) patients had died from COVID-19. Decannulation among those in whom weaning was successful (n = 842) was achieved in 683 (81%) patients. Conclusion To the best of our knowledge, this is the largest cohort of COVID-19 patients undergoing tracheostomy. The critical focus is the unprecedented amount of tracheostomies: 1890 in 7 weeks. Weaning could be achieved in over half of the patients with follow-up. Almost one out of four tracheotomized patients died from COVID-19.

Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.

The use of biologics has significantly changed the management of rheumatoid arthritis over the last decade, becoming the cornerstone treatment for many patients. The current therapeutic arsenal consists of just under 10 biologic agents, with four different mechanisms of action. Several studies have demonstrated a large interindividual pharmacokinetic variability, which translates to unpredictability in clinical response among individuals. The present review focuses on the pharmacokinetics and pharmacodynamics of biologic agents approved for rheumatoid arthritis. The literature relating to their concentration-effect relationship and the use of pharmacokinetic-pharmacodynamic modelling to optimize drug regimens is analysed. Due to the scarcity and complexity of these studies, the current dosing strategy is based on clinical indexes/aspects. In general, dose individualization for biologics should be implemented increasingly in clinical practice as there is a direct benefit for treated rheumatoid arthritis patients. Moreover, there is an indirect benefit in terms of cost-effectiveness.

Rheumatoid arthritis (RA) is the most prevalent immune-mediated chronic rheumatic disease and is associated with joint destruction and disability. Therapeutic strategies, including biological disease-modifying antirheumatic drugs (bDMARDs) have improved the prognosis and quality of life of RA patients. Tocilizumab (TCZ) is a humanized monoclonal antibody against IL-6 receptor licensed in 2009 that has demonstrated clinical efficacy in various adult RA populations. RA management guidelines and recommendations consider TCZ as one of the bDMARDS indicated after methotrexate or other conventional synthetic DMARDs and/or TNF inhibitors failure in adult RA. Of particular interest is the demonstration of its effectiveness in monotherapy in comparison with other bDMARDs. Recent observational studies have shown good results for the safety profile of TCZ with no new alert signals.

Objectives Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. Methods Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA. Results Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF. Conclusions Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.

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Objectives Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. Methods Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. Results Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. Conclusions Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

Aims: Tocilizumab has a direct effect on inflammatory markers. Therefore, composite measures for disease activity assessment in rheumatoid arthritis (RA) using these inflammatory markers may not be suitable for tocilizumab treatment. We used a modelling approach to describe the tocilizumab exposure-response relationship and to investigate the different dynamics of the individual components of the routinely used continuous composite measures.Methods: Pharmacokinetic (PK), clinical and laboratory data were obtained from a prospective, observational, single-centre study involving 35 subjects with RA treated with intravenous tocilizumab. A population PK/pharmacodynamic analysis was performed using nonlinear mixed effects models. Results: The population for model development comprised 1086, 1083 and 1082 observations calculated with the disease activity score based on 28 joint (DAS28) and the simplified and clinical disease activity scores (SDAI, CDAI). The tocilizumab exposure-response relationship was described with an indirect-response model. Two main groups of individual components were identified based on their different dynamics under tocilizumab treatment: (i) tender and swollen joint counts and patient and evaluator global assessment showed a slower decrease of their baseline value (half-life: 4.6 weeks, RSE: 24%) and the need for higher serum drug concentration (EC 50 : 4.60 μg/mL, RSE: 103%, IIV: 359%) than (ii) C-reactive protein and erythrocyte sedimentation rate (half-life: 2.3 weeks, RSE 19%; EC 50 : 0.878 μg/mL, RSE: 41%, IIV: 238%). Conclusion: Our study confirms a different dynamics of the individual components of the most frequently used continuous composite measures under tocilizumab treatment which should be taken into account to avoid misassessment of disease activity.