Predictive factors and treatment outcomes associated with difficult-to-treat rheumatoid arthritis conditions: the ANSWER cohort study.

OBJECTIVES: To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi). METHODS: Retrospective analysis was conducted on data from the ANSWER cohort comprising 3,623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention. RESULTS: Of these, 450 (12.4%) met the first two criteria of EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared to those under 65, HR = 0.46, 95% CI: 0.31 to 0.69), higher rheumatoid factor (RF) titres (HR = 1.005, 95% CI: 1.00 to 1.01), higher clinical disease activity index (HR = 1.02, 95% CI: 1.01 to 1.03), lower methotrexate dosage (HR = 0.97, 95% CI: 0.95 to 0.99), and comorbidities like hypertension (HR = 1.53, 95% CI: 1.2 to 1.95) and diabetes (HR = 1.37, 95% CI: 1.09 to 1.73). Anti-interleukin 6 receptor antibodies (aIL-6R, HR = 0.53, 95% CI: 0.37 to 0.75) and JAKi (HR = 0.64, 95% CI: 0.46 to 0.90) were associated with fewer discontinuations due to ineffectiveness compared to tumour necrosis factor inhibitors. Oral glucocorticoids usage (HR = 1.65, 95% CI: 1.11 to 2.47) was linked to increased discontinuation due to toxic adverse events. CONCLUSION: Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention.

Can we define difficult-to-treat systemic sclerosis?

INTRODUCTION: Systemic sclerosis (SSc) is a chronic autoimmune rheumatic disease characterized by microvascular alterations, immunopathology, and widespread fibrosis involving various organs. It is considered difficult to treat due to several reasons: complex pathogenesis, heterogeneity, late diagnosis, limited treatment options for certain organ manifestations, lack of personalized medicine. AREAS COVERED: This review presents the heterogeneity, survival and organ manifestations with their risk factors of systemic sclerosis and their current treatment options, while drawing attention to difficult-to-treat forms of the disease, based on literature indexed in PubMed. EXPERT OPINION: Despite recent advances in the management of SSc over the last decades, the disease presents significant morbidity and mortality. Although available treatment protocols brought significant advancements in terms of survival in SSc-associated interstitial lung disease and pulmonary arterial hypertension, less success has been achieved in the treatment of Raynaud's phenomenon and digital ulcers and the results are modest in case of heart, gastrointestinal, and renal manifestations. There are patients who do not respond to treatment and deteriorate even with adequate therapy. They can be considered difficult-to treat (D2T) cases. We have created a possible score system based on the individual organ manifestations and highlighted treatment options for the D2T SSc category.

Global trends in carbapenem- and difficult-to-treat-resistance among World Health Organization priority bacterial pathogens: ATLAS surveillance program 2018-2022.

OBJECTIVES: To report trends in carbapenem resistance and difficult-to-treat resistance (DTR) among clinical isolates of Gram-negative priority pathogens collected by the ATLAS global surveillance program from 2018 to 2022. METHODS: Reference broth microdilution testing was performed in a central laboratory for 79,214 Enterobacterales, 30,504 Pseudomonas aeruginosa, and 13,500 Acinetobacter baumannii-calcoaceticus complex isolates collected by a constant set of 157 medical centres in 49 countries in Asia Pacific (APAC), Europe (EUR), Latin America (LATAM), Middle East-Africa (MEA), and North America (NA) regions. MICs were interpreted by 2023 CLSI M100 breakpoints. ß-lactamase genes were identified for meropenem-nonsusceptible (MIC ≥2 mg/L) Enterobacterales isolates. RESULTS: Carbapenem-resistant Enterobacterales (CRE) detection increased (P < 0.05) in APAC, EUR, LATAM, and MEA regions and decreased in NA, while annual DTR percentages increased in all five regions. Carbapenem-resistant P. aeruginosa (CRPA; decreased in MEA region) and carbapenem-resistant A. baumannii-calcoaceticus complex (CRAB; decreased in MEA region and increased in EUR) remained relatively stable over time in all regions, although notably, annual percentages of CRAB and DTR A. baumannii-calcoaceticus complex isolates were consistently >25 percentage points lower in NA than in other regions. For all regions except NA, the majority of changes in CRE percentages could be attributed to hospital-acquired infections. Among meropenem-nonsusceptible Enterobacterales, KPC was the most frequent carbapenemase in NA and EUR each year. NDM was the most prevalent carbapenemase detected in 2022 in other global regions. CONCLUSION: CRE, CRPA, CRAB, and DTR rates vary among global regions over time highlighting the need for continuing surveillance to inform treatment strategies and antimicrobial stewardship.

Number needed to treat (NNT) for ketamine and esketamine in adults with treatment-resistant depression: A systematic review and meta-analysis.

BACKGROUND: Ketamine has been established as efficacious in adults living with Treatment-resistant Depression (TRD). Toward providing a quantifiable estimate of the clinical meaningfulness of the therapeutic benefit of ketamine, herein, we conduct a systematic review that aims to report the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH). METHODS: This systematic review searched Embase, Medline/Pubmed, PsycINFO and ClinicalTrials.gov from inception up to October 15th 2023, for placebo-controlled, Randomized Controlled Trials (RCTs) assessing racemic ketamine or esketamine therapy for unipolar TRD. We calculated NNT and NNH for ketamine treatments over various time points. RESULTS: A total of 21 studies with 2042 participants were included. Racemic ketamine treatments had pooled NNTs for response of 7 at 4 h, 3 from one day to one week and 9 for studies at four weeks. Esketamine treatment was found to have a similar efficacy with an NNT of 2 at one day and 11 at four weeks. NNH values indicated low risk for ketamine treatments. LIMITATIONS: Limitations in the data used include the possibility of functional unblinding and selective reporting bias. Moreover, the meta-analysis may have been limited in its precision by including low threshold definitions of treatment resistance (≥ 1 failed antidepressant) and low-dose ketamine treatments. CONCLUSION: Herein, we determined that the NNT for ketamine treatment in adults living with TRD across different intervals of observation was <10. We conclude that the NNTs observed herein are highly clinically meaningful in this difficult to treat disorder.

Recomendaciones SER sobre el tratamiento del síndrome de Behçet refractario / SER recommendations on treatment of refractory Behçet's syndrome

Objetivo: Elaborar recomendaciones multidisciplinares, basadas en la evidencia disponible y el consenso de expertos, para el manejo terapéutico de los pacientes con síndrome de Behçet refractario (difícil de tratar, resistente grave, recidivante grave) al tratamiento convencional. Métodos: Un panel de expertos identificó preguntas clínicas de investigación relevantes para el objetivo del documento. Estas preguntas fueron reformuladas en formato PICO –paciente, intervención, comparación, outcome o desenlace–. A continuación, se realizaron revisiones sistemáticas; la evaluación de la calidad de la evidencia se realizó siguiendo la metodología del grupo internacional de trabajo Grading of Recommendations, Assessment, Development, and Evaluation. Tras esto, el panel multidisciplinar formuló las recomendaciones. Resultados: Se seleccionaron 4 preguntas PICO relativas a la eficacia y seguridad de los tratamientos farmacológicos sistémicos en los pacientes con síndrome de Behçet con manifestaciones clínicas refractarias a terapia convencional, relacionadas con los fenotipos mucocutáneo y/o articular, vascular, neurológico-parenquimatoso y gastrointestinal. Se formularon un total de 7 recomendaciones estructuradas por pregunta, con base en la evidencia encontrada y el consenso de expertos. Conclusiones: El tratamiento de las manifestaciones clínicas más graves del síndrome de Behçet carece de evidencia científica sólida y no existen documentos de recomendaciones específicas para los pacientes con enfermedad refractaria a la terapia convencional. Con el fin de aportar una respuesta a esta necesidad, se presenta el primer documento de recomendaciones de la Sociedad Española de Reumatología específicas para el abordaje terapéutico de estos pacientes, que servirá de ayuda en la toma de decisiones clínica y la reducción de la variabilidad en la atención.(AU)

Objective: To develop multidisciplinary recommendations based on available evidence and expert consensus for the therapeutic management of patients with refractory Behçet's syndrome (difficult to treat, severe resistant, severe relapse) to conventional treatment. Methods: A group of experts identified clinical research questions relevant to the objective of the document. These questions were reformulated in PICO format –patient, intervention, comparison and outcome–. Systematic reviews of the evidence were conducted; the quality of the evidence was evaluated following the methodology of the international working group Grading of Recommendations, Assessment, Development, and Evaluation. After that, the multidisciplinary panel formulated the specific recommendations. Results: Four PICO questions were selected regarding the efficacy and safety of systemic pharmacological treatments in patients with Behçet's syndrome with clinical manifestations refractory to conventional therapy related to mucocutaneous and/or articular, vascular, neurological parenchymal and gastrointestinal phenotypes. A total of 7 recommendations were made, structured by question, based on the identified evidence and expert consensus. Conclusions: The treatment of most severe clinical manifestations of Behçet's syndrome lacks solid scientific evidence and, besides, there are no specific recommendation documents for patients with refractory disease. With the aim of providing a response to this need, here we present the first official recommendations of the Spanish Society of Rheumatology for the management of these patients. They are devised as a tool for assistance in clinical decision making, therapeutic homogenisation and to reduce variability in the care of these patients.(AU)

Multidrug-resistant pathogens and ventilator-associated pneumonia in critically ill COVID-19 and non-COVID-19 patients: a prospective observational monocentric comparative study.

BACKGROUND: The COVID-19 pandemic has increased the incidence of ventilator-associated pneumonia (VAP) among critically ill patients. However, a comparison of VAP incidence in COVID-19 and non-COVID-19 cohorts, particularly in a context with a high prevalence of multidrug-resistant (MDR) organisms, is lacking. MATERIAL AND METHODS: We conducted a single-center, mixed prospective and retrospective cohort study comparing COVID-19 patients admitted to the intensive care unit (ICU) of the "Città della Salute e della Scienza" University Hospital in Turin, Italy, between March 2020 and December 2021 (COVID-19 group), with a historical cohort of ICU patients admitted between June 2016 and March 2018 (NON-COVID-19 group). The primary objective was to define the incidence of VAP in both cohorts. Secondary objectives were to evaluate the microbial cause, resistance patters, risk factors and impact on 28 days, ICU and in-hospital mortality, duration of ICU stay, and duration of hospitalization). RESULTS: We found a significantly higher incidence of VAP (51.9% - n = 125) among the 241 COVID-19 patients compared to that observed (31.2% - n = 78) among the 252 NON-COVID-19 patients. The median SOFA score was significantly lower in the COVID-19 group (9, Interquartile range, IQR: 7-11 vs. 10, IQR: 8-13, p < 0.001). The COVID-19 group had a higher prevalence of Gram-positive bacteria-related VAP (30% vs. 9%, p < 0.001), but no significant difference was observed in the prevalence of difficult-to-treat (DTR) or MDR bacteria. ICU and in-hospital mortality in the COVID-19 and NON-COVID-19 groups were 71% and 74%, vs. 33% and 43%, respectively. The presence of COVID-19 was significantly associated with an increased risk of 28-day all-cause hospital mortality (Hazard ratio, HR: 7.95, 95% Confidence Intervals, 95% CI: 3.10-20.36, p < 0.001). Tracheostomy and a shorter duration of mechanical ventilation were protective against 28-day mortality, while dialysis and a high SOFA score were associated with a higher risk of 28-day mortality. CONCLUSION: COVID-19 patients with VAP appear to have a significantly higher ICU and in-hospital mortality risk regardless of the presence of MDR and DTR pathogens. Tracheostomy and a shorter duration of mechanical ventilation appear to be associated with better outcomes.

Schema therapy versus treatment as usual for outpatients with difficult-to-treat depression: study protocol for a parallel group randomized clinical trial (DEPRE-ST).

BACKGROUND: About one third of patients with depression are in a condition that can be termed as "difficult-to-treat". Some evidence suggests that difficult-to-treat depression is associated with a higher frequency of childhood trauma and comorbid personality disorders or accentuated features. However, the condition is understudied, and the effects of psychotherapy for difficult-to-treat depression are currently uncertain. The aim of this trial is to investigate the beneficial and harmful effects of 30 sessions of individual schema therapy versus treatment as usual for difficult-to-treat depression in the Danish secondary, public mental health sector. METHODS: In this randomized, multi-centre, parallel-group, superiority clinical trial, 129 outpatients with difficult-to-treat depression will be randomized (1:1) to 30 sessions of individual schema therapy or treatment as usual; in this context mainly group-based, short-term cognitive behaviour or psychodynamic therapy. The primary outcome is the change from baseline in depressive symptoms 12 months after randomization, measured on the observer-rated 6-item Hamilton Rating Scale for Depression. The secondary outcomes are health-related quality of life assessed with the European Quality of Life 5 Dimensions 5 Level Version, functional impairment assessed with the Work and Social Adjustment Scale, psychological wellbeing assessed with the WHO-5 Well-being Index, and negative effects of treatment assessed with the Negative Effects Questionnaire. Exploratory outcomes are improvement on patient self-defined outcomes, personal recovery, anxiety symptoms, anger reactions, metacognitive beliefs about anger, and perseverative negative thinking. Outcomes will be assessed at 6, 12, and 24 months after randomization; the 12-month time-point being the primary time-point of interest. Outcome assessors performing the depression-rating, data managers, statisticians, the data safety and monitoring committee, and conclusion makers for the outcome article will be blinded to treatment allocation and results. To assess cost-effectiveness of the intervention, a health economic analysis will be performed. DISCUSSION: This trial will provide evidence on the beneficial and harmful effects, as well as the cost-effectiveness of schema therapy versus treatment as usual for outpatients with difficult-to-treat depression. The results can potentially improve treatment for a large and understudied patient group. TRIAL REGISTRATION: ClinicalTrials.gov NCT05833087. Registered on 15th April 2023 (approved without prompts for revision on 27th April 2023).

SER recommendations on treatment of refractory Behçet's syndrome.

OBJECTIVE: To develop multidisciplinary recommendations based on available evidence and expert consensus for the therapeutic management of patients with refractory Behçet's syndrome (BS) (difficult to treat, severe resistant, severe relapse) to conventional treatment. METHODS: A group of experts identified clinical research questions relevant to the objective of the document. These questions were reformulated in PICO format (patient, intervention, comparison and outcome). Systematic reviews of the evidence were conducted, the quality of the evidence was evaluated following the methodology of the international working group Grading of Recommendations Assessment, Development, and Evaluation (GRADE). After that, the multidisciplinary panel formulated the specific recommendations. RESULTS: 4 PICO questions were selected regarding the efficacy and safety of systemic pharmacological treatments in patients with BS with clinical manifestations refractory to conventional therapy related to mucocutaneous and/or articular, vascular, neurological parenchymal and gastrointestinal phenotypes. A total of 7 recommendations were made, structured by question, based on the identified evidence and expert consensus. CONCLUSIONS: The treatment of most severe clinical manifestations of BS lacks solid scientific evidence and, besides, there are no specific recommendation documents for patients with refractory disease. With the aim of providing a response to this need, here we present the first official Recommendations of the Spanish Society of Rheumatology for the management of these patients. They are devised as a tool for assistance in clinical decision making, therapeutic homogenisation and to reduce variability in the care of these patients.

In vitro activity of antibiotics potentially effective against difficult-to-treat strains of Gram-negative rods: retrospective study.

Bacterial resistance surveillance is one of the main outputs of microbiological laboratories and its results are important part of antimicrobial stewardship (AMS). In this study, the susceptibility of specific bacteria to selected antimicrobial agents was tested. The susceptibility of 90 unique isolates of pathogens of critical priority obtained from clinically valid samples of ICU patients in 2017-2021 was tested. 50% of these fulfilled difficult-to-treat resistance (DTR) criteria and 50% were susceptible to all antibiotics included in the definition. 10 Enterobacterales strains met DTR criteria, and 2 (20%) were resistant to colistin (COL), 2 (20%) to cefiderocol (FCR), 7 (70%) to imipenem/cilastatin/relebactam (I/R), 3 (30%) to ceftazidime/avibactam (CAT) and 5 (50%) to fosfomycin (FOS). For Enterobacterales we also tested aztreonam/avibactam (AZA) for which there are no breakpoints yet. The highest MIC of AZA observed was 1 mg/l, MIC range in the susceptible cohort was 0.032-0.064 mg/l and in the DTR cohort (incl. class B beta-lactamase producers) it was 0.064-1 mg/l. Two (13.3%) isolates of Pseudomonas aeruginosa (15 DTR strains) were resistant to COL, 1 (6.7%) to FCR, 13 (86.7%) to I/R, 5 (33.3%) to CAT, and 5 (33.3%) to ceftolozane/tazobactam. All isolates of Acinetobacter baumannii with DTR were susceptible to COL and FCR, and at the same time resistant to I/R and ampicillin/sulbactam. New antimicrobial agents are not 100% effective against DTR. Therefore, it is necessary to perform susceptibility testing of these antibiotics, use the data for surveillance (including local surveillance) and conform to AMS standards.

Patient adherence as a predictor of acute and long-term outcomes in concentrated exposure treatment for difficult-to-treat obsessive-compulsive disorder.

BACKGROUND: Exposure and response prevention (ERP) is considered the first-line psychotherapy for obsessive-compulsive disorder (OCD). Substantial research supports the effectiveness of ERP, yet a notable portion of patients do not fully respond while others experience relapse. Understanding poor outcomes such as these necessitates further research. This study investigated the role of patient adherence to ERP tasks in concentrated exposure treatment (cET) in a sample who had previously not responded to treatment or relapsed. METHOD: The present study included 163 adults with difficult-to-treat OCD. All patients received cET delivered during four consecutive days. Patients' treatment adherence was assessed using the Patient EX/RP Adherence Scale (PEAS-P) after the second and third day of treatment. OCD severity was evaluated at post-treatment, 3-month follow-up, and 1-year follow-up by independent evaluators. RESULTS: PEAS-P scores during concentrated treatment were associated with OCD-severity at post-treatment, 3-month follow-up, and 1-year follow-up. Moreover, PEAS-P scores predicted 12-month OCD severity adjusting for relevant covariates. Adherence also predicted work- and social functioning at 1-year follow-up. CONCLUSIONS: These results indicate that ERP adherence during the brief period of cET robustly relates to improvement in OCD symptoms and functioning in both the short and long term. Assessing adherence might identify patients at risk of poor outcomes, while improving adherence may enhance ERP for treatment resistant patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02656342.

Long-Term Immunomodulatory Impact of VNS on Peripheral Cytokine Profiles and Its Relationship with Clinical Response in Difficult-to-Treat Depression (DTD).

Vagus nerve stimulation (VNS) represents a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). Anti-inflammatory effects have been discussed as a key mechanism of action of VNS. However, long-term investigations in real-world patients are sparse. In this naturalistic observational study, we collected data on cytokines in peripheral blood in n = 6 patients (mean age 47.8) with DTD and VNS treatment at baseline and at 6 months follow-up. We have identified clusters of peripheral cytokines with a similar dynamic over the course of these 6 months using hierarchical clustering. We have investigated cytokine changes from baseline to 6 months as well as the relationship between the cytokine profile at 6 months and long-term response at 12 months. After 6 months of VNS, we observed significant correlations between cytokines (p < 0.05) within the identified three cytokine-pairs which were not present at baseline: IL(interleukin)-6 and IL-8; IL-1ß and TNF-α; IFN-α2 and IL-33. At 6 months, the levels of all the cytokines of interest had decreased (increased in non-responders) and were lower (5-534 fold) in responders to VNS than in non-responders: however, these results were not statistically significant. VNS-associated immunomodulation might play a role in long-term clinical response to VNS.

Optimizing care for children with difficult-to-treat and severe asthma through specialist paediatric asthma centres: expert practical experience and advice.

Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition.This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines.Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient's journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nurses to play a significant role in facilitating multidisciplinary working.Through this project is agreed a framework of practical advice to optimize the care of children with severe asthma. We encourage clinicians and policymakers to implement this practical advice to enhance patient care.

Efficacy of the posterior nasal nerve resection combined with hormone transnasal nebulization on difficult-to-treat rhinosinusitis: a retrospective analysis.

OBJECTIVE: A retrospective analysis was performed to explore the clinical effect of the Posterior Nasal Nerve (PNN) resection combined with hormone transnasal nebulization on Difficult-to-Treat Rhinosinusitis (DTRS). METHODS: A total of 120 DTRS patients were selected and divided into a control group (n = 60) and a study group (n = 60) according to different treatments. The control group patients were treated via PNN resection, followed by normal saline transnasal nebulization; the study group patients were given PNN resection and then treated with budesonide suspension transnasal nebulization. Subsequently, the comparison was performed between the two groups in terms of (1) Clinical baseline characteristics; (2) Sino-nasal Outcome Test (SNOT)-22 scores before treatment and after 3-months, 6-months and 12-months of treatment; (3) Lund-MacKay scores before treatment and after 10, 30, 90, and 180 days of treatment; (4) Incidence of adverse reactions during treatment. RESULTS: There was no significant difference in SNOT-22 or Lund-Kennedy scores between the two groups before treatment (p > 0.05). After treatment, the SNOT-22 and Lund-Kennedy scores of the control and the study groups were decreased, and compared with the control group, the SNOT-22 and Lund-Kennedy scores in the study group improved more significantly (p < 0.05). In addition, the study group and the control group presented with 1 and 4 cases of nasal adhesion, 2 and 3 cases of epistaxis, 1 and 4 cases of sinus orifice obstruction, 1 and 3 cases of lacrimal duct injuries, respectively. The incidence of adverse reactions in the study group was significantly lower than that in the control group (8.3% vs. 23.3%) (p < 0.05). CONCLUSION: PNN resection combined with hormone transnasal nebulization treatment can improve the symptoms and quality of life of DTRS patients, with good clinical efficacy but few adverse reactions. Therefore, such combination treatment deserves a promotion and application clinically. LEVEL OF EVIDENCE: Level 3.

Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms: A real-life experience.

AIM: To investigate the efficacy of intravenous (IV) fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) acute and subacute infections with multi-drug-resistant (MDR) Gram-negative bacteria (GNB), and risk factors associated with 90-day mortality. METHODS: A retrospective, observational, monocentric study enrolled patients treated with IV fosfomycin in combination regimens (≥72 h) for proven DTT-MDR-GNB infection. Multi-variate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving fosfomycin was performed to control for confounding factors. RESULTS: In total, 70 patients were included in this study: 54.3% had carbapenem-resistant isolates, 31.4% had ceftazidime/avibactam-resistant isolates and 28.6% had ceftolozane/tazobactam-resistant isolates. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), osteomyelitis (17.1%) and intra-abdominal infections. All-cause 30- and 90-day mortality were 15.7% and 31.4%, respectively (18.9% and 50% considering acute DTT-MDR-GNB infections alone). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock and ceftolozane/tazobactam resistance. The relationship between resistance to ceftolozane/tazobactam and 90-day mortality was confirmed to be significant after adjustment by propensity score analysis (hazard ratio 5.84, 95% confidence interval 1.65-20.68; P=0.006). CONCLUSIONS: Fosfomycin seems to be a promising salvage, combination treatment in DTT-MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are needed urgently to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of DTT-MDR-GNB infections.

A revisionist model for treatment-resistant and difficult-to-treat depression.

OBJECTIVE: The aim of this study is to consider limitations to the heuristics 'treatment-resistant depression' (TRD) and 'difficult-to-treat' depression (DTD) and to offer a revisionist model. METHODS: A number of limitations to the two constructs are noted, particularly the risk of each positioning clinical depression as an entity and then applying a linear sequencing management model. RESULTS: Arguing that clinical depression is heterogenous in nature (with categorical and 'fuzzy set conditions), in cause and in response to treatment, allows an alternate model for addressing depressive conditions that are not readily responsive to treatment. A skeletal model for proceeding is offered for consideration and development. CONCLUSION: If such a model is accepted, then differing criteria for defining treatment resistance and treatment failure might be generated for differing depressive conditions, and condition-specific sequencing algorithms (embracing drug and non-drug strategies) developed for their management.

Effectiveness of Partial Enteral Nutrition as Add-On to Biologics in Patients With Refractory and Difficult-to-Treat Crohn's Disease: A Pilot Study.

Background: Partial enteral nutrition (PEN) is a well-established treatment for children with Crohn's disease (CD). However, its efficacy in adults with CD remains uncertain. We aimed to assess the effectiveness of PEN as an add-on to escalated biological therapy in adults with CD who have lost response to biologics. Methods: We conducted a retrospective observational study including patients who had lost response to biologics and received PEN in combination with escalated treatment, compared to those treated only with escalated therapy. The primary endpoint was steroid-free clinical remission (CR) at 24 weeks. Secondary endpoints included transmural healing (TH) and response (TR) rates along with selected clinical outcomes. Results: Forty-two patients were screened; 12 (28.6%) were excluded for complicated disease and 30 (71.4%) were included in the final analysis. Fourteen (46.7%) patients completed PEN treatment at 8 weeks, while 16 patients (53.3%) discontinued treatment due to intolerance and continued with escalation of biologic (BT group). At 24 weeks, 9 patients (64.3%) in the PEN group achieved CR, compared to 4 patients (25%) in the BT group (P = .03). The TR rate was 64.9% in the PEN group and 25% in the BT group (P = .03). Patients receiving PEN exhibited an increase in albumin levels compared to those in the BT group (Δ = 0.5; P = .02). A higher rate of therapy changes (68.7%) was observed in the BT group compared to 14.2% in the PEN group (P = .004). Prior failure to 2 lines of biological therapy was associated with adherence to PEN (OR = 1.583; CI = 1.06-2.36; P = .01). Conclusions: In patients who had lost response to biologics, PEN in combination with escalated biologics was associated with CR and TR and improved nutritional status. Hence, the addition of PEN should be considered for patients with difficult-to-treat CD.

Combination of Acute and Maintenance Esketamine Treatment With Adjunctive Long-Term Vagus Nerve Stimulation in Difficult-to-Treat Depression.

INTRODUCTION: The antidepressant effect of N-methyl-D-aspartate antagonists is often short lasting, raising the question of the best maintenance strategy, which has remained unanswered. Vagus nerve stimulation (VNS) as a treatment option for refractory and chronic major depression was shown to reduce the need for maintenance treatment sessions in patients receiving electroconvulsive therapy. To our knowledge, there are no published data on the combination of VNS and esketamine in the literature. MATERIALS AND METHODS: This is a naturalistic prospective and retrospective observational study in patients treated with long-term VNS owing to difficult-to-treat depression. These patients also have received esketamine maintenance sessions in addition to short-term treatment. We have investigated the need for maintenance esketamine sessions per month after VNS implantation (number of sessions/number of months between visits), the change in depression severity (mean Montgomery-Asberg Depression Rating Scale [MADRS] score), and the number of hospitalizations per month (number of hospitalizations/number of postoperative observation months). Follow-up visits have been scheduled every three months after VNS implantation (follow-up period 12-24 months, mean 17). RESULTS: All patients (n = 8, mean age 53.1 years) had severe difficult-to-treat depression (DTD) (mean MADRS at baseline 30.9). Mean number of hospitalizations per month decreased from 0.17 to 0.11 after VNS implantation (p = 0.041, T = 2.030, df = 7). Mean MADRS at 12 months was 18.3 (40.8% MADRS reduction, p = 0.008, T = 3.146, df = 7). Six of eight patients were offered maintenance esketamine treatment. Mean number of esketamine treatment sessions per month and case decreased from 2.3 at the six-month visit to 0.8 at 12 months (p = 0.076, T = 1,690, df = 5) after VNS implantation. Termination of maintenance esketamine was possible in four cases after a mean of 11.5 months. CONCLUSIONS: Combination of esketamine and VNS was effective in patients with DTD to relieve disease severity and reduce hospitalizations. The need for esketamine treatment sessions decreased after 6 months of VNS. No safety concerns arose in this study regarding the combination treatment. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03320304.

Personalized Approach in the Management of Difficult-to-Treat and Treatment-Resistant Depression With Second-Generation Antipsychotics: A Delphi Statement.

Background Major depressive disorder (MDD) has many facets including mixed or atypical depression that requires personalized care to improve treatment-related outcomes. Second-generation antipsychotics (SGAs) offer complementary mechanisms for clinical roles in difficult-to-treat depression and treatment-resistant depression cases. Aim/objective To further delineate a consensus on the clinical positioning of SGAs for MDD, mixed, or atypical depression, a Knowledge Attitude Perception (KAP)-mediated Delphi Statement was planned. Material/methods A literature review for the definition, diagnosis, and management of MDD, mixed, and atypical depression as treatment-resistant depression (TRD) or difficult-to-treat depression (DTD) was conducted by a steering committee of academic and clinical experts (n=6) while developing a validated KAP questionnaire. Scientific statements as clinical recommendations were evolved using the Delphi methodology before building a clinical expert consensus with an online survey (n=24). Results Twenty-four psychiatrists highlighted DTD to offer a multidimensional approach to assess treatment strategies involving selective serotonin reuptake inhibitors (SSRIs) or SGAs, while ensuring symptom, functional, and quality of life (QoL) domain improvement for improved outcomes and remission rates. MDD cases with anxiety, anhedonia, comorbidities, and risk traits require personalized care with early induction of SGAs for severe cases or symptom persisters with functional impairment. Early augmentation with SGAs including aripiprazole or cariprazine can provide a favorable risk-benefit profile for clinical cases of MDD with or without the antecedent of mixed depression or personality disorder.  Conclusion The literature review and KAP responses emphasize the importance of early identification for personalized care strategies with SGAs for DTD. Large-scale real-world evidence needs to evolve with due recognition of different phenotypes as TRD or DTD with partial or functional impairment to understand the impact of appropriate treatment pathways with SGAs.

Efficacy and safety of tildrakizumab in elderly patients: real-world multicenter study (ESTER - study).

Purpose of the article: Interleukin-23 inhibitors, such as tildrakizumab, have emerged as safe and effective options for the management of psoriasis. Yet their efficacy in elderly patients (aged 65 years or more), particularly in those with difficult-to-treat areas involvement, remains insufficiently explored. We conducted this real-life retrospective multicentric observational study to assess the effectiveness of tildrakizumab in elderly patients with moderate-to-severe psoriasis, with involvement of difficult-to-treat areas.Materials and methods: We enrolled forty-nine patients aged 65 years old or more (mean age 73.1 ± 6.0), all treated with tildrakizumab for at least 28 weeks. The effectiveness of tildrakizumab was assessed by Static Physician's Global Assessment of Genitalia (sPGA-G), fingernail-PGA (f-PGA), palmoplantar PGA (pp-PGA), scalp-specific PGA (sc-PGA), and Psoriasis Area and Severity Index (PASI) scores.Results: Significant improvements in PASI scores were observed within 28 weeks of treatment, with 77.5%, 60%, and 45.2% of patients achieving PASI75, PASI90, and PASI100, respectively. The mean PASI decreased significantly from baseline (13.6 ± 9.9) to 1.3 ± 1.7 at week 28. More than 90% of patients had clear sPGA-G and pp-PGA scores and over 70% had clear f-PGA and sc-PGA scores after 28 weeks.Conclusions: Our findings suggest that tildrakizumab could be a valuable option for the treatment of elderly patients, including those with difficult-to-treat areas involvement.

Extensively drug-resistant Pseudomonas aeruginosa: clinical features and treatment with ceftazidime/avibactam and ceftolozane/tazobactam in a tertiary care university hospital center in Portugal - A cross-sectional and retrospective observational study.

Introduction: Extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) is a growing concern due to its increasing incidence, limited therapeutic options, limited data on the optimal treatment, and high mortality rates. The study aimed to characterize the population, the outcome and the microbiological characteristics of XDR-PA identified in a Portuguese university hospital center. Methods: All XDR-PA isolates between January 2019 and December 2021 were identified. XDR-PA was defined as resistance to piperacillin-tazobactam, third and fourth generation cephalosporins, carbapenems, aminoglycosides and fluoroquinolones. A retrospective analysis of the medical records was performed. Results: One hundred seventy-eight individual episodes among 130 patients with XDR-PA detection were identified. The most common sources of infection were respiratory (32%) and urinary tracts (30%), although skin and soft tissue infections (18%) and primary bacteremia (14%) were also prevalent. Colonization was admitted in 64 cases. Several patients had risk factors for complicated infections, most notably immunosuppression, structural lung abnormalities, major surgery, hemodialysis or foreign intravascular or urinary devices. XDR-PA identification was more frequent in male patients with an average age of 64.3 ± 17.5 years. One non-susceptibility to colistin was reported. Only 12.4% were susceptible to aztreonam. Ceftazidime-avibactam (CZA) was susceptible in 71.5% of the tested isolates. Ceftolozane-tazobactam (C/T) was susceptible in 77.5% of the tested isolates. Antibiotic regimens with XDR-PA coverage were reserved for patients with declared infection, except to cystic fibrosis. The most frequently administered antibiotics were colistin (41 cases), CZA (39 cases), and C/T (16 cases). When combination therapy was used, CZA plus colistin was preferred. The global mortality rate among infected patients was 35.1%, significantly higher in those with hematologic malignancy (50.0%, p < 0.05), followed by the ones with bacteremia (44.4%, p < 0.05) and those medicated with colistin (39.0%, p < 0.05), especially the ones with respiratory infections (60.0%). Among patients treated with CZA or C/T, the mortality rate seemed to be lower. Discussion: XDR-PA infections can be severe and difficult to treat, with a high mortality rate. Even though colistin seems to be a viable option, it is likely less safe and efficient than CZA and C/T. To the best of the authors' knowledge, this is the first description of the clinical infection characteristics and treatment of XDR-PA in Portugal.