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1.
Int J Antimicrob Agents ; : 106445, 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34614441

RESUMO

Dalbavancin is increasingly used for the treatment of staphylococcal osteoarticular infections. Some population pharmacokinetic studies suggest that a two 1500 mg dosing regimen one-week apart could ensure effective treatment for several weeks. Here we want to provide clinicians with a proof-of-concept of the potential role that therapeutic drug monitoring (TDM) may have in giving a real-time feedback of the estimated duration of optimal treatment of staphylococcal osteoarticular infections with dalbavancin in each single patient.

2.
Front Pharmacol ; 12: 755075, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646143

RESUMO

Introduction: Antimicrobial treatment is quite common among hospitalized children. The dynamic age-associated physiological variations coupled with the pathophysiological alterations caused by underlying illness and potential drug-drug interactions makes the implementation of appropriate antimicrobial dosing extremely challenging among paediatrics. Therapeutic drug monitoring (TDM) may represent a valuable tool for assisting clinicians in optimizing antimicrobial exposure. Clinical pharmacological advice (CPA) is an approach based on the correct interpretation of the TDM result by the MD Clinical Pharmacologist in relation to specific underlying conditions, namely the antimicrobial susceptibility of the clinical isolate, the site of infection, the pathophysiological characteristics of the patient and/or the drug-drug interactions of cotreatments. The aim of this study was to assess the role of TDM-based CPAs in providing useful recommendations for the real-time personalization of antimicrobial dosing regimens in various paediatric settings. Materials and methods: Paediatric patients who were admitted to different settings of the IRCCS Azienda Ospedaliero-Universitaria of Bologna, Italy (paediatric intensive care unit [ICU], paediatric onco-haematology, neonatology, and emergency paediatric ward), between January 2021 and June 2021 and who received TDM-based CPAs on real-time for personalization of antimicrobial therapy were retrospectively assessed. Demographic and clinical features, CPAs delivered in relation to different settings and antimicrobials, and type of dosing adjustments were extracted. Two indicators of performance were identified. The number of dosing adjustments provided over the total number of delivered CPAs. The turnaround time (TAT) of CPAs according to a predefined scale (optimal, <12 h; quasi-optimal, between 12-24 h; acceptable, between 24-48 h; suboptimal, >48 h). Results: Overall, 247 CPAs were delivered to 53 paediatric patients (mean 4.7 ± 3.7 CPAs/patient). Most were delivered to onco-haematological patients (39.6%) and to ICU patients (35.8%), and concerned mainly isavuconazole (19.0%) and voriconazole (17.8%). Overall, CPAs suggested dosing adjustments in 37.7% of cases (24.3% increases and 13.4% decreases). Median TAT was 7.5 h (IQR 6.1-8.8 h). Overall, CPAs TAT was optimal in 91.5% of cases, and suboptimal in only 0.8% of cases. Discussion: Our study provides a proof of concept of the helpful role that TDM-based real-time CPAs may have in optimizing antimicrobial exposure in different challenging paediatric scenarios.

3.
Expert Rev Anti Infect Ther ; : 1-22, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34488527

RESUMO

INTRODUCTION: Prompt implementation of appropriate targeted antibiotic therapy representsa valuable approach in improving clinical and ecological outcome in critically septic patients. Thismultidisciplinary opinion article aims to develop evidence-based algorithms for targeted antibiotictherapy of infection-related ventilator associated complications (IVACs) caused by Enterobacterales,which are among the most common pathogens associated with these conditions. AREAS COVERED: A multidisciplinary team of four experts had several rounds of assessment for developingalgorithms devoted to targeted antimicrobial therapy of IVACs caused by Enterobacterales.A literature search was performed on PubMed-MEDLINE (until March 2021) to provide evidence forsupporting therapeutic choices. Quality and strength of evidence was established according toa hierarchical scale of the study design. Six different algorithms with associated recommendations concerning therapeutic choice and dosing optimization were suggested according to the susceptibilitypattern of Enterobacterales: multi-susceptible, extended-spectrum beta-lactamase (ESBL)-producing,AmpC beta-lactamase-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and metallo-beta-lactamase (MBL)-producing Enterobacterales. EXPERT OPINION: The implementation of algorithms focused on prompt revision of antibiotic regimensguided by results of conventional and rapid diagnostic methodologies, appropriate place in therapy ofnovel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and PK/PD optimization of antibiotic dosing regimens is strongly suggested.

4.
Mycoses ; 64(11): 1317-1327, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34387004

RESUMO

INTRODUCTION: Although echinocandins are recommended as first-line prophylaxis for high-risk orthotopic liver transplant (OLT) recipients, occurrence of breakthrough-invasive fungal infections (IFIs) remains a serious concern. We aim to assess the risk of breakthrough IFIs among OLT recipients exposed to prophylaxis with echinocandins compared to other antifungals. MATERIALS AND METHODS: Two authors independently searched PubMed-MEDLINE, Embase, study registries and reference lists from inception to March 2021, to retrieve randomised controlled trials (RCTs) or observational studies comparing efficacy and safety of echinocandins vs other antifungals for prophylaxis in OLT recipients. Data were independently extracted from two authors, and the quality of included studies was independently assessed according to ROB 2.0 tool for RCTs and ROBINS-I tool for observational studies. The primary outcome was occurrence of breakthrough IFI at the end of prophylaxis (EOP). RESULTS: 698 articles were screened, and ten studies (3 RCTs and 7 observational) were included. No difference between echinocandins and other antifungals in terms of breakthrough IFIs at the EOP emerged both from RCTs (odds ratio [OR] 0.85, 95% CI 0.24-2.99) and observational studies (OR 1.43, 95% CI 0.28-7.40). No difference emerged also for secondary outcomes. In the subgroup comparison between echinocandins and polyenes, a trend for higher risk of breakthrough IFI at the EOP (OR 4.82, 95% CI 0.97-24.03) was noted. CONCLUSIONS: Echinocandins do not seem to be associated with increased risk of breakthrough IFIs in OLT recipients. However, the large diversity in the comparator group hinders a definitive interpretation. Further studies exploring the relationship between echinocandin use and breakthrough IFIs according to specific comparators are warranted.

5.
Drug Des Devel Ther ; 15: 3391-3409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34376973

RESUMO

Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered.

6.
Pharmaceuticals (Basel) ; 14(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34451835

RESUMO

We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered.

7.
Eur J Prev Cardiol ; 28(9): 983-989, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34402868

RESUMO

AIMS: The aim of this study was to characterise clinical priority of adverse events with sacubitril/valsartan for targeting preventive measures. METHODS: We used the US Food and Drug Administration adverse event reporting system (worldwide pharmacovigilance database) to compare adverse events recording sacubitril/valsartan as suspect with other cardiovascular drugs. Disproportionality analyses were performed by calculating the reporting odds ratios, deemed significant when the lower limit of the 95% confidence interval was greater than 1. Clinical priority was assigned to adverse events with significant disproportionality by scoring (range 0-10 points) five features (number of events, magnitude of the lower limit of the 95% confidence interval, mortality frequency, important/designated medical event, biological plausibility). RESULTS: Sacubitril/valsartan was recorded in 20,021 reports, with 178 adverse events associated with significant disproportionality: 71.9%, 25.9% and 2.2% were classified as weak, moderate and strong clinical priorities, respectively. Increased reporting emerged for several cardiovascular adverse events, including 'renal failure' (N = 388; lower limit of the 95% confidence interval 2.26), 'hyperkalaemia' (314; 2.42) and 'angioedema' (309; 1.56). Sudden cardiac death (priority score 9 points) was the only designated medical event with strong clinical priority. Notably, sudden cardiac death occurred early after sacubitril/valsartan administration (average onset 124 days), with concomitant drugs known for pro-arrhythmic potential (e.g. amiodarone, escitalopram, mirtazapine, loop diuretics) in 26.2% of records. CONCLUSION: The increased cardiovascular reporting of sacubitril/valsartan in the real world was largely predictable from pre-approval evidence, underlying disease and likely patients' comorbidities. The unexpected reporting of sudden cardiac death occurred well before the complete development of positive electrical remodelling induced by sacubitril/valsartan, and calls for stringent clinical monitoring (to reduce the pro-arrhythmic burden related to co-medications), and further investigation on appropriate combination with other preventive measures.

8.
Drug Des Devel Ther ; 15: 3349-3378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34376971

RESUMO

Dalbavancin is a novel, long-acting lipoglycopeptide characterized by a long elimination half-life coupled with excellent in vitro activity against multidrug-resistant Gram-positives. Although it is currently approved only for the treatment of acute bacterial skin and skin structure infections, an ever-growing amount of evidence supports the efficacy of dalbavancin as a long-term therapy in osteomyelitis, prosthetic joint infections, endocarditis, and bloodstream infections. This article provides a critical reappraisal of real-world use of dalbavancin for off-label indications. A search strategy using specific keywords (dalbavancin, osteomyelitis, endocarditis, long-term suppressive therapy, bloodstream infection, pharmacokinetic/pharmacodynamic profile) until April 2021 was performed on the PubMed-MEDLINE database. As for other novel antibiotics, a conundrum between approved indications and potential innovative therapeutic uses has emerged for dalbavancin as well. The promising efficacy in challenging scenarios (i.e., osteomyelitis, endocarditis, prosthetic joint infections), coupled with the unique pharmacokinetic/pharmacodynamic properties, makes dalbavancin a valuable alternative to daily in-hospital intravenous or outpatient antimicrobial regimens in the treatment of long-term Gram-positive infections. This makes dalbavancin valuable in the current COVID-19 scenario, in which hospitalization and territorial medicine empowerment are unavoidable.


Assuntos
Assistência Ambulatorial , Antibacterianos/uso terapêutico , COVID-19 , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Uso Off-Label , Participação do Paciente , Teicoplanina/análogos & derivados , Algoritmos , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Infecções por Bactérias Gram-Positivas/diagnóstico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Teicoplanina/efeitos adversos , Teicoplanina/farmacocinética , Teicoplanina/uso terapêutico , Resultado do Tratamento
9.
Expert Opin Drug Saf ; 20(11): 1421-1431, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34280062

RESUMO

BackgroundTo investigate the adverse event (AE) profile of tedizolid and linezolid in post-marketing surveillance.Research design and methodsWe queried the worldwide FDA Adverse Event Reporting System and selected all records where tedizolid and linezolid were reported as suspect by removing potential duplicates. Disproportionality analysis was performed investigating designated medical events (DMEs) and specific AEs of clinical interest reported with tedizolid. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL95%CI)>1, using linezolid as comparator. Case-by-case assessment of AEs reported in at least three cases with tedizolid was performed.ResultsOverall, 271 and 11,259 reports mentioning respectively tedizolid and linezolid were recorded, of which respectively 59 and 4,473 patients with DMEs or selected AEs were found. No difference emerged for the selected AEs except for increased reporting of hepatic failure (N = 3; LL95%CI = 1.06) with tedizolid considering reports collected after 2014. Extensive off-label use in terms of therapeutic indications (83.6%) and treatment duration was reported with tedizolid.ConclusionsSimilar AE reporting between the two oxazolidinones was found. Considering limitations of pharmacovigilance, this hypothesis of comparable safety profile should be tested prospectively through dedicated real-world studies.

10.
Curr Opin Infect Dis ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34261906

RESUMO

PURPOSE OF REVIEW: The aim of this review was to perform a critical reappraisal of the real-world evidence supporting administration by prolonged infusion of novel beta-lactams for the management of multidrug-resistant Gram-negative infections. RECENT FINDINGS: Real-world evidence support the use of novel beta-lactams by prolonged infusion over intermittent infusion in terms of achieving aggressive pharmacokinetic/pharmacodynamic (PK/PD) target for either maximizing efficacy and clinical outcome or suppressing the emergence of resistance development. Continuous infusion of ceftolozane-tazobactam showed a marked superiority toward both intermittent and extended infusion (EI) in achieving a PK/PD target of 100%fT> 4 X MIC in infections caused by less-susceptible Pseudomonas aeruginosa isolates. No resistance development was found in critically ill or immunocompromised patients treated with EI ceftolozane-tazobactam compared to intermittent infusion. Prolonged infusion of ceftazidime-avibactam was negatively associated with mortality in patients affected by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae infections. Different challenging scenarios (patients showing augmented renal clearance of affected by deep-seated infections) could benefit from prolonged infusion to optimize the efficacy of novel agents. SUMMARY: Although available data are still limited, real-world evidence regarding mainly ceftolozane-tazobactam and ceftazidime-avibactam could support the administration of novel beta-lactams by prolonged infusion in some specific scenarios in which achievement of aggressive PK/PD target is quite challenging.

11.
Infect Drug Resist ; 14: 2461-2498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234476

RESUMO

Prompt implementation of appropriate targeted antibiotic therapy represents a valuable approach in improving clinical and ecological outcome in critically septic patients. This multidisciplinary opinion article focused at developing evidence-based algorithms for targeted antibiotic therapy of bloodstream (BSIs), complicated urinary tract (cUTIs), and complicated intrabdominal infections (cIAIs) caused by Enterobacterales. The aim was to provide a guidance for intensive care physicians either in appropriately placing novel antibiotics or in considering strategies for sparing the broadest-spectrum antibiotics. A multidisciplinary team of experts (one intensive care physician, one infectious disease consultant, one clinical microbiologist and one MD clinical pharmacologist), performed several rounds of assessment to reach agreement in developing six different algorithms according to the susceptibility pattern (one each for multi-susceptible, extended-spectrum beta-lactamase-producing, AmpC beta-lactamase-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and Metallo-beta-lactamase (MBL)-producing Enterobacterales). Whenever multiple therapeutic options were feasible, a hierarchical scale was established. Recommendations on antibiotic dosing optimization were also provided. In order to retrieve evidence-based support for the therapeutic choices proposed in the algorithms, a comprehensive literature search was performed by a researcher on PubMed-MEDLINE from inception until March 2021. Quality and strength of evidence was established according to a hierarchical scale of the study design. Only articles published in English were included. It is expected that these algorithms, by allowing prompt revision of antibiotic regimens whenever feasible, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacokinetic/pharmacodynamic optimization of antibiotic dosing regimens, may be helpful either in improving clinical outcome or in containing the spread of antimicrobial resistance.

12.
Clin Pharmacokinet ; 60(10): 1271-1289, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34125420

RESUMO

Acute kidney injury represents a common complication in critically ill patients affected by septic shock and in many cases continuous renal replacement therapy (CRRT) may be required. In this scenario, antimicrobial dose optimization is highly challenging as the extracorporeal circuit may cause several pharmacokinetic alterations, which add up to volume of distribution and clearance variations resulting from sepsis. Variations in CRRT settings (i.e. modality of solute removal, type of filter material, blood flow rate and effluent flow rate), coupled with the presence of residual and/or recovering renal function, may cause dynamic variations in the clearance of hydrophilic antimicrobials. This means that dose reduction may not always be needed. Nowadays, the lack of pharmacokinetic data for novel antimicrobials during CRRT limits evidence-based dose recommendations for critically ill patients in this setting, thus making available evidence hardly applicable in real-world scenarios. This review aims to summarize the major determinants involved in antimicrobial clearance, and the available pharmacokinetic studies performed during CRRT involving novel antibiotics used for the management of multidrug-resistant Gram-positive and Gram-negative infections (namely ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol, imipenem-relebactam, meropenem-vaborbactam, ceftaroline, ceftobiprole, dalbavancin, and fosfomycin), providing a practical approach in guiding dose optimization in this special population.

13.
BMJ Open ; 11(5): e045635, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947736

RESUMO

INTRODUCTION: Junior doctors are responsible for a substantial number of prescribing errors, and final-year medical students lack sufficient prescribing knowledge and skills just before they graduate. Various national and international projects have been initiated to reform the teaching of clinical pharmacology and therapeutics (CP&T) during undergraduate medical training. However, there is as yet no list of commonly prescribed and available medicines that European doctors should be able to independently prescribe safely and effectively without direct supervision. Such a list could form the basis for a European Prescribing Exam and would harmonise European CP&T education. Therefore, the aim of this study is to reach consensus on a list of widely prescribed medicines, available in most European countries, that European junior doctors should be able to independently prescribe safely and effectively without direct supervision: the European List of Essential Medicines for Medical Education. METHODS AND ANALYSIS: This modified Delphi study will recruit European CP&T teachers (expert group). Two Delphi rounds will be carried out to enable a list to be drawn up of medicines that are available in ≥80% of European countries, which are considered standard prescribing practice, and which junior doctors should be able to prescribe safely and effectively without supervision. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Review Committee of VU University Medical Center (no. 2020.335) and by the Ethical Review Board of the Netherlands Association for Medical Education (approved project no. NVMO-ERB 2020.4.8). The European List of Essential Medicines for Medical Education will be presented at national and international conferences and will be submitted to international peer-reviewed journals. It will also be used to develop and implement the European Prescribing Exam.


Assuntos
Educação de Graduação em Medicina , Educação Médica , Competência Clínica , Currículo , Técnica Delfos , Europa (Continente) , Humanos , Países Baixos
14.
Int J Cancer ; 149(3): 675-683, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33844854

RESUMO

Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Fraturas Ósseas/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Farmacovigilância , Idoso , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Seguimentos , Fraturas Ósseas/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco
15.
CNS Drugs ; 35(4): 345-384, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33866523

RESUMO

As many patients with underlying psychiatric disorders may be infected with COVID-19, and COVID-19-affected subjects may frequently experience a new onset of psychiatric manifestations, concomitant use of psychotropic medications and COVID-19 therapies is expected to be highly likely and raises concerns of clinically relevant drug interactions. In this setting, four major mechanisms responsible for drug interactions involving psychotropic agents and COVID-19 therapies may be identified: (1) pharmacokinetic drug-drug interactions mainly acting on cytochrome P450; (2) pharmacodynamic drug-drug interactions resulting in additive or synergistic toxicity; (3) drug-disease interactions according to stage and severity of the disease; and (4) pharmacogenetic issues associated with polymorphisms of cytochrome P450 isoenzymes. In this review, we summarise the available literature on relevant drug interactions between psychotropic agents and COVID-19 therapies, providing practical clinical recommendations and potential management strategies according to severity of illness and clinical scenario.


Assuntos
COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/tendências , Transtornos Mentais/metabolismo , Psicotrópicos/efeitos adversos , Psicotrópicos/metabolismo , Antivirais/efeitos adversos , Antivirais/farmacocinética , COVID-19/genética , COVID-19/metabolismo , Interações Medicamentosas/fisiologia , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Farmacogenética/tendências
16.
Transpl Infect Dis ; 23(4): e13608, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33768656

RESUMO

OBJECTIVE: To investigate the rate of and the risk factors for breakthrough-IFI (b-IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses-Study-Group-Education-and-Research-Consortium (MSG-ERC) and the European-Confederation-of-Medical-Mycology (ECMM). METHODS: Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow-up was 1-year after OLT. B-IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b-IFI were analyzed among patients exposed to prophylaxis by univariable analysis. RESULTS: We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty-nine patients were diagnosed of IFI within 1 year after OLT. Of them, 11 presented with b-IFI within 17 (IQR 11-33) and 16 (IQR 4-30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b-IFI were classified as having high risk of IFI and were receiving anti-mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b-IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re-operation, and CMV infection (whole blood CMV-DNA >100 000 copies/mL). Although non-significant, a higher rate of b-IFI in patients on echinocandins was observed (8.2% vs 1.8%, P = .06). CONCLUSIONS: We observed 5% of b-IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b-IFI risk in this setting should be further explored.


Assuntos
Infecções Fúngicas Invasivas , Transplante de Fígado , Micoses , Adulto , Antifúngicos/uso terapêutico , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/prevenção & controle , Transplante de Fígado/efeitos adversos , Micoses/tratamento farmacológico , Micoses/epidemiologia , Micoses/prevenção & controle , Estudos Prospectivos
17.
Int J Antimicrob Agents ; 57(4): 106320, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33716177

RESUMO

OBJECTIVES: The impact on outcome of five interventions was reviewed in order to investigate the state of the art for management of Enterobacteriaceae bloodstream infection (E-BSI). METHODS: We searched for randomised controlled trials (RCTs) and observational studies published from January 2008 to March 2019 in PubMed, EMBASE and Cochrane Library. Populations consisted of patients with E-BSI. Interventions were as follows: (i) performance of imaging to assess BSI source and/or complications; (ii) follow-up blood cultures (FU-BCs); (iii) use of loading dose followed by extended/continuous infusion (E/CI) of ß-lactams; (iv) duration of treatment (short- versus long-term); and (v) infectious diseases (ID) consultation. Patients without intervention were considered as controls. The main outcome was 30-day mortality. RoB 2.0 and ROBINS-I tools were used for bias assessment. RESULTS: No study was eligible for interventions i, iii and v. For FU-BCs, one observational study including 901 patients with E-BSI was considered. Intervention consisted of repeating BCs within 2-7 days after index BCs. All-cause 30-day mortality was 14.2% (35/247) in the intervention group versus 14.7% (96/654) in the control group. For short treatment duration, two RCTs and six observational studies were included comprising 4473 patients with E-BSI. All-cause mortality was similar in the short and long treatment groups (OR = 1.10, 95% CI 0.83-1.44). CONCLUSION: Of the assessed interventions, only short treatment duration in non-immunocompromised patients with E-BSI is supported by current data. Studies investigating the use of systematic imaging, FU-BCs, E/CI ß-lactams and ID consultation in patients with E-BSI are needed.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Enterobacteriaceae/tratamento farmacológico , Enterobacteriaceae/efeitos dos fármacos , Indicadores de Qualidade em Assistência à Saúde , Sepse/tratamento farmacológico , Hemocultura , Infecções por Enterobacteriaceae/mortalidade , Humanos , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , beta-Lactamas/uso terapêutico
18.
Expert Rev Clin Pharmacol ; 14(5): 583-599, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33687300

RESUMO

INTRODUCTION: Several novel beta-lactams (BLs) and/or beta lactams/beta-lactamase inhibitors (BL/BLIs) have been recently developed for the management of multidrug-resistant bacterial infections. Data concerning dose optimization in critically ill patients with altered renal function are scanty. AREAS COVERED: This article provides a critical reappraisal of pharmacokinetic and clinical issues emerged with novel BLs and/or BL/BLIs in renal critically ill patients. Clinical and pharmacokinetic studies published in English until December 2020 were searched on the PubMed-MEDLINE database. EXPERT OPINION: Several issues emerged with the use of novel BLs and/or BL/BLIs in critically ill renal patients. Suboptimal clinical response rate with ceftazidime-avibactam and ceftolozane-tazobactam was reported in phase II-III trials in patients with moderate kidney injury; data on patients undergoing renal replacement therapy are limited to some case reports; dose adjustment in augmented renal clearance is provided only for cefiderocol. Implementation of altered dosing strategies (prolonged infusion and/or higher dosage) coupled with adaptive real-time therapeutic drug monitoring could represent the most effective approach in warranting optimal pharmacokinetic/pharmacodynamic targets with novel BLs and/or BL/BLIs in challenging scenarios, thus minimizing the risk of clinical failure and/or of resistance selection.


Assuntos
Infecções Bacterianas/tratamento farmacológico , Inibidores de beta-Lactamases/administração & dosagem , beta-Lactamas/administração & dosagem , Infecções Bacterianas/microbiologia , Estado Terminal , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Monitoramento de Medicamentos , Farmacorresistência Bacteriana Múltipla , Humanos , Nefropatias/complicações , Nefropatias/fisiopatologia , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/farmacologia , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologia
19.
JAMA Intern Med ; 181(6): 881, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33646264
20.
Pharmaceutics ; 13(3)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668969

RESUMO

COVID-19 may lead to severe respiratory distress syndrome and high risk of death in some patients. So far (January 2021), only the antiviral remdesivir has been approved, although no significant benefits in terms of mortality and clinical improvement were recently reported. In a setting where effective and safe treatments for COVID-19 are urgently needed, drug repurposing may take advantage of the fact that the safety profile of an agent is already well known and allows rapid investigation of the efficacy of potential treatments, at lower costs and with reduced risk of failure. Furthermore, novel pharmaceutical formulations of older agents (e.g., aerosolized administration of chloroquine/hydroxychloroquine, remdesivir, heparin, pirfenidone) have been tested in order to increase pulmonary delivery and/or antiviral effects of potentially active drugs, thus overcoming pharmacokinetic issues. In our review, we will highlight the importance of the drug repurposing strategy in the context of COVID-19, including regulatory and ethical aspects, with a specific focus on novel pharmaceutical formulations and routes of administration.

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