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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.
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.

3.
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
4.
Mycoses ; 2021 Aug 12.
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.
Int J Antimicrob Agents ; 58(4): 106408, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34314808

RESUMO

Continuous infusion (CI) piperacillin/tazobactam is frequently used to treat infections in very elderly patients. This study aimed to conduct a population pharmacokinetic analysis of CI piperacillin/tazobactam, and to identify optimal dosages for safe and effective probability of target attainment (PTA) against Enterobacterales and Pseudomonas aeruginosa. Non-linear mixed-effects modelling was performed with Pmetrics. Monte Carlo simulations assessed the steady-state concentration (Css) of increasing piperacillin/tazobactam regimens (from 2.25 to 18 g daily by continuous infusion). Permissible doses were defined as those associated with <10% probability of Css >157.2 mg/L. PTA at the pharmacodynamic targets of free plasma steady-state concentration (fCss)/minimum inhibitory concentration (MIC) ≥1 and ≥4 and cumulative fraction of response (CFR) against EUCAST MIC distribution were also calculated. A total of 141 patients (median age 85 years) provided 217 plasma piperacillin Css. Most patients (55.2%) had hospital-acquired pneumonia and intra-abdominal infections. A one-compartment pharmacokinetic model with parallel linear and Michaelis-Menten elimination best described piperacillin data. Creatinine clearance (CLCR) was the covariate retained by the model. Pharmacokinetic estimates were 6.05 L/h for clearance and 3.39 mg/L for the Michaelis-Menten constant. Permissible doses were up to 4.5, 9, 11.25 and 13.5 g daily by continuous infusion for patients with CLCR of 0-19, 20-39, 40-59 and 60-79 mL/min/1.73 m2, respectively. At the clinical breakpoint of 8 mg/L, the permissible doses only achieved optimal PTA for fCss/MIC ≥1 in patients with CLCR 20-79 mL/min/1.73 m2. Optimal CFRs with the permissible doses were only attained against Escherichia coli and Proteus mirabilis. Permissible dosages and CLCR should be considered for prescribing CI piperacillin/tazobactam in very elderly patients.

6.
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.

7.
Infect Dis Ther ; 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34328629

RESUMO

INTRODUCTION: The Italian Society of Anti-Infective Therapy (SITA) and the Italian Society of Pulmonology (SIP) constituted an expert panel for developing evidence-based guidance for the clinical management of adult patients with coronavirus disease 2019 (COVID-19) outside intensive care units. METHODS: Ten systematic literature searches were performed to answer ten different key questions. The retrieved evidence was graded according to the Grading of Recommendations Assessment, Development, and Evaluation methodology (GRADE). RESULTS AND CONCLUSION: The literature searches mostly assessed the available evidence on the management of COVID-19 patients in terms of antiviral, anticoagulant, anti-inflammatory, immunomodulatory, and continuous positive airway pressure (CPAP)/non-invasive ventilation (NIV) treatment. Most evidence was deemed as of low certainty, and in some cases, recommendations could not be developed according to the GRADE system (best practice recommendations were provided in similar situations). The use of neutralizing monoclonal antibodies may be considered for outpatients at risk of disease progression. For inpatients, favorable recommendations were provided for anticoagulant prophylaxis and systemic steroids administration, although with low certainty of evidence. Favorable recommendations, with very low/low certainty of evidence, were also provided for, in specific situations, remdesivir, alone or in combination with baricitinib, and tocilizumab. The presence of many best practice recommendations testified to the need for further investigations by means of randomized controlled trials, whenever possible, with some possible future research directions stemming from the results of the ten systematic reviews.

8.
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.

9.
J Glob Antimicrob Resist ; 26: 140-147, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34144200

RESUMO

OBJECTIVES: Chronic wound infections may delay the healing process and are responsible for a significant burden on healthcare systems. Since inappropriate management may commonly occur in the care of these patients, this review aims to provide a practical guide underlining actions to avoid in the management of chronic wound infections. METHODS: We performed a systematic review of the literature available in PubMed in the last 10 years, identifying studies regarding the management of patients with chronic wound infections. A panel of experts discussed the potential malpractices in this area. A list of 'Don'ts', including the main actions to be avoided, was drawn up using the 'Choosing Wisely' methodology. RESULTS: In this review, we proposed a list of actions to avoid for optimal management of patients with chronic wound infections. Adequate wound bed preparation and wound antisepsis should be combined, as the absence of one of them leads to delayed healing and a higher risk of wound complications. Moreover, avoiding inappropriate use of systemic antibiotics is an important point because of the risk of selection of multidrug-resistant organisms as well as antibiotic-related adverse events. CONCLUSION: A multidisciplinary team of experts in different fields (surgeon, infectious disease expert, microbiologist, pharmacologist, geriatrician) is required for the optimal management of chronic wound infections. Implementation of this approach may be useful to improve the management of patients with chronic wound infections.

10.
Expert Rev Anti Infect Ther ; : 1-11, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33970746

RESUMO

Introduction: New diagnostics may be useful in clinical practice, especially in contexts of high prevalence of multidrug-resistant organisms (MDRO). However, misuse of diagnostic tools may lead to increased costs and worse patient outcome. Conventional and new techniques should be appropriately positioned in diagnostic algorithms to guide an appropriate use of antimicrobial therapy.Areas covered: A panel of experts identified 4 main areas in which the implementation of diagnostic stewardship is needed. Among chronic infections, bone and prosthetic joint infections and subacute-chronic intravascular infections and endocarditis represent common challenges for clinicians. Among acute infections, bloodstream infections and community-acquired pneumonia may be associated with high mortality and require appropriate diagnostic approach.Expert opinion: Diagnostic stewardship aims to improve the appropriate use of microbiological diagnostics to guide therapeutic decisions through appropriate and timely diagnostic testing. Here, diagnostic algorithms based on different patient profiles are proposed for chronic and acute clinical syndromes. In each clinical scenario, combining conventional and new diagnostic techniques is crucial to make a rapid and accurate diagnosis and to guide the selection of antimicrobial therapy. Barriers related to the implementation of new rapid diagnostic tools, such as high initial costs, may be overcome through their rational and structured use.

12.
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
13.
World J Emerg Surg ; 16(1): 15, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761972

RESUMO

Procalcitonin (PCT) is widely considered as a highly sensitive biomarker of bacterial infection, offering general and emergency surgeons a key tool in the management of surgical infections. A multidisciplinary task force of experts met in Bologna, Italy, on April 4, 2019, to clarify the key issues in the use of PCT across the surgical pathway. The panelists presented the statements developed for each of the main questions regarding the use of PCT across the surgical pathway. An agreement on the statements was reached by the Delphi method, and this document reports the executive summary of the final recommendations approved by the expert panel.


Assuntos
Antibacterianos/uso terapêutico , Biomarcadores/análise , Complicações Pós-Operatórias/tratamento farmacológico , Pró-Calcitonina/análise , Gestão de Antimicrobianos , Técnica Delfos , Diverticulite/tratamento farmacológico , Humanos , Itália , Pancreatite/tratamento farmacológico , Peritonite/tratamento farmacológico , Dermatopatias Infecciosas/tratamento farmacológico , Infecção da Ferida Cirúrgica/tratamento farmacológico
14.
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
15.
Expert Rev Anti Infect Ther ; 19(9): 1125-1134, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33682593

RESUMO

INTRODUCTION: The COVID-19 pandemic has dramatically challenged the national health systems worldwide in the last months. Dalbavancin is a novel antibiotic with a long plasmatic half-life and simplified weekly administration regimens, thus representing a promising option for the outpatient treatment of Gram-positive infections and the early discharge of hospitalized patients. Dalbavancin is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Many preliminary data seem to support its use in other indications, such as osteomyelitis, prosthetic joint infections, and infective endocarditis. AREAS COVERED: A search in the literature using validated keywords (dalbavancin, Gram-positive infections, Gram-positive cocci, ABSSSI, intravenous treatment, and long-acting antibiotics) was conducted on biomedical bibliographic databases (PubMed and Embase) from 2004 to 30 September 2020. Results were analyzed during two consensus conferences with the aim to review the current evidence on dalbavancin in Gram-positive infections, mainly ABSSSI, osteomyelitis, and infective endocarditis, highlight the main limitations of available studies and suggest possible advantages of the molecule. EXPERT OPINION: The board identifies some specific subgroups of patients with ABSSSIs who could mostly benefit from a treatment with dalbavancin and agrees that the design of homogenous and robust studies would allow a broader use of dalbavancin even in other clinical settings.


Assuntos
COVID-19 , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Teicoplanina/análogos & derivados , Assistência Ambulatorial/métodos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Esquema de Medicação , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/microbiologia , Teicoplanina/administração & dosagem , Teicoplanina/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-33649108

RESUMO

Background: Dalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections.Objective: To conduct a population pharmacokinetic analysis of dalbavancin in a prospective cohort of adult patients with Gram-positive OA infections and to identify optimal dosing regimens for long term-treatment.Methods: Non-linear mixed-effects modelling was performed with Monolix. Monte Carlo simulations were performed with six dalbavancin regimens (1500mg at day 1; 1000mg at day 1 plus 500mg at day 8; 1500mg at day1 and 8; 1500mg at day1 and 8 plus 500, 1000 or 1500mg at day 36) to assess the PTA of three pharmacodynamic target of fAUC24h/MIC against S. aureus (>27.1, 53.3 and 111.1). Cumulative fraction of response (CFR) was calculated against MIC distribution of both MRSA and MSSA as well. Desirable PTAs and CFRs were ≥90%.Results: Fifteen patients provided 120 plasma concentrations. Most (73.3%) had prosthetic joint infections. Clinical cure rate was 87%. A two-compartment model with linear elimination well described the data. No covariate was retained in the final model. Pharmacokinetic dalbavancin estimates were 0.106L/h for CL and 36.4L for Vss The tested dosing regimens granted desirable CFRs against S. aureus at the most effective PK/PD target for a period ranging 3-to-9 weeks. Conclusion: Giving a two 1500mg dosing regimen of dalbavancin one week apart may ensure efficacy against both MSSA and MRSA up to 5 weeks in patients with OA infections. Clinical assessment at that time may allow for considering whether or not an additional dose should be administered for prolonging effective treatment.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33619055

RESUMO

Background: Fosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to MDR pathogens.Objective: The aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16g/daily by intermittent (II) or continuous infusion (CI), and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections.Methods: Patients underwent blood sampling on day 5 of therapy (2-3 serial samples). Population pharmacokinetics and Monte Carlo simulations were performed to define the probability of target attainment (PTA) of 70% T>MIC, and the cumulative fraction of response (CFR) against common OI pathogens with dosages of 8, 12, 16, and 20g/day administered by II, extended-infusion (EI) or CI.Results: Forty-eight patients were recruited. A two-compartment open model with infusion input and first-order elimination was developed. Estimated creatinine clearance (CLCR) was included as covariate in the final model. Monte Carlo simulations showed that optimal PTAs and CFRs (≥90%) may be achieved in three different classes of renal function by administering a daily dosage of: 2g q6h by II against S. aureus, E. coli, ESBL-producing E. Coli and MRSA; 8g by CI against CoNS, K. pneumoniae and ESBL-producing K. pneumoniae; 12g by CI against P. aeruginosa, and 16g by CI against KPC-producing K. pneumoniae Conclusion: Our study provides a strong rationale for considering fosfomycin dosages of 8-16 g daily by CI in several clinical scenarios for OI patients. Feasibility of administration by CI in an elastomeric pump makes fosfomycin a candidate for OPAT programs.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33359542

RESUMO

BACKGROUND: Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins. OBJECTIVES: To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these. DATA SOURCES: Medline, Embase and Cochrane Library databases were searched on 2 January 2020. STUDY ELIGIBILITY CRITERIA: Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded. PARTICIPANTS: Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included. METHODS: Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model. RESULTS: In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043). CONCLUSIONS: Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens.

20.
Front Oncol ; 10: 582866, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194718

RESUMO

Basal cell carcinoma (BCC) accounts for almost 80% of skin cancers, and its healthcare workload burden is substantial within dermatology departments. Although most BCCs are small, well-defined tumors amenable of surgery or conservative procedures, in a small proportion of patients, BCCs can progress to an advanced stage including locally advanced BCC. The goal of the clinician in the treatment of BCC should be the right therapeutic approach at diagnosis, and different guidelines propose treatment strategies in order to prevent relapses or disease progression. In case of unresectable and untreatable BCC with radiotherapy, the first-choice medical therapy is Hedgehog-GLI (HH) pathway inhibitors. Sonidegib was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a first-line treatment for adult patients with locally advanced BCC, becoming the second HH pathway inhibitor receiving approval after vismodegib. In this review, data on pharmacology, safety, tolerability, and efficacy of sonidegib are summarized and compared to those of vismodegib. Lastly, indications on the management of advanced basal cell carcinoma based on author's clinical experience are provided.

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