RESUMO
OBJECTIVES: Flucloxacillin has the most narrow spectrum to treat staphylococcal infections, but has a large variability in bioavailability which hampers its intravenous (iv) to oral switch. To identify patients with adequate absorption, the use of an oral absorption test (OAT) measuring total plasma concentrations of flucloxacillin before and after an oral dose of 1 gram flucloxacillin, was previously published. The current pilot study aims to evaluate the fraction of patients with adequate absorption using a similar OAT; to assess the therapeutic consequences and to identify potential factors associated with adequate absorption. METHODS: Demographic data of adult patients treated with iv flucloxacillin and requiring prolonged therapy were collected retrospectively between May 2020 and November 2021 at Ghent University Hospital. A previously published OAT protocol was used, with addition of a protocol for intermittent dosing of iv flucloxacillin. Adequate absorption was defined as an increase in plasma concentration of at least 10 mg/L. RESULTS: The flucloxacillin OAT was performed in 99 patients, of which 62% were men, with a median age of 58 years and 95% received intermittent dosing of iv flucloxacillin. Of the 99 patients, 55% had a result indicating an adequate absorption and 49% of all patients were switched to oral flucloxacillin afterwards. Inadequate absorption was found to be associated with higher Body Mass Index and higher flucloxacillin baseline concentration, while co-administration of acetylsalicylic acid was associated with an adequate absorption. CONCLUSIONS: Based on the OAT, 49% of all patients were switched to oral flucloxacillin instead of broader-spectrum anti-staphylococcal antibiotics. This implicates that an OAT could be a valuable antimicrobial stewardship measure by restricting the use of broad-spectrum antibiotics. For each of the associations found, a hypothesis was formulated about the underlying reason or mechanism; these should be confirmed in future studies with prospective and multicentric design.
Assuntos
Antibacterianos , Floxacilina , Humanos , Floxacilina/administração & dosagem , Floxacilina/farmacocinética , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Administração Oral , Idoso , Adulto , Projetos Piloto , Infecções Estafilocócicas/tratamento farmacológico , Disponibilidade BiológicaRESUMO
BACKGROUND: Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics, which may be influenced by various patient-related factors, particularly in critically ill patients. OBJECTIVES: To describe the population pharmacokinetics (PopPK) of the antibiotic flucloxacillin in patients with S. aureus BSI. Subsequently, we sought to translate the model into a user-friendly app for generating a priori and a posteriori time-concentration curves and dose recommendations to optimize dosing regimens. METHODS: Total and unbound flucloxacillin concentrations were included from 49 patients from a prospective cohort study conducted during clinical routine, including non-critically ill and critically ill individuals who received intermittent bolus applications. These data were analysed using non-linear mixed-effects modelling. RESULTS: Most patients (98%) were treated with 2 g of flucloxacillin every 4 h. We developed a joint model that simultaneously described total and unbound concentrations. The model included an allometric effect of glomerular filtration rate on clearance and albumin on the albumin dissociation constant. The latter was especially important, as in our population the unbound fraction was higher at 11.5% (16.7% for critically ill patients) compared with reported values of approximately 5%. Based on our joint model, we developed a web-based app for optimizing dosing regimens of flucloxacillin. CONCLUSIONS: By utilizing data from clinical routine, we were able to create a predictive PopPK model of flucloxacillin and identify influential covariates. The web-based app is currently being validated in a clinical trial.
Assuntos
Antibacterianos , Bacteriemia , Floxacilina , Infecções Estafilocócicas , Humanos , Floxacilina/farmacocinética , Floxacilina/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Idoso , Estudos Prospectivos , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Idoso de 80 Anos ou mais , Adulto , Estado Terminal , Infusões IntravenosasRESUMO
RATIONALE: Cloxacillin and flucloxacillin are prone to degradation and polymerization in humid and hot environments, and their polymers have long been recognized to trigger allergic manifestations. A series of the degradation and polymerized impurities in cloxacillin and flucloxacillin were separated and characterized to ensure safe use of these drugs by the public. METHODS: By studying the chromatographic behavior of the degradation impurities and polymerized impurities in reversed-phase high-performance liquid chromatography (RP-HPLC) gradient elution, the impurities in cloxacillin and flucloxacillin were effectively separated and eluted. RP-HPLC tandem ion trap/time-of-flight mass spectrometry (MS) was applied to characterize the structures of unknown impurities eluted from the RP-HPLC methods for cloxacillin and flucloxacillin. The mechanisms of formation of the impurities in cloxacillin and flucloxacillin were also investigated. RESULTS: The structures of 10 unknown impurities in cloxacillin and 8 unknown impurities in flucloxacillin were elucidated based on the high-resolution MSn data at positive and negative modes, respectively. Six polymerized impurities were found and characterized, of which three were from the polymerization of cloxacillin and three were from the polymerization of flucloxacillin. CONCLUSIONS: The study on the impurity profiles of cloxacillin and flucloxacillin provided a scientific basis for improving their production processes and quality control.
Assuntos
Cloxacilina , Contaminação de Medicamentos , Floxacilina , Espectrometria de Massas em Tandem , Cloxacilina/química , Cloxacilina/análise , Floxacilina/química , Floxacilina/análise , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
After a revision surgery, approximately 1-2 % of patients will develop a periprosthetic joint infection (PJI). During the revision surgery, the infected prosthesis is removed, a debridement is performed and a new or temporary spacer is placed. Additionally, patients are treated with antibiotics during and after the surgery. Adequate exposure of the administered antibiotic to the pathogen is of crucial importance during the treatment of any infection. Inadequately low concentrations are associated with an increase in antibiotic resistance, antibiotic related side effects, treatment failures and prolonged infections. While high concentrations may lead to serious adverse events and potential lasting damage. Despite the importance of optimal dosing, there is a lack of knowledge with respect to the correlation between the plasma concentrations and target site concentrations of the antibiotics. Two of the commonly administered antimicrobial agents during the arthroplasty exchange are cefuroxime and flucloxacillin. Therefore, an accurate, specific, and sensitive quantification method is required in order to assess pharmacokinetics of cefuroxime and flucloxacillin in synovial tissue and bone. The aim of this study is to develop and validate a quantification method for the measurement of cefuroxime and flucloxacillin in human synovial tissue and bone using the UPC2-MS/MS conform Food and Drug Administration guidelines. The method was found linear for both compounds in both matrices (r2 > 0.990) from 1 µg/g to 20 µg/g, except for cefuroxime in bone, which was validated from 1 µg/g to 15 µg/g. We developed and validated a quantification method for cefuroxime and flucloxacillin in synovial tissue and bone using a simple sample preparation and a short analysis run time of 5.0 min, which has been already successfully applied in a clinical study. To our knowledge, no methods have been described earlier for the simultaneous quantification of cefuroxime and flucloxacillin in synovial tissue and bone.
Assuntos
Cefuroxima , Floxacilina , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Cefuroxima/análise , Cefuroxima/farmacocinética , Cefuroxima/sangue , Cromatografia Líquida de Alta Pressão/métodos , Modelos Lineares , Reprodutibilidade dos Testes , Floxacilina/análise , Floxacilina/farmacocinética , Floxacilina/química , Antibacterianos/análise , Antibacterianos/sangue , Antibacterianos/farmacocinética , Osso e Ossos/química , Osso e Ossos/metabolismo , Membrana Sinovial/química , Membrana Sinovial/metabolismo , Limite de DetecçãoRESUMO
BACKGROUND: When performing therapeutic drug monitoring (TDM) for flucloxacillin, it is advised to measure the unbound, not the total, flucloxacillin concentration. To be able to accurately quantify unbound flucloxacillin concentrations, a reliable analytical method is indispensable. OBJECTIVE: To determine the influence of temperature and pH of the sample during ultrafiltration on the measured unbound fraction of flucloxacillin. MATERIALS AND METHODS: We performed three different experiments. In a single laboratory experiment, we investigated the influence of ultrafiltration temperature (10°C, room temperature and 37°C) on the measured unbound fraction of flucloxacillin for three concentration levels. In a multiple laboratory experiment, the results of eight laboratories participating in an international quality control programme measuring unbound flucloxacillin concentrations were analysed. In the third experiment, patient samples were ultrafiltrated using four different conditions: (i) physiological pH and room temperature; (ii) unadjusted pH (pH 9 after freezing) and room temperature; (iii) physiological pH and 37°C and (iv) unadjusted pH and 37°C. RESULTS: For all experiments, measurement of samples that were ultrafiltrated at room temperature resulted in a substantially lower unbound fraction compared to samples that were ultrafiltrated at 37°C. Adjusting the pH to physiological pH only had a minimal impact on the measured unbound fraction. CONCLUSIONS: On the basis of these findings and considering the need for fast, simple and reproducible sample pretreatment for TDM purposes, we conclude that ultrafiltration of flucloxacillin should be performed at physiological temperature (37°C), but adjustment of pH does not seem to be necessary.
Assuntos
Antibacterianos , Monitoramento de Medicamentos , Floxacilina , Temperatura , Ultrafiltração , Floxacilina/farmacocinética , Ultrafiltração/métodos , Humanos , Antibacterianos/farmacocinética , Monitoramento de Medicamentos/métodos , Concentração de Íons de HidrogênioRESUMO
This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.
Assuntos
Acetaminofen , Acidose , Ácido Pirrolidonocarboxílico , Humanos , Acetaminofen/efeitos adversos , Acidose/diagnóstico , Acidose/induzido quimicamente , Floxacilina/efeitos adversos , Floxacilina/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêuticoRESUMO
Flucloxacillin-induced hypokalaemia can be progressive and life-threatening, despite of potassium supplementation. In this case description, a high dose of intravenous flucloxacillin was started after a 68-year-old patient presented with an infected knee replacement. After two days, hypokalaemia was noted with an inadequate response to potassium supplementation. It was decided to change antibiotics and increase potassium supplementation, with good results. It is advisable to include monitoring of potassium levels in local treatment protocols when flucloxacillin is prescribed.
Assuntos
Floxacilina , Hipopotassemia , Idoso , Humanos , Administração Intravenosa , Antibacterianos/efeitos adversos , Floxacilina/efeitos adversos , Hipopotassemia/induzido quimicamente , PotássioRESUMO
OBJECTIVE: To develop and validate an UPLC-MS/MS assay for simultaneous determination of the total concentration of ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, tazobactam, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim, and the protein-unbound concentration of flucloxacillin, in human plasma to be used for research and clinical practice. METHODS: Sample pretreatment included protein precipitation with methanol. For the measurement of protein-unbound flucloxacillin, ultrafiltration was performed at physiological temperature. For all compounds, a stable isotopically labelled internal standard was used. Reliability of the results was assessed by participation in an international quality control programme. RESULTS: The assay was successfully validated according to the EMA guidelines over a concentration range of 0.5-100â mg/L for ceftazidime, 0.05-10â mg/L for ciprofloxacin, 0.4-125â mg/L for flucloxacillin, 0.2-60â mg/L for piperacillin, 0.15-30â mg/L for tazobactam, 1-200â mg/L for sulfamethoxazole and N-acetyl sulfamethoxazole, 0.05-10â mg/L for trimethoprim and 0.10-50â mg/L for unbound flucloxacillin. For measurement of total concentrations, the within- and between-day accuracy ranged from 90.0% to 109%, and 93.4% to 108%, respectively. Within- and between-day precision (variation coefficients, CVs) ranged from 1.70% to 11.2%, and 0.290% to 5.30%, respectively. For unbound flucloxacillin, within-day accuracy ranged from 103% to 106% and between-day accuracy from 102% to 105%. The within- and between-day CVs ranged from 1.92% to 7.11%. Results of the international quality control programme showed that the assay is reliable. CONCLUSIONS: The method provided reliable, precise and accurate measurement of seven commonly prescribed antibiotics, including the unbound concentration of flucloxacillin. This method is now routinely applied in research and clinical practice.
Assuntos
Antibacterianos , Floxacilina , Humanos , Ceftazidima , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Reprodutibilidade dos Testes , Espectrometria de Massa com Cromatografia Líquida , Espectrometria de Massas em Tandem/métodos , Piperacilina , Tazobactam , Ciprofloxacina , Trimetoprima , Sulfametoxazol , Cromatografia Líquida de Alta Pressão/métodosRESUMO
PURPOSE: Antistaphylococcal penicillins and cefazolin have been used as first line therapy in Methicillin-susceptible Staphylococcus aureus bloodstream infection. While efficacy of both regimens seems to be similar, the compounds may differ with regard to tolerability. This study aims to describe the clinical use of cefazolin and flucloxacillin, focussing on discontinuation or change of anti-infective agent due to adverse events. METHODS: This observational prospective study was conducted at two German tertiary care centres with an internal recommendation of flucloxacillin for MSSA-BSI in one, and of cefazolin in the other centre. Adverse events were registered weekly under treatment and at a 90-day follow-up. Descriptive analysis was complemented by a propensity score analysis comparing adverse events (stratified rank-based test applied to the sum of Common Terminology Criteria for adverse events ratings per patient). RESULTS: Of 71 patients included, therapy was initiated with flucloxacillin in 56 (79%), and with cefazolin in 15 (21%). The propensity score analysis indicates a statistically significant difference concerning the severity of adverse events between the treatment groups in favour of cefazolin (p = 0.019). Adverse events led to discontinuation of flucloxacillin in 7 individuals (13% of all patients receiving flucloxacillin). Clinical outcome was not different among treatment groups. CONCLUSION: Using cefazolin rather than flucloxacillin as a first line agent for treatment of MSSA-BSI is supported by these clinical data.
Assuntos
Antibacterianos , Cefazolina , Floxacilina , Infecções Estafilocócicas , Staphylococcus aureus , Humanos , Cefazolina/uso terapêutico , Floxacilina/uso terapêutico , Masculino , Feminino , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Idoso , Staphylococcus aureus/efeitos dos fármacos , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Adulto , Idoso de 80 Anos ou mais , AlemanhaRESUMO
BACKGROUND: Cellulitis is a common acute skin and soft tissue infection that causes substantial morbidity and healthcare costs. AIMS: To audit the impact on cellulitis management, regimen tolerability and outcomes of switching from outpatient parenteral antimicrobial therapy (OPAT) using intravenous (i.v.) cefazolin once daily plus probenecid to oral beta-lactam therapy (OBLT) using oral flucloxacillin plus probenecid. METHODS: We undertook a retrospective audit on cellulitis management, regimen tolerability and outcomes at the Dunedin Public Hospital Emergency Department (ED) before and after a change of the local outpatient cellulitis treatment pathway from OPAT using i.v. cefazolin once daily plus probenecid to OBLT using oral flucloxacillin plus probenecid. RESULTS: OPAT was used in 97/123 (78.9%) patients with cellulitis before compared to 1/70 (1.4%) after the pathway change (odds ratio (OR), 0.04, P < 0.01). OBLT was used in 26/123 (21.1%) patients with cellulitis before and 69/70 (98.6%) after (OR, 218.8, P < 0.01). Antimicrobial change due to intolerance occurred in 4/123 (3.2%) patients with cellulitis before and 4/70 (5.7%) after (OR, 1.8, P, not significant (NS)) the pathway change. Inpatient admission within 28 days occurred in 15/123 (12.2%) cellulitis patients before and 9/70 (12.9%) after (OR, 1.1, P, NS) the pathway change. CONCLUSIONS: Implementation of a change in outpatient cellulitis treatment pathway resulted in a significant change in prescribing practice. Our findings suggest that OBLT was both tolerable and had similar outcomes to OPAT.
Assuntos
Anti-Infecciosos , Celulite (Flegmão) , Humanos , Celulite (Flegmão)/tratamento farmacológico , Antibacterianos/uso terapêutico , Cefazolina , Floxacilina , Probenecid , Pacientes Ambulatoriais , Estudos Retrospectivos , Assistência AmbulatorialRESUMO
BACKGROUND AND PURPOSE: Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem-cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. KEY RESULTS: Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem-cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. CONCLUSIONS AND IMPLICATIONS: Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem-cilastatin in a translational rat model. The combination of vancomycin + imipenem-cilastatin was nephroprotective.
Assuntos
Floxacilina , Vancomicina , Ratos , Masculino , Animais , Combinação Imipenem e Cilastatina , Vancomicina/farmacologia , Clusterina , Ratos Sprague-Dawley , Antibacterianos , Rim , Biomarcadores , Combinação de MedicamentosRESUMO
In microbiology, accessing single-cell information within large populations is pivotal. Here we introduce bio-sCAPA, a technique for patterning bacterial cells in defined geometric arrangements and monitoring their growth in various nutrient environments. We demonstrate bio-sCAPA with a study of subpopulations of antibiotic-tolerant bacteria, known as persister cells, which can survive exposure to high doses of antibiotics despite lacking any genetic resistance to the drug. Persister cells are associated with chronic and relapsing infections, yet are difficult to study due in part to a lack of scalable, single-cell characterisation methods. As >105 cells can be patterned on each template, and multiple templates can be patterned in parallel, bio-sCAPA allows for very rare population phenotypes to be monitored with single-cell precision across various environmental conditions. Using bio-sCAPA, we analysed the phenotypic characteristics of single Staphylococcus aureus cells tolerant to flucloxacillin and rifampicin killing. We find that antibiotic-tolerant S. aureus cells do not display significant heterogeneity in growth rate and are instead characterised by prolonged lag-time phenotypes alone.
Assuntos
Antibacterianos , Infecções Estafilocócicas , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Staphylococcus aureus/genética , Bactérias , Infecções Estafilocócicas/tratamento farmacológico , FloxacilinaRESUMO
BACKGROUND: Flucloxacillin-induced hepatotoxicity is well established in adults. However, there are few paediatric studies of flucloxacillin-induced hepatotoxicity despite this drug being among the most commonly prescribed in children. We aimed to determine the incidence of flucloxacillin-induced hepatotoxicity in children receiving IV therapy as well as identify risk factors for this adverse drug reaction. METHODS: We undertook a 2 year retrospective audit of children aged 0-18 years admitted to the Royal Children's Hospital (March 2019 to March 2021) who had liver function tests determined before and after receiving IV flucloxacillin for at least 24 hours duration. Causality was assessed using the Roussel Uclaf Causality Assessment Method and Naranjo criteria. RESULTS: Overall, the incidence of hepatotoxicity was 66/393 (17%). The median age of children with hepatotoxicity was 1.1 years (IQR 0.3-11.9), 43 (65%) received two or more concomitant hepatotoxic medications and 23 (35%) were receiving total parenteral nutrition. The median timing of onset of hepatotoxicity after commencement of flucloxacillin was 4 days (range 2-7). Severe hepatotoxicity (Common Terminology Criteria for Adverse Events grade 3 or above) occurred in 9/66 (14%) for bilirubin, 13/66 (20%) for ALT and 10/66 (15%) for GGT. Predisposing factors for hepatotoxicity were increasing age (OR 1.06 per additional year, 95% CI 1.01-1.10, Pâ=â0.02), with adolescents aged 12-18 years having the highest risk (OR 5.10, 95% CI 2.02-12.85, Pâ=â0.001), and two or more concomitant hepatotoxic medications (OR 2.51, 95% CI 1.02-6.18, Pâ=â0.05). The median time to resolution of hepatotoxicity after cessation of flucloxacillin was 5 days (range 2-10). CONCLUSIONS: In children, older patients and those receiving two or more concomitant hepatotoxic medications are at greater risk of flucloxacillin-induced hepatotoxicity.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Adulto , Adolescente , Humanos , Criança , Lactente , Pré-Escolar , Floxacilina/efeitos adversos , Estudos Retrospectivos , Incidência , Fatores de Risco , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologiaRESUMO
BACKGROUND: Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. OBJECTIVES: The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. METHODS: NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (nâ=â10â000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. RESULTS: For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively). CONCLUSIONS: NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.
Assuntos
Floxacilina , Piperacilina , Recém-Nascido , Humanos , Criança , Adolescente , Piperacilina/farmacocinética , Amoxicilina , Estudos Prospectivos , Antibacterianos/uso terapêutico , Penicilinas , Testes de Sensibilidade MicrobianaRESUMO
Antibiotic selectivity and bacterial resistance are critical global public health issues. We constructed a multi-class machine learning model to study antibiotic effects on human intestinal microbiota abundance and identified key features. Binding energies of ß-lactam antibiotics with Escherichia coli PBP3 mutant protein were calculated, and a 2D-QSAR model for bacterial resistance was established. Sensitivity analysis identified key features affecting bacterial resistance. By coupling key features from the machine learning model and 2D-QSAR model, we designed ten flucloxacillin (FLU) substitutes that improved intestinal microbiota tolerance and reduced antibiotic bacterial resistance. Concurrently, the substitutes exhibited superior degradability in soil, aquatic environments, and under photolytic conditions, coupled with a reduced environmental toxicity compared to the FLU. Evaluations under combined medication revealed significant improvements in functionality and bacterial resistance for 80% of FLU substitutes, with 50% showing more than a twofold increase. Mechanistic analysis demonstrated enhanced binding to target proteins and increased biodegradability for FLU substitutes due to more concentrated surface charges. Reduced solvent hindrance and increased cell membrane permeability of FLU substitutes, mainly due to enhanced interactions with phospholipid bilayers, contributed to their functional selectivity. This study aims to address poor antibiotic selectivity and strong bacterial resistance, providing guidance for designing antibiotic substitutes.
Assuntos
Microbioma Gastrointestinal , Microbiota , Humanos , Antibacterianos/farmacologia , Floxacilina , Intestinos , Escherichia coli/genéticaRESUMO
BACKGROUND: The use of oral antimicrobial agents in patients with short bowel syndrome (SBS) is challenging due to the changes in gastrointestinal anatomy that may result in diminished absorption and altered drug bioavailability. Prospective studies evaluating bioavailability of antimicrobial agents after oral administration in SBS patients are lacking. OBJECTIVES: To determine the bioavailability of orally administered antimicrobial agents commonly used for treatment in SBS patients to guide clinical decision making when faced with infections. METHODS: We performed an explorative, clinical study investigating the pharmacokinetics (PK) of clindamycin, ciprofloxacin, flucloxacillin and fluconazole in SBS patients with intestinal failure. Participants received a combination of two antimicrobial agents simultaneously. To determine the oral bioavailability, participants received a single oral and IV dose of both agents on two occasions, after which they underwent intensive PK sampling on six predefined time points up to 12 hours after administration. Primary outcome was the oral bioavailability of these antimicrobial agents. Secondary outcomes were intravenous PK characteristics following non-compartmental analysis. RESULTS: Eighteen SBS patients were included: the mean (SD) age was 59 (17) years and 61% of participants were female. The median observed (IQR) bioavailability of ciprofloxacin, clindamycin, flucloxacillin and fluconazole were 36% (24-50), 93% (56-106), 50% (32-76) and 98% (61-107), respectively. CONCLUSION: The bioavailability of selected antimicrobial agents in certain patients with SBS appeared to be better than expected, providing a feasible treatment option. Due to the large observed differences between patients, therapeutic drug monitoring should be part of the treatment to safeguard adequate exposure in all patients. TRIAL REGISTRATION: Registered in the Dutch Trial Register (NL7796) and EudraCT number 2019-002587-28.
Assuntos
Anti-Infecciosos , Síndrome do Intestino Curto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Floxacilina , Clindamicina/uso terapêutico , Estudos Prospectivos , Fluconazol , Administração Oral , CiprofloxacinaRESUMO
AIM: Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index that requires dose adjustment when used with voriconazole, a recognized CYP3A4 inhibitor. Interactions involving flucloxacillin and tacrolimus or voriconazole individually have been shown to result in decreased concentrations of the latter two drugs. Tacrolimus concentrations have been reported to be unaffected by flucloxacillin when voriconazole is administered; however, this has not been extensively investigated. METHODS: Retrospective review of voriconazole and tacrolimus concentrations and subsequent dose adjustment following flucloxacillin administration. RESULTS: Eight transplant recipients (five lung, two re-do lung, one heart) received concurrent flucloxacillin, voriconazole and tacrolimus. Voriconazole trough concentrations were measured before flucloxacillin initiation in three of eight patients and all trough concentrations were therapeutic. Following flucloxacillin initiation, all eight patients exhibited subtherapeutic concentrations of voriconazole (median concentration 0.15 mg/L [interquartile range (IQR) 0.10-0.28]). In five patients, voriconazole concentrations remained subtherapeutic despite dose increases, and treatment for two patients was changed to alternative antifungal agents. All eight patients required tacrolimus dose increases to maintain therapeutic concentrations after flucloxacillin initiation. Median total daily dose prior to flucloxacillin treatment was 3.5 mg [IQR 2.0-4.3] and this increased to 13.5 mg [IQR 9.5-20] (P=0.0026) during flucloxacillin treatment. When flucloxacillin was ceased, the median tacrolimus total daily dose reduced to 2.2 mg [IQR 1.9-4.7]. Supra-therapeutic tacrolimus concentrations were observed in seven patients after flucloxacillin discontinuation (median concentration 19.7 µg/L [IQR 17.9-28.0]). CONCLUSION: A significant three-way interaction was shown between flucloxacillin, voriconazole and tacrolimus, resulting in subtherapeutic voriconazole concentrations, and requiring substantial tacrolimus dose increases. Administration of flucloxacillin to patients receiving voriconazole should be avoided. Tacrolimus concentrations should be closely monitored, and dosing adjusted during and after flucloxacillin administration.
Assuntos
Floxacilina , Tacrolimo , Humanos , Voriconazol/uso terapêutico , Tacrolimo/uso terapêutico , Tacrolimo/farmacologia , Floxacilina/uso terapêutico , Imunossupressores/uso terapêutico , Estudos Retrospectivos , Antifúngicos/farmacologiaRESUMO
Flucloxacillin is a widely used antibiotic. It is an agonist to the nuclear receptor PXR that regulates the expression of cytochrome P450 (CYP) enzymes. Treatment with flucloxacillin reduces warfarin efficacy and plasma concentrations of tacrolimus, voriconazole, and repaglinide. We conducted a translational study to investigate if flucloxacillin induces CYP enzymes. We also investigated if flucloxacillin induces its own metabolism as an autoinducer. We performed a randomized, unblinded, two-period, cross-over, clinical pharmacokinetic cocktail study. Twelve healthy adults completed the study. They ingested 1 g flucloxacillin 3 times daily for 31 days, and we assessed the full pharmacokinetics of the Basel cocktail drugs on days 0, 10, and 28, and plasma concentrations of flucloxacillin on days 0, 9, and 27. The 3D spheroid of primary human hepatocytes (PHHs) were exposed to flucloxacillin (concentration range: 0.15-250 µM) for 96 hours. Induction of mRNA expression, protein abundance, and enzyme activity of CYP enzymes were assessed. Flucloxacillin treatment reduced the metabolic ratio of midazolam (CYP3A4), (geometric mean ratio (GMR) 10 days (95% confidence interval (CI)): 0.75 (0.64-0.89)) and (GMR 28 days (95% CI): 0.72 (0.62-0.85)). Plasma concentrations of flucloxacillin did not change during 27 days of treatment. Flucloxacillin caused concentration-dependent induction of CYP3A4 and CYP2B6 (mRNA, protein, and activity), CYP2C9 (mRNA and protein), CYP2C19 (mRNA and activity), and CYP2D6 (activity) in 3D spheroid PHH. In conclusion, flucloxacillin is a weak inducer of CYP3A4, which may lead to clinically relevant drug-drug interactions for some narrow therapeutic range drugs that are substrates of CYP3A4.
Assuntos
Citocromo P-450 CYP3A , Floxacilina , Humanos , Adulto , Citocromo P-450 CYP3A/genética , Floxacilina/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Hepatócitos/metabolismo , RNA MensageiroRESUMO
Importance: Surgical site infections (SSIs) represent a costly and preventable complication of cutaneous surgery. However, there is a paucity of randomized clinical trials investigating antibiotic prophylaxis for reducing SSIs in skin cancer surgery, and evidence-based guidelines are lacking. Incisional antibiotics have been shown to reduce the rate of SSIs before Mohs micrographic surgery, but this represents a small subset of skin cancer surgery. Objective: To determine whether microdosed incisional antibiotics reduce the rate of SSIs before skin cancer surgery. Design, Setting, and Participants: In this double-blind, controlled, parallel-design randomized clinical trial, adult patients presenting to a high-volume skin cancer treatment center in Auckland, New Zealand, for any form of skin cancer surgery over 6 months from February to July 2019 were included. Patient presentations were randomized to one of 3 treatment arms. Data were analyzed from October 2021 to February 2022. Interventions: Patients received an incision site injection of buffered local anesthetic alone (control), buffered local anesthetic with microdosed flucloxacillin (500 µg/mL), or buffered local anesthetic with microdosed clindamycin (500 µg/mL). Main Outcomes and Measures: The primary end point was the rate of postoperative SSI (calculated as number of lesions with SSI per total number of lesions in the group), defined as a standardized postoperative wound infection score of 5 or more. Results: A total of 681 patients (721 total presentations; 1133 total lesions) returned for postoperative assessments and were analyzed. Of these, 413 (60.6%) were male, and the mean (SD) age was 70.4 (14.8) years. Based on treatment received, the proportion of lesions exhibiting a postoperative wound infection score of 5 or greater was 5.7% (22 of 388) in the control arm, 5.3% (17 of 323) in the flucloxacillin arm, and 2.1% (9 of 422) in the clindamycin arm (P = .01 for clindamycin vs control). Findings were similar after adjusting for baseline differences among arms. Compared with lesions in the control arm (31 of 388 [8.0%]), significantly fewer lesions in the clindamycin arm (9 of 422 [2.1%]; P < .001) and flucloxacillin (13 of 323 [4.0%]; P = .03) arms required postoperative systemic antibiotics. Conclusions and Relevance: This study evaluated the use of incisional antibiotics for SSI prophylaxis in general skin cancer surgery and compared the efficacy of flucloxacillin vs clindamycin relative to control in cutaneous surgery. The significant reduction in SSI with locally applied microdosed incisional clindamycin provides robust evidence to inform treatment guidelines in this area, which are currently lacking. Trial Registration: anzctr.org.au Identifier: ACTRN12616000364471.
Assuntos
Antibacterianos , Neoplasias Cutâneas , Adulto , Humanos , Masculino , Idoso , Feminino , Antibacterianos/uso terapêutico , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Clindamicina/uso terapêutico , Floxacilina , Método Duplo-Cego , Anestésicos Locais , Neoplasias Cutâneas/cirurgia , Procedimentos Cirúrgicos DermatológicosRESUMO
BACKGROUND: Recently, several studies have assessed the effects of therapeutic drug monitoring of frequently prescribed beta-lactam antibiotics, for which they were quantified in human plasma samples. Beta-lactams are considered unstable, leading to extra challenges in quantification. Therefore, to ensure sample stability and minimize sample degradation before analysis, stability studies are crucial. This study investigated the stability of 10 frequently used beta-lactam antibiotics in human plasma at relevant storage conditions for clinical use. METHODS: Amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, imipenem, meropenem, and piperacillin were analyzed using ultraperformance convergence chromatography tandem mass spectrometry and liquid chromatography tandem mass spectrometry. Their short-term and long-term stabilities were investigated by measuring quality control samples at low and high concentrations against freshly prepared calibration standards. Measured concentrations at each time point were compared with the concentrations at T = 0. Antibiotics were considered stable if recovery results were between 85% and 115%. RESULTS: Short-term stability results indicated ceftriaxone, cefuroxime, and meropenem to be stable up to 24 hours at room temperature. All evaluated antibiotics, except imipenem, were stable on ice in a cool box for 24 hours. Amoxicillin, benzylpenicillin, and piperacillin were stable for 24 hours at 4-6°C. Cefotaxime, ceftazidime, cefuroxime, and meropenem were stable at 4-6°C up to 72 hours. Ceftriaxone and flucloxacillin were stable for 1 week at 4-6°C. Long-term stability results showed that all antibiotics were stable up to 1 year at -80°C, except imipenem and piperacillin, which were stable for 6 months at -80°C. CONCLUSIONS: Plasma samples for amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, flucloxacillin, and piperacillin may be stored for a maximum of 24 hours in a cool box. Refrigeration is suitable for plasma samples of amoxicillin, benzylpenicillin, meropenem, and piperacillin for up to 24 hours and cefotaxime, ceftriaxone, ceftazidime and cefuroxime for 72 hours. Plasma samples for imipenem should be frozen directly at -80°C. For long-term storage, plasma samples can be stored at -80°C for a maximum of 6 months for imipenem and piperacillin and 12 months for all other evaluated antibiotics.