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The goal of the study was to describe the population pharmacokinetics of trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole in hospitalized patients. Furthermore, this study used the model to optimize dosing regimens of cotrimoxazole for Pneumocystis jirovecii pneumonia and in patients with renal insufficiency or with continuous renal replacement therapy (CRRT). This was a retrospective multicenter observational cohort study based on therapeutic drug monitoring (TDM) data from hospitalized patients treated with cotrimoxazole. We developed two population pharmacokinetic (POPPK) models: a model of trimethoprim and an integrated model with both sulfamethoxazole and N-acetyl sulfamethoxazole concentrations. Monte Carlo simulations were performed to determine the optimal dosing regimen. A total of 348 measurements from 168 patients were available. The estimated glomerular filtration rate (eGFR) and CRRT were included as covariates on the clearance of all three compounds. Cotrimoxazole TID 1,920 mg and b.i.d. 2,400 mg led to sufficient exposure for infections with P. jirovecii in patients without renal insufficiency. To reach equivalent exposure, a dose reduction of 33.3% is needed in patients with an eGFR of 10 mL/minute/1.73 m2 and of 16.7% for an eGFR of 30 mL/minute/1.73 m2. N-acetyl sulfamethoxazole accumulates in patients with a reduced eGFR. CRRT increased the clearance of sulfamethoxazole, but not trimethoprim or N-acetyl sulfamethoxazole, compared with the median clearance in the population. Doubling the sulfamethoxazole dose is needed for patients on CRRT to reach equivalent exposure.
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Particulate contamination, the unintentional presence of particles in parenteral fluids, is associated with potential risks such as phlebitis and thrombophlebitis. Recent guidelines recommend the use of filter needles when withdrawing parenteral fluid from vials with a rubber stopper. However, the literature is limited and lacks clarity regarding the advantages of filter needles over conventional needles. The aim of this study was to assess the compliance of parenteral fluids regarding particulate contamination after withdrawing fluid using both conventional needles and filter needles, following the guidelines of European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP). Visible particles were counted through visual inspection and sub-visible particles were quantified utilizing the light obscuration particle count test. Particle counts for both types of needles were compared to Ph. Eur. and USP standards and differences in particle contamination were assessed using a Mann-Whitney U test. Both types of needles demonstrated compliance with Ph. Eur. and USP standards regarding particulate contamination of visible and sub-visible particles. However, filter needles exhibited a significantly higher particle count for particles with a size of ≥25 µm compared to conventional needles (p = 0.0029). In conclusion, both types of needles demonstrate suitability for aspirating fluid from vials featuring rubber stoppers regarding particulate contamination. Nevertheless, non-filter needles are preferred for withdrawing fluid from vials with a rubber stopper over filter needles due to their lower cost.
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Limited data on the clinical management of drug-drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population.
Fungal infections are serious complications in Cystic Fibrosis (CF) patients. We evaluated patients concomitantly receiving triazoles and CF transmembrane conductance regulator modulators: subtherapeutic triazole exposure was frequently observed. Posaconazole appears the preferable antifungal agent.
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Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/veterinária , Estudos Retrospectivos , Triazóis/farmacologia , Triazóis/uso terapêutico , MutaçãoRESUMO
BACKGROUND: The use of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCF) after solid organ transplantation is controversial because of potential drug-drug interactions (DDI) with tacrolimus. We aimed to improve insight into the safety and clinical benefits of co-administration of ETI and tacrolimus in liver or kidney transplanted adult pwCF. METHODS: In 5 pwCF, tacrolimus concentrations were monitored during 2 weeks before and 4 weeks after starting ETI treatment. Trough levels, area under the curve (AUC) and clinical effect of ETI were investigated. During the study (6 weeks in total) adverse events were monitored. RESULTS: The DDI between tacrolimus and ETI resulted in an increased exposure of tacrolimus in all subjects, the dose adjusted AUC0-24h was 1.79 (median) times higher at the end of the study. Five dose adjustments were performed in 4 subjects in order to attain tacrolimus target range. No adverse events were reported and all subjects showed clinical improvement during ETI treatment. CONCLUSION: The clinical value of ETI treatment in kidney and liver transplanted pwCF is clear. The use of ETI may increase tacrolimus levels moderately. Therefore, we recommend close monitoring of tacrolimus trough levels in patients who start ETI.
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Aminofenóis , Benzodioxóis , Fibrose Cística , Interações Medicamentosas , Imunossupressores , Indóis , Transplante de Rim , Transplante de Fígado , Quinolonas , Tacrolimo , Humanos , Fibrose Cística/cirurgia , Fibrose Cística/tratamento farmacológico , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Tacrolimo/efeitos adversos , Masculino , Feminino , Adulto , Benzodioxóis/efeitos adversos , Benzodioxóis/administração & dosagem , Benzodioxóis/uso terapêutico , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Transplante de Fígado/métodos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Aminofenóis/administração & dosagem , Aminofenóis/efeitos adversos , Aminofenóis/farmacocinética , Aminofenóis/uso terapêutico , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Combinação de Medicamentos , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/farmacocinética , Pirróis/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Adulto Jovem , Monitoramento de Medicamentos/métodos , PirrolidinasRESUMO
INTRODUCTION: Remdesivir is a registered treatment for hospitalised patients with COVID-19 that has moderate clinical effectiveness. Anecdotally, some patients' respiratory insufficiency seemed to recover particularly rapidly after initiation of remdesivir. In this study, we investigated if this rapid improvement was caused by remdesivir, and which patient characteristics might predict a rapid clinical improvement in response to remdesivir. METHODS: This was a multicentre observational cohort study of hospitalised patients with COVID-19 who required supplemental oxygen and were treated with dexamethasone. Rapid clinical improvement in response to treatment was defined by a reduction of at least 1 L of supplemental oxygen per minute or discharge from the hospital within 72 h after admission. Inverse probability of treatment-weighted logistic regression modelling was used to assess the association between remdesivir and rapid clinical improvement. Secondary endpoints included in-hospital mortality, ICU admission rate and hospitalisation duration. RESULTS: Of 871 patients included, 445 were treated with remdesivir. There was no influence of remdesivir on the occurrence of rapid clinical improvement (62% vs 61% OR 1.05, 95% CI 0.79-1.40; p = 0.76). The in-hospital mortality was lower (14.7% vs 19.8% OR 0.70, 95% CI 0.48-1.02; p = 0.06) for the remdesivir-treated patients. Rapid clinical improvement occurred more often in patients with low C-reactive protein (≤ 75 mg/L) and short duration of symptoms prior to hospitalisation (< 7 days) (OR 2.84, 95% CI 1.07-7.56). CONCLUSION: Remdesivir generally does not increase the incidence of rapid clinical improvement in hospitalised patients with COVID-19, but it might have an effect in patients with short duration of symptoms and limited signs of systemic inflammation.
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BACKGROUND AND OBJECTIVES: Posaconazole is used as prophylaxis of invasive fungal disease in immune-compromised haematological patients with prolonged neutropenia after intensive chemotherapy. During routine therapeutic drug monitoring of posaconazole, we repeatedly observed low posaconazole serum concentrations in patients that were concomitantly treated with flucloxacillin. A possible interaction between flucloxacillin and posaconazole was explored in this case series. PATIENTS AND METHODS: Posaconazole trough serum concentrations during and before/after flucloxacillin treatment were collected from 10 patients. RESULTS: With a median concentration of 0.5 mg/L (IQR 0.3-0.6), the posaconazole trough serum concentration decreased by 47% during flucloxacillin treatment compared with the concentration before/after flucloxacillin treatment (0.9 mg/L, IQR 0.6-1.3). As a result, the posaconazole target trough concentration of ≥0.7 mg/L was only achieved in five out of nine patients during flucloxacillin treatment. CONCLUSIONS: Careful monitoring of posaconazole serum trough concentrations is recommended when concomitant use of flucloxacillin cannot be avoided.
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Micoses , Humanos , Micoses/tratamento farmacológico , Antifúngicos/uso terapêutico , Floxacilina/uso terapêutico , Estudos RetrospectivosRESUMO
Synthetic Cannabinoid Receptor Agonists (SCRAs) are a group of New Psychoactive Substances. They are used recreationally to mimic the effects of THC in cannabis. However, THC is a partial agonist of the CB1-receptor and SCRAs are full agonists. Because of this specificity and potency serious adverse events may occur among which psychological, cardiovascular, and gastro-intestinal symptoms. Because of the low incidence in the Netherlands clinical information on SCRA intoxications is limited, making diagnosis and treatment difficult. In this clinical lesson, two cases of SCRA intoxications are described followed by treatment recommendations.
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Canabinoides , Cannabis , Alucinógenos , Humanos , Canabinoides/efeitos adversos , Agonistas de Receptores de Canabinoides/efeitos adversos , Países BaixosRESUMO
Synthetic Cannabinoid Receptor Agonists (SCRAs) are a group of New Psychoactive Substances. They are used recreationally to mimic the effects of THC in cannabis. However, THC is a partial agonist of the CB1-receptor and SCRAs are full agonists. Because of this specificity and potency serious adverse events may occur among which psychological, cardiovascular, and gastro-intestinal symptoms. Because of the low incidence in the Netherlands clinical information on SCRA intoxications is limited, making diagnosis and treatment difficult. In this clinical lesson, two cases of SCRA intoxications are described followed by treatment recommendations.
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Canabinoides , Cannabis , Alucinógenos , Humanos , Canabinoides/efeitos adversos , Agonistas de Receptores de Canabinoides/efeitos adversos , Países BaixosRESUMO
BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and show robust treatment effects at group level. The individual effect however, is variable which might be (partially) related to differences in drug exposure. The profound influence of fat containing food compared to fasting on drug exposure gives need to investigate if the exocrine pancreatic function changes the degree and rate of absorption of ivacaftor and thereby may contribute to differences in drug exposure. METHODS: Pharmacokinetic parameters of ivacaftor were measured in 10 pancreatic sufficient (PS) and 10 pancreatic insufficient (PI) patients with CF on current treatment with tezacaftor/ivacaftor and compared between both groups. In PI patients pharmacokinetic parameters were investigated with and without the use pancreatic enzymes and compared in each individual. RESULTS: We demonstrated that the pharmacokinetic parameters of ivacaftor did not differ significantly between PS and PI people with CF (pwCF). Pancreatic enzymes did not significantly change the absorption or exposure to ivacaftor in PI pwCF using tezacaftor/ivacaftor. CONCLUSION: The exocrine pancreatic function of pwCF does not significantly influence the absorption and exposure of ivacaftor. The use of pancreatic enzymes in PI pwCF does not change the absorption and exposure of ivacaftor. Therefore, the dosing advice as mentioned in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic function.
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Fibrose Cística , Humanos , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística , Aminofenóis/uso terapêutico , MutaçãoRESUMO
INTRODUCTION: To compare the real-world safety profile of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors between younger and older patients. MATERIALS AND METHODS: All patients receiving pembrolizumab, nivolumab, atezolizumab or durvalumab between September 2016 and September 2019 at Haga Teaching Hospital, The Hague, The Netherlands were included in this retrospective study. Immune-related adverse drug reactions (irADRs) were manually retrieved from the electronic patient files. The cumulative incidence of irADRs were compared between younger (<65 years) and older (≥65 years) patients using a Pearsons Chi-square test. RESULTS: We identified 217 patients who were treated with at least one dose of PD-(L)1 inhibitor. 58% were 65 years or older at the start of immunotherapy. 183 patients (84.3%) received monotherapy PD-(L)1 inhibitors and 34 (15.7%) received chemo-immunotherapy. A total of 278 irADRs were registered. Cutaneous irADRs (53.9%), thyroid gland disorders (20.3%), and non-infectious diarrhoea/colitis (17.5%) were the most frequently reported irADRs. The majority of the irADRs were mild to moderate and no fatal irADRs were observed. 61 (21.9%) of the irADRs needed systemic treatment, of which 19 (6.8%) required treatment with corticosteroids. 18 irADRs (6.5%) were severe and resulted in hospitalisation. The cumulative incidence of cutaneous irADRs was different between the age groups: 45.7% of the patients <65 years and in 60.0% of the patients ≥65 years (p = 0.036). No statistical difference was found in the cumulative incidence of other irADRs between the two age groups. DISCUSSION: Advanced age is not associated with immune-related adverse drug reactions of PD-1 and PD-L1 inhibitors.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Pulmonares , Neoplasias , Idoso , Antígeno B7-H1 , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Fatores Imunológicos/uso terapêutico , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias/tratamento farmacológico , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1 , Estudos RetrospectivosRESUMO
Chronic bacterial prostatitis is increasingly difficult to treat due to rising antimicrobial resistance limiting oral treatment options. In this case series, 11 men with CBP (including patients with urological comorbidities) due to multi-resistant E. coli were treated with once-daily ceftriaxone intravenously for 6 weeks. Nine patients were clinically cured at 3 months follow up. No early withdrawal of medication due to side effects occurred. A literature review was conducted to describe the prostate pharmacokinetics of ceftriaxone and its use in prostatic infection. In conclusion, ceftriaxone can be considered an appropriate treatment of chronic bacterial prostatitis.
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INTRODUCTION: Hypokalaemia is a potentially life-threatening adverse event of flucloxacillin with unknown incidence. The risk of flucloxacillin-induced hypokalaemia has recently been suggested to be increased among females compared to males. The aim of this study is to describe the incidence and to determine the influence of sex and other risk factors on flucloxacillin-induced hypokalaemia. METHODS: A retrospective single-centre cohort study was performed. Patients treated with intravenous flucloxacillin for >24 hours between January 2017 and October 2020, a baseline potassium level of ≥3.5 mmol/L and potassium measurement during treatment were included. The primary endpoint was incidence of hypokalaemia defined as the percentage of patients with a potassium measurement <3.5 mmol/L during flucloxacillin treatment. Logistic regression modelling was used to establish risk factors for hypokalaemia. RESULTS: A total of 835 patients were included, 58.2% male and median age 71.0 years (interquartile range 61.0-81.0). The incidence of hypokalaemia was 23.7% (28.4% in females vs 20.4% in males). A dose-dependent relation between sex and the incidence of hypokalaemia was found. The risk of hypokalaemia was 4.41 (95% confidence interval 1.47-13.24) times higher in females compared to males when receiving a flucloxacillin dose of >8 g/24 h. No sex differences were found for lower daily doses. Other risk factors for hypokalaemia were older age, concomitant antibiotic use, lower bodyweight, lower baseline plasma potassium concentration and longer treatment duration. CONCLUSION: Hypokalaemia is a frequent complication in patients treated with intravenous flucloxacillin. Females receiving >8 g intravenous flucloxacillin per day are more prone to develop hypokalaemia compared to males.
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Hipopotassemia , Idoso , Estudos de Coortes , Feminino , Floxacilina , Humanos , Hipopotassemia/induzido quimicamente , Hipopotassemia/epidemiologia , Incidência , Masculino , Potássio , Estudos Retrospectivos , Fatores de RiscoRESUMO
The optimal drug of choice, its time of administration and duration of antibiotic prophylaxis in patient undergoing a TURP procedure are still matters of debate. In this study, we evaluated the concentrations of cefazolin, ciprofloxacin and fosfomycin in the human prostate in a cohort of men undergoing TURP. We compared prostate tissue concentrations to the serum concentrations and MICs of common uropathogens, to determine the appropriateness of the current presurgical prophylactic antibiotics and to gain supportive data about the suitability of fosfomycin for antibiotic prophylaxis in men undergoing urological procedures of the prostate. After a single intravenous dose of cefazoline or an oral dose of ciprofloxacin prior to TURP, concentrations in serum and prostate tissue of well above the MIC (EUCAST breakpoint) of common uropathogens (Enterobacterales) were reached, and both antibiotics seem potentially effective in preventing postsurgical infections. A single dose of oral and intravenous administration of fosfomycin both led to serum concentrations above the MIC for uncomplicated urinary tract infections (8 µg/mL). The MIC for other infections (32 µg/mL) was only reached after a single dose of intravenous fosfomycin. We were unable to detect fosfomycin concentrations in prostate tissue.
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For many people with cystic fibrosis (pwCF), CFTR modulators will be the cornerstone of their treatment. These modulators show robust treatment effects at group level in pwCF with specific mutations. The individual effect however, is variable. In this review we will explain reasons for reconsideration of dosing regimens of CFTR modulating therapy in order to improve treatment response and prevent side effects. Since the effect of a drug depends on pharmacodynamics and pharmacokinetics, pharmacodynamics and pharmacokinetic properties of CFTR modulators will be discussed. Pharmacokinetic-pharmacodynamic relationships will be used to gain insight in dosage response and exposure response relationships. To understand the cause of variation in drug exposure, pharmacokinetic properties that may change due to CF disease will be explained. We show that with current insight, there are conceivable situations that give reason for reconsideration of dosing regimens, however many questions need to be unravelled.
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BACKGROUND: Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF. METHODS: A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor. RESULTS: We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times. CONCLUSION: Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.
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Aminofenóis/administração & dosagem , Aminofenóis/farmacocinética , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/farmacocinética , Fibrose Cística/tratamento farmacológico , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Adulto , Azitromicina/administração & dosagem , Estudos de Casos e Controles , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ritonavir/administração & dosagemRESUMO
Intoxications with sulpiride, an antipsychotic, are rare, and only limited literature is available. We describe a successful treatment of a sulpiride intoxication. A 67-year-old female, with a history of intentional suicide attempt, was admitted to the emergency department (ED) because of a suspected out-of-hospital cardiac arrest. At presentation, she was haemodynamically unstable, with a Glasgow Coma Scale of 3 and slight prolongation of QTc time. History taken from her husband raised suspicion of a suicide attempt with medication. Consultation of the on-call pharmacist and performance of a toxicology screening accelerated the diagnosis of a sulpiride intoxication. The patient was intubated because of respiratory insufficiency, admitted to the Intensive Care Unit (ICU) and treated with activated charcoal, laxatives and sodium bicarbonate. The following day, she was extubated with stable haemodynamics and a normalized ECG. Treatment of sulpiride intoxications is mainly symptomatic and consists of supportive care. An important note is the avoidance of antiarrhythmic drugs, except for lidocaine, epinephrine and dopamine, as they might worsen arrhythmia and hypotension.
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Antipsicóticos/intoxicação , Parada Cardíaca Extra-Hospitalar/diagnóstico , Tentativa de Suicídio/psicologia , Sulpirida/intoxicação , Idoso , Feminino , Humanos , Parada Cardíaca Extra-Hospitalar/induzido quimicamente , Parada Cardíaca Extra-Hospitalar/psicologia , Parada Cardíaca Extra-Hospitalar/terapia , Resultado do TratamentoRESUMO
We report a case of a man with COVID-19 who developed acute hepatotoxicity related to remdesivir with probable interaction of P-glycoprotein (P-gp) inhibitors. Until further details on this interaction become available, we recommend physicians to be cautious with the prescription of P-gp inhibitors in patients receiving remdesivir therapy.
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Tratamento Farmacológico da COVID-19 , Doença Hepática Induzida por Substâncias e Drogas , Subfamília B de Transportador de Cassetes de Ligação de ATP , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Humanos , Masculino , SARS-CoV-2Assuntos
Anticoagulantes/administração & dosagem , Peso Corporal , Dabigatrana/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Administração Oral , Idoso , Anticoagulantes/efeitos adversos , Estudos Transversais , Dabigatrana/efeitos adversos , Feminino , Humanos , Masculino , Pirazóis/efeitos adversos , Piridonas/efeitos adversosRESUMO
OBJECTIVES: To evaluate the pharmacokinetics and clinical effectiveness of IV and oral fosfomycin treatment in patients with recurrent urinary tract infection (rUTI) with Escherichia coli. PATIENTS AND METHODS: Patients with rUTI treated with 3 g of oral fosfomycin every 72 h for at least 14 days were included in a prospective open-label single-centre study. Serum samples were taken after oral and IV administration of fosfomycin. Urine was collected for 24 h on 3 consecutive days. Fosfomycin concentrations in serum and urine were analysed using validated LC-MS/MS. Pharmacokinetics were evaluated using a population model. EudraCT number 2018-000616-25. RESULTS: Twelve patients were included, of whom nine were also administered IV fosfomycin. Data were best described by a two-compartment model with linear elimination and a transit-absorption compartment. Median values for absolute bioavailability and serum half-life were 18% and 2.13 h, respectively. Geometric mean urine concentrations on Days 1, 2 and 3 were above an MIC of 8 mg/L after both oral and IV administration. Quality of life reported on a scale of 1-10 increased from 5.1 to 7.4 (P = 0.001). The average score of UTI symptoms decreased after fosfomycin dosing (by 3.1 points, 95% CI = -0.7 to 7.0, P = 0.10). CONCLUSIONS: Oral fosfomycin at 3 g every 72 h provides plasma and urine concentrations of fosfomycin above the MIC for E. coli. This pharmacokinetic model can be used to develop optimal dosing regimens of fosfomycin in patients with UTI.
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Fosfomicina , Infecções Urinárias , Antibacterianos/uso terapêutico , Cromatografia Líquida , Escherichia coli , Humanos , Estudos Prospectivos , Qualidade de Vida , Espectrometria de Massas em Tandem , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/prevenção & controleRESUMO
BACKGROUND: Vancomycin is frequently used in hemodialysis (HD) and in hemodiafiltration (HDF) patients and is usually administered in the last 30 or 60 minutes of a dialysis session. Vancomycin pharmacokinetics are not well described in HDF patients. The aim of this study is to develop a population pharmacokinetic (PPK) model and dosing regimen for vancomycin in HDF patients and to evaluate its applicability in low-flux (LF-HD) patients. METHODS: Two-compartment PPK models were developed using data from HDF patients (n = 17), and was parameterized as follows: non-renal clearance (CLm), renal clearance as a fraction of creatinine clearance (fr), central volume of distribution (V1), intercompartmental clearance (CL12), peripheral volume of distribution (V2) and extracorporeal extraction ratio (Eec). We evaluated the final model in a cohort of LF-HD patients (n = 21). Dosing schemes were developed for a vancomycin 24-h AUC of 400 mg*h/L. RESULTS: Model parameters (± SD) were: CLm = 0.473 (0.271) L/h, fr = 0.1 (fixed value), V1 = 0.278 (0.092) L/kgLBMc, CL12 = 9.96 L/h (fixed value), V2 = 0.686 (0.335) L/kgLBMc and Eec = 0.212 (0.069). The model reliably predicted serum levels of vancomycin in both HDF and LF-HD patients during and between dialysis sessions. The median of the prediction error (MDPE) as a measure of bias is -0.7% (95% CI: -3.4%-1.7%) and the median of the absolute values of the prediction errors (MDAPE) as a measure of precision is 7.9% (95% CI: 6.0%-9.8%). In both HDF and LF-HD, the optimal vancomycin loading dose for a typical patient weighing 70 kg is 1700 mg when administered during the last 60 minutes of the hemodialysis session. Maintenance dose is 700 mg if administered during the last 30 or 60 minutes of the hemodialysis session. CONCLUSION: The developed PPK model for HDF is also capable of predicting serum levels of vancomycin in patients on LF-HD. A dosing regimen was developed for the use of vancomycin in HDF and LF-HD.