AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.
- MeSH
- antibakteriální látky škodlivé účinky farmakokinetika MeSH
- ceftazidim škodlivé účinky farmakokinetika MeSH
- chromatografie kapalinová MeSH
- lidé MeSH
- metoda Monte Carlo MeSH
- mikrobiální testy citlivosti MeSH
- nádory * komplikace farmakoterapie MeSH
- off-label použití léčivého přípravku MeSH
- pseudomonádové infekce * farmakoterapie MeSH
- Pseudomonas aeruginosa MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
INTRODUCTION: Colistin is a lipopeptide antibiotic administered as an inactive prodrug-colistin methanesulfonate (CMS). Colistin is a drug with a narrow therapeutic window; the limiting factors are mainly nephrotoxicity and neurotoxicity, dependent on plasma concentrations. The number of patients with infections caused by multidrug-resistant Gram-negative bacteria sensitive only to colistin and the number of patients requiring extracorporeal membrane oxygenation (ECMO) support for severe respiratory failure increased significantly in association with COVID-19-induced infections. ECMO can generally affect the pharmacokinetics of drugs by creating a new compartment. METHODS AND ANALYSIS: The COL-ECMO2022 study is a prospective, non-randomised, single-centre, phase IV pharmacokinetic clinical trial designed to assess the influence of ECMO on the pharmacokinetics of colistin and CMS. Up to 30 patients treated with colistin will be included in the study and assigned to one of two arms, depending on the presence/absence of ECMO. All study participants will receive standard CMS dose intravenously. The plasma concentrations of colistin and CMS taken at defined intervals will be assessed by high-performance liquid chromatography-mass spectrometry. Patients will participate in the clinical trial for a maximum of three monitored dosing intervals. A population pharmacokinetic model will be developed to assess the influence of ECMO on pharmacokinetics. A difference greater than 25% is considered clinically significant. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of St. Anne's University Hospital Brno (Number 10ML/2022-AM). Related manuscripts will be submitted to peer-review journals. TRIAL REGISTRATION NUMBERS: EudraCT Number 2022-000291-19; NCT05542446.
- MeSH
- antibakteriální látky farmakokinetika MeSH
- COVID-19 * MeSH
- kolistin terapeutické užití MeSH
- kritický stav terapie MeSH
- lidé MeSH
- mimotělní membránová oxygenace * MeSH
- prospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
BACKGROUND: The dosing of aminoglycosides (AGs) in patients with kidney disease is challenging due to their markedly prolonged half-life, which renders pulse dosing schedules unsuitable. We performed a review of the literature that describes the pharmacokinetics of, and dosing recommendations for, AG for patients with abnormal renal functions and various renal replacement therapy modalities, focusing on patients treated with intermittent hemodialysis (iHD). SUMMARY: During one iHD session, dialysis removes a remarkable amount of the drug regardless of the dialyzer type. In patients with severely reduced kidney functions, the distribution phase is prolonged, which needs to be taken into account when drawing samples shortly after drug administration or following an iHD session. KEY MESSAGES: The doses recommended for the pulse dosing of patients without kidney disease leads to unacceptably high overall systemic exposure for patients with severely reduced kidney functions even with dosing intervals extended up to 48 h. Therefore, lower doses accompanied by extended dosing intervals must be applied for this patient group. The clinical evidence and current recommendations support the dosing of AG following, rather than before, HD sessions. In patients with end-stage kidney disease, the samples for TDM of AGs should not be drawn earlier than 2 h after end of the infusion and 4 h after the end of iHD session to allow full (re)distribution of the drug.
- MeSH
- aminoglykosidy farmakokinetika terapeutické užití MeSH
- antibakteriální látky farmakokinetika terapeutické užití MeSH
- chronická renální insuficience * komplikace MeSH
- chronické selhání ledvin * komplikace MeSH
- dialýza ledvin MeSH
- lidé MeSH
- náhrada funkce ledvin MeSH
- renální insuficience * komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Kolistin je úzkospektré antibiotikum ze skupiny lipopeptidových antibiotik, indikované pro terapii nozokomiálních infekcí, způsobených multirezistentními gram-negativními patogeny, především u kriticky nemocných pacientů a pacientů s cystickou fibrózou. Kolistin řadíme mezi expozičně závislá antibiotika s variabilní farmakokinetikou, související jednak s heterogenitou cílové populace, jednak s nutností bioaktivace. Kolistin je podáván ve formě inaktivního proléčiva kolistinmetátu sodného. Nejčastějšími nežádoucími účinky jsou nefrotoxicita a neurotoxicita.
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- MeSH
- antibakteriální látky farmakokinetika terapeutické užití MeSH
- antipsychotika farmakokinetika škodlivé účinky MeSH
- infekce močového ústrojí farmakoterapie komplikace MeSH
- klozapin * farmakokinetika škodlivé účinky MeSH
- lékové interakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- paranoidní schizofrenie farmakoterapie komplikace MeSH
- srdeční frekvence účinky léků MeSH
- tachykardie * chemicky indukované etiologie komplikace MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Meropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy. METHODS: Twenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated. RESULTS: Eleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05). CONCLUSIONS: These findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.
- MeSH
- antibakteriální látky metabolismus farmakokinetika MeSH
- APACHE MeSH
- Bayesova věta MeSH
- dospělí MeSH
- farmakokinetika * MeSH
- jednotky intenzivní péče organizace a řízení statistika a číselné údaje MeSH
- kritický stav terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- meropenem metabolismus farmakokinetika MeSH
- prospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sepse farmakoterapie patofyziologie MeSH
- vodní a elektrolytová rovnováha účinky léků MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
The study presents a novel vancomycin-releasing collagen wound dressing derived from Cyprinus carpio collagen type I cross-linked with carbodiimide which retarded the degradation rate and increased the stability of the sponge. Following lyophilization, the dressings were subjected to gamma sterilization. The structure was evaluated via scanning electron microscopy images, micro-computed tomography, and infrared spectrometry. The structural stability and vancomycin release properties were evaluated in phosphate buffered saline. Microbiological testing and a rat model of a wound infected with methicillin-resistant Staphylococcus aureus (MRSA) were then employed to test the efficacy of the treatment of the infected wound. Following an initial mass loss due to the release of vancomycin, the sponges remained stable. After 7 days of exposure in phosphate buffered saline (37°C), 60% of the material remained with a preserved collagen secondary structure together with a high degree of open porosity (over 80%). The analysis of the release of vancomycin revealed homogeneous distribution of the antibiotic both across and between the sponges. The release of vancomycin was retarded as proved by in vitro testing and further confirmed by the animal model from which measurable concentrations were observed in blood samples 24 hours after the subcutaneous implantation of the sponge, which was more than observed following intraperitoneal administration. The sponge was also highly effective in terms of reducing the number of colony-forming units in biopsies extracted from the infected wounds 4 days following the inoculation of the wounds with the MRSA solution. The presented sponges have ideal properties to serve as wound dressing for prevention of surgical site infection or treatment of already infected wounds.
- MeSH
- antibakteriální látky farmakokinetika MeSH
- hojení ran účinky léků MeSH
- kapři MeSH
- karbodiimidy farmakokinetika MeSH
- kolagen farmakokinetika MeSH
- krysa rodu rattus MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků MeSH
- obvazy MeSH
- vankomycin farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: The presence of Propionibacterium acnes in a substantial component of resected disc specimens obtained from patients undergoing discectomy or microdiscectomy has led to the suggestion that this prominent human skin and oral commensal may exacerbate the pathology of degenerative disc disease. This hypothesis, therefore, raises the exciting possibility that antibiotics could play an important role in treating this debilitating condition. To date, however, little information about antibiotic penetration into the intervertebral disc is available. METHODS: Intervertebral disc tissue obtained from 54 microdiscectomy patients given prophylactic cefazolin (n = 25), clindamycin (n = 17) or vancomycin (n = 12) was assayed by high-performance liquid chromatography, with cefaclor as an internal standard, to determine the concentration of antibiotic penetrating into the disc tissue. RESULTS: Intervertebral disc tissues from patients receiving the positively charged antibiotic clindamycin contained a significantly greater percentage of the antibacterial dose than the tissue from patients receiving negatively charged cefazolin (P < 0.0001) and vancomycin, which has a slight positive charge (P < 0.0001). CONCLUSION: Positively charged antibiotics appear more appropriate for future studies investigating potential options for the treatment of low-virulence disc infections. These slides can be retrieved under Electronic Supplementary Material.
- MeSH
- antibakteriální látky farmakokinetika terapeutické užití MeSH
- cefazolin farmakokinetika terapeutické užití MeSH
- degenerace meziobratlové ploténky chirurgie MeSH
- dospělí MeSH
- grampozitivní bakteriální infekce prevence a kontrola MeSH
- klindamycin farmakokinetika terapeutické užití MeSH
- lidé MeSH
- meziobratlová ploténka metabolismus MeSH
- Propionibacterium acnes * MeSH
- vankomycin farmakokinetika terapeutické užití MeSH
- výhřez meziobratlové ploténky chirurgie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The purpose of the present work was to evaluate in vivo different antimicrobial therapies to eradicate osteomyelitis created in the femoral head of New Zealand rabbits. Five phosphate-based cements were evaluated: calcium phosphate cements (CPC) and calcium phosphate foams (CPF), both in their pristine form and loaded with doxycycline hyclate, and an intrinsic antimicrobial magnesium phosphate cement (MPC; not loaded with an antibiotic). The cements were implanted in a bone previously infected with Staphylococcus aureus to discern the effects of the type of antibiotic administration (systemic vs. local), porosity (microporosity, i.e. <5 μm vs. macroporosity, i.e. >5 μm) and type of antimicrobial mechanism (release of antibiotic vs. intrinsic antimicrobial activity) on the improvement of the health state of the infected animals. A new method was developed, with a more comprehensive composite score that integrates 5 parameters of bone infection, 4 parameters of bone structural integrity and 4 parameters of bone regeneration. This method was used to evaluate the health state of the infected animals, both before and after osteomyelitis treatment. The results showed that the composite score allows to discern statistically significant differences between treatments that individual evaluations were not able to identify. Despite none of the therapies completely eradicated the infection, it was observed that macroporous materials (CPF and CPFd, the latter loaded with doxycycline hyclate) and intrinsic antimicrobial MPC allowed a better containment of the osteomyelitis. This study provides novel insights to understand the effect of different antimicrobial therapies in vivo, and a promising comprehensive methodology to evaluate the health state of the animals was developed. We expect that the implementation of such methodology could improve the criteria to select a proper antimicrobial therapy.
- MeSH
- antibakteriální látky aplikace a dávkování farmakokinetika farmakologie MeSH
- doxycyklin aplikace a dávkování farmakologie MeSH
- femur diagnostické zobrazování patologie MeSH
- fosforečnany vápenaté chemie MeSH
- infekční nemoci kostí farmakoterapie terapie MeSH
- kostní cementy chemie farmakologie MeSH
- králíci MeSH
- léky implantované chemie farmakologie MeSH
- osteomyelitida farmakoterapie terapie MeSH
- poréznost MeSH
- regenerace kostí účinky léků MeSH
- stafylokokové infekce farmakoterapie terapie MeSH
- systémy cílené aplikace léků metody MeSH
- uvolňování léčiv MeSH
- viskoelastické látky chemie MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Antikoagulační léčba warfarinem i přímými orálními antikoagulancii (DOAC) každoročně zachraňuje životy mnoha pacientům. Tito pacienti nezřídka užívají současně léky, které mění účinek antikoagulancií. Tento článek se pokouší přehlednou formou prezentovat informace o takových interakcích, které předepisující lékaři potřebují. Ačkoliv warfarin má více interakcí než DOAC, některé interakce DOAC jsou stejně nebezpečné a na rozdíl od warfarinu účinek DOAC nelze jednoduše monitorovat. To může představovat problém, neboť existují pacienti, u kterých léková interakce probíhá intenzivněji než u průměrných pacientů, například při kombinaci dabigatranu s klarithromycinem.
Anticoagulation therapy with warfarin and direct oral anticoagulants annually saves lives of many patients. These patients often take medicines that change the effect of anticoagulants. This article attempts to present in a synopical way information about such interactions that physicians prescribe. Although warfarin has more interactions than DOAC, some DOAC interactions are equally dangerous and, unlike warfarin, the effect of DOAC cannot be easily monitored. This may be a problem because there are patients in whom the drug interaction is more intense than in average patients, for example when dabigatran is combined with clarithromycin.
- MeSH
- amiodaron farmakokinetika MeSH
- antibakteriální látky farmakokinetika MeSH
- antikoagulancia farmakokinetika MeSH
- dabigatran farmakokinetika MeSH
- inhibitory agregace trombocytů farmakokinetika MeSH
- kombinovaná farmakoterapie klasifikace MeSH
- lékové interakce * MeSH
- lidé MeSH
- warfarin * farmakokinetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
