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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 MS n 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., (© 2024 John Wiley & Sons Ltd.)

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 UPC 2 -MS/MS conform Food and Drug Administration guidelines. The method was found linear for both compounds in both matrices (r 2  > 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Ultrafiltration (UF) is a conventional method for isolating the protein-unbound plasma fractions of therapeutic drugs. However, the ideal UF conditions for specific compounds remain largely unexplored. By comparing UF-derived unbound concentrations with the corresponding results obtained using a reference method, the authors sought to identify appropriate UF conditions for cefotaxime, cloxacillin, flucloxacillin, and piperacillin., Methods: In vitro microdialysis (MD) with a no-net-flux approach was used as a reference method for plasma protein separation, for which UF performance was assessed. Four levels of relative centrifugal force (2500-11,290 g ) and 2 levels of temperature (37 vs. 22°C) during 10 minutes of UF centrifugation were evaluated. Ultrafiltrates and reference microdialysates were analyzed using liquid chromatography-tandem mass spectrometry to obtain unbound concentrations. After identifying the appropriate UF conditions in the spiked plasma samples, exploratory analyses of clinical samples (n = 10 per analyte) were performed., Results: Of the evaluated UF alternatives, the best overall agreement with the MD-derived reference concentrations was obtained with 11,290 g UF performed at 22°C. For cloxacillin specifically, 37°C UF yielded better agreement than 22°C UF at 11,290 g. Clinical sample analyses indicated minimal differences between 22°C and 37°C at 11,290 g UF for cefotaxime and piperacillin. However, consistently lower levels of unbound cloxacillin (median: -23%, IQR: -19% to -24%) and flucloxacillin (median: -27%, IQR: -21 to -34%) were observed after UF at 22°C versus 37°C., Conclusions: For the evaluated UF device, 10 minutes of 11,290 g UF at 22°C is appropriate for flucloxacillin, cefotaxime, and piperacillin, and can arguably be justified for cloxacillin as well for laboratory practice purposes. Maintenance of 37°C during high-centrifugal UF may lead to overestimation, particularly for unbound flucloxacillin., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Bacterial resistance is a growing and worrying factor. The high reproducibility of these resistant microorganisms tends to influence the development of new drugs and research related to product quality control. Among the existing antimicrobials, flucloxacillin (FLU) was designed for oral and injectable administration with bactericidal activity. FLU sodium is the form used in pharmaceutical formulations. It is an antimicrobial resistant against penicillinase, an enzyme responsible for cleaving the beta-lactam ring of penicilins, which leads to inactivity of the drug. Qualitative and quantitative analyzes are essential to ensure quality of pharmaceuticals and health of the population. It is important that quality control is effective and appropriate, only then we can win the battle against microbial resistance. In this work, we want to highlight tthe characteristics of FLU as an important antibiotic and methods for the determination of FLU in pharmaceutical products and biological matrices. Among the analytical methods described in the literature for the determination of FLU, high performance liquid chromatography (HPLC) stands out. Anyway, this method uses toxic solvents (e.g. acetonitrile) long columns, which provide long runs, as well as produces large amounts of waste. Currently, the priority changed to develop ecologically correct, conscious and sustainable methods. This new view on analytical methods should be applied to FLU analyzes and used to develop and improve existing methods.

Background: Pharmacokinetic studies and therapeutic drug monitoring of antibiotics require a simple, rapid, and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound concentrations of 3 widely used β-lactam antibiotics (cefalexin, cefazolin, and flucloxacillin) and the often coadministered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories., Methods: Unbound drug was separated from bound drug by ultrafiltration. A simple 1-step protein precipitation was used for sample preparation. Cefalexin, cefazolin, flucloxacillin, probenecid, and their corresponding isotopically labeled internal standards were then resolved on a C18 (2) column. All the compounds were detected using electrospray ionization in the positive mode., Results: Standard curves were linear for all compounds over the concentration range of 0.2-100 mg/L (r > 0.99) for total drug in plasma and 0.01-10 mg/L (r > 0.99) for unbound drug in plasma ultrafiltrate. For both total and unbound drugs, bias was <±10%, and intra- and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 0.2 mg/L for total plasma concentrations and 0.01 mg/L for plasma ultrafiltrate concentrations of all drugs., Conclusions: The method has proven to be simple, rapid, robust, and reliable and is currently being used in clinical pharmacokinetic studies and in the routine clinical service to enhance the effective use of the β-lactam antibiotics.

Three different spectrophotometric methods were applied for the quantitative analysis of flucloxacillin and amoxicillin in their binary mixture, namely, ratio subtraction, absorbance subtraction and amplitude modulation. A comparative study was done listing the advantages and the disadvantages of each method. All the methods were validated according to the ICH guidelines and the obtained accuracy, precision and repeatability were found to be within the acceptable limits. The selectivity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. So, they can be used for the routine analysis of flucloxacillin and amoxicillin in their binary mixtures., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Different chemometric models were applied for the quantitative analysis of amoxicillin (AMX), and flucloxacillin (FLX) in their binary mixtures, namely, partial least squares (PLS), spectral residual augmented classical least squares (SRACLS), concentration residual augmented classical least squares (CRACLS) and artificial neural networks (ANNs). All methods were applied with and without variable selection procedure (genetic algorithm GA). The methods were used for the quantitative analysis of the drugs in laboratory prepared mixtures and real market sample via handling the UV spectral data. Robust and simpler models were obtained by applying GA. The proposed methods were found to be rapid, simple and required no preliminary separation steps., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In the present study we developed and validated a liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay for the determination of flucloxacillin in human plasma and microdialysis samples and cloxacillin in microdialysis samples, using oxacillin as the internal standard for the assay. The samples were separated on a UPLC BEH C18,1.7 μm column (2.1x50mm) and analyzed by a tandem-quadrupole mass spectrometer in multiple reaction monitoring mode using an electronspray ionization interface. For flucloxacillin the method was demonstrated to be accurate and precise in the linearity range of 1-30 mg/L in plasma and 0.05-5.0 mg/L for microdialysate with a regression coefficient (r) of 0.9986 and 0.9989 in plasma and microdialysate respectively. For cloxacillin it was accurate and precise in the range of 0.1-5.0 mg/L for microdialysate with a regression coefficient of 0.9972. The method presents a high sensitivity for flucloxacillin (lower limit of quantification of 1 mg/L for plasma and 0.05 mg/L for microdialysis samples) combined with a low within- and between-day variation (<5.0% for flucloxacillin and cloxacillin in microdialysis samples and <6.5% for plasma samples of flucloxacillin). The validation experiments for the microdialysis probes showed a relative recovery of 85.5% for flucloxacillin at a flow rate of 1.0 μL/min. The results justify the use of this assay for clinical studies for measuring free unbound tissue concentrations of flucloxacillin in patients with a Staphylococcus aureus bacteremia.

A simple, rapid, accurate sensitive spectrophotometry procedure for the determination of amoxycillin (Amox) and flucloxacillin (Fluclox) in bulk samples and in dosage forms are developed. The procedure involves the use of sudan III as chromogenic reagent to produce a violet colored ion-pair with an absorption maximum at 566nm. The ion-pair complexes obey Beer's law and are suitable for the quantitative determination of 0.2-22 and 0.4-25microg/ml of Amox, and Fluclox, respectively. The optimization of different experimental conditions is described in which Amox react after 3min at 25+/-1 degrees C, whereas Fluclox take 10min at 60+/-1 degrees C. Tin(IV) antimonite ion exchanger was utilized to separate a mixture of Amox and Fluclox trihydrate. A column chromatographic technique was applied to separation the antibiotics mixture. Column of 0.3mm diameter and bed height of 3cm of the exchanger was used and the frontal elution technique was utilized. The separation factor for Fluclox and Amox was found to be 2.76. Tin(IV) antimonite ion exchanger exhibit promising feature that can be utilized as stationary phase in either HPLC or HPTLC techniques. The procedure described was applied successfully to determine Amox and Fluclox. The obtained results were compared the official methods. The proposed procedure was successfully applied to determine Amox and Fluclox in their pharmaceutical formulations.

The present study is interested to develop a simple, rapid and accurate spectrophotometric method for determination of sodium flucloxacillin (fluc) in pure form and pharmaceutical formulations. The charge-transfer (CT) interactions between sodium flucloxacillin as electron donor and chloranilic acid (CLA), dichloroquinone 4-chloroimide (DCQ), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and 7,7,8,8 tetracyano-p-quinodimethane (TCNQ), as pi-electron acceptors have been investigated spectrophotometrically. Different variables affecting the reaction were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9979-0.9995) were found between the absorbance and the concentration of the drug in the range 16-880 microg ml(-1). The proposed methods were applied successfully to the determination of the examined drug either in pure or pharmaceutical dosage forms with good accuracy and precision. The formation of the CT-complexes and the sites of interaction were confirmed by elemental analysis CHN, UV-vis, IR, (1)H NMR and mass spectra techniques. Based on Job's method of continuous variation plots, the obtained results indicate the formation of 1:1 charge-transfer complexes with the general formula [(fluc)(acceptor)]. Statistical analysis of the obtained results showed no significant difference between the proposed method and official method.

Iontophoresis is a novel technique which may be used to facilitate the movement of antibiotics into the substance of bone using an electrical potential applied externally. We have examined the rate of early infection in allografts following application of this technique in clinical practice. A total of 31 patients undergoing revision arthroplasty or surgery for limb salvage received 34 iontophoresed sequential allografts, of which 26 survived for a minimum of two years. The mean serum antibiotic levels after operation were low (gentamicin 0.37 mg/l (0.2 to 0.5); flucloxacillin 1 mg/l (0 to 1) and the levels in the drains were high (gentamicin 40 mg/l (2.5 to 131); flucloxacillin 17 mg/l (1 to 43). There were no early deep infections. Two late infections were presumed to be haemotogenous; 28 of the 34 allografts were retained. In 12 patients with pre-existing proven infection further infection has not occurred at a mean follow-up of 51 months (24 to 82).

A simple, rapid and accurate spectrophotometric method for the determination of antibiotic drugs, flucloxacillin (Fluclox) and dicloxacillin (Diclox), in pure form and different pharmaceutical preparations has been developed. The charge transfer (CT) reactions between Fluclox and Diclox as electron donors and 7,7,8,8-tetracyanoquinodimethane (TCNQ) and tetracyanoethylene (TCNE) as pi-acceptors to give highly coloured complex species have been spectrophotometrically studied. The optimum experimental conditions for these CT reactions have been studied carefully. Beer's law is obeyed over the concentration ranges of 4-180 microg mL(-1) and 4-70 microg mL(-1) for Fluclox and Diclox drugs using TCNQ and TCNE reagents, respectively. The Sandell sensitivities (S) are found to be 0.016-0.035 microg cm(-2) and 0.011-0.016 microg cm(-2) for Fluclox and Diclox, respectively, which indicate the high sensitivity of the proposed method. The relative standard deviations (R.S.D.: 0.08-0.49 and 0.15-0.80) for the determination of Fluclox and (R.S.D.: 0.05-0.75 and 0.13-0.75) for Diclox were obtained for four to six replicates using TCNQ and TCNE reagents, respectively, refer to the high accuracy and precision of the proposed method. These results are also confirmed by the between-day precision and the percent recovery of 99.90-100.1 and 99.60-100.4 for Fluclox and 99.90-100.5 and 99.40-100.1 for Diclox using TNCQ and TCNE reagents, respectively. The results obtained for the two reagents are comparable with those obtained by the official method.

The aim of this study was to investigate the microenvironmental factors likely to influence the longitudinal relaxation time of MR visible drugs or compounds in vivo at 1.5 T. The relative influence that viscosity, albumin and paramagnetic contrast agent concentrations have on the observed longitudinal relaxation times of three 19F MR detectable drugs and compounds have been investigated. Our data show that for 5-fluorouracil, flucloxacillin and tetrafluorosuccinic acid-containing phantoms, the presence of albumin at normal physiological concentrations will have relaxation effects of the same order of magnitude as that of a commonly clinically administered contrast agent, gadolinium diethylenetriamine pentaacetic acid. The contribution of viscosity is shown, in the examples studied here, to be of minor importance, contributing less than 6.5% to the observed relaxation effects. It is also demonstrated that in the presence of competitive binding of other ligands for common binding sites on albumin, the 19F longitudinal relaxation time of 5-fluorouracil can increase by up to 340% from its value in the absence of the competing ligand. The relevance of the findings to in vivo studies is discussed.

Some nitrophenols are proposed as chromogenic reagents for the spectrophotometric determination of flucloxacillin. The reagent forms a greenish yellow 1:1 complex with flucloxacillin at pH 9.0. This complex is stable for at least 3.0 h after its formation. The greenish yellow charge transfer complex species has an absorption maximum at 446, 435, 442, 473 and 439 nm for p-nitrophenol (I), 2,4-dinitrophenol (II), 3,5-dinitrosalycilic acid (III), picramic acid (IV) and picric acid (V), respectively, with a molar absorptivity between 1.43 x 10(4) and 2.59 x 10(4) l mol(-1) cm(-1). Beer's low is valid over the concentration range 2.0-40 microg ml(-1) of flucloxacillin. The detection and quantitation limits as well as relative standard deviation were also calculated. The reagents have been successfully used for the spectrophotometric determination of flucloxacillin in pure form and in pharmaceutical preparations.

Per-operative serum and wound fluid concentrations achieved by two flucloxacillin dosage regimens were measured in twelve patients undergoing open heart surgery. One 500 mg bolus dose given after the induction of anaesthesia in six patients resulted in adequate serum concentrations (means decreasing from 69 to 9 mg/l) during surgery, but low wound fluid concentrations (mean 4.6 mg/l, range less than 2-7.8 mg/l) at the time of closure. An additional 500 mg bolus dose given after bypass in six further patients gave more satisfactory wound concentrations (mean 16 mg/l, range 8.6-22.5 mg/l). Disc absorption is a useful technique for assaying antibiotics in wound fluid, but the results are difficult to interpret since they represent a sum of concentrations in a complex and changing mixture of interstitial tissue fluid, blood and cardioplegia solution.

Deep infections caused by staphylococci are serious complications after oral surgery. Intensive antibiotic treatment is always necessary in these infections. Isoxazolylpenicillins are often used. Levels of three isoxazolylpenicillins, namely, cloxacillin, dicloxacillin and flucloxacillin, were measured in serum, dental alveolar serum and mandibular bone in 60 patients undergoing surgical removal of impacted third molars after a single dose of 500 mg. The systemic serum concentrations were higher than the dental alveolar serum concentrations in most patients. The maximum concentration in the alveolar serum was 3.8-6.4 microgram/ml for cloxacillin, 6.0-15.0 microgram/ml for dicloxacillin and 10.0-15.0 microgram/ml for flucloxacillin. The concentration in mandibular bone was 2.0 +/- 0.4 microgram/g for cloxacillin, 2.0 +/- 0.5 microgram/g for dicloxacillin and 2.0 +/- 0.5 microgram/g for flucloxacillin.

A microtechnique, requiring very small amounts of tissue material, was developed for assay of antimicrobial agents in bone. Without previous homogenization or extraction, small bone pieces (mean weight 0.014 g) from human subjects and pigs were placed into wells in agar plates preinoculated with the test strain. Round and distinct zones of inhibition were formed around the pieces. Standards for ampicillin and flucloxacillin were prepared from freeze-dried bone pieces from human subjects and pigs with known amounts of antibiotics as well as in human plasma and phosphate-buffered saline (PBS). Curves obtained from these standards were linear. Bone pieces from human and pig maxilla gave superimposable curves, but differed from curves obtained in plasma or PBS. The method was used in a pharmacokinetic study of bacampicillin in human maxillary bone and plasma. Bacampicillin tablets (2 X 400 mg) were given to patients before oral surgery. Standardized bone pieces and plasma samples were obtained at different times during surgery. The peak ampicillin concentrations estimated from the population curves were 8.0 mg/l in plasma and 1.1 mg/l in maxillary bone. The elimination half-life of ampicillin was similar in plasma and maxillary bone.

A 3 X 3 factorial design has been used to study the effects of pH and acetonitrile concentration of the eluents on the retention and resolution of cloxacillin, flucloxacillin and dicloxacillin on a C18 column. The logarithm of the capacity factors of these solutes have been found to vary linearly with the pH and quadratically with the acetonitrile content. The equations generated have been employed to predict experimental conditions necessary for an optimum separation. The chromatographic condition selected has been applied to the quantitation of flucloxacillin in human plasma using dicloxacillin as the interval standard. Sample preparation consists of protein precipitation and solid-phase extraction. The detection limit of the assay at 220 nm for flucloxacillin is in the region of 0.1 microgram/ml. This assay has been employed in a study of the relative bioavailability of two commercial flucloxacillin sodium capsules in ten healthy volunteers.