Flucloxacillin instantly decreases serum levels of valproic acid: A case report.

Valproic acid (VPA) is used for epilepsy and bipolar disorder. It has near-complete bioavailability and is primarily metabolized by glucuronosyltransferases and mitochondrial oxidation. This case highlights a 79-year-old male with bipolar disorder on VPA therapy that started with flucloxacillin for Staphylococcus aureus bacteraemia and exhibited significantly reduced VPA serum levels. During hospitalization, flucloxacillin treatment correlated with a sharp decline of 75% in VPA total serum levels, a novel drug-drug interaction not previously reported. Nonadherence and absorption issues of VPA were ruled out, confirming flucloxacillin's role in reducing VPA levels. Because free-fraction serum levels of VPA remained within therapeutic range (5-25 mg/L) and our patient's bipolar disorder remained stable at 1000 mg twice daily, a dose increase was not necessary. Previous reports described cytochrome P450 enzyme induction as the mechanism of flucloxacillin lowering serum levels of immunosuppressants and antimycotics. Because only 10% of VPA is metabolized by cytochrome P450 enzymes, this is not plausible for this case. The proposed mechanism for the VPA-flucloxacillin drug-drug interaction is flucloxacillin as inducer of glucuronosyltransferase enzymes via the pregnane X receptor pathway, accelerating VPA metabolism. Because this case showed that free-fraction serum levels remained within therapeutic range, it underscores the need for free-fraction VPA monitoring in bipolar disorder and flucloxacillin therapy. When VPA is used for epilepsy, it is advised to consider alternative antibiotics to avoid this interaction.

Flucloxacillin and cefazolin for treatment of Staphylococcus aureus bloodstream infection.

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.

Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury.

BACKGROUND: Flucloxacillin (FLX)-induced liver injury is immune-mediated and highly associated to HLA-B∗57:01 expression. Host factors leading to drug-induced liver injury are not yet well understood. OBJECTIVE: Characterize in vivo immune mechanisms determining the development of CD8+ T cells reactive to FLX in animals expressing the risk human leukocyte antigen (HLA) allotype. METHODS: HLA-B∗57:01 transgenic mice (Tg) or Tg strains with H2-KbDb knockout (Tg/KO) or H2-KbDb/PD-1 double knockout (Tg/DKO) were treated with drug and/or anti-CD4 antibody. Drug-induced liver injury was evaluated on the basis of liver enzyme and histologic changes at day 10 of treatment. FLX-reactive CD8+ T cells were characterized in vitro by release of effector molecules on drug restimulation, gene expression, and flow cytometry analysis, and functionality tested for hepatic cytotoxicity. RESULTS: CD8+ T-cell responses to FLX in Tg were dependent on both HLA and mouse major histocompatibility complex I presentation and in vivo priming. Eliminating H2-KbDb in Tg/KO to allow exclusive presentation of FLX by HLA resulted in a less robust drug-specific CD8+T-cell response unless CD4+ cells, including regulatory T cells, were depleted. Treatment of Tg/KO with anti-CD4 antibody and FLX led to subclinical liver inflammation associated with an increase in PD1+CD8+ T cells in the lymphoid organs and liver. Impaired PD-1 expression in Tg/DKO led to liver histopathologic and transcriptional alterations but without hepatic enzyme elevations. Moreover, effector lymphocytes accumulated in the liver and showed FLX-dependent hepatic cytotoxicity in vitro when tolerogenic liver cells were depleted. CONCLUSIONS: In our in vivo models, FLX primes CD8+ T cells to recognize drug presented by HLA-B∗57:01 and murine major histocompatibility complex I. HLA-B∗57:01-dependent CD8+ T-cell reaction to FLX is limited by the presence of CD4+ cells, presumably regulatory T cells, and PD-1 expression. Tolerogenic hepatic cells limit clinical disease through PD-L1 or additional unexplored mechanisms.

Target attainment and population pharmacokinetics of flucloxacillin in critically ill patients: a multicenter study.

PURPOSE: Insufficient antimicrobial exposure has been associated with worse clinical outcomes. Reportedly, flucloxacillin target attainment in critically ill patients was heterogeneous considering the study population selection and reported target attainment percentages. Therefore, we assessed flucloxacillin population pharmacokinetics (PK) and target attainment in critically ill patients. METHODS: This prospective, multicenter, observational study was conducted from May 2017 to October 2019 and included adult, critically ill patients administered flucloxacillin intravenously. Patients with renal replacement therapy or liver cirrhosis were excluded. We developed and qualified an integrated PK model for total and unbound serum flucloxacillin concentrations. Monte Carlo dosing simulations were performed to assess target attainment. The unbound target serum concentration was four times the minimum inhibitory concentration (MIC) for ≥ 50% of the dosing interval (ƒT>4xMIC ≥ 50%). RESULTS: We analyzed 163 blood samples from 31 patients. A one-compartment model with linear plasma protein binding was selected as most appropriate. Dosing simulations revealed 26% ƒT>2 mg/L ≥ 50% following continuous infusion of 12 g flucloxacillin and 51% ƒT>2 mg/L ≥ 50% for 24 g. CONCLUSION: Based on our dosing simulations, standard flucloxacillin daily doses of up to 12 g may substantially enhance the risk of underdosing in critically ill patients. Prospective validation of these model predictions is needed.

The Controversial Effect of Antibiotics on Methicillin-Sensitive S. aureus: A Comparative In Vitro Study.

Methicillin-sensitive Staphylococcus (S.) aureus (MSSA) bacteremia remains a global challenge, despite the availability of antibiotics. Primary treatments include ß-lactam agents such as cefazolin and flucloxacillin. Ongoing discussions have focused on the potential synergistic effects of combining these agents with rifampicin or fosfomycin to combat infections associated with biofilm formation. Managing staphylococcal infections is challenging due to antibacterial resistance, biofilms, and S. aureus's ability to invade and replicate within host cells. Intracellular invasion shields the bacteria from antibacterial agents and the immune system, often leading to incomplete bacterial clearance and chronic infections. Additionally, S. aureus can assume a dormant phenotype, known as the small colony variant (SCV), further complicating eradication and promoting persistence. This study investigated the impact of antibiotic combinations on the persistence of S. aureus 6850 and its stable small colony variant (SCV strain JB1) focusing on intracellular survival and biofilm formation. The results from the wild-type strain 6850 demonstrate that ß-lactams combined with RIF effectively eliminated biofilms and intracellular bacteria but tend to select for SCVs in planktonic culture and host cells. Higher antibiotic concentrations were associated with an increase in the zeta potential of S. aureus, suggesting reduced membrane permeability to antimicrobials. When using the stable SCV mutant strain JB1, antibiotic combinations with rifampicin successfully cleared planktonic bacteria and biofilms but failed to eradicate intracellular bacteria. Given these findings, it is reasonable to report that ß-lactams combined with rifampicin represent the optimal treatment for MSSA bacteremia. However, caution is warranted when employing this treatment over an extended period, as it may elevate the risk of selecting for small colony variants (SCVs) and, consequently, promoting bacterial persistence.

Hypokalaemia in patients treated with intravenous flucloxacillin: Incidence and risk factors.

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.

Broad-spectrum azoles and flucloxacillin: a dangerous match.

Both invasive fungal infection with Aspergillus fumigatus and blood stream infection with methicillin-susceptible Staphylococcus aureus (MSSA) have a significant incidence in the critically ill. Voriconazole and, more recently, isavuconazole and high dose flucloxacillin are the standard first line treatments for these respective serious infections. However, an underestimated risk of a significant interaction needs to be taken into consideration, when both co-occur. We wish to highlight this important issue in the management of these patients through two case reports and to point to the inconsistency between different validated databases regarding this significant interaction as well the importance of a strict protocol for readily available therapeutic drug monitoring.

Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue- Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations.

PURPOSE: Flucloxacillin is a ß-lactam penicillin commonly used in the treatment of bone and soft tissue infections. In a recent porcine study, we found surprisingly low time for which the free concentration was maintained above the minimal inhibitory concentration (fT>MIC) in bone and soft tissue, following flucloxacillin oral (PO) and intravenous (IV) administration at 1g every 6h (q6h). In addition to plasma, sampling was obtained from subcutaneous tissue, knee joint, cancellous bone and cortical bone, using microdialysis. To identify flucloxacillin dosing regimens that result in theoretically therapeutic concentrations, we developed a population pharmacokinetic (PK) model for the porcine data, and combined it with a human flucloxacillin population PK model for simulations. METHODS: A four-compartment model was developed, and various dosing regimens and modes of administration were simulated. Predicted concentrations were compared to %fT>MIC (0.5 mg/L and 2 mg/L). RESULTS: Continuous infusion (CI) resulted in higher %fT>MIC compared to intermittent administration. For intermittent IV dosing (4, 8 and 12g/24h), fT>MIC (0.5 mg/L) was ≥70% in plasma, and ranged between 42-96% in the sampled tissue in a typical individual. By applying CI, 4g/day was sufficient to achieve ≥98% fT>MIC (0.5 mg/L) in all sampled tissues. For MIC 2 mg/L, ≥50% fT>MIC was only achieved in plasma at CI 8 and 12g/24h and IV 3g q6h. CONCLUSIONS: To reach efficacious flucloxacillin bone and tissue concentrations, dose increment or continuous infusion needs to be considered.

Interaction between posaconazole and flucloxacillin in a lung transplant patient: decrease in plasma exposure of posaconazole and possible undertreatment of invasive aspergillosis: case report.

BACKGROUND: Variability in triazole plasma concentrations by drug interactions is well known. An interaction between voriconazole and flucloxacillin has already been described. In our case we observed a similar interaction between posaconazole and flucloxacillin, which in our knowledge has not ever been reported in literature. CASE PRESENTATION: A 60-year-old male who had a double lung transplantation for end-stage chronic obstructive pulmonary disease was being treated with voriconazole for invasive pulmonary aspergillosis (IPA). During this treatment he presented at the emergency room and was diagnosed with endocarditis for which a combination of amoxicillin, flucloxacillin and gentamicin was initiated. A known interaction between voriconazole and flucloxacillin was observed, with a drop of the voriconazole levels, and treatment for IPA was switched to posaconazole. After ending the treatment for endocarditis, the patient had a catheter infection for which flucloxacillin was reinitiated. Unexpectedly we saw a similar immediate drop in posaconazole levels, recovering after ending treatment with flucloxacillin. CONCLUSIONS: We describe a new interaction between posaconazole and flucloxacillin. Presumably the underlying mechanism is activation of the pregnane X receptor by flucloxacillin, which can induce cytochrome P450, uridine glucuronosyl transferase (UGT1A4) and P-glycoprotein. We advise caution when combining flucloxacillin and triazoles, because interactions may lead to undertreatment of invasive aspergillosis.

Steady-state concentrations of flucloxacillin in porcine vertebral cancellous bone and intervertebral disc following oral and intravenous administration assessed by microdialysis.

AIMS: Flucloxacillin is a frequently used antibiotic in the treatment of spondylodiscitis. We assessed steady-state concentrations and time above minimal inhibitory concentration (fT > MIC) of flucloxacillin in the intervertebral disc, vertebral cancellous bone, subcutaneous tissue and plasma, after intravenous and oral administration. METHODS: Sixteen pigs were randomized into two groups; Group Peroral (Group PO) and Group Intravenous (Group IV) received 1 g flucloxacillin every 6 h for 24 h orally or intravenously. Microdialysis was used for sampling in the compartments of interest. A flucloxacillin target of 50% fT > MIC was applied for three MIC targets: 0.125, 0.5 and 2.0 µg/mL. RESULTS: Intravenous administration resulted in significantly longer fT > MIC for all targets. Target attainment was only reached for the low target of 0.125 µg/mL in Group IV in vertebral cancellous bone, subcutaneous tissue, and plasma (intervertebral disc 47%). In Group IV, mean fT > MIC values in the investigated compartments were in the range of 47-67% of the dosing interval for 0.125 µg/mL, 20-35% for 0.5 µg/mL, and 0-15% for 2.0 µg/mL. In Group PO, mean fT > MIC values for 0.125 µg/mL were in the range of 1-33%. No pigs reached a concentration of 0.5 µg/mL in any of the investigated compartments in Group PO. CONCLUSION: Administration of 1 g flucloxacillin every 6 h resulted in surprisingly low steady-state fT > MIC after intravenous and oral administration. However, intravenous administration resulted in significantly higher concentrations across compartments compared to oral administration. Sufficient target tissue concentrations for treatment of spondylodiscitis may require a dose increase or alternative dosing regimens.

Population pharmacokinetics of free flucloxacillin in patients treated with oral flucloxacillin plus probenecid.

Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination. METHODS: We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly for proven or probable staphylococcal infections. Steady-state mid-dose-interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration). RESULTS: Flucloxacillin disposition was best described by a 1-compartment model with a lag time and first-order absorption. Free flucloxacillin clearance depended on probenecid, allometrically-scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid. CONCLUSION: The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6-hourly dosing to achieve PK/PD targets. The regimen was well-tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.

Interaction between flucloxacillin and azoles: Is isavuconazole next?

BACKGROUND: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. It has been previously reported that an interaction between flucloxacillin and voriconazole may lead to subtherapeutic voriconazole exposure, when used concomitantly. Since isavuconazole is also metabolised via cytochrome P450 enzymes, the same interaction may be expected. OBJECTIVES: We aim to document exposure to isavuconazole in patients concomitantly treated with flucloxacillin. PATIENTS: We report two patients treated with both isavuconazole and flucloxacillin, in whom we determined isavuconazole concentrations. RESULTS: Low isavuconazole trough concentrations (<1 mg/L) were observed in two patients under concomitant treatment with flucloxacillin. CONCLUSIONS: In combination with flucloxacillin, low isavuconazole concentrations were observed but an adequate isavuconazole exposure may be reached with dose augmentation. Therapeutic drug monitoring of isavuconazole is recommended to ensure an adequate exposure.

Prior administration of chocolate improves the palatability of bitter drugs: The Choc-with-Med study.

AIM: The paediatric population has a low adherence and acceptance rate of unpalatable medicines. This study aimed to determine whether eating chocolate immediately prior to drug administration would help to mask the bitter taste of a drug. The difference in taste masking efficacy between white, milk and dark chocolate was a secondary measure outcome. METHODS: A controlled repeated measures crossover taste trial was conducted using a taste panel of 29 young healthy adults who met the criteria to differentiate intensity in bitterness taste. Participants separately tasted solutions of quinine, flucloxacillin and clindamycin using the swill and spit method, singularly and following blinded prior administration of white, milk or dark chocolate. Drug solutions administered without prior chocolate served as controls. Bitterness score for each tasting was recorded using a 5-point scale. RESULTS: Regardless of chocolate type, mean taste scores with prior chocolate for quinine (range 2.00-2.34), clindamycin (3.72-3.83) and flucloxacillin (3.38-3.45) were all lower than mean scores for respective drugs without chocolate (3.24, 4.75 and 4.28, respectively; P < 0.0001 for all comparisons). Dark chocolate was most efficacious for masking the bitter taste of quinine, but the differences in taste masking efficacy between dark, milk and white chocolates were not statistically significant for flucloxacillin and clindamycin. CONCLUSIONS: Prior administration of chocolate results in lower perceived bitterness compared to control tastings of quinine, flucloxacillin and clindamycin solutions; however, there is no clear difference in this effect between the dark, milk and white chocolates used in this study.

Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study.

PURPOSE: Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. METHODS: In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, flucloxacillin n = 11 patients). RESULTS: The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4-49.7%) during flucloxacillin treatment. After discontinuation of flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5-51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with flucloxacillin compared with before (p = 0.009) and after flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and flucloxacillin treatment, the same pattern was observed. CONCLUSIONS: Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during flucloxacillin treatment and up to 2 weeks after discontinuation of flucloxacillin.

Clinical effectiveness of flucloxacillin delivery using an elastomeric device for outpatient parenteral antimicrobial therapy.

There has been a surging interest in using elastomeric infusion devices to deliver outpatient parenteral antimicrobial therapy (OPAT), which is more cost-effective than standard antibiotic administration, which requires multiple daily home visits. This has been particularly important since the outbreak of the coronavirus pandemic, because reducing patient contact can also help to minimise transmission of COVID-19 to outpatients who are at a high risk of COVID-19-triggered complications. In this retrospective study, the clinical effectiveness of intravenous (IV) infusion of flucloxacillin using an elastomeric device was explored in a convenience sample of patients. Patients with three primary infective diagnoses-bloodstream infection, non-vertebral osteomyelitis and vertebral osteomyelitis-were included in the analyses. In non-vertebral osteomyelitis patients, Accufuser antibiotic infusion shortened the course of OPAT care relative to standard antibiotic administration (p<.05). In contrast, in vertebral osteomyelitis patients, it prolonged the course of OPAT care relative to standard administration (p<.05). In patients with bloodstream infections, no significant difference was found between the treatment modes (p=.93). Thus, the clinical effectiveness of Accufuser antibiotic infusion varies among patients with different infective diagnoses, and there seems to be a complex relationship between the method of antibiotic delivery and the patient's condition.

Severe Disseminated Infection with Emerging Lineage of Methicillin-Sensitive Staphylococcus aureus.

We report a case of severe disseminated infection in an immunocompetent man caused by an emerging lineage of methicillin-sensitive Staphylococcus aureus clonal complex 398. Genes encoding classic virulence factors were absent. The patient made a slow recovery after multiple surgical interventions and a protracted course of intravenous flucloxacillin.

Intravenous flucloxacillin treatment is associated with a high incidence of hypokalaemia.

Intravenous flucloxacillin is one of the most frequently used high-dose penicillin therapies in hospitalized patients, forming the cornerstone treatment of invasive Staphylococcus aureus infection. Being a nonreabsorbable anion, flucloxacillin has been suggested to cause hypokalaemia, although the frequency and magnitude of this unwanted effect is unknown. In a retrospective cohort, we investigated the incidence and extent of hypokalaemia after initiation of intravenous flucloxacillin or ceftriaxone therapy. In total, 77 patients receiving flucloxacillin (62% male, mean age 70.5 years) and 84 patients receiving ceftriaxone (46% male, mean age 70.8 years) were included. Hypokalaemia occurred significantly more often in patients receiving flucloxacillin than ceftriaxone (42% vs 14%, p < 10-4 ). Moreover, follow-up potassium levels were significantly lower during flucloxacillin therapy. In general, women were more prone to develop hypokalaemia than men. In conclusion, intravenous flucloxacillin use is associated with a striking incidence of hypokalaemia. Therefore, standardized potassium measurements are necessary.

A toll-like receptor 9 agonist sensitizes mice to mitochondrial dysfunction-induced hepatic apoptosis via the Fas/FasL pathway.

Early hepatocyte death occurs in most liver injury cases and triggers liver inflammation, which in combination with other risk factors leads to the development of liver disease. However, the pathogenesis of early phase hepatocyte death remains poorly understood. Here, C57BL/6J mice were treated with the hepatotoxic drug flucloxacillin (FLUX) and the toll-like receptor 9 agonist CpG oligodeoxynucleotide (ODN) to reproduce the early phase of drug-induced hepatotoxicity and investigate its pathogenesis. C57BL/6J mice were treated with FLUX (100 mg/kg, gavage) alone or in combination with ODN (40 µg/mouse, intraperitoneally). Plasma alanine aminotransferase (ALT) level was measured as a marker of hepatotoxicity. FLUX or ODN alone was insufficient to induce ALT elevation, whereas combination treatment with FLUX and ODN increased ALT levels 24 h after FLUX treatment and upregulated Fas ligand in natural killer T (NKT) cells and Fas in hepatocytes. FLUX induced mitochondrial permeability transition (MPT), and pretreatment with ODN sensitized mitochondria to FLUX-induced MPT. The increase in ALT levels induced by ODN and FLUX co-treatment was suppressed in Fas ligand (gld/gld)-deficient mice and in mice deficient in a component of MPT pore opening (cyclophilin D-knockout mice). These results suggested that ODN activated the Fas/Fas ligand-mediated pathway in NKT cells and hepatocytes, which may predispose to FLUX-induced mitochondrial dysfunction and lead to early phase hepatocyte apoptosis. Taken together, these findings elucidate a potentially novel mechanism underlying drug-induced early phase hepatocyte death related to the Fas/Fas ligand death receptor pathway and mitochondrial dysfunction.

Beyond Penicillin: Rapid Desensitization for Specific Flucloxacillin Hypersensitivity.

Beta-lactam therapy for severe staphylococcal infections is associated with superior outcomes, compared to non-beta-lactam therapy. For patients with immediate hypersensitivity to beta-lactams, desensitization has been widely employed to allow beta-lactam therapy, but published protocols for antistaphylococcal beta-lactams such as flucloxacillin are lacking. Here, we report a case and describe the desensitization protocol successfully used for a patient with isolated flucloxacillin immediate hypersensitivity, for whom a penicillin desensitization protocol would likely have resulted in an adverse drug reaction.

Total flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with Staphylococcus aureus bacteraemia.

AIMS: Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (fu ) of around 0.04 in healthy individuals. The utility of measuring unbound flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare flucloxacillin fu in non-ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total flucloxacillin and plasma albumin concentrations. METHODS: Data from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma flucloxacillin concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Flucloxacillin fu for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland-Altman plots. RESULTS: The median (range) flucloxacillin fu for healthy (median albumin 45 g l-1 ) and hospitalized individuals (median albumin 30 g l-1 ) were 0.04 (0.02-0.07) and 0.10 (0.05-0.37), respectively (P < 0.0001). The prediction model underpredicted unbound flucloxacillin concentrations with a mean bias (95% limits of agreement) of -54% (-137%, +30%). CONCLUSIONS: The flucloxacillin fu values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.