Population pharmacokinetics of flucloxacillin as intermittent bolus infusion in patients with Staphylococcus aureus bloodstream infection.

BACKGROUND: Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics, which may be influenced by various patient-related factors, particularly in critically ill patients. OBJECTIVES: To describe the population pharmacokinetics (PopPK) of the antibiotic flucloxacillin in patients with S. aureus BSI. Subsequently, we sought to translate the model into a user-friendly app for generating a priori and a posteriori time-concentration curves and dose recommendations to optimize dosing regimens. METHODS: Total and unbound flucloxacillin concentrations were included from 49 patients from a prospective cohort study conducted during clinical routine, including non-critically ill and critically ill individuals who received intermittent bolus applications. These data were analysed using non-linear mixed-effects modelling. RESULTS: Most patients (98%) were treated with 2 g of flucloxacillin every 4 h. We developed a joint model that simultaneously described total and unbound concentrations. The model included an allometric effect of glomerular filtration rate on clearance and albumin on the albumin dissociation constant. The latter was especially important, as in our population the unbound fraction was higher at 11.5% (16.7% for critically ill patients) compared with reported values of approximately 5%. Based on our joint model, we developed a web-based app for optimizing dosing regimens of flucloxacillin. CONCLUSIONS: By utilizing data from clinical routine, we were able to create a predictive PopPK model of flucloxacillin and identify influential covariates. The web-based app is currently being validated in a clinical trial.

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 new similarity method for assessment of pharmacokinetic interaction between flucloxacillin and midazolam.

The purpose of this study was to develop a new similarity method to assess the drug-drug interaction between midazolam and flucloxacillin. Total quantum statistical moment (TQSM) of pharmacokinetic profiles were expressed by parameters AUCT, MRTT, VRTT et al. Statistical moment similarity (SMS) expressions were deduced to evaluate the similarity of the converted pharmacokinetic profiles. A trial of the pharmacokinetic interaction between midazolam and flucloxacillin by the SMS method was conducted. For midazolam, total quantum SMS (SMST) was 0.9582; total deviation was 0.0525; total variable probability was 4.18 %; total confidence of probability ß was 97.17 % under significance level 0.05; AUC0-∞ were 334.3±334.1 ng•h•mL-1 (after administration of midazolam alone) and 206.9±172.2 ng•h•mL-1 (after co-administration of midazolam and flucloxacillin), respectively. While, for 1'-hydroxy midazolam, SMST was 0.6920; total deviation was 0.3960; total variable probability was 30.80 %; total confidence of probability ß was 94.10 % under significance level 0.05; AUC0-∞ were 1364±810.7 ng•h•mL-1 (after administration of midazolam alone) and 1637±632.6 ng•h•mL-1 (after co-administration of midazolam and flucloxacillin), respectively. These results revealed that flucloxacillin might have weak pharmacokinetic interactions on midazolam metabolized into 1'-hydroxy midazolam, indicating that there was weak induction to CYP3A by flucloxacillin and that there was at least 30.80 % of metabolic behaviour in change with bioavailability decreased by 38.11 % that took effect to flucloxacillin metabolism for liver injury in CPY3A4 poor metabolic polymorphisms. SMS can be an optional method applied to characterize and analyze pharmacokinetic profiles.

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.

Adsorption and Leachable Contamination of Flucloxacillin, Cyclosporin and Amiodarone Following Delivery Through an Intravenous Administration Set.

PURPOSE: Interactions between a pharmaceutical drug and its delivery device can result in changes in drug concentration and leachable contamination. Flucloxacillin, amiodarone and cyclosporin were investigated for drug concentration changes and leachable contamination after delivery through an intravenous administration set. METHODS: Flucloxacillin, amiodarone and cyclosporin were delivered through an intravenous administration set and the eluate analysed by HPLC-UV and HPLC-MS. RESULTS: The average recovery of flucloxacillin was 99.7% and no leachable compounds were identified. The average recovery of cyclosporin was 96.1%, which contrasts previous findings that have reported up to 50% loss of cyclosporin. This is likely due to the use of DEHP-free administration sets in this study, as adsorption of cyclosporin is linearly related to DEHP content. The average recovery of amiodarone was 91.5%. 5-hydroxymethylfurfural was identified in the amiodarone solution following delivery through the administration set as well as the 5% glucose solution used for delivery. CONCLUSIONS: Drug/administration set interactions may modify pharmaceuticals during delivery. In this study, only 90% of the amiodarone was delivered through a generic administration set. Given the growing use of generic administration sets in hospital settings, validation of the suitability of their use is required to ensure patient safety and expected levels of efficacy.

Quantification of the risk of liver injury associated with flucloxacillin: a UK population-based cohort study.

Background: Flucloxacillin is an established cause of liver injury. Despite this, there are a lack of published data on both the strength of association after adjusting for potential confounders, and the absolute incidence among different subgroups of patients. Objectives: To assess the relative and absolute risks of liver injury following exposure to flucloxacillin and identify subgroups at potentially increased risk. Methods: A cohort study between 1 January 2000 and 1 January 2012 using the UK Clinical Practice Research Datalink, including 1 046 699 people with a first prescription for flucloxacillin (861 962) or oxytetracycline (184 737). Absolute risks of experiencing both symptom-defined (jaundice) and laboratory-confirmed liver injury within 1-45 and 46-90 days of antibiotic initiation were estimated. Multivariable logistic regression was used to estimate 1-45 day relative effects. Results: There were 183 symptom-defined cases (160 prescribed flucloxacillin) and 108 laboratory-confirmed cases (102 flucloxacillin). The 1-45 day adjusted risk ratio for laboratory-confirmed injury was 5.22 (95% CI 1.64-16.62) comparing flucloxacillin with oxytetracycline use. The 1-45 day risk of laboratory-confirmed liver injury was 8.47 per 100 000 people prescribed flucloxacillin (95% CI 6.64-10.65). People who received consecutive flucloxacillin prescriptions had a 1-45 day risk of jaundice of 39.00 per 100 000 (95% CI 26.85-54.77), while those aged >70 receiving consecutive prescriptions had a risk of 110.57 per 100 000 (95% CI 70.86-164.48). Conclusions: The short-term risk of laboratory-confirmed liver injury was >5-fold higher after a flucloxacillin prescription than an oxytetracycline prescription. The risk of flucloxacillin-induced liver injury is particularly high within those aged >70 and those who receive multiple flucloxacillin prescriptions. The stratified risk estimates from this study could help guide clinical care.

Oral and Topical Antibiotics for Clinically Infected Eczema in Children: A Pragmatic Randomized Controlled Trial in Ambulatory Care.

PURPOSE: Eczema may flare because of bacterial infection, but evidence supporting antibiotic treatment is of low quality. We aimed to determine the effect of oral and topical antibiotics in addition to topical emollient and corticosteroids in children with clinically infected eczema. METHODS: We employed a 3-arm, blinded, randomized controlled trial in UK ambulatory care. Children with clinical, non-severely infected eczema were randomized to receive oral and topical placebos (control), oral antibiotic (flucloxacillin) and topical placebo, or topical antibiotic (fusidic acid) and oral placebo, for 1 week. We compared Patient Oriented Eczema Measure (POEM) scores at 2 weeks using analysis of covariance (ANCOVA). RESULTS: We randomized 113 children (40 to control, 36 to oral antibiotic, and 37 to topical antibiotic). Mean (SD) baseline Patient Oriented Eczema Measure scores were 13.4 (5.1) for the control group, 14.6 (5.3) for the oral antibiotic group, and 16.9 (5.5) for the topical antibiotic group. At baseline, 104 children (93%) had 1 or more of the following findings: weeping, crusting, pustules, or painful skin. Mean (SD) POEM scores at 2 weeks were 6.2 (6.0) for control, 8.3 (7.3) for the oral antibiotic group, and 9.3 (6.2) for the topical antibiotic group. Controlling for baseline POEM score, neither oral nor topical antibiotics produced a significant difference in mean (95% CI) POEM scores (1.5 [-1.4 to 4.4] and 1.5 [-1.6 to 4.5] respectively). There were no significant differences in adverse effects and no serious adverse events. CONCLUSIONS: We found rapid resolution in response to topical steroid and emollient treatment and ruled out a clinically meaningful benefit from the addition of either oral or topical antibiotics. Children seen in ambulatory care with mild clinically infected eczema do not need treatment with antibiotics.

Evaluating an admission avoidance pathway for children in the emergency department: outpatient intravenous antibiotics for moderate/severe cellulitis.

OBJECTIVE: Children with moderate/severe cellulitis requiring intravenous antibiotics are usually admitted to hospital. Admission avoidance is attractive but there are few data in children. We implemented a new pathway for children to be treated with intravenous antibiotics at home and aimed to describe the characteristics of patients treated on this pathway and in hospital and to evaluate the outcomes. METHODS: This is a prospective, observational cohort study of children aged 6 months-18 years attending the ED with uncomplicated moderate/severe cellulitis in March 2014-January 2015. Patients received either intravenous ceftriaxone at home or intravenous flucloxacillin in hospital based on physician discretion. Primary outcome was treatment failure defined as antibiotic change within 48 hours due to inadequate clinical improvement or serious adverse events. Secondary outcomes include duration of intravenous antibiotics and complications. RESULTS: 115 children were included: 47 (41%) in the home group and 68 (59%) in the hospital group (59 hospital-only, 9 transferred home during treatment). The groups had similar clinical features. 2/47 (4%) of the children in the home group compared with 8/59 (14%) in the hospital group had treatment failure (P=0.10). Duration of intravenous antibiotics (median 1.9 vs 1.8 days, P=0.31) and complications (6% vs 10%, P=0.49) were no different between groups. Home treatment costs less, averaging $A1166 (£705) per episode compared with $A2594 (£1570) in hospital. CONCLUSIONS: Children with uncomplicated cellulitis may be able to avoid hospital admission via a home intravenous pathway. This approach has the potential to provide cost and other benefits of home treatment.

Reduction in post-operative acute kidney injury following a change in antibiotic prophylaxis policy for orthopaedic surgery: an observational study.

OBJECTIVES: Evidence has shown that a prophylactic antibiotic regimen of flucloxacillin and gentamicin for orthopaedic surgery was associated with increased rates of post-operative acute kidney injury (AKI). This resulted in changes in the national antibiotic policy recommendation for orthopaedic surgical prophylaxis. This study aimed to assess whether this change from flucloxacillin and gentamicin to co-amoxiclav was associated with changes in the rates of AKI and Clostridium difficile infection (CDI). METHODS: An observational study and interrupted time series analyses were used to assess rates of post-operative AKI separately in patients undergoing neck of femur (NOF) repair and other orthopaedic operations that required antibiotic prophylaxis. Incidence rate ratios were used to evaluate changes in CDI rates. RESULTS: Following the change in policy, from flucloxacillin and gentamicin to co-amoxiclav, there was a relative change in rates of post-operative AKI of -63% (95% CI -77% to -49%) at 18 months in the other orthopaedic operations group. In the NOF repair group, there was no change in the rate of post-operative AKI [-10% (95% CI -35%-15%)] at 18 months. The incident rate ratio for CDI in the other orthopaedic operations group was 0.29 (95% CI 0.09-0.96) and in the NOF repair group was 0.76 (95% CI 0.28-2.08). CONCLUSIONS: The use of co-amoxiclav for antibiotic prophylaxis in orthopaedic surgery was associated with a decreased rate of post-operative AKI compared with flucloxacillin and gentamicin and was not associated with increased rates of CDI.

The effectiveness and safety of two prophylactic antibiotic regimes in hip-fracture surgery.

Antibiotic prophylaxis with cefuroxime can reduce the incidence of deep wound infection (DWI) in hip-fracture surgery, but may increase the risk of C. difficile infection (CDI). An alternative is gentamicin with beta-lactam for which a question exists around clinical effectiveness and safety, given the gentamicin-associated nephrotoxicity particularly in the elderly and narrower sensitivity spectrum. We compared 744 consecutive patients (group I-cefuroxime) with 756 in group II (gentamicin + flucloxacillin) who were well matched. There were 4 cases of CDI in the cefuroxime prophylaxis, whereas none in flucloxacillin plus gentamicin (group II). There was a statistically significant (p = 0.036) increased DWI rate in group II (2.5 %) as compared to group I (1.1 %). However, after controlling for age, gender, ASA grade, surgeon grade, implant type and type of anaesthesia, there was no statistically significant difference between the two groups (p = 0.146). 8.5 % of group I and 16.5 % of group II developed AKI post-operatively (p = 0.023); however, 79 % of group I and 80 % of in group II had complete resolution of AKI prior to their discharge. Further, a significant increase in inpatient deaths (p = 0.057) in group II was observed, but not at 30 days (p = 0.378).

In vivo effect of flucloxacillin in experimental endocarditis caused by mecC-positive staphylococcus aureus showing temperature-dependent susceptibility in vitro.

Methicillin-resistant Staphylococcus aureus (MRSA) carrying the mecC gene (mecC-MRSA) exhibited at 37°C MICs of oxacillin close to those of methicillin-susceptible S. aureus (MSSA). We investigated whether at this temperature, mecC-MRSA strains respond to flucloxacillin treatment like MSSA strains, using a rat model of endocarditis. Flucloxacillin (human-like kinetics of 2 g intravenously every 6 h) cured 80 to 100% of aortic vegetations infected with five different mecC-MRSA strains. These results suggest that mecC-MRSA infections may successfully respond to treatment with ß-lactams.

Low flucloxacillin concentrations in a patient with central nervous system infection: the need for plasma and cerebrospinal fluid drug monitoring in the ICU.

OBJECTIVE: To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections. CASE SUMMARY: We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin-sensitive Staphylococcus aureus infection (minimum inhibitory concentration; MIC, 1 µg/mL). Owing to the complicated nature of the infection, sequential concentrations of free flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of flucloxacillin were below the MIC (0.2-0.4 µg/mL), and the corresponding CSF concentrations were undetectable (<0.1 µg/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 µg/mL) and CSF (0.1 µg/mL) levels were increased, albeit lower than the predefined targets (plasma, 40 µg/mL; CSF, 4 µg/mL). DISCUSSION: The presence of physiological changes associated with critical illness-namely, hypoalbuminemia and augmented renal clearance-may significantly alter antibiotic pharmacokinetics, and this phenomenon may lead to suboptimal antibiotic exposure if they are not accounted for. This case also highlights the value of applying CI in such patient groups and demonstrates the significance of monitoring plasma and CSF drug concentrations in optimizing antibiotic delivery. CONCLUSIONS: Future research should aim to evaluate the utility of such drug monitoring with regard to patient outcomes and cost-effectiveness.

[Septic arthritis of undetermined origin in children: a proposal for the assessment and its therapy]. / Une arthrite septique d'origine indéterminée chez l'enfant.

Septic arthritis is not a frequent, but quite classical pathology in children. It can be followed by a severe outcome in case of delayed and/or inadequate treatment. The drainage of the infected joint associated with a prompt and adapted antibiotherapy are together the cornerstones of this treatment. The isolation and identification of the causative microorganism is also of the highest importance. Up to now, unfortunately, a large proportion of septic arthritis are treated by antibiotics although all culture remain negative. This paper has two objectives: one is to present the different steps to optimize the assessment and diagnosis; the second, to increase the sensitivity of the pathogen identification. At last, we present our proposal for empirical antibiotherapy.

Antibiotic-associated complications following lower limb arthroplasty: a comparison of two prophylactic regimes.

INTRODUCTION: As part of a wider drive to reduce Clostridium difficile rates (CDAD), our trust switched from cefuroxime to gentamicin and flucloxacillin prophylaxis for joint replacement surgery. Anecdotal evidence suggested that we were seeing an increased incidence of acute kidney injury (AKI) following elective total hip replacement (THR) and total knee replacement (TKR) since this change. The aim of this study was to compare rates of AKI and post-operative infection between the two antibiotic regimes. METHODS: We carried out a single-centre retrospective cohort study comparing 200 patients (100 THR and 100 TKR) who received cefuroxime with another age and procedure-matched group who received gentamicin and flucloxacillin (gentamicin 3 mg/kg and 5 g flucloxacillin in total). We compared rates of AKI, haemofiltration, CDAD, surgical site infection (SSI) and return to theatre for infection (RTT). RESULTS: Gentamicin was associated with a significant increase in AKI (1 vs. 8%, p < 0.01). More patients needed haemofiltration (0 vs. 1.5%) although this was not significant. Interestingly, when the groups were subdivided into THR and TKR, significantly more TKR patients receiving gentamicin developed AKI (0 vs. 11, p < 0.01). This difference was not significant following THR (2 vs. 5, p = 0.44). This may be related to tourniquet use in TKR. SSI and RTT were comparable. No patient developed CDAD. CONCLUSIONS: Gentamicin with flucloxacillin is comparable with cefuroxime in rates of SSI and RTT but is associated with a significant increase in AKI. AKI is associated with additional morbidity and mortality. This association should be considered when choosing a suitable prophylactic regime.