Pyroglutamate acidosis 2023. A review of 100 cases.

This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.

[A case of pyroglutamic metabolic acidosis after cotreatment by flucloxacillin and paracetamol]. / Un cas d'acidose métabolique pyroglutamique sur comédication par flucloxacilline et paracétamol.

We report on the case of a 73-year-old man, who was referred to our emergency department for confusion and dyspnea. He had been under a treatment of flucloxacillin for six weeks because of a possible methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis that was complicated by an acute late infection of a knee prosthesis. The laboratory work-up revealed a metabolic acidosis with a high anion gap. After exclusion of the other explanations, we retained a pyroglutamic metabolic acidosis due to concomitant intake of paracetamol and flucloxacillin, favoured by several risk factors. This diagnosis was confirmed by an organic acid dosage in the urine. After discontinuation of the drugs and a treatment with N-acetylcysteine, the evolution was favourable with correction of the metabolic acidosis and the confusional state.

Nous rapportons le cas d'un homme de 73 ans, sous traitement de flucloxacilline depuis 6 semaines pour une possible endocardite à Staphylococcus aureus sensible à la méticilline (SASM) compliquée d'une infection aiguë tardive d'une prothèse de genou. Il est adressé à notre service d'urgences pour un état confusionnel et une dyspnée. Le bilan met en évidence une acidose métabolique à trou anionique élevé. Après exclusion des différentes étiologies, nous retenons une acidose métabolique pyroglutamique d'origine médicamenteuse sur prise concomitante de paracétamol et flucloxacilline, favorisée par plusieurs facteurs précipitants. Ce diagnostic est confirmé par un dosage d'acide organique dans les urines. Après arrêt des médicaments incriminés et traitement par N-acétylcystéine, l'évolution est favorable avec correction de l'acidose métabolique et de l'état confusionnel.

Flucloxacillin-induced liver injury in elderly patient.

Flucloxacillin is a penicillin antibiotic used as first-line treatment for soft tissue infections caused by Staphylococcus aureus It is used frequently in the elderly and is an established cause of cholestatic liver injury. Risk factors for cholestasis include prolonged duration of treatment, female sex and older age. Elderly patients are also more likely to suffer from comorbidities and polypharmacy, which increases the incidence of drug-induced liver injury and hospitalisation, which in turn can lead to irreversible deterioration in functional baseline. Our case report aims to raise awareness of flucloxacillin-induced liver injury in elderly patients and to encourage the use of alternative treatments and/or limited duration. We advocate for further research into individualised treatments and new diagnostic techniques in patients with painless jaundice based on their genotype.

Flucloxacillin-Induced Hepatotoxicity - Association with HLA-B*5701.

Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

Successful liver transplantation for drug-induced vanishing bile duct syndrome.

Drug-induced cholestasis has a wide range of clinical presentations, and in a small number of patients, it can progress to severe ductopenia. A 63-year-old woman was referred to our department with progressive cholestasis and hyperbilirubinaemia following a course of flucloxacillin. Despite the comprehensive laboratory, imaging and genetic investigations, no other cause for the cholestasis was demonstrated. Sequential liver biopsies confirmed the development of vanishing bile duct syndrome. She developed significant cachexia and pruritus that did not respond to medical therapy, and hence she was listed for liver transplantation. She underwent liver transplantation 6 months after the initial drug-induced injury. She has remained well with good graft function at 1-year follow-up. The case highlights an extreme form of drug-induced ductopenia and underscores the need for meticulous hepatology input and consideration of liver transplantation in some patients.

Flucloxacillin-Induced Hepatotoxicity - Association with HLA-B*5701

SUMMARY Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

RESUMO A hepatotoxicidade à flucloxacilina é rara e classifica-se como idiossincrática, uma vez que é dependente da suscetibilidade individual, não expectável e independente da dose. Apresentamos o caso de um homem, 74 anos, antecedentes de gamapatia monoclonal e hábitos alcoólicos de 24 g/dia, com quadro de astenia, anorexia, náuseas, desconforto abdominal e febrícula com três dias de evolução. Referência a dois ciclos de antibioterapia com flucloxacilina por erisipela (três meses e duas semanas antes da admissão). Analiticamente com AST 349 U/L, ALT 646 U/L, FA 302 U/L, GGT 652 U/L, bilirrubina total 3,3 mg/dL, bilirrubina direta 2,72 mg/dL. Excluídas etiologias infecciosa, autoimune, metabólica, bem como patologia das vias biliares por colangio-RM. Biópsia hepática mostrou esteatose multifocal ligeira (predominantemente microvesicular); alterações acentuadas nas áreas centrolobulares (dilatação sinusoidal, congestão acentuada, hemorragia e colapso multifocal de hepatócitos); expansão das áreas portais com constituição de pontes; ductos biliares proliferados e infiltrado inflamatório de densidade variável, predominantemente de tipo mononucleado. Tipagem de HLA-B*5701 positiva. Agravamento analítico atingindo bilirrubina total 24,1 mg/dL, com desenvolvimento de icterícia, prurido e colúria. Admitida a hepatotoxicidade, iniciou terapêutica com ácido ursodesoxicólico. Verificou-se evolução favorável, sem evidência de coagulopatia ou encefalopatia. A normalização analítica foi, no entanto, lenta, com evolução para cronicidade. Os autores apresentam este caso para alertar para a possibilidade de hepatotoxicidade moderada a grave à flucloxacilina, antibiótico de uso comum na prática clínica e associação com o alelo HLA-B*5701 relatada na literatura.

An Under-Recognised Cause of Iatrogenic, Severe Metabolic Acidosis

Case Pyroglutamic acidosis is an uncommonly diagnosed but important cause of a high anion gap metabolic acidosis. Our case report concerns an elderly male admitted to the Intensive Care Unit (ICU) following the acute onset of coma which developed during treatment of a prosthetic joint infection. A diagnosis of pyroglutamic acidosis was ultimately made and later confirmed with laboratory testing. Blood gas analysis revealed a profound high anion gap metabolic acidosis. Treatment Treatment included withdrawal of the precipitating medications, N-acetylcysteine and sodium bicarbonate. Discussion This case highlights an unusual cause of severe metabolic acidosis caused by commonly used medications and readily reversible if recognised. This is of particular relevance in elderly, frail patients as incorrect alternate diagnoses may result in decisions which incorrectly limit critical care therapies.

Lesson of the month 1: A rare adverse reaction between flucloxacillin and paracetamol.

Flucloxacillin, a beta-lactam antibiotic, is a commonly prescribed antibiotic for the treatment of infections caused by staphylococci and streptococci, most notably Staphylococcus aureus Paracetamol is one of the most dispensed medications by NHS England and is used for the treatment of fever and pain.1 However most doctors are unaware that concurrent use of these drugs can cause a potentially fatal drug interaction due to pyroglutamic acidosis (PGA), also known as 5-oxoprolinaemia. PGA is a rare cause of raised anion gap metabolic acidosis due to disruption of the γ-glutamyl cycle. We report the case of a patient with multiple comorbidities who developed PGA due to coadministration of paracetamol and flucloxacillin.

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).

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.

[Gangrene of the hand due to accidental intra-arterial injection of floxacilline: about a case]. / Gangrène de la main après injection accidentelle intra artérielle de floxacilline: à propos d'un cas.

Floxacilline is a beta-lactam antibiotic of the penicillin class. In our context it is used to fight against infections caused by gram-positive bacteria, including staphylococcus aureus. However, floxacilline should be administered with great caution due to its possible side-effects. Our study reports the case of a 6-year old boy who underwent surgery for the treatment of a humeral fracture. The child was treated with injectable floxacilline following a suspected orthopaedic device infection 2 months after surgery. The day after starting antibiotic treatment, the child presented with acute ischemia of the right hand. Then, he was referred to us. Explorations objectified occlusion of the radial artery. The patient underwent relieving fasciotomy and received postoperative heparin. The evolution was marked by gangrene affecting the whole hand. The aim of our study was to educate caregivers about the risk of occurrence of this disastrous complication and about the measures to prevent it.

Cutaneous vasculitis overlap with acute generalised exanthematous pustulosis (AGEP).

A man in his 40s developed a severe cutaneous adverse reaction following treatment of septic arthritis with flucloxacillin. The eruption had overlap features of cutaneous vasculitis and acute generalised exanthematous pustulosis which was complicated by renal and liver impairment. This case heightens the variation in presentation of a severe drug eruption.

T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.

Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the HLA-B(∗)57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8(+) T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3(+) CD8(+) lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B(∗)57:01(+) healthy donors toward autologous target cells and HLA-B(∗)57:01-transduced hepatocytes was analyzed in vitro. Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury.

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.

Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury.

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.

Drug-induced liver injury in the Australian setting.

WHAT IS KNOWN AND OBJECTIVE: The causes of drug-induced liver injury vary worldwide, with limited data regarding drug-induced hepatotoxicity in Australia. This study sought to provide information about the incidence, causes and clinical manifestations of drug-induced hepatotoxicity. METHODS: A retrospective study was performed on all adult inpatients with abnormal liver function tests, defined as an increase of more than twice the upper limit of the normal range in either serum alanine aminotransferase or alkaline phosphatase, over a 12-month period at the major hospital in Tasmania, Australia. A random sample of individual medical records was reviewed and clinical data extracted. The causality of suspected drug-induced liver injury cases was assessed using the Roussel Uclaf Causality Assessment Method. RESULTS: A total of 264 cases were included. Drug-induced liver injury with at least a possible causal relationship was found in 24 cases (9·1%). The mean age at presentation in the 17 patients with possible or probable hepatotoxicity not related to paracetamol or cancer chemotherapy was 60 ± 20·0 years, and 9 (53%) were men. The frequencies of cholestatic, hepatocellular and mixed patterns of liver damage were 9 (53%), 2 (12%) and 6 (35%) respectively. The most common cause was antibiotics (11 of 17; 65%), while flucloxacillin (4 of 17; 24%) was the single agent most often implicated. WHAT IS NEW AND CONCLUSION: Nearly 10% of cases of abnormal liver function could be associated with adverse effects of drugs. The possibility of drug-induced liver injury should always be considered when there is an absence of other apparent hepatic disease.

Renal impairment after high-dose flucloxacillin and single-dose gentamicin prophylaxis in patients undergoing elective hip and knee replacement.

BACKGROUND: Following advice from the Scottish Antimicrobial Prescribing Group, we switched our antibiotic prophylaxis for elective hip and knee replacement surgery from cefuroxime to flucloxacillin with single-dose gentamicin in order to reduce the incidence of Clostridium difficile associated diarrhoea (CDAD). A clinical impression that more patients subsequently developed acute kidney injury (AKI) led us to examine this possibility in more detail. METHODS: We examined the incidence of AKI in 198 consecutive patients undergoing elective hip or knee surgery. These patients were given the following prophylactic antibiotics: cefuroxime (n = 48); then high-dose (HD) flucloxacillin (5-8 g) with single-dose gentamicin (n = 52); then low-dose (LD) flucloxacillin (3-4 g) with single-dose gentamicin (n = 46) and finally cefuroxime again (n = 52). RESULTS: Patients receiving HD flucloxacillin required more vasopressors during surgery (P = 0.02); otherwise, there were no statistically significant differences in pre- and peri-operative characteristics between the four groups. The proportion of patients with any form of AKI by RIFLE criteria was first cefuroxime (8%), HD flucloxacillin with gentamicin (52%), LD flucloxacillin with gentamicin (22%) and second cefuroxime (14%; P < 0.0001). Odds ratios for AKI derived from a multivariate logistic regression model, adjusted also for sex and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, with the first cefuroxime group as a reference category were: HD flucloxacillin with gentamicin 14.53 (4.25-49.71); LD flucloxacillin with gentamicin 2.96 (0.81-10.81) and second cefuroxime 2.01 (0.52-7.73). Three patients required temporary haemodialysis. Biopsies in two of these showed acute tubulo-interstitial nephritis. All three patients belonged to the HD flucloxacillin with gentamicin group. None of the patients developed CDAD. CONCLUSIONS: We have shown an association between the prophylactic antibiotic regimen and subsequent development of AKI following primary hip and knee arthroplasty that appeared to be due to the use of HD flucloxacillin with single-dose gentamicin. We found no evidence to suggest that this association was confounded by any of the co-variates we measured.

Flucloxacillin and diclofenac do not cause recurrence of neuromuscular blockade after reversal with sugammadex.

BACKGROUND: Sugammadex, a modified γ-cyclodextrin, facilitates rapid reversal of rocuronium- and vecuronium-induced neuromuscular blockade (NMB). Cyclodextrins are known for their ability to form inclusion complexes with various drugs. Theoretically, molecules with a high affinity for sugammadex could interact and displace sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, potentially resulting in the recurrence of NMB due to recirculation of free rocuronium or vecuronium. OBJECTIVE: This study aimed to evaluate whether the administration of high doses of flucloxacillin or diclofenac can result in recurrence of NMB through displacement of sugammadex from its complex with rocuronium or vecuronium, following successful reversal of NMB by a suboptimal dose of sugammadex 2 mg/kg. Flucloxacillin has previously been identified using a modelling approach as a drug with displacement potential, while diclofenac was assessed due to its common intravenous use in the peri-operative and post-surgery setting. METHODS: This was a randomized, open-label, parallel, single-centre study conducted at SGS Life Services-CPU, Antwerp, Belgium. Twenty-four healthy, propofol-anaesthetized, adult volunteers were randomized to either rocuronium 0.6 mg/kg or vecuronium 0.1 mg/kg, followed by a suboptimal dose of sugammadex 2 mg/kg 15 minutes after induction of NMB. Five minutes after successful sugammadex reversal, subjects received either diclofenac 75 mg (15-minute infusion) or flucloxacillin 2 g (5-minute infusion) according to randomization. The suboptimal dose of sugammadex and relatively high doses of diclofenac and flucloxacillin were applied to create favourable conditions for the potential displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, and thus possible recurrence of NMB due to recirculation of free rocuronium or vecuronium. Possible recurrence of NMB was assessed by neuromuscular monitoring, performed with acceleromyography, and was continued until ∼90 minutes after the start of diclofenac or flucloxacillin administration. Recurrence of NMB was concluded if three consecutive train-of-four (TOF) ratios were <0.8. RESULTS: Following successful reversal with a suboptimal dose of sugammadex 2 mg/kg administered 15 minutes after NMB induction, subsequent administration of diclofenac or flucloxacillin did not result in recurrence of NMB in any subject based on measurement of TOF ratios during anaesthesia and neuromuscular function tests upon awakening. There were no adverse events considered to be related to sugammadex. CONCLUSION: Administration of flucloxacillin or diclofenac does not result in recurrence of NMB through displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex.