Muscle Damage Due to Fusidic Acid-Statin Interaction: Review of 75 Cases From the French Pharmacovigilance Database and Literature Reports.

BACKGROUND/AREA OF UNCERTAINTY: Statins, which reduce cardiovascular risk in both primary and secondary prevention, are one of the most widely prescribed therapeutic classes in the world. Usually well-tolerated, statin-associated muscle symptoms are a well-known adverse effect. Fusidic acid (FA) is a bacteriostatic antibiotic of interest in the treatment of methicillin-resistant Staphylococcus aureus infections. Cases of rhabdomyolysis, sometimes fatal, have been reported after coprescription of FA and a statin. DATA SOURCES/AREA OF UNCERTAINTY: We studied 75 cases of muscle damage related to interaction between FA and a statin reported in the French national pharmacovigilance database (43 cases) and from a literature review (32 cases). RESULTS: Cases were mostly men (72.5%), often overweight (mean body mass index: 29.4). The most commonly reported statins were atorvastatin (60%), simvastatin (22.7%), and rosuvastatin (8.0%). Muscle disorders appeared on average 30 days after initiation of FA. Symptoms were muscle weakness (82%), dark urine (71%), and myalgia (61%). Mean creatine kinase level at diagnosis was 43,890 UI/mL, and acute renal injury occurred more than half of the cases. Outcome was fatal in 22% of cases and 28% kept sequelae at the end of the follow-up (54 days). CONCLUSIONS: Muscle damage induced by interaction between FA and statin is a potentially life-threatening complication, leading to contraindication of this association in France. This is to be reminded especially because FA is about to get FDA approval and should soon be available in the United States.

Rhabdomyolysis after co-administration of a statin and fusidic acid: an analysis of the literature and of the WHO database of adverse drug reactions.

Following a severe case of rhabdomyolysis in our University Hospital after a co-administration of atorvastatin and fusidic acid, we describe this interaction as this combination is not clearly contraindicated in some countries, particularly for long-term treatment by fusidic acid. All cases of rhabdomyolysis during a co-administration of a statin and fusidic acid were identified in the literature and in the World and Health Organization database, VigiBase® . In the literature, 29 cases of rhabdomyolysis were identified; mean age was 66 years, median duration of co-administration before rhabdomyolysis occurrence was 21 days, 28% of cases were fatal. In the VigiBase® , 182 cases were retrieved; mean age was 68 years, median duration of co-administration before rhabdomyolysis was 31 days and 24% of cases were fatal. Owing to the high fatality associated with this co-administration and the long duration of treatment before rhabdomyolysis occurrence, fusidic acid should be used if there is no appropriate alternative, as long as statin therapy is interrupted for the duration of fusidic acid therapy, and perhaps a week longer. Rarely will interruption of this sort have adverse consequences for the patient.

[Lethal Lyell's syndrome induced by fusidic acid]. / Syndrome de Lyell à l'acide fusidique oral d'évolution fatale.

BACKGROUND: Herein, we report the first case of toxic epidermal necrosis due to oral fusidic acid having a fatal outcome. PATIENTS AND METHODS: An 82-year-old woman was referred to our dermatology department for generalized bullous skin eruption. Clinical examination showed fever, oral and ocular ulcerations, and epidermal detachment involving more than 70 % of her body surface area together with a positive Nikolsky sign. Lyell's syndrome was diagnosed. Cutaneous histology showed total epidermal necrosis and a normal dermis. Oral fusidic acid had been prescribed 12 days earlier for a chronic sacral pressure sore. No other treatment had been introduced during the previous two months. The outcome was fatal within 24 hours. DISCUSSION: Fusidic acid is commonly used topically by dermatologists for limited staphylococcal skin infections. Oral treatment is rare and is recommended only for skin, bone or joint infections. This is the first reported case of toxic epidermal necrolysis due to oral fusidic acid. The French national drug safety monitoring register contains only one case in which fusidic acid was a possible culprit. CONCLUSION: Fusidic acid must be considered a potential source of serious cutaneous adverse reactions, particularly toxic epidermal necrolysis.

Oral fusidic acid for the treatment of mild-to-moderate hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating inflammatory skin disease. Tetracyclines are one of the few therapeutic options recommended for mild-to-moderate disease. This study aimed to investigate the efficacy of systemic fusidic acid's (FA) effectiveness in treating HS. METHODS: This retrospective study analyzed 55 FA therapy cycles (TC, average weekly dose: 6409 mg; range: 5250-9800 mg; 2-12 weeks) in 49 patients. The outcome was evaluated using the Physician's Global Assessment (PGA) scale. Therapy response was defined as any reduction of inflammatory activity without the occurrence of flares. We also characterized adverse events and investigated predictors for treatment success. Results were compared to a matched control group receiving doxycycline. RESULTS: FA treatment (55 treatment cycles (TC); male: 45.5%; female: 54.5%) showed an overall response rate of 70.9% (39 TC). No worsening was observed. Significantly higher response rates were observed in females (83.3%, P = 0.026) and Hurley I (90.9%, P = 0.008). After multivariate adjustment, higher response rates were associated with the Hurley grade (P = 0.046) but not with gender (P = 0.0174). Adverse reactions (21.8% gastrointestinal symptoms) occurred in 27.3% (15 TC) and 46.7% within the first 4 weeks. Similar results were observed in the doxycycline control group (overall response rate: 76.4%). CONCLUSION: Oral FA is safe and improves symptoms in most patients. HS patients could benefit from oral FA treatment, especially in case of contraindications or resistance to tetracyclines.

Pancytopenia in a patient treated with fusidic acid and niraparib: a case report.

Fusidic acid is an antibiotic used in the treatment of staphylococcal infections. Niraparib is an anticancer drug indicated for the treatment of advanced ovarian cancer. The interaction between these two drugs has not been studied and is not referenced in drug databases. We present the case of a patient with pancytopenia who had been treated with fusidic acid and niraparib. No other treatment was taken by this patient. According to the literature, both substances can cause haematological toxicity. It seems unlikely that this is due to niraparib alone because it had been well tolerated by the patient for over a year before the pancytopenia was diagnosed. It was also perfectly well tolerated when it was reintroduced. We cannot determine whether this pancytopenia is due to fusidic acid alone or to a drug interaction between the two treatments. We therefore recommend caution in patients treated with this combination.

Combined antibiotic/corticosteroid cream in the empirical treatment of moderate to severe eczema: friend or foe?

BACKGROUND: Eczema is a common atopic disease associated with pruritus, sleep disturbance, and impaired quality of life. Staphylococcus aureus colonization/infection is important in its pathophysiology. AIM: To evaluate the prevalence of S aureus colonization/infection and the efficacy and acceptability of a combined antibiotic/corticosteroid cream in the empirical treatment of eczema. METHODS: Consecutive patients with moderate to severe eczema were recruited. Swab and cultures from the right antecubital fossa and the worst eczematous area, disease severity (SCORAD) and quality of life (Children's Dermatology Life Quality Index, CDLQI), skin hydration (SH), and transepidermal water loss (TEWL) were obtained prior to and following a two week twice-daily course of treatment with a fucidin/corticosteroid cream. General acceptability of treatment (GAT) was documented at completion. RESULTS: Thirty-five patients (63% males; mean age 13.5, standard deviation 3.6 years; with 21 moderate and 14 severe disease) were recruited. At start, S aureus was isolated from the right antecubital fossa and the worst affected areas in 66% and 71% of these patients, respectively. At completion, S aureus was isolated in 23% and 40% at the antecubital fossae and worst affected areas (P=0.001 and P=0.003, respectively). No methicillin-resistant S aureus was isolated in this series, but the percentage of fucidin-resistant S aureus increased from 8% to 58% (P<0.001). Disease severity and quality of life were significantly improved (pre-Objective SCORAD and post-Objective SCORAD were 38.4±13.7 and 29.7±14.2, P<0.001; pre-CDLQI and post-CDLQI were 9.4±5.2 and 7.1±4.8, P<0.001). At the right antecubital fossa, skin hydration improved from 30.8±14.2 to 36.7±15.2 (P=0.015); and TEWL from 10.7±2.3 to 9.4±2.2 (P<0.001). Eighty percent of patients found the treatment good or very good, and only one (3%) patient found it unacceptable. CONCLUSIONS: The most prevalent organism in moderate to severe eczema was S aureus. Usage of the combined fucidin/corticosteroid cream is convenient and associated with a reduction in disease severity, improvement in quality of life, SH, and TEWL, but caution has to be taken with emergence of fucidin-resistant S aureus.

Pharmacokinetics and safety of single, multiple, and loading doses of fusidic acid in healthy subjects.

A phase 1 trial of fusidic acid (CEM-102), an oral fusidane class antibiotic under development for treatment of gram-positive acute bacterial skin and skin structure infections, evaluating pharmacokinetics and safety is described. A randomized, double-blinded, placebo-controlled, dose escalation study was conducted in healthy adult subjects in the fasting state. Plasma exposure after multiple doses was higher than for single doses, indicating accumulation. Loading doses designed to optimize pharmacodynamic effects were well tolerated and achieved near-steady state concentrations of CEM-102 at 24 h. CEM-102 was safe and generally well tolerated at all single, multiple, and loading doses administered.

The safety record of fusidic acid in non-US markets: a focus on skin infections.

Fusidic acid has been in clinical use outside the United States (US) since 1962 for skin infections, including methicillin-resistant Staphylococcus aureus (MRSA). Non-US labeling reflects safety concerns related to gastrointestinal, allergic, hematologic, and neurologic adverse events. We sought to survey available safety data on fusidic acid through the review of published global literature between 1962 and 2007 that contained data on oral fusidic acid safety and a centralized database (VigiBase) of spontaneous safety reports. Overall, the data were concordant with current product labeling, and no serious adverse events, such as death, hospitalization, or hepatotoxicity, were convincingly linked to fusidic acid monotherapy in skin infection patients. Other indications for fusidic acid use were also common, including osteomyelitis with similar reporting of labeled safety characteristics. Study quality was highly varied with limited structure to safety data collection methodology. Significant concerns for recall bias are present, yet these data remain informative in providing signals that require attention in the design and conduct of adequate and well-controlled clinical studies of fusidic acid for potential registration in the United States.

Efforts to support the development of fusidic acid in the United States.

Fusidic acid (FA), though used widely throughout the world for decades, has never been approved in the United States. There is now a great need for an oral methicillin-resistant Staphylococcus aureus (MRSA) antibiotic with a long track record of safety. Cempra Pharmaceuticals successfully encouraged passage of a congressional amendment to allow for Hatch-Waxman market exclusivity when this antibiotic is approved in the United States. A new dosing regimen has been patented, allowing FA to be used as monotherapy, and decreased resistance selectivity has been shown. With almost no resistance to FA in the United States, the time is right for introduction into this market.

A randomized, double-blind phase 2 study comparing the efficacy and safety of an oral fusidic acid loading-dose regimen to oral linezolid for the treatment of acute bacterial skin and skin structure infections.

Fusidic acid (CEM-102), an orally bioavailable fusidane antibiotic with a unique mode of action, is under development for treatment of acute gram-positive bacterial skin and skin structure infections, including those caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and streptococci. A phase 2, adaptive design, randomized, double-blind, multiple-center study of 198 adult patients with cellulitis or wound infections was conducted to evaluate an oral CEM-102 loading-dose regimen (1500 mg twice per day on day 1 followed by 600 mg twice per day) compared with oral linezolid (600 mg twice per day) administered for 10-14 days. The CEM-102 loading-dose regimen demonstrated efficacy, safety, and tolerability that was comparable to linezolid for the treatment of acute gram-positive bacterial skin and skin structure infections. Clinical Trials registration. NCT00948142.

Severe statin-induced rhabdomyolysis mimicking Guillain-Barré syndrome in four patients with diabetes mellitus treated with fusidic acid.

BACKGROUND: An interaction between fusidic acid and HMG coenzyme A reductase inhibitors (statins), resulting in rhabdomyolysis, has been described. Pain and mild weakness are common presenting symptoms. CASE REPORT: We report four patients with Type 2 diabetes prescribed long-term statin treatment who, following treatment with fusidic acid, presented atypically with painless, severe flaccid paralysis suggestive of Guillain-Barré syndrome. This, together with nerve conduction studies consistent with Guillain-Barré syndrome, resulted in the delayed recognition of rhabdomyolysis in these cases. CONCLUSIONS: The addition of fusidic acid can precipitate rhabdomyolysis in patients with diabetes already taking a statin. This can present with rapidly progressive weakness resembling Guillain-Barré syndrome. We recommend that creatine kinase is checked in patients with diabetes on statin therapy who present with profound weakness and routinely in those commenced on prolonged courses of fusidic acid.

Hepatotoxicity and hematologic complications induced by fusidic acid in a patient with hepatitis B cirrhosis: A case report.

RATIONALE: Fusidic acid (FA) is an active agent against gram-positive bacteria such as Staphylococcus, it is generally well tolerated and the major adverse effects are mild gastrointestinal discomfort, diarrhea, and headache. However, some rare side effects such as granulocytopenia and thrombocytopenia have also been reported. Here we report a case of FA-induced hepatotoxicity and hematologic toxicity. PATIENT CONCERNS: A 54-year-old woman with hepatitis B cirrhosis was referred to us because of fever, Staphylococcus aureus was identified in the twice blood culture, and intravenous FA was given (0.5 g, q8 hours). Twelve days after FA therapy, she developed nausea and jaundice. Meanwhile, complete blood cell count showed neutropenia (white blood cell count of 1360/µL, neutrophil of 619/µL) and aggravated thrombocytopenia (platelet count of 18,000/µL). Adverse drug reaction was suspected, and FA was stopped immediately, after 1 day of discontinuation of FA, nose bleeding occurred and the platelet count declined further and reached the lowest value of 4000/µL. DIAGNOSES: Hepatotoxicity and hematologic complications induced by FA were diagnosed. INTERVENTIONS AND OUTCOMES: The FA was stopped immediately, and concentrated platelet transfusion was used. Five days after withdrawal of FA, jaundice resolved and the hematologic index returned to the level before the medication. LESSONS: Hematologic adverse effect accompanying with hepatotoxicity may be induced by FA. Though the risk is rather low, it should not be overlooked.

Presumed interaction of fusidic acid with simvastatin.

A 63-year-old man was admitted 6 weeks after an elective abdominal aortic aneurysm repair following which methicillin resistant Staphylococcus aureus (MRSA) had been cultured from the aneurysmal sac. He had been commenced on a course of fusidic acid at discharge in addition to his ongoing statin prescription and presented 4 weeks later with symptoms consistent with rhabdomyolysis. Severe rhabdomyolysis was confirmed and despite prolonged and complicated critical care management, his treatment was unsuccessful. Extensive investigations ruled out other known causes of this clinical presentation and failed to identify any other precipitating cause of rhabdomyolysis. We believe the most likely cause was hepatic inhibition of the CYP3A4 hepatic isoenzyme by fusidic acid resulting in an acute severe rise in plasma simvastatin level and extensive myocellular damage. Increasing MRSA colonisation and infection rates together with increased statin usage have the potential to increase the incidence of this presumed drug interaction.

Rhabdomyolysis with atorvastatin and fusidic acid.

Rhabdomyolysis is a rare but life-threatening complication of statin therapy. A 74-year-old man, treated with atorvastatin, developed rhabdomyolysis after the co-administration of fusidic acid and flucloxacillin. The patient recovered with supportive treatment and subsequently tolerated reintroduction of atorvastatin. Pharmacokinetic interactions can cause raised plasma statin concentrations, which can precipitate rhabdomyolysis in the presence of certain predisposing biological factors.

Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid.

There is growing evidence of the efficacy of treating early staphylococcal infections of prosthetic joints with surgical debridement and prosthesis retention, combined with oral antibiotic regimens that include rifampicin in combination with a fluoroquinolone. With rising rates of fluoroquinolone-resistant staphylococci, evidence concerning the efficacy of alternative combinations of antibiotics is required. Twenty patients with staphylococcal prosthetic joint infections who had been treated with surgical debridement and prosthesis retention, and a combination of rifampicin and fusidic acid were analysed. The mean duration of symptoms before initial debridement was 16 (range 2-75) days. The median time of follow-up was 32 (range 6-76) months. Treatment failure occurred in two patients. The cumulative risk of treatment failure after 1 year was 11.76% (95% CI 3.08-39.40%). Two patients had their treatment changed because of nausea. Ten of 11 patients with infections involving methicillin-resistant Staphylococcus aureus had successful outcomes. Debridement without prosthesis removal, in combination with rifampicin and fusidic acid treatment, was effective and should be considered for patients with early staphylococcal prosthetic joint infections, including those with infections involving fluoroquinolone-resistant organisms.

Fusidic acid vs ofloxacin prophylaxis before cataract surgery.

PURPOSE: To evaluate the safety and efficacy of two self-administrated antibiotics in eliminating conjunctival microbial flora. METHODS: A total of 133 patients operated for cataract surgery were divided into three groups. The first group (A), 55 patients, received fusidic acid drops (1%) two times per day during the 3 days before the surgery; a second group (B), 55 patients, received ofloxacin (0.3%) four times per day during the 3 days before the surgery; and the third group (C), 23 patients, did not receive any topical antibiotic before the surgery. On the day of the surgery, cultures were taken from the lower fornix. RESULTS: In Group A, 28 cultures (50.9%) were sterile, and 27 (49.1%) were positive for the presence of microbial agents. In Group B, 25 cultures (45.4%) were sterile, and 30 (54.5%) were positive for the presence of microbial agents. In Group C, 5 cultures (21.7%) were sterile, and 18 (78.2%) were not. Staphylococcus epidermidis was the most common micro-organism isolated in all the groups. Statistical analysis does not reveal a significant difference between Groups A and B for the sterile cultures (p=0.7) (chi-square test), but a statistically significant difference is present between the treated and not treated patients (p= 0.05) (chi-square test). CONCLUSIONS: A preoperative prophylaxis is useful in eliminating conjunctival micro-organism, and both antibiotics (fusidic acid and ofloxacin) are efficient.

Flucloxacillin and fusidic acid-associated neutropenia in a patient with periaortic abscess: rare side effects of commonly used antibiotics.

The use of long-term antibiotics for deep-seated infections is very common, and is associated with many clinically significant side effects. In this report we describe the history of a 48-year-old man who attended West Suffolk Hospital with nausea and vomiting, and was subsequently found to have a deep-seated infection following his repeat aortic valve replacement. He completed a 7-week course of intravenous flucloxacillin and oral fusidic acid, however, prior to finishing this course a random blood test revealed a neutrophil count of zero. He was re-admitted to hospital with fever, and was treated accordingly as per the trust's neutropenic sepsis protocol with the addition of growth colony stimulating factor (GCSF). His neutrophil count recovered after 3 days and has remained within the normal range ever since.

Clinical, immunological, and virological effects of sodium fusidate in patients with AIDS or AIDS-related complex (ARC): an open study.

Fusidic acid has previously been noted to prevent syncytial formation by human immunodeficiency virus (HIV) in vitro. Since this drug is a cheap, usually well-tolerated substance with known toxicity profile, an open, uncontrolled trial was undertaken to evaluate its possible efficacy in HIV disease. Twenty HIV antibody positive patients (10 with AIDS and 10 with ARC) were treated with sodium fusidate 500 mg every 8 h for up to 3 months. One patient died during therapy and six ceased treatment due to adverse events. Rash, nausea, diarrhea, and/or abdominal pain caused difficulties in all patients. There was no significant improvement in clinical state or T-helper cell levels, and no observed decrease in HIV p24 antigen during treatment. We conclude that in this open trial, sodium fusidate had no observable beneficial clinical, virological, or immunological effects.

Treatment of Crohn's disease with fusidic acid: an antibiotic with immunosuppressive properties similar to cyclosporin.

Fusidic acid is an antibiotic with T-cell specific immunosuppressive effects similar to those of cyclosporin. Because of the need for the development of new treatments for Crohn's disease, a pilot study was undertaken to estimate the pharmacodynamics and tolerability of fusidic acid treatment in chronic active, therapy-resistant patients. Eight Crohn's disease patients were included. Fusidic acid was administered orally in a dose of 500 mg t.d.s. and the treatment was planned to last 8 weeks. The disease activity was primarily measured by a modified individual grading score. Five of 8 patients (63%) improved during fusidic acid treatment: 3 at two weeks and 2 after four weeks. There were no serious clinical side effects, but dose reduction was required in two patients because of nausea. Biochemically, an increase in alkaline phosphatases was noted in 5 of 8 cases (63%), and the greatest increases were seen in those who had elevated levels prior to treatment. All reversed to pre-treatment levels after cessation of treatment. The results of this pilot study suggest that fusidic acid may be of benefit in selected chronic active Crohn's disease patients in whom conventional treatment is ineffective. Because there seems to exist a scientific rationale for the use of fusidic acid at the cytokine level in inflammatory bowel disease, we suggest that the role of this treatment should be further investigated.