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PubMed2002

Genetic characterization of the fusidic acid and cadmium resistance determinants of Staphylococcus aureus plasmid pUB101.

We report the cloning of the fusidic acid and cadmium resistance determinants from Staphylococcus aureus plasmid pUB101. The pUB101 fusidic acid resistance determinant was located on a 2.9 kb HindIII fragment. Sequencing of this fragment revealed three putative open reading frames (ORFs) of 213 (far1), 152 (orf152) and 170 amino acids (orf170), which are flanked by the right-hand end of insertion sequence IS431/257 (IS431/257RH) and a partial ORF. Far1 and Orf152 demonstrated homology with a chromosomally encoded fibronectin-binding protein of Listeria monocytogenes and the putative protein YosT, found on the SP beta c2 prophage of Bacillus subtilis, respectively. Transformation of S. aureus with a construct containing a 949 bp far1-specific amplicon led to the isolation of a fusidic acid-resistant transformant, thereby identifying the pUB101 fusidic acid resistance structural gene. Between orf152 and far1 we identified a unique 113 bp symmetrical element and other repeat elements that may be involved with the control of orf152 and/or far1 expression. Hybridization of Southern blots revealed that far1 was not located on the chromosome or plasmid content of a limited number of Australian, UK and Hong Kong fusidic acid-resistant isolates. The pUB101 cadmium resistance determinant was located on a 3.6 kb HindIII fragment that carried a cadDX operon, remnants of two putative plasmid replication protein genes and IS431/257RH. Sequence analysis also demonstrated the presence of a single-stranded origin of replication, normally found on rolling circle replicating plasmids, within the putative promoter region of the cadDX operon.

Anti-Bacterial Agents↗
PubMed1993

Messenger-dependent action of the pokeweed antiviral protein and fusidic acid on in vitro Vicia sativa L. translation.

Plant ribosome sensitivity to either pokeweed antiviral protein (PAP) or fusidic acid has been investigated using a highly coupled translation system obtained from Vicia sativa L., a plant that lacks ribosome-inactivating protein activity. Protein synthesis directed by endogenous messengers was more sensitive to PAP than synthesis of polyphenylalanine directed by polyuridylic acid. Conversely, the effects of fusidic acid were the highest in polyphenylalanine synthesis. Additionally, the concentration of magnesium ions during translation also played a determinant role in the extent of inhibition by both PAP and fusidic acid. The effects seem to be exerted on the interaction of the translational elongation factor 2 with the ribosome.

Cell-Free System↗
PubMed1995

Steroid recognition by chloramphenicol acetyltransferase: engineering and structural analysis of a high affinity fusidic acid binding site.

The antibiotic fusidic acid and certain closely related steroidal compounds are potent competitive inhibitors of the type I variant of chloramphenicol acetyltransferase (CATI). In the absence of crystallographic data for CATI, the structural determinants of steroid binding were identified by (1) construction in vitro of genes encoding chimaeric enzymes containing segments of CATI and the related type III variant (CATIII) and (2) site-directed mutagenesis of the gene encoding CATIII, followed by kinetic characterisation of the substituted variants. Replacement of four residues of CATIII (Gln92, Asn146, Tyr168 and Ile172) by their equivalents from CATI yields an enzyme variant that is susceptible to competitive inhibition by fusidate with respect to chloramphenicol (Ki = 5.4 microM). The structure of the complex of fusidate and the Q92C/N146F/Y168F/I172V variant, determined at 2.2 A resolution by X-ray crystallography, reveals the inhibitor bound deep within the chloramphenicol binding site and in close proximity to the side-chain of His195, an essential catalytic residue. The aromatic side-chain of Phe146 provides a critical hydrophobic surface which interacts with non-polar substituents of the steroid. The remaining three substitutions act in concert both to maintain the appropriate orientation of Phe 146 and via additional interactions with the bound inhibitor. The substitution of Gln92 by Cys eliminates a critical hydrogen bond interaction which constrains a surface loop (residues 137 to 142) of wild-type CATIII which must move in order for fusidate to bind to the enzyme. Only two hydrogen bonds are observed in the CAT-fusidate complex, involving the 3-alpha-hydroxyl of the A-ring and both hydroxyl of Tyr25 and NE2 of His195, both of which are also involved in hydrogen bonds with substrate in the CATIII-chloramphenicol complex. In the acetyl transfer reaction catalysed by CAT, NE2, of His195 serves as a general base in the abstraction of a proton from the 3-hydroxyl of chloramphenicol as the first chemical step in catalysis. The structure of the CAT-inhibitor complex suggests that deprotonation of the 3-alpha-hydroxyl of bound fusidate by this mechanism could produce an oxyanion nucleophile analogous to that seen with chloramphenicol, but one which is incorrectly positioned to attack the thioester carbonyl of acetyl-CoA, accounting for the observed failure of CAT to acetylate fusidate.

Amino Acid Sequence↗
PubMed1988

Penetration and permeation into human skin of fusidic acid in different galenical formulation.

The penetration into the horny layer and permeation through the skin of fusidic acid, incorporated in different bases, e.g., cream, ointment and a gel (Fucidine), was investigated in vitro in a penetration chamber, using human skin. Whereas the horny layer offers a marked barrier to penetration in normal skin, this barrier can be greatly reduced by damaging the horny layer by adhesive tape stripping. Fusidic acid showed penetration into the different layers of skin which was related to the duration of application, including the penetration chamber fluid, i.e., there was penetration of the entire skin thickness. In the presence of spontaneous changes in the horny layer, as in seborrhoeic warts and similar conditions, fusidic acid penetrated well into the deeper layers of the skin. Fusidic acid is thus a substance which permeates better in regions where the horny layer is damaged, and where it can attain high levels, which in practice are antimicrobial. Penetration into the skin is thus a function of damage to the horny layer and the quality of the horny layer itself. From this point of view the amount of absorption in dermatoses depends on the area of skin with damage to the horny layer. Penetration through normal skin can be disregarded.

Fusidic Acid↗
PubMed1989

Topical 2% mupirocin versus 2% fusidic acid ointment in the treatment of primary and secondary skin infections.

The efficacy and side effects of topical mupirocin (Bactroban) and fusidic acid (Fucidin) ointment were compared in a double-blind, randomized trial in 70 patients who came to the Dermatologic Clinic of L'Enfant Jésus Hospital with primary or secondary (or both) skin infections. Thirty-five patients were treated with mupirocin and 35 patients were treated with fusidic acid three times a day for seven days. Clinical and bacteriologic assessments were conducted before and after treatment. The efficacy of mupirocin, in terms of resolution and improvement of clinical signs and symptoms of infection, as well as of the elimination of infecting organisms, was similar to that of fusidic acid. Of 34 patients (1 could not be evaluated) treated with mupirocin, a clinical cure was achieved in 18, and significant improvement was demonstrated in 15. Similarly, of 35 patients treated with fusidic acid, a clinical cure was achieved in 18 and improvement occurred in 15. Bacteriologic cure rates were 97% (30 of 31 patients evaluated) in the mupirocin-treated group, compared with 87% (27 of 31 patients evaluated) in the fusidic acid-treated group. No side effects were observed in either treatment group. Because topical 2% mupirocin has little or no potential for irritation, systemic side effects, or cross-resistance with other antibiotics, its efficacy is likely to make this new compound a useful agent for the treatment of superficial skin infections.

Administration, Topical↗
PubMedDate not supplied

Fusidic acid in infections of the external eye.

A newly developed 1% eye preparation of the potent antistaphylococcal antibiotic fusidic acid, showed an excellent clinical effect in 206 Egyptian children with external eye infections. The 248 patients included in the study were randomized, in the ratio 5:1, to either fusidic acid or chloramphenicol 0.5% eye drops. Both preparations were given four to six times daily for one week. Bacterial conjunctivitis was diagnosed in 56% of the children. Offending eye pathogens were mainly Staphylococcus aureus (60%), Haemophilus aegyptius (10%), Streptococcus pneumoniae (13%) and Neisseria gonorrhoeae (6%). The overall clinical success rate in children with bacterial conjunctivitis was 85% with fusidic acid, compared to 48% with chloramphenicol (p less than 0.001). The better effect of fusidic acid could be ascribed to a lower frequency of in vitro resistance (16%) in comparison to chloramphenicol (55%). Both drugs were apparently well tolerated and no side-effects were observed.

Adolescent↗
PubMed2000

[Comparative diffusion of fusidic acid, oxacillin, and pristinamycin in dermal interstitial fluid after repeated oral administration].

OBJECTIVE: The aim of this study was to use the suction bullae technique to compare skin diffusion of 3 antibiotics commonly used for skin infections (fusidic acid, oxacillin, pristinamycin) and to estimate their potential activity at the site of skin infections. SUBJECTS AND METHODS: This comparative open study was conducted in 12 healthy volunteers using a repeated latin square experimental scheme. Antibiotic concentrations in serum and suction bullae fluid were measured by high performance liquid chromatography after 5.5 days of repeated oral administration of fusidic acid (1 g/d), oxacillin (2 g/d), and pristinamycin (2 g/d). RESULTS: Mean antibiotic concentrations in serum and interstitial fluid (suction bullae fluid) were highest for fusidic acid with a Cmax at 91.3 +/- 23.0 mg/l and 45.5 +/- 18.0 mg/l respectively (interstitial fluid/serum ratio=49 +/- 10 p. 100). For oxacillin, Cmax was 8.3 +/- 3.6 mg/l and 0.98 +/- 0.49 mg/l (ratio 13 +/- 5 p. 100). Pristinamycin concentrations were low with a Cmax at 0.51 +/- 0.40 and 0.26 +/- 0.15 mg/l (ratio 73 +/- 57 p. 100). Comparing the area under the interstitial fluid and the serum concentration-time curves showed that the best diffusion was obtained with pristinamycin (114 +/- 61 p. 100), followed by fusidic acid (57 +/- 13 p. 100) and oxacillin (48 +/- 25 p. 100). DISCUSSION: These data were used to calculate indicators of potential efficacy in the interstitial dermal fluid: inhibitor quotient (Cmax/MIC) and AUIC (ASC/MIC), indicator of the time antibiotic concentrations are maintained above the minimal inhibitor concentration (MIC). This showed that fusidic acid was potentially more active against all staphylococci. For streptococci, the observed interstitial concentrations of pristinamycin and of fusidic acid should theoretically inhibit streptococci A growth, but oxacillin was the most adapted antibiotic.

Administration, Oral↗
PubMed2005

Compensatory adaptation to the loss of biological fitness associated with acquisition of fusidic acid resistance in Staphylococcus aureus.

Recent studies have shown that individual amino acid exchanges within elongation factor G (EF-G) cause fusidic acid resistance in Staphylococcus aureus. The data from the present study illustrate that the fusidic acid resistance-mediating amino acid substitutions P406L and H457Y are associated with a marked impairment of the biological fitness of S. aureus. In particular, strains producing EF-G derivatives with these mutations showed reduced growth, decreased plasma coagulase activity, and an impaired capability to compete with the isogenic wild-type strain. Second-site mutations within EF-G, such as A67T and S416F, that have been encountered in clinical fusidic acid-resistant isolates containing the amino acid exchanges P406L and H457Y, respectively, were shown not to contribute to resistance. Furthermore, the substitution A67T had no impact on the biological fitness in vitro. The exchange S416F, however, was found to function as a fitness-compensating mutation in S. aureus carrying the substitution H457Y in EF-G. In conclusion, the data presented in this report provide evidence at the molecular level that the deleterious effects of fusidic acid resistance-mediating exchanges within EF-G of S. aureus can be reduced considerably by specific compensating mutations in this target protein. This compensatory adaptation most likely plays a significant role in the stabilization of resistant bacteria within a given population.

Amino Acid Substitution↗
PubMed1997

Investigation of the mechanism of action of 2% fusidic acid lotion in the treatment of acne vulgaris.

We describe the results of a single-centre, double-blind, vehicle-controlled, parallel group study on the quantitative effects of 2% fusidic acid lotion (Fucidin lotion) in facial acne vulgaris. The trial was completed by 52 patients aged 15-25 years with mild to moderate acne who had been randomized to either Fucidin Lotion (n = 25) or its base (n = 27). Primary outcome measures included colony counts of Propionibacterium acnes and micrococcaceae and measurements of skin surface lipid free fatty acids and sebum excretion rate. Clinical assessment was based on the acne grade, count of inflamed and non-inflamed lesions and evidence of a primary irritant dermatitis. There was a variable but gradual reduction in lesion counts with the maximum improvement at 12 weeks for inflamed lesions, where the reduction was 19.9% for fusidic acid and 24.7% for the placebo. The non-inflamed lesions decreased by 10.8% in the fusidic acid group and increased by 15.9% in the placebo group; this difference was not statistically significant. Although the fusidic acid reduced the micrococcaceae count by 1 log cycle, inferring adequate compliance, there was no reduction in the counts of P. acnes, surface free fatty acids or sebum excretion rate. This study has failed to explain the mechanism of action of topical fusidic acid.

Acne Vulgaris↗
PubMed2005

Comparison of silver-coated dressing (Acticoat), chlorhexidine acetate 0.5% (Bactigrass), and fusidic acid 2% (Fucidin) for topical antibacterial effect in methicillin-resistant Staphylococci-contaminated, full-skin thickness rat burn wounds.

Acticoat, chlorhexidine acetate 0.5%, and fusidic acid 2% were compared to assess the antibacterial effect of an application on experimental 15% BSA, full-thickness burn wounds in rats swabbed 24 h earlier with a 10(8) standard strain of methicillin-resistant Staphylococci. The swabbed organism was recovered from the eschar of all groups except the fusidic acid group. While there were significant differences between treatment groups and control group, the mean eschar concentrations did not differ significantly between the Acticoat and chlorhexidine acetate groups, but there were significant differences between the fusidic acid group and the other treatment groups. There were no statistically significant differences between treatment groups, and between control group and the chlorhexidine acetate group regarding recovery of the seeded organism from muscle, but there were significant differences between the control group and Acticoat group, and between control the group and the fusidic acid group. While no systemic spread was seen in the treatment groups, it was seen in six animals in the control group. The animal data suggest that fusidic acid is the most effective agent in the treatment of methicillin-resistant Staphylococcus aureus-contaminated burn wounds, and Acticoat is a choice of treatment with the particular advantage of limiting the frequency of replacement of the dressing.

Administration, Topical↗
PubMed1993

Pharmacokinetics of fusidic acid after a single dose of a new paediatric suspension.

The pharmacokinetics of fusidic acid (Fucidine, Leo Laboratories) were studied in 10 children after single oral dosing with 20 mg/kg of a new banana-flavoured paediatric suspension (titrating at 50 mg/ml). Nine blood samples were drawn from each child at 0, 1, 2, 3, 6, 8, 12, 24 and 48 h following dosing with the antibiotic. Serum fusidic acid levels were measured by high-performance liquid chromatography (HPLC). A model-independent method was used for the pharmacokinetic analysis. Results were compared with those obtained after dosing eight healthy adult volunteers with 500 mg of sodium fusidate by parenteral administration (infusion) then per os. The acceptability of the single dose was good. The terminal elimination half-life t1/2 (h) and the mean residence time (MRT, h) of fusidate were similar to those determined in healthy adults after oral dosing, i.e. 16.0 +/- 14.5 versus 16.0 +/- 3.5 and 17.7 +/- 12.1 versus 17.7 +/- 2.5, respectively. In contrast, the oral bioavailability of the suspension (Fapprox., %) was relatively low: of the order of 22.5 versus 91.0% for tablets in the healthy adult, which justifies the use of a relatively higher dose in the child. This led to the calculation of an estimated total clearance (Clest., ml/min) significantly less than that in the healthy adults, while the estimated apparent volume of distribution (Vd, litre/kg) was significantly increased (10.4 +/- 9.1 versus 21.8 +/- 2.1 and 0.73 +/- 0.53 versus 0.30 +/- 0.04, respectively). Fusidic acid is normally excreted in metabolized form (98%). The decrease in clearance could be attributed to the almost immediate saturation of liver enzymes in immature infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Fusidic acid prophylaxis before cataract surgery: patient self-administration.

In a placebo-controlled, randomised, double-blind clinical trial, the authors evaluated the efficacy of patient-administered 1% fusidic acid viscous eye drops in clearing the commonest organisms causing pseudophakic endophthalmitis (Staphylococcus epidermidis and aureus) from the lids and conjunctivae of 79 patients before cataract surgery. The treatment group self-administered fusidic acid viscous eye drops four times daily for seven days before surgery; the placebo group received inert ophthalmic drops. Fellow eyes of both groups remained untreated as a natural control. Lower fornix and lid margin cultures were taken from both eyes before and after treatment. Before treatment, there was no statistical difference in organism counts between the groups. After treatment, eyes receiving fusidic acid were more likely to be free of clinically relevant Staphylococcus spp. than all pre-treatment eyes (for lids, P << 0.001; conjunctivae, P = 0.02). A highly significant (P < 0.001) number of lid margins were rendered 'clinically clean' (i.e., 0-49 organisms/swab) by fusidic acid when compared with untreated eyes. Treatment also effectively (P < 0.05) reduced the numbers of bacteria isolated from conjunctivae. This study indicates that there is a highly significant reduction of Staphylococcus spp. (P << 0.001), non-Staphylococcus spp. (P << 0.001) and attainment of sterile eyes (P << 0.001) at operation gained by patient self-administration of 1% fusidic acid four times daily for seven days before surgery.

Adult↗
PubMed1999

Fusidic acid adverse drug reactions.

Unlike trials conducted today on new antimicrobials, the introduction of fusidic acid was not accompanied by extensive studies on toxicity and side effects. The early studies on small numbers of patients reported fusidic acid to be a nontoxic drug with the main side effects being gastrointestinal tract discomfort, diarrhoea and headache. Case reports of hepatotoxicity were reported from 1972. A retrospective analysis showed this to be reversible and mainly associated with intravenous administration. Rarely reported side effects are granulocytopenia, thrombocytopenia and venous spasm. Skin reactions, including contact dermatitis, are uncommon. After many years of use the most common side effects reported for fusidic acid are minor and relate to the gastrointestinal tract.

Acute Kidney Injury↗
PubMed2004

Sideroblastic anaemia during fusidic acid treatment.

OBJECTIVES AND METHODS: To describe cases of fusidic acid-associated sideroblastic anaemia from the French Pharmacovigilance database. RESULTS: Six cases of sideroblastic anaemia associated with oral fusidic acid treatment were retrieved. Four females and two males (mean age 65.3 yr) developed severe anaemia (mean haemoglobin level: 6.9 g/dL) within 32-190 d (mean: 81 d) of treatment. Bone marrow aspirates showed dyserythropoiesis and ringed sideroblasts in all patients. Four patients required repeated blood transfusions. After fusidic acid discontinuation in five patients, complete recovery was obtained. In one patient, rechallenge with fusidic acid resulted in recurrence of anaemia that resolved after definitive discontinuation of the drug. CONCLUSION: Our data indicate that fusidic acid should be added to the list of drugs that can cause sideroblastic anaemia.

Aged↗
PubMed2005

The treatment of acute infectious conjunctivitis with fusidic acid: a randomised controlled trial.

BACKGROUND: Acute infectious conjunctivitis is a common disorder in primary care. Despite a lack of evidence regarding the effectiveness of topical antibiotics for the treatment of acute infectious conjunctivitis, most patients presenting in primary care with the condition receive topical antibiotics. In The Netherlands, fusidic acid is most frequently prescribed. AIM: To assess the effectiveness of fusidic acid gel compared to placebo for acute infectious conjunctivitis. DESIGN: Double-blind randomised placebo-controlled trial. SETTING: Twenty-five Dutch primary care centres. METHOD: Adults presenting with a red eye and either (muco)purulent discharge or glued eyelid(s) were allocated to either one drop of fusidic acid gel 1% or placebo, four times daily during one week. The main outcome measure was the difference in recovery rates at 7 days. Secondary outcome measures were difference in bacterial eradication rates, a survival time analysis of the duration of symptoms, and the difference in recovery rates in culture-positive and culture-negative patients. RESULTS: One hundred and eighty-one patients were randomised and 163 patients were analysed. Forty-five of the 73 patients in the treatment and 53 of the 90 patients in the placebo group recovered (adjusted risk difference = 5.3% [95% confidence interval {CI} = -11 to 18]). There was no difference between the median duration of symptoms in the two groups. At baseline, the prevalence of a positive bacterial culture was 32% (58/181). The bacterial eradication rate was 76% in the treatment and 41% in the placebo group (risk difference = 35% [95% CI = 9.3 to 60.4]). In culture positive patients, the treatment effect tended to be strong (adjusted risk difference = 23% [95% CI = -6 to 42]). CONCLUSION: At 7 days, cure rates in the fusidic acid gel and placebo group were similar, but the confidence interval was too wide to clearly demonstrate their equivalence. These findings do not support the current prescription practices of fusidic acid by GPs.

Anti-Bacterial Agents↗
PubMed1991

Fusidic acid for Behçet's colitis: a novel approach to T-cell specific immunosuppressive therapy.

A 33-year-old patient suffered from recurring Beh,cet's colitis despite treatment with corticosteroids and later cyclosporin. The patient was then successfully shifted from cyclosporin, a T-cell specific immunosuppressant, to fusidic acid treatment (500 mg t.i.d.). During fusidic acid treatment, he went into complete remission, and his prednisolone dose could be reduced from 30 to 5 mg/day. The case report substantiates recent in vitro data indicating that fusidic acid has a similar effect on T-cell function as cyclosporin. It is suggested that the effect of fusidic acid in other chronic immunoinflammatory diseases should be examined.

Adult↗
PubMed2006

Antimicrobial efficacy of gentamicin-loaded acrylic bone cements with fusidic acid or clindamycin added.

The increasing gentamicin resistance among bacteria in septic joint arthroplasty has stimulated interest in adding a second antibiotic into gentamicin-loaded bone cement. A first aim of this in vitro study is to investigate whether addition of fusidic acid or clindamycin to gentamicin-loaded bone cement has an additional antimicrobial effect against a collection of 38 clinical isolates, including 16 gentamicin-resistant strains. A modified Kirby-Bauer test, involving measurement of the inhibition zone around antibiotic-loaded bone cement discs on agar plates, was used to investigate whether adding a second antibiotic has an additional antimicrobial effect. Second, a selected number of strains was used to study their survival in an interfacial gap made in the different bone cements to mimic the gap between bone and cement as existing near a prosthesis. Gentamicin-loaded bone cement had an antimicrobial activity against 58% of the 38 bacterial strains included in this study, while 68% of the strains were affected by bone cement loaded with a combination of gentamicin and clindamycin. Bone cement loaded with the combination of gentamicin and fusidic acid had antimicrobial activity against 87% of the bacterial strains. In the prosthesis-related gap model, there was a clear trend toward less bacterial survival for gentamicin-loaded bone cement after adding clindamycin or fusidic acid. Addition of clindamycin or fusidic acid into gentamicin-loaded bone cement yields an additional antimicrobial effect. The combination gentamicin and fusidic acid was effective against a higher number of clinical isolates than the combination of gentamicin with clindamycin, including gentamicin-resistant strains.

Anti-Bacterial Agents↗