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PubMed2002

Antimicrobial activity and mechanisms of resistance to cephalosporin P1, an antibiotic related to fusidic acid.

The antimicrobial properties of cephalosporin P1, an antibiotic structurally related to fusidic acid, were examined. Cephalosporin P1 exhibited potent activity against methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus and vancomycin-intermediate S. aureus. Mutants of S. aureus resistant to cephalosporin P1 arose with a frequency of 1.6 x 10(-6) for selections at 4 x MIC, a frequency similar to that for fusidic acid. The mutations conferred cross-resistance to fusidic acid and mapped in fusA, the gene encoding elongation factor G. Cross-resistance between cephalosporin P1 and fusidic acid also occurred for S. aureus fusA mutants selected with fusidic acid, and in fusidic acid-resistant clinical isolates. Plasmid pUB101, which mediates resistance to fusidic acid in S. aureus, also conferred resistance to cephalosporin P1. Escherichia coli was intrinsically resistant to both fusidic acid and cephalosporin P1, but deletion of the AcrAB efflux pump resulted in susceptibility to both antibiotics. Although complete cross-resistance between fusidic acid and cephalosporin P1 was demonstrated, the nature and location of fusA mutations in S. aureus when cephalosporin P1 was the selective agent frequently differed from those selected with fusidic acid. This may reflect differences in the interaction of the two antibiotics with the translational apparatus, which results in the selection of separate mutation classes for each antibiotic. Furthermore, in three of 14 mutants selected with fusidic acid, resistance was attributed to mutations lying outside fusA. In contrast, mutations in 10 mutants selected with cephalosporin P1 were all located in fusA.

Amino Acid Sequence↗
PubMed1989

[A spectrophotometric method of analysis of fusidic acid].

A spectrophotometric method for assay of fusidic acid is described. The method is based on reaction with a reagent consisting of acetic anhydride and concentrated sulfuric acid. Mathematical processing of the results of the main substance determination in fusidic acid preparations showed that the error did not exceed 2 per cent. Procedures for spectrophotometric assay of fusidic acid in control of the processes of its biosynthesis, isolation and purification were developed. The procedures provided control of the technological process of fusidic acid production.

Acetic Anhydrides↗
PubMed1990

A multicentre, open, clinical trial of a new intravenous formulation of fusidic acid in severe staphylococcal infections.

A new intravenous formulation of fusidic acid, containing sodium fusidate, was used to treat 54 seriously ill patients. Forty-nine patients were infected with fusidic acid sensitive staphylococci. Fusidic acid was given with another antibiotic in 46 cases and alone in three instances. Thirty-three (70.2%) of the 47 cases analysed were cured. Five patients failed to respond and five patients died whilst receiving therapy. Superinfection was recorded in four cases. Adverse events, mainly comprising local intolerance at the infusion site or abnormal liver function tests, were recorded in 22 (40.7%) patients. Therapy was withdrawn because of side effects in only four (7.4%) cases.

Adolescent↗
PubMed1992

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.

Adolescent↗
PubMed1987

[Activity of fusidic acid on strictly anaerobic bacteria].

Fusidic acid is a well known antimicrobial agent due to its narrow spectrum of activity against Gram positive bacteria and especially staphylococci. Therefore, it is after used preventively against bacterial infection in traumatology, but the susceptibility of anaerobic bacteria is not well known. We have studied, the in vitro activity of sodium fusidate against 147 strains of anaerobic bacteria. This antibiotic has a moderate activity against Bacteroides, more significant against Clostridium, Peptococcus et Peptostreptococcus; it has no bactericidal activity. Clostridium difficile is different from other anaerobic bacteria because of its slow MIC and its MBC near to its MIC. Fusidic acid could be proposed for the treatment of pseudomembranous and antibiotic-associated colitis induced by Clostridium difficile.

Bacteria, Anaerobic↗
PubMed1990

Staphylococcal bacteraemia and endocarditis and fusidic acid.

In 1980, we reported an association between the use of fusidic acid (particularly the intravenous formulation) and jaundice in patients who had received the drug for the treatment of Staphylococcus aureus bacteraemia during the previous 10 years. We have continued to use fusidic acid for severe staphylococcal infections, but have recommended oral administration whenever possible. In the earlier study the incidence of jaundice in patients given intravenous fusidic acid was 48%, but in the recent study of 145 patients it was 17%. Whereas 71% of patients receiving fusidic acid in the earlier series were given the intravenous drug (with or without oral) only 25% of patients were given the intravenous drug in the recent series. The incidence of jaundice in those patients treated only with the oral formulation was 13% in the earlier study and 6% in the recent study. Although jaundice was usually reversible, it is nevertheless an unwanted side effect. Resistance of S. aureus to fusidic acid remains at around 1%; it may be present on primary isolation or arise during treatment. This seems to occur particularly in patients with endocarditis or bone infection despite the use of fusidic acid in combination with another antibiotic. After some 25 years of clinical use, fusidic acid remains a most useful anti-staphylococcal antibiotic; the intravenous preparation should be avoided when possible.

Anti-Bacterial Agents↗
PubMed2000

Characterisation of methicillin-resistant Staphylococcus aureus from Kuwait hospitals with high-level fusidic acid resistance.

Forty-seven fusidic acid- and methicillin-resistant Staphylococcus aureus isolates from clinical samples in four hospitals in Kuwait were studied for their relatedness by biotyping and pulsed-field gel electrophoresis (PFGE) and for the genetic location of their resistance determinants. Forty-four isolates were resistant to gentamicin, kanamycin and neomycin. Forty-one isolates were resistant to erythromycin and trimethoprim, 10 were resistant to chloramphenicol and four were resistant to ciprofloxacin. They contained two or three plasmids of c. 28, 2.8 and 1.8 kb. Genetic studies demonstrated that resistance to cadmium, propamidine isethionate and ethidium bromide were linked and were carried on the c. 28-kb plasmid. Chloramphenicol resistance was encoded by the 2.8-kb plasmid in resistant isolates. No resistance was associated with the 1.8-kb plasmid and this was considered to be a cryptic plasmid. Resistance to fusidic acid, methicillin, benzylpenicillin, gentamicin, kanamycin, neomycin, tetracycline, trimethoprim, erythromycin and ciprofloxacin were located on the chromosome. All the isolates produced urease, but varied in the production of haemolysins, pigments, lipase and lecithinase and were classified into nine biotypes. In contrast, PFGE divided the isolates into two major patterns with one PFGE type constituting the majority of isolates in all four hospitals. The presence of the dominant PFGE pattern in all four hospitals suggests that it is an epidemic MRSA clone with the capacity to spread. Infection control measures should be directed towards restricting the further spread of this clone.

Anti-Bacterial Agents↗
PubMed1994

Fusidic acid suppresses nitric oxide toxicity in pancreatic islet cells.

Earlier preclinical and clinical trials indicate that fusidic acid, a triterpenoid compound originally described as an antimicrobial drug may protect islet beta cells from destruction in type I (insulin-dependent) diabetes mellitus. Since nitric oxide appears to be an important mediator of inflammatory islet cell death we analyzed whether fusidic acid interferes with nitric oxide production or action. We report here that fusidic acid dose-dependently inhibits lysis of isolated islet cells by activated macrophages, a process mediated by nitric oxide. In the presence of 100 microM fusidic acid macrophage-mediated islet cell lysis was reduced from 52.5 to 1.7% (P < 0.001). Fusidic acid only slightly affected macrophage function and did not inhibit the release of nitric oxide. We therefore tested whether fusidic acid suppresses nitric oxide toxicity in target cells. Isolated islet cells were exposed to the nitric oxide donor nitroprusside which led to DNA strand breaks and plasma membrane lysis. DNA strand breaks were reduced from 54.6 to 34.9% (P < 0.001) in the presence of 100 microM fusidic acid and cell lysis was reduced from 60.1 to 27.5% with 100 microM (P < 0.001). In the presence of 500 microM fusidic acid DNA strand breaks and cell lysis were reduced further to 27.1 and 10.7%, respectively (P < 0.001). No protection by fusidic acid was observed when cells were exposed to oxygen radicals or the alkylating beta cell toxin streptozotocin. The suppression of nitric oxide toxicity by fusidic acid was not due to its known inhibitory action on protein biosynthesis and thus represents a hitherto unknown activity of this drug.

Animals↗
PubMed1999

Concentration and bactericidal activity of fusidic acid and cloxacillin in serum and synovial fluid.

Fusidic acid and cloxacillin were studied in patients who underwent joint aspiration for noninfectious disorders. Nine patients were given oral 500 mg fusidic acid tid for 72 h, the last dose being given 4, 8 or 12 h before the joint aspiration. Cloxacillin was administered in a single 2 g iv dose to 9 patients, 0.5, 4 or 8 h before the aspiration. Bactericidal activity was determined against five isolates each of methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Satisfactory activity (> or = 1:3) was detected in the serum in patients who received fusidic acid, while in the synovial fluids titres reflected borderline effectiveness (c. 1:2). Despite drug concentrations and excellent MICs, fusidic acid demonstrated markedly lower inhibitory and bactericidal activity against S. aureus than did cloxacillin.

Adult↗
PubMed1989

[Outburst of fusidic acid resistant Staphylococcus aureus].

Fusidic acid (FA) resistance (MIC greater than or equal to 12.5) was found in only five of 123 strains of S. aureus isolated during the period from January, 1987, to March, 1988; the FA resistance rate soared up to 42 of 81 strains isolated during the period from April, 1988, to October, 1988. In contrast, all strains of S. aureus isolated in Kochi prefecture during the period from September, 1987, to September, 1988, were susceptible to FA. Our data clearly demonstrate an explosive increase of FA resistant S. aureus in Japan. However, regional differences currently exist in the emergence rate of FA resistant S. aureus.

Drug Resistance, Microbial↗
PubMed1993

Randomized placebo-controlled trial of single-dose antibiotic prophylaxis with fusidic acid in neurosurgery.

In neurosurgery, the antibiotic prophylaxis of choice has not yet been determined. The ideal drug should have an appropriate antimicrobial spectrum and favourable pharmacokinetic properties. In addition it should be nontoxic and easy to apply. We therefore conducted in 90 patients a prospective, randomized, placebo-controlled, double-blind trial in clean neurosurgery at increased risk of wound infection using a single pre-operative dose of 500 mg fusidic acid. Fusidic acid is a steroid-like antibiotic with a serum half-life of about 10 hours and excellent activity against gram-positive bacteria, including methicillin-resistant staphylococci. The neurosurgical infection rates for craniotomies, posterior fossa surgery and implantation of foreign bodies were 2.4% in the treatment group and 9.1% in the placebo group, respectively. This difference is statistically significant at a 95% confidence level.

Adolescent↗
PubMed1979

Synergistic effect of vitamin A and fusidic acid on Hela cells in vitro.

Examinations were made to see if various vitamin A compounds, including retinol, retinal, retinol palmitate, retinol acetate, and retinoic acid, enhance the action of fusidic acid, an antibiotic and inhibitor of protein synthesis, on human carcinoma HeLa cells in vitro. Among these vitamins, retinal and retinol were found to potentiate strongly the effect of fusidic acid on HeLa cells. In this system, however, retinol palmitate, retinoic acid, and retinol acetate in 10 approximately 20 microgram/ml concentration were not found to enhance the effect of fusidic acid significantly.

Cell Survival↗
PubMed1995

The interaction between "R/S domain" of rat 28S ribosomal RNA and ribosome-inactivating proteins investigated by fusidic acid.

The interaction between "R/S domain" of rat 28S rRNA and ribosome-inactivating proteins (RIPs) has been studied by blocking the action site of RIPs on "R/S domain" of 28S rRNA with fusidic acid or S100. Fusidic acid alone could form stable complexes with rat ribosomes and block the action site of RNA N-glycosidases. incubation of fusidic acid and S100 or GDP with ribosomes could also protect ribosomes from the action of ricin A-chain. However, different effect of fusidic acid, S100 an dGDP was observed when alpha-sarcin was used. Fusidic acid alone could not block the action site of alpha-sarcin. Fusidic acid together with the elongation factors in S100 could block the action site of alpha-sarcin. These results are consistent with the previous report that ricin A-chain and alpha-sarcin recognized different conformation of "R/S domain" in rat 28S rRNA.

Animals↗
PubMed1990

Clinical relevance of resistance to fusidic acid in Staphylococcus aureus.

The clinical relevance of resistance to fusidic acid in Staphylococcus aureus is reviewed. Resistance due to a one-step chromosomal mutation emerges readily in vitro. These variants appear defective and are not encountered clinically as frequently as would be expected. The majority of strains isolated from patients probably have plasmid-mediated resistance. The plasmid may be unstable both in vitro and in vivo. There appears to be a low incidence of resistance emerging when fusidic acid is used alone to treat acute infections; however, there is a higher incidence in chronic infections. When fusidic acid is given concurrently with another antibacterial agent to treat severe infection, resistance may be acquired in up to 1% of cases. The use of fusidic acid topically to treat acute skin infection in domiciliary practice does not appear to be epidemiologically hazardous. Over the last 20 years, during which fusidic acid has been used widely in the management of staphylococcal infection, the general level of resistance has remained low at 1-2%.

Drug Resistance, Microbial↗
PubMed1989

Topical antibiotic prophylaxis for cataract surgery: a controlled trial of fusidic acid and chloramphenicol.

The effectiveness of topical fusidic acid 1%, in a viscous drop base, to reduce or eliminate ocular microflora in patients undergoing cataract surgery has been studied. Forty-two patients received fusidic acid on a double-blind basis and for comparison 21 patients were similarly assessed with topical chloramphenicol. A further 17 patients received no treatment other than subconjunctival cephazolin administered to all operated eyes at the time of surgery. Quantitative bacterial counts from the conjunctivae and lash lines of each patient were made 24 hours before surgery, on the morning of operation and again 48 hours after surgery. With a regimen of five administrations on the day prior to surgery, neither topical fusidic acid 1.0% nor chloramphenicol 0.5% produced clinically or statistically significant reductions of the ocular microflora. In contrast perioperative subconjunctival cephazolin effectively reduced or eliminated lid and conjunctival microflora following surgery. This study indicates that the effectiveness of a topical antibiotic preparation for overt ocular infection cannot be directly extrapolated to the effect on resident ocular microflora, at least with short-term use for presurgical prophylaxis.

Administration, Topical↗
PubMed1975

The interaction of fusidic acid with peptidyl-transfer-ribonucleic-acid - ribosome complexes.

The inhibitory action of fusidic acid on peptide-chain elongation was studied with systems in vitro directed by either polyuridylic acid or endogenous messenger (Escherichia coli polysomes washed with 1 M NH4Cl) or R17 RNA, and supplemented with either crude or purified elongation factors. In all cases strong inhibition of synthesis required high concentrations of the antibiotic (approx. 1 mM), while a similar inhibition of the EF-G-plus-ribosome-dependent GTP hydrolysis required between 10 and 100 times less antibiotic. Since most of the GTP hydrolysis observed was presumably due to free ribosomes (without aminoacyl-tRNA or peptidyl-tRNA), fusidic acid seemed to interact far more easily with these ribosomes than with ribosomes engaged in peptide-chain elongation. The role of the GDP-EF-G-ribosome-fusidic acid complex in the inhibition of polypeptide synthesis was assessed by measuring formation of this complex on polysomes engaged in peptide-chain elongation. Using purified elongation factors the complex formed on only 25-35% of ribosomes, as measured either by retention of [3H]GDP or by hydrolysis of [3H, gamma-32P]GTP. In contrast, with crude factors (S 100 extract) it formed on more than 70% of ribosomes. The results are compatible with the postulated role of the complex in polypeptide synthesis inhibition (blockade of the ribosomal acceptor site and subsequent inhibition of aminoacyl-tRNA binding) and indicate that formation of the complex takes place by overriding the control that prevents interaction of EF-G when the donor site is occupied by peptidyl-tRNA. In the polyuridylic-acid-directed system for synthesis of oligophenylalanine the antibiotic inhibits every round of peptide elongation, including dipeptide formation, to roughly the same extent.

Binding Sites↗
PubMed2003

Evaluation of fusidic acid in therapy of experimental Staphylococcus aureus meningitis.

OBJECTIVES: Combination therapy that includes fusidic acid, an antimicrobial agent highly active against staphylococci, has been recommended in the treatment of patients with Staphylococcus aureus meningitis. The aim of this study was to evaluate the pharmacokinetic, CSF bactericidal and anti-inflammatory properties of fusidic acid. METHODS: The pharmacokinetics, treatment efficacy and parameters of the meningeal inflammatory response were studied in rabbits, using an experimental meningitis model against S. aureus (MICs of fusidic acid and methicillin were 0.125 and 1 mg/L, respectively). RESULTS: Fusidic acid entered the CSF, with peak values within 0.5-1 h of the intravenous bolus injection/infusion and with a percentage penetration (AUCCSF/AUCserum) into uninfected and purulent CSF of 1.9% +/- 0.7 and 4.5% +/- 0.7, respectively. Rabbits treated with antibiotics [fusidic acid 80 mg/kg/6 h (n = 6), methicillin 80 mg/kg/3 h (n = 7) and the two combined (n = 6)] had significantly higher bacterial kill rates than untreated controls (n = 6, P < 0.05). Combination therapy was less effective, with significantly less killing after 6 h of treatment than methicillin alone (P < 0.05). CSF white blood cells and CSF levels of interleukin-8 (IL-8), glucose, lactate and protein were altered during staphylococcal meningitis, but with no significant difference between antibiotic-treated and untreated rabbits. CONCLUSIONS: Antagonism between methicillin and fusidic acid was observed in staphylococcal meningitis.

Animals↗