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PubMed1999

Fusidic acid in vitro activity.

Fusidic acid is a narrow spectrum agent that acts to inhibit protein synthesis by inhibition of elongation factor G at the level of the ribosome. Because of high protein binding susceptibility testing in vitro is affected by the presence of blood or serum. In addition, there is a modest inoculum effect in vitro. A breakpoint of 1 or 2 mg/l is most widely used for defining resistance to systemic treatment with fusidic acid. Fusidic acid activity is principally directed at staphylococci, both Staphylococcus aureus and coagulate-negative species which are highly susceptible. It is also active against Gram-positive anaerobic activity, and shows in vitro activity against Neisseria spp., Bordetella pertussis and Moraxella catarrhalis. It has no activity against other aerobic Gram-negative species. Modest activity (MICs just above breakpoint values) is seen with Streptococcus and Enterococcus spp. as well as Gram-negative anaerobic bacteria. Fusidic acid is defined as bacteriostatic. For staphylococci MBC values are generally 8--32-fold that of the MIC. Interaction studies with other antibiotics give varying results depending on methodology. However, interaction with beta-lactams is generally indifferent, as it is with rifampicin, while aminoglycosides and macrolides appear to be synergistic and fluoroquinolones antagonistic. Fusidic acid appears to inhibit the function of neutrophils and T-lymphocytes at clinically achieved concentrations.

Anti-Bacterial Agents↗
PubMed1998

Fusidic acid in dermatology.

Fusidic acid is an antibiotic that belongs to a group of its own, the fusidanes. The molecule has a steroid-like structure but does not possess any steroid activity. The structure is thought to be responsible for the steroid-like high penetration, and for the fact that no cross-resistance or cross-allergy has been seen with other antibiotics in routine clinical use. The anti-microbial activity of fusidic acid is specifically aimed at the most common skin pathogens, including Staphylococcus aureus, towards which it is one of the most potent antibiotics. The place of fusidic acid in dermatology is in the treatment of mild to moderately severe skin and soft-tissue infections, e.g. impetigo, folicullitis, erythrasma, furunculosis, abscesses and infected traumatic wounds, whereas it is of less use in conditions such as hidradenitis suppurativa, chronic leg ulcers, burns and pressure sores. The topical combinations of fusidic acid with either betamethasone or hydrocortisone are extremely useful in the treatment of atopic dermatitis/eczema whenever staphylococcal/secondary infection is suspected, and in more persistent cases of eczema where staphylococcal superantigen may be playing an important exacerbating role.

Anti-Bacterial Agents↗
PubMed1999

Resistance to fusidic acid.

Resistance to fusidic acid is determined by a number of mechanisms. The best described are alterations in elongation factor G, which appear in natural mutants that are harboured at low rates in normal populations of staphylococci (10(6) to 10(8)). Altered drug permeability has also been described, and appears to be plasmid-borne. Binding by chloramphenicol acetyltransferase type I and efflux are other described mechanisms of resistance whose prevalence is unclear. A large number of studies have examined rates of fusidic acid resistance in staphylococci. Most show low levels of resistance. Studies where high levels of resistance have been seen are from areas of the hospital where cross infection is common. Rates of resistance have tended to be slightly higher in methicillin-resistant strains of Staphylococcus aureus. Studies on the evolution of resistance have shown no major trends to the emergence of resistance. In one case this is despite increasing use of both systemic and topical fusidic acid over more than 24 years. Selection for resistant variants during treatment was recognised early in vitro and in vivo. However, evidence suggests that it does not occur at high frequency in clinical practice. Nevertheless, accumulated experience is that fusidic acid in combination with other agents results in less resistance emergence.

Animals↗
PubMed1999

Fusidic acid in other infections.

Fusidic acid, both systemic and topical, has been used for a wide variety of less common infections. Efficacy for oral fusidic acid has been demonstrated in the treatment of Clostridium difficile colitis and in staphylococcal infections in patients with cystic fibrosis. Topical fusidic acid gel is also effective in bacterial conjunctivitis and other minor external eye infections, and may be effective in reducing bacterial flora in the conjunctival sac prior to eye surgery. Studies suggest a potential role for fusidic acid in neurosurgical prophylaxis, as adjunctive therapy in bacterial endophthalmitis and Legionella pneumonia, and in leprosy. Topical fusidic acid has no effect in the treatment of chlamydial conjunctivitis or the prevention of staphylococcal infections in patients on continuous ambulatory peritoneal dialysis.

Anti-Bacterial Agents↗
PubMed1992

An experimental evaluation of the pharmacokinetics of fusidic acid in peritoneal dialysis.

Fusidic acid, an antimicrobial agent with activity against coagulase-positive and coagulase-negative staphylococci, has considerable potential for the management of staphylococcal peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). Whether fusidic acid reaches therapeutic levels in the dialysate once therapeutic serum levels have been achieved is not known. An animal model of CAPD that reproduced essential features of the clinical procedure was used to investigate this issue. Although oral administration was the preferred route, fusidic acid is not absorbed from the gastrointestinal tract of laboratory rats, and a subcutaneous injection of diethanolamine fusidate was used to achieve serum levels of the agent equivalent to those achieved clinically in man. In this model, fusidic acid concentrations up to 28 times the MIC for staphylococci were found in the dialysate when therapeutic levels of the agent were reached in the serum. The data provide support for continued experimental and clinical evaluation of the role of fusidic acid in CAPD-associated peritonitis.

Administration, Oral↗
PubMed1992

Susceptibility of strains of the Mycobacterium tuberculosis complex to fusidic acid.

The activity of fusidic acid was studied in 40 strains of M. tuberculosis (of which 20 strains were mono- or multiresistant to standard antituberculosis drugs) and 10 strains of M. bovis. Minimum inhibitory concentration (MIC) was determined by the radiometric (BACTEC) broth method. The MIC for the 50 strains varied between 8 and 32 mg/l, with a MIC90 of 16 mg/l for M. tuberculosis and a MIC90 of 32 mg/l for M. bovis. Minimal bactericidal concentration (MBC, defined as the lowest concentration of fusidic acid which killed 99% or more of the population) varied between 32 mg/l and 500 mg/l, with a MBC90 of 250 mg/l for M. tuberculosis and 500 mg/l for M. bovis. No cross-resistance to other antituberculosis drugs (ethambutol, isoniazid, rifampicin, streptomycin, pyrazinamide, ofloxacin, ciprofloxacin) was observed as strains resistant to one or more standard antituberculosis drugs were as susceptible to fusidin as sensitive strains of M. tuberculosis. No synergism or antagonism could be demonstrated when fusidic acid was combined with either ethambutol, isoniazid, rifampicin or streptomycin against strains of M. tuberculosis resistant to one or more standard antituberculosis drugs. Addition of pooled human serum to the medium increased both MIC and MBC by factors of 4 and 8 at serum concentrations of 10% and 50%, respectively. Single-step mutation to high-level resistance to fusidic acid at a frequency of less than 1.7 x 10(-8) could be readily selected at four times the MIC. These fusidic acid-resistant organisms had a generation time 2.0-2.7 x longer than their parent organisms.

Drug Combinations↗
PubMed1996

Fusidic acid induced acute immunologic thrombocytopenia.

Fusidic acid is used in hospitals as second-line therapy for multidrug-resistant staphylococcal infections. We report the first fully documented case of fusidic acid induced thrombocytopenia, in a 48-year-old patient. The thrombocytopenia was abrupt and severe but resolved spontaneously 7 d after drug withdrawal. The thrombocytopenia transiently relapsed 6 d later, when fusidic acid was reintroduced. Haemorrhagic signs were observed, but no severe bleeding occurred. Platelet transfusions failed to increase the platelet count. We detected an IgG platelet antibody in the patient's serum, that specifically recognized platelet glycoprotein IIb/IIIa only in the presence of fusidic acid. Fusidic acid induced thrombocytopenia should be considered as a possible cause for the thrombocytopenia frequently seen in the intensive care setting.

Acute Disease↗
PubMed2003

Molecular analysis of fusidic acid resistance in Staphylococcus aureus.

Fusidic acid is a potent antibiotic against severe Gram-positive infections that interferes with the function of elongation factor G (EF-G), thereby leading to the inhibition of bacterial protein synthesis. In this study, we demonstrate that fusidic acid resistance in Staphylococcus aureus results from point mutations within the chromosomal fusA gene encoding EF-G. Sequence analysis of fusA revealed mutational changes that cause amino acid substitutions in 10 fusidic acid-resistant clinical S. aureus strains as well as in 10 fusidic acid-resistant S. aureus mutants isolated under fusidic acid selective pressure in vitro. Fourteen different amino acid exchanges were identified that were restricted to 13 amino acid residues within EF-G. To confirm the importance of observed amino acid exchanges in EF-G for the generation of fusidic acid resistance in S. aureus, three mutant fusA alleles encoding EF-G derivatives with the exchanges P406L, H457Y and L461K were constructed by site-directed mutagenesis. In each case, introduction of the mutant fusA alleles on plasmids into the fusidic acid-susceptible S. aureus strain RN4220 caused a fusidic acid-resistant phenotype. The elevated minimal inhibitory concentrations of fusidic acid determined for the recombinant bacteria were analogous to those observed for the fusidic acid-resistant clinical S. aureus isolates and the in vitro mutants containing the same chromosomal mutations. Thus, the data presented provide evidence for the crucial importance of individual amino acid exchanges within EF-G for the generation of fusidic acid resistance in S. aureus.

Amino Acid Sequence↗
PubMed1994

Clinical trial of fusidic acid for lepromatous leprosy.

Fusidic acid was assessed for antileprosy activity in nine lepromatous leprosy patients. Patients received fusidic acid at either 500 mg/day for 12 weeks or 750 mg/day for 4 weeks followed by 500 mg/day for 8 weeks. All patients showed time-dependent clinical improvement and decreases in bacillary morphological index, radiorespirometric activity and PCR signal, and in serum phenolic glycolipid I. Fusidic acid appears to be a weakly bactericidal antileprosy agent which may have a role in the multidrug treatment of leprosy pending an evaluation of lepra-reaction-suppressive activity.

Adolescent↗
PubMed1999

Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics.

Fusidic acid comes in a variety of formulations for oral, intravenous and topical use. After oral administration of 500 mg Cmax values range from 14.5-3.3 mg/l and an elimination half-life of 8.9-11.0 h. Similar values are obtained with intravenous administration of the sodium salt, although peaks tend to be higher. Bioavailability for the new film-coated tablet is approximately 91% while that of the suspension formulation appears to be much lower. Repeated dosing results in substantial drug accumulation when given 8-hourly, and to a variable extent depending on dose when administered 12-hourly. One study has demonstrated a modest dose-dependency for pharmacokinetics, with decreased clearance at higher doses. Fusidic acid is primarily eliminated by non-renal mechanisms, and a proportion of the drug is metabolised to seven or more breakdown products that can be detected in bile. Hypoalbuminaemia increases fusidic acid clearance, while clearance is decreased in the presence of severe cholestasis, and essentially unchanged in renal failure. Fusidic acid is highly protein-bound (91-98S), but has good penetration to a number of tissues including skin blisters, burns, infected bone and joints. Topical application of fusidic acid results in poor penetration through skin but good penetration into aqueous and vitreous humour. Little is known about the pharmacodynamics of fusidic acid, apart from the fact that it is slowly bactericidal against Staphylococcus aureus, and produces moderate post-antibiotic effects in vitro.

Administration, Oral↗
PubMed2000

Oral fusidic acid fails to eradicate methicillin-resistant Staphylococcus aureus colonization and results in emergence of fusidic acid-resistant strains.

Carriers of methicillin-resistant Staphylococcus aureus (MRSA) in hospital constitute a reservoir of infections and increase the risk of bacteremia and wound infection. In this prospective randomized trial, we tested the effectiveness of oral fusidic acid for eradication of MRSA colonization. From March 1997 through February 1998, patients with MRSA colonization in medical intensive care units in a large urban teaching hospital were randomly assigned to receive fusidic acid 500 mg q8h orally for 7 days or no anti-staphylococcal treatment. Twenty-three MRSA carriers were found during the study period and 16 were eligible for evaluation; six of them received fusidic acid. MRSA colonization was cleared in only two of the six patients with fusidic acid treatment, and later recurred in one of them. MRSA disappeared for 1, 2, 7, 7, and 8 weeks, respectively, in five of the 10 patients without treatment. MRSA persisted in the other five cases. Although all MRSA isolates found in the initial surveillance culture were susceptible to fusidic acid (MIC </= 2 microg/mL), seven isolates from two patients after fusidic acid treatment demonstrated high fusidic acid resistance (MIC 64 to >/= 256 microg/mL). Pulsed-field gel electrophoresis pattern analysis showed that the resistant strains were genetically identical to the susceptible strains isolated from the same patient before fusidic acid treatment, in both cases. However, genetically distinct strains colonized in the same individual during follow-up were found in four out of 16 cases. We conclude that oral fusidic acid alone is not suitable for eradication of MRSA colonization, and may lead to the emergence of resistant strains.

Administration, Oral↗
PubMed2026

A prospective pharmacokinetic interaction study between rifampicin and fusidic acid for the treatment of staphylococcal infections.

OBJECTIVE: Fusidic acid with rifampicin is used for the treatment of severe staphylococcal infection, particularly prosthetic joint infections. Previous studies using twice daily fusidic acid showed rifampicin increases fusidic acid clearance, potentially causing sub-therapeutic concentrations. It is uncertain whether this occurs with three-times daily dosing. This study sought to re-evaluate this potential drug-drug interaction. METHODS: In this prospective, open-label drug-drug interaction population pharmacokinetic (PK) study, participants were randomized to receive fusidic acid or rifampicin for 24&#x2005;hours, followed by combination therapy for the duration of treatment. Drug concentration assays used liquid-chromatography mass spectroscopy on dried blood spots. Population PK models were built for fusidic acid, rifampicin and 25-desacetyl rifampicin. RESULTS: Ten participants were recruited. Inter-individual variability for both absorption (98.1%) and clearance (77.8%) were high for fusidic acid. A population pharmacokinetic model for fusidic acid revealed that early autoinhibition dominated over later rifampicin-mediated induction, resulting in a net decrease in fusidic acid clearance. The mean fusidic acid area under the curve during each dosing interval (AUC&#x3c4;) at steady state was 1.76-fold [0.049, 34.918] higher relative to Day 1, despite high uncertainty.Large inter-individual (110%) variability in absorption was observed for rifampicin. There was no apparent effect on rifampicin metabolism by fusidic acid co-administration, however, fusidic acid decreased clearance of 25-desacetyl rifampicin. CONCLUSION: In patients treated with fusidic acid three times daily in combination with rifampicin, autoinhibition potentially counteracted rifampicin induction such that fusidic acid concentrations were not reduced. Rifampicin clearance was not affected by fusidic acid, but 25-desacetyl rifampicin clearance was decreased. There was large inter-individual variability in the observed concentrations and final parameter estimates.

Fusidic Acid↗
PubMed1993

Pharmacokinetics of intravenous fusidic acid in patients with cholestasis.

The pharmacokinetics of fusidic acid and 3-ketofusidic acid were investigated in cholestatic and noncholestatic patients after intravenous administration of single and multiple doses of 500 mg of sodium fusidate. The patients, all with low serum albumin levels, were divided into three groups. Group I consisted of six noncholestatic patients; group II consisted of nine mildly cholestatic patients with mild hepatic impairment (conjugated bilirubin, 47 mumol liter-1; alkaline phosphatase, 280 IU liter-1; gamma-glutamyltranspeptidase, 190 IU liter-1); group III consisted of six benign intrahepatic cholestatic patients with high isolated conjugated hyperbilirubinemia (98.1 mumol liter-1). Assays were performed by high-pressure liquid chromatography. At steady state, the mean peak concentrations in serum were 63.7, 44.9, and 92.2 micrograms ml-1 in groups I, II, and III, respectively; over a dosage interval, areas under the concentration-time curve were 411.1, 238.7, and 603.4 micrograms.h ml-1 and the mean body clearances were 0.34, 0.53, and 0.25 ml min kg-1 in groups I, II, and III, respectively. The accumulation ratio of fusidic acid increased from 2.8 and 2.4 in groups I and II to 4.2 in group III. At steady state, the ratios of the areas under the concentration-time curve from 0 to 8 h for 3-ketofusidic acid/fusidic acid were 0.11, 0.09, and 0.10 in the three groups, respectively. Only very small amounts of fusidic acid and 3-ketofusidic acid were found in urine. These results substantiate the following hypotheses. In group I and II patients the clearance is higher than that in healthy volunteers because of the increased free, unbound fraction of fusidic acid, a consequence of lower serum albumin concentrations, resulting in increased distribution in tissue and hepatic metabolism. In group III patients, the higher bilirubinemia results in competition with fusidic acid for the limited glucuronidation, thus compensating for the increased elimination with fusidic acid because of the low serum albumin concentration. These results suggest that fusidic acid can be administered normally even to patients with high bilirubinemia because the postoperative serum albumin concentration is usually low.

Adult↗
PubMed1999

Effects of salicylate and related compounds on fusidic acid MICs in Staphylococcus aureus.

Salicylate, acetyl-salicylate, benzoate and ibuprofen increased fusidic acid MICs for fusidic acid-resistant and -susceptible strains of Staphylococcus aureus representing six genetic lineages. The effects of these substances on fusidic acid resistance levels occurred in a strain-dependent manner. The weak acid acetate, and acetaminophen did not alter fusidic acid resistance levels, while the addition of saligenin, the alcohol of salicylate, reduced gradient plate MICs for all strains studied. These findings indicate that a benzoic acid structure is required for the induction of increased intrinsic fusidic acid resistance levels. When 2 mM salicylate was added to media used in population analyses, the number of cells able to survive on high concentrations of fusidic acid increased. This increase in cell survival was observed in two unrelated fusidic acid-resistant strains, with chromosomal (WBG8287) or plasmid (WBG1576) mediated resistance determinants and two unrelated susceptible strains. The salicylate-induced increase in fusidic acid resistance was phenotypic at low fusidic acid concentrations (relative to resistance phenotype) for WBG8287 and a fusidic acid-susceptible strain. On media containing salicylate and high fusidic acid concentrations, the mutation frequency to higher fusidic acid resistance levels was greater for WBG8287, compared with unsupplemented fusidic acid-containing media. These experiments provide evidence for a novel salicylate inducible fusidic acid resistance mechanism in S. aureus.

Anti-Bacterial Agents↗
PubMed1976

Mechanisms of resistance to fusidic acid in Staphylococcus aureus.

The biochemical mechanisms of resistance to fusidic acid in Staphylococcus aureus were investigated. Organisms possessing plasmid genes for resistance showed a high basal level of resistance, but could be induced to higher levels after pre-incubation with fusidic acid. This induction occurred rapidly and probably did not depend on gene dosage effects. Mutants resistant to fusidic acid, obtained from plasmid-negative cultures, expressed resistance constitutively. Protein synthesis in cell-free extracts from staphylococci with plasmid-mediated resistance to fusidic acid was as sensitive to fusidic acid as was synthesis in preparations from sensitive organisms; whereas protein synthesis in preparations from a spontaneous fusidic acid resistant mutant was resistant to the antibiotic. None of the resistant strains caused detectable inactivation of fusidic acid and no new derivative of fusidic acid was found in culture extracts of plasmid-possessing organisms grown in the presence of radioactive antibiotic. Expression of plasmid-mediated resistance to fusidic acid was associated with a decrease in the molar ratio of phosphatidylglycerol to lysylphosphatidylglycerol, but the cardiolipin content remained constant.

Bacterial Proteins↗
PubMed1987

Corneal and intraocular penetration of topical and subconjunctival fusidic acid.

Corneal tissue absorption and intraocular penetration of fusidic acid were assessed in the rabbit after topical or subconjunctival application. Corneal tissue levels of fusidic acid one hour after the last topical application of the drug were well above the minimum inhibitory concentrations (MICs) for most Gram-positive and many Gram-negative organisms. Adequate levels were achieved in the aqueous at one hour following the last topical application, but no significant levels were detected in the vitreous. The corneal tissue and aqueous levels declined at 12 and 24 hours following the last drug application, however, corneal tissue levels at 24 hours were considered to be above the MICs for most Gram-positive organisms. A single subconjunctival injection of 100 mg of fusidic acid produced levels above the MICs of most organisms in the cornea, aqueous, and vitreous which persisted over 24 hours, but subconjunctival injection of fusidic acid at this concentration resulted in conjunctival necrosis and corneal decompensation. Fusidic acid penetrates well into avascular tissue and fully penetrates corneas with both intact and debrided epithelium, as evidenced by the intracameral drug levels. Good corneal penetration and absence of known topical toxicity make fusidic acid suitable for the treatment of microbial keratitis caused by susceptible organisms.

Absorption↗