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PubMed1987

Fusidic acid-induced hyperbilirubinemia.

A 72-year old man developed jaundice while on fusidic acid therapy for suspected osteomyelitis. Hyperbilirubinemia was predominantly of the conjugated variety and elevation in liver enzymes was mild and transient. Although serum bilirubin fell rapidly after fusidic acid was stopped, complete resolution of the hyperbilirubinemia took nearly a month. Other possible causes of jaundice were excluded. Light microscopy of a needle liver biopsy showed focal hepatocyte feathery degeneration, intracellular bile retention, and canalicular bile plugging, most prominent in perivenous regions. Electron microscopy revealed varying degrees of canalicular dilatation, loss of microvilli, and disruption of the canalicular membrane with vesicular bleb formation as well as canalicular bile plugs. Widening of the pericanalicular ectoplasmic zone with accumulation of cytoskeletal filaments was also noted. These findings are similar to those reported in experimental cholestasis induced by bile acids. Possible mechanisms of jaundice caused by fusidic acid are discussed.

Aged↗
PubMed2005

Hyper-susceptibility of a fusidic acid-resistant mutant of Salmonella to different classes of antibiotics.

Fusidic acid resistance (Fus(R)) in Salmonella enterica serovar Typhimurium is caused by mutations in fusA, encoding elongation factor G (EF-G). Pleiotropic phenotypes are observed in Fus(R) mutants. Thus, the fusA1 allele (EF-G P413L) is associated with slow growth rate, reduced ppGpp and RpoS levels, reduced heme levels, and increased sensitivity to oxidative stress. The fusA1-15 allele, (EF-G P413L and T423I) derived from fusA1 in a selection for growth rate compensation, is partially compensated in each of these phenotypic defects but maintains its resistance to fusidic acid. We show here that the fusA1 allele is associated with sensitivity to ultraviolet light and increased susceptibility to the inhibitory action of several unrelated antibiotic classes (beta-lactam, fluoroquinolone, aminoglycoside, rifampicin, and chloramphenicol). The fusA1-15 allele, in contrast, is less susceptible to UV and to other antibiotics than fusA1. The hyper-susceptibility to multiple antibiotics associated with fusA1 and fusA1-15 is revealed in a novel growth competition assay at sub-MIC concentrations, but not in a standard MIC assay.

Aminoglycosides↗
PubMed1986

Fusidic acid-betamethasone combination in infected eczema: an open, randomized comparison with gentamicin-betamethasone combination.

Ninety-nine patients with secondarily infected eczema were allocated at random to receive 10-days' treatment with either 2% fusidic acid plus 0.1% betamethasone cream or 0.1% gentamicin plus 0.1% betamethasone cream. Both preparations were applied to the lesions twice daily and assessment of the signs and symptoms was carried out before, after 2 to 4 days, and after 7 to 12 days of treatment, severity being rated on a 4-point scale. Bacteriological tests were carried out before and after treatment. The results showed that the combination with fusidic acid was marginally superior in clinical effect. Staphylococcus aureus was the most commonly isolated pathogen from eczematous lesions (86%) and fusidic acid showed the lowest resistance rate (9%), followed by gentamicin (21%). Chloramphenicol, neomycin and tetracycline showed resistance rates from 48% to 59%.

Adult↗
PubMed1977

Isolation and characterization of fusidic acid-resistant, sporulation-defective mutants of Bacillus subtilis.

Fusidic acid-resistant, sporulation-defective mutants were isolated from Bacillus subtilis 168 thy trp. About two-thirds of the fusidic acid-resistant (fusr) mutants were defective in sporulation ability and fell into three classes with respect to sporulation character. The representative mutants FUS426 and FUS429 were characterized in detail. FUS426 [fusr spo (Ts)], a temperature-sensitive sporulation mutant, grew well at 30 and 42 degrees C but did not sporulate at 42 degrees C. FUS429 [fusr spo (Con)], conditional sporulation mutant, grew and sporulated normally in the absence of fusidic acid, but its sporulation and growth rates decreased in the presence of fusidic acid, depending on the concentration of the drug. Although electron microscopic observation showed that both mutants were blocked at stage I of sporulation, the physiological analyses indicate that these mutants belong to the SpoOB class. Both mutants formed a thickened cell wall as compared with that of the parental strain. Genetic and in vitro protein synthesis analyses led to the conclusion that the sporulation-defective character of mutants FUS426 and FUS429 resulted from an alteration in elongation factor G caused by a single lesion in the fus locus. The possible role of elongation factor G in sporulation is discussed.

Bacillus subtilis↗
PubMed1986

Comparative in-vitro activity of antibiotics incorporated in acrylic bone cement.

We compared the persistence of antibacterial activity around antibiotic-impregnated acrylic bone cement discs which were serially transferred on seeded agar plates. On plates inoculated with Staphylococcus aureus ATCC 25923, CMW1 discs containing 2.5% by dry weight of cephalothin, coumermycin or fusidic acid (as diethanolamine fusidate) produced zones of inhibition for four to eight weeks when transferred daily. In contrast, ceftriaxone, cotrimoxazole, rifampicin and vancomycin ceased to be inhibitory within a week. Discs made of 'Palacos-R with Garamycin,' which contains gentamicin 1.25%, had an intermediate duration of activity. When Escherichia coli ATCC 25922 was used as the test organism, ceftriaxone and 'Palacos-R with Garamycin' showed activity for almost three weeks, cephalothin and cotrimoxazole were briefly inhibitory and the remainder not at all. When discs were transferred each week instead of daily, the ranking of antibiotics was similar but antibacterial activity persisted for longer. A combination of gentamicin plus fusidic acid in CMW1 was active for a much shorter time than either fusidic acid alone or 'Palacos-R with Garamycin'. We conclude that coumermycin is a promising new agent for incorporation in acrylic cement.

Acrylates↗
PubMed1975

Some characteristics of and structural requirements for the interaction of 24,25-dihydrofusidic acid with ribosome - elongation factor g Complexes.

Fusidic acid inhibits polypeptide chain elongation by binding to the ribosome - elongation factor-G - GDP complex and thereby preventing its dissociation. The experiments reported here quantitate the interaction of the antibiotic [3H]-24,25-dihydrofusidic acid, an active analog of fusidic acid, with the ribosome - elongation factor-G - GDP comples. All components of the complex are essential for [3H]-24,25-dihydrofusidic acid binding. The stoichiometry of the interaction is ca. 1:1, and the Ka apparent, as determined by equilibrium dialysis, is 2.6 times 10-6 M-minus 1. It is further shown that GTP and GDP are equally effective in forming complexes to which the antibiotic may bind, whereas GMP and beta,gamma-methyleneguanosine triphosphate will not form complexes to which the antibiotic may bind. In order to examine the structural basis of the mode of antibiotic action shown by fusidic acid, we have considered two activities of 21 structural analogs of this antibiotic: ability to bind to the aforementioned ternary complex and ability to stabilize this complex. The comparative binding capability of the analogs were extablished through competition experiments with [3H]-24,25-dihydrofusidic acid. The data obtained from these experiments can be summarized as follows. (1) The C17-20 double bond of fusidic acid appears to be critical for both binding and complex stabilization activities. (2) A carboxyl group in the vicinity of the C20 carbon is also essential for both activities. (3) Modifications of other functional groups in the molecule can lead to significantly decreased stabilization of the ternary ribosome complex and/or ability to compete with [3H]-24,25-dihydrofusidic acid for binding to the complex, but do not demonstrate absolute structural requirements for either activity.

Binding Sites↗
PubMed2003

Susceptibility of skin and soft-tissue isolates of Staphylococcus aureus and Streptococcus pyogenes to topical antibiotics: indications of clonal spread of fusidic acid-resistant Staphylococcus aureus.

Staphylococcus aureus (SA) isolates (n = 255) from outpatients with skin and soft-tissue infections were collected in 3 different areas in Norway. Group A streptococci (GAS, n = 68) were isolated from skin or pharyngotonsillar specimens from outpatients. Minimum inhibitory concentrations (MIC) of bacitracin, fusidic acid and mupirocin were tested using the E-test. Pulsed field gel electrophoresis (PFGE) patterns of fusidic acid-sensitive (FusS) and -resistant (FusR) SA were compared. All GAS isolates showed MIC of bacitracin of < or = 1.0 mg/l, of mupirocin of < or = 0.125 mg/l and of fusidic acid 1.0-4.0 mg/l. All the SA showed MIC of mupirocin < or = 0.5 mg/l and of bacitracin of > or = 2.0 mg/l, 91% with MIC > or = 16 mg/l. FusR was shown by 32.5% of the SA strains with similar prevalence rates in 3 different geographical areas of Norway. One particular PFGE pattern (type 1) was shown by 76% of the FusR SA. SA of type 1 belonged to phage group II and produced exfoliative toxins. Thus, the results demonstrated a high prevalence of FusR among SA causing skin infections and that this was mainly due to dissemination of clonally related FusR SA.

Administration, Topical↗
PubMed2003

High levels of fusidic acid-resistant Staphylococcus aureus in dermatology patients.

BACKGROUND: Antibiotic resistance is a significant problem both in hospitals and the community. Topical antibiotics are widely used for dermatological problems and this may be leading to the emergence of resistant bacteria. OBJECTIVE: To assess the level of fusidic acid-resistant Staphylococcus aureus inpatients with dermatological problems. METHODS: All microbiology samples over a 4-month period were tested for antibiotic sensitivities. Patients with cultures positive for S. aureus were studied. RESULTS: The study shows 50% of S. aureus isolates from dermatology patients were resistant to fusidic acid. This figure rose to 78% inpatients with atopic eczema. Of patients with fusidic acid-resistant S. aureus isolates, 96% had used a fusidic acid-containing preparation within the previous 6 months. The level of fusidic acid resistance in S. aureus samples cultured from nondermatology patients was only 9.6%, a level significantly below that for dermatology patients (P < 0.001). CONCLUSIONS: High levels of fusidic acid-resistant S. aureus are found in dermatology patients. Inappropriate use of topical antibiotics in dermatology patients leading to fusidic acid resistance may threaten the efficacy of systemic fusidic acid for the treatment of serious S. aureus infections. Education of health professionals and restriction of the use of fusidic acid is needed.

Administration, Topical↗
PubMed2002

A fusidic acid-resistant clone of Staphylococcus aureus associated with impetigo bullosa is spreading in Norway.

OBJECTIVE: To investigate the possibility that the increased prevalence of fusidic acid-resistant Staphylococcus aureus in Norway is caused by clonal spread. METHODS: Fusidic acid-resistant and -susceptible clinical isolates of S. aureus from patients with skin infections in the Norwegian county of Telemark and fusidic acid-resistant isolates from other parts of Scandinavia were compared. MICs of fusidic acid for bacterial isolates and pulsed-field gel electrophoresis (PFGE) patterns were investigated. Prevalence data for fusidic acid-resistant S. aureus for the period 1992-2001 were obtained. RESULTS: The prevalence of fusidic acid resistance in S. aureus increased from 1992 to 2001. Eighty per cent of the resistant isolates investigated shared an identical PFGE pattern. The same pattern was found in fusidic acid-resistant isolates from other parts of Scandinavia. Fusidic acid-resistant S. aureus was typically found in impetigo bullosa-like skin disease in children mostly in the summer months. CONCLUSIONS: Fusidic acid resistance among S. aureus is increasing in Norway and is predominantly caused by one clone of S. aureus. The clone may spread further to other countries, and dissemination may be facilitated by extensive use of topical fusidic acid.

Clone Cells↗
PubMed2001

Increases in the mutation frequency at which fusidic acid-resistant Staphylococcus aureus arise with salicylate.

Salicylate was shown to increase the frequency at which a fusidic acid-susceptible strain of Staphylococcus aureus underwent mutation to become fusidic acid-resistant. These fusidic acid-resistant mutants had alterations in spectinomycin and kanamycin resistance levels indicative of mutations in fusA, the gene that encodes elongation factor-G, the target of fusidic acid.

Anti-Bacterial Agents↗
PubMed1984

[In vitro study of the cefamandole-fosfomycin combination against methicillin-resistant staphylococci].

In vitro antibacterial activity of cefamandole-fosfomycin (CFM-FOS) combination was studied on 50 methicillin-resistant staphylococci strains. Anti-bacterial effects were evaluated with a bactericidal microtiter checkerboard method. CFM-FOS was compared with other combinations known to be potent against staphylococci. Synergy was consistently recorded with CFM-FOS. Mean MBC of CFM combined with FOS was 1 microgram/ml. Vancomycin-fosfomycin combination was infrequently synergistic (20%). Rifampin-fosfomycin, cefamandole-fusidic acid, and cloxacillin-fusidic acid combinations were usually antagonistic at bactericidal levels. Rifampicin-fusidic acid combination usually yielded additive effects. CFM-FOS killed most methicillin-resistant staphylococci studied at therapeutic concentrations.

Anti-Bacterial Agents↗
PubMed2003

Fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium with low fitness in vivo are defective in RpoS induction.

Mutants of Salmonella enterica serovar Typhimurium resistant to fusidic acid (Fusr) have mutations in fusA, the gene encoding translation elongation factor G (EF-G). Most Fusr mutants have reduced fitness in vitro and in vivo, in part explained by mutant EF-G slowing the rate of protein synthesis and growth. However, some Fusr mutants with normal rates of protein synthesis still suffer from reduced fitness in vivo. As shown here, Fusr mutants could be similarly ranked in their relative fitness in mouse infection models, in a macrophage infection model, in their relative hypersensitivity to hydrogen peroxide in vivo and in vitro, and in the amount of RpoS production induced upon entry into the stationary phase. We identify a reduced ability to induce production of RpoS (sigmas) as a defect associated with Fusr strains. Because RpoS is a regulator of the general stress response, and an important virulence factor in Salmonella, an inability to produce RpoS in appropriate amounts can explain the low fitness of Fusr strains in vivo. The unfit Fusr mutants also produce reduced levels of the regulatory molecule ppGpp in response to starvation. Because ppGpp is a positive regulator of RpoS production, we suggest that a possible cause of the reduced levels of RpoS is the reduction in ppGpp production associated with mutant EF-G. The low fitness of Fusr mutants in vivo suggests that drugs that can alter the levels of global regulators of gene expression deserve attention as potential antimicrobial agents.

Animals↗
PubMed2004

A fusidic acid-resistant epidemic strain of Staphylococcus aureus carries the fusB determinant, whereas fusA mutations are prevalent in other resistant isolates.

Fusidic acid-resistant epidemic Staphylococcus aureus strains causing impetigo bullosa have been reported in Scandinavia. We show that these strains form part of a European epidemic clonotype that carries the fusB determinant. In contrast, resistance to fusidic acid in a collection of nonepidemic strains resulted primarily from mutations in fusA.

Anti-Bacterial Agents↗
PubMed1994

Fusidic acid-resistant mutants define three regions in elongation factor G of Salmonella typhimurium.

We have sequenced fusA, the gene coding for elongation factor G (EF-G), in 18 different mutants of Salmonella typhimurium selected as fusidic acid resistant (FuR). In addition, we have sequenced two previously described FuR mutants from Escherichia coli. In all cases, the resistance is due to a mutation in one of three separate regions in fusA. The three clusters of mutant sites superimpose on regions that are well conserved, suggesting that they are of a more general functional importance. To further classify the mutants, we have measured the minimal inhibitory concentration (MIC) for Fu and for two other antibiotics which interfere with translocation on the ribosome, kanamycin (Km) and spectinomycin (Sp). The levels of resistance to Fu for each of the mutants are significantly higher than in the wild type (wt), and vary by about one order of magnitude between the highest and the lowest. Most of the mutants are also more resistant to Km than the wt, although the level of resistance is low and the variation small. In contrast, about half of the mutants are more sensitive to Sp than the wt, with only one being more resistant. Only three of the twenty mutants behave like the wt with respect to the non-selected phenotypes, KmR and SpR.

Bacterial Proteins↗
PubMed1993

Fusidic acid-dependent ribosomal complexes protect Escherichia coli ribosomes from the action of the type 1 ribosome-inactivating protein crotin 2.

The type 1 ribosome-inactivating protein crotin 2 depurinated Escherichia coli ribosomes which, upon treatment of the isolated rRNA with acid aniline, released a fragment of around 240 nucleotides whose 5'-end sequence was 5'-GAGGACCGGAGUGGAC-3'. The formation of fusidic acid-dependent ribosomal complexes completely prevented release of the fragment. Ribosomes from crotin 2-pretreated fusidic acid complexes were insensitive to acid aniline. They released the RNA fragment only after a second treatment with crotin 2 and acid aniline whereas unprotected ribosomes released the fragment directly after acid aniline.

Apurinic Acid↗
PubMed2002

Comparative frequency of patch test reactions to topical antibiotics.

BACKGROUND: Neomycin, clioquinol and fusidic acid are all topical antibiotics widely used in dermatological practice in the U.K., either as a single agent or in combination with topical corticosteroids. However, an adverse effect of topical antibiotics is contact sensitization. OBJECTIVES: To examine the frequency of positive patch test reactions to fusidic acid, clioquinol and neomycin. METHODS: To compare the frequency of allergic patch test reactions over 1 year, we patch tested all patients attending the St John's Institute of Dermatology contact dermatitis clinic for one calendar year with fusidic acid, neomycin and clioquinol. RESULTS: We patch tested 1119 patients. Positive patch test reactions to neomycin were noted in 40 patients (3.6%), compared with eight patients (0.7%) to clioquinol and three patients (0.3%) to fusidic acid. The frequency of medicament allergy to neomycin was thus five times more common than to clioquinol and ten times more common than to fusidic acid. Although fusidic acid is not part of our extended standard series, it is in our medicaments series. Therefore, in the second part of our study, we reviewed all cases of positive patch test reactions to fusidic acid over the last 20 years. We found that the frequency of hypersensitivity has decreased since the early 1980s despite increasing usage; the current average frequency being 1.62 patch-tested patients per year (1.45%) of those patch tested to the medicaments series). The most common diagnosis in such patients was stasis dermatitis (54.2%). CONCLUSIONS: The frequency of fusidic acid allergy in an eczema population is low and is comparable with published data from over 10 years ago.

Administration, Topical↗
PubMed2004

Fusidic acid-resistant mutants of Salmonella enterica serovar typhimurium have low levels of heme and a reduced rate of respiration and are sensitive to oxidative stress.

Mutations in the translation elongation factor G (EF-G) make Salmonella enterica serovar Typhimurium resistant to the antibiotic fusidic acid. Fus(r) mutants are hypersensitive to oxidative stress and rapidly lose viability in the presence of hydrogen peroxide. We show that this phenotype is associated with reduced activity of two catalase enzymes, HPI (a bifunctional catalase-hydroperoxidase) and HPII (a monofunctional catalase). These catalases require the iron-binding cofactor heme for their activity. Fus(r) mutants have a reduced rate of transcription of hemA, a gene whose product catalyzes the first committed step in heme biosynthesis. Hypersensitivity of Fus(r) mutants to hydrogen peroxide is abolished by the presence of delta-aminolevulinic acid, the precursor of heme synthesis, in the growth media and by the addition of glutamate or glutamine, amino acids required for the first step in heme biosynthesis. Fluorescence measurements show that the level of heme in a Fus(r) mutant is significantly lower than it is in the wild type. Heme is also an essential cofactor of cytochromes in the electron transport chain of respiration. We found that the rate of respiration is reduced significantly in Fus(r) mutants. Sequestration of divalent iron in the growth media decreases the sensitivity of Fus(r) mutants to oxidative stress. Taken together, these results suggest that Fus(r) mutants are hypersensitive to oxidative stress because their low levels of heme reduce both catalase activity and respiration capacity. The sensitivity of Fus(r) mutants to oxidative stress could be associated with loss of viability due to iron-mediated DNA damage in the presence of hydrogen peroxide. We argue that understanding the specific nature of antibiotic resistance fitness costs in different environments may be a generally useful approach in identifying physiological processes that could serve as novel targets for antimicrobial agents.

Anti-Bacterial Agents↗
PubMed2000

Fusidic acid-resistant EF-G perturbs the accumulation of ppGpp.

Reductions in growth rate caused by fusidic acid-resistant EF-G mutants in Salmonella typhimurium correlate strongly with increased mean cell size. This is unusual because growth rate and cell size normally correlate positively. The global transcription regulator molecule ppGpp has a role in co-ordinating growth rate and division, and its basal level normally correlates inversely with cell size at division. We show that fusidic acid-resistant EF-G mutants have perturbed ppGpp basal levels during steady-state growth and perturbed induced levels during starvation. One mutation, fusA1, associated with the slowest growth rate and largest cell size, causes a reduction in the basal level of ppGpp to one-third of that found in the wild-type strain. Other fusA mutants with intermediate or wild-type growth rates and cell sizes have either normal or increased basal levels of ppGpp. There is an inverse relationship between the basal level of ppGpp in vivo and the degree to which translation dependent on mutant EF-G is inhibited by ppGpp in vitro. This enhanced interaction between mutant EF-G and ppGpp correlates with an increased KM for GTP. Our results suggest that mutant EF-G modulates the production of ppGpp by the RelA (PSI) pathway. In conclusion, fusidic acid-resistant EF-G mutations alter the level of ppGpp and break the normal relationship between growth rate and cell size at division. It would not be surprising if other phenotypes associated with these mutants, such as loss of virulence, were also related to perturbations in ppGpp levels effected through altered transcription patterns.

Anti-Bacterial Agents↗