Uncoupling of oxidative phosphorylation by glycyrrhetic acid, fusidic acid and some related triterpenoid acids.
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Adenine Nucleotides↗
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Susceptibility of mycobacteria to fusidic acid.
Fusidic acid was shown to be effective in vitro against 30 clinical isolates of Mycobacterium tuberculosis at concentrations of 32-64 mg/l, concentrations which are readily achieved in serum. All but one of 17 Mycobacterium avium complex strains were resistant to fusidic acid at concentrations up to 64 mg/l. However, synergistic effects were shown for 11 of the 17 strains when fusidic acid was combined with ethambutol. Five of the strains were fully susceptible to the combination of fusidic acid (64 mg/l) and ethambutol (4 mg/l). It is suggested that fusidic acid should be evaluated clinically as a potential supplementary drug for treatment of mycobacterial infections.
Drug Resistance, Microbial↗
The bile acid analog fusidic acid can replace phosphatidylserine in the activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate in vitro.
Protein kinase C (PKC) is a Ca2+- and phospholipid-dependent protein kinase which binds and is activated by tumor promoters such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). PKC can be activated in vitro by phosphatidylserine (PS) plus either TPA or Ca2+. We report here that the bile acid analog fusidic acid can replace the requirement for PS in the activation of PKC by TPA. In addition, fusidic acid can enhance the activation of PKC by Ca2+ and PS as well as by TPA and PS. Fusidic acid is an excellent model compound for in vitro studies of the direct effects of bile acids on PKC activity because, unlike many bile acids, it is completely soluble in standard PKC assay mixtures, obviating the exposure of the enzyme and lipid micelles to organic solvents. The colonic mucosa is exposed to millimolar concentrations of bile acids, and we find that fusidic acid stimulates PKC activity in the presence of TPA with a Ka of 350 microM. There is substantial evidence that bile acids are endogenous tumor promoters, and that colon carcinogenesis is influenced by the composition of bile acids in vivo. Thus, fusidic acid may be a prototype of bile acids which could mediate tumor promotion, at least in part, by replacing the requirement for PS in the activation of PKC.
Animals↗
The antimicrobial activity of fusidic acid.
Fusidic acid, a fusidane that interferes with protein synthesis via the translocase enzyme, is mainly notable for its activity against staphylococci, coagulase-positive and negative, whether or not they are resistant to methicillin and related penicillins. It is also active against corynebacteria and against many genera of strict anaerobes and microaerophiles. Mutants showing resistance, by more than one mechanism, may readily be selected in vitro. Combination of fusidic acid with other antibiotics generally gives addition or indifference, but also delays emergence of resistant mutants.
Bacteria↗
Residual polarity and transcription-translation coupling during recovery from chloramphenicol or fusidic acid.
Fusidic acid or chloramphenicol was used to inhibit peptide synthesis to 1% of normal in Escherichia coli B, strain AS19. After 10 min of inhibition, peptide synthesis could be quickly restored to 80% of the normal rate after washing the bacteria on a filter. However, even in the presence of adenosine 3'-5'-cyclic-monophosphoric acid to block catabolite repression, beta-galactosidase, the first enzyme of the lactose operon (lac), could only be induced to 10% of normal, and the last enzyme of the operon, galactoside acetyltransferase, even less. The first and last enzymes of the operon for tryptophan synthesis could be derepressed to about 30% of normal. The lac ribonucleic acid (RNA) induced during recovery showed a smaller than normal size distribution on sucrose gradients. The operator-proximal or -distal parts of this RNA were specifically labeled. Hybridization to phi80dlac deoxyribonucleic acid (DNA) suggested that although the distal parts of the lac RNA were barely detectable, initiation was occurring at normal rates in recovery. Either normal levels of distal messenger RNA (mRNA) are made but then rapidly degraded or the mRNA is not completed. The small amount that is made decayed abnormally slowly, probably as a result of slower transcription. Total mRNA decay was multiphasic with all components decaying slower than normal. We propose that there is a residual level of inhibition of peptide synthesis during recovery. The probability that a ribosome is blocked at any codon can be estimated from the data. The longer the message, the less likely its complete translation. We propose that the RNA polymerase can transcribe translatable mRNA for only a finite distance beyond the lead ribosome. Because ribosomes can load at the start of each message in a polycistronic mRNA, the probability that a distal message will be synthesized and translated is a function of the number of more proximal messages and the distances between their ribosome-loading sites.
Acetyltransferases↗
Sites of action of fusidic acid in eukaryotes. Inhibition by fusidic acid of a ribosome-independent GTPase from Artemia salina embryos.
1. A ribosome-independent GTPase activity has been isolated from the high-speed supernatant fraction of Artemia salina embryos, and some of its properties have been studied. This activity is inhibited by fusidic acid, an antibiotic generally thought to inhibit only EF-2 in eukaryotes. However, several lines of evidence indicate that the GTPase activity, described here, is distinct from EF-2. The results suggest, therefore, that the inhibitory effect of fusidic acid in eukaryotic systems is not restricted to EF-2 (and ribosome)-dependent functions only. 2. The results of other experiments have revealed that, despite its ability to inhibit the GTPase activity mentioned above, fusidic acid is not a non-specific inhibitor of all ribosome-independent GTPase and ATPase activities present in eukaryotic cells.
Adenosine Triphosphatases↗
Fusidic acid in tear fluid: pharmacokinetic study with fusidic acid viscous eye drops.
Fusidic acid viscous eye drops, Fucithalmic (R), is a new eye antibiotic preparation which shows sustained-release properties. The long-lasting antibiotic concentrations in tear fluid can be ascribed to the carbomer used in the vehicle. Fusidic acid viscous eye drops was found to give significantly higher tear fluid concentrations than chloramphenicol viscous eye drops, the latter based on methylcellulose when investigated in rabbit eyes and dog eyes. In volunteers the excretion half-life of fusidic acid from tears was found to be 1.9 h. From a pharmacokinetic point of view and from already available clinical data, fusidic acid viscous eye drops would seem to be effective when given only twice daily.
Adult↗
Heterogeneous expression of fusidic acid resistance in Staphylococcus aureus with plasmid or chromosomally encoded fusidic acid resistance genes.
Fusidic acid resistance expression in a methicillin susceptible Staphylococcus aureus strain (WBG1576), which carries fusidic acid resistance on plasmid pUB101, and a prevalent Western Australian methicillin-fusidic acid resistant strain (WBG8287) were compared. WBG8287 carries fusidic acid resistance on the chromosome and its plasmid content has no effect on the levels of this resistance. WBG1576 and WBG8287 exhibited similar heterogeneous populations in respect to fusidic acid resistance levels in population analyses. A high-level fusidic acid resistant mutant of WBG1576 (BE8) had alterations in Smal chromosomal profiles, but not in plasmid size or resistance expression. Mutations causing increased fusidic acid resistance in WBG1576 are chromosomally located. A high-level fusidic acid resistant mutant of WBG8287 (BE3) had no alterations in Smal chromosomal profiles, or plasmid content and resistances. Comparison of resistance levels to kanamycin and spectinomycin, between high-level resistant colonies of WBG8287 and WBG8287, indicate that mutations in the chromosomal gene fusA, which encodes elongation factor-G, are probably the cause of the increased resistance levels observed in these mutant strains.
Anti-Bacterial Agents↗
Fusidic acid cream for impetigo. Fusidic acid should be used with restraint.
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Anti-Bacterial Agents↗
Short-term effects of topical fusidic acid or mupirocin on the prevalence of fusidic acid resistant (FusR) Staphylococcus aureus in atopic eczema.
BACKGROUND: Staphylococcus aureus has a role in the pathophysiology of atopic eczema. Topical fusidic acid is widely used in its treatment. There is concern that topical use of fusidic acid may be driving the selection and dissemination of fusidic acid-resistant (FusR) S. aureus. OBJECTIVES: To test the hypothesis that treatment of atopic eczema for 2 weeks with topical fusidic acid/steroid combination can increase carriage of FusRS. aureus. METHODS: Forty-six patients with atopic eczema were allocated randomly to one of two treatment groups. Group 1 (28 patients) were treated with topical 2% fusidic acid plus 0.1% betamethasone cream, and group 2 (18 patients) with topical 2% mupirocin and 0.1% betamethasone cream. The clinical response and nasal and skin colonization with S. aureus were recorded before treatment and after 1 and 2 weeks of therapy. RESULTS: Baseline samples from the site of worst eczema showed S. aureus (sensitive and resistant) in 76% of patients, and FusRS. aureus in 26%, with no significant difference between treatment groups. After 1 and 2 weeks, both groups showed similar significant clinical improvement. The overall median clinical improvement was paralleled by a reduction in prevalence and population density of S. aureus (sensitive and resistant) at the worst eczema site (P < 0.0001). However, for FusRS. aureus there was no significant change in the prevalence of carriage, or population density in either group compared to baseline. Over 50% of patients carried S. aureus in the nerves and over 20% carried FusRS. aureus. Neither regimen affected either the prevalence or population density of S. aureus or FusRS. aureus in the nerves. CONCLUSIONS: In this small study there is no evidence to support the hypothesis that short-term treatment of atopic eczema with fusidic acid/steroid combination increases fusidic acid resistant S. aureus during a 2-week period.
Administration, Topical↗
Fusidic acid in acute conjunctivitis. Single-blind, randomized comparison of fusidic acid and chloramphenicol viscous eye drops.
Fusidic acid 1% and chloramphenicol 0.5% eye drops were in a randomized, single-blind manner given as a one-week treatment to out-patients with acute, purulent conjunctivitis. A clinical success was recorded in 84% (102/121) of patients receiving fusidic acid and in 81% (104/129) of patients receiving chloramphenicol. More patients (14%) receiving chloramphenicol complained of trivial side effects such as stinging and local discomfort, compared with fusidic acid (5%). No serious side effects were recorded. It is concluded that fusidic acid dispensed in a carbomer eye vehicle represents an effective and well tolerated new topical eye preparation with the advantage of being administered twice daily.
Acute Disease↗
Susceptibility to fusidic acid among Danish Staphylococcus aureus strains and fusidic acid consumption.
A total of 8176 Danish Staphylococcus aureus strains isolated from cases of bacteraemia during the years 1963 to 1987 were investigated for resistance to fusidic acid. During the whole period 1% of the strains or less were resistant (MIC of 2 mg/l or more). The total Danish consumption of fusidic acid during the same period increased from 0.008 to 0.029 defined daily doses/1000 inhabitants/day. The resistant strains were mainly sporadic isolates with the phage-types and antibiotic-resistance patterns predominant in Denmark at the time of their isolation.
Anti-Bacterial Agents↗
Fusidic acid resistance in community isolates of methicillin-susceptible Staphylococcus aureus and fusidic acid prescribing.
The level of resistance to fusidic acid among community methicillin-susceptible Staphylococcus aureus (MSSA) isolates in the UK and prescriptions for fusidic acid have both doubled over the past 6 years. It is hypothesized that selective pressure arising from topical use of fusidic acid in the community accounts for this increase. A significant correlation was found between prescribing of fusidic acid and resistance at the practice level (Spearman's rho = 0.46, 95% confidence interval 0.11-0.71, P = 0.01). Further controlled studies are required to determine whether this association is causal.
Anti-Bacterial Agents↗
Staphylococcal bacteraemia, fusidic acid, and jaundice.
Fusidic acid was used to treat 131 out of 250 patients with staphylococcal bacteraemia over 10 years. Other antimicrobial agents were given to the 119 remaining patients. Thirty-seven patients were already jaundiced before antibiotic treatment was started. Jaundice developed during treatment in 38 out of 112 patients given fusidic acid (34%) and in two out of 101 patients given other antimicrobials. The incidence of jaundice was higher in patients given fusidic acid intravenously (48%) rather than by mouth (13%). Jaundice appeared within 48 hours after the administration of fusidic acid in 93% of these cases. When the drug was stopped serum bilirubin concentrations fell to normal values within four days in those patients in whom they had been previously normal and who survived the bacteraemic episode. Fusidic acid was associated with increasing jaundice in 13 of 19 patients (68%) already jaundiced before it was given. In six out of 32 patients who developed jaundice while receiving intravenous fusidic acid serum alkaline phosphatase activity was raised suggestive of cholestatic jaundice. The mechanism in the remaining patients was unknown. Fusidic acid, particularly the intravenous preparation, in invaluable in treating severe staphylococcal infection but should be used with caution in patients with abnormal liver function. Patients receiving intravenous fusidic acid should be given the oral form of the drug as soon as their clinical condition permits.
Adolescent↗
Demonstration of in vitro antagonism between fusidic acid and quinolones.
Fusidic acid is an antibiotic active against staphylococci and other bacterial pathogens. It is used in the treatment of staphylococcal infections usually in combination with other antibacterial agents. Reports of the clinical effects of antimicrobial combinations containing fusidic acid have been somewhat inconsistent. The aim of this study was to investigate the in vitro antagonism of fusidic acid and quinolones. Twenty-six staphylococci strains isolated from various clinical samples were tested. After detecting the diameter of the zone of inhibition around fusidic acid, levofloxacin, ciprofloxacin, ofloxacin and moxifloxacin for each strain, in vitro antagonism between fusidic acid and each quinolone was investigated using disk approximation. In all 26 strains, quinolones and fusidic acid were antagonist in vitro. The reason for this antagonistic effect and its clinical implications are not known. However, care should be exercised in prescribing quinolones and fusidic acid in combination.
Anti-Bacterial Agents↗
Fusidic acid cream for impetigo. Emergence of resistance to fusidic acid limits its use.
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Anti-Bacterial Agents↗
High-performance liquid chromatographic determination of fusidic acid in plasma.
Fusidic acid was determined in plasma by a high-performance liquid chromatographic method. Fusidic acid was extracted from plasma with acetonitrile that was salted out with ammonium sulfate. Prior to salting out cadmium sulfate was mixed with the acetonitrile-plasma mixture to help remove interfering constituents. A 150 mm X 4.6 mm column packed with 5-microns cyanopropyl stationary phase was used for chromatography. The mobile phase was acetonitrile-20 mM sodium dihydrogenphosphate (pH 3.50) (39:61, v/v). An ultraviolet-visible detector was set at 204 nm. The presence of water in the injection solvent had a significant effect on the fusidic acid peak height. A number of clinically important acquired immunodeficiency syndrome drugs did not interfere with the fusidic acid determination. The relative standard deviation varied between 0.99 and 7.8%. A limit of detection of 200 ng/ml was obtained for a 80-microliters injection.
Chromatography, High Pressure Liquid↗
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↗