A unique in vivo stimulation of labeled amino acid incorporation into protein by fusidic acid in the rat.
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Amino Acids↗
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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↗
Frequent emergence of resistance in Clostridium difficile during treatment of C. difficile-associated diarrhea with fusidic acid.
Samples from patients with Clostridium difficile-associated diarrhea (CDAD) that were randomized to fusidic acid (n = 59) or metronidazole (n = 55) therapy for 7 days were cultured for Clostridium difficile in feces on days 1, 8 to 13, and 35 to 40. Of the patients who were culture positive only before treatment, 77% (36/47) were permanently cured (no treatment failure and no clinical recurrence), compared to 54% (22/41) of those with persistence of C. difficile at one or both follow-ups (P = 0.03). A similar association between bacterial persistence and a worse outcome of therapy was seen in both treatment groups. Resistance to fusidic acid was found in 1 of 88 pretherapy isolates available, plus in at least 1 subsequent isolate from 55% (11/20) of patients who remained culture-positive after fusidic acid therapy. In 10 of these 11 patients, the resistant follow-up isolate(s) belonged to the same PCR ribotype as the susceptible day 1 isolate, confirming frequent emergence of resistance to fusidic acid during treatment. Despite this, 5 of these 11 patients were permanently cured with fusidic acid, relative to 5 of 9 patients with susceptible C. difficile at follow-up (P = 1.0). None of the 36 PCR ribotypes of C. difficile identified was associated with any particular clinical outcome or emergence of fusidic acid resistance. In conclusion, culture positivity for C. difficile was common after both fusidic acid and metronidazole therapy and was associated with treatment failure or recurrence of CDAD. Development of resistance in C. difficile was frequent in patients given fusidic acid, but it was without apparent negative impact on therapeutic efficacy in the actual CDAD episode.
Anti-Bacterial Agents↗
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↗
Ciprofloxacin ophthalmic solution in the treatment of conjunctivitis and blepharitis: a comparison with fusidic acid.
The efficacy and safety of ciprofloxacin ophthalmic solution (0.3%) and fusidic acid gel (1%) were compared in the treatment of bacterial conjunctivitis and blepharitis in a randomized, open, parallel group study. Thirty-nine patients, 21 treated with ciprofloxacin solution and 18 treated with fusidic acid gel, were culture-positive on admission and were evaluable for efficacy. At the end of a 7-day treatment, the infecting organism was eradicated in 81% of those treated with ciprofloxacin and 72% of those treated with fusidic acid gel. There was clinical cure or improvement in 95% and 89% respectively. The clinical cure rate appeared to be higher with ciprofloxacin than fusidic acid (62% compared with 28%) but this was related to the higher proportion of patients with acute conjunctivitis in the ciprofloxacin group. Two patients using ciprofloxacin had mild discomfort and stinging on instillation and one given fusidic acid had moderate edema and discomfort; the latter patient stopped treatment. Topical ciprofloxacin is effective and well tolerated and is a useful treatment of bacterial conjunctivitis and blepharitis.
Adolescent↗
The effects of fusidic acid on the inflammatory response in rats.
In the present study the antiinflammatory activity of fusidic acid was investigated in a model of formalin-induced edema formation in rats. Fusidic acid at doses of 50 and 100 mg kg (-1) was administered p.o. to rats for ten days. It was observed that fusidic acid inhibited edema formation significantly (P< 0.05). After this period, gastric mucus secretions were evaluated by the Alcian blue dye binding method. Mucus secretion decreased significantly in the control group. Fusidic acid increased the amount of gastric mucus. Moreover, in all of the animals with paw edema, platelet count was also increased. Red blood cell count, haemoglobin concentration and haematocrit were all higher in the control group than those of the fusidic acid groups. The present observations suggest that fusidic acid suppressed the inflammatory response and stimulated the gastric mucus secretion and it prompts further experiments for delineation of the mechanism of these actions as well as clinical trials.
Animals↗
Extracellular and intracellular killing in neutrophil granulocytes of Staphylococcus aureus with rifampicin in combination with dicloxacillin or fusidic acid.
The effect of rifampicin in combination with dicloxacillin or fusidic acid on the extracellular and intracellular killing of Staphylococcus aureus in human neutrophil granulocytes in the presence of serum was studied. At the extracellular level rifampicin significantly reduced the bactericidal activity of dicloxacillin, but had an indifferent effect on the activity of fusidic acid. The combination of rifampicin with dicloxacillin or fusidic acid led to intracellular killing no different from that produced by rifampicin alone. However, owing to the high intracellular activity of rifampicin, the intracellular killing by the drug combinations was greater than that by dicloxacillin or fusidic acid alone.
Adult↗
In-vitro activity of ciprofloxacin combined with either fusidic acid or rifampicin against Staphylococcus aureus.
Killing kinetic experiments were performed with ciprofloxacin, fusidic acid and rifampicin alone and with ciprofloxacin combined with either fusidic acid or rifampicin against ten strains of Staphylococcus aureus. The strains were all clinical isolates and two strains were methicillin-resistant. The antibiotic concentrations tested were in the range obtainable in the serum with recommended doses. The early bactericidal effect of ciprofloxacin alone was substantially greater than that of fusidic acid or rifampicin; thus the extent of killing after 6 h exposure to these antibiotics was 3.4 log10, 0.8 log10 and 0.6 log10, respectively. Fusidic acid as well as rifampicin antagonized the bactericidal activity of ciprofloxacin. Each combination killed 2 log10 cfu less than ciprofloxacin alone. For each combination the mean decrease in the number of organisms was comparable to that achieved with fusidic acid or rifampicin used alone.
Ciprofloxacin↗
Mutation frequencies for resistance to fusidic acid and rifampicin in Staphylococcus aureus.
Frequencies at which mutants resistant to fusidic acid and/or rifampicin arose in vitro were determined in Staphylococcus aureus strains including methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate resistant S. aureus (VISA) and hetero-VISA. The concentrations of fusidic acid (30 and 15 mg/L) and rifampicin (16 and 1 mg/L) used for selection were equal to the expected maximum and minimum serum concentrations after an oral regimen of rifampicin 900 mg od, together with fusidic acid 500 mg tds. Resistant mutants arose at a frequency of around 10(-8) for selections with rifampicin, but were undetectable (frequency <10(-11)) for selections with fusidic acid. Mutants were not recovered (frequency <10(-11)) after selections in the presence of both fusidic acid and rifampicin at 30/16 and 15/1 mg/L. Our results suggest that these antibiotics, when used in combination, could have a wider role in the management of staphylococcal infections.
Anti-Bacterial Agents↗
Inhibition of HIV replication in vitro by fusidic acid.
A 58-year-old man with AIDS improved clinically after the introduction of fusidic acid, 500 mg three times a day orally, to his therapeutic regimen. Fusidic acid may have had a direct effect against HIV. Fusidic acid has anti-HIV activity in vitro at levels readily attainable in vivo. The drug does not appear to be a reverse transcriptase inhibitor and its mode of action against HIV is unknown. Fusidic acid can be given orally and has few side-effects. These results justify fuller evaluation of fusidic acid as therapy against AIDS and HIV infection.
Acquired Immunodeficiency Syndrome↗
Fusidic acid alone or in combination with vancomycin for therapy of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.
The usefulness of fusidic acid, alone or combined with vancomycin, was investigated for the therapy of experimental endocarditis caused in rabbits by a methicillin-resistant strain of Staphylococcus aureus. In vitro killing curves showed an indifferent interaction between the two antibiotics. In vivo, vancomycin alone was as effective as a vancomycin-fusidic acid combination (P < 0.05 versus control animals). No resistance to fusidic acid emerged during combination therapy. Fusidic acid alone was not effective. Resistance emerged in 5 of 12 animals treated with fusidic acid alone and was responsible for antibacterial failure. Fusidic acid alone was effective (P < 0.001) and did not select resistant strains if therapy was started when animals retained a smaller inoculum. We concluded that the vancomycin-fusidic acid combination exhibited no advantage over vancomycin alone in this model.
Animals↗
Fucithalmic in acute conjunctivitis. Open, randomized comparison of fusidic acid, chloramphenicol and framycetin eye drops.
Fucithalmic, which is 1% fusidic acid in a sustained-release eye preparation, was shown to be superior to both chloramphenicol eye drops and framycetin (Soframycin) eye drops in the treatment of bacterial conjunctivitis in Tanzania. The clinical success rate was 77/83 (93%) on fusidic acid compared with 22/46 (48% on chloramphenicol and 26/35 (74%) on framycetin (P less than or equal to 0.02). The better effect of fusidic acid could be ascribed to a much lower rate of in vitro resistance (17%) compared to chloramphenicol (58%) and framycetin (41%). Because of the low resistance rate to fusidic acid among eye pathogens, especially in areas of the world with a high resistance towards other commonly used eye anti-infectives, Fucithalmic given twice daily would seem to be a valuable new eye anti-infective.
Acute Disease↗
Effect of fusidic acid on the hepatic cytochrome P450 enzyme system.
OBJECTIVE: To investigate the effects of fusidic acid therapy on the hepatic cytochrome P450 (CYP450) enzyme system. METHODS: Thirty HIV-seropositive L-methadone-substituted i.v. drug abusers (stage CDC/WHO B2 - 3 with CD4+-counts ranging from 65 to 293/microl) were randomized into 3 groups (A - C). Ten patients were treated with fusidic acid 500 mg/day over a period of 14 (group A) or 28 days (group B), respectively. Patients in group C served as a control group and did not receive any medication apart from L-methadone. In order to investigate the hepatic monooxygenase system, pharmacokinetics were determined in all patients before initiation and 14 and 28 days after starting therapy with fusidic acid. The concentration of antipyrine and its 3 main metabolites (norantipyrine (NORA), 4-hydroxyantipyrine (OHA), 3-hydroxymethylantipyrine (HMA)) in plasma and urine were measured by high-performance liquid chromatography (HPLC). RESULTS: No effects on antipyrine pharmacokinetics and pharmacokinetics of antipyrine metabolites were found in group A after 14 days of fusidic acid intake and in the control group without therapy. However, in contrast an activation of the CYP450 enzyme system was observed in group B after 28 days of fusidic acid therapy with an increase of total antipyrine clearance (43.0 +/- 7.62 ml/min to 51.0 +/- 9.03 ml/min) as well as clearances to all metabolites (NORA 7.11 +/- 1.75 to 8.60 +/-2.10 ml/min, OHA 11.5 +/- 2.89 to 14.0 +/- 3.97 ml/min, HMA 4.05 +/- 0.99 to 4.94 +/- 1.27 ml/min). Antipyrine half-life was significantly reduced (12.3 +/- 2.8 h to 9.4 +/- 2.2 h) and some patients developed clinical signs of L-methadone underdosage. CONCLUSIONS: Our results suggest that fusidic acid has a time-dependent activating effect on the CYP450 enzyme system. Especially in treatment of patients who are frequently under multidrug regimens such as HIV-positive patients drug interactions should be taken into consideration.
Anti-Bacterial Agents↗
In vitro susceptibility of Mycobacterium tuberculosis to fusidic acid.
The aim of this study was to determine the in vitro susceptibility of 170 clinical isolates of Mycobacterium tuberculosis to fusidic acid using a proportion dilution method. Nineteen isolates were resistant to at least one first-line anti-tuberculosis drug. A total of 1.8% of the isolates were resistant to fusidic acid. Fusidic acid should be evaluated clinically as a potential supplementary drug for the treatment of infections due to multidrug-resistant strains of M. tuberculosis.
Anti-Bacterial Agents↗
Adverse reactions to intravenous administration of fusidic acid.
To study adverse reactions associated with intravenous administration of fusidic acid 6 patients were treated with fusidic acid intravenously in association with a major large bowl operation, and 9 patients were treated in the same way because of staphylococcal infections. The main adverse reaction was thrombophlebitis, which occurred in as many as 12 of 14 patients who were treated for 2 days or longer. Three surgical patients developed postoperative hyperbilirubinaemia, but studies of liver function before and during treatment in 6 of the patients with staphylococcal disease revealed no adverse liver reactions. Intravenous administration of fusidic acid into a peripheral vein for 24 h or more involves an extremely high risk of developing thrombophlebitis.
Adult↗
Effect of fusidic acid on the immune response in mice.
The effect of fusidic acid on the immune response in mice was studied. At the nontoxic dose of 500 mg/kg per day, the cell-mediated immunity was strongly inhibited. A marked and significant prolonged survival of split-heart allografts in treated animals was detected. The survival time of allografts in mice receiving fusidic acid from the day of the transplantation until the grafts were rejected was 26.1 days compared with 14.5 days in untreated animals. In mice treated also before the transplantation, the mean survival of the allografts were even longer. The phytohemagglutinin response, as well as the mixed lymphocyte culture stimulation of spleen lymphocytes from mice given 500 mg of fusidic acid per kg daily for 1 week, were significantly inhibited. At the same dose there was also a significantly decreased primary antibody response to sheep erythrocytes, but it was of limited biological significance. The immunosuppressive effect in animals treated with a human therapeutic dose of fusidic acid (25 mg/kg per day) was less pronounced but significant. The relevance of these results is discussed.
Animals↗
Fusidic acid: new opportunities with an old antibiotic.
The extensive foreign experience with fusidic acid prior to its belated introduction to Canada is reviewed. Fusidic acid is a steroid antibiotic with minimal toxic and hormonal effects that is mainly excreted through the liver. It has a predominantly bactericidal action and does not shown cross-resistance with other antibiotics. Since organisms resistant to this drug form easily in vitro when exposed to low concentrations, complementary treatment with another antibiotic may be required in some clinical situations. Although fusidic acid is active in vitro against a number of organisms, to date it has mainly been used to treat serious infections due to Staphylococcus aureus. The agent appears to be particularly valuable in the treatment of bone and joint infections and in pediatric practice. Fusidic acid will soon be available in Canada for both oral and intravenous administration. Attainable antibiotic levels in many tissues and body fluids greatly exceed the minimum inhibitory concentrations.
Anti-Bacterial Agents↗
Clonal spread among Swedish children of a Staphylococcus aureus strain resistant to fusidic acid.
An increased incidence of fusidic acid-resistant Staphylococcus aureus strains causing superficial infections among children in Sweden has been noted since the mid-1990s. Based on routine susceptibility testing data from 10 laboratories representing 8/21 Swedish counties during 1990-2001, the increase was first demonstrated in southern Sweden and subsequently became apparent throughout the country. Epidemiological typing using pulsed-field gel electrophoresis of recent isolates of fusidic acid-resistant S. aureus from 11 laboratories representing 8/21 Swedish counties revealed a high degree of similarity of band patterns, indicating a clonal relationship. Data from 1 of the laboratories demonstrated a close connection between this clone and impetigo. Sales statistics showed a pronounced increase in the use of fusidic acid ointments in the 0-12 y age group from 1998 onwards. There was, however, no statistically significant correlation between sales of fusidic acid ointments and resistance among S. aureus strains to fusidic acid.
Administration, Topical↗