a Pediatric Infectious Diseases Unit, E. Wolfson Medical Center, Holon, Israel b Clinical Immunology Unit, E. Wolfson Medical Center, Holon, Israel c Infectious Diseases Unit, E. Wolfson Medical Center, Holon, Israel
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Abstract |
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Introduction |
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S. aureus is a major pathogen of bone and joint infections; its eradication often requires prolonged parenteral treatment. The concentration of fusidic acid and its bactericidal activity against S. aureus in serum and synovial fluid was studied following oral administration. For comparison we studied the same parameters after iv administration of cloxacillin.
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Materials and methods |
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Eighteen patients who were candidates for joint aspirations because of rheumatological disorders were enrolled in the study. Patients were excluded if they had evidence of acute infection, renal or liver dysfunction, or if they had received antibiotics in the week preceding the joint aspiration.
Drug administration
The drugs were administered using dosages recommended for acute septic arthritis. Fusidic acid (Leo, Ballerup, Denmark) 500 mg tid was administered orally for 72 h, the last dose being given 4, 8 or 12 h before the scheduled joint aspiration. A single dose of cloxacillin (Bristol-Myers-Squibb, Italy) 2 g was administered iv 0.5, 4 or 8 h before the scheduled aspiration. Three patients were studied for each antibiotic in each time group. Blood samples were taken at the same time as the joint aspiration. The synovial fluid was analysed for leucocyte count and protein concentration. The joint fluid samples and serum samples were stored at -80°C until they were tested for drug levels and bactericidal activity.
Determination of drug concentrations
Concentrations of fusidic acid and cloxacillin in serum and joint fluid were determined by bioassay. Standards were 2, 0.25 and 0.125 mg/L. For fusidic acid assay specimens were first diluted 1:4 with citrate-phosphate buffer and then further diluted with 25% human serum. 5 The indicator organism used was Corynebacterium xerosis (NTCC 9755-L FF-M). Cloxacillin concentrations were determined similarly; the indicator organism used was Micrococcus luteus (ATCC 9341) grown on blood agar and the medium used was tryptic soy agar. Standard concentrations were 25, 12.5, 6.5, 3.1 and 1.56 mg/L. The minimal concentration detectable by the assays was 0.125 mg/L.
Test microorganisms and bactericidal assay
Five clinical isolates each of methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA respectively) were selected for study. The MIC and MBC of test drugs were measured by a microdilution method according to the NCCLS recommendations. 6 The MIC of fusidic acid against both MSSA and MRSA isolates was 0.041 ± 0.015 mg/L (MBC, 0.099 ± 0.038 mg/L). The MIC of cloxacillin was 0.225 ± 0.05 mg/L (MBC, 0.25 mg/L) for MSSA and >64 mg/L for MRSA.
The bacteriostatic and bactericidal activities of serum and joint fluid samples were determined by the standardized microdilution method, performed according to the guidelines proposed by the NCCLS.7
Pharmacodynamics
The arithmetic mean bactericidal or bacteriostatic titre was determined for each drug and organism. Effective bactericidal activity was defined as titres >1:2.
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Results |
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Joint fluid samples were obtained from the knee for each patient. The indication for joint aspiration in all cases was inflammatory arthritis and the underlying illnesses were rheumatoid arthritis (seven cases), crystalloid arthritis (five cases), osteoarthritis (five cases) and non-specific arthritis (two cases).
The mean protein level in the joint fluid was 44 g/L in the fusidic acid group and 43.7 g/L in the cloxacillin-treated patients. The mean leucocyte count was 14.3 x 109/L and 6.5 x 109/L respectively in the two groups. Drug concentrations in serum and synovial fluid are presented in Tables I and II. Mean bacteriostatic and bactericidal activity of the serum and joint fluid against S. aureus after administration of fusidic acid and cloxacillin are shown in Tables I and II respectively. Despite high serum and fluid concentrations of fusidic acid, low bactericidal activity was documented in the serum (1:2.81:4.5); in the synovial fluid low inhibitory activity was detected (1:2.51:4.1) with borderline bactericidal activity. Cloxacillin showed markedly better bactericidal activity.
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Discussion |
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Serum and joint fluid samples in the fusidic acid group were taken after 72 h of oral administration because serum concentrationss are higher in steady state than after one dose. Cloxacillin, on the other hand, does not accumulate, hence only one dose was administered. We elected to compare an oral fusidic acid regimen with an iv cloxacillin regimen in order to assess whether the therapeutic potency of the latter can be assured by the former when used in continuation oral treatment.
While good bactericidal activity of cloxacillin was demonstrated in the serum and the
synovial fluid, the activity of fusidic acid was markedly lower. These findings are in contrast
with the pharmacokinetic parameter of concentration:MIC ratio which was 185 for cloxacillin
(at peak serum level) and 1202 for fusidic acid (in serum). We cannot offer an explanation
for the remarkable discrepancy between the excellent MICs of fusidic acid against both MSSA
and MRSA strains and the high drug levels on one hand, and the very mediocre ex-vivo activity
of the drug, on the other hand. Our findings were not influenced by changing the pH or the
medium used (Mueller-Hinton broth versus molten assay medium; data not shown). Some
authors have questioned the significance of the MICs of fusidic acid determined according to
recommended guidelines1 since these can be markedly
modified by changing the content of serum in the broth.8
Indeed by adding 50% serum to the broth, the MIC of fusidic acid to our test strains
increased 700-fold, while only a three-fold increase in MIC was observed for cloxacillin (data
not shown). We could not identify any previous publication on the ex-vivo bactericidal activity
of fusidic acid in humans to confirm or challenge our findings. Nevertheless, in a study on the
efficacy of fusidic acid in experimental endocarditis due to MRSA, the authors found that the
antibacterial activity of fusidic acid in sera obtained from rabbits `was mainly
bacteriostatic' (data not shown).9
Since the early 1960s, fusidic acid has been extensively used in Europe in a wide spectrum of staphylococcal infections including bacteraemia, osteomyelitis and septic arthritis. 3,4,9,10 Most of the published reports described retrospective clinical experience, and in the vast majority of cases other antistaphylococcal drugs were administered concomitantly (mainly to avoid development of resistance to fusidic acid). The reported high cure rates, which are in disagreement with our ex-vivo results, may nevertheless be attributed to the effect of the concomitantly administered drugs and to a possible synergy with fusidic acid. On the other hand, our findings should be considered with the understanding that they originated in a semiclinical method of evaluation of antimicrobial activity.
With the urgent need to expand the antistaphylococcal armamentarium, especially against MRSA infections, a well conducted, prospective, randomized clinical study to evaluate the efficacy of fusidic acid is highly desired. Until then, fusidic acid should be used with caution in severe staphylococcal infections.
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Notes |
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References |
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2 . Verbist, L. (1990). The antimicrobial activity of fusidic acid. Journal of Antimicrobial Chemotherapy 25 , Suppl. B, 15.[ISI][Medline]
3 . Humble, M. W., Eykyn, S. J. & Phillips, I. (1980). Staphylococcal bacteraemia, fusidic acid, and jaundice. British Medical Journal 280, 14958.[ISI][Medline]
4 . Gosden, P. E., Reeves, B. C., Osborne, J. R. S., Turner, A. & Miller, M. R. (1997). Retrospective study of outcome in patients treated for Staphylococcus aureus bacteraemia. Clinical Microbiology and Infection 3,32 40.[Medline]
5 . Bywater, M. J. (1978). Fusidic acid. In Laboratory Methods in Antimicrobial Chemotherapy (Reeves, D. S., Phillips, I., Williams J. D. & Wise, R., Eds), pp. 219- 21. Churchill Livingstone, Edinburgh.
6 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically Fourth Edition: Approved Standard M7-A4. NCCLS, Villanova, PA.
7 . National Committee for Clinical Laboratory Standards. (1993). Methodology for Serum Bactericidal Tests. Tentative Guideline M21-T. NCCLS, Villanova, PA.
8 . Huebner, J., Kropec, A., Engels, I. & Daschner, F. (1992). In vitro susceptibility of methicillin-resistant Staphylococcus aureus and slime-producing and non-slime-producing coagulase-negative staphylococci to fusidic acid. Chemotherapy 38, 20610.
9 . Fantin, B., Leclercq, R., Duval, J. & Corban, C. (1993). Fusidic acid alone or in combination with vancomycin for therapy of experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 37 , 24669.[Abstract]
10 . Coombs, R. R. (1990). Fusidic acid in staphylococcal bone and joint infection. Journal of Antimicrobial Chemotherapy 25, Suppl. B, 5360.[ISI][Medline]
Received 9 July 1998; returned 20 October 1998; revised 2 December 1998; accepted 15 December 1998