Department of Clinical Microbiology, University College London Hospitals, Grafton Way, London WC1E 6DB, UK
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Abstract |
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Introduction |
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Sitafloxacin (DU-6859a) is a fluoroquinolone with a broad spectrum of activity including staphylococci, streptococci, Enterobacteriaceae and anaerobes.2 A concentration of 1 mg/L is sufficient to inhibit 90% of isolates of MRSA and 50% of isolates of VRE,2 including those resistant to ciprofloxacin. Doses are given once daily because the post-antibiotic effect lasts >6 h and the serum half-life is 7 h.3,4
The purpose of this preliminary study was to determine the efficacy and safety of sitafloxacin (400 mg iv once daily) in the treatment of severe infections caused by MRSA and VRE.
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Materials and methods |
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Pregnant females, patients allergic to quinolones and those with central nervous system disease, liver failure, AIDS, HIV, terminal illness or need for dialysis were excluded. No concomitant antibiotics of any type or known mixed bacterial infections were allowed. The original intention was to recruit 15 evaluable patients per pathogen. However, few patients had clinical VRE infection and patients with MRSA infection were required by the Ethics Committee to have failed treatment with glycopeptides (judged clinically). All other centres failed to recruit any patients. All patients or their relatives gave written informed consent.
At entry to the study, the APACHE score was assessed and cultures made of blood and the site of infection. Physical examinations and cultures were made at entry and on days 1, 4, 7, 912 and day 35 ± 7 days. During treatment, sepsis-related organ failure assessment (SOFA) scores and any adverse events were recorded daily.5 Samples for culture were processed at the local laboratory but significant isolates were passed to a central laboratory (GR Micro, London, UK) to confirm identity and sensitivity to sitafloxacin, teicoplanin and vancomycin (microbroth dilution MIC). Haematological and biochemical tests were performed within 3 days before recruitment, at 1, 2 and 4 days, at the end of treatment and at follow-up (days 912 and day 35 ± 7 days) and processed at a central laboratory.
Cure was defined as disappearance of all infection-related signs and symptoms or improvement of symptoms if no further antibiotic treatment was needed and SOFA score improved. Failure was defined as no change or worsening of symptoms or SOFA score, or death resulting from infection, or concomitant or subsequent antibiotic treatment for persistent infection. Lack of follow-up, early discontinuation of treatment for other reasons, and major protocol violation rendered the outcome indeterminate. Bacteriological outcome was satisfactory if culture 25 days after treatment showed eradication of the pathogen or no sample could be obtained because of clinical improvement. An unsatisfactory outcome was defined as persistence or relapse of the pathogen (including colonization), superinfection within 3 days after treatment, or need for further antibiotics to treat continued infection.
Serum samples were collected just before and at the completion of the infusion of the fourth dose. Samples were separated, frozen at 25°C and assayed for sitafloxacin by a central laboratory (Covance Laboratories Europe Ltd) using HPLC with post-column photolysis and fluorescence detection.
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Results |
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There were 10 infections with MRSA alone, eight with VRE alone and one with MRSA plus VRE (Table I). There were 14 men and five women with a mean age of 47 years (range 2168 years) and weight 68 kg (5388 kg). The pathogens were isolated from the blood in all but two patients. The source of MRSA bacteraemia was soft tissue in six patients and a venous catheter in one. In three patients, prosthetic devices could not be removed. VRE infections were shown to be soft tissue (two patients), central venous catheter (two patients) and urinary tract (one patient). All venous catheters implicated in infection were removed.
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For MRSA infections, four patients were cured 25 days after treatment, in six treatment failed and in one outcome was indeterminate. Three remained cured at 1 month but two relapsed at 5 weeks with susceptible isolates. Bacteriological success was observed in four patients, failure in four and superinfection in one; two were not evaluable. Of the patients with VRE infections, five were cured and four failed treatment. Five remained satisfactory at 1 month. Six patients were a bacteriological success, two were failures and one was indeterminate.
In 18 patients, there were a total of 63 adverse events, 13 (21%) considered severe and 15 (24%) (12 patients) possibly related to the study antibiotic (Table II). Nine patients developed diarrhoea, all but one after receiving earlier broad-spectrum antibiotics. Clostridium difficile was detected in one patient. Four patients developed a maculopapular rash but only one required withdrawal of treatment. One patient developed transient seizures on the fifth day of treatment and was withdrawn. Concurrent propofol may have been the cause.
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Trough serum concentrations of sitafloxacin in 17 patients were between 0.15 and 4.3 mg/L (median 0.89 mg/L). Peak concentrations (16 patients) at the end of infusion were between 3.4 and 29.9 mg/L (median 5.8 mg/L).
There were 17 isolates of MRSA tested from 11 patients on recruitment (10 from blood, four from sputum, two from wounds and one from a catheter tip). The MIC50 (range) of sitafloxacin was 0.5 mg/L (0.251 mg/L) compared with 0.5 mg/L of vancomycin (0.252 mg/L) and 0.5 mg/L of teicoplanin (0.124 mg/L). For patients whose infection was cured, the MIC50 of sitafloxacin was 0.5 mg/L (0.250.5 mg/L) but for those patients who failed treatment or had an indeterminate outcome the MIC50 was 1 mg/L (0.251 mg/L). There was no relationship between MIC of glycopeptides and outcome. The susceptibility of Gram-positive organisms isolated after treatment was not reduced except in one patient who failed treatment, the MIC of S. aureus for sitafloxacin increasing from 1 to 4 mg/L.
For the nine VRE infections, there were 13 isolates on recruitment (10 blood, one wound, one urine, one sputum), comprising seven Enterococcus faecium, four E. faecalis and two Enterococcus casseliflavus. The MIC50 of sitafloxacin was 2 mg/L (18 mg/L). For one isolate of E. faecium the MIC of sitafloxacin was 8 mg/L and for two it was 4 mg/L (classed as resistant). All isolates were resistant to vancomycin (MIC 64 mg/L) and only two isolates (MIC 16 mg/L) showed moderate susceptibility to teicoplanin. There was no correlation between MIC and clinical outcome. All bacteriological failures were caused by organisms susceptible to sitafloxacin (MIC 12 mg/L). No Gram-positive isolates showed reduced susceptibility after treatment.
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Discussion |
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In randomized trials, the efficacy and safety of sitafloxacin have been found to be similar to those of imipenem in the treatment of community-acquired pneumonia (54 patients) and to those of ciprofloxacin plus metronidazole in the treatment of intra-abdominal infection (121 patients) (personal communication, A. Briggs; Daiichi Pharmaceuticals, UK).
The incidence of adverse events reflected the serious nature of the underlying illness in these patients. Rash was the most frequently reported event with a possible relationship to sitafloxacin. Ciprofloxacin was associated with rash in 54 of 3635 patients (1.5%) but these were not critically ill.6 A single patient in the current study developed seizures, as compared with three of 202 critically ill patients given ciprofloxacin.7
Although these results are preliminary, sitafloxacin appeared to be effective in severe systemic infections caused by VRE and in recalcitrant MRSA infections.
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Acknowledgments |
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Notes |
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References |
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2
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Milatovic, D., Schmitz, F. J., Brisse, S., Verhoef, J. & Fluit, A. C. (2000). In vitro activities of sitafloxacin (DU-6859a) and six other fluoroquinolones against 8,796 clinical bacterial isolates. Antimicrobial Agents and Chemotherapy 44, 11027.
3 . Giamarellou-Bourboulis, E. J., Sambatakou, H., Grecka, P., Chryssouli, Z. & Giamarellou, H. (1999). Sitafloxacin (DU-6859a) and trovafloxacin: postantibiotic effect and in vitro interactions with rifampin on methicillin-resistant Staphylococcus aureus. Diagnostic Microbiology and Infectious Disease 34, 3017.[ISI][Medline]
4 . Nakashima, M., Uematsu, T., Kosuge, K., Umemura, K., Hakusui, H. & Tanaka, M. (1995). Pharmacokinetics and tolerance of sitafloxacin (DU-6859a), a new fluoroquinolone, after single and multiple oral doses in healthy volunteers. Antimicrobial Agents and Chemotherapy 39, 1704.[Abstract]
5 . Vincent, J. L., Moreno, R., Takala, J., Willatts, S., De Mendonca, A., Bruining, H. et al. (1996). The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Medicine 22, 70710.[ISI][Medline]
6 . Reiter, C., Pfeiffer, M., Hullmann, R. N. & Schacht, P. (1994). Integrated safety profile of intravenous ciprofloxacin. In Ciprofloxacin i.v.: Defining its Role in Serious Infections, (Garrad, C., Ed.), pp. 719. Springer, Berlin.
7 . Fink, M. P., Syndman, D. R., Niederman, M. S., Leeper, K. V., Johnson, R. H., Heard, S. O. et al. (1994). Treatment of severe pneumonia in hospitalized patients: results of a multi-center, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenemcilastatin. Antimicrobial Agents and Chemotherapy 38, 54757.[Abstract]
Received 21 January 2000; returned 27 March 2000; revised 15 May 2000; accepted 5 June 2000