Journal of Antimicrobial Chemotherapy (2000) 46, 633-638
© 2000 The British Society for Antimicrobial Chemotherapy
Brief report |
Sitafloxacin in the treatment of patients with infections caused by vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus
Department of Clinical Microbiology, University College London Hospitals, Grafton Way, London WC1E 6DB, UK
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Abstract |
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Sitafloxacin is a new quinolone active against multi-resistant Gram-positive pathogens. An open study was conducted in patients with serious systemic infections with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE). Patients with MRSA were recruited if treatment with glycopeptides had failed. Of 11 patients with MRSA infection, four were cured, six failed treatment and one was indeterminate. Of nine patients with VRE infection (one patient had both pathogens), five were cured and four failed. Fifteen adverse events in 12 patients were potentially related to the study drug. Sitafloxacin was effective in VRE and some recalcitrant MRSA infections.
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Introduction |
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Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are difficult to treat, particularly if treatment with glycopeptides has failed. Quinupristin–dalfopristin can be used,1 but not for infections with Enterococcus faecalis.
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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A non-comparative phase II trial was performed using sitafloxacin (400 mg iv over 1 h once a day for 7–14 days) for the treatment of serious systemic infection with MRSA or VRE. Sitafloxacin was supplied by Daiichi Pharmaceuticals, London, UK. Patients had bacteraemia with VRE or MRSA or a positive culture at a site with signs and symptoms of infection and three of: temperature
38°C or <36.5°C, respiratory rate >30/min, platelet count <100 x 109/L or white cell count >15 or <5 x 109/L. Patients had to be 18–70 years old and require intravenous antibiotic therapy. The protocol was approved by the North Thames Multicentre Research Ethics Committee and conducted according to Good Clinical Practice. 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, 9–12 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 9–12 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 2–5 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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Of 94 patients considered for entry, 65 were infected with MRSA, 26 with VRE and three with both. Of these, only 19 fulfilled the entry criteria. In 27 patients, glycopeptide treatment had not been used; another 13 were having haemofiltration and in 16 patients local infection criteria were not fulfilled.
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 21–68 years) and weight 68 kg (53–88 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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Previous antibiotic treatment had failed in all but one patient. Two patients had APACHE scores of >20 at entry. SOFA scores remained constant in VRE infections during treatment but those in MRSA infections fell from a median of 3 to 1. All patients received sitafloxacin at a dose of 400 mg by iv infusion once a day for a mean of 7 days (3–14 days) and, except for five patients (four VRE, one MRSA), became afebrile in an average of 5 days (1–12 days).
For MRSA infections, four patients were cured 2–5 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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During treatment, there were declines in creatine phosphokinase, myoglobulin and bilirubin but no other significant changes in haematological or biochemical characteristics. Blood and myoglobulin were present in the urine by the fourth day of treatment in 10 and six patients, respectively, and absent, except for one patient with haematuria, at baseline. Half of these patients still had the abnormalities at 1 month.
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 (0.25–1 mg/L) compared with 0.5 mg/L of vancomycin (0.25–2 mg/L) and 0.5 mg/L of teicoplanin (0.12–4 mg/L). For patients whose infection was cured, the MIC50 of sitafloxacin was 0.5 mg/L (0.25–0.5 mg/L) but for those patients who failed treatment or had an indeterminate outcome the MIC50 was 1 mg/L (0.25–1 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 (1–8 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 1–2 mg/L). No Gram-positive isolates showed reduced susceptibility after treatment.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Sitafloxacin was effective in four of 11 patients with MRSA infection unresponsive to glycopeptides. Vancomycin-resistant enterococci were eliminated in seven of the nine patients; five of the patients were cured clinically. In some cases, VRE infection may have been eliminated by removal of an infected catheter or was self-limiting. A similar cure rate of vancomycin-resistant E. faecium infection has been reported for quinupristin–dalfopristin (68%).1 Rash in four patients and seizures in another were transient and have been observed with other quinolones.
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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This work was supported by a grant from Daiichi Pharmaceuticals Ltd, UK.
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Notes |
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*Corresponding author. Tel: +44-171-380-9516; Fax: +44-171-388-8514; E-mail: peter.wilson{at}uclh.org
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References |
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1 . Moellering, R. C., Linden, P. K., Reinhardt, J., Blumberg, E. A., Bompart, F. & Talbot, G. H. (1999). The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Journal of Antimicrobial Chemotherapy 44, 251–61.
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, 1102–7.
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, 301–7.[Web of Science][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, 170–4.[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, 707–10.[Web of Science][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. 7–19. Springer, Berlin.
7
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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 imipenem–cilastatin. Antimicrobial Agents and Chemotherapy 38, 547–57.
Received 21 January 2000; returned 27 March 2000; revised 15 May 2000; accepted 5 June 2000
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