Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust and University of Bristol, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK
Sir,
Clinafloxacin, a novel fluoroquinolone which is not yet licensed for clinical use in the UK, exhibits broad-spectrum activity against both Gram-positive and Gram-negative bacteria, including obligate anaerobes.1 The drug is eliminated predominantly by the renal route, but is not cleared by haemodialysis.2 Although dosage adjustments for patients with severe renal impairment are recommended,3 we have been unable to identify advice regarding dosing regimens specifically for patients requiring haemofiltration. We report here our experience of a patient who received clinafloxacin while on continuous veno-venous haemofiltration (CVVH) and the pre- and post-dose serum concentrations of the drug in this patient.
A 66-year-old man was transferred to the intensive care unit at this hospital for management of staphylococcal septicaemia associated with acute hepatic and renal failure. He had presented 2 days earlier at another hospital with increasing pain in his left prosthetic hip joint, fever and generalized myalgia. All six blood cultures taken on admission yielded a methicillin-susceptible strain of Staphylococcus aureus and he was treated with flucloxacillin. Four years earlier he had received antibiotics for an infection of the same prosthetic hip joint caused by a strain of group G ß-haemolytic streptococcus.
The patient was placed on CVVH. He was also mechanically ventilated and required inotropic support. In view of the liver failure, his antibiotic therapy was changed to vancomycin in 1 g stat doses. Several ultrasound scans, including views of the left hip joint, were performed but failed to identify the source of infection. When the patient's liver function stabilized, rifampicin was added to the vancomycin. However, this was followed by a further rise in the serum bilirubin concentration and the rifampicin was discontinued after 3 days. He remained hypotensive and hypoxic and developed diffuse purpura associated with thrombocytopenia. Repeat blood cultures remained sterile, but he continued to deteriorate with signs of persistent sepsis. On day 9, clinafloxacin (provided on a named-patient basis) was added to augment the cover against Gram-positive bacteria and to provide cover against potential Gram-negative and anaerobic pathogens; the S. aureus isolate was shown to be susceptible to clinafloxacin (MIC 0.03 mg/L). A single initial dose of 200 mg was administered by the iv route, followed by 100 mg bd in 1 h infusions, i.e. 50% of the dosage appropriate for patients with normal renal function. Samples of blood were collected immediately before and between 1.5 h and 3 h after each infusion and the concentrations of clinafloxacin were determined (see below). On day 17, in view of multi-organ failure, it was decided that all treatment should be discontinued. A post-mortem examination concluded that the cause of death was renal failure and pneumonia secondary to septicaemia. However, the underlying source of infection was not identified.
Clinafloxacin serum concentrations were measured by high-performance liquid chromatography (HPLC). Briefly, the stationary phase comprised Techsphere 5 C8 (HPLC Technology, Macclesfield, UK) and the mobile phase a mixture of 0.5% phosphoric acid and 10.5% acetonitrile (adjusted to a pH of 4 with tetrabutylammonium hydroxide). Samples were prepared by mixing equal volumes of serum and a solution containing perchloric acid and acetonitrile in a 1:4 ratio. Following centrifugation, 20 µL aliquots of the supernatant were injected on to the column. The pump flow rate was 0.5 mL/min and the retention time of clinafloxacin was approximately 6 min. Detection was by UV absorbance at 380 nm. The mean pre-dose concentration was 1.5 mg/L (s.d., ±0.3 mg/L, range 0.91.9 mg/L) and the mean post-dose concentration was 2 mg/L (s.d., ±0.2 mg/L, range 1.72.5 mg/L). The wide variation in the post-dose concentrations could not be accounted for by variations in the collection times of the samples. On at least three occasions pre- and post-dose concentrations were virtually the samean observation for which we can offer no explanation; all doses of the drug appear to have been administered and the samples were re-assayed in order to confirm the results.
In healthy subjects, clinafloxacin 200 mg bd iv produced steady-state pre- and post-dose serum concentrations of 0.4 mg/L and 2.1 mg/L, respectively.2 Renal clearance accounted for between 50% and 70% of the total clearance.2 For patients with renal impairment (creatinine clearance <40 mL/min), a reduced dosage, as used in the patient described here, has been recommended.3 Clinafloxacin is not cleared by haemodialysis,3 but little is known about its handling in patients undergoing CVVH. As protein binding is relatively high (5060%), clearance by CVVH is therefore expected to be correspondingly low, with total clearance reflecting the residual renal function of the patient. In our patient, serum concentrations were comparable to those observed in healthy volunteers given a standard dosage2 and the mean post-dose concentration was >60-fold greater than the MIC of clinafloxacin for the S. aureus strain that caused his infection. (For levofloxacin, a peak serum concentration to MIC ratio > 12.2 was shown to be associated with successful clinical and microbiological outcomes.4) There was no evidence of accumulation (Figure) and there were no concerns about side-effects, such as hypoglycaemia or phototoxicity.
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Notes
J Antimicrob Chemother 2000; 45: 927928
* Corresponding author. Tel: +44-117-959-5651; Fax: +44-117-959-3154.
References
1 . Cohen, M. A., Huband, M. D., Gage, J. W., Yoder, S. L., Roland, G. E. & Gracheck, S. J. (1997). In-vitro activity of clinafloxacin, trovafloxacin and ciprofloxacin. Journal of Antimicrobial Chemotherapy 40, 20511.[Abstract]
2 . Randinitis, E. J., Brodfuehrer, A. B. & Vassos, A. B. (1998). Pharmacokinetics of clinafloxacin following oral and intravenous single and multiple dosing. In Abstracts of the Sixth International Symposium on New Quinolones, Denver, CO, 1998. Abstract, p. 118.
3 . Randinitis, E. J., Koup, J. R., Rausch, G., Bron, N. J., Hounslow, N. J., Vassos, A. B. et al. (1998). Single-dose clinafloxacin pharmacokinetics in subjects with various degrees of renal function. In Abstracts of the Sixth International Symposium on New Quinolones, Denver, CO, 1998. Abstract, p. 119.
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