Optimising ciprofloxacin dosing in intensive care patients based on pharmacodynamic target attainment
Dalia Khachman (1,2), Jean-Marie Conil (3,4), Bernard Georges (3,4), Sylvie Saivin (2,4), Georges Houin (2), Pierre-Louis Toutain (1) and Celine M. Laffont (1)
(1) INRA, UMR 1331, ToxAlim, F-31027 Toulouse, France. Université de Toulouse, INPT, ENVT, UPS, EIP, F-31076, France; (2) Laboratoire de Pharmacocinétique et Toxicologie Clinique, Hôpital Purpan, Institut Fédératif de Biologie, Toulouse, France; (3) Pôle d’Anesthésie-Réanimation, Hôpital Rangueil, Toulouse, France; (4) GRCB 48, IFR 150 Institut Fédératif de Recherche Biomédicale de Toulouse, Université Paul Sabatier, Toulouse, France.
Objectives: The objective was to explore different dosage regimens of ciprofloxacin for the treatment of Intensive Care Unit (ICU) patients against the main Gram-negative pathogens of interest, in order to maximise clinical efficacy while minimising the risk of bacterial resistance.
Methods: A number of ciprofloxacin dosage regimens were investigated for each pathogen within the limit of 2400 mg/day. Targets to achieve were: free AUC24h/MIC ≥90h as a predictor of clinical outcome [1] and TMSW ≤20% as a predictor of selecting resistance [2], where MIC is the minimum inhibitory concentration and TMSW the time spent within the mutant selection window over 24 h. Ciprofloxacin AUC and TMSW were simulated for 10,000 patients using a previous population pharmacokinetic model for ciprofloxacin developed in 102 ICU patients from the University Hospital of Toulouse-Rangueil, France, and including creatinine clearance as a covariate [3]. Here, creatinine clearance was assumed to follow a uniform distribution over [30;120] mL/min and the unbound fraction of ciprofloxacin to follow a uniform distribution over [0.6;0.8] [4]. Two simulations trials were conducted: Trial 1 took into account the whole MIC distribution for each causative pathogen in line with empirical antibiotherapy; Trial 2 used the MIC breakpoints established by the French antibiogram committee in order to treat the "worst-case" scenario. In both trials, mutant prevention concentrations (MPC) were simulated assuming a uniform distribution of the MPC/MIC ratio over [4;16] [5-7].
Results: Trial 1 showed that for P. aeruginosa and A. baumannii, the common dosage regimens of 400 mg q12h and 400 mg q8h did not achieve the desired target attainment rates (TAR) with respect to TMSW, while suboptimal TAR were found for AUC24h/MIC. Increasing the daily dose did not allow a major improvement of TAR. Trial 2 showed that ≤18% of patients reached the target of TMSW ≤20% for MIC breakpoints of 0.5 and 1 mg/L, regardless of the administered dose.
Conclusions: Based on the mutant selection window concept, our simulations question the use of ciprofloxacin for the treatment of A. baumannii and P. aeruginosa infections in ICU patients due to the potential for developing resistance. They also suggest that the breakpoints of antibiograms should be used with caution and should probably be revised.
References:
[1] Forrest A, Nix DE, Ballow CH et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993;37:1073-81.
[2] Firsov AA, Vostrov SN, Lubenko IY et al. In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus. Antimicrob Agents Chemother 2003;47:1604-13.
[3] Khachman D, Conil J-M, Georges B et al. Population pharmacokinetic analysis of ciprofloxacin in intensive care unit adult patients. 19th PAGE, Berlin: June 2010; abstr 1888 (http://www.page-meeting.org/default.asp?abstract=1888).
[4] Bergogne-Bérézin E. Clinical role of protein binding of quinolones. Clin Pharmacokinet 2002;41:741-50.
[5] Aubert G, Carricajo A, Fonsale N et al. Optimization of the use of ciprofloxacin. Pathol Biol (Paris) 2009;57:236-9.
[6] Hansen GT, Zhao X, Drlica K et al. Mutant prevention concentration 654 for ciprofloxacin and levofloxacin with Pseudomonas aeruginosa. Int J Antimicrob Agents 2006;27:120-4.
[7] Marcusson LL, Olofsson SK, Komp Lindgren P et al. Mutant prevention concentrations of ciprofloxacin for urinary tract infection isolates of Escherichia coli. J Antimicrob Chemother 2005;55:938-43.
Acknowledgment: Dalia Khachman was supported by a doctoral scholarship from the Lebanese National Council for Scientific Research (Beirut, Lebanon).
