JAC Advance Access originally published online on May 30, 2006
Journal of Antimicrobial Chemotherapy 2006 58(2):380-386; doi:10.1093/jac/dkl226
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Which reliable pharmacodynamic breakpoint should be advised for ciprofloxacin monotherapy in the hospital setting? A TDM-based retrospective perspective
1 Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine 33100 Udine, Italy 2 Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine Udine, Italy
*Corresponding author. Tel/Fax: +39-0432-559833; E-mail: federico.pea{at}med.uniud.it
Received 8 July 2005; returned 2 February 2006; revised 8 May 2006; accepted 9 May 2006
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Abstract |
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Objectives: To define in critically ill patients receiving intravenous (iv) ciprofloxacin (200 mg or 400 mg twice daily) and undergoing routine therapeutic drug monitoring (TDM) the interindividual pharmacokinetic variability and the reliable pharmacodynamic breakpoint enabled by these fixed dosing regimens according to the PK/PD principles and to the pattern of susceptibility to this antibiotic.
Methods: Ciprofloxacin plasma concentrations [trough (Cmin) and 30 min post-dose peak (Cmax) levels] were analysed by means of an HPLC method. Optimal pharmacodynamic exposure was assessed by estimating the theoretical pharmacodynamic breakpoints (PD BP) for either Cmax or AUC.
Results: The final database included 177 sets of Cmin and Cmax performed in 89 patients (200 mg twice daily group, n = 68; 400 mg twice daily group, n = 21). A very wide interindividual scatter of results was observed for both the 200 mg group and the 400 mg group. Interestingly, for both groups only moderate log-linear relationships between estimated renal function (CLCR) on one hand and either Cmin (r2 = 0.08, 0.28) or estimated AUC24 (r2 = 0.10, 0.34) on the other hand were found. Median PD BP, respectively, in the 200 mg twice daily group and the 400 mg twice daily group, were 0.16 and 0.28 mg/L for Cmax, and 0.19 and 0.29 mg/L for AUC24.
Conclusions: Lowering ciprofloxacin dosage in the presence of renal failure seems in most cases unnecessary, since drug accumulation occurred only in a few cases. Optimal pharmacodynamic exposure with fixed 200 or 400 mg twice daily regimens of ciprofloxacin may be ensured only against fully susceptible microorganisms with an MIC < 0.3 mg/L. This supports the use of higher dosages in critically ill hospitalized patients, whereas the wide unpredictable interindividual pharmacokinetic variability suggests the usefulness of TDM with the intent of optimizing efficacy with ciprofloxacin therapy.
Keywords: fluoroquinolones , pharmacokinetics , critically ill patients
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Introduction |
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Timely and appropriate antimicrobial treatment is required with the intent of enhancing the likelihood of a good clinical outcome, of preventing the spread of antibacterial resistance and of containing the economic impact of infections.
Although the efficacy of the antibiotic therapy firstly depends on the appropriateness of spectrum of activity and on microorganisms' susceptibility, this may not suffice for cure whenever an inappropriate dosing regimen has been chosen.1,2 In addition, it should not be overlooked that underexposure may result in increasing the risk for spreading of resistance.3
In the past years the pharmacokinetic–pharmacodynamic (PK/PD) relationships were shown to represent the bases for effective antibiotic therapy, highlighting that for antibiotics with concentration-dependent antibacterial activity, such as fluoroquinolones, the two most relevant determinants for clinical cure and prevention of widespread resistance are the Cmax/MIC and AUC24/MIC ratios.4–7 Forrest et al.8 firstly demonstrated that in patients with lower respiratory tract infections treated with ciprofloxacin optimal clinical cure and bacterial eradication rates against Gram-negative pathogens were achieved when the AUC24/MIC ratio was >100–125. Likewise, a Cmax/MIC ratio > 10–12 was shown to be the most important pharmacodynamic determinant in preventing the spread of resistance of Gram-negative pathogens to fluoroquinolones.4,9
Although presently the recommended dose of ciprofloxacin for critically ill patients is 400 mg thrice daily, in the past decade the 200 mg or the 400 mg twice daily regimens were the two most frequently prescribed.8,10–12
The present retrospective observational study has been conducted in critically ill patients receiving intravenous (iv) 200 or 400 mg twice daily ciprofloxacin dosages at the commencement of therapy and undergoing routine therapeutic drug monitoring (TDM). The aim was to assess the interindividual pharmacokinetic variability of ciprofloxacin and to identify the reliable pharmacodynamic breakpoint enabled by these fixed dosing regimens according to the PK/PD principles and the pattern of susceptibility to this antibiotic.
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Study design
Plasma TDM of ciprofloxacin carried out in the period between January 1996 and December 2001 at the Institute of Clinical Pharmacology and Toxicology, University of Udine, represented the starting database. Patients undergoing TDM of ciprofloxacin and included in this retrospective observational study were severely ill patients admitted in intensive care units or respiratory or surgical wards who were treated because of a documented or suspected acute bacterial infection with an iv regimen including ciprofloxacin at a twice daily dosage of 200 or 400 mg at the clinician's discretion. To enable appropriate comparison between groups while receiving these fixed iv regimens of ciprofloxacin, only the TDM carried out before application of TDM-guided dosage adjustments were considered in the analysis. Investigated pharmacokinetic parameters at steady-state included trough plasma concentration (Cmin), peak plasma concentration (Cmax) and estimated daily area under the plasma concentration–time curve (AUC24). Cmin and Cmax samples were always collected in relation to the morning dose of ciprofloxacin. Cmax was detected in the post-distribution phase, that is 30 min after ending the 1 h iv infusion. Only patients having at least one complete set of Cmin and Cmax drawn at steady-state were included. A rough estimation of the steady-state area under the concentration–time curve during a dosing interval (AUC0–
) was performed using the trapezoidal rule over one Cmax and two Cmin (before administration and after 12 h); estimated daily AUC (AUC24) was then calculated as AUC0– x 2. Patients who had undetectable troughs were included in the AUC calculations assuming that Cmin was very near to 0 (0.001 mg/L). Although this approach may have caused some inaccuracy in the assessment of both true Cmax and AUC, as far as AUC is concerned, the underestimation related to the distribution phase may have been balanced by some degree of overestimation in relation to the elimination phase. Since patients received standard ciprofloxacin dosages, to avoid bias due to interindividual differences in body weight, the dose-related pharmacokinetic parameters (Cmin, Cmax and AUC0–) were also normalized with respect to ciprofloxacin dose per kg and subsequently to a 1 mg/kg ciprofloxacin every 12 h dose. Creatinine clearance (CLCR) was estimated by means of Cockcroft and Gault formula considering actual body weight.13
HPLC analysis
Total plasma concentrations of ciprofloxacin were analysed by means of the HPLC method proposed by Mack.14 The between-run coefficient of variation of the assay at the low and high levels of the calibration range was 5.4% and 6.1%, respectively. The lower limit of detection was 0.05 mg/L.
Assessment of pharmacodynamics
In order to assess the appropriateness of the fixed dosing regimen in ensuring optimal pharmacodynamic exposure, the so-called theoretical pharmacodynamic breakpoints (PD BP) were calculated.15 Considering that Cmax/MIC of 10 and AUC/MIC of 125 were shown to be valid thresholds for ensuring optimal exposure with fluoroquinolones, either to prevent the selection of resistant strains or to obtain clinical and microbiological cure against Gram-negative pathogens,8,9,16 the PD BP were estimated, according to the patients' observed Cmax and estimated AUC24, by means of these formulae: PD BP for Cmax = Cmax/10; PD BP for AUC = AUC24/125.
Statistical analysis
The Kolmogorov–Smirnov test was performed to assess whether data were normally or non-normally distributed. Accordingly, descriptive data were expressed as mean ± SD or as median and range. Statistical analysis comparing data between groups was performed using a parametric (unpaired Student's t-test) and a non-parametric test (Mann–Whitney Rank Sum Test) for normally and non-normally distributed data, respectively, by means of SigmaStat software (SPSS Science Software GmbH, Erkrath, Germany). A value of P < 0.05 denoted statistical significance.
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Results |
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The starting database was represented by 248 sets of Cmin and Cmax plasma samples collected in 109 patients. Out of these 248 sets 71 were excluded because of incomplete collection of Cmin–Cmax set and/or of inappropriate collection time. The final database included 177 sets of Cmin and Cmax performed in 89 patients, 128 of which were measured in patients receiving the 200 mg twice daily dosing regimen (200 mg twice daily group, n = 68) and the other 49 in patients receiving the 400 mg twice daily dosing regimen (400 mg twice daily group, n = 21) (Table 1). Median TDM sets per patient in the 200 mg and the 400 mg twice daily groups were 1 and 2, respectively. Looking at patients' characteristics, whereas no significant difference in mean body weight was observed between the two groups, estimated CLCR was significantly lower in the 200 mg twice daily group than in the 400 mg twice daily group (median value, 57.43 versus 107.78 mL/min, P = 0.002), the percentages of cases presenting with CLCR < 30 mL/min being 27% versus 15%, respectively. The pharmacokinetic parameters of ciprofloxacin observed in each study group are reported in Table 2. Median Cmin was significantly lower in the 200 mg twice daily group than in the 400 mg twice daily group (0.30 versus 0.42 mg/L, P = 0.016); in addition, whereas in the 200 mg twice daily group several patients had Cmin< 0.05 mg/L, this was not the case in most of those included in the 400 mg twice daily group. Likewise, both significantly lower Cmax (1.68 versus 2.81 mg/L, P < 0.001) and estimated AUC24 (24.18 versus 37.20 mg/L·h, P < 0.001) were observed in the 200 mg twice daily group. Dose-normalized data showed that for each mg/kg of ciprofloxacin in the 200 mg and the 400 mg twice daily groups, respectively, the median dose-normalized Cmin were 0.10 and 0.07 mg/L; the median dose-normalized Cmax were 0.57 and 0.52 mg/L, whereas the median fractional AUC24 were 4.20 and 3.45 mg/L·h. Box and whiskers plots of plasma Cmin, Cmax and AUC24 of ciprofloxacin according to the estimated renal function are shown in Figure 1.
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Interestingly, for both groups only moderate log-linear relationships between CLCR on one hand and either Cmin (r2 = 0.08, 0.28) or estimated AUC24 (r2 = 0.10, 0.34) on the other hand (Figure 2) were found. Median PD BP (Figure 3), respectively, in the 200 mg twice daily group and in the 400 mg twice daily group were 0.16 and 0.28 mg/L for Cmax, and 0.19 and 0.29 mg/L for AUC24.
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Discussion |
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Our study retrospectively assessed the plasma exposure to ciprofloxacin as a result of routine TDM performed in hospitalized patients treated with a 200 or 400 mg twice daily dosage because of suspected or documented bacterial infections.
The wide interindividual pharmacokinetic variability of ciprofloxacin observed after fixed dosing regimens is in agreement with other authors' findings in severely ill patients.8,12,17 Indeed, although differences in body weight may partially account for this variability and although conflicting opinion on the possible role of sex-related differences of ciprofloxacin pharmacokinetics still exist in the literature,18–20 most authors agree that the multiple routes of clearance of this drug are the most important factors of pharmacokinetic variability. Whereas the renal route and hepatic metabolization account respectively for about 50–60% and 20% of ciprofloxacin elimination in healthy volunteers, significant transintestinal excretion may also occur. Recently, Ramon et al.21 documented that after a single 200 mg iv dose ciprofloxacin peaked at about 4 mg/L in the small bowel of patients undergoing intestinal surgery due to transepithelial intestinal excretion. Additionally, some of the observed pharmacokinetic variability of Cmax and AUC24 might have been related to the changes of volume of distribution that may sometimes occur in critically ill patients as a consequence of variations in the extracellular fluid contents, although this mechanism is expected to be less relevant for lipophilic antimicrobials.22
Interestingly, the 200 mg twice daily group included more patients and had more TDM performed in comparison with the 400 mg twice daily group. This might have been the consequence of the fact that in the 200 mg twice daily group more patients presented with impaired renal function (27% versus 15% of cases presenting with CLCR < 30 mL/min), this possibly representing a major issue for clinicians both in reducing the daily dosage and in performing TDM with the intent of preventing toxicity. However, from our findings lowering ciprofloxacin dosage in the presence of renal failure seems in most cases unnecessary, since dose-normalized data suggest no difference between groups in terms of systemic exposure per each administered mg/kg of ciprofloxacin. Additionally, only in a few cases was renal failure associated with drug accumulation, consistent with the finding of a mild to moderate log-linear relationship between ciprofloxacin plasma exposure and estimated CLCR.
Indeed, several authors documented that in patients with renal failure the decrease in ciprofloxacin total renal clearance was less pronounced than expected from CLCR values,23–25 and more recently other authors suggested that no significant accumulation of ciprofloxacin at either the 200 mg twice daily or the 400 mg twice daily dosage may be anticipated in patients with renal failure.12,26 Actually, this is consistent with transepithelial elimination being a compensatory mechanism that increases in the presence of renal failure, thus preventing drug accumulation. In experimental animal models intestinal elimination of ciprofloxacin following iv administration in nephrectomized rats was shown to compensate partially for the defective renal clearance, since no significant plasma drug accumulation occurred in comparison with the control.27 Additionally, Jones et al.12 in critically ill patients receiving iv ciprofloxacin at 400 mg twice daily highlighted that significantly higher serum concentrations were observed only when renal failure was associated with either bowel or liver pathology, suggesting that ciprofloxacin accumulation should occur only when at least two elimination pathways are compromised. Accordingly, they recommended that in patients with severe sepsis and impaired renal function ciprofloxacin dosage should be reduced only when in the presence of concomitant intra-abdominal disease.
The observed wide interindividual variation in concentrations suggests that the fixed dosing regimens employed may not give predictably high enough in vivo concentrations of ciprofloxacin to effectively treat the pathogens by which critically ill patients may be infected. Among the possible solutions to this, use of higher daily doses, combination therapy with an agent from another class, institution of a TDM programme and any combination of these seem the most interesting. Indeed, a weighted approach could be pursued according to the pattern of susceptibility of the involved pathogens.
As far as dosage increase is concerned, interestingly, our pharmacodynamic analysis suggested that the fixed dosage regimens of 200 or 400 mg twice daily might predict optimal pharmacodynamic exposure to ciprofloxacin in severely ill hospitalized patients, in terms of Cmax/MIC and/or of AUC24/MIC, only against microorganisms showing an MIC < 0.3 mg/L, namely a value far below either the MIC90 documented for several clinical bacterial isolates tested in a recent multicentre Italian study28 or the Clinical and Laboratory Standards Institute (CLSI) breakpoint of 1–2 mg/L. Likewise, in a recent Monte-Carlo simulation study the typical 400 mg twice daily iv ciprofloxacin dosage was estimated to ensure optimal pharmacodynamic target attainment against as much as 80–85% of the Enterobacteriaceae, but only 41–46% of A. baumannii and 53–59% of Pseudomonas aeruginosa.29 Consistently, increasing the dose to 400 mg thrice daily must be considered a suitable option for less susceptible pathogens with MICs of 0.25–0.5 mg/L, as recently confirmed specifically for P. aeruginosa.30
Conversely, co-treatment with a ß-lactam may be a more effective option especially in the presence of borderline susceptible pathogens (MICs of 1–2 mg/L). In a recent in vitro pharmacokinetic model the potential of a fluoroquinolone/ß-lactam combination at simulated human doses to prevent the emergence of resistance during treatment of P. aeruginosa infection was assessed.31 Although with levofloxacin and imipenem alone after an initial rapid killing a rapid regrowth was observed as a result of the selection of resistant subpopulations, the combination of the two drugs rapidly eradicated all the tested P. aeruginosa strains. These data suggest that a fluoroquinolone and a ß-lactam may be an effective combination for preventing the emergence of resistant P. aeruginosa strains.
Finally, the large and unpredictable interindividual pharmacokinetic variability corroborates our previous observations in patients with lower respiratory tract infections suggesting that TDM may be a useful tool with the intent of tailoring therapy with ciprofloxacin in each single patient.32 Indeed, although the high therapeutic index of fluoroquinolones may not warrant TDM for toxicological reasons, it should be highlighted that the frequent observation of higher than expected drug clearance led us to increase the administered daily dosage of ciprofloxacin in most patients with impaired renal function with the intent of achieving therapeutically effective concentrations.
In conclusion, the wide unpredictable interindividual pharmacokinetic variability coupled with the poor and variable Cmax/MIC and AUC24/MIC ratios confirms the need for appropriate interventions to optimize the efficacy of ciprofloxacin therapy in critically ill hospitalized patients. This could be pursued mainly by administering higher daily dosages, eventually supported by TDM for dosage individualization, bearing in mind that lowering ciprofloxacin dosage in the presence of renal failure seems in most cases unnecessary. Additionally, the helpfulness of combination therapy with a ß-lactam in the presence of borderline susceptible microorganisms with the intent of improving efficacy and preventing resistance merits further investigations.
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P. V. has received funds for research from Bayer. All other authors: none to declare.
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No financial support.
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