Department of Surgery, Divisions of Trauma, Burns and Surgical Critical Care, University of Miami School of Medicine, PO Box 016960 (D-40) Miami, FL 33101, USA
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Abstract |
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Introduction |
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The bacterial kill produced by the quinolones is considered to be concentration dependent, and both Cmax (maximum concentration)/MIC (minimum inhibitory concentration) and AUC (area under the curve)/MIC ratios have been identified as predictors of clinical and microbiological outcome.4 High concentrations of ciprofloxacin, well above the MIC for most Gram-negative and Gram-positive aerobic bacteria, are reached in the skin and skin structures, suggesting that ciprofloxacin can be useful in the treatment of soft tissue infections.5 The ciprofloxacin concentrations obtained in inflammatory blisters, which are well above serum values6 and high penetration into skin blister fluid7 suggest that ciprofloxacin might penetrate into burned tissue.
It was decided to investigate the hypothesis that intravenously administered ciprofloxacin could reach adequate concentrations in serum and burn eschar in critically ill patients with burns. The pharmacokinetics of intravenous ciprofloxacin in patients sustaining major thermal injuries was studied, and the relationship between ciprofloxacin serum levels attained and concentration of the drug reaching the burn eschar was determined.
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Materials and methods |
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Ciprofloxacin (Bayer Corp., Pharmaceutical Division, West Haven, CT, USA) 400 mg was administered intravenously during the immediate post-burn period (within 72 h post-burn), and then every 12 h for a total of three doses. A 200 mL dilution (5% dextrose in water) was prepared and administered through a rate control device over 1 h.
Subjects
Prior approval for this protocol was obtained from the University of Miami School of Medicine Investigational Review Board and written informed consent was obtained for 12 patients. Subjects were included in the study on their first admission if they were at least 18 years of age, and had sustained second or third degree burns of more than 20% of their body surface area. Subjects were excluded from the study for any of the following reasons: (i) a history of hypersensitivity to quinolones, carbapenems or multivitamins; (ii) pregnant or lactating women; (iii) receipt of ciprofloxacin within 1 week of this study; (iv) receipt of another investigational drug within 30 days before drug administration; (v) renal impairment indicated by creatinine greater than 3.0 mg/dL or creatinine clearance less than 40 mL/min; (vi) significant liver dysfunction defined as total bilirubin greater than 3 mg%; (vii) granulocytopenia with granulocytes less than 1 x 109 cells/mL; (viii) history of a seizure disorder. Data regarding the subject's age, weight, pre-existing medical condition, total body surface area burn, infectious complications, multiple organ dysfunction syndrome (MODS) and acute physiology and chronic health evaluation (APACHE II) scores were recorded.
Patients developing clinical sepsis or SIRS (systemic inflammatory response syndrome) following their initial pharmacokinetic study underwent a second infusion of three doses of intravenous ciprofloxacin, blood sampling and burn eschar biopsies. SIRS was defined as the clinical picture of sepsis, with two or more of the following: temperature >38°C or <36°C; pulse >90 beats/min; respiratory rate >20 breaths/min or PaO2 <32 torr; WBC >12 x 109/L or <4 x 109/L or >10% immature (band) forms.8
Serum sampling
A 2 mL sample of blood was collected for drug assay from an existing arterial catheter before administration of the drug (baseline) and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0 and 12.0 h after doses one and three. Within 2 h of phlebotomy, samples were centrifuged (30 min at 3000 rpm) and the supernatant placed in cryogenic vials and stored in liquid nitrogen.
Tissue sampling
Biopsies (1 cm3) of the burn eschar were obtained at the time of surgery with a scalpel from two different burned sites, within 12 h of administration of the third dose of ciprofloxacin. These concentrations were averaged. For the purpose of determining the amount of ciprofloxacin reaching the burn eschar, these were placed in cryogenic vials and stored in liquid nitrogen. Serum and tissue samples were shipped on dry ice to Bayer Corporation for drug assay.
Assay
Ciprofloxacin assay was performed (Bayer Corporation, Pharmaceutical Division, Clinical Pharmacology Laboratory, West Haven, CT, USA). Serum and eschar concentrations were determined by high-performance liquid chromatography (HPLC).9 Each 0.5 mL aliquot of the serum or tissue samples was diluted with 0.1 mL of a 0.02 mg/mL solution of internal standard in 0.1 M phosphoric acid and 0.3 mL of 5.0 M trichloroacetic acidacetonitrile (1:1, v:v) solution. The mixture was vortexed and centrifuged for 15 min at 2800 rpm (1500g). The supernatant was transferred with a Pasteur pipette into a glass autosampler vial for HPLC analysis. Quantifications of ciprofloxacin and ciprofloxacin metabolite concentrations were based on the relative peak height response ratios of each compound and the internal standard.
Pharmacokinetic analysis
Pharmacokinetic variables were determined using non-compartmental models. Maximum serum concentrations and time to maximum serum concentration were determined directly from the serum concentrationtime curve derived from the data observed following the first and last dose (steady state). The area under the curve value for each dose interval was determined by the log-linear trapezoidal method.
Statistical analysis
Values are mean ± standard error of the mean (s.e.m.). Between-group statistical analysis was performed by analysis of variance (Anova), using a statistical software package (Statistica, Statsoft Inc., Tulsa, OK, USA). Least square linear regression analysis was used to assess correlation between burn eschar and serum concentrations. The strength of the linear relationship between variables is given by r2 values. Comparisons between straight-line regressions were performed by two-sided Student's t test and statistical significance was determined by P < 0.05.
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Results |
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Mean maximum serum concentration (Cmax) (mg/L) for dose 1 (Cmax1) and dose 3 (Cmax3), area under the serum concentration versus time curve (AUC) (mg.h/L) from t = 0 to 12 h (AUC012), t = 2436 h (AUC2436) and eschar concentrations (µg/g) during 72 h post-burn and clinical sepsis are listed in Table I. A moderate variability in pharmacokinetic parameters was observed for Cmax (range 2.711.4 mg/L) and AUC (range 7.232.1 mg.h/L) during the post-burn period and during clinical sepsis. Ciprofloxacin serum concentrations during 72 h post-burn after dose 1 (Cmax1 = 4.8 ± 3 mg/L and AUC012 = 12.5 ± 7 mg.h/L) and dose 3 (Cmax3 = 4.9 ± 2 mg/L and AUC2436 = 17.5 ± 11 mg.h/L) were comparable to those of normal volunteers.10 Similar serum concentrations were obtained during clinical sepsis after dose 1 (Cmax1 = 4.2 ± 0.2 mg/L and AUC012 = 15.1 ± 3 mg.h/L) and dose 3 (Cmax3 = 5.0 ± 1 mg/L and AUC2436 = 22.8 ± 9 mg.h/L; 41.3 ± 54 µg/g) (see Figure 1
). Rarely however, were Cmax or AUC values less than those found in normal volunteers. Variability in eschar concentrations was also noted (range 3.8103.5 µg/g) in both groups. Mean burn eschar concentration during clinical sepsis was significantly higher than that found at 72 h post-burn (41.3 ± 54 compared with 18 ± 17 µg/g; P < 0.05 by t test). A positive correlation between burn eschar concentrations and Cmax (r = 0.71, r2 = 0.51, P = 0.01) was found by linear regression analysis. Straight-line regressions are shown in Figure 3
. A Cmax/MIC ratio > 10 for an assumed MIC = 0.5 mg/L and an AUC/MIC ratio > 100 SIT1.h (serum inhibitory titre) for an assumed MIC = 0.125 mg/L were achieved (Tables II and III
).
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Discussion |
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It is known that major thermal injury can result in increased clearance of antibiotics that are primarily excreted by the kidney and decreased clearance of antibiotics undergoing significant hepatic oxidation.3 Therefore, antibiotic dosing adjustments are usually required after major burns because of the pharmacokinetic alteration that occurs in this setting. Clinical trials for ceftazidime, ticarcillin, piperacillin and aztreonam have demonstrated increases in volumes of distribution and decreases in maximum concentrations of antibiotics achieved.11
A study in normal volunteers demonstrated ciprofloxacin Cmax and AUC values, after a 400 mg iv dose, similar to the corresponding values observed in our study: Cmax = 4.0 ± 0.6 mg/L and AUC = 11.4 ± 1.6 mg.h/L.10 Garrelts et al. evaluated prospectively the pharmacokinetics of ciprofloxacin in eight burn patients with active infections. Each patient received a 400 mg iv dose of ciprofloxacin every 8 h.12 They observed a highly variable and increased clearance of the drug. Although this study suggested a more frequent dosage regimen and was performed after the resuscitative phase (mean 8 days) following burn injury, pharmacokinetic parameters (Cmax = 4.2 ± 1 mg/L and AUC = 20.7 ± 17 mg.h/L) were similar to those found in the present investigation.
Evaluations of penetration of burned tissue have been described only for gentamicin13 and tobramycin.14 These studies suggested that a concentration of aminoglycoside sufficient to prevent proliferation of organisms cultured from the eschar was obtained and that eradication of organisms was due to concentrations achievable at this site. Ristuccia et al. found a positive correlation between gentamicin burn tissue concentrations and AUC.14 Burn eschar concentrations and Cmax3 and AUC2436 values correlated in this study despite some variability in eschar and serum concentrations.
High ciprofloxacin concentrations were reached in the burn eschar in this study, which were higher than those measured in the serum (Cmax). This finding may be attributable to the large volume of distribution of ciprofloxacin after intravenous dosing and the two-compartment model, which reflects penetration of the drug into most tissues including the burn eschar.15 Variability in eschar concentrations may reflect viability of tissue sampled as well as biopsy depth. Although there are few previous data, our findings are comparable with studies by Bergan, where the total ciprofloxacin concentration for inflammatory blisters was 120% of the serum values6 and with studies demonstrating that penetration of ciprofloxacin into skin blister fluid can be as high as 96%.7
Pharmacokinetic and burn eschar values in septic patients were similar to those in non-septic patients. The low number of patients and inter-subject variation mean that no definitive statements about this subgroup can be made. Quinolones have been shown to exhibit concentration-dependent killing for Gram-negative organisms. Studies have demonstrated that Cmax/MIC and AUC/MIC ratios are important predictors of bacterial killing for these antimicrobial agents. Area under the inhibitory concentrationtime curve (AUIC24) (i.e. AUC24/MIC) is a useful parameter for describing efficacy of these agents, while an adequate peak concentration/MIC ratio seems necessary to prevent selection of resistant organisms.4 Investigators have suggested that those AUC24/MIC ratios of 100125 SIT1.h and Cmax/MIC ratios of
10:1 predict clinical and microbiological success.16 In this study, a Cmax/MIC ratio
10 for an assumed MIC = 0.5 and an AUC/MIC ratio
100 SIT1h for an assumed MIC = 0.125 mg/L were achieved. MICs were chosen as representative values for organisms encountered when treating infections in critically ill burn patients. These data, in addition to the fact that excellent eschar penetration was found, suggest that therapeutic ciprofloxacin serum concentrations can be achieved in critically ill burned patients.
There were some limitations in our study: first, MIC susceptibility testing for pathogens isolated from burn eschar was not performed. Instead representative MICs were considered. Secondly, there was some potential variation in the amount of viable tissue included in each biopsy, as well as the time interval between dose three and biopsy, and lastly, there was heterogeneity in age, total body surface, weight, burn size and intravenous fluids required for resuscitation in this group, which may have contributed to some variability in serum and burn eschar values.
In summary, after recommended doses of intravenous ciprofloxacin, high burn eschar concentrations and similar serum concentrations to those achieved by normal volunteers, are reached in patients sustaining major thermal injuries, in the immediate post-burn period and during clinical sepsis.
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Acknowledgments |
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Notes |
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References |
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Received 28 April 1999; returned 9 August 1999; revised 6 September 1999; accepted 26 October 1999