¹Department of Clinical Pharmacology, Vienna University Hospital, Vienna, Austria

²Division of Infectious Diseases, Department of Internal Medicine I, Vienna University Hospital, Vienna, Austria

³Clinical Institute of Medical and Chemical Laboratory Diagnostics, Vienna University Hospital, Vienna, Austria

Correspondence to: M Müller, Department of Clinical Pharmacology, Vienna University School of Medicine, Vienna General Hospital¾AKH, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: markus.mueller@univie.ac.at

OBJECTIVE: To investigate whether weight adjusted ciprofloxacin dosing results in comparable target site concentrations in obese and lean subjects.

DESIGN: Comparative study in two populations.

SUBJECTS: Twelve obese subjects (mean weight 122±22.6 kg, 28-52 y, male : female ratio 4 : 8) and 12 age- and sex-matched lean controls (mean weight 59±8.6 kg).

METHODS: Sampling of interstitial space fluid by means of calibrated in vivo microdialysis after a weight-adjusted intravenous bolus dose of 2.85 mg/kg ciprofloxacin. Analysis of drug concentration by high pressure liquid chromatography.

RESULTS: We found significantly higher peak and trough levels of ciprofloxacin in plasma for obese subjects (9.97±5.64 and 0.44±0.10 µg/ml vs 2.59±1.06 and 0.19±0.09 µg/ml in lean subjects, P<0.05), while concentration-time curves of interstitial fluid of muscle and subcutaneous fat did not differ between the groups. Tissue penetration, expressed as AUC_tissue/AUC_plasma ratio was significantly lower in obese subjects (0.45±0.27 vs 0.82±0.36, P<0.01).

CONCLUSION: We conclude that the penetration process into the interstitial space fluid is impaired in obese subjects. Therefore antibiotic doses need not be adjusted for an increase in fat/water ratio. Weight-adjusted dosing based on actual body weight will yield adequate tissue levels for ciprofloxacin.

International Journal of Obesity (2001) 25, 354-358

obesity; microdialysis; free interstitial concentration; ciprofloxacin

Introduction

Dose adjustments based on body weight in adults are not routinely employed in clinical practice. While this clearly risks underdosing in overweight or obese patients, there is considerable discrepancy about how to correctly adjust doses. In particular it is not clear whether doses should be based on actual body weight (ABW) or the ideal weight (IBW) of the patient. A review of the English-language literature on antimicrobial pharmacokinetics and dosing in obesity¹ showed that only a limited body of evidence is available on the actual effects of obesity on pharmacokinetics and clinical efficacy of most antimicrobials.

An empirical approach for dose adjustments in obese patients is based on the ideal body weight of the patient, calculated according to the Devine formula,² to which a dosing weight correction factor (DWCF) of 0.3 times the difference between ABW and IBW is added, since approximately 30% of adipose tissue is composed of water. Clinical studies suggest a DWCF of approximately 0.40 for aminoglycosides² and 0.45 for quinolones. Other authors recommend a modification of the dosing interval rather than of daily dose for aminoglycosides.³

One important limitation of these approaches is related to the fact that they do not account for the effect of the drug distribution process which might be substantially altered in obesity. As most infectious processes take place in the tissue, concentrations measured at this effect site rather than in plasma will determine the clinical effectivity of an antibiotic. Although target site concentrations were hardly accessible to date, the microdialysis technique recently generated an opportunity to selectively measure the concentration of substances in the interstitial compartment, thus revealing important information on the antibiotic concentration at the anatomical target site.^4,5 This technique provides the possibility of relating dosing regimens to the concentrations in the interstitial compartment of any tissue of interest.

To validate the suitability of ABW-adapted dosing in obese subjects we compared interstitial compartment concentrations of ciprofloxacin in skeletal muscle and subcutaneous adipose tissue of obese and lean subjects after an ABW based bolus dose of ciprofloxacin. We employed microdialysis to selectively measure interstitial fluid concentrations. Ciprofloxacin was chosen as a study drug because of its broad antimicrobial spectrum and excellent tissue penetration making it a frequently used drug in soft tissue infections.

Methods

Subjects

The study was approved by the local ethics committee. All volunteers were given a detailed description of the study, and their written consent was obtained. The study was performed in accordance with the Declaration of Helsinki and the Good Clinical Practice Guideline of the European Commission. Twenty-four healthy, drug-free volunteers, 28-52 y of age were enrolled in the study. Twelve volunteers (eight female and four male) were obese with a body weight of 122±22.6 kg and a body mass index (BMI) of 41.0±7.8. The control group consisted of 12 age- and sex-matched volunteers with normal weight (59±8.6 kg, BMI 19.8±1.4). The ideal body weight, calculated using the Devine formula, was 65 kg in both groups.

Volunteers were confined to bed-rest for the duration of the study. They were placed in a supine position with the chest tilted up for comfort. No activities apart from reading, watching TV and knitting were allowed. Subjects were fasted until 1 h after the bolus injection of ciprofloxacin, after that, breakfast and later lunch were served.

Microdialysis experiments

The principles of microdialysis have been described in detail previously. Microdialysis is based on sampling of analytes from the extracellular space by means of a semipermeable membrane at the tip of a microdialysis probe. In this study, probes were implanted in the middle third of the anterior aspect of the right thigh. The probe is constantly perfused with a physiological solution at a low flow-rate (1.5 µl/min). Once the probe is implanted into the tissue, substances present in the extracellular fluid at concentration (C_tissue) diffuse out of the extracellular fluid into the probe, resulting in a concentration (C_dialysate) in the perfusion medium. Samples are collected and analyzed. For most analytes, equilibrium between extracellular tissue fluid and the perfusion medium is incomplete, therefore C_tissue>C_dialysate. The factor by which the concentrations are interrelated is termed recovery.

Recovery assessment

To obtain interstitial concentrations from dialysate concentrations, recovery was assessed with the retrodialysis method. The principle of this method relies on the assumption that the diffusion process is quantitatively equal in both directions through the semipermeable membrane. Therefore, the study drug was added to the perfusion medium in a concentration of 30 µg/ml and the disappearance rate through the membrane was taken as the in vivo recovery.

In the present study each subject received ciprofloxacin (CiproxinÒ 200 mg Infusionsflasche, Bayer Austria, Vienna, Austria) as a single i.v. dose of 2.85 mg/kg over 20 min and plasma and interstitial fluid were sampled at 20 min intervals for 6 h thereafter.

Analysis

Ciprofloxacin plasma and interstitial tissue levels were measured by high pressure liquid chromatography (HPLC, Shimadzu, Japan) according to a previously described method.⁶

Pharmacokinetic calculations

Data were fitted by a commercially available computer program (Kinetica) using a two-compartment model for plasma values and a one-compartment model for tissue values. The following pharmacokinetic parameters were determined: area under the concentration-time curve (AUC), time to maximum concentration (t_max), maximum concentration (C_max-calc) and mean residence time (MRT), ie the mean time a single molecule resides in a compartment. Penetration ratios for tissues were determined as AUC_tissue/AUC_plasma.

Statistical analysis

For correlations or comparisons between pharmacokinetic parameters of different compartments Mann-Whitney U-tests were employed, as pharmacokinetic parameters were non-normally distributed. P<0.05 was considered the level of significance. Coefficients of variation (CV) were calculated as 100·s.d.·mean^-1.

Results

Plasma pharmacokinetic data

ABW-adjusted doses of ciprofloxacin resulted in C_max-calc-values of 9.97±5.64 µg/ml and 2.59±1.06 µg/ml in obese and lean subjects, respectively (n=24, P<0.05, Figure 1). Mean levels after 6 h were 0.44±0.10 and 0.19±0.09 µg/ml in obese subjects and in controls, respectively (P<0.05). Key pharmacological parameters for plasma data are shown in Table 1.

Pharmacokinetic data in the interstitial space fluid

Mean interstitial space fluid concentration versus time curves are displayed in Figure 1. For interstitial space fluid of skeletal muscle tissue, C_max-calc-values were 2.16±1.92 and 1.72±0.89 µg/ml for obese subjects and controls, respectively (n=24, P=NS). These levels declined to 0.11±0.08 and 0.06±0.04 µg/ml after 6 h. There was no statistical difference in interstitial space fluid concentrations between the two groups. Similar AUC values were obtained for both (2.57±1.38 µg·min/ml in obese subjects and 2.28±0.83 µg·min/ml for lean subjects, P=NS). Tissue penetration, expressed as AUC_tissue/AUC_plasma ratio, was lower in obese subjects (0.45±0.27 vs 0.82±0.36, P<0.01). The C_tissue/C_plasma ratio vs time profile was approximately two-fold lower in obese subjects than in lean controls throughout the entire observation period (Figure 2).

C_max-calc-values in the interstitial fluid of subcutaneous adipose tissue were 3.10±3.29 and 2.12±1.30 µg/ml in obese subjects and in controls, respectively. Ciprofloxacin concentrations at 6 h after infusion of weight-adjusted doses were 0.09±0.06 and 0.05±0.05 µg/ml (P=NS). The AUC was 2.68±1.85 and 2.21±1.59 µg·min/ml for obese and for lean subjects, respectively (P=NS).

Tissue penetration, expressed as AUC_tissue/AUC_plasma ratio, was lower in obese subjects; however, this difference did not reach statistical significance (0.46±0.36 vs 0.85±0.78, P=0.05); see Figure 2.

Discussion

In the present study we set out to compare interstitial tissue levels of ciprofloxacin in healthy obese subjects with those in lean controls. The rationale for measuring interstitial fluid concentrations by microdialysis in skeletal muscle and subcutaneous adipose tissue is based on the fact that obese patients are especially prone to postoperative infectious complications,^7,8 with the majority being wound and soft tissue infections. As most infections do not take place within cells but in the interstitial space fluid of tissue, antibiotic concentrations at this target site will determine the clinical outcome. Interstitial fluid in this study was sampled with microdialysis, a method that allows to selectively collect interstitial space fluid and to determine concentrations that are not confounded by intracellularly accumulating drug. Ciprofloxacin was chosen as a study drug since it is commonly employed for the treatment of soft tissue infections, due to its broad antibacterial spectrum covering most clinically relevant organisms.

The main finding of our study is that interstitial tissue concentrations were not significantly different in obese subjects compared to lean controls. This held true for both tissues studied, ie skeletal muscle and subcutaneous adipose tissue. Accordingly, the AUC values in interstitial fluid did not differ between both study groups.

In plasma, however, we observed AUC values that were significantly higher in obese subjects (see Table 1 and Figure 1). This finding might be of importance as the frequency of gastrointestinal and central nervous system side effects has been linked to ciprofloxacin concentrations. In the present study population, however, no increase in such events was noted.

Despite considerable differences in weight, ie 120 and 60 kg, there was no difference in V_ss between obese and lean subjects, indicating a similar distribution pattern. Interestingly, however, the AUC_tissue/AUC_plasma ratio was significantly lower in obese subjects with penetration ratios of approximately 0.4 and 0.8 for obese and lean subjects, respectively. How could this finding be explained? One explanation may be related to the fact that fat cells in obesity are not only more numerous but predominantly hypertrophic and the reduced penetration surface area to volume ratio, ie a relatively decreased capillary surface area, might account for the difference in the penetration ratios. In addition, our findings are in line with previous data showing that obese individuals exhibit a markedly reduced tissue perfusion^9,10 as well as an impaired endothelium-dependent vasodilation,¹¹ which results in an impaired blood flow to connective tissues. To our knowledge this is the first report showing that target site distribution of antibiotics is substantially affected in obese subjects, probably due to an impaired peripheral blood flow.

To date only few studies have addressed dosing problems in morbidly obese patients and most of them focussed on antibiotics with a narrow therapeutic index such as the aminoglycosides and glycopeptides.^{12,13,14,15,16} Despite considerable variability among the various study populations, consensus dosing weight correction factors (DWCF) for aminoglycosides of 40% of excess body weight (EBW, EBW=TBW-IBW)+IBW are accepted by most clinicians.¹²

Similar DWCF have been proposed for ciprofloxacin. Allard et al measured ciprofloxacin plasma concentrations after a dose of 400 mg in obese and normal subjects.¹⁷ Based on the resulting V_ss they concluded that ciprofloxacin dosing should be based on IBW+45% of EBW. However, given the obesity-specific changes in drug distribution to target tissues, plasma concentrations cannot adequately predict tissue concentrations. As in our study almost identical ciprofloxacin tissue levels were achieved following a dose based on ABW, a DWCF-based adjustment of ciprofloxacin doses could result in comparably low and possibly subtherapeutic interstitial levels.

We therefore conclude that, partly due to an impaired penetration to the target site, ciprofloxacin doses in obese subjects should be based on actual body weight, to achieve the same tissue concentrations as those found in lean subjects. The resulting higher peak plasma levels, however, might pose a risk for increased side effects.

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Figure 1 Concentration versus time profiles for ciprofloxacin in plasma (panel 1), and interstitial fluid of skeletal muscle (panel 2) and subcutaneous adipose tissue (panel 3) in obese (mean weight 122±22.6 kg, n=12, closed up-triangle) and lean (mean weight 59±8.6 kg, n=12, open down-triangles) subjects following single-dose intravenous administration of 2.85 mg/kg ciprofloxacin (means±s.e.). 0-0.3 h represents the time of ciprofloxacin administration.

Figure 2 Tissue penetration expressed as C_tissue/C_plasma ratio in obese (mean weight 122±22.6 kg, n=12, closed up-triangle) and lean subjects (mean weight 59±8.6 kg, n=12, open down-triangles) following single-dose intravenous administration of 2.85 mg/kg ciprofloxacin (means±s.e.: drug administration 0-0.3 h).

Table 1 Pharmacokinetic parameters for the plasma compartment after intravenous administration of 2.85 mg/kg of ciprofloxacin in obese (n=12) and normal-weight subjects (n=12)