Pharmacokinetics and peritoneal penetration of moxifloxacin in peritonitis
1 Pharma Research Centre Bayer AG, Wuppertal, Germany 2 Department of General Surgery, Leverkusen General Hospital Leverkusen, Germany
*Corresponding author. Institute of Clinical Pharmacology, Bayer HealthCare AG, Aprather Weg, Building 470, D-42096 Wuppertal, Germany. Tel: +49-202-364289; Fax: +49-202-368180; E-mail: Heino.stass{at}bayerhealthcare.com
Received 3 April 2006; returned 15 May 2006; revised 21 June 2006; accepted 4 July 2006
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Abstract |
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Objectives: To investigate the penetration of moxifloxacin into peritoneal exudate in patients with complicated intra-abdominal infections (cIAIs).
Patients and methods: Patients (n = 10) with evidence of peritonitis who required surgery with drainage of the abdominal cavity received a single intravenous infusion of moxifloxacin, 400 mg, over 1 h. Plasma and peritoneal exudate samples were obtained over 24 h, and moxifloxacin concentrations were measured by HPLC with fluorescence detection.
Results: Plasma moxifloxacin concentrations decreased from a geometric mean of 3.61 mg/L at 1 h to 0.36 mg/L at 24 h. Concentrations in peritoneal exudate were highest 2 h after the start of the infusion, reaching a geometric mean of 3.32 mg/L, and declined to a geometric mean of 0.69 mg/L at 24 h. The exudate/plasma concentration ratio rose from 1.45 at 2 h to 1.91 at 24 h; the 95% confidence intervals for the ratio excluded unity at all time points, suggesting that moxifloxacin penetrates and accumulates in peritoneal exudate. The area under the concentration–time curve (AUC) tended to be greater in exudate; the time to peak concentrations (Tmax) was longer in exudate than in plasma, as were half-life and mean residence time (MRT).
Conclusions: Following intravenous administration, moxifloxacin penetrated peritoneal exudate in patients with peritonitis, achieving and maintaining concentrations that exceed the MICs for pathogens commonly isolated in cIAIs. These findings support the clinical use of moxifloxacin as treatment for cIAIs.
Keywords: ascitic fluid , complicated intra-abdominal infections , peritoneal cavity , tissue distribution
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Introduction |
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Complicated intra-abdominal infections (cIAIs), which extend beyond the hollow viscus of origin into the peritoneal space and are associated with peritonitis or abscess formation, are usually polymicrobial in origin, involving a variety of aerobic and anaerobic pathogens. cIAIs therefore require both surgery or interventional drainage procedures and broad-spectrum, empirical antimicrobial therapy to cover probable pathogens and anticipated resistance patterns. An important factor determining the efficacy of antimicrobial therapy is the ability of the antimicrobial to attain concentrations within the peritoneal cavity that are effective against the mixed aerobic and anaerobic flora found in cIAIs. A knowledge of antimicrobial agent pharmacokinetics and pharmacodynamics is therefore useful in choosing an antimicrobial regimen.
Moxifloxacin (Bayer HealthCare AG, Wuppertal, Germany) is a fluoroquinolone with a broad spectrum of activity that includes both aerobic and anaerobic pathogens commonly isolated in cIAIs.1,2 This agent has previously been shown to be effective in the treatment of experimentally induced abdominal abscesses in animal models caused by Bacteroides fragilis3 and to penetrate gastrointestinal mucosal tissue in humans.4 However, there are currently no data on the ability of moxifloxacin to penetrate abdominal exudates in patients with cIAIs. The current study was therefore performed to investigate the penetration of moxifloxacin into peritoneal exudates in patients with acute peritonitis.
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Patients and methods |
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Patients
Adult patients with clinical or computed tomography evidence of peritonitis who were scheduled for surgery with drainage of the peritoneal cavity were eligible for inclusion. Patients with perforation of the stomach or duodenum operated on within 12 h, or of the small or large bowel operated on within 6 h, were excluded, as were those with acute cholecystitis with infection confined to the gallbladder or early acute or non-perforated appendicitis (unless evidence of peritonitis was present). Other exclusion criteria included known hypersensitivity to quinolones, significant cardiovascular disease, end-stage liver disease (Child-Pugh stage C), patients requiring haemodialysis or peritoneal dialysis or with a creatinine clearance below 30 mL/min/1.73 m2, and a history of drug abuse. Written informed consent was obtained from each patient prior to inclusion in the study.
Study design and protocol
The open, non-randomized, study was conducted at Leverkusen General Hospital, Leverkusen, Germany, in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice Guideline and German drug law. The protocol was approved by the Ethics Committee of the University of Cologne Medical Faculty (No. 03-116).
Patients received a single 400 mg dose of moxifloxacin by intravenous (iv) infusion over 1 h, starting 
2 h before surgery. Blood samples (3 mL) were obtained via an iv cannula contralateral to any infusion lines prior to dosing and at 1, 2, 3, 4, 6, 8, 12, 18 and 24 h after the start of the iv infusion. Plasma was separated by centrifugation and stored at –15°C prior to assay. All samples were analysed within 6 months of receiving them. A perioperative exudate sample was obtained (2 h after the start of the infusion) together with a parallel blood sample; fractional peritoneal exudate samples were then obtained via two drains in the abdominal cavity, located at the site of infection and in the Douglas cavity, at 5–7, 7–9, 9–15, 15–21 and 21–27 h after the start of the infusion. Concentrations of moxifloxacin in plasma and peritoneal exudate were measured by HPLC with fluorescence detection.5 The lower limit of quantification was 0.01 mg/L. Accuracy ranged from 99.4% to 100.5%, and coefficients of variation were between 2.2% and 7.8%.
Safety and tolerability were evaluated by clinical assessments at each blood sampling time, by physical examination and clinical laboratory testing before dosing and at follow-up at 30 days, and by documentation of adverse events reported through non-leading questioning or from spontaneous reports.
Statistics
Based on the known inter-subject variability of moxifloxacin pharmacokinetics in other subjects, 10 study participants were deemed sufficient for the intended descriptive pharmacokinetic analysis. Pharmacokinetic parameters [Cmax, Tmax, AUC0–24, Cmax and AUC normalized by dividing by dose per kg body weight (Cmax, norm and AUC0–24, norm), t1/2, mean residence time (MRT), Vss and CL] of moxifloxacin in plasma and peritoneal exudate were calculated by non-compartmental methods with KINCALC software (Bayer, Leverkusen, Germany). Pharmacokinetic parameters were summarized by descriptive statistics. Because pharmacokinetic parameters and plasma concentration data of moxifloxacin are log-normally distributed, they are presented as geometric means with geometric coefficient of variation (%). The tissue fluid/plasma concentration ratio was analysed by analysis of variance (ANOVA), with factors for time of sample collection. Based on this analysis, point estimates (least squares means) and two-sided 95% confidence intervals for the ratio were calculated by back-transformation of log-transformed data.
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Results |
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Of the 11 patients enrolled in the study, one was excluded from the pharmacokinetic analysis because only plasma samples were obtained. The seven men and three women had a median age of 53.0 years (range, 20.0–78.0 years), a median weight of 88.0 kg (range, 54.0–125.0 kg) and a median BMI of 27.9 kg/m2 (range, 21.6–36.9 kg/m2). The most common diagnosis was perforated appendix (four patients).
Plasma concentrations of moxifloxacin were highest at the end of the 1 h infusion, with a geometric mean of 3.61 mg/L, and decreased progressively during the sampling period, reaching a geometric mean of 0.36 mg/L at 24 h (Figure 1). Concentrations in peritoneal exudate were highest at the first sampling time (1 h after the end of the 1 h infusion), reaching a geometric mean of 3.32 mg/L, and declined to a geometric mean of 0.69 mg/L at 24 h (Figure 1). There was greater inter-subject variability in peritoneal exudate concentrations than in plasma concentrations, as shown by the larger standard deviations. The exudate: plasma concentration ratio rose from 1.45 at 2 h after the start of the infusion to 1.91 at 24 h with the corresponding 95% confidence intervals excluding unity at all time points. Cmax was similar in plasma and exudate, whereas AUC tended to be greater in exudate; Tmax was longer in exudate than in plasma, reflecting the time needed for moxifloxacin to penetrate from the systemic circulation into the peritoneal cavity (Table 1). t1/2 and MRT were also longer in exudate than in plasma.
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A total of 29 adverse events were reported in 9/11 patients, of which 24 were rated as mild or moderate in severity. A relationship to study treatment could not be excluded for three adverse events (pulmonary and ventilatory problems during surgery, and bradycardia with a short period of asystole probably caused by anaesthesia in combination with a manipulation of the peritoneum); otherwise all severe adverse events were unrelated to study treatment. No treatment-related changes in vital signs or clinical laboratory variables were observed.
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Discussion |
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In the present study, following a single 400 mg iv infusion of moxifloxacin, the lower limit of the 95% confidence interval for the exudate:plasma concentration ratio was higher than 1.0 at all time points studied, and t1/2 and MRT were longer in peritoneal exudate than in plasma, indicating that moxifloxacin penetrates and accumulates in peritoneal exudate in patients with cIAIs. This contrasts with trovafloxacin, which generally achieved lower concentrations in peritoneal fluid than in serum after a single iv dose, indicating rather poor penetration of the peritoneal cavity.6
Importantly, throughout the 24 h study period, the moxifloxacin concentrations observed in peritoneal exudate exceeded the in vitro MICs of moxifloxacin for the pathogens commonly isolated in cIAIs, which have been reported as 
1 mg/L for a variety of Gram-positive and Gram-negative organisms isolated from patients with intra-abdominal infections.1 Furthermore, moxifloxacin was effective against 87% of B. fragilis strains isolated from patients with intra-abdominal infections at concentrations 1 mg/L and against 87% of Bacteriodes thetaiotaomicron strains at concentrations 2 mg/L; overall, moxifloxacin was effective against 83% of all isolates at concentrations 2 mg/L.2 These in vitro data suggest, therefore, that the moxifloxacin concentrations achieved in peritoneal exudates are likely to be effective in the polymicrobial environment encountered in cIAIs. This conclusion is supported by the recent finding that moxifloxacin was effective in an in vitro pharmacokinetic-pharmacodynamic model with mixed aerobic (Escherichia coli) and anaerobic (B. fragilis) strains.7
Experimental data showing the effectiveness of moxifloxacin against B. fragilis sepsis3,8 have recently been confirmed in a randomized clinical trial involving 656 patients with cIAIs, in which moxifloxacin was at least as effective as piperacillin/tazobactam, producing clinical cure and bacteriological eradication rates of 82% and 78%, respectively, and was well tolerated.9 The good tolerability profile of moxifloxacin seen in the present study is consistent with the results of a review of safety data from over 53 000 patients receiving oral or iv moxifloxacin.10
In conclusion, the results of the study show that moxifloxacin penetrates peritoneal exudate in patients with cIAIs, achieving and maintaining concentrations higher than the MICs for the common causative pathogens. The present study further confirms that once-daily moxifloxacin, a broad-spectrum antibiotic, has the potential to be an effective therapeutic option for the management of patients with a cIAI.
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H. S., H. D. and D. K. are employees of Bayer. A. D. R. and K.-H. V. declare that they have no conflicts of interest in relation to the study.
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Acknowledgements |
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We would like to thank Dr Uwe Thuss for his support in the bioanalytical part of the study. This study was funded by Bayer HealthCare.
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References |
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1 Edmiston CE, Krepel CJ, Seabrook GR, et al. (2004) In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intra-abdominal and diabetic foot infections. Antimicrob Agents Chemother 48:1012–6.
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Goldstein EJC, Citron DM, Warren YA, et al. (2006) In vitro activity of moxifloxacin against 923 anaerobes isolated from human intra-abdominal infections. Antimicrob Agents Chemother 50:379–81.
3 Thadepalli H, Chuah SK, Gollapudi S. (2004) Therapeutic efficacy of moxifloxacin, a new quinolone, in the treatment of experimental intra-abdominal abscesses induced by Bacteroides fragilis in mice. Chemotherapy 50:76–80.[CrossRef][Web of Science][Medline]
4
Wirtz M, Kleeff J, Swoboda S, et al. (2004) Moxifloxacin penetration into human gastrointestinal tissues. J Antimicrob Chemother 53:875–7.
5 Stass H and Dahloff A. (1997) Determination of BAY 12-8039, a new 8-methoxyquinolone, in human body fluids by high-performance liquid chromatography with fluorescence detection using on-column focusing. J Chromatogr B Biomed Sci Appl 702:163–74.[CrossRef][Medline]
6 Melnik G, Schwesinger WH, Dogolo LC, et al. (1998) Concentrations of trovafloxacin in colonic tissue and peritoneal fluid after intravenous infusion of the prodrug alatrofloxacin in patients undergoing colorectal surgery. Am J Surg 176:Suppl 6A, 14–17S.[CrossRef]
7
Schaumann R, Goldstein EJC, Forberg J, et al. (2005) Activity of moxifloxacin against Bacteroides fragilis and Escherichia coli in an in vitro pharmacokinetic/pharmacodynamic model employing pure and mixed cultures. J Med Microbiol 54:749–53.
8 Cisneros RL and Onderdonk AB. (2005) Efficacy of moxifloxacin monotherapy versus gatifloxacin monotherapy, piperacillin-tazobactam combination therapy, and clindamycin plus gentamicin combination therapy: an experimental study in a rat model of intra-abdominal sepsis induced by fluoroquinolone-resistant Bacteroides fragilis. Curr Ther Res 66:222–9.[CrossRef]
9 Malangoni MA, Song J, Herrington J, et al. (2006) Randomized controlled trial of moxifloxacin compared with piperacillin–tazobactam and amoxicillin–clavulanate for the treatment of complicated intra-abdominal infections. Ann Surg 244: pp. 204–11.[CrossRef][Medline]
10 Ball P, Stahlmann R, Kubin R, et al. (2004) Safety profile of oral and intravenous moxifloxacin: cumulative data from clinical trials and postmarketing studies. Clin Ther 26:940–50.[CrossRef][Web of Science][Medline]
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