JAC Advance Access originally published online on March 21, 2006
Journal of Antimicrobial Chemotherapy 2006 57(5):950-954; doi:10.1093/jac/dkl091
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Penetration of moxifloxacin into bone in patients undergoing total knee arthroplasty
1 Department of Experimental Medicine and Biochemical Science, Section of Infectious Diseases, University of Perugia, Perugia, Italy; 2 Department of Gynaecological, Obstetrical and Paediatric Sciences, Section of Paediatry, University of Perugia, Perugia, Italy; 3 Department of Orthopaedics, University of Perugia, Perugia, Italy
* Corresponding author. Tel: +39-075-5784375; Fax: +39-075-5784346; E-mail: mavimoretti{at}yahoo.it
Received 4 March 2005; returned 20 May 2005; revised 28 June 2005; accepted 24 February 2006
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Abstract |
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Objectives: To investigate plasma and bone moxifloxacin concentrations following oral administration of a single or double dose of the drug, in order to consider its potential role in the treatment of osteomyelitis.
Patients and methods: Thirty consecutive patients undergoing total knee arthroplasty were recruited. Three groups, of ten patients each, were formed: group A received moxifloxacin 400 mg orally 2 h (range 1.5–2.5) preoperatively, group B received moxifloxacin 400 mg orally 4 h (range 3.5–4.5) preoperatively and group C received moxifloxacin 400 mg orally 14 h preoperatively, followed by a second dose 2 h (range 1.5–2.5) preoperatively. During surgery, at the time of bone removal, a blood sample and aliquots of cortical and cancellous bone were collected and moxifloxacin concentrations were measured by HPLC.
Results: Mean plasma, cancellous bone and cortical bone concentrations were, respectively: 3.45, 1.89 and 1.43 mg/L for group A; 3.73, 1.81 and 1.56 mg/L for group B; and 6.26, 2.97 and 2.54 mg/L for group C.
Conclusions: These data show a good penetration of moxifloxacin into both cancellous and cortical bone, with concentrations, after double dosing, exceeding the MIC90 for most pathogens involved in osteomyelitis and the clinic susceptibility breakpoint for Mycobacterium tuberculosis.
Keywords: fluoroquinolones , cortical bone , cancellous bone , osteomyelitis
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Introduction |
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Osteomyelitis is a heterogeneous disease as far as its pathophysiology, clinical manifestations and management are concerned. The optimal duration of therapy is still controversial, but many experts advocate a parenteral treatment for at least 6 weeks.1,2
Fluoroquinolones are frequently employed in the management of chronic osteomyelitis with favourable results due to their wide antimicrobial spectrum, good bioavailability and high degree of penetration into peripheral compartments.2–4
Moxifloxacin is a new 8-methoxyquinolone with a broad antibacterial spectrum and improved activity against Gram-positive microorganisms and anaerobes;5–9 it shows an enhanced potency against both methicillin-susceptible and -resistant isolates of Staphylococcus aureus and Staphylococcus epidermidis, when compared with the older fluoroquinolones.10–14
Moreover, moxifloxacin shows a potent activity against Mycobacterium tuberculosis, both for ofloxacin-resistant and ofloxacin-susceptible strains.15,16 Several studies assessed moxifloxacin levels in urine, saliva and various tissues following oral and intravenous drug administration, showing a good distribution in different potential sites of infection; furthermore, serum and tissue concentrations over the MIC90 for the most relevant microorganisms were found.10,17–20 However, penetration of moxifloxacin into bone has never been assessed.
Therefore, we determined plasma and bone moxifloxacin concentrations following oral administration of single or double doses (400 mg every 12 h), in order to evaluate its potential role in the treatment of bone infections, including skeletal tuberculosis.
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Materials and methods |
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Patients
This open, three-armed, non-randomized study was carried out at the Clinic of Infectious Diseases of Perugia University Hospital, Italy. The study was approved by the Ethics Committee of Regione Umbria.
Thirty consecutive patients, 23 women and 7 men, undergoing routine total knee arthroplasty, were enrolled in this study after providing informed consent. Patients were included if they had normal findings after physical examination, ECG and laboratory assessment. Exclusion criteria were: previous history of allergy to fluoroquinolones, history of epilepsy, conditions affecting gastrointestinal absorption of the drug and treatment with quinolones within 2 weeks prior to administration of moxifloxacin.
Drug administration and sample collection
Before fluoroquinolone administration, all patients were under a standard intravenous antimicrobial prophylaxis with teicoplanin. A 400 mg moxifloxacin oral dose was administered by the oral route in a fasting state. No patients received magnesium, calcium, iron or aluminium salts near dosing.
According to the drug regimen the following three study groups (10 patients in each) were constituted: group A, patients receiving moxifloxacin 2 h (range 1.5–2.5) preoperatively; group B, patients receiving moxifloxacin 4 h (range 3.5–4.5) preoperatively; group C, patients receiving moxifloxacin 14 and 2 h (range 1.5–2.5) preoperatively.
Blood samples were collected into heparin-containing tubes before moxifloxacin administration and during surgery at the time of bone removal. Plasma was separated by centrifugation at 1500 g for 10 min at room temperature, transferred into propylene vials and stored at –80°C until analysis. During surgery, bone samples from each patient were also collected, and, after accurately removing any adhering tissue and washing out any residual substances, cancellous and cortical fragments were obtained by dissection and blotted dry of all blood contamination prior to being stored at –80°C until analysis.
Before analysis, in order to convert bone moxifloxacin concentrations from g/kg tissue into mg/L tissue and to compare them with the MICs for the most relevant pathogens, mean bone density was empirically obtained by measuring the volume of distilled water displaced after immersion, in a graduated cylinder, of exactly pre-weighed bone fragments. It resulted in 1.46 and 1.3 kg/L for cancellous and cortical bone, respectively.
HPLC assay procedures and statistical analysis
Total moxifloxacin concentrations in plasma and bone were determined by an isocratic HPLC method, using a Beckman 114M solvent delivery module equipped with a Shimadzu RS-535 fluorescence HPLC monitor (excitation at 295 nm and emission at 510 nm for all analyses). Chromatography was performed at room temperature (
25°C) in a Pinnacle ODS Amine column (3 µm particle size, 150 x 4.5 mm I.D.); a silica guard column (5 µm particle size, 40 x 4.5 mm I.D.) was connected before the injection valve. The mobile phase consisted of an aqueous solution of 0.02 M isopropyl ammonium sulphate, acetonitrile, isopropanol and methanol (820 : 40 : 70 : 100, by vol.). The flow rate was set at a constant value of 0.65 mL/min, and column effluent was continuously recycled for a period necessary for about 500 sample injections without any adverse consequences on the chromatographic baseline. Chromatograms were registered on a Gilson one channel strip chart recorder set at 50 or 20 mV full scale input signal.
The retention time of moxifloxacin was 9 min. No interfering peaks were observed at this interval either in the plasma or in the bone sample chromatographic analyses. Moxifloxacin aqueous and plasma solution calibration curves were linear in the whole operative concentration range (0–6 mg/L). With the recorder input full scale signal set at 20 mV and using a 50 µL injection volume, the lower limit of detection was 0.002 mg/L. The intra- and inter-day coefficients of variation (CV) for plasma were 3.68% (range 2.8–5.0) and 4.45% (range 2.6–6.1), respectively. The intra- and inter-day CV for moxifloxacin aqueous solution were 0.5% (range 0.2–1.0) and 0.8% (range 0.4–1.2), respectively.
Plasma moxifloxacin. Aliquots (100 µL) of plasma were mixed with 1000 µL of a deproteinizing solution, consisting of methanol, water, perchloric acid and phosphoric acid (25 : 25 : 0.5 : 0.05, by vol.) and vortexed for 1–2 min. The resulting suspension was centrifuged at 5000 g for 5 min, obtaining a pellet on the bottom of the tubes and a clear supernatant. The supernatant was thoroughly transferred into a graduated glass container and diluted with the mobile phase up to a final volume of 10 mL. An aliquot of 50 µL of this solution was injected for drug determination. The mean moxifloxacin extraction recovery from plasma was 86.3% (range 84–90%).
Bone moxifloxacin. By means of a surgery scalpel, the cortical and cancellous bone materials were hand minced into 20–30 mg pieces that were suspended in 1 mL of the deproteinizing solution and incubated at 4°C by continuous shaking overnight to ensure the maximal extraction of the bone moxifloxacin. The suspension was centrifuged at 5000 g for 5 min and 50 µL was subjected to HPLC drug determination.
The degree of penetration of moxifloxacin into bone was determined for each study group by calculating the ratio of the drug concentration in bone to the plasma drug concentration.
Statistical analysis was performed by one way analysis of variance (ANOVA test) to determine any significant difference in moxifloxacin concentrations among the three groups (multiple comparison analysis by means of Tukey test). P values of <0.05 were considered significant.
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Results |
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Groups A, B and C were homogeneous according to age, body weight and serum creatinine.
HPLC assay revealed detectable levels of moxifloxacin in all the plasma, cancellous bone and cortical bone samples, but the recovered drug concentrations varied according to the study group. In groups A and B, receiving single moxifloxacin administration, the mean recovered drug concentrations were: 3.45 mg/L (range 1.45–5.03) in plasma, 1.89 mg/L (range 0.43–5.43) in cancellous bone and 1.43 mg/L (range 0.56–3.12) in cortical bone for group A patients; and 3.73 mg/L (range 2.38–4.94) in plasma, 1.81 mg/L (range 1.20–3.08) in cancellous bone and 1.56 mg/L (range 0.82) in cortical bone for group B (Tables 1 and 2). Whereas, in the patients receiving a double dose (group C), the mean recovered concentrations were 6.26 mg/L (range 4.70–7.31) in plasma, 2.97 mg/L (range 1.90–4.67) in cancellous bone and 2.52 mg/L (range 1.3–4.64) in cortical bone (Table 3).
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A statistically significant difference (multiple comparison, Tukey test) in cancellous bone (P = 0.01) and cortical bone (P = 0.015) moxifloxacin concentrations between single (group A and B) and double administration (group C) was observed.
The bone/plasma ratios for the study groups are reported in Table 4. The mean cancellous bone/plasma ratio was 0.52 (range 0.18–1.08) for group A, 0.5 (range 0.27–0.74) for group B and 0.48 (range 0.27–0.68) for group C; the mean cortical bone/plasma ratio was 0.42 (range 0.23–0.95) in group A, 0.42 (range 0.21–0.82) in group B and 0.4 (range 0.09–0.71) in group C. No statistically significant differences were observed among the three groups.
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Finally, no adverse effects related to moxifloxacin administration were reported in any of the three study groups.
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Discussion |
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Osteomyelitis may be an acute or chronic infectious process of bone involving a limited portion (marrow or cortex) of bone that may be localized or diffuse, according to Mader classification.21 It may result from haematogenous dissemination, from a contiguous site of infection following trauma or surgical procedure (such as prosthesis implant), or from surrounding soft tissue infection in the context of vascular insufficiency (i.e. diabetic foot).1
The main agents of infection are staphylococci (coagulase-positive/negative and methicillin-susceptible/resistant strains) although Gram-negative bacilli, streptococci or anaerobes may be implicated in nosocomial infections or infections related to vascular insufficiency.
A particular kind of osteomyelitis is tuberculous spondylitis, in which the earliest focus is the anterior superior or inferior angle of the vertebral body that can spread to the intervertebral disc and adjacent vertebra; furthermore, it may progress to paraspinal cold abscess in 50% of cases.22
Attaining adequate concentrations of antimicrobial agents at the target site is the major prerequisite for optimal clinical outcome, both in treatment of osteomyelitis and in surgical prophylaxis.
Owing to their favourable pharmacokinetic properties and antimicrobial spectrum, fluoroquinolones are frequently employed in the treatment of chronic osteomyelitis with favourable results.3,4,23 In this regard, some authors investigated bone pharmacokinetics of fluoroquinolones, mainly ofloxacin, pefloxacin and levofloxacin, demonstrating a good penetration into bone of such agents.24–27
Moxifloxacin might be proposed as a potential candidate, due to its wide antibacterial spectrum, high activity against Gram-positive microorganisms and anaerobes, high efficacy against M. tuberculosis and its favourable pharmacokinetic properties. In fact, after oral administration of a single dose of 400 mg, it is well absorbed with a bioavailability of about 90% and a mean maximal plasma concentration (Cmax) of 2.5–4.9 mg/L after 1–2 h (time to maximum concentration of drug in plasma, Tmax).19,28,29
Moxifloxacin pharmacokinetics has mainly been studied in the setting of respiratory tract infections.17,18,20 Its optimal degree of penetration in several sites, as well as its elevated intracellular concentrations (e.g. alveolar macrophages and neutrophils), has been confirmed by various authors.30,31 However the degree of its penetration into bone has never been assessed.
Therefore, our purpose was to investigate moxifloxacin bone concentrations following single or double dosing of the drug, in order to consider its potential role in osteomyelitis treatment, including skeletal tuberculosis.
Double dosing was chosen on the basis of the observation that a 800 mg daily dose seems to achieve excellent M. tuberculosis microbial kill and to suppress drug resistance.15
On the basis of its plasma distribution kinetics, we chose to determine bone moxifloxacin concentrations 2 h post-dosing in group A, which is approximately at the plasma Cmax, and 4 h post-dosing in group B in order to establish potential different ratios.
Our results demonstrate a good degree of penetration of moxifloxacin into bone. The recovered plasma and bone concentrations after single administrations were similar between group A and B, showing a stable bone/plasma ratio and without a relevant reduction in plasma or tissue drug levels.
Considering an MIC90 of 0.12 mg/L for methicillin-susceptible staphylococci and of <1 mg/L for most Enterobacteriaceae, the recovered mean moxifloxacin concentrations show that single dosing leads to bone and plasma moxifloxacin levels exceeding the MICs for the most relevant pathogens.
Double moxifloxacin administration gives significantly higher plasma and bone concentrations, with an average of above 2.5 mg/L (range 0.62–4.64) both in cancellous and cortical bone. This value exceeds the MIC90 of moxifloxacin for methicillin-resistant staphylococci, as reported by most authors, of 2 mg/L (range 0.5–8) and the clinical M. tuberculosis susceptibility breakpoint for moxifloxacin of 1 mg/L.6,9,14,32,33
In conclusion, moxifloxacin might be considered a valid option for antimicrobial treatment of osteomyelitis, as demonstrated by the good plasma and bone concentrations observed in our study population.
Unfortunately, published clinical data about the tolerability of 800 mg/day are lacking, so further evaluations are needed.34
Our findings provide the basis for performing clinical trials assessing the effective role of double daily dosing of moxifloxacin to treat osteomyelitis due to methicillin-resistant staphylococci or multidrug-resistant M. tuberculosis, once its tolerability has been shown.
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