A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus

P. Gehanno1, S. Darantière2, C. Dubreuil3, J. C. Chobaut4, S. Bobin5, J. C. Pages6, G. Renou6, F. Bobin7, P. Arvis8,* and H. Stass9

1Otorhinolaryngology Unit, Bichat Claude-Bernard Hospital, 75877 Paris; 2General Hospital, 21033 Dijon; 3CH Lyon Sud, 69495 Pierre-Benite; 4Jean Minjoz Hospital, 25030 Besancon; 5CH Bicêtre, 94275 Le Kremlin Bicetre; 6CH Leon Touhladjian, 78303 Poissy; 7Les Hospitalières Clinic, 86000 Poitiers; 8Bayer Pharma, 92807 Puteaux, France; 9Pharma Research Centre, Bayer AG, 42096 Wuppertal, Germany

Received 21 June 2001; returned 30 September 2001; revised 2 January 2002; accepted 27 January 2002.


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A pharmacokinetic study was carried out to determine moxifloxacin concentrations in sinus tissue, after oral moxifloxacin 400 mg once daily for 5 days to patients with chronic sinusitis, undergoing elective sinus surgery. Patients were randomly allocated to one of seven treatment groups, in which tissues were sampled 2, 3, 4, 6, 12, 24 or 36 h post-dose. A control group with non-infected nasal polyps was also included. Forty-eight patients (13 female, 35 male, mean age 47.1 years) were allocated to one of each active treatment group (n = 42) or to the control group (n = 6). Tissue and plasma samples were taken simultaneously and stored frozen until assayed by HPLC. Thirty-nine patients were fully valid for pharmacokinetic analysis. The geometric mean moxifloxacin plasma concentration increased from 2.32 mg/L at 2 h to a maximum of 3.37 mg/L at 4 h post-dose, decreasing to 0.37 mg/L at 36 h post-dose. The moxifloxacin concentration in sinus mucosa was consistently greater than that in plasma being 4.56–5.73 mg/kg from 2 to 6 h and 2.81–1.25 mg/kg from 12 to 36 h post-dose. The elimination rates in plasma and sinus tissues were similar. The tissue/plasma ratio was c. 200% between 2 and 6 h, and up to 328.9% at 36 h. Results were similar whatever the site of tissue sampling (maxillary sinus, anterior ethmoid sinus or nasal polyps). Tissue levels exceeded the MIC90 of all pathogens commonly causing acute sinusitis (e.g. 5–30 x MIC for Streptococcus pneumoniae: 0.25 mg/L). These results sup-port the use of moxifloxacin 400 mg once daily as a regimen for the treatment of sinus infections.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Acute sinusitis is a common bacterial infection frequently following a viral upper respiratory tract infection (URTI) and complicating up to 5% of URTIs.1,2 The incidence in adults is increasing3 and in 1994 there were 25 million sinus-related consultations with medication prescription in up to 96% of patients in the USA.4

Moxifloxacin is a new 8-methoxyquinolone with activity against a wide range of microorganisms associated with community-acquired respiratory tract infections. In comparison with older quinolones, moxifloxacin has retained high activity against Gram-negative pathogens5,6 but displays significantly improved activity against Gram-positive and anaerobic organisms.79 Against Streptococcus pneumoniae, the MIC90s of moxifloxacin are 0.12–0.25 mg/L; there is no difference between penicillin-susceptible and penicillin-resistant strains.5

Moxifloxacin produces a Cmax in plasma of 0.29–4.74 mg/L after single oral doses of 50–800 mg and a Tmax of about 2 h. It has a relatively low binding to plasma proteins of 45%. The terminal elimination half-life is c. 12 h at all dosages and c. 20% is excreted in urine and 25% in the faeces unmetabolized.10 Multiple-dose, once daily studies11 indicate a Cmax at steady state of 3.2 mg/L (400 mg) or 5.7 mg/L (600 mg).

Four hundred milligrammes once daily is considered appropriate for the treatment of most community-acquired infections, notably sinusitis. However, if the tissue concentration at the site of infection is an important factor for therapeutic success it would be important to know the moxifloxacin concentration in sinus mucosa following multiple oral 400 mg doses.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study design

This was as a multicentre (seven French hospitals), controlled, open-label trial, carried out in seven randomized parallel groups, each receiving the active study drug and one additional control group. The trial was implemented after the protocol had been approved by the St Germain-en-Laye Hospital (France) Ethics Committee.

Patients were excluded from participation on the basis of: <18 years; known hypersensitivity to quinolones; pregnancy and lactation; recent participation in another clinical trial; liver enzyme abnormalities; raised creatinine; positive test for HIV, hepatitis B or C; any laboratory test result that could contraindicate sinus surgery.

The study treatment was moxifloxacin in 400 mg tablets for oral use, administered as hydrochloride. All patients received one 400 mg tablet daily for 5 days, at the same time of day in one given group, with water, before or with food. Each active treatment group was defined according to the time between the last study medication intake and the scheduled sinus surgery: Group A, last drug intake 2 h before surgery; Group B, 3 h before surgery; Group C, 4 h before sur- gery; Group D, 6 h before surgery; Group E, 12 h before surgery; Group F, 24 h before surgery; Group G, 36 h before surgery. Concomitant treatments with magnesium, calcium or aluminium salts, cimetidine, ranitidine, iron and zinc-containing vitamins, as well as drugs likely to increase the QTc interval, were forbidden throughout the study period.

The patients baseline examination was carried out within the 30 days before initiation of therapy and included a medical history, physical examination and blood analysis for haematology and biochemistry. Patients were subsequently evaluated on the last day of therapy, on the day of surgery and on days 28–35 post-study. Laboratory safety tests were repeated at the end of treatment and follow-up.

Study patients

Fifty-two patients were enrolled in this study between February and June 1998, and gave written informed consent. They presented with a chronic sinusitis requiring elective surgery of the sinus. Three patients withdrew and one was subsequently excluded due to concomitant medication, leaving 48 patients (13 female, 35 male) who were finally included in the valid-for-safety population, 42 of whom received moxifloxacin and six of whom were included in the control group. Their mean age (±S.D.) was 47.1 ± 13.0 years, the mean weight was 72.1 ± 10.8 kg. Previous sinus surgery had been carried out in 15 patients (mainly removal of polyps). The origin and location of chronic sinusitis as well as the nature of the surgical procedure carried out in the study are summarized in Table 1. Patients in the control group had non-superinfected nasal polyposis.


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Table 1. Origin, localization of chronic sinusitis and type of surgical procedure in valid-for-safety patients (n = 48)
 
Blood and tissue samples

Two specimens (one blood sample and one tissue sample) were taken from each treated patient during the surgical procedure. Blood samples were drawn by venipuncture (3–4 mL into heparinized tubes) and centrifuged for 5 min at 1600g. Plasma was then stored at –20°C until assayed. For tissue specimens, at least 0.1 g of sinus mucosa or nasal polyp tissue was taken during the surgical procedure, dried on filter paper, and stored at –20°C until assay.

Drug assays

The moxifloxacin concentrations were determined by high-performance liquid chromatography (HPLC) with fluorescence detection.12 For plasma, sample preparation was done with 0.25 mL aliquots treated with a mixture (9:1, v/v) of acetonitrile/0.1 M aqueous phosphate buffer (pH 4) to deproteinate and dilute the sample. Following centrifugation the supernatant was injected on to the column. Tissue samples were extracted with 2 mL of a solvent consisting of acetonitrile/ 0.1 M aqueous phosphoric acid (1:1, v/v). To achieve complete recovery the samples were treated with an Ultraturrax (Janke and Kunkel, Breisgau, Germany) for 2 min at room temperature, followed by ultrasonication (5 min, room temperature). After centrifugation (1900g, 10 min at 10°C) of the resulting suspension, the supernatant was analysed as stated above.

For plasma the mean accuracy was less than ±10% and the mean precision was <10% over the complete working range (proven by co-analysing appropriate quality control samples produced by spiking blank plasma with known concentrations of moxifloxacin). For the tissue samples recovery ranged between 94 and 99%, the mean accuracy was less than ±10% and the mean precision was <12% over the complete working range. The limit of quantification (LOQ) was 0.01 mg/L (plasma) and 0.05 mg/kg (tissues).

Statistics

Demographics, special characteristics and laboratory test parameters were the subject of summary statistics: mean, standard deviation, minimum and maximum for quantitative variables and contingency tables for categorical variables. All results were calculated by group and overall. A count of patients with laboratory test values outside the normal range was also computed. Clinical safety data were the subject of individual patient listing.

The plasma/tissue concentrations versus time were summarized for moxifloxacin. Statistics included: arithmetic mean, standard deviation and coefficient of variation, geometric mean, geometric standard deviation and coefficient of variation, median, minimum and maximum. Tissue/plasma concentration ratios were calculated using all tissue levels and plasma levels over the LOQ.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Protocol deviations and drop-outs

Out of the 48 valid-for-safety patients, two patients dropped out due to an adverse event and two others were invalid for pharmacokinetic analysis due to violation of time schedule or missing/invalid key data. Hence, 44 patients were valid for pharmacokinetic analysis. A few other minor protocol deviations did not require any patient exclusion. In three patients, formerly in Group A (–2 h) with significant deviations between actual and theoretical sampling times, it was necessary to allocate their data to the ‘nearest’ time.

Pharmacokinetics

The changes in geometric mean moxifloxacin concentrations over time are given in Table 2 and are shown in Figure 1. The changes in tissue/plasma ratio are shown in Figure 2. High mean plasma concentrations were observed 3 h after dosing, which then declined over time. Concentrations were about halved between 12 and 24 h post-dose; however, they were still significant 36 h post-dose.


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Table 2. Plasma and tissue moxifloxacin concentrationsa (mg/L or mg/kg) after the last administration of a 5 day moxifloxacin regimen
 


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Figure 1. Tissue and plasma moxifloxacin concentration (geometric mean, mg/kg or mg/L) versus time in patients with chronic sinusitis, after a 5 day moxifloxacin 400 mg once daily regimen (diamonds, plasma; squares, maxillary sinus mucosa; triangles, anterior ethmoid sinus mucosa; circles, nasal polyps).

 


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Figure 2. Tissue/plasma moxifloxacin concentration ratio (geometric mean, %) versus time in patients with chronic sinusitis, after a 5 day moxifloxacin 400 mg once daily regimen (squares, maxillary sinus mucosa; triangles, anterior ethmoid sinus mucosa; circles, nasal polyps).

 
Higher tissue concentrations were observed at 3 h post-dose: mean geometric concentrations were 7.48, 8.19 and 9.09 mg/kg in maxillary sinus mucosa, anterior ethmoid mucosa and nasal polyps, respectively.

Concentrations in sinus tissues were higher than in plasma at each sampling time. These ratios were c. 2.0, 2.1 and 2.6 times for maxillary sinus mucosa, anterior ethmoid mucosa and nasal polyps, respectively, 3 h after dosing.

The tissue concentrations were more or less closely related (both individually and as regards the mean values) with those in plasma, as they declined at similar rates. The tissue/plasma ratio did not change substantially over time: on average, the maxillary sinus mucosa concentrations were 1.9, 2.1, 2.5, 2.5 and 3.3 times higher that those in plasma at 4, 6, 12, 24 and 36 h after dosing, respectively.

Similar results were obtained with anterior ethmoid mucosa and nasal polyps.

Safety

Adverse events were reported for 15 of 42 moxifloxacin-treated patients and for two of six patients in the control group. Considering only drug-related adverse events (defined as events possibly or probably related to the study drug), the most frequently affected body systems in COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) were the digestive system (diarrhoea = 2; vomiting = 1) and the nervous system (dizziness = 1; paraesthesia = 1).

There was no evidence of any treatment-emergent changes in vital signs or laboratory tests, except in one patient having experienced a transitory hypertension episode 3 days after the last study drug intake (data not shown).


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The antibiotic treatment of sinusitis needs to achieve effective concentrations at the site of infection, due to the fact that sinusitis is an infection localized in a bone-enclosed cavity with impaired or occluded drainage associated with a poorly vascularized mucosa.

In contrast with antibacterial agents such as penicillin, erythromycin, cefradine or cefaclor, which have poor tissue penetration, fluoroquinolones have excellent pharmacokinetic properties, which give high concentrations in various body tissues: ciprofloxacin tissue concentrations in patients with chronic sinusitis were 2–3 times higher than concomitant serum concentrations over a 12 h period.15

As regards moxifloxacin, a newer fluoroquinolone with enhanced activity against respiratory pathogens,5 it was necessary to determine its penetration into the various respiratory tissues.

The results of this study with moxifloxacin have to take into account possible variability factors, which are not present when evaluating pharmacokinetics in healthy volunteers. First, general anaesthesia and its associated measures (fasting, pre-medication, etc.) is known to delay gastric emptying and absorption of orally administered drugs,13 and could interfere to a varying extent, according to the sampling times (i.e. the time between administration and anaesthesia). Secondly, the infection process itself can affect the antibiotic blood flow and the volume of extracellular fluid, more in chronically infected tissues than in acute infections.14 For practical reasons, in the present study, concentrations were measured in patients with chronic sinusitis, although moxifloxacin will be used to treat acute sinusitis.

In the context of these constraints, in all the types of tissue sampled (maxillary, ethmoid and polyps), the mean moxifloxacin tissue Cmax (at 3 h) was quite high, ranging from 7.48 to 9.09 mg/kg according to the origin. High mean moxifloxacin levels were still reported 36 h post-dose: 0.77–1.25 mg/kg. This can be partly explained by the relatively high unbound fraction of moxifloxacin, a large portion of the compound being readily distributed from blood to the extravascular space and to most organs and tissues.

Considering S. pneumoniae, one of the most critical respiratory pathogens and the moxifloxacin concentrations in sinus tissues, the Cmax/MIC ratio would be high, even 36 h post-dose.

Mean moxifloxacin concentrations in plasma were similar (3.58–0.38 mg/L between 3 and 36 h post-dose) to those of previous pharmacokinetic studies conducted in healthy volunteers.11 It is interesting that moxifloxacin sinus tissue levels were always higher than the simultaneous plasma levels, at any sampling time and that tissue/plasma ratios were quite homogeneous (extreme values: 167–358%) between the various sampling times and the different sinus specimens (maxillary, ethmoid and polyps).

In contrast with ß-lactams, adequate penetration of moxifloxacin into sinus tissues does not seem to be related to the local inflammatory status (patients were suffering from chronic sinusitis); this is worth mentioning since corticosteroids or non-steroidal anti-inflammatory drugs are frequently administered to patients with acute sinusitis.

These results are similar to those observed with ciprofloxacin.15 In contrast with ß-lactams, which remain predominantly extracellular, tissue levels of fluoroquinolones such as moxifloxacin are mostly high in relation to blood levels as can be shown in this study.

It is concluded that orally administered, moxifloxacin (one 400 mg tablet once daily for 5 days) distributes preferentially to sinus tissues where it reaches concentrations higher than in plasma. In maxillary sinus mucosa, anterior ethmoid mucosa and nasal polyps, the concentrations were 2.0, 2.1 and 2.6 times higher than in plasma, respectively, declining at a similar rate as the concentrations in plasma. The multiple oral doses of moxifloxacin 400 mg were well tolerated.


    Acknowledgements
 
The trial was supported by a grant from Bayer-Pharma, France.


    Footnotes
 
* Correspondence address. Bayer Pharma, Medical Affairs Department, 13 rue Jean Jaurès, 92807 Puteaux Cedex, France. Tel: +33-1-49065779; Fax: +33-1-49063610; E-mail: pierre.arvis.pa{at}bayer-ag.de Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Gehanno, P., Barry, B., Chauvin, J. P. & Hazebrouck, J. (1996). Clarithromycine versus amoxicilline acide-clavulanique dans le traitement de la sinusite maxillaire aiguë de l’adulte. Pathologie Biologie 44, 293–7.[ISI][Medline]

2 . Wald, E. R. (1985). Epidemiology, pathophysiology and etiology of sinusitis. Pediatric Infectious Diseases Journal 4, S51–4.[ISI]

3 . National Center for Health Statistics. (1987). Current Estimates from the National Health Interview Survey, United States, 1986. Vital and Health Statistics Series 10, No. 164. US Government Printing Office, Washington, DC.

4 . Kennedy, D. W. (1995). Medical management of sinusitis: educational goals and management guidelines. In International Conference on Sinus Disease: Terminology, Staging, Therapy. Annals of Otology, Rhinology and Laryngology 104, Suppl. 167, 22–30.[ISI]

5 . Woodcock, J. M., Andrews, J. M., Boswell, F. J., Brenwald, N. P. & Wise, R. (1997). In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrobial Agents and Chemotherapy 41, 101–6.[Abstract]

6 . Fass, R. J. (1997). In vitro activity of Bay 12-8039, a new 8-methoxyquinolone. Antimicrobial Agents and Chemotherapy 41, 1818–24.[Abstract]

7 . Brueggemann, A. B., Kugler, K. C. & Doern, G. V. (1997). In vitro activity of BAY 12-8039, a novel 8-methoxyquinolone, compared to activities of six fluoroquinolones against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrobial Agents and Chemotherapy 41, 1594–7.[Abstract]

8 . Aldridge, K. E. & Ashcraft, D. S. (1997). Comparison on the in vitro activities of BAY 12-8039, a new quinolone, and other antimicrobials against clinically important anaerobes. Antimicrobial Agents and Chemotherapy 41, 709–11.[Abstract]

9 . Boswell, F. J., Andrews, J. M. & Wise, R. (1997). Pharmacodynamic properties of BAY 12-8039 on Gram-positive and Gram-negative organisms as demonstrated by studies of time–kill kinetics and postantibiotic effect. Antimicrobial Agents and Chemotherapy 41, 1377–9.[Abstract]

10 . Stass, H., Dalhoff, A., Kubitza, D. & Schühly, U. (1998). Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrobial Agents and Chemotherapy 42, 2060–5.[Abstract/Free Full Text]

11 . Stass, H., Kubitza, D. & Schüly, V. (2001). Pharmacokinetics, safety and tolerability of moxifloxacin, a novel 8-methoxyfluoroquinolone, after repeated oral administration. Clinical Pharmacokinetics 40, Suppl. 1, 1–9.

12 . Stass, H. & Dalhoff, A. (1997). Determination of BAY 12-8039, a new 8-methoxy-quinolone, in human body fluids by HPLC with fluorescence detection using on column focusing. Journal of Chromatography B 702, 163–74.

13 . Tood, J. G. & Nimmo, W. S. (1983). Effect of premedication on drug absorption and gastric emptying. British Journal of Anaesthesiology 55, 1189–93.

14 . Paavolainen, M., Kohonen, A., Palva, T. & Renkonen, A. V. (1997). Penetration of erythromycin stearate into maxillary sinus mucosa and secretion in chronic maxillary sinusitis. Acta Otolaryngology (Stockholm) 84, 292–5.

15 . Gehanno, P., Farinotti, R., Buffe, P., Cohen, B., Cudennec, Y. & Sterkers, O. (1992). Penetration of ciprofloxacin into middle ear and sinus mucosa after repeated oral administration. In Program and Abstracts of the Fifth International Congress for Infectious Diseases, Nairobi, Kenya, 1992. Abstract 516, p. 147. International Society for Infectious Diseases, Boston, MA, USA.