- Email: [email protected]
Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose
Pharmacological Research 55 (2007) 38–41
Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose Federico Pea a,∗ , Gino Marioni b , Federica Pavan a , Claudia Staffieri b , Raffaele Bottin b , Alberto Staffieri b , Mario Furlanut a a
Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Italy b Department of Otolaryngology Head and Neck Surgery, University of Padova, Italy Accepted 3 October 2006
Abstract Respiratory fluoroquinolones are currently considered by several guidelines among the most effective antimicrobial agents for the treatment of acute bacterial rhinosinusitis. The aim of this study was to assess levofloxacin penetration into paranasal sinuses mucosa of 15 patients with chronic rhinosinusitis 1 h (n = 4), 2 h (n = 5) and 3 h (n = 6) after a single 500 mg oral dose. Levofloxacin concentrations in plasma and tissue samples were assessed by means of HPLC. Median of mucosal concentrations were 0.96 mg l−1 at 1 h, 2.50 mg l−1 at 2 h, 5.84 mg l−1 at 3 h. Average paranasal sinuses mucosa-to-plasma ratios raised from 1.46 at 1 h, to 1.81 at 2 h and to 2.56 at 3 h. These data are consistent with 500 mg oral levofloxacin ensuring appropriate therapeutic exposure in sinonasal tissue of patients with chronic rhinosinusitis, the concentrations between 1 and 3 h post-dosing being almost always higher than the MIC90 against the major bacterial pathogens responsible for upper respiratory tract infections. © 2006 Published by Elsevier Ltd. Keywords: Levofloxacin; Pharmacokinetics; Sinusal mucosa
1. Introduction Acute bacterial rhinosinusitis is a common complication of viral upper respiratory tract infections with an estimated incidence in the United States of about 20 million cases per year [1]. Streptococcus pneumoniae and Haemophilus influenzae are the major causal pathogens in adults, globally accounting for about 70–80%, whereas Moraxella catarrhalis, Staphylococcus aureus, other Streptococcus spp. and anaerobes are usually less frequently involved [1,2]. Respiratory fluoroquinolones, namely, gatifloxacin, levofloxacin and moxifloxacin, can be used for the treatment of mild to moderate acute bacterial rhinosinusitis, particularly after failure of other antimicrobial treatments in the previous 4–6 weeks [1,3,4].
∗ Corresponding author at: Institute of Clinical Pharmacology & Toxicology, DPMSC, University of Udine, P.le S. Maria della Misericordia 3, 33100 Udine, Italy. Tel.: +39 0432 559833; fax: +39 0432 559833. E-mail address: [email protected] (F. Pea).
1043-6618/$ – see front matter © 2006 Published by Elsevier Ltd. doi:10.1016/j.phrs.2006.10.003
Several studies documented the clinical and microbiological efficacy of oral levofloxacin at the dosage of 500 mg once daily in the treatment of acute bacterial rhinosinusitis [5–8]. Considering that appropriate exposure at the infection site is a major factor for optimal cure, it would be of great importance to know levofloxacin concentrations into paranasal sinuses mucosa. Although levofloxacin is more frequently used to treat acute rhinosinusitis, for practical and ethical reasons, the present study was carried out in patients with chronic rhinosinusitis. 2. Patients and methods 2.1. Study design and procedure The aim of this study was to assess in patients with chronic rhinosinusitis undergoing functional endoscopic sinus surgery (FESS) [9] levofloxacin tissue pharmacokinetics into the parasinusal mucosa during the first hours after the administration of a single 500 mg oral dose. The study protocol was approved by the local Ethics Committee of the University Hospital of Padova, Italy and an informed consent to assess levofloxacin concentrations in plasma and in sinonasal mucosa was obtained from each
F. Pea et al. / Pharmacological Research 55 (2007) 38–41
patient. Exclusion criteria were as follows: estimated creatinine clearance [10] of <50 ml/min, age of <18 years and treatment with antacids and/or sucralfate potentially altering oral bioavailability of fluoroquinolones. Patients were randomly assigned to receive levofloxacin 1, 2 or 3 h before surgery according to the scheduled operation time. No patient was pre-treated with nasal vasoconstrictor before FESS. FESS was performed after induction of general anaesthesia with opioids (remifentanil, fentanyl or sufentanil). Intraoperative single maxillary sinus mucosal and blood samples were simultaneously collected from each subject with the intent of assessing and comparing levofloxacin concentrations. Plasma samples (obtained after blood centrifugation) and paranasal sinuses mucosa samples (after being gently blotted on filter paper and carefully weighed) were stored frozen at −80 ◦ C until assayed. 2.2. Drug assay Levofloxacin was quantified by means of a validated HPLC method [11]. Briefly, for plasma, to an aliquot of 250 l, 50 l of internal standard stock solution (tinidazole 60 mg l−1 ) plus 250 l of phosphate buffer and 5 ml of dichloromethane were added for extraction. After centrifugation, the organic portion was separated, evaporated and then reconstituted with 150 l of mobile phase [82% potassium phosphate buffer plus 18% acetonitrile (pH 2.6)] and an aliquot of 50 l was injected into the column. Tissue samples, after addition of 20 l of internal standard stock solution (tinidazole 60 mg l−1 ), were extracted with 250 l of phosphate buffer and 1 ml of dichloromethane. To enable optimal recovery, the sinus mucosa samples (weighing between 30 and 60 mg each) were homogenized by means of a glass pestle. After centrifugation, the organic portion was separated, evaporated and then reconstituted with 150 l of mobile phase and an aliquot of 50 l was subsequently injected into the column. The HPLC system was equipped with an UV detector (280 nm) and with a 5 m C18 precolumn linked to a 5 m C18 column. Precision and accuracy were assessed by performing replicate analyses of quality control samples (0.2, 0.5, 1, 2, 5 and 10 mg l−1 ) against calibration standards, intraand inter-assay coefficients of variation (CV) always being levofloxacin less than 10%. The lower limit of quantification was 0.1 mg l−1 .
39
Fig. 1. Levofloxacin concentrations (mean ± S.D.) in plasma (white triangle) and in paranasal sinuses mucosa (white circle) of patients with chronic rhinosinusitis after a single 500 mg oral dose. Solid lines connect mean plasma and tissue concentrations observed at each time. Dotted lines are the minimum inhibitory concentrations againt 90% of susceptible strains (MIC90 ) of levofloxacin against the major pathogens of acute bacterial rhinosinusitis [20]. MS, methicillin susceptible.
(27–75); weight, 80 kg (58–115); estimated creatinine clearance, 103 ml/min (69–125). No significant difference between the demographics of the patients included in the three study groups existed. Mean (±standard deviation, S.D.) levofloxacin concentrations in plasma and in sinonasal mucosa at the different times are depicted in Fig. 1. Median (range) of plasma concentrations were 0.67 mg l−1 (0.43–8.52 mg l−1 ) at 1 h, 3.45 mg l−1 (0.19–7.27 mg l−1 ) at 2 h, 1.88 mg l−1 (0.65–5.14) at 3 h. Median (range) of mucosal concentrations were 0.96 mg l−1 (0.78–9.87 mg l−1 ) at 1 h, 2.50 mg l−1 (0.19–10.05 mg l−1 ) at 2 h, 5.84 mg l−1 (2.09–9.34) at 3 h. Time to maximum tissue level was observed between 2 and 3 h post-dosing. A good linear relationship between simultaneously collected plasma and tissue levels of levofloxacin (r = 0.86, Fig. 2) has been disclosed. Average paranasal sinuses mucosa-to-plasma ratios (Fig. 3) raised from 1.46 at 1 h, to 1.81 at 2 h and to 2.56 at 3 h.
2.3. Statistical analysis The Kolmogorov–Smirnov test was performed to assess whether data were normally or non-normally distributed. Accordingly, descriptive data were expressed as mean ± S.D. or as median and range. 3. Results Fifteen patients (12 male and 3 female) were enrolled in the study. Patients were administered the single 500 mg oral dose of levofloxacin before undergoing FESS, respectively, in four cases at 1 h, in five cases at 2 h and in six cases at 3 h. Median values (ranges) for the 15 patients follow: age, 38 years
Fig. 2. Relationship between plasma and paranasal sinuses mucosa concentrations of levofloxacin in patients with chronic rhinosinusitis after a single 500 mg oral dose.
40
F. Pea et al. / Pharmacological Research 55 (2007) 38–41
dosage [17], a powerful treatment of acute bacterial rhinosinusitis could be anticipated. The positive trend over time of tissue-to-plasma ratios (with values ≥ 1 in all but one cases) support the hypothesis that levofloxacin, thanks to its moderate lipophilicity, may progressively accumulate into the paranasal sinuses mucosa, similarly to what has been observed with another respiratory fluoroquinolone, namely, moxifloxacin [18]. Additionally, it confirms the good penetration into parasinusal mucosa just previously documented for the racemic mixture ofloxacin [19]. In conclusion, these findings confirm that levofloxacin, in the first hours after a single 500 mg oral dose, may engendered therapeutically relevant levels in the paranasal sinuses mucosa of patients with chronic rhinosinusitis, the concentrations generally being above the MIC90 of common pathogens in upper respiratory tract infections. Fig. 3. Paranasal sinuses mucosa-to-plasma ratios of levofloxacin in patients with chronic rhinosinusitis after a single 500 mg oral dose. Dotted line refers to identity.
4. Discussion To our knowledge, these are the first data assessing penetration of levofloxacin into the paranasal sinuses mucosa of patients with chronic rhinosinusitis. For optimal treatment of bacterial rhinosinusitis, effective concentrations of the antimicrobial agent should be achieved at the infection site. Interestingly, the paranasal sinuses tissue concentrations observed between 1 and 3 h post-dosing were almost always higher than the MIC90 against the major bacterial pathogens responsible of acute rhinosinusitis. Indeed, in some of the samples collected at 1 h and 2 h after dosing, lower than expected both plasma and tissue levels were observed and this might have been related to the short lag time elapsed between the oral drug administration and the induction of anaesthesia. In fact, a delayed absorption of levofloxacin might have occurred in these particular cases considering that the opioids used for pre-operative anaesthesia were shown to slow down the gastro-intestinal motility [12,13]. Additionally, it has to be taken into account that, although levofloxacin is more frequently used to treat acute rhinosinusitis, for practical and ethical reasons, the present study was carried out in patients with chronic rhinosinusitis. It is well known that the chronic infection process may locally affect both blood flow and the volume of extracellular fluid to a greater extent than in presence of acute infection, but, in contrast with beta-lactams, the penetration of fluoroquinolones into sinus tissues is expected to be only minimally affected by the local inflammatory status, thanks to their modarate lipophylicity [14]. It is well known that fluoroquinolones exhibit concentrationdependent bactericidal activity, so that peak-to-MIC ratio of 8–10 should be ensured with the intent of either optimal clinical cure or microbiological eradication and prevention of resistance spread [15,16]. Of note, the excellent correlation between plasma and paranasal sinuses mucosa levels supports the hypothesis that in presence of high peak plasma concentrations of levofloxacin, as usually occurs with the 500 mg once daily oral
Acknowledgements The study was carried out with the help of departmental funds (Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Italy). F. Pea has been a consultant to Sanofi-Aventis and is a member of the speakers’ bureau for GlaxoSmithKline and Sanofi-Aventis. M. Furlanut has received research grants from GlaxoSmithKline and unrestricted research grants from SanofiAventis. All other authors: no conflicts. References [1] Anon JB, Jacobs MR, Poole MD, Ambrose PG, Benninger MS, Hadley JA, et al. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;130:1–45. [2] Gwaltney Jr JM, Sydnor Jr A, Sande MA. Etiology and antimicrobial treatment of acute sinusitis. Ann Otol Rhinol Laryngol Suppl 1981;90:68–71. [3] Poole MD, Portugal LG. Treatment of rhinosinusitis in the outpatient setting. Am J Med 2005;118(Suppl. 7A):45S–50S. [4] Klossek JM, Federspil P. Update on treatment guidelines for acute bacterial sinusitis. Int J Clin Pract 2005;59:230–8. [5] Adelglass J, Jones TM, Ruoff G, Kahn JB, Wiesinger BA, Rielly-Gauvin K, et al. A multicenter, investigator-blinded, randomized comparison of oral levofloxacin and oral clarithromycin in the treatment of acute bacterial sinusitis. Pharmacotherapy 1998;18:1255–63. [6] Lasko B, Lau CY, Saint-Pierre C, Reddington JL, Martel A, Anstey RJ. Efficacy and safety of oral levofloxacin compared with clarithromycin in the treatment of acute sinusitis in adults: a multicentre, double-blind, randomized study. The Canadian Sinusitis Study Group. J Int Med Res 1998;26:281–91. [7] Sydnor TA, Kopp EJ, Anthony KE, LoCoco JM, Kim SS, Fowler CL. Open-label assessment of levofloxacin for the treatment of acute bacterial sinusitis in adults. Ann Allergy Asthma Immunol 1998;80:357–62. [8] Adelglass J, DeAbate CA, McElvaine P, Fowler CL, LoCocco J, Campbell T. Comparison of the effectiveness of levofloxacin and amoxicillinclavulanate for the treatment of acute sinusitis in adults. Otolaryngol Head Neck Surg 1999;120:320–7. [9] Chiu AG, Kennedy DW. Surgical management of chronic rhinosinusitis and nasal polyposis: a review of the evidence. Curr Allergy Asthma Rep 2004;4:486–9. [10] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [11] Pea F, Di Qual E, Cusenza A, Brollo L, Baldassarre M, Furlanut M. Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in
F. Pea et al. / Pharmacological Research 55 (2007) 38–41
[12]
[13]
[14]
[15]
patients with early-onset ventilator-associated pneumonia. Clin Pharmacokinet 2003;42:589–98. Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997;87:765–70. Wallden J, Thorn SE, Wattwil M. The delay of gastric emptying induced by remifentanil is not influenced by posture. Anesth Analg 2004;99:429–34 [table of contents]. Gehanno P, Darantiere S, Dubreuil C, Chobaut JC, Bobin S, Pages JC, et al. A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus. J Antimicrob Chemother 2002;49:821–6. Preston SL, Drusano GL, Berman AL, Fowler CL, Chow AT, Dornseif B, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA 1998;279:125–9.
41
[16] Aminimanizani A, Beringer P, Jelliffe R. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharmacokinet 2001;40:169–87. [17] Hurst M, Lamb HM, Scott LJ, Figgitt DP. Levofloxacin: an updated review of its use in the treatment of bacterial infections. Drugs 2002;62:2127– 67. [18] Dinis PB, Monteiro MC, Martins ML, Silva N, Morais JG. Sinus tissue concentration of moxifloxacin after a single oral dose. Ann Otol Rhinol Laryngol 2004;113:142–6. [19] Tolsdorff P. Penetration of ofloxacin into nasal tissues. Infection 1993;21:66–70. [20] Gesu GP, Marchetti F, Piccoli L, Cavallero A. Levofloxacin and ciprofloxacin in vitro activities against 4003 clinical bacterial isolates collected in 24 Italian laboratories. Antimicrob Agents Chemother 2003;47:816–9.
Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose Federico Pea a,∗ , Gino Marioni b , Federica Pavan a , Claudia Staffieri b , Raffaele Bottin b , Alberto Staffieri b , Mario Furlanut a a
Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Italy b Department of Otolaryngology Head and Neck Surgery, University of Padova, Italy Accepted 3 October 2006
Abstract Respiratory fluoroquinolones are currently considered by several guidelines among the most effective antimicrobial agents for the treatment of acute bacterial rhinosinusitis. The aim of this study was to assess levofloxacin penetration into paranasal sinuses mucosa of 15 patients with chronic rhinosinusitis 1 h (n = 4), 2 h (n = 5) and 3 h (n = 6) after a single 500 mg oral dose. Levofloxacin concentrations in plasma and tissue samples were assessed by means of HPLC. Median of mucosal concentrations were 0.96 mg l−1 at 1 h, 2.50 mg l−1 at 2 h, 5.84 mg l−1 at 3 h. Average paranasal sinuses mucosa-to-plasma ratios raised from 1.46 at 1 h, to 1.81 at 2 h and to 2.56 at 3 h. These data are consistent with 500 mg oral levofloxacin ensuring appropriate therapeutic exposure in sinonasal tissue of patients with chronic rhinosinusitis, the concentrations between 1 and 3 h post-dosing being almost always higher than the MIC90 against the major bacterial pathogens responsible for upper respiratory tract infections. © 2006 Published by Elsevier Ltd. Keywords: Levofloxacin; Pharmacokinetics; Sinusal mucosa
1. Introduction Acute bacterial rhinosinusitis is a common complication of viral upper respiratory tract infections with an estimated incidence in the United States of about 20 million cases per year [1]. Streptococcus pneumoniae and Haemophilus influenzae are the major causal pathogens in adults, globally accounting for about 70–80%, whereas Moraxella catarrhalis, Staphylococcus aureus, other Streptococcus spp. and anaerobes are usually less frequently involved [1,2]. Respiratory fluoroquinolones, namely, gatifloxacin, levofloxacin and moxifloxacin, can be used for the treatment of mild to moderate acute bacterial rhinosinusitis, particularly after failure of other antimicrobial treatments in the previous 4–6 weeks [1,3,4].
∗ Corresponding author at: Institute of Clinical Pharmacology & Toxicology, DPMSC, University of Udine, P.le S. Maria della Misericordia 3, 33100 Udine, Italy. Tel.: +39 0432 559833; fax: +39 0432 559833. E-mail address: [email protected] (F. Pea).
1043-6618/$ – see front matter © 2006 Published by Elsevier Ltd. doi:10.1016/j.phrs.2006.10.003
Several studies documented the clinical and microbiological efficacy of oral levofloxacin at the dosage of 500 mg once daily in the treatment of acute bacterial rhinosinusitis [5–8]. Considering that appropriate exposure at the infection site is a major factor for optimal cure, it would be of great importance to know levofloxacin concentrations into paranasal sinuses mucosa. Although levofloxacin is more frequently used to treat acute rhinosinusitis, for practical and ethical reasons, the present study was carried out in patients with chronic rhinosinusitis. 2. Patients and methods 2.1. Study design and procedure The aim of this study was to assess in patients with chronic rhinosinusitis undergoing functional endoscopic sinus surgery (FESS) [9] levofloxacin tissue pharmacokinetics into the parasinusal mucosa during the first hours after the administration of a single 500 mg oral dose. The study protocol was approved by the local Ethics Committee of the University Hospital of Padova, Italy and an informed consent to assess levofloxacin concentrations in plasma and in sinonasal mucosa was obtained from each
F. Pea et al. / Pharmacological Research 55 (2007) 38–41
patient. Exclusion criteria were as follows: estimated creatinine clearance [10] of <50 ml/min, age of <18 years and treatment with antacids and/or sucralfate potentially altering oral bioavailability of fluoroquinolones. Patients were randomly assigned to receive levofloxacin 1, 2 or 3 h before surgery according to the scheduled operation time. No patient was pre-treated with nasal vasoconstrictor before FESS. FESS was performed after induction of general anaesthesia with opioids (remifentanil, fentanyl or sufentanil). Intraoperative single maxillary sinus mucosal and blood samples were simultaneously collected from each subject with the intent of assessing and comparing levofloxacin concentrations. Plasma samples (obtained after blood centrifugation) and paranasal sinuses mucosa samples (after being gently blotted on filter paper and carefully weighed) were stored frozen at −80 ◦ C until assayed. 2.2. Drug assay Levofloxacin was quantified by means of a validated HPLC method [11]. Briefly, for plasma, to an aliquot of 250 l, 50 l of internal standard stock solution (tinidazole 60 mg l−1 ) plus 250 l of phosphate buffer and 5 ml of dichloromethane were added for extraction. After centrifugation, the organic portion was separated, evaporated and then reconstituted with 150 l of mobile phase [82% potassium phosphate buffer plus 18% acetonitrile (pH 2.6)] and an aliquot of 50 l was injected into the column. Tissue samples, after addition of 20 l of internal standard stock solution (tinidazole 60 mg l−1 ), were extracted with 250 l of phosphate buffer and 1 ml of dichloromethane. To enable optimal recovery, the sinus mucosa samples (weighing between 30 and 60 mg each) were homogenized by means of a glass pestle. After centrifugation, the organic portion was separated, evaporated and then reconstituted with 150 l of mobile phase and an aliquot of 50 l was subsequently injected into the column. The HPLC system was equipped with an UV detector (280 nm) and with a 5 m C18 precolumn linked to a 5 m C18 column. Precision and accuracy were assessed by performing replicate analyses of quality control samples (0.2, 0.5, 1, 2, 5 and 10 mg l−1 ) against calibration standards, intraand inter-assay coefficients of variation (CV) always being levofloxacin less than 10%. The lower limit of quantification was 0.1 mg l−1 .
39
Fig. 1. Levofloxacin concentrations (mean ± S.D.) in plasma (white triangle) and in paranasal sinuses mucosa (white circle) of patients with chronic rhinosinusitis after a single 500 mg oral dose. Solid lines connect mean plasma and tissue concentrations observed at each time. Dotted lines are the minimum inhibitory concentrations againt 90% of susceptible strains (MIC90 ) of levofloxacin against the major pathogens of acute bacterial rhinosinusitis [20]. MS, methicillin susceptible.
(27–75); weight, 80 kg (58–115); estimated creatinine clearance, 103 ml/min (69–125). No significant difference between the demographics of the patients included in the three study groups existed. Mean (±standard deviation, S.D.) levofloxacin concentrations in plasma and in sinonasal mucosa at the different times are depicted in Fig. 1. Median (range) of plasma concentrations were 0.67 mg l−1 (0.43–8.52 mg l−1 ) at 1 h, 3.45 mg l−1 (0.19–7.27 mg l−1 ) at 2 h, 1.88 mg l−1 (0.65–5.14) at 3 h. Median (range) of mucosal concentrations were 0.96 mg l−1 (0.78–9.87 mg l−1 ) at 1 h, 2.50 mg l−1 (0.19–10.05 mg l−1 ) at 2 h, 5.84 mg l−1 (2.09–9.34) at 3 h. Time to maximum tissue level was observed between 2 and 3 h post-dosing. A good linear relationship between simultaneously collected plasma and tissue levels of levofloxacin (r = 0.86, Fig. 2) has been disclosed. Average paranasal sinuses mucosa-to-plasma ratios (Fig. 3) raised from 1.46 at 1 h, to 1.81 at 2 h and to 2.56 at 3 h.
2.3. Statistical analysis The Kolmogorov–Smirnov test was performed to assess whether data were normally or non-normally distributed. Accordingly, descriptive data were expressed as mean ± S.D. or as median and range. 3. Results Fifteen patients (12 male and 3 female) were enrolled in the study. Patients were administered the single 500 mg oral dose of levofloxacin before undergoing FESS, respectively, in four cases at 1 h, in five cases at 2 h and in six cases at 3 h. Median values (ranges) for the 15 patients follow: age, 38 years
Fig. 2. Relationship between plasma and paranasal sinuses mucosa concentrations of levofloxacin in patients with chronic rhinosinusitis after a single 500 mg oral dose.
40
F. Pea et al. / Pharmacological Research 55 (2007) 38–41
dosage [17], a powerful treatment of acute bacterial rhinosinusitis could be anticipated. The positive trend over time of tissue-to-plasma ratios (with values ≥ 1 in all but one cases) support the hypothesis that levofloxacin, thanks to its moderate lipophilicity, may progressively accumulate into the paranasal sinuses mucosa, similarly to what has been observed with another respiratory fluoroquinolone, namely, moxifloxacin [18]. Additionally, it confirms the good penetration into parasinusal mucosa just previously documented for the racemic mixture ofloxacin [19]. In conclusion, these findings confirm that levofloxacin, in the first hours after a single 500 mg oral dose, may engendered therapeutically relevant levels in the paranasal sinuses mucosa of patients with chronic rhinosinusitis, the concentrations generally being above the MIC90 of common pathogens in upper respiratory tract infections. Fig. 3. Paranasal sinuses mucosa-to-plasma ratios of levofloxacin in patients with chronic rhinosinusitis after a single 500 mg oral dose. Dotted line refers to identity.
4. Discussion To our knowledge, these are the first data assessing penetration of levofloxacin into the paranasal sinuses mucosa of patients with chronic rhinosinusitis. For optimal treatment of bacterial rhinosinusitis, effective concentrations of the antimicrobial agent should be achieved at the infection site. Interestingly, the paranasal sinuses tissue concentrations observed between 1 and 3 h post-dosing were almost always higher than the MIC90 against the major bacterial pathogens responsible of acute rhinosinusitis. Indeed, in some of the samples collected at 1 h and 2 h after dosing, lower than expected both plasma and tissue levels were observed and this might have been related to the short lag time elapsed between the oral drug administration and the induction of anaesthesia. In fact, a delayed absorption of levofloxacin might have occurred in these particular cases considering that the opioids used for pre-operative anaesthesia were shown to slow down the gastro-intestinal motility [12,13]. Additionally, it has to be taken into account that, although levofloxacin is more frequently used to treat acute rhinosinusitis, for practical and ethical reasons, the present study was carried out in patients with chronic rhinosinusitis. It is well known that the chronic infection process may locally affect both blood flow and the volume of extracellular fluid to a greater extent than in presence of acute infection, but, in contrast with beta-lactams, the penetration of fluoroquinolones into sinus tissues is expected to be only minimally affected by the local inflammatory status, thanks to their modarate lipophylicity [14]. It is well known that fluoroquinolones exhibit concentrationdependent bactericidal activity, so that peak-to-MIC ratio of 8–10 should be ensured with the intent of either optimal clinical cure or microbiological eradication and prevention of resistance spread [15,16]. Of note, the excellent correlation between plasma and paranasal sinuses mucosa levels supports the hypothesis that in presence of high peak plasma concentrations of levofloxacin, as usually occurs with the 500 mg once daily oral
Acknowledgements The study was carried out with the help of departmental funds (Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Italy). F. Pea has been a consultant to Sanofi-Aventis and is a member of the speakers’ bureau for GlaxoSmithKline and Sanofi-Aventis. M. Furlanut has received research grants from GlaxoSmithKline and unrestricted research grants from SanofiAventis. All other authors: no conflicts. References [1] Anon JB, Jacobs MR, Poole MD, Ambrose PG, Benninger MS, Hadley JA, et al. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;130:1–45. [2] Gwaltney Jr JM, Sydnor Jr A, Sande MA. Etiology and antimicrobial treatment of acute sinusitis. Ann Otol Rhinol Laryngol Suppl 1981;90:68–71. [3] Poole MD, Portugal LG. Treatment of rhinosinusitis in the outpatient setting. Am J Med 2005;118(Suppl. 7A):45S–50S. [4] Klossek JM, Federspil P. Update on treatment guidelines for acute bacterial sinusitis. Int J Clin Pract 2005;59:230–8. [5] Adelglass J, Jones TM, Ruoff G, Kahn JB, Wiesinger BA, Rielly-Gauvin K, et al. A multicenter, investigator-blinded, randomized comparison of oral levofloxacin and oral clarithromycin in the treatment of acute bacterial sinusitis. Pharmacotherapy 1998;18:1255–63. [6] Lasko B, Lau CY, Saint-Pierre C, Reddington JL, Martel A, Anstey RJ. Efficacy and safety of oral levofloxacin compared with clarithromycin in the treatment of acute sinusitis in adults: a multicentre, double-blind, randomized study. The Canadian Sinusitis Study Group. J Int Med Res 1998;26:281–91. [7] Sydnor TA, Kopp EJ, Anthony KE, LoCoco JM, Kim SS, Fowler CL. Open-label assessment of levofloxacin for the treatment of acute bacterial sinusitis in adults. Ann Allergy Asthma Immunol 1998;80:357–62. [8] Adelglass J, DeAbate CA, McElvaine P, Fowler CL, LoCocco J, Campbell T. Comparison of the effectiveness of levofloxacin and amoxicillinclavulanate for the treatment of acute sinusitis in adults. Otolaryngol Head Neck Surg 1999;120:320–7. [9] Chiu AG, Kennedy DW. Surgical management of chronic rhinosinusitis and nasal polyposis: a review of the evidence. Curr Allergy Asthma Rep 2004;4:486–9. [10] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [11] Pea F, Di Qual E, Cusenza A, Brollo L, Baldassarre M, Furlanut M. Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in
F. Pea et al. / Pharmacological Research 55 (2007) 38–41
[12]
[13]
[14]
[15]
patients with early-onset ventilator-associated pneumonia. Clin Pharmacokinet 2003;42:589–98. Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997;87:765–70. Wallden J, Thorn SE, Wattwil M. The delay of gastric emptying induced by remifentanil is not influenced by posture. Anesth Analg 2004;99:429–34 [table of contents]. Gehanno P, Darantiere S, Dubreuil C, Chobaut JC, Bobin S, Pages JC, et al. A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus. J Antimicrob Chemother 2002;49:821–6. Preston SL, Drusano GL, Berman AL, Fowler CL, Chow AT, Dornseif B, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA 1998;279:125–9.
41
[16] Aminimanizani A, Beringer P, Jelliffe R. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharmacokinet 2001;40:169–87. [17] Hurst M, Lamb HM, Scott LJ, Figgitt DP. Levofloxacin: an updated review of its use in the treatment of bacterial infections. Drugs 2002;62:2127– 67. [18] Dinis PB, Monteiro MC, Martins ML, Silva N, Morais JG. Sinus tissue concentration of moxifloxacin after a single oral dose. Ann Otol Rhinol Laryngol 2004;113:142–6. [19] Tolsdorff P. Penetration of ofloxacin into nasal tissues. Infection 1993;21:66–70. [20] Gesu GP, Marchetti F, Piccoli L, Cavallero A. Levofloxacin and ciprofloxacin in vitro activities against 4003 clinical bacterial isolates collected in 24 Italian laboratories. Antimicrob Agents Chemother 2003;47:816–9.