Skip to main page content

• HOME
• Current Issue
• Archive
• Alerts
• About ASM
• Contact us
• Tech Support
• Journals.ASM.org

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Leone, M. Articles by Martin, C. Search for Related Content PubMed PubMed Citation Articles by Leone, M. Articles by Martin, C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2004, p. 638-640, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.638-640.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Moxifloxacin Penetration in Bronchial Secretions of Mechanically Ventilated Patients with Pneumonia

Marc Leone,^1* Jacques Albanèse,¹ Emmanuelle Sampol-Manos,² Nicolas Simon,² Bruno Lacarelle,² Bernard Bruguerolle,² and Claude Martin¹

Department of Anesthesiology and Intensive Care Unit and Trauma Center, Nord Hospital,¹ Department of Pharmacokinetics, Timone Hospital, Marseilles School of Medicine, Marseilles, France²

Received 14 July 2003/ Returned for modification 24 August 2003/ Accepted 14 October 2003

Top Abstract Introduction References

 
The pharmacokinetics of moxifloxacin was studied in 17 mechanically ventilated patients with pneumonia. Patients were given 400 mg of moxifloxacin intravenously. Blood samples and bronchial secretions were taken on days 1 and 4. A dose of 400 mg of moxifloxacin allows one to achieve efficient concentrations in bronchial secretions and plasma.

Top Abstract Introduction References

 
Despite improvements in antimicrobial chemotherapy and supportive care, the incidence of nosocomial pneumonia found in mechanically ventilated patients ranges from 9 to 68% and mortality rates range from 33 to 71% (3). Broad-spectrum antibiotherapy is generally recommended for the empirical treatment of severe pneumonia in intensive-care unit (ICU) patients. The new-broad-spectrum quinolones with activity against gram-positive pathogens and gram-negative organisms constitute one group of agents that may prove useful in the hospital setting (4). However, their pharmacokinetic properties in treatment of mechanically ventilated patients have to be investigated.

The objective of this study was to determine the moxifloxacin concentrations in bronchial secretions, compared with those in plasma, up to 24 h after multiple 400-mg intravenous (i.v.) administrations of the drug to mechanically ventilated patients with pneumonia.

The study was conducted as a multicenter, nonblinded trial. The study was approved by the Ethics Committee of Marseilles. The method of consent used in this study follows the Declaration of Helsinki and the ICH guidelines. Patients had to meet all of the following inclusion criteria: age between 18 and 80 years, weight of 40 to 90 kg, mechanical ventilation, and clinical condition suggesting that they would require at least 4 days of i.v. antimicrobial therapy. They had to present all the following signs and symptoms of severe pneumonia: purulent sputum, a body temperature of 38°C, white blood cell count of >10,000/mm³ or <3,000/mm³, and infiltrate on chest X-ray. Exclusion criteria were as follows: patients with known hypersensitivity to quinolone derivatives, previous history of tendinopathy associated with fluoroquinolones, pregnant or lactating female patients, QT prolongation, renal impairment (creatinine clearance of 30 ml/min/1.73 m² by the Cockroft and Gault formula), Child-Pugh C cirrhosis, and constitutional hemostasis disease.

One treatment regimen was evaluated, i.e., 400 mg of moxifloxacin once daily given i.v. to each patient who entered the study. All patients underwent pretreatment microbiological examination of respiratory samples (bronchoscopic protected catheter, protected catheter/specimen brush, or bronchoalveolar lavage) and blood cultures. MICs of moxifloxacin were determined against baseline pathogens.

Concentrations of moxifloxacin were determined in bronchial secretions after the first i.v. administration. They were also determined in plasma from 1 to 24 h after start of the i.v. infusion on days 1 and 4.

A predose blood sample was taken to check any cross-sensitivity of the assay with possible comedication and/or endogenous compounds contained in the samples that were taken after drug intake.

Blood and bronchial secretion samples were collected on days 1 and 4 before moxifloxacin infusion and 1, 2, 3, 4, 8, 12, and 24 h after the start of the infusion. Samples were centrifuged at 1,600 x g for 5 min. Samples were to be processed within 4 h (centrifugation and freezing) and were stored at -20°C until analysis.

Determination of moxifloxacin concentrations in plasma and in bronchial secretions was carried out with a validated high-performance liquid chromatography method (2). Quality control (QC) data for confirmation of the accuracy and precision of the method used for analysis of trial samples were obtained and are reported together with results of the trial.

The analysis was validated prior to the start of the study by using appropriate QC samples that were provided by the Clinical Pharmacology Department of Bayer AG, Wuppertal, Germany. In addition, internal QC samples were prepared at four concentration levels covering the whole range (15, 30, 500, and 2,000 ng/ml) of concentrations expected for the study. QC samples were stored together with samples taken from patients enrolled in the study. Two replicates of each QC sample were analyzed together with calibration and studied samples in the same analytical sequence. All measured coefficients of variation were below 10%. The limit of quantification of the method was 15 ng/ml.

Three female and 14 male mechanically ventilated patients (46 ± 10 years) were included. At least one causative organism was isolated in 16 of the 17 patients with a total of 29 pathogens isolated. Moxifloxacin promptly appeared in bronchial secretions and reached the maximum concentration of drug in serum (C_max) at 1 to 2 h (Fig. 1). The pharmacokinetics of moxifloxacin obtained in the patients is shown in Table 1. The area-under-the-concentration-time-curve (AUC)/MIC ratios in plasma and bronchial secretions are shown in Table 2. This ratio in plasma and bronchia was 10 or more for all organisms with the exception of Pseudomonas aeruginosa.

View larger version (17K): [in this window] [in a new window]

FIG. 1. Mean concentrations of moxifloxacin in plasma and bronchial secretions following infusions of 400 mg/day. Concentration-versus-time profiles after a single administration (A) and at steady state (B). Results are expressed as mean ± standard deviation.

View this table: [in this window] [in a new window]

TABLE 1. Pharmacokinetic parameters of moxifloxacin following an infusion of 400 mg/day over 4 daysa

View this table: [in this window] [in a new window]

TABLE 2. Microbiological evaluation at inclusion and AUC/MIC ratioa

Moxifloxacin penetration into the respiratory tract following a dose of 400 mg has already been investigated (1, 6) but not in mechanically ventilated patients in ICUs. Mechanical ventilation is known to cause pulmonary histologic damage (8). Moreover, the pharmacokinetics of antibiotics is modified in ICU patients due to the large daily fluid balance, acute changes in body weight, hypoalbuminemia, edema, and low hematocrit values. These modifications lead to a marked change in elimination half-life (t_1/2), volume of distribution (V), and clearance (CL) (7). In this context, our results show that, at all times during the 24-h reporting period, moxifloxacin concentrations in bronchial secretions were adequate and stable. The bronchial secretions were 0.5 to 1.1 times higher after a single administration and were 0.7 to 1.5 times higher at steady state. These results are similar to those observed with ofloxacin administered to mechanically ventilated patients (5). This information needs further clinical trials to confirm the efficacy of moxifloxacin for pneumonia treatment given to mechanically ventilated patients. However, the same results have been described for patients with community-acquired pneumonia undergoing fiber-optic bronchoscopy, in which the concentrations determined in different compartments exceeded the MIC (for common respiratory pathogens) at which 90% of the isolates tested were inhibited (6).

In conclusion, for mechanically ventilated patients with pneumonia, a dose of 400 mg of moxifloxacin makes it possible to achieve efficient concentrations in bronchial secretion and plasma.

 
* Corresponding author. Mailing address: Département d'Anesthésie et de Réanimation, CHU Nord, 13915 Marseille cedex 20, France. Phone: 33491968650. Fax: 33491962818. E-mail: leonem{at}msnotes.wustl.edu.

Top Abstract Introduction References

 

1
1. Finch, R., D. Schürmann, O. Collins, R. Kubin, J. McGivern, H. Bobbaers, J. L. Izquierdo, P. Nikolaides, F. Ogundare, R. Raz, P. Zuck, and G. Hoeffken. 2002. Randomized controlled trial of sequential intravenous (i.v.) and oral moxifloxacin compared with sequential i.v. and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment. Antimicrob. Agents Chemother. 46:1746-1754.[Abstract/Free Full Text]
2
2. Gehanno, P., S. Darantiere, C. Dubreuil, J. C. Chobaut, S. Bobin, J. C. Pages, G. Renou, F. Bobin, P. Arvis, and H. Stass. 2002. A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus. J. Antimicrob Chemother. 49:821-826.[Abstract/Free Full Text]
3
3. Heyland, D. K., D. J. Cook, L. Griffith, S. P. Keenan, C. Brun-Buisson, et al. 1999. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. Am. J. Respir. Crit. Care Med. 159:1249-1256.[Abstract/Free Full Text]
4
4. Lode, H., and M. Allewelt. 2002. Role of newer fluoroquinolones in lower respiratory tract infections. J. Antimicrob. Chemother. 49:709-712.[Free Full Text]
5
5. Martin, C., D. Lambert, B. Bruguerolle, P. Saux, J. Freney, J. Fleurette, H. Meugnier, and F. Gouin. 1991. Ofloxacin pharmacokinetics in mechanically ventilated patients. Antimicrob. Agents Chemother. 35:1582-1585.[Abstract/Free Full Text]
6
6. Soman, A., D. Honeybourne, J. Andrews, G. Jevons, and R. Wise. 1999. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother. 44:835-838.[Abstract/Free Full Text]
7
7. Van Dalen, R., and T. B. Tree. 1990. Pharmacokinetics of antibiotics in critically ill patients. Intensive Care Med. 16:5235-5238.
8
8. Wrigge, H., J. Zinserling, F. Stuber, T. von Spiegel, R. Hering, S. Wetegrove, A. Hoeft, and C. Putensen. 2000. Effects of mechanical ventilation on release of cytokines into systemic circulation in patients with normal pulmonary function. Anesthesiology 93:1413-1417.[CrossRef][Medline]

---

Antimicrobial Agents and Chemotherapy, February 2004, p. 638-640, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.638-640.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Leone, M. Articles by Martin, C. Search for Related Content PubMed PubMed Citation Articles by Leone, M. Articles by Martin, C.