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[Pneumococcus and quinolone resistance].
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[A comparison of moxifloxacin and amoxicillin in the treatment of community-acquired pneumonia in Latin America: results of a multicenter clinical trial].
Since community-acquired pneumonia (CAP) is a common disease with a high morbidity rate, it is important to obtain information concerning its etiology and susceptibility to antibiotics across different geographic areas. This study presents data obtained in 5 Latin American counties in the course of an international clinical trial that evaluated the efficacy and safety of treatment with either moxifloxacin or amoxicillin administered for 10 days to patients suspected of having CAP caused by a pneumococcal infection. Details are given of the pathogens identified, the patterns of sensitivity to antibiotics observed, and the clinical and microbiological results obtained.A total of 84 patients were studied, of whom 70 (83.3%) were evaluated at the end of the trial to determine the efficacy and safety of the treatment received. Gram-positive bacteria were found in samples from 29 patients (80.5%). The pathogen was Streptococcus pneumoniae in 28 of those cases (77.7%). Gram-negative bacteria were found in 7 patients (19.4%), the most common being Haemophilus influenzae in 3 patients (8.3%). The presence of atypical microorganisms was detected in 18 of the 70 patients (25%), mainly Mycobacterium pneumoniae (n=11), and in 6 cases (8.5%) the infection was mixed. Ten strains of S. pneumoniae (35.7%) were shown to be susceptible to penicillin, 2 (7.1%) were highly resistant, and 16 (57.1%) showed moderate resistance. The clinical success rate at the final visit after treatment was 94.1% for moxifloxacin and 91.7% for amoxicillin. The results of this trial demonstrate a high prevalence of S. pneumoniae with reduced susceptibility to penicillin in patients with CAP in Latin America. It also revealed a high incidence of atypical pathogens and mixed infection in 8.6% of patients. This information should be taken into account when establishing protocols for empirical treatment of CAP in Latin America.
[Syncope after administration of moxifloxacin].
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Restriction of gene transcription by nucleotide analogs.
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Purine metabolism pathways in Drosophila cells grown "in vitro" : Phosphoribosyl transferase activities.
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Determination of moxifloxacin (BAY 12-8039) in plasma and lung tissue by high-performance liquid chromatography with ultraviolet detection using a fully automated extraction method with a new polymeric cartridge.
The aim of this study was to develop a high-performance liquid chromatographic (HPLC) assay for the determination of moxifloxacin in human plasma and lung tissue. The assay was based on HPLC with a Supelcosil ABZ+ column and ultraviolet detection set at a wavelength of 296 nm. The extraction procedure was characterized by a fully automated liquid-solid extraction using an OASIS column for the solid phase. The assay has been found to be linear and validated over the concentration range 3.2 to 0.025 microg/ml for moxifloxacin in plasma and from 16 to 0.25 microg/g for moxifloxacin in lung tissue. In future, the assay will support the pharmacokinetic study of the penetration of moxifloxacin in human lung tissue.
Determination of moxifloxacin in growth media by high-performance liquid chromatography.
A direct injection high-performance liquid chromatographic method with column switching has been developed to determine moxifloxacin in Mueller-Hinton broth. A LiChrocart 4-4 pre-column filled with a LiChrospher 100 RP 18, 5 microm and a 150 x 4.6 mm I.D. column packed with a Supelcozil ABZ+ Plus were used and led to a retention time of 5.70 min. Fluorescence detection allowed one to reach a quantification limit of 0.05 microg/ml with a 100-microl sample size. The standard curves were linear from 0.05 to 3.2 microg/ml. Intra- and inter-day imprecisions within the linearity range were < or =4.76 and < or =5.75%, respectively. The mean relative errors for the same day and the day-to-day inaccuracies ranged from -2.93 to +4.50% and from -1.10 to +6.00%, respectively. The method was demonstrated to be useful for pharmacokinetic-pharmacodynamic studies of moxifloxacin in an in vitro model.
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.
A reversed-phase (RP) high-performance liquid chromatographic (HPLC) method with fluorescence detection allowing the sensitive and specific quantification of BAY 12-8039, a new antimicrobially active 8-methoxyquinolone, in biological fluids is described. The method is compared to a microbiological assay (bioassay) based on B. subtilis test strain with a limit of quantification of approximately 60 microg/l. Following dilution and centrifugation, plasma, saliva or urine supernatant is directly injected onto the HPLC system. Concentrations down to a limit of quantification of 2.5 microg/l can be quantified in plasma, saliva and urine. Data on recovery, accuracy and precision of the method throughout the whole working range as well as results on stability of the analyte are presented. The concentration data are correlated with results from the bioassay. BAY 12-8039 is stable in plasma after repeated freeze-thaw cycles and following storage at -20 degrees C for at least 12 months. The results of HPLC measurements excellently agree with bioassay data indicating the relevance of the method as a tool in clinical development to answer pharmacokinetic questions related to antimicrobial activity. The method was applied to human plasma, saliva and urine from subjects after a single oral dose of 400 mg of BAY 12-8039.
Capillary electrophoresis with laser-induced fluorescence: a routine method to determine moxifloxacin in human body fluids in very small sample volumes.
The feasibility of capillary electrophoresis with HeCd laser-induced fluorescence detection as a validated routine method for bioanalytical analysis is reported. Method evaluation, validation and results of the determination of moxifloxacin (BAY 12-8039), a new antimicrobially active 8-methoxy-quinolone, in plasma and microdialysate are described. After a one step sample preparation the samples can be injected directly into the capillary. The volume of microdialysate and plasma, respectively, needed for more than 50 injections is only 10 microl and 20 microl. Total run time is less than 7 min using a 27 cm capillary on commercial instrumentation. An analysis time of less than 1 min was shown to be possible, however it could not be used routinely since appropriate instrumentation was not available. Evaluation is based on the relative corrected peak area (analyte/I.S.). The method's dynamic range comprises three orders of magnitude (plasma: 2.5-5000 microg/l; microdialysate: 5-5000 microg/l). Validation according to international guidelines yielded data on accuracy and precision of the method throughout the entire working range of inter-day precision: plasma <6%, microdialysate <5% and inter-day accuracy: plasma <2%, microdialysate <4%. The crossvalidation with an existing HPLC method utilizing clinical study samples shows linear correlation. In view of its adequate sensitivity and high selectivity capillary electrophoresis with laser-induced fluorescence is a very versatile tool in pharmacokinetic studies of quinolones, especially in situations with limited sample volumes: e. g. pediatrics, patients at risk, animal-, microdialysis- and tissue-kinetic studies. Validation parameters and other features, like high sample throughput and robustness, are comparable to or even better than HPLC. Further necessary improvements of the capillary electrophoresis with laser-induced fluorescence instrumentation (autosampler, vials, parallel capillaries) and its use in bioanalytical routine analysis are discussed.
Spectroscopic study of 1,2-indandione.
This paper describes the spectroscopic study of the new fingerprint reagent, 1,2-indandione, using nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). When 1,2-indandione is dissolved in methanol, NMR and MS show formation of a hemiketal similar to that proposed for DFO when it is dissolved in methanol. In contrast to DFO where reactivity with amino acids appears to be enhanced by hemiketal formation with alcohol solvents, the reactivity of 1,2-indandione towards amino acids is diminished by hemiketal formation. Alcohols should be avoided in 1,2-indandione formulations.
The effect of metal salt treatment on the photoluminescence of DFO-treated fingerprints.
Ninhydrin developed fingerprints can be enhanced by treatment with a zinc or cadmium salt. The resulting fingerprint luminescence has been attributed to the induced coplanarity of the bicyclic indanedione rings of Ruhemann's purple due to complexation with the metal ions. This paper explores whether this effect also occurs in the 1,8-diaza-9-fluorenone (DFO)-amino acid adduct (1), formed from the reaction of DFO with amino acids. Molecular modeling studies of (1) indicate a relatively small out-of-plane angle of 24 degrees. 1H NMR studies indicate (1) is asymmetric about the C2 axis in contrast to what has been previously reported. Little, if any, enhancement of luminescence was observed with Zn, Cd, Ru or Eu treated DFO developed latent fingerprints. This lack of enhancement was also borne out by solution luminescence studies. Given this lack of enhancement of luminescence, solutions of (1) and the four metal ions above were analyzed by electrospray mass spectrometry (ESMS). This indicated the formation of predominantly 1:1 complexes of (1) with both Zn and Cd, and the 2:1 complex with ruthenium. No evidence of a Eu complex was found by ESMS.
Study of the reaction mechanism of 1,8-diazafluoren-9-one with the amino acid, L-alanine.
This paper describes the study of the reaction between 1, 8-diazafluoren-9-one (DFO) with the amino acid L-alanine in methyl alcohol. Particular interest was paid to the possible role of the solvent which appears to react with the DFO to form a hemiketal that is the reactive species. A potential reaction pathway is proposed based on the current data collected. The reaction intermediates and products were identified by a variety of spectroscopic methods including mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, and X-ray crystallography.
Determination of moxifloxacin in human plasma by liquid chromatography electrospray ionization tandem mass spectrometry.
Moxifloxacin is an advanced-generation, 8-methoxy fluoroquinolone that is active against a broad spectrum of pathogens, including antibiotic resistant Streptococcus pneumoniae. Development of a rapid, sensitive and selective method for the determination of moxifloxacin in human plasma is essential for understanding the pharmacokinetics of the drug when administered orally or intravenously. Solid phase extraction (SPE) using Oasis(R) HLB was used to extract moxifloxacin and the internal standard lomefloxacin from plasma. A method based on liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) was developed and validated to quantitate moxifloxacin in human plasma. The precursor and major product ion of the analyte was monitored on a triple quadrupole mass spectrometer with positive ion electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. Mechanisms for the formation of collision-induced dissociation (CID) products of moxifloxacin are proposed. Linear calibration curves were generated from 1 to 1000 ng/ml with coefficients of determination greater than 0.999. The inter-day and intra-day precision (% CV) was less than 11.3% and accuracy (% error) was less than 10.0% for moxifloxacin. The limit of detection (LOD) for the method was 50 pg/ml based on a signal to noise ratio of 3.
Enantiomeric separation of a moxifloxacin intermediate by chiral liquid chromatography using cellulose based stationary phases.
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Benchmarking the in vitro activity of moxifloxacin against recent isolates of Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. A European multi-centre study.
To benchmark the activity of moxifloxacin, a European study comprising 900 Streptococcus pneumoniae, 1051 Haemophilus influenzae, and 226 Moraxella catarrhalis referred from 30 institutions during 1998 is described. For S. pneumoniae, moxifloxacin and trovafloxacin MIC(90) and modal MICs values were 0.12 microg/ml and independent of susceptibility to other drug classes, geography, or site of infection. MIC(90)/modal MICs were, respectively, 0.25/0.12 microg/ml for grepafloxacin, 0.25/0.25 microg/ml for sparfloxacin, and 1.0/0.5 microg/ml for levofloxacin. The moxifloxacin C(max):MIC ratio of 20.8-26.3 is higher than comparator fluoroquinolones. Five isolates were intermediate or resistant to grepafloxacin, sparfloxacin, or levofloxacin of which four and three remained susceptible to trovafloxacin and moxifloxacin, respectively. For moxifloxacin, > 90% of S. pneumoniae isolates demonstrated MICs > or =3 dilutions below the susceptibility breakpoint used. Modal MICs and MIC(90) for M. catarrhalis (both 0.03 microg/ml) and H. influenzae (0.03 microg/ml and 0.06 microg/ml) were independent of beta-lactamase production. These data demonstrate the in vitro activity of moxifloxacin and establish a baseline for future surveillance studies that will be important for detecting and tracking any trends in changing activity of this fluoroquinolone.
Activity of oral agents against pediatric isolates of Streptococcus pneumoniae.
An in vitro study of the activity of 10 oral agents against 153 pediatric isolates of Streptococcus pneumoniae identified moxifloxacin and levofloxacin as the most active agents regardless of penicillin or macrolide susceptibility. Moxifloxacin inhibited all strains at 0.25 microg/ml and was 8- to 16-fold more potent than levofloxacin.
In vitro susceptibility study of BMS-284756 against Legionella species.
Legionella organisms are often associated with respiratory infections, and Legionella pneumonia results in significant mortality unless it is promptly and effectively treated. The present study was undertaken to compare the in vitro activity of BMS-284756 (T-3811ME), a novel des-F(6)-quinolone, against Legionella species versus the activity of other fluoroquinolones (levofloxacin, moxifloxacin, and ciprofloxacin) and of the macrolides erythromycin, clarithromycin, and azithromycin. The most potent agents tested against Legionella pneumophila serogroup 1, the largest group tested, were BMS-284756, moxifloxacin, and levofloxacin (MIC(90) = 0.016 mg/L). The MIC(90) range for BMS-284756 was 0.008-0.03 mg/L against the total panel of L pneumophila serogroups 1-9 and 12, with the lowest MIC(90) observed for serogroup 7 and the highest for serogroup 2. BMS-284756 was one of the most potent agents tested against isolates of L micdadei, L longbeachae, and other Legionella species (MIC(90) range: 0.008-0.06 mg/L). These results and the high intrinsic activity of BMS-284756 against other respiratory pathogens support its use as empiric monotherapy for a wide range of respiratory infections.