In vitro antimicrobial activity of moxifloxacin against bacterial strains isolated from blood of neutropenic cancer patients.
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Anti-Bacterial Agents↗
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Impact of moxifloxacin versus clarithromycin on normal oropharyngeal microflora.
A multiple-dose, randomized, double-blind, controlled, cross-over trial was performed in 12 healthy male subjects in order to investigate the effect of a 7-day treatment with moxifloxacin (400 mg orally, once daily) versus clarithromycin (500 mg orally, twice daily) on the normal oropharyngeal microflora. Moxifloxacin caused significant reductions in levels of alpha-streptococci and Neisseria cocci during the treatment period, while the numbers of gram-negative anaerobic bacteria increased markedly during moxifloxacin administration. Clarithromycin administration caused a suppression of micrococci and corynebacteria, while no significant changes were recorded in the anaerobic microflora. No new colonizing moxifloxacin-resistant strains were isolated during the investigation period.
Adult↗
Antibacterial activity of moxifloxacin (Bay 12-8039) against aerobic clinical isolates, and provisional criteria for disk susceptibility tests.
Moxifloxacin (Bay 12-8039), ciprofloxacin, and levofloxacin were compared in vitro against 1074 clinical isolates gathered from different medical centers throughout North America during the winter months of 1997. Moxifloxacin E tests and broth microdilution tests gave comparable results. Moxifloxacin was particularly potent against respiratory pathogens such as Haemophilus influenzae and Streptococcus pneumoniae. Ciprofloxacin was the most potent study drug against the family of Enterobacteriaceae and Pseudomonas spp. For tests of 5 microg moxifloxacin disks, zone size criteria of < or = 17 mm for resistant (MIC > or = 8 microg/ml) and > or = 21 mm for susceptible (MIC < or = 2 microg/ml) are provisionally proposed for use while clinical trials are under way.
Anti-Infective Agents↗
Comparative activity of moxifloxacin in vitro against obligately anaerobic bacteria.
The antimicrobial activity of moxifloxacin and seven other antibiotics (four of them quinolones) against 292 strains of obligately anaerobic bacteria was assessed employing a broth microdilution technique performed in Wilkens-Chalgren broth. MIC50/MIC90 values (mg/l) for moxifloxacin were as follows: Bacteroides fragilis (n = 62) 0.25/2, Bacteroides ovatus (n = 70) 1/4, Bacteroides vulgatus (n = 29) 0.25/1, Bacteroides thetaiotaomicron (n = 17) 2/2, Bacteroides caccae (n = 11) 1/2, Prevotella spp. (n = 11) 0.25/2, Fusobacterium spp. (n = 17) 1/4, Bilophila wadsworthia (n = 29) 0.5/1, and Clostridium spp. (n = 29) 0.125/0.5, respectively. MIC50 values (mg/l) for Bacteroides distasonis (n = 8) and Peptostreptococcus spp. (n = 9) were 0.25. The results indicated that moxifloxacin was almost as active as trovafloxacin, as active as gatifloxacin, and more active than levofloxacin and ciprofloxacin against the anaerobes tested.
Anti-Bacterial Agents↗
In-vitro activity of moxifloxacin and other fluoroquinolones against Chlamydia species.
The in-vitro activity of moxifloxacin, a new fluoroquinolone, against Chlamydia species was investigated. The minimal inhibitory concentration of moxifloxacin for 10 standard strains of different Chlamydia species and 15 wild-type strains of Chlamydia pneumoniae isolated in Japan, which were morphologically different from clinical isolates from the United States, ranged from 0.031 to 0.125 microg/ml. The activity of moxifloxacin was almost the same as those of sparfloxacin, and it was 16, 8, 2, and 2 times more active than ciprofloxacin, levofloxacin, grepafloxacin, and tosufloxacin, respectively. The minimal chlamydiacidal concentration of moxifloxacin ranged from 0.031 to 0.125 microg/ml. These results suggest that moxifloxacin has potential effects against Chlamydia species.
Anti-Infective Agents↗
[Theoretical study of the structure of adenosine deaminase complexes with adenosine analogues: I. Aza-, deaza- and isomeric azadeazaanalogues of adenosine].
The conformational models of the active site of adenosine deaminase (ADA) and its complexes in the basic state with adenosine and 13 isosteric analogues of the aza, deaza, and azadeaza series were constructed. The optimization of the conformational energy of the active site and the nucleoside bound with it in the complex was achieved in the force field of the whole enzyme (the 1ADD structure was used) within the molecular mechanics model using the AMBER 99 potentials. The stable conformational states of each of the complexes, as well as the optimal conformation of the ADA in the absence of ligand, were determined. It was proved that the conformational state that is close to the structure of the ADA complex with 1-deazaadenosine (1ADD) known from the X-ray study corresponds to one of the local minima of the potential surface. Another, a significantly deeper minimum was determined; it differs from the first minimum by the mutual orientation of side chains of amino acid residues. A similar conformational state is optimal for the ADA active site in the absence of the bound ligand. A qualitative correlation exists between the values of potential energies of the complexes in this conformation and the enzymatic activity of ADA toward the corresponding nucleosides. The dynamics of conformational conversions of the active site after the binding of substrate or its analogues, as well as the possibility of the estimation of the inhibitory properties of nucleosides on the basis of calculations, are discussed.
Adenosine↗
Efficacy and safety of intravenous moxifloxacin versus cefoperazone with azithromycin in the treatment of community acquired pneumonia.
To compare the efficacy, safety, and tolerability of intravenous moxifloxacin with those of a commonly used empirical antibiotic regimen, cefoperazone and azithromycin in the treatment of community acquired pneumonia (CAP) in adult patients requiring initial parenteral therapy, 40 patients with CAP were divided into two groups, a moxifloxacin group (n = 20) and a control group (n = 20), which were treated for 7 to 14 days. The patients in the moxifloxacin group were intravenously given 400 mg of moxifloxacin (Avelox) once a day. Patients in the control group were administered 2.0 g of cefoperazone twice a day and azithromycin 0.5 g once a day. Clinical, bacteriological, and laboratory examinations were performed before the treatment, and at the end of the treatment. Our results showed that there was no significant difference in the clinical efficacy rate between two treatment groups at end of therapy (90% for moxifloxacin, 95% for cefoperazone plus azithromycin) (P > 0.05). The bacteriologic eradication rate at the end of treatment was 90% in the moxifloxacin group and 80% in the cefoperazone-plus-azithromycin group, whereas there was no significant difference between the two groups (P > 0.05). In addition, both drugs were well-tolerated in this trial, with the number of drug-related adverse events being comparable. It is concluded that moxifloxacin is an effective and well-tolerated treatment for CAP and was equivalent to the commonly used empirical treatment of cefoperazone plus azithromycin. Moxifloxacin is likely to offer clinicians an alternative for reliable empirical CAP treatment in the face of increasing antibiotic resistance.
Adolescent↗
Influence of moxifloxacin, comparator drugs and some fractions of pulmonary surfactant on adherence of some respiratory pathogens.
BACKGROUND: This study evaluated the effect of moxifloxacin and comparator drugs with or without some fractions of pulmonary surfactant, as surfactant protein-A (SP-A) and phospholipids, on the adherence of the most common respiratory pathogens. MATERIALS AND METHODS: The adherence of respiratory pathogens to a bronchial epithelial cell line was tested. Antimicrobials were used at 1/2, 1/4 and 1/8 minimum inhibitory concentration (MIC), SP-A at 1 and 5 microg/ml and phospholipids at 50 microg/ml. RESULTS: At 1/2 MIC moxifloxacin, ciprofloxacin, amoxicillin-clavulanate and ceftriaxone reduced the adherence of Staphylococcus aureus and Streptococcus pneumoniae to values of 40-50%. At the same concentration, cotrimoxazole reduced the adherence values of Moraxella catarrhalis and Haemophilus influenzae to about 50%, while beta-lactams showed high efficacy only on H. influenzae, with adherence values of about 40%. The addition of SP-A and/or phospholipids to the tested antibiotics had no effect on bacterial adherence. CONCLUSION: The non-interference of SP-A and/or phospholipids with the suppressive effect that some antibiotics exert on bacterial adherence could represent a favorable event during antibiotic therapy.
Anti-Bacterial Agents↗
Pharmacodynamics of moxifloxacin and levofloxacin simulating human serum and lung concentrations.
Fluoroquinolones are known to penetrate well into the infectious foci such as lung mucosa, epithelial lining fluid and alveolar macrophages achieving higher target site concentrations than the corresponding serum levels. In order to integrate the in vitro antibacterial activity and pharmacokinetics of moxifloxacin and levofloxacin, their bactericidal efficacy was assessed by simulating human serum and lung tissue concentrations using Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae as indicator organisms. The bacteria were exposed to fluctuating moxifloxacin and levofloxacin concentrations simulating the drug levels in serum, lung mucosa, epithelial lining fluid and alveolar macrophages. The following parameters were deduced from the kill curves: area under the bactericidal kill curve normalized to the initial inoculum (AUBKC norm), the time needed to reduce the inoculum by 3 log(10) titers, and the initial bactericidal activity. In general, all these three parameters were for all the bacterial isolates having been exposed to moxifloxacin concentration dependent. In contrast, beyond a levofloxacin concentration of optimal bactericidal effect, higher drug concentrations did not further augment the bactericidal activity of levofloxacin. These data demonstrate that not all fluoroquinolones share the same pharmacodynamic targets needed to maximize their antibacterial effect.
Anti-Bacterial Agents↗
The integrated use of pharmacokinetic and pharmacodynamic models for the definition of breakpoints.
For fluoroquinolones AUC/MIC ratios are known to correlate with clinical outcomes for patients suffering from respiratory tract infections (RTI) and complicated skin and skin structure infections (cSSSI). This paper describes the results of a population PK/PD analysis followed by Monte Carlo simulations to estimate clinical outcome and the microbiological breakpoints for a 400 mg once-daily moxifloxacin (MFX) treatment schedule. Based on PK data from 416 subjects, a non-compartmental population PK model was developed first to describe the expected exposure (AUC) distribution in humans. Height and gender were the main population covariates with moderate influence on PK variability. Albumin, bilirubin, and creatinine clearance (as derived from serum creatinine according to Cockroft and Gault) had a mild effect on AUC. Residual unexplained variability of AUC was low (13.1%). To describe the PD function the MIC distribution pattern of more than 3,000 isolates of S. pneumoniae as the representative pathogen for RTI (MIC90, range: 0.125; 0.006-4 mg/l) was built into the population PK/PD model for RTI, while 126 isolates of methicillin-susceptible Staphylococcus aureus strains (MIC90, range: 0.125; 0.03-4 mg/l) were the basis for the PD function in cSSSI. Simulations for 20,000 (RTI) and 4,000 (cSSSI) subjects were performed to evaluate the AUC/MIC characteristics for moxifloxacin for these two diseases. Overall, a target hit rate was THR = 99% for RTI, while it amounted to THR = 97.5% for cSSSI when applying a threshold of AUIC > 30 [h] as the PK/PD surrogate parameter which is predictive for a positive clinical outcome. A target hit rate of THR = 93.6 % (RTI) and 97.3% (cSSSI), respectively, was predicted when assuming that an AUIC of > 125 [h] is indicative of clinical success (as shown for ciprofloxacin and severe RTIs due to gram-negative infections). In clinical trials with patients receiving 400 mg moxifloxacin once daily for the treatment of community-acquired pneumonia (CAP) success rate was approximately 93.5%. From the simulations performed for RTI an analysis of the overall likelihood of therapeutic failure broken down according to MICs suggests that the risk of a negative clinical outcome at a MIC = 1 mg/l is approximately 0.25% (for MIC = 2 mg/l: predicted likelihood approximately 0.5%) assuming that a cutoff of AUIC = 30 [h] is applicable. Likewise, for cSSSI the probability to fail is predicted as 1.6% at a MIC = 2 mg/l (no strains with MICs between 0.5 and 1 mg/l available from the clinical isolates). These findings are in line with the breakpoint definition of the former National Committee for Clinical Laboratory Standards (NCCLS) for MFX (=1 mg/L to differentiate between susceptible and intermediately susceptible microorganisms; = 2 mg/l to separate intermediate from resistant pathogens). The results of the investigation indicate that the noncompartmental PK/PD model for MFX is suitable to predict clinical outcomes in CAP and cSSSI caused by gram-positive aerobe pathogens. They confirmed that a 400 mg once-daily dosing regimen is suitable to treat these diseases successfully. They are in agreement with the microbiological breakpoints determined by independent methods by the Clinical and Laboratory Standards Institute (CLSI) (former NCCLS).
Anti-Bacterial Agents↗
Contribution of immunocompetence to the antibacterial activities of ciprofloxacin and moxifloxacin in an in vitro pharmacodynamic model.
Traditional in vitro models used to simulate human pharmacokinetics and to characterize the pharmacodynamics of antibacterial agents represent a totally immunosuppressed condition. However, host defense mechanisms contribute to the elimination of the pathogen from the infectious site in most of the patients suffering from infectious diseases. Therefore, the attempt was made to introduce immunocompetence into an in vitro pharmacodynamic model. Immunocompetence was added either by using J774 macrophages growing as adherent monolayers in cell culture flasks, or by using a newly developed ex vivo model. This ex vivo model consists of sponges which have been implanted into rats for 24 h. After 24 h the sponges are explanted; at this point in time the sponges are soaked with an inflammatory exudate to which the bacteria to be tested are added. Into a slightly modified one-compartment model according to Grasso the explanted sponges which are entrapped in dialysis tubings are added. Neither the bacteria nor the inflammatory proteins nor the immunocompetent cells escape from the explants. Thus, it is possible to simulate antibiotic kinetics without diluting bacteria, the polymorphonuclear cells (PMN) or the inflammatory exudates. This ex vivo model and the J774 cell culture model were used to compare the antibacterial effects of ciprofloxacin against Pseudomonas aeruginosa and moxifloxacin against Streptococcus pneumoniae either in the absence or presence of any immunocompetence. In general, the presence of J774 macrophages resulted in an increased reduction of viable counts by 1 log10 titer. However, an increased killing of the bacteria studied by 3 to 4 log10 titers was seen in the presence of PMN and an inflammatory exudate. This increase in bacterial clearance is very well in agreement with the data obtained in animal models of infection in immunocompetent animals as compared to immunocompromised animals. Thus, it is possible to introduce immunocompetence into an in vitro model in order to simulate pharmacokinetics of antibacterial agents in the presence of an inflammatory exudate and immunocompetent cells. The use of this more complex model may complement the well-established in vitro kinetic simulation models.
Animals↗
Moxifloxacin and ciprofloxacin protect human respiratory epithelial cells against Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae in vitro.
The fluoroquinolones moxifloxacin and ciprofloxacin display excellent in vitro activities against many respiratory tract pathogens. Here we show that moxifloxacin and ciprofloxacin accumulate approximately 7- to 10-fold in primary human respiratory epithelial cells, derived from nasal polyps and grown in 3-dimensional vesicles. Furthermore, using these vesicles, we assessed the bactericidal effect of moxifloxacin on Staphylococcus aureus and Streptococcus pneumoniae and that of ciprofloxacin on Pseudomonas aeruginosa and Haemophilus influenzae. Finally, we determined the protective effect of the fluoroquinolones on vesicles infected with these pathogens. All four bacterial strains were highly toxic for vesicles. S. aureus and S. pneumoniae were readily killed by moxifloxacin regardless whether the antibiotics were present intra/extracellularly or only intracellularly in vesicles. Similar results were obtained for the killing of H. influenzae and P. aeruginosa. Exclusively intracellularly located fluoroquinolones rescued 42% to 76% of the cells after bacterial challenge compared to the rescue of 48% to 94% cells when the fluoroquinolones were present intra/ extracellularly. Without addition of fluoroquinolones cell survival in vesicles was 0% to 38%. The results suggest that intracellular accumulation of moxifloxacin and ciprofloxacin is important for the protection of respiratory epithelial cells from the cytotoxic effects of major respiratory tract pathogens.
Anti-Bacterial Agents↗
Moxifloxacin versus standard therapy in patients with pneumonia hospitalized after failure of preclinical anti-infective treatment.
The failure rate of primary empirical anti-infective treatment of community-acquired pneumonia is reported to range between 2 and 7%. These patients are subject to a greater risk of intensive medical treatment and a higher mortality rate than patients who respond to primary treatment. We investigated 63 patients in a "real life scenario" who were admitted to the hospital after failure of primary outpatient therapy for community-acquired pneumonia. Thirty-three patients received intravenous standard therapy (betalactam 14, macrolide 3, levofloxacin 6, doxycycline 1, combinations 9 patients) while 30 patients were treated with intravenous moxifloxacin. The oral antibiotic pretreatment that failed most frequently was clarithromycin (n = 25), followed by amoxicillin/clavulanic acid (n = 16), cefixime (n = 10), cefuroxime/axetil (n = 5), doxycycline (3), cefpodoxime, and ciprofloxacin (2 each). There were no differences between the two groups in respect of age, gender, numbers of patients in nursing homes, numbers of patients with different underlying diseases (chronic bronchitis, coronary heart disease, diabetes mellitus, smoking, etc.), severity of pneumonia at the time of admission, numbers of patients requiring intensive care, and lethality. The group that underwent standard therapy experienced failure of the empirical intra-hospital antibiotic therapy more often during therapy [10 (30%) patients vs 2 (6%) in the moxifloxacin group, p = 0.009] and clinical failure of treatment on day 28 after initiation of therapy [7 (21%) patients vs 2 (6%) in the moxifloxacin group, p = 0.003]. In cases of failure of empirical preclinical antibiotic treatment for community-acquired pneumonia, subsequent intrahospital treatment with moxifloxacin is more successful than standard therapy in our study reflecting a "real life scenario".
Adult↗
1,N6-etheno-2-aza-adenosine 3',5'-monophosphate: a new fluorescent substrate for cycle nucleotide phosphodiesterase.
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Animals↗
The enzymatic synthesis of L-tryptophan analogues.
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Alcohols↗
Biosynthesis of monoterpenes: inhibition of (+)-pinene and (-)-pinene cyclases by thia and aza analogs of the 4R- and 4S-alpha-terpinyl carbocation.
(+)-Pinene cyclase (synthase) from Salvia officinalis leaf catalyzes the cyclization of geranyl pyrophosphate, via (3R)-linalyl pyrophosphate and the (4R)-alpha-terpinyl cation, to (+)-alpha-pinene and to lesser quantities of stereochemically related monoterpene olefins, whereas (-)-pinene cyclase converts the same achiral precursor, via (3S)-linalyl pyrophosphate and the (4S)-alpha-terpinyl cation, to (-)-alpha-pinene and (-)-beta-pinene and to lesser amounts of related olefins. Racemic thia analogs of the linalyl and alpha-terpinyl carbocation intermediates of the reaction sequence were previously shown to be good uncompetitive inhibitors of monoterpene cyclases, and inhibition was synergized by the presence of inorganic pyrophosphate. These results suggested that the normal reaction proceeds through a series of carbocation:pyrophosphate anion paired intermediates. Both the (4R)- and the (4S)-thia and -aza analogs of the alpha-terpinyl cation were prepared and tested as inhibitors with the antipodal pinene cyclases, both in the absence and in the presence of inorganic pyrophosphate. Although the inhibition kinetics were complex, cooperative binding of the analogs and inorganic pyrophosphate was demonstrated, consistent with ion pairing of intermediates in the course of the normal reaction. Based on the antipodal reactions catalyzed by the pinene cyclases, stereochemical differentiation between the (4R)- and the (4S)-analogs was anticipated; however, neither enzyme effectively distinguished between enantiomers of the thia and aza analogs of the alpha-terpinyl carbocation. Enantioselectivity in the enzymatic conversion of (RS)-alpha-terpinyl pyrophosphate to limonene by the pinene cyclases was also examined. Consistent with the results obtained with the thia and aza analogs, the pinene cyclases were unable to discriminate between enantiomers of alpha-terpinyl pyrophosphate in this unusual reaction. Either the alpha-terpinyl antipodes are too similar to allow differentiation by the pinene cyclases, or these enzymes lack an inherent requirement to distinguish the (4R)- and (4S)-forms because they encounter only one enantiomer in the course of the normal reaction from geranyl pyrophosphate.
Aza Compounds↗
Effect of a diazafluoranthen derivative on phospholipases. A study at the air-water interface.
AC-3579 (2-N-methylpiperazinomethyl-1,3-diazafluoranthen 1-oxide) produces in rat hepatocytes a hypertrophy of the endoplasmic reticulum. Two possibilities that can explain this phenomenon are (1) that AC-3579 inactivates the phospholipases, and (2) that an AC-3579-lipid interaction hinders the enzymic activity. To demonstrate these hypotheses, a physicochemical model of biological membrane, the lipid-water interface, has been used. Dipalmitoyl DL-alpha-phosphatidyl-choline was spread at the air-water interface, the enzymes (phospholipase A or phospholipase C) dissolved in the aqueous phase. The enzymic reaction was first studied with and without AC-3579 dissolved in the aqueous phase; no enzymic inactivation was observed. However an AC-3579-lipid complex completely inhibited the enzymic reaction in the case of phospholipase A. An explanation is given in terms of steric hindrance to the enzyme-substrate.
Air↗
Factors affecting substrate cooperativity of rat liver tryptophan hydroxylase.
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1-Propanol↗