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Levofloxacin, sold under the brand name Levaquin among others, is a broad-spectrum antibiotic of the fluoroquinolone drug class. It is the left-handed isomer of the medication ofloxacin. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori (in combination with other medications), urinary tract infections, Legionnaires' disease, chronic bacterial prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis, meningitis, or pelvic inflammatory disease. It is available by mouth, intravenously, and in eye drop form.
Common side effects include nausea, diarrhea, and trouble sleeping. A warning concerning all fluoroquinolones was issued in 2016: "An FDA safety review has shown that fluoroquinolones when used systemically (i.e. tablets, capsules, and injectable) are associated with disabling and potentially permanent serious adverse effects that can occur together. These adverse effects can involve the tendons, muscles, joints, nerves, and central nervous system."
Other serious side effects may include tendon rupture, tendon inflammation, seizures, psychosis, and potentially permanent peripheral nerve damage. Tendon damage may appear months after treatment is completed. People may also sunburn more easily. In people with myasthenia gravis, muscle weakness and breathing problems may worsen. While use during pregnancy is not recommended, risk appears to be low. The use of other medications in this class appear to be safe while breastfeeding; however, the safety of levofloxacin is unclear.
Levofloxacin was patented in 1985 and approved for medical use in the United States in 1996. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2022, it was the 251st most commonly prescribed medication in the United States, with more than 1 million prescriptions. |
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InChI=1S/C18H20FN3O4/c1-10-9-26-17-14-11(16(23)12(18(24)25)8-22(10)14)7-13(19)15(17)21-5-3-20(2)4-6-21/h7-8,10H,3-6,9H2,1-2H3,(H,24,25)/t10-/m0/s1 |
GSDSWSVVBLHKDQ-JTQLQIEISA-N |
C[C@H]1COC2=C(N3CCN(C)CC3)C(F)=CC3=C2N1C=C(C(O)=O)C3=O |
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Homo sapiens
(NCBI:txid9606)
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Found in
blood plasma
(BTO:0000118).
See:
PubMed
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Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor
A topoisomerase inhibitor that inhibits DNA topoisomerase (ATP-hydrolysing), EC 5.99.1.3 (also known as topoisomerase II and as DNA gyrase), which catalyses ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands.
DNA synthesis inhibitor
Any substance that inhibits the synthesis of DNA.
antibacterial drug
A drug used to treat or prevent bacterial infections.
topoisomerase IV inhibitor
A topoisomerase inhibitor that inhibits DNA topoisomerase IV, which catalyses ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands.
antimicrobial agent
A substance that kills or slows the growth of microorganisms, including bacteria, viruses, fungi and protozoans.
(via quinolone antibiotic )
(via heterocyclic antibiotic )
(via fluoroquinolone antibiotic )
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antibacterial drug
A drug used to treat or prevent bacterial infections.
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View more via ChEBI Ontology
(3S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid
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levofloxacin
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KEGG DRUG
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levofloxacine
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ChemIDplus
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levofloxacino
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ChemIDplus
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levofloxacinum
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ChemIDplus
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(−)-ofloxacin
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ChEBI
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(-)-Ofloxacin
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ChemIDplus
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(3S)-(-)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid
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ChEBI
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(S)-(-)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzooxazine-6-carboxylic acid
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ChEBI
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(S)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid
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ChemIDplus
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(S)-ofloxacin
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ChemIDplus
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DR 3355
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ChEBI
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DR-3355
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ChEBI
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L-ofloxacin
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DrugBank
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Ofloxacin S-(-)-form
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KEGG COMPOUND
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S-(−)-ofloxacin
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ChEBI
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1569
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DrugCentral
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1899
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VSDB
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C07660
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KEGG COMPOUND
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D08120
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KEGG DRUG
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DB01137
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DrugBank
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HMDB0001929
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HMDB
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Levofloxacin
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Wikipedia
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LFX
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PDBeChem
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LSM-5270
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LINCS
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View more database links |
100986-85-4
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CAS Registry Number
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ChemIDplus
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5385660
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Reaxys Registry Number
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Reaxys
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Qin X, Zhong X, Wang B, Wang G, Liu F, Weng L (2023) Fractionation of levofloxacin and ofloxacin during their transport in NOM-goethite: Batch and column studies. Environmental pollution (Barking, Essex : 1987) 316, 120542 [PubMed:36328279] [show Abstract] Adsorption and transport of levofloxacin (LEV) and ofloxacin (OFL) enantiomers in a matrix containing goethite and natural organic matter (NOM) were investigated using batch and column experiments. In batch studies, competition and enantioselectivity were observed in the adsorption of LEV and OFL. Enantioselectivity upon adsorption was investigated by comparing changes in the enantiomer fraction (EF) (the ratio of LEV to the sum of LEV and OFL remaining in the solution) after and before adsorption. At pH < 7, there was hardly any selectivity in adsorption of OFL and LEV to goethite. At pH > 7, OFL showed a stronger adsorption than LEV to goethite, and this preference remained when NOM samples of Leonardite humic acid (LHA) and Elliott Soil fulvic acid (ESFA) were added. However, when Suwannee River NOM (SRNOM) was added, the preference was reversed, and LEV was adsorbed more strongly. In single systems, the presence of different types of NOM increased adsorption of LEV and OFL, especially LEV. In column studies, preloaded NOM decreased the transport of LEV and OFL through goethite-coated sand. The EF values in the effluent increased with retention time and reached the largest values (0.59-0.72) at around 1.5 pore volume (PV), and then decreased again, reaching a stable value at 5.0-30.0 PV. Both batch and column experiments showed that, fractionation of LEV and OFL occurred during adsorption and transport in the presence of NOM-goethite complexes, which would eventually affect their environmental fate. | Kaul G, Karale UB, Akhir A, Shukla M, Saxena D, Rode HB, Chopra S (2022) Pyrvinium pamoate potentiates levofloxacin against levofloxacin-resistant Staphylococcus aureus. Future microbiology 17, 1475-1486 [PubMed:36314364] [show Abstract] Background: Drug repurposing is a viable approach to expediting the tedious conventional drug discovery process, given rapidly increasing bacterial resistance. In this context, we have repurposed pyrvinium pamoate (PP) for its antibacterial activity against Staphylococcus aureus. Methods: US FDA-approved non-antibiotics were screened against clinically relevant bacterial pathogens to identify antibacterials. The hits were further evaluated utilizing a variety of preclinical parameters, following which in vivo efficacy was estimated in isolation and in combination in a murine neutropenic thigh infection model. Result: The screening identified PP exhibiting potent activity against S. aureus along with concentration-dependent killing. PP also showed a post-antibiotic effect of >22 h and significantly eradicated preformed S. aureus biofilms and intracellular S. aureus at 1× and 5× MIC, respectively. PP synergized with levofloxacin both in vitro and in vivo, resulting in ∼1.5 and ∼0.5 log10 CFU/g reduction against susceptible and resistant S. aureus infections, respectively, as compared with untreated control. Conclusion: Pyrvinium potentiates levofloxacin against levofloxacin-resistant S. aureus. | Schwarz C, Procaccianti C, Costa L, Brini R, Friend R, Caivano G, Sadafi H, Mussche C, Schwenck N, Hahn M, Murgia X, Bianco F (2022) Differential Performance and Lung Deposition of Levofloxacin with Different Nebulisers Used in Cystic Fibrosis. International journal of molecular sciences 23, 9597 [PubMed:36076992] [show Abstract] We compared the performance and levofloxacin (Quinsair) lung deposition of three nebulisers commonly used in CF (I-Neb Advance, eFlow rapid, and LC Plus) with the approved nebuliser Zirela. The delivered dose, delivery rate, and aerosol particle size distribution (APSD) for each device were determined using the methods described in the Pharmacopeia. High-resolution computed tomography scans obtained from seven adult patients with mild CF were used to generate computer-aided, three-dimensional models of their airway tree to assess lung deposition using functional respiratory imaging (FRI). The eFlow rapid and the LC Plus showed poor delivery efficiencies due to their high residual volumes. The I-Neb, which only delivers aerosols during the inspiratory phase, achieved the highest aerosol delivery efficiency. However, the I-Neb showed the largest particle size and lowest delivery rate (2.9 mg/min), which were respectively associated with a high extrathoracic deposition and extremely long nebulisation times (>20 min). Zirela showed the best performance considering delivery efficiency (159.6 mg out of a nominal dose of 240 mg), delivery rate (43.5 mg/min), and lung deposition (20% of the nominal dose), requiring less than 5 min to deliver a full dose of levofloxacin. The present study supports the use of drug-specific nebulisers and discourages the off-label use of general-purpose devices with the present levofloxacin formulation since subtherapeutic lung doses and long nebulisation times may compromise treatment efficacy and adherence. | Ben Ayed A, Akrout I, Albert Q, Greff S, Simmler C, Armengaud J, Kielbasa M, Turbé-Doan A, Chaduli D, Navarro D, Bertrand E, Faulds CB, Chamkha M, Maalej A, Zouari-Mechichi H, Sciara G, Mechichi T, Record E (2022) Biotransformation of the Fluoroquinolone, Levofloxacin, by the White-Rot Fungus Coriolopsis gallica. Journal of fungi (Basel, Switzerland) 8, 965 [PubMed:36135690] [show Abstract] The wastewater from hospitals, pharmaceutical industries and more generally human and animal dejections leads to environmental releases of antibiotics that cause severe problems for all living organisms. The aim of this study was to investigate the capacity of three fungal strains to biotransform the fluoroquinolone levofloxacin. The degradation processes were analyzed in solid and liquid media. Among the three fungal strains tested, Coriolopsis gallica strain CLBE55 (BRFM 3473) showed the highest removal efficiency, with a 15% decrease in antibiogram zone of inhibition for Escherichia coli cultured in solid medium and 25% degradation of the antibiotic in liquid medium based on high-performance liquid chromatography (HPLC). Proteomic analysis suggested that laccases and dye-decolorizing peroxidases such as extracellular enzymes could be involved in levofloxacin degradation, with a putative major role for laccases. Degradation products were proposed based on mass spectrometry analysis, and annotation suggested that the main product of biotransformation of levofloxacin by Coriolopsis gallica is an N-oxidized derivative. | Wang Y, Li C, Wang J, Bai N, Zhang H, Chi Y, Cai Y (2022) The Efficacy of Colistin Combined with Amikacin or Levofloxacin against Pseudomonas aeruginosa Biofilm Infection. Microbiology spectrum 10, e0146822 [PubMed:36102678] [show Abstract] Pseudomonas aeruginosa (PA) biofilm infection is clinically prevalent and difficult to eradicate. In the present work, we aimed to evaluate the in vitro and in vivo efficacy of colistin (COL)-based combinations against PA biofilm. MICs and fractional inhibitory concentration indexes (FICIs) of four antibiotics (COL, amikacin, levofloxacin, and meropenem) to bioluminescent strain PAO1, carbapenem-resistant PAO1 (CRPAO1), and clinically isolated strains were assessed. Minimal biofilm eradication concentrations (MBECs) of monotherapy and combinations were examined by counting the live bacteria in biofilm, accompanied by visual confirmation using confocal laser-scanning microscopy. An animal biofilm infection model was established by implanting biofilm subcutaneously, and the therapeutic effect was evaluated according to the change in luminescence through a live animal bio-photonic imaging system. In vitro, even combined with 4 or 8 mg/L COL, meropenem needed to reach 128 or 256 mg/L to eradicate the biofilm. Moreover, 2 mg/L COL combined with 32 mg/L amikacin or 4-8 mg/L levofloxacin could kill the PAO1 and CRPAO1 in biofilm within 24 h. In vivo, COL combined with amikacin or levofloxacin could shorten the eradication time of biofilm than monotherapy. For PAO1 biofilm, combination therapy could eradicate the biofilm in all mice on the 5th day, whereas monotherapy only eradicated biofilms in almost half of the mice. For CRPAO1 biofilm, the biofilm eradication rate on the 6th day in the COL+ amikacin, amikacin, or COL alone regimen was 90%, 10%, or 40%, respectively. COL combined with levofloxacin did not show a better effect than each individual antibiotic. COL-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. IMPORTANCE Infections associated with PA biofilm formation are extremely challenging. When monotherapy fails to achieve optimal efficacy, combination therapy becomes the last option. After evaluating multiple drug combinations through a series of experiments in vitro and in vivo, we confirmed that colistin-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. The efficacy of these combinations derives from the different bactericidal mechanisms and the bacterial susceptibility to each antibiotic. This study provided a new regimen to solve the incurable problem of biofilm by using COL combined with other antibiotics. | Le-Deygen IM, Safronova AS, Kolmogorov IM, Skuredina AA, Kudryashova EV (2022) The Influence of Lipid Matrix Composition on the Microenvironment of Levofloxacin in Liposomal Forms. Russian journal of bioorganic chemistry 48, 710-719 [PubMed:36119964] [show Abstract] We have studied the interaction of the antibacterial drug levofloxacin with lipid bilayers of various compositions: 100% DPPC and with the addition of 20% cardiolipin. For DPPC liposomes, levofloxacin was found to penetrate into the subpolar region at the lipid-water interface. The role of the anionic lipid in the interaction of an active molecule with a bilayer has been established: levofloxacin enters the microenvironment of the phosphate group, displacing water, and does not penetrate into the hydrophobic part of the bilayer. For the first time, the study of the microenvironment of levofloxacin in the liposome by IR and CD spectroscopy was carried out. Such an approach based on a combination of several spectral methods opens up new prospects for the creation of new medicinal properties and the possibility of predicting the nature of the interaction of active molecules with biomembranes in order to predict their efficacy and potential side effects. | Kaczmarek M, Staninski K, Stodolny M (2021) New chemiluminescent method of levofloxacin and ofloxacin determination based on terbium (III)-sensitized fluoroquinolone-KBrO3 reaction. Luminescence : the journal of biological and chemical luminescence 36, 1945-1952 [PubMed:34323366] [show Abstract] Fluoroquinolones can be oxidized with some agents, in this study selected fluoroquinolones (levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, pefloxacin and enrofloxacin) were oxidized with potassium bromate in the presence of terbium (III) ions. According to the kinetic and spectral analysis of chemiluminescence emitted by the above systems, the terbium (III) ions were the only emitter. The excitation of the lanthanide ion was a result of the process of energy transfer from the products of fluoroquinolones oxidation to Tb(III) ions. The highest intensity of chemiluminescence was obtained for levofloxacin and ofloxacin containing an alkoxy substituent at C-8 in the quinoline ring. The chemiluminescence intensity was correlated linearly (r = 0.9994) with the concentration of ofloxacin (or levofloxacin) in the range 1 × 10-6 to 4 × 10-5 mol L-1 ; the detection limit was 3 × 10-7 mol L-1 for both fluoroquinolones. In the optimized conditions, the chemiluminescence of the levofloxacin (or ofloxacin)-Tb(III)-KBrO3 -H2 SO4 systems was used to determine these compounds in a mixture of fluoroquinolones and in pharmaceuticals. | Ornik-Cha A, Wilhelm J, Kobylka J, Sjuts H, Vargiu AV, Malloci G, Reitz J, Seybert A, Frangakis AS, Pos KM (2021) Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms. Nature communications 12, 6919 [PubMed:34824229] [show Abstract] Upon antibiotic stress Gram-negative pathogens deploy resistance-nodulation-cell division-type tripartite efflux pumps. These include a H+/drug antiporter module that recognizes structurally diverse substances, including antibiotics. Here, we show the 3.5 Å structure of subunit AdeB from the Acinetobacter baumannii AdeABC efflux pump solved by single-particle cryo-electron microscopy. The AdeB trimer adopts mainly a resting state with all protomers in a conformation devoid of transport channels or antibiotic binding sites. However, 10% of the protomers adopt a state where three transport channels lead to the closed substrate (deep) binding pocket. A comparison between drug binding of AdeB and Escherichia coli AcrB is made via activity analysis of 20 AdeB variants, selected on basis of side chain interactions with antibiotics observed in the AcrB periplasmic domain X-ray co-structures with fusidic acid (2.3 Å), doxycycline (2.1 Å) and levofloxacin (2.7 Å). AdeABC, compared to AcrAB-TolC, confers higher resistance to E. coli towards polyaromatic compounds and lower resistance towards antibiotic compounds. | Veselkov DA, Laponogov I, Pan XS, Selvarajah J, Skamrova GB, Branstrom A, Narasimhan J, Prasad JV, Fisher LM, Sanderson MR (2016) Structure of a quinolone-stabilized cleavage complex of topoisomerase IV from Klebsiella pneumoniae and comparison with a related Streptococcus pneumoniae complex. Acta crystallographica. Section D, Structural biology 72, 488-496 [PubMed:27050128] [show Abstract] Klebsiella pneumoniae is a Gram-negative bacterium that is responsible for a range of common infections, including pulmonary pneumonia, bloodstream infections and meningitis. Certain strains of Klebsiella have become highly resistant to antibiotics. Despite the vast amount of research carried out on this class of bacteria, the molecular structure of its topoisomerase IV, a type II topoisomerase essential for catalysing chromosomal segregation, had remained unknown. In this paper, the structure of its DNA-cleavage complex is reported at 3.35 Å resolution. The complex is comprised of ParC breakage-reunion and ParE TOPRIM domains of K. pneumoniae topoisomerase IV with DNA stabilized by levofloxacin, a broad-spectrum fluoroquinolone antimicrobial agent. This complex is compared with a similar complex from Streptococcus pneumoniae, which has recently been solved. | Blower TR, Williamson BH, Kerns RJ, Berger JM (2016) Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 113, 1706-1713 [PubMed:26792525] [show Abstract] Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are critical agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were determined in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resolution, show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a reduction in contacts to the water shell of an associated magnesium ion, which bridges fluoroquinolone-gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone-enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compounds that have increased potency against Mtb and the ability to overcome resistance. | Laponogov I, Veselkov DA, Crevel IM, Pan XS, Fisher LM, Sanderson MR (2013) Structure of an 'open' clamp type II topoisomerase-DNA complex provides a mechanism for DNA capture and transport. Nucleic acids research 41, 9911-9923 [PubMed:23965305] [show Abstract] Type II topoisomerases regulate DNA supercoiling and chromosome segregation. They act as ATP-operated clamps that capture a DNA duplex and pass it through a transient DNA break in a second DNA segment via the sequential opening and closure of ATPase-, G-DNA- and C-gates. Here, we present the first 'open clamp' structures of a 3-gate topoisomerase II-DNA complex, the seminal complex engaged in DNA recognition and capture. A high-resolution structure was solved for a (full-length ParE-ParC55)2 dimer of Streptococcus pneumoniae topoisomerase IV bound to two DNA molecules: a closed DNA gate in a B-A-B form double-helical conformation and a second B-form duplex associated with closed C-gate helices at a novel site neighbouring the catalytically important β-pinwheel DNA-binding domain. The protein N gate is present in an 'arms-wide-open' state with the undimerized N-terminal ParE ATPase domains connected to TOPRIM domains via a flexible joint and folded back allowing ready access both for gate and transported DNA segments and cleavage-stabilizing antibacterial drugs. The structure shows the molecular conformations of all three gates at 3.7 Å, the highest resolution achieved for the full complex to date, and illuminates the mechanism of DNA capture and transport by a type II topoisomerase. | Rimbara E, Noguchi N, Kawai T, Sasatsu M (2012) Fluoroquinolone resistance in Helicobacter pylori: role of mutations at position 87 and 91 of GyrA on the level of resistance and identification of a resistance conferring mutation in GyrB. Helicobacter 17, 36-42 [PubMed:22221614] [show Abstract]
Background and aimsFluoroquinolone-containing regimens have been suggested as an alternate to standard triple therapy for the treatment of Helicobacter pylori infections. To determine the relationship between fluoroquinolone resistance and mutations of GyrA and GyrB in H. pylori, we exchanged the mutations at positions 87 and 91 of GyrA among fluoroquinolone-resistant clinical isolates. GyrB of a strain with no mutations in GyrA was also analyzed to identify mechanisms of resistance to norfloxacin.Materials & methodsNatural transformation was performed using the amplified fragment of the gyrA and gyrB gene as donor DNA. The amino acid sequences of GyrA and GyrB were determined by DNA sequencing of the gyrA and gyrB genes.ResultsNorfloxacin-resistant strains which had mutations at position 87 and 91 became susceptible when the mutations were converted to the wild type. When the mutation from Asp to Asn at position 91 was exchanged to the mutation from Asn to Lys at position 87, the MIC to levofloxacin, gatifloxacin, and sitafloxacin increased. Norfloxacin-resistant strain TS132 with no mutations in GyrA but had a mutation at position 463 in GyrB. Transformants obtained by natural transformation using gyrB DNA of TS132 had a mutation at position 463 of GyrB and revealed resistant to norfloxacin and levofloxacin.ConclusionMutation from Asn to Lys at position 87 of GyrA confers higher resistance to levofloxacin and gatifloxacin than does mutation from Asp to Asn at position 91. We propose that mutation at position 463 in GyrB as a novel mechanism of fluoroquinolone resistance in H. pylori. | Sonnet P, Izard D, Mullié C (2012) Prevalence of efflux-mediated ciprofloxacin and levofloxacin resistance in recent clinical isolates of Pseudomonas aeruginosa and its reversal by the efflux pump inhibitors 1-(1-naphthylmethyl)-piperazine and phenylalanine-arginine-β-naphthylamide. International journal of antimicrobial agents 39, 77-80 [PubMed:21974858] [show Abstract] To assess the prevalence of efflux-driven fluoroquinolone (FQ) resistance in recent clinical isolates of Pseudomonas aeruginosa, a worrisome and often hospital-acquired pathogen, 115 unique strains were collected over a 5-month period, of which 27 and 33 had decreased susceptibility to ciprofloxacin (CIP) and levofloxacin (LVX), respectively. The MIC(50) (minimum inhibitory concentration for 50% of the organisms) was 16 μg/mL for both FQs. The efflux pump inhibitors (EPIs) phenylalanine-arginine-β-naphthylamide (PAβN) and 1-(1-naphthylmethyl)-piperazine (NMP) were then used to evaluate their efficacy in reducing CIP and LVX MICs. NMP did not significantly modify CIP MICs, whilst PAβN resulted in MIC(50) values of 2 μg/mL and 0.125 μg/mL for CIP and LVX, respectively. With the addition of PAβN, susceptibility to CIP and LVX was recovered in 6 (22.2%) and 31 (93.9%) strains, respectively. The best combination to reverse FQ resistance in this set of strains was LVX with PAβN. The results of this study show that the effect of an EPI is not only dependent on the species on which it is used but also on the molecule associated with it. Therefore, the design of an EPI equally efficient on all resistance-nodulation-cell division (RND) efflux pumps appears to be difficult and, from a practical point of view, if an EPI is developed for clinical use, the efficiency of its combination with a definite molecule should be assessed carefully against a wide range of clinical isolates to evaluate the real benefit of this combination. | Fukuda Y, Takahata M, Sugiura Y, Shinmura Y, Nomura N (2012) In vitro pharmacodynamic evaluation of garenoxacin against quinolone-resistant Streptococcus pneumoniae. International journal of antimicrobial agents 39, 163-167 [PubMed:22088660] [show Abstract] The bactericidal activity and resistance selectivity of garenoxacin against Streptococcus pneumoniae with mutations in ParC (S79F) or both GyrA (S81F) and ParC (D83Y and K137N) were investigated using in vitro pharmacokinetic models simulating plasma concentrations for a standard clinical regimen [400mg once daily (q.d.)]. The efficacy of garenoxacin was compared with that of levofloxacin (500 mg q.d.) and moxifloxacin (400mg q.d.). Garenoxacin showed excellent bactericidal activity against S. pneumoniae, including quinolone-resistant S. pneumoniae (QRSP), achieving ratios of area under the plasma concentration-time curve over 24h to minimum inhibitory concentration (AUC(0-24)/MIC) ≥ 26.3, without emerging resistant subpopulations. The area above the killing curves was greater and the time to achieve 99.9% killing was shorter for garenoxacin than the corresponding values for levofloxacin and moxifloxacin. No resistant subpopulations and no additional substitution of amino acids in GyrA or ParC emerged following treatment with garenoxacin. On the other hand, in the parC mutant strain, levofloxacin and moxifloxacin treatment caused an increase in the frequency of the resistant population and an additional substitution of amino acids in GyrA (levofloxacin, S81Y/F/C; moxifloxacin, S81Y or E85K). In QRSP with mutations in GyrA and ParC, levofloxacin had no bactericidal activity, whilst the bactericidal activity of moxifloxacin was less than that of garenoxacin; moreover, an additional substitution of amino acids in ParC (S79Y) was noted. In conclusion, garenoxacin corresponding to an oral dose of 400mg showed excellent bactericidal activity against S. pneumoniae, including QRSP, without the emergence of resistant mutants. | Khawcharoenporn T, Vasoo S, Ward E, Singh K (2012) High rates of quinolone resistance among urinary tract infections in the ED. The American journal of emergency medicine 30, 68-74 [PubMed:21075586] [show Abstract]
ObjectivesThe objectives of this study are to examine antibiotic resistance rates and to determine appropriate empiric oral antibiotic for patients with urinary tract infections (UTIs) evaluated and discharged from the ED.MethodsA retrospective, single-institution chart review study from August 2008 to March 2009 was conducted. Adult patients seen in the ED with UTI were identified for study inclusion from review of microbiology records. Hospitalized or asymptomatic bacteriuria cases were excluded. Health care-associated (HA)-UTI was defined as UTI with indwelling urinary catheters, health care exposure, or urologic procedures within 3 months. Prevalence of causative bacteria, antibiotic resistance rates, and risk factors for quinolone resistance were determined.ResultsThere were 337 eligible patients with 83% women. The most common uropathogens among 357 bacterial isolates were Escherichia coli (71%) and Klebsiella spp. (9%). Overall levofloxacin resistance rate was 17%. Resistance rates for HA-UTIs were significantly greater than those for community-associated-UTI: levofloxacin, 38% vs 10%; trimethoprim-sulfamethoxazole, 26% vs 17%; amoxicillin, 53% vs 45%; and amoxicillin-clavulanate, 16% vs 6%. Nitrofurantoin resistance rates were similar (9%). Independent risk factors for levofloxacin resistance were long-term medical conditions (adjusted odds ratio [aOR], 4.23; P = .001), HA-UTI (aOR, 2.56; P = .006), and prior quinolone use within 1 week (aOR, 14.90; P = .02) and within 1 to 4 weeks (aOR, 4.62; P = .04).ConclusionsWe report high rates of quinolone resistance in ED patients with UTIs at our institution. For patients with risk factors for quinolone resistance, empiric therapy with cephalosporins or nitrofurantoin may be preferred. Urine culture and susceptibility testing should be performed to guide definitive therapy for HA-UTIs. | Cuadrado-Lavín A, Salcines-Caviedes JR, Carrascosa MF, Mellado P, Monteagudo I, Llorca J, Cobo M, Campos MR, Ayestarán B, Fernández-Pousa A, González-Colominas E (2012) Antimicrobial susceptibility of Helicobacter pylori to six antibiotics currently used in Spain. The Journal of antimicrobial chemotherapy 67, 170-173 [PubMed:21965436] [show Abstract]
BackgroundAntibiotic resistance is directly related to the loss of efficacy of currently accepted Helicobacter pylori therapies. Knowledge of the antibiotic susceptibility in a local area can contribute to the design of specific 'à la carte' treatments. The aim of this study was to analyse the susceptibility of H. pylori isolates to six conventional antibiotics currently used in a northern region of Spain.MethodsSeventy-one isolates were obtained from gastric biopsies of 76 consecutive adult patients suffering from peptic ulcer disease, dyspepsia or familial gastric cancer and known to be infected with H. pylori by conventional methods. Susceptibility testing was performed for amoxicillin, ciprofloxacin, levofloxacin, clarithromycin, metronidazole and tetracycline using the Etest method.ResultsThe prevalence rates of resistance were as follows: amoxicillin, 1.4% [95% confidence interval (CI) 0.0-7.6]; clarithromycin, 14.7% (95% CI 7.3-25.4); ciprofloxacin, 14.3% (95% CI 7.1-24.7); levofloxacin, 14.5% (95% CI 7.2-25.0); metronidazole, 45.1% (95% CI 33.2-57.3); and tetracycline, 0% (95% CI 0.0-5.1).ConclusionsOur study confirms an increasing rate of resistance to levofloxacin that equals that of clarithromycin in our healthcare area. This fact may reflect a wide and indiscriminate use of the former antibiotic and could account for a loss of clinical effectiveness of levofloxacin-containing regimens. Moreover, clarithromycin resistance rates remain stable, which could allow us to maintain its use in our area. | Laponogov I, Pan XS, Veselkov DA, McAuley KE, Fisher LM, Sanderson MR (2010) Structural basis of gate-DNA breakage and resealing by type II topoisomerases. PloS one 5, e11338 [PubMed:20596531] [show Abstract] Type II DNA topoisomerases are ubiquitous enzymes with essential functions in DNA replication, recombination and transcription. They change DNA topology by forming a transient covalent cleavage complex with a gate-DNA duplex that allows transport of a second duplex though the gate. Despite its biological importance and targeting by anticancer and antibacterial drugs, cleavage complex formation and reversal is not understood for any type II enzyme. To address the mechanism, we have used X-ray crystallography to study sequential states in the formation and reversal of a DNA cleavage complex by topoisomerase IV from Streptococcus pneumoniae, the bacterial type II enzyme involved in chromosome segregation. A high resolution structure of the complex captured by a novel antibacterial dione reveals two drug molecules intercalated at a cleaved B-form DNA gate and anchored by drug-specific protein contacts. Dione release generated drug-free cleaved and resealed DNA complexes in which the DNA gate instead adopts an unusual A/B-form helical conformation with a Mg(2+) ion repositioned to coordinate each scissile phosphodiester group and promote reversible cleavage by active-site tyrosines. These structures, the first for putative reaction intermediates of a type II topoisomerase, suggest how a type II enzyme reseals DNA during its normal reaction cycle and illuminate aspects of drug arrest important for the development of new topoisomerase-targeting therapeutics. | Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910-914 [PubMed:19212411] [show Abstract] Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity. | Zhou ZL, Yang M, Yu XY, Peng HY, Shan ZX, Chen SZ, Lin QX, Liu XY, Chen TF, Zhou SF, Lin SG (2007) A rapid and simple high-performance liquid chromatography method for the determination of human plasma levofloxacin concentration and its application to bioequivalence studies. Biomedical chromatography : BMC 21, 1045-1051 [PubMed:17549677] [show Abstract] A high-performance liquid chromatography method with fluorescence detection (HPLC-FLD) for the determination of levofloxacin in human plasma is described. Neutralized with phosphate buffer (pH 7.0), the sample (0.1 mL) was extracted with dichlormethane (1 mL). After voltex-mixing and centrifuged at 3000g for 6 min at 4 degrees C, the upper aqueous layer was aspirated using a micro vacuum pump and the organic layer was directly transferred to a clean test tube without pipetting. The organic solvent was evaporated and the residues were reconstituted with the mobile phase. Levofloxacin and terazosin (internal standard, IS) were chromatographically separated on a C(18) column with a mobile phase containing phosphate buffer (pH 3.0, 10 mm), acetonitrile and triethylamine (76:24:0.076, v/v/v) at a flow rate of 1 mL/min. The analytes were detected using fluorescence detection at an excitation and emission wavelength of 295 and 440 nm, respectively. The linear range of the calibration curves was 0.0521-5.213 microg/mL for levofloxacin with a lower limit of quantitation (0.0521 microg/mL). The retention times of levofloxacin and terazosin were 2.5 and 3.1 min, respectively. Within- and between-run precision was less than 12 and 11%, respectively. Accuracy ranged from -6.3 to 4.5%. The recovery ranged from 86 to 89% at the concentrations of 0.0521, 0.5213 and 5.213 microg/mL. The present HPLC-FLD method is sensitive, efficient and reliable. The method described herein has been successfully used for the pharmacokinetic and bioequivalence studies of a levofloxacin formulation product after oral administration to healthy Chinese volunteers. | Martínez Martínez MS, Gandarillas CI, Martínez Lanao J, Sánchez Navarro A (2005) Comparative study of the disposition of levofloxacin, netilmicin and cefepime in the isolated rat lung. The Journal of pharmacy and pharmacology 57, 861-867 [PubMed:15969945] [show Abstract] An experimental model of artificially perfused and mechanically ventilated lung has been applied to compare the kinetic behaviour of levofloxacin, cefepime and netilmicin in this body tissue. The study has been performed to explore the usefulness of the isolated lung technique in the pharmacokinetic field, particularly to study the disposition of antibiotics in pulmonary tissue. The lung was perfused with Krebs-Henseleit medium containing 3% bovine albumin at a flow rate of 5 mL min(-1). It was ventilated at 60 respirations/min with a 2-mL tidal volume of air previously humidified and warmed to 37 degrees C. The concentrations of the above antibiotics were determined by HPLC techniques and the outflow curves were analysed by stochastic, as well as by model-dependent, methods. The results show pharmacokinetic differences among these antibiotics, which are in accordance with previously reported data, levofloxacin being the drug with the highest distribution coefficient in this tissue (1.25 +/- 0.14 vs 0.39 +/- 0.07 and 0.41 +/- 0.06 mL g(-1) for netilmicin and cefepime, respectively). Accordingly, the isolated lung of the rat, under the experimental conditions used here, constitutes an alternative model to be incorporated to pharmacokinetic studies with a great potential use for those drugs that show a pharmacological or toxicological action depending on the kinetic profile in the lung tissue. | Bielecka-Grzela S, Klimowicz A (2003) Evaluation of ofloxacin penetration into the skin after a single oral dose assessed by cutaneous microdialysis. Polish journal of pharmacology 55, 613-618 [PubMed:14581720] [show Abstract] An antibacterial drug can exert its therapeutic action if it is present in target tissue at proper concentration. Cutaneous microdialysis is a relatively new technique, which allows to determine drug concentration in the skin. The aim of the study was to evaluate the ofloxacin concentrations in plasma and skin following a single oral dose of 0.4 g. Drug concentration in the skin was assessed by applying cutaneous microdialysis. The penetration of the studied agent into dermal microdialysate was compared with its penetration into theoretical peripheral compartment. Maximum ofloxacin concentration in plasma was 9.26 micromol/l on average and was achieved after about 1.7 h. Mean peak concentrations in cutaneous microdialysate and in theoretical peripheral compartment were comparable (4.16 versus 4.50 micromol/l), but time to peak concentration in theoretical peripheral compartment was significantly longer than in microdialysates (5.8 and 2.0 h, respectively). Degree of penetration into cutaneous microdialysate was about 0.54. Cutaneous microdialysis seems to be a valuable technique to evaluate drug penetration into the skin. | Chow AT, Chen A, Lattime H, Morgan N, Wong F, Fowler C, Williams RR (2002) Penetration of levofloxacin into skin tissue after oral administration of multiple 750 mg once-daily doses. Journal of clinical pharmacy and therapeutics 27, 143-150 [PubMed:11975700] [show Abstract]
ObjectiveTo probe the pharmacokinetic basis for the use of levofloxacin for complicated skin and skin-structure infections (SSSIs) at a once-daily dosage of 750 mg by investigating its penetration into skin tissue.MethodTen healthy volunteers were administered three oral, once-daily 750 mg doses of levofloxacin, and levofloxacin concentrations were subsequently measured over time (0.5-24 h) in skin-punch biopsy tissue and plasma.ResultsSkin tissue concentrations consistently exceeded those in plasma at every time point, with tissue/plasma ratios of 1.37 +/- 0.81 for peak concentration and 1.97 +/- 0.35 for area under the concentration versus time curve. Three of the ten subjects reported treatment-emergent adverse events (AEs) that were considered unrelated to treatment. An 11th subject who had enrolled in the study withdrew after AEs of mild severity that were possibly related to the study drug.ConclusionThe results support the clinical usage of levofloxacin 750 mg once-daily for complicated SSSIs. | Ozawa TT, Valadez T (2002) Clostridium difficile infection associated with levofloxacin treatment. Tennessee medicine : journal of the Tennessee Medical Association 95, 113-115 [PubMed:11898264] [show Abstract] Nine cases of Clostridium difficile (CD) infection were observed in the period of six months at a nursing home. Eight of them occurred during or after antibiotic treatment. Levofloxacin was used alone in three cases and in combination with another antibiotic in three other cases. CD infection occurred with other antibiotics in two cases. In one case, CD infection occurred without any antibiotic treatment. It is generally accepted that quinolones rarely cause CD infection. Levofloxacin, a new antibiotic of a quinolone group, appears to be an exception. Considering the endemic level of CD infection and the high mortality and morbidity among elderly residents in the long-term care facilities, CD infection should be considered one of the major adverse effects of antibiotic therapy. Physicians are cautioned to prescribe antibiotics judiciously and to anticipate CD infection during and after antibiotic treatment. | Budanov SV, Smirnova LB (2001) [Levofloxacin (Tavanic)--a novel quinolone of the III generation. Antimicrobial activity, pharmacokinetics, clinical significance]. Antibiotiki i khimioterapiia = Antibiotics and chemoterapy [sic] 46, 31-38 [PubMed:11558453] | Berning SE, Cherry TA, Iseman MD (2001) Novel treatment of meningitis caused by multidrug-resistant Mycobacterium tuberculosis with intrathecal levofloxacin and amikacin: case report. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 32, 643-646 [PubMed:11181130] [show Abstract] We report the case of a 25-year-old HIV-negative man with disseminated multidrug-resistant tuberculosis (MDRTB), who-on a retreatment regimen-experienced total resolution of TB miliary disease, but progressive TB meningitis. Therefore, intrathecal treatment with amikacin and levofloxacin was instituted, with successful clinical and microbiological results. | Kalbermatter V, Bagilet D, Diab M, Javkin E (2000) [Oral levofloxacin versus intravenous ceftriaxone and amoxicillin/clavulanic acid in the treatment of community-acquired pneumonia that requires hospitalization]. Medicina clinica 115, 561-563 [PubMed:11141388] [show Abstract]
BackgroundLevofloxacin, an antibiotic from the quinolone family, which is used with success in the ambulatory treatment of patients with community-acquired pneumonia, has been recently introduced to the pharmaceutical market. The purpose of this study was to compare the effectiveness and tolerance of oral (v.o.) levofloxacin (LVF) versus intravenous (i.v.) amoxicillin/clavulanate (AMX/CL) and ceftriaxone (CTX) in the treatment of the community-acquired pneumonia that require hospitalization (CAPH).Patients and methodIn this prospective and randomized study 84 patients were included, 28 per group, from both sex with CAPH. The patients were assigned randomly to receive one of the next treatments: AMX/CL, 1.02 g i.v. every 8 h, CTX, 1 g i.v. every 12 h or LVF, 500 mg v.o. every 24 h. At the beginning clinical, biochemical and radiological characteristics were recorded from each case and at the 72 h the effect of treatment was evaluated using the evolution of the thermal curve and radiological images. The quantitative variables were analyzed with ANOVA, the qualitatives parameters with *2 test and Yates correction. The level of signification was * = 0.05.ResultsAge, sex, clinical presentation, biochemical measurements and radiological images in the 3 groups were similar and no adverse effects were recorded in any of them. Number of patients with favorable outcome in the groups AMX/CL, CTX and LVF was 25 (89%), 25 (89%) and 26 (93%); p = 0,870.ConclusionsLevofloxacin can be a simple, effective and safe therapeutic option for patients with CAPH. | Isogai E, Isogai H, Hayashi S, Kubota T, Kimura K, Fujii N, Ohtani T, Sato K (2000) Effect of antibiotics, levofloxacin and fosfomycin, on a mouse model with Escherichia coli O157 infection. Microbiology and immunology 44, 89-95 [PubMed:10803495] [show Abstract] There have been some reservations about the treatment of enterohemorrhagic Escherichia coli (EHEC) infection with antibiotics to prevent the occurrence of hemolytic uremic syndrome (HUS). However, the administration of antimicrobial agents for EHEC infection is under discussion. Therefore, we used an experimental mouse model to assess the advantage/disadvantage of two major antibiotics, levofloxacin (LVFX) and fosfomycin (FOM). Germ-free IQI mice were inoculated with EHEC O157 strain EDL931 or #7. Bacteria colonized feces at 10(9)-10(10) CFU/g, and Shiga toxins (STXs) were detected in the feces. From 1 day after infection, mice were assigned to LVFX (20 mg/kg) once daily or FOM (400 mg/kg) once daily. A significant decrease in overall mortality was observed after treatment of LVFX, with EHEC disappearing immediately from the feces of mice. FOM also reduced mortality for one strain, the STX level decreased gradually. LVFX exhibited higher therapeutic efficacy than FOM. Strain differences were observed in the model during the treatment. | Norrby SR (1999) Levofloxacin. Expert opinion on pharmacotherapy 1, 109-119 [PubMed:11249554] [show Abstract] Levofloxacin (DR-3355, Daiichi) is a new fluoroquinolone antibiotic which is the active isomer of ofloxacin (DL-8280, Daiichi). By removing the inactive isomer, the in vitro activity of levofloxacin is 8-128 times higher than that of ofloxacin. This means that bacterial species, which have borderline susceptibility to ofloxacin and other first generation fluoroquinolones (e.g., pneumococci and organisms causing atypical pneumonia), are considerably more sensitive to levofloxacin. The pharmacokinetics of levofloxacin, which is available for both oral and i.v. administration, are characterised by a very high bioavailability, low (30-40%) protein binding, high tissue concentrations and elimination via the kidneys with minimal liver metabolism. As a consequence of the low degree of metabolism, levofloxacin does not interact with other drugs to any major extent. The safety and efficacy of levofloxacin are well documented in lower respiratory tract infections, skin and soft tissue infections, and urinary tract infections. The safety profile seems advantageous and the risks of phototoxicity, CNS toxicity and cardiac reactions (prolongation of QT-time) are low. Serious liver toxicity, leading to the recent withdrawal of trovafloxacin, has not been a problem in levofloxacin studies. Levofloxacin is a valuable addition to the group of fluoroquinolone antibiotics. | Nicodemo AC, Robledo JA, Jasovich A, Neto W (1998) A multicentre, double-blind, randomised study comparing the efficacy and safety of oral levofloxacin versus ciprofloxacin in the treatment of uncomplicated skin and skin structure infections. International journal of clinical practice 52, 69-74 [PubMed:9624783] [show Abstract] A multicentre, randomised, double-blind trial in Latin America compared oral levofloxacin 500 mg once daily for 7 days with oral ciprofloxacin 500 mg twice daily for 10 days in 272 patients with uncomplicated skin and skin structure infections. Among 253 subjects evaluable for clinical efficacy (129 levofloxacin, 124 ciprofloxacin), clinical success (cure and improvement) was observed in 96.1% of levofloxacin-treated patients and in 93.5% of ciprofloxacin-treated patients. Overall, bacteriological eradication rates by pathogen were 93.2% and 91.7%, respectively. Levofloxacin eradicated 94% (66/70) of Staphylococcus aureus and 94% (17/18) of Streptococcus pyogenes isolates, compared with 93% (70/75) and 92% (12/13) for ciprofloxacin. Microbiological eradication rates by subject were approximately 93% and 90% for the levofloxacin and ciprofloxacin groups, respectively. Drug-related adverse events were reported by 8.9% of those receiving levofloxacin and 8.2% of those administered ciprofloxacin. Findings support the efficacy of oral levofloxacin for uncomplicated skin and skin structure infections due to S. aureus and S. pyogenes. | Fish DN, Chow AT (1997) The clinical pharmacokinetics of levofloxacin. Clinical pharmacokinetics 32, 101-119 [PubMed:9068926] [show Abstract] Levofloxacin is a fluoroquinolone antibiotic and is the optical S-(-) isomer of the racemic drug substance ofloxacin. It has a broad spectrum of in vitro activity against Gram-positive and Gram-negative bacteria, as well as certain other pathogens such as Mycoplasma, Chlamydia, Legionella and Mycobacteria spp. Levofloxacin is significantly more active against bacterial pathogens than R-(+)-ofloxacin. Levofloxacin hemihydrate, the commercially formulated product, is 97.6% levofloxacin by weight. Levofloxacin pharmacokinetics are described by a linear 2-compartment open model with first-order elimination. Plasma concentrations in healthy volunteers reach a mean peak drug plasma concentration (Cmax) of approximately 2.8 and 5.2 mg/L within 1 to 2 hours after oral administration of levofloxacin 250 and 500mg tablets, respectively. The bioavailability of oral levofloxacin approaches 100% and is little affected by the administration with food. Oral absorption is very rapid and complete, with little difference in the serum concentration-time profiles following 500mg oral or intravenous (infused over 60 minutes) doses. Single oral doses of levofloxacin 50 to 1000mg produce a mean Cmax and area under the concentration-time curve (AUC) ranging from approximately 0.6 to 9.4 mg/L and 4.7 to 108 mg.h/L, respectively, both increasing linearly in a dose-proportional fashion. The pharmacokinetics of levofloxacin are similar during multiple-dose regimens to those following single doses. Levofloxacin is widely distributed throughout the body, with a mean volume of distribution of 1.1 L/kg, and penetrates well into most body tissues and fluids. Drug concentrations in tissues and fluids are generally greater than those observed in plasma, but penetration into the cerebrospinal fluid is relatively poor (concentrations approximately 16% of simultaneous plasma values). Levofloxacin is approximately 24 to 38% bound to serum plasma proteins (primarily albumin); serum protein binding is independent of serum drug concentrations. The plasma elimination half-life (t1/2 beta) ranges from 6 to 8 hours in individuals with normal renal function. Approximately 80% of levofloxacin is eliminated as unchanged drug in the urine through glomerular filtration and tubular secretion; minimal metabolism occurs with the formation of no metabolites possessing relevant pharmacological activity. Renal clearance and total body clearance are highly correlated with creatinine clearance (CLCR), and dosage adjustments are required in patients with significant renal dysfunction. Levofloxacin pharmacokinetics are not appreciably affected by age, gender or race when differences in renal function, and body mass and composition are taken into account. Important drug interactions exist with aluminium- and magnesium-containing antacids and ferrous sulfate, as with other fluoroquinolones, resulting in significantly decreased levofloxacin absorption when administered concurrently. These agents should be administered at least 2 hours before or after levofloxacin administration. Cimetidine and probenecid decrease levofloxacin renal clearance and increase t1/2 beta; the magnitudes of these interactions are not clinically significant. Levofloxacin appears to have only minor potential for significantly altering the pharmacokinetics of theophylline, warfarin, zidovudine, ranitidine, digoxin or cyclosporin; however, patients receiving these drugs concurrently should be monitored closely for signs of enhanced pharmacological effect or toxicity. Levofloxacin pharmacokinetics are not significantly altered by sucralfate when administration of these drugs is separated by at least 2 hours. | Yoshimura T, Kurita C, Usami E, Nakao T, Watanabe S, Kobayashi J, Yamazaki F, Nagai H (1996) Immunomodulatory action of levofloxacin on cytokine production by human peripheral blood mononuclear cells. Chemotherapy 42, 459-464 [PubMed:8957581] [show Abstract] Levofloxacin (LVFX), the bacteriologically active isomer of ofloxacin, is a fluorinated quinolone. LVFX suppressed the proliferative activity of peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin (PHA). LVFX increased interleukin-2 (IL-2) production by PBMC stimulated with PHA in a dose-dependent manner, with more than 10 micrograms/ml of LVFX causing a significant increase. The granulocyte-macrophage colony-stimulating factor and soluble IL-2 receptor production by PHA-stimulated PBMC was suppressed at high concentrations of LVFX. Interleukin-1 beta production by lipopolysaccharide-stimulated PBMC was suppressed in a concentration-dependent manner by LVFX, and tumor necrosis factor-alpha production was suppressed at only the highest concentration. In contrast, interleukin-8 production was little affected by LVFX. These results show that LVFX has an immunomodulatory action on cytokines production by PBMC independent of its antimicrobial activity. | Oya S, Takemoto A, Hosaka K, Kudou Y, Arakawa M (1995) [In vitro antimicrobial activity of a new quinolone, levofloxacin, against atypical mycobacteria]. Kekkaku : [Tuberculosis] 70, 615-619 [PubMed:8656585] [show Abstract] We measured th in vitro antimicrobial activity of a new quinolone, levofloxacin (LVFX) against seven clinically isolated species of atypical mycobacteria, including 30 strains of M. avium complex. 8 of M. fortuitum, 4 of M. scrofulaceum, 2 of M. kansasii, 2 of M. gordonae, and 1 of M. chelonae (subsp chelonae). LVFX showed a potent antimicrobial activity against M. kansasii, M. gordonae and M. chelonae (subsp chelonae). In addition, it was suggested that LVFX may be effective for the treatment of infections caused by M. avium complex, since satisfactory antimicrobial activity was displayed against some strains of M. avium complex. Considering the fact that LVFX shows good concentration levers in sputum, this drug could be used in the chemotherapy against the infection with M. avium complex. | Tanaka M, Otsuki M, Une T, Nishino T (1990) In-vitro and in-vivo activity of DR-3355, an optically active isomer of ofloxacin. The Journal of antimicrobial chemotherapy 26, 659-666 [PubMed:2079448] [show Abstract] DR-3355 [S-(-)-ofloxacin], an optically active isomer of ofloxacin, showed a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative bacteria and was generally twice as potent as ofloxacin and considerably more active than DR-3354 [R-(+)-ofloxacin]. The activity of DR-3355 was largely unaffected by the type of culture medium, inoculum size and addition of human serum, but decreased under acidic condition at pH 6.0. The protective effect of orally administered DR-3355 in experimental infections in mice with various bacterial pathogens was superior to those of ofloxacin and ciprofloxacin. |
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