linezolid and Staphylococcal-Infections

Topics: Acetamides; Anti-Bacterial Agents; Chromosomes, Bacterial; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Skin Diseases; Staphylococcal Infections; Vancomycin

A set of structurally related diphenylurea derivatives bearing aminoguanidine moiety were synthesized, and their antibacterial activity was assessed against a panel of multi-drug resistant Gram-positive clinical isolates. Two compounds 6 and 24 were identified with better bacteriological profile than the lead compound I. The multi-step resistance development studies indicated that MRSA are less likely to develop resistance toward diphenylurea compounds. Moreover, these compounds demonstrated a prolonged post-antibiotic effect than that of vancomycin. Furthermore, compounds 6 and 24 were able to re-sensitize VRSA to vancomycin, resulting in 8- to more than 32-fold improvement in vancomycin MIC values against clinical VRSA isolates. Finally, when assessed in an in vivo skin infection mouse model, the efficacy of compound 24 was very comparable to that of the commercially available fusidic acid ointment. Additionally, the diphenylurea 24 did not have a pronounced effect on the animal weights along the experiment indicating its safety and tolerability to mice. Taken together, these results indicate that the diphenylurea scaffold merits further investigation as a promising anti-staphylococcal treatment option.

Topics: Animals; Anti-Bacterial Agents; Methicillin; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Vancomycin; Vancomycin-Resistant Staphylococcus aureus

The genus

Topics: Animals; Anti-Bacterial Agents; Artocarpus; Biofilms; Flavonoids; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

Pathogenic bacteria demonstrate incredible abilities to evade conventional antibiotics through the development of resistance and formation of dormant, surface-attached biofilms. Therefore, agents that target and eradicate planktonic and biofilm bacteria are of significant interest. We explored a new series of halogenated phenazines (HP) through the use of

Topics: Aniline Compounds; Animals; Anti-Bacterial Agents; Biofilms; Cell Line; Cell Survival; Disease Models, Animal; Drug Design; Female; Halogenation; Humans; Iron; Iron Deficiencies; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Phenazines; Staphylococcal Infections; Structure-Activity Relationship; Wound Healing

The increasing emergence of antibiotic-resistant bacterial pathogens calls for additional urgency in the development of new antibacterial candidates. N-Phenyl-2-aminothiazoles are promising candidates that possess potent anti-MRSA activity and could potentially replenish the MRSA antibiotic pipeline. The initial screen of a series of compounds in this novel class against several bacterial strains revealed that the aminoguanidine analogues possessed promising activities and superior safety profiles. The determined MICs of these compounds were comparable to, if not better than, those of the control drugs (linezolid and vancomycin). Remarkably, compounds 3a, 3b, and 3e possessed potent activities against multidrug resistant staphylococcal isolates and several clinically important pathogens, such as vancomycin-resistant enterococci (VRE) and Streptococcus pneumoniae. In addition, the compounds were superior to vancomycin in the rapid killing of MRSA and the longer post-antibiotic effects. Furthermore, low concentrations of compounds 3a, 3b, and 3e reduced the intracellular burden of MRSA by greater than 90%. Initial in vitro PK/toxicity assessments revealed that compound 3e was highly tolerable and possessed a low metabolic clearance rate and a highly acceptable half-life.

Topics: Animals; Anti-Bacterial Agents; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Molecular Structure; Staphylococcal Infections; Structure-Activity Relationship; Thiazoles

Antibiotic resistance remains a major global public health threat that requires sustained discovery of novel antibacterial agents with unexploited scaffolds. Structure-activity relationship of the first-generation aryl isonitrile compounds we synthesized led to an initial lead molecule that informed the synthesis of a second-generation of aryl isonitriles. From this new series of 20 compounds, three analogues inhibited growth of methicillin-resistant Staphylococcus aureus (MRSA) (from 1 to 4 µM) and were safe to human keratinocytes. Compound 19, with an additional isonitrile group exhibited improved activity against MRSA compared to the first-generation lead compound. This compound emerged as a candidate worthy of further investigation and further reinforced the importance of the isonitrile functionality in the compounds' anti-MRSA activity. In a murine skin wound model, 19 significantly reduced the burden of MRSA, similar to the antibiotic fusidic acid. In summary, 19 was identified as a new lead aryl isonitrile compound effective against MRSA.

Topics: Animals; Anti-Bacterial Agents; Cell Line; Cell Survival; Disease Models, Animal; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Nitriles; Skin Diseases; Staphylococcal Infections

Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (

Topics: Adamantane; Aminobenzoates; Anilides; Animals; Anti-Bacterial Agents; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Models, Molecular; Peritonitis; Small Molecule Libraries; Staphylococcal Infections; Staphylococcus

A novel series of phenylthiazoles bearing cyclic amines at the phenyl-4 position was prepared with the objective of decreasing lipophilicity and improving the overall physicochemical properties and pharmacokinetic profile of the compounds. Briefly, the piperidine ring (compounds 10 and 12) provided the best ring size in terms of antibacterial activity when tested against 16 multidrug-resistant clinical isolates. Both compounds were superior to vancomycin in the ability to eliminate methicillin-resistant Staphylococcus aureus (MRSA), residing within infected macrophages and to disrupt mature MRSA biofilm. Additionally, compounds 10 and 12 exhibited a fast-bactericidal mode of action in vitro. Furthermore, the new derivatives were 160-times more soluble in water than the previous lead compound 1b. Consequently, compound 10 was orally bioavailable with a highly-acceptable pharmacokinetic profile in vivo that exhibited a half-life of 4 h and achieved a maximum plasma concentration that exceeded the minimum inhibitory concentration (MIC) values against all tested bacterial isolates.

Topics: Amines; Animals; Anti-Bacterial Agents; Cell Line; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Humans; Macrophages; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Molecular Structure; Obesity; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Structure-Activity Relationship; Thiazoles

Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Bacterial; Humans; Linezolid; Methicillin; Mice; Microbial Sensitivity Tests; Molecular Structure; Oxidoreductases; Piperonyl Butoxide; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Vancomycin

A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 9 h.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Caco-2 Cells; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rats, Sprague-Dawley; Staphylococcal Infections; Thiazoles

Platensimycin (PTM), originally isolated from soil bacteria Streptomyces platensis, is a potent FabF inhibitor against many Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. However, the further clinical development of PTM is hampered by its poor pharmacokinetic properties. In this study, 20 PTM derivatives were prepared by Suzuki-Miyaura cross-coupling reactions catalyzed by Pd (0)/C. Compared to PTM, 6-pyrenyl PTM (6t) showed improved antibacterial activity against MRSA in a mouse peritonitis model. Our results support the strategy to target the essential fatty acid synthases in major pathogens, in order to discover and develop new generations of antibiotics.

Topics: Adamantane; Aminobenzoates; Anilides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Docking Simulation; Peritonitis; Staphylococcal Infections

A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.

Topics: Animals; Anti-Bacterial Agents; Caenorhabditis elegans; Carbanilides; Drug Resistance, Bacterial; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

Our previous work ( Wang et al. J. Med. Chem. 2016 , 59 , 4831 - 4848 ) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Drug Resistance, Bacterial; Ether-A-Go-Go Potassium Channels; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Structure-Activity Relationship; Vancomycin; Vancomycin Resistance; Xanthophylls

Drug resistant infections are becoming common worldwide and new strategies for drug development are necessary. Here, we report the synthesis and evaluation of 2,4-dinitrophenylsulfonamides, which are donors of sulfur dioxide (SO2), a reactive sulfur species, as methicillin-resistant Staphylococcus aureus (MRSA) inhibitors. N-(3-Methoxyphenyl)-2,4-dinitro-N-(prop-2-yn-1-yl)benzenesulfonamide (5e) was found to have excellent in vitro MRSA inhibitory potency. This compound is cell permeable and treatment of MRSA cells with 5e depleted intracellular thiols and enhanced oxidative species both results consistent with a mechanism involving thiol activation to produce SO2.

Topics: Anti-Bacterial Agents; Drug Design; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Prodrugs; Staphylococcal Infections; Structure-Activity Relationship; Sulfhydryl Compounds; Sulfur Dioxide

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 μg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.

Topics: Aminopyridines; Animals; Anti-Bacterial Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Diterpenes; Drug Design; Drug Resistance, Bacterial; Drug Stability; Female; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Pleuromutilins; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Solubility; Staphylococcal Infections; Staphylococcus; Streptococcus; Structure-Activity Relationship; Sulfides

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

Topics: Adenosine Triphosphatases; Amides; Animals; Anti-Bacterial Agents; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Mice; Mice, Knockout; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pyrroles; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Thiazoles; Topoisomerase II Inhibitors

The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.

Topics: Animals; Anti-Bacterial Agents; Barbiturates; Female; Fluoroquinolones; Heterocyclic Compounds, 4 or More Rings; Humans; Inhibitory Concentration 50; Isoxazoles; Male; Mice; Pyridones; Rats, Wistar; Spiro Compounds; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Structure-Activity Relationship; Topoisomerase II Inhibitors

We synthesized a series of oxazolidinone analogues bearing a N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit as homologues of an earlier drug candidate, eperezolid. Several of these compounds exhibited potent in vitro antibacterial activities towards not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. Compounds 21a and 21b, bearing a thiocarbamate side chain, showed high in vivo activity against methicillin-resistant Staphylococcus aureus SR3637, together with a promising safety profile in terms of weak inhibition of monoamine oxidase and cytochrome P450 isozymes.

Topics: Animals; Anti-Bacterial Agents; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Models, Chemical; Molecular Structure; Monoamine Oxidase; Oxazolidinones; Prosencephalon; Rats; Staphylococcal Infections; Structure-Activity Relationship

Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. N-Linked amino piperidines, such as 7a, generally show potent antibacterial activity, including against quinolone-resistant isolates, but suffer from hERG inhibition (IC(50) = 44 μM for 7a) and QT prolongation in vivo. We now disclose the finding that new analogues of 7a with reduced pK(a) due to substitution with an electron-withdrawing substituent in the piperidine moiety, such as R,S-7c, retained the Gram-positive activity of 7a but showed significantly less hERG inhibition (IC(50) = 233 μM for R,S-7c). This compound exhibited moderate clearance in dog, promising efficacy against a MRSA strain in a mouse infection model, and an improved in vivo QT profile as measured in a guinea pig in vivo model. As a result of its promising activity, R,S-7c was advanced into phase I clinical studies.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Biological Availability; Dioxanes; DNA Topoisomerase IV; Dogs; Drug Resistance, Bacterial; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Piperidines; Quinolones; Staphylococcal Infections; Stereoisomerism; Structure-Activity Relationship; Topoisomerase II Inhibitors

Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N(2)-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N(2)-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10μg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice.

Topics: Animals; Anti-Bacterial Agents; DNA Polymerase III; Enzyme Inhibitors; Escherichia coli; Gram-Positive Bacteria; Guanine; Mice; Microbial Sensitivity Tests; Staphylococcal Infections

A series of novel benzoxazinyl-oxazolidinones bearing nonaromatic heterocycle or aryl groups were designed and synthesized. Their in vitro and in vivo antibacterial activities were investigated. Most of the (3S, 3aS) biaryl benzoxazinyl-oxazolidinones exhibited potent activity against Gram-positive pathogens. SAR trends were observed; a pyridyl C ring was preferable to other 5- or 6-member aryl C rings, while fluorine substitution on the B ring generated derivatives with reduced activity. Various substituent group positions on the pyridyl ring were also evaluated. The resulting compounds displayed excellent activity against linezolid-resistant strains. Compound 45 exhibited excellent in vitro activity, with a MIC value of 0.25-0.5 μg/mL against MRSA and an activity against linezolid-resistant strains of 8-16-fold higher potency than linezolid. In a MRSA systemic infection model, compound 45 displayed an ED(50) < 5.0 mg/kg, a potency that is nearly 3-fold better than that of linezolid. This compound also showed excellent pharmacokinetic profiles, with a half-life of more than 5 h as well as an oral bioavailability of 81% in rats.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Benzoxazines; Biological Availability; Crystallography, X-Ray; Drug Design; Drug Resistance, Bacterial; Female; Gram-Positive Bacteria; Linezolid; Male; Mice; Microbial Sensitivity Tests; Molecular Structure; Oxazolidinones; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Stereoisomerism; Structure-Activity Relationship

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (methicillin-susceptible S. aureus [MSSA]), S. aureus OC 8525 (MRSA), Pseudomonas aeruginosa OC 4351 (having an inducible AmpC beta-lactamase), and P. aeruginosa OC 4354 (overproducing AmpC beta-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC beta-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Bacterial Proteins; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Dose-Response Relationship, Drug; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Half-Life; Immunocompromised Host; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Hairless; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Skin Diseases, Infectious; Staphylococcal Infections; Staphylococcus aureus

The in vitro activity of TR-700 (torezolid) was evaluated against a collection of 660 staphylococcal blood isolates. TR-700 showed excellent activity against all the staphylococci tested. The MIC(50) and MIC(90) values of TR-700, linezolid, daptomycin, and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) isolates were 0.25 and 0.5, 2 and 4, 0.5 and 0.5, and 1 and 2 microg/ml, respectively. TR-700 demonstrated greater in vitro potency than linezolid against staphylococci, including linezolid-resistant and vancomycin-nonsusceptible strains, and was 32-fold more active than linezolid against the seven cfr-positive MRSA strains tested.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; In Vitro Techniques; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Sepsis; Spain; Staphylococcal Infections; Tetrazoles; Vancomycin

The activity of telavancin and comparators was assessed against a contemporary (2007 and 2008) global collection of 10,000 isolates of Staphylococcus aureus. Telavancin was very active against methicillin-susceptible and -resistant S. aureus (MSSA and MRSA, respectively; MIC(50/90) for both, 0.12/0.25 microg/ml; 100.0% susceptible). This agent was 2-, 4-, and 8-fold more potent than daptomycin (MIC(90), 0.5 microg/ml), vancomycin or quinupristin-dalfopristin (MIC(90), 1 microg/ml), and linezolid (MIC(90), 2 microg/ml) against MRSA, respectively. These data show a potent activity of telavancin tested against a current global collection of S. aureus.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Humans; In Vitro Techniques; Linezolid; Lipoglycopeptides; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log(10) CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Female; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pneumonia; Staphylococcal Infections; Vancomycin

Methicillin-resistant Staphylococcus aureus clonal lineage ST398 and methicillin-susceptible lineage ST9 strains have their main reservoir in swine but can colonize and cause infections in humans. The phenicol/lincosamide/oxazolidinone/pleuromutilin/streptogramin A multidrug resistance gene cfr was detected in isolates of both clonal lineages, rendering a spread to humans with exposure to swine farming possible.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Plasmids; Staphylococcal Infections; Staphylococcus aureus; Swine

We investigated the activity of linezolid, alone and in combination with rifampin (rifampicin), against a methicillin-resistant Staphylococcus aureus (MRSA) strain in vitro and in a guinea pig model of foreign-body infection. The MIC, minimal bactericidal concentration (MBC) in logarithmic phase, and MBC in stationary growth phase were 2.5, >20, and >20 microg/ml, respectively, for linezolid; 0.01, 0.08, and 2.5 microg/ml, respectively, for rifampin; and 0.16, 0.63, >20 microg/ml, respectively, for levofloxacin. In time-kill studies, bacterial regrowth and the development of rifampin resistance were observed after 24 h with rifampin alone at 1x or 4x the MIC and were prevented by the addition of linezolid. After the administration of single intraperitoneal doses of 25, 50, and 75 mg/kg of body weight, linezolid peak concentrations of 6.8, 12.7, and 18.1 microg/ml, respectively, were achieved in sterile cage fluid at approximately 3 h. The linezolid concentration remained above the MIC of the test organism for 12 h with all doses. Antimicrobial treatments of animals with cage implant infections were given twice daily for 4 days. Linezolid alone at 25, 50, and 75 mg/kg reduced the planktonic bacteria in cage fluid during treatment by 1.2 to 1.7 log(10) CFU/ml; only linezolid at 75 mg/kg prevented bacterial regrowth 5 days after the end of treatment. Linezolid used in combination with rifampin (12.5 mg/kg) was more effective than linezolid used as monotherapy, reducing the planktonic bacteria by >or=3 log(10) CFU (P < 0.05). Efficacy in the eradication of cage-associated infection was achieved only when linezolid was combined with rifampin, with cure rates being between 50% and 60%, whereas the levofloxacin-rifampin combination demonstrated the highest cure rate (91%) against the strain tested. The linezolid-rifampin combination is a treatment option for implant-associated infections caused by quinolone-resistant MRSA.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Dose-Response Relationship, Drug; Drug Therapy, Combination; Foreign-Body Reaction; Guinea Pigs; Injections, Intraperitoneal; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Animal; Oxazolidinones; Plankton; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Time Factors

RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibiotic-susceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two- to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log(10) at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log(10) (MSSA) and 2 log(10) (CA-MRSA). In the pneumococcal model, RWJ-416457 was two- to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC(24)) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC(24)/MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Female; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Mice; Oxazolidinones; Pneumococcal Infections; Staphylococcal Infections; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcus pneumoniae; Treatment Outcome; Vancomycin

AFN-1252, a potent inhibitor of enoyl-acyl carrier protein reductase (FabI), inhibited all clinical isolates of Staphylococcus aureus (n = 502) and Staphylococcus epidermidis (n = 51) tested, including methicillin (meticillin)-resistant isolates, at concentrations of 4 microg/ml) against clinical isolates of Streptococcus pneumoniae, beta-hemolytic streptococci, Enterococcus spp., Enterobacteriaceae, nonfermentative gram-negative bacilli, and Moraxella catarrhalis. These data support the continued development of AFN-1252 for the treatment of patients with resistant staphylococcal infections.

Topics: Anti-Bacterial Agents; Benzofurans; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Enterobacteriaceae; Enterococcus; Microbial Sensitivity Tests; Moraxella catarrhalis; Pyrones; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcus pneumoniae

The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) among 1,012 vancomycin-susceptible methicillin (meticillin)-resistant S. aureus isolates collected from 14 cities in China from 2005 to 2007 was 13 to 16%, as determined by a combination of (i) measurement by the modified population analysis profile-area under the curve method (PAP-AUC) and (ii) estimation from the measured sensitivity and specificity of a screening method. Two hundred isolates from blood were chosen as a subset for measurement of the sensitivities and the specificities of several previously described screening methods by using the results of PAP-AUC as the reference. During this testing, one isolate was found to be a vancomycin-intermediate S. aureus (VISA) strain so was not used in the evaluation of the screening tests. Of the other 199 isolates, 26 (13.1%) were hVISA, as assessed by PAP-AUC. A screening cascade of culturing the isolates on brain heart infusion agar containing teicoplanin (5 mg/liter) and then subjecting the positive isolates to a macro-Etest method was applied to the 812 non-blood isolates, yielding 149 positive results. From these results and by adjusting for sensitivity (0.423) and specificity (0.861), the prevalence was estimated to be 15.7%. The precision of that estimate was assessed by reapplying the screening cascade to 120 randomly selected isolates from the 812 non-blood isolates and simultaneously determining their heterogeneous vancomycin-intermediate susceptibility status by PAP-AUC. Because PAP-AUC is impractical for use with large numbers of isolates, the screening-based estimation method is useful as a first approximation of the prevalence of hVISA. Of the 27 VISA or hVISA isolates from blood, 22.2% and 74.1% were staphylococcal chromosome cassette mec types II and III, respectively, while 77.8% and 22.2% were agr type 1 and agr type 2, respectively; the MIC ranges were 0.5 to 4 mg/liter for vancomycin and 0.25 to 1 mg/liter for daptomycin.

Topics: Anti-Bacterial Agents; China; Cities; Drug Resistance, Multiple, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Vancomycin; Vancomycin Resistance

A phosphate prodrug strategy was investigated to address the problem of poor aqueous solubility of pleuromutilin analogues. Water-soluble phosphate prodrugs 6a, 6b and 6c of pleuromutilin analogues were designed and synthesized. Three compounds all exhibited excellent aqueous solubility (>50mg/mL) at near-neutral pH and sufficient stability in buffer solution. In particular, the phenol pleuromutilin prodrug 6c displayed favourable pharmacokinetic profiles and comparable potency with vancomycin against MSSA and MRSA strains in vivo.

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Gram-Positive Bacteria; Mice; Microbial Sensitivity Tests; Phosphates; Pleuromutilins; Polycyclic Compounds; Prodrugs; Rats; Rats, Sprague-Dawley; Solubility; Staphylococcal Infections; Structure-Activity Relationship; Water

Tigecycline (TGC) is an extended-spectrum antibiotic with activity against Staphylococcus aureus, including methicillin (meticillin)-resistant S. aureus strains, which are well-recognized pathogens in nosocomial pneumonia. The objective of this study was to characterize the exposure-response relationship for TGC against S. aureus in an immunocompromised BALB/c murine pneumonia model. Six S. aureus isolates were studied, and the TGC MICs for those isolates ranged from 0.125 to 0.5 mg/liter. The pharmacokinetics (PK) of TGC in serum and bronchoalveolar lavage (BAL) fluid were evaluated, as was the level of protein binding of the compound in this murine species. Administration of TGC at 1.56 to 150 mg/kg of body weight/day in single or two to three divided doses was used in the efficacy studies. TGC displayed linear PK and had a mean half-life of 10.9 +/- 2.5 h. Efficacy was highly correlated with the area under the free concentration-time curve (fAUC)/MIC (r(2) = 0.93). The 80% and 50% effective exposure indexes and the stasis exposure index were similar between the isolates (means +/- standard deviations, 3.04 +/- 1.12, 1.84 +/- 1.3, and 1.9 +/- 1.5, respectively). Maximal efficacy was predicted at a 2.85-log(10)-CFU reduction. TGC appeared to accumulate in the interstitial space, as the ratios of the fAUC from 0 to 8 h of epithelial lining fluid to plasma were 7.02, 15.11, and 23.95 for doses of 12.5, 25, and 50 mg/kg, respectively. TGC was highly effective in this murine pneumonia model. In light of current MIC distributions, the fAUC/MIC targets that we defined against S. aureus are readily achievable in humans given conventional doses of TGC.

Topics: Animals; Anti-Bacterial Agents; Female; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Minocycline; Pneumonia; Staphylococcal Infections; Tigecycline

Following recent reports of ribosomal protein L3 mutations in laboratory-derived linezolid-resistant (LZD(r)) Staphylococcus aureus, we investigated whether similar mutations were present in LZD(r) staphylococci of clinical origin. Sequence analysis of a variety of LZD(r) isolates revealed two L3 mutations, DeltaSer145 (S. aureus NRS127) and Ala157Arg (Staphylococcus epidermidis 1653059), both occurring proximal to the oxazolidinone binding site in the peptidyl transferase center. The oxazolidinone torezolid maintained a >or=8-fold potency advantage over linezolid for both strains.

Topics: Acetamides; Binding Sites; Drug Resistance, Bacterial; Linezolid; Mutation; Oxazolidinones; Protein Structure, Secondary; Ribosomal Protein L3; Ribosomal Proteins; RNA, Ribosomal, 23S; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Tetrazoles

An increase in the distribution of vancomycin MIC values among methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates has been noted. It is postulated that the shift in vancomycin MIC values may be associated with a concurrent rise in the MIC values of other anti-MRSA agents. Scant data are available on the correlation between vancomycin MIC values and the MIC values of other anti-MRSA agents. This study examined the correlation between vancomycin MIC values and the MIC values of daptomycin, linezolid, tigecycline, and teicoplanin among 120 patients with bloodstream infections caused by MRSA at a tertiary care hospital between January 2005 and May 2007. For each included patient, the MIC values of the antibiotics under study were determined by the Etest method and were separated into the following two categories: day 1 (index) and post-day 1 (subsequent). For subsequent isolates, the MIC values for each antibiotic from the post-day 1 terminal isolate were used. Among the index isolates, there was a significant correlation (P value, <0.01) between the MIC values for vancomycin and daptomycin and between the MIC values for vancomycin and teicoplanin. The MIC values for daptomycin were significantly correlated with linezolid, tigecycline, and teicoplanin MIC values. Among the 48 patients with subsequent isolates, vancomycin MIC values were significantly correlated with MIC values for daptomycin, linezolid, and teicoplanin (rho value of >or=0.38 for all comparisons). This study documented an association between vancomycin MIC values and the MIC values of other anti-MRSA antibiotics among patients with bloodstream infections caused by MRSA primarily treated with vancomycin.

Topics: Acetamides; Anti-Bacterial Agents; Cohort Studies; Daptomycin; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Retrospective Studies; Staphylococcal Infections; Vancomycin

Five of the seven cases of vancomycin-resistant Staphylococcus aureus (VRSA) infection identified to date have occurred in southeastern Michigan. VRSA isolates from the four most recent cases (all from Michigan) were characterized. The vanA gene was localized to a single plasmid in each VRSA isolate. The pulsed-field gel electrophoresis patterns of chromosomal DNA and the restriction profile of the plasmid demonstrated that the four isolates were unique and differed from the first three VRSA isolates. Vancomycin-resistant Enterococcus (VRE) isolates, all of which were Enterococcus faecalis, were recovered from case patients 4 to 6. Each VRE isolate transferred vancomycin resistance to E. faecalis JH2-2 by conjugation. PCRs for vanA and the Inc18-like plasmid genes traA and repR confirmed the presence of an Inc18-like vanA plasmid in all VRE isolates and transconjugants. An Inc18-like vanA plasmid was identified in the VRSA isolate from case patient 7. These findings suggest a role of Inc18-like plasmids as vanA donors.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbon-Oxygen Ligases; Conjugation, Genetic; DNA Transposable Elements; DNA, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterococcus faecalis; Humans; Michigan; Microbial Sensitivity Tests; Plasmids; Polymerase Chain Reaction; Restriction Mapping; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

Two investigational anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) beta-lactams, ceftaroline (a cephalosporin) and ME1036 (a carbapenem), were subjected to susceptibility testing by reference broth microdilution methods using 152 strains of community-acquired MRSA from the United States (47 medical centers). Ceftaroline and ME1036 were 64- and >128-fold more potent than ceftriaxone, respectively. All isolates had the Panton-Valentine leukocidin genes and staphylococcal cassette chromosome mec type IV, while 67.8% of isolates displayed pulsed-field gel electrophoresis clonal type USA300-0114.

Topics: Anti-Bacterial Agents; beta-Lactams; Carbapenems; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; United States

Linezolid resistance in Staphylococcus aureus is typically associated with mutations in the 23S rRNA gene. Here we show that the accumulation of a single point mutation, G2576T, in the different copies of this gene causes stepwise increases in resistance, impairment of the biological fitness, and cross-resistance to quinupristin-dalfopristin and chloramphenicol.

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Gene Dosage; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Point Mutation; RNA, Ribosomal, 23S; Staphylococcal Infections; Staphylococcus aureus

The pharmacokinetics and distribution into bone tissue of ceftobiprole in uninfected New Zealand White rabbits were determined after subcutaneous administration of the prodrug ceftobiprole medocaril. Serum exposure (maximum concentration of the drug in serum, trough concentration, area under the concentration-time curve) to ceftobiprole at 20 and 80 mg/kg was dose proportional, and there was no accumulation of ceftobiprole following repeated (every 6 h [q6h]) injections of the antibiotic. Ceftobiprole titers in the tibial matrix and marrow were 3.2 +/- 1.3 microg/g and 11.2 +/- 6.5 microg/g, respectively, in uninfected animals treated with 20 mg/kg of the antibiotic and 13.4 +/- 7.3 microg/g and 66.3 +/- 43.2 microg/g, respectively, in uninfected animals treated with 80 mg/kg of the antibiotic. No differences in ceftobiprole titers were observed between right and left tibiae for either bone matrix or marrow. The efficacies of 4 weeks of treatment with ceftobiprole (40 mg/kg administered subcutaneously [s.c.] q6h), vancomycin (30 mg/kg administered s.c. q12h), or linezolid (60 mg/kg administered orally q8h) were compared, using a rabbit model of methicillin-resistant Staphylococcus aureus tibial osteomyelitis. After treatment with ceftobiprole, the bacterial titers in all infected left tibiae from evaluable rabbits were below the level of detection, whereas only 73% of infected left tibiae from vancomycin- or linezolid-treated animals had bacterial titers below the level of detection; the mean titers of ceftobiprole were 3 to 5 times higher in infected left tibiae than in uninfected right tibiae. These results indicate that ceftobiprole provided effective parenteral treatment of osteomyelitis in this rabbit model.

Topics: Animals; Body Weight; Cephalosporins; Disease Models, Animal; Methicillin Resistance; Microbial Sensitivity Tests; Osteomyelitis; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Tibia

Linezolid resistance has dominantly been mediated by mutations in 23S rRNA or ribosomal protein L4 genes. Recently, cfr has demonstrated the ability to produce a phenotype of resistance to not only oxazolidinones, but also other antimicrobial classes (phenicols, lincosamides, pleuromutilins, and streptogramin A). We describe the first detection of cfr-mediated linezolid resistance in Staphylococcus aureus and Staphylococcus epidermidis recovered from human infection cases monitored during the 2007 LEADER Program.

Topics: Acetamides; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Linezolid; Methyltransferases; Microbial Sensitivity Tests; Molecular Sequence Data; Oxazolidinones; Sequence Analysis, DNA; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis

We evaluated the activity of ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC(50) and MIC(90) values were 1 and 2 microg/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, ceftobiprole was bactericidal at all concentrations tested.

Topics: Acetamides; Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Cross Infection; Daptomycin; Drug Synergism; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Topics: Acetamides; Anti-Bacterial Agents; Community-Acquired Infections; Cross Infection; Drug Resistance, Bacterial; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

Staphylococcus lugdunensis is an atypically virulent coagulase-negative staphylococcal species associated with acute and destructive infections that often resemble Staphylococcus aureus infections. Several types of infection caused by S. lugdunensis (e.g., native valve endocarditis, prosthetic joint infection, and intravascular catheter infection) are associated with biofilm formation, which may lead to an inability to eradicate the infection due to the intrinsic nature of biofilms to resist high levels of antibiotics. In this study, planktonic MICs and MBCs and biofilm bactericidal concentrations of 10 antistaphylococcal antimicrobial agents were measured for 15 S. lugdunensis isolates collected from patients with endocarditis, medical device infections, or skin and soft tissue infections. Planktonic isolates were susceptible to all agents studied, but biofilms were resistant to high concentrations of most of the drugs. However, moxifloxacin was able to kill 73% of isolates growing in biofilms at

Topics: Acetamides; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Biofilms; DNA, Bacterial; Humans; Linezolid; Microbial Sensitivity Tests; Nafcillin; Oxazolidinones; Penicillin-Binding Proteins; Penicillins; Reverse Transcriptase Polymerase Chain Reaction; Staphylococcal Infections; Staphylococcus; Tetracycline

Current treatment for serious infections caused by methicillin-resistant Staphylococcus aureus relies heavily upon the glycopeptide antibiotic vancomycin. Unfortunately, this practice has led to an intermediate resistance phenotype that is particularly difficult to treat in invasive staphylococcal diseases, such as septicemia and its metastatic complications, including endocarditis. Although the vancomycin-intermediate resistance phenotype has been linked to abnormal cell wall structures and autolytic rates, the corresponding genetic changes have not been fully elucidated. Previously, whole-genome array studies listed numerous genes that are overexpressed in vancomycin-intermediate sensitive strains, including graRS (SACOL0716 to -0717), encoding a two-component regulatory system (TCRS), as well as the adjacent vraFG (SACOL0718 to -0720), encoding an ATP-binding cassette (ABC) transporter; but the exact contribution of these genes to increased vancomycin resistance has not been defined. In this study, we showed that isogenic strains with mutations in genes encoding the GraRS TCRS and the VraFG ABC transporter are hypersensitive to vancomycin as well as polymyxin B. Moreover, GraRS regulates the expression of the adjacent VraFG pump, reminiscent of gram-positive bacteriocin-immunity regulons. Mutations of graRS and vraFG also led to increased autolytic rates and a more negative net surface charge, which may explain, in part, to their increased sensitivity to cationic antimicrobial peptides. Taken together, these data reveal an important genetic mediator to the vancomycin-intermediate S. aureus phenotype and may hold clues to the selective pressures on staphylococci upon exposure to selective cationic peptide antibiotics used in clinical practice.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Gene Expression Regulation, Bacterial; Humans; Microbial Sensitivity Tests; Polymyxin B; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Vancomycin Resistance

Using the rabbit endocarditis model, we compared the activity of a new broad-spectrum cephalosporin, ceftaroline, with those of linezolid and vancomycin against methicillin-resistant Staphylococcus aureus. After a 4-day treatment, ceftaroline exhibited superior bactericidal in vivo activity against resistant S. aureus strains and appeared to be the most effective drug against a heterogeneous glycopeptide-intermediate S. aureus strain.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Area Under Curve; Ceftaroline; Cephalosporins; Chromatography, High Pressure Liquid; Colony Count, Microbial; Endocarditis, Bacterial; Immunoenzyme Techniques; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazolidinones; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin; Vancomycin Resistance

A novel oxazolidinone, AM 7359, was evaluated in two mouse models of Staphylococcus aureus infection. AM 7359 and linezolid were equally efficacious in a methicillin-susceptible S. aureus organ burden model and a methicillin-resistant S. aureus localized infection model. However, AM 7359 was eightfold more efficacious than linezolid against a linezolid- and methicillin-resistant S. aureus strain in this localized (thigh) infection model.

Topics: Acetamides; Administration, Oral; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Dose-Response Relationship, Drug; Injections, Intravenous; Linezolid; Methicillin Resistance; Mice; Mice, Inbred C3H; Oxazolidinones; Staphylococcal Infections

Mupirocin resistance in Staphylococcus aureus is increasingly being reported in many parts of the world. This study describes the epidemiology and laboratory characterization of mupirocin-resistant methicillin-resistant S. aureus (MRSA) strains in Canadian hospitals. Broth microdilution susceptibility testing of 4,980 MRSA isolates obtained between 1995 and 2004 from 32 Canadian hospitals was done in accordance with CLSI guidelines. The clinical and epidemiologic characteristics of strains with high-level mupirocin resistance (HLMup(r)) were compared with those of mupirocin-susceptible (Mup(s)) strains. MRSA strains were characterized by pulsed-field gel electrophoresis (PFGE) and typing of the staphylococcal chromosomal cassette mec. PCR was done to detect the presence of the mupA gene. For strains with mupA, plasmid DNA was extracted and subjected to Southern blot hybridization. A total of 198 (4.0%) HLMup(r) MRSA isolates were identified. The proportion of MRSA strains with HLMup(r) increased from 1.6% in the first 5 years of surveillance (1995 to 1999) to 7.0% from 2000 to 2004 (P < 0.001). Patients with HLMup(r) MRSA strains were more likely to have been aboriginal (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5 to 9.4; P = 0.006), to have had community-associated MRSA (OR, 2.2; 95% CI, 1.0 to 5.0; P = 0.05), and to have been colonized with MRSA (OR, 1.7; 95% CI, 1.0 to 3.0; P = 0.04). HLMup(r) MRSA strains were also more likely to be resistant to fusidic acid (21% versus 4% for mupirocin-susceptible strains; P < 0.001). All HLMup(r) MRSA strains had a plasmid-associated mupA gene, most often associated with a 9-kb HindIII fragment. PFGE typing and analysis of the plasmid profiles indicate that both plasmid transmission and the clonal spread of HLMup(r) MRSA have occurred in Canadian hospitals. These results indicate that the incidence of HLMup(r) is increasing among Canadian strains of MRSA and that HLMup(r) MRSA is recovered from patients with distinct clinical and epidemiologic characteristics compared to the characteristics of patents with Mup(s) MRSA strains.

Topics: Aged; Anti-Bacterial Agents; Canada; Cross Infection; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Hospitals; Humans; Male; Methicillin Resistance; Microbial Sensitivity Tests; Mupirocin; Staphylococcal Infections; Staphylococcus aureus

Oxazolidinones possessing a C-5 carboxamide functionality (reverse amides) represent a new series of compounds that block bacterial protein synthesis. These reverse amides also exhibited less potency against monoamine oxidase (MAO) enzymes and thus possess less potential for the side effects associated with MAO inhibition. The title compound (14) showed reduced in vivo myelotoxicity compared to linezolid in a 14-day safety study in rats, potent in vivo efficacy in murine systemic infection models, and excellent pharmacokinetic properties.

Topics: Acetamides; Administration, Oral; Animals; Anti-Bacterial Agents; Biological Availability; Cyclic S-Oxides; Dogs; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Injections, Intravenous; Linezolid; Male; Mice; Microbial Sensitivity Tests; Monoamine Oxidase Inhibitors; Oxazolidinones; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pyogenes; Structure-Activity Relationship

Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, 3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting "AU-FQ" hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU-FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.

Topics: Aniline Compounds; Animals; Anti-Bacterial Agents; DNA Polymerase III; Drug Resistance, Bacterial; Gram-Positive Bacteria; Male; Mice; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Topoisomerase II Inhibitors; Toxicity Tests, Acute; Uracil

Novel oxazolidinones were synthesized containing a number of substituted five-membered heterocycles attached to the 'piperazinyl-phenyl-oxazolidinone' core of eperezolid. Further, the piperazine ring of the core was replaced by other diamino-heterocycles. These modifications led to several compounds with potent activity against a spectrum of resistant and susceptible gram-positive organisms, along with the identification of ranbezolid (RBx 7644) as a clinical candidate.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Furans; Gram-Positive Bacteria; Heterocyclic Compounds; Mice; Microbial Sensitivity Tests; Oxazoles; Oxazolidinones; Staphylococcal Infections; Structure-Activity Relationship

There is an urgent medical need for novel antibacterial agents to treat hospital infections, specially those caused by multidrug-resistant Gram-positive pathogens. The need may also be fulfilled by either exploring antibacterial agents having new mechanism of action or expanding known classes of antibacterial drugs. The paper describes a new chemical entity, compound 21, derived from hitherto little known "floxacin". The choice of the entity was made from a series of synthesized prodrugs and salts of the active chiral benzoquinolizine carboxylic acid, S-(-)-nadifloxacin. The chemistry, physicochemical characteristics, and essential bioprofile of 21 qualifies it for serious consideration as a novel drug entity against hospital infections of multi-drug-resistant Staphylococcus aureus, and its progress up to clinical phase I trials in humans is described.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Clinical Trials, Phase I as Topic; Dogs; Drug Resistance, Multiple, Bacterial; Female; Fluoroquinolones; Half-Life; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Mutation; Prodrugs; Quinolizines; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Structure-Activity Relationship; Vancomycin Resistance

DNA binding ligands with potent antimicrobial activity against Gram-positive bacteria were further optimized by variation of the internal aromatic amino acids. This modification led to compounds with improved in vivo efficacy in lethal murine models of peritonitis (methicillin-resistant S. aureus, MRSA) and lung infection (S. pneumoniae).

Topics: Amino Acids, Aromatic; Animals; Anti-Bacterial Agents; Disease Models, Animal; DNA; Ligands; Lung Diseases; Mice; Peritonitis; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pneumoniae

A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.

Topics: Animals; Anti-Bacterial Agents; Benzene Derivatives; Biological Availability; Crystallography, X-Ray; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Resistance, Bacterial; Gram-Positive Bacteria; Hepatocytes; Humans; In Vitro Techniques; Isoxazoles; Male; Mice; Microbial Sensitivity Tests; Piperazines; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Structure-Activity Relationship

Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.

Topics: Animals; Anti-Bacterial Agents; Gram-Positive Bacteria; Heterocyclic Compounds; Hydrocarbons; Methane; Mice; Microbial Sensitivity Tests; Oxazolidinones; Rats; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship

Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative eperezolid 3. As part of an investigation of the structure-activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values

Topics: Acetamides; Anti-Bacterial Agents; Caco-2 Cells; Enterococcus faecalis; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazoles; Oxazolidinones; Permeability; Piperazines; Pyridines; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Structure-Activity Relationship; Triazenes

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Haemophilus influenzae; Inhibitory Concentration 50; Injections, Intravenous; Male; Mice; Moraxella catarrhalis; Oxazoles; Pyrazoles; Pyrroles; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Structure-Activity Relationship