Abstract:
:Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. Three heart rate corrections to QT were considered: Fridericia's QTcF, Bazett's QTcB, and a population-specific correction, QTcN. QTc increased with the plasma concentrations of pretomanid, bedaquiline's M2 metabolite, and moxifloxacin in a manner described by a linear model in which the three slope coefficients were constant across studies, visits within study, and times postdose within visit but where the intercept varied across those dimensions. The intercepts tended to increase on treatment to a plateau after several weeks, a pattern termed the secular trend. The slope terms were similar for the three QTc corrections, but the secular trends differed, suggesting that at least some of the secular trend was due to the elevated heart rates of tuberculosis patients decreasing to normal levels on treatment. For pretomanid 200 mg once a day (QD) alone, a typical steady-state maximum concentration of drug in plasma (Cmax) resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% confidence interval (CI) limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The contribution to these values from the secular trend was 4.0 ms.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Li H,Salinger DH,Everitt D,Li M,Del Parigi A,Mendel C,Nedelman JRdoi
10.1128/AAC.00445-19subject
Has Abstractpub_date
2019-09-23 00:00:00issue
10eissn
0066-4804issn
1098-6596pii
AAC.00445-19journal_volume
63pub_type
杂志文章abstract::Escherichia coli sequence type 131 (ST131) is a pandemic clonal lineage that is responsible for the global increase in fluoroquinolone resistance and extended-spectrum-β-lactamase (ESBL) producers. The members of ST131 clade C, especially subclades C2 and C1-M27, are associated with ESBLs. We developed a multiplex con...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00179-17
更新日期:2017-07-25 00:00:00
abstract::The pharmacokinetics of azlocillin were studied in 10 cystic fibrosis patients, ranging in age from 11 to 28 years. The patients received a 9- to 23-day course of 350 mg of azlocillin per kg in four or six divided daily doses in combination with am aminoglycoside. Blood and urine samples were collected at specified ti...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.25.5.630
更新日期:1984-05-01 00:00:00
abstract::Spectinomycin resistance in clinical isolates of Neisseria meningitidis and Neisseria gonorrhoeae was found to be due to mutations G1064C and C1192U (Escherichia coli numbering) in 16S rRNA genes, respectively. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.5.1365-1366.2000
更新日期:2000-05-01 00:00:00
abstract::Gentamicin and tobramycin inhibited the accumulation of extracellular proteases secreted by Pseudomonas aeruginosa. The secretion of protease was inhibited at concentrations of these drugs that were below the level required to inhibit general protein synthesis. Neither magnesium ions nor high ionic strength antagonize...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.27.4.468
更新日期:1985-04-01 00:00:00
abstract::Candida albicans biofilms are generally considered to be resistant to azole antifungal agents but susceptible to echinocandins. We demonstrate that in a sequential therapy regimen, treatment with fluconazole first followed by caspofungin leads to a significant decrease of the efficacy of this echinocandin. Cellular st...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01745-13
更新日期:2014-01-01 00:00:00
abstract::The VanR-VanS two-component system is responsible for inducing resistance to glycopeptide antibiotics in various bacteria. We have performed a comparative study of the VanR-VanS systems from two streptomyces strains, Streptomyces coelicolor and Streptomyces toyocaensis, to characterize how the two proteins cooperate t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01367-15
更新日期:2015-12-28 00:00:00
abstract::beta-Lactamase was purified from a strain of Legionella gormanii. The molecular weight of the purified enzyme was 25,000, and its isoelectric point was 10.5. The enzyme hydrolyzed oxyiminocephalosporins, cephamycins, penicillins, and imipenem. The enzyme activity was inhibited by EDTA, Hg2+, and Cu2+, but not by clavu...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.29.5.925
更新日期:1986-05-01 00:00:00
abstract::Vancomycin pharmacokinetics were studied in four patients with peritonitis undergoing chronic intermittent peritoneal dialysis. Serum levels exceeding 4.0 micrograms/ml were maintained for 8 and 13 days after a single 1-g intravenous dose. Vancomycin serum concentrations measured before, during, and upon completion of...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.23.5.710
更新日期:1983-05-01 00:00:00
abstract::Macrolide-resistant group A streptococci (MRGAS) have been recovered from many countries worldwide. However, the strain typing information that is available has been insufficient for estimating the total number of macrolide-resistant clones, their geographic distributions, and their evolutionary relationships. In this...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00325-06
更新日期:2006-09-01 00:00:00
abstract::Teicoplanin was evaluated in 47 patients with severe infections, including 14 patients with bone infections, 11 patients with soft-tissue infections, 7 patients with endocarditis, 5 patients with pneumonia, 3 patients with septic thrombophlebitis, 3 patients with septicemia of unknown origin, and 4 patients with misce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.29.1.52
更新日期:1986-01-01 00:00:00
abstract::The antileishmanial efficacies of four proprietary amphotericin B (AmB) formulations (Fungizone, AmBisome, Abelcet, and Amphocil) and an experimental nonionic surfactant vesicle (NIV) formulation were compared in a murine model of acute visceral leishmaniasis. By a multiple-dosing regimen, groups of Leishmania donovan...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.41.10.2089
更新日期:1997-10-01 00:00:00
abstract::When strains harboring R factor and showing ampicillin (APC) resistance were inoculated on plates containing various concentrations of APC, mutants carrying various levels of APC resistance occurred at high frequencies. Increases in the level of APC resistance were due to a quantitative increase in the formation of pe...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.3.3.315
更新日期:1973-03-01 00:00:00
abstract::The global spread of carbapenem-resistant Klebsiella pneumoniae (CR-Kp) has been largely associated with sequence type 258 (ST258) and its related variants (clonal group 258 [CG258]). Here we describe the molecular epidemiology of CR-Kp from five tertiary care hospitals in Medellín, the second largest city in Colombia...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,多中心研究
doi:10.1128/AAC.01775-15
更新日期:2015-10-26 00:00:00
abstract::Gatifloxacin (GTX), a new fluoroquinolone with extended antibacterial activity, is an interesting candidate for the treatment of chronic bacterial prostatitis (CBP). Besides the antibacterial spectrum, the concentrations in the target tissues and fluids are crucial for the treatment of CBP. Thus, it was of interest to...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.45.1.293-297.2001
更新日期:2001-01-01 00:00:00
abstract::A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB). Compounds 1 to 3, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphyloccocus aureus MurB, and E. coli MurA with 50% inhibitory conce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.50.2.556-564.2006
更新日期:2006-02-01 00:00:00
abstract::CL 188,624, CL 190,294, and CL 191,121 are novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems. The in vitro antibacterial activities of these THF carbapenems were evaluated and compared with those of biapenem, imipenem, and meropenem against 554 recent clinical isolates obtained from geographically dis...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.3.454
更新日期:1999-03-01 00:00:00
abstract::Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination wi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02524-15
更新日期:2016-01-11 00:00:00
abstract::We present case histories of four patients treated with artemether-lumefantrine for falciparum malaria in UK hospitals in 2015 to 2016. Each subsequently presented with recurrent symptoms and Plasmodium falciparum parasitemia within 6 weeks of treatment with no intervening travel to countries where malaria is endemic....
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02382-16
更新日期:2017-02-23 00:00:00
abstract::Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following dose...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1128/AAC.49.5.1881-1889.2005
更新日期:2005-05-01 00:00:00
abstract::The entry of an antibiotic into phagocytes is a prerequisite for its intracellular bioactivity against susceptible facultative or obligatory intracellular microorganisms. Brodimoprim is a dimethoxybenzylpyrimidine that has recently entered into clinical use, and its uptake into and elimination from human polymorphonuc...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.10.2392
更新日期:1996-10-01 00:00:00
abstract::The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levoflo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.01036-07
更新日期:2008-03-01 00:00:00
abstract::The syringopeptins are a group of antimicrobial cyclic lipodepsipeptides produced by several plant-associated pseudomonads. A novel syringopeptin, SP508, was shown to be produced as two homologs (A and B) by Pseudomonas syringae pv. lachrymans strain 508 from apple and to structurally resemble syringopeptin SP22. SP50...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.12.5037-5045.2005
更新日期:2005-12-01 00:00:00
abstract::Pseudomonas aeruginosa pneumonia remains a difficult therapeutic problem. Optimal doses and modes of administration of single agents often do not result in acceptable outcomes. Further, emergence of resistance occurs frequently in this setting with single-agent chemotherapy. The purpose of these experiments was to eva...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02624-12
更新日期:2013-06-01 00:00:00
abstract::Penicillin-binding protein (PBP) 2 is the major PBP of five that have been identified in susceptible strains of Staphylococcus aureus. Beta-lactam antibiotic binding to PBP 2 is important for the antibacterial effect. Antibiotic binding to PBP 2 in strain 209P was examined with sodium dodecyl sulfate-polyacrylamide ge...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.3.656
更新日期:1992-03-01 00:00:00
abstract::Mupirocin is a topical antibiotic used for the treatment of skin infections and the eradication of methicillin-resistant Staphylococcus aureus carriage. It inhibits bacterial protein synthesis by interfering with isoleucyl-tRNA synthetase activity. High-level mupirocin resistance (MIC of ≥ 512 μg/ml) is mediated by th...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.05325-11
更新日期:2012-04-01 00:00:00
abstract::Ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB], is a first-line drug used to treat tuberculosis. To gain insight into the molecular basis of EMB resistance, we characterized the 10-kb embCAB locus in 16 EMB-resistant and 3 EMB-susceptible genetically distinct Mycobacterium tuberculosis strains from divers...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.41.8.1677
更新日期:1997-08-01 00:00:00
abstract::Multiresistant enterococci were tested for susceptibility to trimethoprim (TMP). Although most enterococci are inhibited by less than or equal to 1.0 microgram/ml, the MICs for 7 of 29 selected multiresistant isolates were greater than or equal to 8 micrograms/ml, including for two beta-lactamase positive (Bla+) strai...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.9.1928
更新日期:1991-09-01 00:00:00
abstract::Tilorone is a 50-year-old synthetic small-molecule compound with antiviral activity that is proposed to induce interferon after oral administration. This drug is used as a broad-spectrum antiviral in several countries of the Russian Federation. We have recently described activity in vitro and in vivo against the Ebola...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00440-20
更新日期:2020-04-21 00:00:00
abstract::Major facilitator superfamily (MFS) efflux pumps have been shown to be important for bacterial cells to cope with biocides such as chlorhexidine (CHX), a widely used molecule in hospital settings. In this work, we evaluated the role of two genes, smvA and smvR, in CHX resistance in Enterobacter cloacae complex (ECC). ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01845-19
更新日期:2019-12-20 00:00:00
abstract::The resistance mechanisms of methicillin-resistant strains of Staphylococcus saprophyticus were characterized. Penicillin-binding protein (PBP) studies demonstrated an inducible PBP identical to PBP 2a in the membranes of these isolates. The amount of beta-lactamase produced was minimal. PBP 2a is responsible for the ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.9.1780
更新日期:1990-09-01 00:00:00