Abstract:
:This analysis was conducted to determine whether the hepatitis C virus (HCV) viral kinetics (VK) model can predict viral load (VL) decreases for nonnucleoside polymerase inhibitors (NNPolIs) and protease inhibitors (PIs) after 3-day monotherapy studies of patients infected with genotype 1 chronic HCV. This analysis includes data for 8 NNPolIs and 14 PIs, including VL decreases from 3-day monotherapy, total plasma trough concentrations on day 3 (C(min)), replicon data (50% effective concentration [EC(50)] and protein-shifted EC(50) [EC(50,PS)]), and for PIs, liver-to-plasma ratios (LPRs) measured in vivo in preclinical species. VK model simulations suggested that achieving additional log(10) VL decreases greater than one required 10-fold increases in the C(min). NNPolI and PI data further supported this result. The VK model was successfully used to predict VL decreases in 3-day monotherapy for NNPolIs based on the EC(50,PS) and the day 3 C(min). For PIs, however, predicting VL decreases using the same model and the EC(50,PS) and day 3 C(min) was not successful; a model including LPR values and the EC(50) instead of the EC(50,PS) provided a better prediction of VL decrease. These results are useful for designing phase 1 monotherapy studies for NNPolIs and PIs by clarifying factors driving VL decreases, such as the day 3 C(min) and the EC(50,PS) for NNPolIs or the EC(50) and LPR for PIs. This work provides a framework for understanding the pharmacokinetic/pharmacodynamic relationship for other HCV drug classes. The availability of mechanistic data on processes driving the target concentration, such as liver uptake transporters, should help to improve the predictive power of the approach.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Reddy MB,Morcos PN,Le Pogam S,Ou Y,Frank K,Lave T,Smith Pdoi
10.1128/AAC.06283-11subject
Has Abstractpub_date
2012-06-01 00:00:00pages
3144-56issue
6eissn
0066-4804issn
1098-6596pii
AAC.06283-11journal_volume
56pub_type
杂志文章abstract::(-)-beta-D-2-Aminopurine dioxolane (APD) and (-)-beta-D-2-amino-6-chloropurine dioxolane (ACPD) are recently synthesized dioxolanylpurine nucleoside derivatives being developed as potential prodrugs for the antiviral nucleoside analog (-)-beta-D-dioxolane guanine (DXG). In vitro, APD and ACPD are converted to DXG by x...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.10.2332
更新日期:1996-10-01 00:00:00
abstract::As a consequence of blood-borne bacterial sepsis, endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria can trigger an acute inflammatory response, leading to a series of pathological events and often resulting in death. To block this inflammatory response to endotoxin, a novel lipid A an...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.11.2824
更新日期:1998-11-01 00:00:00
abstract::The activity of MK-0826, a new carbapenem, against 309 Bacteroides fragilis group strains was investigated and compared with that of 11 other beta-lactam and 5 non-beta-lactam agents. MK-0826 showed excellent activity (MICs ranged from < or =0.06 to 4 microg/ml). The new carbapenem may be useful in the treatment of mi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.45.8.2372-2374.2001
更新日期:2001-08-01 00:00:00
abstract::Paradoxical growth of some Candida isolates occurs at concentrations above the MIC for echinocandins. In 60 Candida bloodstream isolates from cancer patients (20 C. albicans isolates and 10 isolates each of C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata), paradoxical growth was more frequent with caspofung...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00095-07
更新日期:2007-06-01 00:00:00
abstract::The pharmacokinetics, oral bioavailability, and ex vivo antimalarial activity of mirincamycin isomers in a healthy rhesus monkey model were assessed to support lead optimization of novel nonhemolytic drugs for radical cure and causal prophylaxis of malaria. Fourteen male rhesus monkeys were randomized to four groups, ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01619-10
更新日期:2011-12-01 00:00:00
abstract::To determine whether low concentrations of aminoglycosides in combination with penicillin could effectively kill enterococci in vitro, we tested penicillin (20 micrograms/ml) in combination with decreasing concentrations of either streptomycin (20, 10, 5, and 1 micrograms/ml) or gentamicin (5, 3, 1, and 0.5 micrograms...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.18.6.944
更新日期:1980-12-01 00:00:00
abstract::Analogues based on the insect cecropin-bee melittin hybrid peptide (CEME) were studied and analyzed for activity and salt resistance. The new variants were designed to have an increase in amphipathic alpha-helical content (CP29 and CP26) and in overall positive charge (CP26). The alpha-helicity of these peptides was d...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.7.1542
更新日期:1999-07-01 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::To compare the effect of ritonavir on plasma amprenavir pharmacokinetics, healthy adults received either fosamprenavir (700 mg twice a day [BID]) or amprenavir (600 mg BID) alone and in combination with ritonavir (100 mg BID). Ritonavir increased plasma amprenavir pharmacokinetic parameters to a similar extent when co...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.50.4.1578-1580.2006
更新日期:2006-04-01 00:00:00
abstract::A novel beta-lactamase gene, blaOXA-61, from Campylobacter jejuni GC015 was cloned and its nucleotide sequence determined. blaOXA-61 encodes a protein of 257 amino acids in which the active-site STFK tetrad and conserved class D beta-lactamase motifs YGN and KTG were identified. A conserved sequence upstream of blaOXA...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.6.2515-2518.2005
更新日期:2005-06-01 00:00:00
abstract::Highly drug-resistant Salmonella enterica serovar Indiana became the most common serovar in broilers with diarrhea in China over the course of this study (15% in 2010 to 70% in 2014). While most S. Indiana isolates (87%, 384/440) were resistant to 13 to 16 of the 16 antibiotics tested, 89% of non-S. Indiana isolates (...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.03009-15
更新日期:2016-01-11 00:00:00
abstract::Since human cytomegalovirus (HCMV) does not infect or replicate in nonhuman cells and tissues, there are few animal models currently available for evaluation of antiviral therapies for these infections. In the present studies, we utilized two different models in which severe combined immunodeficient (SCID) mice were i...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.48.5.1749-1755.2004
更新日期:2004-05-01 00:00:00
abstract::We compared the kinetics of amphotericin B (AMB) lung accumulation and fungal clearance by liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) in a neutropenic murine model of invasive pulmonary mucormycosis (IPM). Immunosuppressed BALB/c mice were inoculated with 1 x 10(6) Rhizopus oryzae spores ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01222-09
更新日期:2010-03-01 00:00:00
abstract::Recently, the first Neisseria gonorrhoeae strain (H041) highly resistant to the expanded-spectrum cephalosporins (ESCs) ceftriaxone and cefixime, which are the last remaining options for first-line gonorrhea treatment, was isolated in Japan. Here, we confirm and characterize a second strain (F89) with high-level cefix...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.05760-11
更新日期:2012-03-01 00:00:00
abstract::Single-dose nevirapine (sd-NVP) and extended NVP prophylaxis are widely used in resource-constrained settings to prevent vertical HIV-1 transmission. We assessed the pharmacokinetics of sd-NVP in 62 HIV-1-positive pregnant Ugandan woman and their newborns who were receiving sd-NVP prophylaxis to prevent mother-to-chil...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00741-11
更新日期:2011-12-01 00:00:00
abstract::KBP-7072 is a novel aminomethylcycline antibiotic in clinical development for community-acquired pneumonia. The goal of present studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter magnitude correlated with efficacy in the murine pneumonia infection model against Staphylococcus aureus and S...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02404-18
更新日期:2019-02-26 00:00:00
abstract::A remarkably high rate of adverse events is associated with the use of trimethoprim-sulfamethoxazole in patients with human immunodeficiency virus type 1 infection. We examined the efficacies of sulfonamides alone in the prevention of Pneumocystis carinii pneumonitis, with the assumption that at least some of the adve...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.4.962
更新日期:1996-04-01 00:00:00
abstract::Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potency against nonreplicating bacteria both in vitro and in vivo. In...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00528-15
更新日期:2015-07-01 00:00:00
abstract::The effect of ethambutol (EMB) is primarily on polymerization steps in the biosynthesis of the arabinan component of cell wall arabinogalactan (AG) of Mycobacterium smegmatis. Inhibition of the synthesis of the arabinan of lipoarabinomannan (LAM) occurred later, and thus in the cases of AG and LAM, the polymerization ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.11.2484
更新日期:1995-11-01 00:00:00
abstract::The in vitro susceptibility of Brucella melitensis was examined vis-a-vis the clinical outcome in 75 patients with brucellosis. The initial MICs for Brucella isolates from patients who relapsed and from those who did not were similar. Furthermore, the MICs for isolates from patients whose infections relapsed were no d...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.30.6.958
更新日期:1986-12-01 00:00:00
abstract::Olorofim is a novel antifungal drug in phase 2 trials. It has shown promising in vitro activity against various molds, except for Mucorales. Initially, we observed a broad range of EUCAST MICs for Aspergillus fumigatus Here, we explored the MIC variability in more detail and prospectively investigated the susceptibili...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01527-20
更新日期:2020-12-16 00:00:00
abstract::The activity of penicillin, alone and in combination with sulbactam, against a heterogeneously methicillin-resistant, penicillinase-producing clinical isolate of Staphylococcus aureus and its penicillinase-negative derivative was investigated in vitro and in a rabbit experimental endocarditis model. Penicillin was sig...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.5.1219
更新日期:1996-05-01 00:00:00
abstract::Streptococcus pneumoniae is a leading pathogen for bacterial pneumonia, which can be treated with bacteriophage lysins harboring a conserved choline binding module (CBM). Such lysins regularly function as choline-recognizing dimers. Previously, we reported a pneumococcus-specific lysin ClyJ comprising the binding doma...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00311-20
更新日期:2020-11-17 00:00:00
abstract::Nosocomial pneumonia and sepsis, as well as severe diffuse peritonitis, must be treated early in order to prevent complications such as septic shock and organ dysfunctions. With the availability of new broad-spectrum and highly bactericidal antibiotics, the need of combining beta-lactams with aminoglycosides for the t...
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.38.6.1309
更新日期:1994-06-01 00:00:00
abstract::We assessed prophylactic or continuous therapy of isavuconazole, posaconazole, or voriconazole in treating pulmonary murine mucormycosis. In the prophylaxis studies, only isavuconazole treatment resulted in significantly improved survival and lowered tissue fungal burden of immunosuppressed mice infected with Rhizopus...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02589-16
更新日期:2017-04-24 00:00:00
abstract::Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01014-06
更新日期:2007-06-01 00:00:00
abstract::Pseudomonas aeruginosa colonizes the sputum of most adult cystic fibrosis patients, forming difficult-to-eradicate biofilms in which bacteria are protected in their self-produced extracellular polymeric substance (EPS) matrices. EPS provide biofilms with viscoelastic properties, causing time-dependent relaxation after...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01972-18
更新日期:2019-03-27 00:00:00
abstract::Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We found a lower total rifapentine concentration but significantly higher free rifapen...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01730-13
更新日期:2014-08-01 00:00:00
abstract::The time-kill effect of moxifloxacin on 20 genetically distinct isolates of Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole was studied. The majority (80%) were killed by a concentration equivalent to four times the MIC; the MIC induced a transient decrease in bacterial counts at 4 h, followed ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.12.3997-3999.2002
更新日期:2002-12-01 00:00:00
abstract::Spontaneous binding of infected erythrocytes to uninfected erythrocytes to form rosettes is a property of some strains of Plasmodium falciparum that is linked to severe complications of malaria. Curdlan sulfate (CRDS) is a sulfated glycoconjugate compound that is chemically similar to known rosette-inhibiting drugs su...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01216-06
更新日期:2007-04-01 00:00:00