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 Streptococcus pneumoniae KBP-7072 pharmacokinetic measurements were performed in plasma and epithelial lining fluid (ELF) at 4-fold-increasing doses from 1 to 256 mg/kg of body weight subcutaneously. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 82% to 238% comparing ELF drug concentrations to plasma free drug concentrations. Twenty-four-hour dose-ranging efficacy studies were then performed in the neutropenic murine pneumonia model against 5 S. aureus (3 methicillin-resistant and 2 methicillin-susceptible) and 6 S. pneumoniae (2 Tetr and 2 Penr) strains. KBP-7072 demonstrated potent in vivo activity resulting in a 3- to 5-log10 kill in CFU burden compared to the start of therapy for all strains. The PK/PD index area under the concentration-time curve (AUC)/MIC corelated well with efficacy (R2, 0.80 to 0.89). Net stasis was achieved at plasma 24-h free drug AUC/MIC values of 1.13 and 1.41 (24-h ELF AUC/MIC values of 2.01 and 2.50) for S. aureus and S. pneumoniae, respectively. A 1-log10 kill was achieved at 24-h plasma AUC/MIC values of 2.59 and 5.67 (24-h ELF AUC/MIC values of 4.22 and 10.08) for S. aureus and S. pneumoniae, respectively. A 2-log10 kill was achieved at 24-h plasma AUC/MIC values of 7.16 and 31.14 (24-h ELF AUC/MIC values of 8.37 and 42.92) for S. aureus and S. pneumoniae, respectively. The results of these experiments will aid in the rational design of dose-finding studies for KBP-7072 in patients with community-acquired bacterial pneumonia (CAP).
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Lepak AJ,Zhao M,Liu Q,Wang P,Wang Y,Bader JC,Ambrose PG,Andes DRdoi
10.1128/AAC.02404-18subject
Has Abstractpub_date
2019-02-26 00:00:00issue
3eissn
0066-4804issn
1098-6596pii
AAC.02404-18journal_volume
63pub_type
杂志文章abstract::Actinobacillus actinomycetemcomitans and Capnocytophaga spp. are gram-negative bacteria implicated in the etiology of periodontal disease (particularly in individuals with neutrophil defects) and life-threatening systemic infections. They are resistant to many antibiotics of microbial origin but are sensitive to the n...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.12.2710
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abstract::The host immune response to human cytomegalovirus (HCMV) is effective against HCMV reactivation from latency, though not sufficient to clear the virus. T cells are primarily responsible for the control of viral reactivation. When the host immune system is compromised, as in transplant recipients with immunosuppression...
journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.01719-17
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journal_title:Antimicrobial agents and chemotherapy
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abstract::Caspofungin (CAS) is approved for second-line management of proven or probable invasive aspergillosis at a dose of 50 mg once daily (QD). Preclinical and limited clinical data support the concept of the dose-dependent antifungal efficacy of CAS with preservation of its favorable safety profile. Little is known, howeve...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01912-12
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journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.00848-18
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journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.00608-09
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abstract::The mecillinam resistance of Escherichia coli K-12 mutants deficient in the enzyme responsible for the synthesis of adenosine 3',5'-monophosphate, adenylate cyclase, has been investigated. The results suggest that resistance to this antibiotic may be a consequence of the slow growth rate of these mutants rather than a...
journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/aac.19.4.540
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abstract::The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02062-16
更新日期:2017-02-23 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.26.3.347
更新日期:1984-09-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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abstract::Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against Mycobacterium tuberculosis in vitro and in animal models of tuberculosis (TB). Prior studies in healthy volunteers showed that once...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
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abstract::In Portugal erythromycin resistance of 26.6% (n = 352) remained constant during 1998 to 2003, however in 1998 the MLS(B) phenotype dominated (85%), whereas in 2003 the M phenotype prevailed (77%). A decline in T12/emm22 MLS(B) isolates could partially explain the drop in this phenotype, but the rise of the M phenotype...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.5.2109-2111.2005
更新日期:2005-05-01 00:00:00
abstract::The present study examined the efficacy of using multiple mechanisms as part of a topical microbicide to inactivate herpes simplex virus (HSV) by combining theaflavin-3,3'-digallate (TF-3) and lactic acid (LA) over the pH range of 4.0 to 5.7 to mimic conditions in the female reproductive tract. Six clinical isolates o...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00659-13
更新日期:2013-08-01 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::An analytical method for the quantitation of amifloxacin, 6-fluoro-1,4-dihydro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid, in plasma and urine has been developed. The method involves extraction with chloroform, back-extraction into 0.1 M sodium hydroxide, and subsequent analysis by re...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.27.5.769
更新日期:1985-05-01 00:00:00
abstract::This report describes linezolid susceptibility testing results for 6,741 Gram-positive pathogens from 60 U.S. sites collected during 2015 for the LEADER Program. In addition, the report summarizes linezolid in vitro activity, resistance mechanisms, and molecular typing obtained for 2011 to 2015. During 2015, linezolid...
journal_title:Antimicrobial agents and chemotherapy
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更新日期:2017-06-27 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.06401-11
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1981-11-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/aac.44.4.1089-1092.2000
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journal_title:Antimicrobial agents and chemotherapy
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更新日期:1995-01-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.00245-10
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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abstract::Clarithromycin is compared with clindamycin for single-dose prophylaxis of streptococcal endocarditis in rats. Human-like kinetics of the two antibiotics prevented endocarditis in animals challenged with both small and large amounts of bacterial inocula. Clarithromycin was marginally superior to clindamycin against sm...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.3.809
更新日期:1996-03-01 00:00:00
abstract::Serious Enterococcus faecalis infections usually require combination therapy to achieve a bactericidal effect. In orthopedic infections, the prognosis of enterococcal etiology is considered poor, and the use of aminoglycosides is questioned. The ampicillin-ceftriaxone combination has recently been accepted as alternat...
journal_title:Antimicrobial agents and chemotherapy
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abstract::UK-18892 is a new aminoglycoside antibiotic, a derivative of kanamycin A structurally related to amikacin. It was found to be active against a wide range of pathogenic bacteria, including many gentamicin-resistant strains. The spectrum and degree of activity of UK-18892 were similar to those of amikacin, and differenc...
journal_title:Antimicrobial agents and chemotherapy
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abstract::Nephrotoxicity was more marked in rats receiving isepamicin at midlight than at middark. And, the once-daily administration at middark induced a lesser degree of nephrotoxicity than the twice-daily injection, which indicates that the once-daily treatment therapy may have potential value in the clinical use of aminogly...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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更新日期:1993-09-01 00:00:00