PMID- 31843995
OWN - NLM
STAT- MEDLINE
DCOM- 20201214
LR  - 20201214
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 64
IP  - 3
DP  - 2020 Feb 21
TI  - Pharmacokinetics and Tolerability of Intravenous Sulbactam-Durlobactam with 
      Imipenem-Cilastatin in Hospitalized Adults with Complicated Urinary Tract 
      Infections, Including Acute Pyelonephritis.
LID - 10.1128/AAC.01506-19 [doi]
LID - e01506-19
AB  - Durlobactam (DUR; ETX2514) is a novel beta-lactamase inhibitor with broad-spectrum 
      activity against Ambler class A, C, and D beta-lactamases. Durlobactam restores the 
      in vitro activity of sulbactam (SUL) against members of the Acinetobacter 
      baumannii-A. calcoaceticus complex (ABC). Sulbactam (SUL)-durlobactam (SUL-DUR) 
      is under development for the treatment of ABC infections. Eighty patients with 
      complicated urinary tract infection (cUTI), including acute pyelonephritis (AP), 
      were randomized 2:1 to receive SUL-DUR at 1 g/1 g intravenously (i.v.) or placebo 
      every 6 h (q6h) for 7 days and background therapy with imipenem-cilastatin (IMI) 
      at 500 mg i.v. q6h to evaluate the tolerability of SUL-DUR in hospitalized 
      patients. Patients with bacteremia could receive up to 14 days of therapy. 
      SUL-DUR tolerability and the values of various pharmacokinetic (PK) parameters 
      were determined. Efficacy was recorded at the test-of-cure (TOC) visit. SUL-DUR 
      was well tolerated, with no serious adverse events (AEs) being reported. Headache 
      (5.7%), nausea (3.8%), diarrhea (3.8%), and vascular pain (3.8%) were the most 
      common drug-related AEs with SUL-DUR and were mostly of mild or moderate 
      severity. The PK profile of DUR and SUL in hospitalized patients was consistent 
      with observations in healthy volunteers. Overall success in the microbiological 
      modified intent-to-treat (m-MITT) population was similar between the groups, as 
      would be expected with IMI background therapy in all patients (overall success at 
      the TOC visit, 76.6% [n = 36] with SUL-DUR and 81.0% [n = 17] with placebo). 
      SUL-DUR in combination with IMI was well tolerated in patients with cUTIs. The 
      pharmacokinetics of SUL-DUR observed in hospitalized patients was similar to that 
      observed in healthy volunteers. (This study has been registered at 
      ClinicalTrials.gov under identifier NCT03445195.).
CI  - Copyright (c) 2020 Sagan et al.
FAU - Sagan, Olexiy
AU  - Sagan O
AD  - Regional Clinical Hospital of Zaporizhzhia, Zaporizhzhia, Ukraine.
FAU - Yakubsevitch, Ruslan
AU  - Yakubsevitch R
AD  - Grodno Regional Clinical Hospital, Hrodna, Belarus.
FAU - Yanev, Krassimir
AU  - Yanev K
AD  - Clinic of Urology, Sofia, Bulgaria.
FAU - Fomkin, Roman
AU  - Fomkin R
AD  - Saratov State Medical University, Saratov, Russia.
FAU - Stone, Emily
AU  - Stone E
AD  - Spero Therapeutics, Cambridge, Massachusetts, USA.
FAU - Hines, Daniel
AU  - Hines D
AD  - Entasis Therapeutics, Inc., Waltham, Massachusetts, USA.
FAU - O'Donnell, John
AU  - O'Donnell J
AD  - Entasis Therapeutics, Inc., Waltham, Massachusetts, USA.
FAU - Miller, Alita
AU  - Miller A
AD  - Entasis Therapeutics, Inc., Waltham, Massachusetts, USA.
FAU - Isaacs, Robin
AU  - Isaacs R
AD  - Entasis Therapeutics, Inc., Waltham, Massachusetts, USA.
FAU - Srinivasan, Subasree
AU  - Srinivasan S
AD  - Entasis Therapeutics, Inc., Waltham, Massachusetts, USA 
      suba.srinivasan@entasistx.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT03445195
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20200221
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Anti-Bacterial Agents)
RN  - 92309-29-0 (Cilastatin, Imipenem Drug Combination)
RN  - S4TF6I2330 (Sulbactam)
SB  - IM
MH  - Acute Disease
MH  - Administration, Intravenous
MH  - Adult
MH  - Aged
MH  - Anti-Bacterial Agents/administration & dosage/*pharmacokinetics/*therapeutic use
MH  - Cilastatin, Imipenem Drug Combination/administration & 
      dosage/*pharmacokinetics/*therapeutic use
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Placebo Effect
MH  - Pyelonephritis/*drug therapy/*microbiology
MH  - Sulbactam/administration & dosage/*pharmacokinetics/*therapeutic use
MH  - Urinary Tract Infections/*drug therapy
PMC - PMC7038258
OTO - NOTNLM
OT  - acute pyelonephritis
OT  - durlobactam
OT  - sulbactam
OT  - urinary tract infection
EDAT- 2019/12/18 06:00
MHDA- 2020/12/15 06:00
PMCR- 2020/02/21
CRDT- 2019/12/18 06:00
PHST- 2019/07/24 00:00 [received]
PHST- 2019/11/26 00:00 [accepted]
PHST- 2019/12/18 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2019/12/18 06:00 [entrez]
PHST- 2020/02/21 00:00 [pmc-release]
AID - AAC.01506-19 [pii]
AID - 01506-19 [pii]
AID - 10.1128/AAC.01506-19 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2020 Feb 21;64(3):e01506-19. doi: 
      10.1128/AAC.01506-19. Print 2020 Feb 21.