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Table 3 List of major randomized, controlled clinical trials of systemic antimicrobial agents actually available for treating NP in the last 10 years

From: Update of the treatment of nosocomial pneumonia in the ICU

Author, year, name of the trial Antimicrobial tested and comparator Phase, blinded, design Microorganism Subject Primary outcome Results of primary outcome Mortality Comments
Freire, 2010 [76] Tigecycline (T)
Imipenem (I)
III, yes, NI All pathogens HAP + VAP Clinical response in CE and c-mITT populations at TOC c-mITT: T, 62.7%; I, 67.6%
CE: T, 67.9%; I, 78.2%
T, 14.1%
I, 12.2%
T was non-inferior to I for c-mITT but not the CE population due to the results in VAP. FDA warning against T use for VAP.
Rubinstein, 2011, ATTAIN 1 and 2 [60] Telavancin (Te) Vancomycin (V) III, yes, NI Gram-positive HAP Clinical response at FU/TOC AT: Te, 58.9%; V, 59.5%
CE: Te, 82.4%; V, 80.7%
Te, 21.5%
V, 16.6%
Increases in serum creatinine level were more common in the telavancin group.
Kollef, 2012 [78] Doripenem (D), 7 days
Imipenem (I), 10 days
IV, yes, NI All pathogens VAP Clinical cure at EOT (day 10) in the MITT D, 45.6%
I, 56.8%
D, 21.5%
I, 14.8%
Non-inferiority of a fixed 7-day treatment with D was no achieved FDA warning against D use for VAP.
Wunderink, 2012, ZEPHIR [79] Linezolid (L)
Vancomycin (V)
IV, yes, NI Meticillin-resistant Staphylococcus aureus HAP + VAP Clinical outcome at EOS in PP patients L, 57.6%
V, 46.5%
L, 15.7%
V, 17%
Nephrotoxicity occurred more frequently with V.
Ramirez, 2013 [80] Tigecycline low dose (TLD)
Tigecycline high dose (THD)
Imipenem
II, yes, NI All pathogens HAP + VAP Clinical response at EOT THD, 85%
TLD, 69.6
I, 75%
THD could be necessary to treat HAP/VAP.
Awad, 2014 [81] Ceftobiprole medocaril (C)
Ceftazidime + Linezolid (CAZ/L)
III, yes, NI All pathogens HAP + VAP Clinical cure at the TOC ITT: C, 49.9%; CAZ/L, 52.8%
CE: C, 69.3%; CAZ/L, 71.3%
C, 16.7%
CAZ/L, 18%
Non-inferiority of C compared with CAZ/L was not demonstrated in VAP patients.
Torres, 2018, REPROVE [82] Ceftazidime/avibactam (CAZ/AVI)
Meropenem (M)
III, yes, NI All pathogens HAP + VAP Clinical cure at the TOC c-mITT: CAZ/AVI, 68.8%; M, 73%
CE: CAZ/AVI, 77.4%; M, 78.1%
CAZ/AVI, 8.1%
M, 6.8%
CAZ/AVI could be a potential alternative to carbapenems in HAP/VAP patients.
Kollef 2019, ASPECT-NP [83] Ceftolozane/tazobactam (CFT-TAZ)
Meropenem
III, yes, NI All pathogens HAP + VAP, only patients on MV 28-day all-cause mortality in ITT CFT-TAZ, 24%
M, 25.3%
CFT-TAZ, 24%
M, 25.3%
In HAP and in those in whom previous antibacterial therapy was unsuccessful, CFT-TAZ showed lower mortality.
Cisneros, 2019, Magic-Bullet [84] Colistin (Co)
Meropenen (M)
IV, no, NI All pathogens Late VAP Mortality at 28 days after randomization in mMITT Co, 23.2%
M, 25.3%
Co, 23.2%
M, 25.3%
The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group (33:3% vs 18.8%).
  1. AT all treated patients, CAZ/AVI ceftazidime/avibactam, CE clinically evaluable population, CFT-TAZ ceftolozane/tazobactam, Co colistin, c-mITT clinical modified intent-to-treat population, D doripenem, EOS end of study, EOT end of treatment, FU follow-up, I imipenem, ITT intention-to-treat population, M meropenem, MITT modified intent-to-treat population, mMITT microbiologically modified intention-to-treat population, MV mechanical ventilation, NI non-inferiority, T tigecycline, Te telavancin, TOC test of cure, THD tigecycline high dose, TLD tigecycline low dose, PP evaluable per-protocol, V vancomycin