さまよう薬剤師のブログ

学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist. Another face is an investor.

Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial

LIDに報告されたVAPを含む肺炎に対するRCTです。

 

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30747-8/fulltext

 

Summary

Background

Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE).

Methods

Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7–14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21–25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than −12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96).

Findings

Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference −4·2% [95% CI −10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference −0·7% [95% CI −7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related.

Interpretation

Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens.

Funding

AstraZeneca.

 

PECO

 

P : Adults with nosocomial pneumonia (including ventilator-associated pneumonia)

E :  2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) for 7–14 days

C : 1000 mg meropenem (by 30-min intravenous infusion every 8 h)

O : 

245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference −4·2% [95% CI −10·8 to 2·5]).

In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference −0·7% [95% CI −7·9 to 6·4])

T : multinational, phase 3, double-blind, non-inferiority trial, ITT

F : Astra Zeneca

 

f:id:akinohanayuki:20180129050749p:plain

f:id:akinohanayuki:20180129050803p:plain

f:id:akinohanayuki:20180129050811p:plain

f:id:akinohanayuki:20180129050824p:plain

f:id:akinohanayuki:20180129050837p:plain

f:id:akinohanayuki:20180129050845p:plain

A key limitation of this trial is that we could not establish optimum duration of treatment with either ceftazidime- avibactamormeropenem,andthusitdoesnotprovideany additional information that a ects the standard of care with respect to these aspects of patient management. Furthermore, various aspects of the design, particularly thedurationofstudytreatmentof 7–14days,although consistent with guidelines available at the start of the study might not be representative of clinical practice and guidelines, which typically involve antibiotic de-escalation based on culture results. Similarly, the mode of meropenem administration (30 min infusions every 8 h) we used was consistent with the approved label and guidelines but might not re ect how the drug is given now (some institutions give prolonged or continuous infusions). Such design constraints are common in non-inferiority trials, in which careful e orts to avoid confounding the results and falsely concluding non-inferiority are required. Furthermore, the small numbers of patients with bacteraemia limits the applicability of the results to patients with sepsis.
 
感想
  
  • カルバペネム様と非劣勢。貴重な治療選択肢が増えた事は歓迎。
  • クリニカルキュアをプライマリーとしているが、28日死亡率にして欲しかった。
  • study対象国は超ワイルドワイドすぎて、リスク分散しすぎて、リアルワールドとの解釈は難しい。
  • study対象年齢も幅の広く、この点もリスク分散しすぎて、臨床判断が難しい。
 

 

レジデントのための感染症診療マニュアル 第3版

レジデントのための感染症診療マニュアル 第3版