Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial

被引：54

作者：

Cisneros, Jose M. ^{[1
]}

Maria Rosso-Fernandez, Clara ^{[2
]}

Roca-Oporto, Cristina ^{[1
]}

De Pascale, Gennaro ^{[3
]}

Jimenez-Jorge, Silvia ^{[2
]}

Fernandez-Hinojosa, Esteban ^{[4
]}

Matthaiou, Dimitrios K. ^{[5
]}

Ramirez, Paula ^{[6
]}

Ortiz Diaz-Miguel, Ramon ^{[7
]}

Estella, Angel ^{[8
]}

Antonelli, Massimo ^{[3
,9
]}

Dimopoulos, George ^{[5
]}

Garnacho-Montero, Jose ^{[10
]}

Di Gravio, V ^{[11
]}

Bello, G. ^{[11
]}

Gonzalez, V ^{[12
]}

Leal, R. ^{[12
]}

Puppo, A. ^{[12
]}

Lepe, J. A. ^{[12
]}

Gutierrez-Pizarraya, A. ^{[12
]}

Villarreal, E. ^{[13
]}

Espinosa, M. C. ^{[14
]}

Polanco, M. J. ^{[14
]}

Lopez, M. D. ^{[15
]}

Herrera-Gutierrez, M. E. ^{[16
]}

Seller, G. ^{[16
]}

Zakinthinos, S. ^{[17
]}

Malachias, S. ^{[17
]}

Komnos, A. ^{[18
]}

Zafeiridis, T. ^{[18
]}

Sierra, R. ^{[19
]}

Gonzalez, A. ^{[20
]}

Zakynthinos, E. ^{[21
]}

Alvarez-Rocha, L. ^{[22
]}

Victoria de la Torre, M. ^{[23
]}

Dominguez, P. J. ^{[24
]}

Bitsan, M. ^{[25
]}

Koutsoukou, A. ^{[26
]}

Zaragoza, R. ^{[27
]}

De Roberts, E. ^{[28
]}

Allegue, J. M. ^{[29
]}

Carlos Pozo, J. ^{[30
]}

Nakos, G. ^{[31
]}

Ferrer, R. ^{[32
]}

Pneumatikos, I ^{[33
]}

Vidal, P. ^{[34
]}

机构：

[1] Univ Seville, Univ Hosp Virgen del Rocio, Inst Biomed Seville IBIS, CSIC,Dept Infect Dis Microbiol & Prevent Med, Ave Manuel Siurot S-N, Seville 41013, Spain

[2] Univ Hosp Virgen del Rocio, Clin Trial Unit, Ave Manuel Siurot S-N, Seville 41013, Spain

[3] Fdn Policlin Univ A Gemelli IRCCS, Rome, Italy

[4] Hosp Univ Virgen del Rocio, Intens Care Clin Unit, Ave Manuel Siurot S-N, Seville 41013, Spain

[5] Univ Athens, Univ Hosp ATTIKON, Dept Crit Care, Athens, Greece

[6] Hosp Univ & Politecn La Fe, Intens Med Unit, Avinguda Fernando Abril Martorell 106, Valencia 46026, Spain

[7] Hosp Gen Univ Ciudad Real, Intens Med Unit, Calle Obispo Rafael Torija S-N, Ciudad Real 13005, Spain

[8] Hosp Univ Jerez, Intens Care Unit, Carretera Nacl 4 S-N, Cadiz 11407, Spain

[9] Univ Cattolica Sacro Cuore, Rome, Italy

[10] Hosp Univ Virgen Macarena, Intens Care Clin Unit, Calle Dr Fedriani 3, Seville 41009, Spain

[11] Gemelli Hosp, Rome, Italy

[12] Virgen del Rocio Hosp, Seville, Spain

[13] La Fe Hosp, Valencia, Spain

[14] Ciudad Real Hosp, Ciudad Real, Spain

[15] Jerez de la Frontera Hosp, Jerez de la Frontera, Spain

[16] Carlos Haya Hosp, Malaga, Spain

[17] Evagelismos Hosp, Paphos, Cyprus

[18] Gen Larissa Hosp, Larisa, Greece

[19] Puerta del Mar Hosp, Cadiz, Spain

[20] Marques Vaidecilla Hosp, Santander, Spain

[21] MSU Thessalia, UH Larissa, Volos, Greece

[22] A Coruna Hosp, La Coruna, Spain

[23] Virgen de la Victoria Hosp, Malaga, Spain

[24] Juan Ramon Jimenez Hosp, Huelva, Spain

[25] Papanikolau Hosp, Pilea Chortiatis, Greece

[26] SOTIRIA Hosp, Athens, Greece

[27] Dr Peset Hosp, Valencia, Spain

[28] Napoli Federico II Hosp, Naples, Italy

[29] Santa Lucia Hosp, San Borja, Peru

[30] Reina Sofia Hosp, Seville, Spain

[31] UH Ioannina MSU Ipirus, Ioannina, Greece

[32] Mutua Tarrassa Hosp, Terrassa, Spain

[33] Alexandroupoli Hosp, Alexandroupolis, Greece

[34] Orense Hosp, Orense, Spain

来源：

CRITICAL CARE | 2019年 / 23卷 / 01期

关键词：

Colistin; Ventilator-associated pneumonia; Multidrug-resistant bacteria; Carbapenem-resistant gram-negative bacilli; RESISTANT ACINETOBACTER-BAUMANNII; INTENSIVE-CARE-UNIT; NON-INFERIORITY; SAFETY; EFFICACY; IMIPENEM; MULTICENTER; MONOTHERAPY; INFECTIONS; PREDICTORS;

D O I：

10.1186/s13054-019-2627-y

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Background Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. Methods A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. Results A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). Conclusions This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination.

引用

页数：13

共 33 条

[1] Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group [J].

Bellomo, R ;

Ronco, C ;

Kellum, JA ;

Mehta, RL ;

Palevsky, P .

CRITICAL CARE, 2004, 8 (04) :R204-R212

[2] The Effectiveness and Safety of High-Dose Colistin: Prospective Cohort Study [J].

Benattar, Yael Dishon ;

Omar, Muna ;

Zusman, Oren ;

Yahav, Dafna ;

Zak-Doron, Yael ;

Altunin, Sergey ;

Elbaz, Michal ;

Daitch, Vered ;

Granot, Michal ;

Leibovici, Leonard ;

Paul, Mical .

CLINICAL INFECTIOUS DISEASES, 2016, 63 (12) :1605-1612

[3] Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia [J].

Betrosian, Alex P. ;

Frantzeskaki, Frantzeska ;

Xanthaki, Anna ;

Douzinas, Emmanuel E. .

JOURNAL OF INFECTION, 2008, 56 (06) :432-436

[4] Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: A multicenter, randomized study [J].

Chastre, Jean ;

Wunderink, Richard ;

Prokocimer, Philippe ;

Lee, Michael ;

Kaniga, Kone ;

Friedland, Ian .

CRITICAL CARE MEDICINE, 2008, 36 (04) :1089-1096

[5] High Prevalence of Multidrug-Resistant Nonfermenters in Hospital-acquired Pneumonia in Asia [J].

Chung, Doo Ryeon ;

Song, Jae-Hoon ;

Kim, So Hyun ;

Thamlikitkul, Visanu ;

Huang, Shao-Guang ;

Wang, Hui ;

So, Thomas Man-kit ;

Yasin, Rohani M. D. ;

Hsueh, Po-Ren ;

Carlos, Celia C. ;

Hsu, Li Yang ;

Buntaran, Latre ;

Lalitha, M. K. ;

Kim, Min Ja ;

Choi, Jun Yong ;

Kim, Sang Il ;

Ko, Kwan Soo ;

Kang, Cheol-In ;

Peck, Kyong Ran .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2011, 184 (12) :1409-1417

[6] Clinical predictors and microbiology of ventilator-associated pneumonia in the intensive care unit: a retrospective analysis in six Italian hospitals [J].

Delle Rose, D. ;

Pezzotti, P. ;

Fortunato, E. ;

Sordillo, P. ;

Gini, S. ;

Boros, S. ;

Meledandri, M. ;

Gallo, M. T. ;

Prignano, G. ;

Caccese, R. ;

D'Ambrosio, M. ;

Citterio, G. ;

Rocco, M. ;

Leonardis, F. ;

Natoli, S. ;

Fontana, C. ;

Favaro, M. ;

Celeste, M. G. ;

Franci, T. ;

Testore, G. P. ;

Andreoni, M. ;

Sarmati, L. .

EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES, 2016, 35 (09) :1531-1539

[7] Colistin and Rifampicin Compared With Colistin Alone for the Treatment of Serious Infections Due to Extensively Drug-Resistant Acinetobacter baumannii: A Multicenter, Randomized Clinical Trial [J].

Durante-Mangoni, Emanuele ;

Signoriello, Giuseppe ;

Andini, Roberto ;

Mattei, Annunziata ;

De Cristoforo, Maria ;

Murino, Patrizia ;

Bassetti, Matteo ;

Malacarne, Paolo ;

Petrosillo, Nicola ;

Galdieri, Nicola ;

Mocavero, Paola ;

Corcione, Antonio ;

Viscoli, Claudio ;

Zarrilli, Raffaele ;

Gallo, Ciro ;

Utili, Riccardo .

CLINICAL INFECTIOUS DISEASES, 2013, 57 (03) :349-358

[8]

EUCAST, 2016, EUR COMM ANT SUSC TE

[9] What Is the Efficacy and Safety of Colistin for the Treatment of Ventilator-Associated Pneumonia? A Systematic Review and Meta-Regression [J].

Florescu, Diana F. ;

Qiu, Fang ;

McCartan, Megan A. ;

Mindru, Cezarina ;

Fey, Paul D. ;

Kalil, A. C. .

CLINICAL INFECTIOUS DISEASES, 2012, 54 (05) :670-680

[10] Acinetobacter baumannii ventilator-associated pneumonia:: epidemiological and clinical findings [J].

Garnacho-Montero, J ;

Ortiz-Leyba, C ;

Fernández-Hinojosa, E ;

Aldabó-Pallás, T ;

Cayuela, A ;

Marquez-Vácaro, JA ;

Garcia-Curiel, A ;

Jiménez-Jiménez, FJ .

INTENSIVE CARE MEDICINE, 2005, 31 (05) :649-655

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