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

José M Cisneros, Clara María Rosso-Fernández, Cristina Roca-Oporto, Gennaro De Pascale, Silvia Jiménez-Jorge, Esteban Fernández-Hinojosa, Dimitrios K Matthaiou, Paula Ramírez, Ramón Ortiz Díaz-Miguel, Angel Estella, Massimo Antonelli, George Dimopoulos, José Garnacho-Montero, Magic Bullet Working Group WP1, V Di Gravio, G Bello, V González, R Leal, A Puppo, J A Lepe, A Gutiérrez-Pizarraya, E Villarreal, M C Espinosa, M J Polanco, M D López, M E Herrera-Gutiérrez, G Seller, S Zakinthinos, S Malachias, A Komnos, T Zafeiridis, R Sierra, A González, E Zakynthinos, L Alvárez-Rocha, M Victoria de la Torre, P J Domínguez, M Bitsan, A Koutsoukou, R Zaragoza, E De Roberts, J M Allegue, J Carlos Pozo, G Nakos, R Ferrer, I Pneumatikos, P Vidal, José M Cisneros, Clara María Rosso-Fernández, Cristina Roca-Oporto, Gennaro De Pascale, Silvia Jiménez-Jorge, Esteban Fernández-Hinojosa, Dimitrios K Matthaiou, Paula Ramírez, Ramón Ortiz Díaz-Miguel, Angel Estella, Massimo Antonelli, George Dimopoulos, José Garnacho-Montero, José M Cisneros, Clara María Rosso-Fernández, Cristina Roca-Oporto, Gennaro De Pascale, Silvia Jiménez-Jorge, Esteban Fernández-Hinojosa, Dimitrios K Matthaiou, Paula Ramírez, Ramón Ortiz Díaz-Miguel, Angel Estella, Massimo Antonelli, George Dimopoulos, José Garnacho-Montero, Magic Bullet Working Group WP1, V Di Gravio, G Bello, V González, R Leal, A Puppo, J A Lepe, A Gutiérrez-Pizarraya, E Villarreal, M C Espinosa, M J Polanco, M D López, M E Herrera-Gutiérrez, G Seller, S Zakinthinos, S Malachias, A Komnos, T Zafeiridis, R Sierra, A González, E Zakynthinos, L Alvárez-Rocha, M Victoria de la Torre, P J Domínguez, M Bitsan, A Koutsoukou, R Zaragoza, E De Roberts, J M Allegue, J Carlos Pozo, G Nakos, R Ferrer, I Pneumatikos, P Vidal, José M Cisneros, Clara María Rosso-Fernández, Cristina Roca-Oporto, Gennaro De Pascale, Silvia Jiménez-Jorge, Esteban Fernández-Hinojosa, Dimitrios K Matthaiou, Paula Ramírez, Ramón Ortiz Díaz-Miguel, Angel Estella, Massimo Antonelli, George Dimopoulos, José Garnacho-Montero

Abstract

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.

Trial registration: ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

Keywords: Carbapenem-resistant gram-negative bacilli; Colistin; Multidrug-resistant bacteria; Ventilator-associated pneumonia.

Conflict of interest statement

JMC has served as a speaker for Novartis, Astellas, Pfizer, Merck Sharp & Dohme, Janssen, and AstraZeneca. PR has received lecture and advisory board fees from Pfizer, MSD, Novartis, and Gilead. During the last 2 years, GD has received advisory board and honoraria/lecture fees from Merck, USA; Gilead, UK; Infectopharm, Germany; Nabriva, USA; Cipla, India; Glenmark, India; Pfizer, Taiwan; and Bayer, Germany. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart. *One patient was excluded from the analysis due to incorrect inclusion (renal replacement therapy). **Two patients were excluded from the analysis due to incorrect inclusion (renal replacement therapy and previous use of meropenem). GNB: gram-negative bacilli; CABP: community-acquired bacterial pneumonia; HIV/AIDS: human immunodeficiency virus infection and acquired immune deficiency syndrome; CPIS: Clinical Pulmonary Infection Score; VAP: ventilator-associated pneumonia
Fig. 2
Fig. 2
Twenty-eight-day all-cause mortality outcomes. mMITT, microbiologically modified intention-to-treat; MITT, modified intention-to-treat; CR-GNB, carbapenem-resistant gram-negative bacilli. The dotted lines represent the noninferiority margins at ≤ 10%
Fig. 3
Fig. 3
a Survival analysis to day 28 after randomization, the microbiologically modified intention-to-treat population. b Survival analysis to day 28 after randomization, the modified intention-to-treat population

References

    1. Timsit J-F, Esaied W, Neuville M, Bouadma L, Mourvllier B. Update on ventilator-associated pneumonia. F1000Res. 2017;6:2061. doi: 10.12688/f1000research.12222.1.
    1. Chung DR, Song JH, Kim SH, Thamlikitkul V, Huang SG, Wang H, et al. High prevalence of multidrug-resistant nonfermenters in hospital-acquired pneumonia in Asia. Am J Respir Crit Care Med. 2011;184:1409–1417. doi: 10.1164/rccm.201102-0349OC.
    1. Delle Rose D, Pezzotti P, Fortunato E, Sordillo P, Gini S, Boros S, et al. Clinical predictors and microbiology of ventilator-associated pneumonia in the intensive care unit: a retrospective analysis in six Italian hospitals. Eur J Clin Microbiol Infect Dis. 2016;35:1531–1539. doi: 10.1007/s10096-016-2694-9.
    1. Garnacho-Montero J, Ortiz-Leyba C, Fernandez-Hinojosa E, Aldabo-Pallas T, Cayuela A, Marquez-Vacaro JA, et al. Acinetobacter baumannii ventilator-associated pneumonia: epidemiological and clinical findings. Intensive Care Med. 2005;31:649–655. doi: 10.1007/s00134-005-2598-0.
    1. Kollef KE, Schramm GE, Wills AR, Reichley RM, Micek ST, Kollef MH. Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria. Chest. 2008;134:281–287. doi: 10.1378/chest.08-1116.
    1. Tumbarello M, De Pascale G, Trecarichi EM, Spanu T, Antonicelli F, Maviglia R, et al. Clinical outcomes of Pseudomonas aeruginosa pneumonia in intensive care unit patients. Intensive Care Med. 2013;39:682–692. doi: 10.1007/s00134-013-2828-9.
    1. Teixeira PJ, Seligman R, Hertz FT, Cruz DB, Fachel JM. Inadequate treatment of ventilator-associated pneumonia: risk factors and impact on outcomes. J Hosp Infect. 2007;65:361–367. doi: 10.1016/j.jhin.2006.12.019.
    1. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases society of america and the american thoracic society. Clin Infect Dis. 2016;63:e61–111. doi: 10.1093/cid/ciw353.
    1. Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European respiratory society (ERS), European society of intensive care medicine (ESICM), European society of clinical microbiology and infectious diseases (ESCMID) and asociacion latinoamericana del torax (ALAT) Eur Respir J. 2017;50:1700582. doi: 10.1183/13993003.00582-2017.
    1. Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ, Barrero-Almodovar AE, Garcia-Garmendia JL, Bernabeu-Wittel IM, et al. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP. Clin Infect Dis. 2003;36:1111–1118. doi: 10.1086/374337.
    1. Kallel H, Hergafi L, Bahloul M, Hakim A, Dammak H, Chelly H, et al. Safety and efficacy of colistin compared with imipenem in the treatment of ventilator-associated pneumonia: a matched case-control study. Intensive Care Med. 2007;33:1162–1167. doi: 10.1007/s00134-007-0675-2.
    1. Paul M, Bishara J, Levcovich A, Chowers M, Goldberg E, Singer P, et al. Effectiveness and safety of colistin: prospective comparative cohort study. J Antimicrob Chemother. 2010;65:1019–1027. doi: 10.1093/jac/dkq069.
    1. Florescu DF, Qiu F, McCartan MA, Mindru C, Fey PD, Kalil AC. What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta-regression. Clin Infect Dis. 2012;54:670–680. doi: 10.1093/cid/cir934.
    1. Gu WJ, Wang F, Tang L, Bakker J, Liu JC. Colistin for the treatment of ventilator-associated pneumonia caused by multidrug-resistant gram-negative bacteria: a systematic review and meta-analysis. Int J Antimicrob Agents. 2014;44:477–485. doi: 10.1016/j.ijantimicag.2014.07.004.
    1. Tulli G, Messori A, Trippoli S, Marinai C. Non-inferiority of colistin compared with standard care for the treatment of ventilator-associated pneumonia. Int J Antimicrob Agents. 2017;49:638–641. doi: 10.1016/j.ijantimicag.2017.01.013.
    1. Betrosian AP, Frantzeskaki F, Xanthaki A, Douzinas EE. Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia. J Inf Secur. 2008;56:432–436.
    1. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, et al. 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. Clin Infect Dis. 2013;57:349–358. doi: 10.1093/cid/cit253.
    1. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018;18:391–400. doi: 10.1016/S1473-3099(18)30099-9.
    1. Rosso-Fernandez C, Garnacho-Montero J, Antonelli M, Dimopoulos G, Cisneros JM. Safety and efficacy of colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia as part of a macro-project funded by the seventh framework program of the European commission studying off-patent antibiotics: study protocol for a randomized controlled trial. Trials. 2015;16:102. doi: 10.1186/s13063-015-0614-4.
    1. Gounden R, Bamford C, van Zyl-Smit R, Cohen K, Maartens G. Safety and effectiveness of colistin compared with tobramycin for multi-drug resistant Acinetobacter baumannii infections. BMC Infect Dis. 2009;9:26. doi: 10.1186/1471-2334-9-26.
    1. Heyland DK, Dodek P, Muscedere J, Day A, Cook D. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med. 2008;36:737–744. doi: 10.1097/01.CCM.0B013E31816203D6.
    1. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. 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. Crit Care. 2004;8:R204–R212. doi: 10.1186/cc2872.
    1. Spellberg B, Talbot G. Recommended design features of future clinical trials of antibacterial agents for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;51(Suppl 1):S150–S170. doi: 10.1086/653065.
    1. Kollef MH, Ricard JD, Roux D, Francois B, Ischaki E, Rozgonyi Z, et al. A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of gram-negative ventilator-associated pneumonia: IASIS trial. Chest. 2017;151:1239–1246. doi: 10.1016/j.chest.2016.11.026.
    1. Chastre J, Wunderink R, Prokocimer P, Lee M, Kaniga K, Friedland I. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study. Crit Care Med. 2008;36:1089–1096. doi: 10.1097/CCM.0b013e3181691b99.
    1. Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18:285–295. doi: 10.1016/S1473-3099(17)30747-8.
    1. Imberti R, Cusato M, Villani P, Carnevale L, Iotti GA, Langer M, Regazzi M. Steady-state pharmacokinetics and BAL concentration of colistin in critically ill patients after IV colistin methanesulfonate administration. Chest. 2010;138(6):1333–1339. doi: 10.1378/chest.10-0463.
    1. Benattar YD, Omar M, Zusman O, Yahav D, Zak-Doron Y, Altunin S, et al. The effectiveness and safety of high-dose colistin: prospective cohort study. Clin Infect Dis. 2016;63:1605–1612. doi: 10.1093/cid/ciw684.
    1. Javan AO, Shokouhi S, Sahraei Z, Salamzadeh J, Armaki SA. Nephrotoxicity of high and conventional dosing regimens of colistin: a randomized clinical trial. Iran J Pharm Res. 2017;16:781–790.
    1. Nation RL, Garonzik SM, Thamlikitkul V, Giamarellos-Bourboulis EJ, Forrest A, Paterson DL, et al. Dosing guidance for intravenous colistin in critically-ill patients. Clin Infect Dis. 2017;64(5):565–571.
    1. European Committee on Antimicrobial Susceptibility Testing (EUCAST). Recommendations for MIC determination of colistin (polymyxin E) as recommended by the joint CLSI-EUCAST polymyxin breakpoints working group. 2016. . Accessed 8 Apr 2019.
    1. Nowak J, Zander E, Stefanik D, Higgins PG, Roca I, Vila J, McConnell MJ, Cisneros JM, Seifert H, MagicBullet Working Group WP4 High incidence of pandrug-resistant Acinetobacter baumannii isolates collected from patients with ventilator-associated pneumonia in Greece, Italy and Spain as part of the MagicBullet clinical trial. J Antimicrob Chemother. 2017;72:3277–3282. doi: 10.1093/jac/dkx322.
    1. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL. International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14:498–509. doi: 10.1016/S1473-3099(14)70036-2.

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