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Infectious Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5265
ISSN (Online): 2212-3989

Clinical Trial

Clinical Effectiveness of a High Dose Versus the Standard Dose of Meropenem in Ventilator-associated Pneumonia Caused by Multidrugresistant Bacteria: A Randomized, Single-blind Clinical Trial

Author(s): Mahila Monajati, Shahram Ala*, Masoud Aliyali, Roya Ghasemian, Fatemeh Heidari, Mohammad Ahanjan, Siavash Moradi, Ali Sharifpour, Mojtaba Mojtahedzadeh and Ebrahim Salehifar

Volume 21 , Issue 2 , 2021

Published on: 27 February, 2020

Page: [274 - 283] Pages: 10

DOI: 10.2174/1871526520666200227102013

Price: $65

Abstract

Background: Meropenem standard doses are based on the minimum inhibitory concentration of sensitive pathogens and the pharmacokinetic parameter of not critically ill patients. We compared the efficacy of high versus standard dose of meropenem in ventilator-associated pneumonia (VAP).

Methods: 24 out of 34 eligible patients were randomized to receive meropenem 3 g q8h (high dose group, 11 patients) or 2 g q8h (standard-dose group, 13 patients) as a 3h infusion. The primary outcome was considered as clinical success that was defined as stable hemodynamic, improved sequential organ failure assessment (SOFA) score, stable or improved PaO2/FiO2 after 7 days. Sputum culture was taken before the intervention.

Results: Clinical success rate was not significantly different between the high and standard-dose group (54.5% vs. 38.5%, P= 0.431). There was a significant difference in the reduction of clinical pulmonary infection score (CPIS) compared to a high dose to the standard group (P=0.038). SOFA score declined significantly in the high dose group throughout the study (P=0.006). A shorter duration of VAP treatment was recorded in the high dose group (P=0.061). We did not observe any significant adverse event related to meropenem. Acinetobacter spp. (34.8%), Klebsiella spp. (32.6%) and Pseudomonas aeruginosa (19.5%) isolated more frequently from sputum cultures.

Conclusion: Treatment with the high dose of meropenem seems to be safe. However, it did not provide a significantly higher clinical success rate in comparison with the standard dose, but could be considered as an appropriate empirical treatment in patients with severe infection due to reduction in SOFA and CPIS.

The trial protocol was registered with IRCT.ir (registration number IRCT2010010700 3014N19 in April 2018).

Keywords: Meropenem, critically ill, ventilator-associated pneumonia, gram-negative pathogens, intensive care unit.

[1]
Torres, A.; Niederman, M.S.; Chastre, J.; Ewig, S.; Fernandez-Vandellos, P.; Hanberger, H.; Kollef, M.; Li Bassi, G.; Luna, C.M.; Martin-Loeches, I.; Paiva, J.A.; Read, R.C.; Rigau, D.; Timsit, J.F.; Welte, T.; Wunderink, R. 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 Asociación Latinoamericana del Tórax (ALAT). Eur. Respir. J., 2017, 50(3), 1700582.
[http://dx.doi.org/10.1183/13993003.00582-2017] [PMID: 28890434]
[2]
Weiner, L.M.; Webb, A.K.; Limbago, B.; Dudeck, M.A.; Patel, J.; Kallen, A.J.; Edwards, J.R.; Sievert, D.M. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014. Infect. Control Hosp. Epidemiol., 2016, 37(11), 1288-1301.
[http://dx.doi.org/10.1017/ice.2016.174] [PMID: 27573805]
[3]
Magill, S.S.; Edwards, J.R.; Bamberg, W.; Beldavs, Z.G.; Dumyati, G.; Kainer, M.A.; Lynfield, R.; Maloney, M.; McAllister-Hollod, L.; Nadle, J.; Ray, S.M.; Thompson, D.L.; Wilson, L.E.; Fridkin, S.K. Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team. Multistate point-prevalence survey of health care-associated infections. N. Engl. J. Med., 2014, 370(13), 1198-1208.
[http://dx.doi.org/10.1056/NEJMoa1306801] [PMID: 24670166]
[4]
Sader, H.S.; Farrell, D.J.; Flamm, R.K.; Jones, R.N. Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalised with pneumonia in US and European hospitals: results from the SENTRY Antimicrobial Surveillance Program, 2009-2012. Int. J. Antimicrob. Agents, 2014, 43(4), 328-334.
[http://dx.doi.org/10.1016/j.ijantimicag.2014.01.007] [PMID: 24630306]
[5]
Ghasemian, R.; Ahanjan, M.; Fatehi, E.; Shokri, M. Prevalence and antibiotic resistance pattern of acinetobacter isolated from patients admitted in ICUs in Mazandaran, Northern Iran. Glob. J. Health Sci., 2016, 8(11), 112.
[http://dx.doi.org/10.5539/gjhs.v8n11p112]
[6]
Kalil, A.C.; Metersky, M.L.; Klompas, M.; Muscedere, J.; Sweeney, D.A.; Palmer, L.B.; Napolitano, L.M.; O’Grady, N.P.; Bartlett, J.G.; Carratalà, J.; El Solh, A.A.; Ewig, S.; Fey, P.D.; File, T.M., Jr; Restrepo, M.I.; Roberts, J.A.; Waterer, G.W.; Cruse, P.; Knight, S.L.; Brozek, J.L. 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(5), e61-e111.
[http://dx.doi.org/10.1093/cid/ciw353] [PMID: 27418577]
[7]
Li, C.; Du, X.; Kuti, J.L.; Nicolau, D.P. Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob. Agents Chemother., 2007, 51(5), 1725-1730.
[http://dx.doi.org/10.1128/AAC.00294-06] [PMID: 17307978]
[8]
Cojutti, P.; Sartor, A.; Righi, E.; Scarparo, C.; Bassetti, M.; Pea, F. Population pharmacokinetics of high-dose continuous-infusion meropenem and considerations for use in the treatment of infections due to kpc-producing klebsiella pneumoniae. Antimicrob. Agents Chemother., 2017, 61(10), e00794-e17.
[http://dx.doi.org/10.1128/AAC.00794-17] [PMID: 28760900]
[9]
Roberts, J.A.; Paul, S.K.; Akova, M.; Bassetti, M.; De Waele, J.J.; Dimopoulos, G.; Kaukonen, K.M.; Koulenti, D.; Martin, C.; Montravers, P.; Rello, J.; Rhodes, A.; Starr, T.; Wallis, S.C.; Lipman, J. DALI Study. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin. Infect. Dis., 2014, 58(8), 1072-1083.
[http://dx.doi.org/10.1093/cid/ciu027] [PMID: 24429437]
[10]
Roberts, J.A.; Lipman, J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit. Care Med., 2009, 37(3), 840-851.
[http://dx.doi.org/10.1097/CCM.0b013e3181961bff] [PMID: 19237886]
[11]
Udy, A.A.; Roberts, J.A.; Boots, R.J.; Paterson, D.L.; Lipman, J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin. Pharmacokinet., 2010, 49(1), 1-16.
[http://dx.doi.org/10.2165/11318140-000000000-00000] [PMID: 20000886]
[12]
Huttner, A.; Von Dach, E.; Renzoni, A.; Huttner, B.D.; Affaticati, M.; Pagani, L.; Daali, Y.; Pugin, J.; Karmime, A.; Fathi, M.; Lew, D.; Harbarth, S. Augmented renal clearance, low β-lactam concentrations and clinical outcomes in the critically ill: an observational prospective cohort study. Int. J. Antimicrob. Agents, 2015, 45(4), 385-392.
[http://dx.doi.org/10.1016/j.ijantimicag.2014.12.017] [PMID: 25656151]
[13]
Giamarellou, H. Multidrug-resistant Gram-negative bacteria: how to treat and for how long. Int. J. Antimicrob. Agents, 2010, 36(Suppl. 2), S50-S54.
[http://dx.doi.org/10.1016/j.ijantimicag.2010.11.014] [PMID: 21129924]
[14]
Guglielmo, B.J. Principle of infectious diseases.Applied Therapeutics: the Clinical Use of Drugs, 11th ed; Zeind, C.S.; Carvalho, M.G., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2018, pp. 1319-1342.
[15]
Dickstein, Y.; Leibovici, L.; Yahav, D.; Eliakim-Raz, N.; Daikos, G.L.; Skiada, A.; Antoniadou, A.; Carmeli, Y.; Nutman, A.; Levi, I.; Adler, A.; Durante-Mangoni, E.; Andini, R.; Cavezza, G.; Mouton, J.W.; Wijma, R.A.; Theuretzbacher, U.; Friberg, L.E.; Kristoffersson, A.N.; Zusman, O.; Koppel, F.; Dishon Benattar, Y.; Altunin, S.; Paul, M. AIDA consortium. Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol. BMJ Open, 2016, 6(4), e009956.
[http://dx.doi.org/10.1136/bmjopen-2015-009956] [PMID: 27098822]
[16]
Bulik, C.C.; Quintiliani, R.; Pope, J.S.; Kuti, J.L.; Nicolau, D.P. Pharmacodynamics and tolerability of high-dose, prolonged infusion carbapenems in adults with cystic fibrosis–A review of 3 cases. Respir. Med. CME, 2010, 3(3), 146-149.
[http://dx.doi.org/10.1016/j.rmedc.2009.09.011]
[17]
Taccone, F.S.; Cotton, F.; Roisin, S.; Vincent, J-L.; Jacobs, F. Optimal meropenem concentrations to treat multidrug-resistant Pseudomonas aeruginosa septic shock. Antimicrob. Agents Chemother., 2012, 56(4), 2129-2131.
[http://dx.doi.org/10.1128/AAC.06389-11] [PMID: 22290984]
[18]
Pea, F.; Della Siega, P.; Cojutti, P.; Sartor, A.; Crapis, M.; Scarparo, C. Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing Klebsiella pneumoniae? Int. J. Antimicrob. Agents, 2016.
[PMID: 28012683]
[19]
Horan, T.C.; Andrus, M.; Dudeck, M.A. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am. J. Infect. Control, 2008, 36(5), 309-332.
[http://dx.doi.org/10.1016/j.ajic.2008.03.002] [PMID: 18538699]
[20]
Carney, N.; Totten, A.M.; O’Reilly, C.; Ullman, J.S.; Hawryluk, G.W.J.; Bell, M.J. Guidelines for the Management of Severe Traumatic Brain InjuryNeurosurg, Fourth Edition; , 2016, 80, pp. (1)6-15.
[21]
The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 7.1, 2017. http://www.eucast.org
[22]
Health UDo. Services H. Common terminology criteria for adverse events (CTCAE) version 4.0. J. Natl. Cancer Inst., 2009.
[23]
Weiss, E.; Essaied, W.; Adrie, C.; Zahar, J-R.; Timsit, J-F. Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials. Crit. Care, 2017, 21(1), 162.
[http://dx.doi.org/10.1186/s13054-017-1755-5] [PMID: 28655326]
[24]
Paul, M.; Daikos, G.L.; Durante-Mangoni, E.; Yahav, D.; Carmeli, Y.; Benattar, Y.D.; Skiada, A.; Andini, R.; Eliakim-Raz, N.; Nutman, A.; Zusman, O.; Antoniadou, A.; Pafundi, P.C.; Adler, A.; Dickstein, Y.; Pavleas, I.; Zampino, R.; Daitch, V.; Bitterman, R.; Zayyad, H.; Koppel, F.; Levi, I.; Babich, T.; Friberg, L.E.; Mouton, J.W.; Theuretzbacher, U.; Leibovici, L. 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(4), 391-400.
[http://dx.doi.org/10.1016/S1473-3099(18)30099-9] [PMID: 29456043]
[25]
Singh, N.; Rogers, P.; Atwood, C.W.; Wagener, M.M.; Yu, V.L. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am. J. Respir. Crit. Care Med., 2000, 162(2 Pt 1), 505-511.
[http://dx.doi.org/10.1164/ajrccm.162.2.9909095] [PMID: 10934078]
[26]
Micek, S.T.; Ward, S.; Fraser, V.J.; Kollef, M.H. A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia. Chest, 2004, 125(5), 1791-1799.
[http://dx.doi.org/10.1378/chest.125.5.1791] [PMID: 15136392]
[27]
Ibrahim, E.H.; Ward, S.; Sherman, G.; Schaiff, R.; Fraser, V.J.; Kollef, M.H. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit. Care Med., 2001, 29(6), 1109-1115.
[http://dx.doi.org/10.1097/00003246-200106000-00003] [PMID: 11395584]
[28]
Burger, R.; Guidi, M.; Calpini, V.; Lamoth, F.; Decosterd, L.; Robatel, C.; Buclin, T.; Csajka, C.; Marchetti, O. Effect of renal clearance and continuous renal replacement therapy on appropriateness of recommended meropenem dosing regimens in critically ill patients with susceptible life-threatening infections. J. Antimicrob. Chemother., 2018, 73(12), 3413-3422.
[http://dx.doi.org/10.1093/jac/dky370] [PMID: 30304491]
[29]
Luyt, C-E.; Aubry, A.; Lu, Q.; Micaelo, M.; Bréchot, N.; Brossier, F.; Brisson, H.; Rouby, J.J.; Trouillet, J.L.; Combes, A.; Jarlier, V.; Chastre, J. Imipenem, meropenem, or doripenem to treat patients with Pseudomonas aeruginosa ventilator-associated pneumonia. Antimicrob. Agents Chemother., 2014, 58(3), 1372-1380.
[http://dx.doi.org/10.1128/AAC.02109-13] [PMID: 24342638]
[30]
Linden, P. Safety profile of meropenem: an updated review of over 6,000 patients treated with meropenem. Drug Saf., 2007, 30(8), 657-668.
[http://dx.doi.org/10.2165/00002018-200730080-00002] [PMID: 17696578]
[31]
Norrby, S.R.; Gildon, K.M. Safety profile of meropenem: a review of nearly 5,000 patients treated with meropenem. Scand. J. Infect. Dis., 1999, 31(1), 3-10.
[http://dx.doi.org/10.1080/00365549950161808] [PMID: 10381210]

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