Semin Respir Crit Care Med 2019; 40(04): 419-434
DOI: 10.1055/s-0039-1696662
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Difficult-to-Treat Antibiotic-Resistant Gram-Negative Pathogens in the Intensive Care Unit: Epidemiology, Outcomes, and Treatment

Jeffrey R. Strich
1   Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland
2   United States Public Health Service, Commissioned Corps, Rockville, Maryland
,
Sameer S. Kadri
1   Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland
› Author Affiliations
Funding This work was supported by the Intramural Research Program of the National Institutes of Health Clinical Center.
Further Information

Publication History

Publication Date:
04 October 2019 (online)

Abstract

Antibiotic resistance among gram-negative pathogens is a world-wide problem that poses a constant threat to patients in the intensive care unit and a therapeutic challenge for the intensivist. Furthermore, the substantial economic burden and increased mortality associated with infections due to highly resistant gram-negative pathogens exacerbate these challenges. Understanding the mechanisms, epidemiology, and risk factors for these infections is paramount to the successful control of outbreaks and for guiding therapy which often entails use of antibiotics with suboptimal efficacy and/or toxicity profiles. In this review we will discuss the global epidemiology, burden, risk factors, and treatment of highly resistant gram-negative infections as they apply to the intensive care population.

Disclaimer

The opinions expressed in this article are those of the authors and do not represent any position or policy of the National Institutes of Health, the U.S. Department of Health and Human Services, or the U.S. government.


 
  • References

  • 1 Lodise T, Ye MJ, Zhao Q. Prevalence of invasive infections due to carbapenem-resistant Enterobacteriaceae among adult patients in U.S. hospitals. Antimicrob Agents Chemother 2017 61. (08): Doi: 10.1128/microbiolspec.VMBF-0016-2015
  • 2 Kadri SS. Recognizing the unique role of critical care providers in confronting antimicrobial resistance. Am J Respir Crit Care Med 2018; 198 (05) 560-562
  • 3 Tacconelli E, Carrara E, Savoldi A. , et al; WHO Pathogens Priority List Working Group. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018; 18 (03) 318-327
  • 4 Burnham JP, Olsen MA, Kollef MH. Re-estimating annual deaths due to multidrug-resistant organism infections. Infect Control Hosp Epidemiol 2019; 40 (01) 112-113
  • 5 Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol Spectr 2016 4. (02): Doi: 10.1128/microbiolspec.VMBF-0016-2015
  • 6 Agodi A, Voulgari E, Barchitta M. , et al. Containment of an outbreak of KPC-3-producing Klebsiella pneumoniae in Italy. J Clin Microbiol 2011; 49 (11) 3986-3989
  • 7 Ruppé É, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in gram-negative bacilli. Ann Intensive Care 2015; 5 (01) 61
  • 8 Kanamori H, Parobek CM, Juliano JJ. , et al. A prolonged outbreak of KPC-3-producing Enterobacter cloacae and Klebsiella pneumoniae driven by multiple mechanisms of resistance transmission at a large academic burn center. Antimicrob Agents Chemother 2017 61. (02): Doi: 10.1128/AAC.01516-16
  • 9 Codjoe FS, Donkor ES. Carbapenem resistance: a review. Med Sci (Basel) 2017 6. (01): 10.1128/AAC.01516-16
  • 10 Nordmann P, Naas T, Poirel L. Global spread of Carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 2011; 17 (10) 1791-1798
  • 11 Magiorakos AP, Srinivasan A, Carey RB. , et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18 (03) 268-281
  • 12 Kadri SS, Adjemian J, Lai YL. , et al; National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative (NIH–ARORI). Difficult-to-treat resistance in gram-negative bacteremia at 173 US hospitals: retrospective cohort analysis of prevalence, predictors, and outcome of resistance to all first-line agents. Clin Infect Dis 2018; 67 (12) 1803-1814
  • 13 Kadri SS, Lai YLE, Ricotta EE. , et al; NIH Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI). External validation of difficult-to-treat resistance prevalence and mortality risk in gram-negative bloodstream infection using electronic health record data from 140 US hospitals. Open Forum Infect Dis 2019; 6 (04) ofz110
  • 14 Hygiene measures for infection or colonization with multidrug-resistant gram-negative bacilli. Commission recommendation for hospital hygiene and infection prevention (KRINKO) at the Robert Koch Institute (RKI) [in German]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2012; 55 (10) 1311-1354
  • 15 Wernli D, Jørgensen PS, Harbarth S. , et al. Antimicrobial resistance: the complex challenge of measurement to inform policy and the public. PLoS Med 2017; 14 (08) e1002378
  • 16 Fuhrmeister AS, Jones RN. The importance of antimicrobial resistance monitoring worldwide and the origins of SENTRY antimicrobial surveillance program. Open Forum Infect Dis 2019; 6 (Suppl. 01) S1-S4
  • 17 Cassini A, Högberg LD, Plachouras D. , et al; Burden of AMR Collaborative Group. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis 2019; 19 (01) 56-66
  • 18 Raoult D, Leone M, Roussel Y, Rolain JM. Attributable deaths caused by infections with antibiotic-resistant bacteria in France. Lancet Infect Dis 2019; 19 (02) 128-129
  • 19 Roberts RR, Hota B, Ahmad I. , et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis 2009; 49 (08) 1175-1184
  • 20 CDC. Antibiotic Resistance Threats in the United States. 2013 . Available at: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf . Accessed August 9, 2019
  • 21 O'Neil J. Review on Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014 https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf
  • 22 de Kraker ME, Stewardson AJ, Harbarth S. Will 10 million people die a year due to antimicrobial resistance by 2050?. PLoS Med 2016; 13 (11) e1002184
  • 23 Kadri SS, Hohmann SF, Orav EJ. , et al. Tracking colistin-treated patients to monitor the incidence and outcome of carbapenem-resistant gram-negative infections. Clin Infect Dis 2015; 60 (01) 79-87
  • 24 Cai B, Echols R, Magee G. , et al. Prevalence of carbapenem-resistant gram-negative infections in the United States predominated by Acinetobacter baumannii and Pseudomonas aeruginosa . Open Forum Infect Dis 2017; 4 (03) ofx176
  • 25 Laxminarayan R, Heymann DL. Challenges of drug resistance in the developing world. BMJ 2012; 344: e1567
  • 26 Alvarez-Uria G, Gandra S, Laxminarayan R. Poverty and prevalence of antimicrobial resistance in invasive isolates. Int J Infect Dis 2016; 52: 59-61
  • 27 Stewardson AJ, Marimuthu K, Sengupta S. , et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study. Lancet Infect Dis 2019; 19 (06) 601-610
  • 28 Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis 2014; 20 (07) 1170-1175
  • 29 McCann E, Srinivasan A, DeRyke CA. , et al. Carbapenem-nonsusceptible gram-negative pathogens in ICU and non-ICU settings in US hospitals in 2017: a multicenter study. Open Forum Infect Dis 2018; 5 (10) ofy241
  • 30 Sader HS, Farrell DJ, Flamm RK, Jones RN. Antimicrobial susceptibility of gram-negative organisms isolated from patients hospitalized in intensive care units in United States and European hospitals (2009-2011). Diagn Microbiol Infect Dis 2014; 78 (04) 443-448
  • 31 Denisuik AJ, Garbutt LA, Golden AR. , et al. Antimicrobial-resistant pathogens in Canadian ICUs: results of the CANWARD 2007 to 2016 study. J Antimicrob Chemother 2019; 74 (03) 645-653
  • 32 Boyd DA, Mataseje LF, Pelude L. , et al; Canadian Nosocomial Infection Surveillance Program. Results from the Canadian Nosocomial Infection Surveillance Program for detection of carbapenemase-producing Acinetobacter spp. in Canadian hospitals, 2010–16. J Antimicrob Chemother 2019; 74 (02) 315-320
  • 33 Sekirov I, Croxen MA, Ng C. , et al. Epidemiologic and genotypic review of carbapenemase-producing organisms in British Columbia, Canada, between 2008 and 2014. J Clin Microbiol 2016; 54 (02) 317-327
  • 34 Durdu B, Kritsotakis EI, Lee ACK. , et al. Temporal trends and patterns in antimicrobial-resistant Gram-negative bacteria implicated in intensive care unit-acquired infections: a cohort-based surveillance study in Istanbul, Turkey. J Glob Antimicrob Resist 2018; 14: 190-196
  • 35 Viderman D, Brotfain E, Khamzina Y, Kapanova G, Zhumadilov A, Poddighe D. Bacterial resistance in the intensive care unit of developing countries: report from a tertiary hospital in Kazakhstan. J Glob Antimicrob Resist 2018; 17: 35-38
  • 36 Tran GM, Ho-Le TP, Ha DT. , et al. Patterns of antimicrobial resistance in intensive care unit patients: a study in Vietnam. BMC Infect Dis 2017; 17 (01) 429
  • 37 Moolchandani K, Sastry AS, Deepashree R, Sistla S, Harish BN, Mandal J. Antimicrobial resistance surveillance among intensive care units of a tertiary care hospital in Southern India. J Clin Diagn Res 2017; 11 (02) DC01-DC07
  • 38 Papadimitriou-Olivgeris M, Bartzavali C, Lambropoulou A. , et al. Reversal of carbapenemase-producing Klebsiella pneumoniae epidemiology from blaKPC- to blaVIM-harbouring isolates in a Greek ICU after introduction of ceftazidime/avibactam. J Antimicrob Chemother 2019; 74 (07) 2051-2054
  • 39 Liu P, Li X, Luo M. , et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection: a meta-analysis. Microb Drug Resist 2018; 24 (02) 190-198
  • 40 Papadimitriou-Olivgeris M, Marangos M, Christofidou M. , et al. Risk factors for infection and predictors of mortality among patients with KPC-producing Klebsiella pneumoniae bloodstream infections in the intensive care unit. Scand J Infect Dis 2014; 46 (09) 642-648
  • 41 Papadimitriou-Olivgeris M, Fligou F, Bartzavali C. , et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infection in critically ill patients: risk factors and predictors of mortality. Eur J Clin Microbiol Infect Dis 2017; 36 (07) 1125-1131
  • 42 Papadimitriou-Olivgeris M, Bartzavali C, Spyropoulou A. , et al. Molecular epidemiology and risk factors for colistin- or tigecycline-resistant carbapenemase-producing Klebsiella pneumoniae bloodstream infection in critically ill patients during a 7-year period. Diagn Microbiol Infect Dis 2018; 92 (03) 235-240
  • 43 Papadimitriou-Olivgeris M, Marangos M, Fligou F. , et al. Risk factors for KPC-producing Klebsiella pneumoniae enteric colonization upon ICU admission. J Antimicrob Chemother 2012; 67 (12) 2976-2981
  • 44 Zimmerman FS, Assous MV, Bdolah-Abram T, Lachish T, Yinnon AM, Wiener-Well Y. Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge. Am J Infect Control 2013; 41 (03) 190-194
  • 45 Schechner V, Kotlovsky T, Tarabeia J. , et al. Predictors of rectal carriage of carbapenem-resistant Enterobacteriaceae (CRE) among patients with known CRE carriage at their next hospital encounter. Infect Control Hosp Epidemiol 2011; 32 (05) 497-503
  • 46 Isendahl J, Giske CG, Hammar U. , et al. Temporal dynamics and risk factors for bloodstream infection with extended-spectrum β-lactamase-producing bacteria in previously-colonized individuals: national population-based cohort study. Clin Infect Dis 2019; 68 (04) 641-649
  • 47 Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M. , et al; Investigators from the REIPI/ESGBIS/INCREMENT Group. A predictive model of mortality in patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae. Mayo Clin Proc 2016; 91 (10) 1362-1371
  • 48 Falcone M, Russo A, Iacovelli A. , et al. Predictors of outcome in ICU patients with septic shock caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Microbiol Infect 2016; 22 (05) 444-450
  • 49 Russo A, Falcone M, Gutiérrez-Gutiérrez B. , et al; REIPI/ESGBIS/INCREMENT investigators. Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum β-lactamase-producing Enterobacteriaceae. Int J Antimicrob Agents 2018; 52 (05) 577-585
  • 50 Lye DC, Earnest A, Ling ML. , et al. The impact of multidrug resistance in healthcare-associated and nosocomial Gram-negative bacteraemia on mortality and length of stay: cohort study. Clin Microbiol Infect 2012; 18 (05) 502-508
  • 51 Nelson RE, Slayton RB, Stevens VW. , et al. Attributable mortality of healthcare-associated infections due to multidrug-resistant gram-negative bacteria and methicillin-resistant Staphylococcus Aureus. Infect Control Hosp Epidemiol 2017; 38 (07) 848-856
  • 52 Peña C, Suarez C, Gozalo M. , et al; Spanish Network for Research in Infectious Diseases REIPI. Prospective multicenter study of the impact of carbapenem resistance on mortality in Pseudomonas aeruginosa bloodstream infections. Antimicrob Agents Chemother 2012; 56 (03) 1265-1272
  • 53 Kang CI, Kim SH, Park WB. , et al. Risk factors for antimicrobial resistance and influence of resistance on mortality in patients with bloodstream infection caused by Pseudomonas aeruginosa. Microb Drug Resist 2005; 11 (01) 68-74
  • 54 Dantas RC, Ferreira ML, Gontijo-Filho PP, Ribas RM. Pseudomonas aeruginosa bacteraemia: independent risk factors for mortality and impact of resistance on outcome. J Med Microbiol 2014; 63 (Pt 12): 1679-1687
  • 55 Kadri SS, Strich JR, Swihart BJ. , et al. Attributable mortality from extensively drug-resistant gram-negative infections using propensity-matched tracer antibiotic algorithms. Am J Infect Control 2019 (e-pub ahead of print). Doi: 10.1016/j.ajic.2019.01.010
  • 56 Zhang Y, Chen XL, Huang AW. , et al. Mortality attributable to carbapenem-resistant Pseudomonas aeruginosa bacteremia: a meta-analysis of cohort studies. Emerg Microbes Infect 2016; 5: e27
  • 57 Tansarli GS, Karageorgopoulos DE, Kapaskelis A, Falagas ME. Impact of antimicrobial multidrug resistance on inpatient care cost: an evaluation of the evidence. Expert Rev Anti Infect Ther 2013; 11 (03) 321-331
  • 58 Thaden JT, Li Y, Ruffin F. , et al. Increased costs associated with bloodstream infections caused by multidrug-resistant gram-negative bacteria are due primarily to patients with hospital-acquired infections. Antimicrob Agents Chemother 2017 61. (03): Doi: 10.1128/AAC.01709-16
  • 59 Lautenbach E, Synnestvedt M, Weiner MG. , et al. Imipenem resistance in Pseudomonas aeruginosa: emergence, epidemiology, and impact on clinical and economic outcomes. Infect Control Hosp Epidemiol 2010; 31 (01) 47-53
  • 60 Bartsch SM, McKinnell JA, Mueller LE. , et al. Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Clin Microbiol Infect 2017; 23 (01) 48.e9-48.e16
  • 61 Lenhard JR, Bulman ZP, Tsuji BT, Kaye KS. Shifting gears: the future of polymyxin antibiotics. Antibiotics (Basel) 2019; 8 (02) E42
  • 62 Talbot GH, Jezek A, Murray BE. , et al. The Infectious Diseases Society of America's 10 × ‘20 initiative (10 new systemic antibacterial agents US Food and Drug Administration approved by 2020): is 20 × ’20 a possibility?. Clin Infect Dis 2019; 69 (01) 1-11
  • 63 Theuretzbacher U, Gottwalt S, Beyer P. , et al. Analysis of the clinical antibacterial and antituberculosis pipeline. Lancet Infect Dis 2019; 19 (02) e40-e50
  • 64 Rex JH, Outterson K. Antibiotic reimbursement in a model delinked from sales: a benchmark-based worldwide approach. Lancet Infect Dis 2016; 16 (04) 500-505
  • 65 Tsai D, Lipman J, Roberts JA. Pharmacokinetic/pharmacodynamic considerations for the optimization of antimicrobial delivery in the critically ill. Curr Opin Crit Care 2015; 21 (05) 412-420
  • 66 Udy AA, Baptista JP, Lim NL. , et al. Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*. Crit Care Med 2014; 42 (03) 520-527
  • 67 Mahmoudi L, Mohammadpour AH, Ahmadi A, Niknam R, Mojtahedzadeh M. Influence of sepsis on higher daily dose of amikacin pharmacokinetics in critically ill patients. Eur Rev Med Pharmacol Sci 2013; 17 (03) 285-291
  • 68 Jamal JA, Udy AA, Lipman J, Roberts JA. The impact of variation in renal replacement therapy settings on piperacillin, meropenem, and vancomycin drug clearance in the critically ill: an analysis of published literature and dosing regimens*. Crit Care Med 2014; 42 (07) 1640-1650
  • 69 Roberts JA, Paul SK, Akova M. , et al; 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 (08) 1072-1083
  • 70 Lodise Jr TP, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007; 44 (03) 357-363
  • 71 Rivera CG, Narayanan PP, Patel R, Estes LL. Impact of Cefepime susceptible-dose-dependent MIC for Enterobacteriaceae on reporting and prescribing. Antimicrob Agents Chemother 2016; 60 (06) 3854-3855
  • 72 Chaijamorn W, Charoensareerat T, Srisawat N, Pattharachayakul S, Boonpeng A. Cefepime dosing regimens in critically ill patients receiving continuous renal replacement therapy: a Monte Carlo simulation study. J Intensive Care 2018; 6: 61
  • 73 Miller BM, Johnson SW. Demographic and infection characteristics of patients with carbapenem-resistant Enterobacteriaceae in a community hospital: development of a bedside clinical score for risk assessment. Am J Infect Control 2016; 44 (02) 134-137
  • 74 Paul M, Daikos GL, Durante-Mangoni E. , 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 (04) 391-400
  • 75 Zak-Doron Y, Dishon Benattar Y, Pfeffer I. , et al; AIDA Study Group. The association between empirical antibiotic treatment and mortality in severe infections caused by carbapenem-resistant gram-negative bacteria: a prospective study. Clin Infect Dis 2018; 67 (12) 1815-1823
  • 76 Maruyama T, Fujisawa T, Ishida T. , et al. A therapeutic strategy for all pneumonia patients: a 3-year prospective multicenter cohort study using risk factors for multidrug-resistant pathogens to select initial empiric therapy. Clin Infect Dis 2018; 68 (07) 1080-1088
  • 77 Rottier WC, Bamberg YR, Dorigo-Zetsma JW, van der Linden PD, Ammerlaan HS, Bonten MJ. Predictive value of prior colonization and antibiotic use for third-generation cephalosporin-resistant enterobacteriaceae bacteremia in patients with sepsis. Clin Infect Dis 2015; 60 (11) 1622-1630
  • 78 Schechner V, Kotlovsky T, Kazma M. , et al. Asymptomatic rectal carriage of blaKPC producing carbapenem-resistant Enterobacteriaceae: who is prone to become clinically infected?. Clin Microbiol Infect 2013; 19 (05) 451-456
  • 79 Borer A, Saidel-Odes L, Eskira S. , et al. Risk factors for developing clinical infection with carbapenem-resistant Klebsiella pneumoniae in hospital patients initially only colonized with carbapenem-resistant K pneumoniae. Am J Infect Control 2012; 40 (05) 421-425
  • 80 Rhodes A, Evans LE, Alhazzani W. , et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017; 43 (03) 304-377
  • 81 Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2014; (01) CD003344
  • 82 Kumar A, Ellis P, Arabi Y. , et al; Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136 (05) 1237-1248
  • 83 Montravers P, Bassetti M. The ideal patient profile for new beta-lactam/beta-lactamase inhibitors. Curr Opin Infect Dis 2018; 31 (06) 587-593
  • 84 Hawkey PM, Warren RE, Livermore DM. , et al. Treatment of infections caused by multidrug-resistant gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother 2018; 73 (Suppl. 03) iii2-iii78
  • 85 Paul M, Carmeli Y, Durante-Mangoni E. , et al. Combination therapy for carbapenem-resistant gram-negative bacteria. J Antimicrob Chemother 2014; 69 (09) 2305-2309
  • 86 Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment options for carbapenem-resistant Enterobacteriaceae infections. Open Forum Infect Dis 2015; 2 (02) ofv050
  • 87 Daikos GL, Tsaousi S, Tzouvelekis LS. , et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014; 58 (04) 2322-2328
  • 88 Tumbarello M, Viale P, Viscoli C. , et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012; 55 (07) 943-950
  • 89 Prasad P, Sun J, Danner RL, Natanson C. Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis 2012; 54 (12) 1699-1709
  • 90 Amat T, Gutiérrez-Pizarraya A, Machuca I. , et al. The combined use of tigecycline with high-dose colistin might not be associated with higher survival in critically ill patients with bacteraemia due to carbapenem-resistant Acinetobacter baumannii. Clin Microbiol Infect 2018; 24 (06) 630-634
  • 91 Cheng A, Chuang YC, Sun HY. , et al. Excess mortality associated with colistin-tigecycline compared with colistin-carbapenem combination therapy for extensively drug-resistant Acinetobacter baumannii bacteremia: a multicenter prospective observational study. Crit Care Med 2015; 43 (06) 1194-1204
  • 92 Tamma PD, Han JH, Rock C. , et al; Antibacterial Resistance Leadership Group. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. Clin Infect Dis 2015; 60 (09) 1319-1325
  • 93 Tamma PD, Rodriguez-Bano J. The use of noncarbapenem β-lactams for the treatment of extended-spectrum β-lactamase infections. Clin Infect Dis 2017; 64 (07) 972-980
  • 94 Harris PNA, Tambyah PA, Lye DC. , et al; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E. coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 2018; 320 (10) 984-994
  • 95 Spapen H, Jacobs R, Van Gorp V, Troubleyn J, Honoré PM. Renal and neurological side effects of colistin in critically ill patients. Ann Intensive Care 2011; 1 (01) 14
  • 96 Tumbarello M, Trecarichi EM, Corona A. , et al. Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Infect Dis 2019; 68 (03) 355-364
  • 97 Sader HS, Castanheira M, Flamm RK, Mendes RE, Farrell DJ, Jones RN. Ceftazidime/avibactam tested against gram-negative bacteria from intensive care unit (ICU) and non-ICU patients, including those with ventilator-associated pneumonia. Int J Antimicrob Agents 2015; 46 (01) 53-59
  • 98 Shields RK, Potoski BA, Haidar G. , et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis 2016; 63 (12) 1615-1618
  • 99 Petty LA, Henig O, Patel TS, Pogue JM, Kaye KS. Overview of meropenem-vaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae . Infect Drug Resist 2018; 11: 1461-1472
  • 100 Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G. , et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther 2018; 7 (04) 439-455
  • 101 Athans V, Neuner EA, Hassouna H. , et al. Meropenem-vaborbactam as salvage therapy for ceftazidime-avibactam-resistant Klebsiella pneumoniae bacteremia and abscess in a liver transplant recipient. Antimicrob Agents Chemother 2018 63. (01): Doi: 10.1128/AAC.01551-18
  • 102 Pogue JM, Bonomo RA, Kaye KS. Ceftazidime/avibactam, meropenem/vaborbactam, or both? Clinical and formulary considerations. Clin Infect Dis 2019; 68 (03) 519-524
  • 103 Theuretzbacher U, Paul M. Developing a new antibiotic for extensively drug-resistant pathogens: the case of plazomicin. Clin Microbiol Infect 2018; 24 (12) 1231-1233
  • 104 Castanheira M, Deshpande LM, Woosley LN, Serio AW, Krause KM, Flamm RK. Activity of plazomicin compared with other aminoglycosides against isolates from European and adjacent countries, including Enterobacteriaceae molecularly characterized for aminoglycoside-modifying enzymes and other resistance mechanisms. J Antimicrob Chemother 2018; 73 (12) 3346-3354
  • 105 Wagenlehner FME, Cloutier DJ, Komirenko AS. , et al; EPIC Study Group. Once-daily plazomicin for complicated urinary tract infections. N Engl J Med 2019; 380 (08) 729-740
  • 106 McKinnell JA, Dwyer JP, Talbot GH. , et al; CARE Study Group. Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med 2019; 380 (08) 791-793
  • 107 Peña C, Suarez C, Ocampo-Sosa A. , et al; Spanish Network for Research in Infectious Diseases (REIPI). Effect of adequate single-drug vs combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections: a post hoc analysis of a prospective cohort. Clin Infect Dis 2013; 57 (02) 208-216
  • 108 Paul M, Leibovici L. Editorial commentary: combination therapy for Pseudomonas aeruginosa bacteremia: where do we stand?. Clin Infect Dis 2013; 57 (02) 217-220
  • 109 Skalweit MJ. Profile of ceftolozane/tazobactam and its potential in the treatment of complicated intra-abdominal infections. Drug Des Devel Ther 2015; 9: 2919-2925
  • 110 Shortridge D, Castanheira M, Pfaller MA, Flamm RK. Ceftolozane-tazobactam activity against Pseudomonas aeruginosa clinical isolates from U.S. hospitals: report from the PACTS antimicrobial surveillance program, 2012 to 2015. Antimicrob Agents Chemother 2017 61. (07): Doi: 10.1128/AAC.00465-17
  • 111 Haidar G, Philips NJ, Shields RK. , et al. Ceftolozane-tazobactam for the treatment of multidrug-resistant Pseudomonas aeruginosa infections: clinical effectiveness and evolution of resistance. Clin Infect Dis 2017; 65 (01) 110-120
  • 112 Dinh A, Wyplosz B, Kernéis S. , et al. Use of ceftolozane/tazobactam as salvage therapy for infections due to extensively drug-resistant Pseudomonas aeruginosa. Int J Antimicrob Agents 2017; 49 (06) 782-783
  • 113 Munita JM, Aitken SL, Miller WR. , et al. Multicenter evaluation of ceftolozane/tazobactam for serious infections caused by carbapenem-resistant Pseudomonas aeruginosa. Clin Infect Dis 2017; 65 (01) 158-161
  • 114 Stone GG, Newell P, Gasink LB. , et al. Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme. J Antimicrob Chemother 2018; 73 (09) 2519-2523
  • 115 Alatoom A, Elsayed H, Lawlor K. , et al. Comparison of antimicrobial activity between ceftolozane-tazobactam and ceftazidime-avibactam against multidrug-resistant isolates of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Int J Infect Dis 2017; 62: 39-43
  • 116 Fishbain J, Peleg AY. Treatment of Acinetobacter infections. Clin Infect Dis 2010; 51 (01) 79-84
  • 117 Oliveira MS, Prado GV, Costa SF, Grinbaum RS, Levin AS. Ampicillin/sulbactam compared with polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter spp. J Antimicrob Chemother 2008; 61 (06) 1369-1375
  • 118 Isler B, Doi Y, Bonomo RA, Paterson DL. New treatment options against carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother 2018 63. (01): Doi: 10.1128/AAC.01110-18
  • 119 Lashinsky JN, Henig O, Pogue JM, Kaye KS. Minocycline for the treatment of multidrug and extensively drug-resistant A. baumannii: a review. Infect Dis Ther 2017; 6 (02) 199-211
  • 120 Goff DA, Bauer KA, Mangino JE. Bad bugs need old drugs: a stewardship program's evaluation of minocycline for multidrug-resistant Acinetobacter baumannii infections. Clin Infect Dis 2014; 59 (Suppl. 06) S381-S387
  • 121 Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother 2014; 58 (09) 5598-5601
  • 122 Durante-Mangoni E, Signoriello G, Andini R. , 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 (03) 349-358
  • 123 Seifert H, Stefanik D, Sutcliffe JA, Higgins PG. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents 2018; 51 (01) 62-64
  • 124 Solomkin JS, Gardovskis J, Lawrence K. , et al. IGNITE4: results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs. meropenem in the treatment of complicated intra-abdominal infections. Clin Infect Dis 2016; 9: 45-52 (e-pub ahead of print). Doi: 10.1093/cid/ciy1029
  • 125 Tillotson GS. Trojan horse antibiotics-a novel way to circumvent gram-negative bacterial resistance?. Infect Dis (Auckl) 2016; 9: 45-52
  • 126 Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 study). Antimicrob Agents Chemother 2017; 61 (09) e00093-17
  • 127 Portsmouth S, van Veenhuyzen D, Echols R. , et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2018; 18 (12) 1319-1328
  • 128 Echols RM, Tillotson GS. DTR, do we need a new definition?. Clin Infect Dis 2019; ciz184 (e-pub ahead of print). Doi: 10.1093/cid/ciz184
  • 129 Tekçe YT, Erbay A, Cabadak H, Sen S. Tigecycline as a therapeutic option in Stenotrophomonas maltophilia infections. J Chemother 2012; 24 (03) 150-154
  • 130 Safdar A, Rolston KV. Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis 2007; 45 (12) 1602-1609
  • 131 Chang YT, Lin CY, Chen YH, Hsueh PR. Update on infections caused by Stenotrophomonas maltophilia with particular attention to resistance mechanisms and therapeutic options. Front Microbiol 2015; 6: 893
  • 132 Tamma PD, Fan Y, Bergman Y. , et al. Successful treatment of persistent Burkholderia cepacia complex bacteremia with ceftazidime-avibactam. Antimicrob Agents Chemother 2018; 62 (04) e02213-17
  • 133 Zhanel GG, Golden AR, Zelenitsky S. , et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant gram-negative bacilli. Drugs 2019; 79 (03) 271-289
  • 134 Karlowsky JA, Hackel MA, Tsuji M, Yamano Y, Echols R, Sahm DF. In vitro activity of cefiderocol, a siderophore cephalosporin, against gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015–2016: SIDERO-WT-2015. Int J Antimicrob Agents 2019; 53 (04) 456-466
  • 135 Yahav D, Franceschini E, Koppel F. , et al; Bacteremia Duration Study Group. Seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: a non-inferiority randomized controlled trial. Clin Infect Dis 2018 (e-pub ahead of print). Doi: 10.1093/cid/ciy1054
  • 136 Chastre J, Wolff M, Fagon JY. , et al; PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 2003; 290 (19) 2588-2598
  • 137 Zilahi G, McMahon MA, Povoa P, Martin-Loeches I. Duration of antibiotic therapy in the intensive care unit. J Thorac Dis 2016; 8 (12) 3774-3780
  • 138 Wenzler E, Fraidenburg DR, Scardina T, Danziger LH. Inhaled antibiotics for gram-negative respiratory infections. Clin Microbiol Rev 2016; 29 (03) 581-632
  • 139 Kofteridis DP, Alexopoulou C, Valachis A. , et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case-control study. Clin Infect Dis 2010; 51 (11) 1238-1244
  • 140 Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas ME. Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin Microbiol Infect 2010; 16 (08) 1230-1236
  • 141 Kwa AL, Falagas ME, Michalopoulos A, Tam VH. Benefits of aerosolized colistin for ventilator-associated pneumonia: absence of proof versus proof of absence?. Clin Infect Dis 2011; 52 (10) 1278-1279 , author reply 1279–1280
  • 142 Kalil AC, Metersky ML, Klompas M. , 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 (05) e61-e111
  • 143 Motley MP, Fries BC. A new take on an old remedy: generating antibodies against multidrug-resistant gram-negative bacteria in a postantibiotic world. MSphere 2017; 2 (05) e00397-17
  • 144 Kobayashi SD, Porter AR, Freedman B. , et al. Antibody-mediated killing of carbapenem-resistant ST258 Klebsiella pneumoniae by human neutrophils. MBio 2018; 9 (02) e00297-18
  • 145 Citorik RJ, Mimee M, Lu TK. Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases. Nat Biotechnol 2014; 32 (11) 1141-1145
  • 146 Strich JR, Chertow DS. CRISPR-Cas biology and its application to infectious diseases. J Clin Microbiol 2019; 57 (04) e01307-18
  • 147 El Haddad L, Harb CP, Gebara MA, Stibich MA, Chemaly RF. A systematic and critical review of bacteriophage therapy against multidrug-resistant ESKAPE organisms in humans. Clin Infect Dis 2018; 69 (01) 167-178
  • 148 Nir-Paz R, Gelman D, Khouri A. , et al. Successful treatment of antibiotic resistant poly-microbial bone infection with bacteriophages and antibiotics combination. Clin Infect Dis 2019; ciz222 (e-pub ahead of print). Doi: 10.1093/cid/ciz222
  • 149 CDC. Antibiotic Resistance Patient Safety Atlas. Atlanta: CDC; 2016