Multidrug-Resistant Gram-Negative Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and Emerging Treatment Options

Microbial Drug Resistance

Volumn 22, Issue 5, 2016, Pages 412-431

  Cerceo, Elizabeth ^a   Deitelzweig, Steven B ^b   Sherman, Bradley M ^c   Amin, Alpesh N ^d  

^a Rowan University ^*  (United States)

^b OCHSNER CLINIC FOUNDATION   (United States)

^c Northwell Health   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOGLYCOSIDE; AMOXICILLIN PLUS CLAVULANIC ACID; AVIBACTAM PLUS CEFTAZIDIME; BETA LACTAM ANTIBIOTIC; CEFDINIR; CEFIXIME; CEFPODOXIME PROXETIL; CEFTOLOZANE PLUS TAZOBACTAM; CILASTATIN PLUS IMIPENEM; CIPROFLOXACIN; COTRIMOXAZOLE; ERAVACYCLINE; ERTAPENEM; FOSFOMYCIN; LEVOFLOXACIN; MEROPENEM; NITROFURANTOIN; PIVMECILLINAM; PLAZOMICIN; POLYMYXIN; QUINOLONE DERIVATIVE; RELEBACTAM; TETRACYCLINE DERIVATIVE; TIGECYCLINE; TIMENTIN; 6'-(HYDROXYLETHYL)-1-(HABA)-SISOMICIN; 7-FLUORO-9-PYRROLIDINOACETAMIDO-6-DEMETHYL-6-DEOXYTETRACYCLINE; ANTIINFECTIVE AGENT; BORONIC ACID DERIVATIVE; SINGLE HETEROCYCLIC RINGS; SISOMICIN; THIENAMYCIN DERIVATIVE; VABORBACTAM;

ABDOMINAL INFECTION; ACINETOBACTER BAUMANNII; ANTIBIOTIC THERAPY; ANTIMICROBIAL THERAPY; ARTICLE; BACTERIAL SKIN DISEASE; BACTERIAL STRAIN; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL PRACTICE; CYSTIC FIBROSIS; ENTEROBACTER; ESCHERICHIA COLI; GRAM NEGATIVE INFECTION; HEALTHCARE ASSOCIATED INFECTION; HIGH RISK PATIENT; HOSPITAL ACQUIRED PNEUMONIA; HOSPITAL PATIENT; HOSPITALIZATION; HUMAN; INFECTION CONTROL; KLEBSIELLA OXYTOCA; KLEBSIELLA PNEUMONIAE; MORBIDITY; MORTALITY; MULTIDRUG RESISTANCE; PHENOTYPE; PREVALENCE; PRIORITY JOURNAL; PROTEUS MIRABILIS; PSEUDOMONAS AERUGINOSA; SERRATIA MARCESCENS; SOFT TISSUE INFECTION; UNITED STATES; VENTILATOR ASSOCIATED PNEUMONIA; ANALOGS AND DERIVATIVES; COMBINATION DRUG THERAPY; DRUG EFFECTS; ENTEROBACTERIACEAE INFECTIONS; GROWTH, DEVELOPMENT AND AGING; HOSPITAL; MICROBIOLOGY; PATHOGENICITY; PATHOLOGY; PHYSIOLOGY;

ACINETOBACTER BAUMANNII; ANTI-BACTERIAL AGENTS; BORONIC ACIDS; DRUG RESISTANCE, MULTIPLE, BACTERIAL; DRUG THERAPY, COMBINATION; ENTEROBACTERIACEAE INFECTIONS; ESCHERICHIA COLI; HETEROCYCLIC COMPOUNDS, 1-RING; HOSPITALS; HUMANS; KLEBSIELLA PNEUMONIAE; PSEUDOMONAS AERUGINOSA; SISOMICIN; TETRACYCLINES; THIENAMYCINS;

EID: 84978264109     PISSN: 10766294     EISSN: 19318448     Source Type: Journal    
DOI: 10.1089/mdr.2015.0220     Document Type: Article

References (154)

1. Abdallah, M., O. Olafisoye, C. Cortes, C. Urban, D. Landman, and J. Quale. 2015. Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York city. Antimicrob. Agents Chemother. 59:1802-1805
2. Aktas, Z., C. Kayacan, and O. Oncul. 2012. In vitro activity of avibactam (NXL104) in combination with betalactams against Gram-negative bacteria, including OXAMULTIDRUG 48 beta-lactamase-producing Klebsiella pneumoniae. Int. J. Antimicrob. Agents 39:86-89
3. Al-Hasan, M.N., J.E. Eckel-Passow, and L.M. Baddour. 2012. Impact of healthcare-associated acquisition on community-onset Gram-negative bloodstream infection: a population-based study: healthcare-associated Gram-negative BSI. Eur. J. Clin. Microbiol. Infect. Dis. 31:1163-1171
4. Albertson, T.E., S. Louie, and A.L. Chan. 2010. The diagnosis and treatment of elderly patients with acute exacerbation of chronic obstructive pulmonary disease and chronic bronchitis. J. Am. Geriatr. Soc. 58:570-579
5. Alekshun, M.N., and S.B. Levy. 2007. Molecular mechanisms of antibacterial multidrug resistance. Cell 128:1037-1050
6. Almaghrabi, R., C.J. Clancy, Y. Doi, B. Hao, L. Chen, R.K. Shields, E.G. Press, N.M. Iovine, B.M. Townsend, M.M. Wagener, et al. 2014. Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents. Antimicrob. Agents Chemother. 58:4443-4451
7. Alvarez-Lerma, F. 1996. Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive Care Med. 22:387-394
8. Ambler, R.P. 1980. The structure of beta-lactamases. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 289:321-331
9. American Thoracic Society and the Infectious Diseases Society of America. 2005. Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia. Am. J. Respir. Crit. Care Med. 171:388-416
10. Amin, A.N., E.A. Cerceo, S.B. Deitelzweig, J.C. Pile, D.J. Rosenberg, and B.M. Sherman. 2014. Hospitalist perspective on the treatment of skin and soft tissue infections. Mayo Clin. Proc. 89:1436-1451
11. Amin, A.N., E.A. Cerceo, S.B. Deitelzweig, J.C. Pile, D.J. Rosenberg, and B.M. Sherman. 2014. The hospitalist perspective on treatment of community-acquired bacterial pneumonia. Postgrad. Med. 126:18-29
12. Babinchak, T., R. Badal, D. Hoban, M. Hackel, S. Hawser, S. Lob, and S. Bouchillon. 2013. Trends in susceptibility of selected gram-negative bacilli isolated from intra-abdominal infections in North America: SMART 2005-2010. Diagn. Microbiol. Infect. Dis. 76: 379-381
13. Balter, M.S., J. La Forge, D.E. Low, L. Mandell, and R.F. Grossman. 2003. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can. Respir. J. 10 Suppl B:3B-32B
14. Biedenbach, D.J., G.J. Moet, and R.N. Jones. 2004. Occurrence and antimicrobial resistance pattern comparisons among bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (1997-2002). Diagn. Microbiol. Infect. Dis. 50:59-69
15. Blizzard, T.A., H. Chen, S. Kim, J. Wu, R. Bodner, C. Gude, J. Imbriglio, K. Young, Y.W. Park, A. Ogawa, et al. 2014. Discovery of MK-7655, a beta-lactamase inhibitor for combination with Primaxin-. Bioorg. Med. Chem. Lett. 24:780-785
16. Boucher, H.W., G.H. Talbot, J.S. Bradley, J.E. Edwards, D. Gilbert, L.B. Rice, M. Scheld, B. Spellberg, and J. Bartlett. 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48:1-12
17. Breidenstein, E.B., C. de la Fuente-Nunez, and R.E. Hancock. 2011. Pseudomonas aeruginosa: all roads lead to resistance. Trends Microbiol. 19:419-426
18. Cabot, G., S. Bruchmann, X. Mulet, L. Zamorano, B. Moya, C. Juan, S. Haussler, and A. Oliver. 2014. Pseudomonas aeruginosa ceftolozane-tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC. Antimicrob. Agents Chemother. 58:3091-3099
19. Cai, Y., D. Chai, R. Wang, B. Liang, and N. Bai. 2012. Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. J. Antimicrob. Chemother. 67:1607-1615
20. Cardoso, T., O. Ribeiro, I.C. Aragao, A. Costa-Pereira, and A.E. Sarmento. 2012. Additional risk factors for infection by multidrug-resistant pathogens in healthcareassociated infection: a large cohort study. BMC Infect. Dis. 12:375
21. Castanheira, M., S.E. Costello, L.N. Woosley, L.M. Deshpande, T.A. Davies, and R.N. Jones. 2014. Evaluation of clonality and carbapenem resistance mechanisms among Acinetobacter baumannii-Acinetobacter calcoaceticus complex and Enterobacteriaceae isolates collected in European and Mediterranean countries and detection of two novel beta-lactamases, GES-22 and VIM-35 Antimicrob. Agents Chemother. 58:7358-7366
22. Castanheira, M., S.E. Farrell, K.M. Krause, R.N. Jones, and H.S. Sader. 2014. Contemporary diversity of beta-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent betalactamase groups. Antimicrob. Agents Chemother. 58:833-838
23. Castanheira, M., P.R. Rhomberg, A. Watters, and R.N. Jones. In vitro activity of meropenem/RPX7009, a carbapenem/ b-lactamase inhibitor combination tested against contemporary populations of Enterobacteriaceae and KPC-producing strains. Poster presented at the Infectious Diseases Society of America (IDSA) Annual IDWeek 2014 Meeting, Philadelphia, PA, October 8-12, 2014
24. Center for Science in the Public Interest. May 2013. Antibiotic Resistance in Foodborne Pathogens. Available at http://cspinet.org/new/pdf/outbreaks-antibiotic- resistance-in-foodborne-pathogens-2013.pdf, accessed February 15, 2015. (Online.)
25. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. Available at http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-2508 .pdf, accessed February 15, 2015. Washington, DC: US Department of Health and Human Services, 2013. (Online.)
26. Centers for Disease Control and Prevention. Checklist for Core Elements of Hospital Antibiotic Stewardship Programs. Available at http://www.cdc.gov/getsmart/ healthcare/implementation/checklist.html, accessed February 15, 2015. (Online.)
27. Centers for Disease Control and Prevention. Clinician Guide for Collecting Cultures. Available at http://www .cdc.gov/getsmart/healthcare/implementation/clinicianguide .html, accessed February 15, 2015. (Online.)
28. Centers for Disease Control and Prevention. 2009. Guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in acute care facilities. MMWR. Morb. Mortal. Wkly. Rep. 58:256-260
29. Chen, Z., J. Wu, Y. Zhang, J. Wei, X. Leng, J. Bi, R. Li, L. Yan, Z. Quan, X. Chen, et al. 2010. Efficacy and safety of tigecycline monotherapy vs. imipenem/cilastatin in Chinese patients with complicated intra-abdominal infections: a randomized controlled trial. BMC Infect. Dis. 10:217
30. Christ-Crain, M., D. Jaccard-Stolz, R. Bingisser, M.M. Gencay, P.R. Huber, M. Tamm, and B. Muller. 2004. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: clusterrandomised, single-blinded intervention trial. Lancet 363: 600-607
31. Christ-Crain, M., D. Stolz, R. Bingisser, C. Muller, D. Miedinger, P.R. Huber, W. Zimmerli, S. Harbarth, M. Tamm, and B. Muller. 2006. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am. J. Respir. Crit. Care Med. 174:84-93
32. Clinical Laboratory Standards Institute (CLSI). M100-S25: Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. Available at http://clsi.org/blog/2012/01/13/clsi-publishes-2012-antimicrobial-susceptibility-testing-standards, accessed February 15, 2015. (Online.)
33. ClinicalTrials.gov. Available at https://www.clinical trials.gov/, accessed March 15, 2015. (Online.)
34. Connors, K.P., S.T. Housman, J.S. Pope, J. Russomanno, E. Salerno, E. Shore, S. Redican, and D.P. Nicolau. 2014. Phase I, open-label, safety and pharmacokinetic study to assess bronchopulmonary disposition of intravenous eravacycline in healthy men and women. Antimicrob. Agents Chemother. 58:2113-2118
35. Dean, C.R., M.A. Visalli, S.J. Projan, P.E. Sum, and P.A. Bradford. 2003. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob. Agents Chemother. 47:972-978
36. Dellit, T.H., R.C. Owens, J.E. McGowan, Jr., D.N. Gerding, R.A. Weinstein, J.P. Burke, W.C. Huskins, D.L. Paterson, N.O. Fishman, C.F. Carpenter, et al. 2007. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin. Infect. Dis. 44:159-177
37. Denys, G.A., S.M. Callister, and M.J. Dowzicky. 2013. Antimicrobial susceptibility among gram-negative isolates collected in the USA between 2005 and 2011 as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Ann. Clin. Microbiol. Antimicrob. 12:24
38. Doi, Y., Y.S. Park, J.I. Rivera, J.M. Adams-Haduch, A. Hingwe, E.M. Sordillo, J.S. Lewis, 2nd, W.J. Howard, L.E. Johnson, B. Polsky, et al. 2013. Communityassociated extended-spectrum beta-lactamase-producing Escherichia coli infection in the United States. Clin. Infect. Dis. 56:641-648
39. Drawz, S.M., K.M. Papp-Wallace, and R.A. Bonomo. 2014. New beta-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob. Agents Chemother. 58:1835-1846
40. Dubois, V., C. Arpin, M. Melon, B. Melon, C. Andre, C. Frigo, and C. Quentin. 2001. Nosocomial outbreak due to a multiresistant strain of Pseudomonas aeruginosa P12: efficacy of cefepime-amikacin therapy and analysis of beta-lactam resistance. J. Clin. Microbiol. 39:2072-2078
41. Eckmann, C., P. Montravers, M. Bassetti, K.F. Bodmann, W.R. Heizmann, M. Sanchez Garcia, X. Guirao, M.R. Capparella, D. Simoneau, and H. Dupont. 2013. Efficacy of tigecycline for the treatment of complicated intra-abdominal infections in real-life clinical practice from five European observational studies. J. Antimicrob. Chemother. 68 Suppl 2:ii25-ii35
42. Evans, H.L., S.N. Lefrak, J. Lyman, R.L. Smith, T.W. Chong, S.T. McElearney, A.R. Schulman, M.G. Hughes, D.P. Raymond, T.L. Pruett, et al. 2007. Cost of Gram-negative resistance. Crit. Care Med. 35:89-95
43. Falagas, M.E., P.I. Rafailidis, and D.K. Matthaiou. 2010. Resistance to polymyxins: mechanisms, frequency and treatment options. Drug Resist. Updat. 13:132-138
44. Falagas, M.E., G.S. Tansarli, D.E. Karageorgopoulos, and K.Z. Vardakas. 2014. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg. Infect. Dis. 20:1170-1175
45. Farrell, D.J., H.S. Sader, R.K. Flamm, and R.N. Jones. 2014. Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012). Int. J. Antimicrob. Agents 43:533-539
46. Fernandez, L., and R.E. Hancock. 2012. Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin. Microbiol. Rev. 25:661-681
47. Fraimow, H., and R. Nahra. 2013. Resistant gramnegative infections. Crit. Care Clin. 29:895-921
48. Freire, A.T., V. Melnyk, M.J. Kim, O. Datsenko, O. Dzyublik, F. Glumcher, Y.C. Chuang, R.T. Maroko, G. Dukart, C.A. Cooper, et al. 2010. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn. Microbiol. Infect. Dis. 68:140-151
49. Gagliotti, C., A. Balode, F. Baquero, J. Degener, H. Grundmann, D. Gur, V. Jarlier, G. Kahlmeter, J. Monen, D.L. Monnet, et al. 2011. Escherichia coli and Staphylococcus aureus: bad news and good news from the European Antimicrobial Resistance Surveillance Network (EARS-Net, formerly EARSS), 2002 to 2009. Euro. Surveill. 16:1-5
50. Gardiner, D., G. Dukart, A. Cooper, and T. Babinchak. 2010. Safety and efficacy of intravenous tigecycline in subjects with secondary bacteremia: pooled results from 8 phase III clinical trials. Clin. Infect. Dis. 50:229-238
51. Giamarellou, H., and G. Poulakou. 2009. Multidrugresistant Gram-negative infections: what are the treatment options? Drugs 69:1879-1901
52. Giamarellou, H., and G. Poulakou. 2011. Pharmacokinetic and pharmacodynamic evaluation of tigecycline. Expert Opin. Drug Metab. Toxicol. 7:1459-1470
53. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2013. Available at http://www.goldcopd.org/uploads/ users/files/GOLD-Report-2013-Feb20.pdf, accessed February 28, 2015
54. Goldstein, E.J., D.M. Citron, K.L. Tyrrell, and C.V. Merriam. 2013. In vitro activity of biapenem plus RPX7009, a carbapenem combined with a serine beta-lactamase inhibitor, against anaerobic bacteria. Antimicrob. Agents Chemother. 57:2620-2630
55. Grgurich, P.E., J. Hudcova, Y. Lei, A. Sarwar, and D.E. Craven. 2012. Management and prevention of ventilator-associated pneumonia caused by multidrugresistant pathogens. Expert Rev. Respir. Med. 6:533-555
56. Grossman, T.H., A.L. Starosta, C. Fyfe, W. O'Brien, D.M. Rothstein, A. Mikolajka, D.N. Wilson, and J.A. Sutcliffe. 2012. Target-and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob. Agents Chemother. 56:2559-2564
57. Gupta, K., and N. Bhadelia. 2014. Management of urinary tract infections from multidrug-resistant organisms. Infect. Dis. Clin. North Am. 28:49-59
58. Gupta, K., T.M. Hooton, K.G. Naber, B. Wullt, R. Colgan, L.G. Miller, G.J. Moran, L.E. Nicolle, R. Raz, A.J. Schaeffer, et al. 2011. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin. Infect. Dis. 52:e103-e120
59. Hawser, S.P., R.E. Badal, S.K. Bouchillon, D.J. Hoban, D.J. Biedenbach, R. Canton, and D.L. Paterson. 2013. Monitoring the global in vitro activity of ertapenem against Escherichia coli from intra-abdominal infections: SMART 2002-2010. Int. J. Antimicrob. Agents 41:224-228
60. Hirsch, E.B., K.R. Ledesma, K.T. Chang, M.S. Schwartz, M.R. Motyl, and V.H. Tam. 2012. In vitro activity of MK-7655, a novel beta-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob. Agents Chemother. 56:3753-3757
61. Hsueh, P.R., D.J. Hoban, Y. Carmeli, S.Y. Chen, S. Desikan, M. Alejandria, W.C. Ko, and T.Q. Binh. 2011. Consensus review of the epidemiology and appropriate antimicrobial therapy of complicated urinary tract infections in Asia-Pacific region. J. Infect. 63:114-123
62. Hurley, J.C. 2013. Towards clinical applications of antiendotoxin antibodies; a re-appraisal of the disconnect. Toxins (Basel) 5:2589-2620
63. Jones, R.N. 2010. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin. Infect. Dis. 51 Suppl 1:S81-S87
64. Kallen, A.J., and A. Srinivasan. 2010. Current epidemiology of multidrug-resistant gram-negative bacilli in the United States. Infect. Control Hosp. Epidemiol. 31 Suppl 1:S51-S54
65. Kanj, S.S., and Z.A. Kanafani. 2011. Current concepts in antimicrobial therapy: extended-spectrum beta-lactamaseproducing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multi-drug resistant Pseudomonas aeruginosa. Mayo Clin. Proc. 86:250-259
66. Kasiakou, S.K., A. Michalopoulos, E.S. Soteriades, G. Samonis, G.J. Sermaides, and M.E. Falagas. 2005. Combination therapy with intravenous colistin for management of infections due to multidrug-resistant Gramnegative bacteria in patients without cystic fibrosis. Antimicrob. Agents Chemother. 49:3136-3146
67. Klastersky, J., and A. Georgala. 2014. Strategies for the empirical management of infection in cancer patients with emphasis on the emergence of resistant gram-negative bacteria. Crit. Rev. Oncol. Hematol. 92:268-278
68. Klein, D.J., D. Foster, C.A. Schorr, K. Kazempour, P.M. Walker, and R.P. Dellinger. 2014. The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial. Trials 15:218
69. Kollef, M.H., Y. Golan, S.T. Micek, A.F. Shorr, and M.I. Restrepo. 2011. Appraising contemporary strategies to combat multidrug resistant gram-negative bacterial infections-proceedings and data from the Gram-Negative Resistance Summit. Clin. Infect. Dis. 53 Suppl 2:S33-S55; quiz S56-S58
70. Kollef, M.H., A. Shorr, Y.P. Tabak, V. Gupta, L.Z. Liu, and R.S. Johannes. 2005. Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia. Chest 128:3854-3862
71. Kumar, A., D. Roberts, K.E. Wood, B. Light, J.E. Parrillo, S. Sharma, R. Suppes, D. Feinstein, S. Zanotti, L. Taiberg, et al. 2006. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 34:1589-1596
72. Kunz, A.N., and I. Brook. 2010. Emerging resistant Gram-negative aerobic bacilli in hospital-acquired infections. Chemotherapy 56:492-500
73. Lagace-Wiens, P., A. Walkty, and J.A. Karlowsky. 2014. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 9:13-25
74. Lahiri, S.D., S. Mangani, T. Durand-Reville, M. Benvenuti, F. De Luca, G. Sanyal, and J.D. Docquier. 2013. Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases. Antimicrob. Agents Chemother. 57:2496-2505
75. Landman, D., S. Bratu, S. Kochar, M. Panwar, M. Trehan, M. Doymaz, and J. Quale. 2007. Evolution of antimicrobial resistance among Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae in Brooklyn, NY. J. Antimicrob. Chemother. 60:78-82
76. Landman, D., P. Kelly, M. Backer, E. Babu, N. Shah, S. Bratu, and J. Quale. 2011. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J. Antimicrob. Chemother. 66:332-334
77. Lautenbach, E., J.B. Patel, W.B. Bilker, P.H. Edelstein, and N.O. Fishman. 2001. Extended-spectrum betalactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin. Infect. Dis. 32:1162-1171
78. Lesho, E., D. Craft, B.C. Kirkup, Jr., P. Waterman, A. Summers, M.T. Vahey, K.E. Kester, and R. Bowden. 2011. Surveillance, characterisation, and preservation of multidrug-resistant bacteria. Lancet Infect. Dis. 11:8-10
79. Levison, M.E., and D. Kaye. 2013. Treatment of complicated urinary tract infections with an emphasis on drugresistant gram-negative uropathogens. Curr. Infect. Dis. Rep. 15:109-115
80. Lichtenberger, P., and T.M. Hooton. 2008. Complicated urinary tract infections. Curr. Infect. Dis. Rep. 10:499-504
81. Lim, L.M., N. Ly, D. Anderson, J.C. Yang, L. Macander, A. Jarkowski, 3rd, A. Forrest, J.B. Bulitta, and B.T. Tsuji. 2010. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy 30:1279-1291
82. Lister, P.D., D.J. Wolter, and N.D. Hanson. 2009. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin. Microbiol. Rev. 22:582-610
83. Livermore, D.M. 2003. Bacterial resistance: origins, epidemiology, and impact. Clin. Infect. Dis. 36:S11-S23
84. Livermore, D.M. 2012. Current epidemiology and growing resistance of Gram-negative pathogens. Korean J. Intern. Med. 27:128-142
85. Livermore, D.M., S. Mushtaq, M. Warner, J. Zhang, S. Maharjan,M. Doumith, and N. Woodford. 2011. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob. Agents Chemother. 55:390-394
86. Livermore, D.M., S. Mushtaq, M. Warner, J.C. Zhang, S. Maharjan, M. Doumith, and N. Woodford. 2011. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J. Antimicrob. Chemother. 66:48-53
87. Livermore, D.M., M. Warner, and S. Mushtaq. 2013. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J. Antimicrob. Chemother. 68:2286-2290
88. Livermore, D.M., and N. Woodford. 2006. The betalactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter. Trends Microbiol. 14:413-420
89. Lucasti, C., E. Hershberger, B. Miller, S. Yankelev, J. Steenbergen, I. Friedland, and J. Solomkin. 2014. Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections. Antimicrob. Agents Chemother. 58:5350-5357
90. Lucasti, C., I. Popescu, M.K. Ramesh, J. Lipka, and C. Sable. 2013. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, phase II trial. J. Antimicrob. Chemother. 68:1183-1192
91. Magill, S.S., J.R. Edwards, W. Bamberg, Z.G. Beldavs, G. Dumyati, M.A. Kainer, R. Lynfield, M. Maloney, L. McAllister-Hollod, J. Nadle, et al. 2014. Multistate point-prevalence survey of health care-associated infections. N. Engl. J. Med. 370:1198-1208
92. Magiorakos, A.P., A. Srinivasan, R.B. Carey, Y. Carmeli, M.E. Falagas, C.G. Giske, S. Harbarth, J.F. Hindler, G. Kahlmeter, B. Olsson-Liljequist, et al. 2012. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 18:268-281
93. Mandell, L.A., R.G. Wunderink, A. Anzueto, J.G. Bartlett, G.D. Campbell, N.C. Dean, S.F. Dowell, T.M. File, Jr., D.M. Musher, M.S. Niederman, et al. 2007. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin. Infect. Dis. 44 Suppl 2:S27-S72
94. Maragakis, L.L., E.N. Perencevich, and S.E. Cosgrove. 2008. Clinical and economic burden of antimicrobial resistance. Expert Rev. Anti. Infect. Ther. 6:751-763
95. Marik, P.E. 2014. Early management of severe sepsis: concepts and controversies. Chest 145:1407-1418
96. Markou, N., H. Apostolakos, C. Koumoudiou, M. Athanasiou, A. Koutsoukou, I. Alamanos, and L. Gregorakos. 2003. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients. Crit. Care 7:R78-R83
97. Maruyama, T., T. Fujisawa, M. Okuno, H. Toyoshima, K. Tsutsui, H. Maeda, H. Yuda, M. Yoshida, H. Kobayashi, O. Taguchi, et al. 2013. A new strategy for healthcare-associated pneumonia: a 2-year prospective multicenter cohort study using risk factors for multidrugresistant pathogens to select initial empiric therapy. Clin. Infect. Dis. 57:1373-1383
98. Mauldin, P.D., C.D. Salgado, I.S. Hansen, D.T. Durup, and J.A. Bosso. 2010. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant Gram-negative bacteria. Antimicrob. Agents Chemother. 54:109-115
99. May, A.K. 2011. Skin and soft tissue infections: the new surgical infection society guidelines. Surg. Infect. (Larchmt) 12:179-184
100. Mazuski, J.E. 2007. Antimicrobial treatment for intraabdominal infections. Expert Opin. Pharmacother. 8:2933-2945
101. McKinnell, J.A., N.S. Stollenwerk, C.W. Jung, and L.G. Miller. 2011. Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis. Mayo Clin. Proc. 86:480-488
102. Mermel, L.A., M. Allon, E. Bouza, D.E. Craven, P. Flynn, N.P. O'Grady, Raad, II, B.J. Rijnders, R.J. Sherertz, and D.K. Warren. 2009. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 49:1-45
103. Micek, S.T., E.C. Welch, J. Khan, M. Pervez, J.A. Doherty, R.M. Reichley, J. Hoppe-Bauer, W.M. Dunne, and M.H. Kollef. 2011. Resistance to empiric antimicrobial treatment predicts outcome in severe sepsis associated with Gram-negative bacteremia. J. Hosp. Med. 6:405-410
104. Michalopoulos, A.S., and M.E. Falagas. 2011. Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Ann. Intensive Care 1:30
105. Miller, D.L., and N.P. O'Grady. 2012. Guidelines for the prevention of intravascular catheter-related infections: recommendations relevant to interventional radiology for venous catheter placement and maintenance. J. Vasc. Interv. Radiol. 23:997-1007
106. Nilsson, L.E., N. Frimodt-Moller, M. Vaara, and G.S. Simonsen. 2011. Comparative activity of tigecycline and tetracycline on Gram-negative and Gram-positive bacteria revealed by a multicentre study in four North European countries. Scand. J. Infect. Dis. 43:707-713
107. O'Fallon, E., A. Pop-Vicas, and E. D'Agata. 2009. The emerging threat of multidrug-resistant gram-negative organisms in long-term care facilities. J. Gerontol. A Biol. Sci. Med. Sci. 64:138-141
108. Pallett, A., and K. Hand. 2010. Complicated urinary tract infections: practical solutions for the treatment of multiresistant Gram-negative bacteria. J. Antimicrob. Chemother. 65 Suppl 3:iii25-iii33
109. Pankuch, G.A., G. Lin, A. Kubo, E.S. Armstrong, P.C. Appelbaum, and K. Kosowska-Shick. 2011. Activity of ACHN-490 tested alone and in combination with other agents against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 55:2463-2465
110. Pfeifer, Y., A. Cullik, and W. Witte. 2010. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J. Med. Microbiol. 300:371-379
111. Pogue, J.M., R.P. Mynatt, D. Marchaim, J.J. Zhao, V.O. Barr, J. Moshos, B. Sunkara, T. Chopra, S. Chidurala, and K.S. Kaye. 2014. Automated alerts coupled with antimicrobial stewardship intervention lead to decreases in length of stay in patients with gram-negative bacteremia. Infect. Control Hosp. Epidemiol. 35:132-138
112. Poirel, L., C. Heritier, V. Tolun, and P. Nordmann. 2004. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 48:15-22
113. Pop-Vicas, A., and S.M. Opal. 2014. The clinical impact of multidrug-resistant gram-negative bacilli in the management of septic shock. Virulence 5:206-212
114. Prabaker, K., and R.A. Weinstein. 2011. Trends in antimicrobial resistance in intensive care units in the United States. Curr. Opin. Crit. Care 17:472-479
115. Rajan, S. 2012. Skin and soft-tissue infections: classifying and treating a spectrum. Cleve. Clin. J. Med. 79:57-66
116. Rello, J., M. Gallego, D. Mariscal, R. Sonora, and J. Valles. 1997. The value of routine microbial investigation in ventilator-associated pneumonia. Am. J. Respir. Crit. Care Med. 156:196-200
117. Rennard, S., B. Thomashow, J. Crapo, B. Yawn, A. McIvor, S. Cerreta, J. Walsh, and D. Mannino. 2013. Introducing the COPD Foundation Guide for Diagnosis and Management of COPD, recommendations of the COPD Foundation. COPD. 10:378-389
118. Ronco, C., and D.J. Klein. 2014. Polymyxin B hemoperfusion: a mechanistic perspective. Crit. Care 18:309
119. Sabet, M., Z. Tarazi, T. Nolan, J. Parkinson, D. Rubio-Aparicio, O. Lomovskaya, M.N. Dudley, and D.C. Griffith. In vivo efficacy of Carbavance (meropenem/ RPX7009) against KPC-producing Enterobacteriaceae. Presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, September 5-9, 2014 (Abstract F-958)
120. Sader, H.S., D.J. Farrell, M. Castanheira, R.K. Flamm, and R.N. Jones. 2014. Antimicrobial activity of ceftolozane/ tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12). J. Antimicrob. Chemother. 69:2713-2722
121. Sanchez, G.V., R.N. Master, R.B. Clark, M. Fyyaz, P. Duvvuri, G. Ekta, and J. Bordon. 2013. Klebsiella pneumoniae antimicrobial drug resistance, United States, 1998-2010. Emerg. Infect. Dis. 19:133-136
122. Shirah, G.R., and P.J. O'Neill. 2014. Intra-abdominal infections. Surg. Clin. North Am. 94:1319-1333
123. Shorr, A.F., Y.P. Tabak, A.D. Killian, V. Gupta, L.Z. Liu, and M.H. Kollef. 2006. Healthcare-associated bloodstream infection: a distinct entity? Insights from a large U.S. database. Crit. Care Med. 34:2588-2595
124. Shorr, A.F., M.D. Zilberberg, S.T. Micek, and M.H. Kollef. 2008. Prediction of infection due to antibioticresistant bacteria by select risk factors for health careassociated pneumonia. Arch. Intern. Med. 168:2205-2210
125. Sievert, D.M., P. Ricks, J.R. Edwards, A. Schneider, J. Patel, A. Srinivasan, A. Kallen, B. Limbago, and S. Fridkin. 2013. 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, 2009-2010. Infect. Control Hosp. Epidemiol. 34:1-14
126. Singh, S., and N.M. Khardori. 2012. Intra-abdominal and pelvic emergencies. Med. Clin. North Am. 96:1171-1191
127. Sipahi, O.R. 2008. Economics of antibiotic resistance. Expert Rev. Anti. Infect. Ther. 6:523-539
128. Sligl, W., G. Taylor, and P.G. Brindley. 2006. Five years of nosocomial Gram-negative bacteremia in a general intensive care unit: epidemiology, antimicrobial susceptibility patterns, and outcomes. Int. J. Infect. Dis. 10: 320-325
129. Snitkin, E.S., A.M. Zelazny, P.J. Thomas, F. Stock, D.K. Henderson, T.N. Palmore, and J.A. Segre. 2012. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci. Transl. Med. 4:148ra116
130. Snydman, D.R. 2012. Empiric antibiotic selection strategies for healthcare-associated pneumonia, intraabdominal infections, and catheter-associated bacteremia. J. Hosp. Med. 7 Suppl 1:S2-S12
131. Solomkin, J., E. Hershberger, B. Miller, M. Popejoy, I. Friedland, J. Steenbergen, M. Yoon, S. Collins, G. Yuan, P.S. Barie, et al. 2015. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin. Infect. Dis. 60:1462-1471
132. Solomkin, J.S., J.E. Mazuski, E.J. Baron, R.G. Sawyer, A.B. Nathens, J.T. DiPiro, T. Buchman, E.P. Dellinger, J. Jernigan, S. Gorbach, et al. 2003. Guidelines for the selection of anti-infective agents for complicated intraabdominal infections. Clin. Infect. Dis. 37:997-1005
133. Solomkin, J.S., M.K. Ramesh, G. Cesnauskas, N. Novikovs, P. Stefanova, J.A. Sutcliffe, S.M. Walpole, and P.T. Horn. 2014. Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult communityacquired complicated intra-abdominal infections. Antimicrob. Agents Chemother. 58:1847-1854
134. Stein, G.E. 1999. Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection. Clin. Ther. 21:1864-1872
135. Stevens, D.L., A.L. Bisno, H.F. Chambers, E.D. Everett, P. Dellinger, E.J. Goldstein, S.L. Gorbach, J.V. Hirschmann, E.L. Kaplan, J.G. Montoya, et al. 2005. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin. Infect. Dis. 41:1373-1406
136. Sutcliffe, J.A., W. O'Brien, C. Fyfe, and T.H. Grossman. 2013. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob. Agents Chemother. 57: 5548-5558
137. Tacconelli, E., M.A. Cataldo, S.J. Dancer, G. De Angelis, M. Falcone, U. Frank, G. Kahlmeter, A. Pan, N. Petrosillo, J. Rodriguez-Bano, et al. 2014. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients. Clin. Microbiol. Infect. 20 Suppl 1:1-55
138. Tamma, P.D., S.E. Cosgrove, and L.L. Maragakis. 2012. Combination therapy for treatment of infections with gram-negative bacteria. Clin. Microbiol. Rev. 25:450-470
139. The White House. Office of the Press Secretary. Fact Sheet: Obama Administration Releases National Action Plan to Combat Antibiotic-Resistant Bacteria. Available at https://www.whitehouse.gov/the-press-office/2015/03/27/ fact-sheet-obama-administration-releases-national-actionplan-combat-ant, accessed February 15, 2015. (Online.)
140. Tumbarello, M., P. Viale, C. Viscoli, E.M. Trecarichi, F. Tumietto, A. Marchese, T. Spanu, S. Ambretti, F. Ginocchio, F. Cristini, et al. 2012. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin. Infect. Dis. 55:943-950
141. Tygacil Physician Prescribing Information. Tygacil-Tigecycline Injection, Powder, Lyophilized, for Solution. Philadelphia, PA: Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc. revised December 2014
142. Vasilev, K., G. Reshedko, R. Orasan, M. Sanchez, J. Teras, T. Babinchak, G. Dukart, A. Cooper, N. Dartois, H. Gandjini, et al. 2008. A phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae. J. Antimicrob. Chemother. 62 Suppl 1:i29-i40
143. Vazquez, J.A., L.D. Gonzalez Patzan, D. Stricklin, D.D. Duttaroy, Z. Kreidly, J. Lipka, and C. Sable. 2012. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr. Med. Res. Opin. 28:1921-1931
144. Vlieghe, E.R., T.D. Huang, T. Phe, P. Bogaerts, C. Berhin, B. De Smet, W.E. Peetermans, J.A. Jacobs, and Y. Glupczynski. 2015. Prevalence and distribution of betalactamase coding genes in third-generation cephalosporinresistant Enterobacteriaceae from bloodstream infections in Cambodia. Eur. J. Clin. Microbiol. Infect. Dis. 34:1223-1229
145. Wagenlehner, F.M., O. Umeh, J. Steenbergen, G. Yuan, and R.O. Darouiche. 2015. Ceftolozanetazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECTcUTI). Lancet 385:1949-1956
146. Walkty, A., H. Adam, M. Baxter, A. Denisuik, P. Lagace-Wiens, J.A. Karlowsky, D.J. Hoban, and G.G. Zhanel. 2014. In vitro activity of plazomicin against 5,015 gram-negative and gram-positive clinical isolates obtained from patients in Canadian hospitals as part of the CANWARD study, 2011-2012. Antimicrob. Agents Chemother. 58:2554-2563
147. Watson, C.M., and M.N. Al-Hasan. 2014. Bloodstream infections and central line-associated bloodstream infections. Surg. Clin. North Am. 94:1233-1244
148. Wilson, R., P. Jones, T. Schaberg, P. Arvis, I. Duprat-Lomon, and P.P. Sagnier. 2006. Antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis. Thorax 61:337-342
149. Xu, Z.Q., M.T. Flavin, and J. Flavin. 2014. Combating multidrug-resistant Gram-negative bacterial infections. Expert Opin. Investig. Drugs 23:163-182
150. Yahav, D., A. Lador, M. Paul, and L. Leibovici. 2011. Efficacy and safety of tigecycline: a systematic review and meta-analysis. J. Antimicrob. Chemother. 66:1963-1971
151. Zavascki, A.P., C.G. Carvalhaes, R.C. Picao, and A.C. Gales. 2010. Multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii: resistance mechanisms and implications for therapy. Expert Rev. Anti. Infect. Ther. 8:71-93
152. Zhanel, G.G., P. Chung, H. Adam, S. Zelenitsky, A. Denisuik, F. Schweizer, P.R. Lagace-Wiens, E. Rubinstein, A.S. Gin, A. Walkty, et al. 2014. Ceftolozane/ tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs 74:31-51
153. Zhanel, G.G., C.D. Lawson, S. Zelenitsky, B. Findlay, F. Schweizer, H. Adam, A. Walkty, E. Rubinstein, A.S. Gin, D.J. Hoban, et al. 2012. Comparison of the nextgeneration aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev. Anti. Infect. Ther. 10:459-473
154. Zilberberg, M.D., and A.F. Shorr. 2013. Prevalence of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among specimens from hospitalized patients with pneumonia and bloodstream infections in the United States from 2000 to 2009. J. Hosp. Med. 8:559-563