Authors

Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Abstract


Evidences regarding the efficacy of different antibiotic regimens proposed for treatment of 
multidrug‑resistant (MDR) Gram‑negative pathogens have been reviewed. Available data in 
Scopus, Medline, EMBASE, the Cochrane central register of controlled trials, and Cochrane 
database of systematic reviews have been collected. Several antibiotic regimens are proposed 
for treatment of MDR Gram‑negative infections (defined as nonsusceptibility to at least 
one agent in three or more antimicrobial categories). The most challenging issue is the 
treatment of carbapenem‑resistant (CR) Gram‑negative pathogens. A carbapenem plus either 
colistin or tigecycline was the most effective regimen for treatment of CR Gram‑negative 
pathogens with low‑level resistance (minimal inhibitory concentration [MIC] ≤ 8 mg/L). 
However, in high‑level resistance (MIC > 8 mg/L), combination of colistin and tigecycline 
showed promising effect.

Keywords

  1. Cloete TE. Resistance mechanisms of bacteria to antimicrobial 
    compounds. Int Biodeterior Biodegradation 2003;51:277‑82.
    2. Tenover FC. Mechanisms of antimicrobial resistance in 
    bacteria. Am J Med 2006;119:S3‑10.
    3. Rice LB. Federal funding for the study of antimicrobial 
    resistance in nosocomial pathogens: No ESKAPE. J Infect Dis 
    2008;197:1079‑81.
    4. Zavascki AP, Bulitta JB, Landersdorfer CB. Combination 
    therapy for carbapenem‑resistant Gram‑negative bacteria. 
    Expert Rev Anti Infect Ther 2013;11:1333‑53.
    5. Zavascki AP, Carvalhaes CG, Picão RC, Gales AC. 
    Multidrug‑resistant Pseudomonas aeruginosa and Acinetobacter 
    baumannii: Resistance mechanisms and implications for 
    therapy. Expert Rev Anti Infect Ther 2010;8:71‑93.
    6. Livermore DM, Woodford N. Carbapenemases: A problem in 
    waiting? Curr Opin Microbiol 2000;3:489‑95.
    7. Clatworthy AE, Pierson E, Hung DT. Targeting virulence: 
    A new paradigm for antimicrobial therapy. Nat Chem Biol 
    2007;3:541‑8.
    8. Queenan AM, Bush K. Carbapenemases: The versatile 
    beta‑lactamases. Clin Microbiol Rev 2007;20:440‑58.
    9. Rossolini GM, Arena F, Pecile P, Pollini S. Update on the 
    antibiotic resistance crisis. Curr Opin Pharmacol 2014;18:56‑60.
    10. Paterson DL. Resistance in gram‑negative bacteria: 
    Enterobacteriaceae. Am J Infect Control 2006;34:S20‑8.
    11. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, 
    Falagas ME, Giske CG, 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;18:268‑81.
    12. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. 
    Carbapenems versus alternative antibiotics for the 
    treatment of bacteraemia due to Enterobacteriaceae producing 
    extended‑spectrum ß‑lactamases: A systematic review and 
    meta‑analysis. J Antimicrob Chemother 2012;67:2793‑803.
    13. Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. 
    Deaths attributable to carbapenem‑resistant Enterobacteriaceae
    infections. Emerg Infect Dis 2014;20:1170‑5.
    14. Maragakis LL, PerlTM. Acinetobacter baumannii: Epidemiology, 
    antimicrobial resistance, and treatment options. Clin Infect Dis 
    2008;46:1254‑63.
    15. Levin AS, Barone AA, Penço J, Santos MV, Marinho IS, 
    Arruda EA, et al. Intravenous colistin as therapy for 
    nosocomial infections caused by multidrug‑resistant 
    Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect 
    Dis 1999;28:1008‑11.
    16. SobieszczykME, FuruyaEY, HayCM, PancholiP, Della‑LattaP, 
    Hammer SM, et al. Combination therapy with polymyxin B 
    for the treatment of multidrug‑resistant Gram‑negative 
    respiratory tract infections. J Antimicrob Chemother 
    2004;54:566‑9.
    17. Kasiakou SK, Michalopoulos A, Soteriades ES, Samonis G, 
    Sermaides GJ, Falagas ME. Combination therapy with 
    intravenous colistin for management of infections due to 
    multidrug‑resistant Gram‑negative bacteria in patients 
    without cystic fibrosis. Antimicrob Agents Chemother 
    2005;49:3136‑46.
    18. Saballs M, Pujol M, Tubau F, Peña C, Montero A, 
    Domínguez MA, et al. Rifampicin/imipenem combination in 
    the treatment of carbapenem‑resistant Acinetobacter baumannii
    infections. J Antimicrob Chemother 2006;58:697‑700.
    19. Tseng YC, Wang JT, Wu FL, Chen YC, Chie WC, Chang SC. 
    Prognosis of adult patients with bacteremia caused by 
    extensively resistant Acinetobacter baumannii. Diagn Microbiol 
    Infect Dis 2007;59:181‑90.
    20. 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;61:1369‑75.
    21. Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, 
    Damala M, Falagas ME. Intravenous fosfomycin for 
    the treatment of nosocomial infections caused by 
    carbapenem‑resistant Klebsiella pneumoniae in critically 
    ill patients: A prospective evaluation. Clin Microbiol Infect 
    2010;16:184‑6.
    22. GoundenR, Bamford C, van Zyl‑SmitR, 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.
    23. Tsioutis C, Kritsotakis EI, Maraki S, Gikas A. Infections by 
    pandrug‑resistant gram‑negative bacteria: Clinical profile, 
    therapeutic management, and outcome in a series of 
    21 patients. Eur J Clin Microbiol Infect Dis 2010;29:301‑5.
    24. Dalfino L, Puntillo F, Mosca A, Monno R, Spada ML, 
    Coppolecchia S, et al. High‑dose, extended‑interval colistin 
    administration in critically ill patients: Is this the right dosing 
    strategy? A preliminary study. Clin Infect Dis 2012;54:1720‑6.
    25. Sbrana F, Malacarne P, Viaggi B, Costanzo S, Leonetti P, 
    Leonildi A, et al. Carbapenem‑sparing antibiotic 
    regimens for infections caused by Klebsiella pneumoniae 
    carbapenemase‑producing K. pneumoniae in intensive care 
    unit. Clin Infect Dis 2013;56:697‑700.
    26. Kontopidou F, Giamarellou H, Katerelos P, Maragos A, 
    Kioumis I, Trikka‑Graphakos E, et al. Infections caused by 
    carbapenem‑resistant Klebsiella pneumoniae among patients 
    in intensive care units in Greece: A multi‑centre study on 
    clinical outcome and therapeutic options. Clin Microbiol Infect 
    2014;20:O117‑23.
    27. Balandin Moreno B, Fernández Simón I, Pintado García V, 
    Sánchez Romero I, Isidoro Fernández B, Romera 
    Ortega MA, et al. Tigecycline therapy for infections due to 
    carbapenemase‑producing Klebsiella pneumoniae in critically 
    ill patients. Scand J Infect Dis 2014;46:175‑80.
  2. 28. Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, 
    Katsiari M, et al. Outcomes of critically ill intensive 
    care unit patients treated with fosfomycin for infections 
    due to pandrug‑resistant and extensively drug‑resistant 
    carbapenemase‑producing Gram‑negative bacteria. Int J 
    Antimicrob Agents 2014;43:52‑9.
    29. Smolyakov R, Borer A, Riesenberg K, Schlaeffer F, Alkan M, 
    Porath A, et al. Nosocomial multi‑drug resistant Acinetobacter 
    baumannii blood stream infection: Risk factors and outcome 
    with ampicillin‑sulbactam treatment. J Hosp Infect 2003;54:32‑8.
    30. Kuo LC, Lai CC, Liao CH, Hsu CK, Chang YL, Chang CY,et al.
    Multidrug‑resistant Acinetobacter baumannii bacteraemia: 
    Clinical features, antimicrobial therapy and outcome. Clin 
    Microbiol Infect 2007;13:196‑8.
    31. Choi JY, Kim CO, Park YS, Yoon HJ, Shin SY, Kim YK, et al.
    Comparison of efficacy of cefoperazone/sulbactam and 
    imipenem/cilastatin for treatment of Acinetobacter bacteremia. 
    Yonsei Med J 2006;47:63‑9.
    32. Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, 
    SkoutelisA, et al. Prospective observational study of the impact 
    of VIM‑1 metallo‑beta‑lactamase on the outcome of patients 
    with Klebsiella pneumoniae blood stream infections. Antimicrob 
    Agents Chemother 2009;53:1868‑73.
    33. Lim SK, Lee SO, Choi SH, Choi JP, Kim SH, Jeong JY, et al. The 
    outcomes of using colistin for treating multidrug resistant 
    Acinetobacter species blood stream infections. J Korean Med 
    Sci 2011;26:325‑31.
    34. Neuner EA, Yeh JY, Hall GS, Sekeres J, Endimiani A, 
    Bonomo RA, et al. Treatment and outcomes in 
    carbapenem‑resistant Klebsiella pneumoniae blood stream 
    infections. Diagn Microbiol Infect Dis 2011;69:357‑62.
    35. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, 
    Tumietto F, Marchese A, et al. Predictors of mortality in 
    blood stream infections caused by Klebsiella pneumoniae 
    carbapenemase‑producing K. pneumoniae: Importance of 
    combination therapy. Clin Infect Dis 2012;55:943‑50.
    36. ZarkotouO, Pournaras S, TseliotiP, Dragoumanos V, Pitiriga V, 
    Ranellou K, et al. Predictors of mortality in patients with 
    blood stream infections caused by KPC‑producing Klebsiella 
    pneumoniae and impact of appropriate antimicrobial treatment. 
    Clin Microbiol Infect 2011;17:1798‑803.
    37. DaikosGL, TsaousiS, TzouvelekisLS, AnyfantisI, PsichogiouM, 
    Argyropoulou A, et al. Carbapenemase‑producing Klebsiella 
    pneumoniae blood stream infections: Lowering mortality by 
    antibiotic combination schemes and the role of carbapenems. 
    Antimicrob Agents Chemother 2014;58:2322‑8.
    38. Schwaber MJ, Carmeli Y. Mortality and delay in effective 
    therapy associated with extended‑spectrum beta‑lactamase 
    production in Enterobacteriaceae bacteraemia: A systematic 
    review and meta‑analysis. J Antimicrob Chemother 
    2007;60:913‑20.
    39. Balkan II, Aygün G, Aydin S, Mutcali SI, Kara Z, 
    Kuskucu M, et al. Blood stream infections due to OXA‑48‑like 
    carbapenemase‑producing Enterobacteriaceae: Treatment and 
    survival. Int J Infect Dis 2014;26:51‑6.
    40. Kalanuria AA, Zai W, Mirski M. Ventilator‑associated 
    pneumonia in the ICU. Crit Care 2014;18:208.
    41. Garnacho‑Montero J, Corcia‑Palomo Y, Amaya‑Villar R, 
    Martin‑Villen L. How to treat VAP due to MDR pathogens in 
    ICU patients. BMC Infect Dis 2014;14:135.
    42. Naesens R, Vlieghe E, Verbrugghe W, Jorens P, Ieven M. 
    A retrospective observational study on the efficacy of colistin 
    by inhalation as compared to parenteral administration for 
    the treatment of nosocomial pneumonia associated with 
    multidrug‑resistant Pseudomonas aeruginosa. BMC Infect Dis 
    2011;11:317.
    43. 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;44:477‑85.
    44. Ye JJ, Lin HS, Kuo AJ, Leu HS, Chiang PC, Huang CT, et al.
    The clinical implication and prognostic predictors of tigecycline 
    treatment for pneumonia involving multidrug‑resistant 
    Acinetobacter baumannii. J Infect 2011;63:351‑61.
    45. Urban C, Go E, Mariano N, Berger BJ, Avraham I, Rubin D, et al.
    Effect of sulbactam on infections caused by imipenem‑resistant 
    Acinetobacter calcoaceticus biotype anitratus. J Infect Dis 
    1993;167:448‑51.
    46. Garnacho‑Montero J, Ortiz‑Leyba C, Jiménez‑Jiménez FJ, 
    Barrero‑Almodóvar AE, García‑Garmendia J L , 
    Bernabeu‑WittelI M, et al. Treatment of multidrug‑resistant 
    Acinetobacter baumannii v e n t i l a t o r ‑ a s s o c i a t e d 
    pneumonia (VAP) with intravenous colistin: A comparison 
    with imipenem‑susceptible VAP. Clin Infect Dis 2003;36:1111‑8.
    47. Wood GC, Hanes SD, Boucher BA, Croce MA, Fabian TC. 
    Tetracyclines for treating multidrug‑resistant Acinetobacter 
    baumannii ventilator‑associated pneumonia. Intensive Care 
    Med 2003;29:2072‑6.
    48. Lee CM, Lim HK, Liu CP, Tseng HK. Treatment of 
    pan‑drug resistant Acinetobacter baumannii. Scand J Infect Dis 
    2005;37:195‑9.
    49. Petrosillo N, Chinello P, Proietti MF, Cecchini L, Masala M, 
    Franchi C, et al. Combined colistin and rifampicin therapy 
    for carbapenem‑resistant Acinetobacter baumannii infections: 
    Clinical outcome and adverse events. Clin Microbiol Infect 
    2005;11:682‑3.
    50. Bassetti M, Repetto E, Righi E, Boni S, Diverio M, 
    Molinari MP, et al. Colistin and rifampicin in the treatment 
    of multidrug‑resistant Acinetobacter baumannii infections. 
    J Antimicrob Chemother 2008;61:417‑20.
    51. Betrosian AP, Frantzeskaki F, Xanthaki A, Georgiadis G. 
    High‑dose ampicillin‑sulbactam as an alternative treatment 
    of late‑onset VAP from multidrug‑resistant Acinetobacter 
    baumannii. Scand J Infect Dis 2007;39:38‑43.
    52. Tasbakan MS, Pullukcu H, Sipahi OR, Tasbakan MI, 
    Aydemir S, Bacakoglu F. Is tigecyclin a good choice in the 
    treatment of multidrug‑resistant Acinetobacter baumannii 
    pneumonia? J Chemother 2011;23:345‑9.
    53. Shields RK, Clancy CJ, Gillis LM, Kwak EJ, Silveira FP, 
    Massih RC, et al. Epidemiology, clinical characteristics and 
    outcomes of extensively drug‑resistant Acinetobacter baumannii 
    infections among solid organ transplant recipients. PLoS One 
    2012;7:e52349.
    54. 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;57:349‑58.
    55. Kalin G, Alp E, Coskun R, Demiraslan H, Gündogan K, 
    Doganay M. Use of high‑dose IV and aerosolized colistin for the treatment of multidrug‑resistant Acinetobacter baumannii 
    ventilator‑associated pneumonia: Do we really need this 
    treatment? J Infect Chemother 2012;18:872‑7.
    56. McLaughlin MM, Advincula MR, Malczynski M, Barajas G, 
    Qi C, Scheetz MH. Quantifying the clinical virulence of 
    Klebsiella pneumoniae producing carbapenemase Klebsiella 
    pneumoniae with a Galleria mellonella model and a pilot study 
    to translate to patient outcomes. BMC Infect Dis 2014;14:31.
    57. Chuang YC, Cheng CY, Sheng WH, Sun HY, Wang JT, 
    Chen YC, et al. Effectiveness of tigecycline‑based versus 
    colistin‑based therapy for treatment of pneumonia caused by 
    multidrug‑resistant Acinetobacter baumannii in a critical setting: 
    A matched cohort analysis. BMC Infect Dis 2014;14:102.
    58. Krol V, Hamid NS, Cunha BA. Neurosurgically related 
    nosocomial Acinetobacter baumannii meningitis: Report of two 
    cases and literature review. J Hosp Infect 2009;71:176‑80.
    59. Wroblewska MM, Dijkshoorn L, Marchel H, van den 
    Barselaar M, Swoboda‑Kopec E, van den Broek PJ, et al.
    Outbreak of nosocomial meningitis caused by Acinetobacter 
    baumannii in neurosurgical patients. J Hosp Infect 2004;57:300‑7.
    60. Nagaveni S, Rajeshwari H, OliAK, Patil SA, ChandrakanthRK. 
    Widespread emergence of multidrug resistant Pseudomonas 
    aeruginosa isolated from CSF samples. Indian J Microbiol 
    2011;51:2‑7.
    61. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. 
    Advances in treatment of bacterial meningitis. Lancet 
    2012;380:1693‑702.
    62. Tsuji Y, Hiraki Y, Matsumoto K, Mizoguchi A, Sadoh S, 
    Kobayashi T, et al. Pharmacokinetics and protein binding 
    of linezolid in cerebrospinal fluid and serum in a case of 
    post‑neurosurgical bacterial meningitis. Scand J Infect Dis 
    2011;43:982‑5.
    63. Di Paolo A, Gori G, Tascini C, Danesi R, Del Tacca M. Clinical 
    pharmacokinetics of antibacterials in cerebrospinal fluid. Clin 
    Pharmacokinet 2013;52:511‑42.
    64. Rodríguez Guardado A, Blanco A, Asensi V, Pérez F, Rial JC, 
    Pintado V, et al. Multidrug‑resistant Acinetobacter meningitis 
    in neurosurgical patients with intraventricular catheters: 
    Assessment of different treatments. J Antimicrob Chemother 
    2008;61:908‑13.
    65. CascioA, ContiA, Sinardi L, Iaria C, Angileri FF, Stassi G, et al.
    Post‑neurosurgical multidrug‑resistant Acinetobacter baumannii 
    meningitis successfully treated with intrathecal colistin. A new 
    case and a systematic review of the literature. Int J Infect Dis 
    2010;14:e572‑9.
    66. Imberti R, Cusato M, Accetta G, Marinò V, Procaccio F, 
    Del Gaudio A, et al. Pharmacokinetics of colistin in 
    cerebrospinal fluid after intraventricular administration of 
    colistin methanesulfonate. Antimicrob Agents Chemother 
    2012;56:4416‑21.
    67. Falagas ME, Bliziotis IA, Tam VH. Intraventricular or 
    intrathecal use of polymyxins in patients with Gram‑negative 
    meningitis: A systematic review of the available evidence. Int 
    J Antimicrob Agents 2007;29:9‑25.
    68. Khawcharoenporn T, Apisarnthanarak A, Mundy LM. 
    Intrathecal colistin for drug‑resistant Acinetobacter baumannii 
    central nervous system infection: A case series and systematic 
    review. Clin Microbiol Infect 2010;16:888‑94.
    69. MarkantonisSL, MarkouN, FousteriM, SakellaridisN, KaratzasS, 
    Alamanos I, et al. Penetration of colistin into cerebrospinal fluid. 
    Antimicrob Agents Chemother 2009;53:4907‑10.
    70. Karaiskos I, Galani L, Baziaka F, Giamarellou H. 
    Intraventricular and intrathecal colistin as the last therapeutic 
    resort for the treatment of multidrug‑resistant and extensively 
    drug‑resistant Acinetobacter baumannii ventriculitis and 
    meningitis: A literature review. Int J Antimicrob Agents 
    2013;41:499‑508.
    71. Georges H, Chiche A, Alfandari S, Devos P, Boussekey N, 
    Leroy O. Adult community‑acquired bacterial meningitis 
    requiring ICU admission: Epidemiological data, prognosis 
    factors and adherence to IDSA guidelines. Eur J Clin Microbiol 
    Infect Dis 2009;28:1317‑25.
    72. Rodríguez‑Baño J, Martí S, Soto S, Fernández‑Cuenca F, 
    Cisneros JM, Pachón J, et al. Biofilm formation in Acinetobacter 
    baumannii: Associated features and clinical implications. Clin 
    Microbiol Infect 2008;14:276‑8.
    73. Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, et al.
    Management of meningitis due to antibiotic‑resistant Acinetobacter 
    species. Lancet Infect Dis 2009;9:245‑55.
    74. Levison ME, Kaye D. Treatment of complicated urinary tract 
    infections with an emphasis on drug‑resistant gram‑negative 
    uropathogens. Curr Infect Dis Rep 2013;15:109‑15.
    75. Takeyama K, Kunishima Y, Matsukawa M, Takahashi S, 
    Hirose T, Kobayashi N, et al. Multidrug‑resistant Pseudomonas 
    aeruginosa isolated from the urine of patients with urinary tract 
    infection. J Infect Chemother 2002;8:59‑63.
    76. Alexander BT, Marschall J, Tibbetts RJ, Neuner EA, Dunne 
    WM Jr, Ritchie DJ. Treatment and clinical outcomes of urinary 
    tract infections caused by KPC‑producing Enterobacteriaceae
    in a retrospective cohort. Clin Ther 2012;34:1314‑23.
    77. Volkow‑Fernández P, Rodríguez CF, Cornejo‑Juárez P. 
    Intravesical colistin irrigation to treat multidrug‑resistant 
    Acinetobacter baumannii urinary tract infection: A case report. 
    J Med Case Rep 2012;6:426.
    78. Rafailidis PI, Falagas ME. Options for treating 
    carbapenem‑resistant Enterobacteriaceae. Curr Opin Infect 
    Dis 2014;27:479‑83.
    79. Michalopoulos A, Kasiakou SK, Mastora Z, Rellos K, 
    Kapaskelis AM, Falagas ME. Aerosolized colistin for the 
    treatment of nosocomial pneumonia due to multidrug‑resistant 
    Gram‑negative bacteria in patients without cystic fibrosis. Crit 
    Care 2005;9:R53‑9