NEW INSIGHT ON EPIDEMIOLOGY AND MANAGEMENT OF BACTERIAL BLOODSTREAM INFECTION IN PATIENTS WITH HEMATOLOGICAL MALIGNACIES

Main Article Content

Sara Lo Menzo
Giulia la Martire
Giancarlo Ceccarelli
Mario Venditti

Keywords

Neutropenia, bacterial bloodstream infection (BSI), hematological malignancies, Multidrug resistant

Abstract

Bloodstream infections (BSI) are an important cause of morbidity and mortality in onco-hematologic patients. The Gram-negative etiology was the main responsible of the febrile neutropenia in the sixties and its impact declined due to the use of fluoroquinolone prophylaxis; this situation was followed by the gradual emergence of Gram-positive bacteria also following of the increased use of intravascular devices and the introduction of new chemotherapeutic strategies. In the last decade the Gram-negative etiology is raising again because of the emergence of resistant strains that make questionable the usefulness of currentstrategies for prophylaxis and empirical treatment. Gram-negative BSI attributable mortality is relevant and the appropriate empirical treatment significantly improves the prognosis; on the other hand the delayed adequate treatment of Gram-positive BSI does not seem to have an high impact on survival. The clinician has to be aware of the epidemiology of his institution and of colonizations of his patients in order to choose the most appropriate empiric therapy. Ina setting of high endemicity of multidrug-resistant infections, even the choice of a targeted therapy can be a challenge, often requiring strategies based on off-label prescriptions and low grade evidences.

In this review we summarize the current evidences for the best targeted therapies for difficult to treat bacteria BSIs and future perspectives in this topic. We also provide a flow chart for a rational approach to the empirical treatment of febrile neutropenia in a multidrug resistant high prevalence setting.

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References

1. Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M e ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th european conference on infections in leukemia. Haematologica. 2013, Vol. 98, 1826-35.

2. Nesher L, Rolston KV. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection. 2014; 42, 5-13.

3. Klastersky J, Ameye L, Maertens J, Georgala A, Muanza F, Aoun M, Ferrant A, Rapoport B, Rolston K, Paesmans M. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents. 2007; 30 S, 51-9.

4. Gaytán-Martínez J1, Mateos-García E, Sánchez-Cortés E, González-Llaven J, Casanova-Cardiel LJ, Fuentes-Allen JL. Microbiological findings in febrile neutropenia. Arch Med Res. 2000; 31, 388-92.

5. Gudiol C1, Bodro M, Simonetti A, Tubau F, González-Barca E, Cisnal M, Domingo-Domenech E, Jiménez L, Carratalà J. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect. 2012; 19, 474-9.

6. Cordonnier C1, Buzyn A, Leverger G, Herbrecht R, Hunault M, Leclercq R, Bastuji-Garin S e Onco-Hématologie., Club de Réflexion sur les Infections en. Epidemiology and Risk Factors for Gram-Positive Coccal Infections in Neutropenia: Toward a More Targeted Antibiotic Strategy. Clin Infect dis. 2003; 36, 149-58.

7. Trecarichi EM, Pagano L, Candoni A, Pastore D, Cattaneo C, Fanci R, Nosari A, Caira M, Spadea A, Busca A, Vianelli N, Tumbarello M. Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect. 2014; pii: S1198-743X(14)00108-6.

8. Mikulska M, Viscoli C, Orasch C, Livermore DM, Averbuch D, Cordonnier C, Akova M e Fourth European Conference on Infections in Leukemia Group (ECIL-4), a joint venture of EBMT, EORTC, ICHS, ELN and ESGICH/ESCMID. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect. 2013; 68, 321-31.

9. Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis. 1999; 29, 490-4.

10. Mikulska M, Del Bono V, Prinapori R, Boni L, Raiola AM, Gualandi F, Van Lint MT, Dominietto A, Lamparelli T, Cappellano P, Bacigalupo A, Viscoli C. Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2010; 6, 505-12.

11. Mandell G L, Bennett J E, Dolin R.Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia : Churcill Livingstone Elsevier, 2010.

12. Costa SF, Barone AA, Miceli MH, van der Heijden IM, Soares RE, Levin AS, Anaissie EJ. Colonization and molecular epidemiology of coagulase-negative Staphylococcal bacteremia in cancer patients: a pilot study. Am J Infect Control. 2006; 34, 36-40.

13. Costa SF, Miceli MH, Anaissie EJ. Mucosa or skin as source of coagulase-negative staphylococcal bacteraemia? Lancet Infect Dis. 2004; 4, 278-86.

14. Falcone M, Micozzi A, Pompeo ME, Baiocchi P, Fabi F, Penni A, Martino P, Venditti M. Methicillin-resistant staphylococcal bacteremia in patients with hematologic malignancies: clinical and microbiological retrospective comparative analysis of S. haemolyticus, S. epidermidis and S. aureus. J Chemother. 2004; 16, 540-8.

15. Mendes RE, Hogan PA, Streit JM, Jones RN, Flamm RK. Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) program: report of linezolid activity over 9 years (2004-12). J Antimicrob Chemother. 2014; 69, 1582-8.

16. Stuart JI, John MA, Milburn S, Diagre D, Wilson B, Hussain Z. Susceptibility patterns of coagulase-negative staphylococci to several newer antimicrobial agents in comparison with vancomycin and oxacillin. Int J Antimicrob Agents. 2011; 37, 248-52.

17. Karavasilis V, Zarkotou O, Panopoulou M, Kachrimanidou M, Themeli-Digalaki K, Stylianakis A, Gennimata V, Ntokou E, Stathopoulos C, Tsakris A, Pournaras S e Resistance., Greek Study Group on Staphylococcal Linezolid. Wide dissemination of linezolid-resistant Staphylococcus epidermidis in Greece is associated with a linezolid-dependent ST22 clone. J Antimicrob Chemother. 2015, Epub ahead of print.

18. Russo A, Campanile F, Falcone M, Tascini C, Bassetti M, Goldoni P, Trancassini M, Della Siega P, Menichetti F, Stefani S, Venditti M. Linezolid-resistant staphylococcal bacteraemia: A multicentre case-case-control study in Italy. Int J Antimicrob Agents. 2015; 45, 255-61.

19. Sader HS, Farrell DJ, Flamm RK, Jones RN. Daptomycin activity tested against 164457 bacterial isolates from hospitalised patients: summary of 8 years of a Worldwide Surveillance Programme (2005-2012). Int J Antimicrob Agents. 2014; 43, 465-9.

20. Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, Kirby A, Tilley R, Török ME, Walker S, Wertheim HF, Wilson P, Llewelyn MJ e Group., UK Clinical Infection Research. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis. 2011; 11, 208-22.

21. Venditti M, Falcone M, Micozzi A, Carfagna P, Taglietti F, Serra PF, Martino P. Staphylococcus aureus bacteremia in patients with hematologic malignancies: a retrospective case-control study. Haematologica. 2004; 88, 923-30.

22. European Antimicrobial Resistance Surveillance Network (EARS-Net). European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2013. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm : ECDC, 2014.

23. Tacconelli E, De Angelis G, Cataldo MA, Pozzi E, Cauda R. Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis. J Antimicrob Chemother. 2008; 61, 26-38.

24. Soriano A, Marco F, Martínez JA, Pisos E, Almela M, Dimova VP, Alamo D, Ortega M, Lopez J, Mensa J. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008; 46, 193-200.

25. Cervera C, Castañeda X, de la Maria CG, del Rio A, Moreno A, Soy D, Pericas JM, Falces C, Armero Y, Almela M, Ninot S, Pare JC, Mestres CA, Gatell JM, Marco F, Miro JM e Group., Hospital Clinic Endocarditis Study. Effect of vancomycin minimal inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus endocarditis. Clin Infect Dis. 2014; 58, 1668-75.

26. Sánchez García M, De la Torre MA, Morales G, Peláez B, Tolón MJ, Domingo S, Candel FJ, Andrade R, Arribi A, García N, Martínez Sagasti F, Fereres J, Picazo J. Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA. 2010; 303, 2260-4.

27. Endimiani A, Blackford M, Dasenbrook EC, Reed MD, Bajaksouszian S, Hujer AM, Rudin SD, Hujer KM, Perreten V, Rice LB, Jacobs MR, Konstan MW, Bonomo RA. Emergence of linezolid-resistant Staphylococcus aureus after prolonged treatment of cystic fibrosis patients in Cleveland, Ohio. Antimicrob Agents Chemother. 2011; 55, 1684-92.

28. Paul M, Dickstein Y, Borok S, Vidal L, Leibovici L. Empirical antibiotics targeting Gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2014 Jan 14;1:CD003914.

29. Vardakas KZ, Samonis G, Chrysanthopoulou SA, Bliziotis IA, Falagas ME. Role of glycopeptides as part of initial empirical treatment of febrile neutropenic patients: a meta-analysis of randomised controlled trials. Lancet Infect Dis. 2005; 5, 431-9.

30. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, Raad II, Rijnders BJ, Sherertz RJ, Warren DK. 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. 2009; 49, 1-45.

31. Venditti M, Tarasi A, Visco Comandini U, Gentile G, Girmenia C, Micozzi A, Martino P. Enterococcal septicemia in patients with hematological malignancies. Eur J Clin Microbiol Infect Dis. 1993; 12, 241-7.

32. Todeschini G, Tecchio C, Borghero C, D'Emilio A, Pegoraro E, de Lalla F, Benedetti P, Spolaore P, Pellizzer G. Association between Enterococcus bacteraemia and death in neutropenic patients with haematological malignancies. J Infect. 2006; 53, 266-73.

33. Vergis EN, Hayden MK, Chow JW, Snydman DR, Zervos MJ, Linden PK, Wagener MM, Schmitt B, Muder RR. Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. a prospective multicenter study. Ann Intern Med. 2001; 135, 484-92.

34. Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, Young JA. Enterococcal bacteremia is associated with increased risk of mortality in recipients of allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012; 55, 764-70.

35. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis. 2005; 41, 327-33.

36. Lisboa LF, Miranda BG, Vieira MB, Dulley FL, Fonseca GG, Guimarães T, Levin AS, Shikanai-Yasuda MA, Costa SF. Empiric use of linezolid in febrile hematology and hematopoietic stem cell transplantation patients colonized with vancomycin-resistant Enterococcus spp. Int J Infect Dis. 2015; 33, 171-76.

37. Balli EP, Venetis CA, Miyakis S. Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia. Antimicrob Agents Chemother. 2014; 58, 734-9.

38. Chuang YC, Wang JT, Lin HY, Chang SC. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. BMC Infect Dis. 2014; 14, 687.

39. McKinnell JA, Patel M, Shirley RM, Kunz DF, Moser SA, Baddley JW. Observational study of the epidemiology and outcomes of vancomycin-resistant Enterococcus bacteraemia treated with newer antimicrobial agents. Epidemiol Infect. 2011; 139, 1342-50.

40. Raber-Durlacher JE, Laheij AM, Epstein JB, Epstein M, Geerligs GM, Wolffe GN, Blijlevens NM, Donnelly JP. Periodontal status and bacteremia with oral viridans streptococci and coagulase negative staphylococci in allogeneic hematopoietic stem cell transplantation recipients: a prospective observational study. Support Care Cancer. 2013;
21, 1621-7.

41. Marron A, Carratalà J, González-Barca E, Fernández-Sevilla A, Alcaide F, Gudiol F. Serious complications of bacteremia caused by Viridans streptococci in neutropenic patients with cancer. Clin Infect Dis. 2000; 31, 1126-30.

42. Venditti M, Baiocchi P, Santini C, Brandimarte C, Serra P, Gentile G, Girmenia C, Martino P. Antimicrobial susceptibilities of Streptococcus species that cause septicemia in neutropenic patients. Antimicrob Agents Chemother. 1989; 33, 580-2.

43. Carratalá J, Alcaide F, Fernández-Sevilla A, Corbella X, Li?ares J, Gudiol F. Bacteremia due to viridans streptococci that are highly resistant to penicillin: increase among neutropenic patients with cancer. Clin Infect Dis. 1995; 20, 1169-73.

44. Rolston KV, Kapadia M, Tarrand J, Coyle E, Prince RA. Spectrum of gram-positive bacteraemia and in vitro activities of daptomycin, linezolid and vancomycin against organisms isolated from cancer patients. Int J Antimicrob Agents. 2013; 41, 516-21.

45. Rozdzinski E, Kern W, Schmeiser T, Kurrle E. Corynebacterium jeikeium bacteremia at a tertiary care center. Infection. 1991; 19, 201-4.

46. Tumbarello M, Sanguinetti M, Montuori E, Trecarichi EM, Posteraro B, Fiori B, Citton R, D'Inzeo T, Fadda G, Cauda R, Spanu T. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother. 2007; 51, 1987-94.

47. Tumbarello M, Spanu T, Caira M, Trecarichi EM, Laurenti L, Montuori E, Fianchi L, Leone F, Fadda G, Cauda R, Pagano L. Factors associated with mortality in bacteremic patients with hematologic malignancies. Diagn Microbiol Infect Dis. 2009; 64, 320-6.

48. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2011; 18, 268-81.

49. Cattaneo C, Quaresmini G, Casari S, Capucci MA, Micheletti M, Borlenghi E, Signorini L, Re A, Carosi G, Rossi G. Recent changes in bacterial epidemiology and the emergence of fluoroquinolone-resistant Escherichia coli among patients with haematological malignancies: results of a prospective study on 823 patients at a single institution. J Antimicrob Chemother. 2008; 61, 721-8.

50. Trecarichi EM, Tumbarello M, Spanu T, Caira M, Fianchi L, Chiusolo P, Fadda G, Leone G, Cauda R, Pagano L. Incidence and clinical impact of extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance in bloodstream infections caused by Escherichia coli in patients with hematological malignancies. J Infect. 2009; 58, 299-307.

51. Kim SH, Kwon JC, Choi SM, Lee DG, Park SH, Choi JH, Yoo JH, Cho BS, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS. Escherichia coli and Klebsiella pneumoniae bacteremia in patients with neutropenic fever: factors associated with extended-spectrum ?-lactamase production and its impact on outcome. Ann Hematol. . 2013; 92, 533-41.

52. EJ, Bow. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis. 2011; 24, 545-53.

53. Lingaratnam S, Thursky KA, Slavin MA. Fluoroquinolone prophylaxis: a word of caution. Leuk Lymphoma. 2011; 52, 5-6.

54. Kang CI, Chung DR, Ko KS, Peck KR, Song JH e Diseases., Korean Network for Study of Infectious. Risk factors for infection and treatment outcome of extended-spectrum ?-lactamase-producing Escherichia coli and Klebsiella pneumoniae bacteremia in patients with hematologic malignancy. Ann Hematol. 2012; 91, 115-21.

55. Pitout JD. Infections with extended-spectrum beta-lactamase-producing enterobacteriaceae: changing epidemiology and drug treatment choices. Drugs. 2010; 70, 313-33.

56. Pakyz AL, Oinonen M, Polk RE. Relationship of carbapenem restriction in 22 university teaching hospitals to carbapenem use and carbapenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009; 53(5): 1983-6.

57. Rodríguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual Á e Group, Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria.?-Lactam/?-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum ?-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012; 54, 167-74.

58. Bucaneve G, Micozzi A, Picardi M, Ballanti S, Cascavilla N, Salutari P, Specchia G, Fanci R, Luppi M, Cudillo L, Cantaffa R, Milone G, Bocchia M, Martinelli G, Offidani M, Chierichini A, Fabbiano F, Quarta G, Primon V, Martino B, Manna A, Zuffa E, Ferrar.Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia. J Clin Oncol. 2014; 32, 1463-71.

59. Girometti N, Lewis RE, Giannella M, Ambretti S, Bartoletti M, Tedeschi S, Tumietto F, Cristini F, Trapani F, Gaibani P, Viale P. Klebsiella pneumoniae bloodstream infection: epidemiology and impact of inappropriate empirical therapy. Medicine (Baltimore). 2014; 93, 298-309.

60. K, Bush. Alarming ?-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol. 2010; 13, 558-64.

61. García-Fernández A, Villa L, Carta C, Venditti C, Giordano A, Venditti M, Mancini C, Carattoli A. Klebsiella pneumoniae ST258 producing KPC-3 identified in italy carries novel plasmids and OmpK36/OmpK35 porin variants. Antimicrob Agents Chemother. 2012; 56, 2143-5.

62. Tsakris A, Kristo I, Poulou A, Markou F, Ikonomidis A, Pournaras S. First occurrence of KPC-2-possessing Klebsiella pneumoniae in a Greek hospital and recommendation for detection with boronic acid disc tests. J Antimicrob Chemother. 2008; 62(6) :1257-60.

63. European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2013. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). ECDC, Stockholm 2014

64. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, Losito AR, Tedeschi S, Cauda R, Bassetti M. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012; 55, 943-50.

65. Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, Sica S, Severino A, Cudillo L, Ciceri F, Scimè R, Lombardini L, Viscoli C, Rambaldi A, (GITMO), Gruppo Italiano Trapianto Midollo Osseo e GITMO., Gruppo Italiano Trapianto Midollo Osseo.Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant. 2015; 50, 282-8.

66. Giannella M, Trecarichi EM, De Rosa FG, Del Bono V, Bassetti M, Lewis RE, Losito AR, Corcione S, Saffioti C, Bartoletti M, Maiuro G, Cardellino CS, Tedeschi S, Cauda R, Viscoli C, Viale P, Tumbarello M. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infection among rectal carriers: a prospective observational multicentre study. Clin Microbiol Infect. 2014; 20, 1357-62.

67. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014; 58, 2322-8.

68. Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, Polsky B, Adams-Haduch JM, Doi Y. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012; 56, 2108-13.

69. Daikos GL, Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect. 2011; 17, 1135-41.

70. Daikos GL, Markogiannakis A, Souli M, Tzouvelekis LS. Bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae: a clinical perspective. Expert Rev Anti Infect Ther. 2012;10(12): 1393-404.

71. Tascini C, Tagliaferri E, Giani T, Leonildi A, Flammini S, Casini B, Lewis R, Ferranti S, Rossolini GM, Menichetti F. Synergistic activity of colistin plus rifampin against colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013; 57, 3990-3.

72. Jernigan MG, Press EG, Nguyen MH, Clancy CJ, Shields RK. The combination of doripenem and colistin is bactericidal and synergistic against colistin-resistant, carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2012; 56, 3395-8.

73. Ceccarelli G, Falcone M, Giordano A, Mezzatesta ML, Caio C, Stefani S, Venditti M. Successful ertapenem-doripenem combination treatment of bacteremic ventilator-associated pneumonia due to colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013; 57, 2900-1.

74. Oliva A, D'Abramo A, D'Agostino C, Iannetta M, Mascellino MT, Gallinelli C, Mastroianni CM, Vullo V. Synergistic activity and effectiveness of a double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream infections. J Antimicrob Chemother. 2014; 69, epub feb 11.

75. Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011; 55, 3002-4.

76. Trecarichi EM, Tumbarello M, Caira M, Candoni A, Cattaneo C, Pastore D, Fanci R, Nosari A, Vianelli N, Busca A, Spadea A, Pagano L. Multidrug resistant Pseudomonas aeruginosa bloodstream infection in adult patients with hematologic malignancies. Haematologica. 2011; 96, 1-3.

77. Peña C, Gómez-Zorrilla S, Suarez C, Dominguez MA, Tubau F, Arch O, Oliver A, Pujol M, Ariza J. Extensively drug-resistant Pseudomonas aeruginosa: risk of bloodstream infection in hospitalized patients. Eur J Clin Microbiol Infect Dis. 2012; 31, 2791-7.

78. Tascini C, Gemignani G, Ferranti S, Tagliaferri E, Leonildi A, Lucarini A, Menichetti F. Microbiological activity and clinical efficacy of a colistin and rifampin combination in multidrug-resistant Pseudomonas aeruginosa infections. J Chemother. 2004; 16(3): 282-7.

79. Landman D, Bratu S, Alam M, Quale J. Citywide emergence of Pseudomonas aeruginosa strains with reduced susceptibility to polymyxin B. J Antimicrob Chemother. 2005; 55(6): 954-7.

80. Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). J Infect. 2014; 69(3): 266-77.

81. Demiraslan H, Sevim M, Pala Ç, Durmaz S, Berk V, Kaynar L, Metan G. Risk factors influencing mortality related to Stenotrophomonas maltophilia infection in hematology-oncology patients. Int J Hematol. 2013; 97, 414-20.

82. Micozzi A, Venditti M, Monaco M, Friedrich A, Taglietti F, Santilli S, Martino P. Bacteremia due to Stenotrophomonas maltophilia in patients with hematologic malignancies. Clin Infect Dis. 2000; 31, 705-11.

83. Bonfiglio G, Cascone C, Azzarelli C, Cafiso V, Marchetti F, Stefani S. Levofloxacin in vitro activity and time-kill evaluation of Stenotrophomonas maltophilia clinical isolates. J Antimicrob Chemother. 2000; 45, 115-7.

84. Venditti M, Monaco M, Micozzi A, Tarasi A, Friedrich A, Martino P. In vitro activity of moxifloxacin against Stenotrophomonas maltophilia blood isolates from patients with hematologic malignancies. Clin Microbiol Infect. . 2001; 7, 37-9.

85. Rizek C, Ferraz JR, van der Heijden IM, Giudice M, Mostachio AK, Paez J, Carrilho C, Levin AS, Costa SF. In vitro activity of potential old and new drugs against multidrug-resistant gram-negatives. J Infect Chemother. 2015; 21(2): 114-7.

86. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev. 2008; 21, 538-82.

87. Durante-Mangoni E, Del Franco M, Andini R, Bernardo M, Giannouli M, Zarrilli R. Emergence of colistin resistance without loss of fitness and virulence after prolonged colistin administration in a patient with extensively drug-resistant Acinetobacter baumannii. Diagn Microbiol Infect Dis. 2015, Vol. Epub ahead of print.

88. Tascini C, Menichetti F, Bozza S, Del Favero A, Bistoni F. Evaluation of the activities of two-drug combinations of rifampicin, polymyxin B and ampicillin/sulbactam against Acinetobacter baumannii. J Antimicrob Chemother. 1998; 42, 270-1.

89. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, Bassetti M, Malacarne P, Petrosillo N, Galdieri N, Mocavero P, Corcione A, Viscoli C, Zarrilli R, Gallo C, Utili R. 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, Vol. 57, 349-58.

90. Metan G, Alp E, Yildiz O, Percin D, Aygen B, Sumerkan B. Clinical experience with tigecycline in the treatment of carbapenem-resistant Acinetobacter infections. J Chemother. 2010; 22(2): 110-4.

91. Metan G, Pala Ç, Kaynar L, Cevahir F, Alp E. A nightmare for haematology clinics: extensively drug-resistant (XDR) Acinetobacter baumannnii. Infez Med. 2014; 22, 277-82.

92. Nesher L, Rolston KV. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection. 2014; 42(1): 5-13.

93. Orasch C, Averbuch D, Mikulska M, Cordonnier C, Livermore DM, Gyssens IC, Klyasova G, Engelhard D, Kern W, Viscoli C, Akova M, Marchetti O; 4th European Conference on Infections in Leukemia (ECIL-4); joint venture of Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation (IDWP-EBMT); Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (IDG-EORTC); International Immunocompromised Host Society (ICHS); European Leukemia Net (ELN) and European Study Group on Infections in Immunocompromised Hosts of the European Society for Clinical Microbiology and Infectious Diseases (ESGICH-ESCMID). Discontinuation of empirical antibiotic therapy in neutropenic leukaemia patients with fever of unknown origin is ethical. Clin Microbiol Infect. 2015; 21(3): e25-7.

94. Korucu B, Inkaya AC, Erbil AA, Okay M, Ascioglu S, Akova M. Early cessation of empirical antibacterial therapy in high-risk febrile neutropenic patients with FUO. 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 25-28 April 2015, Copenhagen, Denmark. P1206.

95. Retamar P, López-Cerero L, Muniain MA, Pascual Á, Rodríguez-Baño J e Group., ESBL-REIPI/GEIH. Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-?-lactamase-producing Escherichia coli. Antimicrob Agents Chemother. 2013; 57, 3402-4.

96. Pagano L, Caira M, Trecarichi EM, Spanu T, Di Blasi R, Sica S, Sanguinetti M, Tumbarello M. Carbapenemase-producing Klebsiella pneumoniae and hematologic malignancies. Emerg Infect Dis. 2014; 20, 1235-6.

97. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR, Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011; 15, e56-93.

98. Viale P, Tumietto F, Giannella M, Bartoletti M, Tedeschi S, Ambretti S, Cristini F, Gibertoni C, Venturi S, Cavalli M, De Palma A, Puggioli MC, Mosci D, Callea E, Masina R, Moro ML, Lewis RE.Impact of a hospital-wide multifaceted programme for reducing carbapenem-resistant Enterobacteriaceae infections in a large teaching hospital in northern Italy. Clin Microbiol Infect. 2015, Vol. 21, 242-7.

99. Cattaneo C, Antoniazzi F, Casari S, Ravizzola G, Gelmi M, Pagani C, D'Adda M, Morello E, Re A, Borlenghi E, Manca N, Rossi G. P. aeruginosa bloodstream infections among hematological patients: an old or new question? Ann Hematol. 2012; 91, 1299-304.

100. Lodise TP Jr, Patel N, Kwa A, Graves J, Furuno JP, Graffunder E, Lomaestro B, McGregor JC. Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection. Antimicrob Agents Chemother. 2007; 51, 3510-5.

101. Deris ZZ, Yu HH, Davis K, Soon RL, Jacob J, Ku CK, Poudyal A, Bergen PJ, Tsuji BT, Bulitta JB, Forrest A, Paterson DL, Velkov T, Li J, Nation RL. The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2012; 56, 5103-12.

102. Sbrana F, Malacarne P, Viaggi B, Costanzo S, Leonetti P, Leonildi A, Casini B, Tascini C, Menichetti F. 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.

103. De Pascale G, Montini L, Pennisi M, Bernini V, Maviglia R, Bello G, Spanu T, Tumbarello M, Antonelli M. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care. 2014, 5, 10.1186/cc13858.

104. Fehér C, Rovira M, Soriano A, Esteve J, Martínez JA, Marco F, Carreras E, Martínez C, Fernández-Avilés F, Suárez-Lledó M, Mensa J. Effect of meropenem administration in extended infusion on the clinical outcome of febrile neutropenia: a retrospective observational study. J Antimicrob Chemother. 2014; 69, 2556-62.

105. Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, Silveira FP, Forrest A, Nation RL. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011; 55, 3284-94.