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Antimicrobial Treatment of Febrile Neutropenia: Pharmacokinetic–Pharmacodynamic Considerations

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Abstract

Patients with cancer or hematologic diseases are particularly at risk of infection leading to high morbidity, mortality and costs. Extensive data show that optimization of the administration of antimicrobials according to their pharmacokinetic and pharmacodynamic parameters improves clinical outcome. Evidence is growing that when pharmacokinetic and pharmacodynamic parameters are used to target not only clinical cure but also eradication, the selection resistance is also contained. This is of particular importance in patients with neutropenia in whom increasing rates of drug-resistant Gram-negative bacteria have been reported, particularly Pseudomonas aeruginosa. Based on experimental and clinical studies, pharmacokinetic and pharmacodynamic parameters are discussed in this review for each antibiotic used in febrile neutropenia in order to help physicians improve dosing and optimization of antimicrobial agents.

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References

  1. Owens RCAP, ed. Pharmacodynamics of quinolones. New York: Marcel Dekker Inc; 2002.

  2. Ramphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens. Clin Infect Dis. 2004;39(Suppl 1):S25–31.

    Article  PubMed  Google Scholar 

  3. Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis. 2004;39(Suppl 1):S32–7.

    Article  PubMed  Google Scholar 

  4. Lortholary O, Lefort A, Tod M, et al. Pharmacodynamics and pharmacokinetics of antibacterial drugs in the management of febrile neutropenia. Lancet Infect Dis. 2008;8:612–20.

    Article  PubMed  CAS  Google Scholar 

  5. Bodey GP, Nies BA, Freireich EJ. Multiple organism septicemia in acute leukemia: analysis of 54 episodes. Arch Intern Med. 1965;116:266–72.

    Article  PubMed  CAS  Google Scholar 

  6. Rolston KV. Challenges in the treatment of infections caused by gram-positive and gram-negative bacteria in patients with cancer and neutropenia. Clin Infect Dis. 2005;40(Suppl 4):S246–52.

    Article  PubMed  Google Scholar 

  7. Cordonnier C, Buzyn A, Leverger G, et al. Epidemiology and risk factors for gram-positive coccal infections in neutropenia: toward a more targeted antibiotic strategy. Clin Infect Dis. 2003;36:149–58.

    Article  PubMed  Google Scholar 

  8. Feld R, DePauw B, Berman S, et al. Meropenem versus ceftazidime in the treatment of cancer patients with febrile neutropenia: a randomized, double-blind trial. J Clin Oncol. 2000;18:3690–8.

    PubMed  CAS  Google Scholar 

  9. Chong Y, Yakushiji H, Ito Y, et al. Cefepime-resistant Gram-negative bacteremia in febrile neutropenic patients with hematological malignancies. Int J Infect Dis. 2010;14(Suppl 3):e171–5.

    Article  PubMed  Google Scholar 

  10. Del Favero A, Menichetti F, Martino P, et al. A multicenter, double-blind, placebo-controlled trial comparing piperacillin-tazobactam with and without amikacin as empiric therapy for febrile neutropenia. Clin Infect Dis. 2001;33:1295–301.

    Article  PubMed  Google Scholar 

  11. Wisplinghoff H, Seifert H, Wenzel RP, et al. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis. 2003;36:1103–10.

    Article  PubMed  Google Scholar 

  12. Reuter S, Kern WV, Sigge A, et al. Impact of fluoroquinolone prophylaxis on reduced infection-related mortality among patients with neutropenia and hematologic malignancies. Clin Infect Dis. 2005;40:1087–93.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. Pagano L, Caira M, Rossi G, et al. A prospective survey of febrile events in hematological malignancies. Ann Hematol. 2012;91:767–74.

    Article  PubMed  CAS  Google Scholar 

  15. Schimpff S, Satterlee W, Young VM, et al. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med. 1971;284:1061–5.

    Article  PubMed  CAS  Google Scholar 

  16. Fletcher M, Hodgkiss H, Zhang S, et al. Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer. Pediatr Blood Cancer. 2013;60(8):1299–306.

    Google Scholar 

  17. Funk D, Sebat F, Kumar A. A systems approach to the early recognition and rapid administration of best practice therapy in sepsis and septic shock. Curr Opin Crit Care. 2009;15:301–7.

    Article  PubMed  Google Scholar 

  18. Zandvliet AS, Schellens JH, Beijnen JH, et al. Population pharmacokinetics and pharmacodynamics for treatment optimization in clinical oncology. Clin Pharmacokinet. 2008;47:487–513.

    Article  PubMed  CAS  Google Scholar 

  19. Sanchez-Navarro A, Sanchez Recio MM. Basis of anti-infective therapy: pharmacokinetic–pharmacodynamic criteria and methodology for dual dosage individualisation. Clin Pharmacokinet. 1999;37:289–304.

    Article  PubMed  CAS  Google Scholar 

  20. Adembri C, Novelli A. Pharmacokinetic and pharmacodynamic parameters of antimicrobials: potential for providing dosing regimens that are less vulnerable to resistance. Clin Pharmacokinet. 2009;48:517–28.

    Article  PubMed  CAS  Google Scholar 

  21. Navas D, Caillon J, Batard E, et al. Trough serum concentrations of beta-lactam antibiotics in cancer patients: inappropriateness of conventional schedules to pharmacokinetic/pharmacodynamic properties of beta-lactams. Int J Antimicrob Agents. 2006;27:102–7.

    Article  PubMed  CAS  Google Scholar 

  22. Paul M, Yahav D, Bivas A, et al. Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams. Cochrane Database Syst Rev. 2010:CD005197.

  23. Freifeld AG, Bow EJ, Sepkowitz KA, et al. 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;52:e56–93.

    Article  PubMed  Google Scholar 

  24. Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis. 1998;27:10–22.

    Article  PubMed  CAS  Google Scholar 

  25. Lodise TP, Lomaestro BM, Drusano GL. Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on beta-lactam antibiotics: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2006;26:1320–32.

    Article  PubMed  CAS  Google Scholar 

  26. Hyatt JM, McKinnon PS, Zimmer GS, et al. The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome: focus on antibacterial agents. Clin Pharmacokinet. 1995;28:143–60.

    Article  PubMed  CAS  Google Scholar 

  27. Vogelman B, Gudmundsson S, Leggett J, et al. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158:831–47.

    Article  PubMed  CAS  Google Scholar 

  28. Craig WA, Vogelman B. The postantibiotic effect. Ann Intern Med. 1987;106:900–2.

    Article  PubMed  CAS  Google Scholar 

  29. Mouton JW, Vinks AA. Relationship between minimum inhibitory concentration and stationary concentration revisited: growth rates and minimum bactericidal concentrations. Clin Pharmacokinet. 2005;44:767–8.

    Article  PubMed  Google Scholar 

  30. Mouton JW, Vinks AA. Pharmacokinetic/pharmacodynamic modelling of antibacterials in vitro and in vivo using bacterial growth and kill kinetics: the minimum inhibitory concentration versus stationary concentration. Clin Pharmacokinet. 2005;44:201–10.

    Article  PubMed  CAS  Google Scholar 

  31. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1–10 (quiz 11–12).

    Google Scholar 

  32. MacGowan AP, Bowker KE. Continuous infusion of beta-lactam antibiotics. Clin Pharmacokinet. 1998;35:391–402.

    Article  PubMed  CAS  Google Scholar 

  33. Bakker-Woudenberg IA, van den Berg JC, Fontijne P, et al. Efficacy of continuous versus intermittent administration of penicillin G in Streptococcus pneumoniae pneumonia in normal and immunodeficient rats. Eur J Clin Microbiol. 1984;3:131–5.

    Article  PubMed  CAS  Google Scholar 

  34. Leggett JE, Fantin B, Ebert S, et al. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis. 1989;159:281–92.

    Article  PubMed  CAS  Google Scholar 

  35. Bustamante CI, Drusano GL, Tatem BA, et al. Postantibiotic effect of imipenem on Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1984;26:678–82.

    Article  PubMed  CAS  Google Scholar 

  36. Roosendaal R, Bakker-Woudenberg IA, van den Berghe-van Raffe M, et al. Impact of the dosage schedule on the efficacy of ceftazidime, gentamicin and ciprofloxacin in Klebsiella pneumoniae pneumonia and septicemia in leukopenic rats. Eur J Clin Microbiol Infect Dis. 1989;8:878–87.

    Article  PubMed  CAS  Google Scholar 

  37. Gerber AU, Brugger HP, Feller C, et al. Antibiotic therapy of infections due to Pseudomonas aeruginosa in normal and granulocytopenic mice: comparison of murine and human pharmacokinetics. J Infect Dis. 1986;153:90–7.

    Article  PubMed  CAS  Google Scholar 

  38. Mordenti JJ, Quintiliani R, Nightingale CH. Combination antibiotic therapy: comparison of constant infusion and intermittent bolus dosing in an experimental animal model. J Antimicrob Chemother. 1985;15(Suppl A):313–21.

    Google Scholar 

  39. Roosendaal R, Bakker-Woudenberg IA, van den Berghe-van Raffe M, et al. Continuous versus intermittent administration of ceftazidime in experimental Klebsiella pneumoniae pneumonia in normal and leukopenic rats. Antimicrob Agents Chemother. 1986;30:403–8.

    Article  PubMed  CAS  Google Scholar 

  40. Fuentes F, Martin MM, Izquierdo J, et al. In vivo and in vitro study of several pharmacodynamic effects of meropenem. Scand J Infect Dis. 1995;27:469–74.

    Article  PubMed  CAS  Google Scholar 

  41. Mouton JW, den Hollander JG. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother. 1994;38:931–6.

    Article  PubMed  CAS  Google Scholar 

  42. Tessier PR, Nicolau DP, Onyeji CO, et al. Pharmacodynamics of intermittent- and continuous-infusion cefepime alone and in combination with once-daily tobramycin against Pseudomonas aeruginosa in an in vitro infection model. Chemotherapy. 1999;45:284–95.

    Article  PubMed  CAS  Google Scholar 

  43. Robaux MA, Dube L, Caillon J, et al. In vivo efficacy of continuous infusion versus intermittent dosing of ceftazidime alone or in combination with amikacin relative to human kinetic profiles in a Pseudomonas aeruginosa rabbit endocarditis model. J Antimicrob Chemother. 2001;47:617–22.

    Article  PubMed  CAS  Google Scholar 

  44. Navas D, Caillon J, Gras-Le Guen C, et al. Comparison of in vivo intrinsic activity of cefepime and imipenem in a Pseudomonas aeruginosa rabbit endocarditis model: effect of combination with tobramycin simulating human serum pharmacokinetics. J Antimicrob Chemother. 2004;54:767–71.

    Article  PubMed  CAS  Google Scholar 

  45. Tam VH, McKinnon PS, Akins RL, et al. Pharmacodynamics of cefepime in patients with Gram-negative infections. J Antimicrob Chemother. 2002;50:425–8.

    Article  PubMed  CAS  Google Scholar 

  46. Nyhlen A, Ljungberg B, Nilsson-Ehle I. Pharmacokinetics of ceftazidime in febrile neutropenic patients. Scand J Infect Dis. 2001;33:222–6.

    Article  PubMed  CAS  Google Scholar 

  47. Drusano GL, Plaisance KI, Forrest A, et al. Steady-state pharmacokinetics of imipenem in febrile neutropenic cancer patients. Antimicrob Agents Chemother. 1987;31:1420–2.

    Article  PubMed  CAS  Google Scholar 

  48. Mouton JW, Touzw DJ, Horrevorts AM, et al. Comparative pharmacokinetics of the carbapenems: clinical implications. Clin Pharmacokinet. 2000;39:185–201.

    Article  PubMed  CAS  Google Scholar 

  49. Engervall P, Kalin M, Dornbusch K, et al. Cefepime as empirical monotherapy in febrile patients with hematological malignancies and neutropenia: a randomized, single-center phase II trial. J Chemother. 1999;11:278–86.

    PubMed  CAS  Google Scholar 

  50. Bohme A, Shah PM, Stille W, et al. Prospective randomized study to compare imipenem 1.5 grams per day vs. 3.0 grams per day in infections of granulocytopenic patients. J Infect. 1998;36:35–42.

    Article  PubMed  CAS  Google Scholar 

  51. Lamoth F, Buclin T, Csajka C, et al. Reassessment of recommended imipenem doses in febrile neutropenic patients with hematological malignancies. Antimicrob Agents Chemother. 2009;53:785–7.

    Article  PubMed  CAS  Google Scholar 

  52. Janmohamed RM, Leyland MJ, Kelly J, et al. Pharmacokinetics of imipenem/cilastatin in neutropenic patients with haematological malignancies. J Antimicrob Chemother. 1990;25:407–12.

    Article  PubMed  CAS  Google Scholar 

  53. Lee DG, Choi SM, Shin WS, et al. Population pharmacokinetics of meropenem in febrile neutropenic patients in Korea. Int J Antimicrob Agents. 2006;28:333–9.

    Article  PubMed  CAS  Google Scholar 

  54. Ariano RE, Nyhlen A, Donnelly JP, et al. Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann Pharmacother. 2005;39:32–8.

    Article  PubMed  CAS  Google Scholar 

  55. Moriyama B, Henning SA, Childs R, et al. High-dose continuous infusion beta-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections in immunocompromised patients. Ann Pharmacother. 2010;44:929–35.

    Article  PubMed  Google Scholar 

  56. Daenen S, Erjavec Z, Uges DR, et al. Continuous infusion of ceftazidime in febrile neutropenic patients with acute myeloid leukemia. Eur J Clin Microbiol Infect Dis. 1995;14:188–92.

    Article  PubMed  CAS  Google Scholar 

  57. Roberts JA, Paratz J, Paratz E, et al. Continuous infusion of beta-lactam antibiotics in severe infections: a review of its role. Int J Antimicrob Agents. 2007;30:11–8.

    Article  PubMed  CAS  Google Scholar 

  58. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56:236–44.

    Article  PubMed  CAS  Google Scholar 

  59. Piccoli L, Larosa M, Marchetti F. Time-kill curves as a tool for targeting ceftazidime serum concentration during continuous infusion. J Antimicrob Chemother. 2003;52:1047–8.

    Article  PubMed  CAS  Google Scholar 

  60. Alou L, Aguilar L, Sevillano D, et al. Is there a pharmacodynamic need for the use of continuous versus intermittent infusion with ceftazidime against Pseudomonas aeruginosa? An in vitro pharmacodynamic model. J Antimicrob Chemother. 2005;55:209–13.

    Article  PubMed  CAS  Google Scholar 

  61. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44:357–63.

    Article  PubMed  CAS  Google Scholar 

  62. Pea F, Viale P, Damiani D, et al. Ceftazidime in acute myeloid leukemia patients with febrile neutropenia: helpfulness of continuous intravenous infusion in maximizing pharmacodynamic exposure. Antimicrob Agents Chemother. 2005;49:3550–3.

    Article  PubMed  CAS  Google Scholar 

  63. Egerer G, Goldschmidt H, Hensel M, et al. Continuous infusion of ceftazidime for patients with breast cancer and multiple myeloma receiving high-dose chemotherapy and peripheral blood stem cell transplantation. Bone Marrow Transplant. 2002;30:427–31.

    Article  PubMed  CAS  Google Scholar 

  64. Falagas ME, Tansarli GS, Ikawa K, et al. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56:272–82.

    Article  PubMed  CAS  Google Scholar 

  65. Nicolau DP, Nightingale CH, Banevicius MA, et al. Serum bactericidal activity of ceftazidime: continuous infusion versus intermittent injections. Antimicrob Agents Chemother. 1996;40:61–4.

    PubMed  CAS  Google Scholar 

  66. Nyhlen A, Ljungberg B, Nilsson-Ehle I. Pharmacokinetics of meropenem in febrile neutropenic patients. Swedish study group. Eur J Clin Microbiol Infect Dis. 1997;16:797–802.

    Article  PubMed  CAS  Google Scholar 

  67. Drgona L, Paul M, Bucaneve G, Calandra T, Menichetti F. The need for aminoglycosides in combination with b-lactams for high risk, febrile neutropenic patients with leukaemia. EJC 2007;5(suppl):13–22.

    Google Scholar 

  68. Zhanel GG, Craig WA. Pharmacokinetic contributions to postantibiotic effects: focus on aminoglycosides. Clin Pharmacokinet. 1994;27:377–92.

    Article  PubMed  CAS  Google Scholar 

  69. Zelenitsky SA, Harding GK, Sun S, et al. Treatment and outcome of Pseudomonas aeruginosa bacteraemia: an antibiotic pharmacodynamic analysis. J Antimicrob Chemother. 2003;52:668–74.

    Article  PubMed  CAS  Google Scholar 

  70. Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med. 1984;77:657–62.

    Article  PubMed  CAS  Google Scholar 

  71. Craig WA, Redington J, Ebert SC. Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections. J Antimicrob Chemother. 1991;27(Suppl C):29–40.

    Google Scholar 

  72. Hassan E, Ober JD. Predicted and measured aminoglycoside pharmacokinetic parameters in critically ill patients. Antimicrob Agents Chemother. 1987;31:1855–8.

    Article  PubMed  CAS  Google Scholar 

  73. Zeitany RG, El Saghir NS, Santhosh-Kumar CR, et al. Increased aminoglycoside dosage requirements in hematologic malignancy. Antimicrob Agents Chemother. 1990;34:702–8.

    Article  PubMed  CAS  Google Scholar 

  74. Fantin B, Ebert S, Leggett J, et al. Factors affecting duration of in-vivo postantibiotic effect for aminoglycosides against gram-negative bacilli. J Antimicrob Chemother. 1991;27:829–36.

    Article  PubMed  CAS  Google Scholar 

  75. Kapusnik JE, Hackbarth CJ, Chambers HF, et al. Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental Pseudomonas pneumonia. J Infect Dis. 1988;158:7–12.

    Article  PubMed  CAS  Google Scholar 

  76. Darras-Joly C, Bedos JP, Sauve C, et al. Synergy between amoxicillin and gentamicin in combination against a highly penicillin-resistant and -tolerant strain of Streptococcus pneumoniae in a mouse pneumonia model. Antimicrob Agents Chemother. 1996;40:2147–51.

    PubMed  CAS  Google Scholar 

  77. Fantin B, Carbon C. In vivo antibiotic synergism: contribution of animal models. Antimicrob Agents Chemother. 1992;36:907–12.

    Article  PubMed  CAS  Google Scholar 

  78. Higa GM, Murray WE. Alterations in aminoglycoside pharmacokinetics in patients with cancer. Clin Pharm. 1987;6:963–6.

    PubMed  CAS  Google Scholar 

  79. Rozdzinski E, Kern WV, Reichle A, et al. Once-daily versus thrice-daily dosing of netilmicin in combination with beta-lactam antibiotics as empirical therapy for febrile neutropenic patients. J Antimicrob Chemother. 1993;31:585–98.

    Article  PubMed  CAS  Google Scholar 

  80. Smyth AR, Bhatt J. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev. 2012;2:CD002009.

    Google Scholar 

  81. Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43:1549–55.

    PubMed  CAS  Google Scholar 

  82. El Bakri F, Pallett A, Smith AG, et al. Ototoxicity induced by once-daily gentamicin. Lancet. 1998;351:1407–8.

    Article  PubMed  Google Scholar 

  83. Tod MM, Padoin C, Petitjean O. Individualising aminoglycoside dosage regimens after therapeutic drug monitoring: simple or complex pharmacokinetic methods? Clin Pharmacokinet. 2001;40:803–14.

    Article  PubMed  CAS  Google Scholar 

  84. Dager WE. Aminoglycoside pharmacokinetics: volume of distribution in specific adult patient subgroups. Ann Pharmacother. 1994;28:944–51.

    PubMed  CAS  Google Scholar 

  85. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39:650–5.

    Article  PubMed  CAS  Google Scholar 

  86. Sung L, Dupuis LL, Bliss B, et al. Randomized controlled trial of once- versus thrice-daily tobramycin in febrile neutropenic children undergoing stem cell transplantation. J Natl Cancer Inst. 2003;95:1869–77.

    Article  PubMed  CAS  Google Scholar 

  87. Torfoss D, Hoiby EA, Tangen JM, et al. Tobramycin once versus three times daily, given with penicillin G, to febrile neutropenic cancer patients in Norway: a prospective, randomized, multicentre trial. J Antimicrob Chemother. 2007;59:711–7.

    Article  PubMed  CAS  Google Scholar 

  88. Cometta A, Zinner S, de Bock R, et al. Piperacillin-tazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. Antimicrob Agents Chemother. 1995;39:445–52.

    Article  PubMed  CAS  Google Scholar 

  89. Levison ME. Pharmacodynamics of antimicrobial drugs. Infect Dis Clin North Am. 2004;18:451–65, vii.

  90. Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA. 1998;279:125–9.

    Article  PubMed  CAS  Google Scholar 

  91. Drusano GL, Preston SL, Fowler C, et al. Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia. J Infect Dis. 2004;189:1590–7.

    Article  PubMed  CAS  Google Scholar 

  92. Ambrose PG, Grasela DM, Grasela TH, et al. Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections. Antimicrob Agents Chemother. 2001;45:2793–7.

    Article  PubMed  CAS  Google Scholar 

  93. Forrest A, Nix DE, Ballow CH, et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother. 1993;37:1073–81.

    Article  PubMed  CAS  Google Scholar 

  94. Schlenkhoff D, Dalhoff A, Knopf J, et al. Penetration of ciprofloxacin into human lung tissue following intravenous injection. Infection. 1986;14:299–300.

    Article  PubMed  CAS  Google Scholar 

  95. Roosendaal R, Bakker-Woudenberg IA, van den Berghe-van Raffe M, et al. Comparative activities of ciprofloxacin and ceftazidime against Klebsiella pneumoniae in vitro and in experimental pneumonia in leukopenic rats. Antimicrob Agents Chemother. 1987;31:1809–15.

    Article  PubMed  CAS  Google Scholar 

  96. Shapiro MA, Dever JA, Sesnie JC, et al. Comparative therapeutic efficacy of clinafloxacin in leucopenic mice. J Antimicrob Chemother. 1997;39:273–6.

    Article  PubMed  CAS  Google Scholar 

  97. Gordin FM, Hackbarth CJ, Scott KG, et al. Activities of pefloxacin and ciprofloxacin in experimentally induced Pseudomonas pneumonia in neutropenic guinea pigs. Antimicrob Agents Chemother. 1985;27:452–4.

    Article  PubMed  CAS  Google Scholar 

  98. Rusnak MG, Drake TA, Hackbarth CJ, et al. Single versus combination antibiotic therapy for pneumonia due to Pseudomonas aeruginosa in neutropenic guinea pigs. J Infect Dis. 1984;149:980–5.

    Article  PubMed  CAS  Google Scholar 

  99. Smith GM, Leyland MJ, Farrell ID, et al. Preliminary evaluation of ciprofloxacin, a new 4-quinolone antibiotic, in the treatment of febrile neutropenic patients. J Antimicrob Chemother. 1986;18(Suppl D):165–74.

    Google Scholar 

  100. Johnson PR, Yin JA, Tooth JA. High dose intravenous ciprofloxacin in febrile neutropenic patients. J Antimicrob Chemother. 1990;26(Suppl F):101–7.

    Google Scholar 

  101. Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353:977–87.

    Article  PubMed  CAS  Google Scholar 

  102. Fantin B, Duval X, Massias L, et al. Ciprofloxacin dosage and emergence of resistance in human commensal bacteria. J Infect Dis. 2009;200:390–8.

    Article  PubMed  CAS  Google Scholar 

  103. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49:325–7.

    Article  PubMed  Google Scholar 

  104. Sakoulas G, Moise-Broder PA, Schentag J, et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol. 2004;42:2398–402.

    Article  PubMed  CAS  Google Scholar 

  105. Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43:925–42.

    Article  PubMed  CAS  Google Scholar 

  106. Kullar R, Davis SL, Levine DP, et al. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis. 2011;52:975–81.

    Article  PubMed  CAS  Google Scholar 

  107. Torney HL, Balistreri FJ, Kenny MT, et al. Comparative therapeutic efficacy of teicoplanin and vancomycin in normal and in neutropenic mice infected with Staphylococcus haemolyticus. J Antimicrob Chemother. 1991;28:261–9.

    Article  PubMed  CAS  Google Scholar 

  108. Candiani G, Abbondi M, Borgonovi M, et al. Experimental lobar pneumonia due to penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae in immunocompetent and neutropenic rats: efficacy of penicillin and teicoplanin treatment. J Antimicrob Chemother. 1997;39:199–207.

    Article  PubMed  CAS  Google Scholar 

  109. Fernandez de Gatta MM, Fruns I, Hernandez JM, et al. Vancomycin pharmacokinetics and dosage requirements in hematologic malignancies. Clin Pharm. 1993;12:515–20.

    Google Scholar 

  110. Chang D, Liem L, Malogolowkin M. A prospective study of vancomycin pharmacokinetics and dosage requirements in pediatric cancer patients. Pediatr Infect Dis J. 1994;13:969–74.

    Article  PubMed  CAS  Google Scholar 

  111. Buelga DS, del Mar Fernandez de Gatta M, Herrera EV, et al. Population pharmacokinetic analysis of vancomycin in patients with hematological malignancies. Antimicrob Agents Chemother. 2005;49:4934–41.

    Article  PubMed  CAS  Google Scholar 

  112. Lortholary O, Tod M, Rizzo N, et al. Population pharmacokinetic study of teicoplanin in severely neutropenic patients. Antimicrob Agents Chemother. 1996;40:1242–7.

    PubMed  CAS  Google Scholar 

  113. Hochart C, Berthon C, Corm S, et al. Vancomycin serum concentration during febrile neutropenia in patients with acute myeloid leukemia. Med Mal Infect. 2011;41:652–6.

    Article  PubMed  CAS  Google Scholar 

  114. Roberts JA, Taccone FS, Udy AA, et al. Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother. 2011;55:2704–9.

    Article  PubMed  CAS  Google Scholar 

  115. del Mar Fernandez de Gatta M, Santos Buelga D, Sanchez Navarro A, et al. Vancomycin dosage optimization in patients with malignant haematological disease by pharmacokinetic/pharmacodynamic analysis. Clin Pharmacokinet. 2009;48:273–80.

    Google Scholar 

  116. Pea F, Viale P, Candoni A, et al. Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population benefiting from higher dosages. Clin Pharmacokinet. 2004;43:405–15.

    Article  PubMed  CAS  Google Scholar 

  117. Wysocki M, Delatour F, Faurisson F, et al. Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother. 2001;45:2460–7.

    Article  PubMed  CAS  Google Scholar 

  118. James JK, Palmer SM, Levine DP, et al. Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented gram-positive infections. Antimicrob Agents Chemother. 1996;40:696–700.

    PubMed  CAS  Google Scholar 

  119. Kasiakou SK, Sermaides GJ, Michalopoulos A, et al. Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials. Lancet Infect Dis. 2005;5:581–9.

    Article  PubMed  CAS  Google Scholar 

  120. Jaksic B, Martinelli G, Perez-Oteyza J, et al. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis. 2006;42:597–607.

    Article  PubMed  CAS  Google Scholar 

  121. Smith PF, Birmingham MC, Noskin GA, et al. Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia. Ann Oncol. 2003;14:795–801.

    Article  PubMed  CAS  Google Scholar 

  122. Andes D, van Ogtrop ML, Peng J, et al. In vivo pharmacodynamics of a new oxazolidinone (linezolid). Antimicrob Agents Chemother. 2002;46:3484–9.

    Article  PubMed  CAS  Google Scholar 

  123. Rayner CR, Forrest A, Meagher AK, et al. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin Pharmacokinet. 2003;42:1411–23.

    Article  PubMed  CAS  Google Scholar 

  124. Lepak AJ, Marchillo K, Pichereau S, et al. Comparative pharmacodynamics of the new oxazolidinone tedizolid phosphate and linezolid in a neutropenic murine Staphylococcus aureus pneumonia model. Antimicrob Agents Chemother. 2012;56:5916–22.

    Article  PubMed  CAS  Google Scholar 

  125. Kollef MH. Limitations of vancomycin in the management of resistant staphylococcal infections. Clin Infect Dis. 2007;45(Suppl 3):S191–5.

    Article  PubMed  CAS  Google Scholar 

  126. Sader HS, Fey PD, Limaye AP, et al. Evaluation of vancomycin and daptomycin potency trends (MIC creep) against methicillin-resistant Staphylococcus aureus isolates collected in nine U.S. medical centers from 2002 to 2006. Antimicrob Agents Chemother. 2009;53:4127–32.

    Google Scholar 

  127. Safdar N, Andes D, Craig WA. In vivo pharmacodynamic activity of daptomycin. Antimicrob Agents Chemother. 2004;48:63–8.

    Article  PubMed  CAS  Google Scholar 

  128. Bearden DT. Clinical pharmacokinetics of quinupristin/dalfopristin. Clin Pharmacokinet. 2004;43:239–52.

    Article  PubMed  CAS  Google Scholar 

  129. Raad I, Hachem R, Hanna H, et al. Treatment of vancomycin-resistant enterococcal infections in the immunocompromised host: quinupristin–dalfopristin in combination with minocycline. Antimicrob Agents Chemother. 2001;45:3202–4.

    Article  PubMed  CAS  Google Scholar 

  130. Bubalo JS, Munar MY, Cherala G, et al. Daptomycin pharmacokinetics in adult oncology patients with neutropenic fever. Antimicrob Agents Chemother. 2009;53:428–34.

    Article  PubMed  CAS  Google Scholar 

  131. Rolston KV. Review: daptomycin for the treatment of gram-positive infections in neutropenic cancer patients. Clin Adv Hematol Oncol. 2008;6:815–7.

    PubMed  Google Scholar 

  132. Fish DN, Choi MK, Jung R. Synergic activity of cephalosporins plus fluoroquinolones against Pseudomonas aeruginosa with resistance to one or both drugs. J Antimicrob Chemother. 2002;50:1045–9.

    Article  PubMed  CAS  Google Scholar 

  133. Urena MT, Barasoain I, Espinosa M, et al. Evaluation of different antibiotic actions combined with rifampicin. In vitro synergism against Pseudomonas and Proteus. Chemotherapy. 1975;21:82–9.

    Article  PubMed  CAS  Google Scholar 

  134. Slavik RS, Jewesson PJ. Selecting antibacterials for outpatient parenteral antimicrobial therapy: pharmacokinetic–pharmacodynamic considerations. Clin Pharmacokinet. 2003;42:793–817.

    Article  PubMed  CAS  Google Scholar 

  135. Mandell LA, Bergeron MG, Gribble MJ, et al. Sequential antibiotic therapy: effective cost management and patient care. Can J Infect Dis. 1995;6:306–15.

    PubMed  CAS  Google Scholar 

  136. de Lalla F. Outpatient therapy for febrile neutropenia: clinical and economic implications. Pharmacoeconomics. 2003;21:397–413.

    Article  PubMed  Google Scholar 

  137. Innes HE, Smith DB, O’Reilly SM, et al. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: a prospective randomised controlled single centre study. Br J Cancer. 2003;89:43–9.

    Article  PubMed  CAS  Google Scholar 

  138. Vidal L, Paul M, Ben dor I, et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematic review and meta-analysis of randomized trials. J Antimicrob Chemother. 2004;54:29–37.

    Article  PubMed  CAS  Google Scholar 

  139. Gee T, Ellis R, Marshall G, et al. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother. 2001;45:1843–6.

    Article  PubMed  CAS  Google Scholar 

  140. Fantin B, Pangon B, Potel G, et al. Ceftriaxone–netilmicin combination in single-daily-dose treatment of experimental Escherichia coli endocarditis. Antimicrob Agents Chemother. 1989;33:767–70.

    Article  PubMed  CAS  Google Scholar 

  141. Maller R, Isaksson B, Nilsson L, et al. A study of amikacin given once versus twice daily in serious infections. J Antimicrob Chemother. 1988;22:75–9.

    Article  PubMed  CAS  Google Scholar 

  142. Potel G, Chau NP, Pangon B, et al. Single daily dosing of antibiotics: importance of in vitro killing rate, serum half-life, and protein binding. Antimicrob Agents Chemother. 1991;35:2085–90.

    Article  PubMed  CAS  Google Scholar 

  143. Verbist L, Tjandramaga B, Hendrickx B, et al. In vitro activity and human pharmacokinetics of teicoplanin. Antimicrob Agents Chemother. 1984;26:881–6.

    Article  PubMed  CAS  Google Scholar 

  144. Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. J Antimicrob Chemother. 2003;52:331–44.

    Article  PubMed  CAS  Google Scholar 

  145. Vinks AA, Brimicombe RW, Heijerman HG, et al. Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics. J Antimicrob Chemother. 1997;40:125–33.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

No sources of funding were used to assist in the preparation of this review. Tiphaine Goulenok and Bruno Fantin have no conflicts of interest that are directly relevant to the content of this review.

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  1. Internal Medicine Department, Beaujon Hospital, APHP and University Paris Diderot, Sorbonne Paris Cité, Paris, France

    Tiphaine Goulenok & Bruno Fantin

  2. Service de Médecine Interne, Hôpital Beaujon, 100 boulevard du general Leclerc, 92110, Clichy, France

    Bruno Fantin

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  1. Tiphaine Goulenok
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Goulenok, T., Fantin, B. Antimicrobial Treatment of Febrile Neutropenia: Pharmacokinetic–Pharmacodynamic Considerations. Clin Pharmacokinet 52, 869–883 (2013). https://doi.org/10.1007/s40262-013-0086-1

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