Therapeutic drug monitoring of anti-infective agents in critically ill patients

Expert Review of Clinical Pharmacology

Volumn 9, Issue 7, 2016, Pages 961-979

  Jager, Nynke G L ^a   van Hest, Reinier M ^a   Lipman, Jeffrey ^b,c   Taccone, Fabio S ^d   Roberts, Jason A ^b,c  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

^b UNIVERSITY OF QUEENSLAND   (Australia)

^c ROYAL BRISBANE AND WOMEN'S HOSPITAL   (Australia)

^d ERASME HOSPITAL   (Belgium)

Author keywords

Anti infectives; Antibiotics; Antifungals; Antivirals; Critically ill; Intensive care; Pharmacokinetic; Therapeutic drug monitoring

Indexed keywords

ACICLOVIR; AMIKACIN; AMINOGLYCOSIDE; ANTIINFECTIVE AGENT; BETA LACTAM ANTIBIOTIC; COLISTIN; DAPTOMYCIN; FLUCONAZOLE; FLUCYTOSINE; GANCICLOVIR; GENTAMICIN; ITRACONAZOLE; LINEZOLID; OSELTAMIVIR; POLYPEPTIDE ANTIBIOTIC AGENT; POSACONAZOLE; QUINOLONE DERIVATIVE; TOBRAMYCIN; VALGANCICLOVIR; VANCOMYCIN; VORICONAZOLE;

ANTIMICROBIAL THERAPY; AREA UNDER THE CURVE; CRITICALLY ILL PATIENT; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG MONITORING; DRUG PROTEIN BINDING; HUMAN; KIDNEY FUNCTION; MINIMUM INHIBITORY CONCENTRATION; RENAL CLEARANCE; REVIEW; TREATMENT OUTCOME; VOLUME OF DISTRIBUTION; ANIMAL; CRITICAL ILLNESS; INFECTION; MICROBIOLOGY; PROCEDURES;

ANIMALS; ANTI-INFECTIVE AGENTS; CRITICAL ILLNESS; DRUG MONITORING; HUMANS; INFECTION; TREATMENT OUTCOME;

EID: 84963511132     PISSN: 17512433     EISSN: 17512441     Source Type: Journal    
DOI: 10.1586/17512433.2016.1172209     Document Type: Review

References (223)

1. J.Vincent, J.Rello, J.Marshall, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–2329.
2. T.Lagu, M.B.Rothberg, M.-S.Shieh, et al. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40(3):754–761.
3. D.A.Harrison, C.A.Welch, J.M.Eddleston The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care. 2006;10(2):R42.
4. J.Stoller, L.Halpin, M.Weis, et al. Epidemiology of severe sepsis: 2008–2012. J Crit Care. 2016;31(1):58–62.
5. M.H.Kollef, G.Sherman, S.Ward, et al. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115(2):462–474.
6. R.D.MacArthur, M.Miller, T.Albertson, et al. Adequacy of early empiric antibiotic treatment and survival in severe sepsis: experience from the MONARCS trial. Clin Infect Dis. 2004;38(2):284–288.
7. A.Kumar, D.Roberts, K.Wood, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–1596.
8. F.Pea, P.Viale. Bench-to-bedside review: appropriate antibiotic therapy in severe sepsis and septic shock--does the dose matter? Crit Care. 2009;13(3):214.
9. J.M.Varghese, J.A.Roberts, J.Lipman. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin. 2011;27(1):19–34.
10. B.M.Power, A.M.Forbes, P.V.van Heerden, et al. Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet. 1998;34(1):25–56.
11. W.Lee, A.Slutsky. Sepsis and endothelial permeability. N Engl J Med. 2010;363(689):691.
12. J.M.O’BrienJr, N.A.Ali, S.K.Aberegg, et al. Sepsis. Am J Med. 2007;120(12):1012–1022.
13. J.M.Conil, B.Georges, M.Lavit, et al. A population pharmacokinetic approach to ceftazidime use in burn patients: influence of glomerular filtration, gender and mechanical ventilation. Br J Clin Pharmacol. 2007;64(1):27–35.
14. F.Pea. Plasma pharmacokinetics of antimicrobial agents in critically ill patients. Curr Clin Pharmacol. 2013;8(1):5–12.
15. SAFE Study Investigators, S.Finfer, R.Bellomo, et al. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ. 2006;333(7577):1044.
16. G.Wong, S.Briscoe, S.Adnan, et al. Protein binding of Beta-lactam antibiotics in critically Ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother. 2013;57(12):6165–6170.
17. O.Fuster-Lluch, M.Gerónimo-Pardo, R.Peyró-García, et al. Glomerular hyperfiltration and albuminuria in critically ill patients. Anaesth Intensive Care. 2008;36(5):674–680.
18. A.L.Hobbs, K.M.Shea, K.M.Roberts, et al. Implications of augmented renal clearance on drug dosing in critically ill patients: a focus on antibiotics. Pharmacotherapy. 2015;35(11):1063–1075.
19. A.A.Udy, J.P.Baptista, N.L.Lim, et al. Augmented renal clearance in the ICU. Crit Care Med. 2014;42(3):520–527.
20. R.A.Cherry, S.R.Eachempati, L.Hydo, et al. Accuracy of short-duration creatinine clearance determinations in predicting 24-hour creatinine clearance in critically ill and injured patients. J Trauma. 2002;53(2):267–271.
21. J.M.Conil, B.Georges, O.Fourcade, et al. Assessment of renal function in clinical practice at the bedside of burn patients. Br J Clin Pharmacol. 2007;63(5):583–594.
22. A.Udy, R.Boots, S.Senthuran, et al. Augmented creatinine clearance in traumatic brain injury. Anesth Analg. 2010;111(6):1505–1510.
23. J.E.Parrillo, M.M.Parker, C.Natanson, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990;113(3):227–242.
24. D.S.McKindley, S.Hanes, B.A.Boucher. Hepatic drug metabolism in critical illness. Pharmacotherapy. 1998;18(4):759–778.
25. M.Ulldemolins, J.A.Roberts, J.Lipman, et al. Antibiotic dosing in multiple organ dysfunction syndrome. Chest J. 2011;139(5):1210–1220.
26. O.Lheureux, E.Trepo, M.Hites, et al. Serum β-lactam concentrations in critically ill patients with cirrhosis: a matched case-control study. Liver Int. 2015 Dec 8. doi:10.1111/liv.13039.
27. W.-T.Wong, G.Choi, C.D.Gomersall, et al. To increase or decrease dosage of antimicrobials in septic patients during continuous renal replacement therapy: the eternal doubt. Curr Opin Pharmacol. 2015;24:68–78.
28. F.Pea, P.Viale, F.Pavan, et al. Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet. 2007;46(12):997–1038.
29. G.Choi, C.D.Gomersall, Q.Tian, et al. Principles of antibacterial dosing in continuous renal replacement therapy. Blood Purif. 2010;30(3):195–212.
30. N.M.Mehta, D.R.Halwick, B.L.Dodson, et al. Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment. Intensive Care Med. 2007;33(6):1018–1024.
31. E.D.Wildschut, M.J.Ahsman, K.Allegaert, et al. Determinants of drug absorption in different ECMO circuits. Intensive Care Med. 2010;36(12):2109–2116.
32. J.-A.Jamal, C.J.P.Economou, J.Lipman, et al. Improving antibiotic dosing in special situations in the ICU. Curr Opin Crit Care. 2012;18(5):460–471.
33. P.R.Rhomberg, T.R.Fritsche, H.S.Sader, et al. Antimicrobial susceptibility pattern comparisons among intensive care unit and general ward Gram-negative isolates from the Meropenem Yearly Susceptibility Test Information Collection Program (USA). Diagn Microbiol Infect Dis. 2006;56(1):57–62.
34. M.N.Samtani, R.Flamm, K.Kaniga, et al. Pharmacokinetic-pharmacodynamic-model-guided doripenem dosing in critically ill patients. Antimicrob Agents Chemother. 2010;54(6):2360–2364.
35. A.Wolfensberger, H.Sax, R.Weber, et al. Change of antibiotic susceptibility testing guidelines from CLSI to EUCAST: influence on cumulative hospital antibiograms. PLoS One. 2013;8(11):1–8.
36. H.Ensom, G.A.Davis, C.D.Cropp, et al. Clinical pharmacokinetics in the 21st century. Clin Pharmacokinet. 1998;34(4):265–279.• A paper describing how to provide rational, selective therapeutic drug monitoring.
37. I.K.Delattre, F.T.Musuamba, J.Nyberg, et al. Population pharmacokinetic modeling and optimal sampling strategy for Bayesian estimation of amikacin exposure in critically ill septic patients. Ther Drug Monit. 2010;32(6):749–756.
38. J.-M.Conil, B.Georges, S.Ruiz, et al. Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations. Br J Clin Pharmacol. 2011;71(1):61–71.
39. F.S.Taccone, P.-F.Laterre, H.Spapen, et al. Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit Care. 2010;14(2):R53.
40. N.Petejova, J.Zahalkova, J.Duricova, et al. Gentamicin pharmacokinetics during continuous venovenous hemofiltration in critically ill septic patients. J Chemother. 2012;24(2):107–112.
41. J.A.Roberts, J.Field, A.Visser, et al. Using population pharmacokinetics to determine gentamicin dosing during extended daily diafiltration in critically ill patients with acute kidney injury. Antimicrob Agents Chemother. 2010;54(9):3635–3640.
42. L.M.van de Vijsel, S.A.N.Walker, S.E.Walker, et al. Initial vancomycin dosing recommendations for critically ill patients undergoing continuous venovenous hemodialysis. Can J Hosp Pharm. 2010;63(3):196–206.
43. D.Roberts, J.Roberts, M.Roberts, et al. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. Crit Care Med. 2012;40(5):1523–1528.
44. A.Jeurissen, I.Sluyts, R.Rutsaert. A higher dose of vancomycin in continuous infusion is needed in critically ill patients. Int J Antimicrob Agents. 2011;37(1):75–77.
45. J.A.Roberts, V.Stove, J.J.De Waele, et al. Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI study. Int J Antimicrob Agents. 2014;43(5):423–430.
46. F.Pea, E.Di Qual, A.Cusenza, et al. Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia. Clin Pharmacokinet. 2003;42(6):589–598.
47. J.A.Roberts, S.K.Paul, M.Akova, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072–1083.• A prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics, showing that a substantial number of critically ill patients does not reach target drug concentrations using regular dosing schedules, resulting in a less likely positive clinical outcome.
48. J.Gonçalves-Pereira, P.Póvoa. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams. Crit Care. 2011;15(5):R206.
49. C.Roger, L.Muller, S.C.Wallis, et al. Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration. J Antimicrob Chemother. 2016;71(2):464–470.
50. N.A.van Lent-Evers, R.A.Mathôt, W.P.Geus, et al. Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Ther Drug Monit. 1999;21(1):63–73.• A prospective, multicenter study showing that a pharmacy-based, active therapeutic drug monitoring service for aminoglycosides results in higher antibiotic efficacy, shorter hospitalization, and reduced incidence of nephrotoxicity.
51. C.Bartal, A.Danon, F.Schlaeffer, et al. Pharmacokinetic dosing of aminoglycosides: a controlled trial. Am J Med. 2003;114(3):194–198.• A prospective controlled trial showing that individualized pharmacokinetic dosing of aminoglycosides reduces the incidence of nephrotoxicity and allows the use of greater doses of aminoglycosides.
52. D.Streetman, A.Nafziger, C.Destache, et al. Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs. Pharmacotherapy. 2001;21(4):443–451.• Retrospective case-control study that shows that individualized pharmacokinetic monitoring of aminoglycosides significantly decreased the frequency of aminoglycoside-associated nephrotoxicity.
53. N.Markou, S.L.Markantonis, E.Dimitrakis, et al. Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study. Clin Ther. 2008;30(1):143–151.
54. N.D.Karnik, K.Sridharan, S.P.Jadhav, et al. Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection. Eur J Clin Pharmacol. 2013;69(7):1429–1436.
55. M.Zoller, B.Maier, C.Hornuss, et al. Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study. Crit Care. 2014;18(4):R148.
56. S.Luque, S.Grau, F.Alvarez-Lerma, et al. Plasma and cerebrospinal fluid concentrations of linezolid in neurosurgical critically ill patients with proven or suspected central nervous system infections. Int J Antimicrob Agents. 2014;44(5):409–415.
57. S.Swoboda, M.C.Ober, C.Lichtenstern, et al. Pharmacokinetics of linezolid in septic patients with and without extended dialysis. Eur J Clin Pharmacol. 2010;66(3):291–298.
58. C.R.Rayner, A.Forrest, A.K.Meagher, et al. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin Pharmacokinet. 2003;42(15):1411–1423.
59. H.Dong, X.Wang, Y.Dong, et al. Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill Intensive Care Unit patients. Int J Antimicrob Agents. 2011;38(4):296–300.
60. C.Reiber, O.Senn, D.Muller, et al. Therapeutic drug monitoring of daptomycin: a retrospective monocentric analysis. Ther Drug Monit. 2015;37(5):634–640.
61. S.L.Buijk, I.C.Gyssens, J.W.Mouton, et al. Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function. Intensive Care Med. 2001;27(1):115–121.
62. M.G.Sinnollareddy, J.A.Roberts, J.Lipman, et al. Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study. Crit Care. 2015;19(1):33.
63. M.Hagihara, H.Kasai, T.Umemura, et al. Pharmacokinetic-pharmacodynamic study of itraconazole in patients with fungal infections in intensive care units. J Infect Chemother. 2011;17(2):224–230.
64. J.Ray, L.Campbell, S.Rudham, et al. Posaconazole plasma concentrations in critically ill patients. Ther Drug Monit. 2011;33(4):387–392.
65. P.Myrianthefs, S.L.Markantonis, P.Evaggelopoulou, et al. Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study. Int J Antimicrob Agents. 2010;35(5):468–472.
66. J.Radej, A.Krouzecky, P.Stehlik, et al. Pharmacokinetic evaluation of voriconazole treatment in critically ill patients undergoing continuous venovenous hemofiltration. Ther Drug Monit. 2011;33(4):393–397.
67. T.Wang, J.Xie, Y.Wang, et al. Pharmacokinetic and pharmacodynamic properties of oral voriconazole in patients with invasive fungal infections. Pharmacother J Hum Pharmacol Drug Ther. 2015;35(9):797–804.
68. M.A.Kamal, R.Gieschke, A.Lemenuel-Diot, et al. A drug-disease model describing the effect of oseltamivir neuraminidase inhibition on influenza virus progression. Antimicrob Agents Chemother. 2015;59(9):5388–5395.
69. W.Kromdijk, M.A.Sikma, M.P.H.van den Broek, et al. Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique. Intensive Care Med. 2013;39(5):977–978.
70. R.F.Eyler, M.Heung, M.Pleva, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy. 2012;32(12):1061–1069.
71. A.C.Pasqualotto, S.J.Howard, C.B.Moore, et al. Flucytosine therapeutic monitoring: 15 years experience from the UK. J Antimicrob Chemother. 2007;59(4):791–793.
72. M.R.Blum, S.H.Liao, P.de Miranda. Overview of acyclovir pharmacokinetic disposition in adults and children. Am J Med. 1982;73(1A):186–192.
73. T.Horvatits, R.Kitzberger, A.Drolz, et al. Pharmacokinetics of ganciclovir during continuous venovenous hemodiafiltration in critically Ill patients. Antimicrob Agents Chemother. 2014;58:94–101.
74. J.C.Scott, N.Partovi, M.H.H.Ensom. Ganciclovir in solid organ transplant recipients. Ther Drug Monit. 2004;26(1):68–77.
75. R.S.Rea, B.Capitano, R.Bies, et al. Suboptimal aminoglycoside dosing in critically ill patients. Ther Drug Monit. 2008;30(6):674–681.
76. S.Buijk, J.Mouton, I.Gyssens, et al. Experience with a once-daily dosing program of aminoglycosides in critically ill patients. Intensive Care Med. 2002;28(7):936–942.
77. W.Duszynska, F.S.Taccone, M.Hurkacz, et al. Therapeutic drug monitoring of amikacin in septic patients. Crit Care. 2013;17(4):R165.
78. F.Pea, L.Brollo, P.Viale, et al. Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing the importance of a loading dose. J Antimicrob Chemother. 2003;51(4):971–975.
79. R.Bellmann, G.Falkensammer, C.Seger, et al. Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration. Int J Clin Pharmacol Ther. 2010;48(4):243–249.
80. M.Beumier, G.Casu, M.Hites, et al. β-lactam antibiotic concentrations during continuous renal replacement therapy. Crit Care. 2014;18(3):R105.
81. J.Goncalves-Pereira, N.E.Silva, A.Mateus, et al. Assessment of pharmacokinetic changes of meropenem during therapy in septic critically ill patients. BMC Pharmacol Toxicol. 2014;15:21.
82. F.B.Sime, A.A.Udy, J.A.Roberts. Augmented renal clearance in critically ill patients: etiology, definition and implications for beta-lactam dose optimization. Curr Opin Pharmacol. 2015;24:1–6.
83. S.R.Bauer, C.Salem, M.J.Connor, et al. Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT. Clin J Am Soc Nephrol. 2012;7(3):452–457.
84. T.M.Chapuis, E.Giannoni, P.A.Majcherczyk, et al. Prospective monitoring of cefepime in intensive care unit adult patients. Crit Care. 2010;14(2):R51.
85. A.M.Spooner, C.Deegan, D.M.D’Arcy, et al. An evaluation of ciprofloxacin pharmacokinetics in critically ill patients undergoing continuous veno-venous haemodiafiltration. BMC Clin Pharmacol. 2011;11(1):11.
86. F.Pea, D.Poz, P.Viale, et al. Which reliable pharmacodynamic breakpoint should be advised for ciprofloxacin monotherapy in the hospital setting? A TDM-based retrospective perspective. J Antimicrob Chemother. 2006;58(2):380–386.
87. E.Szałek, H.Tomczak, A.Kamińska, et al. Pharmacokinetics and pharmacodynamics of ciprofloxacin in critically ill patients after the first intravenous administration of 400 mg. Adv Med Sci. 2012;57(2):217–223.
88. J.Lipman, J.Scribante, A.G.Gous, et al. Pharmacokinetic profiles of high-dose intravenous ciprofloxacin in severe sepsis. The Baragwanath Ciprofloxacin Study Group. Antimicrob Agents Chemother. 1998;42(9):2235–2239.
89. V.Fuhrmann, P.Schenk, W.Jaeger, et al. Pharmacokinetics of moxifloxacin in patients undergoing continuous venovenous haemodiafiltration. J Antimicrob Chemother. 2004;54(4):780–784.
90. J.-M.Conil, B.Georges, A.de Lussy, et al. Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches. Int J Antimicrob Agents. 2008;32(6):505–510.
91. J.A.Rebuck, D.N.Fish, E.Abraham. Pharmacokinetics of intravenous and oral levofloxacin in critically ill adults in a medical intensive care unit. Pharmacotherapy. 2002;22(10):1216–1225.
92. J.A.Roberts, M.O.Cotta, C.PC, et al. Does critical illness change levofloxacin pharmacokinetics? Antimicrob Agents Chemother. 2015;60(3):1459–1463.
93. T.Whitehouse, J.A.Cepeda, R.Shulman, et al. Pharmacokinetic studies of linezolid and teicoplanin in the critically ill. J Antimicrob Chemother. 2005;55(3):333–340.
94. J.M.Wenisch, B.Meyer, V.Fuhrmann, et al. Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration. J Antimicrob Chemother. 2012;67(4):977–983.
95. A.Vilay, M.Grio, D.DePestel, et al. Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis. Crit Care Med. 2011;39(1):19–25.
96. K.Yagasaki, S.Gando, N.Matsuda, et al. Pharmacokinetics and the most suitable dosing regimen of fluconazole in critically ill patients receiving continuous hemodiafiltration. Intensive Care Med. 2003;29(10):1844–1848.
97. F.Lemaitre, C.-E.Luyt, F.Roullet-Renoleau, et al. Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Ther Drug Monit. 2012;34(2):171–175.
98. M.J.Rybak, B.J.Abate, S.L.Kang, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43(7):1549–1555.
99. E.W.Mueller, B.A.Boucher. The use of extended-interval aminoglycoside dosing strategies for the treatment of moderate-to-severe infections encountered in critically ill surgical patients. Surg Infect (Larchmt). 2009;10(6):563–570.
100. M.Lacy, D.Nicolau, C.Nightingale, et al. The pharmacodynamics of aminoglycosides. Clin Infect Dis. 1998;27:23–27.
101. E.J.Begg, M.L.Barclay, S.B.Duffull. A suggested approach to once-daily aminoglycoside dosing. Br J Clin Pharmacol. 1995;39:605–609.
102. A.D.M.Kashuba, A.N.Nafziger, G.L.Drusano, et al. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43(3):623–629.
103. S.A.Zelenitsky, G.K.M.Harding, S.Sun, et al. Treatment and outcome of Pseudomonas aeruginosa bacteraemia: an antibiotic pharmacodynamic analysis. J Antimicrob Chemother. 2003;52(4):668–674.
104. D.P.Nicolau, C.D.Freeman, P.P.Belliveau, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3):650–655.
105. A.Dasgupta. Advances in antibiotic measurement. Adv Clin Chem. 2012;56:75–104.
106. W.A.Craig. Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am. 2003;17(3):479–501.
107. M.J.Rybak, B.M.Lomaestro, J.C.Rotschafer, et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29(11):1275–1279.
108. S.J.Van Hal, D.L.Paterson, T.P.Lodise. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734–744.
109. Y.Suzuki, K.Kawasaki, Y.Sato, et al. Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin- resistant Staphylococcus aureus pneumonia. Chemotherapy. 2012;58:308–312.
110. T.P.Lodise, N.Patel, B.M.Lomaestro, et al. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis. 2009;49(4):507–514.
111. D.N.Gilbert, C.A.Wood, R.C.Kimbrough, Diseases THEI. Failure of treatment with teicoplanin at 6 milligrams / kilogram / day in patients with staphylococcus aureus intravascular infection. Antimicrob Agents Chemother. 1991;35(1):79–87.
112. E.S.R.Darley, A.P.MacGowan. The use and therapeutic drug monitoring of teicoplanin in the UK. Clin Microbiol Infect. 2004;10(1):62–69.
113. I.Harding, A.P.MacGowan, L.O.White, et al. Teicoplanin therapy for Staphylococcus aureus septicaemia: relationship between pre-dose serum concentrations and outcome. J Antimicrob Chemother. 2000;45(6):835–841.
114. E.J.Begg, M.L.Barclay, C.M.J.Kirkpatrick. The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol. 2001;52:35–43.
115. A.P.R.Wilson. Clinical pharmacokinetics of teicoplanin. Clin Pharmacokinet. 2000;39(3):167–183.
116. P.A.Moise-Broder, A.Forrest, M.C.Birmingham, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925–942.
117. S.Zelenitsky, E.Rubinstein, R.Ariano, et al. Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock. Int J Antimicrob Agents. 2013;41(3):255–260.
118. J.Cheong, M.Makmor-Bakry, C.Lau, et al. The relationship between trough concentration of vancomycin and effect on methicillin-resistant Staphylococcus aureus in critically ill patients. South African Med J. 2012;25(102):616–619.
119. L.K.Hidayat, D.I.Hsu, R.Quist, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166(19):2138–2144.
120. T.P.Hanrahan, C.Kotapati, M.J.Roberts, et al. Factors associated with vancomycin nephrotoxicity in the critically ill. Anaesth Intensive Care. 2015;43(5):594–599.
121. P.R.Ingram, D.C.Lye, P.A.Tambyah, et al. Risk factors for nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic therapy. J Antimicrob Chemother. 2008;62(1):168–171.
122. H.D.Spapen, K.Janssen van Doorn, M.Diltoer, et al. Retrospective evaluation of possible renal toxicity associated with continuous infusion of vancomycin in critically ill patients. Ann Intensive Care. 2011;1(1):26.
123. C.M.Tobin, J.M.Darville, A.H.Thomson, et al. Vancomycin therapeutic drug monitoring: is there a consensus view? The results of a UK National External Quality Assessment Scheme (UK NEQAS) for Antibiotic Assays questionnaire. J Antimicrob Chemother. 2002;50(5):713–718.
124. Z.-K.Ye, H.-L.Tang, S.-D.Zhai. Benefits of therapeutic drug monitoring of vancomycin: a systematic review and meta-analysis. PLoS One. 2013;8(10):e77169.• A review evaluating the available evidence for the necessity of TDM in patients given vancomycin to treat Gram-positive infections, showing that TDM significantly increases the rate of clinical efficacy and decreases the rate of nephrotoxicity in patients treated with vancomycin.
125. M.N.Neely, G.Youn, B.Jones, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother. 2014;58(1):309–316.
126. A.Huttner, S.Harbarth, W.W.Hope, et al. Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother. 2015;70:3178–3183.
127. G.Wong, F.B.Sime, J.Lipman, et al. How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? BMC Infect Dis. 2014;14(1):288.
128. G.Wong, A.Brinkman, R.J.Benefield, et al. An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units. J Antimicrob Chemother. 2014;69(5):1416–1423.
129. R.E.Ariano. Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann Pharmacother. 2004;39(1):32–38.
130. P.S.McKinnon, J.A.Paladino, J.J.Schentag. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31(4):345–351.
131. J.L.Crandon, C.C.Bulik, J.L.Kuti, et al. Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2010;54(3):1111–1116.
132. M.Beumier, G.S.Casu, M.Hites, et al. Elevated β-lactam concentrations associated with neurological deterioration in ICU septic patients. Minerva Anestesiol. 2015;81(5):497–506.
133. M.Carlier, V.Stove, S.C.Wallis, et al. Assays for therapeutic drug monitoring of β-lactam antibiotics: a structured review. Int J Antimicrob Agents. 2015;46:367–375.
134. M.Carlier, M.Noë, J.A.Roberts, et al. Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures. J Antimicrob Chemother. 2014;69(10):2797–2803.
135. A.A.Udy, J.M.Varghese, M.Altukroni, et al. Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest [Internet]. 2012;142(1):30–39. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22194591
136. F.S.Taccone, P.-F.Laterre, T.Dugernier, et al. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126.
137. J.A.Roberts, J.Lipman. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840–851.
138. C.-H.Gao, L.-S.Yu, S.Zeng, et al. Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns. Ther Clin Risk Manag. 2014;10:217–227.
139. A.Forrest, D.E.Nix, C.H.Ballow, et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother. 1993;37(5):1073–1081.
140. S.A.Zelenitsky, R.E.Ariano. Support for higher ciprofloxacin AUC24/MIC targets in treating Enterobacteriaceae bloodstream infection. J Antimicrob Chemother. 2010;65(8):1725–1732.
141. J.K.Thomas, A.Forrest, S.M.Bhavnani, et al. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob Agents Chemother. 1998;42(3):521–527.
142. F.Scaglione, L.Paraboni. Influence of pharmacokinetics/pharmacodynamics of antibacterials in their dosing regimen selection. Expert Rev Anti Infect Ther. 2006;4(3):479–490.
143. S.Preston, G.L.Drusano, A.Berman, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA. 1998;279(2):125–129.
144. R.V.Dudhani, J.D.Turnidge, R.L.Nation, et al. fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection models. J Antimicrob Chemother. 2010;65(9):1984–1990.
145. R.V.Dudhani, J.D.Turnidge, K.Coulthard, et al. Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother. 2010;54(3):1117–1124.
146. L.Sorlí, S.Luque, S.Grau, et al. Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. BMC Infect Dis. 2013;13(1):380.
147. P.J.Bergen, J.B.Bulitta, A.Forrest, et al. Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model. Antimicrob Agents Chemother. 2010;54(9):3783–3789.
148. S.Biswas, J.-M.Brunel, J.-C.Dubus, et al. Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther. 2012;10(8):917–934.
149. S.M.Garonzik, J.Li, V.Thamlikitkul, et al. 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(7):3284–3294.
150. H.-Y.Dong, J.Xie, L.-H.Chen, et al. Therapeutic drug monitoring and receiver operating characteristic curve prediction may reduce the development of linezolid-associated thrombocytopenia in critically ill patients. Eur J Clin Microbiol Infect Dis. 2014;33(6):1029–1035.
151. F.Pea, P.Viale, P.Cojutti, et al. Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. J Antimicrob Chemother. 2012;67(8):2034–2042.
152. N.Safdar, D.Andes, W.A.Craig. In vivo pharmacodynamic activity of daptomycin. Antimicrob Agents Chemother. 2004;48(1):63–68.
153. K.Vance-Bryan, T.A.Larson, J.C.Rotschafer, et al. Investigation of the early killing of Staphylococcus aureus by daptomycin by using an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 1992;36(10):2334–2337.
154. P.K.Dandekar, P.R.Tessier, P.Williams, et al. Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model. J Antimicrob Chemother. 2003;52(3):405–411.
155. M.Falcone, A.Russo, M.I.Cassetta, et al. Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? J Infect Chemother. 2013;19(4):732–739.
156. A.A.Firsov, M.V.Smirnova, I.Y.Lubenko, et al. Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model. J Antimicrob Chemother. 2006;58(6):1185–1192.
157. S.M.Bhavnani, C.M.Rubino, P.G.Ambrose, et al. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis. 2010;50(12):1568–1574.
158. J.Martens-Lobenhoffer, J.T.Kielstein, C.Oye, et al. Validated high performance liquid chromatography-UV detection method for the determination of daptomycin in human plasma. J Chromatogr B Anal Technol Biomed Life Sci. 2008;875(2):546–550.
159. M.Grégoire, A.G.Leroy, R.Bouquié, et al. Simultaneous determination of ceftaroline, daptomycin, linezolid and rifampicin concentrations in human plasma by on-line solid phase extraction coupled to high-performance liquid chromatography–tandem mass spectrometry. J Pharm Biomed Anal. 2016;118:17–26.
160. F.Bazoti, E.Gikas, A.Skoutelis, et al. Development and validation of an ultra performance liquid chromatography–tandem mass spectrometry method for the quantification of daptomycin in human plasma. J Pharm Biomed Anal. 2011;56:78–85.
161. J.T.Kielstein, C.Eugbers, S.M.Bode-Boeger, et al. Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing extended dialysis-a pharmacokinetic study. Nephrol Dial Transplant. 2010;25(5):1537–1541.
162. A.Louie, G.L.Drusano, P.Banerjee, et al. Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother. 1998;42(5):1105–1109.
163. D.Andes, M.Van Ogtrop. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother. 1999;43(9):2116–2120.
164. J.W.Baddley, M.Patel, S.M.Bhavnani, et al. Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother. 2009;53(6):2704–2706.
165. M.P.Pai, R.S.Turpin, K.W.Garey. Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother. 2007;51(1):35–39.
166. European Committee for Antimicrobial Susceptibility and Testing (EUCAST). Fluconazole Rationale for the EUCAST clinical breakpoints, version 2.0. Available from: www.eucast.org
167. L.A.Decosterd, B.Rochat, B.Pesse, et al. Multiplex ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification in human plasma of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, anidulafungin, and caspo. Antimicrob Agents Chemother. 2010;54(12):5303–5315.
168. V.J.C.Lempers, J.W.C.Alffenaar, D.J.Touw, et al. Five year results of an international proficiency testing programme for measurement of antifungal drug concentrations. J Antimicrob Chemother. 2014;69(11):2988–2994.• A report showing that one out of five antifungal drug measurements is inaccurate, where the performing laboratory is the main determinant of inaccuracy, suggesting that internal quality assurance is pivotal in preventing inaccuracies, irrespective of the antifungal drug measured, concentration, and analytical equipment.
169. M.Sinnollareddy, S.L.Peake, M.S.Roberts, et al. Pharmacokinetic evaluation of fluconazole in critically ill patients. Expert Opin Drug Metab Toxicol. 2011;7(11):1431–1440.
170. E.K.Manavathu, J.L.Cutright, P.H.Chandrasekar. Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother. 1998;42(11):3018–3021.
171. D.S.Burgess, R.W.Hastings. A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time-kill methodology. Diagn Microbiol Infect Dis. 2000;38(2):87–93.
172. J.Berenguer, N.M.Ali, M.C.Allende, et al. Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma. Antimicrob Agents Chemother. 1994;38(6):1303–1308.
173. A.Glasmacher, C.Hahn, C.Leutner. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses. 1999;42:443–451.
174. M.A.Boogaerts, G.E.Verhoef, P.Zachee, et al. Antifungal prophylaxis with itraconazole in prolonged neutropenia: correlation with plasma levels. Mycoses. 1989;32 Suppl 1:103–108.
175. C.P.W.G.M.V.Wissen, D.M.Burger, P.E.Verweij, et al. Simultaneous determination of the azoles voriconazole, posaconazole, isavuconazole, itraconazole and its metabolite hydroxy-itraconazole in human plasma by reversed phase ultra-performance liquid chromatography with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;887–888:79–84.
176. J.S.Hostetler, J.Heykants, K.V.Clemons, et al. Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: studies of interpatient variations in concentrations. Antimicrob Agents Chemother. 1993;37(10):2224–2227.
177. R.Bellmann. Pharmacodynamics and pharmacokinetics of antifungals for treatment of invasive aspergillosis. Curr Pharm Des. 2013;19(20):3629–3647.
178. S.H.Jang, P.M.Colangelo, J.V.S.Gobburu. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther [Internet]. 2010;88(1):115–119. doi:10.1038/clpt.2010.64.
179. D.Lebeaux, F.Lanternier, C.Elie, et al. Therapeutic drug monitoring of posaconazole: a monocentric study with 54 adults. Antimicrob Agents Chemother. 2009;53(12):5224–5229.
180. A.M.Bryant, D.Slain, A.Cumpston, et al. A post-marketing evaluation of posaconazole plasma concentrations in neutropenic patients with haematological malignancy receiving posaconazole prophylaxis. Int J Antimicrob Agents. 2011;37(3):266–269.
181. M.Hoenigl, R.B.Raggam, H.J.F.Salzer, et al. Posaconazole plasma concentrations and invasive mould infections in patients with haematological malignancies. Int J Antimicrob Agents. 2012;39(6):510–513.
182. C.Cattaneo, A.Panzali, A.Passi, et al. Serum posaconazole levels during acute myeloid leukaemia induction therapy: correlations with breakthrough invasive fungal infections. Mycoses. 2015;58:362–367.
183. T.J.Walsh, I.Raad, T.F.Patterson, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44(1):2–12.
184. S.Trifilio, S.Singhal, S.Williams, et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant. 2007;40(5):451–456.
185. M.J.Dolton, J.E.Ray, S.C.-A.Chen, et al. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother [Internet]. 2012;56(9):4793–4799. doi:10.1128/AAC.00626-12.
186. J.Smith, N.Safdar, V.Knasinski, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother. 2006;50(4):1570–1572.
187. K.Ueda, Y.Nannya, K.Kumano, et al. Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders. Int J Hematol. 2009;89(5):592–599.
188. Y.-J.Lee, S.-O.Lee, S.-H.Choi, et al. Initial voriconazole trough blood levels and clinical outcomes of invasive aspergillosis in patients with hematologic malignancies. Med Mycol. 2013;51(3):324–330.
189. A.Pascual, T.Calandra, S.Bolay, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201–211.
190. A.Pascual, C.Csajka, T.Buclin, et al. Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections. Clin Infect Dis. 2012;55(3):381–390.
191. P.Soler-Palacin, M.A.Frick, A.Martin-Nalda, et al. Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study. J Antimicrob Chemother. 2012;67(3):700–706.
192. P.F.Troke, H.P.Hockey, W.W.Hope. Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients. Antimicrob Agents Chemother. 2011;55(10):4782–4788.
193. V.Fuhrmann, P.Schenk, W.Jaeger, et al. Pharmacokinetics of voriconazole during continuous venovenous haemodiafiltration. J Antimicrob Chemother. 2007;60(5):1085–1090.
194. W.B.Park, N.-H.Kim, K.-H.Kim, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis. 2012;55(8):1080–1087.• A randomized controlled trial demonstrating the added value of TDM during voriconazole treatment by showing a more favorable response in the TDM-group, compared to the non-TDM group.
195. M.A.Pfaller, D.J.Diekema, L.Ostrosky-Zeichner, et al. Correlation of MIC with outcome for candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J Clin Microbiol. 2008;46(8):2620–2629.
196. T.Yamada, Y.Mino, Y.Yagi, et al. Saturated metabolism of voriconazole N-oxidation resulting in nonlinearity of pharmacokinetics of voriconazole at clinical doses. Biol Pharm Bull [Internet]. 2015;38(10):1496–1503. Available from:: https://www.jstage.jst.go.jp/article/bpb/38/10/38_b15-00241/_pdf
197. D.Andes, M.van Ogtrop. In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Antimicrob Agents Chemother. 2000;44(4):938–942.
198. A.Vermes, H.van Der Sijs, H.J.Guchelaar. Flucytosine: correlation between toxicity and pharmacokinetic parameters. Chemotherapy. 2000;46(2):86–94.
199. A.M.Stamm, R.B.Diasio, W.E.Dismukes, et al. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med. 1987;83(2):236–242.
200. C.A.Kauffman, P.T.Frame. Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents Chemother. 1977;11(2):244–247.
201. S.Normark, J.Schonebeck. In vitro studies of 5-fluorocytosine resistance in Candida albicans and Torulopsis glabrata. Antimicrob Agents Chemother. 1972;2(3):114–121.
202. J.E.Bennett, W.E.Dismukes, R.J.Duma, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med. 1979;301(3):126–131.
203. M.I.Goodwin, R.H.Drew. Antifungal serum concentration monitoring: an update. J Antimicrob Chemother. 2007;61(1):17–25.
204. A.Vermes, R.A.A.Math, I.H.van der Sijs, et al. Population pharmacokinetics of flucytosine: comparison and validation of three models using STS, NPEM, and NONMEM. Ther Drug Monit. 2000;22(6):676–687.
205. M.A.Chowdhury, N.Derar, S.Hasan, et al. Acyclovir-induced neurotoxicity: a case report and review of literature. Am J Ther. 2014;1.
206. B.Bean, D.Aeppli. Adverse effects of high-dose intravenous acyclovir in ambulatory patients with acute herpes. Source J Infect Dis. 1985;151(2):362–365.
207. W.E.Haefeli, R.A.Z.Schoenenberger, P.Weiss, et al. Acyclovir-induced neurotoxicity - concentration-side-effect relationship in acyclovir overdose. Am J Med. 1993;94(2):212–215.
208. J.Bradley, N.Forero, H.Pho, et al. Progressive somnolence leading to coma in a 68-year-old man. Chest. 1997;112(2):538–540.
209. M.Yadav, V.Upadhyay, P.Singhal, et al. Stability evaluation and sensitive determination of antiviral drug, valacyclovir and its metabolite acyclovir in human plasma by a rapid liquid chromatography-tandem mass spectrometry method. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(8–9):680–688.
210. H.Wiltshire, C.V.Paya, M.D.Pescovitz, et al. Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients. Transplantation. 2005;79(11):1477–1483.
211. J.A.Fishman, M.T.Doran, S.A.Volpicelli, et al. Dosing of intravenous ganciclovir for the prophylaxis and treatment of cytomegalovirus infection in solid organ transplant recipients. Transplantation [Internet]. 2000;69(3):389–394. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10706048
212. D.W.Kimberlin, E.P.Acosta, P.J.Sánchez, et al. Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis. 2008;197(6):836–845.
213. E.Giménez, C.Solano, J.R.Azanza, et al. Monitoring of trough plasma ganciclovir levels and peripheral blood cytomegalovirus (CMV)-specific CD8+ T cells to predict CMV DNAemia clearance in preemptively treated allogeneic stem cell transplant recipients. Antimicrob Agents Chemother. 2014;58(9):5602–5605.
214. N.Perrottet, C.Csajka, M.Pascual, et al. Population pharmacokinetics of ganciclovir in solid-organ transplant recipients receiving oral valganciclovir. Antimicrob Agents Chemother. 2009;53(7):3017–3023.
215. D.H.Shepp, P.S.Dandliker, P.de Miranda, et al. Activity of 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine in the treatment of cytomegalovirus pneumonia. Ann Intern Med. 1985;103(3):368–373.
216. G.I.Snell, T.C.Kotsimbos, B.J.Levvey, et al. Pharmacokinetic assessment of oral ganciclovir in lung transplant recipients with cystic fibrosis. J Antimicrob Chemother. 2000;45(4):511–516.
217. C.Fletcher, D.Pharm, R.Sawchuk, et al. Human pharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther. 1986;40(3):281–286.
218. J.P.Sommadossi, R.Bevan, T.Ling, et al. Clinical pharmacokinetics of ganciclovir in patients with normal and impaired renal function. Rev Infect Dis. 1988;10 Suppl 3(3):S507–14.
219. J.J.McSharry, Q.Weng, A.Brown, et al. Prediction of the pharmacodynamically linked variable of oseltamivir carboxylate for influenza A virus using an in vitro hollow-fiber infection model system. Antimicrob Agents Chemother. 2009;53(6):2375–2381.
220. C.R.Rayner, C.C.Bulik, M.A.Kamal, et al. Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies. Antimicrob Agents Chemother. 2013;57(8):3478–3487.
221. Y.Wattanagoon, K.Stepniewska, N.Lindegårdh, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother. 2009;53(3):945–952.
222. N.Widmer, P.Meylan, A.Ivanyuk, et al. Oseltamivir in seasonal, avian H5N1 and pandemic 2009 A/H1N1 influenza: pharmacokinetic and pharmacodynamic characteristics. Clin Pharmacokinet. 2010;49(11):741–765.
223. R.E.Ariano, D.S.Sitar, S.A.Zelenitsky, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. Can Med Assoc J. 2010;182(4):357–363.