The effect of pathophysiology on pharmacokinetics in the critically ill patient - Concepts appraised by the example of antimicrobial agents

Advanced Drug Delivery Reviews

Volumn 77, Issue , 2014, Pages 3-11

  Blot, Stijn I ^a,d   Pea, Federico ^b,c   Lipman, Jeffrey ^d,e  

^a GHENT UNIVERSITY   (Belgium)

^b Azienda Ospedaliero Universitaria Santa Maria della Misericordia   (Italy)

^c UNIVERSITY OF UDINE   (Italy)

^d UNIVERSITY OF QUEENSLAND   (Australia)

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

Author keywords

Acute kidney injury; Antimicrobial agents; Hepatic failure; Intensive care unit; Organ failure; Pharmacodynamics; Pharmacokinetics; Sepsis

Indexed keywords

BIOCHEMISTRY; HYDROPHILICITY; INTENSIVE CARE UNITS; MICROORGANISMS; PATIENT MONITORING; PHARMACODYNAMICS; PHARMACOKINETICS;

ACUTE KIDNEY INJURY; CRITICALLY-ILL PATIENTS; LIFE-THREATENING INFECTIONS; ORGAN FAILURE; PATHOPHYSIOLOGICAL CHANGES; SEPSIS; SYSTEMIC INFLAMMATORY RESPONSE SYNDROMES; THERAPEUTIC DRUG MONITORING;

ANTIMICROBIAL AGENTS;

ANTIINFECTIVE AGENT;

ACUTE KIDNEY FAILURE; ANTIMICROBIAL THERAPY; CRITICALLY ILL PATIENT; DRUG DISTRIBUTION; DRUG PROTEIN BINDING; HUMAN; KIDNEY CLEARANCE; LIVER DYSFUNCTION; MAXIMUM PLASMA CONCENTRATION; PATHOPHYSIOLOGY; PHARMACODYNAMICS; PHYSICAL CHEMISTRY; RENAL REPLACEMENT THERAPY; REVIEW; SEPSIS; CHEMICAL PHENOMENA; CHEMISTRY; CRITICAL ILLNESS; DRUG MONITORING; MULTIPLE ORGAN FAILURE; PROCEDURES; TISSUE DISTRIBUTION;

ACUTE KIDNEY INJURY; ANTI-INFECTIVE AGENTS; CRITICAL ILLNESS; DRUG MONITORING; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; MULTIPLE ORGAN FAILURE; SEPSIS; TISSUE DISTRIBUTION;

EID: 84919463993     PISSN: 0169409X     EISSN: 18728294     Source Type: Journal    
DOI: 10.1016/j.addr.2014.07.006     Document Type: Review

References (101)

1. Smith B.S., Yogaratnam D., Levasseur-Franklin K.E., Forni A., Fong J. Introduction to drug pharmacokinetics in the critically ill patient. Chest 2012, 141:1327-1336.
2. Boucher B.A., Wood G.C., Swanson J.M. Pharmacokinetic changes in critical illness. Crit. Care Clin. 2006, 22:255-271. (vi).
3. Roberts D.J., Hall R.I. Drug absorption, distribution, metabolism and excretion considerations in critically ill adults. Expert. Opin. Drug Metab. Toxicol. 2013, 9:1067-1084.
4. De Paepe P., Belpaire F.M., Buylaert W.A. Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin. Pharmacokinet. 2002, 41:1135-1151.
5. McKindley D.S., Hanes S., Boucher B.A. Hepatic drug metabolism in critical illness. Pharmacotherapy 1998, 18:759-778.
6. Udy A.A., Roberts J.A., Boots R.J., Paterson D.L., Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin. Pharmacokinet. 2010, 49:1-16.
7. Bellomo R., Kellum J.A., Ronco C. Acute kidney injury. Lancet 2012, 380:756-766.
8. Pea F., Pavan F., Furlanut M. Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical care patients. Clin. Pharmacokinet. 2008, 47:449-462.
9. Blot S. Limiting the attributable mortality of nosocomial infection and multidrug resistance in intensive care units. Clin. Microbiol. Infect. 2008, 14:5-13.
10. Vincent J.L., Bihari D.J., Suter P.M., Bruining H.A., White J., Nicolas-Chanoin M.H., Wolff M., Spencer R.C., Hemmer M. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 1995, 274:639-644.
11. Vincent J.L., Rello J., Marshall J., Silva E., Anzueto A., Martin C.D., Moreno R., Lipman J., Gomersall C., Sakr Y., Reinhart K. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009, 302:2323-2329.
12. Vandijck D., Decruyenaere J.M., Blot S.I. The value of sepsis definitions in daily ICU-practice. Acta Clin. Belg. 2006, 61:220-226.
13. Vincent J.L., Abraham E., Annane D., Bernard G., Rivers E., Van den Berghe G. Reducing mortality in sepsis: new directions. Crit. Care 2002, 6(Suppl. 3):S1-S18.
14. Vincent J.L., Moreno R., Takala J., Willatts S., De Mendonca A., Bruining H., Reinhart C.K., Suter P.M., Thijs L.G. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996, 22:707-710.
15. Blot S., Vandewoude K.H., Colardyn F.A. Clinical impact of nosocomial Klebsiella bacteremia in critically ill patients. Eur. J. Clin. Microbiol. Infect. Dis. 2002, 21:471-473.
16. Blot S., Vandewoude K.H., Colardyn F.A. Evaluation of outcome in critically ill patients with nosocomial enterobacter bacteremia: results of a matched cohort study. Chest 2003, 123:1208-1213.
17. Dimopoulos G., Koulenti D., Blot S., Sakr Y., Anzueto A., Spies C., Violan J.S., Kett D., Armaganidis A., Martin C., Vincent J.L. Critically ill elderly adults with infection: analysis of the extended prevalence of infection in intensive care study. J. Am. Geriatr. Soc. 2013, 61:2065-2071.
18. Blot S., Cankurtaran M., Petrovic M., Vandijck D., Lizy C., Decruyenaere J., Danneels C., Vandewoude K., Piette A., Vershraegen G., Van Den Noortgate N., Peleman R., Vogelaers D. Epidemiology and outcome of nosocomial bloodstream infection in elderly critically ill patients: a comparison between middle-aged, old, and very old patients. Crit. Care Med. 2009, 37:1634-1641.
19. Cosgrove S.E., Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin. Infect. Dis. 2003, 36:1433-1437.
20. Blot S., Vandewoude K., Hoste E., Colardyn F. Reappraisal of attributable mortality in critically ill patients with nosocomial bacteraemia involving Pseudomonas aeruginosa. J. Hosp. Infect. 2003, 53:18-24.
21. Reynvoet E., Vandijck D.M., Blot S.I., Dhondt A.W., De Waele J.J., Claus S., Buyle F.M., Vanholder R.C., Hoste E.A. Epidemiology of infection in critically ill patients with acute renal failure. Crit. Care Med. 2009, 37:2203-2209.
22. Kollef M.H., Sherman G., Ward S., Fraser V.J. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999, 115:462-474.
23. Roberts J.A., Lipman J. Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin. Pharmacokinet. 2006, 45:755-773.
24. Udy A.A., Roberts J.A., De Waele J.J., Paterson D.L., Lipman J. What's behind the failure of emerging antibiotics in the critically ill? Understanding the impact of altered pharmacokinetics and augmented renal clearance. Int. J. Antimicrob. Agents 2012, 39:455-457.
25. Pea F., Viale P. Bench-to-bedside review: appropriate antibiotic therapy in severe sepsis and septic shock-does the dose matter?. Crit. Care 2009, 13:214.
26. Blot S.I., Rodriguez A., Sole-Violan J., Blanquer J., Almirall J., Rello J. Effects of delayed oxygenation assessment on time to antibiotic delivery and mortality in patients with severe community-acquired pneumonia*. Crit. Care Med. 2007, 35:2509-2514.
27. Kumar A., Roberts D., Wood K.E., Light B., Parrillo J.E., Sharma S., Suppes R., Feinstein D., Zanotti S., Taiberg L., Gurka D., Kumar A., Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 2006, 34:1589-1596.
28. Kollef M.H., Ward S., Sherman G., Prentice D., Schaiff R., Huey W., Fraser V.J. Inadequate treatment of nosocomial infections is associated with certain empiric antibiotic choices. Crit. Care Med. 2000, 28:3456-3464.
29. Leone M., Bourgoin A., Cambon S., Dubuc M., Albanese J., Martin C. Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome. Crit. Care Med. 2003, 31:462-467.
30. Pea F., Viale P. The antimicrobial therapy puzzle: could pharmacokinetic-pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients?. Clin. Infect. Dis. 2006, 42:1764-1771.
31. Roberts J.A., Joynt G.M., Choi G.Y., Gomersall C.D., Lipman J. How to optimise antimicrobial prescriptions in the Intensive Care Unit: principles of individualised dosing using pharmacokinetics and pharmacodynamics. Int. J. Antimicrob. Agents 2012, 39:187-192.
32. Roberts J.A., Lipman J., Blot S., Rello J. Better outcomes through continuous infusion of time-dependent antibiotics to critically ill patients?. Curr. Opin. Crit. Care 2008, 14:390-396.
33. Pea F. Plasma pharmacokinetics of antimicrobial agents in critically ill patients. Curr. Clin. Pharmacol. 2013, 8:5-12.
34. Mouton J.W., Punt N., Vinks A.A. Concentration-effect relationship of ceftazidime explains why the time above the MIC is 40 percent for a static effect in vivo. Antimicrob. Agents Chemother. 2007, 51:3449-3451.
35. Craig W.A. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 1998, 26:1-10. (quiz 11-12).
36. Hosein S., Udy A.A., Lipman J. Physiological changes in the critically ill patient with sepsis. Curr. Pharm. Biotechnol. 2011, 12:1991-1995.
37. Gosling P., Sanghera K., Dickson G. Generalized vascular permeability and pulmonary function in patients following serious trauma. J. Trauma 1994, 36:477-481.
38. Vrhovac B., Sarapa N., Bakran I., Huic M., Macolic-Sarinic V., Francetic I., Wolf-Coporda A., Plavsic F. Pharmacokinetic changes in patients with oedema. Clin. Pharmacokinet. 1995, 28:405-418.
39. Roberts J.A., Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit. Care Med. 2009, 37:840-851. (quiz 859).
40. Westphal J.F., Brogard J.M. Clinical pharmacokinetics of newer antibacterial agents in liver disease. Clin. Pharmacokinet. 1993, 24:46-58.
41. Henriksen J.H., Kiszka-Kanowitz M., Bendtsen F. Review article: volume expansion in patients with cirrhosis. Aliment. Pharmacol. Ther. 2002, 16(Suppl. 5):12-23.
42. Etzel J.V., Nafziger A.N., Bertino J.S. Variation in the pharmacokinetics of gentamicin and tobramycin in patients with pleural effusions and hypoalbuminemia. Antimicrob. Agents Chemother. 1992, 36:679-681.
43. Pea F., Viale P., Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin. Pharmacokinet. 2005, 44:1009-1034.
44. Evers L.H., Bhavsar D., Mailander P. The biology of burn injury. Exp. Dermatol. 2010, 19:777-783.
45. Niemiec P.W., Allo M.D., Miller C.F. Effect of altered volume of distribution on aminoglycoside levels in patients in surgical intensive care. Arch. Surg. 1987, 122:207-212.
46. Marik P.E. Aminoglycoside volume of distribution and illness severity in critically ill septic patients. Anaesth. Intensive Care 1993, 21:172-173.
47. Sandri A.M., Landersdorfer C.B., Jacob J., Boniatti M.M., Dalarosa M.G., Falci D.R., Behle T.F., Bordinhao R.C., Wang J., Forrest A., Nation R.L., Li J., Zavascki A.P. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clin. Infect. Dis. 2013, 57:524-531.
48. Gous A., Lipman J., Scribante J., Tshukutsoane S., Hon H., Pinder M., Mathivha R., Verhoef L., Stass H. Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis. Int. J. Antimicrob. Agents 2005, 26:50-55.
49. Finfer S., Bellomo R., McEvoy S., Lo S.K., Myburgh J., Neal B., Norton R. 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, 333:1044.
50. Roberts J.A., Pea F., Lipman J. The clinical relevance of plasma protein binding changes. Clin. Pharmacokinet. 2013, 52:1-8.
51. Joynt G.M., Lipman J., Gomersall C.D., Young R.J., Wong E.L., Gin T. The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J. Antimicrob. Chemother. 2001, 47:421-429.
52. Ulldemolins M., Roberts J.A., Wallis S.C., Rello J., Lipman J. Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics. J. Antimicrob. Chemother. 2010, 65:1771-1778.
53. Burkhardt O., Kumar V., Katterwe D., Majcher-Peszynska J., Drewelow B., Derendorf H., Welte T. Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration. J. Antimicrob. Chemother. 2007, 59:277-284.
54. Brink A.J., Richards G.A., Schillack V., Kiem S., Schentag J. Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis. Int. J. Antimicrob. Agents 2009, 33:432-436.
55. Udy A.A., Roberts J.A., Lipman J. Implications of augmented renal clearance in critically ill patients. Nat. Rev. Nephrol. 2011, 7:539-543.
56. Udy A.A., Varghese J.M., Altukroni M., Briscoe S., McWhinney B.C., Ungerer J.P., Lipman J., Roberts J.A. Subtherapeutic initial beta-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest 2012, 142:30-39.
57. Lipman J., Udy A.A., Roberts J.A. Do we understand the impact of altered physiology, consequent interventions and resultant clinical scenarios in the intensive care unit? The antibiotic story. Anaesth. Intensive Care 2011, 39:999-1000.
58. Ulldemolins M., Roberts J.A., Lipman J., Rello J. Antibiotic dosing in multiple organ dysfunction syndrome. Chest 2011, 139:1210-1220.
59. Ishikawa M., Nishioka M., Hanaki N., Kikutsuji T., Miyauchi T., Kashiwagi Y., Miki H. Postoperative metabolic and circulatory responses in patients that express SIRS after major digestive surgery. Hepato-Gastroenterology 2006, 53:228-233.
60. Kohl B.A., Deutschman C.S. The inflammatory response to surgery and trauma. Curr. Opin. Crit. Care 2006, 12:325-332.
61. Levy M.M., Fink M.P., Marshall J.C., Abraham E., Angus D., Cook D., Cohen J., Opal S.M., Vincent J.L., Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit. Care Med. 2003, 31:1250-1256.
62. Parrillo J.E., Parker M.M., Natanson C., Suffredini A.F., Danner R.L., Cunnion R.E., Ognibene F.P. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann. Intern. Med. 1990, 113:227-242.
63. Di Giantomasso D., May C.N., Bellomo R. Vital organ blood flow during hyperdynamic sepsis. Chest 2003, 124:1053-1059.
64. Brown R., Babcock R., Talbert J., Gruenberg J., Czurak C., Campbell M. Renal function in critically ill postoperative patients: sequential assessment of creatinine osmolar and free water clearance. Crit. Care Med. 1980, 8:68-72.
65. Di Giantomasso D., May C.N., Bellomo R. Norepinephrine and vital organ blood flow during experimental hyperdynamic sepsis. Intensive Care Med. 2003, 29:1774-1781.
66. Wan L., Bellomo R., May C.N. The effects of normal and hypertonic saline on regional blood flow and oxygen delivery. Anesth. Analg. 2007, 105:141-147.
67. Bellomo R., Kellum J.A., Wisniewski S.R., Pinsky M.R. Effects of norepinephrine on the renal vasculature in normal and endotoxemic dogs. Am. J. Respir. Crit. Care Med. 1999, 159:1186-1192.
68. Pea F., Viale P., Cojutti P., Furlanut M. Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gram-negative infections: a pharmacokinetics/pharmacodynamics-based approach. Antimicrob. Agents Chemother. 2012, 56:6343-6348.
69. Dulhunty J.M., Roberts J.A., Davis J.S., Webb S.A., Bellomo R., Gomersall C., Shirwadkar C., Eastwood G.M., Myburgh J., Paterson D.L., Lipman J. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin. Infect. Dis. 2013, 56:236-244.
70. Taccone F.S., Laterre P.F., Spapen H., Dugernier T., Delattre I., Layeux B., De Backer D., Wittebole X., Wallemacq P., Vincent J.L., Jacobs F. Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit. Care 2010, 14:R53.
71. Conil J.M., Georges B., de Lussy A., Khachman D., Seguin T., Ruiz S., Cougot P., Fourcade O., Houin G., Saivin S. Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches. Int. J. Antimicrob. Agents 2008, 32:505-510.
72. Kullar R., Davis S.L., Levine D.P., Rybak M.J. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin. Infect. Dis. 2011, 52:975-981.
73. Holmes N.E., Turnidge J.D., Munckhof W.J., Robinson J.O., Korman T.M., O'Sullivan M.V., Anderson T.L., Roberts S.A., Warren S.J., Gao W., Howden B.P., Johnson P.D. Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia. Antimicrob. Agents Chemother. 2013, 57:1654-1663.
74. Hoste E.A., Clermont G., Kersten A., Venkataraman R., Angus D.C., De Bacquer D., Kellum J.A. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit. Care 2006, 10:R73.
75. Ali T., Khan I., Simpson W., Prescott G., Townend J., Smith W., Macleod A. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J. Am. Soc. Nephrol. 2007, 18:1292-1298.
76. Levy M.M., Macias W.L., Vincent J.L., Russell J.A., Silva E., Trzaskoma B., Williams M.D. Early changes in organ function predict eventual survival in severe sepsis. Crit. Care Med. 2005, 33:2194-2201.
77. Roberts D.M. The relevance of drug clearance to antibiotic dosing in critically ill patients. Curr. Pharm. Biotechnol. 2011, 12:2002-2014.
78. De Waele J.J., Danneels I., Depuydt P., Decruyenaere J., Bourgeois M., Hoste E. Factors associated with inadequate early vancomycin levels in critically ill patients treated with continuous infusion. Int. J. Antimicrob. Agents 2013, 41:434-438.
79. Pea F., Poz D., Viale P., Pavan F., Furlanut M. Which reliable pharmacodynamic breakpoint should be advised for ciprofloxacin monotherapy in the hospital setting? A TDM-based retrospective perspective. J. Antimicrob. Chemother. 2006, 58:380-386.
80. Taccone F.S., Laterre P.F., Dugernier T., Spapen H., Delattre I., Wittebole X., De Backer D., Layeux B., Wallemacq P., Vincent J.L., Jacobs F. Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit. Care 2010, 14:R126.
81. Korth-Bradley J.M., Troy S.M., Matschke K., Muralidharan G., Fruncillo R.J., Speth J.L., Raible D.G. Tigecycline pharmacokinetics in subjects with various degrees of renal function. J. Clin. Pharmacol. 2012, 52:1379-1387.
82. Blot S., Lipman J., Roberts D.M., Roberts J.A. The influence of acute kidney injury on antimicrobial dosing in critically ill patients: are dose reductions always necessary?. Diagn. Microbiol. Infect. Dis. 2014, 79:77-84.
83. Jamal J.A., Economou C.J., Lipman J., Roberts J.A. Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy and extracorporeal membrane oxygenation. Curr. Opin. Crit. Care 2012, 18:460-471.
84. Pea F., Viale P., Pavan F., Furlanut M. Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin. Pharmacokinet. 2007, 46:997-1038.
85. Roberts D.M., Roberts J.A., Roberts M.S., Liu X., Nair P., Cole L., Lipman J., Bellomo R. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. Crit. Care Med. 2012, 40:1523-1528.
86. Choi G., Gomersall C.D., Tian Q., Joynt G.M., Freebairn R., Lipman J. Principles of antibacterial dosing in continuous renal replacement therapy. Crit. Care Med. 2009, 37:2268-2282.
87. Roberts J.A., Ulldemolins M., Roberts M.S., McWhinney B., Ungerer J., Paterson D.L., Lipman J. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int. J. Antimicrob. Agents 2010, 36:332-339.
88. Chand N., Sanyal A.J. Sepsis-induced cholestasis. Hepatology 2007, 45:230-241.
89. Rawson J.S., Achord J.L. Shock liver. South. Med. J. 1985, 78:1421-1425.
90. Verbeeck R.K. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur. J. Clin. Pharmacol. 2008, 64:1147-1161.
91. Perianez-Parraga L., Martinez-Lopez I., Ventayol-Bosch P., Puigventos-Latorre F., Delgado-Sanchez O. Drug dosage recommendations in patients with chronic liver disease. Rev. Esp. Enferm. Dig. 2012, 104:165-184.
92. Korth-Bradley J.M., Baird-Bellaire S.J., Patat A.A., Troy S.M., Bohmer G.M., Gleiter C.H., Buecheler R., Morgan M.Y. Pharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis. J. Clin. Pharmacol. 2011, 51:93-101.
93. Blot S., Vandewoude K. Management of invasive candidiasis in critically ill patients. Drugs 2004, 64:2159-2175.
94. McCormack P.L., Perry C.M. Caspofungin: a review of its use in the treatment of fungal infections. Drugs 2005, 65:2049-2068.
95. Park G.R. Molecular mechanisms of drug metabolism in the critically ill. Br. J. Anaesth. 1996, 77:32-49.
96. Blot S., Koulenti D., Akova M., Bassetti M., De Waele J.J., Dimopoulos G., Kaukonen K.M., Martin C., Montravers P., Rello J., Rhodes A., Starr T., Wallis S.C., Lipman J., Roberts J.A. Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI Study. Crit. Care 2014, 18:R99.
97. Roberts J.A., Paul S.K., Akova M., Bassetti M., De Waele J.J., Dimopoulos G., Kaukonen K.M., Koulenti D., Martin C., Montravers P., Rello J., Rhodes A., Starr T., Wallis S.C., Lipman J. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients?. Clin. Infect. Dis. 2014, 58:1072-1083.
98. Sime F.B., Roberts M.S., Peake S.L., Lipman J., Roberts J.A. Does beta-lactam pharmacokinetic variability in critically ill patients justify therapeutic drug monitoring? A systematic review. Ann. Intensive Care 2012, 2:35.
99. Couffignal C., Pajot O., Laouenan C., Burdet C., Foucrier A., Wolff M., Armand-Lefevre L., Mentre F., Massias L. Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens. Br. J. Clin. Pharmacol. 2014, 10.1111/bcp.12435.
100. Conil J.M., Georges B., Ruiz S., Rival T., Seguin T., Cougot P., Fourcade O., Pharmd G.H., Saivin S. Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations. Br. J. Clin. Pharmacol. 2011, 71:61-71.
101. Georges B., Conil J.M., Ruiz S., Seguin T., Cougot P., Fourcade O., Houin G., Saivin S. Ceftazidime dosage regimen in intensive care unit patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations. Br. J. Clin. Pharmacol. 2012, 73:588-596.