How do I Adjust Antimicrobial Daily Dosage in Patients with MODS? A Pharmacist’s Contribution

  • Marta Ulldemolins
  • Jason A. RobertsEmail author


Despite knowledge about the significant impact on positive clinical outcomes from early and appropriate antimicrobial therapy in the treatment of severe infections in critically ill patients, there is still little understanding of strategies for dose optimization in multiple organ dysfunction syndrome (MODS). With this chapter, we intend to review the disease-driven changes in antimicrobial pharmacokinetics and pharmacodynamics, and to provide antimicrobial dosing recommendations for critically ill patients with MODS.

From a pharmacokinetic viewpoint, the two main parameters that can be significantly altered in critically ill patients with MODS are the apparent volume of distribution (Vd) and clearance (CL). Most research in this area has described a larger Vd for many antimicrobials as well as impaired CL as the main pharmacokinetic consequences of MODS. The effects of an increased Vd for antimicrobials may be lower than expected plasma and tissue concentrations. However, decreased antimicrobial CL can lead to higher than expected concentrations, which may lead to high antimicrobial concentrations and possible drug toxicity. These pharmacokinetic changes may result in preventing the achievement of pharmacodynamic targets, resulting in suboptimal treatment.

A broad dosing principle to be considered for critically ill patients with MODS would be the administration of loading doses of antimicrobials during the first day of therapy to account for the likely increased Vd. This should occur even in the presence of organ dysfunction. Thereafter, maintenance dosing must be guided by CL and adjusted to the degree of organ dysfunction for the eliminating organ. Further research is still required to define dosing regimens that will facilitate optimal antimicrobial concentrations in MODS.


Minimum Inhibitory Concentration Renal Replacement Therapy Therapeutic Drug Monitoring Total Body Water Multiple Organ Dysfunction Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to acknowledge funding of the Burns, Trauma and Critical Care Research Centre by National Health and Medical Research Council of Australia (Project Grant 519702), Australia and New Zealand College of Anaesthetists (ANZCA 06/037 and 09/032), Queensland Health – Health Practitioner Research Scheme and the Royal Brisbane and Women’s Hospital Research Foundation. Marta Ulldemolins is supported by CIBERES, AGAUR 09/SGR/1226 and FIS 07/90960. Dr. Roberts is funded by a fellowship from the National Health and Medical Research Council of Australia (Australian Based Health Professional Research Fellowship 569917).

Financial support

National Health and Medical Research Council of Australia (Project Grant 519702; Australian Based Health Professional Research Fellowship 569917), Australia and New Zealand College of Anaesthetists (ANZCA 06/037 and 09/032), CIBERES, AGAUR 09/SGR/1226 and FIS 07/90960.

Transparency Declarations

None to declare.


  1. Allard S, Kinzig M, Boivin G, Sorgel F, LeBel M (1993) Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 54:368–373PubMedCrossRefGoogle Scholar
  2. American College of Chest Physicians/Society of Critical Care Medicine (1992) American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874CrossRefGoogle Scholar
  3. Antibiotic Expert Group (2006) Antibiotic therapeutic guidelines, vol 13. Therapeutic Guidelines Limited, MelbourneGoogle Scholar
  4. Barbot A, Venisse N, Rayeh F, Bouquet S, Debaene B, Mimoz O (2003) Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill patients without vasopressors. Intensive Care Med 29:1528–1534PubMedCrossRefGoogle Scholar
  5. Barre J, Mallat A, Rosenbaum J, Deforges L, Houin G, Dhumeaux D, Tillement JP (1987) Pharmacokinetics of erythromycin in patients with severe cirrhosis. Respective influence of decreased serum binding and impaired liver metabolic capacity. Br J Clin Pharmacol 23:753–757PubMedGoogle Scholar
  6. Bauer LA, Edwards WA, Dellinger EP, Simonowitz DA (1983) Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol 24:643–647PubMedCrossRefGoogle Scholar
  7. Begg EJ, Barclay ML, Kirkpatrick CM (2001) The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol 52(Suppl 1):35S–43SPubMedCrossRefGoogle Scholar
  8. Blouin RA, Bauer LA, Miller DD, Record KE, Griffen WO Jr (1982) Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 21:575–580PubMedGoogle Scholar
  9. Boselli E, Breilh D, Saux MC, Gordien JB, Allaouchiche B (2006) Pharmacokinetics and lung concentrations of ertapenem in patients with ventilator-associated pneumonia. Intensive Care Med 32:2059–2062PubMedCrossRefGoogle Scholar
  10. Brink AJ, Richards GA, Schillack V, Kiem S, Schentag J (2009) Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis. Int J Antimicrob Agents 33:432–436PubMedCrossRefGoogle Scholar
  11. Bruggemann RJ, Donnelly JP, Aarnoutse RE, Warris A, Blijlevens NM, Mouton JW, Verweij PE, Burger DM (2008) Therapeutic drug monitoring of voriconazole. Ther Drug Monit 30:403–411PubMedCrossRefGoogle Scholar
  12. Buijk SE, Mouton JW, Gyssens IC, Verbrugh HA, Bruining HA (2002) Experience with a once-daily dosing program of aminoglycosides in critically ill patients. Intensive Care Med 28:936–942PubMedCrossRefGoogle Scholar
  13. Burkhardt O, Majcher-Peszynska J, Borner K, Mundkowski R, Drewelow B, Derendorf H, Welte T (2005) Penetration of ertapenem into different pulmonary compartments of patients undergoing lung surgery. J Clin Pharmacol 45:659–665PubMedCrossRefGoogle Scholar
  14. Burkhardt O, Kumar V, Katterwe D, Majcher-Peszynska J, Drewelow B, Derendorf H, Welte T (2007) Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration. J Antimicrob Chemother 59:277–284PubMedCrossRefGoogle Scholar
  15. Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman J (2009) Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med 37:2268–2282PubMedCrossRefGoogle Scholar
  16. Chow MS (1996) Intravenous amiodarone: pharmacology, pharmacokinetics, and clinical use. Ann Pharmacother 30:637–643PubMedGoogle Scholar
  17. Chumlea WC, Guo SS (1994) Bioelectrical impedance and body composition: present status and future directions. Nutr Rev 52:123–131PubMedCrossRefGoogle Scholar
  18. Cockroft D, Gault M (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefGoogle Scholar
  19. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10PubMedCrossRefGoogle Scholar
  20. Donnelly AJ, Baughman VL, Gonzales JP, Golembiewski J, Tomsik EA (2008) Anesthesiology and critical care drug handbook. Lexi-Comp, HudsonGoogle Scholar
  21. Farrell G, Baird-Lambert J, Cvejic M, Buchanan N (1984) Disposition and metabolism of metronidazole in patients with liver failure. Hepatology 4:722–726PubMedCrossRefGoogle Scholar
  22. Fleck A, Raines G, Hawker F, Trotter J, Wallace PI, Ledingham IM, Calman KC (1985) Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury. Lancet 1:781–784PubMedCrossRefGoogle Scholar
  23. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C (2003) Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 31:2742–2751PubMedCrossRefGoogle Scholar
  24. Gilbert B, Robbins P, Livornese LL Jr (2009) Use of antibacterial agents in renal failure. Infect Dis Clin North Am 23:899–924PubMedCrossRefGoogle Scholar
  25. Greenfield RA, Gerber AU, Craig WA (1983) Pharmacokinetics of cefoperazone in patients with normal and impaired hepatic and renal function. Rev Infect Dis 5(Suppl 1):S127–S136PubMedCrossRefGoogle Scholar
  26. Herrera-Gutierrez ME, Seller-Perez G, Banderas-Bravo E, Munoz-Bono J, Lebron-Gallardo M, Fernandez-Ortega JF (2007) Replacement of 24-h creatinine clearance by 2-h creatinine clearance in intensive care unit patients: a single-center study. Intensive Care Med 33:1900–1906PubMedCrossRefGoogle Scholar
  27. Heyland DK, Tougas G, King D, Cook DJ (1996) Impaired gastric emptying in mechanically ventilated, critically ill patients. Intensive Care Med 22:1339–1344PubMedCrossRefGoogle Scholar
  28. Jacob M, Conzen P, Finsterer U, Krafft A, Becker BF, Rehm M (2007) Technical and physiological background of plasma volume measurement with indocyanine green: a clarification of misunderstandings. J Appl Physiol 102:1235–1242PubMedCrossRefGoogle Scholar
  29. Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B (2005) Quantification of lean bodyweight. Clin Pharmacokinet 44:1051–1065PubMedCrossRefGoogle Scholar
  30. Jones AE, Puskarich MA (2009) Sepsis-induced tissue hypoperfusion. Crit Care Clin 25:769–779PubMedCrossRefGoogle Scholar
  31. Joukhadar C, Frossard M, Mayer BX, Brunner M, Klein N, Siostrzonek P, Eichler HG, Muller M (2001) Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 29:385–391PubMedCrossRefGoogle Scholar
  32. Joynt GM, Lipman J, Gomersall CD, Young RJ, Wong EL, Gin T (2001) The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother 47:421–429PubMedCrossRefGoogle Scholar
  33. Kollef MH, Sherman G, Ward S, Fraser VJ (1999) Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 115:462–474PubMedCrossRefGoogle Scholar
  34. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:1589–1596PubMedCrossRefGoogle Scholar
  35. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470PubMedGoogle Scholar
  36. MacGowan AP (1998) Pharmacodynamics, pharmacokinetics, and therapeutic drug monitoring of glycopeptides. Ther Drug Monit 20:473–477PubMedCrossRefGoogle Scholar
  37. MacLaren R, Bond CA, Martin SJ, Fike D (2008) Clinical and economic outcomes of involving pharmacists in the direct care of critically ill patients with infections. Crit Care Med 36:3184–3189PubMedCrossRefGoogle Scholar
  38. Marshall JC (2001) Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 29:S99–S106PubMedCrossRefGoogle Scholar
  39. Miller ME, Cosgriff JM, Forbes GB (1989) Bromide space determination using anion-exchange chromatography for measurement of bromide. Am J Clin Nutr 50:168–171PubMedGoogle Scholar
  40. MIMS Australia (, MIMS Australia Pty Ltd. Accessed on Dec 2009
  41. Outman WR, Nightingale CH, Sweeney KR, Quintiliani R (1990) Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance doses. Antimicrob Agents Chemother 34:2114–2117PubMedGoogle Scholar
  42. Pannu N, Nadim MK (2008) An overview of drug-induced acute kidney injury. Crit Care Med 36:S216–S223PubMedCrossRefGoogle Scholar
  43. Paul S, Escareno CE, Clancy K, Jaklitsch MT, Bueno R, Lautz DB (2009) Gastrointestinal complications after lung transplantation. J Heart Lung Transplant 28:475–479PubMedCrossRefGoogle Scholar
  44. Pharmaceutical Research and Manufactures of America Accessed on Dec 2009
  45. Plank LD, Hill GL (2000) Similarity of changes in body composition in intensive care patients following severe sepsis or major blunt injury. Ann N Y Acad Sci 904:592–602PubMedCrossRefGoogle Scholar
  46. Pong S, Seto W, Abdolell M, Trope A, Wong K, Herridge J, Harvey E, Kavanagh BP (2005) 12-hour versus 24-hour creatinine clearance in critically ill pediatric patients. Pediatr Res 58:83–88PubMedCrossRefGoogle Scholar
  47. Rello J, Gallego M, Mariscal D, Sonora R, Valles J (1997) The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med 156:196–200PubMedGoogle Scholar
  48. Richens A (1979) Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 4:153–169PubMedCrossRefGoogle Scholar
  49. Roberts JA, Lipman J (2006) Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet 45:755–773PubMedCrossRefGoogle Scholar
  50. Roberts JA, Lipman J (2009) Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 37:840–851PubMedCrossRefGoogle Scholar
  51. Roberts JA, Kruger P, Paterson DL, Lipman J (2008) Antibiotic resistance–what’s dosing got to do with it? Crit Care Med 36:2433–2440PubMedCrossRefGoogle Scholar
  52. Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J (2009a) Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 64:142–150PubMedCrossRefGoogle Scholar
  53. Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J (2009b) Piperacillin penetration into tissue of critically ill patients with sepsis – bolus versus continuous administration? Crit Care Med 37:926–933PubMedCrossRefGoogle Scholar
  54. Rothschild MA, Oratz M, Zimmon D, Schreiber SS, Weiner I, Van Caneghem A (1969) Albumin synthesis in cirrhotic subjects with ascites studied with carbonate-14C. J Clin Invest 48:344–350PubMedCrossRefGoogle Scholar
  55. Rowland M, Tozer TN (1995) Clinical pharmacokinetics. Concepts and applications. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  56. Ryan DM (1993) Pharmacokinetics of antibiotics in natural and experimental superficial compartments in animals and humans. J Antimicrob Chemother 31(Suppl D):1–16PubMedGoogle Scholar
  57. Sakka SG (2007) Assessing liver function. Curr Opin Crit Care 13:207–214PubMedCrossRefGoogle Scholar
  58. Singh G, Harkema JM, Mayberry AJ, Chaudry IH (1994) Severe depression of gut absorptive capacity in patients following trauma or sepsis. J Trauma 36:803–808PubMedCrossRefGoogle Scholar
  59. Son DS, Hariya S, Shimoda M, Kokue E (1996) Contribution of alpha 1-acid glycoprotein to plasma protein binding of some basic antimicrobials in pigs. J Vet Pharmacol Ther 19:176–183PubMedCrossRefGoogle Scholar
  60. Spellberg B, Guidos R, Gilbert D, Bradley J, Boucher HW, Scheld WM, Bartlett JG, Edwards J Jr (2008) The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis 46:155–164PubMedCrossRefGoogle Scholar
  61. Thijs LG, Schneider AJ, Groeneveld AB (1990) The haemodynamics of septic shock. Intensive Care Med 16(Suppl 3):S182–S186PubMedCrossRefGoogle Scholar
  62. van der Poll T (2001) Immunotherapy of sepsis. Lancet Infect Dis 1:165–174PubMedCrossRefGoogle Scholar
  63. Wan L, Bagshaw SM, Langenberg C, Saotome T, May C, Bellomo R (2008) Pathophysiology of septic acute kidney injury: what do we really know? Crit Care Med 36:S198–S203PubMedCrossRefGoogle Scholar
  64. Wells M, Lipman J (1997) Measurements of glomerular filtration in the intensive care unit are only a rough guide to renal function. S Afr J Surg 35:20–23PubMedGoogle Scholar
  65. Westphal JF, Brogard JM (1993) Clinical pharmacokinetics of newer antibacterial agents in liver disease. Clin Pharmacokinet 24:46–58PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Critical Care Department, Vall d’Hebron University HospitalInstitut de Recerca Vall d’Hebron-Universitat Autònoma de Barcelona (UAB)BarcelonaSpain
  2. 2.Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES)MadridSpain
  3. 3.Department of Intensive Care MedicineRoyal Brisbane and Women’s HospitalHerston, BrisbaneAustralia
  4. 4.Burns, Trauma and Critical Care Research CentreThe University of QueenslandHerston, BrisbaneAustralia
  5. 5.Pharmacy DepartmentRoyal Brisbane and Women’s HospitalHerston, BrisbaneAustralia
  6. 6.Burns, Trauma and Critical Care Research CentreRoyal Brisbane and Women’s HospitalHerstonAustralia

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