Individualised antibiotic dosing for patients who are critically ill: Challenges and potential solutions.
Open accessAbstract
Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.
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Some studies in critically ill patients have reported benefits of PK/PD-based dosing in terms of clinical cure.
“Some studies in critically ill patients have reported benefits in terms of clinical cure [237, 250–253].”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [237]
Antibiotics undergo changes in PK/PD parameters in sepsis and septic shock, with concentrations that may be too low risking clinical failure or too high causing toxicity.
“Antibiotics are subject to changes in PK/PD parameters in sepsis and septic shock where resultant concentrations may be too low risking clinical failure, or too high leading to toxicity (Table 3) [237–239].”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [237]
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Passarell, J. A., Meagher, A. K., Liolios, K., et al. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00813-07 · Cited by 107 · see citing works
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Self-citationOptimization of meropenem dosage in the critically ill population based on renal function
Crandon, J. L., Ariano, R. E., Zelenitsky, S. A., Nicasio, A. M., Kuti, J. L., & Nicolau, D. P. (2010) · Intensive Care Medicine · doi:10.1007/s00134-010-2105-0 · Cited by 103 · see citing works
Self-citationBhavnani, S. M., Rubino, C. M., Hammel, J., et al. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01615-10 · Cited by 103 · see citing works
Rhomberg, P. R., Fritsche, T. R., Sader, H. S., et al. (2006) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2005.12.009 · Cited by 101 · see citing works
Boselli, E., Breilh, D., Rimmele, T. R., Poupelin, J.-C., Saux, M., CHASSARD, D., & Allaouchiche, B. (2004) · Intensive Care Medicine · doi:10.1007/s00134-004-2171-2 · Cited by 96 · see citing works
Improving antibiotic dosing in special situations in the ICU
Jamal, J., Economou, C. J. P., Lipman, J., & Roberts, J. A. (2012) · Current Opinion in Critical Care · doi:10.1097/mcc.0b013e32835685ad · Cited by 95 · see citing works
Self-citationFirsov, A. A., Smirnova, M. V., Lubenko, I. Y., et al. (2006) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkl387 · Cited by 95 · see citing works
Antibiotic Dosing in Multiple Organ Dysfunction Syndrome
Ulldemolins, M., Roberts, J. A., Lipman, J., & Rello, J. (2011) · CHEST Journal · doi:10.1378/chest.10-2371 · Cited by 94 · see citing works
Self-citationBinkley, S., Fishman, N. O., LaRosa, L. A., Marr, A. M., Nachamkin, I., Wordell, D. C., Bilker, W. B., & Lautenbach, E. (2006) · Infection Control and Hospital Epidemiology · doi:10.1086/505921 · Cited by 93 · see citing works
Cefepime Versus Cefpirome: The Importance of Creatinine Clearance
Lipman, J., Wallis, S. C., & Boots, R. J. (2003) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000077077.54084.b0 · Cited by 86 · see citing works
Self-citationLee, K., Kim, M., Kim, J., Hong, H. L., Kang, J. O., Shin, J. H., Park, Y.-J., Yong, D., Jeong, S. H., Chong, Y., et al. (2011) · Yonsei Medical Journal · doi:10.3349/ymj.2011.52.5.793 · Cited by 86 · see citing works
Plasma and tissue pharmacokinetics of cefpirome in patients with sepsis
Joukhadar, C., Klein, N., Mayer, B. X., Kreischitz, N., Delle‐Karth, G., Palkovits, P., Heinz, G., & Müller, M. (2002) · Critical Care Medicine · doi:10.1097/00003246-200207000-00013 · Cited by 85 · see citing works
Lomaestro, B. M., & Drusano, G. L. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.1.461-463.2005 · Cited by 84 · see citing works
Self-citationBoselli, E., Breilh, D., Rimmele, T. R., Guillaume, C., Xuereb, F., Saux, M., Bouvet, L., CHASSARD, D., & Allaouchiche, B. (2008) · Critical Care Medicine · doi:10.1097/ccm.0b013e318170ba21 · Cited by 83 · see citing works
Roberts, J. A., & Lipman, J. (2012) · Critical Care Medicine · doi:10.1097/ccm.0b013e31826ab4c4 · Cited by 82 · see citing works
Self-citationZelenitsky, S. A., & Ariano, R. E. (2010) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkq211 · Cited by 81 · see citing works
Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis
Brink, A. J., Richards, G., Schillack, V., Kiem, S., & Schentag, J. J. (2008) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2008.10.005 · Cited by 80 · see citing works
Self-citationPea, F., Viale, P., Cojutti, P. G., & Furlanut, M. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01291-12 · Cited by 78 · see citing works
Pharmacodynamics of tobramycin in patients with cystic fibrosis
Mouton, J. W., Jacobs, N., Tiddens, H. A. W. M., et al. (2005) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2005.02.011 · Cited by 78 · see citing works
Self-citationBoselli, E., Breilh, D., Cannesson, M. P., Xuereb, F., Rimmele, T. R., CHASSARD, D., Saux, M., & Allaouchiche, B. (2004) · Intensive Care Medicine · doi:10.1007/s00134-004-2222-8 · Cited by 77 · see citing works
Scaglione, F., Esposito, S., Leone, S., Lucini, V., Pannacci, M., Ma, L., & Drusano, G. L. (2009) · European Respiratory Journal · doi:10.1183/09031936.00149508 · Cited by 75 · see citing works
Self-citationUse of Pharmacodynamic Indices To Predict Efficacy of Combination Therapy In Vivo
Mouton, J. W., van Ogtrop, M. L., Andes, D. R., & Craig, W. A. (1999) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.43.10.2473 · Cited by 74 · see citing works
Self-citationZeitlinger, M. A., Dehghanyar, P., Mayer, B. X., et al. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.11.3548-3553.2003 · Cited by 72 · see citing works
Sherwin, C. M. T., Fukuda, T., Brunner, H. I., Goebel, J., & Vinks, A. A. T. M. M. (2010) · Clinical Pharmacokinetics · doi:10.2165/11536640-000000000-00000 · Cited by 71 · see citing works
Self-citationRoberts, J. A., Waele, J. J. D., Dimοpoulos, G., Koulenti, D., Martin, C., Montravers, P., Rello, J., Rhodes, A., Starr, T., Wallis, S. C., et al. (2012) · BMC Infectious Diseases · doi:10.1186/1471-2334-12-152 · Cited by 70 · see citing works
Self-citationOng, C. T., Tessier, P. R., Li, C., et al. (2006) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2006.06.014 · Cited by 69 · see citing works
Increased amikacin dosage requirements in burn patients receiving a once-daily regimen
Conil, J., Georges, B., Breden, A., et al. (2006) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2006.04.015 · Cited by 62 · see citing works
Highet, V. S., Forrest, A., Ballow, C. H., et al. (1999) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/43.suppl_1.55 · Cited by 62 · see citing works
Pharmacokinetics-Pharmacodynamics of Tigecycline in Patients with Community-Acquired Pneumonia
Rubino, C. M., Bhavnani, S. M., Forrest, A., Dukart, G., Dartois, N., Cooper, A., Korth-Bradley, J., & Ambrose, P. G. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00277-10 · Cited by 54 · see citing works
Hepatic Drug Metabolism in Critical Illness
McKindley, D. S., Hanes, S. D., & Boucher, B. A. (1998) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/j.1875-9114.1998.tb03898.x · Cited by 53 · see citing works
Tam, V. H., Ledesma, K. R., Vo, G., et al. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01468-07 · Cited by 52 · see citing works
Pharmacokinetic-Pharmacodynamic-Model-Guided Doripenem Dosing in Critically Ill Patients
Samtani, M. N., Flamm, R. K., Kaniga, K., et al. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01843-09 · Cited by 50 · see citing works
Arnold, H. M., Hollands, J. M., Skrupky, L. P., Smith, J. R., Juang, P., Hampton, N. B., McCormick, S., Reichley, R. M., Hoban, A. P., Hoffmann, J., et al. (2013) · Annals of Pharmacotherapy · doi:10.1345/aph.1r523 · Cited by 50 · see citing works
Gous, A. G. S., Lipman, J., Scribante, J., et al. (2005) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2005.04.005 · Cited by 49 · see citing works
Self-citationLipman, J., Udy, A. A., & Roberts, J. A. (2011) · Anaesthesia and Intensive Care · doi:10.1177/0310057x1103900602 · Cited by 44 · see citing works
Self-citationComparative Activity of Carbapenem Testing (COMPACT) study in Germany
Valenza, G., Seifert, H., Decker-Burgard, S., Laeuffer, J., Morrissey, I., & Mutters, R. (2012) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2011.10.015 · Cited by 43 · see citing works
Software for Dosage Individualization of Voriconazole for Immunocompromised Patients
Hope, W. W., VanGuilder, M., Donnelly, J. P., Blijlevens, N. M. A., Brüggemann, R. J. M., Jelliffe, R. W., & Neely, M. N. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02025-12 · Cited by 42 · see citing works
Self-citationImpact of Sample Size on the Performance of Multiple-Model Pharmacokinetic Simulations
Tam, V. H., Kabbara, S., Yeh, R. F., et al. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00337-06 · Cited by 42 · see citing works
Chan, W. C., Li, R. C., Ling, J., et al. (1999) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/43.1.55 · Cited by 38 · see citing works
Design of dosage regimens: A multiple model stochastic control approach
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Muller, A. E., Schmitt‐Hoffmann, A. H., Punt, N. C., et al. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02292-12 · Cited by 32 · see citing works
Validation of the Hartford Nomogram in Trauma Surgery Patients
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Comparison of β-lactams in counter-selecting resistance of Pseudomonas aeruginosa
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Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016.
Rhodes, A., Evans, L. E., Alhazzani, W., Levy, M. M., Antonelli, M., Ferrer, R., Kumar, A., Sevransky, J. E., Sprung, C. L., Nunnally, M. E., et al. (2017) · Intensive Care Medicine · doi:10.1007/s00134-017-4683-6 · Cited by 6,621 · see citing works
Kalil, A. C., Metersky, M. L., Klompas, M., Muscedere, J., Sweeney, D. A., Palmer, L. B., Napolitano, L. M., O'Grady, N. P., Bartlett, J. G., Carratalà, J., et al. (2016) · Clinical Infectious Diseases · doi:10.1093/cid/ciw353 · Cited by 3,892 · see citing works
Self-citationSurviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016.
Rhodes, A., Evans, L. E., Alhazzani, W., Levy, M. M., Antonelli, M., Ferrer, R., Kumar, A., Sevransky, J. E., Sprung, C. L., Nunnally, M. E., et al. (2017) · Critical Care Medicine · doi:10.1097/ccm.0000000000002255 · Cited by 3,652 · see citing works
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021.
Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., Machado, F. R., Mcintyre, L., Ostermann, M., Prescott, H. C., et al. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000005337 · Cited by 2,935 · see citing works
Self-citationGuilhaumou, R., Benaboud, S., Bennis, Y., Dahyot-Fizelier, C., Dailly, E., Gandia, P., Goutelle, S., Lefeuvre, S., Mongardon, N., Roger, C., et al. (2019) · Critical Care · doi:10.1186/s13054-019-2378-9 · Cited by 543 · see citing works
Roberts, J. A., Abdul-Aziz, M.-H., Davis, J. S., Dulhunty, J. M., Cotta, M. O., Myburgh, J., Bellomo, R., & Lipman, J. (2016) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201601-0024oc · Cited by 379 · see citing works
Self-citationWong, G., Briscoe, S., McWhinney, B., Ally, M., Ungerer, J., Lipman, J., & Roberts, J. A. (2018) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dky314 · Cited by 169 · see citing works
Self-citationSurviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021
Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., Machado, F. R., Mcintyre, L., Ostermann, M., Prescott, H. C., et al. (2021) · Intensive Care Medicine · doi:10.1007/s00134-021-06506-y · Cited by 5,082 · see citing works
Self-citationSurviving Sepsis campaign: international guidelines for Management of Sepsis and Septic Shock 2026
Prescott, H. C., Antonelli, M., Alhazzani, W., Møller, M. H., Alshamsi, F., Azevedo, L. C. P., Belley-Cote, E., De Waele, J., Derde, L., Dionne, J. C., et al. (2026) · Critical Care Medicine · doi:10.1097/ccm.0000000000007075 · Cited by 117 · see citing works
Self-citationEhmann, L., Zoller, M., Minichmayr, I. K., Scharf, C., Huisinga, W., Zander, J., & Kloft, C. (2019) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2019.06.016 · Cited by 67 · see citing works
Fleuren, L. M., Roggeveen, L. F., Guo, T., Waldauf, P., van der Voort, P. H. J., Bosman, R. J., Swart, E. L., Girbes, A. R. J., & Elbers, P. W. G. (2019) · Critical Care · doi:10.1186/s13054-019-2438-1 · Cited by 32 · see citing works
- Authors
- Roberts, J. A., Abdul-Aziz, M. H., Lipman, J., Mouton, J. W., Vinks, A. A., Felton, T. W., Hope, W. W., Farkas, A., Neely, M. N., Schentag, J. J., Drusano, G., Frey, O. R., Theuretzbacher, U., & Kuti, J. L.
- Affiliations
- The University of Queensland (AU)
- Radboud University Nijmegen (NL)
- Cincinnati Children's Hospital Medical Center (US)
- University of Liverpool (GB)
- University of Southern California (US)
- University at Buffalo, State University of New York (US)
- University of Florida (US)
- Hartford Hospital (US)
- Corresponding author
- Roberts, Jason A
- ORCID
- Venue
- The Lancet Infectious Diseases
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 14
- Issue
- 6
- Pages
- 498-509
- ISSN
- 1473-3099 (ISSN-L)
- PMC
- PMC4181663
- OpenAlex
- W2153641174
- Cited by
- 1,046
- References
- 150
- Citations by year
- 2026: 110 · 2025: 81 · 2024: 84 · 2023: 85 · 2022: 110 · 2021: 95 · 2020: 93 · 2019: 104 · 2018: 68 · 2017: 86 · 2016: 56 · 2015: 56 · 2014: 17
- FWCI
- 9.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- National Institute for Health and Care Research (CS/08/08/10)
- National Institute of General Medical Sciences (R01GM068968)
- National Institute of Allergy and Infectious Diseases (R01AI079578, P01AI060908)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD070886)
- Topics
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antibiotic Use and Resistance
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- critically ill patients, antibiotic pharmacokinetics, antibiotic susceptibility, pharmacokinetic-pharmacodynamic modeling, serum albumin, renal function, liver function, volume status, antibiotic exposure, sepsis
- MeSH terms
- Anti-Bacterial Agents, Humans, Microbial Sensitivity Tests, Critical Illness, Drug Dosage Calculations, Precision Medicine
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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