Vol 6, No 1 (2019) > Mini Review Article >

Kajian Narrative terhadap Profil Farmakokinetik Antibiotik pada Pasien Kritis: Implikasi terhadap Ketercapaian Target Farmakokinetik-Farmakodinamik

Eko Setiawan , Widyati Widyati , Ferdy Royland Marpaung , Edy Sukandar , Susaniwati Susaniwati , Dwi Lily Lukas , Heru Wijono , Taufin Warindra , Roni Kurniawan , Tjipto Wibowo , Wahyu Hendradi , Menino Osbert Costa , Mohd-Hafiz Abdul-Aziz , Jason Roberts




The severity of diseases, the complexity of treatment, and the use of medical devices in the intensive care unit (ICU) may change the pharmacokinetics (PK) profile of antibiotics among critically ill patients.This narrative review aims to explain the PK profile of critically ill patients compared to other group of patients and to describe the pharmacokinetic-pharmacidynamic (PK-PD) target attainment among this group of patients. Only articles published less than 10 years ago were included in this narrative review. Evidences have indicated that critically ill patients have relatively larger volume distribution (Vd) of hydrophilic antibiotics compared to patients with stable conditions. The fluid shifting to interstitial space, hypoalbuminemia, and aggressive fluid treatment may contribute to the increase value of Vd in critically ill patients. The clearance (CL) of hydrophilic antibiotics in critically ill patients is highly determined by dynamic changing of renal function compared to patients in other wards. The phenomenon of augmented renal clearance and the use of high intensity of renal replacement therapy can increase the CL of hydrophilic antibiotics. The different PK profile of antibiotics may lead to the failure of attaining the PK-PD target if the dose of antibiotics is not adjusted according to such differences.


Tingkat keparahan penyakit yang relatif tinggi dibandingkan pasien di bangsal rawat lain dan penggunaan terapi serta alat medis yang relatif lebih kompleks di ruang intensive care unit (ICU) dapat berdampak pada perubahan profil farmakokinetik (PK) antibiotik pada pasien kritis. Tujuan utama kajian naratif ini adalah untuk memaparkan profil PK dan ketercapaian target farmakokinetik-farmakodinamik (PK-PD) pasien kritis di ICU. Hanya artikel yang diterbitkan dalam kurun waktu 10 tahun terakhir yang digunakan dalam kajian naratif ini. Bukti penelitian menunjukkan bahwa volume distribusi (Vd) antibiotik hidrofilik pada pasien kritis lebih besar dibandingkan dengan pasien yang relatif lebih stabil atau subyek sehat. Perpindahan cairan intravaskuler ke daerah interstitial, hipoalbuminemia, dan terapi cairan khususnya yang diberikan secara agresif merupakan faktor yang berkontribusi terhadap peningkatan Vd pada pasien kritis. Clearance (CL) antibiotik hidrofilik pada pasien kritis ditentukan oleh perubahan fungsi ginjal yang relatif lebih dinamis dibandingkan dengan pasien di ruang rawat inap lain. Fenomena augmented renal clearance yang umum dijumpai pada pasien kritis dan penggunaan renal replacement therapy dengan intensitas yang tinggi dapat meningkatkan CL antibiotik hidrofilik. Perbedaan profil PK tersebut berpotensi menyebabkan kegagalan untuk mencapai target PK-PD apabila tidak dilakukan penyesuaian dosis antibiotik pada pasien kritis. Identifikasi profil PK perlu diupayakan sebagai langkah awal untuk mengoptimalkan pemberian antibiotik pada kelompok pasien kritis.

Keywords: antibiotik; farmakokinetik-farmakodinamik; pasien kritis; ruang rawat intensif; antibiotics; critically ill patients; pharmacokinetics-pharmacodynamics; intensive care unit

Published at: Vol 6, No 1 (2019) pages: 1-12

DOI: 10.7454/psr.v6i1.4274

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Abhilash, B., Tripathi, C.D., Gogia, A.R., Meshram, G.G., Kumar, M., & Suraj, B. (2015). Pharmacokinetic/pharmacodynamic profiling of imipenem in patients admitted to an intensive care unit in India: A nonrandomized, cross-sectional, analytical, open-labeled study. Indian Journal of Critical Care Medicine, 19, 587-592.

Al-Dorzi, H.M., Asiri, A.M., Shimemri, A., Tamim, H.M., Al Johani, S.M., Al Dabbagh, T., et al. (2015). Impact of empirical antimicrobial therapy on the outcome of critically ill patients with Acinetobacter bacteremia. Annals of Thoracic Medicine, 10(4), 256–262.

Allou, N., Bouteau, A., Allyn, J., Snauwaert, A., Valance, D., Jabot, J., et al. (2016). Impact of a high loading dose of amikacin in patients with severe sepsis or septic shock. Annals of Intensive Care, 6, 106.

Álvarez, O., Plaza-Plaza, J.C., Ramirez, M., Peralta, A., Amador, C.A., & Amador, R. (2017). Pharmacokinetic assessment of vancomycin loading dose in critically ill patients. Antimicrobial Agents and Chemotherapy, 61(8), pii: e00280-17.

Bagshaw, S.M., George, C., Gibney, R.T., & Bellomo, R. (2008). A multi-center evaluation of early acute kidney injury in critically ill trauma patients. Renal Failure, 30(6), 581-589.

Bhalodi, A.A., Keel, R.A., Quintiliani, R., Lodise, T.P., Nicolau, D.P., & Kuti, J.L. (2013). Pharmacokinetics of doripenem in infected patients treated within and outside the intensive care unit. The Annals of Pharmacotherapy, 47, 617-627.

Bhave, G., & Neilson EG. (2011). Body fluid dynamics: back to the future. Journal of the American Society of Nephrology, 22(12), 2166–2181.

Bhavnani, S.M., Hammel, J.P., van Wart, S.A., Rubino, C.M., Reynolds, D.K., Forrest, A., et al. (2013). Pharmacokinetic-pharmacodynamic analyses for efficacy of ceftaroline fosamil in patients with community-acquired bacterial pneumonia. Antimicrobial Agents and Chemotherapy, 57(12), 6348–6350.

Boldt, J. (2010). Use of albumin: an update. British Journal of Anaesthesia, 104, 276-284.

Breakpoint tables for interpretation of MICs and zone diameters. Version 8.1;2018. (2018). Retrieved from: The European Committee on Antimicrobial Susceptibility Testing (EUCAST) website: http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_8.1_Break point_Tables.pdf.

Cairns, S., Reilly, J., & Booth, M. (2010). Prevalence of healthcare-associated infection in Scottish intensive care units. Journal of Hospital Infection, 76(4), 308-310.

Campassi, M.L., Gonzalez, M.C., Masevicius, F.D., Vazquez, A.R., Moseinco, M., Navarro, N.C., et al. (2014). Augmented renal clearance in critically ill patients: incidence, associated factors and effects on vancomycin treatment. Revista Brasileira de Terapia Intensiva, 26(1), 13-20.

Chant, C., Smith, O.M., Marshall, J.C., & Friedrich, J.O. (2011). Relationship of catheter-associated urinary tract infection to mortality and length of stay in critically ill patients: a systematic review and meta-analysis of observational studies. Critical Care Medicine, 39(5), 1167-1173.

Chelazzi, C., Pettini, E., Villa, G., & de Gaudio, A.R. (2015). Epidemiology, associated factors and outcomes of ICU-acquired infections caused by Gram-negative bacteria in critically ill patients: an observational, retrospective study. BMC Anesthesiology, 15, 125.

Chelazzi, C., Villa, G., Mancinelli, P., de Gaudio, A.R., & Adembri, C. (2015). Glycocalyx and sepsis- indiced alterations in vascular permeability. Critical Care, 19, 26.

Chen, Y.Y., Wang, F.D., Liu, C.Y., & Chou, P. (2009). Incidence rate and variable cost of nosocomial infections in different types of intensive care units. Infection Control and Hospital Epidemiology, 30(1), 39-46.

Choudhuri, A.H., Chakravarty, M., & Uppal, R. (2017). Epidemiology and characteristics of nosocomial infections in critically ill patients in a tertiary care intensive care unit of Northern India. Saudi Journal of Anaesthesia, 11(4), 402-407.

Clinical and Laboratory and Standards Institute. (2014). Performance standards for antimicrobial susceptibility testing: Twenty-Fourth Informational Supplement M100-S24. Wayne, PA, USA: CLSI.

Couffignal, C., Pajot, O., Laouenan, C., Burdet, C., Foucrier, A., Wolff, M., et al. (2014). Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens. British Journal of Clinical Pharmacology, 78(5), 1022-1034.

Crandon, J.L., Bulik, C.C., Kuti, J.L., & Nicolau, D.P. (2010). Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 54(3), 1111-1116.

François, B., Clavel, M., Vignon, P., & Laterre, P.F. (2016). Perspective on optimizing clinical trials in critical care: how to puzzle out recurrent failures. Journal of Intensive Care, 4, 67.

Garnacho-Montero, J., Gutiérrez-Pizarraya, A., Escoresca-Ortega, A., Fernández-Delgado, E., & López-Sánchez, J.M. (2015). Adequate antibiotic therapy prior to ICU admission in patients with severe sepsis and septic shock reduces hospital mortality. Critical Care, 19(1), 302.

Gatta, A., Verardo, A., & Bolognesi, M. (2012). Hypoalbuminemia. Internal and Emergency Medicine, 7(Suppl 3), S193-S199.

Gemmell, L., Docking, R., & Black, E. (2017). Renal replacement therapy in critical care. BJA Education, 17(3), 88–93.

Hites, M., Taccone, F.S., Wolff, F., Cotton, F., Beumier, M., De Backer, D., et al. (2013). Case-control study of drug monitoring of β-lactams in obese critically ill patients. Antimicrobial Agents and Chemotherapy, 57(2), 708-715.

Holmes, A.H., Moore, L.S., Sundsfjord, A., Steinbakk, M., Regmi S, Karkey A, et al. (2016). Understanding the mechanisms and drivers of antimicrobial resistance. Lancet, 387(10014), 176- 187.

Hotchkiss, R.S., Moldawer, L.L., Opal, S.M., Reinhart, K., Turnbull, I.R., & Vincent, J.L. (2016). Sepsis and septic shock. Nature Reviews Disease Primers, 2, 16045.

Ince, C., Mayeux, P.R., Nguyen, T., Gomez, H., Kellum, J.A., Ospina-Tascon, G.A., et al. The endothelium in sepsis. Shock, 45(3), 259-270.

Jacob, J.T., & DiazGranados, CA. (2013). High vancomycin minimum inhibitory concentration and clinical outcomes in adults with methicillin-resistant Staphylococcus aureus infections: a meta- analysis. International Journal of Infectious Diseases, 17(2), e93-e100.

Jamal, J.A., Mueller, B.A., Choi, G.Y., Lipman, J., & Roberts, J.A. (2015). How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy?. Diagnostic Microbiology and Infectious Disease, 82(1), 92-103.

Jang, T.N., Lee, S.H., Huang, C.H., Lee, C.L., & Chen, W.Y. (2009). Risk factors and impact of nosocomial Acinetobacter baumannii bloodstream infections in the adult intensive care unit: a case-control study. The Journal of Hospital Infection, 73(2), 143-50.

Jorgensen, J.H., & Ferraro, M.J. (2009). Antimicrobial susceptibility testing: a review of general principles and contemporary practices. Clinical Infectious Diseases, 49, 1749-1755.

Jumah, M.T., Vasoo, S., Menon, S.R., De, P.P., Neely, M., & Teng, C.B. (2018). Pharmacokinetic/pharmacodynamic (PK/PD) determinants of vancomycin efficacy in enterococcal bacteremia. Antimicrobial Agents and Chemotherapy, 62(3), pii:e01602-17.

Kallel, H., Dammak, H., Bahloul, M., Ksibi, H., Chelly, H., Ben Hamida, C., et al. (2010). Risk factors and outcomes of intensive care unit-acquired infections in a Tunisian ICU. Medical Science Monitor, 16(8), PH69-75.

Kawano, Y., Morimoto, S., Izutani, Y., Muranishi, K., Kaneyama, H., Hoshino, K., et al. (2016). Augmented renal clearance in Japanese intensive care unit patients: a prospective study. Journal of Intensive Care, 4, 62.

Kes, P., & Jukic, N,B. (2010). Acute kidney injury in the intensive care unit. Bosnian Journal of Basic Medical Sciences, 10(Suppl 1), S8–S12.

Koeppen, B.M., & Stanton, B.A. (2013). Physiology of body fluid. In: Renal physiology (5th ed). Philadelphia: Mosby, Inc.

Kullar, R., Davis, S.L., Levine, D.P., & Rybak, M.J. (2011). Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clinical Infectious Diseases, 52(8), 975-981.

Kuti, J.L. (2016). Optimizing antimicrobial pharmacodynamics: a guide for your stewardship program. Revista Médica Clínica Las Condes, 27(5), 615-624.

Lal, A., Jaoude, P., & El-Solh, A.A. (2016). Prolonged versus intermittent infusion of β-lactams for the treatment of nosocomial pneumonia: a meta-analysis. Infection & Chemotherapy, 48(2), 81–90.

Lambert, M.L., Suetens, C., Savey, A., Palomar, M., Hiesmayr, M., Morales, I., et al. (2011). Clinical outcomes of health-care-associated infections and antimicrobial resistance in patients admitted to European intensive-care units: a cohort study. The Lancet Infectious Diseases, 11(1), 30-38.

Lee, Y.R., Miller, P.D., Alzqhari, S.K., Blanco, D.D., Haqer, J.D., & Kuntz, KS. (2018). Continuous infusion versus intermittent bolus of beta-lactams in critically ill patients with respiratory infections: a systematic review and meta-analysis. European Journal of Drug Metabolism and Pharmacokinetics, 43(2), 155-170.

Lee, Y.T., Kuo, S.C., Yang, S.P., Lin, Y.T., Tseng, F.C., Chen, T.L., et al. (2012). Impact of appropriate antimicrobial therapy on mortality associated with Acinetobacter baumannii bacteremia: relation to severity of infection. Clinical Infectious Diseases, 55(2), 209-215.

Leekha, S., Terrell, C.L., & Edson, R.S. (2011). General principles of antimicrobial therapy. Mayo Clinic Proceedings, 86(2), 156-167.

Levitt, D.G., & Levitt, M.D. (2016). Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements. International Journal of General Medicine, 9, 229-255.

Liebchen, U., Kratzer, A., Wicha, S.G., Kees, F., Kloft, C., & Kees, M.G. (2014). Unbound fraction of ertapenem in intensive care unit patients. The Journal of Antimicrobial Chemotherapy, 69(11), 3108-3111.

McKinnon, P.S., Paladino, J.A., & Schentag, J.J. (2008). 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. International Journal of Antimicrobial Agent, 31(4), 345-351.

Ñamendys-Silva, S.A., González-Herrera, M.O., Texcocano-Becerra, J., & Herrera-Gómez, A. (2011). Hypoalbuminemia in critically ill patients with cancer: incidence and mortality. The American journal of Hospice & Palliative Care, 28(4), 253-257.

Negi, S., Koreeda, D., Kobayashi, S., Iwashita, Y., & Shigematu, T. (2016). Renal replacement therapy for acute kidney injury. Renal Replacement Therapy, 2, 31.

Ohannessian, R., Gustin, M.P., Bénet, T., Gerbier-Colomban, S., Girard, R., Argaud, L., et al. (2018). Estimation of extra length of stay attributable to hospital-acquired infections in adult ICUs using a time-dependent multistate model. Critical Care Medicine, 46(7),1093-1098.

Pae, C.U. (2015). Why systematic review rather than narrative review. Psychiatry Investigation, 12(3), 417–419.

Patel, K., & Kirkpatrick, C.M. (2018). Basic pharmacokinetic principles. In: Udy, A.A., Roberts. J.A., Lipman, J., editors. Antibiotic pharmacokinetic/pharmacodynamics considerations in the critically ill. Singapore: Springer Nature Singapore Pte. Ltd.

Phu, V.D., Wertheim, H.F., Larsson, M., Nadjm, B., Dinh, Q,D., Nilsson, L.E., et al. (2016). Burden of hospital acquired infections and antimicrobial use in Vietnamese adult intensive care units. PLoS One, 11(1), e0147544.

Piccinni, P., Cruz, D.N., Gramaticopolo, S., Garzotto, F., Dal Santo, M., Aneloni, G., et al. (2011). Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT). Minerva Anestesiologica, 77(11), 1072- 1083.

Pouwels, K.B., Van Kleef, E., Vansteelandt, S., Batra, R., Edgeworth, J.D., Smieszek, T., et al. (2017). Does appropriate empiric antibiotic therapy modify intensive care unit-acquired Enterobacteriaceae bacteraemia mortality and discharge?. The Journal of Hospital Infection, 96(1), 23-28.

Rejeb, M.B., Sahli, J., Chebil, D., Khefacha-Aissa, S., Jaidane, N., Kacem, B., et al. (2016). Mortality among patients with nosocomial infections in tertiary intensive care units of Sahloul Hospital, Sousse, Tunisia. Archives of Iranian Medicine, 19(3), 179-185.

Roberts, J.A., & Lipman, J. (2013). Optimal doripenem dosing simulations in critically ill nosocomial pneumonia patients with obesity, augmented renal clearance, and decreased bacterial susceptibility. Critical Care Medicine, 41, 489–495.

Roberts, J.A., Taccone, F.S., Udy, A.A., Vincent, J.L., Jacobs, F., Lipman, J. (2011). Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrobial Agents and Chemotherapy, 55(6), 2704-2709.

Ruiz, J., Ramirez, P., Company, M.J., Gordon, M., Villarreal, E., Concha, P., et al. (2018). Impact of amikacin pharmacokinetic/pharmacodynamics index on treatment response in critically ill patients. Journal of Global Antimicrobial Resistance, 12, 90-95.

Sánchez, J.L., Dominguez, A.R., Lane, J.R., Anderson, P.O., Capparelli, E.V., & Cornejo-Bravo, J.M. (2010). Population pharmacokinetics of vancomycin in adult and geriatric patients: comparison of eleven approaches. International Journal of Clinical Pharmacology and Therapeutics, 48(8), 525- 533.

Schleibinger, M., Steinbach, C.L., Töpper, C., Kratzer, A., Liebchen, U., Kees, F., et al. (2015). Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients. British Journal of Clinical Pharmacology, 80(3), 525–533.

Setiawan, E., & Montakantikul, P. (2018). Pharmacokinetic and pharmacodynamic approach in adult critically-ill patients treated with standard dose of vancomycin for MRSA infection. Journal of the Medical Association of Thailand, 101, 555-62.

Taccone, F.S., Laterre, P.F., Dugernier, T., Spapen, H., Delattre, I., Wittebole, X., et al. (2010). Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Critical Care, 14(4), R126.

Tam, V.H., Chang, K.T., Zhou, J., Ledesma, K.R., Phe, K., Gao, S., et al. (2017). Determining β-lactam exposure threshold to suppress resistance development in Gram-negative bacteria. The Journal of Antimicrobial Chemotherapy, 72, 1421–1428.

Tamimi, N.A., & Ellis, P. (2009). Drug development: from concept to marketing!. Nephron Clinical Practice, 113(3), c125-31.

Taubert, M., Zoller, M., Maier, B., Frechen, S., Scharf, C., Holdt, L.M., et al. (2016). Predictors of inadequate linezolid concentrations after standard dosing in critically ill patients. Antimicrobial Agents and Chemotherapy, 60(9), 5254-5261.

Udy, A.A., Baptista, J.P., Lim, N.L., Joynt, G.M., Jarrett, P., Wockner, L., et al. (2014). Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*. Critical Care Medicine, 42(3), 520- 527.

Udy, A.A., Roberts, J.A., Boots, R.J., Paterson, D.L., & Lipman, J. (2010). Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clinical Pharmacokinetics, 49, 1–16.

Udy, A.A., Roberts, J.A., Shorr, A.F., Boots, R.J., & Lipman, J. (2013). Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Critical Care, 17, R35.

Uwingabiye, J., Lemnouer, A., Baidoo, S., Frikh, M., Kasouati, J., Maleb, A., et al. (2017). Intensive care unit-acquired Acinetobacter baumannii infections in a Moroccan teaching hospital: epidemiology, risk factors and outcome. Germs, 7(4), 193-205.

Yoshizawa, K., Ikawa, K., Ikeda, K., Kumon, H., Ohge, H., & Morikawa, N. (2012). Optimisation of imipenem regimens in patients with impaired renal function by pharmacokinetic-pharmacodynamic target attainment analysis of plasma and urinary concentration data. International Journal of Antimicrobial Agents, 40, 427-433.

Yu, Z., Pang, X., Wu, X., Shan, C., & Jiang, S. (2018). Clinical outcomes of prolonged infusion (extended infusion or continuous infusion) versus intermittent bolus of meropenem in severe infection: a meta-analysis. PLoS One, 13(7), e0201667.

Zarb, P., Coignard, B., Griskeviciene, J., Muller, A., Vankerckhoven, V., Weist, K., et al. (2012). The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcare-associated infections and antimicrobial use. Eurosurveillance, 17(46), pii: 20316.

Zelenitsky, S.A., & Ariano, R.E. (2010). Support for higher ciprofloxacin AUC 24/MIC targets in treating Enterobacteriaceae bloodstream infection. The Journal of Antimicrobial Chemotherapy, 65(8), 1725-1732.

Zhang, Y., Yao, Z., Zhan, S., Yang, Z., Wei, D., Zhang, J., et al. (2014). Disease burden of intensive care unit-acquired pneumonia in China: a systematic review and meta-analysis. International Journal of Infectious Diseases, 29, 84-90.

Zhou, Q.T., He, B., Zhang, C., Zhai, S.D., Liu, Z.Y., & Zhang, J. (2011). Pharmacokinetics and pharmacodynamics of meropenem in elderly chinese with lower respiratory tract infections: population pharmacokinetics analysis using nonlinear mixed-effects modelling and clinical pharmacodynamics study. Drugs & Aging, 28(11), 903-912.