Optimization of Intermittent Vancomycin Dosage Regimens for Thai Critically Ill Population Infected by MRSA in the Era of the “MIC Creep” Phenomenon

Eko Setiawan, Lakkana Suwannoi, Preecha Montakantikul, Busba Chindavijak


Background: the shifting of minimum inhibitory concentration (MIC) of methicillin-resistant Staphylocuccus aureus (MRSA) strains to the higher value has emerged to worsen clinical outcome to the patients particularly critically ill population.  The aim of this study was to identify the most appropriate dosage regimen of vancomycin to treat infection caused by MRSA with higher MIC in critically ill Thai population. Methods: 10,000 replications of intermittent vancomycin dosage regimens were performed using Monte Carlo simulation. Pharmacokinetic parameters were derived from a population pharmacokinetic study conducted specifically in Thai population. The probability of target attainment (PTA) and cumulative fraction of response (CFR) of each dosage regimen were calculated. Risk of nephrotoxicity was also calculated and used as a consideration in determining the most appropriate dosage regimen of vancomycin. Results: in order to achieve desired PTA > 80% vancomycin at higher dosing regimens were needed including 3g/day and 4 g/day for MIC 1.5mg/L and 2.0 mg/L, respectively. Highest CFR of 94.40% and 93.57% were from vancomycin 1 g every 6 h and 2 g every 12h. Standard dose of vancomycin and total dose of vancomycin 3 g/day provided approximately 51% and 73% CFR. Risk of nephrotoxicity afforded by giving 1.5g every 12h and 2g every 12h of vancomycin were 26.59% and 31.20%, respectively. Conclusion: the result from this study recommended intermittent dosage regimen 1.5g every 12h and 2g every 12h should be implemented as definite antibiotic treatment when considered infection caused by MRSA with MIC 1.5 and 2.0 mg/L, respectively.


Vancomycin; Critically Ill; Thai Population; Monte Carlo Simulation; MIC Creep


Choi EY, Huh JW, Lim CM, et al. Relationship between the MIC of vancomycin and clinical outcome in patients with MRSA nosocomial pneumonia. Intensive Care Med. 2011;37(4):639-47.

van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis. 2012;54(6):755-71.

Yeh YC, Yeh KM, Lin TY, et al. Impact of vancomycin MIC creep on patients with methicillin-resistant Staphylococcus aureus bacteremia. J Microbiol Immunol Infect. 2012;45(3):214-20.

Wi YM, Kim JM, Joo EJ, et al. High vancomycin minimum inhibitory concentration is a predictor of mortality in methicillin-resistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents. 2012;40(2):108-13.

Rybak MJ, Lomaestro BM, Rotschafer JC, 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):1275-9.

Zelenitsky S, Alkurdi N, Weber Z, Ariano R, Zhanel G. Preferential emergence of reduced vancomycin susceptibility in health care-associated methicillin-resistant Staphylococcus aureus isolates during continuous-infusion vancomycin therapy in an in vitro dynamic model. Antimicrob Agents Chemother. 2011;55(7):3627-30.

Rose WE, Knier RM, Hutson PR. Pharmacodynamic effect of clinical vancomycin exposures on cell wall thickness in heterogeneous vancomycin-intermediate Staphylococcus aureus. J Antimicrob Chemother. 2010;65(10):2149-54.

DeRyke CA, Alexander DP. Optimizing vancomycin dosing through pharmacodynamic assessment targeting area under the concentration-time curve/minimum inhibitory concentration. Hosp Pharm. 2009;44(9):751-65.

Rowland M, Tozer TN. Clinical pharmacokinetics and pharmacodynamics concepts and applications. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

Ritschel WA, Kearns GL. Handbook of basic pharmacokinetics. 7th ed. Washington DC: American Pharmacists Association; 2009.

Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840-51.

Revilla N, Martín-Suárez A, Pérez MP, González FM, Fernández de Gatta Mdel M. Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmaco-dynamic simulation. Br J Clin Pharmacol. 2010;70(2):201-12.

McMaster J, Booth MG, Smith A, Hamilton K. Meticillin-resistant Staphylococcus aureus in the intensive care unit: its effect on outcome and risk factors for acquisition. J Hosp Infect. 2015;90(4):327-32.

Hetem DJ, Derde LPG, Empel J, et al. Molecular epidemiology of MRSA in 13 ICUs from eight European countries. J Antimicrob Chemother. 2016;71:45–52.

Stevens V, Yoo M, Brown J. Cost and length of stay associated with vancomycin-induced nephrotoxicity. Value Health. 2013;16:A323-A636.

Minejima E, Choi J, Beringer P, Lou M, Tse E, Wong-Beringer A. Applying new diagnostic criteria for acute kidney injury to facilitate early identification of nephrotoxicity in vancomycin-treated patients. Antimicrob Agents Chemother. 2011;55(7):3278-83.

Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis. 2009;49(4):507-14.

van Hal SJ, Paterson DL, Lodise TP. 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):734-44.

Horey A, Mergenhagen KA, Mattappallil A. The relationship of nephrotoxicity to vancomycin trough serum concentrations in a Veteran’s population: a retrospective analysis. Ann Pharmacother. 2012;46(11):1477-83.

Purwonugroho TA, Chulavatnatol S, Preechagoon Y, Chindavijak B, Malathum K, Bunuparadah P. Population pharmacokinetics of vancomycin in Thai patients. ScientificWorld J. 2012;2012:762649.

European Committee on Antimicrobial Susceptibility Testing. Antimicrobial wild type distributions of microorganisms [Internet]. 2013 [cited 2013 Feb 20]. Available from: http://mic.eucast.org/Eucast2/SearchController/search.jsp?action=perform Search&BeginIndex=0&Micdif=mic&NumberIndex=50&Antib=38&Specium=-1.

Keel RA, Kuti JL, Sahm DF, Nicolau DP. Pharmacodynamic evaluation of i.v. antimicrobials against Pseudomonas aeruginosa samples collected from U.S. hospitals. Am J Health - Syst Pharm. 2011;68(17):1619-25.

Kuti JL, Kiffer CR, Mendes CM, Nicolau DP. Pharmacodynamic comparison of linezolid, teicoplanin and vancomycin against clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci collected from hospitals in Brazil. Clin Microbiol Infect. 2008;14(2):116-23.

Patel N, Pai MP, Rodvold KA, Lomaestro B, Drusano GL, Lodise TP. Vancomycin: we can’t get there from here. Clin Infect Dis. 2011;52(8):969-74.

Fernández de Gatta Mdel M, Santos Buelga D, Sanchez Navarro A, Dominguez-Gil A, Garcıa MJ. Vancomycin dosage optimization in patients with malignant haematological disease by pharmacokinetic/pharmacodynamic analysis. Clin Pharmacokinet. 2009;48(4):273-80.

Canut A, Isla A, Betriu C, Gascon AR. Pharmacokinetic-pharmacodynamic evaluation of daptomycin, tigecycline, and linezolid versus vancomycin for the treatment of MRSA infections in four western European countries. Eur J Clin Microbiol Infect Dis. 2012;31:2227-35.

Full Text: PDF


  • There are currently no refbacks.

Copyright (c) 2019 Acta Medica Indonesiana