Abstract
Objectives
The aim of this study was to investigate the effect of daptomycin against methicillin-resistant staphylococci (MRSA and MRSE) bacteremia using computer modeling.
Methods
A pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to explain the data from an in vitro dynamic model employing time-kill curves for MRSA and MRSE was proposed. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed. Monte Carlo simulations were performed using pharmacokinetic parameters and pharmacodynamic data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. Simulations were conducted to assess the reduction in the number of colony-forming units (CFU)/mL for 18 days of treatment with daptomycin at doses of 6, 8, and 10 mg/kg/24 h or 48 h with variations in creatinine clearance (CLCR): 15–29 mL/min/1.73 m2, 30–49 mL/min/1.73 m2, 50–100 mL/min/1.73 m2, as well as for defining the probability of reaching the target fAUC/MIC = 80 in the same dose and clearance range. A PK/PD model with saturation in the number of bacteria in vitro, growth delay, and bacterial death, as well as Hill’s factor, was used to describe the data for both MRSA and MRSE.
Results
Monte Carlo simulations showed that for MRSA there was a reduction > 2 log CFU/mL with doses ≥ 6 mg/kg/day in 75th percentile of the simulated population after 18 days of treatment with daptomycin, whereas for MRSE this reduction was observed in 95th percentile of the population.
Conclusions
The presented in vitro PK/PD model and associated modeling approach were able to characterize the time-kill kinetics of MRSA and MRSE. Our study based on PTAs suggests that doses ≥ 6 mg/kg/day of daptomycin should be used to treat bacteremia caused by MRSA and MRSE in patients with CLCR of 15–29 mL/min/1.73 m2. For patients with CLCR ≥ 50 mL/min/1.73 m2, it would be necessary to employ a dose of 10 mg/kg/day to treat complicated bacteremias.
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References
Ayau P, Bardossy AC, Sanchez G, Ortiz R, Moreno D, Hartman P et al (2017) Risk factors for 30-day mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infections. Int J Infect Dis 61:3–6
Cheung GYC, Otto M (2010) Understanding the significance of Staphylococcus epidermidis bacteremia in babies and children. Curr Opin Infect Dis 23:208–216
Martínez-Meléndez A, Morfín-Otero R, Villarreal-Treviño L, González-González G, Llaca-Díaz J, Rodrígues-Noriega E et al (2015) Staphylococcal cassette chromosome mec (SCC mec) in coagulase negative staphylococci. Medicina Universitária 17:229–233
Paterson DL (2006) Clinical experience with recently approved antibiotics. Curr Opin Pharmacol 6:486–490
García-de-la-Mària C, Marco F, Armero Y, Soy D, Moreno A, Del Río A et al (2010) Daptomycin is effective for treatment of experimental endocarditis due to methicillin-resistant and glycopeptide – intermediate Staphylococcus epidermidis. Antimicrob Agents Chemother 54:2781–2786
Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI (2004) The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 38:1673–1681
Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW et al (2006) Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 355:653–665
Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos MJ (2012) Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: a case- control study. Clin Infect Dis 54:51–58
Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P et al (2013) Early use of daptomycin versus vancomycin for methicillin resistant Staphylococcus aureus bacteremia with vancomycin MIC 1 mg/L: a matched cohort study. Clin Infect Dis 56:1562–1569
Foerster S, Unemo M, Hathaway LJ, Low N, Althaus CL (2016) Time-kill curve analysis and pharmacodynamic modelling for in vitro evaluation of antimicrobials against Neisseria gonorrhoeae. BMC Microbiol 16:216–227
Mueller M, Peña A, Derendorf H (2004) Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. Antimicrob Agents Chemother 48(2):369–377
Cristinacce A, Wright JG, Macpherson M, Iaconis J, Das S (2021) Comparing probability of target attainment against Staphylococcus aureus for ceftaroline fosamil, vancomycin, daptomycin, linezolid, and ceftriaxone in complicated skin and soft tissue infection using pharmacokinetic/pharmacodynamic models. Diagn Microbiol Infect Dis 99 (4): 115292
Safdar N, Andes D, Craig WA (2004) In vivo pharmacodynamic activity of daptomycin. Antimicrob Agents Chemother 48:63–68
Alder J, Li T, Yu D, Morton L, Silverman J, Zhang XX et al (2003) Analysis of daptomycin efficacy and breakpoint standards in a murine model of Enterococcus faecalis and Enterococcus faecium renal infection. Antimicrob Agents Chemother 47:3561–3566
Bradley JS, Dudley MN, Drusano GL (2003) Predicting efficacy of antiinfectives with pharmacodynamics and Monte Carlo simulation. Pediatr Infect Dis J 22:982–992
Czock D, Markert C, Hartman B, Keller F (2009) Pharmacokinetics and pharmacodynamics of antimicrobial drugs. Expert Opinion Drug Metabob Toxicol 5:475–487
Liu Q, Rand K, Derendorf H (2004) Impact of tazobactam pharmacokinetics on the antimicrobial effect of piperacillin-tazobactam combinations. Int J Antimicrob Agents 23:494–497
Grégoire N, Marchand S, Ferrandière M, Lasocki S, Seguin P et al (2019) Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment. J Antimicrob Chemother 74:117–125
EUCAST Steering Committee (2006) EUCAST technical note on daptomycin. Clin Microbiol Infect 12:599–601
Louie A, Kaw P, Liu W, Jumbe N, Miller MH, Drusano GL (2001) Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection. Antimicrob Agents Chemother 45:845–851
Clinical and Laboratory Standards Institute (2014) Performance standards for antimicrobial susceptibility testing: twenty fourth informational supplement, vol. M100- S24. CLSI, Wayne, PA.
Di Paolo A, Tascini C, Polillo M, Gemignani G, Nielsen EI, Bocci G et al (2013) Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections. Intern J Antimicrob Agents 42:250–255
Benvenuto M, Benziger DP, Yankelev S, Vigliani G (2006) Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother 50:3245–3249
EUCAST. 2021. Available at: http// www.eucast.org/clinical_breakpoint (last accessed 19 may 2021).
Wu G, Abraham T, Rapp J, Vastey F, Saad N, Balmir E (2011) Daptomycin: evaluation of a high-dose treatment strategy. Intern J Antimicrob Agents 38:192–196
Duah M (2010) Daptomycin for methicillin-resistant Staphylococcus epidermidis native-valve endocarditis: a case report. Ann Clin Microbiol Antimicrob 9:1–4
Kullar R, Davis SL, Kaye KS, Levine DP, Pogue JM, Rybak MJ (2013) Implementation of an antimicrobial stewardship pathway with daptomycin for optimal treatment of methicillin-resistant Staphylococcus aureus bacteremia. Pharmacotherapy 33:3–10
Gawronski KM (2015) Successful use of daptomycin in a preterm neonate with persistent methicillin-resistant Staphylococcus epidermidis bacteremia. J Pediatr Pharmacol Ther 20:61–65
Nielsen EI, Friberg LE (2013) Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs. Pharmacol Rev 65:1053–1090
Salem AH, Zhanel GG, Ibrahim SA, Noreddin AM (2014) Monte Carlo simulation analysis of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit-isolated methicillin-resistant Staphylococcus aureus. Clin Exp Pharmacol Physiol 41:437–443
Moise PA, Amodio-Groton M, Rashid M, Lamp KC, Hoffman-Roberts HL, Yoon MJ et al (2013) Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant-lactams in patients with Staphylococcus aureus bacteremia and mild to moderate renal impairment. Antimicrob Agents Chemother 57:1192–1200
Cojutti PG, Candoni A, Ramos-Martin V, Lazzarotto D, Zannier ME, Fanin R et al (2017) Population pharmacokinetics and dosing considerations for the use of daptomycin in adult patients with haematological malignancies. J Antimicrob Chemother 72:2342–2350
Bhavnani SM, Ambrose PG, Hammel JP, Rubino CM, Drusano GL (2015) Evaluation of daptomycin exposure and efficacy and safety endpoints to support risk-versus-benefit considerations. Antimicrob Agents Chemother 60:1600–1607
Seaton RA, Menichetti F, Dalekos G, Beiras-Fernandez A, Nacinovich F, Pathan R et al (2015) Evaluation of effectiveness and safety of high-dose daptomycin: results from patients included in the European Cubicin® outcomes registry and experience. Adv Ther 32:1192–1205
Yabuno K, Seki M, Miyawaki K, Miwa Y, Tomono K (2013) High-dose, short-interval daptomycin regimen was safe and well tolerated in three patients with chronic renal failure. Clin Pharmacol 5:161–166
Budha NR, Lee RB, Hurdle JG, Lee RE, Meibohm B (2009) A simple in vitro PK/PD model system to determine time-kill curves of drugs against Mycobacteria. Tuberculosis (Edinb) 89:378–385
Asín-Prieto E, Rodríguez-Gascón A, Isla A (2015) Applications of the pharmacokinetic/pharmacodynamic (PK/PD) analysis of antimicrobial agents. J Infect Chemother 21(5):319–329
Trang M, Dudley MN, Bhavnani SM (2017) Use of Monte Carlo simulation and considerations for PK–PD targets to support antibacterial dose selection. Curr Opin Pharmacol 36:107–113
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Menezes, B., Alves, I., Staudt, K. et al. PK/PD modeling of daptomycin against MRSA and MRSE and Monte Carlo simulation for bacteremia treatment. Braz J Microbiol 52, 1967–1979 (2021). https://doi.org/10.1007/s42770-021-00582-4
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DOI: https://doi.org/10.1007/s42770-021-00582-4