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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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General Research Article

Dose Optimization of Gentamicin in Critically Ill Neonates

Author(s): Kannan Sridharan*, Muna Al Jufairi, Ali Mohamed Qader and Ola A.M. Elsegai

Volume 21, Issue 4, 2020

Page: [270 - 280] Pages: 11

DOI: 10.2174/1389200221666200512111131

Price: $65

Abstract

Background: Appropriate dosing of gentamicin in critically ill neonates is still debated.

Objective: To assess the peak concentration (Cmax) and area-under-the-time-concentration curve (AUC0-24) of gentamicin and to simulate the recommended doses using the Monte Carlo method.

Methods: This was a retrospective study on critically ill neonates carried over a one-year period. The demographic characteristics, dosage regimen and gentamicin concentrations were recorded for each neonate. Using Bayesian pharmacokinetic modeling, Cmax and AUC0-24 were predicted. Dose recommendations for the target Cmax (μg/ml) of 12 were obtained, and Monte Carlo simulation (100,000 iterations) was used for predicting the pharmacokinetic parameters and recommended doses for various birth weight categories.

Results: Eighty-two critically ill neonates (with an average gestational age of 33.7 weeks; and birth weight of 2.1 kg) were recruited. Higher Cmax and AUC0-24 values were predicted in premature neonates, with greater cumulative AUCs in extremely preterm neonates. The average administered dose was 4 mg/kg/day and 75% of the participants had Cmax greater than 12 μg/ml following a single dose, and 85% were found to be at steady state. On the contrary, only 25% of the study population had the recommended AUC0-24 (above 125 μg-hr/ml). Simulation tests indicate that 90% of the critically ill neonates would achieve recommended Cmax with doses ranging between 5 and 6 mg/kg/day.

Conclusion: Currently used dose of 4 mg/kg/day is adequate to maintain Cmax in a large majority of the study population, with one-fourth population reporting the recommended AUC0-24. Increasing the dose to 5-6 mg/kg/day will more likely help to achieve both the recommended Cmax and AUC0-24 values.

Keywords: Aminoglycosides, clinical pharmacokinetics, gentamicin, Bayesian, Monte Carlo simulations, dosing strategy.

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[1]
Cantey, J.B.; Wozniak, P.S.; Sánchez, P.J. Prospective surveillance of antibiotic use in the neonatal intensive care unit: results from the SCOUT study. Pediatr. Infect. Dis. J., 2015, 34(3), 267-272.
[http://dx.doi.org/10.1097/INF.0000000000000542] [PMID: 25191849]
[2]
Stolk, L.M.; Degraeuwe, P.L.; Nieman, F.H.; de Wolf, M.C.; de Boer, A. Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates. Ther. Drug Monit., 2002, 24(4), 527-531.
[http://dx.doi.org/10.1097/00007691-200208000-00011] [PMID: 12142638]
[3]
Rivera-Chaparro, N.D.; Cohen-Wolkowiez, M.; Greenberg, R.G. Dosing antibiotics in neonates: review of the pharmacokinetic data. Future Microbiol., 2017, 12, 1001-1016.
[http://dx.doi.org/10.2217/fmb-2017-0058] [PMID: 28758800]
[4]
Stickland, M.D.; Kirkpatrick, C.M.; Begg, E.J.; Duffull, S.B.; Oddie, S.J.; Darlow, B.A. An extended interval dosing method for gentamicin in neonates. J. Antimicrob. Chemother.,, 2001,, 48,, 887- 893.5...
[http://dx.doi.org/10.1093/jac/48.6.887]
[5]
van Donge, T.; Pfister, M.; Bielicki, J.; Csajka, C.; Rodieux, F.; van den Anker, J.; Fuchs, A. Quantitative analysis of gentamicin exposure in neonates and infants calls into question its current dosing recommendations. Antimicrob. Agents Chemother., 2018, 62(4), e02004-e02017.
[http://dx.doi.org/10.1128/AAC.02004-17] [PMID: 29358294]
[6]
Bergenwall, M.; Walker, S.A.N.; Elligsen, M.; Iaboni, D.C.; Findlater, C.; Seto, W.; Ng, E. Optimizing gentamicin conventional and extended interval dosing in neonates using Monte Carlo simulation - a retrospective study. BMC Pediatr., 2019, 19(1), 318.
[http://dx.doi.org/10.1186/s12887-019-1676-3] [PMID: 31492162]
[7]
Klein, J.M. Drug monitoring levels in the NICU., https://uichildrens. org/health-library/drug-monitoring-levels-nicu[7 Oct 2019];
[8]
Neely, M.N.; Kato, L.; Youn, G.; Kraler, L.; Bayard, D.; van Guilder, M.; Schumitzky, A.; Yamada, W.; Jones, B.; Minejima, E. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob. Agents Chemother., 2018, 62(2), e02042-e17.
[PMID: 29203493]
[9]
Hodiamont, C.J.; Janssen, J.M.; de Jong, M.D.; Mathôt, R.A.; Juffermans, N.P.; van Hest, R.M. Therapeutic drug monitoring of gentamicin peak concentrations in critically ill patients. Ther. Drug Monit., 2017, 39(5), 522-530.
[http://dx.doi.org/10.1097/FTD.0000000000000432] [PMID: 28682925]
[10]
Chotigeat, U.; Narongsanti, A.; Ayudhya, D.P. Gentamicin in neonatal infection: once versus twice daily dosage. J. Med. Assoc. Thai., 2001, 84(8), 1109-1115.
[PMID: 11758844]
[11]
Serane, T.V.; Zengeya, S.; Penford, G.; Cooke, J.; Khanna, G.; McGregor-Colman, E. Once daily dose gentamicin in neonates - is our dosing correct? Acta Paediatr., 2009, 98(7), 1100-1105.
[http://dx.doi.org/10.1111/j.1651-2227.2009.01297.x] [PMID: 19397541]
[12]
Martínková, J.; Pokorná, P.; Záhora, J.; Chládek, J.; Vobruba, V.; Selke-Krulichová, I.; Chládková, J. Tolerability and outcomes of kinetically guided therapy with gentamicin in critically ill neonates during the first week of life: an open-label, prospective study. Clin. Ther., 2010, 32(14), 2400-2414.
[http://dx.doi.org/10.1016/j.clinthera.2011.01.013] [PMID: 21353108]
[13]
Sundaram, A.; Alshaikh, B.; Dersch-Mills, D.; Dobry, J.; Akierman, A.R.; Yusuf, K. Extended-interval dosing of gentamicin in premature neonates born at <32 Weeks’ gestation and >7 days of age. Clin. Ther., 2017, 39(6), 1233-1241.
[http://dx.doi.org/10.1016/j.clinthera.2017.05.343] [PMID: 28579209]
[14]
Sridharan, K.; Al Daylami, A. Clinical audit of gentamicin use by Bayesian pharmacokinetic approach in critically ill children. J Infect Chemother.,, 2020,, S1341-321X(20),, 30021--30020..
[http://dx.doi.org/10.1016/j.jiac.2020.01.007]
[15]
Craig, W.A. Optimizing aminoglycoside use. Crit. Care Clin., 2011, 27(1), 107-121.
[http://dx.doi.org/10.1016/j.ccc.2010.11.006] [PMID: 21144989]
[16]
Lingvall, M.; Reith, D.; Broadbent, R. The effect of sepsis upon gentamicin pharmacokinetics in neonates. Br. J. Clin. Pharmacol., 2005, 59(1), 54-61.
[http://dx.doi.org/10.1111/j.1365-2125.2005.02260.x] [PMID: 15606440]
[17]
Watterberg, K.L.; Kelly, H.W.; Angelus, P.; Backstrom, C. The need for a loading dose of gentamicin in neonates. Ther. Drug Monit., 1989, 11(1), 16-20.
[http://dx.doi.org/10.1097/00007691-198901000-00004] [PMID: 2911847]
[18]
Izquierdo, M.; Lanao, J.M.; Cervero, L.; Jimenez, N.V.; Domínguez-Gil, A. Population pharmacokinetics of gentamicin in premature infants. Ther. Drug Monit., 1992, 14(3), 177-183.
[http://dx.doi.org/10.1097/00007691-199206000-00001] [PMID: 1412601]
[19]
Antolik, T.L.; Cunningham, K.J.; Alabsi, S.; Reimer, R.A. Empirical gentamicin dosing based on serum creatinine levels in premature and term neonates. Am. J. Health Syst. Pharm., 2017, 74(7), 466-472.
[http://dx.doi.org/10.2146/ajhp160061] [PMID: 28336756]
[20]
Garinis, A.C.; Liao, S.; Cross, C.P.; Galati, J.; Middaugh, J.L.; Mace, J.C.; Wood, A.M.; McEvoy, L.; Moneta, L.; Lubianski, T.; Coopersmith, N.; Vigo, N.; Hart, C.; Riddle, A.; Ettinger, O.; Nold, C.; Durham, H.; MacArthur, C.; McEvoy, C.; Steyger, P.S. Effect of gentamicin and levels of ambient sound on hearing screening outcomes in the neonatal intensive care unit: A pilot study. Int. J. Pediatr. Otorhinolaryngol., 2017, 97, 42-50.
[http://dx.doi.org/10.1016/j.ijporl.2017.03.025] [PMID: 28483249]
[21]
El-Barbary, M.N.; Ismail, R.I.; Ibrahim, A.A. Gentamicin extended interval regimen and ototoxicity in neonates. Int. J. Pediatr. Otorhinolaryngol., 2015, 79(8), 1294-1298.
[http://dx.doi.org/10.1016/j.ijporl.2015.05.036] [PMID: 26071016]
[22]
Puia-Dumitrescu, M.; Bretzius, O.M.; Brown, N.; Fitz-Henley, J.A.; Ssengonzi, R.; Wechsler, C.S.; Gray, K.D.; Benjamin, D.K., Sr; Smith, P.B.; Clark, R.H.; Gonzalez, D.; Hornik, C.P. Gray, K.D.; Benjamin, D.K. Sr.; Smith, P.B.; Clark, R.H.; Gonzalez, D.; Hornik, C.P. Evaluation of gentamicin exposure in the neonatal intensive care unit and hearing function at discharge. J. Pediatr., 2018, 203, 131-136.
[http://dx.doi.org/10.1016/j.jpeds.2018.07.101] [PMID: 30244991]
[23]
Cooper, A.C.; Commers, A.R.; Finkelstein, M.; Lipnik, P.G.; Tollefson, L.M.; Wilcox, R.A.; Hoff, D.S. Otoacoustic emission screen results in critically ill neonates who received gentamicin in the first week of life. Pharmacotherapy, 2011, 31(7), 649-657.
[http://dx.doi.org/10.1592/phco.31.7.649] [PMID: 21923451]
[24]
Drusano, G.L.; Louie, A. Optimization of aminoglycoside therapy. Antimicrob. Agents Chemother., 2011, 55(6), 2528-2531.
[http://dx.doi.org/10.1128/AAC.01314-10] [PMID: 21402835]
[25]
Drusano, G.L.; Ambrose, P.G.; Bhavnani, S.M.; Bertino, J.S.; Nafziger, A.N.; Louie, A.; Louie, A. Back to the future: using aminoglycosides again and how to dose them optimally. Clin. Infect. Dis., 2007, 45(6), 753-760.
[http://dx.doi.org/10.1086/520991] [PMID: 17712761]

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