Efficacy and safety of high-dose gentamicin re-dosing in ICU patients receiving haemodialysis

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17.4%, respectively. The Mann – Whitney test indicated that values of median dose-normalized AUC0 – 24 were higher in patients with the 3435 TT genotype, compared with the CC or CT genotype [2.61 (1.96 – 3.14) versus 1.77 (1.51 – 1.98);

P¼0.021]. Similarly, CLsswas lower in patients with the TT genotype compared with CC or CT genotype patients [0.38 (0.32 –0.51) versus 0.57 (0.51 –0.66);P¼0.021] (Figure1). Multiple regression analysis showed that 3435 TT was the only individual factor predictive of dose-normalized AUC0 – 24 (P¼0.01) and CLss(P¼0.012).

The 3435 C.T SNP is the only silent polymorphism that might influence P-gp expression in humans, probably by altering protein folding and function and changing the substrate specificity.⁹In this study we found for the first time an influence of theABCB1 3435 C.T polymorphism on daptomycin dose-normalized AUC0 – 24and CLss. The following limitations should be noted:

there was a small number of patients, and patients were being treated with different daptomycin dosages. These preliminary findings may explain the high inter-subject pharmacokinetic variability in daptomycin disposition and could represent a starting point for individualization of therapy, especially in patients with renal impairment.

Acknowledgements

Some of these data were presented at the Fifty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 2012 (oral presentation A-1769).

Funding

This study was supported by internal funding.

Transparency declarations

None to declare.

References

1 Shoemaker DM, Simou J, Roland WE. A review of daptomycin for injection (Cubicin) in the treatment of complicated skin and skin structure infections.Ther Clin Risk Manag2006;2: 169– 74.

2 Lemaire S, Van Bambeke F, Mingeot-Leclercq MPet al. Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytizedStaphylococcus aureusby the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and madin-darby canine kidney cells.Antimicrob Agents Chemother2007;51: 2748– 57.

3 Chan LM, Lowes S, Hirst BH. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability.Eur J Pharm Sci2004;21: 25– 51.

4 Hoffmeyer S, Burk O, von Richter Oet al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.Proc Natl Acad Sci USA2000;97: 3473– 8.

5 Baietto L, Corcione S, Pacini Get al. A 30-years review on pharmacokinetics of antibiotics: is the right time for pharmacogenetics?Curr Drug Metab2014; doi:10.2174/1389200215666140605130935.

6 Sakurai A, Tamura A, Onishi Y et al. Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implica- tions.Expert Opin Pharmacother2005;6: 2455–73.

7 Baietto L, D’Avolio A, De Rosa FGet al. Development and validation of a simultaneous extraction procedure for HPLC-MS quantification of daptomycin, amikacin, gentamicin, and rifampicin in human plasma.Anal Bioanal Chem2010;396: 791–8.

8 Baietto L, D’Avolio A, Pace Set al. Development and validation of an UPLC-PDA method to quantify daptomycin in human plasma and in dried plasma spots.J Pharm Biomed Anal2014;88: 66 –70.

9 Kimchi-Sarfaty C, Oh JM, Kim IWet al. A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity.Science2007;315: 525–8.

J Antimicrob Chemother2015 doi:10.1093/jac/dku369

Advance Access publication 19 September 2014

Efficacy and safety of high-dose gentamicin re-dosing in ICU patients receiving haemodialysis

Nicolas Venisse¹*, Antoine Dupuis², Julie Badin³, Rene´ Robert^3,4, Michel Pinsard³and Anne Veinstein³

1Pharmacokinetics Department, University Hospital of Poitiers, Poitiers, France;²Pharmacy Department and UMR CNRS 7285, University Hospital of Poitiers, Poitiers, France;³Medical Intensive Care Unit, University Hospital of Poitiers, Poitiers, France;⁴INSERM U927, University of Poitiers, Poitiers, France

*Corresponding author. Tel:+33-549444980; Fax:+33-549443973;

E-mail: nicolas.venisse@chu-poitiers.fr

Keywords:pharmacokinetics, pharmacodynamics, acute kidney injury

Sir,

Aminoglycosides are commonly used to treat severe infections in ICU patients.¹A ratio ofCmax/MIC.8 has been associated with increased clinical cure,²whereas aminoglycoside-related toxici- ties have been associated with AUC and trough plasma concentration.³Aminoglycoside pharmacokinetics in ICU patients may be altered during sepsis.⁴ Increased V results in insufficient plasma drug concentrations and the need for a high loading dose, while altered CL increases the risk of toxicity.⁵Commonly, septic critical-care patients have altered renal function requiring renal replacement therapy, which also interferes with aminoglycoside concentrations. Results of the studies conducted with patients with chronic kidney disease suggest a better pharmacokinetic management if aminoglycosides are administered pre- dialysis.⁶Very few data regarding aminoglycoside use in ICU patients requiring intermittent haemodialysis (IHD)^7,8are available aside from our previous study reporting an original schedule for gentamicin administration in ICU haemodialysed patients. It con- sists of an intravenous injection of 6 mg/kg gentamicin 1 h before dialysis.⁷These recent data involved only a single administration of Research letters

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Table 1. Actual body weight, gentamicin dosing, gentamicinCmaxmeasurement and main pharmacokinetic parameters estimated for each patient after gentamicin administrations

Dose no. Patient no.

Body

weight (kg) Dose (mg) Cmax(mg/L) Cmax/MIC V(L/kg)

CLHD

(mL/min)

CLNHD

(mL/min)

AUC0 – 24

(mg.h/L) AUC0 – 24/MIC C24(mg/L) Ctrough

1 1 80 500 21.8 10.9 0.277 89 17.7 138 69 2.7 1.6

2 62 380 24.1 24.1 0.250 64 3.6 222 222 6.6 2.0

3 60 360 43.0 86.0 0.135 49 6.1 228 456 3.5 1.4

4 63 360 22.3 NA 0.251 90 1.4 170 NA 5.2 2.2

5 102 600 25.9 NA 0.220 112 7.8 195 NA 4.9 1.0

6 72 430 34.1 68.2 0.170 95 4.8 166 332 3.2 1.9

mean+SD 73+16 451+99 28.5+8.4 47.3+35.6 0.217+0.054 83+23 6.9+5.7 187+35 270+164 4.4+1.5 1.7+0.4

Dose no. Patient no.

Body

weight (kg) Dose (mg) Cmax(mg/L) Cmax/MIC V(L/kg)

CLHD

(mL/min)

CLNHD

(mL/min)

AUC0 – 24

(mg.h/L) AUC0 – 24/MIC C24(mg/L)

Delay D1/D2 (h)

2 1 81 500 30.1 15.5 0.210 93 13.1 173 87 2.8 36

2 66 380 37.7 37.7 0.170 69 2.4 233 233 5.8 60

3 60 360 21.8 43.6 0.268 75 10.0 149 298 2.9 47

4 64 360 21.2 NA 0.296 96 1.4 167 NA 5.7 47

5 105 600 20.0 NA 0.310 111 10.9 195 NA 2.2 80

6 76 430 20.3 40.6 0.320 100 10.6 143 286 4.2 43

mean+SD 75+16 451+99 25.2+7.2 34.4+12.8 0.262+0.060 91+16 8.0+4.9 177+33 226+97 3.9+1.6 52+16

Cmax, measured peak concentration;Cmax/MIC, ratio ofCmaxover MIC;V, estimated volume of distribution; CLHD, estimated haemodialysis clearance; CLNHD, estimated interdialytic clearance;

AUC0-24, estimated area under the concentration curve; AUC0-24/MIC, ratio of AUC0-24over MIC;C24, estimated concentration 24 h after the beginning of infusion;Ctrough, measured concentration before re-administration; Delay D1/D2, delay between first and second gentamicin administration; NA, data not available.

All estimated pharmacokinetic parameters were obtained using the developed population pharmacokinetic model.

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gentamicin. However, in severe infections, aminoglycosides are usually administered to patients for 48–72 h.⁹To our knowledge, no data are available concerning the administration of two consecutive doses of gentamicin in ICU haemodialysed patients.

Therefore, the objective of this study was to describe the pharmacokinetics of two consecutive high doses of gentamicin administered before dialysis sessions in ICU haemodialysed patients.

This was a prospective, monocentric, observational study, performed in the medical ICU of our hospital. The study protocol was approved by the French Society for Critical Care ethics committee:

no written informed consent was required, but an informational let- ter had to be given to the patient or relatives. Six adult critical-care patients with acute kidney injury requiring IHD and suffering from infection treated with gentamicin were included. All of the enrolled patients received two consecutive gentamicin doses scheduled 48 – 72 h apart, depending on gentamicin trough concentration.

The gentamicin was re-administered when plasma concentrations below 2 mg/L were achieved. Gentamicin (6 mg/kg, based on actual body weight; Schering Plough, SAS) was infused intravenously over a period of 30 min. IHD was performed using an AK 200^TM ULTRAS machine (Gambro Inc.). All subjects were dialysed accord- ing to a standardized method. The dialysis treatment was carried out for 4 h. Blood flow rate was kept constant between 200 and 300 mL/min. The dialysis session was started 30 min after the end of each gentamicin infusion. Blood samples were drawn 1 (Cmax), 6, 12 and 20 h after the start of infusion and every 12 h until concentrations below 2 mg/L (Ctrough) were attained for the first gentamicin administration (D1) and up to 24 h for the second administration (D2). Measurements of gentamicin concentrations were performed on a Modular analyser (Roche Diagnostics).

A one-compartment model with zero-order input and first- order elimination was developed in WinNonlin (Pharsight). The model was parameterized in terms of interdialytic clearance (CLNHD), haemodialysis clearance (CLHD) andV.^6,7When MIC was available,Cmax/MIC and AUC0 – 24/MIC were calculated in order to assess efficacy.^2,10

All of the enrolled patients were male and completed the study. Their mean age was 64+13 years and their mean admis- sion weight was 73+16 kg with a mean BMI of 25.9+4.9 kg/m². Table1shows individual pharmacokinetic parameters estimated in enrolled patients.

As previously reported,⁷the original regimen proposed here (i.e. pre-haemodialysis infusion of gentamicin) provides benefits in terms of efficacy (Cmax/MIC and AUC0 – 24/MIC) as well as toxicity (Ctroughand AUC0 – 24) in comparison with a commonly recom- mended regimen in renal failure patients (1.7 mg/kg administered post-haemodialysis). Indeed, pre-haemodialysis gentamicin infusion maximizes pharmacokinetic/pharmacodynamic endpoints and no increase in AUC value was observed between D1 and D2 (Table1).

The concentration 24 h post-D1 did not allow re-administration at that time (Table1). Administration of a second gentamicin dose was delayed for a mean time of 52 h (36–80 h) post-dosing when gentamicin concentrations had dropped below 2 mg/L. A moder- ate increase in body weight was observed in patients between D1 and D2, of 2.0 kg on average, but the same dose of gentamicin was administered at D1 and D2, leading to optimalCmaxwhileCmax/MIC and AUC0 – 24/MIC ratios were successfully achieved for each patient for both doses (Table1).¹⁰

The mean value ofVincreased from 0.22 to 0.26 L/kg between D1 and D2 and a fluid gain was recorded in patients at D2, of 6.9 L on average. Furthermore, CLNHDvaried between D1 and D2, but remained very low in all cases (,20 mL/min). Despite high inter- and intra-individual variability of pharmacokinetic and pathophysiological parameters, adequate parameters of efficacy and toxicity were achieved in patients enrolled in this study.

In conclusion, these data highlight that administering high- dose gentamicin just prior to haemodialysis should allow administration of a second dose within a delay consistent with clinical requirements.

Acknowledgements

We wish to thank Jeffrey Arsham for his highly helpful reading of our original text.

Funding

This study was supported by internal funding.

Transparency declarations

None to declare.

References

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10 Drusano GL, Ambrose PG, Bhavnani SMet al. Back to the future: using aminoglycosides again and how to dose them optimally.Clin Infect Dis 2007;45: 753–60.

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