Pharmacokinetics of single dose prophylactic Gentamicin during Cardiac surgery

Objective: • To assess whether patients undergoing cardiac surgery have adequate and safe serum level of gentamicin peri-

operatively and within the first 24 hours of surgery which would provide effective cover for Gram negative organisms causing SSI in cardiac surgery at our Centre.

Backround • Perioperative antibiotic prophylaxis in cardiac surgery is given to reduce surgical site infection (SSI). These

include sternal wound infections and infective endocarditis which are associated with significant morbidity and mortality rates (1, 2).

• A combination of b-lactamase-stable penicillin (usually flucloxacillin) plus an aminoglycoside is commonly used in the UK to provide cover for Staphylococci and Gram negative organisms respectively (3, 4).

• Antibiotic prophylaxis in cardiac surgery is usually given for 24–48 h, although there is evidence that a single dose of antibiotic at induction of anaesthesia is as effective as multiple-dosing regimens (5, 6)

• A single dose of gentamicin 5mg/kg at induction, plus Flucloxacillin for 24hrs, is currently used in our centre. • However routine surveillance has demonstrated a significant increase in the rate of SSI caused by Gram negative

bacteria in our centre recently which has been of great concern. • Pharmacokinetics of gentamicin during cardiac bypass patients is not well described in the literature

Results: • The mean pre-operative eGFR was above 50 ml/min for the first cohort; all 14 patients had gentamicin peak

concentration of > 10 mg/L during cardiac bypass period (CBP). All but one patient had gentamicin level between 4-10 mg / L by the time of arrival to ICU (4-6 hours after first dose).

• The mean pre-operative eGFR for the second cohort was also >50ml/min. All patients with pre-operative eGFR> 90ml/min had gentamicin levels <1mg/L at 24-26 hours.

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Conclusions: • A single dose of 5mg/kg of gentamicin used in cardiac surgery prophylaxis at our centre achieved adequate and safe serum concentration during the first 24 hours of cardiac surgery.

Cohort 1

Methods: • Two separate cohorts of randomly selected patients were recruited in this study • All patients, except one, evaluated in the study had an estimated glomerular filtration rate

(eGFR)>50. • All non-penicillin allergic patients undergoing cardiac surgery received 1 gram of Flucloxacillin and

5mg/kg of gentamicin (maximum of 450 mg) as single dose at time of induction of anaesthesia. Three further doses of Flucloxacillin was given at 4 hourly intervals.

• In the first cohort, 14 patients who were admitted electively for cardiac surgery were randomly selected. Serum gentamicin levels were monitored at 4 time points (30, 90, 240, and 300 minutes after first dose).

• The second cohort involved monitoring serum gentamicin levels of another 16 randomly selected elective patients at time of arrival to intensive care unit (4-6 hours from first dose of gentamicin) and thereafter every four hours for the first twenty-four hours.

Amer Harky1, Benny P Cherian2, Satya Das2, Andrew Smith1, Alex Shipolini3, Robert L Serafino Wani2

1 Department of Perioperative Medicine, Barts Heart Centre, St. Bartholomew’s Hospital, Barts Health, EC1A 7BE, London, UK 2 Department of Infection, St. Bartholomew’s Hospital, Barts Health, EC1A 7BE, London, UK

3 Department of Cardiothoracic Surgery, Barts Heart Centre, St. Bartholomew’s Hospital, Barts Health, EC1A 7BE,

London, UK

Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Age 61 62 30 60 73 60 41 69 62 54 64 57 83 72

Sex M M M M M M M F M M M M M M

Surgery CABG tAVRRt Atrial Mass ExcisionCABG CABG mMVR CABG MVR CABG AVR AVR CABG AVR CABG

Baseline eGFR >90 75 >90 58 67 >90 50 >90 80 87 81 90 >90 >90

BMI 22 24 16 23 33 23 41 21 31 29 31 20 20 32.1

Weight (kg) 79 89 56 83 101 82 114 65 105 99.5 106 69 70 104

Gentamicin dose 400 450 280 400 400 400 450 320 450 240 400 360 360 400

Gent level @ 30min >10 >10 >10 >10 >10 >10 >10 >10 >10 >10 >10 >10 >10 >10

Gent level @90min 7.59 >10 3.64 >10 >10 <1.0 >10 >10 >10 7.48 >10 >10 >10 8.24

Gent level @5hr 5.35 9.82 9.01 >10 >10 5.42 >10 9.14 >10 4.92 >10 9.48 >10 5.45

Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16

Age 56 62 72 24 18 69 75 75 79 59 70 67 85 65 63

Sex M M F M F M M F M M M M M M M

Surgery Type AVR CABG CABG VSARR ASD Repair AAR CABG mMVR CABG MVR CABG CABG CABG tAVR + AAR CABG

Baseline eGFR >90 55 10 >90 >90 79 66 42 87 80 67 78 79 72 >90

BMI 28 20 26 19 22 35 27 28 26 25 28 28 28 30 26

Weight (kg) 99 63 66 84 68 107 69 71 59 86 87 95 83 94 80

Gentamicin dose 400 310 400 400 280 400 300 400 380 440 400 500 400 480 320

Gentamicin level @ 4-6hrs 1.38 6.47 >10 6.26 >10 8.78 >10 9.97 9.65 4.83 8.02 7.94 6.16 8.92 6.12

Gentamicin level @ 8-10 hrs 4.33 >10 >10 2.36 4.13 3.98 >10 6.82 6.39 2.81 3.66 3.72 3.73 5.63 3.41

Gentamicin level @ 12-14 hrs <1.0 5.13 >10 1.24 1.5 1.89 7.06 4.92 4.51 1.51 2.88 2.09 1.97 3.34 1.16

Gentamicin level @ 18-20 hrs <1.0 3.83 5.48 <1.0 <1.0 1.07 5.82 3.27 3.68 <1.0 1.97 <1.0 1.58 1.85 <1

Gentamicin level @ 20-22 hrs <1.0 2.34 >10 <1.0 <1.0 <1.0 3.95 2.32 3.1 <1.0 1.36 <1.0 <1.0 <1.0 <1

Gentamicin level @ 24-26 hrs <1.0 1.52 9.39 <1.0 <1.0 <1.0 3.18 1.94 2.29 <1.0 1.14 <1.0 <1.0 <1.0 <1

References:

1. Calderwood, S. B., Swinski, L. A., Karchmer, A. W. et al., Prosthetic valve endocarditis. Analysis of factors affecting outcome of therapy. Journal of Thoracic and Cardiovascular Surgery,

1986, 92,776–783

2. Demmy, T. L., Park, S. B., Lieber, G. A. et al., Recent experience with major sternal wound complications. Annals of Thoracic Surgery, 1990, 49, 458–462

3. Wilson, A. P. R., Treasure, T., Sturridge, M. F. and Gru¨neburg, R. N., Antibiotic prophylaxis in cardiothoracic surgery in the United Kingdom, current practice. Thorax, 1986, 41, 396–400.

4. Parry, G. W., Holden, S. R. and Shabbo, F. P., Antibiotic prophylaxis for cardiac surgery: current practice. British Heart Journal, 1993, 70, 585–586.

5 . Conte, J. E. Jr, Cohen, S. N., Roe, B. B. et al., Antibiotic prophylaxis and cardiac surgery: a prospective double-blind comparison of single dose versus multiple-dose regimens. Annals of

Internal Medicine, 1972, 76, 943–949.

6. Hall, J. C., Christiansen, K., Carter, M. J. et al., Antibiotic prophylaxis in cardiac operations. Annals of Thoracic Surgery, 1993, 56, 916–922

Cohort 2

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