Therapeutic Drug Monitoring (TDM) Gentamicin

Transcription

1 TDM is required for patients on aminoglycosides (e.g. gentamicin, amikacin, tobramycin) and glycopeptides (e.g.vancomycin). Serum concentration monitoring aims to avoid both excessive and sub-therapeutic concentration thereby preventing toxicity and ensuring efficacy. The following sections provide detailed instructions on how to dose, monitor and administer these agents. Antibiotic doses should not be withheld pending on antibiotic assays unless there are clinical grounds to suspect assay result will be significantly abnormal or the patient is at risk of renal toxicity (e.g on concurrent nephrotoxic agents). Gentamicin In severe Gram-negative bacterial sepsis, the addition of an aminoglycoside antibiotic such as gentamicin broadens the spectrum of cover, specifically to include activity against Pseudomonas aeruginosa. Gentamicin works synergistically in combination with -lactam antibiotics to enhance their activity against enterococci and streptococci. Hence they are often combined when treating endocarditis caused by these organisms. Patient with a family history of deafness should not be given gentamicin due to risk of irreversible otoxicity even when the drug is within therapeutic range 1. Dose recommendations Gentamicin does not distribute well into fatty tissues therefore should be dosed according to the patient s ideal body weight (IBW). Use the following equations to calculate IBW: IBW for males (kg) = 50 + (2.3 x height in inches over 5 ft) IBW for females (kg) = (2.3 x height in inches over 5 ft) Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 1

2 The following chart tabulates height against ideal body weight, and indicates the weight above which the patient is defined as being obese: MEN WOMEN Height IBW (kg) Obese if IBW (kg) Obese if > ft cm >kg kg Patient Category Obese Between IBW and not obese <IBW Gentamicin dosage weight Use adjusted body weight: IBW (actual body weight IBW) Use IBW Use actual body weight Creatinine Clearance (CrCl) The egfr can be used as a quick estimate for calculating initial dose. Do not use egfr in patients at both extremes of weight (BMI <18.5kg/m 2 or greater than 30kg/m 2 ). The absolute glomerular filtration rate or creatinine clearance (calculated from the Cockcroft and Gault formular- see below) should be used in these cases. Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 2

3 *Estimated renal function (Creatinine clearance - CrCl) Creatinine clearance may be estimated using the Cockcroft and Gault equation below: Male Female CrCl = 1.23 (140 age) x Weight* (kg) Serum Creatinine (μmol/l) CrCl = 1.04 (140 age) x Weight* (kg) Serum Creatinine (μmol/l) * Obese patients those whose actual weight is 20% over their IBW, should have their dose calculated on their adjusted IBW (see above) This equation will not work for Muscle wasting (patient s CrCl will be overestimated) Oedematous patients (use IBW) Ascites (use IBW and consider dilutional effect on serum creatinine) Acute renal failure. This may represent non-steady state serum creatinine levels and may underestimate the level of renal impairment CrCl can overestimate renal function in the elderly, consider 20% reduction of calculated CrCl for patients >80 years of age Gentamicin Regimens Gentamicin may be administered in several ways: 1. Single stat dose/once-daily regimen (see page 4-6) 2. Multiple daily dose synergistic regimens (e.g. in endocarditis) in adults: 1mg/kg 12 hourly (see page 7) 3. Conventional multiple daily dose therapeutic regimen: 3-5mg/kg in divided doses (8 hourly). Note: Once daily gentamicin regimen has largely superseded multiple daily dose regimens however may be used in certain circumstances (see page 8-9) Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 3

4 1. Single-dose (STAT) and Once daily (OD) gentamicin regimen (a) 5mg/kg once daily Dose: 5mg/kg OD (Maximum daily dose: 480mg) Administration: in 100ml normal saline or glucose 5% infused over 60mins Single-dose or once-daily administration in patients without pre-existing renal impairment is as effective as multiple daily dosing. There are various advantages in using a single daily dose of aminoglycoside: high peaks are more effective in achieving bacterial kill long post-antibiotic effect therefore not necessary to have levels above the mean inhibitory concentration (MIC) all day reduced risk of nephrotoxicity due to washout period allowed by infrequent dosing no greater risk of ototoxicity. monitoring of levels is simpler less nursing time required to administer the antibiotic Indications for OD regimen Severe sepsis of unknown cause and/or oliguria Intra-abdominal sepsis Urological sepsis Hospital-acquired pneumonia Exclusions for OD regimen Significant renal impairment Pregnant patients Endocarditis Patients with cystic fibrosis Patients with severe burns Most patients will need ONLY ONE DOSE of gentamicin when given in this way and in combination with a -lactam or other appropriate agent (the latter agent should be continued as clinically indicated). Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 4

5 A second dose MAY be given after a 24-hour interval if there is no clinical improvement, and providing the renal function has not become impaired. In this case, it is not necessary to check the serum level of gentamicin before giving the second dose. Should once-daily gentamicin be required for more than two doses, this should be guided by serum trough levels. Unless use for treatment of specific conditions i.e infective endocarditis and neutropenic sepsis, gentamicin should not be given > 5 days as this increase the risk of toxicity. (b) Reduced dose regimen in renal impairment (3mg/kg) Dose: 3mg/kg OD Administration: in 100ml normal saline or glucose 5% infused over 60mins This may be used in patients with severe sepsis and renal impairment (GFR <60ml/min). In patients receiving 2 doses, a post dose gentamicin level should be collected hours after the last dose (i.e a pre-dose level). Subsequent doses can be given when pre-dose level is <1mg/L. Monitoring level for once daily regimen Aim for a pre-dose (trough) level of < 1mg/L. Take a pre-dose level (18-24 hours) before giving the next dose. Clearly mark on the request form how many hours after the dose the sample has been taken. Unless patients are at risk of nephrotoxicity due to pre-existing renal impairment or are receiving multiple nephrotoxic agents (e.g some chemotherapy agents). Do not wait for the result to come back before giving the next dose, adjust the regimen around the next and subsequent dose if applicable. Post dose (peak) levels are not required. When the first dose of gentamicin has been given in the evening or night, the level should be taken by 1500hr the following day if this falls within hour window and sent for analysis immediately. Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 5

6 Serum levels Trough level < 1mg/L Continue current regimen. Provided renal function is stable, and continued gentamicin administration is required, monitor gentamicin levels twice weekly i.e. after the 1 st and 3 rd or 4 th dose. Trough level 1 2mg/L Trough level > 2mg/L Provided renal function is unchanged increase the dosing interval to hours. Omit next dose, re-assay in 24hours. Re-dose if clinically indicated when levels fall 1mg/L but extend the dosing interval accordingly for subsequent doses. If a patient s renal function is poor or deteriorates, await assay result and give dose when level <1mg/L. Always monitor renal function carefully by checking urine output daily and serum creatinine levels 2 3 times per week, especially for courses longer than 5 days duration. Risk of toxicity increases when duration of the treatment course exceeds 5 days. Prolonged courses of gentamicin must only be given only when there is a clear clinical need e.g. endocarditis. Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 6

7 2. Multiple daily dose synergistic regimen for infective endocarditis All cases of infective endocarditis must be referred to a cardiologist. Dose: 1mg/kg every 12 hours (Max 240mg/day) Administration: IV injection in 10-20ml saline or glucose 5% over at 3 5 mins IV infusion in 50ml normal saline or glucose 5% infused slowly over 20mins 30mins Gentamicin is given in low doses primarily for its synergistic effect with -lactam antibiotics. Regular monitoring of serum levels is important to ensure that there is enough present throughout a 24-hour period to act with the -lactam. Because gentamicin may be given for several weeks in this context, it is also important to ensure that the drug is being adequately renally excreted. Baseline audiometry is recommended for patients who require extended treatment (>2 weeks) with this agent. Monitoring levels for multi-dose synergistic regimen Take pre-dose (trough level) sample before giving the 3 rd or 4 th dose after commencement. This should also be the case after any dose adjustment. Post-dose (peak level) should be taken ONE HOUR after the end of the infusion. For streptococcal/enterococcal endocarditis infections aim for: Serum levels Pre-dose level <1mg/L Post-dose level around 3-5mg/L Pre-dose level >2mg/L Post dose level 5mg/L or above Pre-dose level <1mg/L Post dose level <3mg/L Pre-dose levels: <1mg/L Post-dose levels: 3-5mg/L Continue current regimen Re-check levels after a further 3 or 4 doses Omit further doses until level <1mg/L Increase the dosing interval to 24-hourly Re-check levels after a further 3 or 4 doses Increase dose and remain on 12-hourly dosing interval Re-check levels after a further 3 or 4 doses Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 7

8 3. Conventional multiple dose therapeutic regimen Multiple daily doses therapeutic regimen has largely been superseded by once daily gentamicin regimen (see section 1) and is generally not recommended except for pregnant patients, patients with cystic fibrosis or severe burns. Dose: 3-5mg/kg in divided doses (8-12 hourly) Administration: IV injection in 10-20ml saline or glucose 5% over at 3 5 mins IV infusion in 50ml normal saline or glucose 5% infused slowly over 20mins 30mins Monitoring levels for conventional multi-dose therapeutic regimen Both pre and post dose levels are required. Take pre-dose (trough level) sample before giving the 3 rd or 4 th dose after commencement. This should also be the case after any dose adjustment. Pre-dose (trough level) should be taken 8 or 12 hours after the previous dose for tds and bd regimens respectively Post-dose (peak level) should be taken ONE HOUR after the end of the infusion. Aim for pre-dose (trough) level < 2mg/L For most infections, aim for post-dose level of 5 10mg/L. Pre-dose level <2mg/L 2-3mg/L >3mg/L Continue current regimen. Ensure the patient is responding clinically. Further pre-dose level to be monitored twice weekly so long renal function is stable Increase dosing interval i.e. from tds to bd provided renal function is unchanged. Further gentamicin doses should be withheld until level <1mg/L. If further doses are required, re-start with increased interval/decreased dose. Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 8

9 Post-dose level Below target range Check previous dose(s) have been given as prescribed. If the low post-dose level appears genuine, gentamicin is subtherapeutic. Consider increasing the dose. Level is high Ensure level is not taken via an intravenous catheter that is used for the administration of the antibiotic as this will give false high level. Pre and Post dose levels Pre-dose level < 2mg/L (normal) Post dose level is above target range Consider reducing the dose (and the dose frequency). Final action dependent on trough level also. Reduce the dose Both pre-dose and post-dose levels are above target range Omit next dose Review need for further gentamicin Consider increasing the interval between doses Restart gentamicin when pre-dose level <2mg/L Reference: 1. S Rahman, E Russell, C Harry et al. Hearing in 44e45 year olds with m.1555a>g, a genetic mutation predisposing to aminoglycoside-induced deafness: a population based cohort study. BMJ open, Gentamicin prescribing guidelines updated 27 th Mar 2014, AL 9