Pharmacokinetic & Pharmadynamic of Once Daily Aminoglycosides (ODA) and their Monitoring Janis Chan Pharmacist, UCH 25-4-2008 2008
Aminoglycosides (AG) 1. Gentamicin 2. Amikacin 3. Streptomycin 4. Neomycin ( No IV form in HA) 5. Tobramycin 6. Netilmicin 7. Kanamycin 8. Sisomicin
Spectrum of Activity Susceptible strains of gram ve bacteria Monotherapy for less serious infections eg. Uncomplicated UTI Combination therapy: => with β-lactam / quinolone for gram -ve bacteria eg severe Pseudomonas infection => with β-lactam gram +ve bacteria eg. Enterococcal / Staphylococcal endocarditis
Mode of Action
1. Concentration-dependent Killing Peak/MIC > 8-10 => achieves clinical response rate 90% JID 1987:155:93-99
2. Absorption : Poor oral bioavailability (1-2%) 3. Excretion : Mainly via kidney accumulate in renal impairment 4. Volume of distribution : ~25% of total BW (0.25-0.3L/kg) ~ ECF ( altered sign. in malnourished, obese, ascite or in ICU patients) 5. Distribution : Poor tissue penetration into bronchial secretions, eyes and CNS (even with inflammed meninges); except in kidney, urine, perilymph of inner ears 6. t½ : 2-3 hr (normal RFT); 28-86 hr (ESRF)
Toxicity / Side Effects Nephrotoxicity 5-10% Tends to be reversible Ototoxicity (difficult to assess) 0.5-3% (as high as 25% in some studies) Generally irreversible Others eg. Neuromuscular blockade, nausea, headache, hypersensitivity Low rate
Traditional Dosing (Multiple Daily Dosing Regimen: Sanford Guide 2008) Gentamicin/Tobramycin/ Netilmicin 1.7-2mg/kg Amikacin 7.5mg/kg Streptomycin (for TB) 15mg/kg Normal RFT q8h q12h q24h Impaired RFT (ml/min) 10-50 : q12-24h <10 : q48h 10-50: q24h <10 : q48h 10-50 : q24-72h <10 : q72-96h
Why change? Q8h..Q12h..Q24h.. Potential toxicities : 1. Nephrotoxicity 2. Ototoxicity More than 100 studies, reviews.. favoured ODA 1. As least as effective as traditional dosing 2. Less toxic (Course notes from Infectious diseases courses 3; HKU 21-22/07) EXTRA benefits : $$$$$ savings ( what are they??)
Rationales for the ODA Regimen Concentration-Dependent Killing: Higher the peak/mic ratio results higher killing rate Peak / MIC: ODA (10) vs TDA (5) Significant post-antibiotic effect (PAE) Suppress bacteria regrowth even when level below MIC Adaptive resistance (First Exposure Effect) Make organism susceptible to subsequent dose of AG (Enterobacteriaceae and P. aeruginosa in vitro) (International J. Clin Pharmacol & Therap 1997; 35(6):223-226)
Main Objectives of ODA Achieve a high aminoglycoside peak (~10 x MIC) to maximize efficacy Allow a drug-free interval of 3-5 hr to toxicity High peak (>10 x MIC) Drug free 3-5 hr
Eligible Patients ALL adult patients requiring aminoglycoside therapy EXCEPT: 1. Pregnany; 2. Extensive burn (>20% of body surface area) 3. Severe liver disease (e.g., ascites); 4. Severe renal disease (CrCl < 20 ml/min); 5. Neutropenia; 6. Enterococcal endocarditis; 7. Gram positive infections (when the aminoglycoside is used for synergy); 8. Aminoglycosides allergy; (International J. Clin Pharmacol & Therap 1997; 35(6):223-226) 9. History or signs of a hearing loss or vestibular dysfunction. NB. Not well studied in children, thus not recommended
How Popular USA : National Survey of Extended-Interval AG Dosing (EIAD) (CID 2000; 30:433-439) Aim Subjects Method Results & Findings Evaluate the adoption of EIAD 500 acute care hospitals, Random sample survey (questionnaire) 1. Response rate : 49.8% (n=249) 2. Adopted: ~ ¾ (74.7%) (4x yr 1993); 3. Equal or less toxicity (87.1%); 4. Equal efficacy (76.9%); 5. Cost savings (65.6%) 6. Monitoring : Shift to single determination of serum conc at 6-18h (61%) 7. Method to adjust renal dose : - Extend interval with the same dose (47%) - By Hartford method (32%)
How to dose ODA (1). Fixed Dose Approach Initial dose (Fixed dose): Gentamicin/Tobramycin Netilmicin Amikacin 3.5mg/kg 4.4mg/kg 15mg/kg Subsequent dose : same dose, interval based on CrCl CrCl (ml/min) Interval 60 and above 24 hours 40 to 60 36 hours 20 to 40 48 hours < 20 follow serial levels to determine time of next dose (level < 1 ug/ml) (Impact guideline 3rd edition)
Fixed Dose Approach - Criticism 1. Not adjusted for infection type 2. Not individualized based upon kinetic properties 3. Administered to patients with renal insufficiency
How to dose ODA (2). Individualized Single Daily AG Dosing using patient specific and target serum conc Optimize PD parameter Minimize unnecessary excess exposure Desired conc: : Single daily Dosing Pharmacotherapy 1999 Nov 19(11): 1252-60 Peak conc Sepsis Pneumonia Cystitis Pyelonephritis Osteomyelitis Trough conc Gent/ Tobra 10-12 16-20 6-8 12-14 12-16 < 0.3 Amikacin 60-70 60-70 40-50 60-70 60-70 < 5
How to dose ODA (3). Sanford Guide 2008 CrCl >80 60-80 40-60 30-40 20-30 10-20 <10-0 ml/min Gentamicin/ Tobramycin mg/kg 5.1 q24h 4 q24h 3.5 q24h 2.5 q24h 4 q48h 3 q48h 2 q72h Netilmicin 6.5 5 4 2 3 2.5 2 mg/kg q24h q24h q24h q24h q48h q48h Q72h Amikacin/ 15 12 7.5 4 7.5 4 3 Streptomycin mg/kg q24h q24h q24h q24h q48h q48h Q72h
Therapeutic Drug Monitoring (TDM) PURPOSE: Guide AND Monitor dosing regimen Evaluate efficacy AND potential toxicity
TDM for Aminoglycosides NOT indicated in patients : Receiving 24-h dosing regimen (ODA) Without concurrently administered nephrotoxic drugs ( eg. Vancomycin, amphotericin B, cyclosporin) Without exposure to contrast media Not quadriplegic or amputee Not in the ICU Younger than 60 yo Duration of planned therapy < 5-7 days (Impact guideline 3rd edition)
Treatment Duration.. how long? 1. BNF (51) Whenever possible treatment should not > 7 days 2. JAC: 2006 (58) 651-656 Hospital Henri Mondor (France) - conduct an audit to determine appropriate use of AG, based on established guidelines. Guidelines with 5 criteria:..duration of treatment should not > 5 days except for endocarditis or severe infection due to antibiotic - resistant gram -ve bacilli or Pseudomonas.
Monitoring for TDA TDA Initial monitoring : obtain levels after ~4-5 t 1/2 (~3rd to 4th dose ~ reach steady-state); Peak sampling : IM : 1hr post IM IVF : 30 mins post 30-60mins infusion Trough sampling : Immediately before next dose Subsequent monitoring: weekly for prolonged therapy (RFT + drug level) Adjust dose, dosing interval or both
Trough Peak
Monitoring for ODA COMMON METHODS: 1. By measuring peak and trough as TDA Peak : Gentamicin:16-24 ug/ml; Amikacin: 56-64 ug/ml Trough : < 1ug/ml for both (Data provided by UCH Lab) 2. By Hartford Nomogram 3. By Barnes-Jewish Nomogram 4..
Level of TDA vs ODA Gentamicin Peak : Trough: Amikacin Peak : Trough: TDA (µg/ml) 5-10 < 2 20-25 25 < 10 ODA (µg/ml) 16-24 < 1 56-64 64 < 1 # ODA : Higher Peak, Lower Trough Data from UCH Lab
Hartford ODA Program? Initiated by Hartford Hospital in 1994 Aim to maximize bacterial killing by optimizing peak/mic ratio and toxicities Desired model : achieve Peak/MIC ratio 10:1, drug free period <0.5ug /ml for at least 4 hr Use Gentamicin 7mg/kg/day (fixed dose) Confirm by actual patient. Patient were sorted into 3 groups acc. to RFT Outcomes from 2184 patients: Clinically apparent ototoxicity ( n=3) Nephrotoxicity (n=27) Conclusions : clinically effective, less toxicity & the monitoring method is cost effective (ACC, Mar. 1995, p650-655)
Hartford Nomogram ~ Gentamicin (ACC, Mar. 1995, p650-655) CrCl 20ml/min CrCl 40ml/min CrCl 60ml/min
Hartford Nomogram-Adjusted Concentration (ug/m l) 7 6 5 4 3 2 1 0 Gentamicin nomogram (3.5mg/kg) q48h q36h q24 6 7 8 9 10 11 12 13 14 Sample time after start of infusion (h)
Hartford Nomogram ~ Amikacin Concentration (ug/ml) 30 25 20 15 10 5 0 Amikacin nomogram (15mg/kg) q48h q36h q24h 6 7 8 9 10 11 12 13 14 Sample time after start of infusion (h)
Use of Hartford Nomogram to Monitor Once Daily Aminoglycosides 1. Obtain random level 6-14 hrs after dose given (every dose is the 1st dose) MUST state the Time of sampling and Dosing Protocol (mg/kg) 2. Plot the obtained value on the Nomogram 3. Determine the appropriateness of dosing interval
Hartford Nomogram-Adjusted 7 Gentamicin nomogram (3.5mg/kg) C oncentration (ug/m l) 6 5 4 3 2 1 X X X q48h q36h q24h X X X X 0 6 7 8 9 10 11 12 13 14 Sample time after start of infusion (h)
Case study 1 A patient received 3.5mg/kg of gentamicin at 0700. A level drawn at 1530 was 3.8 mcg/ml. Using the nomogram, determine the appropriate dosing interval. Time after infusion to blood drawn : 8.5 hrs Gentamicin level : 3.8mcg/ml Suggested dosing interval : Q36h 7 Gentamicin nomogram (3.5mg/kg) Concentration (ug/ml) 6 5 4 3 2 1 X q48 q36h q24 0 6 7 8 9 10 11 12 13 14 Sample time after start of infusion (h)
Case study 2 A patient received 5mg/kg of gentamicin at 0700. A level drawn at 1900 was 8mcg/ml. Using the nomogram, determine the appropriate dosing interval. Time after infusion to blood drawn : 12 hrs Gentamicin level : (8/1.4)=5.7mcg/ml Suggested dosing interval : Stop 7 Gentamicin nomogram (3.5mg/kg) Concentration (ug/ml) 6 5 4 3 2 1 q48 q36h q24 X 0 6 7 8 9 10 11 12 13 14 Sample time after start of infusion (h)
Pharmacist Role??? Any? Significant? Effective?
Clinical & economic outcomes of Pharm-managed aminoglycoside or vancomycin therapy AJHP Vol 62 Aug 1, 2005 Aim Subjects Method Results & Findings Evaluate the association bet. Pharm-managed AG or VC tx for hospitalized Medicare pat. who had diagnoses indicating probable tx with these abx and the major health care outcomes (death rate, length of stay, Medicare charge, hearing loss, RFT) 199,082 Medicare patients treated in 961 hospitals (in 1995) Questionnaires and data search 484/961 hospitals (>50%) offered this service Hospitals without such services shown: (p < 0.0001) Death rate 6.71% (1048 pt) Length of stay 12.28 % (131660 d) Total Medicare charges 6.3% ($140,745,924) Drug charges 8.15% ($34,769,250) Lab. charges 7.8% ($22,530,474) Hearing loss 46.42% (134 pt) Renal impairment 33.95% (2801pt) Presence of this pharmaceutical service significantly improved health care & economic outcomes in the study group
Pharmacist-managed Drug Therapy Definition: A pharm under the authorization of a prescriber, ordering lab tests, initiating drug therapy or adjusting dosage to obtain the desired therapeutic outcome eg. Anticoagulant, Antibiotics Fastest growing clinical pharmacy service in US hospitals ( 25% of hospitals studied in 1989, 70% in 1998; 180%) Pharmacist-managed AG/VC therapy from >30% of hospitals in 1992 to > 60% in 1998 (~ 100%) 199082/961 hospitals to ALL Medicare pts (730328) results in 3.67 X outcomes AJHP Vol 62 Aug 1, 2005
To Start With 1. PHARMACISTS (~ 15 min/patient/day) 2. Familiarize drug PK/PD eg. training packet for pharmacist, CE. 3. Find useful tools for dose calculation, eg. formulae, automated calculators 4. Communicate with physicians, nurses, hospital administrators