Therapeutic drug monitoring (vancomycin, aminoglycosides, voriconazole)

Cecilia Lau BScPharm, ACPR

ID/ASP Pharmacist – UAH. Edmonton, AB. Canada

cecilia.lau@ahs.ca

2023 JUL 11. ID SSR AHD

OUTLINE

• Vancomycin
• Aminoglycoside
• Tobramycin – CF case
• Gentamicin – IE cases
• Amikacin – MDR PsA case, NTM cases
• Antifungal
• Voriconazole – IA

I’ve picked 5 drugs and let’s:

• Work through cases (commonly encountered scenario) through the eyes of an ID pharmacist
• Just pretend the ID pharmacist gets to tell you this is what the patient should be on

The knowledge:

• Vancomycin … 70 years on!
• Aminoglycosides refresher

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Highly recommended-> Use your local guideline�

• Local guideline = Bugs & Drugs 🡪 under “antibiotics” 🡪 “vancomycin dosing and monitoring guidelines” Use Actual weight, beware of maximum dose recommendation
• Local guideline = Bugs & Drugs 🡪 under “antibiotics” 🡪 “aminoglycoside dosing and monitoring guidelines” 
• High dose EXTENDED interval dosing/monitoring guidelines
• EID in B&D = 7 mg/kg based on IBW.  If patient is cachexic and underweight – use Actual weight.  If actual weight is >20% of IBW, use dosing weight.  
• CONVENTIONAL dosing/monitoring guidelines
• synergy
• When you move or rotate elsewhere, know their local guideline  

Vancomycin

Actual weight!

Loading dose 25 –30 mg/kg to a max of 3G

Maintenance dose of 15 mg/kg to a max of 2G per dose then determine interval by estimation of renal function OR assessment of mode of dialysis

Assess IF you need a level and if you think you do, most patients should have level done during daytime and avoid weekends.

Vancomycin Dose�Local guideline (accessed 2023 JUL 10)

Interval 🡪Current recommendation (2023 JULY 10)

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OLD recommendation (no longer available on Bugs and Drugs APP) that may COME IN HANDY for the REALLY young with healthy kidneys (until they suffer from end organ damage due to ongoing illness)

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Vancomycin �S aureus bacteremia case

• 50M NFA, IVDU, MRSA colonized but otherwise healthy. ID CONSULT for blood culture growing GPC clusters preliminary S aureus – S pending. At time of consult on piptazo, vancomycin 1500 mg x 1 dose JUST given.
• You reviewed the chart to find useful information: Ht 185 cm wt 115 kg BMI = 34 Cr 150 (trending down from last night’s 190 as he’s getting IV fluid, looks like baseline Cr ~90 in the months before).
• You go on to do your usual intake and full consideration of SAB work up.
• Your final recommendation, medications related :
• 1. Change piptazo to cefazolin
• 2. Continue vancomycin IV – so what is your regimen?

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What should be your vancomycin regimen?�S aureus bacteremia case

• 35M 185 cm 115 kg Cr 150 (renal function could go either way, but pick a number for a best guess)
• Step 1 – Are you OK with the 1500 mg dose JUST given? Do you want to LOAD? Remember, IF you were to load, 25-30 mg/kg = 2875 – 3450 mg > round to closest multiples of 250 mg = 2750 or 3000 mg
• Subtract what the patient got from a dose you chose and “top up” > Eg. 3500 – 1500 = 2000 mg top up dose NOW or
• IF you would like to commit to the arbitrary recommended maximum load of 3G, your top up would be 3000 – 1500 = 1500 mg top up dose NOW
• Step 2 MAINTENANCE
• Dose? 15 mg/kg to a max of 2G = 1775 mg, round to the closest multiples of 250 – 1750 mg
• Interval? do a best guesstimate, using Cockcroft gault formula > est Clcr ~ 70 mL/min to help determine your dosing interval. Review your point of care reference, his Clcr falls within Q24H dosing

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Your orders should look like

• By the book (and if this was an exam), if you would like to ensure an adequate load is given, order a top up followed by your maintenance regimen. = Vancomycin 1500 mg x 1 followed by 1750 mg IV q24h
• Eventually, by experience, you may choose to give a top op dose but decide on a more aggressive maintenance due to age of 35 and AKI potentially rapidly resolving imminently = Vancomycin 1500 mg x 1 now followed by 1750 mg IV q12h
• For this case, let’s go with the more aggressive dosing as above.

Think about if you need to order a level? Order it now or order it when dosing timing has been stabilized?

I want a level, but before which dose and what is my target?

Based on that, you ordered a pre 4^th level because it falls on day time collection

• Top up was given at 18:00 = your total load finished then
• Q12H regimen was started at 08 – 20
• Your pre 4^th dose level came back at 22
• As you think about your desired trough
• Assess patient’s hemodynamics
• Assess patient’s urine output, Cr trend

Should I adjust? How do I adjust

• Before you adjust, double check if you actually still need vancomycin, and if the level is interpretable
• SAB now known to be MRSA
• Stop cefazolin
• Adjust vancomycin if needed
• Follow up on vancomycin MIC
• No missed dose?
• Level collected appropriately? Not 4-5 hours early?

SUPPOSE IT WAS COLLECTED CORRECTLY

• Do linear math
• 3500 mg/24H = 22 mg/L (PLUS 1 MORE DOSE) > you want a level somewhere between 10-20 so let’s pick 15 mg/L = your calculation gives you 2386 mg – ROUND to closest 250 mg = 2500 mg as divided doses
• New regimen = 1250 mg IV q12h, start at next dosing time

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Whether you adjust or not, when should you do a next vancomycin level now that you’ve established you will need to keep the vancomycin going?

• If your patient remains hemodynamically stable with no rapid change to renal function, next level in 5-7 days is fine
• Avoiding overnight levels?
• Avoid weekend levels?

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• What would really help you is if there’s ongoing monitoring of some bloodwork
• Specifically, WATCH YOUR KIDNEYS (u/o, cr trend)

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Aminoglycoside

Pay attention to your patient’s weight!

Extended interval dosing 7 mg/kg use, Hartford nomogram (in Bugs & Drugs app)

EID, If using 5 mg/kg, can do math and plot number on Hartfor nomogram OR use Urban & Craig nomogram

Conventional dosing – mostly used for synergy nowadays = peak of 3-4 is good enough

Tobramycin �Cystic Fibrosis Case

• 30M advanced CF admitted for acute exacerbation
• Ht 172 cm
• Ideal body weight = 70 kg
• Actual weight = 55 kg
• Cr 46 umol/L – stable
• Antimicrobial, admitted on this from HPT program:
• Meropenem 2G IV q8h
• Tobramycin 660 mg IV q24h

Dec 14th Sputum Culture

1+ MSSA

S - cloxacillin, TMP-SMX, cefazolin

R - clindamycin

2+ P. aruginosa mucoid

S - ceftazidime, cipro, gent, tobi, piperacillin

I - meropenem

R - imipenem

2+ Achromobacter spp.

S - ceftazidime, TMP-SMX, piperacillin

R - cipro, gent, tobi, amikacin

2+ Achromobacter xylosoxidans

S - ceftaz, TMP-SMX, gent, tobi, amikacin, pip

R - cipro

4+ MOF

What does our local guideline say?

• Dosing is under Pediatric section
• Monitoring is based on Hartford Nomogram
• Within the institute and also for HPT program, there’s varied practices amongst pharmacists monitoring tobramycin
• Some will ask for 8 hour level, perform ratio and extrapolate Hartford nomogram to assess
• Some will ask for trough only 🡪 undetectable being the goal
• Depending on who is assessing, adjustments may be
• 10% dose reduction or
• interval adjustment

• In the next few slides, I will go over what else is out there….

Guidelines?

• “in patients with CF and normal renal function, a dose of 10 mg/kg/d tobramycin given every 24 hours is predicted to produce a peak blood level of 25–35 mg/ml and a 9- to 11-hour period with the drug concentration below detectable levels. A dose of 10 mg/kg/d tobramycin given at 8-hour intervals is predicted to produce a peak blood level of only 7 to 10 mg/ml and with only a 1 to 2-hour period with the drug concentration below detectable levels”
• literature suggest HEID vs conventional – no difference with (controversial) benefit of lower risk of nephrotoxicity
• Their recommendation is 10 mg/kg/day tobramycin IV q24h
• Above approach still supported by 2019 Cochrane systemic review (Bhatt et al)

Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. (Flume et al. Am J Respir Crit Care Med Vol 180. pp 802–808, 2009)

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Literature Search Results

Extended-Interval Once-Daily Dosing of Aminoglycosides in Adult and Pediatric Patients with Cystic Fibrosis (Prescott, Nagel) Published in 2010.

• Systematic review that looked at efficacy and safety of EID.
• Important notes:
• Dosing of once daily aminoglycosides should be determined based on previous TDM.
• For tobramycin-naive patients, 10mg/kg once/day is appropriate, and adjust dosage based on monitoring.
• For monitoring in CF patients, 2 concentrations (one at 2 hours and one at 8-12 hours) after the first or second dose should be attained. From here, extrapolated Cmax and Cmin values calculated (targets or 20-30 mg/L and <1mg/L respectively), or alternatively an AUC of ~100 mgh/L.

Literature Search Results

Pharmacodynamic target attainment with high-dose extended-interval tobramycin therapy in patients with cystic fibrosis (DeGrado et al.) Published Dec 2013.

• Single center retrospective study of 272 adult CF patient admissions who received IV tobramycin at their institution between Sept 2005 to Feb 2011.
• Tobramycin 10mg/kg q24h based on ABW (or DBW if ABW>120% of IBW).
• Trough levels drawn 30-60min before second dose; Peak levels drawn 30-60min after second dose.
• Dosage adjustments made by 10% if outside of target ranges (<0.4 or ≥20 mg/L)
• Primary endpoint was reaching a peak goal of ≥20 mg/L. �

Literature Search Results

• Results
• The mean initial dose was 10.3±1.7 mg/kg and resulted in mean peak levels of 21.5±6.3 mg/kg.
• Out of 277 initial peaks drawn, only 154 (56%) were ≥20mg/L.
• 38% required dose adjustments for subtherapeutic levels (final mean dose of 10.7±1.7mg/kg).
• “Patients who achieved their pharmacodynamic goal received a higher initial dose and required fewer dose adjustments throughout their hospitalization.”
• More research needed to determine the efficacy of high dose extended interval tobramycin.
• Limitations
• Focused on target levels and not clinical outcomes or improvement.
• Early peak levels drawn? Also, some inconsistency on what day the levels were drawn.
• 1 patient could contribute to multiple admissions (282 admissions but only 102 unique patients).
• Limited baseline characteristics (no mention of CF severity, FEV1 measurements).

Literature Search Results

Evaluation of a once/day tobramycin regimen to achieve target concentrations in adult patients with cystic fibrosis (Staubes et al.) Published May 2016.

• Single center retrospective study of 186 adult CF patient encounters who received 10mg/kg of tobramycin IV daily for pulmonary exacerbation between Jan 1, 2009 to Dec 4, 2015.
• Primary outcome was the attainment of a target peak level of 30-50 mg/L with first dosing regimen. Secondary outcomes included looking at trough targets of <0.05 mg/L, as well as combined peak and trough target achievement.
• Levels drawn within the first 3 days at 2 hours and 8 hours after infusion, with peak and trough levels calculated from these.

Literature Search Results

• Results
• Only 77 (41.4%) patient encounters met the target peak range, with 104 (55.9%) being subtherapeutic.
• 116 (62.4%) of encounters met trough targets with initial dosing.
• Only 42 (22.6%) met both the peak and trough targets.
• Through bivariate analyses, the study found that patients with a BMI of 18.5-24.9 achieved the target peak levels more frequently than those with BMIs of <18.5 (50% vs 25%). However, the opposite result was found when looking at target trough values (54% vs 84%).
• “Optimization of the initial CF tobramycin dosing regimen is warranted.”
• Limitations
• Similar to DeGrado (no mention of outcomes, 1 patient could contribute to multiple admissions).
• Some patients on inhaled tobramycin concurrently, but no mention of how many.
• Less specific about when levels were drawn (i.e. the first 3 days). Also are calculated levels better?

Thoughts?

What is the 2 level method?

• 30M Ht 172 cm with Ideal body weight = 70 kg which is bigger than Actual weight = 55 kg and Cr 46 umol/L – stable
• Tobramycin 550 mg IV q24h is a reasonable start
• Two serum concentrations with first dose
• Collect 1 & 5 hours after the end of the 1 hour infusion
• Determine elimination rate and half-life
• Adjust dosing interval based on half life

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What is the 2 level method?

• Then confirm/determine dose with calculation via calculate C max
• If Cmax is outside of goal range (20-30 mcg/mL) 🡪 increase or decrease by 10% and rpt levels with next dose

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Gentamicin�IE STREPTOCOCCAL Case

• 52M
• DM2, alcohol misuse disorder
• Ht: 185.4 cm Actual weight: 139 kg
• IBW: 80 kg
• DW: (139 – 80)0.4 + 80 = 104 kg
• At time of consult Dec 9 Cr = 65
• On Epic, CrCL 82 ml/min/1.73 m2
• On Epic, eGFR 106 ml/min/1.73 m2
• Bugs & Drugs Clcr calculator = 170 mL/min
• Bugs & Drugs N Clcr calculator = 122 mL/min
• (Hand calculated CrCL by Cecilia = 173 mL/min)

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IE STREPTOCOCCAL Case

Infective endocarditis

ID Consult

• “native pulmonic valve endocarditis (2.7cm vegetation) on TEE, complicated by septic pulmonary emboli and heart failure. Treat with high-dose penicillin G x 4-6w and synergistic gentamicin for 14d. Needs inpatient cardiac surgery consultation.”

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ID Pharmacist on the team

• Diabetic A1C last month = 7.7 %
• No AKI now, but recent AKI with Cr ~220 umol/L just 4 weeks ago
• No concurrent nephrotoxin
• In heart failure

IE STREPTOCOCCAL Case

Bugs & Drugs (accessed 2020 May 2)

• Beta-hemolytic Streptococci
• S. agalactiae, Streptococcus Group C,G
• PCN (duration dependent on native or prosthetic valve) + Gentamicin x 2 weeks
• Gentamicin dose & monitoring?
• 3 mg/kg IV daily
• Trough only, target < 1 mg/L
• 1 mg/kg IV q8h
• Trough only, target < 1 mg/L
• Which weight? If you look, it now says IBW. Historically, always said use Dosing Weight if obese.

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52M 185.4 cm 139 kg IBW: 80 kg �Actual = 139 vs IBW = 80 🡪 Dosing wt: 104 kg

Cr = 65

If you pick 1 mg/kg IV q8h, based on the CrCL, what dose & frequency would you choose?

Actual weight: 139 kg �IBW: 80 kg �Dosing wt: 104 kg

Option A – I’ve seen this (ahhhhhh)

Actual wt

Gentamicin 140 mg IV Q8H

Trough level pre-4^th dose

Option B

Dosing wt

Gentamcin 100 mg IV Q8H

Trough level before morning dose of third DAY (Day 1 = prescribing)

Option C

Ideal wt

Gentamicin 80 mg IV Q8H

Trough level pre-4^th dose

considerations

If you have worked with me, you would have heard me:

• Prolong diabetes, or if poorly controlled, how great is his kidneys
• No current AKI, if you believe a static formula, but just off dialysis? Just recovered from recent AKI?
• Not too sure how to assess the nephrotoxin, but if this urine output requires aggressive diuresis, things are not looking good
• Translation of heart failure, expects poor perfusion, expect starting/adjusting diuretics

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You see your pharmacist

put on her thinking face…

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Should I go one “step”

down? Q12H vs Q8H?

WAIT!!!�1 mg/kg IV Q8H REGIMEN SOUNDS COMPLICATED. ��WHY NOT 3 mg/kg iv daily

YEAH, WHY NOT?

Actual weight: 139 kg �IBW: 80 kg �Dosing wt: 104 kg

Option A?

Actual wt

139 kg x 3 =

Gentamicin 420 mg IV QD

Trough level?

Option B – by the book

Dosing wt (because pt Act wt > 20% above IBW)

104 kg x 3 =

Gentamcin 300 mg IV QD

Trough level?

Option C

Ideal wt

80 kg x 3 =

Gentamicin 240 mg IV QD

Synergy aminoglycoside dosing. Monitor trough only to rule out toxicity ( target < 1 mg/L) and ONLY IF: poor renal function, concurrent nephrotoxic drugs, expect >5 days therapy

3 mg/kg IV QD

Broken record

• What are the operating principles of high dose extended interval dosing?
• Peak is high enough – true
• Saturable transport – true
• Lower renal tissue concentration – true
• Drug free period ↓ toxicity – theoretical
• Post-antibiotic effect

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What’s the problem with it?

GUIDELINE 2012 BSAC

GUIDELINE → 2015 AHA �

• Streptococcus pneumoniae….???
• Under native valve “highly PCN susceptible VGS and S gallolyticus (bovis) (MIC ≤ 0.12 ug/mL)

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Although it is preferred that gentamicin (3 mg/kg) be given as a single daily dose to adult patients with endocarditis caused by viridans group streptococci, as a second option,�gentamicin can be administered daily in 3 equally divided doses

WHY IS THE 3 mg/kg PREFERRED? Is it? For whom?

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What is the evidence for 3 mg/kg dosing?

Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients, Antimicrob Agents Chemother, 1995, vol. 39 (pg. 650-5)

• 2184 patients 🡪 Significant reduction in the incidence of nephrotoxicity with the QD aminoglycosides compared with multiple daily doses

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• 3% of the patients had Staphylococcal or Streptococcal IE
• That’s 65 patients

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“3 mg/kg daily with normal renal function”

AHA guideline: present in both 2005, 2015 versions

BSAC guideline: absent in 2004, 2012

“Normal”, in most guidelines, is CrCL > 80-90 ml/min

IE STREPTOCOCCAL Case

In real life:

√ Make a reasonable decision

√ Accept uncertainties

√ Monitor renal function closely

√ Do not hesitate to revisit your decision

• Is your patient stable?
• Am I buying him/her dialysis?
• Is surgery imminent?
• Am I buying him/her dialysis?

√ Communication is important –

Who is monitoring, adjusting for (or with) you?

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Cecilia’s approach:

I would be “OK” with 240 -

300 mg IV daily. I would prefer 100 mg IV q8h. Based on pure experience with aminoglycoside dosing, I know even 1 to 1.5 mg/kg dose will give me “high enough” synergy level vs I still don’t know where this patient’s kidneys are heading. 1. I have an action plan for trough levels 2. I would minimize giving more aminoglycosides to patients than needed. 3. If I need to, I can do both a peak & trough to calculate patient specific PK.

IE ENTEROCOCCAL Case

• 72M presented as “sepsis NYD”
• CAD, CABG X 2 + MVR, DM2, DLD, HTN, depression/anxiety
• Allergies: ciprofloxacin – rash, PCN anaphylaxis
• Ht: 178 cm Actual weight: 70 kg
• IBW: 50 kg + [(178/2.54 – 60) X 2.3] = 73 KG
• DW: not applicable
• At time of consult Cr = 95
• Bugs & Drugs Clcr calculator = 60 mL/min
• Bugs & Drugs N Clcr calculator = 64 mL/min
• (Hand calculated CrCL by Cecilia = 62 mL/min)

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Infective endocarditis

ID Consult

• Presumed E. faecium PVIE based on persistent bacteremia and TTE findings. CT A/P normal; IAI ruled out. Transferred to your center for TEE, kept there as >1 cm mass seen on ECHO and suspicious for perivalvular leak/abscess. Admit today to cardiology. ID consult.

ID Pharmacist on the team

• Diabetic A1C last month = 9 %
• No ↑ in Cr from baseline, but oliguric
• On ACEI
• EF 35%

IE ENTEROCOCCAL Case

Bugs & Drugs (accessed 2023 July 10)

• Enterococcus spp
• Amp R, Gent synergy S
• Vancomycin 15 mg/kg IV q8-12h + Gentamicin 3 mg/kg/day IV divided q8-12h x 6 weeks
• Gentamicin dose & monitoring?
• Synergy dosing. Trough only, target < 1 mg/L
• Which weight?
• Actual weight if cachexic
• Idea body weight for most patients
• Dosing weight if Actual weight >20% above ideal body weight

72M 178 cm 70 kg Cr = 95

Gentamicin in DIVIDED dose is recommended.

• What is your dose?
• What is your frequency?

Ht 178 cm 🡪 Ideal body wt 73 kg�Actual weight: 70 kg / IBW: 73 kg /Dosing wt: NOT applicable�Cr = 95�What is your creatinine clearance?�eGFR ~ 70 (Netcare) Clcr ~ 60 (Bugs & Drugs)

I have seen this

Vancomycin 1G IV Q12H

Gentamicin 70 mg IV Q8H

Vanc lvl: trough, pre 4^th

🡪target: 10- 20

Gent lvl: trough, pre 4^th

🡪 target: < 1

And this….

Vancomycin 1G IV Q24H

Gentamicin 70 mg IV Q12H

Vanc lvl: Trough level before morning dose of third DAY (Day 1 = prescribing) 🡪target: 10-20

Gent lvl: Trough level before morning dose of third DAY (Day 1 = prescribing) 🡪 target: < 1

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And this…

Vancomycin 1G IV Q24H

Gentamicin 100 mg IV Q12H

Vanc lvl: trough, pre 4^th

🡪target: 10-20

Gent lvl: trough, pre 4^th

🡪 target: < 1

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If this was an�Exam Case �

Answer key, by the book:

Vancomycin 1G IV Q24H

Gentamicin 70 mg IV Q12H

Vanc lvl: Trough level before morning dose of third DAY (Day 1 = prescribing)

🡪 target: 10-20

Gent lvl: Trough level before morning dose of third DAY (Day 1 = prescribing)

🡪 target: < 1

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• Vancomycin dose is 15 mg/kg, based on CrCL, 60, should start with q24h to target trough of 10-20
• Gentamicin dose is 1 mg/kg, based on CrCL 60, should start with q12h
• Some sites may insist you round to the nearest 20 mg – so pick one, 60 or 80 mg. Epic will now conveniently round for you!
• Most often afternoon consults
• Expect dosing time to be messed up the first 24 hours
• Morning trough levels guarantee wakefulness of prescriber
• If you dosed well, you are looking for “steady state”. Unless your patient is clinically deteriorating, what is the difference between a “pre 4^th” or a “pre 6, 7, 8” level?

In this case,�YOUR PATIENT WAS TRANSFERRED IN…

Your patient arrived on:

Vancomycin – dose held since level of 24 mg/L

Gentamicin 480 mg IV q36h – next dose due tonight

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What should one do?

• Always review MARs, verify regimen and doses given
• Review previous plans, look for notes
• Assess if you agree (you shouldn’t based on the chart)
• Vancomycin – pre 4^th = 24 mg/L 🡪 YOU REVIEWED THE MAR and noted that the dose was given after this level. Do you need a level?
• Recall, currently still support “do linear math”: 2G/day = 24 mg/L. Pick a number between 10-20 (target level) = 15 🡪 your new dose should be ~1 G per 24 hour. Pick a regimen, closest 250 mg multiples: 1.25 G IV q24h
• If your patient have not had a dose since Day -1 after the 4^th dose – it is very safe to start the new regimen tonight
• Gentamicin …?

IE ENTEROCOCCAL Case

Gent Option 1?

Patient is on gentamicin 480 mg IV q36h – dose due tonight.

Don’t give tonight’s dose

Starting tomorrow 70 mg IV q12h 🡪 Gentamicin dose is 1 mg/kg, based on CrCL 60, should start with q12h

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Gent Option 2? (PICK ME!)

Patient is on gentamicin 480 mg IV q36h – dose due tonight.

Don’t give tonight’s dose

Starting tomorrow 70 mg IV q24h 🡪

Gentamicin dose is 1 mg/kg, based on CrCL 60, should start with q12h BUT wait!!! Is the patient not accumulating vancomycin? Should the patient be on q12h or q24h? Just pick one.

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Why not a level?

You can 🡪 but what will you do about it?

You could/would 🡪 IF you cannot find all the MARs or if fearful of documentation error

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IE ENTEROCOCCAL Case

Non surgical management

Duration: 6 weeks

Remember:

1. Definitely monitor audiometry if an option
2. Interview for other symptoms suggestive of ototoxicity
3. Monitor SCr at least 2-3 times a week
4. Monitor trough levels at least once a week
1. + Cr 🡪 if you see a jump, do a trough
5. If oliguria worsens to the point of dialysis 🡪 IHD dosing

Surgical

management

Duration: 6 weeks from clearance of bacteremia if explanted valve culture is negative

Remember:

1. Definitely monitor audiometry if an option
2. Interview for other symptoms suggestive of ototoxicity
3. Monitor SCr & U/O daily post-op
4. Monitor trough levels at least once a week….
5. But at his age, if peri-op oliguric 🡪 we can almost expect post-op CRRT 🡪 IHD
1. CRRT 🡪 IHD dosing

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Patient has ongoing AKI, should we stop aminoglycoside? Yes

Vancomycin alone? Inhibited but not killed 🡪 killing requires synergy

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Alternatives:

Linezolid

Daptomycin ≥ 10 mg/kg + beta- lactam

Daptomycin + tigecycline

Daptomycin monotherapy

*** Patients infected with DAP-susceptible isolates with MICs close to the breakpoint (3–4 μg/mL) may be at high risk of therapeutic failure and recurrence = CHECK DAPTOMYCIN MIC

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AN ASIDE….

RRT 🡪 dosing?

IHD (intermittent hemodialysis)

CRRT (continuous renal replacement therapy)

PIRRT (prolonged intermittent renal replacement therapy)

= SLED (Sustained low-efficiency daily dialysis)

= EDD (extended daily dialysis)

Remember, efficiency of drug removal: CVVHDF > CVVHD > CVVH > PIRRT ≥ IHD

ECLS

VAD?

ECMO?

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Dearth of information

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RRT + ECLS

For some patients, should consider pharmacist PK consult. This is “easy” when things are “constant”.

With fluctuating�eg. AKI, CRRT, IHD

• High dose extended interval dosing is not recommended (see next slide)
• Summary of an “acceptable” approach in table below for dialysis patients

With fluctuating�eg. AKI, CRRT, IHD

High dose extended interval dosing is not recommended

• Is it wrong to make exceptions?
• Can I give 5 mg/kg or 7 mg/kg x 1 dose and likely be good for the week, and a few dialysis runs?

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Amikacin

• MDR GN infection where other aminoglycosides are not an option due to documented resistance
• NTM
• TB (TB service!)

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MDR Pseudomonas auriginosa HAP

Case

• 63M
• 174.5 cm 🡪 ideal body weight ~ 70 kg
• Actual weight 63.7 kg therefore use Actual wt
• Cr = 72
• eGFR (Netcare) = 94
• ClCr (Bugs & Drugs) = 82
• Recent AKI, resolved

BONUS POINT > ARE THERE NON NEPHROTOXIC, OTOTOXIC AND BETTER PULMONARY PENETRATING ABX ALTERNATES THAT YOU CAN USE? Here, the answer is YES but that’s because we have asked for additional susceptibility report. In most of the patients you are see, we are “waiting” on the expanded GNO coverage.

MDR Pseudomonas aeruginosa HAP

Recall Aminoglycoside

MDR Pseudomonas aeruginosa HAP

Case

• 63M
• 174.5 cm 🡪 ideal body weight ~ 70 kg
• Actual weight 63.7 kg therefore use Actual wt
• Cr = 72
• eGFR (Netcare) = 94
• ClCr (Bugs & Drugs) = 82
• Recent AKI, resolved

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Answer:

• Amikacin 15 mg/kg x acutal body wt 63.7 = 955.5 mg 🡪 round to 1000 mg
• ClCr 82 = interval of q24h as > 60 mL/min per nomogram
• Recent AKI, although resolved and >3 - 5 days treatment, order 8 hour post dose level with first dose to confirm interval is appropriate
• Cr at least 2-3 times per week while on amikacin and other desired bloodwork for monitoring

(In reality, if possible, use a better drug now that we have increased access to them > not “easy” access but improved/increased access)

In NTM cases

• Common dosing recommendation = 7.5 – 10 mg/kg daily (the weight rule still applies here)
• Extrapolation for TB
• Literature/experience on NTM
• Inconsistent recommendations

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• Uncertainty regarding role of TDM for efficacy monitoring
• IF peak desired – target may be dependent on MIC of organism
• Would monitor trough to detect accumulation
• Would suggest baseline Audiogram as possibly long duration of treatment
• Sample cases in the next couple slides

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ID Pharmacist Note

D: 65F admitted for further surgical management and start of antimicrobial therapy for Mycobacterium abscessus hardware associated OM (hardware out). Per d/w Dr.GUESS-WHO, reviewed pre-admission ID consults, literature review conducted.

OR yesterday, 1G amikacin/40G cement placed.

162 cm 96.3 kg (IBW 54 kg, DW 71 kg)

Cr = 58, CrCL 90 ml/min (vs Epic storyboard = 52 ml/min, Netcare eGFR 93 ml/min)

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A: Confirmed dosing for the following, ID consult to order:

Amikacin 1G IV daily (DW 71 kg x 15 mg/kg = 1065 mg, round to 1G)

Imipenem 1G IV q12h

Tigecycline 100 mg x 1 then 50 mg IV q12h

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P:

1. Final antimicrobial for initial/maintenance phase to be assessed by ID consult, including oral options. ID consult pending on this admission.

2. Clofazimine SAP application template sent to Dr. GUESS-WHO

3. ID Pharmacist will follow up on possibility of bedaquiline.

4. Weekly amikacin trough, accept undetectable or at most 4-8 mg/L. Integrated or consultative team pharmacist to follow.

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Cecilia Lau RPh, pager 445 2789

ID Pharmacist Note: Amikacin TDM

D: 56F (Edmonton 167 cm Act BW 55 kg IBW 59 kg NKA)

ID following for Right knee septic arthritis, Mycobacterium abscessus, post steroid injection in India 2 months ago. S/p arthroscopic I&D Apr 14, awaits further debridement

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Abx per ID:

Azithromycin 500 mg PO QD Apr 20 - now

Cefoxitin 2G IV q4h Apr 20 - now

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Mycobacterium abscessus MIC = 16

Amikacin 850 mg IV QD - first dose April 20 at 20:28 and dosing time daily ~20:00

Amikacin levels:

Apr 22 at 19:55 <1 mg/L - pre 3rd trough undetectable

Apr 23 at 04:19 = 8 mg/L – 8hr level not helpful for monitoring in the long term AMK strategy

Apr 23 at 23:17 = 50 mg/L - likely unable to achieve pharmacodynamic target

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A: No change to current dosing regimen required.

P: Expects prolong duration. NTM aminoglycoside monitoring, weekly trough sufficient. Monitor Scr at minimum twice a week. Team pharmacist to help ensure weekly trough of amikacin is within acceptable of <4 mg/L. There is no ID pharmacist next week.

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Cecilia Lau RPh

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VORICONAZOLE

Voriconazole

• 200 mg IV vial, 50 & 200 mg tablets, 40 mg/mL oral suspension
• Mechanism of action
• Interferes with fungal cytochrome P450 activity → inhibits 14-alpha-lanosterol demthylation → ↓ ergosterol synthesis
• Side effects:
• Toxicities include hepatoxicity & visual disturbances which can occur within the therapeutic range, however ↑ concentration can also lead to visual & auditory hallucinations
• Others: What happens with long term use?
• periostitis, sensitivity to sunlight 🡪 SCC
• Spectrum
• Invasive aspergillosis
• Candida, Scedosporium, Fusarium
• Others

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• PK
• Well absorbed
• Adult 96%
• Children variable
• Widely distributed incl CNS
• ½ life – variable, dose dependent
• Hepatic metabolism CYP 2C19 (major), 2C9, 3A4 → metabolite, minimal antifungal activity
• Renal <2% as unchanged drug
• Adjustment?
• Child-Pugh C – Risk vs benefit
• IV formulation – Risk vs benefit in CrCL <50 ml/min
• √ pediatric dosing similar to adults when
• at 12-14 of age + >50 kg
• >/= 15 yo
• Under 12 yo → linear up to a certain point then saturable kinetics (pay close attn)

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66

Voriconazole SCENARIO

• Some Aspergillus, for real
• Adult male →Ht 167 cm, Wt 90 kg,
• IBW 63 kg
• Dosing weight 74 kg
• Liver function √
• CrCL 20 ml/min, urine output √
• Drug interaction √
• On “oral” medications & tube feeds √

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Dose… really?

Wt 90 kg → IBW 63 (167cm) → DW 74

But what’s really important here?

2C19

2C9

3A4

Body weight predicts CYP polymorphism? NO

El Rouby N et al 2018 Exp Opin Drug Metab Toxicology

EXPOSURE vs LEVELS

• The standard weight based dosing, examine exposure levels in AUCτ* (μg•h/mL)
• *Mean AUCτ are predicted values from population pharmacokinetic analysis of data from 236 volunteers
• What we actually can measure in real life 🡪 trough levels mg/L
• Clinical data for target levels
• Efficacy vs toxicity – therapeutic range?
• Vs AUC/MIC → Trough/MIC range of 2-5

So in reality?

• N = 138 → obese (BMI ≥35 kg/m 2 ) and non-obese (BMI <35 kg/m 2 )
• Conclusion: A high-dose voriconazole regimen produced initial supratherapeutic troughs that required dose adjustment downward by nearly 30%. AdjBW dosing in obese patients resulted in a similar MD to actual BW dosing in the non-obese, and appears to be a sensible dosing strategy for these patients.

Richards PG et al 2017 JAC

CDC Target trough 2-5 mg/L

Consistent with other similar articles → nothing too drastically different. Slightly better odds at therapeutic level, slightly less pts at subtherapeutic level

On “oral” medications, tube fed √

• Product Monograph: Tablets/suspension should be at least one hour before, or two hours after a meal
• Vs POC references: 1 hour before or 1 hour after a meal. Hold tube feeds for 1 hour before and 1 hour after a dose
• Vs Handbook of Drug administration via Enteral Feeding Tubes → 1 hour before or at least 2 hours after feed
• Special Admin instructions built in – in Epic?
• Tablets: NOTHING…. scheduled as 08 and 20 🡪 check
• Suspension: 60 min before breakfast & supper or NOTHING 🡪 check

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CrCL 20 ml/min, √ u/o

• IV voriconazole is not recommended in patients with creatinine clearance <50 ml/min to avoid potentially toxic accumulation of sulfobutylether-β-cyclodextrin (SBECD)

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• Why worry?
• At 50x the N dose we would give human, animals → liver necrosis and obstruction of the renal tubules

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What’s the evidence in humans

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• Studies up to Dec 2014
• Screened 312 → full text assessed 39 → included in the review N = 7
• No study thus far has provided direct conclusive evidence for cellular and physiological renal toxicity due to IVV at clinically prevalent doses

Turner RB et al. 2015 Int J Antimicr Agents

What’s the evidence in humans?

• Prospective, open-label PK study in pts >18 on IV for suspected IFI on CRRT
• Blood, effluent samples on Days 1, 3, 5, 7 and every 3-5 days – measured with LC-MS/MS
• N= 10 , on CVVH
• Effectively removed SBECD at a rate similar to the UF rate, drug clearance not clinically significant
• Standard dose, IV OK

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Kiser et al. 2015 Critical Care

Level

• FAQ: which day do we do it again?

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• Since 2016 Sept → HPLC Tandem Mass Spectrometry – Wed and Sun afternoons.
• Must get samples to them BEFORE NOON that day
• Report out next day….
• Consider order to collect either before Tues or Sat morning dose as long as it falls within 5-7 days of dosage changes
• Transport time, even within the building
• Missed bloodwork? If you notice it wasn’t collected Tues (or Sat) morning, you can still order it for the Tues (or Sun) evening

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AHS 2016 Vori TDM

INCLUSION CRITERIA:

1. Not responding adequately to therapy → This is defined as a lack of clinical response despite at least 5 days of therapy, failure of fever to resolve, or ongoing radiographic worsening.
2. Signs/symptoms of voriconazole toxicity (e.g. liver dysfunction, persistent ocular or any CNS toxicity (confusion and visual hallucinations)).
3. Concern of drug interactions leading to ↑ or ↓ serum concentrations of voriconazole
• CYP3A4, 2C19, and 2C9 inhibitor and has many clinically relevant drug interactions
4. Potential CNS involvement of invasive fungal infection.
5. Pediatric patients undergoing treatment for invasive fungal disease.

AHS 2016 Vori TDM

EXCLUSION CRITERIA:

1. Patients on voriconazole prophylaxis. There is no evidence available regarding the dose or target levels required for prophylaxis so monitoring of serum levels is not recommended.

• One consideration for TDM in prophylaxis is for CF patients, post-lung transplant, based on lung transplantation guidelines.

2. Routine levels for patients who do not meet inclusion criteria are not recommended at this time due to lack of evidence.

AHS 2016 Vori TDM

APPROPRIATE SAMPLING AND TARGETS:

1. Levels at steady state (after 5-7 days on same dose regimen).
2. Trough drawn within 0 to 60 minutes prior to next dose
3. Target trough levels should be between 1.0-5.5 mg/L
4. Subsequent levels should only be done if:
1. dosage regimen has been changed (wait for steady state)
2. there is a change in clinical status which has the potential to alter drug absorption, distribution and/or clearance.
3. non-adherence with therapy is suspected.
4. toxicity is suspected
5. drug interaction(s) suspected

Dose modification guideline?

• So….what happens after you order a level?

UAH ID PHARMACIST CONSULT

UAH ID PHARMACIST CONSULT

Evolving practice!�Target level?

IDSA 2016

• Treatment efficacy >1-1.5 mcg/mL
• Limit toxicity <5-6

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British Society for Medical Mycology 2014

• >1 to <4-6

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• higher target of >2 is recommended in the setting of aspergillosis, extensive or bulky infection, multifocal or disseminated infection or CNS disease

Back to this SCENARIO

Option A (Cecilia accepts)

IBW or AdjBW or hybrid

• LD: 400-450 mg PO q12h x 2 doses
• MD: 250-300 mg PO q12h
• Trough level in 5-7 days
• Pick the day before they “run” the levels ( = collect for level Tuesday or Sat 🡪 may need further adjustments if patient lives far away from Edm)
• Follow UAH pilot voriconazole level –dosage adjustment action plan
• Target ~ 2-4
• (Accepting 1-5.5 is also likely OK)

Option B

IBW

• LD: 400 mg PO BID x 2 then
• MD: 250 mg PO BID
• Trough level in 5-7 days
• Adjust per published dose modification guideline, shared in this presentation

Target 1-4 ?

Target 1-6 ?

Target 2-3.5 ?

• Adjust per AHS vori TDM guideline (That’s a trick because there’s no suggestions on dosing adjustments in the guideline)

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REFERENCES