Antibiotics requiring therapeutic drug monitoring(1)
Therapeutic Drug Monitoring
(aminoglycosides and vancomycin)
Dr. Mahen Kothalawala (MBBS, Dip in Micro, MD, MPH(NZ)
Consultant Clinical Microbiologist
Teaching Hospital Kandy
• Some background
knowledge/concepts required to
understand the lesson
absorption, distribution, metabolism,
What will happen to drug
Oral vs IV administration
Oral vs IV
• Follows ADME
• Hepatic first pass metabolism
• Place of absorption depends
on pK of the drug
• (Effect of enteric coat – acid
liable drugs destroyed in
stomach, to prevent it a coat is
• All available for biological
• No hepatic first pass effect
• All drug  available for
• Free form active
• Bound form- inactive
Composition of body water and its
effects of drug distribution
Hydrophobic drugs – moves to ECF as
well ICF (Vd high)
Better for intracellular organisms
Hydrophillic drugs- Ionized and remain
only within ISF and Plasma (Vd less)
Better for infections within Interstitial
fluid – Majority of infection
When the pK of drug similar to pH of the environment it remain unionized
Absorption or Transfer across cells is greater
Unionized form ↑↑↑
oral and IV
a single dose Clearence
Determination of the bioavailability of a drug. (AUC = area
Drug concentrations in serum after a
single injection of drug at time = 0.
Assume that the drug distributes but is
Ex- Renally eliminated drug in renal
Drug concentrations in serum after a
single injection of drug at time = 0.
Assume that the drug distributes and is
Steady state plasma concentration –Repeat dose
given at every t 1/2
Rate of attainment of steady-state concentration of a drug in the plasma during
an continuous infusion – Elimination of drug after stoppage of infusion
After 3 to 5 t ½,
not detectable in
At steady state, input (rate of infusion) equals
output (rate of elimination).
If Vd – is large a
loading dose is
If Vd – small, a no
loading dose necessary
Effect of infusion rate on the steady-state concentration of drug in the plasma. (Ro
= rate of infusion of a drug.)
They are not contact poisons
should reach the target site
Should achieve optimal concentration
come into contact with micro organisms
Bind to target and remain there for sufficient time to exert the effect
Should resist inactivity or Clearance
Should not be inactivated at target site
Above are Pharmacodyamic properties of antibiotics
Bacterial destruction is described in following manner
– concentration-dependence, and
– persistent effects.
If the rate of killing ᾀ exposure time (time-dependent),
Rate of killing ᾀ (concentration-dependent).
Persistent effects - Post-Antibiotic Effect (PAE) and PALE
Pharmacodynamic Predictors of
• The target we plan to achieve at the site of infection
• Under activity →Treatment Failure, Resistance
• Over activity at the site- Toxicity and ↑ cost
• Three predictors
– % T /MIC value
– AUC0 to 24hr / MIC
What factor is common to all
• When MIC is high, Efficacy ↓
• When MIC is low, Efficacy ↑
Target parameter for each drug,
organisms are different…..
% T / MIC
Fluoroquinolones AUC0 to 24hr /
[ ] least 40% time of day
should be above the MIC
[ ] at least 50% time of day
should be above the MIC
ratio should be > 200
Ration should be > 20
Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media
No change in bacteriological cure after %T> MIC > 40%
Response rate increases when ratio increases, Higher
the ratio, higher the response
target attainment profiles of 3.375 g
of piperacillin-tazobactam every 6 or
4 h as a 0.5-h infusion
for hospitalized patients
target attainment profiles of 3.375 g of
piperacillin-tazobactam every 6 or 4 h as a
for healthy subjects.
Probability of target attainment
PD parameter for
40% time of day
At least 90% of the target
should be above the need to be attained with
Probability of target attainment
1. When MIC is < 4, the target is attained
with 6hrly as well as 4 hrly dose
2. When MIC < 8, Target is achieved 100%
with 4 hrly , regimen while only 90%
achieved with 6hrly regime
3. When MIC is 16, 90% of target achieved
with 4hrly regime, 70% is achieved with
4. When MIC is 32, target is achieved only
20% time with 6hrly regime, while only
60% of the target is achieved with 4hrly
What did you learn?
• Activity of antibiotics in human host depend on many
• PK parameters decide antibiotic  reaching the site of
• PD parameters decide microbial killing at target site
• At least 90% of the target should be attained at the
site of infection
• Human body physiology influence the outcome
• MIC of the organism, is the only a in-vitro, parameter
which decide on outcome
• Antibiotic-induced adverse events leads to
– host injury
– diagnostic confusion
– excessive medical costs.
• a "spin-off" of antibiotic-induced adverse
events is the emergence and dissemination of
Antibiotic adverse effects occur by
• Exaggerated response (to known pharmacological
• Immunologic reactions to drug or its metabolites,
• Toxic effects of the compound or its metabolites.
• Most adverse events due to
– drug's normal pharmacology
• avoided by→ dosage adjustment.
Effects of Antibiotics
Toxicity and side effects
Clinical Cure- Symptomatic
Dose related -Predictable
Dose unrelated -unpredictable
Classification of Adverse drug
• According to
– Seriousness and severity
– Overall Drug Risk
Classification of Adverse drug reactions
Overall Drug Risk
Location of the
↑ pharmacologic effects –
dose dependent and predictable
Red (high risk)
Type B: Bizarre effects ---or
idiosyncratic - dose independent
Type C: Chronic effects
Type D: Delayed effects
Blue (general risk)
Type D: Delayed effects
Green (low risk)
Type E: End-of-treatment effects
• Some adverse reactions occur rarely
• Unique to certain drugs only.
– Chloramphenicol-induced aplastic anemia
– Sulfonamide-induced TEN or Stevens-Johnson
Factors affecting side effects or ADR
• Genetic factors
• Integrity of drug elimination mechanisms(renal
and hepatic dysfunction)
• Concomitant medical disorders– in HIV positives infected patients
• oxacillin-induced hepatitis a
• cutaneous reactions with trimethoprim-sulfamethoxazole or
Monitoring for toxicity of antibiotics in
• Direct method – Check for drug levels
• Indirect Method
– Clinical features suggestive of side effects
– Laboratory indicators of end organ damage(in
likely organ damage)
Toxicity and adverse events are common to any drugEven with the drugs which tagged safe,
• Penicillin group → good safety profiles, well tolerated.
• Can cause
– wide range of hypersensitivity reactions, including fever, rash (maculopapular and
– exfoliative dermatitis, erythema multiforme, serum sickness, and hemolytic anemia.[
• IV high doses in renal impairment central nervous system toxicity,
– myoclonic jerks,
– seizures or
• Some members cause particular side effects
– ampicillin, amoxicillin, and amoxicillin/clavulanate with diarrhea and C. difficile
– In CLL pts → nafcillin-induced neutropenia;
• Carbenicillin and ticarcillin (with/without clavulanic acid) hypokalemia,
– platelet dysfunction, and
– fluid overload;
• Methicillin and ampicillin
– interstitial nephritis.[6
Antibiotics requiring therapeutic
Most drugs are well
Some are not tolerated well Some types of drugs, Ae3s
may be common, but under
Wide therapeutic Index
Narrow therapeutic Index
Monitoring often not
Monitoring of levels
indicated in order to
the antifungal agents
Monitoring may required in
special circumstances exrenal, hepatic failures
Why monitor only aminoglycosides
• Low therapeutic index.
• Bactericidal efficacy ᾀ peak concentrations
• Toxicity is related to total drug exposure
• Nephrotoxicity (usually reversible) and ototoxicity
• The desired plasma concentration-time profile for
aminoglycosides differs to most other drugs.
Patho-physiology of Aminoglycoside
• AGs → obligate nephrotoxins
• Long term treatment→ invariable renal damage
• AGs- enter into PCT cells and Inhibit protein (Next Slide)
• It accumulates within lysosomes phospholipd complexLead to rupture and cell death
• Is a tubulopathy
– tubular cell damage and
– tubular dysfunction
• AGs accumulate in the kidney,
– Around 40%of the total
– About 85% in renal cortex
• Drug entry from the lumen through binding to brush
border receptor – megalin
• Animals made Megalin –Deficient – No renal toxicity
• Toxicity varies depending on type of AGs – Gent and
Netil > Tobra and AK
• This accumulation follows satuarable kinetics – when
exceed the capacity no further entry (15 μg/ml) –Basis
of once daily ↓ toxicity
– ↑ in Tubular Glomerular feedback (TGF),
– ↓in GFR,
– Activation of RAAM and
– contraction of renal vessels and mesangeal cells
• Lead to Acute Renal damage (Nephrotoxicity)
Influx of AG into proximal tubule
• Mediated by a carrier- which follow Zero order kinetics
• Intake – dose independent(↑*AG+ in lumen does not
increase uptake in to PCT cells
• Basis of once daily dose
• Demonstrated in animal studies- that renal toxicity
occur >>> with divided doses than daily single large
Nephrotoxicity ↑ when concurrent
• Drugs such as
– loop diuretics,
– cisplatin, and
– vancomycin, (not teicoplanin)
• And when ↓ Renal blood flow
– Diarrhea etc
– Renal failure (need to monitor)
Otto toxicity mechanism and
– auditory (cochlear) and
– vestibular toxicity,
• Damage to sensory hair cells (cochlea) and cells in labyrinth
• Mechanism of cell damage, similar (start with cloudy swelling and necrosis)
• Bot may not occur concurrently
• Manifests as
Bouncing, unsteady vision
Difficulty multi-tasking, particularly when standing
• Aminoglycosides penetrate into the endolymph, vestibular and
• Damages sensory hairy cells in cochlear tissue by entering to
– AG enters to the endolymph slowly,
– Leaves even slower
• Risk factors for oto-toxicity
– Prolonged therapy for 10 days or more (safe if discontinue in 5 to 6 days)
– Preexisting renal impairment(Dose adjustment)
– Prior treatment with AGs.
• Damage - manifest as auditory (cochlear) and vestibular toxicity,
• Can appear separately (Never together)Oto-toxicity is rare if
treatment restricted to 5 to 6 days
• Rare herditory condition –Ototoxicity within few doses (avoid if
family history of similar event)
• Degree of damage Corresponds to AUC
Effect of P-kinetics in AG toxicity
• V and CL change plasma concentration of
• ↑V is reported with (high doses required to
achieve desired effects)
• ↓ Clearance with dehydration – ↑ toxicity
Change with fluid replacement and resolution
of the infection.
Measurement of aminoglycosides (for
BD or TDS doses
• Desired concentration-time profile is
– a high peak concentration (for efficacy)
– low trough concentration (to prevent accumulation).
• Traditionally tested for
– Peak  – for Efficacy
– Trough - for accumulation
• With once-daily dosing- Peak trough testing need to
Therapeutic BD or TDS
Synergistic for IE
Therapeutic with 1.7
mg/kg per dose divided
1mg/kg BD or TDS
BSAC- BD dose
SANFORD- TDS dose
5 to 7 mg/kg IV
15 to 30 minutes after
dose , usually measured 3
to 5 doses after initiation
Immediately before a dose Same
No trough – Measure
12 to 18 hrs after
(usually after first
6–10 mg l−
3 to 5 mg l−1
According to the value
decide next dose by
≤ 2 mg l−
1 to 3 mg l−1
If target higher,
Omit or delay next dose
[ ]24hrs of
mg l−1 reflects
accumulation, usual [
• A pt with normal renal functions was put on c.pen and
• How long would you plan for treatment,
• If patient had three blood cultures of a S.viridans sensitive
and lower level of MIC
• What is the dose you select
• When are planning to asses Gent level, Describe the basis?
• If levels are as follows, what would be your intervention
• At 24hrs, levels are un-recordable with normal
• 24hrs of 0.5–2 mg l−1 → accumulation or over
• Concept of a trough concentration is not relevant
to once-daily dosing.
• 12 to 18 hrs dosage
Collection of specimens for AG assay
• Do not draw from iv line used to give AG
• Take one blood sample (ideally 5 to 10mL)
between 6 and 14 hours after the start of first
infusion in a plain tube (clotted blood)
– Patient details and
– EXACT time and date infusion was set up and
EXACT time and date sample was taken in
Selecting dose interval
Falls in area designated 24
hours, 36 hours or 48 hours,
dosing interval is 24, 36 or 48
If level falls on a line
If level is above 48
hour line then STOP
the treatment. If
gentamicin is to be
continued, take daily
levels, but do not give
any more gentamicin
until level falls below
• Check U & Es and creatinine daily to
monitor renal function.
• If serum creatinine is rising significantly
(≥20%) and time is within 6-14 hours of
infusion, measure level ASAP, otherwise
contact Microbiologist for advice.
Extended interval (once daily)
gentamicin / tobramycin
• Take a pre-dose level 18-24 hours after 1st
• Levels should be <1mg/l
• Normal renal function - (creatinine clearance
>60ml/min) give next dose when due.
• Check pre-dose levels every 3-5 days.
• Impaired renal function – monitor levels daily
Hartford Extended Interval
7mg/kg, with dose frequency altering
according to nomogram based
upon gentamicin serum
Infusion in 50-100ml Sodium
Chloride 0.9% over 30
One sample taken 6-14 hours
after the infusion
Adults: 2mg/kg loading dose, then refer to pharmacy
or microbiology for maintenance dose
Synergistic dosing for endocarditis
1mg/kg TDS (or less frequently)
Paediatrics: 2.5mg/kg TDS
Adjust dose and frequency based upon gentamicin
Bolus over at least 3 minutes
Just before the dose (pre-dose sample) and 1
hour (post-dose sample)
No target - use the nomogram to
identify the patient's required Synergistic dosing for endocarditis:
Rules for Aminoglycoside Treatment
• Usually Aminoglycoside should not prescribe for
longer than 7 days (Practice at TH Kandy <3d)
– Exception – Infective endocarditis, or by inhalation for
• Monitoring need to be individualized
– If patient is unstable - more often
– if stable- Less often
• With once-daily dosing it is logical to follow the
same rules until new information allows these
rules to be re-formulated.
Why monitor vancomycin?
• It too has low Therapeutic Index,
• Can cause
• Toxicity of Vancomycin differ to that of Aminoglycoside –
– Peak levels – Not necessary –
– acceptable PD is %T>MIC
• toxicity – related to total exposures than peak
– >4g/day toxicity likely
• New formulae – No impurities – Less toxicity
PK of Vancomycin
• The PK vancomycin relatively simple,
– with low protein binding,
– 100% renally elimination,
– No metabolism
– no pharmacogenetic problems.
• V is around 0.4 l kg−1 and the CL approximates that
of glomerular filtration rate.
• t1/2 is approximately 6 h in patients with normal
renal function ..
Monitoring Guide of Vanco
• No peak is necessary
• Trough need to be above the MIC of the
• VancomycinMIC is approximately 1.5 mg l−1 for
many susceptible organisms.
Question on Vancomycin dosing>
• Assume 50% protein binding with MIC of the concerned pathogen
– Calculate the minimum required trough for vacomycin in a person with
eGFR of >90.
• If you get a report of [Vanc]trough of 20mg/L,
– What should you do? Explain what should your advice to the attending
• What is your advice to a person who has a eGFR of 50, receiving
– If, serum creatinine was 2.9mmol/l, what is your advice? Calculate the
– If, serum creatinine is 450mg/l, what is your advice?
• What is the level you should achieve for Rx of MRSA Bacteremia?
• In severe life threatening situation would you
recommend same trough? Or would you
sought to a higher trough?
• Total trough concentration necessary should be
at least 3 mg l−1
• Average of 5 to 10 mg l−1 would be enough (for
mild to moderate infections)
• In severe infection – Can have at a trough of 15 to
• MRSA Bacteremia – a trough level of 15 to 20
mg/dl need to be acheived
Individualization of Vancomycin Dose - Normogram
Initial dose and
Initial dose <15mg/kg
Give 250 to 1000mg
several days apart
than giving frequent
Maintenance dose is
to give higher dose
over several days
• Take pre-dose levels prior to 3rd dose.
– Give the 3rd dose as prescribed and amend 4th dose according to
• Pre-dose level 5-15mg/l (in severe infection levels up to
20mg/l may be required)
• Normal renal function - (creatinine clearance >60ml/min)
check levels every 3-5 days.
• Impaired renal function – monitor levels daily
• For severe infections higher levels may be advised by
Monitoring of Teicoplanin
• Monitoring is required for impaired renal function / to
ensure therapeutic plasma levels.
• Ensure that usual BD loading dose is given
– Take pre-dose level on day 4 to 7.
– Severe infection –
• pre-dose level 20-60mg/l
– Mild – moderate infection –
• pre-dose level 10-60mg/l
• Regular monitoring may be required in renal
Monitoring of Amikacin – (multiple
• Pre-dose level 5-10mg/l
• 1 hour peak 20-25mg/l
• When using the normogram, value to
calculate next dose should be taken as
follows:[Amikacin] 6 to 14hrs level/2;
• Pre-dose level 0.25 - 6.00 mg/l
• For further information seek advice from
Gentamicin levels and outcome
Initial serum peak level
Questions - one
• 32 year mother of one child, presented to
obstetric casualty in the night with high fever,
headache, vomiting with two episodes of LOC.
• On presentation→
• Febrile with 102.5F
• HR -110/min, BP-90/60
• No rash
• PMH- on a VP shunt- inserted 3 years back
• On-call obstetrician rings you in the night.
What steps would you take?
• What is the tentative diagnosis?
• How do you manage the acute episode?
• The following day on-call neurosurgeon sees the
• Take the abdominal end out and allows it to drain
freely, Headache settles.
• Fever remains. Pt becomes conscious and claims
that she feels fine compared to time of
– What tests would you request?
– What microbiological tests would you recommend?
• CSF culture and gram stain? Obtained through
the distal end of the VP shunt.
– Gram Positive cells seen with diplo arrangement. No
– Culture – Streptococcus pneumoniae isolated
WBC-17,000 with 87% Neutrophils.
Platelet count -170,000/ml
Blood culture – Negative with single
• What information would you like to have?
• Describe how you handle the case from time
of first contact?
At the time of admission
Culture positive with
Zone of oxacillin
Issue – Penicillin sensitive pneumococcus isolate→ is it a contaminant or not,
How to solve the problem?
• 73yr old doctors mother admitted to
neurologist with sudden onset of LOC. CT scan
reveal a SAH.
• Managed at Neurology unit.
– Pt has no fever, Pulse-90.min
– WBC 9500/ 78% N
– ESR -60
– CRP 144
• Blood culture obtained at day 6 gave a
positivity with gram positive cocci in two
occassions, Identified as enterococci
– CT Scan - SAH
– Pt gives a allergic history for amoxycillin
• What other information would you like?
• What treatment would you start?
– Started IV Vancomycin,
• Comment on the dose?
• If the patient is severely ill, would you recommend a
loading dose? Explain?
• After 13th day of treatment,
• Vancomycin levels as follows
– Pre-dose – 22mg/l, 30 min after 1 hr infusion- 55mg/l,
• If, laboratory policy is performing only single level on a
patient, what level (pre or post)would you request?
• A 24 year old patient admitted to cardiology
unit with a history of fever for 10 days. He had
a history of taking treatment for infective
endocarditis from a DGH in North Central
• No blood culture results were available
• Results of FBC and other tests is shown below
Day 1 Eve
• His CRP was 196, ESR was 100mm/hr
Urine culture – NAD
SAT- O -1/160, A H and Typi H- 1/40
Echo – Oscillating Mass on Mitral Valve
Serum Ferritin – 9,000
• Patient was started on IV C.penicillin and IV
Gentamicin- contimued it for 4 days,
• No responseter 4 days. and patient left against
medical advice to TH Kandy,
• HE presented to private hospital and admitted
to TH Kandy with a letter to microbiologist.
• The night on-call doctor, contacts the
• If you are the microbiologist, what questions
would you ask from the doctor calling you?
• What are you going to start? Give reasons?
• Patient was started IV cetriaxone, IV gentamicin on
• The following day the patient was sitting
comfortably on bed and reading the “Lankadeepa”
– The following day patient felt ok, appetite ok
• Explain how do you ask from the patient about his
• Do you agree with the diagnosis of IE in this
• If not, why?
• If yes, why?
• What investigations would you like?
• Pt was OK for 3 days, and develop very high
fever, patients condition was worsening,
• Counts as follows –
• Now, what should you do?
• Identify the problems/issues?
• How would you mange the patient?
• Started IV Vancomycin and Gentamicin
• Explain what has gone wrong?
• Now patient is really sick. Serum Creatinine is
going up. Platelet count is going down. WBC is
coming further down.
• What should you do?
• Medical Referral done, Heamatologist and
nephrologists referral done.
• A diagnosis of Heamophagocytic syndrom
arrived? Pt was admitted to the MICU.
• Early mane, cardiologist called and suggest
whether changing to linazolid would be of any
use. Microbiologist OKS.
In spite of all efforts,
• Patient dies.
• What possibly has gone wrong in this case
• If is you, how would you manage the patient.
• Select your treatment option?
• Why do you use
– 1. AK
– 2. CAZ
• IF you are using Amikacin, what should you do
prior to start it?
• 76 yr old female 5 days after CABG in ICU
develop Gram Negative Septicemia,
• AST as follows
• CAZ – S
• CTX- R
• CPM- R
• Cipro –R
• Levo – S
• Mero –R
• Imp -R
• What dosage /frequency do you use?
– 15 mg daily
• If, 6 hrs after first dose, AK levels were found
to be 6 mg/l, when do you give the next dose?
• If, you fail to collect the first dose, at
6hrs, when can you collect blood for AK
• Then what would be the AK level?
• In once daily therapy, do you arrange for a pre
dose ? Explain why?
• If after 8 hours, [AK] = 6ng/l, when do you
administer the next dose?
If levels are not available
For Empirical therapy → Gentamicin maximum of 48 hr for all
The initial dose → based on age and weight,
Interval for subsequent doses -depends on renal functions
For a patient with normal renal function MAXIMUM OF three
0, 24 and 48 hours.
monitoring of plasma concentrations is not required as it not
exceeding 3 doses
Subsequent doses for treatment should guided by AST
• Susceptibility results should be used to guide ongoing therapy.
• If susceptibility results are not available by 72 hours and
empirical intravenous therapy is still required, the gentamicin
containing regimen should be ceased and an alternativeregimen
• Drug level monitoring is a compulsory
requirement when potentially toxic drugs.
• It is done to monitor for side effects as well as
find out whether adequate concentration has
achieved at the site for optimum activity.
• It is a way of “optimizing antibiotic therapy”