Transcript Using PK/PD Principles in Antibiotic Prescribing SAHD May 20, 2011

Using PK/PD Principles in
Antibiotic Prescribing
SAHD May 20, 2011
Peter Gayo Munthali
Consultant Microbiologist
UHCW
Honorary Associate Clinical Professor
University of Warwick
Objectives
By the end of this session you should be able to:
1. Appreciate the importance of prescribing antibiotics in a timely
manner
2. Understand the right dosing for major classes of antibiotics
3. Select antibiotics according to the site of infection
4. Safely prescribe Gentamicin and Vancomycin,be able to
monitor levels logically and interpret them
5. Select safe antibiotics for use in renal and hepatic failure
6. Understand the consideration of antibiotic interactions with
other drugs
There are Three in this Relationship
Drug
Host
Infection
Host defence
Bacteria
Improving the probability of
positive outcomes
• Window of opportunity
– Early recognition and treatment of infection
– Selection of appropriate antibiotic
(e.g. through in vitro susceptibility determination)
– Optimization of DOSE using
Pharmacodynamic principles
– Use optimized dosing that would allow for the
minimization of selecting further resistance
Early recognition of infection
(Sepsis)
• Systemic inflammatory response syndrome (SIRS)
Systemic activation of the immune response
 2 of the following in response to an insult:
• T > 38 .C or < 36.C
• HR > 90 bpm
• RR > 20 bpm or PaCO2 < 32 mmHg
• WBC > 12 000 cells/mm3 , < 4 000 cells/mm3 or >10 % bands
• Sepsis
The systemic response to infection
SIRS + suspected or confirmed infection
(Bone et al Crit Care med 1989.;17 :389)
Sepsis
• Severe sepsis
– Sepsis + organ dysfunction, hypoperfusion or hypotension
• Septic shock
– Severe sepsis +
• unresponsive to fluid resuscitation
• need for vasopressor agents
• Multiple organ dysfunction syndrome
– Organ dysfunction
– Homeostasis cannot be maintained without intervention
Severe Sepsis Bundles
Sepsis Resuscitation Bundle
(To be completed as soon as possible and scored over first 6
hours)
1. Serum lactate measured
2. Blood culture obtained prior to antibiotic administration
3. From presentation, broad spectrum antibiotics administered
within 3 hours for ED admission and 1 hour for non-ED ICU
admission
4. In the event of hypotension and /or lactate >4mmol/l
(36mg/dl):
a.
b.
5.
Deliver an initial minimum of 20ml/Kg of crystalloid (or colloid
equivalent)
Apply vasopressors for hypotension not responding to initial fluid
resuscitation to maintain mean arterial pressure >65mmHg
In the event of persistent hypotension despite fluid
resuscitation (septic shock) and /or lactate >4mmmol/L
(36mg/dl):
a.
b.
Achieve central venous pressure (CVP) of >8mmHg
Achieve central venous oxygen saturation (ScvO2) of > 70%
Early treatment of infection
prospective observational study on 101 consecutive adult patients with
severe sepsis or septic shock
• The rate of compliance with the 6-hour sepsis bundle was 52%.
• non-compliant group had a more than twofold increase in hospital
mortality
– (49% versus 23%, RR 2.12 (95% CI 1.20 to 3.76), P = 0.01)
– similar age and severity of sepsis both groups
• Compliance with the 24-hour sepsis bundle in only 30% (21/69).
Hospital mortality was increased in the non-compliant group from
29% to 50%,
– 76% increase in risk for death(RR 1.76 (95% CI 0.84 to 3.64), P
= 0.16).
Role of Antibiotics (Kollef et al
Chest 1999;115:462-474)
•2,000 consecutive patients admitted to surgical or medical ITU
655 patients (33%) had either CA or HA infection
169 infected patients (25.8%) received inadequate antimicrobial treatment
•All Cause Hospital Mortality (RR 4.26, 95% CI 3.52-5.15, p < 0.001)
•Adequate antimicrobial treatment
•Mortality 12.2%
•Inadequate antimicrobial treatment
•Mortality 52.1%
•Infection Related Mortality (RR 2.37, 95% CI 1.83-3.08, p < 0.001)
•Adequate antimicrobial treatment
•Mortality 17.7%
•Inadequate antimicrobial treatment
•Mortality 42.0%
•Most important independent determinant of hospital mortality was inadequate
antibiotic treatment (OR 4.27, 95% CI 3.35-5.44, p < 0.001)
Timing of Antibiotics (Kumar A et al. Crit Care Med
2006;34:1589–1596)
•Retrospective, May 1999-June 2004, N=2731
•Outcome of antibiotic therapy after onset of recurrent or
persistent hypotension
•Overall mortality 56.2%
•Survival decreased by 7.6% for each hour of delay
•Applied to all subgroups of infections regardless of the
source of infection or causative pathogens
Key Message 1
• Diagnose sepsis early and give antibiotics
promptly to reduce mortality from sepsis
Pharmacodynamics
Drug Absorption Curve
MIC Calculation
MIC
Beta-Lactams
• The critical parameter is the time the
antibiotic concentration remains above the
MIC of the organism expressed as
– T > MIC
Beta-Lactams:
Optimising Exposure
• The optimum level of exposure varies for
different agents within the beta-lactam
class
• Required %T>MIC for efficacy:
– ~ 50%–70% for cephalosporins
– ~ 50% for penicillins
– ~ 40% for carbapenems
Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.
Pharmacodynamics of Beta-Lactams and Macrolides in Otitis
Media
Craig et al, Ped Infect Dis 15: 255, 1996
Once-daily vs. Conventional
Three-times Daily Aminoglycoside
Regimens
Concentration (mg/L)
14
Once-daily regimen
Conventional (three-times daily regimen)
12
10
Cmax:MIC model
For optimal response,
Peak concentration: MIC ratio should
be between 8-12.1
8
6
4
MIC
2
0
0
4
8
12
16
Time (hours)
Nicolau DP et al. Antimicrob Agents Chemother. 1995;39:650–655
20
24
Aminoglycosides—
Relationship Between Cmax:MIC
Ratio and Clinical Response
100
90
80
Clinical
70
response 60
(%)
50
40
30
20
10
0
83
65
89
92
10
12+
70
55
2
4
Moore RD et al. J Infect Dis. 1987;155:93-99.
6
8
Cmax:MIC
Key Message 2
• Beta lactams need frequent dosing for
successful therapeutic outcome
– Missing doses will lead to treatment failure
• Aminoglycosides should be given as a large
single dose (except in infective endocarditis) for
a successful therapeutic outcome
– Multiple small doses will lead to treatment failure
and likely to lead to renal toxicity
Pharmacokinetics
Where do bugs Hide?
Early Endosomes
Inclusions
Chlamydia spp
Brucella spp
Salmonella spp
Francisella tularensis
Phagosomes
Endosomes
Lysosomes
ER
Mycobacterium spp
Legionella pneumophila
Cytosol
Coxiella bruneti
Legionella pneumophila Listeria
Staphylococcus aureus
monocytogenes
Shigella flexeneri
Rickettsia spp
Nucleus
Aminoglycosides Use of Pharmacokinetics in
Good
Treatment
Circulating organisms
Poor
Soft tissue
Bone and joints
Abscesses
Lungs
CSF
Beta lactams
Good/variable (Dependant on
individual antibiotic)
Soft tissue
Bone and joints
Examples of good
Tissue Penetrators
Lungs
Tetracyclines
Poor
Macrolides
Abscesses
Quinolones
Clindamycin
CSF
Extra and Intracellular Pharmacokinetics
Antibiotic
Influx
Efflux
Accumulation Factor
Accumulate
s
Beta lactams
Fast
Variable
<1
Cytosol
Erythromycin
Fast
Fast
4-10
Clarithromycin
Fast
Fast
10-20
Azithromycin
Fast
Slow-v. slow
40-300
Two Thirds
Lysosomes/o
ne third
cytosol
Fast to slow
15-50
Telithromycin
Fluoroquinolones
Fastv.fast
Very fast
4-10
Cytosol
Aminoglycosides
V.slow
Very slow
2-4 (after several days)
Lysosomes
Clindamycin
Fast
Fast
5-20
Unknown
Tetracyclines
Fast
?
1-4
Unknown
Vancomycin
slow
?
8 (after 24 hrs)
Lysosomes
(in kidneys)
Teicoplanin
Fast
?
60
Unknown
Accumulation factor =Cellular conc /extracellular conc
V.fast < 3min, Fast 3-15min, slow 15min-3hrs, V.slow >3hrs
Infect Dis Clin N Am
17(2003) 615-634
Key Message 3
• When selecting an antibiotic consider the
following;
– Where is the infection?
– Which antibiotics will reach the site of
infection
• Match the two and select your antibiotic
Antibiotics, Renal Function and Hepatic
Function
Renal Function
Estimated Creatinine clearance (Cockcroft-Gault formula)
140-AgexMass (Kg) x Constant
Serum Creatinine in µmol/l
Constant 1.04 for Women, 1.23 for Men
Stage GFR(ml/min/1.73m²) Description
I
90+
Normal
II
60-89
Mild reduction
IIIa
45-59
Moderate reduction
IIIb
30-44
Moderate reduction
IV
15-29
Severe reduction
V
<15
Very severe (End-stage)
Half Life in Hours
Effect of Creatinine Clearance on the Half Life of an
Antibiotic with a Normal Half Life of 1 Hour
25
20
20
15
10
5
1
2
Normal
50% Normal
4
0
25% Normal
Creatinine Clearance
5% Normal
Antibiotic Renal
Handling
Major Renal Excretion i.e. ≥
50%
Generally innocuous
Excretion Less than 15% in
urine and
Examples
•Penicillins
Generally innocuous
•Cephalosporins
Examples
•Carbapenems
•Macrolides (erythromycin)
•Sodium fusidate
•Clindamycin
•Tetracyclines
Not Innocuous
Examples
Generally no dosage adjustment
required
•Aminoglycosides
•Exception
•Polymyxin B, Colistin
•Chloramphenicol-not innocuous
•Vancomycin
•Amphotericin
Excretion Less than 15% in urine and
Generally innocuous
Dose adjustment required only at moderate to severe renal
impairment
Examples
Antibiotic
Creatinine
Clearance
Dose
adjustment
Clindamycin
Any
None
Erythromycin
Any
None
Major Renal Excretion i.e. ≥ 50%
Generally innocuous
Antibiotic
Creatinine Clearance
(CrCl)
Dose
Adjustment
Amoxicillin
>30
Nil
Co-amoxiclav
>15
Nil
Tazocin
>40
Nil
Ceftriaxone
Any
Nil
Meropenem
>50
Nil
Doxycycline and Minocycline (All Any
other tetracyclines to be avoided)
Nil
Major Renal Excretion i.e. ≥ 50% AND Poisonous
Antibiotic
Aminoglycosides
(Gentamicin 5mg/Kg
trough levels after 1st
dose)
Creatinine
Clearance (CrCl)
Dose Adjustment
Reduced
Severe
↑ dose interval
↑ dose interval and
↓dose
Avoid
<20
In all cases monitor
levels
Vancomycin (1g BD, trough
levels before 4th Dose)
In all cases monitor levels
Reduced
Severe
Monitor Trough levels
Give only after trough
levels known
Amphotericin
Reduced
Avoid
Gentamicin monitoring 1
Hartford Nomogram
7 mg/Kg OD
•Precise Times of collection required
•Collection 6-12Hrs after dose
Gentamicin monitoring 2
• Gentamicin 5-7mg/Kg OD
– Collect around 24Hrs post dose
– Aiming for <1mg/l
• Checking if patient is clearing gentamicin
• High levels
• Blood collected too early
• Patient not clearing Gentamicin
• Blood collected from lumen used to infuse
Gentamicin earlier on
Gentamicin monitoring 2
• Corrective measures
– Re-check levels
– Stop, look for alternative antibiotic
– Omit dose and repeat levels after 12 Hrs
• Frequency
– 2-3x/week after steady state
• More frequently if renal function changing or
concurrent nephrotoxic drugs
Vancomycin Monitoring
Glycopeptide
•ONLY active against Gram-positive bacteria including MRSA
•IV only except for Clostridium Difficile associated diarrhoea
when oral route is used (NOT absorbed from GI and not
enough levels get into GI by IV route)
•1g BD IV standard dose
Vancomycin trough level
Collect serum specimen 30 minutes or less before next dose
• Frequency of collection:
•First level at steady state (3rd - 5th dose)
•Subsequent levels once or twice/week
•More frequently if renal function changing or concurrent
nephrotoxic drugs
•
Therapy
Trough Dosing Interval Adjustment
Level
(mg/L)
•On ≥q24h , decrease interval by 12 hours
Vancomycin <5
•On q12h, consult microbiology/pharmacist
5-15
15-20
>20
Vancomycin <5
with
Aminoglyco 5-10
side
10-20
>20
No change
Increase interval by 12 hours
Consult microbiologist/pharmacist/Stop
•On ≥q24h , decrease interval by 12 hours
•On q12h, consult microbiology/pharmacist
No change
Increase interval by 12 hours
Consult microbiologist/pharmacist/Stop
Hepatic failure
Antibiotic Handling
Comments
Penicillins
Kidneys
Generally safe in liver failure,
check individual drug for possible
cholestatic jaundice
Tetracyclines
Concentrated in the
liver and excreted via
bile and reabsorbed in
the intestine.
Eliminated in urine
Avoid or use with caution
Aminoglycosides
Kidneys
Safe
Macrolides
Liver metabolism
May worsen liver dysfunction,
avoid
Chloramphenicol
85-95% conjugated in
the liver
Avoid, increased probability of
bone marrow toxicity
Glycopeptides
Kidneys
Safe
Co-trimoxazole
Significant metabolism
by liver
Avoid
Key Message 4&5
• Aminoglycosides are toxic drugs and require
monitoring
– Avoid use in renal failure but safe in liver failure
– Avoid concomitant use with other renal toxic drugs
– Check renal clearance, frequency according to renal function
• Vancomycin dosing should be BD dose and adjusted
according to levels at steady state
– Frequency of monitoring depends on renal function
• Beta lactams are the safest antibiotics in renal and
hepatic failure
– Adjustments to dose may still be required in severe failure
Antibiotic Interactions
Antibiotic Interacting
Drug
Comments
Penicillins
Methotrexate
Allopurinol
reduce excretion of Methotrexate
Increased risk of rash when given with
amoxicillin or Ampicillin
Tetracyclines
Rifampicin
Carbamazepine,
barbiturates
(Cytochrome
P450 Inducers)
Plasma Doxycycline levels reduced
Accelerates metabolism of
Doxycycline
Aminoglycosides Amphotericin, loop
diuretics,
Taccrolimus
Neostigmine
Increased nephrotoxicity /ototoxicity
Antagonise effect
Macrolides
Check BNF
Many
Rifampicin
Too many
(Cytochrome
P450 Inducer)
Check BNF
Key Message 6
• Always check the impact of an antibiotic
on other drugs that a patient is on
– Consult BNF
And So!
Necrotising Fascitis
Patient
•Severe sepsis with septic shock
•Acute renal failure
•On Gentamicin, Clindamycin,
•co-amoxiclav
Beta haemolytic Streptococcus group A
isolated from tissue
Beta haemolytic Streptococcus group A
Sensitive to:
Amoxicillin, meropenem, Clindamycin
Gentamicin, doxycycline, Vancomycin,
Erythromycin, Gentamicin
What would you do?
a.
b.
c.
d.
Stop Gentamicin
Switch Co-amoxiclav to Benzylpenicillin
Continue with the same treatment
Add meropenem to the current treatment
What would you do?
On 11/05/11 you are called by a nurse at 2300hrs to make a
decision whether to give gentamicin or not since the level was not
done that day.
Previous Renal Function and Gentamicin Levels
Date
Urea (mmol/L)
(Normal Ref
2.5-7.8)
09/05/11 6
Creatinine µmol/L Gent
( Normal Ref 50- Levels
90)
99
<1
07/05/11 7
98
<1
04/05/11 8
102
<1
30/04/11 8
103
<1
How do you proceed?
a) Send urgent Gentamicin levels before
giving it
b) Change to another antibiotic until you get
levels back the following day
c) Omit Gentamicin dose
d) Give the Gentamicin and check levels
the following day
What would you do?
On 11/05/11 you are called by a nurse at 2300hrs to make a
decision whether to give gentamicin or not since the level was
not done that day.
Previous Renal Function and Gentamicin Levels
Date
Urea (mmol/L)
(Normal Ref
2.5-7.8)
09/05/11 15
Creatinine µmol/L Gent
( Normal Ref 50- Levels
90)
110
Not done
07/05/11 9
90
<1
04/05/11 3
60
<1
31/04/11 2.7
53
<1
How do you proceed?
a. Send urgent Gentamicin levels before
giving it
b. Change to another antibiotic until you get
levels back the following day
c. Omit Gentamicin dose
d. Give the Gentamicin and check levels
the following day
A 40 year old engineer comes in with SOB
and fever of 40ºC. What is your diagnosis?
a. Pneumothorax
b. Community acquired pneumonia
c. Pulmonary embolus
Which antibiotics would you use?
a. Benzylpenicillin
b. Amoxicillin
c. Erythromycin
d. Clarithromycin
Ask type of allergy
Patient says she is allergic to
Penicillin. What next?
It made my pint taste funny and my fish and chips were not the
same. Which statements are correct?
a. Penicillin is safe
b. I would avoid the use of penicillin
It made me itchy all over and I had a rash. Which of these is
correct ?
a. Amoxicillin can be given safely
b. Ertapenem can be given with caution
c. Doxycycline can be given safely
d. Ceftriaxone can be given safely
The laboratory phones and informs you that they have grown
a pneumococcus
Sensitive to:
Gentamicin
Penicillin
Vancomycin
Chloramphenicol
Ciprofloxacin
Which antibiotics can be safely used to treat Chidongo who has
severe penicillin allergy?
a) All of the above
b) Gentamicin
c) Vancomycin
d) Chloramphenicol
e) Ciprofloxacin
What would you do?
You are called at night to prescribe warfarin for a patient with PE.
Her INR has fallen below therapeutic range since Rifampicin
was prescribed 5 days ago for Staphylococcus aureus
bacteraemia
a. Reduce Rifampicin dose
b. Increase warfarin dose
c. Wait and see
d. Stop Rifampicin and replace it with something else
A patient on furosemide for CCF has been started on Gentamicin
for UTI. Two days later her renal function has become
severely deranged,
a. Stop furosemide
b. Stop Gentamicin
c. Stop Gentamicin and replace with another antibiotic