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Pharmacokinetic/Pharmacodynamic Dose Optimization of Antibiotics for the Treatment of Gram-Negative Infections – Adult – Inpatient

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1
Pharmacokinetic/Pharmacodynamic Dose
Optimization of Antibiotics
(β-lactams, aminoglycosides, and ciprofloxacin) for
the Treatment of Gram-Negative Infections – Adult –
Inpatient –
Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
TABLE 1. PK/PD OPTIMIZED DOSING REGIMENS ............................................................... 4
TABLE 2. AMINOGLYCOSIDE DOSING STRATEGIES .......................................................... 5
SCOPE ...................................................................................................................................... 6
METHODOLOGY ...................................................................................................................... 7
DEFINITIONS AND ABBREVIATIONS ..................................................................................... 8
INTRODUCTION ....................................................................................................................... 8
RECOMMENDATIONS .............................................................................................................. 8
UW HEALTH IMPLEMENTATION ............................................................................................21
APPENDIX A. COMPATIBILITY INFORMATION .....................................................................22
APPENDIX B. MONTE CARLO SIMULATIONS ......................................................................24
APPENDIX C. ANTIBIOTIC ALTERNATIVES TO FLUOROQUINOLONES ............................32
TABLE 1. RECOMMENDED ALTERNATIVE EMPIRIC REGIMENS – GENERAL CARE .......32
TABLE 2. RECOMMENDED ALTERNATIVE EMPIRIC REGIMENS – INTENSIVE CARE
MEDICINE ................................................................................................................................34
TABLE 3. RECOMMENDED ALTERNATIVE EMPIRIC REGIMENS – ABDOMINAL
TRANSPLANT ..........................................................................................................................35
APPENDIX D. TWO-POINT KINETIC CALCULATIONS FOR TRADITIONAL OR SYNERGY
DOSING WITH GENTAMICIN AND TOBRAMYCIN 30-MINUTE INFUSIONS .........................37
REFERENCES .........................................................................................................................42
Note: Active Table of Contents
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CPG Contact for Changes: CPG Contact for Content:
Philip J Trapskin, PharmD, BCPS Lucas Schulz, PharmD, BCPS AQ-ID
Phone Number: 608-263-1328 Phone Number: 608-890-8617
Email: PTrapskin@uwhealth.org Email: LSchulz2@uwhealth.org

Guideline Authors:
Andrew Berti, PhD, PharmD; Jeffrey Fish, PharmD, BCPS; Lucas Schulz,
PharmD, BCPS AQ-ID

Coordinating Team Members:
Barry Fox, MD; Kurt Reed, MD
Joshua Vanderloo, PharmD, Drug Policy Program

Review Individuals/Bodies:
UW Health Antimicrobial Use Subcommittee
UW Health Lab Practice Committee
UW Health Pharmacy Practice Subcommittee

David Andes, MD; Alex Lepak, MD; William Craig, MD; Teresa Darcy, MD
Philip Trapskin, PharmD, BCPS; Marie Pietruszka, PharmD, BCPS; Erin
McCreary, PharmD, BCPS

Committee Approvals/Dates:
UW Health Antimicrobial Use Subcommittee: November 2014, November 2015,
January 2017, May 2017
UW Health Lab Practice Committee: December 2014
UW Health P&T Committee: December 2014, December 2015
ξ Interim Revisions: December 2015, February 2017, May 2017

Release Date:
December 2014

Next Review Date:
December 2017

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3
Executive Summary
Guideline Overview
This guideline describes dosing optimization of selected β-lactams (cefepime, meropenem, doripenem,
piperacillin/tazobactam), fluoroquinolones (ciprofloxacin), and aminoglycosides (amikacin, gentamicin,
tobramycin).

Key Revisions
Interim Update – May 2017
Addition of Appendix D to provide guidance for pharmacokinetic calculations for aminoglycosides

Interim Update – February 2017
Addition of Appendix C to provide guidance for selecting alternatives to fluoroquinolones.

Interim Update – November 2015
With the addition of doripenem to UWHC formulary, guidance on prolonged infusion doripenem based on
renal function is provided. Additionally, Appendix B is updated with relevant Monte Carlo simulation
information.

Key Practice Recommendations
Pharmacokinetic/pharmacodynamics (PK/PD) principles should be used to optimize (improve efficacy and
minimize toxicity) antimicrobial utilization when possible due to increasing antimicrobial resistance and the
limited availability of novel antimicrobial agents.1-6 (Class I, Level A)
1. The dosing of antibiotics for included patient populations should be based upon
recommendations outlined in Table 1. In general, dosing regimens in Table 1 provide PK/PD
optimized empiric therapy for high-MIC pathogens. When the MIC of the pathogen is known
and is low, dose reductions should be completed to re-optimize antibiotic therapy. (Class IIa,
Level B)
2. Patients EXCLUDED from this guideline:
a. Cystic fibrosis patients
b. Patients receiving antibiotic treatment for central nervous system infections.
c. Pediatric patients
3. Patients in the ICU, receiving antibiotics for treatment of septic shock, should receive their
first dose of antibiotic as a 30-minute infusion to reduce the time to a therapeutic
concentration. (Class IIa, Level B)
4. Patients not in septic shock may or may not receive their first dose of antibiotic over 30
minutes and may have prolonged infusion started immediately. (Class IIb, Level B)
5. Occasionally, dose optimization can achieve concentrations sufficient to treat organisms
reported as resistant.7 This may be an alternative to more toxic antibiotics, such as colistin.
Dosing of antimicrobials in this scenario should be done under the guidance of the Infectious
Disease service via consult and an infectious disease pharmacist. (Class IIb, Level C)
6. Line Time/Incompatibility: Patients requiring significant intravenous access for other
medications may receive standard intermittent infusions (30-60 minute) of β-lactam antibiotics
to minimize antibiotic line time and drug incompatibility (Class IIb, Level C)
a. These patients should be transitioned to prolonged infusion as soon as it is clinically
appropriate. (Class IIb, Level C)
7. Empiric dosing of aminoglycosides occurs via three strategies: traditional dosing, extended
interval dosing (EID), or synergy dosing.
a. Refer to Table 2 for aminoglycoside dosing recommendations by patient population.
b. Aminoglycoside concentration monitoring should occur after five half-lives for synergy
and traditional dosing. (Class IIa, Level B) This is usually between 24 and 36 hours
after starting therapy.
c. A single aminoglycoside concentration monitoring should occur between 6 and 14
hours after initiation of extended interval dosing. (Class I, Level B)
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4
Table 1. PK/PD optimized dosing regimens
Drug
Est
CrCL
(mL/min)
Empiric Definitive Therapy
Sepsis, Septic
Shock
Indication
Non-sepsisA
Indication Obese
B Non-obese ObeseB
CefepimeC
- 4hr infusion
> 50 2 g IV Q8H 1 g IV Q6H
Based on
indication
1 g IV Q6H if MIC ≤4 or no
organism is cultured
30 – 50 2 g IV Q12H 1 g IV Q8H 1 g IV Q8H if MIC ≤4 or no
organism is cultured
15 – 29 2 g IV Q24H 1 g IV Q12H 1 g IV Q12H if MIC ≤4 or
no organism is cultured
<15 / HD 1 g IV Q24H 1 g IV Q24H 1 g IV Q24H if MIC ≤4 or
no organism is cultured

Piperacillin/
tazobactam
- 4hr infusion
> 20 4.5 g IV Q8H 3.375 g IV Q8H 4.5 g IV Q8H
3.375 g IV
Q8H
4.5 g IV
Q8H
< 20 4.5 g IV Q12H 3.375 g IV Q12H
4.5 g IV
Q12H
3.375 g IV
Q12H
4.5 g IV
Q12H

MeropenemC
- 3hr infusion
> 50 500 mg IV Q6H 500 mg IV Q8H
500 mg IV
Q6H
500 mg IV Q8H if MIC ≤2
or no organism is cultured
26 – 50 500 mg IV Q8H 500 mg IV Q8H
500mg IV
Q8H
500 mg IV Q8H if MIC ≤2
or no organism is cultured
10 – 25 500 mg IV Q12H 500 mg IV Q12H
500mg IV
Q12H
500 mg IV Q12H if MIC ≤2
or no organism is cultured
< 10 /
HD 500 mg IV Q24H
500 mg IV
Q24H
500mg IV
Q24H
500 mg IV Q24H if MIC ≤2
or no organism is cultured

Doripenem –
4hr infusion
> 50
500 mg IV Q8H
500 mg IV
Q8H
Based on
indication
500 mg IV Q8H
30 – 50
250 mg IV
Q8H 250 mg IV Q8H
10 – 29 500 mg IV Q12H 250 mg IV Q12H 250 mg IV Q12H
Doripenem –
1hr infusion
< 10 /
HD 500 mg IV Q24H
250 mg IV
Q24H 250 mg IV Q24H

Ciprofloxacin
- 1hr infusion
> 30
400 mg IV Q8H
or 600 mg IV
Q12H
400 mg IV
Q12H
400 mg IV
Q8H
400 mg IV Q12H if MIC
≤0.25 or no organism is
cultured
10 – 30 400 mg IV Q12H 400 mg IV Q12H
400 mg IV
Q12H
400 mg IV Q24H if MIC
≤0.25 or no organism is
cultured
<10 / HD 400 mg IV Q24H 400mg IV Q24H
400 mg IV
Q24H
400 mg IV Q24H if MIC
≤0.25 or no organism is
cultured
A
includes neutropenic fever
B
obesity is defined as BMI ≥40 OR actual body weight >120kg8
C
patients with a concern for seizure disorders should receive prolonged infusions whenever clinically possible to
minimize the risk of precipitating seizures
MIC – Minimum Inhibitory Concentration; HD – Hemodialysis
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5

Table 2. Aminoglycoside dosing strategies
Dosing
strategy Patient population
Initial Dose
(normal renal
function)
Dosing weight Goal peak/Cmax
Goal
trough/Cmin
Timing of
Concentration
Monitoring
T
ra
d
it
io
n
a
l
ξ Pregnancy
ξ Neonates
ξ Severe burns (>
20% body surface
area)
ξ Anasarca
ξ Ascites
ξ Meningitis
ξ Endocarditis
See Table 9 Ideal body
weight unless:

(1) total body
weight is less
than ideal body
weight, then
use total body
weight

(2) total body
weight is 120%
or more of
ideal body
weight, then
use adjusted
body weight
(see
definitions)
8-10 mcg/mL
<1 mcg/mL
(<0.5
mcg/mL
preferred)
See Table 9
Ex
te
n
d
e
d

In
t
er
va
l
D
os
in
g

ξ Gram-negative
infections
7 mg/kgA for
respiratory
infections

5mg/kgA for all
other infections
Dosing per extended interval
dosing nomograms After first dose
Sy
ne
rg
y

ξ Enterococcal
endocarditis
ξ Streptococcal
endocarditis
1 mg/kg IV
every 8 hours
3-4 mcg/mL
<1 mcg/mL
(<0.5
mcg/mL
preferred)
See Table 8
A
Multiply dose and drug concentration monitoring by a factor of three if using amikacin


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6
Companion Documents
ξ Renal Function-Based Dose Adjustments – Adult – Inpatient – Clinical Practice Guideline
ξ UWHC Guideline for Continuous Renal Replacement Therapy Based Dose Adjustments – Adult –
Inpatient – Clinical Practice Guideline

Pertinent UWHC Policies & Procedures
ξ Renal Function-Based Dose Adjustment Delegation Protocol - Adult - Inpatient/Oncology
ξ Continuous Renal Replacement Therapy (CRRT)-Based Dose Adjustments – Adult – Inpatient
Scope
Disease/Conditions:
All adult patients requiring antimicrobial therapy with piperacillin/tazobactam, meropenem, doripenem,
cefepime, gentamicin, tobramycin, amikacin or ciprofloxacin should receive PK/PD optimized therapy with
the following exclusions:
a. Individuals with cystic fibrosis are excluded from this guideline. These patients may receive
intermittent or prolonged infusions of β-lactam antibiotics at the discretion of the primary team.
b. Patients with documented or suspected central nervous system (CNS) infection are excluded from
this guideline due to the higher peak antibiotic concentrations required for CNS penetration.
c. Patients under the age of 18 years are excluded from this guideline. These patients may receive
intermittent or prolonged infusions of β-lactam antibiotics at the discretion of the pediatric primary
team.

Clinical Specialty:
This guideline may be used by any prescriber treating a patient with a suspected or confirmed Gram-
negative infection.

Intended Users:
This guideline is intended to be used by physicians, pharmacists, and nurses

CPG objective:
The objective of this guideline is to improve the use of antibiotic agents with activity against Gram-
negative organisms by optimizing the pharmacokinetic and pharmacodynamics antibiotic characteristics
through prolonged infusion, extended interval dosing, appropriate drug concentration monitoring, or dose
modification based on minimum inhibitory concentration.

Target Population:
All adult patients requiring antimicrobial therapy with piperacillin/tazobactam, meropenem, doripenem,
cefepime, gentamicin, tobramycin, amikacin or ciprofloxacin should receive PK/PD optimized therapy with
the following exclusions:
a. Individuals with cystic fibrosis are excluded from this guideline. These patients may receive
intermittent or prolonged infusions of β-lactam antibiotics at the discretion of the primary team.
b. Patients with documented or suspected central nervous system (CNS) infection are excluded from
this guideline due to the higher peak antibiotic concentrations required for CNS penetration.
c. Patients under the age of 18 years are excluded from this guideline. These patients may receive
intermittent or prolonged infusions of β-lactam antibiotics at the discretion of the pediatric primary
team.

Interventions and Practices Considered:
ξ Prolonged infusion of piperacillin/tazobactam, cefepime, meropenem, and doripenem
ξ Extended interval, synergy, and traditional dosing of aminoglycoside antibiotics
ξ Ciprofloxacin dose reduction based on an pathogen MIC
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7

Major Outcomes Considered:
Successful management (infection treatment, toxicity avoidance) of patients treated with antibiotics.
Cost savings from utilization of treatment strategies.

Guideline Metrics:
Successful management (infection treatment, toxicity avoidance) of patients treated with antibiotics.
Cost savings from utilization of treatment strategies.
Methodology
Methods Used to Collect/Select the Evidence:
A review of PubMed database, International Pharmaceutical Abstracts database, and Google Scholar
was conducted with the keywords: pharmacokinetic, pharmacodynamics, antibiotic,
piperacillin/tazobactam, cefepime, meropenem, doripenem, tobramycin, gentamicin, amikacin, and
ciprofloxacin. References from the articles were also searched. Finally, the personal libraries of the
authors were queried.

Methods Used to Assess the Quality and Strength of the Evidence:
Review of the literature and weighing according to the rating scheme (see below).

Rating Scheme for the Strength of the Evidence and
Recommendations:
A modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE)
developed by the American Heart Association and American College of Cardiology was used to assess
the Quality and Strength of the Evidence in this Clinical Practice Guideline.9


Cost Analysis:
No cost analysis was performed
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8
Definitions and Abbreviations
1. Total body weight (TBW): actual total mass of the patient in kilograms.
2. Body mass index (BMI):
ξ BMI = TBW/(height (m2))
3. Ideal body weight (IBW):
ξ Males IBW = 50 kg + 2.3 kg for each inch over 5 feet in height
ξ Females IBW = 45.5 kg + 2.3 kg for each inch over 5 feet in height
4. Adjusted body weight (AdjBW)
ξ AdjBW = IBW + (0.4 x (TBW – IBW)
5. Lean body weight (LBW)
ξ Males LBW = (9270 x TBW)/(6680 + 216 x BMI).
ξ Females LBW = (9270 x TBW)/(8780 + 244 x BMI).
6. MIC – minimum inhibitory concentration
7. EID – extended interval dosing
8. Empiric therapy10: Selection of antimicrobials based on clinical presentation prior to culture
results
9. Definitive therapy10: Deescalation of antimicrobial selection to narrower spectrum based on
specific pathogen-directed treatment with culture results or with no culture results after 72
hours
Introduction
As a result of continuously developing antimicrobial resistance and a paucity of novel antimicrobial
development, new dosing strategies have been proposed to optimize the pharmacodynamics of existing
antimicrobials. Antimicrobial activity can be separated into two broad categories: time-dependent or
concentration-dependent killing. Time-dependent antimicrobials demonstrate maximum efficacy when the
percent of time above the minimum inhibitory concentration (%T>MIC) is optimized. In contrast, the
efficacy of concentration-dependent antimicrobials is dependent on the ratio of the area under the
concentration-time curve and the minimum inhibitory concentration (AUC/MIC) or concentration/MIC
ratio.11
Recommendations
Pharmacokinetic/pharmacodynamic (PK/PD) principles should be used to optimize (improve efficacy and
minimize toxicity) antimicrobial utilization when possible due to increasing antimicrobial resistance and
limited availability of novel antimicrobial agents.1-6 (Class I, Level A)
1. Consider administering antimicrobials with short half-lives that exhibit time-dependent
antimicrobial activity (e.g. β-lactam agents) by prolonged infusion because this dosing strategy
results in an increased likelihood of successful antimicrobial activity, (Class I, Level A) shorter
hospital stays, and reduced mortality. 5-6,12 (Class IIa, Level B)
1.1. Providing some β-lactam antimicrobials by prolonged infusion can reduce hospital costs
and reduce the total daily dose of drug administered without compromising antimicrobial
efficacy.3
1.2. A retrospective study of 121 patients was conducted at a surgical/medical ICU after
implementing prolonged infusions of piperacillin/tazobactam and meropenem.13 The
study showed statistically significant decreases in ventilator days (16.8 days to 9.6 days,
95% CI: -12.4 to -2.4), ICU length of stay (15.3 days to 10.7 days, 95% CI: -8.3 to -1.4),
and hospital length of stay (30.9 days to 22.4 days, 95% CI: -18.7 to -1.2) between the
intermittent infusion and the prolonged infusion group. There was also a decrease in
mortality in the prolonged infusion group (20.7% to 12.4%, OR 0.54 (95% CI 0.18-1.66))
that did not reach statistical significance. The use of the prolonged infusion was also
associated with an estimated $10,000 drug cost savings for the 54 patients included in
the prolonged infusion group.
2. When administering β-lactam agents as a prolonged infusion, the difference in time to a
therapeutic concentration between intermittent and prolonged infusions is not considered to be
clinically significant for non-critically ill patients.14-16 Therefore, a ‘loading’ dose administered over
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9
30 minutes is not recommended for all patients, but should be given in patients with severe
sepsis and septic shock. (Class IIb, Level B)
2.1. Patients in the ICU who are receiving antibiotics for treatment of septic shock, should
receive the first dose as a 30-minute infusion. (Class IIb, Level B) Subsequent doses
should be given as prolonged infusion.17,18 (Class IIa, Level B)
2.2. Non-ICU patients may or may not receive the first dose as a 30-minute infusion. The time
to ƒT>MIC without a loading dose for meropenem and piperacillin/tazobactam is 12 and
96 minutes, respectively.17 This is not expected to be clinically significant in the non-ICU
patient.
3. Consider administering concentration-dependent antimicrobials with a post-antibiotic effect (e.g.
aminoglycosides) at a high dose and with extended dosing interval because this dosing strategy
results in an increased likelihood of successful antimicrobial activity and a lower incidence of
adverse drug events.19,20 (Class IIb, Level B) Additionally, high-dose extended interval dosing has
been shown to reduce hospital costs and total daily dose of drug administered without
compromising antimicrobial efficacy.19,21 (Class I, Level B)
4. Occasionally, dose optimization can achieve concentrations sufficient to treat organisms reported
as resistant.7 This may be an alternative to more toxic antibiotics, such as colistin. Dosing of
antimicrobials in this scenario should be done under the guidance of an Infectious Disease
consult and an infectious disease pharmacist. (Class IIb, Level C)
4.1. Monte Carlo simulations of various patient populations are listed in Appendix A. These
may be used to help select alternative dosing regimens. When selecting a dose, the goal
should be to achieve at least 90% probability of target attainment (y-axis) at the expected
or reported minimum inhibitory concentration (MIC) value (x-axis).
5. Line Time/Incompatibility
5.1. Patients requiring significant intravenous access for other medications may receive
standard intermittent infusions (30-60 minutes) of β-lactam antibiotics to minimize
antibiotic line time and drug incompatibility. (Class IIb, Level C)
5.2. These patients should be transitioned to prolonged infusion antibiotics as soon as it is
clinically appropriate. (Class IIb, Level C)

β-lactam Antibiotics

Beta-lactam antibiotics including piperacillin/tazobactam, cefepime, meropenem, and doripenem all
exhibit time-dependent killing. Prolonged and continuous infusions of β-lactams increase the fraction of
time when the antibiotic concentration exceeds an organism’s MIC and, as a result, the antibiotic’s
efficacy is improved. Prolonged infusions have beneficial effects over continuous infusions including not
needing a dedicated line/catheter and usually using a lower total daily dose.3

6. Piperacillin/Tazobactam Recommendations and Evidence
6.6. Administration of piperacillin/tazobactam by four-hour prolonged infusion is recommended
for most patients; exceptions include patients receiving therapy for meningitis and
patients with line-time issues. Dosing should be based on Table 3 (Class I, Level A)

Table 3: Prolonged Infusion Piperacillin/Tazobactam (infuse over 4 hours)
Estimated CrCL (mL/min) Standard Dosing ObesityA Dosing
> 20 3.375 g IV Q8H 4.5 g IV Q8H
< 20 / HD 3.375 g IV Q12H 4.5 g IV Q12H
A
Obesity defined in most studies as a BMI >40

6.7. Administering piperacillin/tazobactam by prolonged infusion results in shorter hospital
stays and reduced mortality.6,13
6.8. Providing piperacillin/tazobactam by prolonged infusion can reduce hospital costs and
reduce the total daily dose of drug administered to the patient without compromising
antimicrobial efficacy.22
6.9. Patients who are morbidly obese (BMI > 40) are candidates for prolonged infusion
piperacillin/tazobactam therapy.
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10
6.9.1. Providers may consider administering 4.5 g piperacillin/tazobactam over four
hours every eight hours in the morbidly obese population (BMI > 40) to increase
the likelihood of target attainment. (Class IIb, Level B)
6.9.1.1. A Monte Carlo simulation of piperacillin/tazobactam dosing in obese
patients (weight 161 ± 29 kg, BMI 52.3 ± 10.8) predicted a piperacillin
target attainment (50% time > piperacillin MIC) of >99% for 3.375 g, 4.5
g, and 6.75 g piperacillin/tazobactam given as a prolonged infusion over
four hours with an organism MIC of 8 mg/L. At an organism MIC of 16
mg/L, 4.5 g piperacillin/tazobactam given as a prolonged infusion has a
probability of target attainment of 91.3%.8
7. Patients receiving prolonged infusion in the ICU for treatment of septic shock, should receive the
first dose as a 30-minute infusion. Subsequent doses should be given as prolonged infusion.17,18
(Class IIa, Level B)
8. The differences between intermittent and prolonged infusions in the time to achieve therapeutic
concentrations of piperacillin/tazobactam are not considered to be clinically significant for the
non-critically ill patient.14 (Class IIb, Level C)
8.6.1. The median time to attain a therapeutic unbound concentration of piperacillin
(>16 mg/L) is approximately 30 minutes when 3.375 g piperacillin/tazobactam is
administered over four hours.14

9. Meropenem Recommendations and Evidence
9.1. Administration of meropenem by three-hour prolonged infusion is recommended for most
patients; exceptions include patients receiving therapy for meningitis and patients with
line-time issues. Dosing should be based on Table 4. (Class I, Level A)

Table 4: Prolonged Infusion Meropenem (infuse over 3 hours)
Estimated CrCL
(mL/min) Initial/Empiric Dosing
Dose Reduction for
Definitive Therapy
Obesity Dosing for
Definitive TherapyA
>50 500 mg IV Q6H 500 mg IV Q8H 500 mg IV Q6H
26-50 500 mg IV Q8H 500 mg IV Q8H 500 mg IV Q8H
10-25 500 mg IV Q12H 500 mg IV Q12H 500 mg IV Q12H
< 10 / HD 500 mg IV Q24H 500 mg IV Q24H 500 mg IV Q24H
A Obesity defined in most studies as a BMI >40

9.2. Administering meropenem by prolonged infusion results in a longer time above the MIC
that correlates with efficacy in carbapenem-class antibiotics.5 (Class I, Level A)
9.3. Providing meropenem by prolonged infusion can reduce hospital costs and reduce the
total daily dose of drug administered to the patient without compromising antimicrobial
efficacy. 13
9.4. Patients who are morbidly obese (BMI >40) are candidates for prolonged infusion
meropenem therapy.
9.4.1. A Monte Carlo simulation of meropenem dosing in morbidly obese patients
(weight 152 ± 31 kg, BMI 54.7 ± 8.6) predicts a target attainment (40% time
above MIC) of 82% for 500 mg meropenem given as a prolonged infusion over
three hours every eight hours with the organism MIC of 4 mg/L. The target
attainment for the same dose and duration infused over 0.5 hours is 68%. Target
attainment for 500 mg meropenem given as a prolonged infusion over three
hours every six hours is 92% whereas the same dose and duration infused over
0.5 hours is 76%. For organisms with a meropenem MIC ≤2mg/L, the likelihood
of target attainment is greater than 95% for 500 mg prolonged infusion
meropenem dosed either every six or every eight hours, greater than 83% for
500 mg intermittent infusion meropenem dosed every eight hours, and greater
than 90% for 500 mg intermittent infusion meropenem dosed every six hours.
Pharmacokinetic values were calculated based on samples obtained from nine
morbidly obese patients treated with either 500 mg meropenem infused over 0.5
hours every six hours or 1 g meropenem infused over 0.5 hours every six
hours.23
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11
9.5. A Monte Carlo simulation for an estimated creatinine clearance of 40 mL/min (500 mg
Q6H), 30 mL/min (500 mg Q8H), and 17 mL/min (500 mg Q12H) (George Drusano MD,
personal communication). The results in Table 5 show percent of patients with
meropenem concentrations greater than MIC for 40% of the dosing interval.

Table 5: Simulated probability of target attainment at various renal functions for meropenem
MIC (mg/L) Est. CrCL = 40 mL/min Est. CrCL = 30 mL/min Est. CrCL = 17 mL/min
2 99% 99% 96%
4 92% 88% 75%

9.6. Patients receiving prolonged infusion in the ICU for the treatment of septic shock should
receive the first dose as a 30-minute infusion. Subsequent doses should be given as
prolonged infusion.17,18 (Class IIa, Level B)
9.7. The differences between intermittent and prolonged infusions in the time to achieve
therapeutic concentrations of meropenem are not considered to be clinically significant in
the non-critically ill patient. (Class IIb, Level C)
9.7.1. The median time to attain a therapeutic unbound concentration of meropenem
(>4 mg/L) is approximately 30 minutes when 500 mg meropenem is administered
over three hours.15
9.7.2. A recent Monte Carlo simulation using population data from healthy volunteers
demonstrated that it took 12 minutes to achieve concentration exceeding the MIC
of a resistant Pseudomonas isolate (MIC 2 mcg/mL).24
9.8. Dose Reduction
9.8.1. Patients who have no organism cultured after 72 hours of meropenem therapy
OR who have an organism recovered with an MIC to meropenem that is ≤2
mcg/mL, should receive a dose reduction based on Table 4 (above). (Class IIa,
Level B)
9.8.2. Patients who have an organism recovered with an MIC to meropenem that is >2
mcg/mL are not eligible for a dose reduction and should not be dose reduced
unless their renal function changes. (Class IIa, Level B)

10. Doripenem Recommendations and Evidence
10.1. Doripenem is a carbapenem with FDA approval for complicated intra-abdominal
infections and complicated urinary tract infections.25 Doripenem product labeling does
carry a warning for use in ventilator-associated pneumonia as an increase in all-cause
mortality was demonstrated in patients treated with doripenem compared to imipenem in
a Phase III trial.
10.1.1. Subsequent metaanalyses demonstrated that doripenem was non-inferior to
other treatments in nosocomial and ventilator-associated pneumonias.26,27
10.1.2. It is reasonable to increase doripenem dose for patients being treated for severe
sepsis or in the ICU setting. (Class IIb, Level C)
10.2. Administration of doripenem by four-hour prolonged infusion is recommended for all
patients receiving doripenem. 28-30 Dosing guidance is in Table 6. (Class I, Level B).
10.2.1. A retrospective cohort study compared clinical outcomes associated with
doripenem infused over one hour or four hours.28 Clinical success was similar
between standard infusion and prolonged infusions while clinical success in
critically ill patients was increased in the prolonged infusion group compared to
standard infusion (72.7% vs. 47.6%, p=0.017).

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Table 6: Prolonged Infusion Doripenem
Estimated
CrCL
(mL/min)
Infusion
Duration
Empiric Dosing
(ICU/Severe Sepsis) Definitive Therapy
Obesity Dosing for
Definitive TherapyA
>50
4 hours
500 mg IV Q8H 500 mg IV Q8H 500 mg IV Q8H
30-50 250 mg IV Q8H 250 mg IV Q8H
10-29 500 mg IV Q12H 250 mg IV Q12H 250 mg IV Q12H
< 10 / HD 1 hour 500 mg IV Q24H 250 mg IV Q24H 250 mg IV Q24H
A Obesity defined in most studies as a BMI >40

10.3. Administering doripenem by prolonged infusion results in a longer time above the MIC
that correlates with efficacy in carbapenem-class antibiotics.5,29,30
10.4. Providing doripenem by prolonged infusion can reduce hospital costs and reduce the
total daily dose of drug administered to the patient without compromising antimicrobial
efficacy.13
10.5. Patients receiving prolonged infusion in the ICU for the treatment of septic shock may
receive the first dose as a one-hour infusion. Subsequent doses should be given as
prolonged infusion.17,18 (Class IIa, Level B)
10.6. The differences between intermittent and prolonged infusions in the time to achieve
therapeutic concentrations of doripenem are not considered to be clinically significant in
the non-critically ill patient. (Class IIb, Level C)
10.7. Prolonged infusion doripenem in morbidly obese (BMI >40) patients is reasonable (Class
IIa, Level B).
10.7.1. A Monte Carlo simulation of doripenem dosing in morbidly obese patients (total
body weight 180±61 kg) predicted target attainment (40% time above MIC) of
greater than 90% for 500 mg doripenem administered as either four-hour or one-
hour infusion at an MIC 2 mg/L or lower.31 At MIC 4 mg/L, a four-hour infusion
achieved target attainment of greater than 90% while a one-hour infusion did not.
10.7.2. A second Monte Carlo simulation demonstrated that it is progressively more
difficult to achieve doripenem target attainment with increasing weight and that a
four-hour infusion improves this probability.30
10.8. It is reasonable to adjust doripenem dose and/or frequency when administering by
prolonged infusion.32 (Class IIa, Level B)
10.8.1. A Monte Carlo simulation demonstrated doripenem target attainment (35% time
above MIC) at varying doripenem MICs and renal function. With normal renal
function or mild impairment (CrCl greater than or equal to 50 mL/min), a dose of
500 mg infused over four hours every eight hours resulted in ≥90% target
attainment for MIC ≤4 mcg/mL. At moderate renal function (CrCl 30 – ≤50
mL/min), 250 mg infused over 4 hours every 8 hours resulted in ≥99% target
attainment for MIC ≤4 mcg/mL. At severe renal impairment (CrCl <30 mL/min),
250 mg infused over 4 hours every 12 hours resulted in 100% target attainment
for MIC ≤4 mcg/mL. At normal renal function or mild impairment, a dose of 1000
mg infused over 4 hours every 8 hours resulted in ≥90% target attainment for
MIC ≤8 mcg/mL.
10.8.2.
10.9. Hemodialysis may alter doripenem clearance and it is reasonable to adjust doripenem
doses in patients receiving hemodialysis. (Class IIa, Level B)
10.9.1. A pharmacokinetic observational study demonstrated that a doripenem dose of
250 mg Q24H (one-hour infusion) attained 92% T>MIC (MIC of 2 mcg/mL), while
an initial loading dose of 500 mg twice daily followed thereafter by 500 mg Q24H
(all 1-hour infusions) attained 69% T>MIC (MIC of 8 mcg/mL).33
10.9.2. A small, prospective, open-label study found that hemodialysis did not
significantly affect doripenem kinetics at a dose of 500 mg IV Q24H,
administered following hemodialysis.34 This dosing scheme was similarly
observed in a retrospective cohort study for those patients with CrCL <10
mL/min.28
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10.10. The use of doses greater than 500mg may be considered in the treatment of highly
resistant organisms, preferably under the guidance of the Infectious Disease consult
service. (Class IIb, Level C)

11. Cefepime Recommendations and Evidence
11.1. Administration of cefepime by four-hour prolonged infusion is recommended for most
patients; exceptions include patients receiving therapy for meningitis and patients with
line-time issues. Dosing should be based on Table 7. (Class IIa, Level B)
11.2. Patients with a concern for seizure disorders should receive prolonged infusions
whenever clinically possible to minimize the risk of precipitating seizures.

Table 7: Prolonged Infusion Cefepime (infuse over 4 hours)A
Estimated
CrCL
(mL/min)
Empiric Dosing
(ICU/Severe Sepsis)
Empiric Dosing
(General Medicine and
Neutropenic Fever)B
Dose Reduction Based
on Organism
> 50 2 g IV Q8H 1 g IV Q6H* 1 g IV Q6H
30-50 2 g IV Q12H 1 g IV Q8H 1 g IV Q8H
15-29 2 g IV Q24H 1 g IV Q12H 1 g IV Q12H
<15 / HD 1 g IV Q24H 1 g IV Q24H 1 g IV Q24H
A
Patients with a concern for seizure disorders will receive prolonged infusions whenever clinically
possible to minimize the risk of precipitating seizures
B
May consider using ICU dosing in obese (BMI ≥40) regardless of patient’s current location or service

11.3. Administering cefepime by prolonged infusion results in a longer time above the MIC that
correlates with efficacy in cephalosporin-class antibiotics.5
11.4. Administering cefepime by prolonged infusion can result in shorter hospital stays,
reduced hospital costs, and reduced mortality.35
11.4.1. A retrospective pre/post study compared patients with lab-confirmed Gram-
negative bacteremia or pneumonia treated with 2 g cefepime given every eight
hours (adjusted for renal function) as a 0.5 hour (pre-) or four hour (post-)
infusion. There were no differences in length of stay, hospital costs, or mortality.
However, in a pre-defined subgroup analysis of patients with lab-confirmed P.
aeruginosa infection, overall mortality (20% vs. 3%, p = 0.03) and ICU median
length of stay (18.5 vs. 8 days, p = 0.04) were significantly reduced in the
prolonged-infusion group. Median length of stay (14.5 vs. 11 days, p = 0.36),
median hospital costs ($51,231 vs. $28,048, p = 0.13) favored the prolonged
infusion group, but did not reach statistical significance. After adjusting for
significant confounders (APACHE-II score, admission to the ICU), the authors
calculate an odds ratio of in-hospital death of 16.7 for intermittent infusion (95%
CI: 1.57-949.35).
11.5. Patients who are obese are candidates for prolonged infusion cefepime therapy. Due to
the apparent increased clearance of cefepime in obese patients, providers may consider
using ICU dosing (2 g cefepime infused over four hours every 8 hours) in this population
regardless of location or service, particularly if the organism MIC is ≥4 mg/L.36
11.6. Patients receiving prolonged infusion in the ICU, for treatment of septic shock, should
receive the first dose as a 30-minute infusion. Subsequent doses should be given as
prolonged infusion.17,18 (Class IIa, Level B)
11.7. The differences between intermittent and prolonged infusions in the time to achieve
therapeutic concentrations of cefepime are not considered to be clinically significant for
non-critically ill patients.16 (Class IIb, Level C)
11.8. The mean time to attain a therapeutic unbound concentration of cefepime (> 4 mg/L) is
approximately 30 minutes when 1 g cefepime is administered over four hours.16
11.9. Dose Reduction
11.9.1. All patients from whom no organism is isolated after 72 hours of cefepime
therapy OR for whom a non-Pseudomonas organism is isolated should receive a
dose reduction based on Table 7 (above) regardless of patient’s location in the
hospital. (Class IIa, Level B)
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11.9.2. All patients from whom a Pseudomonas organism is recovered will be maintained
at (or escalated to) 2 g every 8 hours infused over 4 hours (adjusted based on
renal function) until cefepime is discontinued regardless of the patient’s location
in the hospital.

Aminoglycosides

Aminoglycosides demonstrate rapidly bactericidal, concentration-dependent killing with a prolonged post-
antibiotic effect. Administering a higher dose of gentamicin, tobramycin, or amikacin increases the
maximum concentration to MIC ratio and improves efficacy Administering a higher dose less frequently
(”HEAT”, high-dose extended-interval aminoglycoside therapy or “EID” extended interval dosing) takes
advantage of the significant post-antibiotic effect, providing equivalent efficacy and minimizing AUC-
associated toxicity.19

Empiric dosing of aminoglycosides occurs via three strategies: (1) extended interval dosing (EID), (2)
traditional dosing, and (3) synergy dosing. Refer to the following recommendations for appropriate
patient populations, dosing weight, timing of concentration monitoring, and goal peak/trough
concentrations.

12. Aminoglycoside Recommendations and Evidence
12.1. Appropriate dosing weight should be used for all dosing schemes. (Class IIa, Level B)
12.1.1. For all dosing regimens, use ideal body weight unless total body weight is greater
than 20% in excess of ideal body weight or total body weight is below ideal body
weight
12.1.1.1. If total body weight is greater than 20% in excess of ideal body
weight, use adjusted body weight.37
12.1.1.2. AdjBW = IBW + (0.4 x (TBW – IBW)
12.1.1.3. Use total body weight if total body weight is below ideal body
weight.37
12.1.2. In EID, altered volume of distribution and glomerular filtration in morbidly obese
patients increases the risk of both supratherapeutic and subtherapeutic drug
concentrations.38
12.1.2.1. A retrospective evaluation of morbidly obese patients (>190% IBW)
receiving EID of gentamicin or tobramycin assessed the
appropriateness of an adjusted body weight-based nomogram.
Gentamicin concentrations obtained 16 hours after an infusion in this
population were as follows: therapeutic (71%), subtherapeutic (13%),
and supratherapeutic (16%). The authors correlate older age with an
increased likelihood of supratherapeutic values (61.5 ± 12.3
[supratherapeutic] vs. 50.5 ± 12.4 [therapeutic], p=0.04).38

12.2. Synergy Dosing
12.2.1. Synergy dosing of aminoglycosides in conjunction with another antibiotic is
recommended for treatment of enterococcal endocarditis39,40 (Class I, Level B)
and may be considered for streptococcal endocarditis40 (Class IIa, Level B).
12.2.1.1. Empiric gentamicin or tobramycin synergy dose for a patient with a
calculated creatinine clearance of greater than 50 mL/min is 1 mg/kg
IV every 8 hours with subsequent dosing based on drug
concentration monitoring.40,41 (Class IIa, Level B).
12.2.1.2. Patients with a calculated creatinine clearance of ≤50 mL/min should
receive 1 mg/kg dose at an interval of every 12 or 24 hours based on
subsequent drug concentration monitoring41 (Class IIa, Level B)
12.2.1.3. An EID nomogram should not be used for synergy. (Class III, Level
B)
12.2.1.4. Empiric gentamicin synergy dosing of 3 mg/kg IV every 24 hours
may be considered as an alternative dosing strategy for highly
penicillin-susceptible viridans group streptococci or Streptococcus
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gallolyticus (bovis) if the patient has native-valve endocarditis. (Class
IIa,, Level B).42
12.2.1.4.1. Every 24 hour dosing may be appropriate when needed
to facilitate discharge to a skilled nursing facility or to
simplify antimicrobial administration in the home after
aminoglycoside concentrations and patient-specific
pharmacokinetics are assessed. (Class III, Level C)
12.2.1.4.2. Target concentrations for synergy dosing using 3 mg/kg
IV every 24 hours have not been defined, but can be
estimated based on the volume of distribution for
aminoglycosides.
12.2.1.4.2.1. Peak concentrations (drawn no sooner
than 60 minutes after the end of the
infusion) of 9-12 mcg/mL can be
expected with this dosing scheme and
the Cmin should be below 0.5 mcg/mL.37
12.2.1.4.2.2. A mid-point (random) concentration
should be drawn no sooner than 3 half-
lives (about 10-12 hours after the start
of the infusion) for two-point
pharmacokinetic calculations with the
assistance of the clinical pharmacist.
12.2.2. Peak and trough aminoglycoside drug concentrations for synergy dosing using 1
mg/kg IV every 8, 12 or 24 hours should be drawn after three to five half-lives
and according to Table 8.37 (Class IIb, Level C)
12.2.2.1. A peak aminoglycoside concentration does not need to be
mathematically extrapolated to a Cmax given that the distributional
phase is very short with low aminoglycoside doses given for synergy
(Class IIa, Level B)
12.2.2.2. The peak should be drawn no sooner than 30 minutes after the end
of the infusion to avoid the distribution phase.37 (Class IIa, Level A)
12.2.2.3. Drawing the trough 60 minutes prior to the next dose is acceptable if
needed to ensure a detectable concentration.37 (Class IIa, Level A)

Table 8. Recommended monitoring for aminoglycoside synergy dosing37,43,44
Dosing
Interval 1 mg/kg IV Q8H 1 mg/kg IV Q12H 1 mg/kg IV Q24H
Goal
aminoglycoside
concentration
Trough 30 minutes before
the 4th dose
30-60 minutes before
the 3rd dose
30-60 minutes before
the 2nd dose
<1 mcg/mL
(<0.5 mcg/mL
preferred)
Peak
30-60 minutes after
the end of the
infusion following the
3rd dose
30-60 minutes after
the end of the
infusion following the
3rd dose
30-60 minutes after
end of the infusion
following the 2rd dose
3-4 mcg/mL

12.3. Extended Interval Dosing (EID)
12.3.1. Empiric EID should be considered for all eligible patients (Class IIa, Level B)
12.3.2. Patients excluded from empiric EID dosing and who should receive
traditional dosing include45 (Class III, Level A):
ξ pregnant patients
ξ neonates
ξ severe burns(>20% BSA)
ξ anasarca
ξ ascites
ξ cystic fibrosis
ξ meningitis
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ξ endocarditis
ξ patients with a calculated creatinine clearance < 20 mL/min
ξ patients with unstable renal function
12.3.3. Administering aminoglycosides using a combination of a higher dose (compared
to traditional dosing regimens) and an extended interval can result in increased
likelihood of successful antimicrobial activity, reduced hospital costs, reduced
total daily dose of drug administered to the patient without compromising
antimicrobial efficacy, and lower incidence of adverse drug events.19-20
12.3.3.1. A 1997 retrospective cost analysis at the Mayo medical center
assessed the relative costs of EID versus intermittent gentamicin
dosing based on acquisition, preparation, and administration costs;
therapeutic drug monitoring; and treatment of nephrotoxicity. The
mean per-patient cost of 4.5 days of aminoglycoside therapy was
$36.77 (EID) versus $87.32 (traditional dosing). Due to a reduced
incidence of nephrotoxicity observed with the EID regimen (1.2% vs.
4%), the authors also concluded that there exist significant cost-
savings in nephrotoxicity management costs (per-patient cost, $55
vs. $182, extended-interval vs. intermittent dosing).46
12.3.3.2. Parker and Davey provide an excellent review of direct and indirect
savings of EID. The authors conclude that EID accrues fewer costs
in: (1) product preparation and administration, (2) product wastage
and (3) therapeutic monitoring. There are also indirect savings in
delayed development of toxicity, reduced risk of litigation due to
adverse drug events, fewer treatment failures and fewer
venipuncture events.47
12.3.3.3. A mathematical model system analogous to a Monte Carlo
simulation used patient data provided in other publications to create
a representative model of aminoglycoside concentrations,
antibacterial efficacy, nephrotoxicity, and ototoxicity. The authors
conclude that EID reduced both onset and extent of nephrotoxicity
and ototoxicity, but did not eliminate the need for therapeutic drug
monitoring.48
12.3.4. Patients receiving EID therapy for the treatment of lower respiratory infections
should receive a single dose of 7 mg/kg IV tobramycin or gentamicin calculated
using appropriate body weight (see 1.11).45 If amikacin is selected, a 21 mg/kg
dose should be used.45 (Class I, Level A)
12.3.4.1. Although EID dosing does not require 2-point kinetics, 7 mg/kg in an
appropriate patient population would yield a predicted peak of 20-25
mcg/mL with a trough < 1 mcg/mL for tobramycin and gentamicin.45
A 21 mg/kg amikacin dose would yield an expected peak of 40-60
mcg/mL and a trough <4 mcg/mL.45
12.3.5. Patients receiving EID therapy for all other indications should receive a single
dose of 5 mg/kg IV tobramycin or gentamicin calculated using appropriate dosing
weight (see 1.11.1). If amikacin is selected, a 15 mg/kg dose should be used.
(Class I, Level A)
12.3.5.1. Although EID dosing does not require 2-point kinetics, 5 mg/kg in an
appropriate patient population would yield a predicted peak of 15-18
mcg/mL with a trough < 1 mcg/mL for tobramycin and gentamicin.45
A 15 mg/kg amikacin dose would yield an expected peak of 35-50
mcg/mL and a trough <4 mcg/mL.

12.4. Drug Concentration Monitoring for EID
12.4.1. A single drug concentration should be obtained between 6 and 14 hours after the
start of the 60 minute aminoglycoside infusion. This drug concentration should be
used with the appropriate nomogram below to determine the appropriate interval
for subsequent doses.45 (Class I, Level A)
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12.4.2. If the drug concentration falls within the area designated as Q24h, Q36h, or
Q48h according to the nomogram, then the interval should be Q24, Q36, or Q48
hours respectively. If the drug concentration falls on the line, then the longer
dosing interval should be chosen.45




12.4.3. A subtherapeutic or supratherapeutic initial drug concentration indicates that the
individual patient pharmacokinetic parameters are not consistent with the
population studied for the nomogram. This patient should receive traditional
dosing based on two-point pharmacokinetics.
12.4.3.1. If a supratherapeutic drug concentration occurs (i.e. above the upper
limit of the nomogram), a second aminoglycoside concentration
should be drawn and two-point pharmacokinetics should be drawn to
determine the appropriate dose and interval via traditional dosing.37
(Class A, Level B) See section 11.6.2
12.4.3.2. If a subtherapeutic concentration (< 2 mcg/mL for
gentamicin/tobramycin or < 6 mcg/mL for amikacin) is obtained with
the initial concentration, then two-point pharmacokinetics should be
used to guide therapy.
12.4.3.3. The clinical pharmacist should investigate the possibility of a
contaminated blood draw causing an initial concentration to fall
outside of the nomogram.
12.4.4. If the patient is expected to have good clearance (young, critically ill patients),
consider checking an early aminoglycoside concentration (< 10 hours) to
minimize the risk of finding an undetectable concentration.49,50
12.4.4.1. While EID dosing via the nomogram may be used, for these young,
critically ill patients, two-point kinetics may be considered (Class III,
Level C).

12.5. Traditional Aminoglycoside Dosing
12.5.1. Patients who are not eligible for EID and who are not receiving aminoglycosides
for synergy should receive traditional aminoglycoside dosing, excepting cystic
fibrosis patients. (Class III, Level A)
12.5.2. Empiric dosing and monitoring parameters are listed in Table 9.
12.5.2.1. Two peripheral aminoglycoside concentrations should be obtained to
guide further therapy.43

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Table 9. Traditional aminoglycoside dosing: empiric dosing and concentration monitoring

Creatinine clearance

≥ 60 mL/min 40-59 mL/min <40 mL/min Hemodialysis
Gentamicin or
tobramycin
1.5-2 mg/kg every 8
hours
1.5-2 mg/kg every
12 hours
2 mg/kg load, then
1.5 mg/kg every 24
hours or longer
2 mg/kg load, then
1.5 mg/kg post-
dialysis
Amikacin 5-7.5 mg/kg every 8
hours
5-7.5 mg/kg every
12 hours
5-7.5 mg/kg every
24 hours or longer
7.5 mg/kg load,
then 5-7.5 mg/kg
post-dialysis
Trough 30-60 minutes
before the 4th dose
30-60 minutes
before the 3rd dose
Mid-point (random)
concentration 10-12
hours following the
2nd dose
Allow 2 hours after
the end of dialysis
session for
redistribution, then
draw the trough
Peak
(gentamicin/
tobramycin)
30-60 minutes after the end of the 30
minute infusion following the 3rd dose
30-60 minutes after end of the 30 minute
infusion following the 2rd dose
Peak
(Amikacin)
60-120 minutes after the end of the 60
minute infusion following the 3rd dose
60-120 minutes after the end of the 60
minute infusion following the 2rd dose

12.5.2.2. Pharmacokinetic parameters should be calculated, including volume
of distribution, Cmax, Cmin, elimination rate constant, and elimination
half-life. (Class IIa, Level C)
12.5.2.3. Based on the pharmacokinetic calculations, the dose and dosing
interval should be adjusted to meet the following parameters
associated with efficacy for aminoglycosides20,51 (Class IIa, Level B)
12.5.2.3.1. Peak to MIC ratio (peak:MIC) of 8-10 for pneumonia,
meningitis, fever and neutropenia, Gram-negative
bacteremia
12.5.2.3.1.1. Two-point kinetics must be used if higher
peaks are needed.
12.5.2.3.2. Peak concentration 6-8 mcg/mL for abdominal
infections, peritonitis, skin and soft tissue infections.
12.5.2.3.3. Peak concentration 4-6 mcg/mL for urinary tract
infections

12.6. Drug Concentration Monitoring for Traditional Dosing
12.6.1. After the initial two-point pharmacokinetics are calculated, additional drug
monitoring is not necessary if the expected duration of therapy is equal to or
fewer than five days, unless the patient’s renal function changes. (Class IIb,
Level C)
12.6.2. Patients who have a supratherapeutic concentration (i.e. above the upper limit of
the nomogram) should be monitored with two-point kinetics52 (Class A, Level B)
12.6.2.1. As the aminoglycoside distribution phase in high-dose (e.g. 5 or 7
mg/kg) is prolonged due to high doses, timing of concentrations
must be considered
12.6.2.1.1. The peak concentration should be drawn no sooner than
2.7 hours after the start of a 60-minute infusion
12.6.2.1.2. A midpoint (random) concentration should be drawn six
to eight hours after the initial concentration
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12.7. Drug Concentration Monitoring for Long-term Aminoglycoside Therapy
12.7.1. Traditional/synergy dosing: trough drug concentrations and creatinine should be
monitored at least once weekly during prolonged therapy. (Class I, Level A)
12.7.2. EID
12.7.2.1. Trough concentrations should be drawn 30-60 minutes before the
dose and can be used to monitor for nephrotoxicity and drug
accumulation in patients with extended course of EID therapy with
every 24 hour interval.37
12.7.2.2. The target gentamicin/tobramycin trough concentration is less than1
mcg/mL and less than 4-6 for mcg/mL for amikacin for every 24 hour
interval
12.7.2.2.1. A higher trough may indicate the need for two-point
pharmacokinetics to monitor therapy
12.7.2.3. Monitoring EID every 36 and 48 hour intervals has not been well
defined.
12.7.2.3.1. Monitoring for change in renal function and checking a 6-
to 14-hours post-dose concentration may be reasonable.
12.7.2.3.2. Monitoring a 24-hour concentration for two-point
pharmacokinetics if may be reasonable.
12.7.3. The target gentamicin and tobramycin trough is less than 0.5 mcg/mL for synergy
dosing.
12.7.4. If therapeutic failure is suspected at any point after starting the course of therapy,
two-point pharmacokinetics should be used to guide therapy
12.8. Audiology Testing for Long-term Aminoglycoside Therapy
12.8.1. For patients on long-term aminoglycoside therapy, consider baseline audiometry
and subsequent monitoring for ototoxicity.53

Ciprofloxacin

Ciprofloxacin demonstrates optimal efficacy when the ratio of the AUC to the MIC is ≥ 125.4 A regimen of
at least 400 mg IV ciprofloxacin given every 8 hours is necessary to reliably attain the desired AUC/MIC
ratio when the organism MIC >0.25 mg/L. However, a regimen of 400 mg IV ciprofloxacin given every 12
hours is sufficient to reliably attain the desired AUC/MIC ratio when the organism MIC is ≤ 0.25mg/L. In
this situation, providing higher doses of ciprofloxacin or more frequent administration does not result in
any additional benefit.54 Therefore, a program of dose reduction dependent on an organism’s MIC is a
reasonable way to minimize ciprofloxacin exposure without compromising antibacterial efficacy.

13. Ciprofloxacin Recommendations and Evidence
13.1. Pharmacokinetic- and pharmacodynamics-optimized ciprofloxacin dosing should be
provided for all critically ill patients (Class I, Level B) and can be beneficial for non-
critically ill patients (Class IIa, Level B) due to increasing rates of resistant organisms.
13.1.1. Pharmacokinetic data were calculated in a prospective observational study of 32
ICU patients receiving 400 mg ciprofloxacin every 12 hours. The resulting AUC
was used to create models of several simulated dosing intervals ranging from
400 mg ciprofloxacin every 12 hours to 400 mg ciprofloxacin every 3 hours.
Target attainment of an AUC/MIC >125 was calculated with MICs ranging from
0.125 mg/L to 2 mg/L based on prevalence of that MIC in organisms recovered
from the single study-site ICU over the previous two-year period. The probability
of target attainment for 400 mg ciprofloxacin every 12 hours decreases
dramatically from > 90% at MICs ≤0.25 mg/L to < 40% at MICs ≥0.5 mg/L. At an
MIC of 0.5 mg/L, 400 mg ciprofloxacin every 8 hours has a probability of target
attainment of 69% while 400 mg ciprofloxacin every 6 hours has a probability of
target attainment of 91%.54
13.1.2. A Monte Carlo simulation (1000 subjects per arm) evaluated target attainment
(AUC/MIC >123) in patients receiving ciprofloxacin to treat P. aeruginosa
infection. The simulated regimens consisted of 400 mg ciprofloxacin every 12
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20
hours, 400 mg ciprofloxacin every 8 hours, and a variable-frequency regimen that
post-hoc would have attained AUC/MIC >123. The probability of target
attainment was greater than 98% for all regimens at MIC ≤0.125 mg/L. At an MIC
of 0.25 mg/L, 12-hour dosing had a probability of target attainment of 69% while
8-hour dosing target attainment was 77%. At 0.5 mg/L, 12-hour dosing had a
probability of target attainment of 11% whereas 8-hour dosing target attainment
was 38%.55
13.2. An internal review of organisms recovered from TLC during calendar year 2008 found 36
of 100 (36%) Gram-negative isolates with MIC sensitivities to ciprofloxacin ≥0.5 mg/L.
The same review found 507 patients receiving 1674 total days of therapy with an average
length of therapy of 3.3 days (range 0-63 days). Implementation of a dose reduction
protocol reduced projected ciprofloxacin usage by 19% and resulted in a savings of
$2,916 per year.
13.3. Initial/Empiric dosing:
13.3.1. Patients with severe sepsis or admitted to the ICU or obese should receive
empiric ciprofloxacin dosed according to Table 10. (Class IIa, Level B)
13.3.2. Patients admitted to the general medicine service without a severe infection may
be considered for 1200 mg per day of ciprofloxacin empirically. (Class IIb, Level
B).

Table 10: Ciprofloxacin Dosing (infuse over 1 hour)

13.4. Dose Reduction
13.4.1. All patients from whom no organism is isolated after 72 hours or who have an
organism recovered with an MIC to ciprofloxacin that is ≤0.25 mg/L are eligible
for ciprofloxacin dose reduction based on Table 10. (Class IIa, Level B)
13.4.2. Patients who have an organism recovered with an MIC to ciprofloxacin that is
>0.25 mg/L should not be dose reduced and should continue to receive high-
dose ciprofloxacin. (Class IIa, Level B)


Estimated CrCL
(mL/min) Initial/Empiric Dosing
Dose Reduction for Definitive
Therapy
>30 400mg IV q8hrs or
600mg IV q12hrs 400mg IV q12hrs
10-30 400mg IV q12hrs 400mg IV q24hrs
<10 / HD 400mg IV q24hrs 400mg IV q24hrs
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21
UW Health Implementation
Potential Benefits:
This guideline provides guidance on optimization of antimicrobial dosing to enhance treatment of Gram-
negative infections while reducing toxicities. Additional benefits may also include cost-savings, reduction
in hospitalization days, and reduced days in the ICU.

Potential Harms:
This guideline may reduce dosing of antimicrobials to prevent optimal dosing. Also, increased line time
with prolonged infusions may be a patient dissatisfier.

Implementation Plan and Tools
1. Guideline will be housed on U-Connect in a dedicated folder for clinical practice guidelines.
2. Release of the guideline will be advertised in the Clinical Knowledge Management within the Best
Practice Newsletter.
3. Pharmacists will be educated of the new guideline at staff and team meetings.

Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and treatment of
patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that
some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely
establish the only appropriate approach to a problem.
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Appendix A. Compatibility Information
Piperacillin/Tazobactam Compatibilities56,57
Compatible Incompatible
Amikacin Vancomycin Acyclovir
Calcium Vasopressin Amiodarone
Cisatracurium Voriconazole Amphotericin (all formulations)
Clindamycin Azithromycin
Cyclosporin Ciprofloxacin
Daptomycin Diltiazem
Dexamethasone Dobutamine
Dexmedetomidine Doxycycline
Diazepam Droperidol
Digoxin Drotrecogin
Diphenhydramine Gancyclovir
Dopamine Gentamicin
Enalaprilat Haloperidol
Epinephrine Hydralazine
Esmolol Insulin
Fenoldopam Labetalol
Fentanyl Midazolam
Fluconazole Phenytoin
Fosphenytoin Tobramycin
Furosemide
Heparin
Hydrocortisone
Hydromorphone
Lidocaine
Linezolid
Lorazepam
Magnesium
Mannitol
Methylprednisolone
Metoclopramide
Metoprolol
Metronidazole
Milrinone
Morphine
Naloxone
Nitroglycerin
Nitroprusside
Norepinephrine
Ondansetron
Pantoprazole
Phenylephrine
Potassium Chloride
Potassium Phosphate
Ranitidine
Sodium Bicarbonate
Sodium Phosphate
Sulfamethoxazole-
trimethoprim

Tacrolimus
TNA


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Meropenem Compatibilities56
Compatible Incompatible No Information
Atropine Acyclovir Amiodarone
Daptomycin Amphotericin (all formulations) Azithromycin
Dexamethasone Diazepam Calcium
Dexmedetomidine Doxycycline Ciprofloxacin
Digoxin Fenoldopam Cisatracurium
Diltiazem Metronidazole Droperidol
Diphenhydramine Mannitol Drotrecogin
Dobutamine Ondansetron Esmolol
Dopamine Pantoprazole Fentanyl
Enalaprilat Sodium Bicarbonate Fosphenytoin
Fluconazole Ganciclovir
Furosemide Haloperidol
Gentamicin Hydralazine
Heparin Hydrocortisone
Hydromorphone Labetalol
Insulin Lidocaine
Linezolid Methylprednisolone
Lorazepam Metoprolol
Magnesium Micafungin
Metoclopramide Midazolam
Milrinone Naloxone
Morphine Nitroglycerin
Norepinephrine Nitroprusside
Potassium Chloride Phenylephrine
Ranitidine Potassium Phosphate
Tacrolimus Propofol
TNA Sodium Phosphate
Vancomycin Tobramycin
Vasopressin
Voriconazole

Doripenem Compatibilities56
Compatible Incompatible
Acyclovir
Amikacin
Ciprofloxacin
Gentamicin
Tobramycin
Vancomycin


Cefepime Compatibilities56,58
Compatible Incompatible
Amikacin Ciprofloxacin
Gentamicin
Tobramycin
Vancomycin
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24
Appendix B. Monte Carlo Simulations
The data contained in Appendix A is the supporting evidence for prolonged infusion β-lactams.
Occasionally, dose optimization can achieve concentrations sufficient to treat organisms reported as
resistant.7 This may be an alternative to more toxic antibiotics, such as colistin. Dosing of antimicrobials
in this scenario should be done under the guidance of Infectious Disease consult and infectious disease
pharmacist. (Class IIb, Level C)

Monte Carlo simulations of various patient populations are listed in below and sorted by drug. These may
be used to help select alternative dosing regimens. When selecting a dose, the goal should be to achieve
at least 90% probability of target attainment (y-axis) at the expected or reported minimum inhibitory
concentration (MIC) value (x-axis).

Piperacillin/tazobactam Monte Carlo simulations:
The probability of achieving 50% unbound time above the MIC (fT>MIC evaluated as a cumulative
fractional response where probability of target attainment was calculated at several MICs, adjusted by the
prevalence of that MIC among 470 representative P. aeruginosa isolates and summated) and based on a
5000-subject Monte Carlo simulation was as follows24:













Probability of target attainment at doubling minimum inhibitory concentration dilutions for
piperacillin/tazobactam regimens containing piperacillin 12 g/day (Left). Low CFR (top/right) is due to a
high incidence of isolates with piperacillin/tazobactam MICs ≥16 mcg/mL (bottom/right).17,18




Monte Carlo simulation for the following regimens: (A) 4 g piperacillin administered over 30 min or 4 h
every 8 h as well as for 30 min or 3 h every 6 h; (B) 3 g piperacillin administered over 30 min or 4 h every
8 h as well as for 30 min or 3 h every 6 hrs.14
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Parallel first-order/Michaelis-Menten mathematical models for prolonged infusion piperacillin. Lines
represent the median, 5th-percentile, and 95th-percentile of unbound piperacillin concentrations at steady
state for piperacillin (3 g) administered for 4 h. Open circles represent observed piperacillin plasma
concentrations.14



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26
Meropenem Monte Carlo Simulations
Probability of PK-PD target attainment (40% T>MIC) by MIC for various meropenem dosing regimens.59


The probability of achieving 40% unbound time above the MIC (fT>MIC) evaluated as a cumulative
fractional response where probability of target attainment was calculated at several MICs, adjusted by the
prevalence of that MIC among 8096 representative P. aeruginosa isolates and summated and based on a
2000-subject Monte Carlo simulation was as follows.60


Mean simulated steady-state free meropenem concentration-time profile based on final population
pharmacokinetic parameters for 1g as a 0.5-hour infusion (solid line) and as a 3-hour infusion (dashed
line). Please note that these values are for 1g meropenem, not for 500mg.15 The 40-48h represents a
sampling after steady state was achieved. Residual meropenem is 3mcg/mL at time of infusion and
8mcg/mL 30 minutes into the 3-hour infusion, analogous to a 5mcg/mL increase if the patient weren’t at
steady-state


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27
Doripenem Monte Carlo Simulations
Healthy Patients
Probability of target attainment for 500 mg infused IV over 1 hour (Panel A) and 4 hours (Panel B). Monte
Carlo parameters include data from healthy volunteers.61 Circles indicate 25% time above the MIC
(T>MIC), triangles indicate 30% T>MIC, and plus signs indicate 35% T>MIC.



Obesity
This graph shows the probability of target attainment of 40% T>MIC for doripenem in obese patients (total
body weight 180±61 kg; BMI 65±28 kg/m2).31 Meropenem Monte Carlo simulations were conducted in this
study as well. The horizontal dotted line corresponds to an optimum probability of target attainment
(90%).

The probability of target attainment for achieving 40% T>MIC for 500 mg doripenem infused IV at varying
body weights.30 Panel A is a 1-hour infusion; Panel B is a 4-hour infusion.

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Renal Insufficiency
Below are the probabilities of target attainment for achieving 40% f T>MIC for various simulated
doripenem doses (every eight hours) in patients with a total body weight of 80 kg and various glomerular
filtration rates (A) 30 mL/min; (B) 50 mL/min; (C) 100 mL/min; and (D) 150 mL/min against a theoretical
minimum inhibitory concentration range.30


The following chart demonstrates the probability of achieving the target of T>MIC ≥35% with varying renal
function and MIC based on Monte Carlo simulations.32 Normal renal status is defined as CrCL of 80
mL/min; mild impairment, 50 - <80 mL/min; moderate impairment, 30 - <50 mL/min; severe impairment,
<30 mL/min.

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29
Cefepime Monte Carlo Simulations
Probability of target attainment (PTA) at 60% fT > MIC for six prolonged infusion regimens of cefepime at
specific minimum inhibitory concentrations (MICs). The dotted line indicates a PTA ≥ 90%.16



The probability of target attainment (50% time > MIC of 4 mg/L) based on a 5000-subject Monte Carlo
simulation is shown below.62 All regimens tested achieved target attainment when the cefepime MIC was
≤ 4 mg/L. Cefepime scenarios tested included: 2g infused over 30 minutes every 6 hours, 2g infused over
30 minutes every 8 hours, 2g infused over 30 minutes every 12 hours, 2g infused over 3 hours every 6
hours, 2g infused over 3 hours every 8 hours, 1g infused over 30 minutes every 8 hours, 1g infused every
30 minutes over 12 hours, 2g daily continuously, 4g daily continuously and 6g daily continuously.


A separate Monte Carlo simulation (5000 subjects) evaluated target attainment (60% fT > MIC of 8 mg/L)
of six different prolonged infusion cefepime regimens.16 Probability of target attainment was > 90% for the
following regimens: 2g cefepime infused over four hours every 8 hours, 1g cefepime infused over three
hours every 6 hours and 2g cefepime infused over three hours every 6 hours. Regimens that did not
achieve target attainment include: 1g cefepime infused over four hours every 8 hours, 1g cefepime
infused over four hours every 12 hours and 2g cefepime infused over four hours every 12 hours. When
the MIC is increased to 16 mg/L, the probability of target attainment was > 90% for 2g cefepime infused
over four hours every 8 hours and 2 g cefepime infused over three hours every 6 hours. Organism-
specific target attainment at an MIC of 8 mg/L are:16
a. E. coli: All regimens listed above had a probability of target attainment > 96.9%.
b. K. pneumoniae: All regimens listed above had a probability of target attainment > 90.9% except
for: 1g cefepime infused over four hours every 12 hours (88.6%).
c. Enterobacter spp.: All regimens listed above had a probability of target attainment > 95.0%.
d. S. marcescens: All regimens listed above had a probability of target attainment > 98.6%.
e. Citrobacter spp.: All regimens listed above had a probability of target attainment > 97.1%.
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P. aeruginosa: All regimens listed above had a probability of target attainment > 92.7% except for: 1g
cefepime infused over four hours every 12 hours (73.8%), 2g cefepime infused over four hours every 12
hours (87.1%) and 1g cefepime infused over four hours every 8 hours (88.6%).

A third Monte Carlo simulation (5000 subjects) evaluated target attainment (50% fT > MIC) of different
intermittent and prolonged infusion cefepime regimens. This target attainment is a cumulative fractional
response where probability of target attainment was calculated at several MICs, adjusted by the
prevalence of that MIC in a recently-collected large (>1000) population of organisms and summated.
Organism-specific target attainment is as follows63:
a. E. coli target attainment: 1g infused over 30 minutes every 12 hours (96.4%), 2g infused over 30
minutes every 12 hours (97.0%), 2g infused over 30 minutes every 8 hours (97.6%).
b. K. pneumoniae target attainment: 1g infused over 30 minutes every 12 hours (93.6%), 2g infused
over 30 minutes every 12 hours (95.0%), 2g infused over 30 minutes every 8 hours (95.9%).
c. A. baumanii target attainment: 2g infused over 30 minutes every 12 hours (52.9%), 2g infused
over 30 minutes every 8 hours (60.9%), 2g infused over 3 hours every 8 hours (64.0%).
d. P. aeruginosa target attainment: 2g infused over 30 minutes every 12 hours (83.6%), 2g infused
over 30 minutes every 8 hours (90.1%), 2g infused over 3 hours every 8 hours (93.2%).

Simulated steady-state concentration-time profile of cefepime 1g every 8 hours infused over 4 hours16


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31
Ciprofloxacin Monte Carlo Simulations
Figure 6.1. Fractional attainment of AUC/MIC ≥ 125. Each ciprofloxacin dose was 400mg intravenous and
the total daily dose of ciprofloxacin is displayed (i.e. 800mg represents 400mg ciprofloxacin every 12
hours, 1200mg represents 400mg ciprofloxacin every 8 hours, etc.)54


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32
Appendix C. Antibiotic alternatives to Fluoroquinolones
From: PK/PD Dose Optimization of Antibiotics for the Treatment of Gram-negative Infections – Adult – Inpatient Clinical Practice Guideline
Last Reviewed 1/2017; Last Updated 1/2017
Contact information: Lucas Schulz, PharmD, Phone Number: (608)890-8617, LSchulz2@uwhealth.org

Table 1. Recommended alternative EMPIRIC regimens – GENERAL CARE
Diagnosis Historical Empiric Therapy Proposed New Empiric Therapy Comments/Step Down Therapy
A

Cystitis or
Uncomplicated
Urinary Tract Infection
Ciprofloxacin OR
Levofloxacin
Nitrofurantoin
Fosfomycin
Cefpodoxime
Do not treat asymptomatic bacteruria

Base on final culture results:
nitrofurantoin, fosfomycin, TMP/SMX,
cefpodoxime

Ceftriaxone susceptibility predicts
activity for cefpodoxime
Pyelonephritis Ciprofloxacin OR
Levofloxacin
No risk for MDRO: cefpodoxime or ceftriaxone
If no oral options, page 3333 for
fluoroquinolone approval

Tailor therapy based on final culture
results

Ceftriaxone susceptibility predicts
activity for cefpodoxime
With risk factors for MDRO: cefepime and vancomycinB
With risk factors for MDRO and IgE-mediated or severe reaction to
β-lactam: gentamicin OR TMP/SMX
Spontaneous
bacterial peritonitis
(SBP) prophylaxis
Ciprofloxacin Oral therapy: TMP/SMX OR cefpodoxime
Intravenous therapy: ceftriaxone
May transition to oral equivalent of
empiric regimen OR to ciprofloxacin at
discharge
Intra-abdominal
infection – community
or healthcare
associated
Ciprofloxacin AND
metronidazole
No risk factors for MDRO:
ξ cefpodoxime AND metronidazole OR
ξ ceftriaxone AND metronidazole
Base on final culture results, some
examples of potential oral options:
ξ cefpodoxime OR cefuroxime PLUS
metronidazole
ξ amoxicillin/clavulanic acid

If final culture results require
fluoroquinolone step down (e.g.
Pseudomonas) single oral dose prior
to discharge is acceptable
Vancomycin PLUS
Piperacillin/
tazobactam AND
Ciprofloxacin
With risk factors for MDRO or severe community-acquired
infection:
ξ vancomycinB PLUS piperacillin/tazobactam OR
ξ vancomycinB PLUS cefepime AND metronidazole

With risk factors for MDRO and IgE-mediated or severe reaction to
β-lactam: vancomycinB PLUS aztreonam PLUS metronidazole
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Diagnosis Historical Empiric Therapy Proposed New Empiric Therapy Comments/Step Down Therapy
A

Community-acquired
PneumoniaD
Moxifloxacin OR
Levofloxacin
No risk factors for MDRO:
ξ ceftriaxone PLUS doxycycline OR
ξ ceftriaxone PLUS azithromycin
Potential oral options: cefpodoxime
OR cefuroxime PLUS azithromycin OR
doxycycline

If no oral options, page 3333 for
fluoroquinolone approval
For patients with IgE-mediated or severe reaction to β-lactam:
vancomycinB PLUS aztreonamC
Healthcare-associated
PneumoniaD
Vancomycin PLUS
Cefepime AND
Ciprofloxacin
With risk factors for MDRO: vancomycinB PLUS cefepime

If patient in septic shock: ADD tobramycin (Pending transfer to
higher care level)

If concern for atypical bacteria: ADD azithromycin
Double coverage for Pseudomonas is
not required in clinically stable, general
care patient

If no oral options, page 3333 for
fluoroquinolone approval For patients with IgE-mediated or severe reaction to β-lactam:
vancomycinB PLUS aztreonamC
Sepsis (without septic
shock) of urinary
origin/pyelonephritis
Vancomycin
AND/OR
ciprofloxacin
No risk factors for MDRO: ceftriaxone

With risk factors for MDRO: vancomycinB PLUS cefepime

For patients with IgE-mediated or severe reaction to β-lactam:
vancomycinB PLUS tobramycin

Septic Shock –
unknown origin
empiric coverage of
Pseudomonas
Vancomycin PLUS
Piperacillin/tazoba
ctam AND
Ciprofloxacin
ξ VancomycinB PLUS piperacillin/tazobactam PLUS tobramycin
OR
ξ VancomycinB PLUS cefepime PLUS tobramycin

For patients with IgE-mediated or severe reaction to β-lactam:
VancomycinB PLUS aztreonamC PLUS tobramycin PLUS
metronidazole

A Base step down therapy on culture results, if no oral step down therapy except fluoroquinolones exist, please page 3333 for approval or other options
B
Vancomycin therapy targeted to trough goal of 15-20 mcg/mL
C Empiric aztreonam use is approved for 72 hours. Further therapy with aztreonam will require approval via 3333 pager or ID consult
D
If severe or immediate IgE-mediated beta-lactam allergy, please page 3333 for alternative options
MDRO: Multidrug-resistant organism
TMP/SMX: trimethoprim/sulfamethoxazole

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34
Table 2. Recommended alternative EMPIRIC regimens – INTENSIVE CARE MEDICINE
Diagnosis Historical Empiric Therapy Proposed New Empiric Therapy
Septic Shock –
unknown origin
empiric coverage of
Pseudomonas
Vancomycin PLUS
Piperacillin/tazoba
ctam AND
Ciprofloxacin
ξ VancomycinA PLUS piperacillin/tazobactam PLUS tobramycin OR
ξ VancomycinA PLUS cefepime PLUS tobramycin OR
ξ VancomycinA PLUS meropenem PLUS tobramycin
For patients with IgE-mediated or severe reaction to β-lactam: vancomycinA PLUS aztreonam PLUS
tobramycin PLUS metronidazole
Community-acquired
Pneumonia Moxifloxacin
No risk factors for MDRO: ceftriaxone OR ampicillin/sulbactam

If concern for atypical bacteria or Legionnaires’ disease: ADD azithromycin
For patients with IgE-mediated or severe reaction to β-lactam: vancomycinA AND aztreonam
Healthcare-associated
Pneumonia
Vancomycin PLUS
Piperacillin/tazoba
ctam AND
Ciprofloxacin
With risk factors for MDRO: vancomycinA PLUS piperacillin/tazobactam OR cefepime

If patient in septic shock: ADD tobramycin

If concern for atypical bacteria or Legionnaires’ disease: ADD azithromycin
For patients with IgE-mediated or severe reaction to β-lactam: vancomycinA PLUS aztreonam
Sepsis (without septic
shock) of urinary
origin/pyelonephritis
Vancomycin
AND/OR
ciprofloxacin
No risk factors for MDRO: ceftriaxone

With risk factors for MDRO: vancomycinA PLUS cefepime

For patients with IgE-mediated or severe reaction to β-lactam: vancomycinA PLUS tobramycin
Intraabdominal
infection – with or
without septic shockB
Ciprofloxacin AND
metronidazole
No risk factors for MDRO:
ξ ceftriaxone AND metronidazole OR
ξ cefoxitin OR
ξ piperacillin/tazobactam
Vancomycin PLUS
Piperacillin/tazoba
ctam AND
Ciprofloxacin
With risk factors for MDRO:
ξ vancomycinA PLUS piperacillin/tazobactam PLUS tobramycin OR
ξ vancomycinA PLUS cefepime PLUS tobramycin PLUS metronidazole OR
ξ vancomycinA PLUS meropenem with or without tobramycin
For patients with IgE-mediated or severe reaction to β-lactam: vancomycinA PLUS aztreonam PLUS
tobramycin PLUS metronidazole
A Vancomycin therapy targeted to trough goal of 15-20 mcg/mL
B Assess patient for risk factors for invasive candidiasis and need for empiric antifungal coverage
MDRO: Multidrug-resistant organism
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Table 3. Recommended alternative EMPIRIC regimens – ABDOMINAL TRANSPLANT
Diagnosis Historical Empiric Therapy Proposed New Empiric Therapy Comments/Step Down Therapy
A

Cystitis or
Uncomplicated
Urinary Tract Infection
(non-renal transplant)
Ciprofloxacin OR
Levofloxacin
Nitrofurantoin
Fosfomycin
Cefpodoxime
Base on final culture results:
nitrofurantoin, fosfomycin,
cefpodoxime
Positive urine culture
in the deceased renal
transplant donor
Ciprofloxacin

ADD Vancomycin
IF concern for
Gram-positive
organisms
No risk factors for MDRO: ceftriaxone

Concern for extended spectrum Gram-negative rods: cefepime or
piperacillin/tazobactam
Base on final culture results

Ceftriaxone susceptibility predicts
activity for cefpodoxime

If no oral options, page 3333 for
fluoroquinolone approval
For patients with IgE-mediated or severe reaction to β-lactam:
tobramycin or aztreonamB
Cystitis in renal
transplant patient Ciprofloxacin
ASYMPTOMATIC <3
months post renal
transplant
No empiric antibiotic. Await final
culture results to start therapy. If
treatment started, provide 5-7 day
therapy course
Base on final culture results

Ceftriaxone susceptibility predicts
activity for cefpodoxime

If no oral options, page 3333 for
fluoroquinolone approval
ASYMPTOMATIC >3
months post renal
transplant
No treatment, unless associated rise
in creatinine
SYMPTOMS present
Nonsystemic therapies
ξ nitrofurantoin if CRCL >40 mL/min
ξ fosfomycin if CRCL <40 mL/min
or concern for drug resistant
isolates
Continuation of empiric, non-systemic
therapies or based on final culture
results
Pyelonephritis in
renal transplant
patient
Ciprofloxacin

ADD Vancomycin
IF concern for
Gram-positive
organisms
No risk factors for MDRO: ceftriaxone

Concern for extended spectrum Gram-negative rods: cefepime or
piperacillin/tazobactam

For patients with IgE-mediated or severe reaction to β-lactam:
tobramycin (while awaiting pathogen identification) OR
aztreonamB
Base on final culture results

Ceftriaxone susceptibility predicts
activity for cefpodoxime

If no oral options, page 3333 for
fluoroquinolone approval
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Diagnosis Historical Empiric Therapy Proposed New Empiric Therapy Comments/Step Down Therapy
A

Cholangitis in the
historical liver
transplant recipient
Ciprofloxacin
PLUS amoxicillin
OR moxifloxacin
ξ Piperacillin/tazobactam PLUS metronidazole OR
ξ Cefepime PLUS metronidazole

For patients with IgE-mediated or severe reaction to β-lactam:
ξ vancomycin (trough goal 10-20 mcg/mL) PLUS tobramycin OR
ξ vancomycin (trough goal 10-20 mcg/mL) PLUS aztreonam
Cefpodoxime OR cefuroxime PLUS
amoxicillin (Enterococcus coverage)

If no oral options, page 3333 for
fluoroquinolone approval
Intra-abdominal
infection – Other
community or
healthcare associated
Ciprofloxacin AND
metronidazole No risk factors for MDRO: ceftriaxone AND metronidazole
Base on final culture results, some
examples of potential oral options:
ξ cefpodoxime OR cefuroxime PLUS
metronidazole
ξ amoxicillin/clavulanic acid

If final culture results require
fluoroquinolone step down (e.g.
Pseudomonas) single oral dose prior
to discharge is acceptable
Vancomycin PLUS
Piperacillin/
tazobactam AND
Ciprofloxacin
With risk factors for MDRO:
ξ vancomycinC PLUS piperacillin/tazobactam OR
ξ vancomycinC PLUS meropenem

With risk factors for MDRO and IgE-mediated or severe reaction to
β-lactam: vancomycinC PLUS aztreonam PLUS metronidazole
Community-acquired
PneumoniaD
Moxifloxacin OR
Levofloxacin
No risk factors for MDRO:
ξ ceftriaxone PLUS doxycycline OR
ξ ceftriaxone PLUS azithromycin
Potential oral options: cefpodoxime
OR cefuroxime PLUS azithromycin OR
doxycycline

If no oral options, page 3333 for
fluoroquinolone approval
For patients with IgE-mediated or severe reaction to β-lactam:
vancomycinC PLUS aztreonamB
Healthcare-associated
PneumoniaD
Vancomycin PLUS
Cefepime AND
Ciprofloxacin
With risk factors for MDRO: vancomycinB PLUS cefepime

If patient in septic shock: ADD tobramycin (pending transfer to
higher care level)

If concern for atypical bacteria: ADD azithromycin
Double coverage for Pseudomonas is
not required in clinically stable, general
care patient

If no oral options, page 3333 for
fluoroquinolone approval For patients with IgE-mediated or severe reaction to β-lactam:
vancomycinB PLUS aztreonamC
A Base step down therapy on culture results, if no oral step down therapy except fluoroquinolones exist, please page 3333 for approval or other options
B Empiric aztreonam use is approved for 72 hours. Further therapy with aztreonam will require approval via 3333 pager or ID consult
C
Vancomycin therapy targeted to trough goal of 15-20 mcg/mL
D
If severe or immediate IgE-mediated beta-lactam allergy, please page 3333 for alternative options
MDRO: Multidrug-resistant organism
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37
Appendix D. Two-point kinetic calculations for traditional or synergy dosing with
gentamicin and tobramycin 30-minute infusions

From: PK/PD Dose Optimization of Antibiotics for the Treatment of Gram-negative Infections – Adult –
Inpatient Clinical Practice Guideline
Last Reviewed 3/2017; Last Updated 3/2017
Contact: Erin McCreary, PharmD, BCPS; emccreary@uwhealth.org or Marie Pietruszka, PharmD,
BCPS; mpietruszka@uwhealth.org

Aminoglycoside Pharmacokinetic and Pharmacodynamic Properties1,2
ξ Hydrophilic (volume of distribution approximates the volume of extracellular fluid)
ξ Rapidly bactericidal and concentration-dependent activity
ξ Post-antibiotic effect (bactericidal activity persists even after serum concentrations fall below minimum
inhibitory concentration)
ξ Trough concentrations above target correlate to toxicities (e.g. ototoxicity, nephrotoxicity)
ξ Factors leading to faster drug clearance (e.g. dehydration, children)
o
o
ξ Factors leading to slower drug clearance (e.g. edema, ascites, sepsis, obesity)
o
o

Definitions for calculations (note: all times are in hours)







;

-1
)


References:
1. Bauer, Larry A. The Aminoglycoside Antibiotics In: Weitz M, Pancotti R eds. Applied Clinical
Pharmacokinetics. 2nd ed. New York McGraw Hill; 2008:97-115.
2. MacDougall C, Chambers HF. Aminoglycosides In: Brunton L, Chabner B, Knollamn B eds.
Goodmans and Gillman's The Pharmacological Basis of Therapeutics. 12th ed. New York McGraw
Hill;2011:1507-1512.


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38
Selecting an appropriate initial gentamicin or tobramycin dosing regimen (to be infused over 30
minutes) based on desired PK target regimen (traditional dosing)1,2

1. Choose an appropriate dosing weight
a. Use ideal body weight unless total body weight is below ideal body weight, then use total body
weight.
b. If total body weight is greater than 20% in excess of ideal body weight, use adjusted body weight.
2. Calculate patient specific CrCl (in mL/min) using appropriate equation
3. Estimate



4. Estimate



5. Estimate using dosing weight established in Step 1




** NOTE: If both fluid overloaded and obese, use 0.26L/kg to avoid overestimating Vd

6. Calculate initial dosing interval



** NOTE: If patient is HD-dependent, administer dose after each dialysis session. Round dosing interval to
nearest 8, 12, 18, 24, 36, or 48 hours.
See guideline for target Cmax (peak) and Cmin (trough) based on infection site

7. Calculate initial loading dose (based on desired Cmax, which is the PK peak target) and subsequent
maintenance dose required to maintain desired target peak concentration

 Use only for life-threatening infections


** NOTE: Consider aiming for the lower end of the PK range (Cmax) for initial dose estimation for patients with
BMI > 30 kg/m2 to avoid overestimating the dose required for this population. For example, aim for a peak of 8
mcg/mL for pneumonia instead of 10 mcg/mL.

8. Round calculated maintenance dose to nearest 10 mg or available stock bag dose, then recalculate
the estimated Cmax based on rounded dose



9. Estimate Cmin (trough) as a safety check


T = estimated time between peak and trough (e.g. plug in 7 hours if the patient has an 8-hour dosing interval)

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39
Evaluating gentamicin and tobramycin steady state concentrations and making recommendations
for dose adjustments (traditional or synergy dosing)1,2

1. Verify administration time, duration of infusion (should be 30 minutes) and sampling time
2. Calculate patient-specific



3. Calculate patient specific (using patient-specific )



4. Calculate (using patient-specific )



5. Calculate patient-specific (using patient-specific )



6. Calculate new patient-specific dosing interval (using patient specific )



**Note: Round dosing interval to nearest 8, 12, 18, 24, 36, or 48 hours.

7. Calculate new dose (using patient-specific )




8. Dose check : Use calculated dose, patient specific Vd, patient specific ke and calculated dosing
interval to verify expected (estimated peak) and (estimated trough) with the new dosing
regimen



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40
Graphical representations of steady-state aminoglycoside dosing regimens with adjustments


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41



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42
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