Dropping the MIC: Mono- versus Combination

Therapy for Carbapenem-Resistant

Enterobacteriaceae Bacteremia

Andrew Thompson, Pharm.D.

PGY2 Infectious Diseases Pharmacy Resident
South Texas Veterans Health Care System
Division of Pharmacotherapy, University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center,
University of Texas Health Science Center at San Antonio

December 18, 2015

Learning Objectives:
1. Describe the emergence of carbapenemases in Enterobacteriaceae
2. Understand the current epidemiology of carbapenem-resistant Enterobacteriaceae
3. Explain the rational of combination therapy
4. Describe the therapeutic options available for treating carbapenem-resistant Enterobacteriaceae bacteremia

Background
I.

Enterobacteriaceae Microbiology1
a. Normal human gut flora and environmental organisms
b. More than 70 species
c. Involved in a range of infections
d. Important cause of healthcare and community-associated infections

II.

Gram-negative Rod (GNR) Bacteremia2

a. Significant problem in both hospitalized and community patients
b. 25% of all blood stream infections (BSI) are caused by GNR
c. Major cause of morbidity and mortality
i. 15-40% mortality
d. Rise in multi-drug resistant (MDR) infections poses increased difficulties

III.

The Rise of Antibiotics Resistance3

a. The treatment of gram-negative bacteremia is increasingly complicated by the rising prevalence of
multidrug-resistant strains of GNR
b. The CDC illness and mortality estimates caused by antibiotic resistance
i. 2,049,422 illnesses
ii. 23,000 deaths

IV.

Mortality Associated with Antibiotic Resistance4-13

a. Numerous studies have shown that inappropriate initial antimicrobial therapy has an independent
adverse effect on mortality
b. High mortality rates remain when controlling for confounders, such as infection type, pathogen, and
APACHE II score

Figure 1: Impact of inappropriate initial antimicrobial therapy on mortality4-13

A. Thompson |

V.

Mechanisms of Resistance14
a. Porin channels
b. Efflux pumps
c. Target modification
d. Enzymatic

Figure 2: Examples of mechanisms of antibiotic resistance15

VI.

Beta-Lactamases16
a. Categorized into 1 of 4 classes
i. Ambler class A through D
ii. Class A or class C most commonly encountered
b. Class A
i. Inhibited by -lactamase inhibitors
ii. Widely seen in Enterobacteriaceae
c. Class B
i. Hydrolyze all -lactams except aztreonam
ii. Not inhibited by ANY available -lactamase inhibitors
d. Class C
i. Encoded on chromosome and inducible
ii. Not inhibited by OLDER -lactamase inhibitors
Table 1: Ambler classification of beta-lactamases16
Classification Enzyme Common Organisms
Class A
TEM
E. Coli
K. pneumoniae
SHV
CTX-M
KPC
Class B
IMP
P. aeruginosa
A. baumannii
VIM
NDM
Class C
AmpC SPACE bugs
Class D
OXA
P. aeruginosa
(SPACE = Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter)

A. Thompson |

VII.

Beta-Lactamases Through the Years

Figure 3: Evolution of beta-lactamases17

VIII.

Defining CRE18
a. 2014 CDC Definition
i. Nonsusceptible to imipenem, meropenem, or doripenem, and resistant to all 3rd generation
cephalosporins
b. 2015 CDC Definition
i. Resistant to imipenem, meropenem, doripenem, or ertapenem
ii. Documentation that the isolate possess a Carbapenemase

IX.

Mechanisms of Carbapenem Resistance

Figure 4: Mechanisms of carbapenem resistance19

X.

Carbapenemase Classification
Table 2: Carbapenemase Classification16
Enzyme
Classification
Activity
KPC
Class A
Hydrolyzes all beta-lactams
NDM-1
Class B
Hydrolyzes all beta-lactams except aztreonam
IMP
VIM
A. Thompson |

OXA

Class D

Hydrolyzes carbapenems, but not active against 3rd

generation cephalosporins

XI.

Epidemiology of Resistance
a. Carbapenem Resistant Enterobacteriaceae (CRE)20
i. Uncommon in the United States before 1992
1. National Nosocomial Infection Surveillance (NNIS) data from 1986 to 1990, reported
only 2.3% of 1825 Enterobacter isolates tested nonsusceptible to imipenem
ii. Rapidly increasing prevalence
1. The first isolate harboring the KPC beta-lactamase was collected in 1996 and reported in
2001
2. National Healthcare Safety Network (NHSN) data from 20062007, carbapenem
resistance was reported in 10.8% of K. pneumoniae isolates as compared to <1% in 2000

XII.

Global Spread of CRE

Figure 5: Global spread of carbapenemases in Enterobacteriaceae21

XIII.

Incidence of CRE
Table 3: Incidence of CRE infections3
Organism
2001
Klebsiella
1.6%
pneumoniae
E. coli
1%
Enterobacter spp.
1.4%

XIV.

2011
11%
12%
3.6%

KPC Epidemiology

A. Thompson |

XV.

Figure 6: Distribution of Klebsiell pneumonia carbapenemases infections18

Increase in Last Resort Antibiotic Use

Figure 7: Utilization of last resort antibiotics, polymyxins and tigecycline, 127 VAMC22
XVI.

New Antibiotic Approvals

Figure 8: New antibiotic approval from 1983 to 201223

XVII.

Combating Antibiotic-Resistant Bacteria24

a. Slow the emergence of resistance
A. Thompson |

b.
c.
d.
e.
f.

Prevent the spread

Strengthen national One-Health surveillance efforts
Advance rapid identification and characterization
Accelerate therapeutic development
Improve international collaboration

Therapeutic Options
XVIII.

Antimicrobials25-28
a. Aminoglycosides
i. Poor penetration and activity into lungs, abscesses, and the central nervous system
ii. Inferior outcomes as monotherapy
1. Higher microbiologic failure
2. Higher mortality
b. Polymyxins
i. Associated with emergence of resistance during therapy
ii. High mortality monotherapy
c. Tigecycline
i. High volume of distribution with low serum concentrations
ii. Associated with increased mortality
1. Boxed warning
d. Carbapenems
Pharmacokinetics

XIX.

MICs and Breakpoints

a. Minimum Inhibitory Concentration (MIC)
i. Lowest concentration that prevents visible growth of a microorganism on agar or in broth
b. Breakpoint
i. Used in interpretation of results of susceptibility testing to define isolates
1. Susceptible
2. Intermediate
3. Resistant

XX.

Carbapenem Breakpoints
Table 4: Carbapenem Breakpoints for 2009 and 201029-30
Antimicrobial
CLSI 2009 Breakpoints
Agent
Susceptible Intermediate Resistant
Ertapenem
2
4
8
Imipenem
4
8
16
Meropenem
4
8
16
Doripenem
(CLSI = Clinical and Laboratory Standards Institute)

XXI.
7

CLSI 2010 Breakpoints

Susceptible Intermediate Resistant
0.5
1
2
1
2
4
1
2
4
1
2
4

Pharmacokinetics/Pharmacodynamics (PK/PD)
A. Thompson |

Figure 9: Pharmacokinetics/Pharmacodynamics of antibiotics31

XXII.

Pharmacokinetic of Carbapenems32-33
a. Time
i. 30% Time > MIC
1. Possibly 50% Time > MIC
b. Concentration
i. 4-5x MIC

XXIII.

Prolonged Meropenem Infusion

Figure 10: Pharmacokinetics of prolonged versus intermittent infusion of meropenem34

XXIV.

Prolonged Meropenem Infusion

A. Thompson |

Figure 11: Target attainment for 50% time above MIC for each meropenem dosage regimen at each MIC34

Literature Review
XXV.

Literature Review

Table 5: Qureshi et al. Antimicrob Agents Chemother. 2012; 56(4):21082113.35

Treatment Outcome of Bacteremia Due to KPC-Producing Klebsiella pneumoniae: Superiority of Combination
Antimicrobial Regimens
Objective
To describe the treatment and outcomes of KPC-Producing Klebsiella pneumoniae BSI in a single
large tertiary care center
Design
Non-interventional, retrospective chart review of KPC-Producing Klebsiella pneumoniae BSI
from Jan 2007 to May 2009 at Cleveland Clinic
Population
All pts with positive BSI for KPC-Producing Klebsiella pneumoniae (first episode only)
Only pts who received active in vitro therapy for >24 hours
Endpoints
Primary
o 28-day mortality
Secondary
o Risk factors for mortality
Results
41 patients identified
Appropriate therapy
o Treatment with at least one agent for at least 48 hours to which the isolate was
susceptible in vitro based on the interpretative criteria from the CLSI published in 2011
Empirical therapy
o Treatment given before final culture results became available
Definitive therapy
o Antimicrobial therapy given after the susceptibility testing results became available,
regardless of the in vitro susceptibility to the agent
Combination therapy
o Administration of two antimicrobials with Gram-negative activity for at least 48 hours
after the susceptibility results became available, regardless of the in vitro susceptibility
to each agent
Baseline Characteristics
9

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Variable
Combination (n=15) Monotherapy (n=19) P value
Demographics
Age 65
6 (40)
11 (57.8)
0.49
Severity of Illness
ICU at enrollment
10 (66.6)
10 (52.6)
0.49
APACHE II
17.4 6.65
21.3 8.69
0.15
Underlying Diseases
Immunocompromised
11 (73.3)
9 (47.3)
0.17
Chronic renal failure
3 (20)
3 (15.8)
1
Malignancy
3 (20)
3 (15.8)
1
Transplant
8 (53.3)
0
0.001

Sources of Infection
o IV catheter (13; 31.7%)
o Pneumonia (10; 24.4%)
o Urinary tract infection (7; 17.1%)
o Unknown (6; 14.6%)

Antibiotic Suseptibility
o 40 (75.5%) to colistin
o 45 (89.9%) to tigecycline
o 51 (96.2%) to gentamicin
o 21 (39.6%) to meropenem
Treatment Regimens
Treatment
n (%)
Infection Mortality n (%)
Combination
15 (44)
2 (13.3)
Colistin-polymixin B with:
Carbapenem
5 (33)
1 (20)
Tigecycline
1 (7)
0
Tigecycline with:
Carbapenem
3 (20)
0
Aminoglycoside
2 (12)
0
Monotherapy
19 (46)
11 (57.8)
Colistin-polymyxin B 7 (36.8)
4 (57.1)
Tigecycline
5 (26.3)
4 (80)
Carbapenem
4 (21)
2 (50)
Total
34 (83)
13 (38.2)
Endpoints
Overall 28-day mortality
o 39% (16/41)
Definitive therapy 28-day mortality
o 38.3% (13/34)
Combination therapy
o 13.3% (2/15)
Monotherapy
o 57.8% (11/19)
Univariate and Multivariate Analysis
10

A. Thompson |

Variable
Univariate Analysis
Pneumonia
Cardiovascular
disease
Chronic liver disease
Combination Therapy
Multivariate Analysis
Combination Therapy

Authors
Conclusions
Critique

Take Home
Points

Survived
(n=25)

Died
(n=16)

OR (95% CI)

P
value

3 (12)

7 (43.7)

5.7 (0.983.68)

0.03

5 (31.2)

(1.59)

0.01

0
13 (60)

3 (18.7)
2 (12.5)

(0.72)
0.13 (0.010.82)

0.05
0.01

13 (60)

2 (12.5)

0.07 (0.009
0.71)

0.02

The use of combination therapy for definitive therapy appears to be associated with improved
survival in bacteremia due to KPC-producing K. pneumoniae
Small sample size
Retrospective, observational study
Choice of regimen closely associated with clinical status
Treatment was based on old CLSI breakpoints
Trend towards high severity of illness in monotherapy arm
More transplant patients in combination therapy arm
Most common successful combo was colistin or tigecycline with a carbapenem
Colistin and tigecycline monotherapy were associated with >50% mortality

Table 6: Zarkotou et al. Clin Microbiol Infect. 2011;17(12):1798-803.36

Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and
impact of appropriate antimicrobial treatment
Objective
To investigate outcomes, risk factors for mortality and impact of appropriate antimicrobial
treatment in patients with BSIs caused by molecularly confirmed KPC-producing K. pneumoniae
Design
Observational, case-control study
2008 to 2010
Population
53 patients
Endpoints
All-cause mortality
Risk factors for mortality
Results
Appropriate empirical treatment
o Administration of in vitro active antimicrobials against the study isolates, within 24
hours from infection onset
Appropriate definitive treatment
o Administration of in vitro active antibiotics for at least 48 hours
Microbiological
o 2009 CLSI breakpoints for carbapenems
o FDA breakpoint for tigecycline
o EUCAST breakpoint for colistin
Source of infection
o Central venous catheters 12 (22.6%)
o Respiratory 7 (13.2%)
o Urinary tract 6 (11.3%)
11

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o Skin or soft tissue 4 (7.6%)

o Central nervous system 1 (1.9%)
o Unknown 23 (43.4%)
Susceptibilities
o 40 (75.5%) to colistin
o 45 (89.9%) to tigecycline
o 51 (96.2%) to gentamicin
o 21 (39.6%) to meropenem
Treatment Regimens
Treatment
n (%)
Infection Mortality, n (%)
Combination
20 (57.1)
0
Tigecycline with:
Colistin
9 (26.5)
0
Gentamicin
3 (8.8)
0
Colistin + carbapenem 2 (5.9)
0
Carbapenem
1 (2.9)
0
Colistin + gentamicin
1 (2.9)
0
Amikacin
1 (2.9)
0
Colistin + gentamicin
2 (5.8)
0
Carbapenem + gentamicin
1 (2.9)
0
Monotherapy
15 (42.9)
7 (46.7)
Colistin
7 (20)
4 (66.7)
Tigecycline
5 (14.7)
2 (40)
Gentamicin
2 (5.9)
0
Carbapenem
1 (2.9)
1 (100)
Total
35
7 (20)

Endpoints
Overall mortality
o 52.8% (28/53)
Infection mortality
o 34% (18/53)
Appropriate therapy infection mortality
o 20% (7/35)
Combination
o 0% (0/20)
Monotherapy
o 46.7% (7/15)
Univariate Factors of Infection Mortality
Characteristic
Older age
Non-catheter-related bacteremia
Appropriate antimicrobial treatment
Combination schemes
APACHE II score
Severe sepsis or septic shock
Multivariate Factors of Infection Mortality
Characteristic
APACHE II score at infection onset
12

OR (95% CI)
P value
-<0.001
0.13 (0.011.09)
0.04
0.16 (0.040.56) 0.003
-0.001
-<0.001
14 (3.5055.98) <0.001
OR (95% CI)
1.26 (1.041.53)

P value
0.021
A. Thompson |

Age
1.21 (1.021.44)
Appropriate antimicrobial treatment 0.05 (0.0030.74)

Authors
Conclusions
Critique

Take Home
Points

0.029
0.030

Mortality associated with severity of illness, older age, and inappropriate treatment

Small sample size

Retrospective design
Older CLSI breakpoint
Baseline characteristics were not stratified between mono vs combination therapy
Active in vitro antimicrobials associated with better outcomes
Combination therapy associated with improved survival

Table 7: Tumbarello et al. Clin Infect Dis. 2012;55(7):943-50.37

Predictors of Mortality in Bloodstream Infections Caused by Klebsiella pneumoniae CarbapenemaseProducing K.
pneumoniae: Importance of Combination Therapy
Objective
To pinpoint risk factors for mortality in bloodstream infections caused by KPC-producing K.
pneumoniae
Design
Multicenter retrospective cohort study
2010 to 2011
Population
125 patients with BSIs caused by KPC-K. pneumoniae
Endpoints
Risk factors for mortality
Impact of antimicrobial regimens used in the nonempirical phase of treatment
Results
Adequate therapy
o Therapy including at least 1 drug displaying in vitro activity against the KPC-K.
pneumoniae isolate
Combination therapy
o >1 in vitroactive drugs

13

Microbiological
o Revised CLSI breakpoints for carbapenems
o FDA breakpoint for tigecycline
o EUCAST breakpoint for colistin
Source of infection
o Central venous catheters 13 (10.4%)
o Respiratory 28 (22.4%)
o Urinary tract 17 (13.6%)
o Other 5 (4%)
o Unknown 75 (60%)
Susceptibilities
o Meropenem
16mg/L 78 (62.4%)
8 mg/L 17 (13.6%)
4 mg/L 16 (12.8%)
2 mg/L 13 (10.4%)
o 1 mg/L 1 (0.8%)
o Colistin 110 (88%)
o Tigecycline 114 (91.2%)
A. Thompson |

o Gentamicin 118 (94.4%)

Baseline Characteristics
Variable
Demographics
Age
Severity of Illness
ICU
APACHE III
Underlying Diseases
Immunocompromised
Chronic renal failure
Diabetes mellitus
Shock
Isolates with suboptimal
colistin/tigecycline MICs

Monotherapy
(n=46)

Combination
(n=79)

P
value

65 15

61 16

0.08

14 (30.4)
30 20

39 (49.4)
34 21

0.04
0.27

7 (15.2)
5 (10.9)
9 (19.6)
8 (17.4)

9 (11.4)
7 (8.9)
20 (25.3)
9 (11.4)

0.54
0.71
0.46
0.35

4 (8.6)

22 (27.9)

0.01

Treatment Regimens
Treatment
Died (n = 52) Survivors (n = 73) P value
Monotherapy
25 (48.1)
21 (28.7)
0.02
Tigecycline
10 (19.2)
9 (12.3)
0.28
Colistin
11 (21.5)
11 (15.1)
0.37
Gentamicin
4 (7.6)
1 (1.3)
0.09
Combination therapy
27 (51.9)
52 (71.2)
0.02
2-drug combinations
23 (44.2)
33 (45.2)
0.91
Tigecycline + colistin
7 (13.4)
16 (21.9)
0.22
Tigecycline + gentamicin
6 (11.5)
6 (8.2)
0.53
3-drug combinations
4 (7.7)
19 (26.1)
0.009
Tigecycline + colistin + meropenem
2 (3.8)
14 (19.2)
0.009

Endpoints
30-day mortality
o 41.6% (52/125)
Monotherapy
o 54.3% (25/46)
Combination therapy
o 34.1% (27/79) - P = .02
Outcomes stratified by carbapenem MIC
Outcomes of Meropenem Combinations Stratified by MIC
No. (%)
Meropenem MIC (mcg/mL) Total
Nonsurvivors Survivors
1
1
0
1 (100)
2
4
0
4 (100)
4
10
2 (20)
8 (80)
8
4
1 (25)
3 (75)
16
17
6 (35.2)
11 (64.7)
Total
36
9 (25)
27 (75)
Multivariate Predictors of Mortality
14

A. Thompson |

Authors
Conclusions
Critique

Take Home
Points

Variable
OR (95% CI)
P value
Septic shock
7.17 (1.6531.03)
0.008
Inadequate initial antimicrobial treatment
4.17 (1.6110.76)
0.03
High APACHE III scores
1.04 (1.021.07)
<0.001
Definitive therapy with tigecycline + colistin
0.11 (.02.69)
0.01
+ meropenem
KPC-K. pneumoniae BSIs are associated with high mortality
Combination therapy is more effective than active monotherapy
Small sample size
Retrospective design
Clinical decisions based on old CLSI breakpoints for a portion of the study period
High-dose extended infusions
Combination of tigecycline, colistin, and meropenem was associated with lower mortality
Meropenem high-dose extended infusions utilized
Benefits of carbapenem seen up to MIC of 8

Table 8: Daikos et al. 2014. Antimicrob Agents Chemother. 2014;58(4):2322-838

Carbapenemase-Producing Klebsiella pneumoniae Bloodstream Infections: Lowering Mortality by Antibiotic
Combination Schemes and the Role of Carbapenems
Objective
To evaluate the clinical outcome of patients with carbapenemase producing-K. pneumoniae (CPKp) bloodstream infections, identify predictors of mortality, and evaluate the various antibiotic
schemes employed
Design
Retrospective, Observational Study of 2 tertiary hospitals
2009 to 2010
Population
205 patients identified
o 163 (79.5%) were infected with KPC or KPC and VIM, and 42 were infected with VIM
producers
Endpoints
Primary
o Mortality
Secondary
o Predictors of mortality
o Evaluate the various antibiotic schemes employed
Results
Appropriate therapy
o Treatment with at least one agent for at least 48 hours to which the isolate was
susceptible in vitro based on the interpretative criteria from the CLSI published in 2011
Definitive therapy
o Antimicrobial therapy given after the susceptibility testing results became available,
regardless of the in vitro susceptibility to the agent
Combination therapy
o Administration of two antimicrobials with Gram-negative activity for at least 48 hours
after the susceptibility results became available, regardless of the in vitro susceptibility to
each agent
Source of infection
o Lung 43 (21%)
o Abdomen 29 (14.1%)
o Intravascular catheter 22 (10.7%)
o Genitourinary tract 19 (9.3%)
o Skin or soft tissue 6 (2.9%)
o CNS 3 (1.5%)
o Unknown 83 (40.5%)
Susceptibilities
15

A. Thompson |

o Ciprofloxacin (2.4%)
o Meropenem (46.3%)
o Tigecycline (84.9%)
o Colistin (74.6%)
o Gentamicin (68.8%)
o Amikacin (31.7%)
Baseline Characteristics
Characteristic
Monotherapy (n=72) Combination therapy (n=103) P value
Age
66.5 (14.4)
58.4 (19.5)
0.002
ICU
39 (54.2)
62 (60.2)
0.427
Charlson comorbidity index
2 (0-3)
2 (0-3)
0.474
Neutropenia
7 (9.7)
7 (6.8)
0.483
Urinary source
7 (9.7)
6 (5.8)
0.333
Septic shock
15 (20.8)
16 (15.5)
0.629
Treatment Regimens
Treatment
Survived
Died
Mortality, %
Combination
75
28
27.2
Carbapenem-containing regimen:
25
6
19.3
Tigecycline + aminoglycoside or colistin
11
0
Tigecycline
2
2
Aminoglycoside
8
1
Colistin
4
3
Carbapenem-sparing regimen:
50
22
30.6
Tigecycline + aminoglycoside + colistin
8
3
Tigecycline + aminoglycoside
11
9
Tigecycline + colistin
16
5
Aminoglycoside + colistin
12
5
Monotherapy
40
32
44.4
Tigecycline
16
11
Colistin
10
12
Aminoglycoside
7
2
Carbapenem
5
7
Endpoints
28-day all-cause mortality
o 40% (82/205)
Appropriate therapy mortality
o 38.3% (13/175)
Combination therapy
27.2% (28/103)
Monotherapy
44.4% (32/72)
Factors associated with mortality
Characteristic
HR (95% CI)
P value
Septic shock/sepsis
2.15 (1.163.96) 0.015
Ultimately fatal/nonfatal
3.25 (1.517.03) 0.003
Rapidly fatal/nonfatal
4.20 (2.198.08) <0.001
Monotherapy/combination therapy 2.08 (1.233.51) 0.006
Therapy by severity of illness

16

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Authors
Conclusions
Critique

Take Home
Points

Outcomes of stratified by carbapenem MIC

Carbapenem MIC (mcg/mL) Carbapenem combination with:
In vitro active agent(s)
In vitro inactive agent(s)
Survived/Died Mortality, % Survived/Died Mortality, %
8
25/6
19.3
5/7
58.3
>8
20/11
35.5
4/2
33.3
Combination therapy was strongly associated with survival, mostly due to the effectiveness of the
carbapenem containing regimens
Small sample size
Retrospective in nature
Breakpoints used for carbapenems
Meropenem MIC analysis
Combinations with carbapenem containing regimens were most effective
Combination therapy more beneficial in severely ill patients
Beneficial carbapenem effect up to MIC of 8

Conclusions
XXVI.

17

Future Direction
a. Beta-lactams
i. Ceftazidime-Avibactam
ii. Ceftazidime-Avibactam
iii. Aztreonam-Avibactam
iv. Ceftaroline-Avibactam
v. Imipenem/cilastatin+relebactam
vi. Carbavance
b. Aminoglycosides
i. Plazomicin
c. Fluoroquinolone
i. Finafloxacin
d. Tetracyclines
i. Eravacycline
ii. Omadacycline
A. Thompson |

XXVII. Therapeutic Recommendations

a. Infectious diseases consult
b. MIC 8 g/mL
i. High dose extended infusion meropenem/doripenem backbone
1. Consider additional in vitro active antimicrobial(s) for critically ill patients
a. Colistin and/or high-dose tigecycline and/or aminoglycoside
c. MIC >8 g/mL
i. Combination of 2 or 3 in vitro active antimicrobials
1. Colistin and/or high-dose tigecycline and/or aminoglycoside
Appendix
Breakpoints - Carbapenems
Antimicrobial
Agent
Ertapenem
Imipenem
Meropenem
Doripenem

Susceptible
0.5
1
1
1

CLSI Breakpoints
Intermediate Resistant
1
2
2
4
2
4
2
4

EUCAST Breakpoints
Susceptible Intermediate Resistant
0.5
1
2
2
4-8
16
2
4-8
16
1
2
4

Breakpoints Aminoglycosides
Antimicrobial
CLSI Breakpoints
Agent
Susceptible Intermediate Resistant
Gentamicin
4
8
16
Tobramycin
4
8
16
Amikacin
16
32
64
Breakpoints - Tigecycline
Antimicrobial
US FDA Breakpoints
Agent
Susceptible Intermediate Resistant
Tigecycline
2
4
8
Breakpoint Colistin
Antimicrobial
EUCAST Breakpoints
Agent
Susceptible Intermediate Resistant
Colistin
2
-4
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