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Epidemiology and treatment of KPC’S…What’s the news?
02/17/12
Epidemiology and
treatment of
KPC’S…What’S the
news?
Review of Current Evidence
Learning Objectives:
• Describe the epidemiology of KPCs
• Identify the risk factors associated with KPC infections
• Identify problems with laboratory detection of KPCs using current CLSI breakpoints
• Evaluate the evidence of treatment outcomes for KPC-infections
Pharmacotherapy Rounds 2012 |Lee, G
Grace C. Lee, Pharm.D, BCPS
Pharmacotherapy Rounds 2012
2/17/2012
2
Table of Contents
Rise of KPCs
Figure 1
.………………………………...................................3
The spread of KPCs
Figure 2
Figure 3
.………………………………...................................4
Clinical features of KPCs
.………………………………...................................5
Laboratory Detection of KPC
CLSI breakpoints
Treatment Options
Table 1. In vitro susceptibility
.………………………………...............................6-7
.………………………………...................................7
Treatment Considerations
.………………………………...................................8
Review Methodology
.………………………………...................................9
Study flow diagram
.………………………………...................................10
Results Table 1-3
Table 1. Study characteristics
Table 2. Study publication year
Table 3. study characteristics
.……………………………….................................11
Results Table 4-5
Table 4. Infection characteristics
Table 5. Overall treatment outcome
.……………………………….................................12
Results Table 6
Table 6. Treatment failure
Monotherapy/Combination
.……………………………….................................13
Results Table 7
Table 7. Treatment failure combination
Limitations
.……………………………….................................14
Querishi et al. study
.……………………………….................................15
Key Points
.……………………………….................................16
References
.…………………………….…………….………..17-18
Appendix A
Appendix B
Pharmacotherapy Rounds 2012 | Lee, G
Epidemiology and treatment of KPC’S…What’s the news?
3
Patient Case
JK is a 30 yo male s/p multi-organ transplant including small bowel, pancreas, stomach, bilateral kidney, liver secondary to
autoimmune enteritis. He has had multiple prolonged admissions in the last year and multiple courses of antibiotics due
to infections in the past including C.diff colitis, VRE and ESBL-producing K. pneumoniae in the last 3 months. He was
admitted from a long-term acute care hospital with respiratory failure requiring ventilator support. Now on Day 68 of
admission, he becomes septic. The medical team has started him on vancomycin and meropenem. Three days later, he
continues to spike fevers and clinically deteriorate. He also has a central venous catheter and urinary catheter.
Preliminary blood cultures are growing 2 of 2 K. pneumoniae
1. Rise of the Klebsiella pneumoniae carbapenemase (KPC)
I.
II.
Two mechanisms of carbapenem resistance: 1, 2
a. Carbapenemase
i. β-lactamase that can hydrolyze carbapenems
b. Cephalosporinase combined with porin loss
i. Cephalosporinases (e.g., AmpC-type β-lactamases or certain ESBLs
i.e. CTX-M)
ii. Porin loss limits entry of the carbapenem into the periplasmic space
The most common mechanism of carbapenem resistance in the United States is
due to Klebsiella pneumoniae carbapenemase (KPC).
a. KPC was first described in 2001, in a Klebsiella pneumoniae isolate from a
hospital in North Carolina3
b. KPC is an Ambler molecular class A enzyme which utilizes serine at the
active site to facilitate hydrolysis of β-lactams.2,4
i. KPCs hydrolyze all β-lactams including penicillins, cephalosporins,
monobactams and carbapenems
ii. Weakly inhibited by clavulanic acid and tazobactam
c. KPC enzymes are found to be located on plasmids2,5
i. Additional resistance mechanisms are frequently found on the same
plasmid (i.e., extended-spectrum β-lactamases, aminoglycoside
resistance, and fluoroquinolone resistance genes)
ii. KPC gene carried in a Tn3-based transposons, Tn4401
iii. Currently there are 10 variants of KPC (KPC-2 to KPC-11)
d. KPCs have also been found in many other gram-negative species including:6
Escherichia coli, Enterobacter species, Salmonella enterica, Proteus mirabilis
and Citrobacter freundii, Serratia species, Pseudomonas species, and
Acinetobacter baumannii
Pharmacotherapy Rounds 2012 | Lee, G
↑↑Resistance
(ESBLs)
↑↑Carbapenem
use
Selection of
Carbapenem
Resistant Isolates
Figure 1
The most common
mechanism of
carbapenem
resistance in the
United States is due
to Klebsiella
pneumoniae
carbapenemase
(KPC)
4
2. The Problem Grows: the Spread of KPC



KPCs were infrequently isolated in the United States until 20013,7,8
o First KPC isolate was reported in 2001 from North Carolina
o KPC-producing Enterobacteriaceae were reported in several extended
outbreaks in metropolitan hospitals of New York
o KPC-producing organisms have continued to spread and have now been
reported in 37 states in the United States (figure 2)
o Reports of KPCs in Texas9,10
 Post-liver transplant co-infected with Pseudomonas putida and
Enterobacter cloacae in San Antonio (University Hospital)
 Four cases of Klebsiella pneumoniae in Houston
KPCs have been reported globally
o The first outbreak of KPC-producing K. pneumoniae outside of the U.S
was in Israel11
o KPC have been reported in many countries including: China, Brazil,
France, Greece, England, France, Sweden, Belgium, Germany, Korea,
India, Italy, Denmark, Finland, Switzerland, Spain, Columbia, Argentina,
Norway and Israel2,12
o Endemic in areas such as northeastern part of the US, Israel, Columbia,
and Greece
KPCs have been reported in hospital and non-hospital settings
o The CDC recommends in areas where carbapenem-resistant
Enterobacteriaceae are not endemic, acute care facilities review
microbiological records for the preceding 6-12 months.13 (Appendix A)
o Several investigations have described patients carrying KPC-producing
organisms in post-acute care facilities (i.e., long-term acute care
hospitals (LTACHs))14,15
o Reports of community-onset infections with KPC-producing organisms
have been documented14
o Spread of blakpc in hospital sewage systems have been reported2
Figure 2.
KPC-producing
bacteria are
becoming
increasingly
prevalent in the
United States
Pharmacotherapy Rounds 2012 | Lee, G
1996 – 1st Case of
KPC in North
Carolina
2002- KPC
Outbreaks
reported in New
York
2005- First case
of KPC outside of
US – in France
2006 first KPC-2
producing PSDA
was found in
Columbia
2007 First
outbreak
outside of US in
Israel
2009-First
outbreak report
of KPC detected
in LTACHs and 1st
KPC-producing
infection in Texas
2010 – blakpc-11
discovered
Figure 3. Timeline
Epidemiology and treatment of KPC’S…What’s the news?
5
3. Clinical Features of KPC

Risk Factors for
KPC Infections:
-Advanced Age
-Severity of Illness
-Previous antibiotic
treatment
-Organ or stem-cell
transplantation
-Mechanical ventilation
-Long hospitalizations



KPC-producing organisms have been associated with increased length of stay,
costs, frequent treatment failures, and death16,17
Mortality rates of >50% have been reported16,18
Risk factors for infection include advanced age, being severely ill, previous
treatment with antibiotics, organ or stem-cell transplantation, mechanical
ventilation, and long hospital stays13,19,20
Mixed reports of whether previous carbapenem use is associated with the
development of infections caused by KPC producing bacteria
21
Patel et al. Outcomes of Carbapenem-Resistant Klebsiella pneumoniae Infection and the
Impact of Antimicrobial and Adjunctive Therapies
Design: Two matched case control studies July 1, 2004 through June 30, 2006
Methods: Cases defined as patients with invasive carbapenem-resistant K. pneumoniae
infection. Control defined as patients with invasive carbapenem-susceptible K. pneumoniae
infection. Matching was performed at a ratio of 1:1 according to anatomic site of infection.
Results:
Case
Control
(n=99)
(n=99)
OR(95% CI)
P
Characteristics
60.67
59.39
0.70
Age -years (mean)
58
(59)
58
(59)
0.51
Men
Bacteremia
56 (57)
56 (57)
41 (41)
39 (39)
34 (34)
90 (91)
65 (66)
21
14 (14)
29 (29)
23 (23)
55 (56)
22 (22)
1
5.70 (2.65–12.16)
1.67 (0.90-3.08)
1.75 (0.94-3.27)
8.32 (3.74-18.53)
6.62 (3.53–12.43)
1.09 (1.01–1.12)
<.001
0.10
0.08
<.001
†
<.001
†
<.001
63 (64)
6 (14)
31 (31)
4 (10)
3.82 (2.11-6.91)
2.30 (1.30-4.10)
<.001
<.005
36 (36)
54 (55)
6(6)
14 (14)
23 (23)
6 (6)
1(1)
3(3)
1.87 (1.00-3.48)
19.25 (7.61-48.70)
7.04 (0.82-60.68)
5.44 (1.49-19.85)
0.05
†
<.001
0.08
0.01
3.2
0.8
48
38
20
12
Risk Factors
Transplant recipient
Liver Disease
Renal Insufficiency
Use of CVC
Mechanical ventilation
Length of stay before infection,
days (Median)
†
Class of Prior Antibiotic Therapy
“Carbapenemresistant K.
pneumoniae
infection is
associated with
numerous
healthcare-related
risk factors and with
high mortality”
Cephalosporin
β-lactam and/or β-lactamase
inhibitor
Fluoroquinolone
Carbapenem
Monobactam
Aminoglycoside
†
Clinical Outcomes
Time between specimen
collection to antibiotics with in
vitro activity (days)
Death during hospitalization (%)
Death due to K. pneumoniae
infection (%)
<.001
3.71 (1.97-7.01)
4.5 (2.16-9.35)
<.001
<.001
Conclusion Carbapenem-resistant K. pneumoniae infection is associated with numerous
healthcare-related risk factors and with high mortality
NOTE: †Statistically significant in multivariable analysis (p<0.5) performed by logistic regression. Only those variables that
achieved P value of 0.02 or less in the univariable analysis were included in the multivariable analysis. CI, confidence
interval; CVC, central venous catheter; OR, odds ratio. All numbers within parenthesis denotes percentage.
Pharmacotherapy Rounds 2012 | Lee, G
6
4. Laboratory Detection of KPCs
Problems with Detection:22-24
 Some automated susceptibility testing systems fail to detect low-level carbapenem resistance
o 15-60% of KPC-producing bacteria had MICs in the susceptible range
 Some KPC-producing isolates test susceptible, but the carbapenem MICs are elevated
Carbapenem
Population
Ertapenem
WT
KPC
WT
KPC
WT
KPC
Imipenem
Meropenem
Cumulative % inhibited at MIC (µg/mL)
0.5
1
2
4
8
100
0
97.9
0
98.9
0.5
1.2
100
0
100
0.5
4.2
10.8
20.5
4.8
14.4
39.9
8
17.6
29.3
# tested
1974
166
5989
188
5989
188
WT: wildtype
Sentry; R Jones. CLSI 07.
Dashed lines indicate 2009 CLSI breakpoints for Enterobacteriaceae
25
Weisenberg et al. Clinical outcomes of patients with Klebsiella pneumoniae carbapenemaseproducing K. pneumoniae after treatment with imipenem or meropenem
Design: Historic cohort 2006
Objective: To study the clinical and microbiologic outcomes of infections caused by KPC K. pneumoniae
and compare outcomes of infections with isolates initially reported as susceptible to imipenem or
meropenem
Methods: Retrospective review of patients infected with KPC K. pneumoniae was conducted from a
convenience sample. Success or failure of treatment was determined by clinical response and/or
subsequent culture results. Two physicians independently reviewed charts of all patients.
Results: n=28 patients
Characteristics
Age -years median
Hospitalized for >3 wks at time
of culture
64
14/28 (50%)
Class of Prior Antibiotic Therapy
β-lactams
Fluoroquinolones
Carbapenems
Glycopeptide
Total
18/28 (64.3%)
10/28 (35.7%)
6/28 (21.4%)
15/28 (53.6%)
KPC-producer reported as
imipenem susceptible
13/28 (46.4%)
KPC-producer reported as
imipenem non-susceptible
15/28 (53.6%)
APACHE II Score
21.1
21.1
Colonized
Treated with IMI or MER
2/13(15%)
9/11 (81.8%)
Reported as imipenem
susceptible and contained KPC
†
(MIC < 4µg/mL)
4/9 (44.4%)
5/9 (55.6%)
4/15 (26.6%)
Treatment Outcomes
Overall Treatment success
Overall Treatment failure
KPC-producer reported as
imipenem non-susceptible
§
(MIC > 4µg/mL)
8/10 (80%)
2/10 (20%)
P
0.99
P
0.17
Conclusion
Patients infected with KPC K. pneumoniae initially determined to be imipenem non-susceptible had a higher rate
of successful treatment when compared with patients infected with KPC K. pneumoniae with initial testsusceptible test results.
†
NOTE: Among patients
treated with IMI orRounds
MER. Two
of the|11Lee,
in theGKPC-producer reported as imipenem susceptible group
Pharmacotherapy
2012
received tigecycline (1 success /1 failure). IMI, imipenem; MER, meropenem
§
One patient did not receive any treatment due to comfort care measures and was excluded from outcome analysis
7
Epidemiology and treatment of KPC’S…What’s the news?
CLSI Carbapenem Breakpoints for Enterobacteriaceae
Previous breakpoints MIC (µg/mL)
New 2011 CLSI
Carbapenem
breakpoints for
Enterobacteriaceae
Agent
Susceptible
Intermediate
Resistant
Ertapenem
Imipenem
Meropenem
<2
<4
<4
4
8
8
>8
>16
>16
Revised breakpoints MIC (µg/mL)
Agent
Susceptible
Intermediate
Resistant
Ertapenem
Imipenem
Meropenem
Doripenem
<0.5
<1
<1
<1
1
2
2
2
>2
>4
>4
>4
CLSI: Clinical and Laboratory Standards Institute
4. Treatment Options
In-vitro susceptibility
o KPC-producing isolates demonstrate resistance to many agents
including β-lactams, fluoroquinolones, aminoglycosides, and cotrimoxazole26,27
o Most isolates remain susceptible to tigeycline and polymyxins16,28
o Various in-vitro/in-vivo studies have documented synergistic activity of
combination based regimens29-32 (Appendix B)
Table 3. Susceptibility of Selected Antimicrobials
Susceptible (%)
Agent
Amikacin
Gentamicin
Polymyxin B
Colistin
Tigecycline
Neuner et al.
(n=60)
45
22
86
98
7
Bratu et al.
(n=62)
6
65
73
-
16
Bratu et al.
(n=96)
45
61
91
100
28
Castanheira et al.
(n=60)
53
58
93
100
31
Souli et al.
(n=50)
14
70
86
15
33
b
MICs were determined using Etest and were interpreted in accordance with the European Committee on
Antimicrobial Susceptibility Testing (EUCAST)
Case –Continued
The blood culture returns both growing K. pneumoniae with the following susceptibilities:
Amikacin
Amoxicillin+Clav
Ampicillin+Sulbactam
Cefazolin
Cefepime
Cefotaxime
Cefotetan
>32
>16/8
>16/8
>16
>8
>32
>32
R
R
R
R
R
R
R
How would you treat this patient?
Moxifloxacin
Piperacillin+Tazo
Tobramycin
Cefoxitin
Ceftazidime
Ceftriaxone
>4
> 64
>8
>16
>16
>32
R
R
R
R
R
R
Cefuroxime
Ciprofloxacin
Ertapenem
Gentamicin
Meropenem
Trimethoprim+Sulfa
Pharmacotherapy Rounds 2012 | Lee, G
>16
>2
>4
>8
16
>2/38
R
R
R
R
R
R
8
Epidemiology and treatment of KPC’S…What’s the news?
Treatment Considerations:
o Due to broad-resistance to several antimicrobial classes, treatment options
are very limited
o Tigeycline and polymyxins remain the most susceptible in-vitro
o Pharmacokinetic/Pharmacodynamic Considerations
 Tigecycline (Glycylcycline antibiotic)34,35
 Low serum concentrations
o FDA approved breakpoint 2 µg/mL
o Mean Cmax 0.67-0.87 µg/mL
 Low urinary concentrations
o 22% excreted renally unchanged
 Polymyxins (Colistin and Polymyxin B)36-38
 Optimal dosing is not well defined
 Potential concern for nephrotoxicity and neurotoxicities
 Resistance during therapy against KPC-producing organisms
have been documented
39
Lee et al. Decreased susceptibility to polymyxin B during treatment of carbapenemresistant Klebsiella pneumoniae (CRKP) infection
Objective:
Evaluate treatment of patients with KPC-producing K. pneumoniae infections with
persistent positive blood cultures despite 3 days of treatment
Methods:
Patients hospitalized between July 2004 and June 2006 with CRKP infections who
persistently had positive cultures despite > 3 days of treatment with either polymyxin B alone or
polymyxin B and tigecycline were reviewed. The history of antibiotic therapy and the duration of
treatment were obtained from patients’ medical records and hospital pharmacy records. All of the
subsequent CRKP isolates were recovered from blood samples. The KPC gene was present in all initial
and subsequent isolates as confirmed by PCR analysis.
Results:
•
•
•
N=16 patients
•
12 Polymyxin B alone
•
4 Polymyxin B plus Tigecycline
3 out 12 (25%) treated with polymyxin B monotherapy had significant increase in MIC
•
1.5 μg/ml to 32 μg/ml
•
0.75 μg/ml to 12 μg/ml
•
0.75 μg/ml to 1024 μg/ml
•
The mean durations of treatment with polymyxin B for these three patients were not
different from those for the other nine patients whose subsequent isolates did not
have an increased MIC (mean, 15.7 days versus 10.8 days; P 0.46)
None of the patients who received polymyxin B plus tigecycline developed resistance
Conclusion
Combination therapy may have prevented resistance in patients who received both polymyxin B and
tigecycline
The optimal therapy for infections with Enterobacteriaceae
that produce KPC is not well defined
Pharmacotherapy Rounds 2012 |Lee, G
Due to broadresistance to
several
antimicrobial
classes, treatment
options for KPCinfections are very
limited
Epidemiology and treatment of KPC’S…What’s the news?
9
Literature Review Methodology
•Systematic review of case series and case reports of treatment outcomes using combination versus
monotherapy for the treatment of KPCs
Objective
Data
Source
Study
Selection
Data
Extraction
Analysis
•A systematic review of English articles using MEDLINE (2001-2011). Additional studies were identified by
searching bibliographies and abstracts presented at Interscience Conference on Antimicrobial Agents and
Chemotherapy (2008-2011). Search terms included kpc.mp, Drug Therapy/mt, mo, Treatment Outcome,
Case Reports, Disease Outbreaks/pc limited to humans.
•Eligibility assessment was performed by an independent reviewer in an unblinded standardized manner. All
reports were reviewed in duplicate. Articles were eligible if they reported on patients with infections due to
KPC-producing bacteria. Articles were excluded from further review if they fulfilled at least 1 of the following
criteria: no individual patient reported, no treatment regimen specified, no treatment outcome specified,
cases of colonization stated, greater than 3 antibiotics or multiple antibiotic regimen(s) directed at the KPC
infection.
•An electronic data collection sheet was developed. A pilot sheet was tested on randomly selected studies
then refined accordingly. Several characteristics from the cases were extracted including the patient’s age,
sex, medical history, site(s) of infection, type of infection, organism, KPC subtype, APACHE II score,
admission to ICU, LOS before infection, LOS total, MIC (carbapenem, polymyxin, and tigeycline),
antimicrobial therapy before isolation, antimicrobial therapy directed at KPC-infection, treatment outcome,
and final outcome. Combination therapy was defined as two antibiotics with gram-negative activity
directed at KPC infection. Clinical success and failures were defined as reported by the authors of each
study.
•Analysis of the proportion of clinical failures was calculated as the number of failures divided by the number
of treated patients with available data. This was repeated for the various treatment subgroups. Statistical
analysis was performed in an exploratory manner. Comparisons were made using the chi-square or fisher's
exact test for categorical variables
Pharmacotherapy Rounds 2012 | Lee, G
10
Epidemiology and treatment of KPC’S…What’s the news?
Eligibility
Screening
Identification
Study Flow Diagram
Citations identified
in MEDLINE (n=54)
Citations identified in
Bibliography: (n=12)
Meeting abstracts: ICAAC
(n=61) keyword ‘KPC’
127 total citations
screened on basis of
title and abstracts
Excluded: (n=65)
-No clinical information (n=54)
-Duplicates (n=7)
-Not related to KPC-infection (n=4)
Articles eligible for
inclusion (n=62)
Articles excluded (n=24)
-No patient specific treatment
and/or outcomes (n=18)
-Greater than 3 active agents (n=4)
-Colonization (n=2)
Included
38 Articles included
Patients = 143
Patients = 105
†Individual patients excluded from case series due to insufficient data
Pharmacotherapy Rounds 2012 |Lee, G
Patients excluded† (n=34)
-No Patient specific treatment
and/or outcomes (n=15)
-Greater than 3 active agents (n=13)
-Colonization (n=10)
11
Epidemiology and treatment of KPC’S…What’s the news?
Descriptive Analysis:
Table 1. Study Characteristics10,19,25,33,40-59,9,15,27,28,60-69
Study Type
Study Source (n=38)
Patient Source (n=105)
18(47%)
18 (47%)
2(5%)
18 (17%)
49 (47%)
38 (35%)
Case Reports
Case Series
Retrospective Cohort
The most common source of patient records were from case series (47%).
Majority of the reports were from the US (42%), followed by Greece (10%).
Table 2. Study Publication Year
Year
(n)
2004
2006
2007
2008
2009
2010
2011
1
1
4
3
11
7
11
Table reflects publication year (not year of the study or case occurrence)
Majority of the articles were published in 2011 and 2009 which accounted
for 58% of the articles
Table 3. Patient Characteristics
Characteristic
Age – mean (SD)
Male gender n(%)
ICU admission n(%)
APACHE II Score – mean (SD)
LOS before infection – mean (SD)
LOS, total – mean (SD)
Data Available (n)
88
60
57
38
48
24
62 (+19)
33 (55)
41(72)
20.6(+8)
17.5(+19)
54.8(+40)
Of the reported data, patients had high ICU admission status (72%), high
severity of illness, and long mean length of stay.
SD, Standard deviation; ICU, intensive care unit; APACHE II, Acute Physiology and Chronic
Health Evaluation II; LOS, length of stay
Pharmacotherapy Rounds 2012 |Lee, G
Reports from
different countries:
USA, Greece, Brazil,
Canada, China,
Colombia, France,
Germany, Italy,
Korea, Switzerland,
Taiwan, and Trinidad
12
Descriptive Analysis:
Table 4. Infection Characteristics
Characteristic
Data Available (n)
KPC-subtype
Number of Cases (%)
_______________
98
KPC-2
KPC-3
84(86)
14(14)
Organisms
104
K. pneumoniae
E. coli
S. marcescens
Pseudomonas spp
E. cloacae
Site of infection
Blood
Pulmonary
Urine
Skin/Wound
CSF
Bone
92(89)
3(3)
3(3)
4(4)
2(2)
Site of infection:
The most common
site of infection was
blood followed by
pulmonary
_________________
105
56(52)
32(30)
11(10)
4(4)
1(0.9)
1(0.9)
Majority of the reports were due to blakpc-2 (86%). The most common
organism reported was K. pneumoniae (89%). The most common site of
infection was blood (52%) followed by pulmonary (32%) and urine (10%).
Table 5. Overall Treatment Outcome
Overall treatment success
Overall treatment failure
Blood
Pulmonary
Source (failure)
Data Available
105
105
105
Blood
Pulmonary
Urine
KPC-type
KPC-2
KPC-3
Treatment Outcome (%)
67/105 (63)
38/105 (36)
21/38(55)
15/38(39)
22/56(39)
15/32(47)
1/11(9)
98
30/84(36)
7/14(50)
Overall treatment failure was 36%. A majority of treatment failure was
associated with blood as source of infection (55%) followed by pulmonary
(39%). Source of infection associated with the highest rate of treatment
failure is pulmonary (47%) followed by blood (39%). Infections with blakpc-3
had a higher rate of treatment failure (50%) compared to blakpc-2.
Pharmacotherapy Rounds 2012 | Lee, G
_________________
Over one-third
of patients had
treatment
failure
_____________
Epidemiology and treatment of KPC’S…What’s the news?
13
Table 6. Treatment failure monotherapy vs. combination
Overall treatment failure
Source:
Blood
Pulmonary
Urine
Monotherapy (%)
Combination (%)
P
24/49(49)
14/56(25)
0.01
12/24 (50)
10/15(67)
1/8(13)
9/32(28)
5/17(29)
0/3(0)
0.09
0.03†
0.4
Overall treatment failure was higher in patients who received monotherapy versus combination therapy (49% versus 25% p 0.01).
Pulmonary site of infection was associated with higher rates of treatment failure with monotherapy compared to combination therapy
†
(67% versus 29% p 0.03). Fisher’s exact test
Polymyxin Treatment failure
Source:
Blood
Pulmonary
Urine
8/11(73)
10/34(29)
0.02†
6/9(67)
2/2(100)
5/18(28)
5/13(38)
0/2(0)
0.1
0.2
Polymyxin monotherapy had higher rates of treatment failure compared to polymyxin-based combination therapy (73% vs. 29% p
0.02). Both patients who received polymyxin monotherapy for pneumonia experienced treatment failure (Villegas). All colistin MICs
were initially susceptible (<2 µg/mL would be considered susceptible for Acinetobacter and P. aeruginosa). The optimal dosing of
polymyxins is not well-defined. Polymyxin resistance in KPC-infections have been documented. Outbreaks of colistin-resistant KPC
†
infections recently reported in the US and Greece. Fisher’s exact test
Carbapenem Treatment failure
Source:
Blood
Pulmonary
Urine
Carbapenem MIC (µg/ml):
Monotherapy
Combination
12/20(60)
5/19(26)
3/8(38)
7/8(88)
1/3(33)
<8
7/12(58)
1/2(50)
4/14(29)
1/2(50)
0/3(0)
>8
5/8(63)
1/2(50)
0.03
Carbapenem monotherapy had higher rates of treatment failure compared to carbapenem-based combination therapy (60% versus
26% p 0.03). Carbapenem MIC <8 µg/mL and MIC >8 µg/mL resulted in similar failure rates for monotherapy (58% and 63%). Of the
patients who received carbapenem monotherapy with MIC <8 µg/mL, 11 out of 12 had MICs <4 µg/mL. One patient received highdose continuous infusion meropenem monotherapy (MIC =8 µg/mL) for a bloodstream infection (BSI) with success.
Tigecycline Treatment failure
Source:
Blood
Pulmonary
Urine
2/7(29)
7/19(37)
0.4
1/2(50)
1/3(33)
0/2(0)
4/8(20)
3/8(37)
0.5
Total of 2 out of 7 patients who received tigecycline monotherapy experienced treatment failure. One patient was being treated for
urosepsis and the other was treated for ventilator-associated pneumonia (VAP) and empyema. Interestingly, both patients who were
treated for UTI with tigecycline monotherapy had treatment success. Of the 19 patients who received tigecycline combination, 14
(74%) received polymyxin plus tigecycline. Tigecycline is bacteriostatic and low concentrations in blood and urine may be concerning.
However, successful reports of tigecycline used for these indications have been reported.
Aminoglycoside Treatment failure
Source:
Blood
Pulmonary
Urine
0/6(0)
4/24(17)
0/3(0)
0/1(0)
0/1(0)
4/4(100)
0/6(0)
0.6
All patients who received aminoglycoside monotherapy had success. Patients who received aminoglycoside based combination, most
received treatment with amikacin. All patients who failed therapy with aminoglycoside-based therapy had BSIs.
Pharmacotherapy Rounds 2012 | Lee, G
14
Table 7. Treatment failure by Combination
Polymyxin plus Carbapenem
Polymyxin plus Tigecycline
Polymyxin plus Aminoglycoside
Carbapenem plus Tigecycline
Carbapenem plus Aminoglycoside
β – lactam / β-lactamase inhibitor plus Aminoglycoside
Aminoglycoside plus Fluoroquinolone
Polymyxin plus β – lactam / β-lactamase inhibitor
Polymyxin plus Fluoroquinolone
Tetracycline plus Aminoglycoside
Tigecycline plus Aminoglycoside
Aminoglycoside plus monobactam
Carbapenem plus β – lactam / β-lactamase inhibitor
Carbapenem plus Cephalosporin
Carbapenem plus Trimethoprim/Sulfamethoxazole
Treatment failure (%)
3/10 (30)
4/14(29)
2/8(25)
2/2(100)
0/4(0)
0/3(0)
1/5(20)
0/1 (0)
1/1(100)
0/1(0)
1/3(33)
0/1(0)
0/1(0)
0/1(0)
0/1(0)
Patients who received combination-based therapy received the above regimens.
Similar treatment failure were observed in the 3 most common combinations
(Polymyxin+Carb, Polymyxin+Tig, Polymxin+AG) P=0.6. Both patients who received
carbapenem plus tigecycline experienced treatment failure for BSI.
Limitations:
-
Cannot determine causality on the basis of spontaneous reports (case reports)
Publication bias should be considered, owing to the uncertainty inherent in
estimating the degree of under-reporting
Individual studies did not always define treatment failure or treatment success
Antimicrobial dosing was not always reported
Reports did not always detail procedures or other source control measures
Retrospective analysis – residual colonization is difficult to exclude.
The time at which active therapy was initiated to the time of isolation of
organism was unknown.
The degree to which the treatment contributed to these outcomes is still difficult
to ascertain
Pharmacotherapy Rounds 2012 | Lee, G
_______________
No difference in
success rates
among
combination
therapy
_________________
15
Epidemiology and treatment of KPC’S…What’s the news?
70
Qureshi et al. Treatment Outcome of Bacteremia due to KPC-Producing Klebsiella pneumoniae: Superiority of
Combination Antimicrobial Regimens
Design:
Objective:
Methods:
Statistics:
Results:
Retrospective cohort
Evaluate the clinical outcome of patients with bacteremia caused by KPC-producing pneumoniae
after various treatment regimens
Cases of bacteremia due to K. pneumoniae were identified from 2005-2009. Cases whose isolates
were confirmed KPC gene were included in the analysis. Appropriate therapy was defined as
treatment with at least one agent for at least 48 hours to which the isolate was susceptible in vitro
based on CLSI guidelines. Primary outcome measure was death within 28 days.
2
Student t-test, χ , Fisher’s exact test. OR and 95% CI were estimated. Conditional multivariate
logistic regression model was used to identify independent predictors of mortality. P values <0.15
were included into the model. Alpha was set at <0.05.
N=41 cases
Demographics
Age > 65
Male
APACHE II >20
Survived
(n=25)
Died
(n=16)
Univariate analysis
OR(95% CI)
Multivariate analysis
OR (95% CI)
14(56)
10(40)
12(48)
6(37.5)
7(43)
9(56)
0.4 (0.10-2.02)
1.1 (0.27-5.02)
0.7 (0.13-4.24)
0.34
1
0.72
21(65.6)
13(60)
11(34.3)
2(12.5)
0.2 (0.07-2.33)
0.13(0.01-0.82)
0.27
0.01
18(78.2)
10(62.5)
0.46(0.08+2.35)
0.30
3(12)
9(36)
5(20)
5(20)
7(43.7)
4(25)
1(6.2)
1(6.2)
5.7(0.98-3.68)
0.5(0.12-2.88)
0.2(0.01-2.87)
0.2(0.01-2.87)
0.03
0.51
0.38
0.38
5(20)
5(20)
2(8)
1.8(0.35-9.67)
0.5(0.06-4.16)
0(0-6.72)
0.48
0.68
0.51
n(%)
15(44)
5(31.2)
2(12.5)
0(0)
Mortality
n(%)
2(13.3)
5(33)
1(7)
1(7)
1(20)
0
0
Monotherapy
Colistin/Polymyxin B
Tigecycline
Carbapenem
Gentamicin
Amp/sulbactam
Pip/tazo
n(%)
19(46)
7(36.8)
5(26.3)
4(21)
1(5.2)
1(5.2)
1(5.2)
3(20)
2(12)
0
0
1(7)
1(100)
P
P
Therapy
Inappropriate Therapy
Combination definitive
therapy
Appropriate therapy at any
time
0.07(0.009-0.71) 0.02
Source of Infection
Pneumonia
Line-related
Urinary tract
Primary bacteremia
Underlying diseases
Diabetes
Solid organ transplant
COPD
Definitive treatment
Combination
Colistin/polymyxin B
combined with
Carbapenem
Tigecycline
Fluoroquinolone
Tigecycline combined with
Carbapenem
Aminoglycoside
Carbapenem +
fluoroquinolone
Conclusions
Limitations
Mortality
n(%)
11(57.8)
4(57.1)
4(80)
2(50)
0
0
1(100)
The use of combination therapy for definite therapy appears to be associated with
improved survival in patients with KPC producing K pneumoniae bacteremia
Retrospective, small N
Pharmacotherapy Rounds 2012 | Lee, G
16
Current Situation
Carbapenems are broad spectrum antibiotics that are often used as last-resort treatments for resistant
gram-negative infections, such as those caused by extended spectrum β-lactamase (ESBL) producing
Enterobacteriaceae. The rise of carbapenem-resistant Enterobacteriaceae (CRE) has become a significant
public health challenge in the last decade.1 Data regarding health-care-associated infections reported to the
Centers for Disease Control and Prevention (CDC) indicated that 8% of all Klebsiella pneumoniae isolates were
carbapenem resistant in 2007 compared with less than 1% in 2000. CREs are highly-resistant to almost, if not,
all available antimicrobial agents and present clinicians with serious treatment challenges.
Key Points:
 KPCs are rapidly spreading globally
 Detection has been difficult since many KPC-producing isolates fall within the
susceptible range
 Infections caused by KPC-producing bacteria have been associated with high mortality
and treatment failure
 Tigecycline and polymyxins remain the most active in-vitro
 Clinical data on treatment is limited and therapy for KPC infections is not well defined
 Combination therapy may be associated with less failure than monotherapy
 No data on which combination therapy is superior
Pharmacotherapy Rounds 2012 | Lee, G
Epidemiology and treatment of KPC’S…What’s the news?
17
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67. Benenson S, Navon-Venezia S, Carmeli Y, Adler A, Strahilevitz J, Moses AE, Block C. Carbapenem-resistant klebsiella pneumoniae
endocarditis in a young adult. successful treatment with gentamicin and colistin. Int J Infect Dis 2009 Sep;13(5):e295-8.
68. Ho VP, Jenkins SG, Afaneh CI, Turbendian HK, Nicolau DP, Barie PS. Use of meropenem by continuous infusion to treat a patient
with a bla(kpc-2)-positive klebsiella pneumoniae blood stream infection. Surg Infect (Larchmt) 2011 Aug;12(4):325-7.
69. Beirao EM, Furtado JJ, Girardello R, Ferreira Filho H, Gales AC. Clinical and microbiological characterization of KPC-producing
klebsiella pneumoniae infections in brazil. Braz J Infect Dis 2011 Jan-Feb;15(1):69-73.
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Appendix A
Pharmacotherapy Rounds 2012 | Lee, G
Epidemiology and treatment of KPC’S…What’s the news?
Pharmacotherapy Rounds 2012 | Lee, G
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22
Epidemiology and treatment of KPC’S…What’s the news?
Appendix B – Combination therapy for KPC-producing organisms: in vitro studies29-32
Author (year)
Organism(s)
Therapy
Outcome
Pournaras et al. (2011)
8 KPC-producing
organisms (4
K.pneumoniae, 2 E.
coli, 1 Enterobacter
cloacae, 1 Serratia
marcescens)
14 KPC-producing K.
pneumoniae
TK curves performed
with TIG, COL, MER
alone and in
combination (TIG +
COL)
At most drug concentrations, TIG, COL and MER as single
agents do not exhibit efficient bactericidal activity against
most of the KPC-producing strains. TIG and COL were
bactericidal against all strains at most time intervals and
concentrations and synergistic against most strains. All
monotherapy had regrowth.
TKA showed synergy with all combinations of PB (1/4, 1/2, 1x
MIC) in 9/14 isolates (64%) PB+MER.
Pankey et al. (2011)
Bratu et al. (2005)
16 KPC-producing K.
pneumoniae
TK performed with
POLB with either MER
or RIF
TK POLB plus IMI or
RIF
Le et al. (2011)
4 KPC-producing K.
pneumoniae
ERT, IMI or MER in
combination with AMI
Pharmacotherapy Rounds 2012 |Lee, G
POLB demonstrated concentration-dependent killing, and
was bactericidal against most strains at 2 or 4 mg/L. The
combination of POLB plus RIF was bactericidal and synergistic
against 15/16 isolates. The combination of POLB (0.5 × MIC)
with imipenem was synergistic for 10/16 isolates. The
addition of IMI to the combination of POLB plus RIF had no
effect.
As monotherapy, none of the carbapenems nor AMI
achieved bactericidal activity. Synergy and bactericidal
activity was achieved with MER and IPM with AMI.