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Journal of The Association of Physicians of India ■ Vol. 63 ■ July 2015
Original Article
Treatment and Outcome of CarbapenemResistant Gram-Negative Bacilli Blood-Stream
Infections in a Tertiary Care Hospital
Pooja G Shah1, Sweta R Shah2
Abstract
Editorial Viewpoint
Context: Infections caused by carbapenem-resistant bacteria constitute
a major challenge for current medical practice.
• G r a m - n e g a t i v e b a c i l l i
(GNBs) are adding to
the menace by causing
carbapenem resistance as
supported by this study.
Objective: To describe treatment and outcome of carbapenem-resistant
Gram-negative bacilli (GNB) blood-stream infection (BSI) caused by these
organisms at a tertiary care hospital in Mumbai.
Methods: Carbapenem-resistant isolates from blood cultures were
collected from January 2013 to April 2013. Identification and antimicrobial
susceptibility testing were performed using Vitek 2 analyzer (Biomerieux
Ltd.). Carbapenemase production was detected by modified Hodge’s test
(MHT). Patient’s medical history, treatment and co-morbid conditions
were noted. Outcomes of BSIs were evaluated.
Results: Forty-two isolates of carbapenem-resistant GNB isolated from
BSIs were Enterobacteriaceae spp. (19), Acinetobacter baumannii (15),
and Pseudomonas aeruginosa (8). Colistin had maximum in vitro activity
with 97% against Enterobacteriaceae, 100% against Acinetobacter, and
100% activity against Pseudomonas aeruginosa isolates. Positivity of MHT
was 92.9%. Outcome of colistin mono and combination therapy was
comparable with 83% and 79%, respectively. Outcome of colistin and
carbapenem combination therapy was found to be 100 percent.
Conclusions: High incidences of bacteremia by carbapenem-resistant
GNB including Enterobacteriaceae is a worrisome trend. Treatment options
are compromised and only available option is colistin which has its
own limitation. Colistin monotherapy may be non-inferior compared to
combination therapy for treating BSIs caused by isolates with minimum
inhibitory concentration (MIC) for colistin as ≤0.5 mg/l. Combined use
of the colistin and carbapenem may provide good therapeutic options
for BSI caused by carbapenem-resistant GNB and warrants further
investigations.
Introduction
C
arbapenem such as imipenem
and meropenem are
recommended as first-line therapy
for severe infections caused
by multidrug-resistant (MDR)
Gram-negative bacilli. 1 Resistance
to carbapenem is commonly
seen in non-fermenting Gramnegative bacilli (GNB); emergence
of carbapenem resistance in
• A d d i t i o n o f c o l i s t i n
or tigecycline with
carbapenem are the
current treatment options
for curbing infections
caused by GNBs.
• The study needs further
validation by the
multicentric reporting.
Enterobacteriaceae has also been
observed. The later raises an added
risk of its dissemination in the
community.2-4 Very few therapeutic
options are available for treatment
of carbapenem-resistant GNB
blood stream infection (BSI), and
are basically limited to colistin
and tigecycline. 1 However, the
low plasma concentrations of
tigecycline and the toxicity
associated with colistin make
these less appealing options for
use in BSI. In addition to these
concerns, there is limited literature
on the clinical consequences of
such infections. 5 This study aims
to describe the epidemiology
and clinical outcome of bloodstream infections associated with
Sr. Technical Officer, 2Consultant, Microbiology Department, Kokilaben Dhirubhai Ambani Hospital and Medical
Research Institute, Mumbai, Maharashtra
Received: 01.04.2015; Accepted: 20.04.2015
1
Journal of The Association of Physicians of India ■ Vol. 63 ■ July 2015
carbapenem-resistant Gramnegative bacilli.
according to the manufacturer’s
guidelines (BioMerieux Ltd).
Subjects and Methods
Phenotypic method
Study location
The study was conducted in a
750 bedded tertiary care hospital
in Mumbai from January 2013 to
April 2013 (4 months). This study
was approved by the Institutional
Scientific and Ethics Board (ISEB)
of the hospital.
Clinical isolate
All isolates obtained from blood
cultures received in Microbiology
Laboratory during the study
period, that exhibited an imipenem
or meropenem minimal inhibitory
concentration (MIC) of >1 mg/l,
according to CLSI (Clinical and
Laboratory Standard Institute)
guidelines, were considered. 6 All
samples were processed as per
standard microbiology protocol.
Antibiotic susceptibility testing
Automated systems were used
to process blood cultures (BacT
Alert®) and for identification (Vitek
2). Antimicrobial susceptibility
testing was performed using the
automated broth microdilution
system (Vitek 2). For isolates of
Acinetobacter baumannii sensitivity
testing against amikacin and
meropenem was done using Kirby
Baur disk diffusion method as
per CLSI guidelines, due to the
limitation of sensitivity testing
card used in Vitek 2 analyzer.
Carbapenem resistance in all
isolates was rechecked by Kirby
Baur disk diffusion method and
interpreted as per CLSI standards. 6
For tigecycline interpretive criteria
approved by the US Food and Drug
A d m i n i s t r a t i o n ( U S - F D A) 7 f o r
Enterobacteriaceae were used for both
Enterobacteriaceae and Acinetobacter
baumannii. For colistin, break points
proposed by European Committee
on Antimicrobial Susceptibility
Te s t i n g ( E U C A S T ) 8 we r e u s e d
b e c a u s e r e l e va n t b r e a k - p o i n t s
were not available from CLSI.
MIC of colistin-resistant isolate
was rechecked by E-test method
A Modified Hodge’s test (MHT)
wa s p e r f o r m e d o n a l l i s o l a t e s
to determine carbapenemase
production, as described. 9
Patients and data collection
Data, including patient
demographics, co-morbid
conditions, source of infection,
and treatment were collected from
the electronic medical records,
laboratory data and medication
administration records from the
date of admission till discharge.
Only first episode of BSI from the
patient was included. Outcome at
the end of treatment was defined
as successful (partial or complete
improvement of signs/symptoms
of infection or positive microbial
response in terms of sterile
culture results post or during
the treatment), and failure (no
improvement or deterioration of
signs/symptoms of infection or
negative microbial response in
terms of persistent positive culture
results with the same organism 3
days after initiation of antibiotic
therapy). Final disposition was
defined as death, discharged
during illness or transferred to
ward or discharged.
Results
A total of 42 clinically significant
carbapenem-resistant Gramnegative bacilli were isolated from
blood cultures during the study
period of 4 months. Epidemiology
Table 1: Epidemiology of
carbapenem-resistant Gramnegative bacilli from bloodstream infection
Carbapenem-resistant isolates
from BSI
Acinetobacter baumannii
Enterobacteraiceae spp.
Klebsiella pneumoniae
Escherichia coli
Enterobacter cloacae
Citrobacter freundii
Pseudomonas aeruginosa
Total
Total
15
15
1
2
1
8
42
15
of carbapenem-resistant isolates
in BSI is depicted in (Table 1).
Antimicrobial susceptibility of
all isolates is shown in (Table
2). Kirby Baur disk diffusion
method confirmed the carbapenem
resistance amongst all the isolates
and did not show any discrepancy
in results of susceptibility for
imipenem and meropenem. Except
three isolates of Pseudomonas
aeruginosa all other (92.9%) isolates
were positive for carbapenemase
production by MHT.
The medical records of patients
included in study cohort were
reviewed. Their characteristics are
given in (Table 3).
The source of bacteremia
included central venous catheter
(71.5%), respiratory tract infection
(7.1%), urinary tract infection
(2.4%), and uncertain in eight cases
(19%). In these eight cases patients
were diagnosed with bacteremia
from the blood culture collected on
the first day of admission and were
known to have previous history
of hospitalisation. Eleven (26%)
patients died within 48 hours from
the day of initial blood culture,
of which four did not receive any
effective antimicrobial therapy
and seven received effective
clinical therapy for less than 24
hours. These were not included in
further analysis. In one of the cases
patient suffered from secondary
bacteremia caused by colistinresistant Klebsiella pneumonia (MIC
of colistin – 8 mg/l) while the patient
wa s o n c o l i s t i n m o n o t h e r a p y .
Patient died within 24 hours from
the time of collection of blood
culture. Antimicrobial regimen
received by 31 patients having BSI
and their clinical outcome is given
in (Table 4).
Discussion
Carbapenem-resistant Gramnegative bacilli pose a serious
threat to current medical practices.
Carbapenem has been the treatment
of choice for serious infections
(MDR infections) caused by
16
Journal of The Association of Physicians of India ■ Vol. 63 ■ July 2015
Table 2: Antimicrobial susceptibility
Susceptibility of 19 isolates of Enterobacteriaceae spp.
Antimicrobial agent
MIC range
MIC50
Imipenem
≤1 to ≥16
4
Meropenem
1 to ≥16
8
Amikacin
4 to ≥64
32
Tobramycin
2 to ≥16
≥16
Gentamycin
≤1 to ≥16
≥16
Colistin
≤0.5 to 8
≤0.5
Tigecycline
≤0.5 to ≥8
≥8
Ciprofloxacin
≥4
≥4
MIC90
≥16
≥16
≥64
≥16
≥16
≤0.5
≥8
≥4
% Sensitivity
5.3
5.3
47.4
5.3
15.8
94.7
36.8
0
Susceptibility of 15 isolates of Acinetobacter baumannii
Antimicrobial agent
MIC range
MIC50
Imipenem
8 to ≥16
≥16
Meropenem
ND
Amikacin
ND
Tobramycin
4 to ≥16
≥16
Gentamycin
8 to ≥16
≥16
Colistin
≤0.5
≤0.5
Tigecycline
≤0.5 to ≥8
4
Ciprofloxacin
≥4
≥4
Ampicillin sulbactam
8 to ≥32
≥32
Cefoperazone sulbactam
16 to ≥64
≥64
MIC90
≥16
≥16
≥16
≤0.5
≥8
≥4
≥32
≥64
% Sensitivity
0
0
0
6.7
0
100
46.7
0
6.7
13.3
Susceptibility of 8 isolates of Pseudomonas aeruginosa
Antimicrobial agent
MIC range
MIC50
MIC90
% Sensitivity
Imipenem
≤1 to ≥16
8
≥16
12.5
Meropenem
1 to ≥16
≥16
≥16
12.5
Amikacin
≥64
≥64
≥64
0
Tobramycin
≥16
≥16
≥16
0
Gentamycin
≥16
≥16
≥16
0
Colistin
≤0.5
≤0.5
≤0.5
100
Tigecycline
NA
-
-
-
1 to ≥4
≥4
≥4
12.5
Ciprofloxacin
Note: MIC, Minimum inhibitory concentration in mg/l; MIC50, MIC required to inhibit the growth
of 50% isolates of this study; MIC90, MIC required to inhibit 90% isolates of this study; MICs were
determined by broth dilution method; ND – Not Done; NA – Not Applicable.
MDR Gram-negative bacilli but
unfortunately the resistance to
carbapenem compromises the
treatment options. Carbapenemase
production is one mechanism
of resistance; other carbapenem
resistance mechanisms also exist
like porin loss, efflux of drug and
target alteration. However, it is well
known that multiple mechanisms of
resistance and enzyme production
can coexist in a single organism. 10
Carbapenem resistance is most
commonly seen in non-fermenter
Gram-negative organisms (nonEnterobacteriaceae) i.e., Pseudomonas
and Acinetobacter. 3 Recent surveys
have identified extended spectrumβ-lactamase (ESBLs) in 70-90%
of Enterobacteriaceae in India,
making widespread use of reserved
antibiotics such as carbapenems
necessary. 10 Consequently, there is
selection pressure for carbapenem
resistance in Enterobacteriaceae.
This results in an increasing
incidence of carbapenem resistance
in Enterobacteriaceae family as
well. The treatment options are
limited especially for BSI hence
the current study aims to add to
the limited literature available on
the optimum treatment options for
treating blood stream infections
by carbapenem-resistant Gram
negative bacilli.
Of the 42 isolates obtained
from BSI, 19 (45%) isolates
were carbapenem-resistant
Enterobacteriaceae. This is an
increasingly important threat due
Table 3: Characteristics of patients
having bacteremia with
carbapenem-resistant strain
Variable
n (%)
Demographics
Age [median
54 yrs
(range)]
(1 month – 89 yrs)
Sex (male)
21 (50.0)
Comorbidity
Heart dysfunction
12 (28.6)
Malignancy
3 (7.1)
Diabetes mellitus
12 (28.6)
Hypertension
18 (42.9)
Chronic renal failure
6 (14.3)
Admission to ICU
37 (88.1)
Prior surgery
3 (7.1)
Prior antibiotic use
40 (95.2)
BL/BLI
26 (61.9)
Carbapenem
24 (57.1)
Aminoglycosides
6 (14.3)
Colistin
5 (11.9)
Fluoroquinolones
4 (9.5)
Tigecycline
2 (4.8)
Prior hospitalization
17 (40.5)
12.83 ± 13.13
Time to develop
(0 to 62)
infection with CR-GNB*
38.12 ± 31.12
Duration of
(1 to 111)
hospitalization*
Note: BL/BLI - β-lactam/β-lactamase inhibitor,
ICU - intensive care unit. *mean ± standard
deviation (range) in days
to its ability to disseminate in the
community. The susceptibility
profile of isolates recovered during
the present study underscores
the extremely limited therapeutic
choices available for treatment of
patients infected with carbapenemresistant strains. Colistin had
maximum in vitro activity, with
94.7% against Enterobacteriaceae,
100% against Acinetobacter
baumannii, and 100% activity
against Pseudomonas aeruginosa.
A total of 92.9% isolates were
positive for carbapenemases by
MHT indicating carbapenemase
production as one of the important
mechanism of resistance. In other
isolates resistant mechanisms other
than carbapenemase production
may be responsible for resistance
to carbapenem.
Presence of severe underlying
conditions and previous exposure
to multiple antibiotics in the
present study cohort indicate the
patient to be critically ill. In 71.5%
Journal of The Association of Physicians of India ■ Vol. 63 ■ July 2015
Table 4: Antibiotic treatment and
outcome of patient having
bacteremia with carbapenemresistant strain
Antibiotic regimen Outcome of treatment
Total
Successful
Colistin therapy
(mono and
25
20 (80)
combination)
Colistin
6
monotherapy
5 (83)
Colistin
combination
therapy
19
15 (79)
Colistin +
carbapenem
12
12 (100)
Colistin
+noncarbapenem
7
3 (43)
Colistin +
Tigecycline
5
1 (20)
Colistin +
Amikacin
1
1 (100)
Colistin +
Sulbactam
1
1 (100)
4
4 (100)
Carbapenem*
1
1 (100)
Tigecycline*
Tigecycline +
carbapenem
1
0 (0)
Total
31
25 (81)
Note: *Catheter removal associated with
antimicrobial regimen
of cases the source of bacteremia
was found to be central venous
catheter, thus severe underlying
illness, susceptibility to infection
and antibiotic selection pressure
may lead to increasing risk of
infection with multidrug-resistant
organisms. Smaller studies have
reported similar risk factors. 11
Colistin-containing
c o m b i n a t i o n s we r e m o s t o f t e n
used in our study (81% i.e. 25
out of 31) either as monotherapy
(24%) or combination therapy
(76%). 160 to 240 mg (2 to 3 MIU)
of colistimethate sodium (CMS)
per 8 or 12 hours was administered
and doses were adjusted according
to the renal functions. Among
colistin combination therapy,
colistin and carbapenem was the
most commonly used combination
(63% i.e. 12 out of 19). Colistin
monotherapy showed success
rate of 83% whereas colistin and
carbapenem combination therapy
s h o we d 1 0 0 % s u c c e s s r a t e . O f
the 12 BSI successfully treated
with colistin and carbapenem
combination therapy, six were
caused by Enterobacteriaceae spp.,
four by Acinetobacter baumannii,
and two by Pseudomonas aeruginosa,
indicating its effectiveness against
all strains. This may be due to
the synergistic or additive effect
of colistin and carbapenem
combination as reported by many
in vitro studies. 12-14 This study
supports the data from the small
number of relevant human studies
suggesting non-inferiority of
colistin monotherapy compared
w i t h c o m b i n a t i o n t h e r a p y . 14
However, one patient developed
secondary BSI with colistinresistant Klebsiella pneumoniae while
on colistin monotherapy. This
raises concern regarding potential
problem of heteroresistance among
Gram-negative bacterial population
exposed to colistin alone. In that
case combination therapy may be
helpful in improving outcomes
and preventing bacterial resistance,
as there has been reported
development of resistance to
colistin during monotherapy. 15
A special attention needs to be
given to the relationship between
pharmacokinetics (PK) and
pharmacodynamics of colistin. In
2008, Markou et al 16 published PK
data of the colistin in critically ill
patients using a chromatographic
assay. In this study, CMS dosage
regimens administered to those
critically ill adult patients were
associated with suboptimal
C max/MIC ratios for many strains of
Gram-negative bacilli. Markou et
al 16 and Imberti et al 17 reported
plasma colistin C max at a steady
state of 1.15–5.14 mg/l (Dosage of
CMS – 3 MIU per 8 or 12 hours) and
0.68–4.65 mg/l (Dosage of CMS – 2
MIU per 8 hours), respectively,
in critically ill patients with
moderate-to-good renal function.
Very recently, Garonzik et al 18
described the effects of CMS and
formed colistin in 105 critically
ill patients. This population PK
analysis suggests the traditional
CMS doses are often suboptimal
17
considering the breakpoint for
colistin susceptibility of ≤2 mg/l.
Thus the success of colistin
monotherapy obtained in present
study may be attributed to MIC 90
for colistin being ≤0.5 mg/l for
clinical isolate and for infections
caused by isolates with MICs of
>1.0 mg/l colistin may best be
used as part of a highly active
combinations as recommended by
Garonzik et al. 18
Clinical success with
carbapenem monotherapy and
tigecycline monotherapy was noted
in the present study cohort, but
the degree to which it contributed
to the successful outcome was
difficult to ascertain as all cases
were associated with removal of
foci of infection (catheter removal)
which may have a role to play. 11
Clinical isolates obtained from
bacteremia treated with colistin
and tigecycline combination
t h e r a p y s h o w e d M I C 50 o f
2 mg/l for tigecycline. Clinical
success was achieved in 20% (1/5)
cases treated with colistin and
tigecycline combination therapy.
Thus present study supports
reports on raised concern about
the use of tigecycline to treat
bloodstream infections caused by
organisms with MIC value ≥1 mg/l
given the low mean peak serum
concentrations of tigecycline. 19
Limitation of our study is
that it’s a small study which was
conducted over a short period
of 4 months. Characterization of
carbapenemases produced by these
isolates was performed but it is not
a part of this study.
Carbapenemase production
is currently associated with
nosocomial isolates; one of the most
worrisome concerns is the spread
of these carbapenemase producing
isolates in the community. This
represents a significant threat to
public health, warranting increased
e f f o r t s t o wa r d s d e t e c t i o n a n d
infection control strategies.1
Severe underlying condition,
use of invasive procedures and
antibiotic selection pressure in
18
Journal of The Association of Physicians of India ■ Vol. 63 ■ July 2015
critically ill patient may predispose
them to acquiring infection with
carbapenem-resistant Gramnegative bacilli. For strains with
colistin MIC of ≤0.5 mg/l, colistin
monotherapy may be non-inferior
compared to colistin combination
t h erapy . Colist in-carbap enem
combination may be a promising
regimen to treat BSI caused by
carbapenem-resistant GNB and it
need to be further evaluated.
Performance standard for antimicrobial
susceptibility testing: Twenty-second
informational supplement. M100-S23 CLSI,
2013. Wayne P.A.
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United States Food and Drug Administration
(FDA), Highlights of prescribing information
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ucm132714.htm (Accessed 19 February
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Noyal MJC, Menezes GA, Harish BN, Sujatha
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