Scandinavian Journal of Infectious Diseases, 2012; 44: 312–314

CASE REPORT

Successful treatment of NDM-1 Klebsiella pneumoniae

bacteraemia in a neutropenic patient

JAIME MEI FONG CHIEN1, TSE HSIEN KOH2, KIAN SING CHAN2,
THUAN HENG CHARLES CHUAH3 & THUAN TONG TAN1
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From the 1Department of Infectious Diseases, 2Department of Pathology, and 3Department of Haematology,
Singapore General Hospital, Singapore

Abstract
The rapid emergence of novel multidrug-resistant organisms coupled with the slow development of new antibiotics is of
great concern. With the discovery of New Delhi metallo-beta-lactamase 1 (NDM-1)-producing Klebsiella pneumoniae,
clinicians are faced with problems in the treatment of infections caused by this multidrug-resistant organism. Therapeutic
experiences are limited. We share our experience of the successful treatment of a febrile neutropenic patient with NDM-
1-producing K. pneumoniae bacteraemia.
For personal use only.

Keywords: NDM-1, polymyxin, neutropenia, treatment, stool surveillance

Introduction diagnosed with acute myeloid leukaemia in July 2010

in Jakarta. She had received induction chemotherapy
Carbapenems are widely employed for the treatment of
with idarubicin and cytarabine in Jakarta. Her condi-
infections due to extended-spectrum beta-lactamase
tion was complicated by cytarabine-induced toxic ery-
(ESBL)-producing Enterobacteriaceae. Isolates of New
thema and sepsis due to a perianal abscess while
Delhi metallo-beta-lactamase 1 (NDM-1)-producing
neutropenic. She then came to Singapore for consolida-
Enterobacteriaceae are increasingly being reported.
tion chemotherapy. She completed 2 cycles of high-
This is a frightening phenomenon, as the novel NDM-1
dose cytarabine (HIDAC) at our institution and was
enzyme is able to hydrolyse most beta-lactam antibiot-
admitted electively for the third cycle of HIDAC.
ics, including carbapenems, leaving few therapeutic
On day 3 post-chemotherapy she became febrile;
options. NDM-1-positive Enterobacteriaceae have
her white cell count was 3.01 ⫻ 109/l, with an abso-
been described in intricate molecular detail in the lit-
lute neutrophil count (ANC) of 1.88 ⫻ 109/l. She had
erature, and their emergence has been reported in
a few episodes of passing loose stools during her
developed countries [1–3]. Data on the clinical presen-
febrile illness, with no other foci of sepsis noted. Sep-
tation of such infections are scarce. Reports have mainly
tic work-up was unrevealing and her temperature
described the demographics of acquisition of the infec-
normalized on empirical intravenous (IV) cefepime
tion, with little mention of its management [4–6].
on day 4 post-chemotherapy. She was continued on
Hence, there is a paucity of clinical experience with this
IV cefepime. As expected, she developed neutropenia
novel and deadly organism. We report the successful
from day 8 post-chemotherapy. She was again febrile
treatment of bacteraemia due to NDM-1-positive Kleb-
on day 9. Her white cell count was 0.74 ⫻ 109/l.
siella pneumoniae in a severely neutropenic patient.
This episode was associated with chills and 2
episodes of passing loose stools. She was clinically
Case report
non-toxic and her vital parameters were stable with-
A 65-y-old Indonesian woman with hypertension and out hypotension. We were alerted to the isolation of
diabetes mellitus, and carrying the hepatitis B virus, was NDM-1-positive K. pneumoniae in her stool sample

Correspondence: J. Chien, Department of Infectious Diseases, Singapore General Hospital, Outram Road, Singapore 169608. Tel: ⫹ 65 6321 3479. Fax: ⫹ 65
6227 5247. E-mail: jaime.chien.m.f@singhealth.com.sg

(Received 28 May 2011; accepted 30 September 2011)

ISSN 0036-5548 print/ISSN 1651-1980 online © 2012 Informa Healthcare
DOI: 10.3109/00365548.2011.633549
 Treatment of NDM-1 K. pneumoniae bacteraemia
by the microbiology laboratory on the day of fever.
In the choice of treatment, a decision was made to
cover the NDM-1-positive K. pneumoniae infection.
Cefepime was discontinued and she was started on
IV polymyxin B at 25,000 units/kg/day in combina-
tion with aztreonam 2 g every 8 h and vancomycin
1 g every 12 h.
Blood cultures grew NDM-1-positive K. pneu-
monia, which was resistant to all beta-lactams,
including aztreonam, by disc diffusion method. In
addition, the isolate’s doripenem minimum inhibi-
tory concentration (MIC) was more than 32 μg/ml,
meropenem MIC was 8 μg/ml, polymyxin B MIC
was 0.5 μg/ml, and tigecycline MIC was 4 μg/ml by
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E-test (bioMérieux SA, Marcy l’Etoile, France).
Both her stool and blood culture K. pneumoniae iso-
lates tested positive for NDM-1 by real-time poly-
merase chain reaction (PCR) following previously
described protocols [1], and this was confirmed with
sequencing of the PCR products. Pulsed field gel
electrophoresis showed that the stool and blood iso-
lates were the same strain, which suggested that the
infection originated from the gastrointestinal tract.
After receiving empirical antibiotics for 2 days,
the regimen was tailored on receipt of the antibiotic
For personal use only.
susceptibility results to IV polymyxin B at the above
described dose, in combination with meropenem
infusion 2 g every 8 h, with each infusion running
over 3 h. The patient’s Hickman line was removed.
The rest of the septic work-up did not reveal an alter-
native source of bacteraemia; urine culture and cul-
ture of the Hickman line tip were negative. Blood
cultures were sterile after 3 days of treatment and she
was treated with a total of 14 days of antibiotics. Her
white blood cell count recovered 2 days before com-
pletion of the antibiotics. She was discharged in good
condition.
Discussion
NDM-1-positive K. pneumoniae was first discovered
in 2008 in an asymptomatic bacteriuric patient who
had possibly acquired the organism in New Delhi,
India [2]. In Singapore, our first 2 cases of NDM-1-
positive K. pneumoniae were identified early in 2010,
and both patients had positive travel and hospitaliza-
tion histories [6]. The organisms in both cases were
regarded as colonizers and the patients did not
receive antibiotic treatment. To our knowledge, there
is no reported case of a favourable outcome after
treatment of bacteraemia due to NDM-1-producing
K. pneumonia. A recent case of polymicrobial bacte-
raemia due to NDM-1-producing Escherichia coli
and Staphylococcus haemolyticus in a febrile neutro-
penic patient has been reported. The patient was a
traveller from Bangladesh, and although she had
313
clearance of bacteraemia, she eventually died of a
perforated viscus [5].
It is observed that patients colonized or infected
with these organisms have had a history of travel to
India or Pakistan. Our patient originated from Jakarta,
Indonesia and had no recent travel history. She had
been in Singapore for 7 months for her consolidation
chemotherapy treatment. This case suggests that a
positive travel history may not always be available.
Due to its recent discovery, there are no reports
in the literature on the treatment of bacteraemia
caused by NDM-1-positive organisms in neutropenic
patients. The 2010 Infectious Diseases Society of
America (IDSA) guidelines for the treatment of
febrile neutropenia recommend initial monotherapy
with an anti-pseudomonal beta-lactam such as
cefepime, piperacillin–tazobactam, or a carbapenem
in high-risk patients who require hospitalization.
Other antimicrobials like aminoglycosides, fluoro-
quinolones, and/or vancomycin may be given in com-
bination [7]. In the haematology unit at our centre,
we have a consensus guideline to guide the choice of
antibiotics in febrile neutropenic patients [8]. In this
guideline, the recommended initial first-line agent
for empirical treatment is cefepime. Further escala-
tion of antibiotics with the addition of aminoglyco-
sides and/or vancomycin is recommended after 48–72
h. A carbapenem remains the third line of escalation
for the coverage of Gram-negative bacterial infec-
tions. However, it was noted in an audit that the
compliance rate to the guideline was, not surpris-
ingly, as low as 31% [8]. A recent prospective audit
of a protocol in another tertiary centre in Singapore,
which uses carbapenem in high-risk patients or
patients with previous colonization by cephalosporin-
resistant Enterobacteriaceae, showed an overall com-
pliance to protocol of 56.7% [9]. Hence, if one
adheres strictly to available guidelines, empirical
treatment of a patient with an infection due to NDM-
1-producing bacteria may potentially be missed,
which might have been very serious in our case.
A targeted surveillance of gastrointestinal colo-
nizers by stool cultures to identify carbapenemase
(KPC)-producing K. pneumoniae has been recom-
mended for high-risk situations (endemic and epi-
demic) [10]. Our microbiology laboratory started an
in-house surveillance project for NDM-1-producing
isolates in the stools of immunocompromised patients
after the emergence of this new pathogen [6]. This
project benefited our case patient, as it alerted us to
the fact that she was a gastrointestinal carrier of
NDM-1-producing K. pneumoniae. Hence, we chose
to start polymyxin B before the final blood culture
results were available. We believe that the good
outcome was due to a timely and appropriate
antimicrobial treatment.
 314 J. M. F. Chien et al.
NDM-1 hydrolyses all beta-lactam antibiotics
except aztreonam. However, NDM-1-producing organ-
isms frequently carry other resistance genes that code
for enzymes including ESBL and AmpC beta-lactama-
ses, rendering most available antibiotics inactive. These
organisms are usually susceptible to polymyxin and
tigecycline. However, achievable tigecycline serum lev-
els are low and there are concerns about using tigecy-
cline for bloodstream infections [11,12]. Treatment
failure with tigecycline has been reported [13]. The 2
clinically used polypeptides colistin and polymyxin B
are effective against NDM-1-positive organisms. Hence,
the choice in patients with febrile neutropenia sus-
pected of such infections should be a combination that
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includes polymyxin B or colistin. This is supported by
data from patients infected with KPC-producing Enter-
obacteriaceae, where monotherapy with colistin led
to rapid regrowth of resistant subpopulations [12].
Although the literature available regarding the use of
polymyxin B is limited [14], we used polymyxin B as
we are experienced with the drug and its delivery. Com-
bination therapy of infections with NDM-1-positive
K. pneumoniae has not previously been reported, and
future experiences are eagerly awaited.
In conclusion, NDM-1-positive Enterobacteriaceae
For personal use only.
have been increasingly isolated since their first identifi-
cation. Infection with such organisms is difficult to treat
due to the limited antibiotic choices. Our patient had a
good outcome with no complications from treatment.
We believe that a high index of suspicion and perhaps
a surveillance programme for immunocompromised
hosts will aid in the early diagnosis and contribute to a
better prognosis for this fatal infection.
Declaration of interest: No conflict of interest. We
do not have commercial or other associations that
might pose a conflict of interest. This report did not
receive any source of financial support.
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