antibiotics
Case Report

Frequent Klebsiella pneumoniae Urinary Tract
Infections in a Patient Treated with Ruxolitinib
Ramy M. Hanna 1,2, *, Maham Khalid 2 , Lama Abd El-Nour 1 and Umut Selamet 1,3123*

Division of Nephrology, Department of Medicine UCLA, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095, USA; labdelnour@mednet.ucla.edu (L.A.E.-N.);
uselamet@hotmail.com (U.S.)
Division of Nephrology, Department of Medicine, UCI School of Medicine, Irvine, CA 92868, USA;maham.khalid@yahoo.com
Division of Nephrology, Department of Medicine, Brigham Women’s and Children’s Hospital, Boston,MA 02101, USA
Correspondence: rhannamd81@yahoo.com or ramyh1@uci.edu; Tel.: +1-310-206-6741

Received: 12 August 2019; Accepted: 11 September 2019; Published: 16 September 2019

Abstract: Ruxolitinib is a targeted agent that inhibits Janus 2 Kinase and is approved for use in
Polycythemia Vera and Primary Myelofibrosis. Its mechanism of action involves inhibition of cellular
proliferation via the Janus kinase/signal transducer and activator of transcription proteins pathway.
Ruxolitinib has different immune modulating effects that result in functional immunosuppression,leading to an increased susceptibility to certain infections. Klebsiella pneumoniae infections, in particular,
were common among the reported pathogens contracted by ruxolitinib users. We report a 75-year-old
male patient who had recurrent K. pneumoniae urinary tract infections while on ruxolitinib for
Polycythemia Vera. This case is reported to add to the literature describing an increased susceptibilityof patients to this often-resistant bacteria and to raise awareness about the immune modulating effects
of JAK inhibitors.
Keywords: Ruxolitinib; Klebsiella pneumonia; Immunemodulation; JAK kinase (Janus Kinase); STAT(Signal Transducer and Activator of Transcription proteins) kinase

1. Introduction
Ruxolitinib is an oral Janus Kinase (JAK) 1 and 2 inhibitor that is part of the family of tyrosine
kinase inhibitors (TKI) [1]. This agent is approved by the US Food and Drug administration for
the treatment of Polycythemia Vera (PCV) and Primary Myelofibrosis (PMF) [2]. While a rare
condition, (2.8/100,000 in males, 1.3/100,000 in females), PCV had few modern therapy options withphlebotomy still being used as an option [3]. The efficacy of Ruxolitinib has been established in
the Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera (RESPONSE) for
PCV [2,4], and Controlled MyeloFibrosis Study with ORal JAK inhibitor Treatment I and II (COMFORT
I and II) for myelofibrosis [2]. It is also being used in hemophagocytic lymphohistiocytosis [5].
The JAK/STAT (Signal Transducer and Activator of Transcription proteins) pathway is intimately
involved with cellular division in hematopetic progenitor cell division and proliferation of adaptive
immunity T cells [6]. Given its role in many dividing cells of the immune system, it can be expected tohave an immune modulatory effect [7].
Evidence of this effect emerged when many patients using ruxolitinib were reported to have anincreased susceptibility to bacterial infections. This was first reported in myelofibrosis patients [6],but later was also found to be true in PCV patients [8]. In addition to increased susceptibility to bacterial
infections, increased risk of fungal [9] and viral infections were subsequently reported [9]. The cells

Antibiotics 2019, 8, 150; doi:10.3390/antibiotics8030150

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Antibiotics 2019, 8, 150

2 of 4affected by ruxolitinib include T cells, natural killer cells, and dendritic cells [10]. One particularbacterial pathogen that has been reported in association with Ruxolitinib use has been K. pneumoniae,
with the best-known reported patient developing a hepatic abscess [11,12]. We report another patient
on ruxolitinib who developed frequent K. Pneumoinae urinary tract infections, given these reports,
this case is documented to show the clinical link between ruxolitinib use and infection with an often
resistant and virulently pathogenic organism.
Case Report
Our patient is a 75-year-old Caucasian male who was diagnosed with PCV that transitioned tomyelofibrosis. He also had a history of non-ischemic cardiomyopathy with an ejection fraction of30%, who was treated with ruxolitinib 20 mg by mouth twice a day. He presented to nephrology
care for monitoring for myelofibrosis related nephropathy, which was suppressed due to angiotensin
converting enzyme (ACE) inhibitor use. The patient’s serum creatinine improved when he wasinstructed to avoid non-steroidal anti-inflammatory agents. His serum potassium rose despite an
improving serum creatinine and he had to be taken off his ACE inhibitors. His serum creatinine ranged
between 1.3–1.7 mg/dL on ACE inhibitor and afterwards dropped to 1.2–1.3 mg/dL. The estimatedglomerular filtration rate of 40 mL/min improved to 54 mL/min after ACE inhibitor discontinuation.
He had some proteinuria at 0.6 grams protein/gram creatinine but further investigation of his urine
with a urinary culture being sent revealed a urinary tract infection and the patient noted frequency
symptoms. His first infection was noted 12/2018 he was treated with a course of ciprofloxacin.
His urinary culture returned with only one organism: >100,000 colony forming units (cfus) ofK. pneumoniae. This isolate was resistant to ampicillin, susceptible with a minimum inhibitory
concentration (MIC) of ≤1 µg/mL ceftriaxone, ≤0.25 µg/mL for ciprofloxacin, ≤1 µg/mL for gentamicin,≤16 µg/mL for nitrofurantoin, susceptible to oral cephalosporins, ≤4 µg/mL for piperacillin/tazobactam,and ≤20 µg/mL for trimethoprim/sulfamethoxazole. Despite a week long course of ciprofloxacin
250 mg orally twice a day for a week, the patient reported ongoing symptoms. In 2/2019, a repeat
urinary culture was drawn. This culture showed one organism, again >100,000 cfu of K. pneumoniae,
with the same sensitivity pattern as the 12/2018 isolate except for ≤32 µg/mL MIC for nitrofurantoin.
This time the patient was treated with cephalexin 500 mg by mouth for 1 week, and experienced somerelief from symptoms. One month later, 3/2019, the patient reported urinary symptoms again and asimilar isolate of K. pneumoniae was found with the same sensitivity pattern except now it was resistantto ampicillin and nitrofurantoin. This final time the patient was treated with cefuroxime 250 mg
orally twice for 10 days. He finally reported resolution of urinary frequency, but is being monitored
for recurrent symptoms and infection. The patient had no indwelling catheters, instrumentalization,
kidney stones, or any other reason for a complicated urinary tract infection. It was felt clinicallythe patient may be having trouble clearing his K. pneumoniae infection, and the literature discussed
earlier regarding ruxolitinib was discussed as a possible explanation for these recurrent urinary tract
infections (UTIs).
2. Discussion
The nearly ubiquitous role of tyrosine kinase inhibitors in cell division across red cell and immune
cell progenitors provide a clear context for the classification of ruxolitinib as an immune modulating oreven immunosuppressing agent [6–12]. Figure 1 shows the JAK/STAT kinase pathway as a schematicdrawing. It is noted that ruxolitinib was postulated as a main etiology for why the reported patient
could not clear his underlying K. Pneumoinae. urinary tract infections in this case. It is important in
PCV, PMF, and other patients receiving this agent that the potential for viral, fungal, and bacterial
infections [6–10] be appreciated and the patients should be monitored accordingly.

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Antibiotics 2019, 8, 150

3 of 43 of 4Figure 1. Schematic of Janus kinase 2 pathway (JAK/STAT pathway). CytR, cytokine receptor; DNA,deoxyribonucleic acid; Grb, Growth factor receptor-bound protein 2; JAK-Janus Kinase 1, 2; MAPK,a mitogen-activated protein kinase; P, phosphorous; Ras, rat sarcoma protein; Raf, serine/threonine
Figure 1. Schematicof Janus
kinasepathwaypathway).
CytR,cytokine
receptor;kinase/cellularhomologof viral
RAF2gene;
SoS, (JAK/STAT
son of sevenless;STAT,
signaltransducer
and DNA,
activator
deoxyribonucleicacid;
Grb,Growthfactor
receptor-boundprotein2;
JAK-Janus
Kinase1,2; MAPK,of transcription.
a mitogen-activated protein kinase; P, phosphorous; Ras, rat sarcoma protein; Raf, serine / threonine
kinase most/ cellularhomolog associatedof viral RAFwith
gene; ruxolitinib
SoS, son of sevenless;transducer
andWhile
infections
are mildSTAT,
and signal
treatedsuccessfully
withactivatoroftranscription.
antibiotics [1,2], the potential for rare [9], fungal [9], viral [8], and bacterial [6–8,10–12] infections thatmay present with abscesses, non-clearing infections, or even life threatening ways must be recognized
While most infections associated with ruxolitinib are mild and treated successfully withand anticipated [10–13]. Please see Table 1 for the three reported cases of K. pneumoniae infections inantibiotics [1,2], the potential for rare [9], fungal [9], viral [8], and bacterial [6–8,10–12] infections thatpatients receiving ruxolitinib.
may present with abscesses, non-clearing infections, or even life threatening ways must be recognized
and anticipated Table[10–13].
Pleaseofsee
Table 1 for infections
the three reported
K. pneumoniae
1. CasesK. Pneumoniaeassociatedcaseswith ofruxolitinib
use. infections inpatients receiving ruxolitinib.
AgeGender
Race and infectious
Indication
Infection
Location
It isReference
important for oncologists,onconephrologists,
diseasespecialists
to recognize
the immune12suppressing
effects
ofruxolitinib,
andthepredilectionforvariousatypical78
MNR
PMF
Liver abscessorganisms[6–8,10–13],13 includingNRthe risk NR
for the often
K. pneumoniae UTI
species. Given
NR resistant NRCC75
M
PCVthe risk of atypical
UTI and clinicallyimmunomodulatory/immune
suppression
risk Caucasianof JAK 1,2 inhibitors,
silentmust
alsoNR,be kept
in mindPCV,
whenevaluating
thePMF,patient
on ruxolitinib.
The
beneficial
CC,infections
current case;M, male;not reported;
polycythemia
vera,
primary
myelofibrosis;
UTI;
urinary
tractofinfection.
effects
ruxolitinib on patients with myelofibrosis and PCV also warrant continued use of this agent,
but with a vigilant eye for increased infection risks [14].
It is important for oncologists, onconephrologists, and infectious disease specialists to recognize theTable
1. Casesof K. Pneumoniae
associatedwithruxolitinib
use. organisms [6–8,10–immune suppressing
effectsof ruxolitinib,
andinfections
the predilection
forvarious
atypical13], including the Reference
risk for the Age
often resistantspecies. Given
immunomodulatory/immune
Gender K. pneumoniae
Race
Indication
Infection
Locationsuppression risk of JAK
1,2
inhibitors,
theriskofatypicalandclinicallysilent infections must also
1278
M
NR
PMF
Liver abscessbe kept in mind whentheon ruxolitinib.
13 evaluating
NR
NRpatient NR
NR The beneficial
UTI effects of ruxolitinib onCC75 PCV M
Caucasian
PCVuse of this agent,
UTI but with a vigilant eyepatients with myelofibrosis
andalso warrant
continued
CC, current
case; M,male;NR, not reported; PCV, polycythemia vera, PMF, primary myelofibrosis;
for increased
infection
risks
[14].
UTI; urinary tract infection.
3. Conclusions
3. Conclusions
This report is to increase awareness of ruxolitinib as an immunomodulatory/immuno-suppressive
reportis to increaseawarenessof ruxolitinib
as an agents
immunomodulatory/immunoagent. ThisKlebsiellapneumoniae
infection
can be seenwith JAK kinase
like ruxolitinib. Reported
suppressive
agent.
Klebsiellapneumoniae
infection
canbeseen
withJAKkinaseagentscases include recurrent urinary tract infections and one case of a hepatic
abscess
withlike
K. ruxolitinib.
pneumoniae inusers of ruxolitinib.
Author Contributions: R.M.H. was the primary author of the manuscript; M.K. assisted with table construction,
writing text, editing text; L.A.E.-N. assisted with writing and editing manuscript, and the figure. U.S. oversaw
writing of this case report as the ranking onconephrology specialist at UCLA.

Antibiotics 2019, 8, 150

4 of 4Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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