Archives de Pédiatrie 26 (2019) 12–15

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Research paper

Klebsiella pneumoniae and Klebsiella oxytoca meningitis in infants.

Epidemiological and clinical features
C. Carrie a, V. Walewski b,c, C. Levy d,e,f,g, C. Alexandre h, J. Baleine i, C. Charreton j,
B. Coche-Monier k, L. Caeymaex e,g, F. Lageix a, M. Lorrot l, S. Klosowski m, L. Hess n,
O. Zafer o, J. Gaudelus a,f, D. Pinquier f,p, E. Carbonnelle b,c, R. Cohen d,e,f,g, L. de Pontual a,f,*
a
Service de pédiatrie, hôpitaux universitaires Paris Seine-Saint-Denis (HUPSSD) site Jean Verdier, université Paris XIII, AP–HP, avenue du 14 Juillet, 93140
Bondy, France
b
Service de bactériologie-virologie, hygiène, hôpitaux universitaires de Paris-Seine-Denis (HUPSSD), laboratoire de microbiologie hôpital Avicenne, hôpitaux
universitaires de Paris-Seine-Denis (HUPSSD), 125, rue de Stalingrad, 93000 Bobigny, France
c
Université Paris Nord, IAME, UMR 1137, Sorbonne Paris Cité, 75018 Paris, France
d
IMRB GRC GEMINI, ACTIV et université Paris-Est, 27, rue Inkermann, 94100 Saint-Maur-des-Fossés, France
e
Service de médecine néonatale, centre hospitalier intercommunal de Créteil, 40, avenue de Verdun, 94000 Créteil, France
f
Groupe de pathologie infectieuse pédiatrique, 57, avenue de la Californie, 06200 Nice, France
g
IMRB-GRC GEMINI, université Paris-Est, 40, avenue de Verdun, 94000 Créteil, France
h
Service de néonatologie et réanimation néonatale, 14033 Caen, France
i
Service de pédiatrie néonatale et réanimations, CHU Arnaud de Villeneuve, 371, avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France
j
Service de néonatologie et réanimation néonatale, avenue des Tamaris, 13616 Aix-en-Provence, France
k
Service de pédiatrie, centre hospitalier Simone Veil, 14, rue de Saint-Prix, 95600 Eaubonne, France
l
Service de pédiatrie, hôpital Armand-Trousseau, AP–HP, 26, avenue du Docteur Arnold Netter, 75571 Paris cedex 12, France
m
Service de pédiatrie, 99, route de la Bassée, 62300 Lens, France
n
Service d’urgence et de réanimation pédiatrique, hôpital, 59, boulevard Pinel, 69500 Bron, France
o
Service de pédiatrie, boulevard Laennec, 60100 Creil, France
p
Pediatrie néonatale et réanimation, Pavillon Mère-Enfant, hôpital Charles Nicolle, CHU de Rouen, université de Normandie, 76000 Rouen, France

A R T I C L E I N F O A B S T R A C T

Article history: Background: The incidence of meningitis caused by Klebsiella pneumoniae (Kp) and Klebsiella oxytoca (Ko)
Received 9 February 2018 in high-income countries is unknown, and no series have been published to date.
Accepted 30 September 2018 Methods: We conducted a nationwide multicenter observational study in France between 2006 and
Available online 14 December 2018
2016. All children from the French national registry for paediatric bacterial meningitis under the age of
1 year and hospitalized for Kp or Ko meningitis were included. Virulence factors of four Klebsiella spp.
Keywords: strains were explored by whole genome sequencing.
Klebsiella pneumoniae
Results: Of 1859 cases of meningitis in children under the age of 1 year, 13 cases (0.7%) of Klebsiella spp.
Klebsiella oxytoca
Meningitis
meningitis (nine for Kp meningitis and four for Ko meningitis) were registered in the French national
Infants registry. Three of the patients died and 50% of the survivors had developmental delays.
Conclusions: Prematurity, low birth weight, and congenital anomalies of the urinary tract appear to be
risk factors for Klebsiella spp. meningitis as well as virulence factors of the strain.
C 2018 Elsevier Masson SAS. All rights reserved.

1. Introduction severe sequelae in 20–50% of cases [2]. Causative organisms are

Bacterial meningitis is a major cause of morbidity and mortality
in children [1]. In the neonatal period, bacterial meningitis is
associated with a mortality rate of over 10% and is responsible for
* Corresponding author. Service de pédiatrie, hôpital Jean Verdier, avenue du
14 Juillet, 93140 Bondy, France.
E-mail address: loic.de-pontual@jvr.ap-hop-paris.fr (L. de Pontual).
mainly Streptococcus agalactiae, a group B streptococcus (GBS), and
Escherichia coli, found in 50% and 20% of cases, respectively. Beyond
the neonatal period, Neisseria meningitis and Streptococcus
pneumoniae are more frequently found.
In neonates and young children, various other Gram-negative
bacilli account for a small albeit unknown proportion of the
remaining cases. The incidence of meningitis caused by Klebsiella
pneumoniae (Kp) and Klebsiella oxytoca (Ko) is unknown, but
particularly severe neurological complications such as hydroceph-

https://doi.org/10.1016/j.arcped.2018.09.013
0929-693X/ C 2018 Elsevier Masson SAS. All rights reserved.
 C. Carrie et al. / Archives de Pédiatrie 26 (2019) 12–15 13

aly, empyema, and brain abscesses have been described in these
cases [3,4]. In non-high-income countries, Gram-negative bacilli
such as Klebsiella and E. coli are the primary causes of neonatal
meningitis [5] and are associated with higher rates of mortality
and morbidity than GBS meningitis [6].
The clinical and radiological follow-up of children presenting
meningitis due to Klebsiella has not been standardized. The
objectives of the present study were to assess the epidemiological
and clinical features of pediatric cases of Kp and Ko meningitis in
France, and to gain a better understanding of the short- and long-
term clinical outcomes in these patients.
2. Patients and methods
We conducted a nationwide multicenter observational study in
France between 2006 and 2016. All infants under the age of 1 year,
hospitalized for Kp or Ko meningitis were included. The case data
were extracted from the French national registry for paediatric
bacterial meningitis [7]. A total of 233 pediatric departments and
168 microbiology laboratories (located throughout France) par-
ticipated in the study. The main inclusion criterion was based on:
 bacterial meningitis associated with a positive cerebrospinal
fluid (CSF) culture for Kp/Ko or;
 CSF pleocytosis (> 10 cells/mm3) associated with a positive
blood culture for Kp/Ko.
The clinical and paraclinical characteristics of each case were
documented on a 308-item case report form. Imaging results were
reviewed by two experienced pediatric radiologists. The data were
analyzed by calculating the number (percentage), mean, median,
and range, as appropriate. The study protocol was approved by a
local independent ethics committee (Comité local d’éthique pour la
recherche clinique; reference: CLEA-2016-028, July 12th, 2016).
Genomic DNA was extracted using QIAamp DNA Mini Kit from
three non redundant Kp isolates and one Ko isolate followed by
running on the Miseq platform. In silico determination of MLST,
virulence factors, and serotype were obtained using the BIGSdb
platform (http://bigsdb.pasteur.fr/klebsiella/) [8,9].
3. Results
Between 2006 and 2016, of 1859 cases of meningitis in children
under the age of 1 year, 13 cases (0.7%) of Klebsiella spp. meningitis
– nine Kp and four Ko – were registered in the French national
registry. The clinical and biological characteristics of each case are
summarized in Table 1.
Out of 13 children, 11 were admitted from home and two (cases
8 and 10) were admitted to a neonatal intensive care unit at birth.
The mean age at diagnosis was 48.5 days (32.9 days for Kp
meningitis and 83.5 days for Ko meningitis). Eleven of the
13 infants (84%) were male. The mean gestational age at birth
was 36 weeks, with four of the 13 infants born prematurely, with a
gestational age ranging from 25 to 36 weeks. The mean (range)
birthweight was 2494 g (960–4840). Six of the 13 infants were
small for gestational age: five out of the nine infants with Kp
meningitis, and one out of the four with Ko meningitis.
Apart from premature birth, few risk factors for maternal–fetal
infections were found; the risk factors for bacteremia or meningitis
were congenital anomalies of the urinary tract in four cases and
sacrococcygeal fistula in one case. None of the infants presented
with congenital or acquired immunodeficiency.
The CSF culture was positive in six of the nine cases (67%) of Kp
meningitis but in only one of the four cases (25%) of Ko meningitis.
When CSF culture was negative, the diagnosis was based on a
combination of a positive blood culture and a meningeal
syndrome. In the CSF, the mean cellularity was 669/mm3 and
the mean protein level was 2 g/L [0.76–7.38]. Three of the nine
infants with Kp meningitis had a high Kp count in the urine, and all
three were found to have a congenital anomaly of the urinary tract.
All children presented with a marked inflammatory syndrome,
with a mean (range) serum CRP level of 152 mg/L (39–306) and a
mean serum procalcitonin level of 12.4 mg/L (positive if > 0.5 mg/
L).
The mean duration (range) of antibiotic treatment was 29 days
(1–180). Although all the children received a third-generation
cephalosporin, the other antibiotics prescribed (aminoglycoside,
amoxicillin, vancomycin, ciprofloxacin, etc.) varied from one unit
to another and depended on the child’s gestational age at birth. A
combination therapy with aminoglycosides was given in 12 out of
13 cases (92%) and with ciprofloxacin in nine out of 13 (69%).
Only one extended-spectrum beta-lactamase (ESBL)-producing
strain of Kp was detected, and there were no ESBL-producing Ko
strains. Congenital anomalies of the kidney and urinary tract were
diagnosed in four cases (vesicoureteral reflux in three cases and
obstructive uropathy in one newborn).
Brain imaging was performed within 1 week of diagnosis in
12 of the 13 cases (92%) (transfontanellar ultrasound in two, brain
CT scan in two, and brain MRI in eight), showing pathological
features in five of them (42%), four Kp meningitis cases of the eight

Table 1
Clinical characteristics of the 13 cases of Klebsiella spp. meningitis in children registered in the French national registry.

Case 1 2 3 4 5 6 7 8 9 10 11 12 13

Pathogen Kp Kp Kp Kp Kp Kp Kp Kp Kp Ko Ko Ko Ko
Gestational age at birth (weeks) 37 38 25 38 37 37.3 36 38 39 32.6 40 32 38
Age at diagnosis (days) 7 71 47 37 38 10 72 1 13 5 15 270 44
Sex F M M M M M M M M M M M F
Birth weight (g) 1660 3888 960 2350 1660 1630 1950 4840 3680 1720 3940 2020 2120
CAKUT + + + +
Blood culture Kp Kp Kp Kp Kp Kp Kp Ko Ko Ko Ko
CSF culture Kp Kp Kp Kp Kp Kp Ko
CSF cells (/mm3) 9 2020 61 823 1750 1800 46 60 18 800 330 950 29
CSF protein (g/L) 1.05 1.59 4.57 1.08 7.38 1.92 0.96 1.7 0.64 1.39 2.13 0.95 0.76
C-reactive protein (mg/L) 104 115 306 63 39 278,9 180 113 97.7 224 161 173 126
Urinary tract infection + + +
Pathologic MRI + + + + +
Brain abscess +
Abnormal electroencephalogram + + + + + +
Long-term sequelae + + + + +
Follow-up (months) 41 15 12 23 21 12 10 115 12 13 6 1 1
Death + + +

CAKUT: congenital anomalies of the kidney and urinary tract; CSF: cerebrospinal fluid; MRI: magnetic resonance imaging.
14 C. Carrie et al. / Archives de Pédiatrie 26 (2019) 12–15

Fig. 1. Brain MRI (magnetic resonance imaging), with axial (A) and coronal (B) views of patient #8 revealing a large number of ventriculitis-like micro-abscesses (arrows) in
the hemispheres and thalami.

with brain imaging data and one Ko meningitis case of the four
with brain imaging data. Cerebral white matter injury was noted in
all the eight patients with abnormal MRI, one developed
hydrocephaly, and one a brain abscess, for which surgery was
not required (Fig. 1).
Nine of the 13 patients had an electroencephalogram recorded
at some point in the course of the disease; abnormal features
(absence of a sleep-wake cycle or low voltage) were observed in six
of these nine cases (66%). Auditory or visual evoked potentials
were rarely investigated (in six and two cases, respectively).
Three of the patients died, two in the acute phase and one in the
post-acute period as a result of encephalopathy. All three deceased
patients had Kp meningitis.
The ten survivors were monitored on a regular basis following
their discharge from the hospital. This consisted of regular follow-
up consultations in the hospital, a psychomotor and neuropsycho-
logical evaluation, and local monitoring by the patient’s primary
care physician. The follow-up enabled the detection of develop-
mental delays in five of the ten cases (50%) after a mean (range)
period of 23.7 months (1–115).
The developmental delays ranged from moderate language
delay to severe motor delays such as the inability to sit up or walk.
Four of the six cases (67%) with Kp meningitis presented with long-
term developmental delay, compared with one of the four cases
(25%) with Ko meningitis.
In silico characterization of three K. pneumoniae and one
K. oxytoca isolates is summarized in Table 2.
4. Discussion
These results show that, in children, Klebsiella is a rare cause of
meningitis in France. Although our survey of pediatric bacterial
meningitis was not exhaustive, about two-thirds of France’s
pediatric departments and microbiology laboratories participated
[7]. The literature on Klebsiella meningitis in children is sparse,
with no published case series and only a few case reports on Kp
meningitis in children under the age of 1 year [3,4,10]. The mean
age at diagnosis of the reported cases in the literature was 15 days,
lower than in our series (48.5 days). Prematurity and low birth
weight–known risk factors for meningitis regardless of the type of
pathogen [5] – were observed in our series as in the literature. In
the literature, all the meningitis-causing Kp strains found in
children under the age of 1 year were ESBL-producing. Brain
abscesses were noted in most of the reports.
The early detection of brain abscesses with an appropriate
imaging technique is a major challenge in young children. The lack
of follow-up data in the literature prevents us from commenting in
detail on mortality and long-term sequelae. However, our results
suggest that Kp and Ko meningitis is associated with complicated
neurodevelopmental outcomes: the neurological sequelae appear
to be more severe for Kp and Ko meningitis than for GBS or E. coli
meningitis [2]; this difference may be correlated with a higher
incidence of brain abscesses. Brain abscesses caused by Klebsiella
are less necrotizing than those caused by Citrobacter spp. or Proteus
spp., and are not strongly symptomatic in the early stages of the
infection; this characteristic may be responsible for a delay in
diagnosis [11]. According to the literature, the mortality rates for
meningitis caused by GBS, S. pneumoniae, E. coli or Listeria
monocytogenes range from 10% to 12% [10]. Our results suggest
that Kp meningitis is associated with a high mortality rate (30%),
maybe higher than the other pathogens.
Some Klebsiella strains seem to be particularly virulent, which
might explain the rapidity and severity of the infections. Five major
virulence factors of K. pneumoniae are known to contribute to the

Table 2
Distribution of sequence types, beta-lactamase, capsule types, and virulence factors among four Klebsiella spp. isolates from clinical samples.

Case Pathogen gapA infB mdh pgi phoE rpoB tonB ST Clonal group Bla wzi ST Virulence factors

1 Kp B 2 1 1 6 7 1 12 45 cg45 SHV-1 101 24 Fimbriae type 3

Yersiniabactin
3 Kp L 2 1 2 1 7 1 7 36 cg36 SHV-1 27 27 Aerobactin
5 Kp T 48 22 18 59 92 13 51 1308 ND OKP 6 NT NT Fimbriae type 3
Aerobactin
Klebsiella ferric iron uptake
12 Ko B 3 5 21 13 20 6 12 151 ND OXY-1 NT NT None

ND: not determined; NT: non-typeable; ST: serotype.

 C. Carrie et al. / Archives de Pédiatrie 26 (2019) 12–15
pathogenesis of infection: capsular serotype, hypermucoviscosity
phenotype, lipopolysaccharide, siderophores (iron uptake), and pili
[12]. Kp can be classified into 77 serotypes based on capsular
polysaccharide antigens. The serotype K1 and K2 isolates are
generally more virulent in terms of lethality in a murine model [13]
and more often display a hypermucoviscosity phenotype than non-
K1/K2 strains. Hypervirulent Kp (hvKp) had a propensity for
community-acquired liver abscesses, metastatic spread, and
unusual sites of infection, including endophthalmitis and menin-
gitis [12].
In the current study, the three Kp isolates studied did not belong
to the hvKp serotypes K1/K2, were not hypermucoviscous (magA-
and rmpA-negative) but were not completely devoid of virulence
factors. All sequenced Kp isolates were able to synthesize
siderophores (yersiniabactin, aerobactin, klebsiella ferric iron
uptake system). Aerobactin and kfu systems have been shown to
be strongly associated with liver abscess formation and distant
metastatic infections [14]. In our study, two out of three Kp isolates
studied harbored type 3 fimbrial adhesion genes. The type
3 fimbrial adhesion protein (MrkD adhesin) plays a central role
in the virulence of Kp by attaching to host cells, such as of the
urogenital, respiratory, and intestinal tracts, but the role of type
3 pili adherence in the pathogenesis of meningitis is largely
unknown [12].
In the present study, we found no virulence factor in the Ko
isolate studied. Only a few studies have examined virulence factor
expression in this species, but Ko was recently shown to share
some virulence genes with Kp [15].
Interestingly, pathogens isolated from extremely premature
infants 3 and 12, who were born before 33 weeks of gestation,
showed no known virulence factors, whereas patients 1 and
5 showed virulence factors.
Although hypervirulent and antimicrobial-resistant popula-
tions of Kp were largely non overlapping, some isolates with
combined virulence and resistance were reported. One Kp strain in
our series and three Kp strains in the literature (isolated from CSF
samples) were ESBL-producing [11,16]. The emergence of carba-
penemase-producing Kp strains is noteworthy [17]. Kp is likely to
produce several types of carbapenemase (KPC, NDM-1, and OXA-
48). Considering the high risk of abscesses in Kp meningitis, the use
of ciprofloxacin might be appropriate for the early treatment of
these forms of meningitis.
Kp and Ko meningitis cases are rare, which makes it impossible
to identify risk factors specifically associated with these patho-
gens. Our case series showed a high proportion of patients born
small for gestational age, or with congenital anomalies of the
urinary tract causing bacteremia. In most cases, the source of the
infection was not known. Although none of the mothers reported a
history of genitourinary tract infections, the retrospective nature of
this data collection means that no firm conclusions can be drawn in
this respect.
Even in the absence of initial complications, the long-term
follow-up of children after bacterial meningitis is essential. This
enables anomalies such as neurodevelopmental complications to
be detected and managed as soon as possible. Kp/Ko meningitis
mainly affects children in the 1st year of life, a key period for brain
development. In view of our study, results and the scarcity of the
literature data, more thorough follow-up of these infections is
warranted.
15
5. Conclusion
In neonates and infants with meningitis, Klebsiella are rarely
involved. If involved, severe, complicated meningitis in the early
phase and frequent neurodevelopmental complications in the
aftermath can occur.
Financial statement
Pfizer group participate to financial support of this study.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgments
We wish to thank H. Ducou Le Pointe, MD PhD, service de
radiologie, hôpital Trousseau, Paris, for reviewing the MRIs, and Dr.
François Guerin, Prof. Martine Pestel Caron, Dr. Eric Vallée for
microbiologist diagnosis.
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