Download Pacemaker lead infection and related bacteraemia caused by

Journal of Medical Microbiology (2013), 62, 940–944
Case Report
DOI 10.1099/jmm.0.051987-0
Pacemaker lead infection and related bacteraemia
caused by normal and small colony variant
phenotypes of Bacillus licheniformis
Evgeny A. Idelevich,1 Christian A. Pogoda,2 Britta Ballhausen,1
Jörg Wüllenweber,1 Lars Eckardt,3 Helmut Baumgartner,4
Johannes Waltenberger,2 Georg Peters1 and Karsten Becker1
Correspondence
Karsten Becker
[email protected]
1
Institute of Medical Microbiology, University Hospital Münster, Domagkstr. 10, 48149 Münster,
Germany
2
Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer-Campus
1, 48149 Münster, Germany
3
Division of Electrophysiology, Department of Cardiology and Angiology, University Hospital
Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
4
Adult Congenital and Valvular Heart Disease Center, Department of Cardiology and Angiology,
University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
Received 5 September 2012
Accepted 18 March 2013
Here, we report what we believe to be the first case of bacteraemia with small colony variants of
Bacillus licheniformis related to a pacemaker lead infection by B. licheniformis displaying the
normal phenotype. Arbitrarily primed PCR analysis showed a clonal strain. The infection was
cured after the removal of the infected device.
Case report
A 42-year-old immunocompetent man was admitted to the
Department of Cardiology of the University Hospital
Münster for the treatment of pacemaker lead (PL)
infection. Fourteen years previously, the patient had
undergone mitral valve replacement with an artificial
mechanical valve (TEKNA, size 27 mm) after the removal
of a papillary fibroelastoma. Due to a post-operative third
degree atrioventricular block, a dual-chamber pacemaker
(MDT Kappa 401 DR, Medtronic) had been implanted on
the right side of the chest. Eight years later, at the age of 36,
a left-sided reimplantation of a dual-chamber pacemaker
(Biotronik Axios DR, Biotronik) with right atrial
(Medtronic CapSureFix 5076, Medtronic) and right
ventricular PLs (Biotronik Merox 60-15 BP) became
necessary because of PL dysfunction. The old right-sided
pacemaker and PL were removed. Three years following
reimplantation (i.e. 3 years prior to the present hospitalization), the patient was admitted with sepsis, and
Bacillus licheniformis was identified in five blood cultures.
This was preceded by recurrent pneumonia over 6 months
and a 12 kg weight loss. A transoesophageal echocardiogram (TOE) showed no evidence of cardiac infection at
that time, and positron emission tomography/computed
tomography revealed multiple pulmonary densities.
Abbreviations: IE, infective endocarditis; NP, normal phenotype; PL,
pacemaker lead; SCV, small colony variant; TOE, transoesophageal
echocardiogram.
940
Following antibiotic therapy with amoxicillin/clavulanic
acid and gentamicin, laboratory parameters normalized
and the patient clinically recovered. Three months prior to
the present admission, a partial right-lung lobectomy was
performed in another hospital after the radiological
detection of lung lesions, and the histopathology showed
multiple segmental pulmonary embolism. At that time,
several TOEs remained non-diagnostic with regard to
infective endocarditis (IE).
Upon the present admission, the patient reported
decreased functional capacity during the last 3 years. He
suffered from frequent night sweats, orthostatic dizziness
and recurrent pulmonary infections. The patient had a
reduced general condition. Upon admission, his C-reactive
protein level was 52 mg l21 and the level of leukocytes was
6840 ml21. A TOE revealed a vegetation near the right
ventricular PL. Before the initiation of antimicrobial
treatment, peripheral blood cultures were collected and
three sets grew B. licheniformis. Vancomycin and ceftriaxone therapy was initiated. After identification and
antimicrobial susceptibility testing, antibiotic therapy was
changed to intravenous amoxicillin/clavulanic acid. The
pacemaker and the PLs were removed, and B. licheniformis
was also isolated from both atrial and ventricular PLs. At
the same time, a new pacemaker (Medtronic Relia SR
RESR01) was placed in an abdominal position using an
epicardial PL. A surgical revision was later necessary twice
for local haematoma. The four blood cultures taken on
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B. licheniformis – small colony variant bacteraemia
different days in the post-operative period remained
negative. The patient was discharged and continued oral
amoxicillin/clavulanic acid for 2 weeks. At 4- and 8-month
follow-up visits, the patient showed clinical recovery and a
good exercise capacity. C-reactive protein was below the
limit of detection and blood cultures remained negative.
The blood cultures obtained from the patient were incubated
in the BACTEC 9240 automated blood culture analyser
(Becton Dickinson) and positive cultures were plated onto
Columbia blood agar, chocolate agar and Schaedler agar with
5 % sheep blood. Three sets (both aerobic and anaerobic
bottles) became positive and showed Gram-positive rods by
microscopy and growth on all three agar plates. Colonies on
blood agar appeared small (,1 mm), white and round (Fig.
1). VITEK-2 (bioMérieux) biochemically identified the
micro-organism recovered from the blood as B. licheniformis
and matrix-assisted laser desorption ionization time-of-flight
(MALDI-TOF) MS with microflex LT system (Bruker
Daltonics) yielded the same result. One blood culture
positive for B. licheniformis was a mixed culture, in which
tiny a-haemolytic colonies also grew on blood agar plates,
producing green coloration. This organism was identified by
the same identification methods as Granulicatella adiacens.
Atrial and ventricular leads grew large, irregular, wrinkled,
opaque, pleomorphic, ‘licheniform’ colonies on blood agar
(Fig. 1). These isolates were also identified unambiguously by
both the VITEK-2 and MALDI-TOF systems as B. licheniformis. The identification of all isolates was confirmed
additionally by 16S rRNA gene sequence analysis, as previously
described (Becker et al., 2004; Breitkopf et al., 2005).
Fig. 1. Colony morphology of B. licheniformis isolates. NP isolate
from PL after 24 (a) and 72 h (b) incubation and SCV isolate from
blood culture after 24 (c) and 72 h (d) incubation.
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Although the isolates from blood and PLs belong to the
same species, the morphology and particularly the size of
colonies differed considerably (Fig. 1). Pleomorphism of
colonies well known for B. licheniformis (Logan et al., 2011)
was noticeable with each isolate, despite multiple attempts
to subcultivate a single colony type. However, the
difference in appearance between isolates from blood
cultures and those from PLs was tremendous. While the
isolates from PLs yielded large colonies typical for B.
licheniformis, colonies of blood isolates were at least tenfold
smaller, resembling the small colony variant (SCV)
phenotype as reported for staphylococci and other bacterial
pathogens (Proctor et al., 2006). This phenotype remained
stable for up to ten passages on solid medium. If grown for
3 days, colonies from blood cultures became only slightly
larger (Fig. 1). Also, the phenotype of PL isolates did not
change after ten cultural passages. The blood culture isolate
grew much slower than the PL isolate and the B.
licheniformis type strain DSM 13 in the brain heart infusion
(BHI) broth at 37 uC and did not achieve the optical
density of these two strains, which is indicative for the SCV
nature of blood culture isolates, whereas the growth of the
PL isolate was, by growth curve analysis, very similar to
that of the type strain DSM 13 (data not shown). The
biofilm formation was affected in blood culture isolates, as
determined in an assay with standing incubation in BHI
broth and lysogeny broth for 72 h at 37 uC. Compared
with the formation of a biofilm (pellicle) on the broth
surface (air–liquid interface) by the PL isolate and the type
strain DSM 13, and described previously also for Bacillus
subtilis by Branda et al. (2006), a pellicle was formed at the
bottom of the tube (glass–liquid interface) by the blood
culture isolate (data not shown). We did not observe any
difference between the isolates in their cell morphology
evaluated by the Gram stain and did not see any lack of
motility in blood culture isolates. Since the colony
morphology and growth characteristics of blood culture
isolates were unusual for B. licheniformis and differed from
the characteristics of PL isolates, we performed genotyping
for all B. licheniformis isolates of this patient and compared
them with the B. licheniformis type strain DSM 13, applying
arbitrarily primed PCR (AP-PCR), as previously described
(Becker et al., 2002; Ellinghaus et al., 1999). AP-PCR has
previously been successfully used for heterogeneity determination of Bacillus spp. isolates (Hsueh et al., 1999). All
isolates had similar patterns, providing evidence that they
are clonally identical (Fig. 2). Thus, isolates from blood
cultures represent morphologically an SCV phenotype of B.
licheniformis, with the corresponding parental isolates
recovered from PLs displaying the normal phenotype (NP).
Antimicrobial susceptibility testing (AST) was performed
using the disc diffusion method and was interpreted
according to CLSI breakpoints for Staphylococcus aureus
(CLSI, 2011), because there are no disc diffusion breakpoints
available for Bacillus spp. Susceptibility to vancomycin was
tested by a gradient MIC method (Etest; bioMérieux)
according to the manufacturer’s instructions. AST was
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E. A. Idelevich and others
moderate (2–4 mm) diameter, exceptionally variable in
their appearance and often appearing to be mixed cultures
(Logan et al., 2011). B. licheniformis like other Bacillus nonanthracis species is a common contaminant in cultures of
clinical material, but numerous reports have described
serious disease including ophthalmitis, brain abscess,
central venous catheter infections, prosthetic-valve endocarditis and neonatal sepsis (Blue et al., 1995; Jones et al.,
1992; Lépine et al., 2009; Santini et al., 1995; Thurn &
Goodman, 1988). Quan et al. described a case of
pacemaker wire infection caused by B. licheniformis
(Quan et al., 2000), but, to our best knowledge, SCVs of
this pathogen have not been previously reported.
Fig. 2. Arbitrarily primed PCR patterns of B. licheniformis isolates.
Lanes: M, DNA molecular size marker (New England Biolabs); 1,
B. licheniformis type strain DSM 13; 2, 3, 4, 5 and 9, SCV isolates
from three different blood cultures (lanes 3, 4 and 9 – slightly
different SCV colony types within a single blood culture); 6 and 7,
NP isolate from the atrial lead with two slightly different NP colony
types; 8, isolate from the ventricular lead; 10, negative control.
Lanes 2–9, similar banding patterns indicating that the isolates
represent the same strain.
performed with a standard 0.5 McFarland inoculum on
Mueller–Hinton agar without supplementation. The growth
of blood culture isolates (SCVs) was slightly reduced
compared with that of PL isolates (NP isolates).
Nevertheless, the growth of both SCV and NP isolates was
confluent and readings were possible for both isolate types.
When blood culture isolates were streaked onto Mueller–
Hinton agar to observe single colony morphology, the colonies
were also smaller in comparison with those of PL isolates and
the type strain B. licheniformis DSM 13. Thus, the differences
between blood culture and PL isolates could be confirmed on
this medium. All B. licheniformis isolates were susceptible to
amoxicillin/clavulanic acid, cefoxitin, cefazolin, imipenem,
gentamicin, amikacin, levofloxacin, erythromycin, vancomycin, rifampicin and trimethoprim–sulfamethoxazole, and were
resistant to clindamycin. Interestingly, B. licheniformis SCV
blood isolates were susceptible to cefuroxime and cefotaxime,
while B. licheniformis NP PL isolates were categorized as
intermediately susceptible. Susceptibility testing results of
penicillin G and ampicillin were highly variable, most
indicated resistance, but some results indicated susceptibility
for some SCV and NP isolates. Therefore, the Etest was
performed with these agents and the same variability was also
noted applying this method. This variability might be related
to the extensive growth variability of B. licheniformis.
Discussion
B. licheniformis is a Gram-positive, rod-shaped, aerobic,
endospore-forming organism, which forms colonies of a
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SCVs reported for several bacterial species represent a slowgrowing, pathogenic phenotype which facilitates persistent
and relapsing infections, such as chronic osteomyelitis,
abscesses and foreign body-associated infections (Proctor
et al., 2006). Due to their atypical colony morphology and
unusual metabolic and proteomic characteristics, SCVs
represent a challenge in terms of recovery from clinical
specimens, their identification and susceptibility testing
(Becker et al., 2006; Kriegeskorte et al., 2011; von Eiff et al.,
2006). Best characterized for staphylococcal SCVs, common traits of SCVs are their ability to escape the host’s
immune response by intracellular persistence, reduced
susceptibilities to antibiotics and enhanced biofilm formation (Baumert et al., 2002; Singh et al., 2010; Tuchscherr
et al., 2010). In the past, a few cases of pacemaker
infections associated with staphylococcal SCVs have been
described (Maduka-Ezeh et al., 2012; Nielsen et al., 2009;
Seifert et al., 2003, 2005; von Eiff et al., 1999), while
pacemaker infections caused by SCVs of other species have
not been described so far. However, some non-staphylococcal SCVs, such as SCVs of Brucella melitensis,
Burkholderia spp., Escherichia coli, Neisseria gonorrhoeae
and Pseudomonas aeruginosa, have been documented as the
cause of infections (Proctor et al., 2006). To our best
knowledge, this is a first report of a B. licheniformis SCV.
For other Bacillus species, in vitro generation of SCVs has
been documented (Maughan & Nicholson, 2011; Rettger &
Gillespie, 1933); however, isolation of bacillary SCVs from
clinical samples has not been hitherto reported.
Although we isolated G. adiacens only in one of three
positive blood cultures, it is difficult to distinguish between
secondary contamination and mixed infection in this case,
and the latter cannot be excluded. Indeed, G. adiacens,
formerly known as ‘nutritionally variant streptococci’ or
‘satellite streptococci’, is able to cause cardiac infections
(Baddour et al., 2005). We also observed its satellite growth
on the plate around the colonies of B. licheniformis
(although no apparent haemolysis was seen around B.
licheniformis colonies) similar to the well-known satellite
growth of Haemophilus influenzae in the haemolysis zone
of S. aureus colonies. It is conceivable that a similar
pathogen association may exist in vivo. While the clinical
relevance of this additional finding remains unclear, the
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Journal of Medical Microbiology 62
B. licheniformis – small colony variant bacteraemia
antibiotics administered in this clinical case also included
G. adiacens in their antimicrobial spectrum.
Bacillus species including B. licheniformis are able to
produce biofilms (Banerjee et al., 1988) and the activity
of various antibiotics, e.g. vancomycin, is known to be
reduced in biofilms due to insufficient penetration into the
biofilm matrix (Kassar et al., 2009). The combination of
the known ability of B. licheniformis to form spores and to
produce biofilms with, as shown in this study, the ability to
exist as the SCV phenotype makes the persistent and
recurrent infection even more possible and supports the
concept that a clinical cure requires removal of all foreign
materials, which has been stressed by other authors for this
and other Bacillus species (Blue et al., 1995; Quan et al.,
2000; Santini et al., 1995).
Although the main mechanism of cardiac-device-related
infective endocarditis is contamination by local bacterial
flora at the time of device implantation, another possible
mechanism includes haematogenous seeding from a distant
focus of infection (Habib et al., 2009). In this case study it
was difficult to elucidate the origin of infection, since
3 years had elapsed since the reimplantation of the
pacemaker and the first episode of B. licheniformis
bacteraemia. However, the recurrent lung infections which
preceded this bacteraemia were, in retrospect, most
probably a consequence and manifestation of pulmonary
embolism, even if a TOE could not reveal vegetations on
PLs or right heart valves at that time. Pulmonary embolism
is a frequent complication of PL-related IE (Habib et al.,
2009). Interestingly, in a reported case of B. licheniformis
PL infection, a TOE revealed no vegetation on PLs or heart
valves, although lead tip and a number of blood cultures
yielded B. licheniformis (Quan et al., 2000). Removal of the
cardiac device is recommended in all cases of proven
cardiac-device-related IE and should also be considered if
cardiac-device-related IE is only suspected in the case of
occult infection without any other apparent source
(Baddour et al., 2010; Habib et al., 2009). This report
provides evidence that consideration to remove pacemakers should be especially strong if B. licheniformis is
isolated from blood cultures in pacemaker patients with
infections that are difficult to diagnose.
B. licheniformis can cause recurrent foreign-body-related
infections due to its ability to form biofilms. As shown here
for the first time, B. licheniformis isolates displaying the SCV
phenotype must not be disregarded and careful microbiological examination is mandatory to confirm species affiliation
and involvement of those isolates as causative agents.
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