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Current Treatment Options in Infectious Diseases (2014) 6:425438

DOI 10.1007/s40506-014-0029-x

Bacterial Infections and Drug Resistant Pathogens (H Wisplinghoff, Section Editor)

Treatment of Infections Caused

by Carbapenem-Resistant
Axel Hamprecht, MD1*
Stephan Gottig, MD, PhD2
*,1Institute for Medical Microbiology, Immunology and Hygiene, University Hospital
of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany
Institute of Medical Microbiology and Infection Control, Hospital of Johann
Wolfgang Goethe-University, Frankfurt am Main, Germany

Published online: 30 August 2014

* Springer Science+Business Media New York 2014

Keywords Carbapenemase I Therapy I E. coli I K. pneumoniae I NDM I KPC

Opinion statement
Treatment of infections by carbapenem-resistant enterobacteriaceae (CRE) is challenging
because of the limited choice of active antibiotics and the scarcity of good data supporting
any treatment regimen. Currently, there are no randomized controlled trials on the treatment
of CRE infections and all data have been obtained from case report and retrospective cohort
studies; thus, there are no treatment guidelines available. In the absence of good evidence,
it is essential to tailor the treatment to the individual patient, considering different factors:
The focus of the infection and attainable tissue concentrations by an antibiotic in that
the results of antimicrobial susceptibility testing (preferably MIC data) and the resistance
pharmacokinetic/pharmacodynamic (PK/PD) data.
Among the different antibiotics, colistin, tigecycline, fosfomycin and aminoglycosides have
usually the lowest rate of resistance. All of these antibiotics have certain disadvantages
compared to -lactam antibiotics and their use has to be carefully monitored. Tigecycline,
fosfomycin or aminoglycosides should not be used in monotherapy for systemic CRE
infections. Combination therapy with 2 active agents potentially improves the outcome
of CRE infections. The combination regimen should contain a carbapenem if a MIC of 8 mg/
L is recorded, as this has resulted in an improved outcome in several studies. When
meropenem is used, a high dose therapy administered by a prolonged infusion regimen is
recommended. If colistin is used, it is likely better to start with a loading dose followed by
doses that are within the upper limit of currently used regimen.
426 Bacterial Infections and Drug Resistant Pathogens (H Wisplinghoff, Section Editor)

Carbapenem resistance in enterobacteriaceae (CRE) has most frequent, and their distribution worldwide
dramatically increased in recent years worldwide [1]. differs greatly [1]. Carbapenemases can be divided
Treatment options for infections caused by CRE are very into different functional classes according to the
limited, with often very few or even no antibiotic agent Ambler scheme (Table 1).
remaining active [2, 3]. Carbapenemases can lead to a varying degree of
Carbapenem resistance can be mediated by different carbapenem resistance, with ertapenem showing
mechanisms: by carbapenemases, bacterial enzymes which t he h i g h e s t M I C s c o m p a r e d t o i m i p e n e m ,
hydrolyze carbapenems and most other -lactams; or by meropenem, or doripenem, which sometimes have
the combination of an extended spectrum -lactamase MICs that are within the intermediate or even sus-
(ESBL) or AmpC in combination with alterations of mem- ceptible range (Fig. 1).
brane proteins (e.g., porin loss, efflux pump). The four most prevalent carbapenemases (KPC,
Carbapenemases can be detected in many differ- NDM, VIM, and OXA-48) are discussed in more detail
ent species, with Klebsiella pneumoniae being the below.

Klebsiella pneumoniae carbapenemase (KPC)

KPC positive isolates were first reported in the USA in 1996 and have since then
spread across many countries [4]. KPCs are most often found in K. pneumoniae,
but can occur also in other enterobacteriaceae [5]. They hydrolyze all -lactams
and frequently exhibit co-resistance to most other antibiotic classes. Colistin,
one or more aminoglycosides, and tigecycline often remain susceptible.
New Delhi metallo-beta-lactamase (NDM)
NDM is a metallo--lactamase (MBL) which confers resistance to all -lactams
except monobactams [7, 10]. In contrast to other carbapenemases, NDM has
a very broad host range and can be found in many gram-negative species, but
mostly in enterobacteriaceae and Acinetobacter baumannii [7, 11, 12]. NDM is
endemic to the Indian subcontinent, where it is also present in the environ-
ment. It has spread worldwide remarkably fast since its first description in 2009
[11, 12, 13, 14].

Verona integron-encoded metallo--lactamase (VIM)

VIM is a MBL which was first described in an isolate of P. aeruginosa from Italy in
1999 [6]. Since 2001, it quickly spread in K. pneumoniae and E. coli within
Greece [15, 16]. Like all MBLs, VIM hydrolyzes most -lactams with the ex-
ception of aztreonam. Co-resistance to most other antibiotic classes is common.

OXA-48 is a carbapenem-hydrolyzing oxacillinase and mediates resistance
towards penicillins and reduced susceptibility to carbapenems, but spares third
and fourth generation cephalosporins (Fig. 1) [9]. However, most isolates are
Treatment of Infections Hamprecht and Gttig 427

Table 1. Most important carbapenemases according to ambler classification

Ambler class Carbapenemase prototype Most common species Geographic distribution

A (serin -lactamase) KPC-2 (KPC-2 to KPC-20) K. pneumoniae North and South America,
[4, 5] Israel, Greece, Italy, China
B (metallo--lactamase) NDM-1 (NDM-1 to NDM-12) K. pneumoniae, E. coli India, Pakistan, UK,
[68] Balkan states, Middle East
VIM-1 (VIM-1 to VIM-41) E. coli, K. pneumoniae, Italy, Greece
Enterobacter spp.
IMP, GIM-1, Others E. cloacae, C. freundii Asia, Germany
D (oxacillinases) OXA-48 like (OXA-48, K. pneumoniae Europe, North Africa,
[9] OXA-162, OXA-181, etc.) Middle East
Ambler class C group includes AmpC lactamases but no carbapenemases and is therefore not enlisted. All current variants of the respective
carbapenemases are in parentheses as found at

resistant to all -lactams because of ESBL co-expression. The OXA-48 gene is

usually located on a plasmid and can therefore be easily transmitted to other
bacteria. Initially identified in a K. pneumoniae isolate from Turkey in 2001,
outbreaks of OXA-48 producing enterobacteriaceae have been reported mostly
from North Africa, Europe, and Asia [17]. Today, OXA-48 is the most prevalent
carbapenemase in Europe [1, 16, 17].

Associated resistance in carbapenemase producing

Frequently, carbapenemase producing isolates are resistant to many antibiotics
besides -lactams, because they encode further resistance genes, such as
aminoglycoside-modifying enzymes, or harbor mutations in target enzymes
(e.g., DNA gyrase), leading to fluoroquinolone resistance. Therefore, the

Figure 1. Spectrum of -lactamases. Sim-

plified depiction of antibiotic susceptibili-
ties of Enterobacteriaceae (e.g., E. coli)
producing the respective -lactamase.
Green: usually susceptible; yellow: varying
degree of susceptibility; red: resistant. As-
terisks indicate resistance in isolates co-
expressing other -lactamases (ESBL,
AmpC); e.g., OXA-48 isolates are frequently
resistant to 3rd generation cephalosporins
(Ceph 3rd G) because of ESBL production.
428 Bacterial Infections and Drug Resistant Pathogens (H Wisplinghoff, Section Editor)

antibiotic choice is often very limited and old antibiotics such as colistin or
fosfomycin have regained interest in recent years because of a comparatively
low resistance rate [18, 19].

Pharmacological treatment
Evidence for antibiotic treatment of CRE infections
In spite of the increasing number of CRE infections, there is a lack of data on the
best management of infections with these pathogens. Currently, there are no
randomized controlled trials, and most data have been obtained from retrospec-
tive case series with few patients or observational studies. Because of the diversity
of carbapenemases which can occur in different species, matters become more
complicated; e.g., results of studies on VIM producing K. pneumoniae isolates
might not be universally valid for a different type of carbapenemase or a
different species. Most data on treatment have been gathered in high
endemicity countries such as Greece, Italy, the USA, or Israel, and from
infections with K. pneumoniae. Most studies report on infections with
isolates producing KPC, followed by VIM. There is considerably less clinical
data on treatment of infections with other carbapenemase producing bacteria
(e.g., OXA-48 or NDM) [20].

Choosing the right antibiotic agent

The empiric therapy of an infection should be based on the local epidemiology
and resistance rates, taking into account the focus of the infection and attainable
tissue concentrations; e.g., antibiotics that reach low concentrations in the
lungs, like tigecycline, should not primarily be used for the treatment of
For definite therapy, the results of susceptibility testing, preferably deter-
mined by an MIC method, should be used to guide treatment. The advice of an
expert or infectious disease specialist with experience in treatment of multidrug-
resistant (MDR) organisms should be obtained if possible.
Patients who are only colonized should not receive antibiotic treat-
ment in the absence of infection, since eradication from the intestine,
which serves as a reservoir, cannot be achieved by antibiotic therapy.
Moreover, antibiotic treatment in this setting can lead to the develop-
ment of resistance [21].

Non -lactam antibiotics

Colistin (polymyxin E) belongs, together with polymyxin B, to the
clinically used polymyxin antibiotics and often represents the last-resort
antibiotic for the treatment of CRE, since resistance rates are in general
G5 % [22, 23]. It is bactericidal and displays concentration-dependent
killing against susceptible strains [24]. Colistin interacts with the lipo-
polysaccharide of the outer membrane of gram-negative bacteria, by
replacing Mg2+ and Ca2+ and binding to its negatively charged compo-
nent, lipid A [25, 26]. In contrast to most other antibiotics, resistance to
Treatment of Infections Hamprecht and Gttig 429

colistin can develop through adaptive or mutational mechanisms, rather

than acquisition of a resistance gene. Morganella spp., Serratia spp. and
Proteus spp. are intrinsically resistant to colistin.
Two forms of colistin are commercially available: colistin sulfate for oral
and topical use; and colistimethate sodium (CMS) for parenteral or
inhalative use [19]. Colistin sulphate is poorly resorbed in the digestive
tract and is therefore being used for selective oropharyngeal decontamina-
tion (SOD) of gram-negative bacteria, especially in ventilated patients, or
high-risk patients at intensive care units [27]. For parenteral use, colistin is
administered as its inactive prodrug CMS, which is renally cleared; only
about 20 % of CMS is hydrolyzed to colistin, which in turn is eliminated
extrarenally [28]. Thus, clearance and dose requirements are dependent on
kidney function. The main adverse reactions described with intravenous
treatment are nephrotoxicity and neurotoxicity.
Establishing optimal dose regimens is difficult, especially considering
that there are multiple conventions used to describe doses of colistin: 1
million international units (IU) is equivalent to 80 mg CMS or 50 mg
colistin base activity (CBA). The upper limit dose for a 960 kg patient is
480 mg of CMS/day in three divided doses [19]. Even with high dosing of
CMS, patients with good renal function will not be able to achieve plasma
colistin levels likely to be effective [29]. Thus, it has been suggested using a 9
million IU loading dose and high daily dosages (4.5 million IU twice daily)
of colistin to increase serum levels, and to apply combination therapy in
order to prevent the selection of resistant strains, and to ameliorate therapy
outcome [2931]. The available evidence on combining colistin with a
carbapenem, or tigecycline, stems from non-randomized studies that in-
vestigated mortality of critically ill patients with infections due to
carbapenemase-producing Klebsiella spp. [3032]. However, the possible
advantages of colistin-containing combination therapy over monotherapy
and associated toxicity is still a matter of debate.
Tigecycline is the first glycylcycline, which is derived from tetracy-
clines and most closely related to minocycline [33]. It has good anti-
gram-negative activity and is not affected by -lactamases and tra-
ditional tetracycline resistance mechanisms. Resistance to tigecycline
results mainly from the expression of efflux pumps. Since suscepti-
bility testing for tigecycline is problematic and false-resistant results
are frequent, it is recommended that resistance is verified by a
second method (e.g., broth microdilution) [34].
Tigecycline has been approved for the treatment of soft tissue and intra-
abdominal infections. Because of a low resistance rate of enterobacteriaceae
in vitro, the drug has been used for other indications (off label), e.g.,
pneumonia or blood stream infections. Some studies indicate a
higher mortality in infections treated with tigecycline than by com-
parator antibiotics, and in 2010 the FDA issued a warning on the
use of tigecycline [35, 36]. However, when studies focusing on
approved indications for tigecycline were analyzed in a meta-analysis
from 2012, the use of tigecycline was not associated with a signif-
icantly higher mortality than comparators [37].
430 Bacterial Infections and Drug Resistant Pathogens (H Wisplinghoff, Section Editor)

With standard dosing (50 mg twice a day), peak serum concentrations

reach 0.50.9 mg/L; concentrations in epithelial lining fluid and urine are
much lower [38]. For this reason, tigecycline should not be used as
monotherapy for blood stream infections (BSI), pneumonia, or urinary
tract infection (UTI). A higher dosage schedule (2x 75100 mg/day)
could be useful for infections with isolates that have tigecycline
MICs of 90.5 mg/L. Several studies report on the use of tigecycline for
carbapenem resistant Klebsiella spp. (mostly KPC), either as monotherapy,
or in combination with gentamicin, colistin, or a carbapenem [3941]. In
BSI by KPC producing K. pneumoniae, combination therapy of tigecycline
with a second antibiotic was associated with lower mortality than mono-
therapy [30, 31, 42].
Aminoglycosides like gentamicin, amikacin, or tobramycin are protein
synthesis inhibitors and have a rapid bactericidal effect against most gram-
negative aerobic bacteria. Among carbapenemase producers (except NDM),
the resistance rate is lower than for many other antibiotics (e.g., ciproflox-
acin), but depends on the local epidemiology. Both gentamicin and
amikacin have been used in studies on treatment of CRE. There is no good
evidence to use aminoglycosides as monotherapy (mortality ranging from
6.3 % to 80 %) [42, 43], except possibly for UTI. For combination therapy,
the results vary considerably [42, 43, 44]. Nephrotoxicity and ototoxicity
are serious side effects associated with the use of aminoglycosides. Thera-
peutic drug monitoring (trough drug levels) should be done in all patients
if aminoglycosides are applied.
Fosfomycin is an old antibiotic that has been rediscovered recently because
of its low rate of resistance in MDR gram-negatives [18]. It belongs to the
class of phosphonic antibiotics, inhibiting cell wall biosynthesis, and is
bactericidal against most enterobacteriaceae isolates. Fosfomycin has a very
small molecular mass, good tissue penetration, and reaches high concen-
tration in serum and cerebrospinal fluid, especially in inflamed meninges
[45]. It reaches high urinary concentrations, which make it a good choice
for the treatment of UTI. There is an oral preparation (fosfomycin-
trometamol), which is only approved for the treatment of uncomplicated
UTI in women; and an intravenous preparation (fosfomycin-disodium) for
systemic infections.
There is considerably less data on susceptibility and treatment of CRE
infections using fosfomycin than other antibiotics. From the available data,
it has a low resistance rate in carbapenem-resistant E. coli [22], with higher
rates for K. pneumoniae, E. cloacae, or Proteus spp. It was tested susceptible in
a study on KPC K. pneumoniae in 92.6 % of isolates [46].
Except for uncomplicated UTI in women, fosfomycin should not be
used as monotherapy because of the possible development of resistance.
This has mostly been demonstrated in vitro, but has also been observed
during treatment of infections, even though less frequently. From the
little data that is available, the development of resistance in vivo seems
to occur more frequently in infections by P. aeruginosa or K. pneumonia,
Treatment of Infections Hamprecht and Gttig 431

than in E. coli [47]. In a recent study on treatment of carbapenemase

producing gram-negatives (including P. aeruginosa), fosfomycin treat-
ment was successful in 56.5 % (defined by the resolution of all signs of
infection at day 14), and the microbiological eradication rate was
65.2 % in the subgroup of K. pneumoniae infection [48].
Because of its high sodium content (1 g contains 14.5 mmol Na+),
hypernatriemia, and hypokaliemia can occur; electrolytes should therefore
be monitored in all patients receiving fosfomycin.
Ciprofloxacin is the quinolone with the highest activity against enterobacte-
riaceae. Co-resistance to ciprofloxacin is high in CRE (975 % in the study of
Livermore et al.) [22], since many CRE isolates harbor genes encoding
quinolone resistance, such as qnr. For this reason, there is not much data on
the treatment of CRE using ciprofloxacin or other quinolones. Studies on
treatment in infections with ciprofloxacin-susceptible, non-CRE isolates show
a good clinical response in UTI, pneumonia, and bacteremia [49]. If tested
susceptible in vitro, ciprofloxacin is likely a valuable agent for CRE infections.

Other agents: chloramphenicol, minocycline, nitrofurantoin

Chloramphenicol, minocycline and nitrofurantoin are non--lactam
agents which are rarely used for the treatment of enterobacteriaceae
(except nitrofurantoin in uncomplicated UTI). Less than 25 % of
CRE isolates were tested susceptible to these agents in a study from
2011 [22], and there is practically no data on treatment of CRE
infections using these drugs. Furthermore, minocycline and chlor-
amphenicol are not available in some countries [50]. Nitrofurantoin
is only approved for the treatment of uncomplicated UTI in women.
In this case, nitrofurantoin therapy might be considered when the
causative bacterium has been tested susceptible.

-lactam antibiotics

Depending on the type of carbapenemase, some carbapenemase producing
enterobacteriaceae exhibit imipenem, meropenem, or doripenem MICs in
the intermediate or even susceptible range (weak hydrolyzing activity, e.g.,
OXA-48). Data from human pharmacokinetic/pharmacodynamic (PK/PD)
studies show that higher serum concentration (94 mg/L) can be reached
over several hours using high dose meropenem (2 g every 8 hours), com-
bined with a prolonged infusion time (3 hours instead of 30 minutes) [51].
For this reason, carbapenems might be a treatment option in infections
with isolates that have carbapenem MICs of 4 mg/L. Unfortunately, there
is only little data from few patients treated by carbapenem monotherapy in
CRE infections; three different studies showed a mortality ranging from
21 % to 58 % [32, 41, 52]. Daikos and Markogiannakis concluded from a
collection of published cases that the mortality was lower for infections
432 Bacterial Infections and Drug Resistant Pathogens (H Wisplinghoff, Section Editor)

with CRE that had a MIC of 4 mg/L [53], which is in line with available
PK/PD data.
In several studies, carbapenems have been used in combination with
colistin, gentamicin, tigecycline, or other antibiotic agents, and a lower
mortality was noted in patients receiving carbapenem containing combi-
nation schemes, compared to monotherapy or carbapenem-sparing com-
bination treatment [32, 42, 54]. In a recent study from Greece, the lowest
mortality was observed in patients infected by carbapenem-resistant
K. pneumoniae with a MIC of 8 mg/L, who were on combination therapy
with at least two active antibiotic agents, one of which was a carbapenem

Temocillin is a derivative of the carboxypenicillin ticarcillin. It is one

of the older antibiotics that are currently being rediscovered and is
available only in a few countries (e.g., UK, Belgium) [50]. Compared
to other -lactams it is relatively stable to ESBL- and AmpC -
lactamases, but less stable to carbapenemases [55]. There are no
clinical breakpoints by CLSI or EUCAST, only the British Society for
Antimicrobial Therapy (BSAC) issued breakpoints for the interpreta-
tion of temocillin susceptibility testing. Only 4/81 (5 %) CRE iso-
lates were tested susceptible to temocillin using the BSAC breakpoint
for systemic infections (8 mg/L), but 26/81 (32 %) were suscepti-
ble using the BSAC breakpoint for urinary tract infections (32 mg/L)
[22]. Temocillin might be an alternative to other drugs in UTI, but there
are no current studies on the use of temocillin in CRE infections.
Aztreonam is a monobactam which is not hydrolyzed by MBLs.
Therefore, it could be a treatment option in infections by NDM-,
VIM-, IMP-, or GIM-producing organisms; but often isolates co-
harbor ESBL or AmpC -lactamases, which render aztreonam inac-
tive [14, 15]. Currently, there is a lack of data on treatment of CRE
infections using aztreonam, so its value cannot be established at the
A new development is the combination of aztreonam with the -
lactamase inhibitor avibactam (see below), which is effective also when
ESBL or AmpC is co-expressed; but so far there are no results from clinical
studies available.

Monotherapy versus combination therapy

Combination therapy has been a controversial issue for years [56], with
evidence that a number of traditionally used combination regimens
(e.g., -lactam plus aminoglycoside in P. aeruginosa infection), offer no
advantage over monotherapy with a -lactam, if the latter is tested
susceptible [57]. Furthermore, combination therapy can result in addi-
tive toxicity, especially when aminoglycosides or colistin are used [56].
For CRE, combination therapy has been widely applied, but at the
Treatment of Infections Hamprecht and Gttig 433

moment the evidence level for this practice is low, as most data has
been obtained from case series and observational studies. However, a
number of studies have shown a statistically significant lower mortality
in patients receiving combination therapy, with tigecycline plus genta-
micin, tigecycline plus colistin, or carbapenem with either colistin or
tigecycline, being the most common combinations [30, 31, 42].
Combination therapy of a non lactam and a carbapenem was
associated with a lower mortality over monotherapy, or combination
therapy excluding carbapenems, in several studies from the USA, Greece
and Italy [30, 32, 42]. However, the benefit of adding a carbapenem is
restricted to infections with an isolate that has a carbapenem MIC of
8 mg/L [32].
In summary, in the case of a serious infection by a CRE isolate and given the
lack of effective antibiotics available, combination therapy should be considered.
A carbapenem should be part of the combination regimen if a MIC 8 mg/L is

Future developments
Several new antibacterial agents with activity against CRE are currently being
developed. Of those, plazomicin, eravacycline and avibactam have entered
phase II and phase III trials.
Plazomicin is an aminoglycoside, a derivative of sisomicin, which is
less affected by common aminoglycoside-modifying enzymes and there-
fore frequently remains susceptible even in gentamicin-resistant, or
amikacin-resistant isolates [58, 59]. However, NDM-producing isolates
are commonly resistant to plazomicin because of the presence of other
aminoglycoside resistance genes (e.g., armA, rmtC) [60]. Plazomicin has
rapid bactericidal activity against enterobacteriaceae, with the exception
of Proteus spp. [59]. Currently, a phase III study on plazomicin versus
colistin combination therapy for nosocomial pneumonia due to CRE is
Avibactam is a -lactamase-inhibitor which is active against ESBL, AmpC,
and KPC enzymes, but not against MBLs. Avibactam is usually combined with
either ceftazidime, aztreonam, or ceftaroline [61, 62]. In a large collection of
enterobacteriaceae, ceftazidime-avibactam was shown to be active against most
-lactamase-producing isolates, with the exception of NDM [63]. The
ceftazidime-avibactam combination is currently being evaluated in phase III
Eravacycline is a fluorocycline, a tetracycline derivative, which shows
good activity against ESBL-, and carbapenemase-producing enterobacte-
riaceae. It is not affected by common tetracycline resistance mechanisms
and has demonstrated MICs that were 12 dilutions lower than tige-
cycline in most enterobacteriaceae isolates [64]. Eravacycline has com-
pleted a phase II study on complicated intra-abdominal infections and
has shown to be as efficacious as ertapenem [65]; phase III studies are
More experimental therapy strategies include: vaccination approaches
against essential bacterial outer membrane proteins; or the development of
so-called anti-ligands, which represent peptides that tightly bind to bacterial
434 Bacterial Infections and Drug Resistant Pathogens (H Wisplinghoff, Section Editor)

proteins, thereby blocking their function [66, 67]. However, none of these
substances have entered clinical studies as yet.
The therapy of infections with CRE is challenging because of the limited
number of active antibiotic agents and the scarcity of good evidence for any
treatment regimen. The therapy should be adapted to the individual case, taking
into account the focus of the infection, the results of antimicrobial susceptibility
testing (preferably MIC data), and PK/PD data. The use of tigecycline or ami-
noglycosides as monotherapy is discouraged. Except for uncomplicated UTI,
fosfomycin should also not be used as a single agent.
Combination therapy with 2 active agents could improve the outcome of
CRE infections. Imipenem or meropenem should be incorporated into com-
bination therapy when the carbapenem MIC of the infecting CRE is 8 mg/L. In
the case of meropenem, high dose therapy administered by a prolonged infu-
sion regimen is recommended. If colistin is used, higher daily doses in combi-
nation with a loading dose are likely advantageous.
A few new drugs for the treatment of CRE infections are in development,
but most of them are not likely to be available outside of clinical studies for the
next 5 to 10 years. For the time being, we will have to make more efforts to
contain the dissemination of CRE, gather more evidence for the best treatment
strategies for CRE infections, and use the existing antibiotics prudently.

Compliance with Ethics Guidelines

Conflict of Interest
Axel Hamprecht received a grant from Pfizer and payment for an educational presentation by MSD.
Stephan Gttig has no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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