Abstract
Extended Spectrum Beta-Lactamase-producing Enterobacteriaceae (ESBL-PE) are an
emerging concern in public health. Antimicrobial use, hospitalization and foreign travel
are associated with human carriage of ESBL-PE. Duration of carriage with ESBL-PE can
vary. The main objective of this thesis is to provide an overview of the current scientific
knowledge on persistence of ESBL carriage in humans. In addition, risk factors for
duration of ESBL carriage will be described. After a literature search, 14 studies met the
criterion that duration of ESBL-PE was assessed. Eight studies were conducted in
patients, two in NICU patients, and four in non-patients (travelers, adopted children,
medical students). Approximately half of adult (hospitalized) patients carried ESBL-PE
after 6 months (range 33-53%). After 12 months, this percentage was around 25%.
Median carriage time was reported from 98 days till more than 9 months. For a minority
of patients carriage time was more than three years. Prolonged carriage with ESBL-PE
was associated with outpatient oral use of antibiotics, urine catheters, chronic wounds,
immobility and percutaneous gastrostomy, E. coli phylogroup B2, and CTX-M group 9. In
NICU patients, median carriage time was 12.5 months, but carriage persisted after 12
months for 5% of individuals. Prolonged duration was observed for K. pneumonia or K.
oxytoca species compared to S. marcensens, antibiotic treatment and caesarian section.
Of travelers, 24% carried ESBL-producing E. coli after 3-8 months. Mean carriage time
for 22 adopted children from Mali was 9 months. Out of 41 Chinese medical students,
68% remained colonized for 4 months. Results vary greatly and are hard to compare or
generalize for many reasons such as small sample size, different definitions for duration,
persistence and clearance, absence of molecular information, selection bias, and global
differences. A longer duration of carriage with ESBL-PE might influence the risk of
carriage with ESBL-PE for the patient itself and transmission to household members and
the general population. Routine screening and/or contact restriction is suggested for
previously ESBL-PE positive patients. Perhaps focus should be more on prevention of
transmission than on clearance, because clearance is hard to accomplish. To estimate
duration of carriage with ESBL-PE in the general population, large studies are needed.
1
Introduction
Infections with antimicrobial resistant bacteria are associated with high mortality,
morbidity, and health care costs (1). Antimicrobial use is generally regarded as one of
the main reasons for selection and transmission of antimicrobial resistant bacteria (2).
Beta-lactam antimicrobials are widely used in human medicine. Bacterial resistance to
beta-lactams is attributable to at least three mechanisms: inaccessibility of drugs to their
target (penicillin-binding proteins), alterations of the drug target, and/or inactivation of
the drugs by beta-lactamases. The predominant mechanism of beta-lactam resistance in
Gram-negative bacteria is the production of (Extended-Spectrum) Beta-Lactamases,
which inactivate beta-lactams by hydrolysis (3).
Enterobacteriaceae that produce Extended Spectrum Beta-Lactamases (ESBL) are an
emerging concern in public health. The major ESBL-producing Enterobacteriaceae (ESBLPE) involved in human infections are Escherichia coli and Klebsiella pneumonia (4).
ESBLs cause resistance to different beta lactam antimicrobials, including penicillins and
cephalosporins (5). Most regularly observed ESBL genes belong to the TEM, SHV, and
CTX-M groups (6). Occurrence of CTX-M group, specifically CTX-M-15 and CTX-M-14, has
increasingly been reported over the past decade (7). The genes encoding for ESBLs are
often located on plasmids, which can be transferred within and between different
bacterial species. Furthermore, coexistence with other types of antimicrobial resistance
occurs (1).
Besides antimicrobial use, hospitalization and foreign travel are known risk factors for
human carriage of ESBL-PE (8, 9). In addition, ESBL-PE have been reported in healthy
and diseased companion animals (10, 11), wildlife (12), vegetables (13), drinking water
(14), and sewage (13). Apart from the complex dynamics on how humans can become
carriers of ESBL-PE, the duration and persistence of human ESBL carriage can vary
greatly (15, 16). Until now, determinants influencing the duration and persistence of
carriage are not well understood. Although some research has been pursued on duration
and persistence of ESBL carriage and the influence of different risk factors, most of the
results are not comparable due to different definitions of persistent carrier ship and nongeneralizable study populations. Once a person carries ESBLs, duration of ESBL carriage
is not only important for assessing the risk of infection, but very likely also for the risk of
transmission of ESBLs from high risk groups into the general population as well.
Guidelines on surveillance regarding ESBL carriage should be made on extended
knowledge, including the duration of ESBL carriage.
The aim of this thesis is to provide an overview of the current scientific knowledge on
persistence and duration of ESBL carriage in humans. In addition, risk factors for
persistence and duration of ESBL carriage will be described as well. Consequently, the
gaps in the literature for obtaining a proper estimate for the duration of ESBL carriage
2
under different circumstances will be explored and recommendations for future research
will be addressed.
3
Overview of literature
Literature was searched in Pubmed and Scopus. Keywords were (combinations of) ESBL,
Extended-Spectrum Beta-Lactamase, duration, colonization, persistence, carriage, fecal,
stool, long-term, after outbreak, after discharge, antimicrobial resistant. Reference lists
from studies found were also screened for additional relevant publications. Duration of
ESBL-PE had to be assessed as a criterion for inclusion. After this literature search, 14
studies met the criterion. Several studies have been conducted with the purpose to
estimate the duration of colonization with ESBL-PE. Some other studies had a different
main objective, but also assessed the duration of ESBL-PE. Since hospitalization is a
major risk factor for acquiring ESBL-PE (8), the majority of these studies is focusing on
hospital patients (n=10) (including Neonatal Intensive Care Unit (NICU) (n=2)).
Duration was assessed during hospitalization, after discharge or at readmission. Another
important risk factor is international travel (9), therefore some included studies were
exploring duration in travelers (n=2) or adopted children (n=1). Another study was
conducted on medical students and potentially also of higher risk due to contact with
colonized patients (n=1) (17, 18). The main findings regarding duration of ESBL-PE and
potential risk factors for prolonged duration are described for the different
subpopulations.
Adult patients
Most studies focusing on duration of carriage with ESBL-PE were performed in (former)
hospitalized patients. A study by Papst et al. (2012) showed that after three months, 22
out of 33 hospital patients (66.7%) were still positive for ESBL-producing E. coli and K.
pneumoniae (rectal swab, urine and throat). After six months, 17 out of 33 patients
(51.5%) were still positive (19). Titelman et al. (2014) found that fecal carriage was
common 12 months after clinical infection with ESBL-PE. Carriage was observed in 51
out of 61 patients (84%) after 1 month, 36 out of 61 (55%) after 3 months, 31 out of 61
(51%) after 6 months and 26 out of 61 (43%) after 12 months. At 12 months, 5 out of
26 carriers had previous negative samples. In 17 out 61 patients, ESBL was found in
another species or strain than originally found (20). In a study by Zahar et al. (2010) in
62 readmitted patients, 50% was still positive for ESBL-PE at readmission. Median
duration time of fecal carriage was 132 days (range 65-228). Within 3 months, 21
patients were readmitted of which 13 (62%) were still positive. Of 19 patients
readmitted after 3-6 months, 10 patients (53%) were positive. Seven out of 14 patients
(50%) were positive when readmitted between 6-12 months and only 1 out of 8 patients
(13%) readmitted after 12 months (21). All above three studies described around half of
the patients still colonized with ESBL-PE after 6 months. Apisarntharnarak et al. (2008)
found somewhat different results. From 24 patients, 8 patients (33%) remained
4
colonized with E. coli or K. pneumoniae after 6 months. Median duration of outpatient
colonization was 98 days (range 14-182) (22). Since sample sizes were small, the
differences found might be due to power issues.
In a study to determine the prevalence of ESBL-PE in high-risk units, 54 colonized
patients were screened with a rectal swab at a subsequent hospital admission. Out of 40
patients readmitted within one year after the initial positive culture, 15 (37.5%) was still
colonized. After one year, 2 out of 14 patients (14.3%) were positive when screened
again (23). In 14-year retrospective study in readmitted patients, 448 previously ESBLPE positive patients were tested at readmission of which 180 (40%) tested positive again
for ESBL-PE. Median time to clearance was 6.6 months (range 3.4-13.4 months). After
one year, 115 out of 448 patients (25.6%) were still carrier. After two years, 40 out of
448 patients (8.9%) still carried ESBL-PE (15). Zahar et al. (2010) and Reddy et al.
(2007) reported 13-14% of patients still positive for ESBL-PE after 12 months, while
Titelman et al. (2014) reported a percentage of 43%. However, the latter study is
conducted in solely patients with a clinical infection with ESBL-PE. Birgand et al. (2013)
found 25.6% still carrier after one year. This seems the most reliable estimate, since
sample size was large (n=448).
Another estimate sometimes used in assessing the persistence and duration of carriage
with ESBL-PE is median carriage time. After an outbreak in Sweden, carriage time was
screened in faeces and/or urine in 42 older patients (of which 27 patients related to the
outbreak) for approximately 5 years or until they presented three consecutive negative
cultures. Out of 39 patients, 16 died carrying ESBL-PE (median carriage time: 9 months
(range:0-38)). Median carriage time was 7.5 months (range 0-39) for 18 out of 39
patients (41%). (24). Apisarntharnarak et al. (2008) and Zahar et al. (2010) reported
shorter median duration time with 98 and 132 days respectively in both younger patient
populations.
Kola et al. (2007) investigated the role of surveillance and contact isolation in case of
ESBL-producing Enterobacteriacea. Also, 123 hospital patients were screened for
persistent ESBL-PE until 3 consecutive negative clinical and/or peri-rectal samples (one
week or more apart) were obtained in the absence of an antibiotic therapy directed
against ESBL-PE. Only 10 out of 123 patients (6.8%) were cleared from ESBL-PE. During
the 3-year follow-up period some patients remained positive throughout (25). This is
consistent with findings by Alsterlund et al. (2012), who reported that 5 out of 39
patients carried ESBL-PE for more than 3.5 years. PFGE revealed identical or closely
related isolates at the beginning and end of this period (24).
Several risk factors associated with prolonged carriage or clearance were described,
although all in small studies. Outpatient oral use of antibiotics was associated with
longer duration of colonization in one study (22). However, Alsterlund et al. (2012) did
5
not find this association. The remaining patient studies did not include quantitative data
on the use of antibiotics. Urine catheters, chronic wounds, immobility and percutaneous
gastrostomy were associated with carriage after 6 months (19). While another study
found no associations with clinical characteristics, type of micro-organism, severity or
illnesses (22). Carriage after 12 months was associated with E. coli phylogroup B2 and
CTX-M group 9 (20). Clearance was associated with having the first positive culture on a
screening sample only (no positive clinical sample) and having the first sample in a later
time span (2005-2011 vs 1997-2004). Species and whether the ESBL-PE seemed to be
imported or hospital-acquired was not associated with clearance (15).
There were quite some conditions which could have led to over- or underestimation of
carriage duration. Perirectal or rectal sampling could have led to under-detection
because of low sensitivity or incorrect (self-)sampling (20, 23, 25). In some studies
clearance was defined as three consecutive negative samples (24, 25). Negative samples
do not necessarily imply that clearance has occurred, since Titelman et al. (2014) found
carriers after 12 months with one or several negative previous samples. This might be
due to low numbers of ESBL resistant species present in the gut compared to susceptible
Enterobacteriaceae. And possibly ecological disturbances, resulting from the use of
antibiotics, might promote overgrowth which causes again a positive sample (20). This
could all have led to underestimation of duration. Overestimation also could have
occurred since sometimes intervals between discharge and readmission can be long (15,
21). In most of the described studies in patients no typing of genes, strains or plasmids
has been performed. Therefore it is unclear if ESBL-PE is persistent or newly acquired.
Another possibility is that more types and/or strains are present throughout. This
missing information is decreasing the reliability of the duration estimates.
Since admission of positive patients might introduce and disseminate ESBL-PE in health
care settings, several studies suggest routine screening and/or isolation procedures for
readmitted patients previously positive for ESBL-PE (15, 19, 21, 25). Caution is still
needed when samples are negative during screening (20). Retaining focus on
antimicrobial stewardship is also recommended (26).
NICU patients
Prevalence of ESBL-PE can be high in the NICU. Also, several outbreaks of ESBL-PE have
been described (27). Duration of fecal ESBL carriage was determined in 25 colonized
NICU patients 1,2,4,6,9, and 12 months after discharge in a Austrian Medical University
Hospital (28). Overall, 39% still carried the same ESBL producing strain (primary strain)
after 1 month, 16% after 6 months and 5% after 12 months. These percentages were
higher when additional strains, which were found in one third of the NICU patients, were
included. Since no plasmid typing has been performed, it cannot be ascertained whether
6
these strains were newly acquired or resulting from horizontal transfer of ESBL harboring
plasmids. A shorter duration of carriage was seen with Serratia marcescens compared to
carriage of K. pneumonia or Klebsiella oxytoca. Several household members were
sampled as well, they showed shorter duration of carriage. Lohr et al. (2013) found an
on average longer carriage time with CTX-M-15 producing K. pneumonia after discharge
from a NICU with an outbreak (29) (also when comparing to only Klebsiella spp. in the
Austrian study (28)). Measured every 1-3 months after discharge in 51 colonized NICU
patients up to 36 months, median carriage length was 12.5 months. Carriage length for
household members was also significantly shorter (2.5 months) than described by
Strenger et al. (2013). Both studies were similar in sampling method (fecal) and both
were conducted in NICU patients after discharge. However, comparing results of these
two studies results in different levels of persistence of carriage, characterized by
duration of carriage in NICU patients. This might be the result of power issues, since
sample sizes are modest to small in both studies.
Lohr et al (2013) found antibiotic treatment and caesarian section to be associated to
long-term fecal carriage. In the study by Strenger et al (2013) they did assess potential
risk factors like antibiotic treatment and feeding, but the sample size was too low to
estimate possible associations. Fecal carriage might be prolonged in infants due to their
developing intestinal flora (28). Besides, different circumstances such as antibiotic
treatment, parenteral feeding and caesarian section might alter the flora and therefore
vulnerable to prolonged carriage of ESBL-producing bacteria (29). Strenger et al. (2013)
recommends intensified hygiene precautions at readmission because of the possible long
carriage time. Although these studies give relevant insight in the carriage duration in
NICU patients, it is hard to draw any conclusions about median carriage time in the
general population since the study participants were so specific. Underlying health issues
might be of influence.
Non-patient studies
Prevalence of carriage with ESBL-PE can differ greatly over the world (30). In many
countries it is a major clinical concern. High prevalence is reported in especially Asia and
South America (30-32). Foreign travel is a risk factor for acquiring ESBL-PE. In a study
by Tängdén et al (2010), to determine foreign travel as a risk factor for acquisition of
ESBL producing Enterobacteriaceae, 21 healthy travelers which became colonized during
international travel were followed. After 6 months, 5 out of 21 (24%) travelers still
carried ESBL producing E. coli. None of the participants reported clinical infection or
antibiotic treatment (9). Tham et al (2012) reported similar results; 10 out of 41 (24%)
international travelers still carried ESBL-producing E. coli after 3-8 months (16). After 3
years, 4 out of 41 (10%) were still carriers. Approximately half of the persistent carriers
7
carried the same E. coli strain at the different follow-up points as in the beginning. It is
unclear whether other E. coli strains are newly acquired or a result from transfer trough
plasmids. If newly acquired, clearance of the primary strain may be assumed. This would
have resulted in overestimation of rate and duration of persistent colonization.
Unfortunately, sample size in both studies is small and there were only one or two
follow-up times. However, these studies imply that persistent colonization with ESBL-PE
in patients who have been traveling internationally does occur. This is of importance for
guidelines regarding traveling history in health care. More research is needed to
establish a proper time interval in which traveling is a concern in case of hospitalization,
especially in countries with a relatively low prevalence of ESBL-PE.
As international adoption is associated with higher carriage of ESBL-PE (33, 34), Tande
et al (2010) performed research on intrafamilial transmission of ESBL-producing E. coli
and Salmonella enterica Babelsberg among families of adopted children from Mali (35).
Adopted children were screened monthly till three consecutive negative samples. Mean
carriage time for 22 colonized children was 9 months (range 1-15 months). The authors
suggested routine screening for adopted children and their families. The risk of
transmission into health care settings can be present for a longer period of time, since
colonization can persist for more than one year.
In a Chinese study, duration of ESBL producing E. coli stool colonization of healthy
medical students was assessed (36). They were followed for 4 months and provided fecal
samples every 2 weeks. The median duration of colonization was 59 days (range 14112). Out of 41 medical students, 28 (68%) remained colonized during the 4 month
follow-up time. No association with gender or antibiotic treatment, which was used by 10
students during follow-up, were found. Since ESBL types and E. coli strains are not
known, duration time might be overestimated. Transmission from patient to student or
student to student might have occurred.
8
Discussion
For adult hospital patients, most studies reported that approximately half of them still
carried ESBL-PE after 6 months (range 33-53%) (19-22). After 12 months, a study by
Birgand et al. (2013) with a large sample size (n=448) reported 25.6%(15). Other
studies with considerable smaller sample sizes (n=33-62) found percentages from 13 till
43% (20, 21, 23). Median carriage time was reported from 98 days till more than 9
months, as where the latter was found in elderly people dying carrying ESBL-PE (21, 22,
24). Both Alsterlund et al. (2012) and Kola et al. (2007), although for a minority of
patients, reported carriage time for more than three years. Prolonged carriage with
ESBL-PE was associated with outpatient oral use of antibiotics, urine catheters, chronic
wounds, immobility and percutaneous gastrostomy, E. coli phylogroup B2, and CTX-M
group 9 (19, 20, 22). However, these associations were not consistently found
throughout the different studies. Clearance was associated with having the first positive
culture on a screening sample only (no positive clinical sample) and having the first
sample in a later time span (2005-2011 vs 1997-2004) (15).
Two studies with relatively small sample sizes (n=25, n=51) were available for NICU
patients. Median carriage time was 12.5 months by Lohr et al. (2013), while Strenger et
al. (2013) reported 5% carriage after 12 months. Prolonged duration was associated
with K. pneumonia or K. oxytoca compared to S. marcensens, antibiotic treatment and
caesarian section (28, 29).
Of travelers, 24% carried ESBL-producing E. coli after 3-8 months (9, 16). Mean carriage
time for 22 adopted children from Mali was 9 months (range 1-15 months) (35). Out of
41 Chinese medical students, 28 (68%) remained colonized for 4 months.
There is great variation in duration of carriage with ESBL-PE described by the different
studies. There are various reasons to consider for these differences found. In several
studies, sample size was small. This have led to uncertainty in the estimates found due
to power issues. Also, persistence and duration was determined by different definitions
and criteria. Sometimes intervals between first sampling and follow-up were really long,
which could have led to overestimation. Measurements below detection level, or errors in
sampling might have led to underestimation of the carriage period. Intermittent carriage
has also been reported. Strain typing was mostly absent in the majority of studies and
therefore it is unknown, when persistent carriage with ESBL-PE occurred, and whether
the same strain was detected. In many studies it cannot be excluded that a primary
strain was lost and that a new ESBL-producing strain might have been acquired.
On the other hand, when strain information is present results are still hard to interpret.
If a secondary strain but no primary strain was detected at follow-up, different scenarios
have to be considered illustrating the complexity of ESBL epidemiology. First, both
9
strains could have been present from the beginning, but not picked up consistently due
to the detection level. Second, plasmid transfer might have occurred from the primary to
the secondary strain. Third, the secondary strain could have been newly acquired.
Plasmid typing could have given some clearance on these issues, but this information is
unfortunately mostly absent. Shorter follow-up intervals could also give more insight in
the dynamics of the ESBL-PE strain present.
Most studies were conducted in hospital patients. Due to underlying conditions, such as
(chronic) illnesses and the use of antibiotics, duration might be prolonged compared to
non-patients. When results were originating from non-patient populations, there might
still be a higher risk for prolonged duration since other risk factors like international
traveling or contact with patients were present. Studies were conducted in different
countries with different circumstances. Policy regarding carriage with ESBL-PE might
differ from country to country, but also from hospital to hospital. Thus, study populations
were really specific and therefore hard to compare with each other, and also difficult to
generalize to the general population.
Patients with ESBL-PE colonization are at increased risk of ESBL-PE infection (23, 3739). A longer duration of carriage with ESBL-PE might influence the risk of carriage with
ESBL-PE for the patient itself, since infection from original gut colonization can occur for
a longer time span. In addition, within household transmission is often described (28,
29, 35, 40, 41). Duration of ESBL-PE carriage might also affect these dynamics.
Routine screening and/or contact restriction is suggested for previously ESBL-PE positive
patients. Surveillance during hospital stay might not be a feasible strategy, because
patients remain colonized for periods that surpasses the average duration of
hospitalization. Also, clearance does not seem as a common event. It seems more
relevant to focus on prevention of transmission instead on clearance, because clearance
is hard to accomplish.
It is clear that carriage with ESBL-PE can occur for a long period of time within patients.
To draw any conclusion about persistence and duration of carriage of ESBL-PE research
in the general population is needed. An extensive number of study participants will be
needed to begin with, due to the relatively low prevalence in the general population.
10
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