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Title Listeriosis in Hong Kong
Author(s) Lam, Kwok-wai;g—WP
Citation
Issued Date 2012
URL http://hdl.handle.net/10722/173738
Rights Creative Commons: Attribution 3.0 Hong Kong License
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Listeriosis in Hong Kong
By
Lam Kwok Wai
This work is submitted to
Faculty of Medicine of The University of Hong Kong
In partial fulfillment of the requirements for
The Postgraduate Diploma in Infectious Diseases, PDipID (HK)
Date: 19-06-2012
Supervisor: Dr Samson Wong
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Declaration
I, Lam Kwok Wai, declare that this dissertation represents my own work and that it
has not been submitted to this or other institution in application for a degree, diploma
or any other qualifications.
I, Lam Kwok Wai, also declare that I have read and understand the guideline on
“What is plagiarism?” published by The University of Hong Kong (available at
http://www.hku.hk/plagiarism/) and that all parts of this work complies with the
guideline.
Candidate: Lam Kwok Wai
Signature:
Date:
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Acknowledgements
Dr Wong, Samson Sai Yin. Assistant Professor, Dept of Microbiology, Li Ka Shing
Faculty of Medicine, University of Hong Kong
Dr Christopher Lai, Dept of Microbiology, Queen Elizabeth Hospital.
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Abstract
Background
Listeria monocytogenes is an uncommon but important cause of bacteremia and
meningitis in Hong Kong. Our aim is to study the local epidemiology, clinical
features, antibiotic susceptibility pattern and outcome of Listeriosis in Hong Kong.
Methods
A retrospective study was carried out in two local microbiology laboratories in Hong
Kong. All patients with positive Listeria monocytogenes isolates in any clinical
specimens over the past 10 years were included.
Results
A total of 31 patients with 41 Listeria monocytogenes isolates were identified in our
series. Fever was the most common presentation (80% of patients). There were 20
cases of bacteremia, 3 cases of meningitis and 3 cases of bacteremic meningitis. In
non-perinatal cases, most of the patients had underlying medical conditions. The most
common associated co-morbidity was underlying malignancy. The mortality of
Listeria monocytogenes infection was 24%. The stillbirth rate in pregnant women was
40%. 27% of patients were documented to have consumed dairy products or other
high-risk foods. There were 2 isolates intermediate sensitivity to penicillin while all
tested isolates were 100% sensitive to ampicillin, Septrin and vancomycin. Mortality
was not associated with appropriate antibiotic use, use of immunosuppressants or
advanced age.
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Conclusions
Human Listeriosis is a rare but important infection in Hong Kong. It particularly
affects newborns, pregnant women and immunocompromised hosts, and carries a high
risk of mortality and stillbirth.
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Introduction
Human listeriosis is an uncommon bacterial infection caused by Listeria
monocytogenes, which is a facultatively anaerobic, nonsporulating, catalase-positive,
oxidase-negative, short, nonbranching, beta-hemolytic gram-positive organism (1).
This organism can be found in soil, vegetation and animals. The main route of
transmission is through consumption of contaminated food. Many foods are
contaminated with Listeria monocytogenes, with variable detection rates from 15% to
70%, in raw vegetables, raw milk, cheese and meats (2). However, infection can
rarely be transmitted from infected animals to humans, as well as between humans
(3). It is also worth noting that the organism has been isolated in around 5% of stool
from healthy individuals (4). In neonatal infections, Listeria can be transmitted from
mother to child, in utero or during passage through the infected birth canal.
Listeria monocytogenes primarily affects immunocompromised hosts, individuals at
the two extremes of age and pregnant women. Bacteremia and meningo-encephalitis
are two common presentations in these individuals while healthy adults only
experience self-limiting gastroenteritis. Nevertheless, Listeria has the second highest
mortality rate (about 20%) among food-borne infections in the United States (5).
In the United States, the incidence of human listeriosis in 2007 was 0.3 per 100,000
persons (6), whereas in Europe, the incidence in 2008 was 0.31 per 100,000 persons
(7). In both series, the incidence has been decreasing in the recent few years.
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After listeriosis was made a notifiable disease in Hong Kong in July 2008, the
Department of Health has recorded approximately 10 cases of listeriosis in Hong
Kong annually (8). While most of the epidemiology and clinical studies about
listeriosis were done by Western countries, local studies are lacking.
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Objectives
Our aim is to study the local epidemiology, clinical presentations, antibiotic
susceptibility pattern and prognostic factors of listerosis.
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Methods
In this retrospective case series, all patients with positive Listeria monocytogenes
isolates in any clinical specimens were included. Data was collected from two local
microbiology laboratories, those of Queen Mary Hospital (QMH) and Queen
Elizabeth Hospital (QEH). The study period was from Jan 2004 to Jul 2011 in QMH,
and Jan 2001 to Jul 2011 in QEH. Demographic, clinical and laboratory data was
retrieved from Electronic Patient Record (ePR) and clinical notes. Appropriate
antibiotic usage is defined as either that the patient received an antibiotic to which the
organism showed in-vitro sensitivity or that the antibiotic was substituted by one to
which the organism showed sensitivity before the patient deteriorate clinically.
Hematological and biochemical results were those from closest to the day on which
the positive specimens were sent, if not from the same day.
Mortality is defined as all-cause mortality during the period of the index
hospitalization for listeriosis. Poor clinical outcome is defined as stillbirth in pregnant
women or any cause of mortality of the index hospitalization.
Statistical analysis was performed by using the International Business Machines
Statistical Package for Social Sciences (IBM SPSS) version 20.0 for Windows. The
mean ± standard deviation (SD) was calculated for continuous variables. Chi-square
(χ 2) test was used to test for the significance of the association between the
independent (predictor) and the dependent (outcome or mortality) variables in the
categorical variables. Student t test was used to determine the continuous variable that
will predict the outcome. The level of significance is defined as P < 0.05.
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Results
A total of 31 patients with 41 Listeria monocytogenes isolates were identified. 21
cases were from QMH and 10 cases were from QEH. Fewer cases were identified in
the recent three years (Table 1). More cases were identified between June and October
(Table 2). There were 13 male cases and 18 female cases. The most prevalent age
group was 31-40 years old, with 8 cases. 10 cases were aged above 60 (Table 3).
Among the 41 clinical isolates, there were 27 blood cultures, 6 cerebrospinal fluids, 1
eye swab, 2 placental swabs and 5 genital specimens including high vaginal swabs
and endocervical swabs. For 2 cases, clinical specimens were sent from private
hospitals and clinical information could not be retrieved. As a result, the clinical
information of 29 out of all patients was analyzed
Table 1 Number of cases by year in different hospitals
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Table 2 Number of cases by month
Table 3 Number of cases by age
Only 8 out of 29 patients (27%) were documented to have consumption of dairy
products or other raw foods.
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Antibiotic susceptibility pattern among 41 specimens was shown in Table 4. Of note,
there were two isolates showing intermediate susceptibility towards penicillin.
Listeria was found to be 100% sensitive to ampicillin, Septrin and vancomycin.
Table 4 Antibiotic susceptibility
Newborn listeriosis
There were 3 cases of newborn listeriosis. One case of Listeria bacteremia was a
baby born at full term by Cesarean section. He was put on Augmentin on induction
and then Penicillin. He died soon after birth before positive blood culture growing
Listeria monocytogenes was available. This was the case in which Listeria showed
intermediate susceptibility to penicillin. Another case of Listeria bacteremia was an
extreme preterm baby born at 26 weeks of gestation. She was given penicillin and she
survived the infection. However, due to other complications of extreme prematurity,
like intra-ventricular hemorrhage, she was found to have developmental delay in
subsequent follow-up. For another baby born at 29 weeks of gestation by normal
spontaneous delivery, Listeria monocytogenes was isolated in the eye swab. He was
given ampicillin empirically and he survived with full recovery. The mortality rate of
newborn listeriosis was 33%.
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Listeriosis in pregnant women
There were 5 cases of listeriosis in healthy pregnant women, aged 34-39. There was
1 case of repeated Listeria bacteremia in a pregnant woman with gestational diabetes
mellitus. She was put on penicillin and she gave birth to a healthy baby at full term.
There were another 2 cases of Listeria bacteremia. In one of them, the patient was
given ampicillin, but resulted in abortion. Listeria monocytogenes was isolated in the
placental swabs in two cases. In one of them, amoxicillin was given, but resulted in
abortion. There were no maternal deaths. Stillbirth rate was 40%.
Non-perinatal patients
There were 21 cases of listeriosis in non-perinatal patients, with age ranging from 8
months to 90 years. Bacteremia was the clinical manifestation in 18 cases (86%), with
the organism also isolated in the cerebrospinal fluids (CSF) in 3 of them. In the
remaining 3 non-bacteremic cases, Listeria monocytogenes was isolated in the CSF in
2 cases and in the endocervical swab in 1 case.
There was a case of a 71-year-old lady receiving target therapy for carcinoma of
lung who suffered from Listeria meningitis and bacteremia. She was put on ampicillin
initially but she developed an allergic rash soon after initiation of the antibiotic. The
antibiotic was switched to vancomycin and then linezolid, followed by poor clinical
response and persistent fever. Eventually she was given intravenous Septrin with good
clinical response and full recovery from the infection.
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Another case in which Listeria showed intermediate susceptibility to penicillin was
an 18-year-old gentleman with underlying systemic lupus erythematosus (SLE) had
Listeria meningitis. He was initially treated with penicillin. The antibiotic was
subsequently switched to ampicillin after the antibiotic susceptibility results were
available. He made a full recovery from the infection.
Nearly all of the patients (19 out of 21) had underlying chronic medical conditions or
some sort of immunodeficiencies (Table 5).
Table 5. Comorbidities of non-perinatal patients
The most common associated comorbidity was malignancy, including 2 cases of
hematological malignancy and 6 cases of solid organ malignancy. For patients taking
immunosuppressants, there were 5 cases of rheumatological diseases, 1 case of IgA
nephropathy and 1 case of nephrotic syndrome. Immunosuppressants included
prednisolone, azathiprine and mycophenolate mofetil (MMF).
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One patient, aged 8 months with good past health, suffered from Listeria meningitis
and bactermia. The baby survived with full recovery after appropriate antibiotic
treatment.
There as one patient of whom the clinical record could not be traced.
Clinical presentation
All newborn patients with listeriosis presented with fetal distress. Fever was the
most common presentation, which happened for 20 out of 25 patients (80%).
Gastrointestinal symptoms were present for 6 patients (24%). Central nervous system
symptoms were present for 5 patients (20%), namely confusion and mental dullness.
There was a case of listeriosis for which the diagnosis was made long after
hospitalization. A 65-year-old man with alcoholic cardiomyopathy initially presented
with ventricular fibrillation and was stabilized with medical treatment. He developed
fever around three weeks after hospitalization and blood culture grew Listeria
monocytogenes. He was given tetracycline according to the sensitivity result. He died
around one week after tetracycline was started.
For the use of antibiotics, most patients either received appropriate antibiotics
empirically or were switched to an appropriate antibiotic according to the sensitivity
result before clinical deterioration. Yet, there were a few exceptional cases.
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A 69-year-old gentleman with metastatic carcinoma of colon was admitted for
decreased general condition. He was not given any antibiotics and he died on the
second day of admission. Blood culture taken on the day of admission grew Listeria
monocytogenes.
A 55-year-old lady with metastatic carcinoma of breast was admitted for fever and
decreased general condition. She was given Zinacef and Flagyl empirically. Blood
culture later grew Listeria and the same antibiotic regimen was continued for a course
of seven days. She made a full recovery from the infection and managed to attend the
outpatient clinic around one month later. Subsequent clinical notes were not available.
Mean total white cell, neutrophil and lymphocyte counts were 14.5 (+/- SD 7.9),
11.6 ( +/- SD 6.3), 1.5 (+/- SD 1.8) x 109 cells per liter respectively. 57% of the
patients had lymphopenia (lymphocyte count less than 1.0 x 109 cells per liter) and
86% of patients had neutrophilia (neutrophil count greater than 5.8 x 109 cells per
liter).
All-cause mortality was 24% (7 deaths in 29 patients). 31% (9 of 29 patients) of the
patients had poor clinical outcome. Factors including age, whether the patient had
received appropriate antibiotics and use of immunosuppressants were included in the
calculation to determine if any of these was associated with mortality or poor clinical
outcome.
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Concerning the choice of antibiotics, 50% (2 out of 4) of patients who had not
received appropriate antibiotics had a poor clinical outcome whilst 30% (7 out of 24)
of patients who had received appropriate antibiotics had a poor clinical outcome. The
difference is not statistically significant ( p = 0.40).
Excluding perinatal cases, for patients who were taking immunosuppressants, 18%
(2 out of 11) of them died from the infection. The percentage was lower than that for
patients who were not taking immunosuppressants, which was 45% (4 out of 9). The
difference is not statistically significant ( p = 0.20).
Regarding age, after excluding perinatal cases, the mean age of patients who died
from the infection was 64 years old while the mean age of patients who survived the
infection was 55 years old. The difference is not statistically significant ( p = 0.09).
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Discussion
In this review, a total of 31 patients were enrolled in epidemiological and
microbiological study and 29 patients were enrolled in the study of clinical features
and outcome. Although the study period in different hospitals is not identical, we
could appreciate that the incidence of listeriosis peaked at the years 2007 and 2008
and ran a decreasing trend afterwards. This is consistent with the overall incidence in
Hong Kong (8) and Western countries (6,7). Regarding seasonality, more cases were
identified between July and October, which is again consistent with that in Western
countries (7) and other food-borne infections. The male-to-female ratio of patients
was 0.72. This ratio varies among different age groups. More females were affected
by Listeria infection in younger age groups (especially 31-40 years) because of the
higher prevalence of infection in pregnant women. 8 out of 29 patients were
documented to have consumption of dairy products or other raw foods in the clinical
notes. However, in more detailed epidemiological studies done by Department of
Health, half of the patients with reported human listeriosis recalled consumption of
dairy products or other high-risk foods (8). In our series, around one-third of patients
were aged greater than 60 years, compared with more than half in Western countries
(7).
25 out of 29 patients had severe Listeria infection, with the organism isolated in
blood cultures or CSF. In the other 4 non-severe cases, Listeria monocytogenes was
isolated in eye swabs, female genital tracts or gestational products. This correlates
well with our understanding that Listeria monocytogenes usually causes bacteremia
with or without meningitis. In a local study in Hong Kong, Listeria is a rare pathogen
causing bacterial meningitis, ranked the seventh comprising only 3% of 65 cases (9).
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This differs from the situation in Western countries. In a recent study in Europe,
Listeria ranked the third as a causative pathogen of adult bacterial meningitis, with
more than 16% in 278 cases (10).
In our case series, the most common comorbidity associated with listeriosis is
malignancy. In a recent study on the long-term mortality in patients with Listeria
monocytogenes meningitis, it was found that these patients had an increased risk of
death due to cancer in the first five years of follow-up. Besides, in the same age-
matched population at above 50 years of age, patients with Listeria meningitis had a
2-fold increase in risk of being diagnosed with cancer in early follow-up. The authors
concluded that patients with listeriosis in this age group should be actively screened
for underlying malignancy to improve long-term survival (11).
Neonatal Listeria infection was known to carry a high mortality of up to 50% (12).
In our series, the mortality rate of neonatal Listeria infection was 33%. Pregnant
women with listeriosis had a stillbirth rate of around 40% in our series, while in
earlier studies this rate was quoted to be around 20% (13). The mortality rate of non-
perinatal patients was 28%, which was similar to that according to textbooks (1).
It was not found that use of immunosuppressants affects the prognosis of patients
with listeriosis. In a study conducted in Finland (14), it was also found that patients on
immunosuppressive therapy did not die more frequently from listeriosis than those
with underlying diseases but not on immunosuppressive therapy.
In our study, patients receiving inappropriate antibiotics tend to have poor clinical
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outcome (50% vs. 30%). This difference did not reach statistical significance
probably due to small sample size. In our series, patients with older age tend to have
worse clinical outcome, and this is usually true for many types of infections.
For the case of listeriosis treated with one-week course of Zinacef and Flagyl, the
patient made a full recovery, was discharged and was then followed up in the
outpatient department for more than one month after discharge. Zinacef and Flagyl
are supposed to have no anti-Listeria activity and similar case reports or experience of
using these antibiotics to treat Listeria infection are lacking in the literature. Untreated
invasive listerosis is usually fatal, except for pregnant women who can deliver their
babies early enough so that they may be cleared of the infection. In experimental
animal models, spontaneous resolution of invasive listeriosis occurs (15). Some
strains of rats and mice are intrinsically resistant to the infection while others develop
sepsis and die following Listeria inoculation.
There was a mortality case of a patient with Listeria monocytogenes bacteremia
receiving tetracycline. Although the organism was tested to be sensitive to
tetracycline, the evidence or experience of using tetracycline to treat severe listeriosis
is lacking. As in other types of bacteremia, the tetracycline group of antibiotics is
usually not a first-line treatment.
There were two isolates showing intermediate susceptibility to penicillin and all
isolates were sensitive to ampicillin, Septrin or vancomycin, if the senstivitiy tests
were carried out. The baby, infected with Listeria monocytogenes with intermediate
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sensitivity to penicillin, was given Augmentin and then penicillin. He later died of
bacteremia. Another 18-year-old patient with had Listeria meningitis recovered with
ampicillin. Information about the clinical outcome of patients infected with Listeria
which show intermediate sensitivity to penicillin is lacking in the literature.
Therefore, when facing a strain of Listeria with intermediate sensitivity to penicllin,
whether one should treat with ampicillin or switch to another group of antibiotics like
Septrin remains uncertain.
Clinical specimens of penicillin-resistent Listeria monocytogenes are rare. A study
in the United States showed that 2.3% (2 out of 84) clinical isolates were resistant to
peniciilin, both of which were found decades ago (16). A more recent study in France
showed that there were no penicillin-resistant strains, as detected by disk diffusion
according to the breakpoints of European Committee on Antimicrobial Susceptibility
Testing (EUCAST), in more than 4,800 clinical isolates (17). However, the authors
did show a statistically significant increase in the minimal inhibitory concentration
(MIC) of penicillin and aminopenicillin in recent isolates. For other antibiotic
susceptibility patterns in this large study, the authors found that resistant rates were
very low (< 1%) for trimethoprim, tetracycline, erythromycin and ciprofloxacin (17).
More than 90% Listeria monocytogenes were found to be clindamycin-resistant in a
series (21). Listeria monocytogenes isolated from food products could be a totally
different story. Studies showed that up to 90% of Listeria monocytogenes found in
dairy-based food products were penicillin-resistant (18).
Septrin has been known to be a good alternative in treating patients with listeriosis
who were allergic to beta-lactam (19). In a case report, there was clinical cure after
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adding Septrin to a patient with Listeria meningitis who failed to respond to
ampicillin plus gentamicin, due to its relatively good cerebrospinal fluid penetration
and high intracellular concentration (20). This is similar to one of our cases of Listeria
meningitis in which the patient who developed allergic reaction to ampicillin and
failed to respond to vancomycin and even linezolid subsequently did respond well to
Septrin and made a full recovery.
The small sample size is a major limitation of this study. Other limitations include
the retrospective design and limited geographic scope.
Larger local epidemiological studies are needed for us to have a better understanding
of the clinical features and antibiotic susceptibility pattern of human listeriosis in
Hong Kong and to facilitate the study of the prognostic factors. Furthermore, longer
follow-up duration is necessary to study whether there is truly an increased risk of
developing malignancy or other associated medical conditions for listeriosis.
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Conclusion
Human listeriosis is a rare but important infection in Hong Kong. It carries a
mortality rate of 24%. Intake of contaminated dairy products or other high-risk foods
is a well-known route of transmission. Neonates, elderly, pregnant women and
immunocompromised patients are at higher risks of the infection. Common
presentations are bacteremia with or without meningitis and stillbirth in pregnant
women. Penicillin and ampicillin are reliable antibiotics for treatment while Septrin is
a good alternative in case of IgE-mediated allergic reactions towards beta-lactam
antibiotics. Even if the organism is shown to have good in-vitro susceptibility to other
antibiotics, there is not enough clinical experience to recommend routine usage,
especially when treating severe infection
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