Clinical Listeriosis: What’s
New?
W F Schlech MD, FACP, FRCPC
Listeria monocytogenes
Organisms are widespread (ubiquitous)-- found in soil, food, water, sewage
L. monocytogenes is a food-borne pathogen (LISTERIOSIS).
Because of the organism’s exceptional abilities to cross three tight barriers,
the mortality rate is high (~30%).
(1) Intestinal barrier
(2) Blood-brain barrier (meningitis)
(3) Placental barrier (abortion)
Individuals exceptionally vulnerable to death via. listeriosis
(1) AIDS patients
(2) Chemotherapy patients
(3) Diabetics
(4) Organ transplant recipients
(5) Unborn
Healthy adults do show transient fecal carriage of L. monocytogenes.
Syndromes caused by Listeria monocytogenes
• Neonatal sepsis
• Neonatal meningitis
– ‘Early’
– ‘Late’
• Adult meningitis
– Rhombencephalitis
• Peritonitis
• Liver / spleen
abscess
•
•
•
•
•
•
•
Cutaneous disease
Pneumonia
Septic arthritis
Osteomyelitis
Endocarditis
Endopthalmitis
Febrile
gastroenteritis
Most distinctive syndromes...
• Neonatal sepsis and meningitis
• Sepsis in the compromised host
• Listeria rhombencephalitis**
**see good review by Oevermann et al.
Interdiscp Perspect Infect Dis, 2010
Suggestive features of Listeria
meningitis/rhombencephalitis in adults
• Presentation may be subacute
• Nuchal rigidity less common (only 80%
of adults)
• Movement disorders more common
(ataxia, tremors, myoclonus) (1520%)
• Seizures more common (25%)
• Fluctuating mental status common
• Positive blood cultures more likely
(75%)
Suggestive features of Listeria
meningitis/rhombencephalitis in adults
• CSF findings:
– Negative gram stain (60%)
– Glucose level not low (normal in >60%)
– Mononuclear cells predominate (30%
cases)
• Most importantly, less likely to be
immunocompromised
Recent Updates on Risk Factors
Non-Pregnancy-Associated Human Listeriosis
in England and Wales, 2001 to 2007
Increasing sepsis
in elderly
…Gillespie et al. J Clin Micro, 2009
Non-Pregnancy-Associated Human Listeriosis
in England and Wales, 2001 to 2007
• 780 cases
• Risk factors identified for sepsis vs
CNS disease:
– Presence of underlying disease (OR 3.1)
– Malignancies (OR 1.8)
– GI malignancy (OR 5.6)
– Use of cytotoxic drugs (OR 2.1)
– Rx to reduce acid secretion (OR 1.7)
…Gillespie et al. J Clin Micro, 2009
Gastric acidity as protective factor
…Gillespie et al. J Clin Micro, 2009
Gastric acidity as protective factor
-Increasing use of PPIs vs H2 receptor antagonists
possible association with increases of Listeria bacteremia?
…Gillespie et al. J Clin Micro, 2009
Non-Pregnancy-Associated Human Listeriosis
in England and Wales, 2001 to 2007
…Gillespie et al. J Clin Micro, 2009
Other papers at this meeting
• Mook et al, XVII ISOPOL, CO 26 – UK
update on risk factors
• Hershko-Clement et al, XVII ISOPOL,
CO 29 – Israeli experience
• Goulet et al XVII ISOPOL, CO 31 Estimation of incubation period ( CNS
median 10 days (2-19) vs perinatal 28
days (14-88). Has implications for
investigation of outbreaks.
Listeriosis in Scandinavia
• 289 cases reported from Norway
between 1977-2003
• 12 cases from 2 outbreaks
• 39 perinatal cases
• Perinatal cases stable 34/1,000,000)
• Non-pregnancy cases increased from
1.1 to 3.7/1,000,000
…Antal et al, Scand J Infec Dis, 2007
Listeriosis in Scandinavia
…Jensen et al, Eurosurveillance, 2010
“Quargel” Cheese Outbreak 2009-2010
• Sourmilk curd cheese
• Multinational
• Austria,Germany, and
Czech Republic
• Serotype 1/2a
• 2 clones
• 34 cases, adults
…Fretz et al, Eurosurveillance, 2010
Risk Factors, Clinical Features, and Outcomes
of Listeriosis in Solid-Organ Transplant Recipients:
•
•
•
•
Matched case-control study
30 cases in SOT (n=25,997)
15 transplant centers in Spain
No outbreaks or clusters noted
…Nuria et al. CID, 2009
Risk Factors, Clinical Features, and Outcomes
of Listeriosis in Solid-Organ Transplant Recipients:
…Nuria et al. CID, 2009
Risk Factors, Clinical Features, and Outcomes
of Listeriosis in Solid-Organ Transplant Recipients:
…Nuria et al. CID, 2009
Risk Factors, Clinical Features, and Outcomes
of Listeriosis in Solid-Organ Transplant Recipients:
• Manifestations of Listeria infection
–
–
–
–
–
–
Bacteremia
Meningoencephalitis
Spontaneous peritonitis
Pleural empyema
Liver abscesses
Brain abscesses
26 (86.7)
10 (33.3)
2 (6.7)
1 (3.3)
1 (3.3)
1 (3.3)
…Nuria et al. CID, 2009
Risk Factors, Clinical Features, and Outcomes
of Listeriosis in Solid-Organ Transplant Recipients:
• Antibiotic treatment
– Ampicillin 28 (93.3)
– Gentamicin 11 (36.7)
– TMP-SMZ 11 (36.7)
• Length of IV treatment, median days 21 (3–43)
• Length of treatment, median days 21 (7–56)
• Length of hospitalization, median days 30 (7–210)
• 30-Day mortality 8 (26.7)
…Nuria et al. CID, 2009
LM Meningitis in HIV
• Review of ~300 pts with SBM at a
Spanish hospital
• 32 HIV (+) (RR for SBM = 19x)
• Patients with HIV generally sicker
with their SBM
• LM a significant pathogen in this
setting
…Domingo et al. J AIDS, 2009
LM Meningitis in HIV
HIV (+)
N=32
HIV (-)
N=267
…Domingo et al. J AIDS, 2009
Risk factors for perinatal infection
• Review of 37 maternal-foetal cases
from Denmark, 1995 – 2005
• Incidence 4.8/10,000 deliveries,
higher then in previous 10 years
• 24 survivors, 12 abortion/stillbirths
• No differences in demographics
between groups although
abortion/stillbirths more common in
mothers with previous miscarriage
…Smith et al. Scand J Infec Dis, 2009
Risk factors for perinatal infection
• 80% of children born to mothers with
listeriosis developed neonatal
listeriosis (early infection)
• Typical skin rash was not noted in any
cases
• 23/24 infants discharged in good
health
• Only 4 women had known risk factors
for non-pregnancy related infection
…Smith et al. Scand J Infec Dis, 2009
Spontaneous abortion – the debate
continues !
• Case-control study from Iran
• 250 women with spontaneous abortion
vs 200 with normal term deliveries
from a single hospital 2002-2003
• Seropositivity using an IFA for antiListeria IgG (serotypes 1/2a and 4b)
from Euroimmune AG
…Jamshidi et al. Taiwan J Obs Gynec, 2009
Spontaneous abortion – the debate
continues !
…Jamshidi et al. Taiwan J Obs Gynec, 2009
Spontaneous abortion – the debate
continues !
…Jamshidi et al. Taiwan J Obs Gynec, 2009
Risk factors for mortality in
non-perinatal listeriosis
• 13 year retrospective cohort study
from passive surveillance in LA County,
California – 1992-2004
• 285 patients identified through LA
County laboratories
• Invasive isolates as well as stool
isolates during an outbreak
…Guevara et al. J Infec Dis, 2009
Risk factors for mortality in
non-perinatal listeriosis
…Guevara et al. J Infec Dis, 2009
Risk factors for mortality in
non-perinatal listeriosis
…Guevara et al. J Infec Dis, 2009
Risk factors for mortality in
non-perinatal listeriosis
-Risk of death higher at age >65
RR 1.85 (CI 1.09-3.14)
…Guevara et al. J Infec Dis, 2009
Risk factors for mortality in
non-perinatal listeriosis
• Multivariant analysis of 29 factors
for mortality was significant for:
– Age >70 (OR 3.44)
– Non-hematologic Ca (OR 5.92)
– Use of corticosteroids (OR 3.34)
– Alcoholism (OR 4.63)
– Renal disease (OR 2.94)
• All other CI’s overlap 1.0
…Guevara et al. J Infec Dis, 2009
Bacterial meningitis in the elderly
• Review of 185 cases in Spain in patients
>65 years between 1977-2006
• Most common organisms:
– S. pneumoniae 74
– N. meningitidis 49
– L. monocytogenes 17
• Outcomes poor (31% mortality)
• Neurologic presentations severe in
comparison to younger patients
…Cabellos et al. Medicine (Baltimore), 2009
TNF inhibitors
are a new
risk factor
for listeriosis
….Slifman, A&R, 2003
Atopy a new risk factor?
• Atopic mouse model v s outbred mice
• LD50 much lower and bacterial counts
in liver and spleen much higher in
NC/Nga mice given an oral inoculum of
LM
• Associated with marked inc in IL-10levels
• “Asthma” noted in other cohorts as
risk
…Kawamoto et al. XVII ISOPOL, BO 16
Genetic/gender predisposition?
• In a humanized mouse model, a long
variant mutation in caspase 12 inhibits
immune response to listeriosis
• Inhibited by estrogen, possibly
conferring greater protection in innate
immunity in females, especially
African-Americans
…Yeretssian et al. PNAS, 2009
New Syndromes
NF due to LM: First report
• 82yo man with hx of chronic lower
extremity lymphedema, cirrhosis, and
adrenal insufficiency
• L Lower extremity erythema and
swelling with progression
• Rx with ceftriaxone but progressed
• OR revealed NF and debrided
…Sendi et al. CID, 2009
NF due to LM: First report
• Treated with amox/clav, clindamycin ,
and gentamicin
• Blood and tissue cultures grew LM
only
• Risk factors?
– Prednisone 17.5 mg OD x 2 mo
– Cirrhosis
– Had consumed a lot of unpasteurized
sheep’s milk cheese !
…Sendi et al. CID, 2009
Listeria sclerokeratitis
• A 25-year-old non–contact lens–wearing male rugby player
was referred with progressive infective sclerokeratitis unresponsive
to topical antivirals and antibiotics. On examination, visual acuity
was perception of light, and a large corneal abscess with overlying
epithelial defect and hypopyon was present. The corneal lesion was
cheesy white and raised with nasal scleritis. This raised the suspicion
of a fungal keratitis. Empirical treatment with intensive topical
antifungals was unsuccessful. A previous corneal scrape had been
negative for bacteria and fungi. A corneal biopsy was performed, and
Listeria monocytogenes was eventually isolated from enrichment culture.
Antibiotic sensitivities showed it to be resistant to cefuroxime,
methicillin, and ceftazidime but sensitive to all other antibiotics tested
including ofloxacin. The treatment course was complicated by a
corneal perforation that needed an emergency therapeutic penetrating
Keratoplasty
• 4 other case reports since 1988
…Tay et al. Cornea, 2006
Treatment Issues
Susceptibility of Listeria
monocytogenes to antibiotics
• Fully susceptible
– Penicillin, ampicillin, azlocillin,
imipenem
– All aminoglycosides
– Vancomycin, teichoplanin
– Cotrimoxazole, rifampin, tetracycline
– Linezolid
Susceptibility of Listeria
monocytogenes to antibiotics
• Intermediate susceptibility
– Quinolones
– Chloramphenicol
– Clindamycin
– Other macrolides
Susceptibility of recent food isolates
to antibiotics
…Conter et al. Int J Food Microbiol, 2008
Susceptibility of recent food isolates
to antibiotics
…Conter et al. Int J Food Microbiol, 2008
Antibiotic susceptibility of LM
Retail food isolates from Denmark
…Aarestrup et al, Foodborne Pathog Dis, 2007
Antimicrobial resistance of Listeria monocytogenes
human strains isolated in France.
Abstract
• Susceptibility to antibiotics of 4,816 clinical L. monocytogenes
isolated since 1926 was studied and the temporal evolution of
susceptibility to antibiotic was analyzed through several decades.
The mechanisms of resistance were studied in each resistant
strain. The prevalence of resistant strains was estimated at
1.27% among human isolates. Resistance to tetracyclines and
fluoroquinolones was more common and has recently emerged.
Although acquired-resistance in clinical L. monocytogenes did not
implicate clinically-relevant antibiotics, the possibility of
resistance gene transfers, the description of the first clinical
isolate with high-level resistance to trimethroprim, and the
recent increase in penicillin MICs with values up to 2 mug/mL
reinforce the need for microbiological surveillance.
…Morvan et al, AAC, 2010
Linezolid Anecdote
• 76 yo man with recurrent fever and
diagnosis of LM prosthetic valve
endocarditis with splenic abscesses
• Rx with vancomycin,gentamicin, ceftriaxone
• PCR (+) at AVR surgery
• CRF suggested change to linezolid with rx
for 4 weeks
• Successfully discharged
• Previous rhombencephalitis case (Morosi et
al 2006)
…Munoz et al, Int J Microbial Agents 2006
Activity of Daptomycin against Listeria
monocytogenes Isolates from Cerebrospinal Fluid
• New lipopeptide antibiotic for
treatment of Gram (+) infections
• 76 isolates from CSF in Netherlands
tested
• MIC’s and E-tests showed
unacceptably high values
• Daptomycin not likely to be useful in
LM meningitis
…Spanjaard and Vandenbroucke-Grauls, AAC, 2008
Levofloxacin Anecdote
• 74 yo woman with acute LM meningitis
• Alcoholism a risk factor
• Treated with cefotaxime and levofloxacin
empirically
• Switch to meropenem + levo on ID of LM in CSF
• LP 1 hr post-infusion yielded levofloxacin levels
7.79 and 5.28 mg/L in blood and CSF respectively
• Meropenem D/C’d day 8, switch to po levofloxacin
• Would levo be a good addition to regimen of a
beta-lactam?
…Viali et al, DiagMicrobiolInfDis 2007
Predictors of mortality and impact of
aminoglycosides on outcome
• Retrospective mortality study in a
large tertiary care hospital in
Barcelona 1983-2006
• Adult, non-pregnant cases
• 118 episodes (16 excluded as died in
<48hrs)
• 69 had beta-lactam monotherapy, 33
had combination therapy with Ags
…Mitja et al. J Antimicrob Chemo, 2009
Predictors of mortality and impact of
aminoglycosides on outcome
• Evenly matched except > corticosteroid
exposure (p =<.001) and > number
presented with coma (p=.027) in
combination rx group
• Overall mortality 33% in combination
group vs 14.5% in monotherapy (p=.03)
• Early mortality 8 x greater in
combination rx group (OR = 2-33)
…Mitja et al. J Antimicrob Chemo, 2009
Antibiotic therapy of LM
meningitis
• Comparison of moxifloxacin vs
ampicillin + gentamicin
• Experimental infection in NZ rabbits
• LM injected in cisterna magna
• 16 hrs later antibiotics started
• Comparisons to controls without ATBs
…Sipahi et al, JAC, 2008
Antibiotic therapy of LM
meningitis
•Persistant infection in all groups
– no advantage to moxifloxacin use
…Sipahi et al, JAC, 2008
Predictors of mortality and impact of
aminoglycosides on outcome
• 57% of combination group received
“inadequate therapy” including a
cephalosporin (42%)
• Multivariate analyses demonstrated
age, corticosteroids, and renal failure
as significant predictors of early
mortality and neoplastic disease and
coma as late predictors
…Mitja et al. J Antimicrob Chemo, 2009
Predictors of mortality and impact of
aminoglycosides on outcome
• Conclusions – aminoglycosides are not
beneficial and may be harmful in
treatment of listeriosis but noncephalosporin beta-lactams are key to
effective treatment
…Mitja et al. J Antimicrob Chemo, 2009
Use of steroids in LM
meningitis/encephalitis?
• Corticosteroids have become a
standard adjunct to antibiotics in
bacterial meningitis (S. pneumoniae)
• Anecdotal case reports continue to
suggest a potential role in LM
infection
– Kayaaslan et al, Int J Infec Dis, 2009
– Orton-Castano et al, Rev Neurol, 2002
– Popescu et al, J Clin Path, 2004
Probiotics for protection?
• Guinea pig model
• Yogurt with Bifidobacteria and
Lactobacilli reduced invasion and
number of stillbirths in pre-treated
animals given 10 9 oral LM
• Implications for advice to pregnant
women?
…Smith et al. XVII ISOPOL, BO 14
Summary
• Recent reviews suggest an upswing in non-perinatal
listeriosis, especially sepsis
• Risk factors include age and immunosuppression,
including use of newer agents such as monoclonals
and TNF-alpha inhibitors
• NF has now been reported with LM
• Recent data suggests that aminoglycosides may be
harmful but more data required before altering
standard beta-lactam + Ag treatment
• Newer agents such as linezolid and moxifloxacin
may not be as useful as expected
• Use of adjunctive corticosteroid treatment
continues to be anecdotal – perhaps best reserved
for abscess or severe illness
Obrigado!
Listeriosis in Scandinavia
…Antal et al, Scand J Infec Dis, 2007
Listeriosis in Scandinavia
…Antal et al, Scand J Infec Dis, 2007
Listeriosis in Scandinavia
…Jensen et al, Eurosurveillance, 2010
MRI vs SPECT scan in
rhombencephalitis
• This report describes a case of brain-stem listeriosis in a
previously healthy 51-year-old woman. The diagnosis was based
on clinical findings, the results of cerebrospinal fluid (CSF)
analysis, CSF culture, and magnetic resonance imaging (MRI)
findings. MRI demonstrated upper brain stem and cerebellar
peduncle involvement. In addition, Tc-99m exametazime
(HMPAO)-labeled single photon emission computed tomography
(SPECT) of the brain revealed bilateral cerebellar
hypoperfusion. Antibiotic therapy resulted in partial clinical
recovery after 3 weeks. At the end of 6 months, brain-stem
findings had nearly resolved. However, although minimal residual
findings were observed on MRI at 6 months, bilateral diffuse
cerebellar hypoperfusion remained on Tc-99m HMPAO brain
SPECT.
…Sahin et al, MedGenMed, 2007
Czech LM Outbreak 2006
• 75 cases
• Mixed adult and perinatal cases,
primarily in elderly
• Serotype 1/2b, 26/30 isolates pulse
type A
• Same type found in cheese and salad
…Vit et al, Eurosurveillance, 2007
Czech LM Outbreak 2006
…Vit et al, Eurosurveillance, 2007
Czech LM Outbreak 2006
…Vit et al, Eurosurveillance, 2007
Listeriosis in UK 2001-2004
Outbreaks
…Gillespie et al, Emerg Infec Dis, 2006
Listeriosis in UK 2001-2004
Increases in non-perinatal cases
…Gillespie et al, Emerg Infec Dis, 2006
Listeriosis in UK 2001-2004
Age of Cases
…Gillespie et al, Emerg Infec Dis, 2006
Listeriosis in UK 2001-2004
Bacteremia accounts for increase in age >60
…Gillespie et al, Emerg Infec Dis, 2006
Listeriosis in Portugal 1994-2003
• 10 year retrospective study
• All cases identified in 23 hospital labs and
Portuguese NIH Porto
• Most blood/CSF isolates
• 35 cases, 5 perinatal
• CFR ~17-36%
• Increases in 2003 (reporting bias?) –
incidence at least 1.4/1,000,000
• Minimal clinical information was available
…Almeida et al, BMC Infect Dis, 2006
Age Distribution with and without
Comorbidities, 1990-2001
Without Underlying Condition
Without Underlying Condition
(n=248)
(n=248)
With Underlying Condition
(n=2207)
With Underlying Condition
(n=2207)
…Fontanet, Martin, Schreiber, Inst Pasteur, 2005
Incidence in Males vs. Females
(Including Pregnancy-Associated Cases)
Males (n=2520)
Mean:
52yrs
52yrs
Median: 62yrs
Median: 62yrs
Mean:
Females
Females(n=2463)
(n=2463)
Mean:
41yrs
Mean:
41yrs
Median: 35yrs
Median: 35yrs
…Fontanet, Martin, Schreiber, Inst Pasteur, 2005
Clinical Presentation, 1996-2001
• 87% had an underlying condition
• 8.6% (94) presented with other clinical
presentations, most commonly ascites &
peritonitis, infected aortic aneurysm,
abscess, gastroenteritis, lung infection, and
UTI
• Sepsis more common in patients with
comorbidities, EXCEPT alcoholism, which
was more commonly associated with CNSI
(p<0.0001)
…Fontanet, Martin, Schreiber, Inst Pasteur, 2005
Susceptibility of Listeria
monocytogenes to antibiotics
• Resistant
– Cephalosporins
• Only aminoglcosides and glycopeptides are
bactericidal
• In vitro synergism with ampicillin and
gentamicin
• In vitro indifference and antagonism with
some other combinations
…adapted from Hansen, Gerner-Smidt, Bruun, APMIS, 2005
Treatment of CNS LM
CNS Penetration
Good Diffusion
Penicillins
3rd & 4th Gen Cephs
Chloramphenicol
Rifampin
TMP-SFX
Poor Diffusion
Early Gen Cephs
Clindamycin
AMGs
Tetracyclines
Macrolides
Linezolid- the newest kid on the
block?
• Leiti, CID, 2005 reported a case treated
with oral linezolid/rifampin for 107 days
after a 40 day course of ampicillin
• Morosi, J Infection, 2006 reported
successful rx of rhombencephalitis after
“failure” of amp/gent, followed by TMPSFX/vanco. TMP-SFX was continued
• Munoz, Int J Antimicrob Agents, 2006
reported a case of culture (-) endocarditis
(16S (+) for LM!) treated with 2 wks of
vanco followed by 4 weeks of linezolid
Treatment Listeria
monocytogenes infections
• Ampicillin and gentamicin remains the best
studied regimen
• Cephalosporins are uniformly inactive
• Moxifloxacin active (Grayo, XVI ISOPOL)
• Linezolid active
• Length of treatment should be 3 weeks for
sepsis and meningitis and 6 weeks for brain
abscess or endocarditis (Lorber, CID, 1997)