Clinical Listeriosis: What’s New? W F Schlech MD, FACP, FRCPC.

Clinical Listeriosis: What’s New?

W F Schlech MD, FACP, FRCPC

Individuals exceptionally vulnerable to death via. listeriosis(1) AIDS patients(2) Chemotherapy patients(3) Diabetics(4) Organ transplant recipients(5) Unborn

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)

Organisms are widespread (ubiquitous)-- found in soil, food, water, sewage

Healthy adults do show transient fecal carriage of L. monocytogenes.

Listeria monocytogenes

Syndromes caused by Listeria monocytogenes

• Neonatal sepsis• Neonatal meningitis

– ‘Early’– ‘Late’

• Adult meningitis– Rhombencephalit

is• Peritonitis• Liver / spleen

abscess

• Cutaneous disease• Pneumonia • Septic arthritis • Osteomyelitis• Endocarditis• Endopthalmitis• Febrile

gastroenteritis

Most distinctive Most distinctive syndromes...syndromes...

• Neonatal sepsis and Neonatal sepsis and meningitismeningitis

• Sepsis in the compromised Sepsis in the compromised hosthost

• ListeriaListeria rhombencephalitis** 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) (15-20%)

• 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

…Gillespie et al. J Clin Micro, 2009

Increasing sepsis in elderly


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)


Gastric acidity as protective factor


Gastric acidity as protective factor


-Increasing use of PPIs vs H2 receptor antagonists possible association with increases of Listeria bacteremia?


to 2007


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


…Jensen et al, Eurosurveillance, 2010

http://hinari-gw.who.int/whalecomwww.eurosurveillance.org/whalecom0/images/dynamic/EE/V15N12/Listeria_Denmark_Fig3.jpg

“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 Outcomesof 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


Recipients:



Recipients:



Recipients:


• Manifestations of Listeria infection– Bacteremia 26 (86.7)– Meningoencephalitis 10 (33.3)– Spontaneous peritonitis 2 (6.7)– Pleural empyema 1 (3.3)– Liver abscesses 1 (3.3)– Brain abscesses 1 (3.3)


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)

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 anti-Listeria IgG (serotypes 1/2a and 4b) from Euroimmune AG

…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 of death higher at age >65 RR 1.85 (CI 1.09-3.14)


• 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


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-10- levels

• “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 playerwas referred with progressive infective sclerokeratitis unresponsiveto topical antivirals and antibiotics. On examination, visual acuitywas perception of light, and a large corneal abscess with overlyingepithelial defect and hypopyon was present. The corneal lesion wascheesy white and raised with nasal scleritis. This raised the suspicionof a fungal keratitis. Empirical treatment with intensive topicalantifungals was unsuccessful. A previous corneal scrape had beennegative for bacteria and fungi. A corneal biopsy was performed, andListeria 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 testedincluding ofloxacin. The treatment course was complicated by acorneal perforation that needed an emergency therapeutic penetratingKeratoplasty

• 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


• Intermediate susceptibility–Quinolones–Chloramphenicol–Clindamycin–Other macrolides

…Conter et al. Int J Food Microbiol, 2008

Susceptibility of recent food isolates to antibiotics

…Conter et al. Int J Food Microbiol, 2008

Susceptibility of recent food isolates to antibiotics

Antibiotic susceptibility of LM

…Aarestrup et al, Foodborne Pathog Dis, 2007

Retail food isolates from Denmark

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


• 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)


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

…Sipahi et al, JAC, 2008

•Persistant infection in all groups – no advantage to moxifloxacin use


• 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



• Conclusions – aminoglycosides are not beneficial and may be harmful in treatment of listeriosis but non-cephalosporin beta-lactams are key to effective treatment


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!


…Antal et al, Scand J Infec Dis, 2007


…Antal et al, Scand J Infec Dis, 2007


…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





Listeriosis in UK 2001-2004Outbreaks

…Gillespie et al, Emerg Infec Dis, 2006

Listeriosis in UK 2001-2004Increases in non-perinatal

cases


Listeriosis in UK 2001-2004Age of Cases


Listeriosis in UK 2001-2004Bacteremia accounts for increase in

age >60


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

With Underlying Condition(n=24

8)(n=2207)

…Fontanet, Martin, Schreiber, Inst Pasteur, 2005

Without Underlying Condition

(n=248)

With Underlying Condition(n=2207

)

Incidence in Males vs. Females(Including Pregnancy-Associated Cases)

Females (n=2463)

Mean: 52yrs

Median: 62yrs

Mean: 41yrs

Median: 35yrs


Males (n=2520)Mean: 52yrs

Median: 62yrs

Females (n=2463)

Mean: 41yrs

Median: 35yrs

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)



• 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 LMCNS 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 TMP-SFX/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)

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Clinical Listeriosis: What’s New? W F Schlech MD, FACP, FRCPC.

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