Lorenzo Minoli Università Pavia Fondazione IRCCS

Terapia delle infezioni da Listeria monocytogenes

Lorenzo Minoli

Università Pavia

Fondazione IRCCS

Policlinico "San Matteo"

Un po‟ di storia• 1924 – Australia: Murray descrive un nuovo germe che chiama

Bacterium monocytogenes

• 1940 – USA : Pirie intitola il germe a Lister

• 1949 – Germania: caso di granulomatosi infanti septica (85 feti

abortiti e neonati morti)

• Patel isola da tutti un battere che crede un Corynebacterium;

Seelinger vi riconosce Listeria

• 1983- Francia: Rocourt distingue L. monocytogenes da altre Listerie

e intuisce che è l’unica patogena per l’uomo

• 1983 – Canada: Schlech descrive il primo caso di listeriosi umana da

alimenti (crauti fermentati)

• 1999 - Francia-USA: Charpentier e Courvalin, AAC;43 (9): 2103

"Listeria stil considered to be susceptible to almost all antibiotics,

will evolve toward multiresistence".

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

Impatto stimato di alcune tossinfezioni alimentari, Stati Uniti (stime del 1997)

Patogeno Malati Decessi Case-fatality

rate

Campylobacter 2.453.926 124 0.1%

Salmonella 1.412.498 582 0.8%

E. coli O157:H7 73.480 61 0.8%

Listeria 2.518 504 20.0%

Mead, EID Journal, 1999*

“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

Syndromes caused by Listeriamonocytogenes

• 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 Listeriameningitis/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%)

Meningite da ListeriaCaratteristiche

Presentazione subacuta > 24 ore 60%

Rigidità nucale 75%

Disturbi movimento (atassia, tremori, mioclono)

15-20%

Convulsioni 10-25%

Alterazioni stato mentale 75%

Alterazioni neurologiche focali 35-40%

Emocolture positive 50-75%

Liquido cefalo-rachidiano

- colorazione Gram +

- glicorrachia normale

- citometria: predominanza neutrofili

30-40%

> 60%

70%

Lorber et al, Clin Inf Dis,1997;24:1, Mylonakis et al, Medicine, 1998;77:313;

Brouwer et al, Clin Inf Dis,2006;43,1233

Fattori di Rischio

Si verifica in soggetti con uno o più condizioni predisponenti

• Gravidanza

• Corticosteroidi, agenti biologici• Età estreme ( <2 or >60 anni)• altre condizioni immunosoppressive :

– Neoplasie ematologiche

– Tumori solidi

– Trapianti d’organo (Schuchat JAMA 1992;257:2041)– Diabete

– Malattie renali terminali

– AIDS, prima della HAART

• Accumulo di ferro (emocromatosi)

Lorber Clin Infect Dis 1997;24:1 Southwick NEJM 1996;334:770

0 2 4 6 8 10 12 14

Deficit immunitario

Trapianto

Insufficienza renale

HIV

altro

Insufficienza epatica

Diabete

Dialisi

Gravidanza

Emopatia

Neoplasia

Trattamento immunosoppressore

Fattori di rischio per listeriosigiugno 2006-giugno 2008

Solo 10/45 casi non segnalavano fattori di rischio

Dott. Mirella Pontello

Incidenza della malattia

0,7-1/100.000 persone

2/100.000 in bambini < 2 anni e anziani > 70 anni

5/100.000 tra alcoolisti e diabetici

12/100.000 tra le donne gravide

15-20/100.000 nei soggetti con neoplasie o steroidi

50-100/100.000 nei trapiantati

600-1000/100.000 nei pazienti leucemici

0

1

2

3

4

5

6

7

0-12 m

esi1-1

011-2

021-3

031-4

041-5

051-6

061-7

071-8

081-9

0

Classi di età

N p

azie

nti

Femmine

Maschi

Distribuzione dei casi per età e sesso in Italia (periodo 2000-2006)

Incidenza di listeriosi in Lombardia 0,38/100.000 .

Dott. Mirella Pontello

In Lombardia 2006-2008: 72 casi = 36 x anno, 6 materno infantili, 3 decessi

Isolamenti da: emocolture 30, liquor 8 e 7 altri materiali: valvola mitrale, CVC, liquido amniotico, trombo aneurismatico, placenta, faringe, aspirato gastrico

Non-Pregnancy-Associated Human Listeriosis in England and Wales, 2001 to 2007

…Gillespie et al. J Clin Micro, 2009

Increasing sepsisin elderly


• 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 antagonistspossible association with increases of Listeria bacteremia?



La mortalità per Listeriosi è cambiata nel tempo?

Dati dei decessi della sorveglianza attiva, Stati Uniti

1986 31%

1989 24%

1993 23%

1997 20%

2001 20%

Listeria monocytogenesCaratteristiche dell‟infezione (817 casi in 33 anni)

Infezioni non perinatali su particolari tipologie di ospiti (Mylonakis et al. Medicine 1998;77:313)

• Tumori solidi e ematologici……………. 24%

• Trapianto organi………................ 21%

• Alcoolismo/cirrosi………………………………13%

• Steroidi/altre immunosoppressioni….11%

• Diabete mellito……………………………………8%

• HIV/AIDS…………………………………………….. 7%

Risk factors for mortality innon-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

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

Risk Factors, Clinical Features, and Outcomes

of Listeriosis in Solid-Organ Transplant Recipients:



of Listeriosis in Solid-Organ Transplant 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)


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)

Endocardite

• Colpisce la popolazione a rischio per endocarditi da

streptococchi viridanti.

• Fattori di rischio cardiaci

• Fattori di rischio non cardiaci (intestino!!)

• Colpisce sia le valvole native sia quelle protesiche, con

predominanza del cuore sx

• Un’alta percentuale di pazienti ha fenomeni vascolari

(59%)

• Mortalità globale: 50%

Gallagher, Scand J Infect Dis 1988;20:359

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

Listeria monocytogenes (LM) Meningitis in HIV

• Review of ~300 pts with spontaneous

bacterial meningitis (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 HIVHIV (+)N=32

HIV (-)N=267

…Domingo et al. J AIDS, 2009

TNF inhibitors

are a new risk factor for listeriosis

….Slifman, A&R, 2003

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





Necrotizing Fascitis (NF) due to Listeria monocytogenes:first report

• 82yo man with chronic lower extremity

lymphedema, cirrhosis, and adrenal

insufficiency

• Lower extremity erythema and swelling

with progression

• Rx with ceftriaxone but progressed

• MR 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

Listeriosi - Trattamento

• Antibiotici

• Buona penetrazione

– Penetrazione intracellulare

– Legame stretto ai bersagli intracellulari

– Interazione con il batterio

– pH della cellula

• Battericida

• Inibizione produzione fattori di virulenza

Hof Clin Micro Rev 1997;10:345

Listeriosi: le scelte terapeutiche

• Sono raccomandazioni sulla base di dati di suscettibilità

antibiotica "in vitro", modelli animali ed esperienze clinica su

piccoli numeri di pazienti comparati a controlli storici che

danno luogo ad interpretazioni e preferenze individuali

• Non disponiamo di studi clinici controllati per stabilire scelte

e d u r a t a d e l l e t e r a p i e p e r l e L i s t e r i o s i

• Ci sono revisioni complete sulle attività anti- microbiche

c o n t r o l a L i s t e r i a e i l s u o t r a t t a m e n t o

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

…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

Listeriosi - antibatterici raccomandati

Raccomandati

1^ scelta

Alternativa

2^ scelta

Efficaci

Ampicillina TMP-SMX Penicillina (alte dosi)

APAG sinergici

Macrolidi (?)

Cefalosporine e fosfomicina resistenti

Acquisizione resistenza plasmidica di Listeria monocytogenes per: tetracicline (> 10

ug/ml), minociclina, eritromicina (> 32 ug/ml), CAF, streptomicina (32-64 ug/ml)

ciprofloxacina, trimethoprim (1024 ug/ml)

Ceppo MDR in Grecia in neonato con meningite a 21 gg dalla nascita: gentamicina > 8,

streptomicina > 1000, CAF > 16, Clinda >2, tobra >=8

Treatment recommendation

Lorber Clin Inf Dis, 1997;24:1

LM and Linezolid

• 76 yo man with recurrent fever and diagnosis of LM prosthetic valve endocarditis with splenic abscesses

• Rx with vancomycin,gentamicin, ceftriaxone

• PCR (+) at aortic valve replacement 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

LM and Levofloxacin

• 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

• Lumbar puncture 1 hr post-infusion yielded

levofloxacin levels 7.79 and 5.28 mg/L in blood and

CSF respectively

• Meropenem discontinued day 8, switch to po

levofloxacin

• Would levo be a good addition to regimen of a beta-

lactam?

…Viale et al, DiagMicrobiolInfDis 2007

Auteur(s) / Author(s)

VIALE Pierluigi (1) ; FURLANUT Mario (2) ; CRISTINI Francesco (1) ; CADEO Barbara (1) ;

PAVAN Federica (2) ; PEA Federico (2) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)(1) Department of Medical and Morphological Research, Medical School, Clinic of Infectious

Diseases, University of Udine, 33100 Udine, ITALIE(2) Department of Experimental and Clinical Pathology and Medicine, Institute of Clinical

Pharmacology and Toxicology, Medical School, University of Udine, ITALIE

Résumé / Abstract

We report a case of acute bacterial meningitis due to Listeria monocytogenes whose

successful treatment was mainly attributable to high-dose levofloxacin

therapy (500 mg iv bid). This supports the hypothesis that

levofloxacin may be an effective option for the treatment of

l i s t e r i a l m e n i n g i t i s .

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)



• 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


• Conclusions – aminoglycosides are not

beneficial and may be harmful in

treatment of listeriosis but non-

cephalosporin beta-lactams are key to

effective treatment


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

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

Treatment Listeriamonocytogenes infections

• Ampicillin and gentamicin remains the best studied regimen

• Cephalosporins are uniformly inactive

• Moxifloxacin active (Grayo, XVI ISOPOL)

• Linezolid active, Torezolid

• Length of treatment should be 3 weeks for sepsis and meningitis and 6 weeks for brain abscess or endocarditis (Lorber, CID, 1997)

Listeriosi e MoxifloxacinaGrayo et al, AAC, 2008;52:1697

Listeriosi e oxazolidoniJAC, 2009;64: 1035

Meningiti batteriche (sub)-acuteTerapia empirica e.v.

Gram su liquor -

Immunocompetente

Pretermine/< 1 mese7%

AMP 2 g q4h +Cefotaxime 2 g q4-6 h

o

AMP + gentamicina 1^ dose 2mg/kg e poi 1,7

q8h

> 1 mese/ < 50 anni

immunocompetente

Cefotaxime 2 g q4-6 h o

Ceftriaxone 2 g q12h

±

(AMP 2 g q4h)

Età > 50 anni

Alcool o # patologie

immunocompromessi

AMP + gentamicina±

Cefotaxime 2 g q4-6 h oCeftriaxone 2 g q12h

oMeropenem 2g q8h

?eccezionale

7-24%

Se allergia Pen: TMP-SMZ 5 mg/kg q6-8 h. Desametazone 0,15 mg/kg 1^ dose per

bloccare TNF eventualmente q6h per 2-4 gg.

Meningiti batteriche (sub)-acuteTerapia specifica, mirata, e.v.

Liquor con bacilli o coccobacilli Gram +

AMP 2g q4 h ±

gentamicina 1^ dose

2mg/kg e poi 1,7 q8h

se allergia

TMP-SMZ 5 mg/kg q 6-8h

Coltura LCR +, ATB

Studio non randomizzato (Merle-Melet et al,J Infect,1996;33:79: AMP+TMP-SMZ

meno fallimenti e sequele di AMP+APAG.

Desametazone 0,15 mg/kg 1^ dose per blocco TNF eventualmente q6h per 2-4 gg.

AMP 2g q4 h ±

gentamicina 1^ dose

2mg/kg e poi 1,7 q8h

o

Meropenem 2g q8h

o

Linezolid 600 mg bid +

Rifampicina 600 po q12h

(CID 2005; 40:908)

Sepsi neonataleprecoce < 1 settimana, empirica

AMP 25 mg/kg q8 h +

+ cefotaxime 50 mg/q12h

AMP 50 mg q8 h +

+ gentamicina 2,5mg/kg q8h ±

± cefotaxime 50 mg/q12

Linezolid 10 mg/kg q8h

(PIDJ 2003; 22 (Suppl):S158

Polmonite neonataledalla nascita fino a 1 mese, empirica

AMP 25 mg/kg q8 h +

+ gentamicina 2,5mg/kg q24h

Gastroenteritenon isolabile da coprocolture standard (NEJM,1997;336:100 e 130)

AMP 50 mg/kg e.v. q6 h +

+ cefotaxime 50 mg/q12h

con amnioite: AMP + gentamicina

Senza amnioite: AMP ± gentamicina

TMP-SMZ 20 mg/kg die e.v. q 6-8h

Infezione in gravidanza

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

Documents

Lorenzo Minoli Università Pavia Fondazione IRCCS