Terapia delle infezioni da Listeria monocytogenes - IRCCS Lorenzo Minoli Università Pavia Fondazione Policlinico "San Matteo"
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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".
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.
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 Listeria
monocytogenes
• Neonatal sepsis • Cutaneous disease
• Neonatal meningitis • Pneumonia
– „Early‟ • Septic arthritis
– „Late‟
• Osteomyelitis
• Adult meningitis
• Endocarditis
– Rhombencephalitis
• Peritonitis • Endopthalmitis
• Liver / spleen abscess • Febrile gastroenteritis
Most distinctive syndromes...
• Neonatal sepsis and
meningitis
• Sepsis in the compromised
host
**see good review by Oevermann et al.
• Listeria rhombencephalitis**
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%)
Meningite da Listeria
Caratteristiche
Presentazione subacuta > 24 ore 60%
Rigidità nucale 75%
Disturbi movimento (atassia, tremori, 15-20%
mioclono)
Convulsioni 10-25%
Alterazioni stato mentale 75%
Alterazioni neurologiche focali 35-40%
Emocolture positive 50-75%
Liquido cefalo-rachidiano
- colorazione Gram + 30-40%
- glicorrachia normale > 60%
- citometria: predominanza neutrofili 70%
Lorber et al, Clin Inf Dis,1997;24:1, Mylonakis et al, Medicine, 1998;77:313;
Brouwer et al, Clin Inf Dis,2006;43,1233Fattori di Rischio
Si verifica in soggetti con uno o più condizioni
predisponenti
• Gravidanza
• Corticosteroidi, agenti biologici
• Età estreme ( 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;334:770Fattori di rischio per listeriosi
giugno 2006-giugno 2008
Trattamento immunosoppressore
Neoplasia
Emopatia
Gravidanza
Dialisi
Diabete
Insufficienza epatica
altro
HIV
Insufficienza renale
Trapianto
Deficit immunitario
0 2 4 6 8 10 12 14
Solo 10/45 casi non segnalavano fattori di rischio
Dott. Mirella PontelloIncidenza 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 leucemiciDistribuzione dei casi per età e sesso in
Italia (periodo 2000-2006)
7
Incidenza di listeriosi in Lombardia
0,38/100.000 .
6
5
N pazienti
4
3
2
1
0
esi 10 -20 -30 -40 -50 -60 -70 -80 -90
m 1- 11 21 31 41 51 61 71 81
12 Femmine
0-
Classi di età Maschi
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
Dott. Mirella PontelloNon-Pregnancy-Associated Human Listeriosis in
England and Wales, 2001 to 2007
Increasing sepsis
in elderly
…Gillespie et al. J Clin Micro, 2009Non-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, 2009Gastric acidity as protective factor
…Gillespie et al. J Clin Micro, 2009Gastric 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, 2009Non-Pregnancy-Associated Human Listeriosis in
England and Wales, 2001 to 2007
…Gillespie et al. J Clin Micro, 2009La 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 monocytogenes
Caratteristiche 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 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, 2009Risk 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, 2009Risk Factors, Clinical Features, and Outcomes
of Listeriosis in Solid-Organ Transplant Recipients:
…Nuria et al. CID, 2009Risk Factors, Clinical Features, and Outcomes
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)
…Nuria et al. CID, 2009Risk 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, 2009Endocardite
• 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;20:359Bacterial 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), 2009Listeria 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, 2009LM Meningitis in HIV
HIV (+) HIV (-)
N=32 N=267
…Domingo et al. J AIDS, 2009TNF 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, 2009Risk 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, 2009Spontaneous 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, 2009Spontaneous abortion – the debate
continues !
…Jamshidi et al. Taiwan J Obs Gynec, 2009Spontaneous abortion – the debate
continues !
…Jamshidi et al. Taiwan J Obs Gynec, 2009Necrotizing 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, 2009NF 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, 2009Listeria 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, 2006Listeriosi - 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;10:345Listeriosi: 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 durata delle terapie per le Listeriosi • Ci sono revisioni complete sulle attività anti- microbiche contro la Listeria e il suo trattamento
Susceptibility of Listeria
monocytogenes to antibiotics
• Fully susceptible
– Penicillin, ampicillin, azlocillin,
imipenem
– All aminoglycosides
– Vancomycin, teichoplanin
– Cotrimoxazole, rifampin, tetracycline
– LinezolidSusceptibility 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, 2008Susceptibility of recent food isolates
to antibiotics
…Conter et al. Int J Food Microbiol, 2008Listeriosi - antibatterici raccomandati
Raccomandati Alternativa Efficaci
1^ scelta 2^ scelta
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 >=8Treatment recommendation
Lorber Clin Inf Dis, 1997;24:1LM 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 2006Activity 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, 2008LM 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 2007Auteur(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
high-dose levofloxacin
successful treatment was mainly attributable to
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 inPredictors of mortality and impact of
aminoglycosides on outcome
• Evenly matched except > corticosteroid
exposure (p = 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, 2009Predictors 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, 2009Predictors of mortality and impact of
aminoglycosides on outcome
• Conclusions – aminoglycosides are not
beneficial and may be harmful in
treatment of listeriosis but non-
cephalosporin beta-lactams are key to
effective treatment
…Mitja et al. J Antimicrob Chemo, 2009Antibiotic 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, 2008Antibiotic therapy of LM
meningitis
•Persistant infection in all groups
– no advantage to moxifloxacin use
…Sipahi et al, JAC, 2008Use 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, 2004Probiotics 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 14Treatment Listeria
monocytogenes 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 Moxifloxacina
Grayo et al, AAC, 2008;52:1697Listeriosi e oxazolidoni
JAC, 2009;64: 1035Meningiti batteriche (sub)-acute
Terapia empirica e.v.
AMP 2 g q4h +
Cefotaxime 2 g q4-6 h
Gram su liquor - o
Immunocompetente 7% AMP + gentamicina 1^
Pretermine/< 1 mese dose 2mg/kg e poi 1,7
q8h
Cefotaxime 2 g q4-6 h o
> 1 mese/ < 50 anni Ceftriaxone 2 g q12h
? ±
immunocompetente eccezionale (AMP 2 g q4h)
AMP + gentamicina
Età > 50 anni ±
Cefotaxime 2 g q4-6 h o
Alcool o # patologie Ceftriaxone 2 g q12h
immunocompromessi 7-24% o
Meropenem 2g q8h
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)-acute
Terapia specifica, mirata, e.v.
AMP 2g q4 h ±
Liquor con bacilli o gentamicina 1^ dose
coccobacilli Gram + 2mg/kg e poi 1,7 q8h
se allergia
TMP-SMZ 5 mg/kg q 6-8h
AMP 2g q4 h ±
gentamicina 1^ dose
Coltura LCR +, ATB
2mg/kg e poi 1,7 q8h
o
Meropenem 2g q8h
o
Linezolid 600 mg bid +
Rifampicina 600 po q12h
(CID 2005; 40:908)
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.Sepsi neonatale
precoce < 1 settimana, empirica
AMP 25 mg/kg q8 h +
+ cefotaxime 50 mg/q12h
AMP 25 mg/kg q8 h +
+ gentamicina 2,5mg/kg q24h
Polmonite neonatale
dalla nascita fino a 1 mese, empirica
AMP 50 mg q8 h +
+ gentamicina 2,5mg/kg q8h ±
± cefotaxime 50 mg/q12
Linezolid 10 mg/kg q8h
(PIDJ 2003; 22 (Suppl):S158Gastroenterite
non isolabile da coprocolture standard (NEJM,1997;336:100 e 130)
AMP 50 mg/kg e.v. q6 h +
+ cefotaxime 50 mg/q12h
TMP-SMZ 20 mg/kg die e.v. q 6-8h
Infezione in gravidanza
con amnioite: AMP + gentamicina
Senza amnioite: AMP ± gentamicinaSummary • 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
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