Journal of Infection (2012) 64, 19e33

www.elsevierhealth.com/journals/jinf

Listeriosis: An emerging public health problemespecially among the elderly

Patricia Mu~noz a,b,c,*, Loreto Rojas a, Eleonora Bunsow a, Elena Saez a,Laura S�anchez-Cambronero a, Luis Alcal�a a,c, Marta Rodrı́guez-Creixems a,b,c,Emilio Bouza a,b,c

aDepartment of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Mara~n�on,Doctor Esquerdo 46, 28007 Madrid, SpainbUniversidad Complutense de Madrid, SpaincCIBERES, Spain

Accepted 17 October 2011Available online 21 October 2011

KEYWORDSListeriamonocytogenes;Meningitis;Bloodstream infection

* Corresponding author. Servicio deDoctor Esquerdo 46, 28007 Madrid, Sp

E-mail address: pmunoz@micro.hg

0163-4453/$36 ª 2011 The British Infedoi:10.1016/j.jinf.2011.10.006

Summary Objectives: To analyze the incidence trend of listeriosis, its present epidemiologyand the potential benefit of aminoglycosides during the last two decades.Methods: We reviewed all cases of invasive listeriosis detected during a 22-year period ina large tertiary hospital. Two equal periods of 11 years were compared.Results: We detected 111 cases of listeriosis (32 during the first 11-year period and 79 duringthe second). Incidence of listeriosis increased significantly (from 4.66/106 inhabitants to10.39/106 inhabitants; P Z .001). In the second period, there were more patients >65 years(21.9%e45.6%; P Z .02) and with no significant underlying diseases (0 vs. 16.5%; P Z .02).Comparing clinical presentations between the two periods, primary bacteremia increased(40.6% vs. 55.7%), while central nervous system infections decreased (34.4% vs. 27.8%). Cotri-moxazole (SXT) use increased significantly in the second period (from 6.3% to 40.5%, P Z .001)while the administration of aminoglycosides decreased (from 40.6% to 21.5%, PZ .04). The useof combination therapy did not have any impact on mortality, however it did increase toxicity.Conclusions: Listeriosis should be considered an emerging health problem, especially amongthe elderly, including those with no underlying medical conditions. The use of aminoglycosidesdoes not seem to be justified according to our data.ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Microbiologı́a Clı́nica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Mara~n�on,ain. Tel.: þ34 91 5868453; fax: þ34 91 504 49 06.gm.es (P. Mu~noz).

ction Association. Published by Elsevier Ltd. All rights reserved.

20 P. Mu~noz et al.

Introduction

Listeriosis is a severe infection caused by Listeria monocyto-genes, a facultative intracellular gram-positive rod widelydistributed in nature.1,2 The most common route of humaninfection is ingestion of contaminated food, although verti-cal and nosocomial transmission have also been de-scribed.3-5 The trends of listeriosis incidence in recentyears differ around the world, perhaps in relation to dietarypreferences and food safety policies.6e12 An increased inci-dence was found by some researchers,13,14 while othersfound a reduction in the number of cases of listeriosis.15,16

Epidemiological reports also suggest a change in theunderlying conditions of patients with listeriosis, nowaffecting elderly patients more often and pregnant womenless frequently.6,10 This shift may increase the occurrenceof inadequate empirical therapy due to a reduced clinicalsuspicion in affected patient groups. As for treatment,the role of aminoglycosides is also being questioned dueto its associated nephrotoxicity and lack of evidence ofthe superiority of combination treatment including amino-glycosides.17 Mortality remains at around 20%.8,9,11,15e19

Research papers of human listeriosis usually consist ofless than 100 cases and are restricted to specific patientpopulations (eg, transplant recipients, HIV-infected indi-viduals)20e25 or specific syndromes (eg, central nervous sys-tem [CNS] disease).7 We present 22 years of data from alladult listeriosis cases (N Z 111) observed in our hospitalin Madrid, Spain. We describe the underlying conditions,clinical presentation, and impact of antimicrobial therapyduring the study period. A review of all series from the lit-erature with more than 30 cases is also included.

Patients and methods

Study period and patient selection

We conducted a retrospective study of all adult patientswith L. monocytogenes detected in normally sterile bodyfluids between January 1986 and December 2007. Ten casesof listeriosis in children were excluded according to our ini-tial design. Eight of them were newborns and the remaining2 were two-year old siblings. All patients were cared for bythe same team in a single institution. In order to emphasizethe potential changes of the disease profile, we divided ourstudy into two periods of 11 years each. The study has beenapproved by the local ethical board.

Overall, the province of Madrid has 34 other publichospitals attending a population of 6,360,241 inhabitants.During the study period the population of the city increasedfrom 3,120,941 to 3,273,006. Our institution is a teaching,tertiary, referral hospital. We cover a large urban popula-tion, with an area of influence that increased from 608,594to 752,687 inhabitants with a median-low socioeconomiclevel. The number of beds in our hospital decreased from2500 to approximately 1750 during the study period.

Clinical data

Medical records were reviewed according to a pre-established protocol by trained physicians and the data

recorded were age, sex, Charlson comorbidity index,McCabe and Jackson stage, underlying conditions, riskfactors, place of acquisition, season, clinical presentation,syndromes, therapy (empirical and definite), and deathrelated to the episode of listeriosis.

We analyzed the characteristics of listeriosis according tothe main underlying conditions: pregnancy, HIV infection,hematological malignancy, solid tumor, solid organ trans-plantation (SOT), liver disease, and no underlying condition.

Definitions

McCabe and Jackson criteriaClassification of the severity of the underlying illness intorapidly fatal (death expected in less than one month- score3), ultimately fatal disease (death expected within 5 years-score 2) and non-fatal (score 1).26

Charlson comorbidity indexPredicts the ten-year mortality for a patient who may havedifferent comorbid conditions. Each condition is assignedwith a score of 1, 2, 3 or 6 depending on the risk of dyingassociated with this condition. Then the scores are summedup and given a total score which predicts mortality.27

Patient with listeriosis was defined as one with a com-patible illness from whom L. monocytogenes was isolatedfrom a normally sterile site (all L. monocytogenes wereconfirmed by culture).

CNS diseaseWas based on clinical criteria (fever, headache, alteredconsciousness, focal neurological deficit, or convulsions),pleocytosis in cerebrospinal fluid (CSF) (5 leukocytes/mm3)and/or involvement of cerebral parenchyma on neuroimag-ing. Lumbar puncture was not performed systematically inpatients with no neurological manifestations or neuroimag-ing abnormalities. Patients with altered consciousness, sei-zures, and movement disorders with/without cerebralparenchymal abnormalities in the MRI were considered tohave meningoencephalitis.

Primary bacteremiaRecovery of L. monocytogenes from blood cultures with noevident infectious origin or focal clinical manifestations.

GastroenteritisL. monocytogenes bacteremia in patients whose only focalsymptoms were vomiting, diarrhea, and abdominal pain.

Nosocomial acquisitionlisteriosis was considered to be nosocomial in all cases forwhich cultures were positive in samples obtained >72 hafter admission and there was no evidence of presence ofthe disease at the moment of admission. Cases attributedto contaminated hospital food are specified. The episodewas considered health careerelated when the patient hadbeen hospitalized during the previous three months or rou-tinely required medical assistance inside or outside the hos-pital (eg, dialysis, chemotherapy).

Adequate therapyIntravenous administration of an active drug against L.monocytogenes (ampicillin, cotrimoxazole [SXT],

Listeriosis: An emerging problem 21

carbapenem, piperacillin/tazobactam, amoxicillin/clavu-lanic acid, or vancomycin).

Empirical treatmentTreatment initiated before knowing the isolation ofL. monocytogenes.

Definite treatmentTreatment initiated after knowing the isolation ofL. monocytogenes.

Therapy was classified as combined, when the patientreceived two of the following drugs: ampicillin, SXT, andgentamicin. As a general practice, both drugs are adminis-tered close in time when feasible.

Related deathDeath during the treatment period that could not be clearlyattributed to another cause.

Overall mortalityDeath occurring during hospital admission.

Microbiological data

L. monocytogenes was isolated from blood, CSF, peritonealfluid, hip prosthesis material, and vascular tissue. Themethods used for processing positive blood cultures andidentification of isolates were standard.28 Antimicrobialsusceptibility testing was performed according to the Clin-ical and Laboratory Standards Institute (CLSI) recommenda-tions, which provide breakpoints for Listeria susceptibilityto penicillin, ampicillin and SXT.29 For gentamicin CLSI-criteria for staphylococci are applied.30

Blood culture systems: There were three major changesin the laboratory processing of blood cultures. From 1986 to1986, we used the Vacutainer System (Becton Dickinson Co,Rutherford, NJ) with manual reading. From 1986 to 1995,we used the BACTEC-NR 640 (Johnston Laboratories, Inc).From 1995 to 2007, blood cultures were processed usingBACTEC 9240 (Becton Dickinson Microbiology Systems),which is more automatic and includes continuous shaking.Blood cultures were sampled and transported using stan-dard procedures.31,32 All positive samples were subculturedand Gram stained.

Statistical analysis

Data were entered and categorized using Microsoft AC-CESS�. Annual incidence of Listeria bloodstream infection(BSI) episodes, provided as episodes per 1000 admissions,was calculated as the number of episodes detected eachyear divided by the number of admissions (in thousands)of the institution over the same period. The analysis ofthe evolution of Listeria BSI rates over the study periodwas performed by applying an autoregressive integratedmoving average model (ARIMA), with data in monthly inter-vals. For the analysis of Listeria BSI episodes per 1000 ad-missions, the ARIMA model was adjusted by the bloodculture system used in each period and the percentage ofblood cultures with growth of significant microorganisms(as a measurement of index of suspicion). Besides,

comparison of incidences occurred in two periods of 11years each (1986e1996 vs. 1997e2007) was performedwith Fisher’s exact test.

For univariate analysis, continuous variables were as-sessed using the ManneWhitney’s U test, and qualitativevariables were studied with Fisher’s exact test or c2 test.A P value <0.05 was considered significant. All statisticaltests were two-tailed.

A multivariable logistic regression model was defined toassess the independent value of mortality risk factors.Because a stepwise model severely reduces the scientificbasis of the multivariable model, the modeling takes intoaccount the inter-relationships of all variables selected forthe analysis. Variables were selected based on their preva-lence in the study population, strength of the generalrelationship of the variables with death, and the clinicalrelevance on these variables in the literature as risk factorsfor listeriosismortality. Because the 95% CI or P value for thatmatter are not as important as the OR, variables selected inthe final multivariable model were those with a OR value lessthan 0.66 (>50% decrease in the odds of death) or greaterthan 1.5 (>50% increase in the odds of death). Continuousand ordinal variables were reduced to dichotomous variables(absence of variableZ 0; presence of variableZ 1) in orderto simplify the analysis. Results are presented as adjustedodds ratios with 95% confidence intervals and the P value.

All statistical procedures were performed using SPSSsoftware package (SPSS Inc., Chicago).

Literature review

We performed a MEDLINE search (English and Spanish) usingthe key words L. monocytogenes and listeriosis. We presenta summaryof 13 studies of listeriosis in thegeneral populationincluding more than 30 patients each that provided at leastthe following data: type of study, incidence, percentage ofpatients older than 65 years, percentage of patients with nounderlying condition, use of aminoglycosides, and mortality.

Results

Incidence

During the 22 years of the study, our institution had 111cases of listeriosis: 32 during the first period (11 years) and79 in the second. This increase holds true when consideringonly the number of Listeria BSIs per 1000 admissions, whichincreased from 0.69 in the first period to 1.38 in the secondperiod (P < .0001). This trend also persisted when datawere expressed as population-based figures: the mean inci-dence increased from 4.66 to 10.39 episodes/million inhab-itants in the area of influence of the hospital (P < .001)(Fig. 1 and Table 1).

Clinical characteristics of listeriosis during the two studyperiodsEpidemiologyThe main characteristics of patients with listeriosis arecompared in Table 2. There was a significant increase in theage of patients diagnosed with listeriosis in the second andmost recent study period (53.0 vs. 60.0 years; PZ .043) and

22 P. Mu~noz et al.

in theproportion of patients aged� 65 years (21.9% vs. 45.6%;PZ .02).We could not find clear seasonality for theepisodes.

Underlying conditionsThe most common underlying conditions were non-hematologic malignancy (24 cases; 21.6%), diabetes mellitus(21 cases; 18.9%), liver disease (20 cases; 18%), and chronicobstructive pulmonary disease (COPD) (17 cases; 15.3%).

Episodes of Listeria monocytogenes b1,000,000 inhabitans duri

0

2

4

6

8

10

12

14

16

18

1986

1987

1988

1989

1990

1991

1992

1993

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1995

1996

Y

Epi

sode

s pe

r 1,

000,

000

inha

bita

ns

Patients aged 65 years or olde

Patients aged less than 65 yea

Episodes of listeriosis(n=111) expressethe study pe

0

2

4

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8

10

12

14

16

18

1986

1987

1988

1989

1990

1991

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1995

Epi

sode

s pe

r 1,

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Patients aged 65 years or olde

Patients aged less than 65 yea

a

b

Figure 1 Episodes of Listeria monocytogenes bacteremia (nZ 96inhabitants during the study period. a. Episodes of L.monocytogenesduring the study period. b. Episodes of listeriosis (n Z 111) expresse

From the first to second period of our study, having nounderlying medical conditions becamemore prevalent [0 vs.13(16.5%), PZ .018; 0 vs. 1.71 episodes/millions inhabitans;p < .01]. There was a significant reduction in the proportionof SOTrecipients [7(21.9%) vs. 5(6.3%);PZ .037] anda reduc-tion in the proportion of patients with liver disease [9(28.1%)vs. 11(13.9%); PZ .078]. Surprisingly, the proportion of caseswith HIV infection increased [1(3%) vs. 9(11.4%); P Z .27].

acteremia (n=96) expressed as cases per ng the study period

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

ear

r

rs

d as cases per 1,000,000 inhabitans during riod

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

Year

r

rs

) and total listeriosis (nZ 111) expressed as cases per 1,000,000bacteremia (nZ 96) expressed as cases per 1,000,000 inhabitansd as cases per 1,000,000 inhabitans during the study period.

Table 1 Incidence of Episodes of Listeria bacteremia and total listeriosis during the study period.

Year Inhabitantsa Admissions Number ofepisodesof Listeriabacteremia/totallisteriosis

Episodes of Listeriabacteremia/totallisteriosis per1000 admissions

Episodes ofListeriabacteremia/totallisteriosis per1,000,000 inhabitants

1986 608,594 50,365 1/1 0.02/0.02 1.64/1.641987 612,284 49,367 4/4 0.08/0.08 6.53/6.531988 615,974 48,558 1/1 0.02/0.02 1.62/1.621989 619,664 47,789 2/2 0.04/0.04 3.23/3.231990 623,354 46,443 2/2 0.04/0.04 3.21/3.211991 627,043 45,792 1/1 0.02/0.02 1.59/1.591992 629,040 45,565 3/3 0.07/0.07 4.77/4.771993 631,037 48,582 5/5 0.10/0.10 7.92/7.921994 633,034 48,275 5/7 0.10/0.15 7.90/11.061995 635,031 47,972 3/4 0.06/0.08 4.72/6.301996 637,028 49,687 2/2 0.04/0.04 3.14/3.141997 642,091 51,604 4/4 0.08/0.08 6.23/6.231998 647,154 50,371 3/3 0.06/0.06 4.64/4.641999 650,597 49,097 1/2 0.02/0.04 4.54/3.072000 653,849 50,873 9/11 0.18/0.22 13.76/16.822001 668,942 52,249 8/8 0.15/0.15 11.96/11.962002 684,754 52,889 7/8 0.13/0.15 10.22/11.682003 704,030 54,781 6/6 0.11/0.11 8.52/8.522004 717,326 61,299 8/10 0.13/0.16 11.15/13.942005 738,481 62,773 5/8 0.08/0.13 6.77/10.832006 743,387 65,681 8/9 0.12/0.14 10.76/12.112007 752,687 67,882 8/10 0.12/0.15 10.63/13.29Overall e 1,147,894 96/111 e e

Annual average 657,972 52,177 4.36/5.05 0.08/0.10 6.63/7.67Annual increase(95% CI)

6,141.3(5,074.4e7,208.2)

81.4(38.2e117.7)

e 0.010(0.005e0.015)/0.013(0.008e0.018)

0.067(0.048e0.086)/0.086(0.051e0.121)

P <.0.001 <.0.001 e <0.001/<0.001 <0.001/<0.001Period 1986e1996 624,735 (average) 528,395 29/32 0.05/0.06 4.22/4.66Period 1997e2007 691,209 (average) 619,499 67/79 0.11/0.13 8.81/10.39P e e e <0.001/<0.001 <0.001/<0.001a Population data obtained from www.ine.es.

Listeriosis: An emerging problem 23

The proportion of patients with an ultimately fataldisease decreased between the first and second periodfrom 17 patients (53.1%) to 21(26.6%) (P Z .008), while theproportion of patients with a non-fatal underlying conditionincreased from 12 patients (37.5%) to 55(69.6%) (P Z .002).The Charlson comorbidity index also decreased during thesecond period (from 3.72 � 2.3 to 2.4 � 2.6).

AcquisitionThe proportion of nosocomial listeriosis remained stable[5(15.6%) to 13(16.5%)], despite an outbreak, probablyrelated to hospital food, that affected 10 patients in2000e2001. Health careerelated listeriosis decreasedfrom 6 cases (18.8%) to 4(5.1%) (P Z .02).

Presenting syndromesOverall, the most common clinical presentation of listeriosiswas primary bacteremia (57 episodes; 51.4%), followed by CNSinfection (35; 31.5%)dmeningitis in 22(19.8%) and meningo-encephalitis in 13(11.7%)dand bacteremic gastroenteritis (9;

8.1%). The most important change between the study periodswas the increase of patients with primary bacteremia (from 13episodes e 40.6% to 44 episodes e 55.7%) (Table 2).

Clinical manifestations and microbiological dataThemost commonpresenting symptomswere fever (90 cases;81.1%), altered consciousness (48; 43.2%), headache (26;23.4%), vomiting (15; 13.5%), and diarrhea (14; 12.6%)(Table 2). L. monocytogenes was isolated in blood culturesin 96 opportunities (86.5%), in CSF in 31 (27.9%), in peritonealfluid in 5 (4.5%) and from joint prosthesis, andamycotic aneu-rism in2 (1.8%).Weusually askedall patients if theyhadeatenready-to-eat food and ifmoremembers of the familywere ill,but we could not demonstrate a clear relationship of caseswith any concrete food, with the exception of the previouslymentioned nosocomial outbreak that involved 10 cases.

Management and outcomeAmpicillin was the most commonly antimicrobial used in 76cases (68.5%), either alone in 24(21.6%) or combined with

Table 2 General characteristics of 111 patients with Listeria monocytogenes infection.

Characteristic OverallN Z 111 (%)

Period 1(1986e1996)N Z 32 (%)

Period 2 (1997e2007)N Z 79(%)

P

Median age in years (IQR) 59.0(42.0e71.0) 53.0(39.0e63.8) 60.0(46.0e74.0) 0.043.Age � 65 years 43(38.7) 7(21.9) 36(45.6) 02SeasonNoveApr 45(40.5) 11(34.4) 34(43) 0.4MayeOct 66(59.5) 21(65.6) 45(57) 0.4SexMale 65(58.6) 20(62.5) 45(57) 0.59McCabe and Jackson stageNon-fatal 67(60.4) 12(37.5) 55(69.6) .0.002Ultimately fatal 38(34.2) 17(53.1) 21(26.6) 0.008Rapidly fatal 6(5.4) 3(9.4) 3 (3.8) 0.352Median Charlson index 2.85 � 2.64 3.72 � 2.38 2.4 � 2.6 13Underlying conditionsNone 13 (11.7) 0 13(16.5) 0.018Solid tumor 24(21.6) 6(18.8) 18(22.8) 0.64Diabetes mellitus 21(18.9) 6(18.8) 15(19) 0.97Liver disease 20(18) 9(28.1) 11(13.9) 0.078COPD 17(15.3) 4(12.5) 13(16.5) 0.77Solid organ transplantation 12(10.8) 7(21.9) 5(6.3) 0.037Liver 7(6.3) 3(9.4) 4(5.1) 0.41Heart 2(1.8) 1(3.1) 1(1.3) 0.49Kidney 3(2.7) 3(9.4) 0 0.022HIV 10(9) 1 (3.1) 9(11.4) 0.27Hematologic malignancy 10(9) 4(12.5) 6(7.6) 0.47Pregnancy 9(8.1) 3(9.4) 6(7.6) 0.71Renal disease 9(8.1) 3(9.4) 6(7.6) 0.71IBD 4(3.6) 0 4(5.1) 0.32Risk factorsCorticosteroid therapy 21(18.9) 9(28.1) 12(15.2) 0.11Alcoholism 15(13.5) 7(21.9) 8(10.1) 0.12AcquisitionCommunity 83(74.8) 21(65.6) 62(78.5) 0.15Nosocomial 18(16.2) 5(15.6) 13(16.5) 0.91Health careerelated 10(9) 6(18.8) 4(5.1) 0.02Clinical syndromesPrimary bacteremia 57(51.4) 13(40.6) 44(55.7) 0.15CNS disease 35(31.5) 11(34.4) 22(27.8) 0.68Meningitis 22(19.8) 8(25) 14(17.7) 0.38Meningoencephalitis 13(11.7) 3(9.4) 10(12.7) 0.75Gastroenteritis 9(8.1) 2(6.2) 7(8.9) 1Peritonitis 6(5.4) 3(9.4) 3(3.8) 0.14Endocarditis 2(1.8) 1(3.1) 1(1.3) 0.49Hip prosthesis infection 1(0.9) 1(3.1) 0 0.28Vascular prosthesis infection 1(0.9) 1 (3.1) 0 0.28Clinical characteristicsFever 90(81.1) 30(93.8) 60(65.9) 0.03Altered consciousness 48(43.2) 10(31.2) 38(48.1) 0.10Headache 26(23.4) 9(6.2) 17(21.5) 0.45Vomiting 15(13.5) 32(100) 15(19) 0.005Diarrhea 14(12.6) 3(9.4) 11(13.9) 0.75Shock 13(11.7) 4(12.5) 9(11.4) 1Seizures 6(5.4) 5(15.6) 1(1.3) 0.007Arthralgia 3(2.7) 2(6.2) 1(1.3) 0.19Blood characteristicsLeukocytosis 43(38.7) 14(43.8) 29(36.7) 0.49Leukopenia 11(9.9) 3(9.4) 8(10.1) 1

(continued on next page)

24 P. Mu~noz et al.

Table 2 (continued )

Characteristic OverallN Z 111 (%)

Period 1(1986e1996)N Z 32 (%)

Period 2 (1997e2007)N Z 79(%)

P

Positive cultureBlood 96(86.5) 29(90.6) 67(84.8) 0.55CSFa 31(27.9) 9(28.1) 22(27.8) 0.97Peritoneal fluidb 5(4.5) 1(3.1) 4(5.1) 1Abscess 2(1.8) 2(6.2) 0 0.08Empirical treatmentAdequate empirical therapy 45(40.5) 13(40.6) 32(40.5) 0.99Single agent 52(46.8) 14(43.8) 38 (48.1) 0.67Combined 53(47.7) 14(43.8) 39(49.4) 0.59Definite treatmentAmpicillin alone 24(21.6) 11(34.4) 13(16.5) 0.038AMP þ GEN 29(26.1) 12(37.5) 17(21.5) 0.08SXT alone 10(9) 0 10(12.7) 0.06AMP þ SXT 24(21.6) 2(6.3) 22(27.8) 0.01Carbapenems 2(1.8) 0 2(2.5) 1Cephalosporin 3(2.7) 1(3.1) 2(2.5) 1Quinolones 1(0.9) 1(3.1) 0 0.29Others 13(11.7) 2(6.3) 11(13.9) 0.34Use of SXT 34(30.6) 2(6.3) 32(40.5) 0.00Use of ampicillin 76(68.5) 24(75) 52(65.8) 0.34Use of aminoglycosides 30(27) 13(40.6) 17(21.5) 0.04Hospital stay: Median (IQR) 21.0(11.0e39.0) 27.0(9.0e52.5) 18.0(11.0e34.0) 0.40Overall mortality 36(32.4) 11(34.4) 25(31.6) 0.78Related mortality 27(24.3) 10(31.3) 17(21.5) 0.27

AMP þ GEN, ampicillin with gentamicin; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CSF, cerebrospinalfluid; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; Others, amoxicillin/clavulanic acid, tobramycin andpiperacillin-tazobactam; SD, standard deviation; SXT, trimethoprim/sulfamethoxazole.a Recovered from 52(46.8%) episodes in which CSF cultures were performed.b Recovered from 11(9.9%) episodes in which peritoneal fluid cultures were performed.

Listeriosis: An emerging problem 25

gentamicin in 29(26.1%) or SXT in 24 (21.6%). SXT wasadministered to 34 patients (30.6%) and aminoglycosides to30 patients (27%). The most important difference in antimi-crobial management between the periods was the significantincrease in theuseof SXT [2(6.3%) vs. 32(40.5%),P�.001] andthe decrease in the administration of aminoglycosides [from13 cases (40.6%) to 17 (21.5%), P Z .04].

Median hospital stay for patients in this series was211e39 days. Overall mortality was (32.4%; 36 patients)and Listeria-related mortality was (24.3%; 27 patients)[10 patients in the first period (31.3%) and 17 (21.5%) inthe second].

Prognostic factors for mortalityPoor prognostic factors for mortality in the univariateanalysis included an ultimately or rapidly fatal underlyingcondition according to the McCabe and Jackson classifica-tion, presence of a solid tumor, health careerelatedacquisition, and shock (Table 3). When analyzing differentantibiotic treatments, administration of ampicillin, eitheralone, or combined with SXT or gentamicin, decreasedthe risk of mortality.

Multivariate analysis showed that age � 65 years old(OR, 1.582; 95% CI, 0.434e5.776; P Z .487), an ultimatelyfatal or rapidly fatal McCabe and Jackson stage (OR,4.014; 95% CI, 1.301e12.388; P Z .016), solid tumor(OR, 1.581; 95% CI, 0.374e6.686; P Z .534), CNS disease

(OR, 2.284; 95% CI, 0.573e9.106; P Z .242), shock (OR,7.458: 95% CI, 1.294e42.977; P Z .025), and isolation ofListeria spp. from blood (OR, 4.954; 95% CI,0.634e38.717; P Z .127) increased at least 50% the oddsof death, whereas pregnancy (OR, <0.01: PZ .044) and ad-ministration of ampicillin (OR, 0.146; 95% CI, 0.034e0.619;P Z .009) were protective factors. Despite forcing the vari-able in the model, we could not find any independent pro-tective effect for aminoglycosides, or any combinedtherapy, not even when we analyzed separately patientswith CNS listeriosis (P Z .4).

Characteristics of listeriosis in different populations andwith different underlying conditionsCNS listeriosisThirty-five (31.5%) patients had CNS listeriosis [22 (62.8%)with meningitis and 13 (37.2%) with meningoencephalitis]confirmed with image data,3 CSF positive cultures,31 or CSFabnormalities1 We compared patients with and without CNSlisteriosis to determine indicators of CNS involvement(Table 4). Patients with CNS infection were younger [8 pa-tients (22.9%) vs. 35 (46.1%) older than 65 years] andtended to have a higher proportion of hematologic malig-nancy. None of the patients with CNS listeriosis were preg-nant. CNS involvement was usually indicated by alteredconsciousness in 26 cases (74.3%), headache in 21 (60%),and/or seizures in 6 (17.1%), all of which led to

Table 3 Outcome and poor prognostic factors.

Characteristic Died Survived P Risk ratios (95% CI) Multivariate analysis

N Z 36 N Z 75 OR 95% CI (p)

Median Age (SD) 62.2(18.5) 55(17.8) 0.05Age � 65 years (%) 17(47.2) 26(34.7) 0.200 1.415(0.832e2.407) 1.582 0.434e5.776 0.487Male Sex 19(52.8) 46(61.3) 0.390 0.791(0.464e1.350)Charlson comorbidity index (SD) 3.44(2.7) 2.6(2.6) 0.1McCabe and Jackson stage 0.001 4.014 1.301e12.388 0.016Non-fatal 13(36.1) 54(72.0) 0.371(0.211e0.652)Ultimately-Rapidly fatal 23(63.9) 21(28.0) 2.695(1.534e4.739)Underlying conditions (%)None 5(13.9) 8(10.7) 0.620 1.216(0.576e2.565)Any 31(86.1) 67(89.3) 0.002 0.822(0.390e1.736)Solid tumor 14(38.9) 10(13.3) 0.922 2.307(1.407e3.783) 1.581 0.374e6.686 0.534Diabetes mellitus 7(19.4) 14(18.7) 0.772 1.034(0.527e2.032)COPD 5(13.9) 12(16) 0.725 0.892(0.404e1.967)Hematologic malignancy 4(11.1) 6(8) 1 1.263(0.561e2.842)Solid organ transplantation 4(11.1) 8(10.7) 0.111 1.031(0.441e2.411)Liver disease 3(8.3) 17(22.7) 0.099 0.414(0.141e1.216)IBD 3(8.3) 1(1.3) 0.715 2.432(1.291e4.580)Renal disease 2(5.6) 7(9.3) 0.495 0.667(0.190e2.333)HIV 2(5.6) 8(10.7) 0.030 0.594(0.167e2.114)Pregnancya 1(2.8) 9(12) <0.01 e 0.044Risk factorsCorticosteroid therapy 7(19.4) 14(18.7) 0.922 1.034(0.527e2.032)Alcoholism 2(5.6) 13(17.3) 0.137 0.376(0.101e1.407)AcquisitionCommunity 22(61.1) 61(81.3) 0.022 0.530(0.317e0.887)Nosocomial þ health careerelated 14(38.9) 14(18.7) 1.886(1.127e3.158)Clinical syndromesSepsis 22(61.1) 35(46.7) 0.154 1.489(0.853e2.599)CNS disease 11(30.6) 24(32) 0.878 0.955(0.532e1.716) 2.284 0.573e9.106 0.242Shock 8(22.2) 5(6.7) 0.017 2.154(1.266e3.665) 7.458 1.294e42.977 0.025Gastroenteritis 2(5.6) 7(9.3) 0.715 0.667(0.190e2.333)Peritonitis 1(2.8) 5(6.7) 0.662 0.500(0.082e3.054)Site of isolationBlood 34(94.4) 62(82.7) 0.089 2.656(0.711e9.925) 4.954 0.634e38.717 0.127CSF 7(19.4) 24(32) 0.168 0.623(0.305e2.407)Appropriate empirictreatment

Single agent 11(30.6) 34(45.3) 0.138 0.645(0.354e1.175)Combined therapy 19(52.8) 33(44) 0.386 1.268(0.741e2.171)

13(36.1) 40(53.3) 0.089 0.619(0.350e1.093)Definite treatmentAmpicillin 4(11.1) 20(26.7) 0.085 0.453(0.178e1.155)AMP þ GEN 7(19.4) 22(29.3) 0.267 0.683(0.336e1.386)SXT 5(13.9) 5(6.7) 0.213 1.629(0.821e3.234)AMP þ SXT 6(16.7) 1824 0.380 0.725(0.342e1.536)Carbapenems 1(2.8) 1(1.3) 0.545 1.557(0.379e6.394)Cephalosporin 2(5.6) 1(1.3) 0.245 2.118(0.908e4.940)Quinolones 1(2.8) 0 0.320 e

Others 6(16.7) 7(9.3) 0.261 1.508(0.780e2.913)Use for SXT 11(30.6) 23(30.7) 0.991 0.996(0.556e1.785)Use of ampicillin 17(47.2) 59(78.7) 0.001 0.421(0.0.246e0.691) 0.146 0.034e0.619 0.009Use of aminoglycosides 8(22.2) 22(29.3) 0.430 0.771(0.397e1.500)

AMP þ GEN, ampicillin with gentamicin; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CSF, cerebrospinalfluid; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; Others, amoxicillin/clavulanic acid, tobramycin andpiperacillin-tazobactam SXT, trimethoprim/sulfamethoxazole. All qualitative variables are dichotomous.a Pregnancy: No mother died and only one miscarriage occurred. The multivariate unconditional logistic regression model consisted of

independent variables for age >Z 65year, Ultimately or Rapidly Fatal McCabe and Jackson score, solid tumor, pregnancy, CNS disease,shock, blood as site of isolation and use of aminoglycosides.

26 P. Mu~noz et al.

Listeriosis: An emerging problem 27

a significantly higher percentage of appropriate empirictherapy [in 19 cases (54.3%) vs. 26 (34.2%), P Z .04]. Pa-tients with CNS listeriosis more frequently received com-bined therapy [in 23 cases (65.7%) vs. 30 (39.5%),P Z .01], which consisted mainly of the combination of am-picillin plus SXT in 14 cases (40%) or ampicillin plus gentami-cin in 9 (25.7%).

Listeriosis according to underlying conditionsTable 5 shows the case characteristics of patients with lis-teriosis according to their main underlying condition.

PregnancyNine pregnant women developed listeriosis (8.1%), 4 in thesecond term and 5 in the third. One woman, who becameinfected in week 13, had a miscarriage. The remainingnewborns did not present Listeria infection. All pregnant pa-tients presented with community-acquired primary bacter-emia and empirical therapy was inappropriate in 2pregnant women (22.2%). The most common antimicrobialdrug was ampicillin, which was administered alone in 3 cases(33.3%) and with gentamicin in a further 3 cases (33.3%). SXTwas not used in this population. No pregnant women died.

HIV-infectionTen listeriosis patients had HIV infection (9%). All thepatients, except one, were younger than 50 years (meanage 40 � 7.6). Median CD4þ count was 166 (IQR 92-339)cells/ml. None of the patients were taking prophylaxis withSXT for different reasons (eg, poor adherence, leukopenia).Clinical presentation in this population included CNS in-fection in 4 patients (40%), primary bacteremia in 3 (30%),gastroenteritis in 2(20%), and peritonitis in 1(10%). Empir-ical therapy was inappropriate in 7 episodes (70%). Themost common antimicrobial drug was ampicillin, which wasadministered with gentamicin in 5 cases (50%), alone in 3cases (30%), and with SXT in 2 cases (20%). One patient withC3 stage AIDS died due to CNS listeriosis (10%).

Hematologic malignancyTen listeriosis patients had hematologic malignancy (9%): 5with leukemia (2 underwent transplantation), 1 Hematologicstemcells transplant (HSCT) recipient, 2withmyelodysplasticsyndrome, 1 with multiple myeloma, and 1 with mycosisfungoides. Neurological infection predominated in 6 patients(60%), followed by primary bacteremia in 3 (30%) and 1bacteremic gastroenteritis (10%). Empirical therapy was in-appropriate in 20%. Themost common antimicrobial drug wasampicillin (60%),whichwas administeredwith gentamicin in 3cases (30%),withSXT in2cases (20%)andalone in1 case (10%).Four patients receiving chemotherapy died (40%).

Solid tumorSolid tumor was the most frequent underlying condition inour series (21.6%, 24 patients). The tumors most commonlyaffected the lung (n Z 6), breast, prostate, endocrine sys-tem, and small bowel (2 each). The predominant clinicalpresentation in this population was primary bacteremia in18 patients (75%), followed by CNS infection in 5 patients(20.8%) and 1 endocarditis (4.2%). Empirical therapy was in-appropriate in 75%. SXT was the most commonly used drug(45%): it was administered with ampicillin in 4 cases (16.7%)and alone in 7 (29.2%). Ten patients died of the infection(41.7%). The underlying tumors of the patients who died in-volved the breast (n Z 2, 8.3%), lung (n Z 3, 12.5%), bowel(n Z 2, 8.3%), and genitourinary tract (n Z 2, 8.3%), and 1

patient had Ewing sarcoma (4.2%). Six of the patients whodied had metastatic disease (25%).

Solid organ recipientsSolid organ transplant (SOT) recipients were the second most

commonly affected population in our series (12 patients[10.8%];7 liver, 3 kidney, and2heart). Listeriosiswasdetecteda mean of 29 months after transplantation (from 3 weeks to 9years). None of the SOT patientswho developed listeriosis wasreceiving SXT prophylaxis when the disease was diagnosed.The most common clinical presentations in this populationwere CNS infection and primary bacteremia (5 patients, 41.7%each), followed by gastroenteritis (kidney recipient) andperitonitis (liver recipient). Empirical therapywas inappropri-ate in 5 cases (41.7%). Combined therapy was used in 11 cases(92%) (highest rate) and ampicillin was the most commonlyused drug [with gentamicin in 6 cases (50%), with SXT in 5(41.7%), and alone in 1 (8.3%)]. Three patients (2 liverrecipients and 1 kidney recipient) died of the infection (25%).

Liver diseaseLiver disease was the main underlying condition in 16patients (14.4%): Eleven had alcoholic cirrhosis, 2 HCVrelated cirrhosis, and 3 cryptogenic cirrhosis. Four HIV-infected patients also had severe liver disease, althoughthey were analyzed together with the AIDS patients. Themost common clinical presentation in this population wasCNS infection in 6 patients (37.5%), followed by primarybacteremia in 4 (25%) and peritonitis in 4 (25%). One patient(6.3%) had endocarditis and another bacteremic gastroen-teritis. Empirical therapy was inappropriate in 8 cases(50%). The most common antimicrobial drug was ampicillin,which was administered alone in 6 cases (37.5%), withgentamicin in 5 (31.3%), and with SXT in 2 (12.5%). Twopatients died of the infection (10%) (one of meningoen-cephalitis and the other of peritonitis).

No underlying conditionThirteen listeriosis patients had no underlying conditions(11.7%). All these cases occurred during the second period.Interestingly, all were over 50 years old, except for onewoman 39 years old. None of these patients had alcoholismor were taking immunosuppressive therapy. All patients hada stage 1 of the McCabe and Jackson score. The mostcommon clinical presentation in this population was pri-mary bacteremia in 7 patients (53.8%), followed by CNSinfection in 4 (30.8%). Two patients had bacteremicgastroenteritis (15.4%). Empirical therapy was inappropri-ate in 11 cases (84.3%). The most common antimicrobialdrug was ampicillin, which was administered with SXT in 3cases (23.1%), with gentamicin in 2 (15.4%), and alone in7.7%. Four patients died of the infection (30.8%).

Review of the literatureThe characteristics of the most important series on listeri-osis are shown in Table 6. We were able to identify 12 stud-ies of listeriosis with more than 30 cases, besides thepresent report (PR), published from 1971e2007.6,8e19

Eleven reports came from Europe and two from US.16,18,19

Most studies (10 out of 12) reflect national registries andonly 3 came from single center experiences (includingPR). Overall, 6907 patients were included (354 from singlecenter studies). Incidence of listeriosis ranged from 1.6/million inhabitants in Austria12 to 10.3 cases/million inhab-itants in our area of Madrid, Spain. The other study from

Table 4 Characteristics of 111 patients with central nervous system listeriosis by infection status of the central nervoussystem.

Characteristic Non-CNS N Z 76(%) CNS N Z 35(%) P

Median age(SD) 58.3(19.4) 55.1(15.6) 0.40Age � 65 years 35(46.1) 8(22.9) 0.02Male sex 47(61.8) 18(51.4) 0.30Underlying conditionsNone 9(11.8) 4(11.4) 1Solid tumor 19(25) 5(14.3) 0.20Diabetes mellitus 15(19.7) 6(17.1) 0.74COPD 14(18.4) 3(8.6) 0.25Liver disease 10(13.2) 6(17.1) 0.57Pregnancy 9(11.8) 0 0.05Solid organ transplantation 7(9.2) 5(14.3) 0.42Heart 1(1.3) 1(2.9) 0.53Liver 4(5.3) 3(8.6) 0.67Kidney 2(2.6) 1(2.9) 1Renal disease 7(9.2) 2(5.7) 0.71HIV 6(7.9) 4(11.4) 0.72Hematologic malignancy 4(5.3) 6(17.1) 0.07Inflammatory bowel disease 3(3.9) 1(2.9) 1Risk factorsCorticosteroid therapy 13(17.1) 8(22.9) 0.47Alcoholism 11(14.5) 4(11.4) 0.77Community-acquired 55(72.4) 28(80) 0.39Clinical characteristicsAltered consciousness 22(28.9) 26(74.3) 0.00Shock 9(11.8) 4(11.4) 1Headache 5(6.6) 21(60) 0.00Seizures 0 6(17.1) 0.001Adequate empiric therapya 26(34.2) 19(54.3) 0.04TreatmentSingle agent 40(52.6) 12(34.3) 0.07Combined 30(39.5) 23(65.7) 0.01Definite treatmentAmpicillin alone 15(19.7) 9(25.7) 0.47AMP þ GEN 20(26.3) 9(25.7) 0.94SXT alone 8(10.5) 2(5.7) 0.5AMP þ SXT 10(13.2) 14(40) 0.001Carbapenems 2(2.6) 0 1Cephalosporin 2(2.6) 1(2.9) 1Quinolones 1(1.3) 0 1Others 12(15.8) 1(2.9) 0.06Use of SXT 18(23.7) 16(45.7) 0.01Use of ampicillin 45(59.2) 31(88.6) 0.002Use of aminoglycosides 21(27.6) 9(25.7) 0.83Overall mortality 25(32.9) 11(31.4) 0.87Related mortality 17(22.4) 10(28.6) 0.47

AMP þ GEN, ampicillin with gentamicin; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; HIV, human immu-nodeficiency virus; IBD, inflammatory bowel disease; Others, amoxicillin/clavulanic acid, tobramycin and piperacillin-tazobactam SXT,trimethoprim/sulfamethoxazole.a Adequate empirical therapy: intravenous administration of an active drug (ampicillin, cotrimoxazole [SXT], carbapenem, piperacil-

lin/tazobactam, amoxicillin/clavulanic acid, or vancomycin) initiated before knowing the isolation of L. mococytogenes.

28 P. Mu~noz et al.

Spain that provided incidence data, reported 6 cases/mil-lion inhabitants during the period 1971e19996; this figurewas very similar to the incidence of Finland (7 cases/mil-lion),9 Denmark (4.2e7.5),15 Germany (6.2).14 or France(3.5e5.6)10 In all series a substantial proportion of patientswere older than 65 years old (mean 54.9%) and the

proportion ranged from 38.7 in the PR to 76% in Germany(71% in England or France, 76% in Germany, 68% in theUS). No underlying condition was detected in a mean of15.5% of the patients with listeriosis. This proportionranged from 4.2% in Finland to 29% in the Netherlands or30% in Denmark.11 Only four studies (all from Spain)

Table 5 Case characteristics among listeriosis patients (N Z 111) by main underlying condition.

Main underlyingcondition Variable

Pregnancyn Z 9(%)

HIVn Z 10(%)

Hematologicmalignancyn Z 10(%)

Solid tumorn Z 24(%)

SOTn Z 12(%)

Liver diseasen Z 16(%)

Nonen Z 13(%)

Median age (IQR) 26(23e34) 39(34e46) 58(47e76) 71(57e76) 48(39e63) 54(46e66) 74(54e83)Clinical syndromesCNS 0 4(40) 6(60) 5(20.8) 5(41.7) 6(37.5) 4(30.8)Sepsis 9(100) 3(30) 3(30) 18(75) 5(41.7) 4(25) 7(53.8)Endocarditis 0 0 0 1(4.2) 0 1(6.3) 0Gastroenteritis 0 2(20) 1(10) 0 1(8.3) 0 2(15.4)Peritonitis 0 1(10) 0 0 1(8.3) 4(25) 0Clinical characteristicsFever 9(100) 10(100) 10(100) 18(75) 9(75) 13(81.3) 6(46.2)Diarrhea 0 3(30) 2(20) 1(4.2) 0 2(12.5) 3(23.1)Vomiting 0 1(10) 4(40) 3(12.5) 1(8.3) 2(12.5) 2(15.4)Headache 0 3(30) 3(30) 4(16.7) 4(33.3) 5(31.3) 4(30.8)Altered consciousness 0 7(70) 4(40) 11(45.8) 7(58.3) 7(43.8) 6(46.2)Seizures 0 0 2(20) 2(8.3) 1(8.3) 1(6.3) 0Shock 0 1(10) 0 2(8.3) 4(33.3) 4(25) 1(7.7)Positive cultureBlood 9(100) 7(70) 10(100) 22(91.7) 11(91.7) 13(81.3) 10(76.9)CSF 0 4(40) 3(30) 6(25) 4(33.3) 6(37.5) 4(30.8)Peritoneal fluid 0 1(10) 0 0 1(8.3) 3(18.8) 0Adequate empirictreatmenta

7(77.8) 3(30) 8(80) 6(25) 7(58.3) 8(50) 2(15.4)

Combined definitetreatment

3(33.3) 7(70) 5(50) 8(33.8) 11(91.7) 7(43.8) 5(38.5)

Definite treatmentAmpicillin alone 3(33.3) 3(30) 1((10) 1(4.2) 1(8.4) 6(37.5) 1(7.7)AMP þ GEN 3(33.3) 5(50) 3(30) 4(16.7) 6(50) 5(31.3) 2(15.4)SXT alone 0 0 0 7(29.2) 0 1(6.3) 0AMP þ SXT 0 2(20) 2(20) 4(16.7) 5(41.7) 2(12.5) 3(23.1)Carbapenems 0 0 0 1(4.2) 0 1(6.3) 0Cephalosporin 0 0 2(20) 1(4.2) 0 0 0Quinolones 0 0 0 1(4.2) 0 0 0Others 2(22.2) 0 2(20) 2(8.3) 0 1(6.3) 5(38.5)Use of ampicillin 6(66.7) 10(100) 6(60) 9(37.5) 12(100) 13(81.3) 6(46.2)Use of SXT 0 2(20) 2(20) 11(45.8) 5(41.7) 3(18.8) 3(23.1)Use of aminoglycosides 3(33.3) 5(50) 3(30) 5(20.8) 6(50) 5(31.3) 2(15.4)Overall mortality 0b 2(20) 4(40) 14(58.3) 4(33.3) 2(12.5) 5(38.5)Related mortality 0 1(10) 4(40) 10(41.7) 3(25) 2(12.5) 4(30.8)

AMP þ GEN, ampicillin with gentamicin; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CSF, cerebrospinalfluid; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; IQR, interquartile range; Others, amoxicillin/clavulanicacid, tobramycin and piperacillin-tazobactam SOT: solid organ transplant, heart,2 kidney,3 liver;7 SXT, trimethoprim/sulfamethoxazole.a Adequate empirical therapy: intravenous administration of an active drug (ampicillin, cotrimoxazole [SXT], carbapenem, piperacil-

lin/tazobactam, amoxicillin/clavulanic acid, or vancomycin) initiated before knowing the isolation of L. mococytogenes.b One pregnant patient had a miscarriage.

Listeriosis: An emerging problem 29

reported the use of aminoglycosides which was surprisinglylow (27%e32%).6,8,17[PR] Mean mortality rate was 24.8% inour literature review (ranging from 61% to 9%).

Discussion

We present one of the largest series of invasive listeriosisever reported from a single institution. Our data werecollected from 1986 to 2007 in the same institution ofMadrid, which essentially served the same population andused similar methodology throughout the study period. Wepresent case characteristics by specific patient populations

and have included the severity of illness and antibiotictreatment in the multivariable modeling for invasive liste-riosis mortality.

We showed that the incidence of listeriosis has increasedin recent years (from 4.66 cases/million inhabitants in thefirst period to 10.39 cases/million inhabitants in thesecond) and that it has specially augmented in patientswith no underlying medical conditions. We found thatclinical suspicion is hampered by non-specific clinical pre-sentation in the form of primary bacteremia. Consequently,the rate of appropriate empirical therapy is low, especiallyin patients with HIV infection, neoplasia, or no underlying

Table 6 Characteristics of the studies of listeriosis with more than 30 cases, 1971e2007.

Ref Country Type of study Study period No. of patients IncidenceCases/millioninhabitants

Percentage of patientsolder than 65 years

Percentage fpatients wi outunderlyingconditions

Percentage ofuse ofaminoglycosides

Percentageof mortality

6 Spain Single center 1971e1999 31 6 42 22 32 6117 Spain Single center 1983e2006 102 No data 44.1 19.6 32 20.613 England

and WalesNationalregistry

1990e2004 1180 2.13e3.47 71 14 No data 44

8 Spain Single center 1991e2005 110 No data No data 4.5 31 (data of 35patients withmeningitis)

16.3

19 France Nationalregistry

1992 225 No data 71 (older than59 years old)

19 No data 24

18 US Nationalregistry

1992e2004 285 No data 53.3 4.9 No data 18.6

15 Denmark Nationalregistry

1994e2003 298 4.2e7.5 50 (older than70 years old)

30 No data 21

9 Finland Nationalregistry

1995e2004 75 7 57 4.2 No data 16

11 Netherlands Nationalregistry

1995e2003 159 2 40 29 No data 18

16 US Nationalregistry

1996e2003 766 3.1e4.1 68 (older than50 years old)

No data No data 21

12 Austria Nationalregistry

1997e2007 150 1.6 48.6 12.6 No data 28.7

14 France Nationalregistry

1999e2006 1896 3.5e5.6 No data No data No data No data

10 Germany Nationalregistry

2001e2005 1519 6.2 76 (older than60 years old)

No data No data 9

PR Spain Single center 1986e2007 111 4.6e10.3 38.7 11.7 27 24.3

30P.

Mu~nozetal.

oth

Listeriosis: An emerging problem 31

condition. Changes have also occurred in therapy, witha significant increase in the use of SXT and a decrease in theadministration of aminoglycosides. The mortality rate re-mains high despite fewer ultimately fatal underlying con-ditions in the target population.

The incidence of human listeriosis varies widely (inWestern Europe from 1.6 to 10.3 episodes/million inhabi-tants)9,11,15. We found only a few national studies from Eu-rope and the US comparing the incidence of listeriosisbetween different periods. Recent data point to an in-crease in Europe and a decrease in the US.6,9e13,15 A Frenchstudy showed that the incidence increased from 3.5 cases/million inhabitants in 2005 to 4.7 cases/million inhabitantsin 2006 and to 5.6 cases/million inhabitants in 2007.14 In theUS, Voetsh analyzed 776 cases of listeriosis and showed a re-duction in incidence from 4.1 cases/million inhabitants in1996 to 3.1 cases/million inhabitants in 2003 after the im-plementation of new food management policies.16 TheFoodNet data report shows that incidence remained stablein 2007 (2.7 cases/million inhabitants). Our recent inci-dence of 10.39 cases/million inhabitants is the highest re-ported in the published series with more than 30 cases oflisteriosis (Table 6).

The causes of the increased incidence of listeriosis insome studies are not clear. Changes in diet and foodpreparation may be important and part of the explanationmay be related to the increase in the consumption ofrefrigerated food in Europe. However, we could not findany food-related explanation for this trend in our geographicarea. Someauthors hypothesize that the reduction in the saltcontent of ready-to-eat food products may play a role,14 anddifferent studies have demonstrated the impact of foodmanagement policies.16,33 European projects, such as BIOL-ISME, have the objective to develop more efficient systemsto monitor the contamination levels of L. monocytogenesin industrial food producing-plants (http://www.biolisme.eu). Other potential explanations include improved case de-tection, undiagnosed outbreaks, or the increasing use of pro-ton pump inhibitors in the elderly, as suggested recently ina German study,34 among others.

One of the most important findings of our study is thesignificant increase in the episodes of listeriosis amongpatients older than 65 years (from 21.9% in the first 11 yearsto 45.6% in the second period), even though our rate issignificantly lower than in other studies in which patientsolder than 65 years account for more than 70% of the cases oflisteriosis (Table 6).10,13,19 This trend has also been observedby other authors. Julian et al.6 reported that, from 1971 to1999, the median age of patients with listeriosis increasedfrom 55 to 68 years. Other authors found that age >60 yearsinvolves an increased risk of listeriosis (OR 1.49e1.6),13,14

and that the incidence in this population increased moresteeply than in younger patients (2.6 vs. 1.7).10 This maybe due to immunosenescence and changes in innate andadaptive immunity leading to increased susceptibility to in-fection. The importance of this finding is stressed by thefact that, in most countries, the population is becomingolder. For example, in the province of Madrid the proportionof inhabitants older than 65 years old increased from10.4% in1986 to 14.2% in 2007. The proportion of male/female re-mained stable (0.93 and 0.94, respectively) (http://www.madrid.org/iestadis/fijas/estructu/demograficas/ censos/

retro108 htm).Given the highmortality anddifficulty inmak-ing the appropriate call for antibiotic treatment, we recom-mend that listeriosis should therefore be always consideredin elderly patients with fever.

A small proportion of our cases (15%) were classified asnosocomial, although this definition may be problematicdue to the unknown period of incubation of listeriosis whichmay depend on the ingested dose.

Underlying conditions

Our study shows that, at present, listeriosis predominatesin patients with non-fatal underlying diseases (69%) andthat it has significantly increased in patients with nounderlying conditions (0 patients in the first period and 13patients in the second period). In our study, the mostprevalent underlying conditions are malignancy, diabetesmellitus, COPD, and liver disease. HIV infection, pregnancy,and SOT, well recognized underlying conditions in listerio-sis,20,25,35,36 no longer represents the most important pre-disposing condition in our area. Listeriosis has significantlydecreased in SOT patients and in our study only 9% of thepatients have HIV infection. Possible explanations includethe widespread use of SXT prophylaxis among immunosup-pressed patients and strategies to prevent food-borne in-fections in susceptible populations which are usuallyadvised to avoid undercooked food.16,33 In our experience,none of the transplant recipients or HIV-infected patientswho developed listeriosis were receiving SXT prophylaxis;and in fact, very few cases of listeriosis in transplant recip-ients have been reported in the literature.24,37 A recent re-view of 30 SOT recipients demonstrated that diabetesmellitus, previous CMV infection, and high-dose prednisonewithin the preceding 6 months increase the risk of listeriosisin this population.25

Presenting syndromes

Primary bacteremia has become a more common clinicalpresentation of listeriosis (51%) than CNS infections. Rates ofprimary bacteremia in other studies vary from52% to 70%.6,18

Primary bacteremia clearly predominates in pregnantwomen and patients with non-hematological malignancy.This unspecific presentation may explain the low rate of ef-ficacious empirical therapy in HIV-infected patients (30%),patients with solid tumors (20.8%) or with no underlying con-dition (15.4%). However, evenwhen signs ofmeningeal irrita-tion are not present, neurological involvement should beexcluded in all patients with listeriosis.6,7

We detected 9 patients with only gastrointestinal man-ifestations, 6 peritonitis, 2 endocarditis and 2 infections ofprosthetic material. In the literature, focal Listeria infec-tions are uncommon, but peritonitis has been well de-scribed in patients with liver disease23 and Listeriaendocarditis is an unusual but very severe event.38e40

Treatment

Although no controlled trials on the treatment of listeriosishave been performed, many text-books and experts rec-ommend the use of ampicillin plus gentamicin to treat CNS

32 P. Mu~noz et al.

infections, endocarditis, and infections in immunocompro-mised patients.36,41,42 The IDSA guidelines of Listeria en-cephalitis recommends the use of ampicillin plusgentamicin or SXT (evidence A-III).43 The recommendationof adding an aminoglycoside are based on the delayedin vitro bactericidal activity of ampicillin, the synergic ef-fect of both agents in vitro, and on results of animalmodels.44 However, the risk of nephrotoxicity and the pos-sible teratogenic effect in pregnant women42 may exceedthe potential benefit attained with the addition of anaminoglycoside.

We could not demonstrate any benefit with combinedtherapy with aminoglycosides, not even in patients with CNSlisteriosis. The same finding was recently reported by Mitj�aet al, who analyzed 102 patients, 33(32%) treated withcombined beta-lactam and aminoglycosides and 69 (68%)with beta-lactams alone. Gentamicin had no impact on latemortality and increased early mortality.17 We believe thatcurrent recommendations should be reconsidered.

Cotrimoxazole is an excellent alternative for associa-tion, not only for allergic patients. It is effectivein vitro45and bactericidal, and has proven more effectivewhen combined with ampicillin than the combination ofampicillin plus gentamicin (93.3% vs. 43%).46 In our study,ampicillin was the most commonly used agent (68.5%) anda protective factor for mortality. The use of SXT increasedsignificantly in the second period (from 6.3% to 40.5%),while the use of aminoglycosides decreased (from 40.6%to 21.5%). We prefer the combination SXT and ampicillin,because of its decreased toxicity, but we could not demon-strate a therapeutic benefit with this combination. A pro-spective multicenter study analyzing this aspect iswarranted.

Outcome and poor prognostic factors

Listeriosis mortality remains at around 20%worldwide8,9,11,15e19 during the last two decades. In our re-view of the reports with more than 30 cases of listeriosis,mean mortality rate was 24.8% (Table 6), although therewere wide variations. Highest reported mortality was 61%in a single center study performed from 1971 to 99 with42% of patients older than 65 years.6 Lowest mortality ratewas 9% in a national German study with 76% patients olderthan 60 years.10 In our study, related mortality was slightlylower in the secondperiod (31%e21%), despite the significantdecrease in comorbidity ebut increase in agee of our popu-lation. Using amultivariate, unconditional logistic regressionmodel, we found that the presence of shock or a solid tumoras the underlying condition increased the risk of mortality,while the administration of ampicillin was a protective fac-tor. Other authors have reported increased mortality to beassociated with older age, non-hematological malignancy,alcoholism, corticosteroids, kidney disease, serogroup 4,and incorrect treatment.15,17e19

A limitation of our study is its retrospective nature, al-though most patients were attended by a member of our in-fectious diseases department. This retrospective designmade it impossible to analyze the potential implication ofH2-receptors antagonist or proton pump inhibitors in the in-creasing incidence of listeriosis.

Conclusion

Listeriosis has become an emerging public health problemin our area, and the causes of this increased incidence mustbe identified and solved especially with relatively higherrelated mortality among cases with no underlying medicalconditions. Most affected population is now elderly people,with or without concomitant underlying conditions, inwhom empiric therapy effective against Listeria must beconsidered. Use of combined treatment does not seem tobe justified, and optimal antimicrobial management shouldbe addressed in a well-designed multicenter study. An ef-fort addressed to control L. monocytogenes in food and toimprove preventive education in susceptible patients iswarranted.

Funding sources

Loreto Rojas is an infectious disease fellow with a grantsponsored by Fundaci�on Carolina-Fundaci�on BBVA.

Conflict of interest

None declared.

Acknowledgments

We thank Thomas O’Boyle for editing the manuscript.

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