CASE REPORT

Capnocytophaga canimorsus Meningitis: DiagnosisUsing Polymerase Chain Reaction Testingand Systematic Review of the Literature

Megan Hansen . Nancy F. Crum-Cianflone

Received: December 16, 2018 / Published online: January 31, 2019� The Author(s) 2019

ABSTRACT

Introduction: Capnocytophaga canimorsus infec-tions are associated with dog bites, especially inasplenic or immunocompromised patients, andtypically manifest as sepsis and/or bacteremia.Meningitis has been rarely described, and itsdiagnosis may be delayed due to poor or slowgrowth using traditional culture techniques. Weprovide our experience using polymerase chainreaction (PCR) to establish the diagnosis andperform a comprehensive review of C. canimor-sus meningitis cases to provide summary dataon the clinical manifestations, diagnosis, andoutcomes of this unusual infection.Methods: A systematic review of the peer-re-viewed English literature (PubMed, Embase,Ovid Medline) from January 1966 to March2018 was conducted to identify cases of C.canimorsus meningitis. Data collected includeddemographics, risk factors, cerebrospinal fluid(CSF) findings, PCR results, treatments, and

outcomes. Descriptive statistics are presented asnumbers (percentages) and medians (ranges).Results: A total of 37 patients were reviewedwith a median age of 63 years (12 days to83 years) with a male predominance (76%). Arelatively low proportion had an immunocom-promised state (16% splenectomy and 5% ster-oid use); the most common risk factor wasalcoholism (19%). Fifty-nine percent reported adog bite (all within B 14 days prior to presen-tation), while 22% reported a non-bite dogexposure, 3% reported cat bite, and 3% reportedboth dog and cat exposures; 11% reported noanimal contact. CSF parameters included amedian white count of 1024 cells/mm3, 81%had neutrophilic predominance, median pro-tein of 190 mg/dl, and median glucose CSF/serum ratio 0.23. In 54% of cases, blood cultureswere positive for C. canimorsus (median, 4 days)and 70% had positive CSF cultures (median,5 days). PCR established the diagnosis in eight(22%) cases. Antibiotic therapy was given for amedian of 15 days (range, 7 to 42 days). Prog-nosis was overall favorable with only one (3%)death reported and adverse neurologic and/orphysical sequelae in 19% of the survivors.Conclusion: C. canimorsus meningitis is a rarebut increasingly important clinical entityoccurring in patients of all ages, typically afterdog exposure. While classically considered aninfection among immunocompromisedpatients, most cases have occurred in previouslyhealthy, immunocompetent persons. Diagnosis

Enhanced digital features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.7599065.

M. Hansen � N. F. Crum-Cianflone (&)Internal Medicine Department, Scripps MercyHospital, San Diego, CA, USAe-mail: Nancy32red@yahoo.com

N. F. Crum-CianfloneInfectious Disease Division, Scripps Mercy Hospital,San Diego, CA, USA

Infect Dis Ther (2019) 8:119–136

https://doi.org/10.1007/s40121-019-0233-6

may be rapidly established by PCR, and this testshould be considered in culture-negative caseswith associated exposures. Outcome was gen-erally favorable after a median antibiotic dura-tion of 15 days.

Keywords: Capnocytophaga canimorsus; Menin-gitis; Review

INTRODUCTION

Capnocytophaga canimorsus, known formerly as‘‘dysgonic fermenter-2’’, is part of the normalflora in the mouths of dogs and, less commonly,cats. Data suggest that nearly a quarter of dogscarry this organism in their mouths with alower proportion among cats [1]. Transmissionto humans may occur via bites, scratches, orlicking; occasionally cases have been reportedafter non-contact-related exposures. Clinicalinfections caused by C. canimorsus include bac-teremia, septic shock, arthritis, endocarditis,and rarely meningitis [2, 3]. While Capnocy-tophaga is thought to be pathogenic primarilyamong immunocompromised persons, espe-cially those with a prior splenectomy, casesamong immunocompetent persons have beendescribed [3].

Capnocytophaga is a fastidious, gram-negativebacillus. Diagnosis can be made by culture;however, since the organism grows slowly (2–7 days) and requires blood or chocolate agarincubated with 10% carbon dioxide, the diag-nosis can be missed. Polymerase chain reaction(PCR) can be a valuable tool in establishing thediagnosis in cases of suspected infection, espe-cially in the setting of negative cultures and/orprior antibiotic exposure. While treatment isgenerally with beta-lactam antibiotics, includ-ing penicillins, there is a lack of clinical data onthe optimal treatment type and duration espe-cially for severe infections such as meningitis.

We report a case of C. canimorsus meningitisand provide a comprehensive review of theEnglish literature reviewing 36 additional pub-lished cases. Given the rarity of this condition,we summarize the risk factors, exposure history,symptoms, cerebrospinal fluid (CSF)

parameters, diagnosis, treatment, and outcomesof this condition.

METHODS

We report a case of C. canimorsus meningitisthat was diagnosed using PCR technology. CSFwas sent for cell counts and cultures and to theUniversity of Washington for testing using amultiplex PCR. Informed consent was obtainedfrom the individual participant reported on inthis article.

In addition to our case, a comprehensivesearch of peer-reviewed English literature(1961–present) was performed to identify pub-lished cases of Capnocytophaga meningitis andcompile relevant clinical data from these cases.The MEDLINE database was interrogated withthe following MeSH terms: ‘‘Capnocytophaga’’[MeSH], ‘‘Meningitis’’ [MeSH] and ‘‘Gram-Nega-tive Bacterial Infections’’ [MeSH] with addi-tional keyword searches with the terms‘‘Capnocytophaga,’’ ‘‘dysgonic fermenter-2,’’ and‘‘df-2.’’ Additionally, a search of Embase wasperformed with the following Emtree SubjectHeadings: ‘‘Capnocytophaga,’’ ‘‘Meningitis,’’ and‘‘Gram-Negative Infection.’’

Cases involving species other than C. cani-morsus were excluded (e.g., C. gingivalis [5], C.cynodegmi [6]), as were cases not published inEnglish literature or that did not include indi-vidual case data [7]. Additionally, C. canimorsuscausing other types of central nervous infec-tions (e.g., brain abscess) were excluded. Addi-tional cases included in this review wereidentified through a review of articles on Cap-nocytophaga canimorsus meningitis as well asreviews of severe Capnocytophaga canimorsusinfections.

Data collected included demographic andclinical information including age, sex, preex-isting medical conditions, history of splenec-tomy, animal contact, symptoms, serum whitecell count, time to positive blood cultures,results of head imaging, CSF counts and cultureresults, antibiotic selection and duration, andpatient outcome. A total of 37 cases of Capno-cytophaga canimorsus meningitis were identifiedincluding the current case.

120 Infect Dis Ther (2019) 8:119–136

RESULTS

Case Report

A 71-year-old Caucasian female was foundaltered at home and transferred to an outsidehospital. On presentation, she complained offevers and severe headaches; however, she wasuncertain of the length of her illness. Vitalssigns included a temperature of 38.8 �C, pulse of100 beats per minute, respiration 20 breaths perminute, and blood pressure of 182/86 mmHg.She had an altered mental status andmeningismus including neck stiffness. Therewere no focal neurologic deficits or otherexamination findings.

Past medical history was remarkable forrecently diagnosed lung cancer status-postlobectomy; she did not require adjunctivechemoradiation therapy. She also had a historyof hypertension and chronic subdural hema-toma. She denied diabetes, alcohol abuse, orprior splenectomy. She lived in Southern Cali-fornia and reported no recent travel history. Sheowned a dog and frequented a dog park withcontact with several canines on a regular basis;she reported no dog bites.

Laboratory data on presentation werenotable for a white blood count of 19,900 cells/mm3 (92% neutrophils), hemoglobin 13 g/dl,and platelets of 196 9 103/mm3. Lactate levelwas 2.4 mmol/l, creatinine was 1.0 mg/dl, andglucose was 109 mg/dl. Liver function tests andurinalysis were within normal limits.

A magnetic resonance image (MRI) with andwithout gadolinium showed left occipital andparietal acute infarcts without mass effect andstable small bilateral frontal subdural hemato-mas. A lumbar puncture was performed duringthe first 24 h of admission and revealed neu-trophilic pleocytosis (590 white cells/mm3; 95%polymorphonuclear cells), red cell count of2600 cells/mm3, low glucose of 12 mg/dl (ref-erence range, 40–70 mg/dl), and elevated pro-tein level of 413 mg/dl (reference range,15–59 mg/dl). Gram stain did not show anyorganisms.

The patient was started on empiric antibiotictherapy with intravenous vancomycin and

piperacillin-tazobactam prior to the lumbarpuncture, but antibiotics were changed after thelumbar puncture revealed meningitis to intra-venous vancomycin 500 mg every 8 h, ampi-cillin 2 g every 4 h, and ceftriaxone 2 g every12 h; no steroids were administered.

Blood cultures (two sets) were drawn onadmission using BD Plus Aerobic/F and BDLytic/10 Anaerobic/F media. The first set waspositive at approximately 4 days (98 h) and thesecond set at 4.6 days (110 h), in both the BDLytic/10 Anaerobic/F media. The gram stain wasreported as gram-negative rods with bacterialgrowth on plates by day 6. Matrix Assisted LaserDesorption/Ionization Time of Flight MassSpectrometry (MALDI-TOF) was performed, butno identification was obtained. A Remel RapIDANA II test system was used for a biochemicalidentification, and Capnocytophaga was identi-fied. The organism could not be successfullygrown on culture for susceptibility testing.

Cerebrospinal fluid (CSF) cultures obtainedon admission were sterile; however, antibioticshad been given prior to the lumbar puncture.Due to high suspicion of Capnocytophaga cani-morsus as the causative organism given thepatient’s exposure to dogs, a CSF specimen wassent to the University of Washington for mul-tiplex broad-range bacterial polymerase reac-tion (PCR) testing, which was positive for C.canimorsus.

Antibiotic therapy was modified to mer-openem 2 g IV q8 h. A transthoracic echocar-diogram did not show vegetations and a chest,abdominal, and pelvic CT scan was unremark-able except for post-surgical finding consistentwith prior lung lobectomy. The spleen appearedwithin normal limits. Repeat blood culturesafter the initiation of antibiotics showed nogrowth.

The patient’s meningismus resolved duringher hospital stay, and at the time of dischargeher headache was significantly improved. Shecompleted a 21-day total course of antibioticsand subsequently made a full recovery. She waseducated on the potential infectious risks asso-ciated with dog ownership/exposure.

Infect Dis Ther (2019) 8:119–136 121

Review of the Literature

A total of 37 cases of Capnocytophaga canimorsusmeningitis were identified including the currentcase (Table 1) [2, 4, 8–28]. Median age at pre-sentation was 63 years (range, 12 days to83 years) with a male predominance (28/37,76%). While C. canimorsus meningitis has clas-sically been characterized as a disease ofimmunocompromised patients, particularlypatients who are asplenic, only 16% (6/37) ofpublished cases occurred in patients withsplenectomies. Five percent (2/37) had activesteroid use. When summating all possibleimmunosuppressive states (e.g., medications orthe presence of splenectomy or hematologic/autoimmune condition that impairs theimmune system), 24% (9/37) of cases had one ofthese conditions: 5 splenectomy, 1 splenectomyand lymphoma, 2 steroid use, and 1 rheumatoidarthritis. Additionally, alcoholism was noted in19% (7/37) and was the most common singlemedical condition identified.

Regarding animal exposure history, themajority of patients (59%; 22/37) reported arecent dog bite. The timing between the dogbite and presentation was a median of 6 days(range, 3 to 14 days). A smaller proportionreported non-bite dog exposures (22%; 8/37)and single cases of non-bite exposures to bothdog and cat (3%, 1/37) and a cat bite (3%; 1/37).In addition, there was one reported case ofindirect contact through two health providerswho owned dogs. Overall, 11% (4/37) indicatedno known animal contact prior to developmentof meningitis.

Presenting symptoms often included fever,headache, neck stiffness, altered mental status,and photophobia (Table 1). Other manifesta-tions included rash in six cases, which wasdescribed as macular/papular in most cases; twocases had a rash that had a petechial/purpuricappearance. Other symptoms included seizures,myalgias, vomiting, fatigue, and hearing loss.Serum white blood cell (WBC) count wasreported elevated in 11 (69%) of 16 cases thatreported these data with a median WBC countof 13,500 cells/mm3 (range, 8000–25,000 cells/mm3).

CSF studies demonstrated a pattern consis-tent with bacterial meningitis with elevated CSFwhite counts of a median of 1024 cells/mm3

(range, 0–15,630 cells/mm3) with only one casewith a normal white count. Most cases hadneutrophilic predominance (81%, 26/32 caseswith data). In addition, an elevated CSF proteinwas noted in 92% (22/24) of cases with a med-ian value of (190 mg/dl) and low CSF/serumglucose ratio in all cases (median, 0.23). In casesthat reported brain imaging, it was typicallynormal but in three cases (19%; 3/16 withimaging data), including the present case, acuteinfarcts were noted, and one additional casehad cerebritis.

Blood cultures were found to be positive in20 (54%) cases with a median growth time of4 days (range, 2–9 days); 9 (24%) had negativeblood cultures and 8 (22%) did not reportresults. CSF cultures were positive in 26 (70%) ofcases with a median growth time of 5 days(range, 1–9 days). Due to the relatively longtime for cultures to become positive, PCR isemerging as an important diagnostic technique.PCR was utilized to establish the diagnosis inthe current case and overall in eight (22%) casesin this review.

Treatment involved extended courses ofantibiotics with median treatment duration of15 days (7–42 days). The most commonly uti-lized antibiotics were penicillin, ampicillin, andcephalosporins. Antibiotic susceptibilities werepresented in eight cases in the literature withmany cases lacking data, often because ofinsufficient growth of the bacteria on culturemedia. Overall, penicillins (including ampi-cillin), second- and third-generation cephalos-porins, carbapenems (e.g., imipenem), andfluoroquinolones were susceptible in all casesreporting data for these antibiotics (Table 2).

Outcomes were generally favorable with onlyone (3%) death observed in the published cases;this death may have been unrelated to theinfection as the patient died of a cardiac arrest10 days after discharge and had known coro-nary artery disease. Overall, 19% of survivors (7/36) had chronic sequelae of the disease includ-ing four with hearing loss, one with chronicheadaches/disorientation, one with extremityamputations and chronic neurologic

122 Infect Dis Ther (2019) 8:119–136

Table1

Summaryof

Capnocytophagacanimorsusmeningitiscasesin

thepublishedliterature,n=37

Case

no.

First

author,

year

[reference]

Age/sex

Medical

cond

itions

History

ofsplenectom

y,y/n

Animal

contact

Symptom

sSerum

WBC

(cells/m

m3)

Blood

cultures,

positive

y/n,

time

toresult

1Bobo,

1976

[8]

42/M

Alcoholism

NDog

bites(two)

6and

7days

before

Fevers,seizures,headache

8,900

Yes,3

days

2Butler,

1977

[2]

26/M

Splenectom

yY

Dog

bite

4days

prior

NR

NR

Yes;time

not

reported

3Butler,

1977

[2]

25/M

Splenectom

yY

Dog

bite

3days

prior

NR

NR

Yes;time

not

reported

4Butler,

1977

[2]

17/M

Splenectom

yY

Dog

biteseveraldaysprior

NR

NR

Yes;time

not

reported

5Ofori-

Adjei,

1982

[9]

66/F

None

NDog

exposure

butno

historyof

bites

Fever,myalgias,headache,p

hotophobia,

vomiting,neck

stiffness,m

acular

rash

confi

nedto

trun

k

10,800

Negative

6Chan,

1986

[10]

63/M

Hypertension

NDog

bite,1

4days

before

Fevers,rigors,arthralgiaanderythematous

rash

ontrun

k14,500

Yes,2

days

7Carpenter,

1987

[11]

26/M

Splenectom

y,

Hodgkin’s

lymphom

ain

remission

YCat

bite,scratches

Fevers,m

yalgias,malaise,p

hotophobia,

headache

13,400

Yes,3

days

8Westerink,

1989

[12]

26/M

None

NDog

exposure

Fevers,h

eadaches,m

yalgias,vomiting,

erythematousandpruriticrash

starting

onback

andspreadingto

extrem

ities,

confl

uent,b

lanching

maculopapular

rash

over

forehead,b

ackandanterior

dorsal

aspectsof

upperandlower

extrem

ities,

dorsum

ofhand

sandfeet;petechialrash

onlower

extrem

ities.Palms/solesspared.

11,500

Yes,4

days

9Im

anse,

1989

[13]

39/F

None

NDog

andcatexposure

Fever,malaise,h

eadache,vomiting,dizziness,

completehearingloss,gaitinstability

11,300

Yes,5

days

Infect Dis Ther (2019) 8:119–136 123

Table1

continued

Case

no.

First

author,

year

[reference]

Age/sex

Medical

cond

itions

History

ofsplenectom

y,y/n

Animal

contact

Symptom

sSerum

WBC

(cells/m

m3)

Blood

cultures,

positive

y/n,

time

toresult

10Herbst,

1989

[14]

47/F

Alcoholism

NDog

exposure

Unresponsive,febrile,hypotensive,w

idespread

purpuricrash;purple-red

patchesin

reticulatedpatternarms/abdomen/thighs/

lower

legs/feetwithpetechiaeat

periphery

20,700

w/significant

leftshift

Yes,tim

enot

reported

11Krol-van

Straaten,

1990

[15]

75/F

Splenectom

yY

Dog

bite

9days

earlier

Fevers,changeof

mentalstatus

25,000

Negative

12Blanche,

1994

[16]

57/M

None

NDog

bite,9

days

earlier

Fevers

NR

Yes,5

days

13Kristensen,

1996

[17]

74/M

Heartfailure

NDog

bite,severaldays

earlier

Fever,confusion

NR

Negative

14Pers,1

996

[18]

74/M

CAD

NDog

bite

7days

prior,

received

unknow

nabx

prophylactically

Meningitis,symptom

snotspecified

NR

NR

15Pers,1

996

[18]

80/M

CAD

NDog

bite

3days

prior

Meningitis,symptom

snotspecified

NR

NR

16Pers,1

996

[18]

83/M

Rheum

atoid

arthritis

NNoknow

nanim

alexposure

Meningitis,symptom

snotspecified

NR

NR

17Pers,1

996

[18]

42/M

None

NNoknow

nanim

alexposure

Meningitis,symptom

snotspecified

NR

NR

18Pers,1

996

[18]

74/M

None

NDog

exposure

withno

historyof

bites

Meningitis,symptom

snotspecified

NR

NR

19Lion,

1996

[3]

54/M

Alcoholism

NDog

bite,1

0days

earlier

NR

NR

Yes,3

days

124 Infect Dis Ther (2019) 8:119–136

Table1

continued

Case

no.

First

author,

year

[reference]

Age/sex

Medical

cond

itions

History

ofsplenectom

y,y/n

Animal

contact

Symptom

sSerum

WBC

(cells/m

m3)

Blood

cultures,

positive

y/n,

time

toresult

20Risi,2000

[19]

65/F

None

NPo

ssiblesecond

hand

exposure

?procedure

performed

byradiologisthad3dogs

andtech

had2dogs

Chills,m

yalgias,fatigue,confusion

Not

reported

NR

21LeMoal,

2003

[20]

45/M

Alcoholism

NDog

bite

9days

prior

Fevers,h

eadache,confusion,

photophobia,

meningism

us15,700

Negative

22Rosenman,

2003

[21]

12days/

FRecentsteroiduse,

gonadal

dysgenesis

NAbrasionfrom

dogtooth

Fevers,p

oorfeeding,irritability

23,900

Negative

23Gottwein,

2006

[22]

56/M

Alcoholism

NDog

bite,1

0days

earlier

Headache,fever,chillsdiarrhea,vom

iting,

arthralgia

12,900

Yes,7

days

24Meybeck,

2006

[23]

65/M

Pulmonary

embolism

NDog

bite,5

days

earlier

Fever,headache,confusion

8,000

Yes,2

days

25de

Boer,

2007

[24]

69/M

COPD

onsteroids

NDog

bite,4

days

earlier

Fevers,chills,confusion

20,500

Yes,9

days

26de

Boer,

2007

[24]

58/M

None

NNone

Headache,fever,malaise,n

ausea

13,700

Yes,9

days

27Gasch,

2009

[25]

64/M

None

NDog

bite

7days

earlier

Fever,headache,severehearingloss,d

izziness

Normal(#

not

reported)

Negative

28Monrad,

2012

[26]

66/M

Alcoholism

NRecentdogbite

Confusion,tachycardia,fever;neck

stiffness

andbilateralhearinglossnotedafter48

hNR

Negative

Infect Dis Ther (2019) 8:119–136 125

Table1

continued

Case

no.

First

author,

year

[reference]

Age/sex

Medical

cond

itions

History

ofsplenectom

y,y/n

Animal

contact

Symptom

sSerum

WBC

(cells/m

m3)

Blood

cultures,

positive

y/n,

time

toresult

29Monrad,

2012

[26]

67/F

Splenectom

yY

2dogs

inhousehold;

nobites

Fever,headache,confusion,transient

right

arm

paresis

NR

Negative

30Monrad,

2012

[26]

79/M

None

NDog

bite

7days

prior

Unconscious

athome

NR

NR

31Beernink,

2016

[27]

52/M

None

NDog

lickedscratcheson

knee

severaldays

prior

toadmission

Headache,dizziness

12,000

NR

32Van Sa

mkar,

2016

[28]

78/M

None

NDog

bite

4days

prior

Neckstiffness,alteredmentalstatus

NR

Positive,

3days

33Van Sa

mkar,

2016

[28]

37/M

Alcoholism

NDog

bite

4days

prior

Headache,fever,nausea,generalized

rash

NR

Negative

34Van Sa

mkar,

2016

[28]

60/M

None

NNoknow

nanim

alexposures

Headache,fever,alteredmentalstatus,

generalized

rash

NR

Positive,

5days

35Bertin,

2018

[4]

69/F

HTN

NDog

bite

3days

prior

Fever,dyspnea,fatigue

NR

Positive,

days

togrow

thnot

reported

PCR?

36Bertin,

2018

[4]

65/M

HTN

NDog

bite

3days

prior

Headache,nu

chalrigidity

NR

Positive,

1day

126 Infect Dis Ther (2019) 8:119–136

Table1

continued

Case

no.

First

author,

year

[reference]

Age/sex

Medical

cond

itions

History

ofsplenectom

y,y/n

Animal

contact

Symptom

sSerum

WBC

(cells/m

m3)

Blood

cultures,

positive

y/n,

time

toresult

37Current

Case

71/F

Lun

gcancer

s/p

resection,

HTN,

hypothyroidism

,chronicsubdural

hematom

as

NDog

exposure,o

ngoing;

noreported

bites

Alteredmentalstatus,fever,h

eadache

19,900

Positive,

4days

Caseno

.Brain

imaging

CSF

white

coun

t(cells/m

m3)

CSF

protein

(mg/dl)

CSF

glucose-to-serum

ratio(value

inmg/dl)

CSF

gram

stainand

culture,timeto

result

(days)

Antibiotics,type

and

duration

(days)

Outcome

1NR

2,300(30%

PMN)

722

0.17

Gram

stainwithGNRs,

cultu

repositive,

3days

Ampicillin,

gentam

icin,

chloramphenicol

and

carbenicillin

?Ampicillin

(14days

total)

Recovered

2NR

NR

NR

NR

NR

NR

Recovered

3NR

NR

NR

NR

NR

NR

Recovered

4NR

NR

NR

NR

NR

NR

Recovered

5NR

575(90%

PMN)

240

0.24

Gram

stainGNR;

cultu

repositive

5days

Penicillin(7),

Chloram

phenicol

(10);(10days

total)

Recovered

6NR

1,121(80%

PMN)

175

37.8;0.45

Gram

stainGNRS;

cultu

repositive,

2days

Chloram

phenicol,

Ampicillin(7

days

total)

Recovered

7CTnorm

al520(70%

PMN)

143

0.2

Gram

stainnegative;

cultu

repositive;time

NR

PenicillinG

and

cefotaxime(14days

total)

Recovered

8NR

031

0.53

Gram

stainnegative;

cultu

repositive,

4days

Chloram

phenicol

(4d)

?Pen(10d);

(14days

total)

Recovered

Infect Dis Ther (2019) 8:119–136 127

Table1

continued

Caseno

.Brain

imaging

CSF

white

coun

t(cells/m

m3)

CSF

protein

(mg/dl)

CSF

glucose-to-serum

ratio(value

inmg/dl)

CSF

gram

stainand

culture,timeto

result

(days)

Antibiotics,type

and

duration

(days)

Outcome

9CTnorm

al480(70%

PMN)

32NR

Culture

negative

None

Survived

with

persistent

deafness

10CTwith

multiple

brain

infarctions

820(74%

PMN)

465

CSF

39.24mg/dl;0.08

NR

Imipenem

/cilastatin

?Penicillin(14days

total)

Survived;bilateral

below-knee

amputations,

persistent

neurologic

deficits

11NR

6000,‘‘mainlyPM

N)

NR

NR

Culture

positive,4

days

Chloram

phenicol

IVfor

5days

andpo

for

6days

(11days

total)

Recovered

12NR

43(74%

lymph)

153

0.3

Culture

positive,5

days

Amoxicillin

(21days

total)

Recovered

13NR

240(80%

PMN)

NR

NR

Gram

stainGNRs;

cultu

repositive,tim

eNR

Penicillin(15daystotal)

Recovered

14NR

*240([

80%

PMN)

NR,elevated

NR,low

Positive

cultu

re,tim

eNR

Erythromycin

?Penicillin

Died,

cardiac

arrest10

days

afterdischarge

15NR

[1700

([80%

PMN)

NR,elevated

NR,low

Positive

cultu

re,tim

eNR

Ampicillin

Recovered

16NR

*245([

80%

PMN)

NR,elevated

NR,low

Positive

cultu

re,tim

eNR

Penicillin?

Ampicillin,

Gentamicin

Recovered

17NR

[1700

([80%

PMN)

NR,elevated

NR,low

Gram

stainGNRs,

cultu

renegative

Penicillin?

Ceftazidime,

Metronidazole

Recovered

128 Infect Dis Ther (2019) 8:119–136

Table1

continued

Caseno

.Brain

imaging

CSF

white

coun

t(cells/m

m3)

CSF

protein

(mg/dl)

CSF

glucose-to-serum

ratio(value

inmg/dl)

CSF

gram

stainand

culture,timeto

result

(days)

Antibiotics,type

and

duration

(days)

Outcome

18NR

[1700

([80%

PMN)

NR,elevated

NR,low

Positive

cultu

re,tim

eNR

Ceftriaxone,

Ampicillin?

Ampicillin,

Netilm

icin,

Metronidazole?

Penicillin

Recovered

19NR

NR

NR

NR

Culture

positive,4

days

Cefotaxim

e,Amoxicillin

Recovered

20CTnorm

al11,138

(99%

PMN)

192

\0.01

Gram

stainGNR,

cultu

repositive,tim

eNR,also

partial16

srRNAsequencing

(PCR)

Cefepim

e,am

picillin,

metronidazole(total

duration

not

provided)?

Ceftriaxone

(14days

total)

Recovered

21CTnorm

al1240

(65%

PMN)

165

0.21

Gram

stainGNRs;

cultu

repositive,

2days

Cefotaxim

e(9

d)?

Amoxicillin

(12d);(21

daystotal)

Recovered

22CTnorm

al15,630

(92%

PMN)

146

CSF

glucose20

?0.14

Gram

stainnegative;

cultu

repositive,

5days

Ampicillin,

gentam

icin,

cefotaxime;(21days

total)

Recovered

23NR

1001

(82%

PMN)

169

0.3

Gram

stainnegative,

cultu

repositive,

5days;PC

R?

Ceftriaxone

(13days

total)

Recovered

24CTandMRInorm

al1226

(96%

PMN)

328

0.24

Gram

stainGNRs;

cultu

repositive,tim

eNR

Cefotaxim

eand

gentam

icin

(1d)

?Cefotaxim

eand

metronidazole?

amoxicillin;

(15days

total)

Recovered

25NR

1024

(100%

PMN)

173

0.43

Gram

stainGNRs;

cultu

repositive,

9days

Ceftriaxone

Recovered

26CTnorm

al1566

(54%

PMN)

130

0.5

Gram

stainGNRs;

cultu

renegative

Ceftriaxone

Recovered

Infect Dis Ther (2019) 8:119–136 129

Table1

continued

Caseno

.Brain

imaging

CSF

white

coun

t(cells/m

m3)

CSF

protein

(mg/dl)

CSF

glucose-to-serum

ratio(value

inmg/dl)

CSF

gram

stainand

culture,timeto

result

(days)

Antibiotics,type

and

duration

(days)

Outcome

27CTnorm

al730(22%

PMN)

1342

0.125

Gram

stainnegative,

cultu

repositive

at2days

Ampicillin(14days

total)

Survived

withnear

totaldeafness

28CTnorm

al1814

(74%

PMN)

276

0.03

Gram

stainGNR;

cultu

repositive

at9days;PC

R?

Penicillin(48h)

?ceftriaxoneand

ampicillin(6

d)?

ceftriaxoneadditional

14d;

(22days

total)

Survived

with

persistent

bilateral

sensorineural

hearingloss

29NR

2120

(81%

PMN)

191

0.24

Gram

stainGNR;

cultu

repositive

at5days;PC

R?

Ceftriaxone

?meropenem

(21d);

(21days

total)

Survived

with

persistent

hearingloss

30CTnorm

al234(85%

PMN)

221

0.02

Gram

stainGNR;

cultu

repositive

at6days;PC

R?

Ampicillin,

ceftriaxone,

acyclovir?

meropenem

3days

?ceftriaxone21

days;

(24days

total)

Recovered

31Noim

aging

5,210

515

CSF

glucose0

GNRon

gram

stain,

cultu

reneg,PC

R?

Ceftriaxone,amoxicillin

92days?

penicillin

912

days

(14days

total)

Recovered

32CTnorm

al901

346

CSF

glucose25.2

?0.07

Culture

positive,3

days

Amoxicillin

(10d),

ceftriaxone(14days

total)

Recovered

33CTnorm

al2,376

261

CSF

glucose66.6

?0.26

Culture

positive,5

days

Amoxicillin

(3d),

ceftriaxone(20d),

acyclovir3d(23days

total)

Survived

with

headache,

disorientation

34Noim

aging

828

190

CSF

glucose54

?0.28

Culture

positive,5

days

Amoxicillin

(14d),

ceftriaxone(1

d),

meropenem

(12d);

(27days

total)

Recovered

130 Infect Dis Ther (2019) 8:119–136

Table1

continued

Caseno

.Brain

imaging

CSF

white

coun

t(cells/m

m3)

CSF

protein

(mg/dl)

CSF

glucose-to-serum

ratio(value

inmg/dl)

CSF

gram

stainand

culture,timeto

result

(days)

Antibiotics,type

and

duration

(days)

Outcome

35CTwith3

ischem

iclesions

NR

NR

NR

NR

Vancomycin,

piperacillin-

tazobactam

(28days

total)

Survived;

amputations

ofextrem

ities

ofbilateral

upperand

lower

limbs

36CTnorm

alon

admission.

MRIat

8days

withcerebritis

443

970.24

Gram

stainGNR;

cultu

repositive,

1day;PC

R?

Ceftriaxone,ampicillin

2weeks

?am

picillin-sulbactam,

moxifloxacin

4weeks;

(42days

total)

Recovered

37MRI

stablebifrontal

subdural

hematom

as,

acuteoccipital

andparietal

lobe

infarcts

590(95%

PMN)

413

0.11

Gram

stainandcultu

renegative;PC

R?

Vancomycin,

ceftriaxone,am

picillin

(4d)

?Meropenem

(17d);(21days

total)

Recovered

CAD

coronary

artery

disease,COPD

chronicobstructivepulmonarydisease,CSF

cerebrospinalfluid,C

Tcomputedtomography,D

days,F

female,GNRgram

-negativerod,

HTN

hypertension,M

male,MRImagneticresonanceim

aging,N

no,N

Rnotreported,P

CRpolymerasechainreaction,P

MN

polymorphonuclear

cell,

WBCwhite

bloodcell,

Yyes

Infect Dis Ther (2019) 8:119–136 131

abnormalities, and one with extremity ampu-tations. Both patients who underwent amputa-tions also had brain imaging showing acuteinfarcts. Of the seven patients with chronicsequelae, three had a history of alcohol abuseand one was asplenic. No clear relationshipbetween antibiotic duration and adverse out-comes was noted.

DISCUSSION

Since the first reported case of Capnocytophagacanimorsus meningitis in 1976 [8], there havebeen 36 additional cases including the presentcase. We provide a comprehensive summaryand provide a novel case of Capnocytophagacanimorsus meningitis to add to the existing

literature. While this pathogen was previouslyreported to primarily cause severe disease inimmunocompromised patients (e.g., history ofsplenectomy), our literature review revealedthat most cases occurred among healthy,immunocompetent persons. As most cases hada recent dog exposure, C. canimorsus should besuspected in cases of bacterial meningitis withthis exposure history.

Regarding underlying medical conditions,only 24% had an underlying immunosuppres-sive medical condition. While classically asple-nia was deemed to be the characteristiccondition associated with this pathogen, in ourreview only 16% (6 patients) with C. canimorsusmeningitis were asplenic and 5% (2 patients)were receiving chronic steroids. The mostcommon risk factor found in our review was

Table 2 Antibiotic susceptibilities for the Capnocytophaga canimorsus isolates among meningitis cases in the publishedliterature

First author,year (references)

Susceptible Intermediate Resistant

Bobo, 1976,

n = 1 [8]

‘‘All tested abx’’ including ampicillin NR Gentamicin

Chan, 1986,

n = 1 [10]

Penicillin, erythromycin, chloramphenicol, cefuroxime NR Gentamicin, trimethoprim,

sulphafurazole,

metronidazole

Krol-van

Straaten, 1990,

n = 1 [15]

Penicillin, amoxicillin, cephalothin, norfloxacin, rifampin,

chloramphenicol

NR Aminoglycosides

Risi, 2000, n = 1

[19]

Penicillin, third-generation cephalosporin and

ciprofloxacin

NR NR

Le Moel, 2003,

n = 1 [20]

Ampicillin, cephalothin, cefotaxime, pefloxacin, and

vancomycin

Erythromycin gentamicin, colistin,

trimethoprim-

sulfamethoxazole

Meybeck, 2006,

n = 1 [23]

Penicillin, amoxicillin, cefotaxime, cefixime, clindamycin,

erythromycin, rifampin, pefloxacin, tetracycline,

chloramphenicol

NR Kanamycin, gentamicin,

sulfamethoxazole,

trimethoprim

Gasch, 2009,

n = 1 [25]

Ampicillin, cefotaxime, imipenem and ciprofloxacin NR Aminoglycosides

Monrad, 2012,

n = 1 [26]

Penicillin, cefuroxime, erythromycin, ciprofloxacin NR Gentamicin

NR not reported

132 Infect Dis Ther (2019) 8:119–136

alcoholism present in 19% (7 patients). Thesedata suggest that Capnocytophaga is pathogenicand can cause severe disease in all hosts of allages regardless of underlying risk factors.

A history of exposure to dogs was commonin our review and emphasizes the importance ofthis historical feature in the early suspicion anddiagnosis of this pathogen. Dog exposure,mostly common via a dog bite, was present in86% of cases. Cat exposure was less commonly(3%) reported; only 11% of cases reported noknown animal exposure. The incubation periodwas relatively short between animal exposureand presentation (median 6 days between biteand presentation). Whether antibiotic exposureafter dog or cat bites would have prevented thereported cases of C. canimorsus meningitis isunclear, but prophylactic antibiotics did notprevent its occurrence in one previously pub-lished case although erythromycin was usedrather than a b-lactam [18]. Among casesreviewed, there was a notable male predomi-nance (3:1) perhaps related to an increased riskof canine bites or exposures among men.

Patients with C. canimorsus meningitis com-monly presented with classic meningismussymptoms. In several of the cases, the coursewas fulminant and mimicked that of meningo-coccal disease. Of note, some C. canimorsus caseshad purpuric or petechial rashes at presentationand required subsequent extremity amputa-tions similar to the clinical course of Neisseriameningitidis [14]. CSF analysis was consistentwith bacterial meningitis with an elevatedleukocyte count with neutrophil predomi-nance, elevated protein, and low glucose valuesoccurring in most cases. Given the lack of dif-ferentiating clinical or laboratory findings for C.canimorsus meningitis compared with other bac-terial organisms, clinicians must have a highindex of suspicion suspecting this pathogenamong patients presenting with findings ofbacterial meningitis along with recent animalexposure.

The identification of Capnocytophaga sp. issupported by its growth using specific cultureconditions as well as its colony morphology andmicroscopic characteristics [29]. The organismgrows best at 35–37 �C on 5% sheep’s blood orchocolate agar (but not MacConkey’s) using

anaerobic or aerobic conditions with 5–10%CO2. Even with ideal growing conditions,growth can take up to 7 days, and identificationcan be missed if culture plates are discarded atthe traditional day 5 of incubation. The organ-ism displays fingerlike projections on agar andgliding motility on microscopy, which mayprovide clues to its identification. A variety ofbiochemical identification systems and stripscan be utilized for species determination.MALDI-TOF mass spectrometry using an enri-ched database may also aide in species levelidentification [30].

Capnocytophaga canimorsus is a relativelydifficult organism to identify given its longincubation and specific culture requirements asnoted above. In this review, only 54% of bloodcultures and 70% of CSF cultures were positivewith median growth times of 4 and 5 days,respectively. Two cases in the literature hadgram stains showing gram-negative bacilli, butnegative cultures. In cases where gram stainsand/or cultures are negative, PCR can be helpfulin definitively identifying the causative organ-ism and improving the rapidity of the diagnosis[31], as was done in eight (22%) of the cases inour literature review. The value of PCR tech-nology is particularly important in casesinvolving slow-growing or fastidious organisms(such as Capnocytophaga sp.) and in the settingof prior antibiotic exposure before cultures areobtained. Commercial PCR tests are becomingmore widely available; however, C. canimorsusmay not be included in all testing platforms(e.g., BioFire FilmArray Meningitis/EncephalitisPanel) [32] and hence may require broad-rangePCR technology.

Regarding treatment, penicillin has beenreported as the drug of choice in the past,although clinical comparative trials are lacking[12]. Since beta-lactamase activity has beenreported among some Capnocytophaga species[33], clinical isolates should be tested for b-lac-tamase production to inform the optimaltreatment regimen. Because the organism canbe difficult to grow, susceptibilities may not befeasible. To provide further guidance on treat-ment options, we reviewed the published sus-ceptibility data from C. canimorsus meningitiscases. These data suggest that C. canimorsus is

Infect Dis Ther (2019) 8:119–136 133

typically susceptible to penicillins (includingampicillin), third-generation cephalosporins,carbapenems such as imipenem, and fluoro-quinolones. Despite being a gram-negativeorganism, aminoglycosides and aztreonam aretypically inactive. Isolates were also typicallyresistant to trimethoprim-sulfamethoxazole. Inour review, the median treatment time was15 days although the optimal duration isunknown. The current Infectious Disease Soci-ety of America (IDSA) Meningitis Guidelinessuggest 21 days for meningitis involving aerobicgram-negative organisms (other than Hae-mophilus influenzae) [34].

The outcome of C. canimorsusmeningitis wasoverall favorable and had a lower overall mor-tality rate compared with both other bacterialcauses of meningitis (* 14–25%) [35] and C.canimorsus sepsis (* 30%) [3, 18]. Only onepatient in our review died, and this event wasunlikely related to the infection. Adversesequalae, however, were notable with 19% ofpatients suffering from a residual deficit, whichwas most commonly hearing loss. Additionally,19% of those with C. canimorsus meningitiswith reported brain imaging had evidence ofacute infarcts. Cerebral infarctions are potentialcomplications of bacterial meningitis and in aprior study were reported among 36% ofpatients with pneumococcal meningitis, 9%with meningococcal meningitis, and 28% dueto other bacteria; patients with infarctions areoften older and have an immunocompromisedstate [36].

Limitations of this review include the overallsmall number of C. canimorsus meningitis casesin the literature and the lack of complete indi-vidualized data for some cases. Additionally, ourreview only included cases in the English liter-ature. Strengths include this being the largestand most comprehensive review to date. Giventhat animal exposures are increasingly common[29], understanding this disease entity isimportant. Unlike other bacteria pathogensassociated with animal bites (e.g., Pasteurella,streptococci), this organism is not typicallyassociated with local wound infections, butrather presents as severe, disseminated infec-tions including bacteremia, sepsis, andmeningitis.

CONCLUSION

Capnocytophaga canimorsus is a rare but impor-tant cause of bacterial meningitis and should beconsidered in cases following a recent dog biteor exposure. Given the increasing incidence ofinfections associated with animal exposures,knowledge regarding the clinical manifesta-tions, diagnosis, and treatment of this clinicalentity is important. This case and review pro-vides the most up-to-date information aboutthe clinical management of this importantinfection. Furthermore, it highlights the valueof PCR technology to enhance the timely diag-nosis of C. canimorsus meningitis.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Prior Presentation. Part of the contents ofthis paper was presented at ID Week, San Fran-cisco, CA, 3–7 October 2018.

Disclosures. Megan Hansen and Nancy F.Crum-Cianflone have nothing to disclose.

Compliance with Ethics Guidelines. In-formed consent was obtained from the indi-vidual participant included in the paper.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,

134 Infect Dis Ther (2019) 8:119–136

provide a link to the Creative Commons license,and indicate if changes were made.

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