Capnocytophaga canimorsus Meningitis: Diagnosis Using ...
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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: [email protected]
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.
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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
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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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