Thirty-four patients with bacterial meningitis and 97 patients with aseptic meningitis were enrolled. Table 1 shows a comparison of bacterial and aseptic meningitis cases. Patient age ranged from 22 to 91 in bacterial meningitis cases and from 15 to 76 in aseptic meningitis cases.
Table 1
Comparison between bacterial and aseptic meningitis.
|
Bacterial meningitis
|
|
Aseptic meningitis
|
|
p value
|
|
N = 34
|
|
N = 97
|
|
|
Median age (IQR)
|
60 (44–68)
|
|
30 (23–34)
|
|
0.0000*
|
Male sex
|
19/34 (55.9%)
|
|
51/97 (52.6%)
|
|
0.74
|
Medical histories
|
|
|
|
|
|
Symptom duration days (IQR)
|
2.5 (0–5)
|
|
3 (1–4)
|
|
0.71
|
Shaking chills
|
9/34 (26.5%)
|
|
6/97 (6.2%)
|
|
0.001*
|
Previous antibiotic exposure within 48 h
|
12/34 (35.3%)
|
|
9/97 (9.2%)
|
|
0.000*
|
Immunocompromised host
|
17/34 (50.0%)
|
|
8/97 (8.2%)
|
|
0.000*
|
Vital signs and physical examinations
|
|
|
|
|
|
Systolic blood pressure (mmHg) (IQR)
|
136 (120–150)
|
|
112 (100–120)
|
|
0.0000*
|
Pulse rate (/min) (IQR)
|
113 (100–126)
|
|
88 (80–96)
|
|
0.0000*
|
Respiratory rate (/min) (IQR)
|
24 (20–30)
|
|
20 (18–22)
|
|
0.0002*
|
Body temperature (℃) (IQR)
|
38.6 (37.9–39.3)
|
|
37.7 (37.1–38.4)
|
|
0.0000*
|
Glasgow Coma Scale (IQR)
|
11 (9–14)
|
|
15 (15–15)
|
|
0.0000*
|
Neck stiffness
|
28/33 (84.9%)
|
|
47/95 (49.5%)
|
|
0.002*
|
Jolt accentuation
|
5/6 (83.3%)
|
|
53/64 (82.8%)
|
|
0.97
|
Laboratory data
|
|
|
|
|
|
White blood cell counts (/µL) (IQR)
|
13800 (11000–16200)
|
|
7800 (5900–9900)
|
|
0.0000*
|
C-reactive protein (mg/dL) (IQR)
|
6.7 (1.3–19.4)
|
|
0.18 (0.02–0.9)
|
|
0.0000*
|
CSF cell counts (/µL) (IQR)
|
1116 (140–4200)
|
|
80 (37–156)
|
|
0.0000*
|
CSF monocytes (%) (IQR)
|
5 (3–17)
|
|
74 (27–95)
|
|
0.0000*
|
CSF protein (mg/dL) (IQR)
|
287 (100–420)
|
|
66 (51–94)
|
|
0.0000*
|
CSF glucose (mg/dL) (IQR)
|
37 (1–59)
|
|
57 (53–63)
|
|
0.0001*
|
CSF glucose/blood glucose ratio (IQR)
|
0.17 (0.006–0.43)
|
|
0.55 (0.50–0.60)
|
|
0.0000*
|
CSF bacteria confirmed with PCGS
|
31/34 (91.2%)
|
|
1/97 (1.0%)
|
|
0.000*
|
CSF culture positivity
|
34/34 (100%)
|
|
0
|
|
0.000*
|
Blood culture positivity
|
29/34 (85.3%)
|
|
0
|
|
0.000*
|
Etiologic agent
|
Streptococcus pneumoniae
|
20
|
Mumps virus
|
8
|
|
|
Klebsiella pneumoniae
|
5
|
Varicella zoster
|
5
|
|
|
Streptococcus bovis
|
4
|
Cytomegalovirus
|
2
|
|
|
Bacteroides fragilis
|
1
|
Herpes simplex
|
2
|
|
|
Escherichia coli
|
1
|
Unknown
|
80
|
|
|
Haemophilus influenzae
|
1
|
|
|
|
|
Lactococcus lactis cremoris
|
1
|
|
|
|
|
Listeria monocytogenes
|
1
|
|
|
|
Complications
|
|
|
|
|
|
Infection sites other than meningitis
|
9/34 (26.7%)
|
|
13/97 (13.4%)
|
|
0.079
|
Strongyloides coinfection
|
10/34 (29.4%)
|
|
0
|
|
0.000*
|
Treatment
|
|
|
|
|
|
Antibiotics other than acyclovir
|
34/34 (100%)
|
|
38/97 (39.2%)
|
|
0.000*
|
Steroid use
|
4/34 (11.8%)
|
|
0
|
|
0.005*
|
Antimicrobial treatment days (IQR)
|
14 (12–14)
|
|
3 (3–5)
|
|
0.0001*
|
Outcome
|
|
|
|
|
|
Death
|
4/34 (11.8%)
|
|
0
|
|
0.004*
|
Neurological sequelae
|
4/30 (13.3%)
|
|
0
|
|
0.004*
|
CSF: cerebrospinal fluid, IQR: interquartile range, PCGS: point-of-care Gram stain |
* p < 0.05 |
In twelve patients with bacterial meningitis, antibiotics had previously been prescribed; these were amoxicillin, amoxicillin/clavulanic acid, piperacillin, cefotiam (2nd generation cephalosporin), cefmetazole, cefotaxime, ceftriaxone, cefoperazone/sulbactam, clarithromycin, ofloxacin and levofloxacin. No antiviral agents were prescribed. In nine patients with aseptic meningitis, penicillin G, amoxicillin/clavulanic acid, cefalexin, clarithromycin, fleroxacin, levofloxacin, acyclovir, or oseltamivir had been administered within 48 hours prior to arrival.
There was only one patient with pneumococcal meningitis whose CSF cell count was 0. This patient’s CSF protein was not elevated (48 mg/dL) and CSF glucose was decreased (49 mg/dL) relative to blood sugar (127 mg/dL). Gram-positive diplococci were detected with PCGS.
S. bovis was reclassified into three different biotypes in 2003 [25]. Among the four S. bovis cases, only one could be more specifically identified as Streptococcus infantarius subsp. coli. The other three cases were of unidentified subtype because they were old cases from before the subtypes were defined. The five cases in which CSF cultures were positive but blood cultures were negative were two S. pneumoniae, one H. influenzae, one K. pneumoniae, and one S. bovis infection. Only one patient was infected with two bacterial species: Bacteroides fragilis was cultured from the CSF, and both B. fragilis and E. coli were cultured from the blood. No ESBL-producing bacteria were found in this study.
In the aseptic meningitis cases, mumps, Varicella zoster, Herpes simplex, and cytomegalovirus were identified as the etiologic agents either clinically or through serologic tests or polymerase chain reactions, but not through viral cultures.
Among the bacterial meningitis cases, the point of entry varied: four cases were suspected to have arisen through contiguous spread from local infection: these were three cases of otitis media and one case of sinusitis. The remaining seven cases were suspected to have emerged from distant foci of infection: these were three cases of pneumonia, two cases of septic arthritis, and one case each of infective endocarditis and osteomyelitis. Both septic arthritis cases were co-infected: one with infective endocarditis and one with osteomyelitis. Thus, nine patients had other simultaneous infections. Among the aseptic meningitis patients, thirteen cases had simultaneous other infections: eight of these were mumps in the parotid gland, four were skin lesions of Varicella zoster, and one was Herpes simplex virus in the genital area.
Strongyloides stercoralis coinfection was determined based on the presence of S. stercoralis larvae or eggs in the stool, gastric juice or sputum, or on previous episodes of proven strongyloidiasis associated with repeated meningitis. Ivermectin or thiabendazole was used with antimicrobials to treat S. stercoralis coinfection.
Among the 38 aseptic meningitis cases treated with empirical antimicrobial treatments, the antimicrobial agents were as follows: 19 ceftriaxone, 15 cefotaxime, 6 ampicillin, 3 vancomycin, and 1 doxycycline. Doxycycline was empirically chosen for possible leptospirosis, although the possibility of leptospirosis was later disproven. More than one antimicrobial was used simultaneously in several cases. In addition, acyclovir was empirically used in 10 patients for possible herpes infection.
Four bacterial meningitis patients survived with neurological sequelae; these included one with both sensory hearing loss and facial palsy, and one each with sensory hearing loss, neurogenic bladder, and impaired consciousness. In all of these, the etiologic agent was S. pneumoniae. Dexamethasone was administered in one case but not in the others.
Four patients died because of bacterial meningitis. In one of them, small Gram-negative rods were observed in PCGS, and ceftazidime and clindamycin were chosen accordingly. In this case, Bacteroides fragilis was cultured from the CSF, and both B. fragilis and E. coli were cultured from the blood.
Table 2 compares the effectiveness of PCGS with that of other variables for differentiating between bacterial and aseptic meningitis. Among the age and history variables, age over 45 had the highest area under the ROC curve (AUC). Among the vital signs and physical examination variables, Glasgow Coma Scale (GCS) less than 15 had the highest AUC. Among PCGS and laboratory data, PCGS had the highest AUC. Among all variables, PCGS was the most accurate predictor. When age was less than 45, GCS was 15, and PCGS was negative, 98.8% (84/85) of cases were aseptic meningitis.
Table 2
Effectiveness of different variables at correctly predicting a diagnosis of bacterial vs. aseptic meningitis.
|
Sensitivity
|
Specificity
|
Accuracy
|
LR+
|
LR-
|
AUC (95% CI)
|
Age and history
|
|
|
|
|
|
|
Age ≧ 45
|
73.5
|
89.7
|
85.5
|
7.1
|
0.30
|
0.82 (0.73–0.90)
|
Immunocompromised host
|
50.0
|
91.2
|
80.9
|
6.1
|
0.54
|
0.71 (0.62–0.80)
|
Shaking chills
|
26.5
|
93.8
|
76.3
|
4.3
|
0.78
|
0.60 (0.52–0.68)
|
Vital signs and physical examinations
|
|
|
|
|
|
|
Glasgow Coma Scale < 15
|
81.2
|
97.9
|
93.7
|
38.2
|
0.19
|
0.90 (0.83–0.97)
|
Pulse rate ≧ 100(/min)
|
76.4
|
80.0
|
79.1
|
3.8
|
0.29
|
0.78 (0.70–0.86)
|
Systolic BP ≧ 120(mmHg)
|
85.3
|
61.1
|
67.4
|
2.2
|
0.24
|
0.73 (0.65–0.81)
|
Respiratory rate ≧ 22(/min)
|
64.7
|
73.9
|
71.4
|
2.5
|
0.48
|
0.69 (0.60–0.79)
|
Neck stiffness
|
84.9
|
50.5
|
59.4
|
1.7
|
0.30
|
0.68 (0.60–0.76)
|
Body temperature ≧ 38.0(℃)
|
69.7
|
61.1
|
63.3
|
1.8
|
0.50
|
0.65 (0.56–0.75)
|
PCGS and laboratory data
|
|
|
|
|
|
|
CSF PCGS
|
91.2
|
99.0
|
97.0
|
88.4
|
0.09
|
0.95 (0.90-1.00)
|
CSF monocyte ≦ 20(%)
|
85.3
|
83.3
|
83.9
|
5.1
|
0.18
|
0.84 (0.77–0.91)
|
CSF glucose/blood glucose ratio ≦ 0.5
|
85.3
|
75.5
|
78.1
|
3.5
|
0.20
|
0.80 (0.73–0.88)
|
WBC ≧ 10000(/µL)
|
78.8
|
76.8
|
77.3
|
3.4
|
0.28
|
0.78 (0.70–0.86)
|
CSF protein ≧ 100(mg/dL)
|
76.5
|
77.3
|
77.1
|
3.4
|
0.30
|
0.77 (0.69–0.85)
|
CRP ≧ 1.0(mg/dL)
|
77.4
|
76.0
|
76.4
|
3.2
|
0.30
|
0.77 (0.68–0.85)
|
CSF cell ≧ 100(/µL)
|
76.5
|
58.8
|
63.4
|
1.9
|
0.40
|
0.68 (0.59–0.76)
|
AUC: area under curve, BP: blood pressure, CI: confidence interval, CRP: C-reactive protein, CSF: cerebrospinal fluid, GCS: Glasgow Coma Scale, LR: likelihood ratio, PCGS: point-of-care Gram stain, WBC; white blood cell |
Table 3 shows the concordance between PCGS and CSF cultures. The kappa coefficient was 0.922 (95% Confidence Interval 0.881–0.951). The four cases whose PCGS results did not match their CSF culture results were one false-positive and three false-negatives. None of them had previous antimicrobial administration. In the one false-positive case, Gram-positive coccus was detected through PCGS but not cultured. The number of Gram-positive cocci in this case was low. In one of the false-negatives, no bacteria were observed through PCGS, but a Gram-positive rod species identified as L. monocytogenes was cultured. This patient was an alcohol abuser. In another false-negative, no bacteria was observed through PCGS, but S. pneumoniae was cultured. This patient also had septic arthritis of the knee and infective endocarditis. In the third false-negative, no bacteria was confirmed through PCGS, but a Gram-negative rod identified as H. influenzae was cultured. The blood culture was also negative. This patient had a past medical history of CSF leakage.
Table 3
Concordance between point-of-care Gram stain and CSF culture results.
|
CSF culture
|
|
GPC
|
GNR
|
GPR
|
Negative
|
Point-of-care Gram stain
|
|
|
|
|
GPC
|
24
|
0
|
0
|
1
|
GNR
|
0
|
7
|
0
|
0
|
GPR
|
0
|
0
|
0
|
0
|
Negative
|
1(Sp)
|
1(Hi)
|
1(Lm)
|
87
|
CSF: cerebrospinal fluid, GNR: Gram-negative rod, GPC: Gram-positive coccus, GPR: Gram-positive rod, Hi: Haemophilus influenzae, Lm: Listeria monocytogenes, Sp: Streptococcus pneumoniae |
Kappa coefficient 0.922 (95%CI 0.881–0.951)
Table 4 compares the targeted antimicrobial agent that was chosen based on PCGS results with the agent that would have been chosen in the same situation in the absence of PCGS data according to the current Japanese guidelines, i.e., the simulated empirical agent. When PCGS data was used, third-generation cephalosporins (cefotaxime and ceftriaxone) were used more frequently, and ceftazidime and meropenem were used less frequently, than they would have been in empirical treatment based on the Japanese guidelines. Meropenem was used in only one case in which Gram-negative rods were observed despite cefotaxime administration.
Drug susceptibility tests of CSF cultures revealed that all antimicrobial treatments that were chosen based on PCGS results were effective against bacterial meningitis. All treatments that would have been chosen in the absence of PCGS findings were also effective.
The median dose (interquartile range) on the first day of admission for each antimicrobial chosen based on PCGS was as follows: ampicillin 8.5 g (8–12 g), penicillin G 24 million units (24–24 million units), cefotaxime 9 g (8–12 g), ceftriaxone 4 g (4–4 g), vancomycin 2 g (2–2 g), meropenem 6 g (6–6 g). The total cost on the first day of admission for all antimicrobials chosen based on PCGS was 80.0% of the total cost of all antimicrobials that would have been chosen under the Japanese guidelines (424433/530091 Japanese yen).
In aseptic meningitis, 39.2% (38/97) of patients were treated with empiric antibiotics despite having negative PCGS findings (Table 1). This proportion was lower than that in a previous study on adult aseptic meningitis in which Gram staining was not available (60.8%, 45/74) (p = 0.006) [11].
Table 4
Initial antibiotics selected based on PCGS versus those that would have been chosen under the Japanese guidelines.
|
Point-of-care Gram stain (N = 34)
|
Japanese guidelines (N = 34)
|
p value
|
|
GPC
(N = 24)
|
GNR
(N = 7)
|
False-
negative
(N = 3)
|
Subtotal
|
Immuno-
competent
|
Immuno-
compromised
(N = 17)
|
Subtotal
|
|
Age < 50
(N = 7)
|
Age ≧ 50
(N = 10)
|
Ampicillin/Penicillin G
|
10/1
|
4/0
|
1/0
|
16
|
0
|
5/0
|
8/0
|
13
|
0.62
|
Cefotaxime/Ceftriaxone
|
18/6
|
4/1
|
3/0
|
32
|
0
|
3/2
|
0
|
5
|
0.000*
|
Ceftazidime
|
0
|
1
|
0
|
1
|
0
|
0
|
8
|
8
|
0.027*
|
Vancomycin
|
19
|
1
|
2
|
22
|
0
|
10
|
17
|
27
|
0.28
|
Meropenem
|
0
|
1
|
0
|
1
|
7
|
5
|
7
|
19
|
0.000*
|
Clindamycin
|
0
|
1
|
0
|
1
|
0
|
0
|
0
|
0
|
1.000
|
GNR: Gram-negative rod, GPC: Gram-positive coccus, PCGS: point-of-care Gram stain |
*: p < 0.05 |