Epidemiologie en antibiotische behandeling
Uitgangsvraag
Epidemiology and empirical antibiotic treatment of community-acquired bacterial meningitis.
Aanbeveling
Empirical antibiotic therapy in neonates with bacterial meningitis should consist of amoxicillin and cefotaxime. If a microorganism is cultured, therapy can be adjusted accordingly (see module ”Antimicrobiële behandeling meningitis")
Empirical antibiotic therapy in children aged 1 month-16 years with bacterial meningitis should consist of a third generation cephalosporin (cefotaxime or ceftriaxone). Meropenem may be used as an alternative in specific cases (e.g. known allergic reactions). If a microorganism is cultured, therapy can be adjusted accordingly (see module ”Antimicrobiële behandeling meningitis”).
Empirical antibiotic therapy in adults with bacterial meningitis should consist of the combination of amoxicillin and a third generation cephalosporin (ceftriaxone or cefotaxime).
If a microorganism is cultured in adults with bacterial meningitis, therapy can be adjusted accordingly (see module ”Behandeling van bacteriële meningitis”). If cultures are negative after 48 hours, the third generation cephalosporin can be discontinued, and monotherapy amoxicillin will suffice.
Overwegingen
For this module no considerations have been formulated.
Onderbouwing
Conclusies
Level 1 |
Early neonatal meningitis is most commonly caused by S. agalactiae, E. coli, and L. monocytogenes. Late neonatal meningitis is most commonly caused by staphylococci, and Gram-negative bacilli
A2 Garges (2006)13, Holt (2001)15, NRLBM (2011)20 B Hristeva (1993)14 |
Level 2 |
Bacterial meningitis in children is caused by S. pneumoniae (44%), N. meningitidis (39%) and H. influenzae (11%)
A2 NRLBM20 |
Level 2 |
Bacterial meningitis in adults is caused by S. pneumoniae (62%), N. meningitidis (23%) L. monocytogens (5%) and H. influenzae (3%)
A2 NRLBM20 |
Level 3 |
Cefotaxime and meropenem are equally effective as empirical therapy for bacterial meningitis in children. However, meropenem should only be given in specific cases and kept as last resort.
B Odio (1999)21 |
* |
No comparative studies have been performed to evaluate empirical antibiotic therapy regimens for community-acquired bacterial meningitis in neonates and adults. |
Samenvatting literatuur
What is the epidemiology and optimal empirical antibiotic therapy of bacterial meningitis in the Netherlands in neonates (0-28 days)?
Common causative microorganisms of neonatal meningitis during the first week of life are Streptococcus agalactiae (Group B streptococci), Escherichia coli, and Listeria monocytogenes (Supplementary table 1).6,13-15 Late-onset neonatal meningitis is formally classified as meningitis after the first week until the 28thday of life.13,16,17 Late-onset neonatal meningitis may be caused by a wide variety of species, including staphylococci, and Gram-negative bacilli.6 Children born with a hydrocephalus or those that develop a hydrocephalus after an intraventricular bleeding (on the neonatal intensive care unit) are often treated with repetitive CSF drainage from an Ommaya reservoir, or a temporary or permanent CSF shunt and are at increased risk of nosocomial meningitis.4,18 The causative microorganisms in these children are different from those in “spontaneous” meningitis and are similar to those seen in nosocomial meningitis (module “Epidemiologie van nosocomiale en posttraumatische bacteriële meningitis”).
Empirical therapy for neonatal meningitis should consist of amoxicillin combined with cefotaxime (Table 1). The use of gentamicin to cover neonatal meningitis due to Gram-negative bacteria has been debated. The recommendation for the addition of gentamicin has been based on data from in vitro studies, which showed synergistic activity with amoxicillin in antimicrobial killing of S. agalactiae.6,19However, as CSF concentrations are usually only minimally above the MIC, third generation cephalosporins are considered superior to gentamicin.17 In neonates with suspected sepsis gentamicin is combined with amoxicillin, but physicians should be aware this regimen is sub-optimal for meningitis treatment. In neonates with suspected sepsis or meningitis CSF examination to establish whether concurrent meningitis is present is vital to determine the optimal empirical treatment. We recommend amoxicillin and cefotaxime in children with a high suspicion of bacterial meningitis. The dose is depends on gestational age and birth weight, and is given in the online SWAB-ID (www.swab.nl). Ceftriaxone is contraindicated in children < 4 weeks because of a high risk of precipitation of calcium-ceftriaxone complexes in the gallbladder.
Table 1 Causative organisms of bacterial meningitis in neonates
Data source |
Garges (2006)13 |
Holt (2001)15 |
Hristeva (1993)14 |
NRLBM |
Total |
||||||
Country |
US |
UK |
UK |
NL |
|
||||||
Age |
0-150 days (NICU) |
2-28 days |
0-28 days |
0-28 days |
|
||||||
Study period |
1997-2004 |
1996-1997 |
1984-1991 |
2005-2010 |
|
||||||
Gram-positive Streptococcus agalactiae |
37 |
69 |
7 |
71 |
178 (54%) |
||||||
Streptococcus mitis |
0 |
0 |
1 |
0 |
1 (0.3%) |
||||||
Listeria monocytogenes |
1 |
7 |
1 |
1 |
10 (3.0%) |
||||||
Streptococcus pneumoniae |
2 |
8 |
0 |
3 |
13 (3.9%) |
||||||
Gram-positive cocci (not specified) |
12 |
0 |
0 |
0 |
12 (3.6%) |
||||||
Enterococcus spp. |
6 |
0 |
0 |
0 |
6 (1.8%) |
||||||
Staphylococcus aureus |
4 |
0 |
0 |
1 |
5 (1.5%) |
||||||
Other Gram-positive bacteria (not specified) 0 |
17 |
0 |
2 |
19 (5.7%) |
|||||||
Gram-negative |
|
|
|
|
|
|
|||||
Haemophilus influenzae |
2 |
1 |
0 |
0 |
3 (0.9%) |
|
|||||
Escherichia coli |
12 |
26 |
0 |
25 |
57 (15.7%) |
|
|||||
Enterobacter spp. |
4 |
0 |
0 |
0 |
4 (1.2%) |
|
|||||
Serratia spp. |
2 |
0 |
1 |
0 |
3 (0.9%) |
|
|||||
Acinetobacter spp. |
3 |
0 |
0 |
0 |
3 (0.9%) |
|
|||||
Pseudomonas spp. |
3 |
0 |
1 |
0 |
4 (1.2%) |
|
|||||
Proteus spp. |
1 |
0 |
0 |
0 |
1 (0.3%) |
|
|||||
Citrobacter spp. |
1 |
0 |
0 |
0 |
1 (0.3%) |
|
|||||
Salmonella spp. |
1 |
0 |
0 |
1 |
2 (0.6%) |
|
|||||
|
|
|
|
|
|
|
|
|
|
|
|
SWAB Guidelines Bacterial CNS Infections
Neisseria spp. |
2 |
5 |
0 |
0 |
7 (2.1%) |
Klebsiella spp. |
0 |
0 |
2 |
0 |
2 (0.3%) |
Achromobacter xylosoxidans |
0 |
0 |
1 |
0 |
1 (0.3%) |
Other Gram-negative bacteria |
0 |
11 |
1 |
7 |
19 (5.7%) |
Total |
93 |
144 |
15 |
111 |
363
|
What is the epidemiology and optimal empirical antibiotic therapy of bacterial meningitis in the Netherlands for children (29 days – 16 years)?
The most common causative bacteria of community-acquired bacterial meningitis in children aged 1 month and older are S. pneumoniae and N. meningitidis, causing 80% of cases in the Netherlands (Supplementary table 2). The remainder of cases is caused by group B streptococci, E. coli, H. influenzae, other Gram-negative bacilli, L. monocytogenes, and group A streptococci. The epidemiology has shifted substantially in the past 10 years and is still changing due to the introduction of the meningococcus group C vaccine (2002), and the 7- (2006) and 10valent (2011) pneumococcal conjugate vaccines.6
Empirical coverage with a third generation cephalosporin (cefotaxime or ceftriaxone) is recommended based on a broad spectrum of activity and excellent penetration into the CSF under inflammatory conditions. Third generation cephalosporins are preferred in this age group above amoxicillin as resistance of H. influenzae to amoxicillin due to beta-lactamase production occurs in 11% of meningitis cases.20 A clinical trial comparing cefotaxime with meropenem showed similar efficacy; therefore meropenem may be considered as alternative empirical treatment in children >3 months of age in specific cases (e.g. cephalosporin allergy).21 However, the committee recommends keeping the use of meropenem restricted to the use as last resort antibiotic in bacterial meningitis patients.
Table 2 Causative organisms of bacterial meningitis in children aged 29 days-16 years
Data source NRLBM
Study period 2005-2010
Gram-positive bacteria |
|
Streptococcus pneumoniae |
305 (43.6%) |
Streptococcus agalactiae |
9 (1.3%) |
Streptococcus pyogenes |
14 (2.0%) |
Streptococcus sanguinis |
1 (0.1%) |
“α-haemolytic” streptococcus |
1 (0.1%) |
Staphylococcus aureus |
4 (0.6%) |
Staphylococcus lugdunensis |
1 (0.1%) |
Staphylococcus capitis |
1 (0.1%) |
Staphylococcus epidermidis |
2 (0.3%) |
Coagulase-negative staphylococcus 1 (0.1%)
Listeria monocytogenes 3 (0.4%)
Gram-negative bacteria |
|
Neisseria meningitidis |
271 (38.8%) |
Haemophilus influenzae |
76 (10.9%) |
Escherichia coli |
10 (1.4%) |
Total |
699 (100.0%)
|
What is the epidemiology and optimal empirical antibiotic therapy of bacterial meningitis in the Netherlands for adults (> 16 years)
All causative organisms of bacterial meningitis in adults from two nation-wide prospective cohort studies in the Netherlands, including 1500 patients, are presented in Supplementary table 3. S. pneumoniae is the most common causative microorganism of adult bacterial meningitis, and was identified in 70% of culture positive cases included between 2006 and 2010.22N. meningitidis was the second most common causative microorganism and is predominantly found in young adults.23 The proportion of meningococcal meningitis decreased from 37% of bacterial meningitis cases between 1998-2002 to 16% in 2006-2010, probably due to vaccination against serogroup C and to normal variation in meningococcal disease incidence. Patients over 50 years of age and those with an immunocompromised state are at increased risk for Listeria monocytogenes, which is found in 5% of cases.24However, L. monocytogenes meningitis also occurs in previously healthy adults without risk factors (Supplementary table 4). Therefore age and immunocompromised status cannot be used to rule out L. monocytogenes meningitis. Meningitis due to mostly unencapsulated H. influenzae and group A streptococci occurs in 3-4% of cases. Other causative organisms occur sporadically.
There have been no randomized controlled trials or comparative studies to evaluate the optimal empirical antibiotic treatment in adults with bacterial meningitis. Therefore all recommendations are based on epidemiological data (level 4 evidence – expert opinion).
The committee recommends empirical therapy for bacterial meningitis in adults to consist of amoxicillin and a third generation cephalosporin (ceftriaxone or cefotaxime). Use of these antibiotics will ensure coverage of the four most common causative microorganisms (pneumococci, N. meningitidis, L. monocytogenes and H. influenzae) and most sporadic causes. This combination therapy is preferred over monotherapy with third generation cephalosporins, as this does not cover L. monocytogenes, while monotherapy with amoxicillin does not cover β-lactamase producing H. influenzae strains and E.coli.
In the majority of patients the CSF or blood cultures will show the causative microorganism within 48 hours, with the exception of L. monocytogenes which is a notably slow grower.6If a microorganism is cultured, therapy can be adjusted accordingly (see module "Behandeling van bacteriële meningitis"). If cultures are negative after 48 hours, the third generation cephalosporins can be discontinued, and monotherapy with amoxicillin will suffice because infection with β-lactamase producing H. influenzae is virtually excluded.
Table 3 Causative organisms in 1500 episodes of culture-proven community-acquired bacterial meningitis in adults
Data source |
DBMS10 |
MeninGene11 |
|
Study period |
1998-2002 |
2006-2010 |
Total (%) |
Gram-positive bacteria Streptococcus pneumoniae |
352 |
582 |
934 (62.3%) |
Streptococcus pyogenes |
6 |
11 |
17 (1.1%) |
Streptococcus agalactiae |
5 |
9 |
14 (0.9%) |
Streptococcus constellatus |
1 |
0 |
1 (0.1%) |
Streptococcus milleri |
0 |
1 |
1 (0.1%) |
Streptococcus parasanguinis |
0 |
1 |
1 (0.1%) |
Streptococcus oralis |
1 |
1 |
2 (0.1%) |
Streptococcus suis |
4 |
5 |
9 (0.6%) |
Streptococcus salivarius |
2 |
2 |
4 (0.3%) |
Streptococcus bovis |
1 |
2 |
3 (0.2%) |
Streptococcus equi |
1 |
3 |
4 (0.3%) |
Streptococcus mitis |
1 |
2 |
3 (0.2%) |
Group G Streptococcus |
1 |
1 |
2 (0.1%) |
Streptococcus (not specified) |
1 |
2 |
3 (0.2%) |
Enterococcus faecalis |
0 |
2 |
2 (0.1%) |
Staphylococcus aureus |
9 |
12 |
21 (1.4%) |
Staphylococcus epidermidis |
1 |
0 |
1 (0.1%) |
Listeria monocytogenes |
30 |
42 |
72 (4.8%) |
Gram-negative bacteria Neisseria meningitidis |
257 |
91 |
348 (23.2%) |
Haemophilus influenzae |
14 |
26 |
40 (2.7%) |
Haemophilus parainfluenzae |
1 |
1 |
2 (0.1%) |
Escherichia coli |
4 |
7 |
11 (0.7%) |
Klebsiella pneumoniae |
1 |
1 |
2 (0.1%) |
Salmonella enteritidis |
0 |
1 |
1 (0.1%) |
Capnocytophaga canimorsus |
0 |
1 |
1 (0.1%) |
Pseudomonas aeruginosa |
0 |
1 |
1 (0.1%) |
Total |
693 |
807 |
1500 (100%) |
Table 4 Causative organisms in culture-proven community-acquired bacterial meningitis in adults aged 17-50 without risk factors.
Data source |
MeninGene11 |
|
Study period |
2005-2010 |
|
Study group |
17-50 years no risk factorsa |
old, |
Gram-positive bacteria Streptococcus pneumoniae |
96 (52.4%) |
|
Streptococcus pyogenes |
6 (3.3%) |
|
Streptococcus agalactiae |
3 (1.6%) |
|
Streptococcus suis |
3 (1.6%) |
|
Streptococcus equi |
2 (1.1%) |
|
Streptococcus mitis |
1 (0.5%) |
|
Staphylococcus aureus |
2 (1.1%) |
|
Listeria monocytogenes |
3 (1.6%) |
|
Gram-negative bacteria Neisseria meningitidis |
59 (32.2%) |
|
Haemophilus influenzae |
7 (3.8%) |
|
Mixedb |
2 (1.1%) |
|
Total |
183 |
|
aRisk factors: recent head injury, cerebrospinal fluid leak, diabetes mellitus, immunosuppressive therapy, splenectomy, infection with human immunodeficiency virus (HIV).
bStreptococcus equi + Pseudomonas aeruginosa, Streptococcus milleri + Fusobacterium nucleatum.
Table 5 Empirical antimicrobial therapy for community-acquired bacterial Meningitis, stratified for age.
Age / risk group |
Treatment Alternative |
||
Neonates* Children |
amoxicillin 100-200 mg/kg/day (6h)and cefotaxime 50-150 mg/kg/day(8h)
ceftriaxone 100 mg/kg/day (max 4g) (24h) or cefotaxime 150 mg/kg/day (max 12g) (6h)
|
|
amoxicillin 100-200 mg/kg/day(6h) and gentamicin 4 mg/kg/day(24- 48h) meropenem 120 mg/kg/day(max 6 g) (8h) |
|
|||
|
|||
Adults |
amoxicillin 6x2 g/dag plusceftriaxone 2x2 g/day orcefotaxime 6x2 g/day |
|
Dosages derived from: SWAB-ID: Nationale antibioticaboekje van de SWAB, Between brackets interval between dosages.
* Dose and dosage interval dependent on gestational age and weight, see SWAB-ID for exact recommendations.
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Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 01-01-2012
Laatst geautoriseerd : 01-01-2012
Geplande herbeoordeling :
Algemene gegevens
The Dutch Working Party on Antibiotic Policy (SWAB; Stichting Werkgroep Antibiotica Beleid), established by the Dutch Society for Infectious Diseases (VIZ), the Dutch Society of Medical Microbiology (NVMM) and the Dutch Society for Hospital Pharmacists (NVZA), develops evidence-based guidelines for the use of antibiotics in hospitalized patients in order to optimize the quality of prescribing, thus, contributing to the containment of antimicrobial drug costs and resistance. By means of the development of national guidelines, SWAB offers local antibiotic and formulary committees a guideline for the development of their own, local antibiotic policy. These are the first SWAB guidelines on bacterial central nervous system infections. It is developed according to the Evidence Based Guideline Development method (EBRO; www.cbo.nl). The AGREE criteria
(www.agreecollaboration.org) provided a structured framework both for the development and the assessment of the draft guideline.
Relationship between the SWAB Guidelines and the 2012 Guidelines on Meningitis by the Dutch Society for Neurology (Nederlandse Vereniging voor Neurologie)
The SWAB guidelines cover the antimicrobial therapy in children and adults with bacterial meningitis, brain abscesses and tuberculous meningitis. They do not cover other treatment components of bacterial meningitis, such as corticosteroids, osmotic agents and anticoagulants.2 This is discussed extensively in the 2012 guidelines by the Dutch Society for Neurology (Nederlandse Vereniging voor Neurologie). The Nederlandse Vereniging voor Neurologie guidelines adopted the SWAB guidelines on meningitis to be the treatment part of their meningitis guidelines.
Doel en doelgroep
Core issues on cryptococcal meningitis are extensively discussed in the 2008 SWAB guidelines on fungal infections. Diagnostics for bacterial meningitis are briefly discussed in the introduction, but not systematically reviewed in these guidelines. Encephalitis falls outside the scope of these guidelines.
For this guideline we made a distinction based on the setting in which bacterial meningitis was acquired: community-acquired versus nosocomial. Further, we provide recommendations for empirical antimicrobial therapy for clinical subgroups of bacterial meningitis patients. The choice of initial antimicrobial therapy for these subgroups is based on the bacteria most commonly causing the disease, taking into account the patient’s age and clinical setting, and patterns of antimicrobial susceptibility. After the results of culture and susceptibility testing have become available, antimicrobial therapy can be modified for optimal treatment.
Samenstelling werkgroep
Preparatory Committee: Dr. M.C. Brouwer, Drs. S.G.B. Heckenberg, Dr. G.T.J. van Well (Nederlandse Vereniging voor Kindergeneeskunde), Dr. A. Brouwer (Vereniging voor Infectieziekten), Dr. E.J. Delwel (Nederlandse Vereniging voor Neurochirurgie), Dr. L. Spanjaard (Nederlandse Vereniging voor Medisch Microbiologie), Prof. dr. D. van de Beek (Nederlandse Vereniging voor Neurologie), Prof. dr. J.M. Prins (SWAB).
Methode ontwikkeling
Evidence based
Werkwijze
Twelve key questions were formulated concerning the antibiotic treatment of bacterial central nervous system infections. Using several data sources (see data sources) conclusions were drawn, with their specific level of evidence, according to the CBO grading system adopted by SWAB (Table 1).1
Subsequently, specific recommendations were formulated. Each key question will be answered in a separate chapter.
Table 1a
Methodological quality of individual studies.1
|
Intervention |
Etiology, prognosis |
A1 |
Systematic review of at least two independent A2-level studies |
|
A2 |
Randomised Controlled Trial (RCT) of sufficient methodological quality and power |
Prospective cohort study with sufficient power and with adequate confounding corrections |
B |
Comparative Study lacking the same quality as mentioned at A2 (including patientcontrol and cohort studies) |
Prospective cohort study lacking the same quality as mentioned at A2, retrospective cohort study or patient-control study |
C |
Non-comparative study |
|
D |
Expert opinion |
Table 1b
Level of evidence of conclusions
|
Conclusions based on |
1 |
Study of level A1 or at least two independent studies of level A2 |
2 |
One study of level A2 or at least two independent studies of level B |
3 |
One study of level B or C |
4 |
Expert opinion |
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