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Epidemiologie en antibiotische behandeling

Beoordeeld: 01-01-2012

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

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.

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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Autorisatiedatum en geldigheid

Laatst beoordeeld  : 01-01-2012

Laatst geautoriseerd  : 01-01-2012

Geplande herbeoordeling  :

Initiatief en autorisatie

Initiatief:
  • Stichting Werkgroep Antibioticabeleid
Geautoriseerd door:
  • Nederlandse Vereniging voor Kindergeneeskunde
  • Nederlandse Vereniging voor Medische Microbiologie
  • Nederlandse Vereniging voor Neurochirurgie
  • Nederlandse Vereniging voor Neurologie

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 

Zoekverantwoording

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Nosocomiale bacteriële meningitis