Antibiotic guidelines and antibiotic use in adult bacterial meningitis in The Netherlands

Diederik van de Beek,*, Jan de Gans, Lodewijk Spanjaard, Marinus Vermeulen and Jacob Dankert

Department of Neurology and The Netherlands Reference Laboratory for Bacterial Meningitis/Department of Medical Microbiology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In The Netherlands, national guidelines for the treatment of adult patients with bacterial meningitis were introduced in October 1997. In 1998 we began a prospective, nationwide study to evaluate the compliance with these consensus-based guidelines. In addition, we evaluated whether the recommended initial treatment provides adequate microbiological coverage. From October 1998 to January 2000, 365 adults with bacterial meningitis were identified using information from The Netherlands Reference Laboratory for Bacterial Meningitis; 263 patients were classified into four categories depending on patient's age and underlying health status. In the first category, patients 16–60 years without risk factors, Neisseria meningitidis was the most common pathogen (53%); 62 of 127 patients (49%) received treatment in compliance with the guidelines. In the second and third categories, patients >60 years without risk factors and those with risk factors independently of age, Streptococcus pneumoniae caused 61% and 58% of cases, respectively. Compliance in these categories was about 17%. Overall, 33% of patients received treatment in compliance with the guidelines. The microbiological coverage of patients treated in compliance and not in compliance with the guidelines was 98% and 93%, respectively. In conclusion, 1 year after national consensus-based guidelines for the initial treatment of adult patient with bacterial meningitis were introduced in The Netherlands, only one-third of Dutch physicians were adhering to the guidelines. The microbiological coverage for the patients who were treated in compliance with the guidelines was almost complete (98%).


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Since chemotherapeutics and antibiotics became clinically available, bacterial meningitis has become a curable disease. Nevertheless, the lethality of this disease and frequency of sequelae among those surviving remain substantial.1–4 Early administration of an optimal antibiotic therapy for bacterial meningitis has been shown to be essential to minimize lethality and morbidity.5,6 For many years, penicillin was the drug of choice in the treatment of adult bacterial meningitis.7 The increasing prevalence of resistant bacteria and the reduction in incidence rates of Haemophilus influenzae type b (Hib) meningitis through the use of Hib vaccination have changed the behaviour of most physicians in prescribing antibiotics for patients with meningitis in the last 10 years.5,7 Recommendations in various countries for the initial antibiotic therapy in children and adults with bacterial meningitis have been provided.5,7–9 In The Netherlands in 1996, a working group was asked to provide national guidelines for the initial treatment of patients with bacterial meningitis. This working group consisted of 17 Dutch experts in the field of bacterial meningitis, and included paediatricians, neurologists, medical microbiologists, internists, neurosurgeons and public health care workers. They prepared draught guidelines, which were discussed and adjusted in a national consensus meeting in 1997. All medical doctors involved in the treatment of patients with bacterial meningitis were invited to participate in the consensus meeting, and all received a booklet containing the guidelines.10 After the meeting, this booklet was widely disseminated in 1997. In 1998, 1 year after the guidelines were published, we began a prospective, nationwide study to evaluate the compliance with these consensus-based guidelines. In addition, we evaluated whether the recommended initial treatment provided adequate microbiological coverage.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Patients at least 16 years of age with meningitis in the period from October 1998 to January 2000 were identified using the database of The Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM). This laboratory is a collaboration of the Academic Medical Centre (AMC, Amsterdam, The Netherlands) and the National Institute of Public Health and the Environment (RIVM, Bilthoven, The Netherlands). Since 1975, the NRLBM has received cerebrospinal fluid (CSF) and blood isolates from c. 85% of all patients with bacterial meningitis in The Netherlands (15.8 million inhabitants).11,12

Daily, the NRLBM provided the investigators with the names of the physicians and hospitals where adult patients with bacterial meningitis had been admitted 2–6 days earlier. Physicians were contacted by telephone, and were informed about the study. All patients received written information concerning the study and were asked to give informed consent for participation. Subsequently, data on patient's history, microbiological features and treatment were collected by questionnaire [case record form (CRF)]. According to the national guidelines, patients were classified into four categories depending on patient's age and underlying health status (Table 1Go). The antibiotic therapy started on admission to the hospital was assumed to be the initial therapy. This observational study with anonymous patient data was carried out in accordance with the Dutch privacy legislation. Written informed consent to use data made anonymous was obtained from the patient (if possible) or from the patient's legal representative.


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Table 1. National recommendations for the initial treatment of adults with bacterial meningitis in The Netherlands (1997)10
 
Penicillin susceptibility of meningococci was determined by inoculating strains on chocolate agar containing 0.1 mg/L penicillin. Penicillin resistance in pneumococci was determined using a 1 µg oxacillin disc. Whenever a strain showed antibiotic resistance, the Etest (AB Biodisk, Solna, Sweden) was used to determine the MIC of the antibiotic. Inoculation procedure and susceptibility testing were performed according to the guidelines described by the NCCLS.13 The MIC criteria used for the Etest were those used for microorganisms tested by dilution susceptibility test methods.13

Initial antimicrobial treatment was defined as compliant if antibiotics were used as recommended in the national guidelines. The microbiological coverage for Neisseria meningitidis, Streptococcus pneumoniae and H. influenzae was based on the results of in vitro antibiotic susceptibility testing. Intermediate resistance for penicillin was categorized as inadequate coverage if penicillin monotherapy was given. For the other isolates, coverage was based on the antimicrobial spectrum of the antibiotic agents, as mentioned previously.14


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
From October 1998 to January 2000, isolates from 365 adult patients with meningitis (>16 years old) were received by the NRLBM. Distribution of species was as follows: S. pneumoniae in 164 patients, N. meningitidis in 119 patients, H. influenzae in 10 patients and various bacterial species in 72 patients. In total, 324 (89%) questionnaires were sent to the patient's physician. Of the 41 patients not included, 33 patients were untraceable and eight physicians refused to participate. The response rate in returning the CRF was 263 of 324 (81%).

The distribution according to species of the 263 meningitis patients for each category formulated in the guidelines (Table 1Go) is shown in Table 2Go. N. meningitidis, the most common causative microorganism of community-acquired meningitis in the category of adult patients >=60 years of age without risk factors, accounted for 54% of all species in this category. S. pneumoniae occurred particularly in the elderly and in patients with risk factors, and accounted for 61% and 58% of all species in these two categories, respectively. Gram-negative enteric bacteria (Escherichia coli and Klebsiella pneumoniae) were isolated from three patients >60 years old without risk factors (3%) and from one patient with a history of recent neurosurgery (6%). Listeria monocytogenes was isolated from the CSF in six patients with risk factors (19%). From meningitis patients with a history of recent neurosurgery, Staphylococcus aureus was isolated from six patients (33%); Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium were each isolated from one patient, accounting for 6% in this category. Results of Gram staining were available for 227 CSF specimens from 264 patients (86%). In 189 of 227 (83%) cases, microscopic examination of the Gram-stained CSF specimens revealed the presence of the microorganism cultured later on.


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Table 2. Distribution of species causing bacterial meningitis within guideline treatment categories among 263 Dutch adult patients Risk factor present Recent neurosurgery
 
Susceptibility testing showed that 1.6% of the 122 S. pneumoniae isolates had a decreased susceptibility to penicillin (with MICs ranging from 0.25 to 0.75 mg/L). One of the 84 (1.2%) N. meningitidis isolates had a decreased susceptibility to penicillin (MIC 0.75 mg/L).

On the first day of hospitalization the most frequently prescribed antibiotics were amoxicillin and penicillin (44%), a third-generation cephalosporin (18%) and a combination of penicillin or amoxicillin with a third-generation cephalosporin (14%) (Table 3Go). Of the patients without risk factors and >=60 years old and of those aged >60 years, 39% and 30%, respectively, were initially treated with a third-generation cephalosporin with or without amoxicillin or penicillin. Of the patients with risk factors, 38% received a third-generation cephalosporin.


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Table 3. Initial antibiotic therapy in 263 adult bacterial meningitis patients in The Netherlands Risk factor present Recent neurosurgery
 
In total, only 87 patients (33%) received treatment in compliance with the guidelines. Treatment regimens for patients with positive CSF Gram-staining and for patients with negative CSF Gram-staining were similar. In the first category (patients <60 years old without risk factors), 62 of 127 (49%) received treatment in compliance with the guidelines. In the other three categories, c. 16–19% of patients were treated in compliance with the guidelines (Table 3Go).

Despite the low compliance in these three categories, evaluation of microbiological coverage showed that 249 of 263 (95%) patients received treatment that provided adequate coverage (Table 4Go). Of the 87 patients treated in compliance with the guidelines, the microbiological coverage was 98%; 12 of 176 (7%) patients not treated in compliance with the guidelines received antibiotics with an insufficient spectrum. Six of the 11 (55%) patients with meningitis due to L. monocytogenes and not treated in compliance with the guidelines received inappropriate antibiotics.


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Table 4. The proportion of treatments microbiologically appropriate for patients treated in compliance or non-compliance with national guidelines by patient category
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In guidelines, the initial treatment should be based on the most common bacterial species that cause the disease in different age groups or clinical settings, and on antibiotic susceptibility patterns of the predominant microorganisms. In The Netherlands, a guideline with recommendations for the initial treatment of four patient categories with meningitis was provided in 1997. Our analysis of compliance and microbiological coverage 1 year after the guidelines became available shows that the distribution of species for each patient category is consistent with reports in the literature.2,15,16 Although prospective, nationwide data are lacking in most countries, in The Netherlands the distribution of species is reported annually.11,16 These data also showed that among adult patients with bacterial meningitis the distribution of the species causing meningitis has been stable during the last decade.11,16 Antibiotic resistance among isolates was low. Of the meningococci and pneumococci only 1.2% and 1.6%, respectively, showed intermediate penicillin resistance. Similar rates were found in a nationwide study in The Netherlands on antimicrobial susceptibility of CSF isolates from patients with meningitis during 1993 and 1994.17 With such low resistance rates, penicillin remained the drug of choice for the initial treatment of patients 16–60 years old with meningitis predominantly caused by S. pneumoniae and N. meningitidis. For the initial treatment of patients >=60 years old, and of patients with risk factors, a combination of penicillin or amoxicillin with a third-generation cephalosporin was recommended (Table 1Go). The use of third-generation cephalosporins is necessary, since a substantial portion of patients in these two categories had meningitis due to S. aureus or Gram-negative coliform bacteria (E. coli and K. pneumoniae) and the activity of penicillin or amoxicillin on such bacteria is poor. Cephalosporins are combined with penicillin or amoxicillin because L. monocytogenes, rather a common cause of meningitis in these categories, is resistant to cephalosporins. Our study showed that 12 (10%) patients in these two categories had meningitis due to L. monocytogenes. Finally, for meningitis patients with a history of recent neurosurgery, vancomycin plus a third-generation cephalosporin (a broad-spectrum combination effective against both Gram-positive and -negative organisms) was recommended in the national guidelines. Vancomycin is not found in the CSF of persons without meningitis, but bactericidal levels have been found in the CSF of most patients with bacterial meningitis.14 Although a rare cause of post-neurosurgical meningitis, enterococci show a bacteriostatic response to vancomycin and are cephalosporin resistant, and are therefore not covered by this combination of antibiotics.

The highest compliance was found in the first patient category (patients <60 years old without risk factors): 49% of them were treated according to the recommendations. Penicillin, recommended as the initial treatment in this patient category, covered isolates from all except five of the 127 patients. H. influenzae was cultured from four of these patients, and S. aureus from one. In the UK and USA, a combination of amoxicillin and cephalosporins has been recommended for the treatment of patients 16–60 years old.5,7–9 A major reason for the usage of third-generation cephalosporins is the emerging problem of microbial resistance, found particularly among S. pneumoniae.5,7 In the USA, Spain, Hungary and other countries, antibiotic-resistant S. pneumoniae strains have become prevalent and have emerged as a major problem in the treatment of patients with bacterial meningitis.18 In a recent surveillance study in the USA on antimicrobial resistance of invasive S. pneumoniae strains, 24% were resistant to penicillin.18 In the UK, a trend analysis revealed the prevalence of penicillin-resistance among pneumococci causing bacteraemia ranging from 1% in 1990 to 3.6% in 1998.19 In The Netherlands, the recommendation to treat this patient group with penicillin is still valid for patients with meningitis due to N. meningitidis and S. pneumoniae. For the small minority of patients in this category with meningitis due to other bacteria, this recommendation will not be optimal for all cases, and a third-generation cephalosporin would usually have been more appropriate. For the other categories the compliance was rather low, ranging from 17% to 18%.

Only one-third of the physicians adhered to the recommendations contained within the guidelines. The microbiological coverage for the 87 patients who were treated in compliance with the guidelines was almost complete (98%). Although guidelines can be varied by a clinician according to the circumstances, the question arises why was the compliance so poor? First, national guidelines are often of limited efficacy because medical practices are most often locally driven.20 In The Netherlands, >70% of hospitals have antibiotic formularies recommending antibiotic treatment.21 Local hospital committees preparing guidelines for antibiotic treatment should have been aware of the existence of the national consensus, since after the consensus meeting in 1997 a booklet containing the guidelines was widely disseminated. However, the current antibiotic policies of the eight Dutch academic hospitals still recommend a considerable diversity of antibiotics for the initial treatment of bacterial meningitis. Secondly, the meningitis guidelines have probably not been disseminated effectively. Dissemination must be supported by various interventions. Simply publishing guidelines has been associated with low rates of compliance before.20 In 1997, all medical specialists in The Netherlands involved in the treatment of patients with bacterial meningitis were invited to participate in the consensus meeting, and received a booklet with the guidelines. At this meeting the recommendations were approved by experts in the field of bacterial meningitis. However, other interventions have not been made, and the guidelines were not published in a national medical journal until 2001.22 Thirdly, despite the availability of the guidelines, the individual doctor has to decide which antibiotic to prescribe. Leibovici et al.23 clearly describe the dilemma of the individual doctor in making the decision about which antibiotic should be used. Doctors fear that the recommended initial treatment will not match the antibiotic susceptibility of the bacteria and feel uneasy in prescribing a drug that affords less than the maximum coverage. Following antibiotic guidelines may well slow down the development of resistance, and give future patients a better chance of an uneventful recovery, but the main duty of a doctor is to treat the present patient. This dilemma may also explain why so few physicians adhere to the national guidelines. Although Dutch doctors receive annual information about antibiotic susceptibility of isolates causing meningitis,16 the great majority do not use the guidelines.

Treatment of adult meningitis patients was not according to the guidelines in 167 of 273 (61%) cases. The microbiological coverage in these 167 patients was 93%. Twelve (7%) of them were treated inappropriately according to our criteria. Six of these patients (50%) had meningitis due to L. monocytogenes and received inappropriate therapy, since treatment consisted of a third-generation cephalosporin only. The other patients had meningitis due to S. aureus, Pseudomonas aeruginosa, E. faecalis, E. coli and S. epidermidis.

In this study only the compliance of the initial antibiotic treatment, recommended in the Dutch guidelines for treatment of adult meningitis patients, was analysed. Therapy can be modified when results of CSF Gram staining and CSF culture and antibiotic susceptibility testing become available. Analysis of the step-down therapy, narrowing the initial treatment, and the outcome of this approach has been carried out. The results will be presented separately.

In conclusion, 1 year after national consensus-based guidelines for the initial treatment of adult patients with bacterial meningitis in The Netherlands were provided, only one-third of the Dutch physicians were adhering to the guidelines. The microbiological coverage for the patients who were treated in compliance with the guidelines was almost complete (98%), whereas of the patients who were not treated in compliance with the guidelines, 7% received inappropriate antibiotic therapy.

Conflict of interest

This study was financially supported by means of a research grant from Roche Pharmaceuticals, The Netherlands, and was designed, conducted and analysed independently of any company and without any financial interests of investigators.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We thank Roche, The Netherlands, for financial support, Ms C. J. J. M. Schouten for her assistance in data management, and Professor P. Speelman for his remarks on the manuscript. We are indebted to many physicians in The Netherlands for their cooperation. The results were presented at the Eleventh Meeting of the European Neurological Society, Paris, 21–25 April 2001.


    Notes
 
* Corresponding author. Tel: +31-20-5663842; Fax: +31-20-6971438; E-mail: D.vandeBeek{at}amc.uva.nl Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Received 10 May 2001; returned 24 October 2001; revised 21 November 2001; accepted 29 November 2001