Neisseria meningitidis with Decreased Susceptibility

Scandinavian Journal of Infectious Diseases

ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19

Neisseria meningitidis with Decreased Susceptibility to Penicillin in Istanbul, Turkey Metin Punar, Haluk Eraksoy, A. Atahan Cagatay, Halit Ozsut, Arif Kaygusuz, Semra Calangu & Murat Dilmener To cite this article: Metin Punar, Haluk Eraksoy, A. Atahan Cagatay, Halit Ozsut, Arif Kaygusuz, Semra Calangu & Murat Dilmener (2002) Neisseria meningitidis with Decreased Susceptibility to Penicillin in Istanbul, Turkey, Scandinavian Journal of Infectious Diseases, 34:1, 11-13, DOI: 10.1080/00365540110077344 To link to this article: http://dx.doi.org/10.1080/00365540110077344

Published online: 08 Jul 2009.

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Date: 03 May 2016, At: 04:06

Scand J Infect Dis 34: 11 – 13, 2002

Neisseria meningitidis with Decreased Susceptibility to Penicillin in Istanbul, Turkey METIN PUNAR 1 , HALUK ERAKSOY1 , A. ATAHAN CAGATAY1 , HALIT OZSUT1 , ARIF KAYGUSUZ2 , SEMRA CALANGU1 and MURAT DILMENER3

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From the Departments of 1 Clinical Bacteriology and Infectious Diseases, 2 Microbiology and Clinical Microbiology and 3 Internal Medicine, Istanbul Faculty of Medicine, Istanbul Uni×ersity, Istanbul, Turkey This study was conducted to estimate the rate of decreased susceptibility to penicillin (MIC\ 0.06 – 1 mg/ ml) in Neisseria meningitidis isolates in Istanbul, Turkey. A total of 30 isolates collected during a 1-y period from patients with meningitis and from nasopharyngea l carriers were tested for penicillin and cefotaxime susceptibility using the E-test. Two out of 12 (17%) clinical isolates and 11/ 18 (61%) nasopharyngea l isolates showed decreased susceptibility to penicillin with MICs in the range 0.094 – 1.0 mg/ ml, giving an overall resistance of 43% (n 5 13). These data show that continued surveillance of trends in antimicrobial susceptibility of N. meningitidis is important for detecting the emergence of N. meningitidis strains with MICs \ 1 mg/ ml which may pose serious therapeutic problems. M. Punar, MD, Department of Clinical Bacteriology and Infectious Diseases, Istanbul Faculty of Medicine, Istanbul UniØersity, C ¸ apa, TR-34390 Istanbul, Turkey

INTRODUCTION Neisseria meningitidis remains a leading cause of bacterial meningitis resulting in signi cant morbidity and mortality. It is distinguished from most other bacteria by its continued sensitivity to antimicrobial agents commonly used to treat patients with bacterial meningitis. Penicillin has been the drug of choice in the treatment of meningococcal diseases (1). Although the penicillin resistance of N. meningitidis was de ned previously and its clinical impact was not clearly known, the rst clinical isolates with decreased susceptibility to penicillin were identi ed in Spain in 1985 (2). Since then, such microorganisms have been reported in several parts of the world, mostly in increasing numbers (3– 6). Isolates with decreased susceptibility to penicillin exhibit a penicillin MIC of \ 0.06 – 1.0 mg ml (7). In Turkey, meningococcal infections are endemic, but data concerning the antimicrobial susceptibility patterns of N. meningitidis isolates are limited (8). After the rst clinical isolate was found in our hospital, we conducted this study in order to estimate the rate of decreased susceptibility to penicillin among clinical and nasopharyngeal N. meningitidis isolates in Istanbul, Turkey. MATERIALS AND METHODS A total of 30 N. meningitidis isolates, comprising a rst group of 12 invasive isolates and a second group of 18 carriage isolates, were analyzed. Carriage isolates were obtained from the nasopharynx of 84 healthy school children (39 boys, 45 girls; age range 9 – 11 y) living in the vicinity of the Istanbul Medical School during the winter of 1997. The clinical isolates were obtained from cerebrospinal uid (CSF) cultures from adult patients with meningoccocal meningitis (age range 15 – 60 y; median age 20 y; male:female ratio 5 : 7). The 12 patients were epidemiologically unrelated and were selected from a group of 27 adult patients with communityacquired bacterial meningitis who presenting at the hospital of the Istanbul Medical School in 1997. The city was settled on a large area and the hospital is located at one of the centers. The Depart© 2002 Taylor & Francis. ISSN 0036-5548

ment of Infectious Diseases has 20 beds for adult patients only. Additionally, the Department also has a bacteriology laboratory, which received : 15,000 clinical specimens from a variety of clinics, including emergency units for adults, during the same time period. As no other meningococcal strain was isolated from these specimens, the 12 clinical isolates also represented the total number of isolates from adult patients in the hospital. The isolates were identi ed as N. meningitidis using the API NH test (BioMe´rieux, Paris, France) in addition to standard bacteriological methods. Susceptibility testing was performed using the E-test (AB Biodisk, Solna, Sweden) in accordance with the manufacturer’s instructions and in accordance with the NCCLS criteria (9) for penicillin and cefotaxime. Penicillin-susceptible isolates were de ned as those having a MIC of 5 0.06 mg ml and isolates with decreased susceptibility to penicillin were de ned as those having a MIC of \0.06– 1 mg ml (7). The x2 test was used to compare the proportions of decreased susceptibility between the clinical and carriage isolates. The isolates were also tested for b-lactamase production with chromogenic cephalosporin and nitroce n (Oxoid, Basingstoke, UK). Serogroups were determined by slide agglutination with antisera for serogroups A, B, C, W135 and WXYZ (Minsap, Havana, Cuba). General quality control procedures were followed. Enterococcus faecalis ATCC 29212 and Escherichia coli ATCC 25922 were used as control strains.

RESULTS A total of 30 isolates, 12 from the CSF of patients with meningitis and 18 from the nasopharynx of carriers, were tested for penicillin and cefotaxime susceptibility. Among the invasive isolates, the most common serogroup was group B (n¾ 6). Serogroups A, C and W135 were represented by 1 case each. Three isolates did not produce any reaction with any of the antisera. For the 18 nasopharyngeal isolates, 4 serogroups were represented. The most common serogroup was group C (n¾ 5), followed by groups A (n ¾ 2), B (n ¾ 2) and W135 (n¾ 1). Nearly half of the isolates (n ¾ 8) in this group were non-serogroupable. Two out of 12 clinical isolates, one with serogroup A and another with serogroup W135, exhibited decreased susceptiDOI: 10.1080 00365540110077344


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bility to penicillin, with MICs of 0.25 and 1 mg ml, respectively. The serogroup W135 isolate was the rst isolate with decreased susceptibility to penicillin found in Turkey and was recovered from a patient with complement de ciency who experienced a second attack of meningococcal meningitis. Of the 18 carriage isolates, 11 (61%) exhibited decreased susceptibility to penicillin, with MICs of 0.094– 1.0 mg ml. The distribution of these isolates among serogroups did not differ signi cantly. However, decreased susceptibility to penicillin was more common among the nasopharyngeal isolates (61%) than among those from CSF (17%). Fig. 1 shows the proportions of decreased susceptibility to penicillin in the 2 populations. A statistically signi cant difference was observed (pB 0.05). All of the isolates in both groups were uniformly susceptible to cefotaxime (MIC B 0.016 mg ml) and none produced b-lactamase. DISCUSSION N. meningitidis with decreased susceptibility to penicillin is being reported with increasing frequency in several parts of the world (3– 6). When these strains were described for the rst time in clinical isolates in Spain in 1985, the intermediate penicillin resistance rate was only 0.4% (2). In 1990, the frequency of these strains was 44% (10) and later became as high as 71% in some hospitals, with the result that penicillin is no longer the rst-line therapy for meningococcal meningitis in Spain (6). In some other countries the resistance rate was as low as 3% in 1991 and as it has not changed over a 7-y period, penicillin is still regarded as the initial antimicrobial agent for treating meningococcal disease (4, 11). In our study, 2 12 (17%) CSF isolates were intermediately resistant to penicillin, but the overall incidence was 43%, which is higher than the rates in many other countries and almost equal to the rates in some parts of Spain. The rate of intermediate resistance among nasopharyngeal isolates was even higher (61%). The signi cant difference observed in the proportions of bacteria with decreased susceptibility to penicillin between invasive and nasopharyngeal carriage isolates con rms the assumption that the nasopharynx may

Fig. 1. Distribution of penicillin susceptibility of N. meningitidis from patients and carriers.

Scand J Infect Dis 34

be an important reservoir of penicillin-resistant N. meningitidis. Long-term persistence in the nasopharnyx may provide nasopharyngeal strains of N. meningitidis with the opportunity to obtain penicillin resistance by interspecies horizontal gene transfer of penicillin-binding proteins (PBP) from commensal Neisseria species, which are intrinsically more resistant (12, 13). Resistant nasopharyngeal N. meningitidis strains can, eventually, be the pathogen or the donor of resistance for pathogenic isolates. The reduced susceptibility to penicillin among N. meningitidis strains is not fully understood, but altered PBP with decreased af nity to penicillin are the mainstay of pathogenesis (14). Although b-lactamase-producing strains with MICs \ 2 mg ml have been reported very rarely (15), none of our isolates produced b-lactamase. Decreased susceptibility to penicillin among N. meningitidis strains has been reported from a variety of countries but there is still a standardization problem with regard to susceptibility testing of meningococci. The E-test is a useful test for determining penicillin susceptibility in N. meningitidis and is easy to perform and interpret. The correlation between E-test MICs and NCCLS standardized agar dilution MICs has been shown previously (16). The clinical signi cance of decreased susceptibility to penicillin in N. meningitidis strains is unclear. Most of the infections with these strains have been treated successfully with penicillin. However, treatment failures with low-dose penicillin in 1 case of meningococcal meningitis and highdose ampicillin in another have been described (17, 18). In patients with meningitis treated with penicillin, decreased susceptibility to penicillin was shown to cause no difference in outcome, but a higher rate of complications, a longer period of fever and a delayed clinical response to therapy were observed (19, 20). Therefore, high doses of penicillin were recommended. The 2 patients with meningitis caused by isolates with decreased susceptibility to penicillin in this study were treated with ceftriaxone initiated empirically. One of them recovered completely but the other experienced had some sequelae. This patient, a 30-y-old woman with complement de ciency who had a second attack of the disease, was brought to the hospital in meningococcal shock. Her clinical condition was probably more important for the outcome than the resistance pattern of the isolate. Although penicillin is regarded as the rst-line therapy for meningococcal diseases, in practice it is rarely used as the initial antimicrobial agent in the treatment of meningitis or sepsis (1). In many countries, third-generation cephalosporins, such as cefotaxime or ceftriaxone, are preferred for empiric therapy of meningococcal meningitis due to their superior activity, lower MICs and favorable pharmacokinetics. In this study, cefotaxime, which is also used to predict the activity of ceftriaxone in the therapy of meningitis, showed a high degree of activity against N. meningitidis, with MICs of B 0.016 mg ml for all of the isolates.

Scand J Infect Dis 34

Given a high rate of decreased susceptibility to penicillin in clinical isolates and a higher rate in the nasopharyngeal isolates in Turkey, all clinical isolates of N. meningitidis must be routinely tested for penicillin susceptibility. Owing to the theoretical risk of penicillin resistance, continued surveillance is important to monitor trends in antimicrobial susceptibility of N. meningitidis and to detect the emergence of N. meningitidis strains with MICs \ 1 mg ml which may cause serious therapeutic problems.


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Submitted January 8, 2001; accepted April 26, 2001