Year: 2024
Type: article
Abstract: Neisseria meningitidis can be surrounded by a polysaccharide capsule that defines one of the 12 meningococcal serogroups, of which 6 (A, B, C, W, X and Y) are the most frequent among invasive meningococcal disease (IMD) cases. Unencapsulated or non-serogroupable (NG) isolates are usually encountered in carriers, although IMD cases are sometimes reported with NG isolates. Isolates are also characterized based on DNA sequences that classify isolates into MLST STs according to homologies of gene fragments of seven housekeeping genes. Related STs are further grouped into clonal complexes.1 IMD is dominated by meningitis and septicaemia, which leads to a severe disease burden. As such, it requires prophylactic measures including antibiotic prophylaxis and vaccination. N. meningitidis is still susceptible to most antibiotics that are used for treatment and prophylaxis.2 Ciprofloxacin is recommended for antibiotic prophylaxis. Resistance to this antibiotic in N. meningitidis (MIC > 0.016 mg/L) was previously extremely rare in Europe and was reported only from sporadic cases.3 However, several recent reports from India and China have described increased ciprofloxacin resistance.2 Moreover, recent reports have described meningococcal isolates among travellers or migrants in Europe.4,5 Here we describe four cases of IMD due to ciprofloxacin-resistant N. meningitidis isolates in 2023 in France. During the year 2023, an important rebound of IMD cases was reported in France, which started in the fall of 2022 and occurred after the progressive lifting of non-pharmaceutical measures that were undertaken to control the COVID-19 pandemic.6 From October 2022 to the end of 2023, six IMD cases were reported in France with isolates that were characterized as resistant to ciprofloxacin. Therefore, we have screened our National Reference Centre for Meningococci and Haemophilus influenzae (NRCMHi) database for all IMD cases from 2017 to the end of 2023, including ciprofloxacin-resistant isolates. Data on isolates and samples were collected anonymously and full phenotyping, including antibiotic susceptibility testing and genotyping, including WGS, were performed as part of the national surveillance of IMD in France based on mandatory reporting and sending of the isolates and samples for typing to the NRCMHi.6 These data are available through the PUBMLST website (https://pubmlst.org).1 A total of 2373 IMD cases were identified with a total of 10 ciprofloxacin-resistant invasive isolates during this period, accounting for 0.4% of all cases (MIC range 0.063–4 mg/L). Serogroups were determined and antibiotic susceptibility testing (MIC of ciprofloxacin and benzylpenicillin) was performed using ETEST. Alleles of penA and gyrA genes that are involved in resistance to benzylpenicillin and ciprofloxacin, respectively, were extracted from WGS data through the PubMLST website.1 The number of ciprofloxacin-resistant isolates was low; their number has been significantly higher since 2020 (2 of 1258 isolates for the period 2017–19 and 8 of 1115 isolates for the period 2020–23; P = 0.04). Resistant isolates were of several serogroups (B, C, W and Y) and also included two non-capsulated isolates (Table 1). These two isolates belonged to the clonal complex cc175. It is noteworthy that non-groupable ciprofloxacin-resistant isolates belonging to cc175 were described in several European countries among disease/carrier isolates and several of these were linked to travellers or asylum seekers.4 Also, resistance to ciprofloxacin was reported to be prevalent in China and India but remained extremely rare in Europe.2 Like the data from the UK,4 the ciprofloxacin-resistant isolates reported here were heterogeneous, belonged to several serogroups, several clonal complexes and were not exclusively linked to travellers or asylum seekers (Table 1). Characteristics of isolates and IMD cases N/A, not available. aIntermediate isolates are defined as 0.125 mg/L ≤ MIC ≥ 1 mg/L. bPresence of mutations at F504L, A510V, I515V, H541N or I566V. cResistance to ciprofloxacin (MIC > 0.016 mg/L). Amino acid substitutions in DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) confer resistance to quinolones, including ciprofloxacin.2 gyrA alleles were distinct among our ciprofloxacin-resistant isolates, but all these alleles had mutations in the QRDR of gyrA. Four isolates had the mutation T91I, five showed the mutation D95N, and one isolate had a mutation in both codons (T91I and D95N) (Table 1). None of these isolates had mutations in gyrB, parC and parE. However, the high MIC (4 mg/L) of one isolate from 2018 may reflect additional genetic modifications to be explored (Table 1). These observations suggest that those isolates correspond to different emerging events that seem to occur locally in France. Of interest, one isolate (NG/cc175) was reported in a patient under anti-complement treatment for paroxysmal nocturnal haemoglobinuria using the anti-C5 monoclonal antibody eculizumab (Table 1). Such a treatment increases the risk of IMD with NG isolates.7 High proportions of ciprofloxacin-resistant isolates were reported in a recent carriage study among travellers attending the Hajj pilgrimage, which may be linked to the widespread use of ciprofloxacin among pilgrims from high-risk countries.8 Another concern is that most of these isolates were also non-susceptible to benzylpenicillin (Table 1), suggesting that MDR isolates are also reported. Meningococcal antibiotic multiresistance was also reported to be frequent in Southeast Asia and the USA.9,10 Increased use of antibiotics worldwide for various bacterial infections has driven the selection of antimicrobial resistance in N. meningitidis, which nevertheless remains susceptible to most antibiotics. However, this golden era may have reached an end and meningococcal antibiotic resistance may now be an ongoing source of concern. Enhanced surveillance of meningococcal resistance, particularly using molecular methods, is required. We thank the NRCMHi for their excellent technical assistance. This work was supported by the Institut Pasteur (024519E) and Santé Publique France (024598E). The authors declare no conflict of interest. The genome assembly and FASTA data were submitted and are available at https://pubmlst.org. Data were collected anonymously as part of the mission of the NRCMHi for routine surveillance of IMD and isolate identification and typing. The procedure for collecting samples and information was submitted and approved by the Commission Nationale de l’Informatique et des Libertés (CNIL no. 1475242/2011) and the requirement for consent was waived.
DOI: 10.1093/jac/dkae433
Institutions: Institut Pasteur, Université Paris Cité
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,851
Funder: Institut Pasteur
Award: G1771991147
OpenAlex ID: W4404787217