Neisseria meningitidis Antimicrobial Resistance in Italy, 2006 to 2016

The aim of this study was to evaluate the antimicrobial susceptibilities of 866 Neisseria meningitidis invasive strains during 11 years of surveillance in Italy. Two and six strains were resistant to ciprofloxacin and rifampin, respectively.

I nvasive meningococcal disease (IMD) is a serious and rapidly progressive illness; third-generation cephalosporins or penicillin G are usually used for the treatment of patients with invasive diseases (1,2). Ciprofloxacin or rifampin is recommended for chemoprophylaxis of close contacts of the case (2).
This study was conducted to evaluate the antimicrobial susceptibilities of 866 meningococcal invasive strains isolated from 2006 to 2016 in Italy. Genotyping and determination of the penA gene of Pen i strains from 2014 to 2016 were also performed.
Clinical data, strains, and/or clinical samples of each IMD case are collected throughout the country and sent to the National Reference Laboratory (NRL) at the Istituto Superiore di Sanità (ISS), within the activities of the National Surveillance System.
Six strains were rifampin resistant (6/866 [0.7%]), with 3 strains from serogroups B, C, and NG, with MIC values ranging from 0.38 g/ml to 2 g/ml, and 3 strains of serogroup C with a high level of resistance (MIC, 32 g/ml). Rifampin-resistant strains were isolated from unvaccinated patients (from 5 to 54 years of age), one of whom died.
A total of 472 strains (472/866 [55%]) were susceptible to penicillin G (Pen s ) (MIC,     A total of 6 penicillin G-resistant (Pen r ) strains, with 5 strains in 2006 and 1 strain in 2009, with an MIC range of 0.38 to 0.5 g/ml (Table 1), were detected. Pen r meningococci were isolated from unvaccinated patients (1 patient with meningitis, 4 patients with sepsis, and 1 patient with unknown clinical presentation), with an age range of 1 to 83 years. The 83-year-old patient, who had sepsis, died.
As shown in Fig. 1, the antimicrobial susceptibility trend of penicillin G changed over the time frame. In particular, starting from 2012, a statistically significant increase in Pen i strains (P Ͻ 0.05) has been observed.
The sequence of a 402-bp DNA fragment of the 3= part of penA was obtained for 132 Pen i strains of more recent isolation (2014 to 2016). Twenty-three penA alleles were identified, of which penA248 was the most prevalent. Out of 23 penA alleles, 20 alleles coded for a peptide with 5 amino acid substitutions in the C-terminal region of PBP2 (Table 2). penA327 and penA648 harbored 4 substitutions (lacking I566V). The penA1 wild-type allele was found in 3 Pen i strains (MIC, 0.094 to 0.25 g/ml) ( Table 2).
Here, in 11 years of IMD surveillance in Italy, invasive meningococcal strains showed a wide range susceptibility to the antimicrobials used for treatment and chemoprophylaxis. The exception was 6 rifampin-resistant strains, of which 3 strains were highly resistant and 2 strains were ciprofloxacin resistant. Of note, an increase in the proportion of Pen i strains, starting from 2012, has been observed.
It is likely that the increase in Pen i strains was due to the spread of the hypervirulent strain C-CC11 that is of a concern in our country (13). The penA248 allele was the predominant allele and was associated with the finetype C: P1. 5-1, 10-8:F3-6: ST-11 CC11) (data not shown), which is responsible for severe sporadic cases and outbreaks in Italy (13).
Interestingly, 3 Pen i strains harboring the penA327 allele showed an increased MIC to cefotaxime even though they were within the susceptibility category. Two of these strains were isolated from men who have sex with men (MSM) with sepsis. This occurrence has been already reported by others (4), underlying that the similarity between penA327 of N. meningitidis and penA-XXXIV of N. gonorrhoeae might determine a genetic exchange between the two Neisseria spp. in the urethra (4,9).
To conclude, resistant meningococci are rare in this country; however, an increase in Pen i strains was observed mainly associated with the spread of C-CC11 meningococci. Because of the concern over the epidemic potential of this strain, it is crucial to link the molecular traits of invasive meningococcal strains with antimicrobial susceptibility, with a particular attention to the emergence of meningococci with reduced susceptibility to cephalosporins (4).