Neisseria meningitidis, a Gram-negative diplococcus, causes serious disease showing a clinical spectrum ranging from transient fever with bacteraemia to meningitis and fulminant septicaemia.
Asymptomatic nasopharyngeal carriage of N. meningitidis is common in healthy people and has an age-dependent frequency ; transmission is facilitated by close contact, climatic factors and others . Some factors that may determine whether an individual becomes an asymptomatic carrier or develops disease have been proposed and it is well known that the risk of meningitis remains higher in family households and among close contacts of an index case with meningococcal disease (MD) . For this reason, treatment of close contacts with antimicrobial agents is applied routinely during outbreaks of MD to prevent the spread of the disease. Generally speaking, the antibiotics used in the treatment of cases of MD are ineffective in eradicating nasopharyngeal carriage so it is possible to distinguish between antibiotics used in chemoprophylaxis and those used in clinical treatment of disease.
Because of this, N. meningitidis is under strong antibiotic pressure which might act by selecting for antibiotic resistant variants. In fact, N. meningitidis is a naturally transformable pathogenic bacterium with a panmitic population structure, characterised by horizontal genetic exchange . Meningococcal strains are able to acquire antibiotic resistance in this way, through novel mosaic genes as a result of intra-genic recombination. Moreover, closely related Neisseria species harbour plasmids associated with antibiotic resistance which can be mobilised to meningococci , introducing antibiotic resistance. Finally, point mutation in the target chromosomal genes is an additional mechanism for the acquisition of antibiotic resistance .
RESISTANCE TO ANTIMICROBIAL AGENTS
Sulfonamides have been used widely in the past in the treatment of meningococcal disease and especially in chemoprophylaxis to prevent secondary cases in close contact of patients . Their target is dihydropterate synthase (DHPS); this catalyses the formation of dihydropteroic acid on the folate synthesis pathway in bacteria and some eukaryotic cells, although it is not present in human cells. This is the reason for the selective action of sulfonamides which act as competitive inhibitors of DHPS.
Because sulfonamide drugs have been used for decades, resistance now is common and widespread, and sulfonamide is not used for prophylaxis of meningococcal disease unless the sensitivity of the strains has been established. Data about sulfonamide resistance around Europe during 1997/1998  are presented in Table 1. There is a wide ranging variation between Romania or Spain, with 100 % and 90 % of the strains resistant to sulfadiazine (Sr) respectively and the Czech Republic with only 6.35 % of samples tested for Sr. Data from the USA show that fully susceptible strains represented 46 % in a recent study .
Sulfonamide resistance in N. meningitidis is mediated by altered forms of the chromosomal dhps gene. As a result of these alterations a DHPS that does not bind sulfonamides is produced by resistant isolates. Generally speaking, Sr meningococci have a dhps gene which is about 10 % different in sequence from the corresponding gene of sulfonamide-sensitive strains . Two types of resistance genes have been described in N. meningitidis, one frequently found with a typical 6 bp insertion which is known to reduce the affinity for sulfonamides, and the other, less common form, differs by lacking the 6 bp insert . It has been suggested that these sulfonamide resistance determinants might appear as a result of recombination with a different species , but also they might be mutant variants of the wild-type dhps genes as has been described for another bacterial species . However, after their introduction into meningococci both types of resistant genes have spread among different meningococcal isolates. For example, a Sr allele found in a serogroup A strain isolated in Sudan presents a 423 bp central fragment identical to that found in Norwegian sulfonamide-resistant B and C serogroup strains , showing that the dhps genes can move among different N. meningitidis strains and also across different geographical areas.
Plasmid-borne sulfonamide resistance has been reported in Gram-negative bacteria, including a N. sicca isolate . However, sulfonamide resistance associated with plasmid has been described only once in three related N. meningitidis strains . Thus this mechanism of sulfonamide resistance does not appear to be common in meningococcal strains.
Since the first reports of sulfonamide-resistant meningococci, rifampicin has been widely recommended for use in chemoprophylaxis of MD. Rifampicin acts on the β subunit (encoded by rpoB gene) of DNA-directed RNA polymerase and inhibits the elongation of the initiated RNA chain. A single point mutation in a specific region of the rpoB gene is responsible for this resistance . In addition, changes in membrane permeability have been proposed recently to have a role in the resistance to rifampicin .
Although nasopharyngeal carriage of meningococci is reduced by more than 90 % by the use of this antibiotic, it may not work in systemic infections , and rifampicin-resistant isolates (Rr) can develop rapidly as result of treatment . Horizontal transfer of resistance to this drug from one Neisseria species to another has been pointed out, but Nolte  failed to show evidence of this. Nevertheless, the existence of horizontal spread of rifampicin resistance among the meningococcal carrier population has been well documented . N. lactamica, a very closely related species which shares a habitat with meningococci, has shown decreased susceptibility to rifampicin at least since 1985 . Fortunately N. meningitidis strains resistant to rifampicin are still uncommon (Table 1) but surveillance for this characteristic should be carried out routinely.
Minocycline, an oral tetracycline, has been tested either alone or together with rifampicin for use in chemoprophylaxis of MD  and its effectiveness is not in question. However, because of the unacceptably high incidence of side-effects, tetracycline is not recommended. Although susceptibility to tetracycline is not investigated routinely, resistance to this antibiotic has been described in meningococci, associated with the presence of a conjugative plasmid with the insertion of the tet M determinant . Plasmid-carrying N. meningitidis isolates might be uncommon  but the tet M resistance determinant could also be inherited through conjugative events with other Neisseria species .
Meningococci are highly susceptible to ciprofloxacin, and its efficacy to eliminate carriage is over 93 % . A single dose is as effective as rifampicin, and with the use of only one dose, the side-effects should be minor temporary problems . Because of high level of resistance to penicillin and tetracycline, gonocococcal strains have been treated with fluoroquinolones at least since 1993 . Only a few years later N. gonorrhoeae isolates with clinically significant resistance to fluoroquinolones were reported widely, and specific alterations within the quinolone resistance-determining regions of gyr A and par C have been characterised . Perhaps an increase in the use of the fluoroquinolones in the treatment of respiratory diseases and others might write a similar history for meningococci. However, N. meningitidis strains resistant to ciprofloxacin have not been described yet either before or after therapy , so this antibiotic may be a good alternative in chemoprophylaxis of MD.
Moderate susceptibility to penicillin
N. meningitidis strains were considered to be extremely susceptible to penicillin with most of the isolates showing minimum inhibitory concentrations (MIC) ≤ 0.06 mg/l. However, as far as I know, meningococcal isolates with decreased susceptibility to penicillin have been reported from asymptomatic carriers at least since 1964 . Since then, these type of strains have been widely described in Europe [18,21–26], North [27,28] and South America [29,30] and also in Israel , reporting different rates of these strains with decreased susceptibility to penicillin in each case, with MICs of 0.12–1 mg/l.
Meningococcal isolates with this low level of resistance to penicillin have been described as ‘moderately penicillin-resistant', with ‘decreased susceptibility’ or some other definitions , but the tendency now is to refer to them as ‘moderately susceptible’ strains (Penms) because of their uncertain clinical significance. In fact, only two cases of treatment failure associated with Penmsmeningococci have been reported: one in the UK  because a low dose of penicillin was used with a strain having a MIC of 0.64 mg/l; the other case, in Argentina, was associated with a meningococcal isolate with a MIC of 0.5 mg/l . MIC are still at levels similar to those found several years ago, with most of the Penms showing an MICs of 0.12 mg/l or 0.25 mg/l. Even though penicillin is still recommended as the drug of choice for the treatment of MD , clinicians are concerned about this problem and alternative antibiotics to penicillin are being recommended, at least when such less susceptible strains are isolated [36,37]. Cefotaxime, ceftriaxone or chloramphenicol appear to be good alternatives in these cases [38,39].
These less-susceptible isolates are detected preferably by MIC determination with the agar dilution or broth microdilution methods  or by the E-test [41,42]. The use of a disc diffusion test with 2 U penicillin or 1 μg oxacillin has been proposed for that purpose  but there is controversy about the reliability of this method [42,43] particularly in those strains with MIC close to the > 0.06 mg/l cut-off point used. Further multi-centre studies need to be performed to clarify not only the use of antibiotic discs but also the cut-off points to be used if the E-test is employed. In addition, the culture medium used might be a determinant in the MIC definition, and it should be well standardised.
The resistance of these isolates is due, at least in part, to a decrease in the affinity of penicillin-binding protein 2 (PBP2) . The PBPs are targets for β-lactam antibiotics which form permanent antibiotic–PBP complexes , causing cell death because of inefficient cell wall synthesis. Altered forms of the PBP2 are due to the expression of different sequences of the penA gene encoding that protein: while penA genes from fully susceptible strains appear to be highly uniform in sequence, those from Penms are quite diverse , showing mosaic structures (very conserved areas alternated with highly diverse regions). These mosaic genes have arisen as result of natural events of horizontal genetic exchange involving penA genes, particularly of N. flavescens, but also the closely related species N. cinerea, N. mucosa and N.lactamica [3,46,47]. The mechanism might be the result of different and separate recombination events because many different mosaic penA alleles have been found in Penms meningococci . The analysis of sequences of moderately susceptible meningococci and other Neisseria species has revealed an insertion codon in the position 573 (Asp), which has been proposed as a potential mechanism in susceptibility to penicillin . This mechanism to form hybrid PBP genes by recombination might be more significant in nature than the accumulation of mutations in these genes .
With the purpose of improving knowledge of the origin of the mechanism of resistance and also how it spreads, several analyses of the genetic structure of populations of meningococcal strains have been carried out [39,49]. The results show a similar genetic diversity among both fully susceptible (Pens) and Penms isolates. Apparently, moderate susceptibility to penicillin did not appear in a new clone that was distinct from those already established. It is possible that the mechanism of resistance appeared in more than one line and further spreading took place by genetic interchange . Although we failed to show a direct relationship between the increase in the rate of Penms isolates and a rise in the number of cases of serogroup C MD, a possible association between the C:2b phenotype and moderate susceptibility to penicillin was suggested . Although the 2b serotype has been the most common phenotype among Spanish serogroup C strains , C:2a was the main phenotype across the rest of Europe . Perhaps Spain is the country where these moderately susceptible strains have become more frequent and this is a cause of major concern. The incidence of these type of strains increased from 0.4 % to 43 % in only 5 years, and it is still higher than 40 % (Fig. 1). During 1996 and 1997, we suffered an epidemic outbreak associated with C:2b:P1.2,5 meningococci, and even now more than 60 % of the MD cases produced by serogroup C isolates are characterised as this antigenic phenotype. This C:2b:P1.2,5 epidemic strain is moderately susceptible to penicillin, so the maximum incidence of MD cases in 1997 was parallel with an increase in the percentage of Penms strains (Fig. 1). Of course, we can not discount the badly regulated use of antibiotics. However, if the association between the 2b serotype and a decreased susceptibility to penicillin is finally shown, we will be able to explain in part the highest rate of Penms meningococci in Spain.
Fortunately, MICs are still at a similar level to those found several years ago, as mentioned above. N. gonorrhoeae strains with high level of resistance to penicillin show alterations not only in the PBP2 gene (penA) but also in the PBP1 gene (ponA) and the permeability of the outer membrane protein (encoded on the penB and mtr genes) is also affected . There is great concern that such a mechanism of resistance could spread to meningococci. Although genetic exchange of entire gene and plasmid DNA have been described [4,52], evidence of genetic isolation between both Neisseria species has been reported .
High level of resistance to penicillin by β-lactamase production
Penicillin-resistance by β-lactamase production is still apparently rare in N. meningitidis, and there have been only four reports of meningococcal resistance associated with this mechanism [54–57]. The β-lactamase gene is borne on a plasmid; it has been sequenced only once  and was found to be almost identical to the pJD5 and pJD4 gonococcal plasmids. These results imply that the plasmid might have been picked up from a N. gonorrhoeae strain by conjugative transfer . Once again, if N. gonorrhoeae and N. meningitidis frequently share the same ecosystem this will increase the possibilities for genetic transfer.
Other β-lactam antibiotics
Broad-spectrum cephalosporins are now used in the treatment of cases of MD. The MIC of certain β-lactam drugs such as cefuroxime and aztreonam in Penms isolates are much greater than those found in fully susceptible strains . Several studies have shown that both cefotaxime and ceftriaxone have high activity in vitro and that this is not generally altered in Penms meningococci [31,58], with only a very slight increase in the MIC for these strains. It is well known that ceftriaxone is also effective in eradicating meningococcal nasopharangeal carriage, so this antibiotic appear as a good alternative for treatment and chemoprophylaxis of MD cases.
Chloramphenicol is the antibiotic used as the standard therapy for MD in developing countries. High levels of resistance have been described in Vietnam and in France since 1987 . The resistance is due to the presence of the catP gene, which is a fragment of the transposon Tn4451 from Clostridium perfringens which has undergone a large deletion that encompasses around 80 % of the total sequence . The transposon in N. meningitidis chloramphenicol-resistant strains become immobile because it has lost the genes necessary for excision. There is no evidence as to how the initial acquisition of the resistance in a meningococcal strain occurred, so it might have appeared as result of transformation or conjugation events. By means of genetic transformation process, the resistance to chloramphenicol has spread into different N. meningitidis strains. It is highly possible that these chloramphenicol-resistant meningococci will become more prevalent in those countries where the antibiotic is widely used for treatment of MD.
Evidence of acquisition and spread of mechanisms of resistance to antimicrobial agents have increased during the last 15 years among the N. meningitidis population. Sometimes the mechanism is the result of transformation or conjugation events, but point mutations can also give rise to a decrease in the susceptibility to antibiotics. In both cases, the ‘new’ genes spread into the meningococcal population by intra-species recombination. These mechanisms of resistance to antibiotics might not be a consequence of a wide use of antimicrobial agents. The alleles encoding resistance might have appeared even before the antibiotics era and so be strongly selected with the introduction and use of them. Some specific clonal lines might be specially involved in resistance, but this has only been proposed as a possibility.
Fortunately, we still have sufficient types of antimicrobial agents that can be used in the treatment and chemoprophylaxis of meningococcal disease. However, because commensal and closely related bacteria appear to be the origin of the mechanisms of resistance, meningococci can acquire them by horizontal genetic interchange. Therefore, continued surveillance should be carried out to detect future changes in the susceptibility of N. meningitidis to antimicrobial drugs.
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