S98
Antibiotic Resistance in Neisseria meningitidis
Beryl A. Oppenheim
From the Public Health Laboratory, Withington Hospital, West
Didsbury, Manchester, United Kingdom
Penicillin has long been recognized as the antibiotic of choice for treatment of meningococcal
infections, but clinicians have recently become concerned about the susceptibility of meningococci to
penicillin and other antibiotics used in the management of meningococcal disease. Strains relatively
resistant to penicillin (minimum inhibitory concentrations ranging from 0.1 mg/L to 1.28 mg/L) have
been reported from a large number of countries, although the frequency with which such isolates are
found varies widely. The mechanism of relative resistance to penicillin involves, at least in part, the
production of altered forms of one of the penicillin-binding proteins. Although treatment with penicillin
is still effective against these relatively resistant strains, there is evidence that low-dose treatment
regimens can fail. /3-lactamase production in meningococci is extremely rare but has been reported,
and this finding is of great concern. Resistance to sulfonamides and rifampin is of particular concern
in regard to the management of contacts of patients with meningococcal disease.
Neisseria meningitidis is a gram-negative diplococcus that
is closely related to the gonococcus. It causes a spectrum of
disease, ranging from transient fever and bacteremia to meningitis and fulminant septicemia. For many years penicillin has
been recognized as the antibiotic of choice for meningococcal
disease, and the meningococcus has seemed to be one of the
least problematic of bacteria causing serious infections in terms
of antibiotic resistance. However, relative resistance to penicillin has now been reported from a large number of countries,
and complete resistance has been noted in a small number
of cases. In addition, our knowledge of the development of
resistance in the closely related gonococcus has led to concern
about the almost inevitable progressive resistance of N. meningitidis.
Resistance to /3-Lactam Antibiotics
Penicillin has long been the antibiotic of choice for treatment
of meningococcal disease. For fully susceptible strains of meningococci, the MIC of penicillin is -0.05 mg/L. During the
1970s and 1980s, the first reports started to emerge of meningococci with decreased susceptibility to penicillin. For the majority of these strains, the MICs ranged from 0.1 to 1.28 mg/L
(although some investigators use a cutoff of 0.25 mg/L [1,
2]), and such strains have been varyingly referred to in the
literature as relatively penicillin-resistant, moderately penicillin-susceptible, or of diminished susceptibility to penicillin. It
has been suggested that the term moderately susceptible and
the criterion of an MIC between 0.12 and 1 mg/L would be
Reprints or correspondence: Beryl A. Oppenheim, Public Health Laboratory,
Withington Hospital, West Didsbury, Manchester M20 2LR, United Kingdom.
Clinical Infectious Diseases 1997;24(Suppl 1):S98-101
0 1997 by The University of Chicago. All rights reserved.
1058-4838/97/2401-0044$02.00
most consistent with the criteria used to define similar strains
of Streptococcus pneumoniae and Neisseria gonorrhoeae [3].
Meningococcal strains for which the MICs of penicillin are
>1 mg/L are rare, and only four 0-lactamase-producing clinical isolates have been reported to date. The first two cases
were reported from South Africa [4]. Both isolates had caused
meningococcal disease and were said to be associated with
penicillin MICs of >256 mg/L and to be positive by the chromogenic cephalosporin testing method, but attempts to type
the 0-lactamase or determine its plasmid were unsuccessful.
A third /3-lactamase-producing isolate, probably of urogenital
origin, has been characterized by Dillon et al. [5]. For this strain
the MICs of penicillin and ampicillin were 256 mg/L, and the
strain harbored two plasmids with molecular masses of 4.5 and
24.5. The fourth isolate was again isolated in a case of meningococcal disease, and the MIC of penicillin was 4 mg/L [6].
Although /3-lactamase production is still apparently extremely rare, the potential for such production by meningococci
is of great concern. The possibility of transfer of this type
of resistance from the closely related gonococcus has been
highlighted by investigators, particularly in view of the occasional coexistence of both bacteria in the genitourinary tract,
and in vitro it has been possible to transfer /3-lactamase-producing plasmids from N gonorrhoeae to N meningitidis [7, 8].
Relatively penicillin-resistant meningococci, on the other
hand, have now been widely reported from areas such as Spain
[9, 10], Italy [11], Greece [12], the United Kingdom [13], the
United States [14], Canada [15], and Israel [16]. However, the
frequency with which such isolates are found varies widely
from place to place. In Spain the frequency of relative penicillin
resistance in isolates submitted to a reference laboratory increased from 0.4% in 1985 to 46% during the first months of
1990 [17]; a high percentage of such strains were isolated in
the Barcelona area [18]. In the United Kingdom the incidence
of relative penicillin resistance increased from —1%-3% during 1986/1987 to 8% during 1991 [19], but it does not appear
to have increased since then [20].
CID 1997;24 (Suppl 1)
Antibiotic Resistance of N. meningitidis
In these relatively resistant strains, no plasmids and no 0lactamase activity can be noted, and it appears that the mechanism of resistance involves, at least in part, the production of
altered forms of one of the physiologically important penicillinbinding proteins, PBP 2. In contrast to PBP 2 genes of susceptible strains, which are highly uniform in sequence, those of
penicillin-resistant isolates are very variable [21] and have mosaic structures consisting of regions that are almost identical
to corresponding regions in susceptible strains, alternating with
regions that are highly divergent [22].
These mosaic genes appear to have arisen by replacement
with corresponding regions of the PBP 2 gene from closely
related species such as Neisseriaflavescens and other commensal Neisseria species [22-24]. However, the production of a
low-affinity form of PBP 2 should provide the meningococcus
with only low levels of resistance to penicillin, since killing
still occurs by the inactivation of PBP 1; it is possible that in
those strains for which the MICs are >0.1 mg/L, additional
factors such as decreased permeability of the outer membrane
may be operating [18].
There is little information available regarding associations
between penicillin resistance and serogroup or any other
aspects of genetic relatedness. Saez-Nieto et al. [18] found
that although most resistant isolates were of serogroup B,
strains of serogroup C and nongroupable strains were about
three times more common among the penicillin-resistant organisms than in the total meningococcal population. BerrOn
and Vazquez [25] noted that the increase in penicillin resistance of meningococci in Spain had coincided with an increase in disease due to meningococci of serogroup C, but
their studies failed to show a direct relationship between the
two events.
Mendelman et al. [26] studied a small number of relatively
resistant meningococci isolated in Spain and failed to show
an association with specific serotypes, whereas BerrOn and
Vazquez [25] suggested a possible association between serotype 2b and relative resistance. Campos et al. [27] looked
at the genetic relatedness of 42 relatively resistant meningococci from a single hospital, using multilocus enzyme electrophoresis and restriction fragment—length polymorphism
analysis of PBP 2 genes, and concluded that there was considerable diversity in the PBP 2 genes and in the overall
genetic relatedness of these strains.
To date, there appears to be no information on the progression of antibiotic resistance in meningococci causing large
epidemics such as those that occur in sub-Saharan Africa,
and surveillance of these strains should be regarded as a
priority.
The clinical significance of penicillin resistance in meningococci is not entirely clear. All three of the patients infected
with /3-lactamase-producing strains were treated with alternative antibiotics, but experience with other /3-lactamase-producing bacteria suggests that penicillin therapy would have been
S99
unsuccessful. With regard to relatively resistant strains, however, it is clear that many infections have been treated successfully with penicillin [9, 10].
Uriz et al. [28] were not able to show any clinical significance of infection with such strains other than a longer defervescence period. Perez-Trallero et al. [1] found that pediatric
patients tended to have a higher rate of complications. However, Turner et al. [29] described a case of meningitis caused
by a strain of N. meningitidis for which the MIC of penicillin
was 0.6 mg/L, in which treatment with penicillin (0.5 million
units every 6 h) failed; in light of this finding, it has been
recommended that higher doses of penicillin (1-2 million
units every 4 h) should always be used [30].
Broad-spectrum cephalosporins are now widely used in
the treatment of meningitis, and a number of studies have
addressed the issue of their activity against fully susceptible
and moderately susceptible meningococci. In general, the
broad-spectrum cephalosporins show very good activity, and
ceftriaxone in particular shows a high degree of activity,
which is not altered against moderately susceptible strains
[16, 31]. The MICs of other /3-lactam drugs, such as cefuroxime and aztreonam, and of the carbapenem imipenem have
been up to 50 times greater for the moderately susceptible
strains [31].
Resistance in Other Antibiotic Groups
Sulfonamides. Sulfonamides have been extensively used
for both treatment of and prophylaxis against meningococcal
disease since the first reports of successful outcomes in the late
1930s [32, 33]. They had a dramatic effect on mortality and
were successful in eradication programs carried out among
military personnel during World War II [34].
However, by 1963 reports had emerged about outbreaks of
sulfonamide-resistant serogroup B meningococcal infections in
U.S. Army recruits training for the Vietnam War [35]. By 1972
Abbott and Graves [36] had reported that 6% of strains in the
United Kingdom were resistant to sulfonamides, and this figure
has increased steadily to —30% in the 1990s [37]. Resistance
is now widespread [12, 31, 38], and as a result, sulfonamides
have lost their place in the armamentarium of agents used for
meningococcal infection or carriage.
The target of action for sulfonamides is the enzyme dihydropteroate synthase, and sulfonamide resistance in meningococci is mediated by altered forms of the chromosomal gene
for this enzyme. It is possible that the resistance genes have
been transferred from other Neisseria species, as is the case in
penicillin resistance [39, 40].
Rifampin. Rifampin is widely recommended for the prevention of secondary cases among contacts of patients with
meningococcal disease. Although rifampin resistance is rare,
resistant strains have been isolated from recipients of the drug,
and there have been reports of meningococcal disease due to
S100
Oppenheim
rifampin-resistant strains, particularly in the context of failure
of prophylaxis [41-44].
Conclusions
Although N meningitidis remains one of the few bacteria
causing serious infections for which penicillin is still routinely
recommended, evidence of the development of resistance to
penicillin and other antibiotics used in the management of meningococcal disease is now mounting. Mechanisms of resistance similar to those found in gonococci and pneumococci
are being seen, and there is great concern that similarly serious
problems might develop in meningococci. Since resistance appears to originate from commensal or coexisting bacteria, it is
likely that pressure from the widespread use of antibiotics is
an important factor. In the case of meningococci, the ultimate
answer to the problem of antibiotic resistance would be to
eradicate meningococcal disease by vaccination.
References
1. Perez-Trallero E, Aldamiz-Echeverria L, Perez-Yarza EG. Meningococci
with increased resistance to penicillin [letter]. Lancet 1990; 335:1096.
2. Riley G, Brown S, Krishnan C. Penicillin resistance in Neisseria meningitidis [letter]. N Engl J Med 1991; 324:997.
3. Buck GE, Adams M. Meningococcus with reduced susceptibility to penicillin isolated in the United States. Pediatr Infect Dis J 1994; 13:156-8.
4. Botha P. Penicillin-resistant Neisseria meningitidis in southern Africa [letter]. Lancet 1988; 1:54.
5. Dillon JR, Pauze M, Yeung K-H. Spread of penicillinase-producing and
transfer plasmids from the gonococcus to Neisseria meningitidis. Lancet
1983; 1:779-81.
6. Fontanals D, Pineda V, Pons I, Rojo JC. Penicillin-resistant beta-lactamase-producing Neisseria meningitidis in Spain [letter]. Eur J Clin Microbiol Infect Dis 1989; 8:90-1.
7. Ikeda F, Tsuji A, Kaneko Y, Nishida M, Goto S. Conjugal transfer of betalactamase-producing plasmids of Neisseria gonorrhoeae to Neisseria
meningitidis. Microbiol Immunol 1986; 30:737-42.
8. Roberts MC, Knapp JS. Transfer of 0-lactamase plasmids from Neisseria
gonorrhoeae to Neisseria meningitidis and commensal Neisseria species
by the 25.2-megadalton conjugative plasmid. Antimicrob Agents Chemother 1988; 32:1430-2.
9. Saez-Nieto JA, Fontanals D, Garcia de Jalon J, et al. Isolation of Neisseria
meningitidis strains with increase of penicillin minimal inhibitory concentrations. Epidemiol Infect 1987; 99:463-9.
10. Van Esso D, Fontanals D, Uriz S, et al. Neisseria meningitidis strains with
decreased susceptibility to penicillin. Pediatr Infect Dis J 1987; 6:
438-9.
11. Stroffolini T, Congiu ME, Occhionero M, Mastrantonio P. Meningococcal
disease in Italy. J Infect 1989; 19:69-74.
12. Tzanakaki G, Blackwell CC, Kremastinou J, Kallergi C, Kouppari G,
Weir DM. Antibiotic sensitivities of Neisseria meningitidis isolates from
patients and carriers in Greece. Epidemiol Infect 1992; 108:449-55.
13. Sutcliffe EM, Jones DM, el-Sheikh S, Percival A. Penicillin-insensitive
meningococci in the UK [letter]. Lancet 1988; 1:657-8.
14. Woods CR, Smith AL, Wasilauskas BL, Campos J, Givner LB. Invasive
disease caused by Neisseria meningitidis relatively resistant to penicillin
in North Carolina. J Infect Dis 1994; 170:453-6.
CID 1997; 24 (Suppi 1)
15. Blondeau JM, Ashton FE, Isaacson M, Yaschuck Y, Anderson C, Ducasse
G. Neisseria meningitidis with decreased susceptibility to penicillin in
Saskatchewan, Canada. J Clin Microbiol 1995; 33:1784-6.
16. Block C, Davidson Y, Melamed E, Keller N. Susceptibility of Neisseria
meningitidis in Israel to penicillin and other drugs of interest [letter]. J
Antimicrob Chemother 1993; 32:166 -8.
17. Saez-Nieto JA, Vazquez JA, Marcos C. Meningococci moderately resistant
to penicillin [letter]. Lancet 1990; 336:54.
18. Saez-Nieto JA, Lujan R, BerrOn S, et al. Epidemiology and molecular
basis of penicillin-resistant Neisseria meningitidis in Spain: a 5-year
history (1985-1989). Clin Infect Dis 1992; 14:394-402.
19. Jones DM, Kaczmarski EB. Meningococcal infections in England and
Wales: 1992. PHLS Communicable Disease Report Review 1993; 3:
R129-31.
20. Jones DM, Kaczmarski EB. Meningococcal infections in England and
Wales: 1994. PHLS Communicable Disease Report Review 1995; 5:
R125-30.
21. Zhang Q-Y, Jones DM, Saez-Nieto JA, Perez-Trallero E, Spratt BG. Genetic diversity of penicillin-binding protein 2 genes of penicillin-resistant strains of Neisseria meningitidis revealed by fingerprinting of amplified DNA. Antimicrob Agents Chemother 1990; 34:1523-8.
22. Spratt BG, Zhang Q-Y, Jones DM, Hutchison A, Brannigan JA, Dowson
CG. Recruitment of a penicillin-binding protein gene from Neisseria
flavescens during the emergence of penicillin resistance in Neisseria
meningitidis. Proc Natl Acad Sci USA 1989; 86:8988-92.
23. Bowler LD, Zhang Q-Y, Riou J-Y, Spratt BG. Interspecies recombination
between the penA genes of Neisseria meningitidis and commensal Neisseria species during the emergence of penicillin resistance in N. meningitidis: natural events and laboratory simulation. J Bacteriol 1994; 176:
333 -7.
24. Saez-Nieto JA, Lujan R, Martinez-Suarez JV, et al. Neisseria lactamica
and Neisseria polysaccharea as possible sources of meningococcal betalactam resistance by genetic transformation. Antimicrob Agents Chemother 1990; 34:2269-72.
25. Ben& S, Vazquez JA. Increase in moderate penicillin resistance and
serogroup C in meningococcal strains isolated in Spain. Is there any
relationship? Clin Infect Dis 1994; 18:161-5.
26. Mendelman PM, Caugant DA, Kalaitzoglou G, et al. Genetic diversity of
penicillin G-resistant Neisseria meningitidis from Spain. Infect Immun
1989; 57:1025-9.
27. Campos J, Fuste MC, Trujillo G, et al. Genetic diversity of penicillinresistant Neisseria meningitidis. J Infect Dis 1992; 166:173-7.
28. Uriz S, Pineda V, Grau M, et al. Neisseria meningitidis with reduced
sensitivity to penicillin: observations in 10 children. Scand J Infect Dis
1991;23:171-4.
29. Turner PC, Southern KW, Spencer NJB, Pullen H. Treatment failure in
meningococcal meningitis [letter]. Lancet 1990; 335:732-3.
30. Jones DM, Sutcliffe EM. Meningococci with reduced susceptibility to
penicillin [letter]. Lancet 1990; 335:863 -4.
31. Perez-Trallero E, Garcia-Arenzana JM, Ayestaran I, Murioz-Baroja I.
Comparative activity in vitro of 16 antimicrobial agents against penicillin-susceptible meningococci and meningococci with diminished susceptibility to penicillin. Antimicrob Agents Chemother 1989; 33:
1622-3.
32. Schwentker FF. Treatment of meningococcic meningitis with sulfanilamide. J Pediatr 1937; 11:874-80.
33. Schwentker FF, Gelman S, Long PH. The treatment of meningococcic
meningitis with sulfanilamide: preliminary report. JAMA 1937; 108:
1407-8.
34. Feldman HA. The meningococcus: a twenty-year perspective. Rev Infect
Dis 1986; 8:288-94.
35. Millar JW, Siess EE, Feldman HA, Silverman C, Frank P. In vivo and in
vitro resistance to sulfadiazine in strains of Neisseria meningitidis.
JAMA 1963; 186:139-41.
CID 1997; 24 (Suppl 1)
Antibiotic Resistance of N. meningitidis
36. Abbott JD, Graves JFR. Serotype and sulphonamide sensitivity of meningococci isolated from 1966 to 1971. J Clin Pathol 1972;25:528-30.
37. Jones DM, Kaczmarski EB. Meningococcal infections in England and
Wales: 1993. PHLS Communicable Disease Report Review 1994;4:
R97 —100.
38. Kristiansen B-E, RidstrOm P, Jenkins A, Ask E, Facinelli B, SkOld 0.
Cloning and characterization of a DNA fragment that confers sulfonamide resistance in a serogroup B, serotype 15 strain of Neisseria meningitidis. Antimicrob Agents Chemother 1990; 34:2277-9.
39. Fermer C, Kristiansen B-E, SkOld 0, Swedberg G. Sulfonamide resistance
in Neisseria meningitidis as defined by site-directed mutagenesis could
have its origin in other species. J Bacteriol 1995;177:4669-75.
40. RaAstrOm P, Fermer C, Kristiansen B-E, Jenkins A, SkOld 0, Swedberg
G. Transformational exchanges in the dihydropteroate synthase gene of
S101
Neisseria meningitidis: a novel mechanism for acquisition of sulfonamide resistance. J Bacteriol 1992;174:6386-93.
41. Cooper ER, Ellison RT III, Smith GS, Blaser MJ, Reller LB, Paisley JW.
Rifampin-resistant meningococcal disease in a contact patient given
prophylactic rifampin. J Pediatr 1986;108:93-6.
42. Berkey P, Rolston K, Zukiwski A, Gooch G, Bodey GP. Rifampin-resistant
meningococcal infection in a patient given rifampin chemoprophylaxis.
Am J Infect Control 1988;16:250-2.
43. Yagupsky P, Ashkenazi S, Block C. Rifampicin-resistant meningococci
causing invasive disease and failure of chemoprophylaxis [letter]. Lancet 1993; 341:1152-3.
44. Almog R, Block C, Gdalevich M, Lev B, Wiener M, Ashkenazi S. First
recorded outbreaks of meningococcal disease in the Israel Defence
Force: three clusters due to serogroup C and the emergence of resistance
to rifampicin. Infection 1994; 22:69-71.