S93
Antimicrobial Resistance in Neisseria gonorrhoeae
Inga Lind
The changing patterns of antimicrobial resistance in Neisseria gonorrhoeae have been reviewed
regularly since the introduction of antimicrobial therapy in the 1930s. At present, ceftriaxone,
fluoroquinolones, and spectinomycin have remained efficient as single-dose treatment of gonorrhea
worldwide. To ensure that limited resources can be used in the best possible way, continuous
surveillance of gonococcal resistance to antimicrobials is needed.
The versatile nature of the gonococcus and its capacity to
cope with changing conditions in the microenvironment were
noticed shortly after the introduction of the first efficacious
therapeutic agents, sulfonamides [1]. Changing patterns of anti-
microbial resistance [2-6] and studies of the mechanisms gov-
erning this evolution [7-12] have been reported since the
1970s.
Briefly, the genetic background for the evolution of antimi-
crobial resistance in gonococci is either chromosomal muta-
tions or the acquisition of R plasmids. Strains with mutations
in chromosomal genes emerged in the late 1950s [2]. Two
types of chromosomal resistance have been described. The first
type is drug-specific; it is due to single-step mutation to high-
level resistance. The second type involves mutations at several
chromosomal loci. The combination of mutations at these vari-
ous loci determines the level as well as the pattern of resistance.
In 1976, a new aspect of penicillin resistance was recognized
when strains that had acquired plasmids coding for the produc-
tion of 0-lactamase appeared simultaneously in England and
the United States [13, 14]. In 1985, the gonococcus acquired
another R plasmid that coded for high-level resistance to tetra-
cycline. The first report of this resistance was from the United
States [15]. This evolution is a result of the interactions between
genetic factors and the environmental selective effect (either
an inappropriate use of antibiotics in the treatment of gonorrhea
and other infectious diseases or the use of antibiotics in media
used for isolation of gonococci from clinical specimens).
Epidemiology of Antibiotic Resistant Neisseria
-
gonorrhoeae
Plasmid Mediated Resistance in N. gonorrhoeae
-
Penicillinase-producing N. gonorrhoeae (PPNG). Surveil-
lance of the occurrence of PPNG is easy to establish in any
Reprints or correspondence: Dr. Inga Lind, Neisseria Department, Statens
Seruminstitut, Artilerivej 5, DK-2300 Copenhagen S, Denmark.
Clinical Infectious Diseases 1997; 24(Suppl 1):S93-7
1997 by The University of Chicago. All rights reserved.
1058-4838/96/2401 0043$02.00
From the WHO Collaborating Centre for Reference and Research in
Gonococci at the Neisseria Department, Statens Seruminstitut,
Copenhagen, Denmark
laboratory performing gonococcal cultures. Simple and reliable
methods are available. Therefore, reports on the spread of
PPNG strains in various parts of the world can be compared
directly. Since 1976, PPNG strains have spread throughout the
world [16-20]. In many African countries, the spread of PPNG
strains has been characteristic of an epidemic. For example, in
Nigeria, the proportion of cases of gonorrhea caused by PPNG
increased from zero to >70% in less than 5 years [21]. In the
Far East, a rapid increase was also noted, but the prevalence
seems to have stabilized at 35% [22].
In the United States, Europe, and Australia, the prevalence
of PPNG infections increased slowly; in many countries in
Europe, most infections were acquired abroad. However, in
recent years, a more marked increase has been noted, and the
proportion of PPNG infections being acquired locally has also
been increasing. In Denmark, the percentage of PPNG infec-
tions increased from 2% in 1984-1985 to 5% in 1990;
simultaneously, the rate of gonorrhea fell significantly [23].
Localized outbreaks of PPNG infections have also been re-
ported [23-25]. Representative up-to-date regional data on the
prevalence of PPNG infections are presented in table 1.
Tetracycline-resistant N. gonorrhoeae (TRNG). Plasmid-
mediated high-level resistance to tetracycline was first reported
from the United States [15]. Recent reports have indicated a
spread within the United States [28, 34] and the appearance of
this resistance in European countries as well [35, 36]. Gonococ-
cal strains carrying both resistance plasmids have now been
isolated in several countries [34, 36, 37]. A recent report [38]
has indicated a rapid spread of TRNG in an African country.
Chromosomally Mediated Resistance in N. gonorrhoeae
Penicillin. Changes in the prevalence of gonococcal strains
with high-level or intermediate chromosomal resistance to
penicillin are much more difficult to assess than are those in
the prevalence of gonococci with plasmid-mediated resistance.
The aim of a collaborative study in Dakar, Senegal [20], was
to describe the evolution of plasmid-mediated as well as chro-
mosomally mediated resistance in gonococci during the period
1982-1986. A significant change in antimicrobial susceptibil-
ity was observed: the percentage of non-PPNG strains suscepti-
S94 Lind CID 1997;24 (Suppl 1)

Table 1. Up-to-date regional data on the prevalence of PPNG infec- tration achieved after the recommended dose (500 mg) is up
tions. to 100-fold more than the MIC for N gonorrhoeae [54]. Recent
No. of Percent of
reports confirm that gonococcal strains resistant to the fluoro-
Location Year(s) isolates PPNG isolates [Reference] quinolone that is most active in vitro (ciprofloxacin) are still
rare [27, 55].
Denmark 1990 1,990 4.8 [23] Cephalosporins. Ceftriaxone, the most active third-genera-
Norway 1991 656 10.8 [26] tion cephalosporin, has remained highly efficacious as single-
United Kingdom 1988-1991 3,000 5.4 [27]
United States 1989 4,689 7.4 [28]
dose therapy for gonorrhea and even as treatment of pharyngeal
New Zealand 1988 486 2.2 [29] infections [56, 57]. The only drawback of this agent is that it
The Gambia 1989 1990 249 49 [30] has to be administered intramuscularly. Recently, another third-
Malawi 1991 151 36 [PR] generation cephalosporin, cefixime, that can be administered
Philippines 1989 140 55 [31] orally has become available in certain countries. The first re-
Taiwan 1989 1992 305 50 [32]
Hong Kong 1990 2,039 31 [33]
ports on its efficacy, even those from countries in which the
prevalence of penicillin-resistant strains is high, are very prom-
NOTE. PPNG = penicillinase-producing Neisseria gonorrhoeae; PR = ising, and the efficacy of cefixime seems to be equivalent to
present report. that of ceftriaxone [58, 59].

Surveillance of Antimicrobial Resistance

ble to penicillin fell from 66 to 22, and the percentage of
resistant strains increased from 12 to 31. Since PPNG was
detected in a reliable manner, approximately all PPNG strains
were identified locally, whereas an increase in the occurrence
of strains with chromosomally mediated resistance could not
be revealed.
It has been shown that changes in the prevalence of gonococ-
cal strains with chromosomally mediated resistance are associ-
ated with changes in treatment regimens [39, 40] but not with
changes in the rate of gonorrhea per se [41]. Localized out-
breaks due to such strains may also occur [42].
Thiamphenicol. A single oral dose of thiamphenicol
(2.5 g) has been successfully used as treatment of gonorrhea
in France [43] and Africa [44] for many years. There is a
strong positive correlation between chromosomally mediated
resistance to penicillin and resistance to thiamphenicol [45];
therefore, the spread of penicillin-resistant strains also indicates
a spread of strains less susceptible to thiamphenicol and conse-
quently implies an increased risk of failure of thiamphenicol
therapy [46, 47].
Spectinomycin. In many areas, spectinomycin became the
drug of choice for treatment of PPNG infections. Spectino-
mycin-resistant N. gonorrhoeae strains were reported as early
as 1973 [48], and the first spectinomycin-resistant PPNG strain
appeared in 1981 [49]. Resistance to spectinomycin is not
linked with resistance to other antibiotics used as treatment of
gonorrhea. Infections with spectinomycin-resistant gonococci
are still rare, although outbreaks occurred in Korea [50] and
the United Kingdom [51] when spectinomycin was used as
primary treatment.
Fluoroquinolones. Gonococci resistant to earlier genera-
tions of quinolones appeared rapidly when these drugs were
used as treatment of gonorrhea [52, 53]. However, emergence
of strains resistant to the new fluoroquinolones and hence fail-
ure of therapy are unlikely to be rapid, since the serum concen-
Standardization of methods for susceptibility testing is
needed to permit comparisons of results obtained in different
laboratories within a country or in different countries and to
provide a basis for comparison of results of treatment studies
in different geographic areas. These requirements were put
forward by a working group of the World Health Organization
(WHO) some years ago [60]. The group recommended that
this goal should be achieved by the establishment of reference
strains for each antimicrobial in clinical use and by continuous
surveillance of the antimicrobial susceptibility patterns of
gonococci. The gonococcus is a fastidious organism. Whatever
the test, it is crucial for the reliability and reproducibility of
the results that the handling of the cultures, the media, and the
incubation conditions ensure optimal growth of the bacteria.
As mentioned before, standardization of methods for the in
vitro determination of chromosomally mediated antimicrobial
resistance has proved to be difficult and controversial. As far
as I can see, the two main reasons for the controversy are that
standardization should imply that the same MICs or inhibition
zone diameters can be produced exactly in different laboratories
(this is an impossible task and is not necessary) and that the
agar disk diffusion test has got a bad reputation.
For each antibiotic that was used clinically to treat gonor-
rhea, the optimal load for disks in the agar disk diffusion test
was determined by experiments performed in my laboratory;
the performance of these disks was evaluated at laboratories
in Singapore and at Institut Pasteur in Paris [41]. In the Dakar
study [20], a total of 460 gonococcal strains were investigated
by the agar disk diffusion method as well as by the determina-
tion of MICs. The WHO reference strains were included on
each of 22 experimental days. There was a strong positive
correlation between MIC and inhibition zone diameter, and the
different levels of susceptibility could be identified by both
methods without any overlapping. However, differences in in-
CID 1997; 24 (Suppl 1) Antimicrobial Resistance in N. gonorrhoeae S95
terpretative criteria, media, and methods make comparisons
with results obtained in other laboratories [61-63] difficult.
An external quality assessment scheme has proved to be useful
for standardization of methods used within a country [64-66].
Global Surveillance for Antimicrobial Susceptibility in
N. gonorrhoeae
The development and implementation of a global network
for the surveillance of antimicrobial susceptibility in N. gonor-
rhoeae has been initiated by WHO [67]. The currently recom-
mended main treatments for gonorrhea are ceftriaxone, ci-
profloxacin, and spectinomycin. None of these agents are
inexpensive. To ensure that limited resources are used in the
best possible way, continuous surveillance of gonococcal resis-
tance to these drugs is critically important; the surveillance of
the prevalence of PPNG or TRNG strains in most areas has
no clinical significance anymore.
A crucial point in the development of a global network is
to describe standardized methods and quality control for the
agar disk diffusion test as well as the MIC determination and
to describe appropriate sampling methods and sample sizes for
sentinel studies. Technical guidelines for the Pacific region and
Australia are already available, and those for the European,
African, and eastern Mediterranean regions are being worked
out. Sampling methods for monitoring major changes in a
gonococcal population have been studied [68, 69], and an ap-
propriate sample size that allows statistical comparison can be
determined [70].
The key points in the WHO program for the global surveil-
lance of antimicrobial susceptibility in N gonorrhoeae will be
to assist local laboratories by providing technical guidelines, a
panel of control strains, and an inquiry to participate in a quality
assurance scheme.
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