Antimicrobial Susceptibility of Neisseria gonorrhoeae in Cuba
Implications for Treatment of Gonorrhea
RAFAEL LLANES, MD,* JORGE SOSA, MD, PhD,* DAYMI GUZMA´N, MB,* ALINA LLOP, MD,*
EDUARDO A. VALDE´S, MB, MSc,* ISABEL MARTI´NEZ, MD,* SARA PALMA, MD,* AND MARI´A I. LANTERO, MD†
Background: Antibiotic-resistant strains of Neisseria gonorrhoeae,
especially those resistant to penicillin and tetracycline, have spread
with remarkable rapidity in many Caribbean countries.
Goal: The goal of the study was to survey the antibiotic suscepti-
bilities of N gonorrhoeae strains isolated from 1995 to 1999 in Cuba
and to discuss the impact of antimicrobial resistance on the manage-
ment of gonorrhea in the country.
Study Design: Susceptibility of the strains to penicillin, tetracycline,
cefuroxime, ceftriaxone, ciprofloxacin, spectinomycin, and azithromy-
cin were determined by an agar dilution method.
Results: Penicillin and tetracycline resistance was noted in 60.8%
and 54.2%, respectively, of the N gonorrhoeae strains tested. A total of
63.35 (76/120) of the N gonorrhoeae strains exhibited plasmid-medi-
ated resistance to penicillin, tetracycline, or both. Strains with chro-
mosomally mediated resistance to these antibiotics accounted for 10%
(12/120) of the strains. The strains were susceptible to ceftriaxone,
cefuroxime, spectinomycin, and ciprofloxacin. One strain’s ciprofloxa-
cin MIC was 0.125 ?g/ml. Of the 52 strains tested, 23.1% displayed
intermediate resistance to azithromycin.
Conclusions: N gonorrhoeae strains exhibited a high frequency of
resistance and multiresistance to penicillin and tetracycline. There-
fore, these antibiotics should no longer be used to treat gonococcal
infections in Cuba and should be substituted with effective drugs such
as third-generation cephalosporins, spectinomycin, and fluoroquino-
lones. The detection of intermediate resistance to azithromycin and
ciprofloxacin underlines the importance of periodic surveillance for
susceptibility of N gonorrhoeae strains to antimicrobials agents used as
primary therapy for gonorrhea.
GONORRHEA and other sexually transmitted infections (STIs)
are among the most common causes of illness in the world and
have far-reaching health, social, and economic consequences that
not only result in complications and sequelae but also facilitate the
spread of HIV.1In Cuba, gonorrhea is the STI most frequently
reported to the health authorities. However, the number of reported
cases has decreased during the past decade, from 45,200 (411
cases per 100,000 population) in 1995 to 23,225 (208 cases per
100,000 population) in 1999 and to 14,792 cases (131.70 cases per
100,000 population) in 2001.2
Control of gonococcal infection is a difficult and a complex
issue due to the emergence of strains resistant to different antibi-
otics. The development of antibiotic resistance by Neisseria gon-
orrhoeae may involve both chromosomal and extrachromosomal
(plasmid) mechanisms, and for some antibiotics both may be
Several authors have reported a high frequency and an in-
creasing prevalence of antibiotic resistance of N gonorrhoeae in
Latin American and the Caribbean region, especially resistance
to penicillin and tetracycline.4–7However, in Cuba, the major
island in the Caribbean, few studies related to antimicrobial
susceptibility of gonococci have been conducted, and penicillin
and tetracycline are the drugs of choice for treatment of gono-
The current work was conducted to gather baseline data on
antimicrobial susceptibility of N gonorrhoeae strains isolated in
Cuba. This is part of a broader regional Gonococcal Antimicrobial
Susceptibility Project (GASP) in Latin America and the Caribbean.
The GASP Network was developed to gather data from different
countries and to make this information available for implementa-
tion of effective treatment regimens at global, regional, and na-
Materials and Methods
Bacterial Strains and Identification
A total of 621 isolates, presumptively identified as gonococci,
were recovered from urogenital samples from both males and
females in all three regions of Cuba, including the provinces of
Havana (western Cuba), Camagu ¨ey and Cienfuegos (central
Cuba), and Santiago de Cuba (eastern Cuba). The isolates were
transported to the Neisseria Reference Laboratory (NRL), Tropical
Medicine Institute “Pedro Kouri” (IPK), Havana, during the period
of January 1995 through December 1999, in a new transport
medium for gonococci.10Of the 621 isolates, 121 were identified
as N gonorrhoeae at the NRL on the basis of growth on Thayer-
Martin agar, gram stains, oxidase activity, and carbohydrate utili-
The authors thank Dr. V. Capo ´ for English-language revision of the
manuscript and Prof. J. W. Tapsall for his revisions and comments on the
Reprint requests: Rafael Llanes Caballero, MD, Tropical Medicine In-
stitute “Pedro Kouri,” PO Box 601, Marianao 13, Havana, Cuba. E-mail:
Received for publication September 5, 2001, revised March 26, 2002,
and accepted March 28, 2002.
From the *Microbiology Branch, Tropical Medicine Institute “Pedro
Kourı ´,” and†Cuban Ministry of Public Health, Havana, Cuba
zation in CTA medium (Difco).11Isolates were stored frozen at
?70 °C in trypticase soy broth (Biocen, Cuba) containing 20%
Penicillinase (?-lactamase) activity was detected by the chro-
mogenic cephalosporin method (Nitrocefin, Oxoid). N gonor-
rhoeae GC-159 and ATCC 49226 were used as control strains.
Antimicrobial Susceptibility Testing
Susceptibilities to penicillin G, tetracycline, cefuroxime, ceftri-
axone (Sigma, USA), spectinomycin (Upjohn, Belgium), cipro-
floxacin (Bayer, UK), and azithromycin (Daichii, Japan) were
studied in duplicate by the agar dilution method with GC agar base
medium (Biocen) supplemented with 1% Vitox (Oxoid, England)
and containing serial twofold dilutions of each agent.12Azithro-
mycin susceptibilities were determined for 43.3% of the strains
studied, beginning in the middle of 1997, and susceptibility to
cefuroxime was determined for approximately 90% of all strains
recovered between 1995 and 1998.
The frozen isolates were thawed at room temperature and sub-
cultured twice onto chocolate agar enriched with 2% Vitox before
susceptibility testing was done. The inoculum was prepared in
Mueller-Hinton broth (Biocen) from a 24-hour culture on enriched
chocolate agar. Media were inoculated with 104CFU with a
MIC values were determined after incubation for 24 hours at
35 °C in a 5% CO2atmosphere (Incubator Assab, Sweden) and were
defined as the lowest antibiotic concentrations that completely inhib-
ited visible growth. The strains were grouped into susceptibility
categories according to the following breakpoints for suscepti-
bility (S), intermediate resistance (IR), and resistance (R):
penicillin, S ? 0.06 ?g/ml, IR ? 0.125 to 1 ?g/ml, and R ? 2
?g/ml; tetracycline, S ? 0.25 ?g/ml, IR ? 0.5 to 1 ?g/ml, and
R ? 2 ?g/ml; spectinomycin, S ? 32 ?g/ml; IR ? 64 ?g/ml;
and R ? 128 ?g/ml; cefuroxime, S ? 1 ?g/ml, IR ? 2 ?g/ml, and
R ? 4 ?g/ml.12
For the activity of ceftriaxone against N gonorrhoeae, the Na-
tional Committee for Clinical Laboratory Standards (NCCLS) has
defined susceptibility (MIC ? 0.25 ?g/ml) but not resistance.
Therefore, we categorized strains for which the ceftriaxone MIC
was ?0.25 ?g/ml as having decreased susceptibility to this drug.12
Proposed criteria13were used to interpret ciprofloxacin MICs.
Strains with MICs ?1 ?g/ml were classified as resistant to cipro-
floxacin, and those with MICs of 0.125 to 0.5 ?g/ml were inter-
preted as exhibiting decreased susceptibility to this agent. Al-
though breakpoints describing resistance to azithromycin have not
been established, the published data suggest that values of 0.25 to
1 ?g/ml describe decreased susceptibility and values ?2 ?g/ml
denote resistance.7,14,15Therefore, an MIC of 2 ?g/ml or more was
used to classify strains as resistant to azithromycin.
We also classified our strains into six categories according to
whether their resistance to penicillin and tetracycline was chromo-
somally mediated or plasmid-mediated: (1) PPNG ? penicillinase-
producing N gonorrhoeae (?-lactamase-positive and tetracycline
MIC ?16 ?g/ml); (2) TRNG ? plasmid-mediated tetracycline-
resistant N gonorrhoeae (?-lactamase-negative and tetracycline
MIC ?16 ?g/ml); (3) PP-TRNG ? ?-lactamase-positive and
tetracycline MIC ?16 ?g/ml); (4) chromosomally resistant to
penicillin (CMTP) ? non-PPNG and non-TRNG, with penicillin
MIC ?2 ?g/ml and tetracycline MIC ?2 ?g/ml; (5) chromosoma-
lly resistant to tetracycline (CMTR) ? non-PPNG and non-TRNG,
with MIC of tetracycline ?2 ?g/ml and MIC of penicillin ?2
?g/ml; and (6) CMRNG ? chromosomally resistant to penicillin
and tetracycline (non-PPNG, non-TRNG, with MIC of tetracycline
and penicillin ?2 ?g/ml).16Four N gonorrhoeae reference strains,
ATCC 49226, WHO III, WHO V, and WHO VII, were included in
each test run.
Susceptibility to Penicillin and Tetracycline
Of the 120 strains of N gonorrhoeae evaluated, 60.8% were
resistant and 5% exhibited an intermediate resistance to penicillin,
while only 34.2% were susceptible to this antibiotic. The percent-
ages of strains that were resistant and less susceptible to tetracy-
cline were 54.2% and 10%, respectively, while 35.8% were en-
tirely susceptible to this drug. The MIC50values for penicillin and
tetracycline (16 ?g/ml and 2 ?g/ml, respectively) and the MIC90
value (32 ?g/ml) for both antibiotics were above the accepted
criteria for resistance12(Table 1).
In our study, ?-lactamase activity was determined for 10 of the
120 strains studied. The results for the remaining 110 strains were
recently published.17Overall, 64/120 strains of N gonorrhoeae
(53.3%) were ?-lactamase producers. All forms of resistance to
these antibiotics were observed. Seventy-six (63.3%) of the 120
gonococcal strains tested exhibited plasmid-mediated resistance to
penicillin, tetracycline, or both; these included PP/TRNG (46/120;
38.3%), PPNG (18/120; 15%), and TRNG (12/120; 10%) isolates.
Strains with chromosomally mediated resistance to penicillin, tet-
racycline, and penicillin/tetracycline accounted for 10% (12) of the
120 strains: 5 CMPR, 3 CMTR, and 4 CMRNG (Table 1).
A total of 50 strains (41.7%) were resistant to both penicillin and
tetracycline (multiresistance). In our study, the geographical dis-
tribution of gonococcal strains resistant and multiresistant to these
drugs included all three Cuban regions (data not shown).
Susceptibility to Spectinomycin, Cefuroxime, Ceftriaxone,
Ciprofloxacin, and Azithromycin
Two PPNG strains from Havana and Santiago de Cuba dis-
played an intermediate resistance to spectinomycin (MIC, 64
TABLE 1.Susceptibility to Penicillin and Tetracycline of 120 Neisseria gonorrhoeae Strains From Cuba
No. (%) of IsolatesMIC Values (?g/ml)No. of Isolates of Indicated Characterization
PPNG ? penicillinase-producing N gonorrhoeae; TRNG ? tetracycline-resistant N gonorrhoeae; PP/TR ? PPNG and TRNG; CMTR ?
chromosomally mediated tetracycline resistance; CMPR ? chromosomally mediated penicillin resistance; CMRNG ? chromosomally mediated
resistance to penicillin and tetracycline.
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SUSCEPTIBILITY OF N GONORRHOEAE IN CUBA
?g/ml), while two CMRNG strains isolated in Havana showed
an intermediate resistance to cefuroxime (MICs, 2 ?g/ml).
Except for one PP/TRNG strain isolated in Cienfuegos with
decreased susceptibility to ciprofloxacin (MIC, 0.125 ?g/ml),
all other strains were susceptible to this antibiotic (MIC range,
0.002–0.125 ?g/ml). In addition, all gonococcal strains were
susceptible to ceftriaxone (MIC range, 0.002–0.016 ?g/ml).
However, reduced susceptibility to azithromycin accounted for
12 (23.1%) of the 52 strains tested (MIC range, 0.064–0.5
?g/ml) (Table 2). Ten of these strains were also resistant to
penicillin (5 PP/TRNG, 4 CMPR, and 1 PPNG), and the two
other were susceptible. These strains were isolated in the three
regions of Cuba (data not shown).
The current work has established baseline data about antimicro-
bial susceptibility of N gonorrhoeae strains in Cuba. It has docu-
mented a high resistance to penicillin and tetracycline and the
emergence of strains displaying intermediate resistance to azithro-
mycin and ciprofloxacin. The prevalence of high-level plasmid-
mediated resistance to penicillin, tetracycline, or both antibiotics is
an important indicator in the epidemiologic surveillance of resis-
tant gonococci. This report also documented a high proportion of
PPNG, TRNG, and PP/TRNG strains, accounting for 63.3% of the
Previous studies done in Cuba, during the 1980s, revealed the
existence of gonococcal strains susceptible or only intermediately
resistant to penicillin, but no resistant strains were identified.18In
1989, 37.5% of 24 strains of N gonorrhoeae were PPNG, and
8.33% displayed chromosomal resistance to this antibiotic (J. A. R.
Dillon, personal communication, 1990). Data from other surveys
in this country reflect lower percentages of PPNG strains than in
our study.19,20The high prevalence of PPNG strains in the present
investigation is comparable with rates obtained in some develop-
ing countries: 54% in Uruguay,2158.6% in Jamaica,450% in
Puerto Rico,22and 47% in Rwanda.23
In the current study, 48.3% of the strains analyzed were pre-
sumably TRNG. These strains were first recognized in the United
States and the Netherlands in 1985, and since then, they have
rapidly spread worldwide.5In Cuba, such strains were not encoun-
tered before 1995 (Dillon, personal communication, 1990). Thus,
this is the first report of the emergence of TRNG strains in Cuba.
High percentages of these strains have been noted in some Latin
American and Caribbean countries: Guyana (87.1%),6Jamaica
(69%),4Manaus, Brazil (76.5%),7Nicaragua (22%),24St. Vincent
(22%),6and Trinidad (15.3%).6
It is noteworthy that most TRNG strains tested (79.3%; 46/58)
were PP/TRNG. This association has also been observed in Co ˆte
d’Ivoire (66%),23Guyana (57.1%),6and Jamaica (47.4%).4In
contrast, less than 3% of TRNG strains isolated in the United
States between 1988 and 1994 were also PPNG.25
The percentages of isolates with chromosomally mediated re-
sistance to penicillin, tetracycline, or both (MIC ? 2–4 mg/l)
among our strains are comparable with those obtained in King-
ston,4Manila,26Kinshasa,23and in some areas of the United
States: West Palm Beach, Atlanta, and Nassau County.25Resis-
tance to spectinomycin was first described in 1973 and emerged as
a widespread phenomenon in the early 1980s, but it is relatively
rare in some parts of the world,4–7,25,26as observed in our study.
Ciprofloxacin and other fluoroquinolones have excellent in vitro
activity against N gonorrhoeae, including PPNG, TRNG, and
strains with chromosomally mediated resistance to penicillin
and/or tetracycline. However, emergence of clinical strains of N
gonorrhoeae with decreased susceptibility or resistance to the
fluoroquinolones has been reported in different countries, mainly
in the Western Pacific and Southeast Asia but even in Cuba.3,26–29
In the current study, one strain exhibited a decreased susceptibility
All gonococcal strains investigated appeared to be highly sus-
ceptible to ceftriaxone and many were susceptible to cefuroxime,
which is a finding described in previous reports.4–7,25,29
An interesting finding in our study was that 12 of the 52 strains
tested (23.1%) showed decreased susceptibility to azithromycin, a
new macrolide antimicrobial recommended for the treatment of
coexisting chlamydial and gonococcal infections3,7,25and for the
primary treatment of gonorrhea in some Latin American coun-
tries.7Reports of gonococcal isolates displaying decreased suscep-
tibility or resistance to azithromycin have come from a few coun-
tries,6,7,14,15where an association between such isolates and those
showing any type of resistance to penicillin has also been ob-
served,6,7,30as occurred in our study. Azithromycin has never been
used to treat gonococcal infections in Cuba, but erythromycin, a
first-generation macrolide, has been widely used to treat several
infections in this country, including gonococcal infections resistant
to penicillin and/or tetracycline (M. E. Rodriguez, personal com-
munication, 2001). Cross-resistance between azithromycin and
erythromycin has been described previously.6,7
Implications of Gonococcal Resistance on the Treatment of
Gonorrhea in Cuba
According to the results of the current study, the gonococci
population in Cuba is characterized by the high proportion resis-
tant to penicillin, tetracycline, or both. Such resistance can be
Susceptibilities of Neisseria gonorrhoeae Strains From Cuba to Ceftriaxone, Cefuroxime, Ciprofloxacin, Spectinomycin, and
No. (%) of IsolatesMIC Values (?g/ml)
Tested Susceptible IntermediateMIC RangeMIC50
*Two strains had a MIC of 2 ?g/ml.
†One strain had a MIC of 0.125 ?g/ml.
‡Two strains had a MIC of 64 ?g/ml.
§Ten strains had a MIC of 0.125 ?g/ml, and another two strains had a MIC of 0.5 ?g/ml.
Sexually Transmitted Diseases ● January 2003
LLANES ET AL
explained by the fact that these antibiotics have been the drugs of
choice since 1979 to treat gonococcal infections in Cuba.8In
addition, these antibiotics are cheap, and their use is very common
among the Cuban population for a broad range of infectious
diseases (Ministerio de Salud Pu ´blica de Cuba, unpublished data,
Concerns over the increase in resistance to penicillin and tetra-
cycline worldwide has led the WHO to change the recommenda-
tions for therapeutic agents for gonorrhea from these antibiotics to
spectinomycin, ceftriaxone, cefixime, or ciprofloxacin.3,5No in
vitro resistance to these drugs was detected among the Cuban
strains analyzed; more than 98% of these strains were susceptible
to them. Thus, we recommend that any of the mentioned agents
replace penicillin and tetracycline as first-line therapy for gono-
coccal infections in Cuba, as early as possible.
Surveillance of the antimicrobial susceptibility of N gonor-
rhoeae isolates in many developing countries has been restricted
largely to sporadic sentinel studies because of other health prior-
ities, inadequate technical expertise for testing gonococci, or in-
sufficient financial and logistical resources.9,31In Cuba, despite a
probable natural decrease in reported cases of gonorrhea in the past
several years, there have also been severe economic constrictions,
especially since the 1990s.32–34In consequence, the major limita-
tion of this study is the limited sample size, particularly in the
years 1998 and 1999, owing to the inability to recover a large
number of gonococcal isolates on the island. Thus, the develop-
ment of strategies for maintenance and improvement of this sur-
veillance program requires urgent attention in Cuba.
In conclusion, the data show a dramatic shift in gonococcal
strains in Cuba during the period of 1995 to 1999 and the need
for periodic, if not continual, surveillance of antimicrobial
susceptibility of gonococcal isolates. Such activities can pro-
vide the necessary information to the public health authorities
and physicians in order to guide the selection of the most
appropriate treatment for gonorrhea. In addition, the detection
of intermediate resistance to azithromycin and ciprofloxacin
indicates that susceptibility to these drugs should be closely
monitored in the near future in Cuba.
As result of the findings of this study, the Cuban Ministry of
Public Health has decided to change the treatment of uncompli-
cated gonorrhea in Cuba. Now, ciprofloxacin is the recommended
drug (Ministry of Public Health of Cuba, 2002).
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