January-April 2023

Vol.42- No.1

UNIVERSA MEDICINA

REVIEW ARTICLE
pISSN: 1907-3062 / eISSN: 2407-2230

Resistance genes of neisseria gonorrhoeae
to cefixime and azithromycin
Louisa Ivana Utami1,2 and Yeva Rosana3*
ABSTRACT
Gonorrhea is the second most common sexually transmitted bacterial
infection (STI), following Chlamydia. Neisseria gonorrhoeae resistant
to antibiotics are increasing globally in the world. In recent years, many
studies have reported reduced susceptibility of N.gonorrhoeae to almost
all clinically useful antibiotics and also reported cases of multiresistance. Resistance mechanisms for N. gonorrhoeae can occur
through genetic and non-genetic changes. Resistance to cefixime and
azithromycin as first-line antibiotics for monotherapy recommended by
the World Health Organization (WHO) has been reported from several
countries. Genetic changes were reported as the main cause of
N.gonorrhoeae resistance to cefixime and azithromycin. Based on the
WHO and the United States Centers for Disease Control and Prevention
recommendations, countries are increasingly using a combination of
cephalosporin and azithromycin for the treatment of gonorrhea. The aim
of this review is to analyze genetic variation of N.gonorrhoeae resistance
to cefixime and azithromycin. Articles published in English in the last
12 years (from 2010 to 2021) were retrieved from Science Direct,
PubMed, Springerlink, Oxford and Nature using relevant searching
terms. Mutants of cefixime-resistant N.gonorrhoeae are mediated by
mosaic and non-mosaic penA genes encoding penicillin binding protein
2. In addition, mutations in the repressor and promoter genes of mtrR
were also found that caused overexpression of the microbial efflux
pump. Meanwhile, N. gonorrhoeae resistance to azithromycin
reportedly occurs through two strategies, namely overexpression of the
efflux pump (mutation of the mtrR codon region) and decreased affinity
for antibiotics (single base mutation in the 23S rRNA gene). With the
limited choice of antibiotics for the management of N.gonorrhoeae, it is
necessary to do regular surveillance for monitoring drug resistance. By
understanding the mechanism of resistance, the use of these antibiotics
can be rationally optimized.
Keywords : Neisseria gonorrhoeae, resistance, cefixime, azithromycin
Abbreviations:
mtrR = multiple transferable resistance repressor; PBP2 = Penicillinbinding protein 2; 23S rRNA = 23S ribosomal RNA

108

1Magister Program in Biomedical

Science, Faculty of Medicine,
Universitas Indonesia, Jakarta,
Indonesia
2Microbiology Department,
Faculty of Medicine,
Sultan Ageng Tirtayasa University,
Serang, Indonesia
3Microbiology Department,
Faculty of Medicine Universitas
Indonesia - Ciptomangunkusumo
Hospital, Jakarta, Indonesia
*Correspondence:
Yeva Rosana
Microbiology Department,
Faculty of Medicine
Universitas Indonesia Ciptomangunkusumo Hospital,
Jakarta, Indonesia
Phone: +62 3160492
Fax: +62 3100810,
Email: yeva.rosana@ui.ac.id
Date of first submission, July 24, 2022
Date of final revised submission,
February 9, 2023
Date of acceptance, February 21, 2023
This open access article is distributed
under a Creative Commons AttributionNon Commercial-Share Alike 4.0
International License
Cite this article as: Utami LI, Rosana
Y. Resistance genes of neisseria
gonorrhoeae
to
cefixime
and
azithromycin. Univ Med 2023;42: 108118. doi: 10.18051/UnivMed. 2023.v42:
108-118.

DOI: http://dx.doi.org/10.18051/UnivMed.2023.v42:108-118
Copyright@Author(s) - https://univmed.org/ejurnal/index.php/medicina/article/view/1354

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INTRODUCTION
Treatment of gonorrhea in the late 1930s
was started using sulfonamide antibiotics.(1)
However, several years later clinical isolates were
found to be resistant to sulfonamides resulting in
decreased effectivity of these antibiotics. (2)
Currently, five classes of antibiotics are used to
treat N.gonorrhoeae, namely penicillins,
cephalosporins, tetracyclines, fluoroquinolones,
and macrolides.(1,3) The increasing resistance of
N.gonorrhoeae to these antibiotics is reportedly
associated with the accumulation of
N.gonorrhoeae resistance genes.(4,5) Treatment
failure persists even though the drug dose is
increased.(6) Failure of this treatment can lead to
increased spread of multiresistant N.
gonorrhoeae and potentially serious
complications in patients such as infertility,
abortion and fetal death.(7,8)
Varied mechanisms of resistance in
N.gonorrhoeae cause decreased sensitivity or
increased resistance to antibiotics, including target
modification of antibiotics, overexpression of the
efflux pumps, decreased influx of antibiotics
through changes in the permeability of the porin

proteins and enzymatic destruction of antibiotics.
Combinations of these mechanisms are most
commonly found in N. gonorrhoeae resistant to
cefixime and azithromycin, such as horizontal
transfer of genetic material or spontaneous
mutations that alter N.gonorrhoeae structural
and non-structural genes.(9)
In this review paper, a total of 56 articles
published in English in the last 12 years (from
2010 to 2021) were retrieved from Science Direct,
PubMed, Springerlink, Oxford Academic and
Nature databases using the following keywords:
Neisseria gonorrhoeae AND mutation AND
cefixime AND azithromycin AND sexually
transmitted infections.
Initially, 192 articles were found to match
the inclusion criteria, but in the end 136 articles
were removed due to duplication, failure of
access, and irrelevant topic (shown in Figure 1).
Finally, the writing of this review was carried out
using the 56 articles that met the inclusion criteria
to be written into a full paper.
Neisseria gonorrhoeae pathogenesis
Neisseria gonorrhoeae is a Gram-negative
diplococcus that is pathogenic in humans.

Figure 1. Schematic of literature study in journals using relevant keywords

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Utami, Rosana

Neisseria gonorrhoeae can live in a
microaerophilic environment with low oxygen (210%) and high carbondioxide (5-10%)
concentrations. (10-13) On direct microscopic
examination of a specimen, a characteristic
appearance of diplococci is found in
polymorphonuclear leukocytes.(14)
Neisseria gonorrhoeae adheres to the
mucous membranes of the genitourinary tract,
eyes, rectum, and throat, producing an acute
suppuration that can spread to the tissues.(15-17)
Gonorrheal urethritis in men shows a clinical
picture of yellowish pus and dysuria. (14,17)
Complications can occur, including epididymitis,
prostatitis, and periurethral abscess. Primary
infections in women occur in endocervical and
urethral columnar epithelial cells.(17) Gonorrheal
infection in prepubertal children can occur in the
vagina because of the immature mucosal
epithelium. The atrophic vaginal mucosa of
postmenopausal women can also be a site of
N.gonorrhoeae infection. Clinical symptoms in
women are generally a mucopurulent discharge
from the vagina, dysuria and abdominal
pain.(14,17,18)
Untreated infection can progress to chronic
inflammation, including extension to tissues
surrounding the site of infection or spread upward
(ascending) into the fallopian tubes and cause
salpingitis, fibrosis and tubal obliteration.(14)
Infertility occurs in 20% of women with
salpingitis. (7) Disseminated infection with
septicemia and infection of the skin and joints
occur in 1-3% of infected women.(14-16) Many
symptoms are found, such as fever, pain on
moving the joints, and skin lesions on the
extremities, from hemorrhagic papules and
pustules on the hands, feet, and legs to suppurative
arthritis, usually in the knees (gonorrheal arthritis),
ankles, and hands.(17) Endocarditis can also be
caused by N. gonorrhoeae although it is rarely
found.
Since 2016, the WHO has recommended a
combination of a single dose of ceftriaxone 250
mg intramuscularly and a single dose of
azithromycin 1 g orally OR cefixime 400 mg orally
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Neisseria gonorrhoeae

single dose and azithromycin 1 g orally single dose
for empirical therapy of genital and anorectal
gonorrhea. Single dose antibiotic therapy can be
given (according to the sensitivity pattern) of a
choice of ceftriaxone 250 mg intramuscular
injection, OR cefixime 400 mg orally, OR
spectinomycin 2 g intramuscular injection.(7)
Cefixime belongs to the class of β-lactam
antibiotics and acts by inhibiting the peptidoglycan
cross-link in the bacterial cell wall through binding
to the β-lactam ring on penicillin binding protein 2
(PBP2).(2,19) Azithromycin belongs to the class
of macrolide antibiotics that bind to the 50S
ribosome and inhibit protein synthesis through
elongation of the peptide chain.(20–25)
The mechanism of N. gonorrhoeae
resistance to cefixime and azithromycin is
influenced by mutations or transfer of Neisseria
resistance genes (as shown in Table 1 and Figure
2), including mtrR mutations, single base mutations
in the 23S rRNA gene, porB1B mutations and
mosaic and non-mosaic alleles on PBP2 target
proteins, efflux pump for antibiotics, and
decreased antibiotic influx into cells.(1,3, 26, 29)
Cefixime resistance mechanism
Neisseria gonorrhoeae resistance to
cefixime is mainly caused by mutations that modify
PBP2 protein as an antibiotic target.(11,30–34)
Changes in PBP2 target protein are most often
caused by the presence of a mosaic gene
consisting of 60-70 amino acid changes without
Asp345a insertion in N. gonorrhoeae resistant
to penicillin.(1,9,11,12,24) These mosaic genes are
transferred through DNA transformation from
commensal Neisseria in the oropharynx, because
transfer of genetic material occurs during N.
gonorrhoeae infection in the pharynx. These
amino acid changes form varied patterns including
patterns X, XXXIV, and XII, with the substitution
of a single amino acid, for example: A501P and
A501V as shown in Figure 3.(13,21,35-42)
Studies in the US and Canada reported that
the penA mosaic pattern XXXIV was most
commonly found in clinical isolates of resistant
N. gonorrhoeae. These results differ from those

Table 1. Resistance genes of N. gonorrhoeae to cefixime and azithromycin

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Neisseria gonorrhoeae

Figure 2. Mechanism of resistance of N. gonorrhoeae to cefixime and azithromycin

of a study conducted by Peng et al. (13) in China,
reporting that pattern X predominated in N.
gonorrhoeae resistance. A Korean study found
that 16% of resistant N. gonorrhoeae isolates
had penA X patterns with high MIC values that
will lead to treatment failure.(35) Non-mosaic
penA patterns, including patterns IV, V, XII, XVI,
XVII, and XVIII, can also cause N.
gonorrhoeae resistance such as those caused
by penA mosaic alleles including the PBP2 XIII
allele which has five specific amino acid changes
(A501V, F504L, A510V, A516G and P551S). This
finding is supported by Lee et al.(35), in that nonmosaic PBP2 sequence pattern XIII is most
commonly found in resistant N. gonorrhoeae
isolates followed by patterns IV and V.
Several studies also reported that an
increase in efflux of antibiotics caused
N.gonorrhoeae resistance to β-lactams such as
cefixime. (1,13) The presence of a missense
mutation in the DNA binding domain in the codon
region encoding the mtrR repressor causes
mutations in the G45D helix-turn-helix
112

domain.(35,36, 46,48,53,60) This deletion causes frame
shifts and premature stop codons to form an
incomplete mtrR protein.(22,24,26,31) In addition to
resistant N. gonorrhoeae strains with high MIC
values, mutations are most often found in the form
of a single base deletion at 13-bp inverted repeat
sequences (IR) on the mtrR promoter.(32,51,53,60)
The outer membrane of N. gonorrhoeae
acts as a permeability barrier to various
components, including cefixime. The decreased
influx of cefixime antibiotic that diffuses into the
periplasmic space through a protein channel on
the outer membrane, namely the porin protein, is
one of the mechanisms of resistance of N.
gonorrhoeae. (44,45,47,48,52,53) However, the
PorB1a and PorB1b genes belonging to N.
gonorrhoeae were reported to be more
influential in the occurrence of N. gonorrhoeae
resistance to penicillin and ceftriaxone antibiotics
than in its resistance to cefixime.(10) A study in
Korea reported that mutations in porB and mtrR
contributed to increased MIC values in resistant
N. gonorrhoeae isolates. The penB resistance

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Figure 3. Amino acid alignment of penicillin binding protein 2 related to resistance of N. gonorrhoeae to
cefixime.35

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Utami, Rosana

determinant causes amino acid changes at
positions 120 and 121 (G120D/A121D), leading
to a decrease in the entry of antibiotics.
Interestingly, the effect of the penB phenotype
is only seen in the N. gonorrhoeae mutant strain
that overexpresses the mtrCDE efflux pump.(54)
Azithromycin resistance mechanism
Many cases of macrolide resistance are
associated with specific nucleotide changes in 23S
rRNA in the 50S ribosomal subunit.(22,51,55,61) In
general, bacterial resistance to macrolides can
result from modification of ribosomal targets
through modification of rRNA via the methylase
enzyme of 23S rRNA or specific mutations in
23S rRNA itself and/or from the fact that the
efflux pump system is overexpressed. (8,27,56)
Modification of RNA via methylase enzymes is
mediated by the ermB, ermC, and ermF genes
from other bacteria, leading to modification of the
antibiotic.(59,61)
The study conducted by Pham et al.(62) also
reported that resistant N. gonorrhoeae strains
showed single base mutations in the V domain
of their 23S rRNA, namely mutations A2059G
and C2611T.(30) Mutations at this position involved
more than 1 of the 4 alleles of Neisseria
gonorrhoeae (NG). (30,56,57) An enzymatic
mechanism through rRNA methylase causing
blocking of azithromycin binding to 23S rRNA at
position 2058 as found in studies in Seattle and
Uruguay was also reported as a mechanism of
N. gonorrhoeae resistance to azithromycin.(30)
Another mechanism of azithromycin
resistance involves mutations in mtrR leading to
overexpression of the efflux pump. Mutations can
occur in the mtrR promoter region in the form of
adenine deletion or the mtrR A39T/G45D
repressor as found in a study in Portugal.
According to a study by Shigemura in Japan,
deletion mutations in the mtrR promoter region
can cause an increase in MIC values (>0.5 mcg/
ml).(59) Mutations in the promoter region can also
increase the binding of RNA polymerase or
activator to the mtrC promoter due to decreased

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Neisseria gonorrhoeae

competition for binding to the same DNA region,
thereby inducing higher resistance.(3)
CONCLUSION
Modification of target proteins is the main
mechanism of N. gonorrhoeae resistance to
cefixime. Meanwhile, N. gonorrhoeae
resistance to azithromycin is more influenced by
the overexpression of the efflux pump. By
understanding these mechanisms, the WHO
recommends giving cefixime and azithromycin for
the treatment of gonorrhea which aims to reduce
resistance rates.
CONFLICT OF INTEREST
The authors declare that they have no
conflict of interest.
FUNDING
No funding was received for conducting this
study.
ACKNOWLEDGEMENTS
The authors would like to thank Magister
Program Biomedical Science, Faculty of
Medicine, Universitas Indonesia for giving the
opportunity and facilitating the writing of this
manuscript.
CONTRIBUTORS
LIU searched the journals. YR supervised
the journals choice. LIU and YR analysed the
result. LIU and YR wrote the draft of the report.
All authors contributed to revisions and approved
the final version.
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