Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: A retrospective study of national surveillance data from 2013 to 2016.

BACKGROUND: Gonorrhea remains one of the most common sexually transmitted diseases worldwide. Successful treatment has been hampered by emerging resistance to each of the antibiotics recommended as first-line therapies. We retrospectively analyzed the susceptibility of gonorrhea to azithromycin and ceftriaxone using data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) in order to provide evidence for updating the treatment recommendations in China. METHODS AND FINDINGS: In this study, we included 3,849 isolates collected from patients with a confirmed positive Neisseria gonorrhoeae (N. gonorrhoeae) culture at clinic visits during the period of 1 January 2013 through 31 December 2016 in 7 provinces. Antimicrobial susceptibility testing of gonorrhea isolates using agar dilution was conducted to determine minimum inhibitory concentration (MIC). Resistance to azithromycin (RTA) was defined as MIC ≥ 1.0 mg/l, and decreased susceptibility to ceftriaxone (DSC) was defined as MIC ≥ 0.125 mg/l. The prevalence of isolates with RTA was 18.6% (710/3,827; 95% CI 17.4%-19.8%). The percentage of patients with DSC fluctuated between 9.7% and 12.2% over this period. The overall prevalence of isolates with both RTA and DSC was 2.3% (87/3,827; 95% CI 1.9%-2.8%) and it increased from 1.9% in 2013 to 3.3% in 2016 (chi-squared test for trend, P = 0.03). Study limitations include the retrospective study design and potential biases in the sample, which may overrepresent men with symptomatic infection, coastal residents, and people reporting as heterosexual. CONCLUSIONS: To our knowledge, this is the first national study on susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone in China. Our findings indicate high rates of RTA and DSC from 2013 to 2016. Although dual therapy with azithromycin and ceftriaxone has been recommended by WHO and many countries to treat gonorrhea, reevaluation of this therapy is needed prior to its introduction in China.

Will targeting oropharyngeal gonorrhoea delay the further emergence of drug-resistant Neisseria gonorrhoeae strains?

Gonorrhoea is an important sexually transmitted infection associated with serious complications and enhanced HIV transmission. Oropharyngeal infections are often asymptomatic and will only be detected by screening. Gonococcal culture has low sensitivity (<50%) for detecting oropharyngeal gonorrhoea, and, although not yet approved commercially, nucleic acid amplification tests (NAAT) are the assay of choice. Screening for oropharyngeal gonorrhoea should be performed in high-risk populations, such as men-who-have-sex-with-men(MSM). NAATs have a poor positive predictive value when used in low-prevalence populations. Gonococci have repeatedly thwarted gonorrhoea control efforts since the first antimicrobial agents were introduced. The oropharyngeal niche provides an enabling environment for horizontal transfer of genetic material from commensal Neisseria and other bacterial species to Neisseria gonorrhoeae. This has been the mechanism responsible for the generation of mosaic penA genes, which are responsible for most of the observed cases of resistance to extended-spectrum cephalosporins (ESC). As antimicrobial-resistant gonorrhoea is now an urgent public health threat, requiring improved antibiotic stewardship, laboratory-guided recycling of older antibiotics may help reduce ESC use. Future trials of antimicrobial agents for gonorrhoea should be powered to test their efficacy at the oropharynx as this is the anatomical site where treatment failure is most likely to occur. It remains to be determined whether a combination of frequent screening of high-risk individuals and/or laboratory-directed fluoroquinolone therapy of oropharyngeal gonorrhoea will delay the further emergence of drug-resistant N. gonorrhoeae strains.

Patrones de resistencia de Neisseria gonorrhoeae aisladas en el área de Cuenca / Resistance patterns of Neisseria gonorrhoeae isolated in patients from the area of cuenca (Spain)

El artículo es un estudio retrospectivo para conocer la sensibilidad antibiótica de los aislados de Neisseria gonorhoeae de muestras genitales de pacientes durante los últimos 4 años en el área de Cuenca (España) para así establecer cuáles serían las mejores pautas de tratamiento para esta enfermedad en nuestra región. De un total de 26 cepas aisladas de Neisseria gonorrhoeae, la resistencia a fluorquinolonas fue del 61,54%. Todas las cepas fueron sensibles a cefotaxima, por lo que consideramos que el tratamiento empírico de elección de las infecciones gonocócicas no complicadas en nuestro medio debería ser las cefalosporinas de tercera generación (AU)

A retrospective study was conducted to determine the antibiotic susceptibility of Neisseria gonorrhoeae isolates from genital samples of patients over the last four years in Cuenca (Spain), in order to establish what would be the best treatment regimens for this disease in our region. Of a total of 26 isolates of Neisseria gonorrhoeae, fluoroquinolone resistance was 61.54%. All strains were susceptible to cefotaxime, so we believe that the choice of empirical treatment of uncomplicated gonococcal infections should be third generation cephalosporins in our region (AU)

In vitro activity of ertapenem versus ceftriaxone against Neisseria gonorrhoeae isolates with highly diverse ceftriaxone MIC values and effects of ceftriaxone resistance determinants: ertapenem for treatment of gonorrhea?

Clinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining treatment options for gonorrhea, is being reported. Gonorrhea may become untreatable, and new treatment options are crucial. We investigated the in vitro activity of ertapenem, relative to ceftriaxone, against N. gonorrhoeae isolates and the effects of ESC resistance determinants on ertapenem. MICs were determined using agar dilution technique or Etest for international reference strains (n = 17) and clinical N. gonorrhoeae isolates (n = 257), which included the two extensively drug-resistant (XDR) strains H041 and F89 and additional isolates with high ESC MICs, clinical ESC resistance, and other types of clinical high-level and multidrug resistance (MDR). Genetic resistance determinants for ESCs (penA, mtrR, and penB) were sequenced. In general, the MICs of ertapenem (MIC(50) = 0.032 µg/ml; MIC(90) = 0.064 µg/ml) paralleled those of ceftriaxone (MIC(50) = 0.032 µg/ml; MIC(90) = 0.125 µg/ml). The ESC resistance determinants mainly increased the ertapenem MIC and ceftriaxone MIC at similar levels. However, the MIC ranges for ertapenem (0.002 to 0.125 µg/ml) and ceftriaxone (<0.002 to 4 µg/ml) differed, and the four (1.5%) ceftriaxone-resistant isolates (MIC = 0.5 to 4 µg/ml) had ertapenem MICs of 0.016 to 0.064 µg/ml. Accordingly, ertapenem had in vitro advantages over ceftriaxone for isolates with ceftriaxone resistance. These in vitro results suggest that ertapenem might be an effective treatment option for gonorrhea, particularly for the currently identified ESC-resistant cases and possibly in a dual antimicrobial therapy regimen. However, further knowledge regarding the genetic determinants (and their evolution) conferring resistance to both antimicrobials, and clear correlates between genetic and phenotypic laboratory parameters and clinical treatment outcomes, is essential.

Chitosan-iron oxide nano-composite platform for mismatch-discriminating DNA hybridization for Neisseria gonorrhoeae detection causing sexually transmitted disease.

Electrochemically fabricated nano-composite film of chitosan (CH)-iron oxide (Fe(3)O(4)) has been used to detect gonorrhoea, a sexually transmitted disease (STD) via immobilization of biotinylated probe DNA (BDNA) using avidin-biotin coupling for rapid and specific (mismatch-discriminating) DNA hybridization. The presence of Fe(3)O(4) nanoparticles (∼18nm) increases the electro-active surface area of the nano-biocomposite that provides desirable environment for loading of DNA with better conformation leading to increased electron transfer kinetics between the medium and electrode. The differential pulse voltammetric (DPV) studies have been conducted using BDNA/avidin/CH-Fe(3)O(4)/ITO electrode owing to the reduction of the methylene blue (MB) indicator and investigate electron transfer between MB moieties and electrode for one and two-bases mismatch. This STD biosensor is found to have a detection limit (1 × 10(-15)M) and a wide dynamic range (from 1 × 10(-16)M to 1 × 10(-6)M) using the complementary target DNA. In addition, the sensing system can be utilized to accurately discriminate complementary sequence from mismatch sequences.

Characteristics and dissemination of mosaic penicillin-binding protein 2-harboring multidrug-resistant Neisseria gonorrhoeae isolates with reduced cephalosporin susceptibility in northern Taiwan.

Among 254 Neisseria gonorrhoeae isolates from a sexually transmitted infection (STI) clinic in northern Taiwan, 69 isolates were found to contain the mosaic penA (MA) gene and were associated with elevated cefixime and ceftriaxone MICs. Most of these MA gene-harboring isolates were also resistant to penicillin (71.4%) and ciprofloxacin (100%) and were from men who have sex with men (MSM) or from bisexual men (81.2%). Three major sequence types (ST835, ST2180, and ST2253) constituted 55.7% of these isolates. The major sequence types harboring the mosaic penA gene may represent major sexual networks responsible for the emergence/introduction and the spread of the multidrug-resistant clones in Taiwan.

Neisseria gonorrhoeae antibiotic resistance in Paris, 2005 to 2007: implications for treatment guidelines.

Quinolone-resistant Neisseria gonorrhoeae rates have increased worldwide since 1994. The objective of this study was to appraise: (i) the antimicrobial susceptibility of Neisseria gonorrhoeae in a venereology clinic in Paris, between 2005 and 2007; and (ii) the factors associated with quinolone-resistant N. gonorrhoeae. A prospective study of consecutive cases was performed for the period 2005 to 2007. Susceptibility of N. gonorrhoeae to five antibiotics (ciprofloxacin, ceftriaxone, spectinomycin, penicillin G and tetracycline) was tested systematically. Clinical and epidemiological data were collected using a standardized form. Male-to-female sex ratio was 22.0. Median age was 30.0 years. Of 115 cases, 84 occurred in men having sex with men (72.6%) and 22 involved the anorectal area (19.1%). The rate of quinolone-resistant N. gonorrhoeae was 37.4% (43/115), without significant association with gender, age, sexual behaviour, past history of sexually transmitted diseases and susceptibility to other antibiotics. All N. gonorrhoeae were susceptible to ceftriaxone and spectinomycin. The rate of quinolone-resistant N. gonorrhoeae in Paris has been increasing since 2004. Ceftriaxone remains the gold standard treatment.

Metal binding specificity of the MntABC permease of Neisseria gonorrhoeae and its influence on bacterial growth and interaction with cervical epithelial cells.

mntABC from Neisseria gonorrhoeae encodes an ABC permease which includes a periplasmic divalent cation binding receptor protein of the cluster IX family, encoded by mntC. Analysis of an mntC mutant showed that growth of N. gonorrhoeae could be stimulated by addition of either manganese(II) or zinc(II) ions, suggesting that the MntABC system could transport both ions. In contrast, growth of the mntAB mutant in liquid culture was possible only when the medium was supplemented with an antioxidant such as mannitol, consistent with the view that ion transport via MntABC is essential for protection of N. gonorrhoeae against oxidative stress. Using recombinant MntC, we determined that MntC binds Zn(2+) and Mn(2+) with almost equal affinity (dissociation constant of approximately 0.1 microM). Competition assays with the metallochromic zinc indicator 4-(2-pyridylazo)resorcinol showed that MntC binds Mn(2+) and Zn(2+) at the same binding site. Analysis of the N. gonorrhoeae genome showed that MntC is the only Mn/Zn metal binding receptor protein cluster IX in this bacterium, in contrast to the situation in many other bacteria which have systems with dedicated Mn and Zn binding proteins as part of distinctive ABC cassette permeases. Both the mntC and mntAB mutants had reduced intracellular survival in a human cervical epithelial cell model and showed reduced ability to form a biofilm. These data suggest that the MntABC transporter is of importance for survival of Neisseria gonorrhoeae in the human host.

Fluoroquinolone-resistant Neisseria gonorrhoeae: the inevitable epidemic.

The worldwide incidence of fluoroquinolone-resistant Neisseria gonorrhoeae has increased dramatically in the last few years. Single doses of fluoroquinolones can no longer be used to treat N gonorrhoeae infections acquired in the Far East, parts of the Middle East, the Pacific Islands, and parts of Western Europe and the United States. Although California and Hawaii account for most of the current United States cases, the increased incidence of FQR in some high-risk groups independent of geography heralds an imminent spread of drug-resistant strains throughout the rest of the population. The use of molecular tests has revolutionized the diagnostic field in STIs. The main limitation of their application in N gonorrhoeae testing has been the loss of culture specimens that allow antimicrobial sensitivity testing. New molecular methods have made it possible to detect antimicrobial resistance without the use of live organisms. These tests hold the promise of improving epidemiologic tracking of N gonorrhoeae drug resistance, leading to better patient management at the local level. The loss of fluoroquinolones limits available oral regimens to a single CDC-recommended antibiotic, cefixime. Oral, inexpensive, single-dose alternatives are needed to ensure continued therapeutic success.

Gonococia genital femenina / Gonorrhea of the female genital tract

No disponible

A proposed feedback loop of sexually transmitted diseases and sexual behavior: the Red Queen's Dilemma.

(Micro)organisms, such as bacteria, which cause sexually transmitted diseases (STDs) in humans are presented with an interesting ecological challenge. These microorganisms need humans to have sexual contact with each other in order for the microorganisms to spread to other hosts as well as to have subsequent generations of descendants. However, diseases tend to lower the sex drive and to render the host less sexually attractive. It is argued that, over time, selective advantages sculpted organisms which cause STDs to be minimally symptomatic and to indirectly increase the number of sexual partners of the host. Neisseria gonorrhoeae which cause the STD gonorrhea are used as a prototype for these putative sexual dynamics. As a counter to the (micro)organisms' biological adaptations, human cultural innovations emerged and became integrated into the various traditions of social structures.

Eficacia de una monodosis de azitromicina para el tratamiento de la uretritis aguda masculina / Efficacy of azithromycin monodose for treatment of male acute urethritis

La uretritis aguda es causa frecuente de consulta en nuestro medio en centros de enfermedades de transmisión sexual y los principales agentes etiológicos son Neisseria gonorrhoeae y Chlamydia trachomatis. Un problema para el manejo de esta patología, es la emergencia de resistencia en N. gonorrhoeae; datos de 1991 mostraban una resistencia en cepas chilenas de N. gonorrhoeae de 30,3 por ciento a penicilina y 39,8 por ciento a tetraciclina, los antibióticos que se utilizaban empíricamente. Estas cifras se mantienen con tendencia al ascenso en algunas regiones. En estas situaciones, la OMS recomienda usar ceftriaxona intramuscular, una dosis de 125 mg, lo cual resulta costoso y poco práctico para nuestra realidad y no cubre a C. trachomatis. Para evaluar otras alternativas terapéuticas con un enfoque sindromático, se estudió la eficacia y seguridad de una dosis de 1 gramo oral de azitromicina en 61 pacientes masculinos que consultaron por uretritis aguda. A cada paciente que accedió a ingresar al estudio se le efectuaron tres controles clínicos y bacteriológicos: el día 1, entre 7 a 10 y 21 a 38 días, después del tratamiento. En estos pacientes, la etiología de la uretritis correspondió a N. gonorrohoeae en 67 por ciento, a C. trachomatis en 3 por ciento, en 11,5 por ciento a una coinfección por estos dos agentes y en 18 por ciento no se detectó el agente causal. Se observó curación clínica en 85,2 por ciento a los 7-10 días y 91,5 por ciento a los 21-28 días. La erradicación bacteriológica fue del 95 por ciento. Dos pacientes (3,2 por ciento) presentaron efectos adversos y de corta duración que se manifestaron por vómitos, hipotermia y epigastralgia. En conclusión, azitromicina resultó una alternativa eficaz, segura y práctica para el tratamiento de pacientes con uretritis aguda; la eficacia fue excelente para los dos agentes más frecuentemente observados

Identification of a human cDNA clone that mediates adherence of pathogenic Neisseria to non-binding cells.

Neisseria gonorrhoeae and Neisseria meningitidis are exclusively human pathogens. A crucial property of the pathogenicity of neisserial infection is the ability to adhere to human epithelial cells. Pili mediate adherence of these bacteria to target cells and thereby promote colonization and infection of mucosal surfaces. In order to identify and to learn more about the initial event during infection, a cDNA clone from a human cervical epithelial cell line was identified in a panning experiment using purified gonococcal pili as probe. Upon transfection of the cloned cDNA into COS-7 cells, both gonococci and meningococci adhered to these otherwise non-binding cells. The deduced amino acid sequence of the cDNA clone showed homology to a recently reported human cDNA, called WWP2, that encodes an N-terminal C2-like domain. The C2 domain has been shown to bind membrane phospholipids in a calcium-dependent manner and is thought to function in the intracellular compartmentalization of proteins. Antiserum raised against the product encoded by the cDNA did not inhibit bacterial adherence, indicating that the cloned gene is most likely involved in up-regulation of a surface receptor for pathogenic Neisseria.

Temporal trends in gonococcal antibiotic resistance in Baltimore.

Each month from August 1986 through July 1990, clinical and laboratory data were evaluated for the first 25 urethral isolates of Neisseria gonorrhoeae from men attending a Baltimore sexually transmitted disease (STD) clinic as part of an effort to understand factors that contribute to changes in gonococcal antimicrobial susceptibility. During the 48-month study period, 1193 gonococcal isolates were evaluated; the proportion of penicillinase-producing N. gonorrhoeae (PPNG) isolates steadily increased, the prevalence of tetracycline-resistant N. gonorrhoeae (TRNG) remained relatively stable, and chromosomally mediated penicillin resistance increased steadily during the first 5 6-month intervals, then decreased, only to increase again during the final 2 6-month intervals. Changes in antibiotic treatment regimens for gonorrhea were associated with changes in the prevalence of chromosomally mediated penicillin resistance. In a supplementary study to characterize patterns of antibiotic use among men and women attending the STD clinics, 9% of patients reported antibiotic use in the 2 weeks prior to clinic visit. Antibiotics were taken prior to clinic attendance by 65% of patients reporting antibiotic use, because of concerns regarding possible STD or STD exposure. These patients were significantly less likely to be culture positive for N. gonorrhoeae when compared with patients who did not report antibiotic use. Temporal trends in N. gonorrhoeae antibiotic resistance appear to be influenced by many factors, including treatment regimens and self medication.

Isolation and characterization of a mutant of Neisseria gonorrhoeae that is defective in the uptake of iron from transferrin and haemoglobin and is avirulent in mouse subcutaneous chambers.

Iron-uptake mutants of Neisseria gonorrhoeae strain 340 were obtained following treatment with streptonigrin, and one such mutant (Fud14) was characterized. N. gonorrhoeae strain Fud14 was unable to grow with human transferrin or haemoglobin as the sole source of iron, but grew normally with heat-inactivated normal human serum or haemin. Internalization of 55Fe from transferrin by strain Fud14 was only 25% of the parent level. Strain Fud14 (less than or equal to 1 x 10(8) c.f.u.) did not grow in subcutaneous chambers implanted in mice, whereas the parent strain was infective at an ID50 of 4.3 x 10(1) c.f.u. Supplementation of chambers with either normal human serum or haemin resulted in the establishment of strain Fud14 in vivo for at least 240 h post-inoculation. Electroporation of Fud14 with wild-type DNA and selection for growth on medium containing human transferrin resulted in a recombinant (Fud15) that was capable of utilizing haemoglobin, and was virulent in mice. These results suggest that a gonococcal strain defective in the ability to utilize in vivo iron sources is not capable of survival in vivo.

Effects of amino acids on colony phenotype of Neisseria gonorrhoeae.

The effects of amino acid supplementation of commercially available semidefined GC media (Oxoid GC medium and Difco GC base) on the stability of the virulent colony phenotype of Neisseria gonorrhoeae were studied. The -SH-containing amino acids, together with glycine, were found to cause segregation of avirulent colony types followed by growth inhibition after addition of 40 mg/100 ml. Proline and arginine were found to change the colony phenotype profile significantly without reducing the viable count. Arginine supplementation in both media caused a progressive loss of virulent colony types, whereas proline had the opposite effect.

Dosis única de ciprofloxacina en el tratamiento de la uretritis gonocóccica / Single dose of ciprofloxacin in the gonococcal urethritis treatment

Para estudiar la efectividad de una nueva quinolona en el tratamiento de la uretritis gonocóccica no complicada, se administraron 500 mg de ciprofloxacina como dosis única en 89 varones con diagnóstico clínico y bacteriológico de esta enfermedad. Se efectuaron controles a los 3 y 7 días y se observó que todos los pacientes menos uno (98,9%) respondieron efectivamente al tratamiento con curación tanto clínica como bacteriológica en los controles practicados. Ningún paciente presentó reacción adversa. La Ciprofloxacina en dosis única de 500 mg representa una nueva alternativa en el tratamiento de la uretritis gonocóccica no complicada