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Multi-Drug Resistant Neisseria gonorrhoeae

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A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 62581

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Special Issue Editors

Prof. Dr. Jo-Anne R. Dillon

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Guest Editor

Department of Biochemistry, Microbiology and Immunology, College of Medicine, c/o 120 Veterinary Road, Saskatoon, SK S7N 5E3, Canada
Interests: Neisseria gonorrhoeae; antimicrobial resistance; molecular epidemiology; diagnostics
Special Issues, Collections and Topics in MDPI journals

Dr. Sidharath Dev Thakur

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Guest Editor

Department of Veterinary Public Health and Epidemiology, DGCN College of Veterinary and Animal Sciences, Himachal Pradesh Agricultural University, Palampur 176062, Himcahal Pradesh, India
Interests: antimicrobial resistance; Neisseria gonorrhoeae; veterinary public health; zoonoses; Brucella

Special Issue Information

Dear Colleagues,

The prevalence of infections caused by Neisseria gonorrhoeae is rising globally. Coupled with this rise, the ever-present possibility that gonococcal infections will be untreatable in the future has resulted in increased attention by public health agencies worldwide to diagnose infections quickly and to ensure that patients are treated with effective antibiotics.

Over the past 70 years, different antibiotics have been introduced to treat gonococcal infections. Steadily, N. gonorrhoeae has developed an array of resistance mechanisms to each antibiotic. This has resulted in the successive withdrawal of older antibiotics when resistance in gonococcal populations (>5 percent resistant) precludes their effective use. Choices for effective treatment of gonococcal infections are now severely limited. Presently, therapy with an injectable third generation cephaloporin coupled with azithromycin is the globally-recommended treatment for uncomplicated gonococcal infections. Resistance to both of these antibiotics has been reported, along with treatment failure using dual therapy.

The present Special Issue will seek to highlight the most recent information and advances on antimicrobial resistant N. gonorrhoeae. To combat drug resistance, improvements in simple, inexpensive and rapid diagnostics for gonorrhea infections are needed. Surveillance is required to establish local and regional antimicrobial resistance profiles to advise on treatment regimens which reflect local conditions. The molecular epidemiology of resistant isolates should be better monitored globally to ascertain the dispersal of common resistant strains and the introduction of new phenotypes. New diagnostic methods for antimicrobial resistance (AMR) must be developed and evaluated as many regions of the world have no capacity for diagnostic or antimicrobial susceptibility (AMS) testing of N. gonorrhoeae using presently-recommended methods. Further, the widespread use of nucleic acid amplification tests for diagnosing N. gonorrhoeae infections in resource-rich areas precludes AMS testing because culture of the organism is not possible. In this Special Issue, we hope to highlight advances that lead to a better understanding of AMR in N. gonorrhoeae, as well as strategies being developed to advance effective treatment, including the development of point-of-care tests.

Suggested topics for consideration include:

Advances in national and international surveillance of antibiotic resistant N. gonorrhoeae isolates
Molecular epidemiology of resistant isolates
Advances in new technologies and/or molecular detection of AMR
Point-of-care testing for N. gonorrhoeae and its AMR
New antimicrobial agents for treating gonococcal infections
Whole genome sequencing as a strategy to understand gonococcal AMR and transmission
Identification of sexual networks for AMR transmission
Will a gonococcal vaccine end the AMR crisis?
Modelling gonococcal AMR—does one size fit all?
Effect of co-infections on gonococcal AMR

Prof. Dr. Jo-Anne R. Dillon
Dr. Sidharath Dev Thakur
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

N. gonorrhoeae
antimicrobial susceptibility
molecular epidemiology
mechanisms of resistance
molecular tests/point-of-care
new AMS technologies

Published Papers (9 papers)

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Research

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7 pages, 809 KiB

Open AccessArticle

Antimicrobial Susceptibility of Neisseria gonorrhoeae Isolates in Baltimore, Maryland, 2016: The Importance of Sentinel Surveillance in the Era of Multi-Drug-Resistant Gonorrhea

by Johan H. Melendez, Justin Hardick, Mathilda Barnes, Kathleen R. Page and Charlotte A. Gaydos

Antibiotics 2018, 7(3), 77; https://doi.org/10.3390/antibiotics7030077 - 17 Aug 2018

Cited by 11 | Viewed by 4660

Abstract

The increasing rates of gonorrhea infections and the global emergence and spread of multi-drug-resistant Neisseria gonorrhoeae (NG) threaten the successful management of gonorrhea. In the era of nucleic acid amplification tests (NAATs), surveillance projects are urgently needed to monitor prevalence and trends in the antimicrobial susceptibility of NG. In this study, we retrospectively determined the susceptibility profile of NG isolates to previously and currently prescribed antimicrobials. NG isolates collected in Baltimore, Maryland between January and October 2016 were evaluated by the E-test method and/or molecular methods for susceptibility to ceftriaxone, azithromycin, ciprofloxacin, tetracycline, gentamicin, and penicillin. One-hundred and forty-three NG isolates from African-American males (98.6%), primarily heterosexual (88.8%), ranging in age from 15 to 69 years of age were included in the study. Ciprofloxacin resistance was observed in 44.1% of isolates. Plasmid-mediated resistance to penicillin and tetracycline resistance was detected in 22.4% and 10.1% of isolates, respectively. Three isolates (2.1%) displayed high-level resistance to azithromycin (minimum inhibitory concentration (MIC) > 256 μg/mL). Forty-three percent of isolates were resistant or had decreased susceptibility to three antimicrobials (ciprofloxacin, tetracycline, and penicillin). All isolates were susceptible to ceftriaxone and gentamicin. Overall, the epidemiology of antimicrobial resistant NG in Baltimore continues to evolve, and the emergence of azithromycin resistance in this population emphasizes the need for continued sentinel surveillance programs to monitor susceptibility trends and aid in treatment recommendations. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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11 pages, 271 KiB

Open AccessArticle

Evaluation of a Hydrogel-Based Diagnostic Approach for the Point-of-Care Based Detection of Neisseria gonorrhoeae

by Sumudu R Perera, Ali Taheri, Nurul H Khan, Rajinder P Parti, Stephanie Stefura, Pauline Skiba, Jason P Acker, Irene Martin, Anthony Kusalik and Jo-Anne R Dillon

Antibiotics 2018, 7(3), 70; https://doi.org/10.3390/antibiotics7030070 - 04 Aug 2018

Cited by 6 | Viewed by 4819

Abstract

Eleven primer pairs were developed for the identification of Neisseria gonorrhoeae. The sensitivity and specificity of these primers were evaluated by Real Time (RT)-PCR melt curve analyses with DNA from 145 N. gonorrhoeae isolates and 40 other Neisseria or non-Neisseria species. Three primer pairs were further evaluated in a hydrogel-based RT-PCR detection platform, using DNA extracted from 50 N. gonorrhoeae cultures. We observed 100% sensitivity and specificity in the hydrogel assay, confirming its potential as a point-of-care test (POCT) for N. gonorrhoeae diagnosis. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

9 pages, 400 KiB

Open AccessFeature PaperArticle

Surveillance for Antimicrobial Resistance in Gonorrhea: The Alberta Model, 2012–2016

by Jennifer Gratrix, Anmmd Kamruzzaman, Irene Martin, Petra Smyczek, Ron Read, Lindsay Bertholet, Prenilla Naidu and Ameeta E. Singh

Antibiotics 2018, 7(3), 63; https://doi.org/10.3390/antibiotics7030063 - 20 Jul 2018

Cited by 6 | Viewed by 4642

Abstract

Alberta established a surveillance system in 2001 to monitor resistance to antibiotics used for the treatment of gonorrhea. A retrospective review of gonorrhea cases during the last five years was conducted. All cases of gonorrhea were reportable to public health by testing laboratories and clinicians. Specimens were primarily submitted for nucleic acid amplification testing (NAAT); three sentinel sites obtained specimens for culture and NAAT. The Provincial Laboratory for Public Health conducted E-tests on isolates for multiple antibiotics. A proportion of isolates and NAAT specimens were submitted to the National Microbiology Laboratory for sequence typing (ST). Data were combined and analyzed using SAS version 9.4. Between 2012 and 2016, 13,132 gonorrhea cases were reported; 22.0% (n = 2891) had isolates available for susceptibility testing. All culture positive isolates were susceptible to ceftriaxone. Decreased susceptibility (0.5 ug/mL) to cefixime was reported in four cases in 2014. Resistance to azithromycin (≥2 ug/mL) ranged between 0.4% and 1.8%. Many (n = 509) unique STs were identified; the most prevalent sequence groups (SG) were SG-7638 (n = 367), SG-5985 (n = 145), and SG-11299 (n = 127). The Alberta model for maintaining surveillance for antimicrobial resistance in gonorrhea employs culture and NAAT specimens, providing information crucial to informing provincial treatment guidelines. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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8 pages, 542 KiB

Open AccessFeature PaperCommunication

The Growing Threat of Gonococcal Blindness

by Victoria Dolange, Colin P. Churchward, Myron Christodoulides and Lori A. S. Snyder

Antibiotics 2018, 7(3), 59; https://doi.org/10.3390/antibiotics7030059 - 12 Jul 2018

Cited by 23 | Viewed by 5764

Abstract

Antibiotic-resistant gonorrhea is now a reality, as well as the consequences of untreatable infections. Gonococcal eye infections result in blindness if not properly treated; they accounted for the vast majority of infections in children in homes for the blind in the pre-antibiotic era. Neisseria gonorrhoeae infects the eyes of infants born to mothers with gonorrhea and can also infect the eyes of adults. Changes in sexual practices may account for the rise in adult gonococcal eye infections, although some cases seem to have occurred with no associated genital infection. As gonorrhea becomes increasingly difficult to treat, the consequences for the treatment of gonococcal blindness must be considered as well. Monocaprin was shown to be effective in rapidly killing N. gonorrhoeae, and is non-irritating in ocular models. Repeated passage in sub-lethal monocaprin induces neither resistance in gonococci nor genomic mutations that are suggestive of resistance. Here, we show that 1 mM monocaprin kills 100% of N. gonorrhoeae in 2 min, and is equally effective against N. meningitidis, a rare cause of ophthalmia neonatorum that is potentially lethal. Monocaprin at 1 mM also completely kills Staphylococcus aureus after 60 min, and 25 mM kills 80% of Pseudomonas aeruginosa after 360 min. Previously, 1 mM monocaprin was shown to eliminate Chlamydia trachomatis in 5 min. Monocaprin is, therefore, a promising active ingredient in the treatment and prophylaxis of keratitis, especially considering the growing threat of gonococcal blindness due to antimicrobial resistance. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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11 pages, 1026 KiB

Open AccessArticle

Trends in Neisseria gonorrhoeae Antimicrobial Resistance over a Ten-Year Surveillance Period, Johannesburg, South Africa, 2008–2017

by Ranmini Kularatne, Venessa Maseko, Lindy Gumede and Tendesayi Kufa

Antibiotics 2018, 7(3), 58; https://doi.org/10.3390/antibiotics7030058 - 12 Jul 2018

Cited by 27 | Viewed by 5241

Abstract

Background: In South Africa, sexually transmitted infections (STIs) are managed through a syndromic approach at primary healthcare centres (PHCs). Neisseria gonorrhoeae is the predominant cause of male urethritis syndrome. We describe antimicrobial resistance patterns and trends in Neisseria gonorrhoeae during a ten-year surveillance period at a large PHC in Johannesburg. Methods: Neisseria gonorrhoeae was cultured from genital discharge swab specimens obtained from consenting adult patients presenting at the Alexandra Health Centre in Johannesburg between 2008 and 2017. Isolates were tested for antimicrobial susceptibility by Etest™ (cefixime, ceftriaxone, ciprofloxacin) or agar dilution (penicillin, tetracycline, azithromycin). Results: During the period of surveillance, high-level resistance prevalence increased from 30% to 51% for penicillin (p-value for trend < 0.001), 75% to 83% for tetracycline (p-value for trend = 0.008), and 25% to 69% for ciprofloxacin (p-value for trend < 0.001). Analysis did not reveal high-level resistance to spectinomycin or a minimum inhibitory concentration (MIC) creep for extended-spectrum cephalosporins, and the prevalence of intermediate-resistance to azithromycin was less than 5%. Conclusions: High prevalence resistance to penicillin, tetracycline, and ciprofloxacin in N. gonorrhoeae obviates their use in future national treatment algorithms for genital discharge. It is essential to continue monitoring for emerging resistance to currently recommended antimicrobial therapy in this rapidly evolving pathogen. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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10 pages, 4855 KiB

Open AccessArticle

Neisseria gonorrhoeae Aggregation Reduces Its Ceftriaxone Susceptibility

by Liang-Chun Wang, Madeline Litwin, Zahraossadat Sahiholnasab, Wenxia Song and Daniel C. Stein

Antibiotics 2018, 7(2), 48; https://doi.org/10.3390/antibiotics7020048 - 15 Jun 2018

Cited by 11 | Viewed by 5840

Abstract

Antibiotic resistance in Neisseria gonorrhoeae (GC) has become an emerging threat worldwide and heightens the need for monitoring treatment failures. N. gonorrhoeae, a gram-negative bacterium responsible for gonorrhea, infects humans exclusively and can form aggregates during infection. While minimal inhibitory concentration (MIC) tests are often used for determining antibiotic resistance development and treatment, the knowledge of the true MIC in individual patients and how it relates to this laboratory measure is not known. We examined the effect of aggregation on GC antibiotic susceptibility and the relationship between bacterial aggregate size and their antibiotic susceptibility. Aggregated GC have a higher survival rate when treated with ceftriaxone than non-aggregated GC, with bacteria in the core of the aggregates surviving the treatment. GC lacking opacity-associated protein or pili, or expressing a truncated lipooligosaccharide, three surface molecules that mediate GC-GC interactions, reduce both aggregation and ceftriaxone survival. This study demonstrates that the aggregation of N. gonorrhoeae can reduce the susceptibility to antibiotics, and suggests that antibiotic utilization can select for GC surface molecules that promote aggregation which in turn drive pathogen evolution. Inhibiting aggregation may be a potential way of increasing the efficacy of ceftriaxone treatment, consequently reducing treatment failure. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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Review

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14 pages, 544 KiB

Open AccessReview

Antibiotic Targets in Gonococcal Cell Wall Metabolism

by Krizia M. Pérez Medina and Joseph P. Dillard

Antibiotics 2018, 7(3), 64; https://doi.org/10.3390/antibiotics7030064 - 21 Jul 2018

Cited by 3 | Viewed by 6047

Abstract

The peptidoglycan cell wall that encloses the bacterial cell and provides structural support and protection is remodeled by multiple enzymes that synthesize and cleave the polymer during growth. This essential and dynamic structure has been targeted by multiple antibiotics to treat gonococcal infections. Up until now, antibiotics have been used against the biosynthetic machinery and the therapeutic potential of inhibiting enzymatic activities involved in peptidoglycan breakdown has not been explored. Given the major antibiotic resistance problems we currently face, it is crucial to identify other possible targets that are key to maintaining cell integrity and contribute to disease development. This article reviews peptidoglycan as an antibiotic target, how N. gonorrhoeae has developed resistance to currently available antibiotics, and the potential of continuing to target this essential structure to combat gonococcal infections by attacking alternative enzymatic activities involved in cell wall modification and metabolism. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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15 pages, 1714 KiB

Open AccessReview

Epidemiological Trends of Antibiotic Resistant Gonorrhoea in the United Kingdom

by Lilith K. Whittles, Peter J. White, John Paul and Xavier Didelot

Antibiotics 2018, 7(3), 60; https://doi.org/10.3390/antibiotics7030060 - 13 Jul 2018

Cited by 26 | Viewed by 10957

Abstract

Gonorrhoea is one of the most common sexually-transmitted bacterial infections, globally and in the United Kingdom. The levels of antibiotic resistance in gonorrhoea reported in recent years represent a critical public health issue. From penicillins to cefixime, the gonococcus has become resistant to all antibiotics that have been previously used against it, in each case only a matter of years after introduction as a first-line therapy. After each instance of resistance emergence, the treatment recommendations have required revision, to the point that only a few antibiotics can reliably be prescribed to treat infected individuals. Most countries, including the UK, now recommend that gonorrhoea be treated with a dual therapy combining ceftriaxone and azithromycin. While this treatment is still currently effective for the vast majority of cases, there are concerning signs that this will not always remain the case, and there is no readily apparent alternative. Here, we review the use of antibiotics and epidemiological trends of antibiotic resistance in gonorrhoea from surveillance data over the past 15 years in the UK and describe how surveillance could be improved. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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10 pages, 1432 KiB

Open AccessReview

Future Prospects for Neisseria gonorrhoeae Treatment

by Beatriz Suay-García and María Teresa Pérez-Gracia

Antibiotics 2018, 7(2), 49; https://doi.org/10.3390/antibiotics7020049 - 15 Jun 2018

Cited by 47 | Viewed by 13560

Abstract

Gonorrhea is a sexually transmitted disease with a high morbidity burden. Incidence of this disease is rising due to the increasing number of antibiotic-resistant strains. Neisseria gonorrhoeae has shown an extraordinary ability to develop resistance to all antimicrobials introduced for its treatment. In fact, it was recently classified as a “Priority 2” microorganism in the World Health Organization (WHO) Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery and Development of New Antibiotics. Seeing as there is no gonococcal vaccine, control of the disease relies entirely on prevention, diagnosis, and, especially, antibiotic treatment. Different health organizations worldwide have established treatment guidelines against gonorrhea, mostly consisting of dual therapy with a single oral or intramuscular dose. However, gonococci continue to develop resistances to all antibiotics introduced for treatment. In fact, the first strain of super-resistant N.gonorrhoeae was recently detected in the United Kingdom, which was resistant to ceftriaxone and azithromycin. The increase in the detection of resistant gonococci may lead to a situation where gonorrhea becomes untreatable. Seeing as drug resistance appears to be unstoppable, new treatment options are necessary in order to control the disease. Three approaches are currently being followed for the development of new therapies against drug-resistant gonococci: (1) novel combinations of already existing antibiotics; (2) development of new antibiotics; and (3) development of alternative therapies which might slow down the appearance of resistances. N. gonorrhoeae is a public health threat due to the increasing number of antibiotic-resistant strains. Current treatment guidelines are already being challenged by this superbug. This has led the scientific community to develop new antibiotics and alternative therapies in order to control this disease. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)

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