High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: NovelpenAMosaic Allele in a Successful International Clone Causes Treatment Failure

ABSTRACTRecently, the firstNeisseria gonorrhoeaestrain (H041) highly resistant to the expanded-spectrum cephalosporins (ESCs) ceftriaxone and cefixime, which are the last remaining options for first-line gonorrhea treatment, was isolated in Japan. Here, we confirm and characterize a second strain (F89) with high-level cefixime and ceftriaxone resistance which was isolated in France and most likely caused a treatment failure with cefixime. F89 was examined using six species-confirmatory tests, antibiograms (33 antimicrobials),porBsequencing,N. gonorrhoeaemultiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of known gonococcal resistance determinants (penA,mtrR,penB,ponA, andpilQ). F89 was assigned to MLST sequence type 1901 (ST1901) and NG-MAST ST1407, which is a successful gonococcal clone that has spread globally. F89 has high-level resistance to cefixime (MIC = 4 μg/ml) and ceftriaxone (MIC = 1 to 2 μg/ml) and resistance to most other antimicrobials examined. A novelpenAmosaic allele (penA-CI), which waspenA-XXXIVwith an additional A501P alteration in penicillin-binding protein 2, was the primary determinant for high-level ESC resistance, as determined by transformation into a set of recipient strains.N. gonorrhoeaeappears to be emerging as a superbug, and in certain circumstances and settings, gonorrhea may become untreatable. Investigations of the biological fitness and enhanced understanding and monitoring of the ESC-resistant clones and their international transmission are required. Enhanced disease control activities, antimicrobial resistance control and surveillance worldwide, and public health response plans for global (and national) perspectives are also crucial. Nevertheless, new treatment strategies and/or drugs and, ideally, a vaccine are essential to develop for efficacious gonorrhea management.

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Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00325-11 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3538-3545 ◽

Cited By ~ 413

Author(s):

Makoto Ohnishi ◽

Daniel Golparian ◽

Ken Shimuta ◽

Takeshi Saika ◽

Shinji Hoshina ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Resistance Mechanisms ◽

New Drugs ◽

Public Health Response ◽

Detailed Characterization ◽

Content Type ◽

Resistance Determinants ◽

Confirmatory Tests ◽

High Level

ABSTRACTRecently, the firstNeisseria gonorrhoeaestrain (H041) that is highly resistant to the extended-spectrum cephalosporin (ESC) ceftriaxone, the last remaining option for empirical first-line treatment, was isolated. We performed a detailed characterization of H041, phenotypically and genetically, to confirm the finding, examine its antimicrobial resistance (AMR), and elucidate the resistance mechanisms. H041 was examined using seven species-confirmatory tests, antibiograms (30 antimicrobials),porBsequencing,N. gonorrhoeaemultiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of ESC resistance determinants (penA,mtrR,penB,ponA, andpilQ). Transformation, using appropriate recipient strains, was performed to confirm the ESC resistance determinants. H041 was assigned to serovar Bpyust, MLST sequence type (ST) ST7363, and the new NG-MAST ST4220. H041 proved highly resistant to ceftriaxone (2 to 4 μg/ml, which is 4- to 8-fold higher than any previously described isolate) and all other cephalosporins, as well as most other antimicrobials tested. A newpenAmosaic allele caused the ceftriaxone resistance. In conclusion,N. gonorrhoeaehas now shown its ability to also develop ceftriaxone resistance. Although the biological fitness of ceftriaxone resistance inN. gonorrhoeaeremains unknown,N. gonorrhoeaemay soon become a true superbug, causing untreatable gonorrhea. A reduction in the global gonorrhea burden by enhanced disease control activities, combined with wider strategies for general AMR control and enhanced understanding of the mechanisms of emergence and spread of AMR, which need to be monitored globally, and public health response plans for global (and national) perspectives are important. Ultimately, the development of new drugs for efficacious gonorrhea treatment is necessary.

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In VitroActivity of the New Fluoroketolide Solithromycin (CEM-101) against a Large Collection of Clinical Neisseria gonorrhoeae Isolates and International Reference Strains, Including Those with High-Level Antimicrobial Resistance: Potential Treatment Option for Gonorrhea?

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00036-12 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2739-2742 ◽

Cited By ~ 63

Author(s):

Daniel Golparian ◽

Prabhavathi Fernandes ◽

Makoto Ohnishi ◽

Jörgen S. Jensen ◽

Magnus Unemo

Keyword(s):

Neisseria Gonorrhoeae ◽

Treatment Option ◽

Treatment Options ◽

Effective Treatment Option ◽

Content Type ◽

New Treatment ◽

High Level ◽

Drug Resistant Strains ◽

Reference Strains

ABSTRACTGonorrhea may become untreatable, and new treatment options are essential. We investigated thein vitroactivity of the first fluoroketolide, solithromycin. ClinicalNeisseria gonorrhoeaeisolates and reference strains (n= 246), including the two extensively drug-resistant strains H041 and F89 and additional isolates with clinical cephalosporin resistance and multidrug resistance, were examined. The activity of solithromycin was mainly superior to that of other antimicrobials (n= 10) currently or previously recommended for gonorrhea treatment. Solithromycin might be an effective treatment option for gonorrhea.

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Global Network Analysis of Neisseria gonorrhoeae Identifies Coordination between Pathways, Processes, and Regulators Expressed during Human Infection

mSystems ◽

10.1128/msystems.00729-19 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Ryan McClure ◽

Ashwini Sunkavalli ◽

Phillip M. Balzano ◽

Paola Massari ◽

Christine Cho ◽

...

Keyword(s):

Network Analysis ◽

Neisseria Gonorrhoeae ◽

Treatment Strategies ◽

High Morbidity ◽

Gene Coexpression Network ◽

Transmitted Infection ◽

Content Type ◽

Sexually Transmitted ◽

Gene Coexpression ◽

New Treatment

ABSTRACT Neisseria gonorrhoeae is a Gram-negative diplococcus that is responsible for the sexually transmitted infection gonorrhea, a high-morbidity disease in the United States and worldwide. Over the past several years, N. gonorrhoeae strains resistant to antibiotics used to treat this infection have begun to emerge across the globe. Thus, new treatment strategies are needed to combat this organism. Here, we utilized N. gonorrhoeae transcriptomic data sets, including those obtained from natural infection of the human genital tract, to infer the first global gene coexpression network of this pathogen. Interrogation of this network revealed genes central to the network that are likely critical for gonococcal growth, metabolism, and virulence, including genes encoding hypothetical proteins expressed during mucosal infection. In addition, network analysis revealed overlap in the response of N. gonorrhoeae to incubation with neutrophils and exposure to hydrogen peroxide stress in vitro. Network analysis also identified new targets of the gonococcal global regulatory protein Fur, while examination of the network neighborhood of genes allowed us to assign additional putative categories to several proteins. Collectively, the characterization of the first gene coexpression network for N. gonorrhoeae described here has revealed new regulatory pathways and new categories for proteins and has shown how processes important to gonococcal infection in both men and women are linked. This information fills a critical gap in our understanding of virulence strategies of this obligate human pathogen and will aid in the development of new treatment strategies for gonorrhea. IMPORTANCE Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, a disease with high morbidity worldwide with an estimated 87 million cases annually. Current therapeutic and pharmacologic approaches to treat gonorrhea have been compromised by increased antibiotic resistance worldwide, including to the most recent FDA-approved antibiotic. New treatment strategies are urgently needed to combat this organism. In this study, we used network analysis to interrogate and define the coordination of pathways and processes in N. gonorrhoeae. An analysis of the gonococcal network was also used to assign categories to genes and to expand our understanding of regulatory strategies. Network analysis provides important insights into pathogenic mechanisms of this organism that will guide the design of new strategies for disease treatment.

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Whole-Genome Phylogenomic Heterogeneity of Neisseria gonorrhoeae Isolates with Decreased Cephalosporin Susceptibility Collected in Canada between 1989 and 2013

Journal of Clinical Microbiology ◽

10.1128/jcm.02589-14 ◽

2014 ◽

Vol 53 (1) ◽

pp. 191-200 ◽

Cited By ~ 78

Author(s):

Walter Demczuk ◽

Tarah Lynch ◽

Irene Martin ◽

Gary Van Domselaar ◽

Morag Graham ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Large Scale ◽

Epidemiological Studies ◽

23S Rrna ◽

Genome Comparison ◽

Whole Genome ◽

Content Type ◽

Genomic Epidemiology ◽

High Level ◽

Sequence Types

A large-scale, whole-genome comparison of CanadianNeisseria gonorrhoeaeisolates with high-level cephalosporin MICs was used to demonstrate a genomic epidemiology approach to investigate strain relatedness and dynamics. Although current typing methods have been very successful in tracing short-chain transmission of gonorrheal disease, investigating the temporal evolutionary relationships and geographical dissemination of highly clonal lineages requires enhanced resolution only available through whole-genome sequencing (WGS). Phylogenomic cluster analysis grouped 169 Canadian strains into 12 distinct clades. While someN. gonorrhoeaemultiantigen sequence types (NG-MAST) agreed with specific phylogenomic clades or subclades, other sequence types (ST) and closely related groups of ST were widely distributed among clades. Decreased susceptibility to extended-spectrum cephalosporins (ESC-DS) emerged among a group of diverse strains in Canada during the 1990s with a variety of nonmosaicpenAalleles, followed in 2000/2001 with thepenAmosaic X allele and then in 2007 with ST1407 strains with thepenAmosaic XXXIV allele. Five genetically distinct ESC-DS lineages were associated withpenAmosaic X, XXXV, and XXXIV alleles and nonmosaic XII and XIII alleles. ESC-DS with coresistance to azithromycin was observed in 5 strains with 23S rRNA C2599T or A2143G mutations. As the costs associated with WGS decline and analysis tools are streamlined, WGS can provide a more thorough understanding of strain dynamics, facilitate epidemiological studies to better resolve social networks, and improve surveillance to optimize treatment for gonorrheal infections.

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Not your typical “historian”

Disaster Prevention and Management An International Journal ◽

10.1108/dpm-05-2018-0136 ◽

2018 ◽

Vol 27 (5) ◽

pp. 523-533

Author(s):

Adrienne Lefevre ◽

Madison Walter-Garcia ◽

Kimberly Hanson ◽

Julia Smith-Easley

Keyword(s):

Public Health ◽

Lessons Learned ◽

Incident Management ◽

Public Health Response ◽

Content Type ◽

Incident Command ◽

Health Community ◽

Health Response ◽

Decision Making Processes

Purpose In the incident command system (ICS) structure, response documentation is formally found within the planning section. However, longer term emergency responses have demonstrated the need for a flexible and innovative role that encompasses a variety of activities, including response documentation, communications science, real-time evaluation of major themes, and information management. The paper aims to discuss this issue. Design/methodology/approach This need can be universally met through the functional role of “Historian,” a term specific to ICS, or in the case of public health response, incident management system (IMS). It should be noted that the Historian role discussed is not related to the academic study of history, but to archiving key successes and challenges during a response. Ideally the Historian should be activated at the start of an emergency response and remain active to capture the overall picture of the response, including internal information, such as lessons learned, response activities, and decision-making processes. Findings The Historian compiles details of response activities that inform leadership, donors and external communications products while alleviating pressures on the planning section. The primary, minimum output of an IMS Historian is a response timeline, which notes major internal and external events during a response with emphasis on major themes, lessons learned, and creating a user-friendly interface to display this information (see the list “Abbreviated Example of Hurricane Matthew Response Timeline” in the text). Originality/value In a world with competing priorities and ongoing emergencies, the Historian’s role of archiving details of response efforts can help the international public health community to share lessons learned and contribute to lower morbidity and mortality among those affected by emergencies.

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Molecular Analyses of TEM Genes and Their Corresponding Penicillinase-Producing Neisseria gonorrhoeae Isolates in Bangkok, Thailand

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05665-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 916-920 ◽

Cited By ~ 32

Author(s):

Shu-ichi Nakayama ◽

Chanwit Tribuddharat ◽

Sasiprapa Prombhul ◽

Ken Shimuta ◽

Somporn Srifuengfung ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Public Health Problem ◽

Major Public Health Problem ◽

Sexual Network ◽

Genetic Event ◽

Content Type ◽

Extended Spectrum ◽

Resistance To Penicillin ◽

High Level ◽

International Awareness

ABSTRACTNeisseria gonorrhoeaeis a major public health problem globally, especially because the bacterium has developed resistance to most antimicrobials introduced for first-line treatment of gonorrhea. In the present study, 96N. gonorrhoeaeisolates with high-level resistance to penicillin from 121 clinical isolates in Thailand were examined to investigate changes related to their plasmid-mediated penicillin resistance and their molecular epidemiological relationships. A β-lactamase (TEM) gene variant,blaTEM-135, that may be a precursor in the transitional stage of a traditionalblaTEM-1gene into an extended-spectrum β-lactamase (ESBL), possibly causing high resistance to all extended-spectrum cephalosporins inN. gonorrhoeae, was identified. Clonal analysis using multilocus sequence typing (MLST) andN. gonorrhoeaemultiantigen sequence typing (NG-MAST) revealed the existence of a sexual network among patients from Japan and Thailand. Molecular analysis of theblaTEM-135gene showed that the emergence of this allele might not be a rare genetic event and that the allele has evolved in different plasmid backgrounds, which results possibly indicate that it is selected due to antimicrobial pressure. The presence of theblaTEM-135allele in the penicillinase-producingN. gonorrhoeaepopulation may call for monitoring for the possible emergence of ESBL-producingN. gonorrhoeaein the future. This study identified ablaTEMvariant (blaTEM-135) that is a possible intermediate precursor for an ESBL, which warrants international awareness.

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Lipid A’s Structure Mediates Neisseria gonorrhoeae Fitness during Experimental Infection of Mice and Men

mBio ◽

10.1128/mbio.00892-13 ◽

2013 ◽

Vol 4 (6) ◽

Cited By ~ 44

Author(s):

Marcia M. Hobbs ◽

James E. Anderson ◽

Jacqueline T. Balthazar ◽

Justin L. Kandler ◽

Russell W. Carlson ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Genital Tract ◽

Lipid A ◽

Female Genital Tract ◽

Treatment Strategies ◽

Wild Type ◽

Genital Tract Infection ◽

Content Type

ABSTRACT Phosphoethanolamine (PEA) on Neisseria gonorrhoeae lipid A influences gonococcal inflammatory signaling and susceptibility to innate host defenses in in vitro models. Here, we evaluated the role of PEA-decorated gonococcal lipid A in competitive infections in female mice and in male volunteers. We inoculated mice and men with mixtures of wild-type N. gonorrhoeae and an isogenic mutant that lacks the PEA transferase, LptA. LptA production conferred a marked survival advantage for wild-type gonococci in the murine female genital tract and in the human male urethra. Our studies translate results from test tube to animal model and into the human host and demonstrate the utility of the mouse model for studies of virulence factors of the human-specific pathogen N. gonorrhoeae that interact with non-host-restricted elements of innate immunity. These results validate the use of gonococcal LptA as a potential target for development of novel immunoprophylactic strategies or antimicrobial treatments. IMPORTANCE Gonorrhea is one of the most common bacterial sexually transmitted infections, and increasing antibiotic resistance threatens the use of currently available antimicrobial therapies. In this work, encompassing in vitro studies and in vivo studies of animal and human models of experimental genital tract infection, we document the importance of lipid A’s structure, mediated by a single bacterial enzyme, LptA, in enhancing the fitness of Neisseria gonorrhoeae. The results of these studies suggest that novel agents targeting LptA may offer urgently needed prevention or treatment strategies for gonorrhea.

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Trends in antimicrobial susceptibility for azithromycin and ceftriaxone in Neisseria gonorrhoeae isolates in Amsterdam, the Netherlands, between 2012 and 2015

Eurosurveillance ◽

10.2807/1560-7917.es.2017.22.1.30431 ◽

2017 ◽

Vol 22 (1) ◽

Cited By ~ 12

Author(s):

Carolien M Wind ◽

Maarten F Schim van der Loeff ◽

Alje P van Dam ◽

Henry JC de Vries ◽

Jannie J van der Helm

Keyword(s):

The Netherlands ◽

Neisseria Gonorrhoeae ◽

Treatment Strategies ◽

Sex Partners ◽

Hiv Status ◽

Transmitted Infection ◽

Sexually Transmitted ◽

New Treatment ◽

Sex With Men ◽

Infection Clinic

Resistance of Neisseria gonorrhoeae to azithromycin and ceftriaxone has been increasing in the past years. This is of concern since the combination of these antimicrobials is recommended as the first-line treatment option in most guidelines. To analyse trends in antimicrobial resistance, we retrospectively selected all consultations with a positive N. gonorrhoeae culture at the sexually transmitted infection clinic, Amsterdam, the Netherlands, from January 2012 through September 2015. Minimum inhibitory concentrations (MICs) for azithromycin and ceftriaxone were analysed per year, and determinants associated with decreased susceptibility to azithromycin (MIC > 0.25 mg/L) or ceftriaxone (MIC > 0.032 mg/L) were assessed. Between 2012 and 2015 azithromycin resistance (MIC > 0.5 mg/L) was around 1.2%, the percentage of isolates with intermediate MICs (> 0.25 and ≤ 0.5 mg/L) increased from 3.7% in 2012, to 8.6% in 2015. Determinants associated with decreased azithromycin susceptibility were, for men who have sex with men (MSM), infections diagnosed in the year 2014, two infected sites, and HIV status (HIV; associated with less decreased susceptibility); for heterosexuals this was having ≥ 10 sex partners (in previous six months). Although no ceftriaxone resistance (MIC > 0.125 mg/L) was observed during the study period, the proportion of isolates with decreased ceftriaxone susceptibility increased from 3.6% in 2012, to 8.4% in 2015. Determinants associated with decreased ceftriaxone susceptibility were, for MSM, infections diagnosed in 2014, and pharyngeal infections; and for heterosexuals, infections diagnosed in 2014 or 2015, being of female sex, and having ≥ 10 sex partners. Continued decrease of azithromycin and ceftriaxone susceptibility will threaten future treatment of gonorrhoea. Therefore, new treatment strategies are warranted.

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A simple model of COVID-19 explains disease severity and the effect of treatments

10.1101/2021.11.29.21267028 ◽

2021 ◽

Author(s):

Steven Sanche ◽

Tyler Cassidy ◽

Pinghan Chu ◽

Alan S. Perelson ◽

Ruy M. Ribeiro ◽

...

Keyword(s):

Disease Severity ◽

Treatment Strategies ◽

Clinical Findings ◽

Interferon Response ◽

Type I ◽

Infected Cells ◽

New Treatment ◽

High Level ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

ABSTRACTConsiderable effort was made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue. The model focuses on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or the lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation. It identifies the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and the conditional impact of treatments on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.

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Corynebacterium hindlerae sp. nov., derived from a human granuloma, which forms black colonies and black halos on modified Tinsdale medium but is not closely related to Corynebacterium diphtheriae and related taxa

INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY ◽

10.1099/ijsem.0.004919 ◽

2021 ◽

Vol 71 (8) ◽

Author(s):

Kathryn A. Bernard ◽

Tamara Burdz ◽

Ana Luisa Pacheco ◽

Deborah Wiebe ◽

Anne-Marie Bernier

Keyword(s):

Diphtheria Toxin ◽

Type Species ◽

Corynebacterium Diphtheriae ◽

Contact Tracing ◽

Public Health Response ◽

Potassium Tellurite ◽

Content Type ◽

Link Type ◽

Corynebacterium Ulcerans ◽

Health Response

Corynebacterium diphtheriae , Corynebacterium belfantii , Corynebacterium rouxii , Corynebacterium ulcerans , Corynebacterium pseudotuberculosis and Corynebacterium silvaticum are the only taxa from among ~121 Corynebacterium species deemed potentially able to harbour diphtheria tox genes. Subsequently tox-gene bearing species may potentially produce diphtheria toxin, which is linked to fatal respiratory distress if a pharyngeal pseudomembrane is formed or toxaemia develops in those unimmunized or under-immunized. Detection of diphtheria toxin-producing species may also invoke a public health response and contact tracing. Recovery of such species from the respiratory tract or other contaminated sources such as non-healing ulcerative wounds are expedited by use of differential and selective media such as modified Tinsdale medium (MTM). This medium is supplemented with potassium tellurite, which supresses most normal flora present in contaminated specimens, as well as l-cystine and thiosulphate. Most diphtheria-tox-gene bearing species grow well on MTM, producing black colonies with a black halo around each colony. This is due to an ability to produce cystinase in the presence of tellurite, cystine and thiosulphate, resulting in black tellurium deposits being observed in the agar. Other Corynebacterium species may/may not be able to grow at all in the presence of tellurite but if able to grow, will have small beige or brownish colonies which do not exhibit black halos. We describe here an unusual non-tox-gene-bearing isolate, NML 93-0612T, recovered from a human wrist granuloma, which produced black colonies with black halos on MTM agar but was otherwise distinguishable from Corynebacterium species which can bear tox genes. Distinctive features included its unusual colony morphology on MTM and sheep blood agar, by proteomic, biochemical and chemotaxonomic properties and by molecular methods. Its genome contained 2 680 694 bytes, a G+C content of 60.65 mol% with features consistent with the genus Corynebacterium and so represents a new species for which we propose the name Corynebacterium hindlerae sp. nov.

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