Neisseria gonorrhoeae antimicrobial resistance (AMR) monthly UPDATES - February, 2019

Neisseria gonorrhoeae antimicrobial resistance (AMR) monthly UPDATES

February, 2019

Recommendations



Ocular Prophylaxis for Gonococcal Ophthalmia Neonatorum: US Preventive Services Task Force Reaffirmation Recommendation Statement.

US Preventive Services Task Force, Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW Jr, Kemper AR, Kubik M, Landefeld CS, Mangione CM, Silverstein M, Simon MA, Tseng CW, Wong JB. (Full Text)

JAMA. 2019 Jan 29;321(4):394-398. doi: 10.1001/jama.2018.21367.

Abstract

IMPORTANCE:

In the United States, the rate of gonococcal ophthalmia neonatorum was an estimated 0.4 cases per 100 000 live births per year from 2013 to 2017. Gonococcal ophthalmia neonatorum can cause corneal scarring, ocular perforation, and blindness as early as 24 hours after birth. In the absence of ocular prophylaxis, transmission rates of gonococcal infection from mother to newborn are 30% to 50%.



OBJECTIVE:

To reaffirm the US Preventive Services Task Force (USPSTF) 2011 recommendation on ocular prophylaxis for gonococcal ophthalmia neonatorum.



EVIDENCE REVIEW:

The USPSTF commissioned a reaffirmation evidence update to identify new and substantial evidence sufficient enough to change its prior recommendation.



FINDINGS:

Using a reaffirmation process, the USPSTF found no new data that would change its previous conclusion that topical ocular prophylaxis is effective in preventing gonococcal ophthalmia neonatorum and related ocular conditions. The USPSTF found no new data that would change its previous conclusion that there is convincing evidence that topical ocular prophylaxis of all newborns is not associated with serious harms. Therefore, the USPSTF reaffirms its previous conclusion that there is convincing evidence that topical ocular prophylaxis for all newborns provides substantial benefit.



CONCLUSIONS AND RECOMMENDATION:

The USPSTF recommends prophylactic ocular topical medication for all newborns to prevent gonococcal ophthalmia neonatorum. (A recommendation).

 

Reviews and Commentary

Using genomics to understand antimicrobial resistance and transmission in Neisseria gonorrhoeae.

Sánchez-Busó L, Harris SR. (Full Text)

Microb Genom. 2019 Jan 30. doi: 10.1099/mgen.0.000239. [Epub ahead of print]

Abstract

Gonorrhoea infections are on the increase and strains that are resistant to all antimicrobials used to treat the disease have been found worldwide. These observations encouraged the World Health Organization to include Neisseria gonorrhoeae on their list of high-priority organisms in need of new treatments. Fortunately, concurrent resistance to both antimicrobials used in dual therapy is still rare. The fight against antimicrobial resistance (AMR) must begin from an understanding of how it evolves and spreads in sexual networks. Genome-based analyses have allowed the study of the gonococcal population dynamics and transmission, giving a novel perspective on AMR gonorrhoea. Here, we will review past, present and future treatment options for gonorrhoea and explain how genomics is helping to increase our understanding of the changing AMR and transmission landscape. This article contains data hosted by Microreact.

Epidemiology and Surveillance

Typing and antimicrobial susceptibility of 134 Neisseria gonorrhoeae strains from Southern Spain.

Cobo F, Cabezas-Fernández MT, Avivar C. (Full Text)

Microb Genom. 2019 Jan 30. doi: 10.1099/mgen.0.000239. [Epub ahead of print]

Abstract

OBJECTIVE:

Last guidelines have recommended the introduction of dual antimicrobial therapy in order to avoid treatment failure. In the present report, the susceptibility to some antibiotics was evaluated, and the typing of Neisseria gonorrhoeae strains was performed.



METHODS:

Gonococcal isolates were tested for susceptibility according to the recommendations of both CLSI and EUCAST. A total of 134 isolates were typed by the NG-MAST technique.



RESULTS:

Seventy-two different N. gonorrhoeae types were found, and the most frequent types obtained were ST 1407, ST 14958, ST 7192, ST 13251 and ST 5405. If CLSI/EUCAST criteria were applied, a ST 9807 type was found nonsusceptible to ceftriaxone and cefixime (MIC 0.5 mg/L), and a ST 12800 type was found nonsusceptible only to cefixime (MIC 0.25 mg/L). When only EUCAST breakpoints were taken into account, three strains were also resistant to cefixime (MIC 0.25 mg/L) and three isolates were resistant to ceftriaxone (MIC 0.19, 0.16 and 0.25 mg/L, respectively). The majority of strains were resistant to ciprofloxacin (68.6%), and all N. gonorrhoeae strains were susceptible to spectinomycin; 9.7% of isolates were resistant to azithromycin.



CONCLUSIONS:

Molecular typing may be a useful tool to predict antimicrobial resistance. High rates of resistance to penicillin, tetracycline and ciprofloxacin were found in this area. It is highly recommended to carry out antimicrobial susceptibility in all gonorrhoea cases and to identify treatment failures to verify emerging resistance.

Novel detection strategies and diagnostics

A multisite implementation of a real-time polymerase chain reaction assay to predict ciprofloxacin susceptibility in Neisseria gonorrhoeae.

Ellis O, Hemarajata P, Shahkolahi A, Masinde G, Buchs K, Humphries RM, Klausner JD. (Full Text)

Diagn Microbiol Infect Dis. 2019 Jan 14. pii: S0732-8893(19)30028-8. doi: 10.1016/j.diagmicrobio.2018.12.018. [Epub ahead of print]

Abstract

There are no commercially available Food and Drug Administration-cleared rapid tests for Neisseria gonorrhoeae antimicrobial susceptibility testing. This study evaluated the performance of a laboratory-developed real-time polymerase chain reaction assay for genotyping the gyrA gene to determine antimicrobial susceptibility to ciprofloxacin. Validation and clinical performance of the gyrA assay were evaluated across 3 geographic locations (Los Angeles, San Francisco, Philadelphia). Following validation, clinical specimens were collected in Aptima Combo2® CT/NG transport medium from asymptomatic persons who tested positive for Neisseria gonorrhoeae and evaluated for assay percent reportable (i.e., proportion of N. gonorrhoeae-positive specimens that yielded a gyrA genotype). The percentage of gyrA genotyping results differed by laboratory and specimen type. The proportion of specimens that were reportable was best for urine/genital specimens (genotyped = 76.4% (95% confidence interval, 69.9-82%)) followed by rectal (genotyped = 67.2% (95% confidence interval, 63.4-70.6%)) and then pharyngeal specimens (genotyped = 36.1%, (95% confidence interval, 31.9-40.5%)). Overall, asymptomatic patients with N. gonorrhoeae yielded an interpretable genotype 57.2% (784/1370) of the time, of which 480 were wild-type gyrA, resulting in 61% (480/784) being potentially treatable with ciprofloxacin.

Novel antibiotics, mechanisms, vaccine, and other advances

Evolution of the exclusively human pathogen Neisseria gonorrhoeae: Human-specific engagement of immunoregulatory Siglecs.

Landig CS, Hazel A, Kellman BP, Fong JJ, Schwarz F, Agarwal S, Varki N, Massari P, Lewis NE, Ram S, Varki A. (Full Text)

Evol Appl. 2019 Jan 3;12(2):337-349. doi: 10.1111/eva.12744. eCollection 2019 Feb.

Abstract

Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host sialic acids that cap and mask lipooligosaccharide termini, while restricting complement activation. We hypothesized that gonococci selectively target human anti-inflammatory sialic acid-recognizing Siglec receptors on innate immune cells to blunt host responses and that pro-inflammatory Siglecs and SIGLEC pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. N. gonorrhoeae can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract--including Siglec-11 (inhibitory) and Siglec-16 (activating), which we detected for the first time on human cervical epithelium. Surprisingly, in addition to LOS sialic acid, we found that gonococcal porin (PorB) mediated binding to multiple Siglecs. PorB also bound preferentially to human Siglecs and not chimpanzee orthologs, modulating host immune reactions in a human-specific manner. Lastly, we studied the distribution of null SIGLEC polymorphisms in a Namibian cohort with a high prevalence of gonorrhea and found that uninfected women preferentially harbor functional SIGLEC16 alleles encoding an activating immune receptor. These results contribute to the understanding of the human specificity of N. gonorrhoeae and how it evolved to evade the human immune defense.

 

Neisseria gonorrhoeae evades autophagic killing by downregulating CD46-cyt1 and remodeling lysosomes.

Kim WJ, Mai A, Weyand NJ, Rendón MA, Van Doorslaer K, So M. (Full Text)

PLoS Pathog. 2019 Feb 12;15(2):e1007495. doi: 10.1371/journal.ppat.1007495. [Epub ahead of print]

Abstract

The Gram-negative human pathogen N. gonorrhoeae (Ngo) quickly attaches to epithelial cells, and large numbers of the bacteria remain on the cell surface for prolonged periods. Ngo invades cells but few viable intracellular bacteria are recovered until later stages of infection, leading to the assumption that Ngo is a weak invader. On the cell surface, Ngo quickly recruits CD46-cyt1 to the epithelial cell cortex directly beneath the bacteria and causes its cleavage by metalloproteinases and Presenilin/γSecretease; how these interactions affect the Ngo lifecycle is unknown. Here, we show Ngo induces an autophagic response in the epithelial cell through CD46-cyt1/GOPC, and this response kills early invaders. Throughout infection, the pathogen slowly downregulates CD46-cyt1 and remodeling of lysosomes, another key autophagy component, and these activities ultimately promote intracellular survival. We present a model on the dynamics of Ngo infection and describe how this dual interference with the autophagic pathway allows late invaders to survive within the cell.

 

The Pathogenic Neisseria Use a Streamlined Set of Peptidoglycan Degradation Proteins for Peptidoglycan Remodeling, Recycling, and Toxic Fragment Release.

Schaub RE, Dillard JP. (Full Text)

Front Microbiol. 2019 Jan 31;10:73. doi: 10.3389/fmicb.2019.00073. eCollection 2019.

Abstract

Neisseria gonorrhoeae and Neisseria meningitidis release peptidoglycan (PG) fragments from the cell as the bacteria grow. For N. gonorrhoeae these PG fragments are known to cause damage to human Fallopian tube tissue in organ culture that mimics the damage seen in patients with pelvic inflammatory disease. N. meningitidis also releases pro-inflammatory PG fragments, but in smaller amounts than those from N. gonorrhoeae. It is not yet known if PG fragment release contributes to the highly inflammatory conditions of meningitis and meningococcemia caused by N. meningitidis. Examination of the mechanisms of PG degradation and recycling identified proteins required for these processes. In comparison to the model organism E. coli, the pathogenic Neisseria have far fewer PG degradation proteins, and some of these proteins show differences in subcellular localization compared to their E. coli homologs. In particular, some N. gonorrhoeae PG degradation proteins were demonstrated to be in the outer membrane while their homologs in E. coli were found free in the periplasm or in the cytoplasm. The localization of two of these proteins was demonstrated to affect PG fragment release. Another major factor for PG fragment release is the allele of ampG. Gonococcal AmpG was found to be slightly defective compared to related PG fragment permeases, thus leading to increased release of PG. A number of additional PG-related factors affect other virulence functions in Neisseria. Endopeptidases and carboxypeptidases were found to be required for type IV pilus production and resistance to hydrogen peroxide. Also, deacetylation of PG was required for virulence of N. meningitidis as well as normal cell size. Overall, we describe the processes involved in PG degradation and recycling and how certain characteristics of these proteins influence the interactions of these pathogens with their host.



Modelling the in-host dynamics of Neisseria gonorrhoeae infection.

Jayasundara P, Regan DG, Seib KL, Jayasundara D, Wood JG. (Full Text)

Pathog Dis. 2019 Feb 16. pii: ftz008. doi: 10.1093/femspd/ftz008. [Epub ahead of print]

Abstract

The bacterial species Neisseria gonorrhoeae (NG) has evolved to replicate effectively and exclusively in human epithelia, with its survival dependent on complex interactions between bacteria, host cells and antimicrobial agents. A better understanding of these interactions is needed to inform development of new approaches to gonorrhoea treatment and prevention but empirical studies have proven difficult, suggesting a role for mathematical modelling. Here we describe an in-host model of progression of untreated male symptomatic urethral infection, including NG growth and interactions with epithelial cells and neutrophils, informed by in vivo and in vitro studies. The model reproduces key observations on bacterial load and clearance and we use multivariate sensitivity analysis to refine plausible ranges for model parameters. Model variants are also shown to describe mouse infection dynamics with altered parameter ranges that correspond to observed differences between human and mouse infection. Our results highlight the importance of NG internalisation, particularly within neutrophils, in sustaining infection in the human model, with ∼80% of the total NG population internalised from day 25 on. This new mechanistic model of in-host NG infection dynamics should also provide a platform for future studies relating to antimicrobial treatment and resistance and infection at other anatomical sites.

Genus-Wide Comparative Genomics Analysis of Neisseria to Identify New Genes Associated with Pathogenicity and Niche Adaptation of Neisseria Pathogens.

Lu QF, Cao DM, Su LL, Li SB, Ye GB, Zhu XY, Wang JP. (Full Text)

Int J Genomics. 2019 Jan 15;2019:6015730. doi: 10.1155/2019/6015730. eCollection 2019.

Abstract

N. gonorrhoeae and N. meningitidis, the only two human pathogens of Neisseria, are closely related species. But the niches they survived in and their pathogenic characteristics are distinctly different. However, the genetic basis of these differences has not yet been fully elucidated. In this study, comparative genomics analysis was performed based on 15 N. gonorrhoeae, 75 N. meningitidis, and 7 nonpathogenic Neisseriagenomes. Core-pangenome analysis found 1111 conserved gene families among them, and each of these species groups had opening pangenome. We found that 452, 78, and 319 gene families were unique in N. gonorrhoeaeN. meningitidis, and both of them, respectively. Those unique gene families were regarded as candidates that related to their pathogenicity and niche adaptation. The relationships among them have been partly verified by functional annotation analysis. But at least one-third genes for each gene set have not found the certain functional information. Simple sequence repeat (SSR), the basis of gene phase variation, was found abundant in the membrane or related genes of each unique gene set, which may facilitate their adaptation to variable host environments. Protein-protein interaction (PPI) analysis found at least five distinct PPI clusters in N. gonorrhoeae and four in N. meningitides, and 167 and 52 proteins with unknown function were contained within them, respectively.

Photo-inactivation of Neisseria gonorrhoeae: A paradigm changing approach for combating antibiotic-resistant gonococcal infection.

Wang Y, Ferrer-Espada R, Baglo Y, Goh XS, Held KD, Grad YH, Gu Y, Gelfand JA, Dai T. (Full Text)

J Infect Dis. 2019 Jan 9. doi: 10.1093/infdis/jiz018. [Epub ahead of print]

Abstract

Antimicrobial resistance in Neisseria gonorrhoeae is a major issue of public health, and there is a critical need for the development of new anti-gonococcal strategies. In this study, we investigated the effectiveness of antimicrobial blue light (aBL; 405 nm wavelength), an innovative non-pharmacological approach, for the inactivation of N. gonorrhoeae. Our findings indicated that aBL preferentially inactivated N. gonorrhoeae, including antibiotic-resistant strains, over human vaginal epithelial cells in vitro. Furthermore, no genotoxicity of aBL to the vaginal epithelial cells was observed at the radiant exposure for inactivating N. gonorrhoeae. aBL also effectively inactivated N. gonorrhoeae that had attached to and invaded into the vaginal epithelial cells in their co-cultures. No gonococcal resistance to aBL developed after 15 successive cycles of sub-therapeutic aBL inactivation. Endogenous aBL-activatable photosensitizing porphyrins in N. gonorrhoeae were identified and quantified using ultra-performance liquid chromatography, with coproporphyrin being the most abundant species in all the N. gonorrhoeae strains studied. Singlet oxygen was involved in aBL inactivation of N. gonorrhoeae. Taken together, aBL represents a potent potential treatment for antibiotic-resistant gonococcal infection.

In vitro activity of the novel oral antimicrobial SMT-571, with a new mechanism of action, against MDR and XDR Neisseria gonorrhoeae: future treatment option for gonorrhoea?

Jacobsson S, Mason C, Khan N, Meo P, Unemo M. (Full text)

J Antimicrob Chemother. 2019 Feb 18. pii: dkz060. doi: 10.1093/jac/dkz060. [Epub ahead of print]

Abstract

BACKGROUND:

Lack of effective treatment of gonorrhoea due to increasing antimicrobial resistance in Neisseria gonorrhoeae is a serious threat to the management and control of the infection. Novel antimicrobials are required to prevent the infection becoming untreatable.



OBJECTIVES:

Herein, we investigated the in vitro activity of a novel small-molecule antimicrobial with a new mechanism of action, SMT-571, against a large collection of clinical N. gonorrhoeae isolates (n = 228) and international gonococcal reference strains (n = 34), including numerous MDR and XDR gonococcal isolates.



METHODS:

MICs of SMT-571 were determined by agar dilution and MICs of ceftriaxone, cefixime, azithromycin, ciprofloxacin, ampicillin, spectinomycin and tetracycline were determined by Etest.



RESULTS:

SMT-571 showed potent in vitro activity against all the tested N. gonorrhoeae isolates (n = 262). The MICs ranged from 0.064 to 0.125 mg/L and the MIC50, MIC90 and modal MIC were all 0.125 mg/L. No cross-resistance or correlation between the MICs of SMT-571 and comparator agents was seen.



CONCLUSIONS:

SMT-571 demonstrated potent in vitro activity against all tested gonococcal isolates and no cross-resistance to previously and currently used antimicrobials was seen. With its promising supplementary in vitro and in vivo preclinical data, including high levels of oral bioavailability, SMT-571 could be an effective option for the oral treatment of gonorrhoea. Randomized controlled clinical trials for gonorrhoea that examine the treatment efficacy, pharmacokinetics/pharmacodynamics, toxicity and safety of SMT-571, and include urogenital and extragenital (rectal and pharyngeal) samples, are crucial.