Choosing New Therapies for Gonorrhoea: We Need to Consider the Impact on the Pan- Neisseria Genome. A Viewpoint

Abstract

The development of new gonorrhoea treatment guidelines typically considers the resistance-inducing effect of the treatment only on Neisseria gonorrhoeae. Antimicrobial resistance in N. gonorrhoeae has, however, frequently first emerged in commensal Neisseria species and then been passed on to N. gonorrhoeae via transformation. This creates the rationale for considering the effect of gonococcal therapies on resistance in commensal Neisseria. We illustrate the benefits of this pan-Neisseria strategy by evaluating three contemporary treatment options for N. gonorrhoeae-ceftriaxone plus azithromycin, monotherapy with ceftriaxone and zoliflodacin.

Keywords: N. gonorrrhoeae; Neisseria; antimicrobial consumption; antimicrobial resistance; dual therapy.

Figure 1

A schematic illustration of select differences between the monospecies and pan-Neisseria approaches to evaluating the risk of inducing resistance of proposed antimicrobial therapy for N. gonorrhoeae (NG/G). The monospecies approach only considers the effects of the treatment on NG. It thus favours dual therapy with ceftriaxone (CRO) and azithromycin (AZM), as this combination minimises the risk of treatment failure that could result in resistance. In the pan-Neisseria approach, monotherapy is favoured, as this is highly efficacious at eradicating NG and does this without selecting for widespread resistance (red bacteria) to macrolides in commensal Neisseria 14 days post-therapy (second panel). The pan-Neisseria, but not the monospecies approach, is cognisant of the risk of the genes conferring macrolide resistance in commensal Neisseria being passed on to a NG reinfection via horizontal gene transfer (HGT; third panel). The rationale for only representing CRO and CRO/AZM as treatment options is that these are the predominant treatments currently recommended by the United States CDC and European IUSTI guidelines.

Figure 2

Model of relationship between zoliflodacin consumption for 3 indications and induction of zoliflodacin resistance in N. gonorrhoeae (NG: red) and commensal Neisseria (blue). Zoliflodacin is a promising, novel anti-gonococcal therapy that also shows promise for a range of other infections. Zoliflodacin (ZF) usage could select for AMR directly in NG via 1. ZF used to treat NG, 2. ZF used to treat other STIs and 3. ZF used to treat other infections. It could also select for AMR in commensal Neisseria via 4. ZF used to treat NG, 5. ZF used to treat other STIs or 6. ZF used to treat other infections. Each of these could select for ZF resistance in commensal Neisseria, which could then be transferred to NG via transformation (7). The probability of ZF inducing AMR in NG (1,2,3) and commensal species (4,5,6) could be determined via in vitro experiments. These experiments could also estimate the efficiency of transformation given the co-occurrence of NG and a specific commensal Neisseria (7). The commensal Neisseria in the figure is bigger than NG to reflect the orders of magnitude of the higher prevalence of commensal Neisseria.

Figure 3

Schematic illustration of the importance of considering the selection of antimicrobial resistance in N. gonorrhoeae (left) and commensal Neisseria (right) at both the individual (top) and population levels (bottom). Whereas dual therapy with ceftriaxone/azithromycin (AB; red arrows) eradicates N. gonorrhoeae in an infected individual, it only reduces the abundance of commensal Neisseria. The resilience of commensal Neisseria results in their returning to baseline abundance in a process that selects for resistant isolates. The greater the decline in abundance of commensal abundance, the greater the ‘force of resistance’ (grey arrows). At a population level, high exposure to ceftriaxone/azithromycin will push the prevalence of both N. gonorrhoeae and commensal Neisseria species below the equilibrium prevalences (100% for commensals and 0.1–10% for N. gonorrhoeae, depending on sexual network connectivity). This will select for resistance to these agents in both N. gonorrhoeae and commensal Neisseria. (CFU: colony forming units).

Figure 4

An illustration of individual- and population-level mechanisms that select for antimicrobial resistance (AMR) in commensal Neisseria, using the example of zoliflodacin (ZF). (A) In the individual level selection scenario (top), Martha takes ZF, and this eradicates the ZF-susceptible Neisseria (blue bacteria), leaving Martha with predominantly ZF-resistant Neisseria (red bacteria) post-treatment. (B) Recent studies have found that commensal Neisseria can be transmitted by kissing. Population-level selection of AMR by widespread use of ZF (bottom) works by eradicating the susceptible Neisseria from Paul and Pedro, leaving only resistant Neisseria to be transmitted by both of them to others.