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Does Intense Sexually Transmitted Infection Screening Cause or Prevent Antimicrobial Resistance in Sexually Transmitted Infections? It Depends on One's Underlying Epistemology. A Viewpoint

Kenyon, Chris MBChB, MSc, MA, PhD∗,†

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Sexually Transmitted Diseases: August 2020 - Volume 47 - Issue 8 - p 506-510
doi: 10.1097/OLQ.0000000000001199

The incidence of sexually transmitted infections (STIs) and their resistance to antimicrobials are increasing in many populations around the world.1 This has led to calls for intensified STI screening and treatment efforts in high STI prevalence populations to reverse this trend.2,3 Some authors have argued that intensified screening is crucial to both reducing STI prevalence and antimicrobial resistance (AMR). Wi et al,2 for example, argue that “gonococcal AMR will only be effectively mitigated when the global gonorrhea burden is reduced. Increased detection and effective treatment of asymptomatic gonorrhea in general and pharyngeal gonorrhea in particular are critical, because these infections are potential gonococcal reservoirs in which AMR (especially extended spectrum cephalosporin AMR) can emerge. Oropharyngeal infections are prevalent, mostly asymptomatic, and more difficult to treat; accordingly, screening and treatment in high-risk patients are important.” Other authors have argued the opposite—increased screening in high prevalence populations is one of the drivers of AMR in Neisseria gonorrhoeae and other pathobionts.4–6 What explains these differences in opinion, and which is correct? In this viewpoint I propose that these radical differences in outlook stem in part from different conceptual frameworks of the determinants of STI prevalence and AMR. In the absence of strong evidence from randomized controlled trials (RCTs), we interpret the weaker evidence, such as that from observational studies, in different ways based on our underlying epistemologies. I contrast a predominantly biomedical individualist conceptual framework with a more ecological conceptual framework. I argue that if one's conceptual framework is based in biomedical individualism, then one is more likely to think that screening reduces STI prevalence and less likely to appreciate the connection between screening, antimicrobial exposure, and AMR than perspectives grounded in ecological conceptual frameworks (see Table 1). I acknowledge 2 major limitations upfront: first, all major STI conceptual frameworks include elements of both biomedical individualist- and ecological-conceptual frameworks and secondly, I may be wrong in attributing specific claims to particular conceptual frameworks. The primary objective is, thus, necessarily modest. I aim to see if, given the currently available evidence, the promotion of an intense screening approach is more logically consistent with a predominantly biomedical individualist—as opposed to a predominantly ecological conceptual framework. The focus is largely on screening for N. gonorrhoeae in men who have sex with men (MSM).

Select Key Differences Between Biomedical Individualist and Ecological Conceptual Frameworks

The Importance of Understanding What Is Driving the Current STI Epidemics and AMR in STIs: The Ecological Conceptual Framework

It is axiomatic that our underlying conceptual framework heavily influences the hypotheses we generate as well as how we gather and interpret evidence to test these hypotheses.7 It is, thus, crucial that we chose conceptual frameworks that include all the determinants of the outcomes of interest. Ecological and social processes are important determinants of both STI prevalence and the genesis and spread of AMR.8–10 As a result, the proponents of ecological conceptual frameworks argue that STI conceptual frameworks need to explicitly include ecological and social processes.8,11 Ecology is the formal study of the interdepencies between groups of organisms, populations, and species and their surroundings.12,13 As illustrated in Figure 1, it follows that an ecosocial framework for the determinants of STI prevalence and AMR is explicitly multilevel, including interactions at levels such as: subcellular, between microorganisms, individual humans, populations of humans in sexual networks and the social networks within which these are found.10,13

Figure 1:
Schematic illustration of differences between biomedical individualist- and ecological-conceptual frameworks for understanding the determinants of N. gonorrhoeae prevalence and the effect of intensive screening on gonococcal prevalence and genesis of AMR. In the ecological framework (right), gonococcal prevalence is a function of sexual network connectivity (black/green humans uninfected/infected, respectively). Intense screening leads to high antibiotic (AB) exposure particularly in the high gonorrhea/connectivity network. This generates a selection pressure for the emergence of AMR to the antibiotics used in N. gonorrhea (Ng) and even more so in commensal Neisseriae species. Resistance conferring DNA can then be shared between commensals and N. gonorrhoeae via transformation (bidirectional blue arrows). Screening has little long-term effect on gonococcal prevalence but a major effect on inducing AMR (red), as seen in the prevalence figures as well as at each ecological level (Neisseriae depicted as diplococci, wild-type commensal Neisseriae and N. gonorrhoeae indicated in tan-green and bright-green respectively, AMR strains in red). According to the Biomedical Individualist Conceptual Framework, AMR is the result of inadequate treatment or import via travel. Intensive screening, contact tracing and strengthened therapy are effective ways to reduce both gonococcal and AMR prevalence.

Determinants of STI Prevalence and Efficacy of Screening From an Ecological Conceptual Framework

Whereas individual-level parameters may influence which individuals in a given population acquire infection, it is population-level parameters that affect the presence and prevalence of infection to be acquired.

Sevgi Aral8

The ecological conceptual framework proponents argue that there is increasing evidence from cross sectional and longitudinal studies that STI prevalence is largely a function of population level processes, such as how connected a population's sexual network is.8,14 As a result, they argue that a standout reason why only a small number of national populations experienced generalized human immunodeficiency virus (HIV) epidemics was that these populations had more densely connected sexual networks than other populations.11,14,15 This higher network connectivity also parsimoniously explains why the prevalence of other STIs, such as syphilis, herpes simplex virus 2, and gonorrhea, were considerably higher than other populations prior to the HIV epidemic.11,16,17 It also helps explain how the widespread deaths from acquired immune deficiency syndrome (AIDS), in conjunction with behavior changes resulted in a shattering of sexual networks and a subsequent steep decline in STI incidence in these populations after the AIDS epidemic.18,19 In a very similar fashion, higher network connectivity goes a long way to explain the order of magnitude higher incidence of STIs in MSM compared with heterosexuals in high-income countries in the 1970s.11,20,21 As in Africa, this was followed by STI incidence crashing in the wake of the AIDS epidemic and the deaths and behavior change that ensued—both of which broke up sexual networks (Fig. 2).22 The current epidemics of STI in high-income countries are predominantly occurring in MSM and from an ecological perspective, are a logical consequence of factors, such as increases in partner number and declines in condom usage that have together resulted in a return to very dense sexual networks.1,11 For example, the behavioral and STI prevalence data from the Prevenir preexposure prophylaxis (PrEP) study in France is not unusual for HIV PrEP cohorts (Fig. 3). Participants reported 15 to 20 partners per 3 months and condom usage at last sex of around 20%.23 Seen from the perspective of an ecological framework, these behavioral parameters would translate into dense sex networks commensurate with the high incidence of chlamydia, gonorrhea, and syphilis seen in this cohort. Likewise, the ecological viewpoint would not be too surprised that the high STI incidence was apparently not reduced by 3 monthly screening/treatment of Prevenir participants23 (Fig. 3—a finding no different to that from a systematic review on the topic.24

Figure 2:
Estimated annual incidence of primary/secondary syphilis among MSM and men who have sex with women only (MSW) in the United States, 1963 to 2013. Changes in the approximate density of sexual networks of MSM is illustrated schematically based on11 (modified from11,21).
Figure 3:
Incidence of bacterial STIs and mean number of sex partners reported in prior 3 months in Prevenir PrEP Study23 (Graphic produced using data digitalized using WebPlotDigitizer 4.2).

Determinants of AMR and Resistogenicity of Screening From an Ecological Conceptual Framework

An ecological framework of the determinants of AMR would use a similar interconnected multilevel-level framework (Fig. 1).9 This would include AMR selection at the level of genes, clones, species, consortia of microbes, individual humans, and the 5 ecologic pathways to AMR described in the literature.13,25,26 One of these key ecological level pathways to gonococcal AMR is illustrated in Figure 1. In a high-connectivity population, intensive screening may temporarily reduce gonococcal prevalence below its equilibrium prevalence for this degree of connectivity. If a gonococcus acquired AMR in this setting, it would have a fitness advantage as this would enable it to return to the equilibrium prevalence.26 A well-established way that N. gonorrhoeae acquires AMR is via taking up resistance conferring DNA from commensal Neisseria.27–29 By selecting for AMR in commensal Neisseriae, the intensive antimicrobial exposure resulting from screening, thus, provides both the selection pressure for the spread of resistant gonococci, as well as the DNA to effect AMR.6,26 The ecological framework would thus actively search for evidence not only between antimicrobial consumption and homologous AMR in STIs such as N. gonorrhoeae [30, 31s] and Treponema pallidum [32s] but also in potential AMR donors, such as commensal Neisseriae.6 Taken together, these considerations would make those operating within an ecological conceptual framework reluctant to introduce intensive screening to reduce the prevalence of bacterial STIs until there was high-quality evidence that intense screening both reduced prevalence and did not induce AMR in N. gonorrhoeae, commensal Neisseriae or other bacteria (Table 1).4,26

Determinants of STI Prevalence and Efficacy of Screening From a Biomedical Individualist Conceptual Framework Perspective

For a variety of reasons, many branches of epidemiology, including STI epidemiology, have downplayed or ignored the population-level determinants of disease and have instead focused on individual humans or microbes as the fundamental level of analysis [7, 8, 11, 12, 33s]. Populations tend to be viewed as merely aggregates of individuals without inherent population-level attributes.8,12 As far as STI epidemiology is concerned, the extreme biomedical individualist conceptual framework perspective views STI prevalence as largely dependent on factors relating to biomedical interventions—such as the adequacy and intensity of STI screening and treatment, circumcision prevalence, condom use [2, 3, 34s, 35s]. The focus is downstream—on microbes and individuals and not population-level processes.10 Less attention is given to why STI incidence varies so dramatically between populations and within populations over time.10,11

Seen from a biomedical individualist perspective, increased screening and early treatment reduce the duration that STIs can be transmitted to others and thereby reduce the number of secondary infections [8, 35s]. They are, thus, seen as a logical way to reduce STI prevalence [34s].

Determinants of AMR and Resistogenicity of Screening From a Biomedical Individualist Perspective

From an individualistic perspective, the emergence of AMR in STIs is frequently portrayed as being close to an inevitable result of antimicrobial exposure—a new antigonococcal therapy is introduced and followed shortly, thereafter, by the emergence of homologous AMR.29 One key modifiable variable is optimal antimicrobial therapy that eradicates the STI with a low risk of inducing AMR in that STI.1,29 This provided the rationale for introducing dual ceftriaxone/azithromycin therapy for gonorrhea [1, 36s]. A further focus area of the biomedical individualist perspective has been the early detection of resistant isolates of N. gonorrhea related to risks, such as travel [37s–40s]. If these could be detected early and eliminated, then this could reduce the probability of AMR spreading [37s–40s].

If the major determinants of AMR are inadequate treatment and import via travel, then improved therapy and screening for resistant isolates plus intensive contact tracing would be appropriate ways to reduce the risk of AMR emerging and spreading [40s].

Does the Evidence Show That Intensive Gonorrhea/Chlamydia Screening Results in Reduced Prevalence?

Unfortunately, the answer from the available empirical evidence is largely no. Thus, 2 cluster RCTs have assessed the effects of repeated rounds of chlamydia testing targeting young men and women in the general population and found no reduction in estimated prevalence [41s, 42s]. Likewise, repeated population-based cross-sectional studies have found that screening had little or no effect on prevalence [43s, 44s]. The evidence base for screening gonorrhea and chlamydia in MSM is even poorer. No RCTs have been performed, and the observational data suggest that screening has no effect on prevalence.24 Even 3 monthly, 3-site screening is not associated with reductions in incidence or prevalence23,24 (Fig. 3).

Evidence That Intensive Screening Induces AMR

Three ecological studies from the United States and Europe have found some evidence of an association between the intensity of gonorrhea/chlamydia screening in MSM and the prevalence of gonococcal AMR [45s–47s]. These studies did not, however, control for possible confounders. Studies of mass antimicrobial therapy for both N. gonorrhoeae and the related N. meningitidis have also found that mass treatment was associated with the emergence of AMR [5, 48s, 49s].

Intense screening will also induce AMR in other pathobionts. A single dose of azithromycin, for example, results in steep increases in macrolide resistance in commensal streptococci [50s]. Because screening typically detects gonorrhea/chlamydia in around 10% of MSM in PrEP programs, this translates into very high antimicrobial exposures to treat these infections—levels that have been found to be strongly associated with the induction of AMR in a range of pathobionts [4, 32s, 50s].

Where One Stands Depends on Where One Sits – The Role of Conceptual Frameworks

In the absence of high-quality evidence, such as that provided by RCTs, we do not know if screening in MSM on PrEP does more good than harm or the reverse. We will be commencing an RCT in Belgium in the next few months (with the cumulative incidence of chlamydia plus gonorrhea as the primary outcome) to try to answer this question. In the absence of RCT evidence, it is instructive to reflect on the reasons underpinning the diametrically opposed views in the STI field on the relationship between screening and AMR/STI prevalence. I have argued that it is more logically consistent for those operating within a biomedical individualist perspective to view intense screening in a positive light. In addition to the limitations already noted, I should also consider other problems with this argument. I acknowledge that I am biased toward multilevel ecological conceptual frameworks.26 I have also not considered other explanations for the differences in opinion as regard STI screening, such as those deriving from vested interests in the topic (Table 1). This analysis is also largely limited to gonorrhea and chlamydia screening in MSM. There are of course other reasons for screening for chlamydia and gonorrhea in general heterosexual populations, such as reducing STI morbidity and mortality and reducing the transmission of other STIs including HIV.1 A strong case can be made for screening for HIV, hepatitis C, and syphilis in MSM [1, 51s]. This article also oversimplifies the drivers of AMR in STIs. In particular, a range of factors known to be determinants of AMR, such as the underdosing of antibiotic therapy, have been ignored. Finally, I have not considered the possibility that particularly intensive screening may eradicate gonorrhea transmission and thereby reduce the probability of AMR emerging. Much remains to be learned about the relative importance of different pathways between antimicrobial consumption and resistance for different bug-drug combinations. These pathways include direct-, bystander- and bystander-via-commensal-selection [13, 52s]. For bug-drug combinations where direct selection is predominantly responsible for AMR, biomedical individualist perspectives may be adequate. If bystander selection via commensal and other bacteria is responsible, then ecological frameworks would be preferable.

Calls for intensified screening are not limited to MSM. The World Health Organization's STI plan, for example, lists enhanced screening in high prevalence populations as one of the ways to achieve its ambitious goals of reducing the global incidence of gonorrhea, chlamydia, and syphilis by 90% by 2030 [53s]. Once again, there are no RCTs or even observational data, that I am aware of, to show this would be efficacious. The risks of high antimicrobial exposure and induction of AMR would, however, be analogous to those in MSM populations [54s]. For example, Lewis and others have cogently argued that gonococcal AMR has typically emerged in core groups, such as MSM or sex workers (typically in the Asian/Western Pacific region) [55s]. One of the reasons advanced for why sex workers in particular Asian countries were particularly at risk was the high levels of antimicrobials consumed by the general population in these countries [56s]. Gonococcal resistance to extended spectrum cephalosporins, for example, first emerged in Japanese core groups in 2000, which may have been due to the fact that community consumption of cephalosporins in Japan in 2000 was twice as high as any other country in the world [56s]. The World Health Organization is one of a number of bodies that strongly promotes only introducing screening programs when a set of criteria have been fulfilled [57s]. These criteria have not been met for screening gonorrhea/chlamydia in MSM or other high prevalence populations. Explicitly incorporating ecological thinking may help prevent this type of error from occurring in the future.


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