A public health ethics analysis of Doxy-PEP: arguments for and against – the ‘no’ case

Introduction

Rising antimicrobial resistance (AMR) is a serious global public health threat and was associated an estimated 4.95 million deaths worldwide in 2019.¹ Consideration of doxycycline pre-exposure prophylaxis (Doxy-PEP) for STI prevention in high-risk gay, bisexual and other men who have sex with men (GBMSM) foregrounds a longstanding tension between individual antibiotic prescription and the societal risks of rising AMR.^2–5 Although multiple recent studies have demonstrated efficacy of this regime for reducing rates of syphilis, chlamydia and gonorrhoea, this also risks inducing AMR, with potentially serious consequences, as I will outline below.^5–10

Using a public health ethics lens, I will consider both the potential benefits in disease prevention and the potential harms of AMR, and argue that the risks of AMR associated with doxycycline PEP outweigh the potential benefits. To guide my analysis, I will use the Kass framework for public health ethics (Box 1), which comprises considerations of utility, liberty and social justice in a structured model.

What are the public health goals, and how effective is the intervention at achieving them?

The position outlined in the 2023 ASHM Consensus Statement on Doxy-PEP has a clear public health goal of reducing rates of STIs within high-risk individuals, which, in particular, are becoming increasingly prevalent among the populations of GBMSM, and also arguably trans women. The efficacy of this approach is now well-described, with studies focused on the highest-risk subset of this population (those who engage in condomless sex and have had a previous history of chlamydia, gonorrhoea or syphilis) and finding meaningful reductions in the rates of these three infections, with minimal evidence of individual harm.^2–5

What are the known or potential burdens?

As already discussed, the main burden of this program is the potential for AMR, and a number of studies have identified that Doxy-PEP programs may contribute to this risk. Thus, from a Kass perspective, there is a clear public health goal, evidence of efficacy and evidence of potential burdens.¹¹ The questions then are whether the burdens are justified, how these burdens interact with alternative solutions and whether implementation is fair.

Much of the concern around antibiotic prescribing is focused on the risk of impacts on non-target organisms, which can facilitate resistance in various pathogens. The main concern around Doxy-PEP is that widespread prophylactic roll out without adequate surveillance may not produce net benefits, given the risks posed by AMR.⁸ We note that prescription of antibiotics in the absence of a target infection is not unusual – much of antibiotic prescribing, even with suspected infection, occurs on an empiric basis without specific knowledge of the underlying pathogen, and therefore is undertaken based on a probability of benefit rather than a certainty.^12,13 Nevertheless, using antibiotics prophylactically in a setting where they have previously been reserved for actual or presumptive treatment raises questions about stewardship. The position outlined in the 2023 ASHM Consensus Statement on Doxy-PEP aligns with the values of antibiotic stewardship in some respects, in being reserved only for high-risk individuals, in whom there is demonstrated evidence of reduced rates of infection, which thereby also reduces the potential for future transmission to other individuals.³

Unfortunately, the same specific Doxy-PEP prescribing model has been demonstrated to increase AMR genes.¹⁴ The nature of STIs again magnifies this effect, as resistant infections can then be passed to other individuals, with modelling suggesting that any benefit from Doxy-PEP prescribing would therefore be short-lived, specifically for gonorrhoea.^6,7,9,10 If gonorrhoea quickly becomes highly resistant to doxycycline in a context of prophylactic use, which is likely, regular testing and treatment with other antibiotics will still be required to control it. This begs the question of whether the benefits of Doxy-PEP with respect to chlamydia and syphilis are worth it, if it becomes ineffective for gonorrhoea.

The literature suggesting increased AMR in other bacterial pathogens is potentially of even greater concern. Some of the other pathogens with induced resistance as a result of Doxy-PEP include Staphylococcus aureus and Klebsiella pneumoniae, two of the leading contributors to deaths from AMR worldwide, and both infections for which doxycycline is an important treatment option.^1,6,7 Alarmingly, exposure to doxycycline appears to not only induce tetracycline resistance in these pathogens, but also appears to induce resistance to other important treatment options; for example, methicillin resistance for S. aureus and third-generation cephalosporin resistance for K. pneumoniae. This implies that Doxy-PEP could lead to significant reductions in the treatment options available for highly pathogenic bacteria that contribute heavily to global morbidity and mortality. Given the potentially short-lived benefit in STI reductions with increased AMR in sexually transmitted bacteria as a result, from a utilitarian analysis the potential benefits of Doxy-PEP appear to be outweighed by the harms of AMR.

Are there alternative approaches?

Although Doxy-PEP combined with a vaccine for gonorrhoea looked like a promising combination strategy for control of bacterial STIs, recent data on vaccine efficacy are not encouraging.^15,16 Although condoms are well known to be an effective means of prophylaxis against STIs, research has identified significant barriers to their usage, both psychosocial and structural.¹⁷ Thus, frequent testing and treatment, as prescribed in national guidelines,¹⁸ remains the most viable alternative to Doxy-PEP.

How can the benefits and burdens be fairly balanced?

Withholding doxycycline, despite evidence of benefit due to a societal concern of AMR, clashes with the goal of patient autonomy. However, considerations of individual patient autonomy must be balanced against the rights of the ‘future patient’, who by their nature cannot speak for themselves.¹² Using Rawls’ ‘Veil of Ignorance’ from his theory of justice, Leibovici et al. suggest that people ‘behind the veil’ would elect the minimisation of harm to future patients over the autonomy of those present. People ‘behind the veil’ in this instance would mean hypothetical people making moral decisions about what to do, not knowing whether, in this instance, they are a GBMSM seeking to prevent STIs, or a person from the future reliant upon antibiotics retaining their efficacy.^12,19 In the case of Doxy-PEP, individual liberty also clashes with collectivism in terms of alternative means of STI preventions.

This raises further considerations of justice, as the individual’s right to choose a prevention strategy beneficial to them may lead to harm to other individuals. Utilitarian analyses of benefit and harm from multiple ethics scholars suggest that from an intergenerational justice perspective, the rights of future patients outweigh the autonomy of the present individual.^12,20 The other consideration is social justice, as the GBMSM population is one that has been identified as being specifically vulnerable to STIs compared with the general population.³ However, this must be weighed against the fact that resistant S. aureus species also tend to be over-represented in vulnerable populations, including regions in Australia that have high proportions of Aboriginal and Torres Strait Islander peoples.^21,22

In conclusion, although Doxy-PEP has a clear public health goal and demonstrated efficacy, the weight of utilitarian and justice perspectives against the libertarian perspective suggest that the harms of Doxy-PEP outweigh the benefits, undermine alternative solutions and unfairly burden other vulnerable groups in the global community.