The plague is generally considered to be a disease of the past, so it may come as a surprise that it hasn’t and the plague hasn’t gone away (it just doesn’t get much media attention). Josephine Bourner and her colleagues discuss the threat posed by the plague in our modern world today and why clinical trials are very important for treatments.

In 2018, 248 cases of (mostly bubonic plague) were reported worldwide, 98% of which came from just two countries (Madagascar and the Democratic Republic of the Congo) – a 90% decrease in a decade and a far cry from the pandemics that hit the world’s population by the end of 19thNS Century.

So why bother doing clinical trials on plague treatments? Especially since they are so demanding that none have been successfully completed?

Precisely because no hard evidence from clinical trials – the robust tests we want to be sure that a given treatment is safe and effective – exists today for all currently recommended and used drugs and therapies. And because the plague is not gone.

A number of drugs have been approved by the US Food and Drug Administration (FDA) for use in plague based on the so-called “Animal Rule”, which applies to situations in which human studies are not feasible and instead experimental data be used. Some of these drugs have been used for a long time and doctors are generally comfortable using them.

However, there are several different therapies, and some have significant disadvantages. Many countries rely heavily on aminoglycosides such as streptomycin (used since the late 1940s) and gentamycin to treat the plague. Although effective, aminoglycosides are highly toxic to the patient and would require extensive kidney and hearing tests, which many health facilities in low and middle income countries are not equipped to perform. Streptomycin, in particular, is poorly available worldwide and, coupled with its high prices and administration only by injection, is becoming less practical in poorly equipped settings. Because of these safety concerns, some countries use doxycycline, but it is bacteriostatic and is for oral use only and is therefore not suitable for more severe forms of the plague. Both aminoglycosides and tetracyclines are contraindicated in pregnancy.

There are other options that are less of a burden on the patient and on health system resources. For example, ciprofloxacin has shown equivalent or superior therapeutic efficacy to streptomycin and gentamycin in non-human studies; it can be administered orally or by injection, which allows the route of administration to be changed when clinically appropriate; and it does not require extensive monitoring.

There have been some attempts to clinically test therapies, but field conditions (the plague occurs mostly in remote rural areas) and civil unrest have conspired against their implementation. There are other challenges as well: there is no consolidated study methodology and no agreed core results to assess treatment effectiveness.

It is for this reason that the University of Oxford, the Institut Pasteur de Madagascar, the Center Hospitalier Universitaire Joseph Raseta Befelatanana and the Center d’Infectiologie Charles Mérieux have partnered a randomized in response to the growing need for more solid and comprehensive evidence of the effectiveness of all available treatment regimens Organize clinical trial in Madagascar in which patients receive either the country’s first-line treatment (streptomycin followed by ciprofloxacin) or third-line treatment (ciprofloxacin alone). The study is titled “An open label, randomized, unsuccessful study of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY)” and the protocol was recently published.

With the prevalence of plague cases around the world, most of which are now in low-income countries, it is particularly important to expand the evidence base for a safer, easier-to-follow regimen that can be used in resource-poor health environments. Our aim is to find out whether a regimen based on the administration of ciprofloxacin alone can become the first-line treatment and meet these global health needs. But this treatment would also be valuable in all settings.

Let’s not forget Yersinia pestis – the plague bacterium – is found in fleas and rodents around the world and that cases are sporadic on a regular basis in high, middle and low income countries including the US and China.

Let’s not forget Yersinia pestis – the plague bacterium – is found in fleas and rodents around the world and that cases are sporadic on a regular basis in high, middle and low income countries including the US and China. In places where cases are more frequently observed, the plague has proven that it still has epidemic potential: in 2017, Madagascar reported an urban pulmonary plague outbreak that resulted in 1,878 cases in two of its main urban areas. On the other hand, the plague can also occur where it has not been reported in humans for years or even decades, such as in Libya, where no plague cases were found for 25 years until 2009. Finally, in August 2020, California reported its first case of bubonic plague in 5 years, a shepherd was hospitalized in China with plague, and a teenager died of bubonic plague in Mongolia.

The plague is a zoonosis with epidemic potential that has an active reservoir in many countries, including advanced economies, and can dormant for long periods of time. Human-wildlife contact is increasing, risking more zoonotic spreads and more human cases. Before we get to the next plague epidemic and questions arise about which treatment option is best, we need to test. And epidemic or not, we need to get the evidence we need to improve patient care and outcomes in all health care facilities for a disease that has literally “plagued” humanity for five millennia.

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