Transmission of Antimicrobial Resistant Yersinia pestis During a Pneumonic Plague Outbreak

Abstract

Background Pneumonic plague (PP), caused by Yersinia pestis, is the most feared clinical form of plague due to its rapid lethality and potential to cause outbreaks. PP outbreaks are now rare due to antimicrobial therapy. Methods A PP outbreak in Madagascar involving transmission of a Y. pestis strain resistant to streptomycin, the current recommended first-line treatment in Madagascar, was retrospectively characterized using epidemiology, clinical diagnostics, molecular characterization, and animal studies. Results The outbreak occurred in February 2013 in the Faratsiho district of Madagascar and involved 22 cases, including three untreated fatalities. The 19 other cases participated in funeral practices for the fatal cases and fully recovered after combination antimicrobial therapy: intramuscular streptomycin followed by oral co-trimoxazole. The Y. pestis strain that circulated during this outbreak is resistant to streptomycin resulting from a spontaneous point mutation in the 30S ribosomal protein S12 (rpsL) gene. This same mutation causes streptomycin resistance in two unrelated Y. pestis strains, one isolated from a fatal PP case in a different region of Madagascar in 1987 and another isolated from a fatal PP case in China in 1996, documenting this mutation has occurred independently at least three times in Y. pestis. Laboratory experiments revealed this mutation has no detectable impact on fitness or virulence, and revertants to wild-type are rare in other species containing it, suggesting Y. pestis strains containing it could persist in the environment. Conclusion Unique AMR strains of Y. pestis continue to arise in Madagascar and can be transmitted during PP outbreaks.

Yersinia pestis antibiotic resistance: a systematic review

“…However, as the first strain discovered exhibited the novel mechanism of antibiotic resistance, S19960127 displayed quite high resistance to streptomycin (MIC = 4,096 μg/mL). It shared the same SNP (215373) as those found in Madagascar [47,48].…”

“…To date, 5 Y. pestis strains with unique AMR and multidrug resistance (MDR) were isolated and identified in Madagascar with complete genome sequencing (Table 2) [47]. In addition, 1 streptomycin-resistant strain of the bacterium was found, and the genome was recently sequenced in the Tibetan region of China [48].…”

“…For strains carrying mutated rpsl genes, a study documented that these AMR Y. pestis isolates can be transmitted among individuals via respiratory droplets during a pneumonic plague outbreak [47]. Since bubonic plague can cause secondary pneumonic plague without appropriate treatment, an immediate surveillance system seems quite important to detect and identify patients infected with AMR strains.…”

“…Mutations associated with streptomycin resistance have been consistently identified in the rpsl, rrs, and gidB genes in Mycobacterium tuberculosis (MTB) since 1993 in diverse geographic localities [65]. In contrast, this mechanism of AMR in Y. pestis was never reported until 2021, while Y. pestis strains containing mutated rpsl genes have existed since 1987 according to recent studies [47]. It is probable that detecting strains with a single method (Table 3) [53][54][55], such as PCR for target genes in plasmids, would reduce the accuracy of streptomycin susceptibility monitoring since it may have missed gene-mutated isolates.…”

The impact of COVID-19 on clinical research for Neglected Tropical Diseases (NTDs): A case study of bubonic plague

“…Streptomycin has been widely used historically as the first-line treatment recommendation for plague in many countries. Several Y. Pestis strains have however demonstrated antimicrobial resistance to streptomycin [13] and its limited global supply is anticipated to become completely unavailable within the next 1-2 years. There is therefore an urgent need to assess available therapeutics for the treatment of plague.…”