in monotherapeutic treatment of plague. guidelines on treatment and prophylaxis of plague were published by the centers for disease control and prevention in 2021. the plague bacterium could develop drug resistance and again become a major health threat. one case of a drug-resistant form of the bacterium was found in madagascar in 1995. further outbreaks in madagascar were reported in november 2014 and october 2017. epidemiology main article: epidemiology of plague distribution of plague-infected animals 1998 globally about 600 cases are reported a year. in 2017, the countries with the most cases include the democratic republic of the congo, madagascar and peru. it has historically occurred in large outbreaks, with the best known being the black death in the 14th century which resulted in more than 50 million dead. in recent years, cases are distributed between small seasonal outbreaks which occur primarily in madagascar, and sporadic outbreaks or isolated cases in endemic areas. in 2022 the possible origin of all modern strands of yersinia pestis dna was found in human remains in three graves located in kyrgyzstan, dated to 1338 and 1339. the siege of caffa in crimea in 1346, is known to have been the first plague outbreak with following strands, later to spread over europe. sequencing dna compared to other ancient and modern strands paints a family tree of the bacteria. bacteria today affecting marmots in kyrgyzstan, are closest to the strand found in the graves, suggesting this is also the location where plague transferred from animals to humans. biological weapon the plague has a long history as a biological weapon. historical accounts from ancient china and medieval europe detail the use of infected animal carcasses, such as cows or horses, and human carcasses, by the xiongnu/huns, mongols, turks and other groups, to contaminate enemy water supplies. han dynasty general huo qubing is recorded to have died of such contamination while engaging in warfare against the xiongnu. plague victims were also reported to have been tossed by catapult into cities under siege. in 1347, the genoese possession of caffa, a great trade emporium on the crimean peninsula, came under siege by an army of mongol warriors of the golden horde under the command of jani beg. after a protracted siege during which the mongol army was reportedly withering from the disease, they decided to use the infected corpses as a biological weapon. the corpses were catapulted over the city walls, infecting the inhabitants. this event might have led to the transfer of the black death via their ships into the south of europe, possibly explaining its rapid spread. during world war ii, the japanese army developed weaponized plague, based on the breeding and release of large numbers of fleas. during the japanese occupation of manchuria, unit 731 deliberately infected chinese, korean and manchurian civilians and prisoners of war with the plague bacterium. these subjects, termed "maruta" or "logs", were then studied by dissection, others by vivisection while still conscious. members of the unit such as shiro ishii were exonerated from the tokyo tribunal by douglas macarthur but 12 of them were prosecuted in the khabarovsk war crime trials in 1949 during which some admitted having spread bubonic plague within a 36-kilometre (22 mi) radius around the city of changde. ishii innovated bombs containing live mice and fleas, with very small explosive loads, to deliver the weaponized microbes, overcoming the problem of the explosive killing the infected animal and insect by the use of a ceramic, rather than metal, casing for the warhead. while no records survive of the actual usage of the ceramic shells, prototypes exist and are believed to have been used in experiments during wwii. after world war ii, both the united states and the soviet union developed means of weaponising pneumonic plague. experiments included various delivery methods, vacuum drying, sizing the bacterium, developing strains resistant to antibiotics, combining the bacterium with other diseases (such as diphtheria), and genetic engineering. scientists who worked in ussr bio-weapons programs have stated that the soviet effort was formidable and that large stocks of weaponised plague bacteria were produced. information on many of the soviet and us projects are largely unavailable. aerosolized pneumonic plague remains the most significant threat. the plague can be easily treated with antibiotics. some countries, such as the united states, have large supplies on hand if such an attack should occur, making the threat less severe.