is also very cost-effective: prices are normally less than us$1 per dose. because the price is low, poverty-stricken communities are more willing to take advantage of the vaccinations. although vaccination programs for typhoid have proven effective, they alone cannot eliminate typhoid fever. combining vaccines with public-health efforts is the only proven way to control this disease. since the 1990s, the who has recommended two typhoid fever vaccines. the vips vaccine is given by injection, and the ty21a by capsules. only people over age two are recommended to be vaccinated with the vips vaccine, and it requires a revaccination after 2–3 years, with a 55%–72% efficacy. the ty21a vaccine is recommended for people five and older, lasting 5–7 years with 51%–67% efficacy. the two vaccines have proved safe and effective for epidemic disease control in multiple regions. a version of the vaccine combined with a hepatitis a vaccine is also available. results of a phase 3 trial of typhoid conjugate vaccine (tcv) in december 2019 reported 81% fewer cases among children. treatment oral rehydration therapy the rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent many of the deaths of diarrheal diseases in general. antibiotics where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin. otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice. cefixime is a suitable oral alternative. properly treated, typhoid fever is not fatal in most cases. antibiotics such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin, and ciprofloxacin have been commonly used to treat it. treatment with antibiotics reduces the case-fatality rate to about 1%. without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly, abdominal symptoms, and occasionally pneumonia. in white-skinned patients, pink spots, which fade on pressure, appear on the skin of the trunk in up to 20% of cases. in the third week, untreated cases may develop gastrointestinal and cerebral complications, which may prove fatal in 10%–20% of cases. the highest case fatality rates are reported in children under 4. around 2%–5% of those who contract typhoid fever become chronic carriers, as bacteria persist in the biliary tract after symptoms have resolved. surgery surgery is usually indicated if intestinal perforation occurs. one study found a 30-day mortality rate of 9% (8/88), and surgical site infections at 67% (59/88), with the disease burden borne predominantly by low-resource countries. for surgical treatment, most surgeons prefer simple closure of the perforation with drainage of the peritoneum. small-bowel resection is indicated for patients with multiple perforations. if antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. cholecystectomy is sometimes successful, especially in patients with gallstones, but is not always successful in eradicating the carrier state because of persisting hepatic infection. resistance as resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and streptomycin is now common, these agents are no longer used as first–line treatment of typhoid fever. typhoid resistant to these agents is known as multidrug-resistant typhoid. ciprofloxacin resistance is an increasing problem, especially in the indian subcontinent and southeast asia. many centres are shifting from ciprofloxacin to ceftriaxone as the first line for treating suspected typhoid originating in south america, india, pakistan, bangladesh, thailand, or vietnam. also, it has been suggested that azithromycin is better at treating resistant typhoid than both fluoroquinolone drugs and ceftriaxone. azithromycin can be taken by mouth and is less expensive than ceftriaxone, which is given by injection. a separate problem exists with laboratory testing for reduced susceptibility to ciprofloxacin; current recommendations are that isolates should be tested simultaneously against ciprofloxacin (cip) and against nalidixic acid (nal), that isolates sensitive to both cip and nal should be reported as "sensitive to ciprofloxacin", and that isolates sensitive to cip but not to nal should be reported as "reduced sensitivity to ciprofloxacin". but an analysis of 271 isolates found that around 18% of isolates with a reduced susceptibility to fluoroquinolones, the class which cip belongs (mic 0.125–1.0 mg/l), would not be detected by this method. epidemiology main article: epidemiology of typhoid fever typhoid fever incidence; most common in asia, africa, central and south america strongly endemic areas moderately endemic areas in 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths. it occurs most often in children and young adults between 5 and 19 years old. in 2013, it resulted in about 161,000 deaths – down from 181,000 in 1990. infants, children, and adolescents in south-central and southeast asia have the highest rates of typhoid. outbreaks are also often reported in sub-saharan africa and southeast asia. in 2000, more than 90% of morbidity and mortality due to typhoid fever occurred in asia. in the u.s., about 400 cases occur each year, 75% of which are acquired while traveling internationally. before the antibiotic era, the case fatality rate of typhoid fever was 10%–20%. today, with prompt treatment, it is less than 1%, but 3%–5% of people who are infected develop a chronic infection in the gall bladder. since s. enterica subsp. enterica serovar typhi is human-restricted, these chronic carriers become the crucial reservoir, which can persist for decades for further spread of the disease, further complicating its identification and treatment. lately, the study of s. enterica subsp. enterica serovar typhi associated with a large outbreak and a carrier at the genome level provides new insight into the pathogenesis of the pathogen. in industrialized nations, water sanitation and food handling improvements have reduced the number of typhoid cases. developing nations have the highest rates. these areas lack access to clean water, proper sanitation systems, and proper health-care facilities. in these areas, such access to basic public-health needs is not expected in the near future. in 2004–2005 an outbreak in the democratic republic of congo resulted in more than 42,000 cases and 214 deaths. since november 2016, pakistan has had an outbreak of extensively drug-resistant (xdr) typhoid fever. in europe, a report based on data for 2017 retrieved from the european surveillance system (tessy) on the distribution of confirmed typhoid and paratyphoid fever cases found that 22 eu/eea countries reported a total of 1,098 cases, 90.9% of which were travel-related, mainly acquired during travel to south asia. outbreaks map of typhoid fever outbreaks 1989–2018 plague of athens (suspected) "burning fever" outbreak among indigenous americans. between 1607 and 1624, 85% of the population at the james river died from a typhoid epidemic. the world health organization estimates the death toll was over 6,000 during this time. maidstone, kent outbreak in 1897–1898: 1,847 patients were recorded to have typhoid fever. this outbreak is notable because it was the first time a typhoid vaccine was deployed during a civilian outbreak. almoth edward wright's vaccine was offered to 200 healthcare providers, and of the 84 individuals who received the vaccine none developed typhoid whereas 4 who had not been vaccinated became ill. american army in the spanish-american war: government records estimate over 21,000 troops had typhoid, resulting in 2,200 deaths. in 1902, guests at mayoral banquets in southampton and winchester, england, became ill and four died, including the dean of winchester, after consuming oysters. the infection was due to oysters sourced from emsworth, where the oyster beds had been contaminated with raw sewage. jamaica plain neighborhood, boston in 1908 - linked to milk delivery. see history section, "carriers" for further details. outbreak in upperclass new yorkers who employed mary mallon - 51 cases and 3 deaths from 1907 to 1915. aberdeen, scotland, in summer 1964 - traced back to contaminated canned beef sourced from argentina sold in markets. more than 500 patients were quarantined in the hospital for a minimum of four weeks, and the outbreak was contained without any deaths. dushanbe, tajikistan, in 1996–1997: 10,677 cases reported, 108 deaths kinshasa, democratic republic of the congo, in 2004: 43,000 cases and over 200 deaths. a prospective study of specimens collected in the same region between 2007 and 2011 revealed about one third of samples obtained from patient samples were resistant to multiple antibiotics. kampala, uganda in 2015: 10,230 cases reported history early descriptions the plague of athens, during the peloponnesian war, was most likely an outbreak of typhoid fever. during the war, athenians retreated into a walled-in city to escape attack from the spartans. this massive influx of humans into a concentrated space overwhelmed the water supply and waste infrastructure, likely leading to unsanitary conditions as fresh water became harder to obtain and waste became more difficult to collect and remove beyond the city walls. in 2006, examining the remains for a mass burial site from athens from around the time of the plague (~430 b.c.) revealed that fragments of dna similar to modern day s. typhi dna were detected, whereas yersinia pestis (plague), rickettsia prowazekii (typhus), mycobacterium tuberculosis, cowpox virus, and bartonella henselae were not detected in any of the remains tested. it is possible that the roman emperor augustus caesar had either a liver abscess or typhoid fever, and survived by using ice baths and cold compresses as a means of treatment for his fever. there is a statue of the greek physician, antonius musa, who treated his fever. definition and evidence of transmission the french doctors pierre-fidele bretonneau and pierre-charles-alexandre louis are credited with describing typhoid fever as a specific disease, unique from typhus. both doctors performed autopsies on individuals who died in paris due to fever – and indicated that many had lesions on the peyer's patches which correlated with distinct symptoms before death. british medics were skeptical of the differentiation between typhoid and typhus because both were endemic to britain at that time. however, in france only typhoid was present circulating in the population. pierre-charlles-alexandre louis also performed case studies and statistical analysis to demonstrate that typhoid was contagious - and that persons who already had the disease seemed to be protected. afterward, several american doctors confirmed these findings, and then sir william jenner convinced any remaining skeptics that typhoid is a specific disease recognizable by lesions in the peyer's patches by examining sixty-six autopsies from fever patients and concluding that the symptoms of headaches, diarrhea, rash spots, and abdominal pain were present only in patients who were found to have intestinal lesions after death; these observations solidified the association of the disease with the intestinal tract and gave the first clue to the route of transmission. in 1847 william budd learned of an epidemic of typhoid fever in clifton, and identified that all 13 of 34 residents who had contracted the disease drew their drinking water from the same well. notably, this observation was two years prior to john snow discovering the route of contaminated water as the cause for a cholera outbreak. budd later became health officer of bristol and ensured a clean water supply, and documented further evidence of typhoid as a water-borne illness throughout his career. cause polish scientist tadeusz browicz described a short bacillus in the organs and feces of typhoid victims in 1874. browicz was able to isolate and grow the bacilli but did not go as far as to insinuate or prove that they caused the disease. in april 1880, three months prior to eberth's publication, edwin klebs described short and filamentous bacilli in the peyer's patches in typhoid victims. the bacterium's role in disease was speculated but not confirmed. in 1880, karl joseph eberth described a bacillus that he suspected was the cause of typhoid. eberth is given credit for discovering the bacterium definitively by successfully isolating the same bacterium from 18 of 40 typhoid victims and failing to discover the bacterium present in any "control" victims of other diseases. in 1884, pathologist georg theodor august gaffky (1850–1918) confirmed eberth's findings. gaffky isolated the same bacterium as eberth from the spleen of a typhoid victim, and was able to grow the bacterium on solid media. the organism was given names such as eberth's bacillus, eberthella typhi, and gaffky-eberth bacillus. today, the bacillus that causes typhoid fever goes by the scientific name salmonella enterica serovar typhi. chlorination of water most developed countries had declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. in 1893 attempts were made to chlorinate the water supply in hamburg, germany and in 1897 maidstone, england, was the first town to have its entire water supply chlorinated. in