The Topic of This Month Vol.22 No.3(No.253)

Typhoid fever and paratyphoid fever are both systemic infectious diseases caused respectively by Salmonella Typhi and S. Paratyphi A. According to the previous law, these diseases used to be notifiable as legally defined communicable diseases. Nowadays, they are classified into Category II notifiable infectious diseases under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (the Infectious Diseases Control Law) enacted in April 1999. Physicians who have diagnosed confirmed cases, suspected cases, or asymptomatic carriers (carriers) must notify the prefectural governor through the nearby health center of any cases. The prefectural health department must in turn notify the Ministry of Health, Labor and Welfare (MHLW) of the cases and also forward the strains isolated from cases and carriers to the National Institute of Infectious Diseases (NIID) to apply the analytical results, e.g., the phage types, for epidemic control and carrier counterplan (Notices Nos. 788 and 60, 1966 and No. 44, 1999 from MHLW). Some other Salmonella serovars (S. Sendai, S. Paratyphi B, and S. Paratyphi C) could rarely cause typhoid fever and similar diseases, though these are regarded as merely salmonellosis.

Notified patients, after enactment of the Infectious Diseases Control Law, stood at 66 and 82 of typhoid fever and 24 and 19 of paratyphoid fever during April through December 1999 and January through December 2000, respectively. It was estimated that 108 (73%) of 148 typhoid fever cases and 31 (72%) of 43 paratyphoid fever cases had acquired the infection in various foreign countries. Male cases at the age of 20s were the largest in number as usual (Fig. 1). Indian Subcontinent was ascribed to the indication of the area acquiring infection of 58 typhoid and 18 paratyphoid fever cases.

The Department of Bacteriology, NIID, carries out phage typing/drug-susceptibility tests of the forwarded isolates and returns the results obtained to each prefecture. The information attached to the invoices of the isolated strains and the tests of the isolates since 1974 revealed such a characteristic tendency that the total typhoid fever cases are in the decrease and the ratio of imported cases relatively in the increase. Cases of typhoid fever (the sum of patients and carriers) counted at 76 in 1997, 61 in 1998, 86 in 1999, and 51 in 2000. Those of paratyphoid fever counted at 36 in 1997, 49 in 1998, 28 in 1999, and 13 in 2000 (Table 1). The number of strains forwarded to NIID after enactment of the Infectious Diseases Control Law was actually smaller than that of notified patients, since notifications to prefectures involve suspected cases and in some cases strains are not forwarded to NIID.

Monthly incidents during January 1990 through December 2000 are shown in Fig. 2. Both typhoid and paratyphoid fever cases tend to increase from spring toward summer yearly. Increased domestic paratyphoid fever cases were seen during April and May of 1998; this was ascribed to an outbreak occurring in Chiba Prefecture (see IASR, Vol. 20, No. 7), in which customers of a certain restaurant who ate during a period of a week were attacked by paratyphoid fever. From 19 of 26 symptomatic patients, S. Paratyphi A was isolated. All the isolates were of phage type (PT) 4, showing an identical DNA pattern in pulsed-field gel electrophoresis (PFGE) analysis, indicating that all the 19 strains originated from the same source of infection. Nevertheless, various investigations performed failed to identify the source of infection after all.

Tables 2 and 3 show the results of S. Typhi and S. Paratyphi A phage typing, respectively. For S. Typhi, PTs D2, E1, and M1 were predominant and the ratio of PT E1 was high particularly in 1999 and 2000. In S. Paratyphi A, PTs 1 and 4 predominated as usual.

Multidrug-resistant S. Typhi is prevalent even nowadays in Indian Subcontinent, Central Asia, and Southeast Asia, occasionally provoking outbreaks. Such multidrug-resistant S. Typhi strains often involve PTs E1 and UVS. In Japan, multidrug-resistant S. Typhi, resistant to five drugs, ampicillin (ABPC), chloramphenicol (CP), tetracycline (TC), streptomycin (SM), and sulfamethoxazole/trimethoprim (ST) have been isolated from travelers returning from Indian Subcontinent and Thailand (Table 4). Few multidrug-resistant S. Paratyphi A organisms have been seen; nevertheless resistant organisms to CP, SM or ST singly are in the increase.

Typhoid and paratyphoid fever patients until recently used to be treated by dosing with any one of CP, ABPC or ST. As the effects of conventional antibiotics can no longer be expected in association with the increase in multidrug-resistant organisms, fluoroquinolones have recently been used and it is now the first choice in therapy of typhoid and paratyphoid fever. Since roughly 1995, many strains resistant to fluoroquinolones have been reported in foreign countries and S. Typhi and S. Paratyphi A strains with decreased susceptibility to fluoroquinolones (fluoroquinolone-low resistant strain) have already been isolated in Japan. Some cases, whose fever does not break immediately after dosing fluoroquinolones, have been reported in Japan. Strains with decreased susceptibility to fluoroquinolones are such that the minimum inhibitory concentration (MIC) of ciprofloxacin (CPFX) being at 0.125-4.0 ƒĘg/ml. Although such strains may be judged as "susceptible" in the drug-susceptibility test (MIC†4.0 ƒĘg/ml as "resistant"), they may often be found because of the lack of therapeutic effects. According to the investigation undertaken by the Department of Bacteriology, NIID, S. Typhi and S. Paratyphi A with decreased susceptibility to fluoroquinolones showed a rapid increase from 1998 toward 2000. The strains with decreased susceptibility accounted for 10% of all S. Typhi isolates in 1997, while such organisms increased to 32% in 1999, and 49% in 2000 (Fig. 3) (Hirose, K. et al., Antimicrob. Agents Chemother., 45, 956-958, 2001). Such strains were isolated mostly from travelers returning from India. Fortunately, strains with decreased susceptibility to the third generation cephem drugs have not yet been recognized. Since it is anticipated that S. Typhi and S. Paratyphi A with decreased susceptibility to fluoroquinolones will further increase, it is recommended to monitor strictly the changes in the drug susceptibility from now on. In order to meet the recommendation, isolation of the pathogenic agents from patients is more than ever in need.

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