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CID 1997;24 (Suppl 1)ultidrug-Resistant Typhoid Fever107

Table 1. Data regarding outbreaks due to m ultiresistant S. typhi, 1989-995.

Reference(s) Year(s) of outbreak Country or area Vi phage type(s)

Resistance type

(ant ibiogram)* Plasmid type

[10,1] 1989 Pakistan M 1 ACSSuTTm H 1

[12-14] 1990-95 India El, 51, 0 ACSSuTTm H i[20-22] 1990-95 Arabian Gulf El, Ml, 51 ACSSuTTm H 1

... 1990-93 Kuala Lumpur El ACSSuTTm H i[19] 1991 United Kingdom M 1 CSTTm li,[18] 1991 South Africa A A CKS S uT H i[17] 1991-92 Egypt E2, Cl, Dl-N ACSSuTTm H 1... 1992-94 Vietnam ACSSuTTm[16] 1993 —94 Philippines CKSSuTTm[15] 1994 Bangladesh El ACSSuTTm H 1

1994-95 Pakistan El ACSSuTTm H 1

* A = ampicillin; C = chloramphenicol; K = kanamycin; S = streptomycin; Su = sulfonamides; T = tetracyclines; Tm = trimethoprim.

in the United Kingdom [19], Vi phage type A in South Africa[18], and Vi phage types E2, C l, and Dl-N in Egypt [17]. Thephage types of M DR strains isolated in the Arabian Gulf (E 1,M 1, and 51) correspond to those that have caused outbreaksin the Indian subco ntinent. Strains of Vi pha ge types El andM 1 have also been isolated in Austral ia [19] and Canada [23].

One outbreak of particular interest was that which occurredin the Philippines (metropolitan Manila) from July 1993 to

April 1994, in which 252 cases of MD R S. typhi in 13 ho spitalswere reported [16]; the strains were not phage-typed. The

strains were resistant to chloramphenicol, co-trimoxazole,

kanamycin, streptomycin, and tetracyclines (antibiogram,

CKSS uTTm ; see footnote to table 1) but susceptible to ampicil-

lin. Although the vehicle of infection was n ot microb iologicallyconfirmed, epidemiological f indings suggested an associationbetween typhoid fever and the consumption of flavored-icedrinks purchased from street vendors.

The recent explosive emergence in developing cou ntries ofstrains of S. typhi with resistance to trimethoprim and ampicil-l in has caused man y problems, as since 1980 these an tibioticshad been used extensively for the treatment of p atients infectedwith chloramphenicol-resistant strains [24]. Without exception,in al l outbreaks of M DR S. typhi so far studied, the completespectrum of multiple resistance has been encoded by plasmidsof the H 1 incompatibil ity grou p.

Dru g Resistance in British Isolates

In the United Kingdom, of 2,356 strains of S. typhi isolatedbetween 1978 and 1985, only six (0.25%) were resistant to

chloramphenicol at a clinically significant level (MIC, >32

mg/L). On the basis of these findings, in 1987 it was recom -mended that in the United Kingdom chloramphenicol shouldremain the first-l ine drug for treatmen t of typhoid fever and,in particular, that it should be used un til the results of laboratorysusceptibil ity tests are known [25]. In the succeeding 4-yearperiod (1986-1989), the isolation of chloramphenicol-resistant

S. typhifrom patients in the United Kingdom increased slightly,from 0.25% to 1.5% [26], but the increase was not considered

sufficient to justify altering the recommendation made in 1987.The situation has chan ged dramatically since 1990. In that

year 20% of strains were resistant not only to chloramphenicolbut also to trimethoprim (M IC, > 125 mg /L) and ampicil l in(MIC, > 125 mg/L) [21]. The situation has worsened in thesucceeding 5 years, and since 1994 abou t 35% of strains frompatients with typhoid fever have been resistant to chloramphen-

icol (table 2); the majority of chloram phenicol-resistant strainsalso are resistant to am pici ll in and trimethoprim [27].

In 1990 the majority of chloramphenicol-resistant strainsisolated in the United Kingdom belonged to Vi ph age type

M 1 and were from patients recently returned from Pakistan,although som e strains of Vi phage type El were also isolated[21]. In subsequent years the proportion of M DR strains be-longing to Vi phage type El has increased, and in 1995 almostal l MD R strains belonged to this ph age type (table 3).

From 1990 to 1993 the major i ty of pat ients infected withM DR strains of Vi phage type El had recently returned fromIndia, but since 1994 an increasing number of patients infected

Table 2. Isolations of chloramphenicol-resistant S. typhi in theUnited Kingdom, 1978-1995.

Year(s)

No. of isolates

studied

No. (%) of isolates resistant* to

chloramphenicol

1978-85 2,345 6 (0.3)

1986-89 79 0 12 (1.5)

1990 24 8 50 (20)

1991 22 6 48 (21)

1992 20 4 49 (24)

1993 19 4 49 (25)

1994 25 9 94 (36)

1995 29 1 100 (34)

NOTE. Data are from the Laboratory of Enteric Pathogens (London).* MIC, >32 mg/L.



S108owe, Ward, and ThrelfallID 1997; 24 (Suppl 1)

Table 3. Phage-type distribution among chloramphenicol-resistant S. typhi isolates recovered in theUnited Kingdom, 1978-1995.

Year(s)

Total no. of

chloramphenicol-

resistant isolates

No. of isolates of indicated phage type

A El M 1 0 Others

1978-85 6 2 4

1986-89 12 1 2 8 11990 50 8 36 2 4

1991 48 20 25 3

1992 49 27 12 10

1993 49 29 18 1 11994 94 1 81 8 4

1995 100 96 4

NOTE. Data are from the Laboratory of Enteric Pathogens (London).

with MD R V i phage type El had recently returned from Paki-

stan. Other countr ies v is ited by pat ients from whom M DRS. typhi has been isolated include Sri Lanka, Bangladesh, Ne-pal, and Somalia [27]. In all MDR S. typhi isolated in theUnited Kingdom since 1990, resistance to chloramp henicol,amp icillin, and trimetho prim, together with resistance to strep-tomycin and sulfonamides (antibiogram, ACSSuTTm; see foot-note to table 1), has been encoded by a plasmid of the H 1incompatibil ity group [9, 21].

Recommendations for Therapy

M DR S. typhi is now endem ic in many developing countries

but also has been isolated from returning travelers in developedcountries. As a result of the proliferation of such strains, theuse of chloramphenicol has been com promised, and that ofampici l lin and tr imethoprim s imi lar ly impaired. In October1990, because 20% of strains of S. typhi isolated in the UnitedKingdom were resistant to chloramp henicol, it was suggestedthat physicians in the United Kingdom should consider ci-

profloxacin as an alternative to chloramphenicol for the treat-ment o f enteric fever [26].

In 1991 , in l ight of the increasing isolation of M DR strainsin the United Kingdom after reports of outbreaks in the Indiansubcontinent and A rabian Gulf, the use of ciprofloxacin for the

treatment of typhoid was recommended, particularly for pa-tients returning from areas where MDR strains are endemic[21]. Ciprofloxacin is no w used ex tensively for the treatme ntof typhoid in both developing and developed countries [12, 24,28, 29].

Resistance to Ciprofloxacin

In 1992, the isolat ion in the United Kingdom of an M DRstrain of S. typhi Vi phage type El with plasmid-encoded resis-tance to chloramp henicol, ampicil l in, and trimethoprim (andchromosom al resistance to ciprofloxacin at a concentration o f

0.30 mg/L) w as reported [19] . The pat ient was a 1-year-old

child who had been infected in India and did not respond totreatment with ciprofloxacin [29]. Concern was expressed tha tresistance to this important antibiotic had appe ared in an isolateof MDR S. typhi [19].

Subsequently, chromosom ally encoded ciprofloxacin resis-tance has been observed in a total of 14 strains of S. typhi

isolated in the United Kingdom since 1991, of which 10 havealso been resistant to chloram phen icol, ampicillin, and trimeth-oprim [27]. All MD R strains with additional resistance to ci-profloxacin have b elonged to V i phage type El . Patients in-fected with such strains had recently returned from severalcountries in the Indian subcontinent, where this antibiotic

has been used to control outbreaks of MDR typhoid since1990 [12].

Although it is regrettable that resistance to ciprofloxacin isnow em erging, ciprofloxacin sti l l remains the drug o f choicefor the treatment of M DR typho id fever. To maintain the effi-cacy of ciprofloxacin for typhoid fever, however, unnecessaryusage shou ld be avoided. In particular, any prophylactic useof this important drug should be strongly discouraged. It isunfortunate that a range of fluoroquinolones, including ci-

profloxacin, have been recom mended for prop hylaxis againsttraveler's diarrhea [30].

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