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S106 Multidrug-Resistant Salmonella typhi: A Worldwide Epidemic Bernard Rowe, Linda R. Ward, and E. John Threlfall rom the WHO Collaborating Centre for Phage Typing and Drug Resistance in Enterobacteria, Laboratory of Enteric Pathogens, Central Public Health Laboratory, London, United Kingdom Since 1989, strains of Salmonella typ hi resistant to chloramphenicol, amp icillin, and trimethoprim (i.e., multidrug-resistant [MDR] strains) have been responsible for numerous outbreaks in countries in the Indian subcon tinent, Southeast Asia, and Africa. MD R strains have also been isolated with increasing frequency from im m igrant workers in countries in the Arabian Gulf, as well as in developed countries from returning travelers. In all MDR strains so far examined, multiple resistance has been encoded by plasmids of the H 1 incompatibility group. As a result of the widespread dissemination of such strains, chloramphenicol can n o longer be regarded as the first-line drug for typhoid fever. Because strains are also resistant to ampicillin and trimethop rim, the efficacy of these antibiotics has also been im paired, and ciprofloxacin is now the drug of choice for typhoid fever. Chrom osomally encoded resistance to ciprofloxacin has now been observed in a small numb er of strains isolated in the United Kingdom from patients returning from the Ind ian subcontinent, and in at least one case the patient did n ot respond to treatment w ith this antibiotic. It is regrettable that resistance to ciprofloxacin has now em erged in M DR S. typhi, and it is of paramount importance to limit the un necessary use of this vital drug so that its efficacy should not be further jeopardized. Although precise figures are not available, in 1986 the num- ber of cases of typhoid fever worldwide was estimated at 33 million [1]. The disease is endemic in many developing cou n- tries, particularly in the Indian subco ntinent, South and C entral America, and Africa, with an estimated mean incidence (per 100,000 people per annum) of 150 in Sou th America and 900 in Asia [2]. Travelers to these areas are at risk, and in develop ed countries of northwest Europe, most cases involve returning travelers. In Britain, for example, —200-300 cases occur each year, an overall incidence of —0.5 per 100,000 [3], and at least 70% of the patients have a history of recent foreign travel. Emergence of Drug Resistance Treatment with an appropriate antibiotic is essential for ty- phoid fever, and because o f the nature of the disease it should commence as soon as the clinical diagnosis is made rather than after the results of antimicrobial susceptibility tests are available. Until the mid-1970 s chloramphenicol was the undis- puted drug for treatment of typhoid fever, and in developed countries the use of this antibiotic resulted in a reduction in mortality from 1 0% to <2% [4]. Although before 1970 a few sporadic isolations of chloram- phenicol-resistant Salmonella typhi had been reported from Aden, Chile, and Kuwait [5], the first epidemic caused by a Reprints or correspondence: Dr. E. John Th relfall, WHO Collaborating C en- tre for Phage Typing and Drug Resistance in Enterobacteria, Laboratory of Enteric Pathogens, Central Public Health Laboratory, 61 Colindale Avenue, London NW9 5HT, United Kingdom. Clinical Infectious Diseases 1997; 24(Suppl 1):S106-9 © 1997 by The University of Chicago. All rights reserved. 1058-4838/97/2401-0046$02.00 chloramphenicol-resistant strain was that wh ich occurred in Mexico in 1972 [6, 7]. At about the same time, there was a second sub stantial outbreak in Kerala, India [8], and in both outbreaks m ortality was high. In the succeeding 5 years out- breaks occurred in several other countries, notably, Vietnam, Indonesia, Korea, C hile, and Bangladesh (for review, see [9]). A notable feature of all chloramphenicol-resistant strains from outbreaks in M exico, the Indian subcontinent, and South- east Asia was that although the strains belonged to different Vi phage types, resistance to chloramphenicol was encoded by a plasmid of the H 1 incompatibility group, often in c omb ination with resistance to streptom ycin, sulfonamides, and tetracycl ines (antibiogram, CSSuT; see footnote to table 1) [7, 9]. Outbreaks of Multidrug-Resistant Typhoid Since 1989 outbreaks caused by strains of S. typhi resistant to chloramphenicol, ampicillin, and trimethoprim and with ad- ditional resistance to streptomycin, sulfonamides, and tetracy- clines (antibiogram, ACSSuTTm; see footnote to table 1) have been repo rted in many developing countries, especially Paki- stan [10, 11] and India [9, 12-14]. Such strains have been termed multidrug-resistant (MDR). MDR strains have also caused outbreaks in Bangladesh [15], several countries in Southeast Asia [16], and both North and South Africa [17, 18], and in 1991 there was a sm all outbreak associated with a food- handler in a take-out restaurant in Britain [19] (table 1). MDR strains linked to immigrant workers from the Indian subconti- nent have been isolated with increasing frequency in several countries in the Arabian Gulf [20-22]. The most common Vi phage types have been those of El and M 1, but outbreaks have been caused by MDR strains of Vi phage types 51 and 0 in India [13, 14], Vi phage type M 1   b  y  g  u  e  s  t   o n D  e  c  e m  b  e r  5  , 2  0 1 1 h  t   t   p  :  /   /   c i   d  .  o x f   o r  d  j   o  u r n  a l   s  .  o r  g  /  D  o  w n l   o  a  d  e  d f  r  o  

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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.

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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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