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Trends of Multiple-Drug Resistance among Salmonella Serotype Typhi Isolates during a 14-Year Period in Egypt Momtaz O. Wasfy,1 Robert Frenck,1 Tharwat F. Ismail,1 Hoda Mansour,2 Joseph L. Malone,1 and Frank J. Mahoney1,3 United States Naval Medical Research Unit Number 3 and 2Abbassia Fever Hospital, Cairo, Egypt; and 3Centers for Disease Control and Prevention, Atlanta, Georgia
1
A total of 853 isolates of Salmonella serotype Typhi recovered from patients with typhoid fever who were admitted to a major infectious disease hospital in Cairo, Egypt, from 1987 through 2000 underwent antibiotic susceptibility testing to determine multiple-drug resistance. The observed resurgence of chloramphenicol susceptibility (P p .002 ) may suggest reuse of this drug for the treatment of typhoid fever in Egypt. Typhoid fever is common among individuals in developing countries, with 120 million infections estimated to occur worldwide annually, resulting in 700,000 deaths [1, 2]. The disease has become rare in industrialized regions, except among subjects returning from international travel to areas of endemicity [3]. Historically, the infection has been treated with either chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole (TMP-SMX). However, the widespread emergence of antibiotic-resistant Salmonella serotype Typhi has presented an important public health problem during the past 2 decades. In Egypt, despite the endemicity of typhoid fever [4, 5] and the easy accessibility of such antibiotics as ampicillin and chloramphenicol, the first report of chloramphenicol-resistant S. Typhi did not appear until 1981 [6]. By 1993, Mourad et Received 20 February 2002; accepted 26 June 2002; electronically published 28 October 2002. Financial support: US Naval Medical Research and Development Command (Bethesda, MD) and the Global Surveillance Programme, Naval Medical Research Center (Washington, DC). The opinions expressed in this manuscript are those of the authors and do not necessarily reflect those of the US Navy, the US Department of Defense, the US Government, the World Health Organization, or the Egyptian Ministry of Health. Reprints or correspondence: Momtaz O. Wasfy, c/o Commanding Officer, US Naval Medical Research Unit No. 3, PSC 452, Box 5000, FPO AE 09835-0007, USA (
[email protected]. navy.mil). Clinical Infectious Diseases 2002; 35:1265–8 This article is in the public domain, and no copyright is claimed. 1058-4838/2002/3510-0019
al. [7] found that 43% of S. Typhi isolates recovered at Alexandria Fever Hospital (Alexandria, Egypt) were multiple drug–resistant (MDR) isolates. This observation was confirmed by other studies that reported high rates of isolation of MDR S. Typhi in Egypt during the late 1980s and early 1990s [2, 8, 9]. In a Vi-phage typing study, Mourad et al. [7] found that the MDR S. Typhi isolates identified in Egypt were E2 or D1-N types, which are different from the types identified on the Indian subcontinent, an area where MDR S. Typhi is common and that serves as a potential source of introduction of MDR S. Typhi into Egypt. Unlike the isolates from India, the isolates from Egypt carried a 120-MDa plasmid of the H1 compatibility group and were found to be positive for b-lactamase and acetyltransferase [7]. During a 14-year period (1987–2000), the US Naval Medical Research Unit Number 3 (NAMRU-3), located in Cairo, Egypt, collected S. Typhi isolates from patients participating in numerous clinical trials and surveillance activities, thereby allowing us to gain information on the long-term antibiotic susceptibility trends for S. Typhi within the country. The present report is a summary of our experience. Materials and methods. The study site was the Abbassia Fever Hospital (Cairo, Egypt), a 1500-bed primary care and referral hospital that serves an estimated population of 16 million people and that had been established for the evaluation and treatment of infectious diseases in children and adults. S. Typhi was recovered from the blood of patients who were admitted to the Abbassia Fever Hospital from 1987 through 2000 and who were participating either in a trial of treatment for typhoid fever or in a surveillance project established to determine the burden of typhoid fever within Egypt. On the day of admission to the hospital, before the initiation of antibiotic therapy, an aliquot of each patient’s blood was collected, inoculated onto Bi-phasic blood culture bottles (PML Microbiologicals), and incubated at 37C. A separate blood culture was performed for each patient. Bottles were checked daily for 14 days, and, when growth was noted, an aliquot of blood was streaked onto MacConkey, Salmonella-Shigella, and blood agar plates to allow for definitive identification of the organism by use of standard biochemical and serological methods [10]. Susceptibility to ampicillin (10 mg), chloramphenicol (30 mg), erythromycin (15 mg), tetracycline (30 mg), and TMP-SMX (25 mg) was determined for all isolates, and, after 1997, susceptibility to ciprofloxacin (5 mg) and ceftriaxone (30 mg) was also assessed. All antibiotic susceptibility testing was performed usBRIEF REPORT • CID 2002:35 (15 November) • 1265
Table 1. Percentage of multiple drug–resistant (MDR) Salmonella serotype Typhi isolates recovered from patients with typhoid fever at a hospital in Cairo, Egypt, during a 14-year period, according to the results of susceptibility testing. Percentage of MDR S. Typhi isolates (total no. of S. Typhi isolates) Year
Amp
Chl
TMP-SMX
Em
NA
80 (70)
Tet
MDR
NA
19 (60)
1987
19 (75)
20 (60)
1988
24 (58)
25 (28)
24 (28)
75 (2)
11 (28)
24 (28)
1989
45 (51)
30 (10)
45 (38)
69 (51)
41 (41)
45 (51)
1990
65 (48)
59 (48)
29 (48)
92 (48)
NA
60 (48)
1991
65 (114)
61 (93)
55 (111)
90 (93)
56 (111)
61 (127)
1992
66 (114)
28 (114)
53 (114)
100 (110)
49 (114)
53 (114)
1993
100 (27)
100 (27)
100 (27)
NA
NA
100 (27)
1994
45 (20)
45 (20)
45 (20)
NA
NA
45 (9)
1995
62 (50)
62 (50)
62 (50)
NA
NA
62 (31)
1996
4 (29)
4 (29)
4 (29)
NA
NA
14 (4)
1997
20 (85)
15 (85)
22 (83)
NA
19 (42)
15 (83)
1998
15 (41)
15 (41)
17 (41)
NA
NA
15 (41)
NA
NA
1999 2000 Total
9 (100) 5 (41) 43.4 (853)
9 (100) 5 (41) 33 (746)
9 (100) 5 (41) 37.4 (730)
NA
NA
88 (400)
43.5 (336)
9 (100) 5 (41) 37.7 (764)
NOTE. “Multiple-drug resistance” was defined as resistance to 12 antibiotics, including ampicillin and chloramphenicol. Antibiotics tested included ampicillin (Amp; 10 mg), chloramphenicol (Chl; 30 mg), trimethoprim-sulfamethoxazole (TMP-SMX; 25 mg), erythromycin (Em; 15 mg), and tetracycline (Tet; 30 mg). Testing for Em and Tet was inconsistently performed because the 2 drugs are not among the recommended treatments for typhoid fever [2]. NA, not available.
ing the disk-diffusion Kirby-Bauer method [11]. MDR S. Typhi infections were defined as infections due to S. Typhi isolates that were resistant to 12 antibiotics, including ampicillin and chloramphenicol. Results. From 1987 through 2000, a total of 853 S. Typhi isolates were identified in blood cultures and underwent antibiotic susceptibility testing. For the isolates in aggregate, the antibiotic to which there was the highest percentage of resistance was ampicillin (39% of isolates), followed closely by TMP-SMX (36% of isolates), tetracycline (35% of isolates), and chloramphenicol (34% of isolates) (table 1). However, resistance to individual antibiotics varied dramatically during the reporting period, as exemplified by the prevalence of ampicillinresistant isolates, which was 100% in 1993 but which decreased to only 5% by 2000. None of the 182 isolates collected after 1987 were resistant to either ciprofloxacin or ceftriaxone. The prevalence of MDR S. Typhi isolates, similar to that of S. Typhi isolates with single-drug resistance, increased from 19% in 1987 to 100% in 1993, but it subsequently decreased again to only 5% by 2000 (figure 1). Discussion. With the exception of a report of a single chloramphenicol-resistant isolate, until the early 1980s, S. Typhi isolates recovered in Egypt were routinely found to be susceptible to all antibiotics tested [6]. However, once drug-resistant S. Typhi isolates emerged, they quickly became a significant problem, a pattern that has been repeated in many areas of the 1266 • CID 2002:35 (15 November) • BRIEF REPORT
world where S. Typhi is prevalent [12–16]. Whether the resistance of S. Typhi isolates in Egypt developed de novo or was transferred from other parts of the world is beyond the scope of this study. However, evidence suggestive of de novo development of resistance includes recognition of unique phagetype strains of S. Typhi in Egypt [7]. Risk factors frequently associated with the development of antibiotic resistance include excessive or indiscriminate use of antibiotics, high endemicity of disease [4, 5], and poor hygiene, all of which are present in developing countries [2, 6, 7, 17]. The development of S. Typhi strains that are resistant to
Figure 1. Percentage of multiple drug–resistant Salmonella serotype Typhi isolates in Egypt during a 14-year period. “Multiple-drug resistance” was defined as resistance to 12 antibiotics (ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole or tetracycline).
antibiotics historically used to treat S. Typhi infection has forced physicians to prescribe fluoroquinolones or third-generation cephalosporins [3, 18, 19]. So far, data from the present study show that neither quinolone resistance nor third-generation cephalosporin resistance has emerged in Egypt. However, extrapolation from data in the literature suggests that quinolone resistance is likely to develop unless use of this drug class is restricted [3, 20]. An interesting finding in our study was the decrease in the prevalence of MDR S. Typhi isolates that have been recovered since 1996, with the prevalence reaching only 5% in 2000. This finding is in agreement with reports from some parts of the world where typhoid is endemic. For instance, in India, a resurgence in chloramphenicol-susceptible S. Typhi strains has been reported in recent years [21, 22]. Eighty percent of Indian strains isolated in 1991–1993 were susceptible to chloramphenicol, compared with only 33.3% of such strains isolated in 1990–1991 (P ! .001). This observation was attributed to the restricted use of chloramphenicol for 2.5 years. Saha et al. [17] reported similar findings from Bangladesh and claimed that the finding of increased chloramphenicol resistance among S. Typhi strains may have been an exaggeration, because most studies conducted in this field involved hospitalized patients who presented with the most severe, refractory, or complicated infections. It is likely that the use of more-effective antibiotics could have caused a decrease in the prevalence of persons in the community with chronic infection and a decrease in the circulation of resistant strains. A preliminary study at our laboratory showed that most susceptible S. Typhi isolates have been cured of the resistance plasmid (data not shown), whereas some MDR strains did not harbor any plasmids. Further studies of these observations are underway. For S. Typhi isolates from Egypt, the significant shift in the antibiotic susceptibility pattern—from resistance to susceptibility to most antibiotics—increases (P p .002 ) the possibility that drugs that have been historically useful for the treatment of typhoid fever, such as chloramphenicol and ampicillin, should again be considered for first-line treatment of the infection. The advantages of a return to the use of these drugs include their availability in the developing world, their cheaper cost, and their well-established clinical efficiency [23]. However, the risk of relapse and the development of a carrier state were significantly higher among patients treated with ampicillin than among those treated with chloramphenicol [24]. The present study shows that the antibiotic resistance patterns among S. Typhi isolates from Egypt can change significantly over relatively short periods, with the prevalence of MDR S. Typhi isolates increasing from nonexistence to 160% and then decreasing to only 5% within a 15-year period. Therefore, collection of data that document antibiotic resistance patterns
is critical, and treatment of infection needs to vary on the basis of current patterns of resistance. Although it appears that chloramphenicol and ampicillin may again be used as the primary antibiotics for the treatment of typhoid fever in Egypt, further monitoring is needed before a definitive statement can be made.
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