Decreased Susceptibility to Ciprofloxacin in Salmonella enterica serotype Typhi, United Kingdom.In 1999, 23% of Salmonella enterica Salmonella enterica is a rod shaped, flagellated, Gram-negative bacterium, and a member of the genus Salmonella. Serovars
S. enterica has an extraordinarily large number of serovars serotype serotype /se·ro·type/ (ser´o-tip) the type of a microorganism determined by its constituent antigens; a taxonomic subdivision based thereon.
v. Typhi isolates from patients in the United Kingdom exhibited decreased susceptibility to ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt.
n. (MIC 0.25-1.0 mg/L); more than half were also resistant to chloramphenicol chloramphenicol (klōr'ămfĕn`əkŏl'), antibiotic effective against a wide range of gram-negative and gram-positive bacteria (see Gram's stain). It was originally isolated from a species of Streptomyces bacteria. , ampicillin ampicillin (ăm'pĭsĭl`ĭn), a penicillin-type antibiotic that is effective against both gram-negative microorganisms and gram-positive microorganisms such as Escherichia coli. , and trimethoprim trimethoprim /tri·meth·o·prim/ (-meth´o-prim) an antibacterial closely related to pyrimethamine; almost always used in combination with a sulfonamide, primarily for the treatment of urinary tract infections. . Increasing numbers of treatment failures have been noted. Most infections have been in patients with a recent history of travel to India and Pakistan.
Salmonella enterica serotype Typhi is endemic in developing countries in Africa, South and Central America Central America, narrow, southernmost region (c.202,200 sq mi/523,698 sq km) of North America, linked to South America at Colombia. It separates the Caribbean from the Pacific. , and the Indian subcontinent Indian subcontinent, region, S central Asia, comprising the countries of Pakistan, India, and Bangladesh and the Himalayan states of Nepal, and Bhutan. Sri Lanka, an island off the southeastern tip of the Indian peninsula, is often considered a part of the subcontinent. , with an estimated incidence of 33 million cases each year (1). By contrast, in developed countries such as the United Kingdom or the USA, incidence is much lower, and most cases are in travelers returning from endemic areas. For example, 150 to 300 cases occur each year in the U.K., at least 70% in patients with a history of recent foreign travel.
For patients with typhoid fever typhoid fever acute, generalized infection caused by Salmonella typhi. The main sources of infection are contaminated water or milk and, especially in urban communities, food handlers who are carriers. , administration of an effective antibiotic should begin as soon as clinical diagnosis is made, without recourse A phrase used by an endorser (a signer other than the original maker) of a negotiable instrument (for example, a check or promissory note) to mean that if payment of the instrument is refused, the endorser will not be responsible. to results of antimicrobial sensitivity tests. From 1948 to the mid-1970s, chloramphenicol was the first-line drug of choice, and in developed countries its use resulted in a reduction in mortality rates from 10% to [is less than] 2%. After extensive outbreaks of typhoid fever occurred in Mexico and India in the early and mid-1970s, in which epidemic strains were resistant to chloramphenicol (2,3), the efficacy of this antimicrobial agent was in doubt.
Alternative drugs for typhoid fever are ampicillin and trimethoprim. However, following outbreaks in the Indian subcontinent, the Arabian Gulf Arabian Gulf: see Persian Gulf. , the Philippines, and South Africa South Africa, Afrikaans Suid-Afrika, officially Republic of South Africa, republic (2005 est. pop. 44,344,000), 471,442 sq mi (1,221,037 sq km), S Africa. in the late 1980s and early 1990s, in which causative strains were resistant to ampicillin and trimethoprim in addition to chloramphenicol, the efficacy of these antimicrobial agents Antimicrobial agents
Chemical compounds biosynthetically or synthetically produced which either destroy or usefully suppress the growth or metabolism of a variety of microscopic or submicroscopic forms of life. has also been impaired (4).
The Laboratory of Enteric enteric /en·ter·ic/ (en-ter´ik) within or pertaining to the small intestine.
1. Of, relating to, or within the intestine.
2. Pathogens of the Public Health Laboratory Service of England and Wales England and Wales are both constituent countries of the United Kingdom, that together share a single legal system: English law. Legislatively, England and Wales are treated as a single unit (see State (law)) for the conflict of laws. is the reference center in the U.K. for strains of S. Typhi. Strains are identified by Vi-phage typing; all strains are tested with an agar dilution method for resistance to a panel of antimicrobial drugs. The final plate concentrations for selected antimicrobial drugs were chloramphenicol 8 mg/L, ampicillin 8 mg/L, trimethoprim 2 mg/L, nalidixic acid nalidixic acid /nal·i·dix·ic ac·id/ (nal-i-dik´sik) a synthetic antibacterial agent used in the treatment of genitourinary infections caused by gram-negative organisms.
n. 16 mg/L, ciprofloxacin 0.125 mg/L, ceftriaxone ceftriaxone /cef·tri·ax·one/ (cef?tri-ak´son) a semisynthetic, ß–resistant, third-generation cephalosporin effective against a wide range of gram-positive and gram-negative bacteria, used as the sodium salt. 1 mg/L, and cefotaxime 1 mg/L.
For isolates resistant to ciprofloxacin at 0.125 mg/L, full MICs are determined either by incorporating doubled concentrations of the antimicrobial agent into the agar substrate or by E-test. All isolates resistant to ciprofloxacin at 0.125 mg/L were also resistant to nalidixic acid at 16 mg/L. In contrast, isolates sensitive to nalidixic acid at 16 mg/L had MICs to ciprofloxacin of [is less than] 0.025 mg/L. All strains with resistance to chloramphenicol, ampicillin, trimethoprim, or nalidixic acid/ciprofloxacin were tested for the ability to transfer these resistances to a drug-sensitive strain of Escherichia coli Escherichia coli (ĕsh'ərĭk`ēə kō`lī), common bacterium that normally inhabits the intestinal tracts of humans and animals, but can cause infection in other parts of the body, especially the urinary tract. K12. Resultant resistance plasmids were characterized by incompatibility grouping and agarose gel electrophoresis Agarose gel electrophoresis is a method used in biochemistry and molecular biology to separate DNA, RNA, or protein molecules by size. This is achieved by moving negatively charged nucleic acid molecules through an agarose matrix with an electric field (electrophoresis). after extraction of plasmid DNA from donor strains of S. Typhi and recipient strains of E. coli E. coli: see Escherichia coli.
in full Escherichia coli
Species of bacterium that inhabits the stomach and intestines. E. coli can be transmitted by water, milk, food, or flies and other insects. K12.
From 1978 to 1985, resistance to chloramphenicol was identified in 11 (0.47%) of 2,356 strains studied (5); therefore, chloramphenicol remained the first-line drug for typhoid fever before results of laboratory sensitivity tests became available. From 1986 to 1989, chloramphenicol resistance increased threefold: 12 (1.5%) of 790 isolates were resistant. However, this increase was not considered sufficient to change recommendations about therapy. In 1990, there was a dramatic change, with 20% of 248 isolates resistant to chloramphenicol; most were also resistant to ampicillin and trimethoprim (6). In 1991, because of this increased chloramphenicol resistance, ciprofloxacin was recommended as an alternative for patients with a history of recent travel to epidemic areas (7).
From 1990 to 1999, 151 to 291 (mean 210) patients per year in the U.K. had typhoid fever. The incidence of multidrug resistance multidrug resistance,
n the adaptation of tumor cells or infectious agents to resist chemotherapeutic agents. (MDR MDR,
n See multidrug resistance.
n the abbreviation for minimum daily requirement, specifically the Minimum Daily Requirements for Specific Nutrients compiled by the United States Food and Drug Administration. ) to chloramphenicol, ampicillin, and trimethoprim increased from 21% in 1991 to 36% in 1994, declined to 13% in 1997, and then increased to 26% in 1999 (Table 1). More than 90% of patients infected with MDR strains had recently returned from the Indian subcontinent, particularly Pakistan and India. The reasons for the decline in MDR strains in 1997 followed by the return to 1996 levels in 1998 and 1999 are not known but may be related to changes in climatic conditions in the Indian subcontinent in the mid-1990s, followed by reestablishment of MDR strains in different parts of India in the late 1990s. Epidemiologic investigations to test these hypotheses are in progress.
Table 1. Incidence of multidrug resistance and decreased susceptibility to ciprofloxacin in Salmonella enterica serotype Typhi, U.K., 1990-1999 Decreased susceptibility MDR(b) to [CP.sub.L] Year Strains(a) no. (%) no. (%) 1990 248 50 (20) 0 (0) 1991 226 48 (21) 2 (0.9) 1992 204 49 (24) 1 (0.5) 1993 194 49 (25) 1 (0.5) 1994 259 94 (36) 5 (2) 1995 291 100 (34) 8 (3) 1996 210 52 (25) 11 (7) 1997 174 22 (13) 9 (5) 1998 151 34 (23) 32 (21) 1999 179 47 (26) 42 (23) [CP.sub.L] strains also resistant to: Year Strains(a) C A Tm Ct Cf 1990 248 0 0 0 0 0 1991 226 1 1 1 0 0 1992 204 0 0 0 0 0 1993 194 1 1 1 0 0 1994 259 5 5 5 0 0 1995 291 5 5 5 0 0 1996 210 7 7 7 0 0 1997 174 6 6 6 0 0 1998 151 19 19 19 0 0 1999 179 25 25 25 0 0 (a) Strains referred to Laboratory of Enteric Pathogens. (b) MDR = multidrug resistant (to chloramphenicol, ampicillin, and trimethoprim). Resistance symbols: C, chloramphenicol; A, ampicillin; Tm, trimethoprim; [CP.sub.L], ciprofloxacin (MIC 0.25-1.0 mg/L); Ct, ceftriaxone; Cf, cefotaxime. Percentages of total isolates in parentheses.
In the early 1990s, the most common Vi-phage type in MDR strains was phage phage: see bacteriophage.
phage - A program that modifies other programs or databases in unauthorised ways; especially one that propagates a virus or Trojan horse. See also worm, mockingbird. The analogy, of course, is with phage viruses in biology. type M1, and almost all patients infected with strains of this phage type had acquired the infections in Pakistan. The last isolations of MDR phage type M1 in the U.K. were in 1994 (4). Since 1993, the most common MDR phage type has been E1. Most patients infected with MDR strains of phage type E1 had acquired the infections in India or Pakistan. However, infections were also recorded in patients returning from Bangladesh, Sri Lanka, and Afghanistan. Regardless of phage type, in all MDR strains resistance to chloramphenicol, ampicillin, and trimethoprim has been encoded by plasmids of approximately 100 megadaltons belonging to the [H.sub.1] incompatibility group.
In 1991, a strain of S. Typhi with plasmid-encoded resistance to chloramphenicol, ampicillin, and trimethoprim and with chromosomally encoded resistance to nalidixic acid (MIC 512 mg/L) was isolated from a 1-year-old child who had recently returned from India. The strain also showed a marked decrease in sensitivity to ciprofloxacin (MIC 0.6 mg/L). The patient did not respond to treatment with ciprofloxacin despite serum levels of 1.5 mg/L. In 1995, 8 (3%) of 291 isolates showed decreased sensitivity to ciprofloxacin (MICs 0.38-0.75 mg/L by E-test); 5 were also resistant to chloramphenicol, ampicillin, and trimethoprim. In 1998, 32 (21%) of 151 strains exhibited decreased susceptibility to ciprofloxacin. One patient, a 65-year-old woman who returned from India infected with a strain of phage type E1 (MIC to ciprofloxacin of 1.0 mg/L) did not respond to twice a day treatment with ciprofloxacin, 400 mg intravenously. After 5 days, treatment was changed to amoxicillin amoxicillin /amox·i·cil·lin/ (ah-mok?si-sil´in) a semisynthetic derivative of ampicillin effective against a broad spectrum of gram-positive and gram-negative bacteria.
n. and ceftriaxone. Within 3 days, the patient's condition improved, and after a further 5 days she was apyrexial (8).
S. Typhi with decreased susceptibility to ciprofloxacin increased to 23% in the U.K. in 1999 (Table 1). All strains with decreased sensitivity to ciprofloxacin were also resistant to nalidixic acid (MIC 512 mg/L). The predominant phage types have been E1 (81% of cases) and E9 (4%). However, strains of phage types C2, E7, M1, untypeable Vi (UVS UVS Ultraviolet Spectrometer (Galileo instrument)
UVS Unabhängiger Verwaltungssenat (Austria)
UVS Unmanned Vehicle Systems
UVS Ultraviolet-Sensitive (syndrome) ), and Vi-negative have also been identified. Most patients had recently returned from India or Pakistan. However, in 1998 and 1999, strains with decreased susceptibility to ciprofloxacin were also isolated from travelers returning from Sri Lanka, Nepal, Bangladesh, and Thailand (Table 2). Furthermore, in both years [is greater than] 50% of isolates with decreased susceptibility to ciprofloxacin were also MDR (Table 1). In 1999, at least 10 patients infected with strains with decreased susceptibility to ciprofloxacin did not respond to treatment with fluoroquinolone fluoroquinolone /flu·o·ro·quin·o·lone/ (-kwin´o-lon) any of a subgroup of fluorine-substituted quinolones, having a broader spectrum of activity than nalidixic acid.
n. antimicrobials. In such cases, ceftriaxone was the most frequently used alternative. In contrast to resistance to chloramphenicol, ampicillin, and trimethoprim, resistance to ciprofloxacin has been chromosomally encoded in all isolates with decreased sensitivity to this antimicrobial agent.
Table 2. Phage types in Salmonella Typhi isolates with decreased susceptibility to ciprofloxacin ([C.sub.pL], United Kingdom, 1991-1999 Phage types Year [C.sub.pL] E1 M1 E9 Others 1991 2 2 0 0 0 1992 1 0 0 0 1 (B2) 1993 1 0 0 0 1 (E14) 1994 5 5 0 0 0 1995 8 6 1 0 1 (D1) 1996 11 11 0 0 0 1997 9 8 0 0 1(A) 1998 32 23 0 6 3 (G2,2;O,1) 1999 42 27 1 3 11 (UVS, 7; E7, 1; C2, 1; Vi-negative, 1) Year [C.sub.pL] Country of origin (no.) 1991 2 India (1), Nepal (1) 1992 1 India (1) 1993 1 Bangladesh (1) 1994 5 India (3), Nepal (1), Bangladesh (1) 1995 8 India (4), Pakistan (3), NS(a) (1) 1996 11 India (9), Pakistan (2) 1997 9 India (5), Pakistan (2), Nepal (1), NS (1) 1998 32 Pakistan (14), India (9), Sri Lanka (1), Bangladesh (1), NS (7) 1999 42 India (31), Pakistan (6), Bangladesh (1), Thailand (1), NS (3) (a) NS = details of travel itinerary not provided; UVS = untypeable with the Vi typing phages.
Since 1993, strains of S. Typhi with decreased susceptibility to ciprofloxacin have been isolated with increasing frequency in Vietnam (9). In 1997, [is greater than] 6,000 cases occurred in an extensive epidemic in Tajikistan of nalidixic acid-resistant S. Typhi with decreased susceptibility to ciprofloxacin (10). The epidemic strain was untypeable with the Vi typing phages but had a pulsed-field profile indistinguishable from that of isolates of MDR Vi-phage type E1 from patients infected in India (11). In both Vietnam and Tajikistan, treatment failures with fluoroquinolone antibiotics have been noted.
The accepted British Society for Antimicrobial Chemotherapy and National Committee for Clinical Laboratory Standards' zone size equivalents for resistance to ciprofloxacin in disc diffusion tests are 2 mg/L and 4 mg/L, respectively, for Enterobacteriaceae. However, testing for resistance at these levels could result in decreased susceptibilities not being detected. As all strains with decreased susceptibility to ciprofloxacin have also been resistant to nalidixic acid, we suggest that the latter antimicrobial agent be included in the panel of drugs used for sensitivity testing. If resistance to nalidixic acid is detected, full MICs to ciprofloxacin should be performed in the event of treatment failure.
Our findings suggest that strains of S. Typhi with decreased sensitivity to ciprofloxacin are now endemic in several countries in the Indian subcontinent and that such strains are increasing in travelers returning to the U.K. Despite the low level of resistance, treatment failures are being increasingly noted. In such cases, possible alternatives such as ceftriaxone or cefotaxime could be considered. In this respect, it is reassuring that all strains of S. Typhi so far tested were sensitive to these antimicrobial drugs.
Dr. Threlfall is head of the Antibiotic Resistance antibiotic resistance,
n the ability of certain strains of microorganisms to develop resistance to antibiotics.
antibiotic resistance and Molecular Epidemiology molecular epidemiology Molecular medicine An evolving field that combines the tools of standard epidemiology–case studies, questionnaires and monitoring of exposure to external factors with the tools of molecular biology–eg, restriction endonucleases, Laboratory at the Central Public Health Laboratory of the Public Health Laboratory Service of England and Wales.
Mrs. Ward is head of the Salmonella Reference Unit in the Public Health Laboratory Service of England and Wales.
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Address for correspondence: E. John Threlfall, Laboratory of Enteric Pathogens, Central Public Health Laboratory, 61 Colindale Avenue, London NW9 5HT, U.K.; fax: + 44 0208 905 9929; e-mail: email@example.com