How multidrug resistance in typhoid fever affects treatment options.

Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Antimicrobial Therapeutics Reviews

How multidrug resistance in typhoid fever affects treatment options Aparna Tatavarthy,1 Vicki A. Luna,1 and Philip T. Amuso2,3 1 Center for Biological Defense, College of Public Health, University of South Florida, Tampa, Florida. 2 Florida Department of Health, Bureau of Public Health Laboratories, Tampa, Florida. 3 Morsani College of Medicine, University of South Florida, Tampa, Florida

Address for correspondence: Aparna Tatavarthy, Ph.D., U.S. Food and Drug Administration (FDA), Department of Health and Human Services (HHS), CFSAN/ORS, 5100 Paint Branch Pkwy., College Park, MD 20740. [email protected]

Salmonella enterica serotype Typhi (S. Typhi) is an enteric pathogen that causes typhoid fever. The infection can be severe, with significant morbidity and mortality, requiring antimicrobial therapy. Cases of S. Typhi infection in the United States and other developed countries are often associated with travel to endemic regions. The empirical use of first-line drugs for therapy, including ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole, has resulted in transmissible multidrug resistance. With the global increase in multidrug-resistant S. Typhi, use of ciprofloxacin, with excellent oral absorption, few side effects, and cost-effectiveness, has become popular for treatment. However, decreased ciprofloxacin susceptibility due to point mutations in the S. Typhi genes gyrA and/or parC has caused treatment failures, necessitating alternative therapeutic options. S. Typhi is typically genetically homogenous, with phylogenetic and epidemiological studies showing that identical clones and diverse S. Typhi types often coexist in the same geographic region. Studies investigating point mutations have demonstrated that selective pressure from empirical use of first-line drugs and fluoroquinolones has led to the global emergence of haplotype H-58. Antibiotic resistance is subject to high selective pressure in S. Typhi and thus demands careful use of antimicrobials. Keywords: Salmonella Typhi; typhoid fever; antibiotic resistance; fluoroquinolones

Introduction Salmonella enterica serotype Typhi (S. Typhi) is a human-specific, enteric pathogen that causes typhoid fever. The infection is characterized by high fever, chills, headache, and abdominal pain. The mortality rate of the disease is high (12–30%), and requires antimicrobial intervention.1 Asymptomatic carriers are reservoirs and also serve as vehicles in the transmission of this organism through the fecal–oral route by ingesting contaminated food and water.2 The disease is endemic in certain regions of the world, including the Indian subcontinent, the Caribbean region, Africa, and South and Central America. These regions, especially South Asia, are therefore considered high-risk areas for foreign travelers.3 Two types of vaccines are commercially

This review is dedicated to Kealy K Peak.

available and have been shown to be partially effective in preventing the disease: the live attenuated Ty21a and the parenteral Vi vaccines.4 However, these vaccines have certain limitations, including low efficacy in children younger than 2 years of age and short-lived immunity in adults.5 According to the World Health Organization, the injectable Vi capsular polysaccharide vaccine (ViCPS vaccine) results in a protective efficacy of about 72% at 1.5 years post-vaccination; after 3 years it is only about 50% protective. To maintain protection, revaccination is recommended every 3 years.a The oral vaccine, based on the live, attenuated mutant strain of S.Typhi Ty21a (Ty21a vaccine), is supplied in enteric coated capsules to help protect it from stomach acid; again, revaccination is recommended every 3 years for individuals living in countries or areas a

http://www.who.int/ith/vaccines/typhoidfever/en/ doi: 10.1111/nyas.12490

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Therapeutic options for typhoid fever

Table 1. Clinical and Laboratory Standards Institute7 (CLSI) and European Committee on Antimicrobial Suscepti-

bility Testing (EUCAST) clinical breakpoints6 CLSI MIC interpretive criteria (␮g/mL) Antibiotic Ampicillin Cefotaxime or ceftriaxone Ciprofloxacin Levofloxacin Oflaxacin Nalidixic acid Trimethoprim/ sulfamethoxazole Chloramphenicol

S

I

R

Zone diameter interpretive criteria (nearest whole mm) §

ࣘ8 16 ࣙ32 10 ࣘ1 2 ࣙ4 30 ࣘ1 2 ࣙ4 ࣘ0.06 0.12–05 ࣙ1 5 ࣘ0.12 0.25–1 ࣙ2 – ࣘ0.12 0.25–1 ࣙ2 – ࣘ16 – ࣙ32 30 ࣘ2/38 – ࣙ4/76 1.25/ 23.75 ࣘ8 16 ࣙ32 30

S

I

R

ࣙ17 ࣙ26 ࣙ23 ࣙ31 – – ࣙ19 ࣙ16

14–16 23–25 20–22 21–30 – – 14–18 11–15

ࣘ13 ࣘ22 ࣘ19 ࣘ20 ࣘ0.12 ࣘ0.12 ࣘ13 ࣘ10

ࣙ18

13–17 ࣘ12

EUCAST MIC (mg/L)

Zone diameter breakpoint (mm)

S

R

§

S

R

ࣘ8 ࣘ1

ࣙ8 ࣙ2

10 5

ࣙ14 ࣙ20

ࣘ14 ࣘ17

ࣘ0.06 ࣘ1 ࣘ0.1 NA ࣘ2b

ࣙ0.06 5 ࣙ2 5 ࣙ1 5 NA ࣙ4b 1.25/ 23.75 ࣙ8 30

ࣙ24a ࣙ22 ࣙ22 NA ࣙ16b

ࣘ24a ࣘ19 ࣘ19 NA ࣘ13b

ࣙ17

ࣘ17

ࣘ8

Notes: There are no clinical breakpoints for azithromycin. However, according to EUCAST, azithromycin has been used in the treatment of infections with S. Typhi (MIC ࣘ16 mg/L for wild-type isolates) and Shigella spp. Per CLSI recommendations in an M100–S24 publication, antimicrobial tests of fecal isolates of Salmonella should only routinely report the ampicillin, fluoroquinolone, and trimethoprim-sulfamethoxazole results. For extraintestinal Salmonella, isolates should have a third-generation cephalosporin tested and reported. Chloramphenicol is considered a valid option for testing and therapy. a Pefloxacin disc diffusion susceptibility test results for interpretation of ciprofloxacin susceptibilities. b Trimethoprim:sulfamethoxazole in the ratio of 1:19; breakpoints are expressed as the trimethoprim concentration. § = disc content in ␮g. NA, not applicable.

at risk. These limitations make the use of current vaccines in undeveloped countries less than ideal because maintaining immunity in an at-risk population is resource intensive. Resistance of S. Typhi to multiple antibiotics, including the first-line drugs and floroquinolones, has greatly limited treatment options. Knowledge of resistance trends based on geographical distribution and typing patterns of S. Typhi is essential for empirical treatment of typhoid fever. In this review, we will discuss the current resistance trends, global circulation of dominant clones, and treatment options for S. Typhi infection. Our discussion is limited to multidrug-resistant S. Typhi (MDRST). For detailed information on drug resistance in Europe of Salmonella species in humans and animals, the reader is referred to the European Food Safety Authority (EFSA) Web sites.b Detailed information on

antibiotic resistance in Salmonella in humans and animals in the United States can be found in the National Antibiotic Resistance Monitoring System for Enteric Bacteria (NARMS).c The European and U.S. methods of antimicrobial resistance testing are slightly different. Table 1 shows clinical breakpoints for antimicrobials according to the European Committee on Antimicrobial Susceptibility Testing6 (EUCAST) and Clinical and Laboratory Standards Institute7 (CLSI) guidelines. EUCAST uses epidemiological cutoff (ECOFF) values as interpretation criteria for Salmonella in animals and food. An ECOFF value indicates the minimum inhibitory concentration (MIC) or zone diameter above which the pathogen shows detectable reduced susceptibility. In the EUCAST system, a microorganism is considered wild type when no acquired or mutational resistance mechanisms are present for the particular antimicrobial. To categorize a microorganism as wild type for a given

b

http://www.efsa.europa.eu/en/search/doc/3196.pdf and www.efsa.europa.eu/efsajournal

c

http://www.cdc.gov/narms


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bacterial species, the appropriate ECOFF value is applied in a defined phenotypic test system. A microorganism is considered nonwild type when it has an acquired or mutational resistance for the given antibiotic. Nonwild-type organisms are considered to show microbiological resistance, as opposed to clinical resistance. The clinical breakpoints that determine the therapeutic effectiveness of a drug may not detect microbial resistance. ECOFF values that are set to detect minor deviation in the wild-type population may not be appropriate for determining clinical resistance or the success or failure of a given antimicrobial. The ECOFF value is often lower than the clinical breakpoints. In our discussion here, resistance refers to clinical resistance unless otherwise specified. The discussion below is divided into three broad categories. The first includes plasmid-mediated multidrug resistance (MDR) first reported in early 1970s, caused by the H1 plasmid. The second is nalidixic acid–resistant S. Typhi (NARST), due to chromosomal mutations and its clonal emergence in the 2000s driven by ciprofloxacin usage. The third is the reduction of MDR from loss of the MDR plasmid, with advancement of NARST and clonal dominance of haplotype H-58. Plasmid-mediated MDR Emergence of MDR in S. Typhi Resistance to chloramphenicol, ampicillin, and trimethoprim/sulfamethoxazole (SXT) leads to MDR in S. Typhi. Because it significantly decreased the mortality rate of typhoid infections, chloramphenicol was the drug of choice for treating S. Typhi infections until widespread resistance was observed.8 In a 1989–1990 retrospective study of cases in Indonesia, van den Bergh et al. showed that the patient group receiving appropriate doses of chloramphenicol had a lower mortality rate and a zero relapse rate when compared to the groups that did not receive any antibiotics or to the group that received inappropriate doses of chloramphenicol. Despite its known bone marrow toxicity and associated aplasia, chloramphenicol was still the drug of choice until resistance to antibiotics became a concern. A moderate level of resistance and a trend of increasing MIC to chloramphenicol was reported in 1959–1961 in an Indian study.9 Resistance was observed in several other studies in the late 1960s.10–12 A large outbreak in 1972 in Mexico caused by 78

a chloramphenicol-resistant strain was alarming11 because of the large number of affected people (approximately 10,000). The characteristic feature of the outbreak strain was its resistance to multiple antibiotics, including chloramphenicol, tetracycline, streptomycin, and the sulfonamides, which was caused by a genetic element—referred to at the time as the R factor—that was transferrable to Escherichia coli.13 Cases of typhoid acquired in Mexico with a similar resistance pattern were spread worldwide and observed in British and Swedish travelers.10,12 The other interesting feature of this notable outbreak was an observed increase in resistance to ampicillin.11 In the late 1970s, as the R factor increasingly conferred resistance to chloramphenicol, sulfonamides, tetracycline, and streptomycin, the alternative therapy of ampicillin and SXT was found to be effective.14 While resistance to sulfa drugs was already being noted, the addition of trimethoprim proved an effective therapy.15 However, resistance to many classes of previously effective drugs, including ampicillin, chloramphenicol, and SXT, was soon observed (we refer to ampicillin, chloramphenicol, and SXT as classic first-line drugs, and resistance to these as MDR or MDRST). Resistance to multiple drug classes has been identified in various parts of the world over the years (e.g., in Korea in 197713 and in Hong Kong during a 1973–1982 study16 ). Researchers in an Indian hospital in the late 1980s found 84% of the strains to be resistant to chloramphenicol, ampicillin, tetracycline, and streptomycin, and demonstrated the presence of plasmids contributing to the transferable resistance.17 Plasmids of the H incompatibility group (IncHI1) harboring resistance to the classic first-line drugs were observed by various researchers in several parts of Asia.18,19 Molecular characterization of these isolates by pulsed-field gel electrophoresis (PFGE) and subsequently by ribotyping revealed the presence of not only identical clones20,21 but also multiple types in one geographic location.18,19,22 Integrons are genetic elements harboring one to several mobile gene cassettes that can lead to horizontal gene transfer.23,24 In the early 2000s, researchers reported the presence of class1 integrons in S. Typhi carrying multiple resistance genes, including dfr7 and aadA1, that conferred resistance to trimethoprim and streptomycin from Asia and Canada.20,22,25


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Nalidixic acid–resistant S. Typhi and its clonal emergence Fluoroquinolone resistance in S. Typhi With the increasing frequency of MDR, fluoroquinolone became the treatment choice. Advantages including effectiveness against MDR strains, good oral absorption, good tolerance, minimal side effects, and cost-effectiveness made ciprofloxacin a drug of choice for the treatment of S. Typhi infections.26–28 Although the incidence of side effects from ciprofloxacin use are usually minimal, they can be life threatening, including renal failure and severe effects to the central nervous and cardiovascular systems, especially for patients with underlying conditions.29–31 In one of the first clinical studies that examined patients with salmonellosis, shigellosis, and Campylobacter jejuni infections, the group that received ciprofloxacin had a lower duration of fever and diarrhea, compared to the placebo group.32 Ciprofloxacin was also very effective in treating children and carrier-state individuals.33–35 However, because of possible severe side effects, including arthropathy, ciprofloxacin usage in children and young adolescents under 18 years of age is recommended only for life-threatening infections.36,37 The short treatment course for S. Typhi infection has contributed to the popularity of ciprofloxacin among clinicians.38 After the introduction of ciprofloxacin, cases of fluoroquinolone-resistant S. Typhi were reported in the early 1990s.39,40 However, reports of nalidixic acid– and ciprofloxacin-susceptible strains continued into the early to mid 2000s.41 For example, a U.K.-based 1999 study reported that 23% of S. Typhi strains showed decreased ciprofloxacin susceptibility (DCS) (MIC = 0.25–1 ␮g/mL), and more than half of these were also MDR.42 A challenge with the DCS phenomenon was accurately identifying the reduced susceptibility. On the basis of observed treatment failures with ciprofloxacin, Thelfall et al. suggested that in cases of treatment failure with ciprofloxacin MIC to ciprofloxacin should be considered, rather than the breakpoints of the former National Committee for Clinical Laboratory Standards or the British Society for Antimicrobial Chemotherapy. In agreement, other studies also suggested that clinical breakpoints cannot identify DCS and may delay the administration


of an alternate antimicrobial to the patient.43,44 A study examining 60 S. Typhi isolates demonstrated that the MICs of ciprofloxacin ranged from 0.125 to 1 ␮g/mL, and yet the strains were reported as being sensitive, leading to treatment failure.43 This example demonstrates that routine clinical susceptibility testing may not necessarily produce relevant data. On the basis of available data and evidence, Crump et al., suggested reevaluating fluoroquinolone breakpoints to more accurately assess the anticipated clinical response.45 In addition, on the basis of the distribution of MICs for naldixic acid and ciprofloxacin among Salmonellae, it was suggested that nalidixic acid be used as an indicator for DCS. Three trends of antimicrobial resistance were observed following the introduction of ciprofloxacin for the treatment of typhoid fever: (1) continuing resistance to classic first-line drugs and low prevalence of quinolone-resistant S. Typhi; (2) equal prevalence of NARST and MDRST; and (3) a gradual increase of NARST and reduced prevalence of MDRST (Table 2). In a 1996–1997 U.S. public health laboratory surveillance study, Ackers et al. investigated 293 isolates associated with travel, particularly to Southeast Asia and Mexico, and observed that 17% were MDRST and 7% were NARST.46 A similar trend of combined resistance to first-line drugs and relatively higher resistance to nalidixic acid or DCS (MIC = 0.12–1 ␮g/mL; full-resistance is ࣙ2 ␮g/mL47 ) was observed in India,48 in a retrospective study of isolates from Pakistan and Bangladesh,49 and in two studies investigating isolates from children in Pakistan50 and in Cambodia.51 Other recent studies have demonstrated a trend of higher percentages of isolates showing nalidixic acid resistance compared to MDR from the first-line drugs. From a large pool of clinical isolates collected during 2005–2009 in South India, Menezes et al. observed that 78% were NARST and 22% were MDRST.52 Similar trends of lower incidence of MDR strains and higher numbers of NARST were noted in Vietnam in 2004,53 Africa during 2001–2008,54 Nepal,55 several parts of India,56,57 and in a U.S. study.58 In the recent 2011 EFSA report analyzing nontyphoidal Salmonella species in humans using clinical breakpoints, it was summarized that resistance was high (20–30%) for ampicillin, sulfonamides,


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Table 2. Table displaying emergence and global resistance trends of S. Typhi to multiple drugs, nalidixic acid, and

ciprofloxacin Country (origin of isolates)

Percentage of NARST or DCS

Year

Number of isolates

Percentage of MDRST

India

1989–1990

20

84

India Asia (Pakistan, India, Kuwait, Bangladesh) U.S.A.a Vietnam and India Korea

1992–1994 1990–1995

21 193

71.4 100

1996–1997 1999–2000

293 25

17 72

7 0

1999

6

100

16

Pakistan

2000

39

Pakistan Jordon

2002–2004 2004–2005

127 48

Nepal India U.S.A.a Denmarka U.S.A.a

2004–2006 2006–2007 2006–2010 2006–2010 2007–2011

Congo Cambodia Nepal India

2007–2011 2007–2011 2009–2010 2009–2011

94.8

0 ND 0

0

65 75

58 0

93 95 17 19 31

7.5 10 23.5 0 16

53.70 31.50 76 78.9 48

201 148 114 85

30.3 85 0.06 mg/L) and susceptibility or intermediate resistance to nalidixic acid (8–16 mg/L) in nontyphoidal Salmonella and other enteric species.72,73 Conjugative and nonconjugative types of plasmids carrying qnrB and qnrS genes were observed in multiple non-Typhi Salmonella serotypes in a large NARMS survey.73 Similarly, qnrB and qnrS genes were identified in a Dutch study in multiple Salmonella serotypes of human and poultry origin.74 QnrS genes were identified in multiple non-Typhi Salmonella serotypes associated with foreign travel and imported foods in the United Kingdom.75 An increased occurrence of qnrS genes was soon observed by the same group in the United Kingdom examining local Salmonella isolates and those associated with foreign travel or foods.76 Qnr genes were also seen in 66% of Salmonella isolates selected on the basis of DCS (MIC, 0.125–1.0 ␮g/mL) and susceptibility or intermediate resistance to nalidixic acid in a Danish study.77 The presence of qnr genes in S. Typhi has not been frequently reported. However, some studies have shown the possibility of qnrS in S. Typhi isolates.77,78 The resistance mechanisms associated with AcrAB–TolC and qnr not only lead to quinolone resistance but also to resistance to multiple classes of drugs. The AcrAB–TolC system, involved in decreased susceptibility to tetracycline, chloramphenicol, and florfenicol,67,69 is also associated with an increase in the MICs of ␤-lactams, including penicillin, carbenicillin, and cefoxitin.70 Plasmid-mediated quinolone resistance also often cotransmits resistance to two or more classes of antimicrobials, including ␤-lactmases.75 Cotransmission of qnr and ␤-lactamase genes is a major concern because of potential coselection of resistance to the drugs,76 which can be a particular concern in the case of S. Typhi because fluoroquinolones are not recommended for treatment of children, leaving extended-spectrum ␤-lactams as the treatment of


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Table 3. Mutations causing ciprofloxacin resistance (full or DCS)

Year of study

Ciprofloxacin MIC (␮g/mL)

1992–1994 (India)

0.256

1995–2001 (Japan) 2003–2004 (India)

0.25–0.5 0.5–ࣙ32

2004–2006 (India)

8–ࣙ512

2005–2009 (India)

0.25–64

2006–2007 (Kuwait, travel associated from Bangladesh) 2007–2010 (India, Pakistan, Bangladesh, United States) 2011 (Nepal)

12

a

Mutations Single at Ser-83 (9/12) or Asp-87 (1/12); double at Ser-83 and Asp-87 (2/12) Single at Ser-83 (20/25) or Asp-87 (5/25) Double mutations at Ser-83 of gyrA and Ser-80, Gly-78, or Glu-69 of parC (3/6); triple mutation at Ser-83 and Asp-87 of gyrA and Ser-80 of parC (3/6) Triple mutation at Ser 83, Asp-87, and Glu-133 of gyrA and at Met-52a outside QRDR (5/13); double mutations at Asp-76 and Leu-44 outside QRDR (1/13), Phe-72 of gyrA (3/13), Asp-76 of gyrA (4/13) Single mutation at Ser-83 in gyrA (2/10); double mutations at Ser-83 of gyrA and Thr-57 of parC (3/10); double mutations at Ser-83 of gyrA and Ser-80 of parC (3/10); double mutation at Ser-83 and Asp-87 of gyrA(1/10); and triple mutation at Ser-83 and Asp-87 of gyrA and Ser-80 of parC Four mutations at Leu-55, Ser-83, Asp-87, and Gln-106 of gyrA and triple mutations at Glu-84a , Trp-106a , and Tyr-128a of parC (2/2)

References Brown et al.39 Hirose et al.82 Gaind et al.79

Capoor et al.83

Menezes et al.52

Dimitrov et al.84

0.12–0.25

Single at Ser-83 (11/12) or Asp-87 (1/12)

Tatavarthy et al.58

ࣙ32

Double mutation at Ser-83 and Asp-87a of gyrA and a single mutation at Ser-80 in parC (1 isolate)

Koirala et al.80

Indicates first-time observed mutations.

choice.75 Possible coresistance to tetracycline, streptomycin, and sulfonamide is also alarming.77 Mutations in gyrA and parC and decreased ciprofloxacin susceptibility Mutations in the quinolone resistance–determining region (QRDR) of gyrA or parC are responsible for the observed higher MIC with quinolones and fluoroquinolones.52,58,78 Generally, a single mutation in the QRDR leads to DCS, and two or more mutations in gyrA and/or parC cause higher MICs for fluoroquinolones. Three or more mutations in the QRDR of gyrA or parC typically cause high ciprofloxacin resistance.52,78–81 A point mutation at Ser-83 in gyrA, leading to an amino acid change to Phe or Tyr,39,52,58,79,82 is com82

monly associated with a ciprofloxacin MIC ranging from 0.12 to 0.5 ␮g/mL (Table 3). A point mutation in gyrA, causing substitution of Asp at 87 with Tyr or Gly,39,58,82 produces a similar MIC range. Double mutations in gyrA or two single mutations each at gyrA and parC, leading to a ciprofloxacin MIC ranging from 0.25 to 0.5 ␮g/mL, are fairly common.39,58,79 Furthermore, triple mutations, including two in gyrA and one in parC, with a high MIC of ࣙ32 ␮g/mL, have been observed in India, Taiwan, and Nepal isolates.52,79–81 Four mutations, including three in gyrA and a novel mutation outside the QRDR associated with a very high ciprofloxacin MIC of ࣙ512 ␮g/mL, was observed in one of 13 ciprofloxacin-resistant strains in a 2004– 2006 Indian study.83 Seven mutations, including


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four in gyrA and three novel ones in parC, with a ciprofloxacin MIC of 12 ␮g/mL, were reported in two Bangladeshi isolates during 2006–2007 in Kuwait.84 Because isolates displaying DCS may cause treatment failure or relapse, identification of DCS is important for effective treatment of infection. Typhi isolates are routinely tested for nalidixic acid susceptibility because resistance to nalidixic acid is generally a good indicator of DCS. However, there are a few exceptions where an isolate displays DCS without nalidixic acid resistance with or without MDR,52,56,58,59,83 which could be the result of efflux pumps eliminating the drug. Nalidixic acid–resistant S. Typhi and clonal dominance Homogeneous nature of S. Typhi genome and resistance Compared to other serotypes of S. enterica, S. Typhi is a relatively contemporary organism.85 It is known to be a clonal or genetically homogenous organism on the basis of typing methods that highlight the conservative aspects of the genome, including multilocus sequence typing (MLST) and multilocus enzyme electrophoresis (MLEE).86,87 Phylogenetic studies suggest that only a few clones circulate globally and cause infections.54,88 For epidemiological investigations, fingerprinting methods that target areas that undergo genome rearrangements or point mutations have been more successful in discriminating closely related strains, compared to MLST and MLEE.89–92 These highly discriminatory methods include PFGE, ribotyping, and multilocus variable number of tandem repeats analysis. Single nucleotide polymorphism (SNP) analysis has been useful for both epidemiological as well as phylogenetic studies.91,93,94 A typical S. Typhi distribution pattern, noted by several groups employing various methods, including PFGE, ribotyping, variable number of tandem repeats typing, and SNP analysis, is the presence of similar clones in different geographical areas and coexistence of diverse clones in the same geographical area.58,88–92,95 Selective pressure from empirical antimicrobial use has fostered the emergence of MDR S. Typhi as a predominant clone from Southeast Asia. SNP analysis demonstrated that MDR S. Typhi primarily belonged to the haplotype H-58.88 Comparison of SNP analysis and PFGE showed that the haplo-


type H-58 and its variants with resistance to multiple drugs and or nalidixic acid have undergone a clonal expansion in Southeast Asia.53 Th H-58 haplotype has also undergone microevolution, and can be typed into several pulsotypes.53 The global clonal expansion of H-58 was evident in a Kenyan study investigating S. Typhi isolates during 1988–2008.54 An increasing trend of MDR followed by a combination of MDR and DCS (MIC, 0.1–1 ␮g/mL), with an eventual shift to NARST, was observed in that study. A study by Roumaganac et al. examined 55 polymorphic coding fragments in 295 S. Typhi strains from Southeast Asia during 1986–2004 by using mutational analysis.94 They noted that a majority of nalidixic acid–resistant isolates carrying gyrA or parC mutations belonged to haplotype H-58, suggesting that selection for nalidixic acid resistance resulted in the clonal expansion of H-58 and its related haplotypes. In a comparative wholegenome analysis with Southeast Asia haplotype H58 and the Indonesian haplotype H-59, Holt et al. demonstrated that gyrA mutations causing fluoroquinolone resistance are one of the few SNPs that have been adaptively selected.93 Their study investigated the presence of dissimilar SNPs, a sign of adaptive selection. They established that the majority of S. Typhi genes contained no SNPs, nor did they detect any signals of selection in the genes that had SNPs, with the exception of a few genes, including gyrA. This strongly suggests that selective pressure due to antibiotic use led to the success of fluoroquinolone-resistant S. Typhi. Roumaganac et al. and Holt et al. demonstrated that the selective pressure for gyrA mutations is very strong and has resulted in the global clonal expansion of this haplotype. Sporadic infection by MDRST and by nalidixic acid–sensitive strains is indicative of neutral evolution from healthy carriers,94 as pathogens carried by healthy individuals are generally not subjected to great selective pressure. The clonal nature of S. Typhi likely has an important role in the resistance trends. Several studies have observed that only a few clonal varieties circulate globally and cause infections.54,88,91,92 It is also clear that an MDR-type emerged as a dominant clone in the 1990s, causing infection as revealed by PFGE.89 The H-58 haplotype and its variants with MDR and DCS phenotypes are responsible for recent infections in several parts of the world, including Vietnam and Kenya.53,54 Antibiotic resistance


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clearly provides a great advantage to the organism, leading to the spread of the resistant type, as seen with the MDRST isolates with plasmids and later with the NARST isolates with gyrA mutations.93,94 The adaptive selection of gyrA mutations and H-58 haplotype likely led to global clonal expansion of this haplotype.53,93,94 The carrier state is subjected to less selective pressure as compared to the infected state and therefore it undergoes a slower evolution.94 The lack of nonhuman carriers leaves less room for genetic heterogeneity compared to pathogens that can colonize multiple hosts, which therefore likely leads to selection of the few successful clones. Clonality is also an indication of the spread of the organism from to poor hygiene and horizontal transmission. Treatment options based on current trend of resistance Strains that exhibit the MDR phenotype and are fully sensitive to ciprofloxacin have been reported.41,46,62 Therapeutic options for treatment of these strains include fluoroquinolones (e.g., ciprofloxacin and oxafloxacin) and extended-spectrum cephalosporins, such as ceftriaxone.46,96–98 In travelers returning from the Indian subcontinent, empirical treatment with ciprofloxacin should be reconsidered given the DCS and nalidixic acid resistance observed in that region. Extended-spectrum cephalosporins, including ceftriaxone, have been successfully used as an alternative for the treatment of S. Typhi with DCS.59,62 DCS S. Typhi has also been successfully treated with meropenam and aztreonam.61 Azithromycin and ceftazidime have also been used for treating patients with DCS or strains highly resistant to fluoroquinolones.60,80 Infections caused by ciprofloxacin-resistant strains have been successfully treated with ceftriaxone as shown by several investigators.81,83,84,99 Table 4 shows a detailed regimen and clinical efficacy of the empirical treatment and also includes patient travel history, ages, the resistance patterns observed after laboratory testing, and relapses and retreatments where available. It is interesting to note that, in the majority of cases, the empirical treatment is ciprofloxacin (Table 4). Though ceftriaxone and azithromycin are currently good alternative drugs for fluoroquinoloneresistant S. Typhi, emerging resistance is a concern. In a 2006–2007 Indian study, 6% of the S. Typhi 84

isolates were resistant to ceftriaxone.48 Intermediate resistance to ceftriaxone was also observed in 3.5% of strains in a study in Nepal in 2009–2010.55 Resistance or intermediate resistance to azithromycin was noted in more than half of S. Typhi and S. enterica serotype Paratyphi isolates in a 2009–2011 study in India.56 With the increasing frequency of nalidixic acid–resistant strains from the Indian subcontinent and the growing concern of global spread of DCS strains leading to treatment failures, careful use of ceftriaxone and azithromycin appears to be a prudent option when these drugs are affordable (in the case of azithromycin) and when there is sufficient medical personnel to perform the injections (as in the case of ceftriaxone). The apparent decrease in the MDR phenotype to the classic drugs also makes the use of ampicillin, SXT, and chloramphenicol an option. Because antimicrobial resistance in S. Typhi is responsive to selective pressure, as seen with MDRST and NARST, the reuse of these classic drugs may not be the best approach for the long-term; nevertheless, their use may be the only viable option in developing countries. Even though the current trends suggest the disappearance or decrease of MDRST, it is important to remember that carriers are an important reservoir for this organism. While there appears to be a lack of field data showing a significant association between asymptomatic carriers of S. Typhi and the maintenance of endemic typhoid, it seems logical to infer that such carriers do play some role in maintaining the endemicity of this bacterium. Carriers also represent the population of S. Typhi that may not be subject to strong selective pressure. Also, it is plausible that healthy carriers are maintaining the MDRST population. Therefore, if physicians return to reusing classic drugs, rapid reappearance of MDRST is likely to occur, as well as a trend of high NARST along with low MDRST. It is important to emphasize that the majority of both NARST and MDRST belong to the haplotype H-58; thus, clonal expansion of the H-58 will likely continue, maintaining the mutations in the QRDR. Ceftriaxone and azithromycin are likely the best options for empirical treatment of infections among populations in the Indian subcontinent, whenever possible.4 Conclusions and disease control Antimicrobial resistance in S. Typhi has been a major force in adaptive selection of MDRST and


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Table 4. Regimen implemented for typhoid patients with resistant S. Typhi

Number of cases (age)

Country

71 (1–51 years)

U.S. study: 75% foreign travel associated

26 (also includes S. Paratyphi)

Netherlands: travel related to Indian subcontinent

19 (15–40 years)

Copenhagen: travel to Indian subcontinent, Middle East, and Africa

1 (13 years)

Nepal

228 blood culture Vietnam positive cases: 207 S. Typhi, 19 S. Paratyphi (0–79 years) 42

Resistance pattern (overall percentage to a given drug)

Treatment regimen (empirical)

Clinical outcome

DCS (34%), ciprofloxacin MIC, 0.12–1 ␮g/mL; MDR (7%)

Patients were treated with Treatment failures in floroquinolones. Fever 17% with DCS and clearance median = 2% without DCS. 90 h for DCS and 64 h Relapse in 20% with for non-DCS. DCS and 7% without DCS.59 DCS (65%), Empirical treatment with One relapse each in ciprofloxacin MIC, ciprofloxacin and DCS and non-DCS 0.12–1 ␮g/mL, therapy switched to groups.60 ciprofloxacinceftazidime or SXT resistant (34%), after identification of MDR (7%) DCS. Non-DCS was treated with ciprofloxacin and ceftazidime and oral azithromycin. DCS ciprofloxacin Patients treated Relapse in 37% of (MIC, empirically with overall cases of all 0.125–1 ␮g/mL) ceftriaxone and DCS, including the (79%), fully ciprofloxacin. patients treated with susceptible to ceftriaxone. All were ciprofloxacin (21%) retreated with ceftriaxone, ciprofloxacin, pivmecillinam, and gentamicin.62 Resistant to nalidixic Initially received Treated with acid (MIC, ofloxacin (300 mg azithromycin.80 256 ␮g/mL), twice daily) for ciprofloxacin, and 2 weeks; afterwards, ofloxacin fever declined with oral (>32 ␮g/mL) dose of azithromycin (20 mg/kg/day). 91% MDR Two groups of ofloxacin All recovered except treatment: 15 mg/kg one treatment for 3 days or 10 mg/kg failure.97 for 5 days. MDR


20 patients received 27% clinical failure in ciprofloxacin (500 mg the ceftriaxone twice daily for 7 days); group. All recovered 22 patients received in the ciprofloxacin ceftriaxone (3 g group.98 parenterally for 7 days). Continued

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Table 4. Continued

Number of cases (age)

Country

1 (25 years)

Travel to India

198: 158 S. Typhi, India 40 S. Paratyphi (20–30 years most common age) 2 (29 and 2 years) Travel to Bangladesh

1 (19 years)

India

Resistance pattern (overall percentage to a given drug)

Treatment regimen (empirical)

MDR and DCS (cipro MIC, 1 ␮g/mL)

Initially treated with ampicillin but was treated with ciprofloxacin after relapse; was unresponsive to ciprofloxacin and was then treated with meropenam and aztreonam 2 g each/day. 168 DCS (MIC, Patients empirically 0.125–1 ␮g/mL), 25 treated with S. Typhi resistant to ciprofloxacin and were ciprofloxacin, of switched to ceftriaxone which 6.6% MDR on therapeutic failure. Resistant to nalidixic Adults were empirically acid, ciprofloxacin, treated with levofloxacin, amoxicillin and chloramphenicol, children with amoxicillin, and amoxicillin and cotrimoxazole cotrimoxazole. Strain resistant to Initial regimen was ciprofloxacin ciprofloxacin orally (64 ␮g/mL) (500 mg twice daily) for 10 days; switched to ceftriaxone, 1g intravenously every 12 h.

Clinical outcome Patient recovered after treatment with meropenam and aztreonam.61

Patients recovered with ceftriaxone.83

Successfully treated with ceftriaxone.84

Patient responded within 3 days and was discharged after 10 days with no relapse.99

Note: The table includes patient ages, travel history, and dosage, wherever available.

NARST. Haplotype H-58 with MDR and nalidixic acid resistance patterns became a predominant clone that emerged from Southeast Asia and spread across the globe. The current scenario seems to be a decrease in the MDR properties of S. Typhi and an increase in resistance to nalidixic acid and ciprofloxacin. For the treatment of typhoid fever, it would be ideal if the results of antimicrobial susceptibility testing could be available in conjunction with the diagnosis. However, rapid laboratory testing for antibiotic resistance may not be available in the developing countries, where the disease is en-

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demic. Even in developed countries, where the disease is frequently travel associated, treatment often begins before the laboratory susceptibility results are available. Therefore, for empirical treatment, it is important to know the travel history of the patient. Carriers are an important reservoir of this disease, since they are able to shed S. Typhi, resulting in contamination of drinking water and food. Where practical and possible, the screening and treatment of carriers in areas of endemicity will likely be very beneficial in preventing the spread of S. Typhi, thus


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reducing the overall burden of disease. Furthermore, continued monitoring of resistance patterns is essential for successful treatment of travel-related bacterial infections. With the increased globalization of the food supply and the large number of travelers to regions of endemicity, typhoid is not only a problem for developing countries but also for developed countries. An increased focus on improving sanitary conditions, the quality of food and water, identification and treatment of carriers, surveillance for disease, and an effective immunization program will all help reduce the incidence and burden of disease in regions where typhoid is endemic. Conflicts of interest The authors declare no conflicts of interest. References 1. House, D., A. Bishop, C. Parry, et al. 2001. Typhoid fever: pathogenesis and disease. Curr. Opin. Infect. Dis. 14: 573– 578. 2. Kanungo, S., S. Dutta & D. Sur. 2008. Epidemiology of typhoid and paratyphoid fever in India. J. Infect. Dev. Ctries. 2: 454–460. 3. Basnyat, B., A.P. Maskey, M.D. Zimmerman & D.R. Murdoch. 2005. Enteric (typhoid) fever in travelers. Clin Infect. Dis. 41: 1467–1472. 4. Crump, J.A. & E.D. Mintz. 2010. Global trends in typhoid and paratyphoid Fever. Clin. Infect. Dis. 50: 241–246. 5. Marathe, S.A., A. Lahiri, V.D. Negi & D. Chakravortty. 2012. Typhoid fever & vaccine development: a partially answered question Indian. J. Med. Res. 135: 161–169. 6. European Committee on Antimicrobial Susceptibility Testing. EUCAST Version 4, 2014. 2014. Ref Type: Electronic Citation. 7. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. CLSI M100-S24 [Twenty Fourth Informational Supplement]. 2014. 8. Van den bergh, E.T., M.H. Gasem, M. Keuter & M.V. Dolmans. 1999. Outcome in three groups of patients with typhoid fever in Indonesia between 1948 and 1990 Trop. Med. Int. Health 4: 211–215. 9. Agarwal, S.C. 1962. Chloramphenicol resistance of Salmonella species in India, 1959–61. Bull. World Health Organ 27: 331–335. 10. Anderson, E.S. & H.R. Smith. 1972. Chloramphenicol resistance in the typhoid bacillus. Br. Med. J. 3: 329–331. 11. Olarte, J. & E. Galindo. 1973. Salmonella typhi resistant to chloramphenicol, ampicillin, and other antimicrobial agents: strains isolated during an extensive typhoid fever epidemic in Mexico Antimicrob. Agents Chemother. 4: 597– 601. 12. Waldvogel, F.A. & J.S. Pitton. 1973. Typhoid fever imported from Mexico to Switzerland. Studies on R factor mediated chloramphenicol resistance. J. Hyg. (Lond.) 71: 509–513.


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