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. 1998 Feb;42(2):440–443. doi: 10.1128/aac.42.2.440

Antimicrobial Resistance in Shigella flexneri and Shigella sonnei in Hong Kong, 1986 to 1995

Yiu-wai Chu 1, Elizabeth T S Houang 1, Donald J Lyon 1,*, Julia M Ling 1, Tak-keung Ng 2, Augustine F B Cheng 1
PMCID: PMC105431  PMID: 9527803

Abstract

Three hundred and thirty-three Shigella isolates obtained in 1986 to 1995 were tested for their susceptibilities to 19 antimicrobial agents. Nalidixic acid resistance had emerged in 59.6% of Shigella flexneri isolates during 1994 to 1995, with all tested resistant isolates having the mutation in gyrA encoding the Ser-83 alteration. Multiresistance (resistance to four or more agents) was more common in S. flexneri than in Shigella sonnei.

Bacillary dysentery is an important cause of traveler’s diarrhea worldwide (13, 14, 16, 18). Appropriate antibiotic therapy reduces the duration of symptoms and excretion of organisms (15) but increases the risk of developing antibiotic resistance. High frequencies of resistance in Shigella flexneri (2, 6, 12) and Shigella sonnei (1) to many of the first-line antimicrobial agents have been reported in recent years from many parts of the world. The purpose of this study was to review the antimicrobial susceptibility patterns of Shigella spp. isolated in Hong Kong from 1986 to 1995, with particular reference to resistance to the 4-quinolones.

Bacterial strains.

We studied all the available 144 Shigella isolates obtained from 1988 to 1995 at the Prince of Wales Hospital (PWH) in Hong Kong and 90 1995 isolates obtained at the Princess Margaret Hospital (PMH) in Hong Kong. In addition, 99 isolates that had been collected in 1986 to 1987, obtained from the same laboratories, studied by Ling et al. (7), and stored since then at −70°C were also included for comparison. Both hospitals are regional general hospitals serving a predominantly urban area with a population of approximately 2 million, and PMH has the Infectious Diseases Unit serving all Hong Kong, with a population of 6 million. The primary medium for Shigella isolation was desoxycholate-citrate agar (DCA) (Oxoid, Basingstoke, United Kingdom) at PWH and DCA plus xylose-lysine-desoxycholate agar (Oxoid) at PMH. The identification of the 222 S. flexneri and 111 S. sonnei isolates was confirmed by standard laboratory methods (4). Of 204 isolates of S. flexneri which were serotyped, 148 were type 2, 27 were type 1, 20 were type 3, 7 were type 4, 1 was type 6, and 1 was the X variant.

Antimicrobial susceptibility testing.

MICs for 19 antimicrobial agents were determined by the agar dilution method as previously described (19). The 19 antimicrobial agents used in this study were ampicillin, chloramphenicol, nalidixic acid, sulfamethoxazole, trimethoprim, and tetracycline (all from Sigma Chemical Co., St. Louis, Mo.), amoxicillin-clavulanic acid (SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.), amikacin, and cefepime (all from Bristol-Myers Squibb Co., Princeton, N.J.), cefotaxime and gentamicin (both from Hoechst Marion Roussel, Paris, France), cefuroxime and ceftazidime (both from Glaxo Group Research Ltd., Greenford, Middlesex, United Kingdom), piperacillin (Lederle Laboratories, Pearl River, N.Y.), ciprofloxacin (Bayer AG, Leverkusen, Germany), imipenem (Merck & Co., Inc., West Point, Pa.), netilmicin (Schering Canada Inc., Pointe Claire, Québec, Canada), ofloxacin (Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan), and sparfloxacin (Rhône-Poulenc Rorer, Vitry-sur-Seine, France). Inocula of 104 CFU/spot were inoculated onto Iso-Sensitest agar (Oxoid) with a multipoint inoculator (Dynatech Laboratories, Alexandria, Va.), and the plates were incubated at 37°C for 18 h. The MIC was defined as the lowest concentration which inhibited visible growth. Control strains Escherichia coli NCTC 10418 and Pseudomonas aeruginosa NCTC 10662 were included. The rates of resistance to antimicrobial agents were expressed by using the breakpoints of the National Committee for Clinical Laboratory Standards (10).

Detection of the gyrA mutation.

A previously described PCR-restriction fragment length polymorphism method (11) for detecting the gyrA mutation encoding the Ser-83 alteration was performed on 55 S. flexneri isolates, all showing nalidixic acid MICs of ≥32 μg/ml, and 12 randomly selected susceptible isolates as negative controls.

Results.

Table 1 shows the geometric-mean MIC, MIC at which 50% of the isolates are inhibited (MIC50), MIC90, and the percentage of resistance for 14 of the 19 antimicrobial agents. No isolates were resistant to imipenem, cefepime, ceftazidime, cefotaxime, or amikacin, and MIC data for these isolates are not shown in the table. The S. flexneri isolates had high frequencies of resistance to ampicillin, amoxicillin-clavulanic acid, chloramphenicol, tetracycline, trimethoprim, and sulfamethoxazole. There was a marked increase in resistance to nalidixic acid, rising from 0% in 1986 and 1987 isolates to 59.6% in 1994 and 1995 isolates and an increase in the geometric-mean MICs for the fluoroquinolones, although only two isolates were resistant to ciprofloxacin (≥2 μg/ml). The Ser-83 mutation was detected only among the 55 isolates of S. flexneri with nalidixic acid MICs of ≥32 μg/ml, all of which also showed ciprofloxacin MICs of ≥0.25 μg/ml. These mutation-positive isolates had significantly higher MICs than mutation-negative isolates from the same time period for tetracycline, trimethoprim, sulfamethoxazole, chloramphenicol, gentamicin, imipenem, cefepime, and amoxicillin-clavulanic acid as well as the 4-quinolones (P < 0.03 to P < 0.0001 by the Mann-Whitney test). All mutation-positive, nalidixic acid-resistant isolates were of serotype 2. In the S. sonnei isolates, high frequencies of resistance were also seen for some agents. With the exception of tetracycline, trimethoprim, and sulfamethoxazole, S. sonnei isolates had significantly lower MICs than S. flexneri for all agents tested (P < 0.02 to P < 0.0001 by the Mann-Whitney test).

TABLE 1.

MICs and percentages of resistance of 14 antimicrobial agents in 222 S. flexneri and 111 S. sonnei isolatesa

Antimicrobial agent, species, and yr isolated n GMb (μg/ml) MIC50 (μg/ml) MIC90 (μg/ml) R%c
Ampicillin
 S. flexneri
  1986–1987 65 17.61 ≥64 ≥64 56.9
  1988–1990 25 29.45 ≥64 ≥64 68.0
  1991–1993 38 32.00 ≥64 ≥64 81.6
  1994–1995 94 44.90 ≥64 ≥64 89.4
 S. sonnei
  1986–1987 34 14.50 8 ≥64 35.3
  1988–1990 21 16.50 16 ≥64 52.4
  1991–1993 23 14.60 16 ≥64 60.9
  1994–1995 38 13.00 8 ≥64 36.4
Amoxicillin-clavulanic acid
 S. flexneri
  1986–1987 65 8.71 16 ≥32 50.8
  1988–1990 25 12.13 16 ≥32 68.0
  1991–1993 38 9.73 16 16 68.4
  1994–1995 94 19.10 16 ≥32 88.3
 S. sonnei
  1986–1987 34 8.3 8 16 23.5
  1988–1990 21 8.5 8 16 23.8
  1991–1993 23 8.5 8 ≥32 21.7
  1994–1995 38 8.7 8 ≥32 30.3
Piperacillin
 S. flexneri
  1986–1987 65 4.04 8 32 12.31
  1988–1990 25 5.90 16 32 16.00
  1991–1993 38 7.72 16 16 21.05
  1994–1995 94 12.40 16 32 13.80
 S. sonnei
  1986–1987 34 4.10 2 32 17.60
  1988–1990 21 4.30 2 32 14.29
  1991–1993 23 5.57 2 ≥256 17.40
  1994–1995 38 8.30 2 ≥256 33.30
Cefuroxime
 S. flexneri
  1986–1987 65 2.16 2 4 1.5
  1988–1990 25 2.71 2 4 0
  1991–1993 38 2.35 2 4 0
  1994–1995 94 2.60 2 4 0
 S. sonnei
  1986–1987 34 3.51 4 4 2.9
  1988–1990 21 4.27 4 8 0
  1991–1993 23 4.51 4 8 0
  1994–1995 38 3.80 4 8 0
Gentamicin
 S. flexneri
  1986–1987 65 1.42 1 2 9.2
  1988–1990 25 2.06 1 ≥64 12.0
  1991–1993 38 1.31 1 2 2.6
  1994–1995 94 1.50 2 2 2.1
 S. sonnei
  1986–1987 34 1.50 0.5 ≥64 1.50
  1988–1990 21 0.67 0.5 1 0.67
  1991–1993 23 0.86 1.0 1 0.86
  1994–1995 38 0.77 0.5 8 0.77
Netilmicin
 S. flexneri
  1986–1987 64d 1.15 1 1 7.7
  1988–1990 25 2.06 1 ≥64 12
  1991–1993 38 1.31 1 2 5.3
  1994–1995 94 1.3 1 2 0
 S. sonnei
  1986–1987 34 1.3 0.5 16 14.7
  1988–1990 21 0.7 0.5 2 0
  1991–1993 23 0.7 0.5 1 4.4
  1994–1995 38 0.57 0.5 2 0
Nalidixic acid
 S. flexneri
  1986–1987 65 2.11 2 2 0
  1988–1990 25 1.69 2 2 0
  1991–1993 38 2.11 2 2 2.6
  1994–1995 94 22.5 ≥128 ≥128 59.6
 S. sonnei
  1986–1987 34 2.78 2 4 0
  1988–1990 21 2.97 2 2 9.5
  1991–1993 23 1.70 2 2 0
  1994–1995 38 1.96 2 2 3.0
Ciprofloxacin
 S. flexneri
  1986–1987 65 0.008 0.01 0.01 0
  1988–1990 25 0.012 0.02 0.02 0
  1991–1993 38 0.015 0.02 0.02 0
  1994–1995 94 0.128 0.50 1.00 2.1
 S. sonnei
  1986–1987 34 0.01 0.01 0.02 0
  1988–1990 21 0.02 0.01 0.25 0
  1991–1993 23 0.01 0.02 0.02 0
  1994–1995 38 0.01 0.01 0.02 0
Ofloxacin
 S. flexneri
  1986–1987 65 0.03 0.03 0.03 0
  1988–1990 25 0.05 0.06 0.06 0
  1991–1993 38 0.06 0.06 0.06 0
  1994–1995 94 0.35 1.00 2.00 0
 S. sonnei
  1986–1987 34 0.029 0.03 0.03 0
  1988–1990 21 0.062 0.06 0.06 0
  1991–1993 23 0.050 0.06 0.06 0
  1994–1995 38 0.037 0.03 0.06 0
Sparfloxacin
 S. flexneri
  1986–1987 65 0.007 0.01 0.01 NAe
  1988–1990 25 0.014 0.02 0.03 NA
  1991–1993 38 0.016 0.02 0.03 NA
  1994–1995 93d 0.120 0.50 1.00 NA
 S. sonnei
  1986–1987 34 0.008 0.01 0.0075 NA
  1988–1990 21 0.016 0.02 0.03 NA
  1991–1993 23 0.016 0.02 0.03 NA
  1994–1995 38 0.010 0.01 0.03 NA
Tetracycline
 S. flexneri
  1986–1987 65 85.35 128 ≥256 90.8
  1988–1990 25 84.45 128 ≥256 88.0
  1991–1993 38 56.30 128 ≥256 81.6
  1994–1995 94 129.90 ≥256 ≥256 96.8
 S. sonnei
  1986–1987 34 58.00 128 ≥256 88.2
  1988–1990 21 80.60 ≥256 ≥256 81.0
  1991–1993 23 23.70 128 ≥256 56.5
  1994–1995 38 63.49 128 ≥256 78.8
Trimethoprim
 S. flexneri
  1986–1987 65 0.70 0.25 ≥256 16.9
  1988–1990 25 5.89 1 ≥256 28.0
  1991–1993 38 58.30 ≥256 ≥256 76.3
  1994–1995 94 129.90 ≥256 ≥256 90.4
 S. sonnei
  1986–1987 34 4.60 0.25 ≥256 35.3
  1988–1990 21 2.80 0.50 ≥256 33.3
  1991–1993 23 53.30 ≥256 ≥256 78.3
  1994–1995 38 16.76 ≥256 ≥256 60.6
Sulfamethoxazole
 S. flexneri
  1986–1987 65 327.2 ≥2,048 ≥2,048 69.2
  1988–1990 25 347.3 ≥2,048 ≥2,048 64.0
  1991–1993 38 382.0 ≥2,048 ≥2,048 68.4
  1994–1995 94 378.0 1,024 ≥2,048 74.7
 S. sonnei
  1986–1987 34 868.2 ≥2,048 ≥2,048 82.4
  1988–1990 21 603.9 1,024 ≥2,048 85.7
  1991–1993 23 713.2 ≥2,048 ≥2,048 87.0
  1994–1995 38 446.4 1,024 ≥2,048 78.8
Chloramphenicol
 S. flexneri
  1986–1987 65 49.02 64 256 84.6
  1988–1990 25 26.35 64 128 64.0
  1991–1993 38 19.00 64 128 68.4
  1994–1995 94 49.80 64 128 90.4
 S. sonnei
  1986–1987 34 30.0 4 ≥512 35.3
  1988–1990 21 11.9 4 ≥512 28.6
  1991–1993 23 6.5 4 64 13.0
  1994–1995 38 6.7 4 64 15.2
Open in a new tab
a

Of the 19 antimicrobial agents examined, the results of imipenem, ceftazidime, cefotaxime, cefepime, and amikacin are not shown here (see Results). 

b

GM, geometric-mean MIC. 

c

R%, percentages of resistance for antimicrobial agents with the following breakpoints of the National Committee for Clinical Laboratory Standards (10): ciprofloxacin, ≥2 μg/ml; ofloxacin, ≥4 μg/ml; gentamicin, nalidixic acid, tetracycline, and trimethoprim, ≥8 μg/ml; ampicillin, amoxicillin-clavulanic acid (2:1), cefuroxime, netilmicin, and chloramphenicol, ≥16 μg/ml; piperacillin, >32 μg/ml; and sulfamethoxazole, >64 μg/ml. 

d

Result of one isolate not available. 

e

NA, no breakpoint available for sparfloxacin. 

Table 2 compares the resistance patterns of isolates of both species for two periods: 1986 to 1987 and 1994 to 1995. For S. sonnei, the proportions of isolates showing resistance to four or more agents were not statistically different (13 of 34 versus 9 of 38; P > 0.05 by the chi-square test). For S. flexneri, a significantly greater proportion of isolates was resistant to at least four agents in 1994 to 1995 (38 of 65 versus 88 to 94; P < 0.001 by the chi-square test). One antibiogram showing resistance to seven antimicrobials was seen in 47% of S. flexneri isolates from 1994 to 1995.

TABLE 2.

Distribution of resistance patterns in S. flexneri and S. sonnei

No. of antibiotics Drug resistance patterna,b No. of isolatesb
S. sonnei
S. flexneri
1986–1987 1994–1995 1986–1987 1994–1995
1–3 Total 19 21 23 5
4 A AC C T 1 14
C T TM SX 1 2
Other patternsc 3 1 1
Total 5 0 15 3
5 A AC C T TM 12
A AC C T SX 1 8 1
Other patterns 4 4
Total 1 0 12 17
6 A AC PI C T TM 4
A AC PI T TM SX 5 1
A AC C T TM SX 1 7
A AC NX C T TM 3
Other patterns 1 2 4 1
Total 1 7 6 15
7 A AC PI C T TM SX 1 1 2
A AC NX C T TM SX 44
Other patterns 1 1 1
Total 1 1 2 47
8 A AC PI NX C T TM SX 4
Other patterns 2 2 1
Total 2 0 2 5
9–10 A AC PI G NT C T TM SX 3 1
Other patterns 1 1
Total 3 1 1 1
Totald 32 30 61 93
Open in a new tab
a

Drug resistance abbreviations: A, ampicillin; AC, amoxicillin-clavulanic acid; C, chloramphenicol; T, tetracycline; TM, trimethoprim; SX, sulfamethoxazole; PI, piperacillin; NX, nalidixic acid; G, gentamicin; NT, netilmicin. 

b

The total number of isolates in each category is shown in boldface type. 

c

Other patterns, resistance patterns shown by one strain of the period studied. 

d

Total (shown in boldface type) of all the totals for individual categories; excludes 15 fully sensitive strains. 

Discussion.

The genetic basis of resistance to quinolones has been defined mainly in E. coli, where the gyrA mutation encoding the Ser-83 substitution is frequently associated with resistance to nalidixic acid (3). Other point mutations leading to amino acid changes in gyrA, gyrB (encoding the gyrase subunit B), and parC (encoding topoisomerase IV) have been reported in the presence of high levels of fluoroquinolone resistance (3, 17). A study of S. sonnei isolates suggested that the decreased quinolone susceptibility was due to mutation of the gyrA gene (5). Enhanced efflux of fluoroquinolones from the bacterial cell, such as the multiple-drug-resistance phenotype conferred by mutations in the marRAB operon (9) may also contribute to resistance. Our study in S. flexneri has shown the mutation encoding the Ser-83 alteration to be present in all isolates with nalidixic acid MICs of ≥32 μg/ml and also revealed a close association between the presence of the mutation and resistance to other classes of antimicrobials.

The relative antimicrobial susceptibilities of different Shigella spp. may vary geographically. For example, S. sonnei was found to be more resistant than S. flexneri in Israel but not in Africa, Asia, and South America (1, 2, 6, 12). It is not clear why resistance to 4-quinolones has emerged in S. flexneri, but not S. sonnei, in our region. A previous study of Hong Kong Shigella isolates (8) showed S. sonnei to be genetically more diverse than S. flexneri. It may be that one or a few clones of quinolone-resistant S. flexneri have become predominant under selective antibiotic pressure, as suggested by the finding of one antibiogram accounting for 47% of S. flexneri isolates in 1994 to 1995 and all the nalidixic acid-resistant isolates being of serotype 2. Further studies on the antibiotic resistance mechanisms and genetic relatedness of isolates are required to understand the progression of antibiotic resistance in Shigella.

Acknowledgments

We thank Lui Sau Lai for excellent technical assistance.

This project was supported by Hong Kong University Research Grants Council direct grant no. 2040496.

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