Surveillance for Travel and Domestically Acquired Multidrug-Resistant Human Shigella Infections

Abstract

Shigellosis is a leading cause of enteric infections in the United States. We compared antimicrobial resistance in Shigella infections related to overseas travel (travel-associated) and in those acquired domestically by analyzing antimicrobial resistance patterns, geographic distributions, and pulsed-field gel electrophoresis (PFGE) patterns. We tested samples (n = 204) from a collection of isolates recovered from patients in Pennsylvania between 2006 and 2014. Isolates were grouped into travel- and non-travel-associated categories. Eighty-one (79.4%) of the Shigella isolates acquired during international travel were resistant to multiple antibiotics compared to 53 (52.1%) of the infections transmitted in domestic settings. A majority (79.4%) of isolates associated with international travel demonstrated resistance to aminoglycosides and tetracyclines, whereas 47 (46.1%) of the infections acquired domestically were resistant to tetracycline. Almost all isolates (92.2%) transmitted in domestic settings were resistant to aminoglycosides, and 5 isolates from adult male patients were resistant to azithromycin, a drug often used for empiric treatment of severe shigellosis. Twenty (19.6%) isolates associated with illnesses acquired during overseas travel in 4 countries were resistant to quinolones. One S. sonnei PFGE pattern was traced to a multidrug-resistant isolate acquired overseas that had caused a multistate outbreak of shigellosis, suggesting global dissemination of a drug-resistant species. Resistance to certain drugs—for example, tetracycline—increased in both overseas- and domestic-acquired infections during the study period. The prevalence of resistance to macrolides (azithromycin) and third-generation cephalosporins (ceftriaxone) was less than 1%; however, efforts to better monitor changes in drug resistance over time combined with increased antimicrobial stewardship are essential at the local, national, and global levels.

The authors compared antimicrobial resistance in Shigella infections related to overseas travel and in those acquired domestically by analyzing antimicrobial resistance patterns, geographic distributions, and pulsed-field gel electrophoresis (PFGE) patterns.

Shigella is a leading cause of domestically acquired and travel-associated enteric infections in the United States. It causes approximately 500,000 diarrheal illnesses, 5,500 hospitalizations, and 40 deaths each year. Among these illnesses, 27,000 (5.4%) were caused by a drug-resistant Shigella species.¹ The annual economic cost of Shigella infections is estimated at $4.5 billion; the burden of travel-associated shigellosis is over $21 million and continues to rise.^2,3 Because a high proportion of Shigella infections are not susceptible to first-line drugs (eg, ampicillin and trimethoprim-sulfamethoxazole), clinicians have turned to broad-spectrum antibiotics such as ciprofloxacin and azithromycin for initial treatment.²

Surveillance for shigellosis and other nationally notifiable diseases in the United States is conducted by state and local health jurisdictions. To facilitate public health responses, Pennsylvania has mandated reporting of shigellosis cases by healthcare providers through a web-based surveillance system.^4,5 Pennsylvania requires that clinical laboratories, in addition to reporting, submit Shigella isolates to the Department of Health's Bureau of Laboratories, where they are serotyped and analyzed by pulsed-field gel electrophoresis (PFGE).^6,7 PFGE patterns are uploaded to a national molecular subtyping surveillance system, PulseNet, to enable comparisons of DNA patterns of bacteria associated with foodborne illnesses.⁸ A subset of confirmed Shigella isolates is submitted to the National Antimicrobial Resistance Monitoring System (NARMS)⁹ for antimicrobial susceptibility testing. Recent NARMS reports have documented emergence of resistance to antimicrobials that are essential in the clinical management of Shigella infections, including resistance to ciprofloxacin (a quinolone) and azithromycin (a macrolide).¹⁰ Of the isolates tested recently by NARMS, 1.6% were resistant to ciprofloxacin and 3% were resistant to azithromycin.²

There have been multiple outbreaks of antimicrobial-resistant Shigella infections in Pennsylvania and in other states.¹¹ Despite this, surveillance for antimicrobial-resistant shigellosis in Pennsylvania is limited, as there are inadequate resources to allow our laboratory to routinely conduct susceptibility on bacteria isolates. We conducted a study to characterize shigellosis infections in Pennsylvania. Our main objective was to compare antimicrobial susceptibility of travel-associated Shigella isolates with those acquired domestically.

Methods

Data Source and Sampling

From the Pennsylvania laboratory information system, we identified data on 1,062 Shigella isolates received by the Bureau of Laboratories from 2006 to mid-2014. We matched these records with patient-level data submitted by clinicians to Pennsylvania's web-based disease reporting system.¹² Because the Philadelphia Department of Public Health uses a separate electronic reporting system to conduct surveillance for Shigella and other enteric infections, we excluded isolates from this jurisdiction.

Of the 1,062 isolates, 897 were not travel associated, and the rest were travel associated. We systematically sampled 102 isolates from each of these 2 categories by selecting the first Shigella isolate received each month, yielding 12 each year. If there were no isolates in a certain month, the first 2 isolates of the following month were selected.

Bacteriology and PFGE Typing

We used standard methods to analyze Shigella isolates by PFGE with XbaI digestion⁷ and uploaded patterns to the Centers for Disease Control and Prevention's (CDC) PulseNet database. Then we downloaded Pennsylvania-specific Shigella data to our own electronic surveillance system, described elsewhere in a recent publication.¹³ We analyzed the most common species, S. sonnei and S. flexneri, for resistance patterns. We compared patterns associated with international travel with those involved in domestically acquired shigellosis.

Antimicrobial Susceptibility Testing

Using standard methods,¹⁴ the Pennsylvania Veterinary Laboratory tested 93.1% (n = 190) of the 204 selected Shigella isolates. Fourteen (6.9%) of the study isolates were tested by NARMS laboratories at the CDC for antimicrobial susceptibility (AST). All isolates were tested using a NARMS protocol for 14 drugs in 9 antimicrobial classes (Table 1).¹⁵ We obtained minimum inhibitory concentrations for drugs and used interpretive criteria defined by the Clinical Laboratory Standards Institute (CLSI) when available.¹⁴ Otherwise, we used NARMS interpretive criteria—for example, in the case of azithromycin.

Table 1.

AST-Tested Antimicrobial Classes and Associated Antimicrobial Agents

Class	Agent
Aminoglycosides	Streptomycin gentamicin
Tetracyclines	Tetracycline
Sulfonamides	sulfisoxazole trimethoprim-sulfamethoxazole
Penicillins	ampicillin
Phenicols	chloramphenicol
Quinolones	ciprofloxacin nalidixic acid
Cephems	cefoxitin ceftiofur ceftriaxone
β-lactamase/β-lactamase combinations	amoxicillin-clavulanic acid
Macrolides	azithromycin

Statistical Analyses

For each species and XbaI pattern for which 3 or more isolates were identified (eg, S. flexneri JZXX01.0003), we calculated prevalence of high resistance (defined as resistance to 6 or more classes of drugs). We analyzed antimicrobial resistance trends by prevalence using linear regression models in Microsoft Office Excel (Microsoft Corp., Redmond, WA). For correlation of antimicrobial resistance by PFGE patterns, we calculated positive likelihood ratios and positive predictive values using 2X2 contingency tables. We conducted the analysis with MedCalc software (MedCalc Software, Mariakerke, Belgium).

Results

Demographic Characteristics, Onset of Illness, and Shigella Species

Travel-associated illnesses occurred in individuals with a median age of 36.5 years. Individuals infected domestically had a median age of 15.5 years. Of those infected during overseas travel, 42 (41.2%) developed shigellosis symptoms before they returned home, 56 (54.9%) had symptoms within 1 to 3 days, and 4 (3.9%) had symptoms within 4 to 7 days after they returned home (Table 2). Of 204 Shigella isolates characterized at the species level, S. sonnei (n = 145) and S. flexneri (n = 48) were most often associated with infections. These 2 species accounted for 93.1% of shigellosis acquired during international travel and 96% of infections acquired in the United States. Of the individuals with travel-associated illnesses, there were 27 males and 38 females infected with the S. sonnei species, and 21 males and 9 females were infected with S. flexneri species. Of the group who acquired infections domestically, 34 males and 46 females had S. sonnei infections, and 12 males and 6 females were infected with S. flexneri. Other species associated with shigellosis acquired overseas and in the United States were S. boydii and S. dysenteriae (Table 2).

Table 2.

Patient Travel, Demographic Characteristics, Onset of Illness, and Shigella Species

		Patient Information			No. (%) Onset Shigellosis Related to Returning Home			No. (%) Shigella Species
Overseas Travel	No. Isolates	No. (%) Male	No. (%) Female	Median Age (years)	Before Return	1-3 Days After Return	4-7 Days After Return	S. sonnei	S. flexneri	S. boydii	S. dysenteriae
Yes	102	51 (50)	51 (50)	36.5	42 (41.2)	56 (54.9)	4 (3.9)	65 (63.7)	30 (29.4)	4 (3.9)	3 (2.9)
No	102	49 (48)	53 (52)	15.5	0	6 (5.9)^a	0	80 (78.4)	18 (17.6)	3 (2.9)	1 (1.1)
Total	204	100 (49)	104 (51)	28	42 (38.9)	62 (57.4)^b	4 (37.0)	145 (71.1)	48 (23.5)	7 (3.4)	4 (2.1)

Shigella infections linked to travel within the US.

Based on 108 Shigella infections contracted outside Pennsylvania.

Antimicrobial-Resistant Shigella Isolates

Overall, 194 (95.1%) of the 204 isolates studied exhibited resistance to drugs in at least 1 class, and 134 (66.1%) were multidrug-resistant (Table 3). Eighty-one (79.4%) of the shigellosis illnesses acquired during international travel were multidrug-resistant compared to 53 (52.1%) of the illnesses acquired in the United States. Eighty (78.4%) of the isolates associated with shigellosis infections acquired overseas were resistant to aminoglycosides and tetracyclines. Of the infections acquired domestically, 94 (92.2%) were resistant to aminoglycosides and 47 (46.1%) were not susceptible to tetracycline. The 5 isolates resistant to macrolides (azithromycin) were associated with infections in adult males. A single isolate was received in 2008, 2013, and 2014, and 2 isolates were collected in 2012.

Table 3.

Antimicrobial Resistance in Shigella Isolates

			No. (%) Resistant to Each Antimicrobial Class									No. (%) Resistant to Multiple Antimicrobial Classes
Overseas Travel	No. Isolates	Species	Aminoglycosides	Tetracyclines	Sulfonamides	Penicillins	Phenicols	Quinolones	Cephems	β-lactam/β-lactamase combinations	Macrolides^a	≥1	≥2	≥3	≥4	≥5
Yes	102		80 (78.4)	80 (78.4)	77 (75.5)	43 (42.2)	25 (24.5)	29 (28.4)	1 (1)	1 (1)	0	95 (93.1)	85 (83.3)	81 (79.4)	53 (52.1)	17 (16.7)
		S. flexneri	24	28	21	21	19	8	0	0	0	3	0	3	8	15
		S. sonnei	50	46	51	18	5	18	1	1	0	7	4	25	23	1
		Others	6	6	5	4	1	3	0	0	0	0	0	0	5	1
No	102		94 (92.2)	47 (46.1)	51 (50)	44 (43.1)	11 (10.8)	4 (3.9)	6 (5.9)	5 (4.9)	5 (4.9)	99 (97.1)	68 (66.7)	53 (52.1)	29 (28.4)	10 (9.8)
		S. flexneri	15	15	14	13	8	1	1	0	3	0	0	3	5	7
		S. sonnei	75	29	33	31	3	2	5	5	2	31	14	19	13	3
		Others	4	3	4	0	0	1	0	0	0	0	1	2	1	0
Total	204		174 (85.3)	127 (62.3)	128 (62.7)	87 (42.6)	36 (17.6)	33 (16.2)	7 (3.4)	6 (2.9)	5 (2.6)^b	194 (95.1)	153 (75)	134 (66.1)	82 (40.1)	27 (13.2)

100 domestic and 96 overseas travel-related Shigella isolates were tested for macrolide AST.

Percentage of 196 isolates tested.

PFGE Patterns

Among 95 infections acquired during overseas travel, 26 (27.3%) were caused by S. flexneri and S. sonnei isolates with PFGE patterns that were observed at least 3 times (Table 4). The same S. flexneri PFGE pattern, JZXX01.0357, was observed 4 times. Each S. flexneri isolate was resistant to at least 1 agent in each of 5 of the 9 antimicrobial classes (aminoglycosides, sulfonamides, tetracyclines, penicillins, and phenicols). Twenty-two (84.6%) of the 26 isolates were in 4 S. sonnei XbaI patterns and were associated with multidrug-resistant infections (Table 4). S. sonnei J16X01.0232 was observed 7 times. The remaining 3 patterns that were observed at least 3 times in our set of isolates were S. sonnei J16X01.0297 (6.2%), S. sonnei J16X01.0283 (6.2%), and S. sonnei J16X01.0213 (4.6%). Of Shigella isolates from these 26 XbaI patterns, 20 (21%) were resistant to aminoglycosides and 17 (17.8%) were resistant to tetracyclines. All 4 isolates of S. sonnei pattern J16X01.0297 were resistant to drugs in 4 classes: aminoglycosides, sulfonamides, tetracyclines, and penicillins (Table 4). S. sonnei J16X01.0232 was associated with illnesses acquired overseas and was also observed in a previously reported domestically acquired multistate shigellosis outbreak (PulseNet Outbreak-1407MLJ16-2).

Table 4.

Correlation of Antimicrobial Resistance and Common PFGE Patterns^a

		Number with Same XbaI Pattern	Number Resistant to Each Antimicrobial Class (% same XbaI pattern)
Species	XbaI Pattern	(% species)^b	Aminoglycosides	Sulfonamides	Tetracyclines	Penicillins	Quinolones	Phenicols
Travel-Associated
S. flexneri	JZXX01.0357	4 (13.3)	4 (100)	4 (100)	4 (100)	3 (75)	0	4 (100)
S. sonnei	J16X01.0232^c	7 (10.8)	5 (71.4)	5 (71.4)	5 (71.4)	0	7 (100)	0
S. sonnei	J16X01.0297	4 (6.2)	4 (100)	4 (100)	4 (100)	4 (100)	0	0
S. sonnei	J16X01.0283	4 (6.2)	4 (100)	3 (75)	3 (75)	0	0	0
S. sonnei	J16X01.0213	3 (4.6)	2 (66.7)	1 (33.3)	0	2 (66.7)	0	0
S. sonnei	J16X01.0775	4 (6.2)	1 (25)	1 (25)	1 (25)	0	2 (50)	0
Total (%)^d		26 (27.3)	20 (21)	18 (18.9)	17 (17.8)	9 (9.5)	9 (9.5)	4 (4.2)

Non-Travel Associated		(% species)^e
S. flexneri	JZXX01.0003	4 (22.2)	4 (100)	4 (100)	4 (100)	4 (100)	0	4 (100)
S. sonnei	J16X01.1166^f	14 (17.5)	14 (100)	5 (35.7)	2 (14.3)	1 (7.1)	0	0
S. sonnei	J16X01.1148^f,g	9 (11.3)	9 (100)	2 (22.2)	1 (11.1)	0	0	0
S. sonnei	J16X01.0283	6 (7.5)	6 (100)	1 (16.7)	5 (83.3)	5 (83.3)	0	0
S. sonnei	J16X01.0172	3 (3.8)	3 (100)	3 (100)	3 (100)	3 (100)	0	0
S. sonnei	J16X01.2996	3 (3.8)	2 (66.7)	0	0	0	0	0
Total (%)^h		39 (39.8)	38 (38.8)	15 (15.3)	15 (15.3)	13 (13.3)	0	4 (4.1)

PFGE XbaI patterns present ≥3times.

Percentage of 30 S. flexneri and 65 S. sonnei isolates.

PulseNet Outbreak 1407MLJ16-2.

Percentage of 95 isolates.

Percentage of 18 S. flexneri and 80 S. sonnei isolates.

PulseNet Outbreak 0902PAJ16-1.

PulseNet Outbreak 1406MLJ16-1.

Percentage of 98 isolates.

Among 98 domestically acquired infections, 39 (39.8%) were caused by S. flexneri and S. sonnei of 6 distinct patterns (Table 4). The pattern J16X01.1166 had at least 1 isolate resistant to drugs in 4 classes of antibiotics. This pattern was linked to an outbreak of Shigella infections in Pennsylvania (PulseNet Outbreak-0902PAJ16-1). The pattern J16X01.1148 was also observed in a multistate outbreak (PulseNet Outbreak-1406MLJ16-1).

Correlation with Antimicrobial Resistance

Of the 193 Shigella sonnei and flexneri isolates in our 204 samples, 59 (30.6%) had XbaI patterns that were found in both travel-associated and domestically acquired Shigella infections. Forty-five of the 59 were S. sonnei species, and the remaining 14 were S. flexneri. The 3 most frequently observed shared patterns were S. flexneri JZXX01.0003 (10.4%), S. flexneri JZXX01.0357 (10.4%), and S. sonnei J16X01.0283 (6.9%). Approximately two-thirds of these isolates were resistant to 7 or more antimicrobial classes. Twenty-two (11.4%) of the domestically acquired isolates were resistant to tetracyclines, whereas 17 (8.8%) travel-associated isolates were resistant to tetracyclines. For the quinolone class, 2 domestically acquired isolates showed resistance, and 11 travel-related isolates were resistant.

PFGE clusters from domestically acquired Shigella isolates had an edge of higher positive predictive value for drug resistance than did the travel-associated PFGE clusters, which had increased diversity of PFGE patterns. Whereas CIs were overlapping, the positive likelihood ratio was 2.4 (95% CI 1.1-5.3) vs 2.0 (95% CI 0.9-4.3), the positive predictive value (%) was 90.9 (95% CI 80-97%) vs 81.3 (95% CI 63.6-92.8%), and the prevalence (%) of related resistant antimicrobial classes was 80.4 (95% CI 71.4-87.6%) vs 68.6 (95% CI 58.7-77.5%), respectively.

Prevalence of Antimicrobial Resistance Over Time

At least 6 of the 12 travel-associated isolates from each year (50%) were resistant to aminoglycosides, tetracycline, and sulfonamide. Resistance to sulfonamide increased from 50% in 2006 to 67% in 2013. Ten (83.3%) domestically acquired isolates were resistant to aminoglycosides in 2006, and by 2014 all isolates tested (n = 6) were resistant. Aminoglycoside resistance was prevalent in domestic isolates; 83.3% or more of the isolates tested for each year were resistant. Resistance to chloramphenicol remained in less than 20% of domestic isolates during the study period.

Distribution of Antimicrobial- Resistant Shigella Isolates

In our analysis, of the 96 isolates from Pennsylvania, 71 (74%) were associated with illnesses acquired in the southern Pennsylvania regions, from the densely populated areas along US Route 30, which extends from Philadelphia in the southeast to Pittsburgh in the southwest. Approximately 42% (40/96) of isolates were from the southeastern region, 18.8% (18/96) from the southwestern region, and 13.5% (13/96) were from south-central Pennsylvania. We identified resistance to aminoglycosides, tetracyclines, and penicillins in isolates from most parts of the state. Macrolide-resistant Shigella isolates were found in samples from the southern region, and quinolone-resistant isolates were found in samples from the northern Pennsylvania region. Shigella isolates acquired from eastern and western Pennsylvania showed resistance to cephems, sulfonamides, phenicols, and/or β-lactam/β-lactamase combinations.

Global Distribution

Of the 102 Shigella isolates linked to overseas travel, 58% of infections were associated with 4 countries: India (n = 21, 20.6%), the Dominican Republic (n = 15, 14.7%), Haiti (n = 8, 8.8%), and Mexico (n = 14, 13.7%) (Figure 1). Shigella infections resistant to aminoglycosides, tetracyclines, and sulfonamides were acquired from infections around the world. Of the 102 isolates, 81 were multidrug-resistant. Twenty of the isolates (19.6%) were resistant to quinolones; infections with these isolates were acquired in India, Haiti, and the Dominican Republic. In addition to India, 2 other South Asian countries (Pakistan and Nepal) had highly resistant isolates. Countries in 2 other regions (the Caribbean and Central America) had the most resistant isolates (Figure 1).

Note: Southern Asia: India, Nepal, Pakistan; Caribbean: Dominican Republic, Haiti, Jamaica, Aruba; Central America: Mexico, Guatemala, Belize, Costa Rica, El Salvador, Honduras, Nicaragua, Panama; South America: Peru, Colombia, Ecuador; Western Africa: Ghana, Niger, Nigeria; Western Asia: Iraq, Israel; Northern Africa: Morocco, Egypt; Eastern Africa: Burundi; Eastern Asia: China; Southeast Asia: Thailand; North America: Canada; Polynesia: Hawaii; Western Europe: France.

Resistance to phenicols was detected in 4.9% (n = 5), and resistance to penicillins was detected in 9.8% (n = 10) of the isolates linked to travel outside the United States. Resistance to cephems or the β-lactam/β-lactamase combination was infrequently associated with overseas travel (Table 3).

Discussion

In this study, we analyzed the antimicrobial resistance profiles and PFGE patterns of 204 Shigella isolates from Pennsylvanians who acquired illnesses in the United States or overseas from 2006 through 2014. Widespread Shigella antimicrobial resistance has previously been discussed;^16,17 however, our study evaluated the differences between Shigella antimicrobial resistance found in travel-associated infections compared with domestically acquired infections. Shigellosis is contagious, and the prevalence of travel-associated drug-resistant isolates is of significant domestic public health concern. This concern is further supported by a recent NARMS report documenting emergence of resistance to ciprofloxacin in Shigella infections.¹⁰ Our results found quinolone resistance in both travel-associated and domestic isolates.

We found that individuals who acquired S. sonnei infections domestically were younger than those who contracted S. sonnei shigellosis during overseas travel. The low median age of S. sonnei–infected patients may be attributed to Shigella outbreaks in childcare centers and schools in Pennsylvania. For all tested species, larger proportions of S. sonnei and S. flexneri isolates were observed in those infected overseas than in Pennsylvania, similar to the findings in previous studies.^18,19 Our data showed that travel-associated Shigella isolates were likely to be resistant to more antimicrobial classes than were domestic isolates. In the United States, recent studies have shown an increase in shigellosis infections resistant to azithromycin and ciprofloxacin among adult males—mainly men who have sex with men.²⁰ In Pennsylvania, azithromycin resistance was observed in 5 infections that occurred in males of a median age of 47 (range 37-73) years, all living in or close to large metropolitan areas (Montgomery and Delaware counties, Pittsburgh, and Harrisburg). Taken together with recent reports, these data underscore the need for clinicians to culture stool specimens of men who have sex with men and HIV-infected men who are experiencing diarrhea and determine antimicrobial susceptibility of Shigella to guide antibiotics treatment.²¹

Shigella isolates studied in this analysis were generally susceptible to macrolides, cephems, and β-lactam/β-lactamase combinations. A possible explanation for the diversified PFGE patterns is the Shigella genetic convergent evolution in the population.²² There was little correlation between PFGE pattern and antimicrobial resistance of travel-associated Shigella isolates. PFGE pattern diversities within Shigella species have been observed in other studies.²³ As PFGE DNA fingerprints are not reflective of detailed genetic variations among Shigella isolates, different testing procedures, such as whole genome sequencing, will be needed to reveal underlying genetic differences.²⁴ Interestingly, Shigella isolates contracted domestically exhibited a higher degree of correspondence between PFGE patterns and antimicrobial resistance profiles than did the travel-associated isolates.

Our data illustrated that PFGE patterns for S. flexneri have a stronger correlation to antimicrobial resistance than do those of S. sonnei. Patterns JZXX01.0357 and JZXX01.0003 were observed in analysis of S. flexneri serotype 2 isolates that were resistant to aminoglycosides, sulfonamides, tetracyclines, penicillins, and phenicols. This finding is consistent with results found in a previous multidrug-resistance study of S. flexneri serotype 2.²⁵ The PFGE pattern associated with most S. sonnei isolates was correlated with aminoglycoside resistance. J16X01.0232 was correlated with quinolone resistance. Quinolone resistance is of particular interest, since one of the primary drugs used to treat shigellosis, ciprofloxacin, is in the quinolone antimicrobial class.

Isolates from individuals living in the eastern and western regions of Pennsylvania were found to be resistant to 8 and 9 antimicrobial classes, respectively. Most of the analyzed Shigella isolates were from infections contracted in the southern region of Pennsylvania, where many isolates were resistant to aminoglycosides and sulfonamides. The emergence of these multidrug-resistant species is of critical epidemiologic and public health concern as described in the recent CDC report on multidrug-resistant Shigella outbreaks.¹⁰ The distribution of macrolide-resistant Shigella isolates was relatively low among all Pennsylvania regions compared with the levels of resistance to cephems and β-lactam/β-lactamase combinations.

Global distribution of multidrug-resistant Shigella isolates was indicated by a high occurrence in the central and southern hemisphere regions; isolates from infections acquired in these regions were often resistant to aminoglycosides, tetracyclines, and sulfonamides.²⁶ Isolates from Asian countries were resistant to up to 8 antimicrobial classes; thus, it is possible that shigellosis that is resistant to treatment with all antimicrobial classes will become a problem there. It should be noted that the similar Shigella antimicrobial-resistant distributions were shown among Central America and the neighboring Caribbean countries. As antimicrobial-resistant Shigella infections circulate around the world, novel strategies and interventions are needed.

Limitations

This study has several limitations. First, Philadelphia and out-of-state isolates were not included in this study because patient survey information was not available. Second, the small sample size hindered our ability to accurately measure certain determinants of epidemiologic and public health importance. Also, because of the small sample size, data on regional distribution should be interpreted cautiously. Third, the data on antimicrobial agents to which Shigella species are not usually resistant or on Shigella species that do not often cause human infections (eg, S. boydii and S. dysenteriae) are often removed from analyses to avoid bias, consequently losing the valuable antimicrobial-resistance information. Because of our small sample size, we cannot assume that our data are representative of events in populations.

Conclusion

This study presents a novel analysis of Shigella antimicrobial resistance that compares resistance of isolates from infections acquired in Pennsylvania with those associated with travel outside the United States. Shigella isolates acquired from overseas infections were generally resistant to more antimicrobial classes than domestic Shigella isolates. Overseas isolates showed increasing trends of resistance to tetracyclines and sulfonamides from 2006 to 2014, whereas domestic Shigella became more resistant to aminoglycosides, tetracyclines, and sulfonamides. As overseas travelers bring antimicrobial-resistant Shigella to the United States, tracking Shigella antimicrobial-resistance transformations in domestic populations may provide critical information to enable effective epidemiologic and public health interventions.

PFGE patterns of travel-associated Shigella isolates were dissimilar, indicative of origins in different geographic regions. Shigella infections acquired in Pennsylvania resulted from isolates that showed strong correlations between PFGE patterns and antimicrobial resistance with a positive predictive value of 90.9%. JZXX01.0357 and JZXX01.0003 S. flexneri isolates were prevalent among S. flexneri infections and were resistant to more antimicrobials than other patterns. S. sonnei J16X01.0232 travel-associated isolates were mostly resistant to quinolones.

Although antimicrobial-resistant Shigella strains were mostly acquired during international travel, especially in Asian countries, infections with similar PFGE patterns were transmitted in domestic settings. The prevalence of resistance to macrolides (azithromycin) and third-generation cephalosporins (ceftriaxone) remained less than 1%; however, efforts to better monitor changes over time combined with increased antimicrobial stewardship are essential at the local, national, and global levels.

Footnotes

Acknowledgments

The auhtors acknowledge with gratitude the vital contributions from the following collaborators: Carol C. Sandt, Jacqueline Wyatt, CDC PulseNet, for naming PFGE patterns; Bureau of Laboratories Bacteriology Section for speciating human Shigella isolates; Bureau of Laboratories Molecular Microbiology Section for testing PFGE. The authors declare no conflicts of interest. The views expressed are those of the authors and do not necessarily represent those of the Pennsylvania Department of Health.

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