Increasing Antibiotic Resistance in Shigella spp. from Infected New York City Residents, New York, USA

Approximately 20% of Shigella isolates tested in New York City, New York, USA, during 2013–2015 displayed decreased azithromycin susceptibility. Case-patients were older and more frequently male and HIV infected than those with azithromycin-susceptible Shigella infection; 90% identified as men who have sex with men. Clinical interpretation guidelines for azithromycin resistance and outcome studies are needed.

S higella bacteria are transmitted through the fecal-oral route by direct contact with an infected person, by ingestion of contaminated food or water, or by fomites. Shigellosis is associated with travel to disease-endemic areas, men who have sex with men (MSM), crowding, poverty, and attendance at childcare centers (1); illness is generally self-limited. Antibiotics may shorten the duration and decrease the illness severity (2,3). Because Shigella spp. may be resistant to ampicillin and trimethoprim/sulfamethoxazole (TMP/SMX), azithromycin and ciprofloxacin are often prescribed to treat shigellosis. In 2016, the Clinical Laboratory Standards Institute (CLSI) published MICs of azithromycin that indicated Shigella resistance; values are based on in vitro data and are not clinical breakpoints (4).
In 2013, public health laboratories in New York City (NYC), New York, USA, began testing susceptibility of Shigella isolates to azithromycin. We identified factors associated with infection with isolates that exhibited decreased susceptibility to azithromycin (DSA) or resistance to ciprofloxacin.

The Study
After submission to NYC public health laboratories, representative colonies of Shigella isolates are identified with conventional biochemical tests and tested for susceptibility to ampicillin, cefixime, ciprofloxacin, azithromycin, and TMP/SMX using the Etest antibiotic gradient (bioMérieux, Durham, NC, USA). MICs are interpreted according to CLSI guidelines (5). After consultation with the Centers for Disease Control and Prevention (CDC), we defined DSA isolates as those with an MIC of azithromycin of >32 µg/mL (J. Whichard, CDC, pers. comm., 2013).
Using a standard questionnaire, we interviewed persons infected with DSA or ciprofloxacin-resistant Shigella isolates, diagnosed during March 22, 2013-May 31, 2015; we abstracted antibiotic use data from medical charts. Shigella-infected case-patients were matched to the NYC HIV Surveillance Registry (6). We determined neighborhood poverty level as described (7) and compared proportions of those infected by age group, sex, and HIV status using χ 2 tests. To identify factors associated with DSA or ciprofloxacin-resistant Shigella infection and with hospitalization, we used logistic regression analysis (SAS version 9.2; SAS Institute, Cary, NC, USA).
Persons infected with DSA or ciprofloxacin-resistant Shigella spp. were older and more likely to be male than those with DSA-or ciprofloxacin-susceptible isolates; no association with neighborhood poverty was found. Although most infections were caused by S. sonnei, most isolates displaying DSA were S. flexneri. Isolates displaying DSA or ciprofloxacin resistance were more likely to be ampicillin-and TMP/SMX-resistant than were azithromycin-and ciprofloxacin-susceptible isolates (Tables 1, 2). Of the 683 shigellosis case-patients, 183 (27%) had diagnosed HIV infection. Among these, 76 (42%) were infected with DSA isolates, and 7 (4%) were infected with ciprofloxacin-resistant isolates; 108 (59%) were infected with S. flexneri, 73 (40%) with S. sonnei, and 1 each (0.5%) with S. boydii and S. dysenteriae. Of 47 (62%) HIV-diagnosed persons with DSA Shigella infection, 45 (95%) identified as MSM.

Conclusions
In NYC, 19% of nonoutbreak shigellosis cases were caused by organisms with an azithromycin MIC >32 µg/mL, a much higher proportion than the national estimate of 3.8% (9).This finding is troubling because, when antibiotics are indicated, azithromycin is recommended (2,3).
DSA Shigella infection occurred almost exclusively among men, most infected with HIV. Of these, few reported travel, which suggests local acquisition. Transmission of Shigella spp. within networks of MSM has been described by using molecular characterization of isolates to link cases; some NYC cases are likely associated with these networks (10). Whether DSA Shigella infection results in more severe illness or in increased shedding time is unknown. Ten (59%) of 17 persons infected with ciprofloxacin-resistant Shigella spp. reported no exposure to disease-endemic areas (11). Half of non-travel-associated cases occurred among MSM, most were caused by S. sonnei, and few patients were hospitalized, suggesting milder illness. Strains exhibiting both ciprofloxacin resistance and DSA exist in NYC.
HIV-positive MSM may be at increased risk for acquiring infections caused by antibiotic-resistant Shigella spp. due to transmission-facilitating behavior (10) or because of increased exposure to macrolides and fluoroquinolones used to treat sexually transmitted infections, which could increase selective pressure on Shigella organisms (12). HIV infection may increase the risk of acquiring and transmitting Shigella infection due to increased carriage and shedding time or altered immune response (2).
To limit the emergence of resistance, the NYC Department of Health and Mental Hygiene and CDC recommend that antibiotics be avoided in treating Shigella infections except in cases of severe illness or among those at risk for systemic infection (13,14). When antibiotics are prescribed, therapy should be modified on the basis of sensitivity testing; however, without CLSI-defined clinical breakpoints for azithromycin, this process will be challenging (4,14,15).
We were unable to compare illness, exposures, and treatments between persons infected with susceptible versus resistant Shigella spp. We may have overestimated resistance if persons with resistant strains were more likely to have severe or persistent infections, seek care, and have cultures obtained. The clinical significance of resistance is not clear. Finally, molecular characterization of isolates to describe resistance mechanisms and transmission patterns was not done.
Although Shigella infections are generally selflimited, resistant organisms could lead to complications among those who develop systemic infection if they cannot be adequately treated. Studies of clinical breakpoints for azithromycin susceptibility and clinical outcomes are needed. In the meantime, providers should avoid treating otherwise healthy shigellosis patients with antibiotics. When antibiotics are indicated, providers should use available susceptibility results and monitor patient outcomes.