A treatment dilemma: Extensively drug-resistant Shigella
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There has been an alarming increase in extensively drug-resistant Shigella infections reported through national surveillance systems.
In February, the CDC published a health advisory via the Health Alert Network to bring more attention to this major public health issue.
Shifting epidemiology
Shigella is a facultative gram-negative bacteria comprising four species: Shigella dysenteriae, Shigella boydii, Shigella flexneri and Shigella sonnei, with each having several serotypes. The geographic distribution and epidemiologic importance of the different Shigella strains vary in significance, so it is important to know what is common in your geographic region. In the United States, S. sonnei and S. flexneri are the predominant species.
There are approximately 450,000 people infected annually with Shigella in the U.S. Worldwide, there are an estimated 80 million to 165 million cases annually, including 600,000 associated deaths, with most deaths occurring among children, according to the CDC.
Shigella bacteria are highly transmissible via the fecal-oral route. Transmission occurs through consuming contaminated food or water, direct person-to-person contact — including sexual contact — or contact with contaminated surfaces. Most patients will fall ill within 72 hours, but the incubation period can range from several hours up to 8 days.
Shigellosis is a significant public health threat because of the ease with which it can spread due to the low inoculum (10 to 100 organisms) needed to cause disease. Outbreaks can occur in settings where there is close contact or crowded conditions.
Shigellosis usually begins with constitutional symptoms such as fever, fatigue, malaise and stomach cramps, followed by watery, mucoid or bloody diarrhea.
There are several mechanisms by which drug resistance occurs in Shigella, such as decreased cellular permeability, active efflux pumps, beta-lactamase production, drug-modifying enzymes or target site modifications.
The CDC currently defines extensively drug-resistant (XDR) Shigella as strains with resistance to all commonly recommended empiric and alternative antibiotics. The percentage of XDR Shigella in the U.S. has increased from 0% in 2015 to 5% in 2022. S. sonnei accounted for 66% of the XDR isolates, with S. flexneri making up the remainder.
Although shigellosis can affect people of all ages, children have been disproportionately affected, especially those living in low- to middle-income countries. However, the epidemiology of XDR Shigella isolates has shifted more to the adult population, especially among men who have sex with men, people experiencing homelessness, international travelers and people with HIV.
Treatment options
Supportive care is recommended for all patients with shigellosis, and that may be all that is needed for those with mild illness. Hydration and maintenance of electrolytes through oral hydration is usually sufficient treatment for these patients. Antidiarrheal agents such as loperamide should be avoided because they could prolong symptoms and bacterial shedding.
Antibiotic therapy can help reduce the duration of illness by 1 to 2 days and help prevent secondary transmission. Antibiotic treatment is recommended for patients with severe illness or risk factors for progression of symptoms such as immunocompromised patients.
The choice of antimicrobial therapy can be complicated by factors such as availability, route of administration and resistance. Further complicating treatment decisions, as well as identification of resistant isolates, is the use of nonculture-based diagnostic tests. Use of molecular diagnostic tests such as PCR technology can speed up the diagnosis compared with culture, but susceptibility testing is not available when using these testing methods.
Treatment guidelines for shigellosis are available from the Infectious Diseases Society of America and WHO (Table). Although oral antibiotics can be used for most patients, IV ceftriaxone can be considered for those with severe disease or immunocompromising conditions.
Second-line options should be used only when susceptibility is known. The challenge with XDR Shigella is that these isolates are resistant to all of the recommended antibiotics, and data are lacking on optimal treatment options with these isolates. Some antibiotics that are effective for other diarrheal diseases have no role in shigellosis treatment because they do not penetrate the intestinal mucosa well, limiting their activity. These include first- and second-generation cephalosporins, amoxicillin, aminoglycosides and nitrofurans. Availability of potentially effective antibiotics is also an issue. Chloramphenicol and pivmecillinam may retain susceptibility against some Shigella, but these agents are unavailable in the U.S. The CDC currently does not have definitive treatment recommendations for XDR Shigella.
Fosfomycin and meropenem may prove to be options for XDR Shigella infections, but robust clinical data are lacking at this time. To date, the CDC has not found resistance among Shigella isolates with meropenem, and fosfomycin resistance has been rare. However, neither fosfomycin nor meropenem have been sufficiently studied in shigellosis. There are limited data with fosfomycin in management of infectious diarrhea, but most of the data are from outside the U.S. and involve pathogens other than Shigella.
A recent epidemiological study detailed an outbreak of XDR S. sonnei in the United Kingdom. There were 72 cases of S. sonnei that were genotypically multidrug-resistant or XDR isolates. Phenotypic testing concluded that all isolates were susceptible to ertapenem, meropenem, temocillin and fosfomycin. Oral pivmecillinam and fosfomycin were recommended for cases with prolonged symptoms or as oral step down after IV treatment. Meropenem or ertapenem was recommended as IV treatment options for hospitalized patients with suspected or confirmed cases with complications or severe infection.
Focus on prevention
Because of the lack of current available treatment options for XDR Shigella, we need to focus our attention on prevention. Patients should stay home from school or from high-risk jobs such as food service, child care or health care until it is safe to return based on local health department guidance. While the patient has diarrhea and for 2 weeks after it ends, patients should abstain from sex, practice good hand hygiene, stay out of recreational water such as pools and avoid preparing food for others.
Shigella vaccine development has been a battle that has been ongoing for the last century. Thus far, it has been exceedingly difficult to balance an adequate immune response along with an acceptable side effect profile. Although there are several Shigella vaccines at various stages of clinical development, it is unlikely that one will be available in the near future.
When faced with a patient with shigellosis, clinicians should determine if antimicrobial treatment is needed to reduce selective pressures that may lead to increased resistance. When antimicrobial susceptibility testing results are available, this should guide treatment options. However, for confirmed or suspected XDR isolates, consultation with an infectious diseases specialist is recommended because of limited available treatment options for these patients.
- References:
- CDC. Center for Preparedness and Response – Epidemiology, testing and management of extensively drug-resistant shigellosis. https://emergency.cdc.gov/coca/ppt/2023/022823_slides.pdf. Published Feb. 28, 2023. Accessed June 22, 2023.
- CDC. Division of Foodborne, Waterborne, and Environmental Diseases (DFWED) https://www.cdc.gov/ncezid/dfwed/index.html.
- CDC. Increase in extensively drug-resistant shigellosis in the United States. https://emergency.cdc.gov/han/2023/han00486.asp. Published Feb. 24, 2023. Accessed June 22, 2023
- CDC. Shigella – shigellosis: Questions & answers. https://www.cdc.gov/shigella/general-information.html. Last reviewed April 6, 2023. Accessed June 22, 2023.
- CDC. Shigellosis. CDC Yellow Book 2022. https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/shigellosis. Last reviewed June 13, 2023. Accessed June 22, 2023.
- Charles H, et al. Lancet Infect Dis. 2022;doi:10.1016/S1473-3099(22)00370-X.
- Kotloff KL, et al. Lancet. 2018;doi:10.1016/so140-6736(17)33296-8.
- MacLennan CA, et al. Vaccines. 2022;doi:10.3390/vaccines10091376.
- Ranjbar R, Farahani A. Infection and Drug Resistance. 2019;doi;10.2147/IDR.S219755.
- Shane AL, et al. Clin Infect Dis. 2017.doi:10.1093/cid/cix669.
- WHO. Guidelines for the control of shigellosis, including epidemics due to Shigella dysenteriae type 1. https://www.who.int/publications/i/item/9241592330. Published Jan. 1, 2005. Accessed June 22, 2023.
- For more information:
- Jeff Brock, PharmD, MBA, BCIDP, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at jeff.brock@mercyoneiowa.org.
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