Shigella Infection Medication
- Author: Jaya Sureshbabu, MBBS, MRCPCH(UK), MRCPI(Paeds), MRCPS(Glasg), DCH(Glasg); Chief Editor: Russell W Steele, MD more...
Various antimicrobial agents are effective in the treatment of shigellosis, although options are becoming limited because of globally emerging drug resistance. Resistance of Shigella species to sulfonamides, tetracyclines, ampicillin, and trimethoprim-sulfamethoxazole (TMP-SMX) has been reported worldwide, and these agents are not recommended as empirical therapy.
The World Health Organization (WHO) recommends that all suspected cases of shigellosis based on clinical features be treated with effective antimicrobials (antibiotics). The choice of antimicrobial drug has changed over the years as resistance to antibiotics has occurred, with different patterns of resistance being reported around the world. Evidence is insufficient to consider any class of antibiotic superior in efﬁcacy in treating Shigella dysentery. The following antibiotics are used to treat Shigella dysentery:
Beta-lactams: Ampicillin, amoxicillin, third-generation cephalosporins (ceﬁxime, ceftriaxone), and pivmecillinam (not available in the United States)
Quinolones: Nalidixic acid, ciproﬂoxacin, norﬂoxacin, and oﬂoxacin
Others: sulfonamides, tetracycline, cotrimoxazole, and furazolidone.
Most clinical infections with S sonnei are self-limited (48-72 h) and may not require antimicrobial therapy.
If an ampicillin and TMP-SMX resistant strain is isolated or if susceptibility is unknown, parenteral ceftriaxone sodium, fluoroquinolone (eg, ciprofloxacin, ofloxacin), azithromycin dihydrate (off-label indication), or oral cefixime are the drugs of choice.[8, 19, 20] Amoxicillin is less effective than ampicillin for treatment of ampicillin-sensitive strains. Oral first- and second-generation cephalosporins are inadequate despite in vitro susceptibility. Recently, Shigella isolates with decreased susceptibility to azithromycin (DSA-Shigella), with minimum inhibitory concentration (MIC) greater than 16 µ g/mL has been described by the CDC.
In June 2015, the Centers for Disease Control and Prevention (CDC) warned that they received reports of infections with Shigella strains that are not susceptible to ciprofloxacin and/or azithromycin. CDC is seeing resistance to ciprofloxacin in 1.6% of the Shigella cases tested and resistance to azithromycin in approximately 3%. The CDC added that most cases have been reported among gay, bisexual, and other men who have sex with men in Illinois, Minnesota, and Montana and among international travelers, but cases are also occurring among other populations.[22, 23, 24]
Because shigellosis is self-limiting, some authorities recommend withholding antibiotic therapy. When an effective antibiotic is given, clinical improvement is anticipated within 48 hours. This lessens the risk of serious complications and death, shortens the duration of symptoms, and hastens the elimination of Shigella and the subsequent spread of infection. The risk of continued shedding of organisms in stool increases the risk of transmission of further disease among contacts argues against withholding antimicrobial treatment.
Antimicrobial therapy is typically administered for 5 days. Antibiotic treatment decreases the duration of illness, person-to-person spread, and cases in household contacts. Treatment in malnourished children (eg, in developing countries) is likely to reduce the risk of worsening malnutrition morbidity after shigellosis. In persons infected with S dysenteriae type 1, early administration of effective antibiotics decreases Shiga toxin (Stx) concentrations in the stool and lowers HUS risk. However, the risk of HUS caused by E coli O157-H7 may be increased with the early administration of antibiotics. Prophylactic antibiotics are not recommended for contacts.
Antidiarrheal medications (diphenoxylate hydrochloride with atropine [Lomotil] or loperamide [Imodium]) should not be used because of the risk of prolonging the illness. WHO has introduced the use of zinc for 10-14 days as part of a diarrheal disease control program in addition to oral rehydration therapy. Initiating zinc at the time of diarrhea leads to shorter duration and fewer loose stools.[17, 26]
A child with typical dysentery that responds to initial empirical antibiotic treatment should continue taking the same drug for a full 5-day course, even if the stool culture is negative.
Immunity and vaccination
Once someone has had Shigella infection, they are not likely to become infected with that specific type again for at least several years. However, they can still become infected with other types of Shigella. Presumably, this immunity could be due to secretory IgA. Circulating antibodies can be detected in immune individuals.
Presently, no US Food and Drug Administration (FDA)–approved vaccines are available. However, research is underway to develop live oral vaccines to prevent shigellosis.[27, 28] Three approaches to Shigella vaccine development that are under active investigation are (1) parenteral O–specific polysaccharide conjugate vaccine, (2) nasal proteasomes delivering Shigella lipopolysaccharide, and (3) live attenuated invasive Shigella deletion mutants that are administered orally.
Researchers have launched an early-stage human clinical trial of two related candidate vaccines to prevent infection with Shigella. The trial is being conducted at the Cincinnati Children’s Hospital Medical Center, one of the eight NIAID-funded Vaccine and Treatment Evaluation Units in the United States funded by the National Institute of Allergy and Infectious Diseases (NIAID).
Ampicillin and TMP-SMZ are effective for susceptible strains; amoxicillin is less effective than this because of its rapid absorption high in the GI tract. The oral route is preferred except for seriously ill patients. In the United States, sentinel surveillance data from 2003-2006 indicated that 94% of S sonnei and 67% of S flexneri organisms were resistant to ampicillin and TMP-SMZ. The WHO now recommends that clinically diagnosed cases of Shigella dysentery be treated with ciproﬂoxacin as ﬁrst line treatment, and pivmecillinam (not available in the United States), ceftriaxone, or azithromycin as second line treatment and lists the others as ineffective (WHO 2005a). . However, resistance to quinolones has also been observed since the late 1990s, and some authors have questioned the effectiveness of this class for Shigella. The choice of antibiotic to use as ﬁrst line against Shigella dysentery should be governed by periodically updated local antibiotic sensitivity patterns of Shigella isolates.
First-line treatment for shigellosis. Fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Has no activity against anaerobes. Continue treatment for total of 5 days, even empirical treatment in patient with typical bloody diarrhea who responds clinically with negative stool culture. (7-14 d typical)
Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin binding proteins. Exerts antimicrobial effect by interfering with synthesis of peptidoglycan, a major structural component of bacterial cell wall. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.
Highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of dose excreted unchanged in urine, and remainder secreted in bile and ultimately in feces as microbiologically inactive compounds. Reversibly binds to human plasma proteins, and binding have been reported to decrease from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.
Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It has enhanced activity against gram-negative organisms. Concentrates in phagocytes and fibroblasts, as demonstrated with in vitro incubation techniques; hence, plasma concentrations are very low but tissue concentrations are very high. It has a long tissue half-life and once daily dosage is recommended. In vivo data suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Broad-spectrum penicillin. Interferes with bacterial cell-wall synthesis during active replication, causing bactericidal activity against susceptible organisms.
Nalidixic acid (NegGram)
First-generation quinolone. Blocks bacterial DNA gyrase. Useful in patients with sulfas and cephalosporin allergy. WHO guidelines state most Shigella strains are now resistant to nalidixic acid.
Third-generation oral cephalosporin with broad activity against gram-negative bacteria. By binding to one or more of the penicillin-binding proteins, it arrests bacterial cell wall synthesis and inhibits bacterial growth. For outpatient use in drug-resistant Shigella infections.
Combination effective for shigellosis in the past, but WHO states most Shigella strains are now resistant. Produces sequential blockade in folic acid synthesis. Effect frequently synergistic and bactericidal.
WHO has introduced the use of zinc for 10-14 days as part of a diarrheal disease control program in addition to oral rehydration therapy. Initiating zinc at the time of diarrhea leads to shorter duration and fewer loose stools.[17, 26]
Zinc supplementation has been found to decrease duration and severity of diarrheal episodes.
Gomez HF, Cleary TG. Shigella species. Principles and Practice of Pediatric Infectious Diseases. New York, NY: Churchill Livingstone; 1997. 429-34.
Phalipon A, Sansonetti PJ. Shigella's ways of manipulating the host intestinal innate and adaptive immune system: a tool box for survival?. Immunol Cell Biol. 2007 Feb-Mar. 85(2):119-29. [Medline].
Edwards BH. Salmonella and Shigella species. Clin Lab Med. 1999 Sep. 19(3):469-87, v. [Medline].
Friedrich AW, Bielaszewska M, Zhang WL, et al. Escherichia coli harboring Shiga toxin 2 gene variants: frequency and association with clinical symptoms. J Infect Dis. 2002 Jan 1. 185(1):74-84. [Medline].
Richardson SE, Rotman TA, Jay V, et al. Experimental verocytotoxemia in rabbits. Infect Immun. 1992 Oct. 60(10):4154-67. [Medline].
Ingersoll MA, Zychlinsky A. ShiA abrogates the innate T-cell response to Shigella flexneri infection. Infect Immun. 2006 Apr. 74(4):2317-27. [Medline].
Keusch GT, Jacewicz M, Acheson DW, et al. Globotriaosylceramide, Gb3, is an alternative functional receptor for Shiga-like toxin 2e. Infect Immun. 1995 Mar. 63(3):1138-41. [Medline].
Schuller S. Shiga toxin interaction with human intestinal epithelium. Toxins (Basel). 2011 Jun. 3(6):626-39. [Medline].
Crim SM, Iwamoto M, Huang JY, Griffin PM, Gilliss D, Cronquist AB, et al. Incidence and trends of infection with pathogens transmitted commonly through food--Foodborne Diseases Active Surveillance Network, 10 U.S. sites, 2006-2013. MMWR Morb Mortal Wkly Rep. 2014 Apr 18. 63 (15):328-32. [Medline].
CDC. Vital signs: incidence and trends of infection with pathogens transmitted commonly through food--foodborne diseases active surveillance network, 10 U.S. sites, 1996-2010. MMWR Morb Mortal Wkly Rep. 2011 Jun 10. 60(22):749-55. [Medline].
Baer JT, Vugia DJ, Reingold AL, et al. HIV infection as a risk factor for shigellosis. Emerg Infect Dis. 1999 Nov-Dec. 5(6):820-3. [Medline].
Khan WA, Dhar U, Salam MA, et al. Central nervous system manifestations of childhood shigellosis: prevalence, risk factors, and outcome. Pediatrics. 1999 Feb. 103(2):E18. [Medline].
Ochoa TJ, Cleary TG. Shigella. Kliegman, Behrman, Jenson, Stanton, eds. Nelson Textbook of Paediatrics. 19th ed. Philadelphia, PA: Saunders Elsevier; 2011. 191-Pg 959-961. [Full Text].
Mitra AK, Alvarez JO, Wahed MA, et al. Predictors of serum retinol in children with shigellosis. Am J Clin Nutr. 1998 Nov. 68(5):1088-94. [Medline].
Nataro JP. Treatment of bacterial enteritis. Pediatr Infect Dis J. 1998 May. 17(5):420-1. [Medline].
Rahman MJ, Sarkar P, Roy SK. Effect of zinc supplementation as adjunct therapy on the systemic immune response in shigellosis. Am J Clin Nutr. Feb, 2005. 81(2):495-502. [Medline].
World Health Organization. Zinc in a diarrhoeal disease control programme. 2008. Available at http://whqlibdoc.who.int/publications/2008/9789241596473_eng.pdf. Accessed: June 19, 2012.
Christopher PR, David KV, John SM, Sankarapandian V. Antibiotic therapy for Shigella dysentery. Cochrane Database Syst Rev. 2010 Aug 4. CD006784. [Medline].
Basualdo W, Arbo A. Randomized comparison of azithromycin versus cefixime for treatment of shigellosis in children. Pediatr Infect Dis J. 2003 Apr. 22(4):374-7. [Medline].
Niyogi SK. Shigellosis. J Microbiol. 2005 Apr. 43(2):133-43. [Medline].
Heiman KE, Karlsson M, Grass J, Howie B, Kirkcaldy RD, Mahon B, et al. Notes from the field: Shigella with decreased susceptibility to azithromycin among men who have sex with men - United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2014 Feb 14. 63(6):132-3. [Medline].
Brooks M. Growing Concern Over Drug-Resistant Shigella in US. Medscape Medical News. Available at http://www.medscape.com/viewarticle/846038. June 06, 2015; Accessed: April 22, 2016.
Ciprofloxacin- and Azithromycin-Nonsusceptible Shigellosis in the United States. Centers for Disease Control and Prevention. Available at http://www.bt.cdc.gov/han/han00379.asp. June 4, 2015; Accessed: April 22, 2016.
Bowen A, Eikmeier D, Talley P, Siston A, Smith S, Hurd J, et al. Notes from the Field: Outbreaks of Shigella sonnei Infection with Decreased Susceptibility to Azithromycin Among Men Who Have Sex with Men - Chicago and Metropolitan Minneapolis-St. Paul, 2014. MMWR Morb Mortal Wkly Rep. 2015 Jun 5. 64 (21):597-8. [Medline].
Appannanavar SB, Goyal K, Garg R, Ray P, Rathi M, Taneja N. Shigellemia in a post renal transplant patient: a case report and literature review. J infect Dev Ctries. Feb 13, 2014. 8:237-239. [Medline].
World Health Organization. Implementing the new recommendations on the clinical management of diarrhea. 2006. Available at http://whqlibdoc.who.int/publications/2006/9241594217_eng.pdf. Accessed: June 19, 2012.
Katz DE, Coster TS, Wolf MK, et al. Two studies evaluating the safety and immunogenicity of a live, attenuated Shigella flexneri 2a vaccine (SC602) and excretion of vaccine organisms in North American volunteers. Infect Immun. 2004 Feb. 72(2):923-30. [Medline].
National Institute of Allergy and Infectious Diseases (NIAID). Safety and Immunogenicity of Two Live, Attenuated Oral Shigella Sonnei Vaccines: WRSs2 and WRSs3. Available at http://clinicaltrials.gov/ct2/show/NCT01336699. Accessed: June 6, 2014.
World Health Organization. Guidelines for the control of Shigellosis, including epidemics due to Shigella dysenteriae type 1. Available at http://whqlibdoc.who.int/publications/2005/9241592330.pdf. Accessed: June 19, 2012.
Plotz FB, Arets HG, Fleer A, et al. Lethal encephalopathy complicating childhood shigellosis. Eur J Pediatr. 1999 Jul. 158(7):550-2. [Medline].
Bennish ML, Khan WA, Begum M, et al. Low risk of hemolytic uremic syndrome after early effective antimicrobial therapy for Shigella dysenteriae type 1 infection in Bangladesh. Clin Infect Dis. 2006 Feb 1. 42(3):356-62. [Medline].
Tzipori S, Sheoran A, Akiyoshi D, et al. Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev. 2004 Oct. 17(4):926-41, table of contents. [Medline].
Gomez HF, Cleary TG. Shigella. Textbook of Pediatric Infectious Diseases. Philadelphia, PA: WB Saunders; 1998. 1207-317.
Bishop R, Strockbine N, Nygren B, Mintz E. Annual Summary-Shigella 2006. Centres for Disease Control and Prevention, US Department of Health and Human Services. Nov 2008. Available at http://www.cdc.gov/ncidod/dbmd/phlisdata/shigella.htm.
Huicho L, Sanchez D, Contreras M, et al. Occult blood and fecal leukocytes as screening tests in childhood infectious diarrhea: an old problem revisited. Pediatr Infect Dis J. 1993 Jun. 12(6):474-7. [Medline].
Kaminski RW, Oaks EV. Inactivated and subunit vaccines to prevent shigellosis. Expert Rev Vaccines. 2009 Dec. 8(12):1693-704. [Medline].
Martinez-Becerra FJ, Kissmann JM, Diaz-McNair J, et al. Broadly protective Shigella vaccine based on type III secretion apparatus proteins. Infect Immun. 2012 Mar. 80(3):1222-31. [Medline].
Nathoo KJ, Porteous JE, Siziya S, et al. Predictors of mortality in children hospitalized with dysentery in Harare, Zimbabwe. Cent Afr J Med. 1998 Nov. 44(11):272-6. [Medline].
Navia MM, Gascon J, Vila J. Analysis of the mechanisms of resistance to several antimicrobial agents in Shigella spp. causing travellers' diarrhoea. Clin Microbiol Infect. 2005 Dec. 11(12):1044-7. [Medline].
Oaks EV, Turbyfill KR. Development and evaluation of a Shigella flexneri 2a and S. sonnei bivalent invasin complex (Invaplex) vaccine. Vaccine. 2006 Mar 20. 24(13):2290-301. [Medline].
Pazhani GP, Ramamurthy T, Mitra U, et al. Species diversity and antimicrobial resistance of Shigella spp. isolated between 2001 and 2004 from hospitalized children with diarrhoea in Kolkata (Calcutta), India. Epidemiol Infect. 2005 Dec. 133(6):1089-95. [Medline].
Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000 Jun 29. 342(26):1930-6. [Medline].
Yang F, Yang J, Zhang X, et al. Genome dynamics and diversity of Shigella species, the etiologic agents of bacillary dysentery. Nucleic Acids Res. 2005. 33(19):6445-58. [Medline].