Cephalosporin treatment of Shigella in the age of antimicrobial resistance

Shigella, one of the world’s most infectious bacterial pathogens and a leading cause of deadly diarrheal disease in young children, is rapidly slipping out of the reach of the antibiotics doctors rely on most when everything else fails. A comprehensive new review published in the journal New Microbes and New Infections synthesizes nearly four decades of evidence on how third-generation cephalosporins—the backbone of therapy for severe and pediatric shigellosis—are being undermined by the relentless spread of resistance, and the picture it paints is one of a therapeutic pipeline running dangerously dry.

The review, conducted by Wenqing Wang, Yutian Qin, Yiqiong Wang, Xinyi Li, Dai Kuang, and Mamy Jayne Nelly Rajaofera, screened more than 4,000 records drawn from PubMed/MEDLINE, Scopus, Web of Science, ScienceDirect, and the World Health Organization’s Global Antimicrobial Resistance and Use Surveillance System (GLASS) database, ultimately including 105 studies published between 1986 and 2025. The starting point was deliberate: third-generation cephalosporins such as ceftriaxone and cefotaxime were introduced in the early 1980s, and the first clinical data on their use against Shigella appeared shortly thereafter. By tracing the entire arc of cephalosporin deployment against the pathogen, the authors were able to document how a once-reliable class of drugs has been progressively compromised in real time.

The stakes could hardly be higher. Shigella is a genus of Gram-negative, facultatively anaerobic bacteria comprising four major species—Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei—capable of causing disease with a staggeringly small infectious dose of just 10 to 100 organisms. Transmission occurs predominantly through the fecal-oral route via contaminated food and water or direct person-to-person contact, which makes the pathogen especially devastating in settings with poor sanitation. Globally, an estimated 164.7 million cases occur each year, and children under five bear the greatest burden, with roughly 60,000 child deaths annually attributable to infection. In low- and middle-income countries, between 2.0 and 7.0 per 100 children experience clinically significant Shigella infection during childhood, a striking contrast to the 0.02 cases per child-year seen in high-income settings. Epidemiological patterns have also shifted: while S. sonnei once predominated in many low- and middle-income countries, S. flexneri has now become the dominant species in these regions, while S. sonnei remains prevalent in wealthier nations.

The bacterium’s clinical repertoire ranges from mild diarrhea to severe dysentery marked by bloody stools, fever, and abdominal pain, with potentially fatal complications including hemolytic uremic syndrome, toxic megacolon, and septicemia. Much of this virulence stems from an elegant and brutal molecular toolkit. Shigella invades the colonic epithelium using a Type III Secretion System (T3SS) encoded on the large virulence plasmid pINV. Structurally, the T3SS comprises a cytosolic sorting platform, a basal body spanning both the inner and outer bacterial membranes, and an extracellular needle. Upon contact with a host cell, the needle tip recruits translocon proteins IpaB and IpaC, which are secreted to form a pore in the host membrane. Through this pore, the bacterium injects effector proteins that trigger cytoskeletal remodeling and facilitate M cell-mediated internalization. Once inside, Shigella escapes the phagosome, replicates in the cytoplasm, and hijacks the host cell’s actin polymerization machinery to build propulsive actin tails that drive it laterally into neighboring cells—spreading without ever exposing itself to the extracellular immune environment. The result is progressive epithelial necrosis, inflammatory infiltration, and the hallmark bloody diarrhea of shigellosis. S. dysenteriae type 1 adds a further weapon: Shiga toxin, which can precipitate hemolytic uremic syndrome.

Against this formidable pathogen, the treatment landscape has been systematically eroded by antimicrobial resistance. The review documents how first-line antibiotics fell one after another. Resistance to trimethoprim-sulfamethoxazole and ampicillin, the historical mainstays, is now so widespread that both agents are considered unreliable for empirical therapy. Shigella resistance to ampicillin reached 60 percent in the Tehran and Qazvin region of Iran and 75 percent in China, while trimethoprim-sulfamethoxazole resistance hit 55 percent in China and up to 100 percent in Iran. Global estimates suggest that around 30 percent of antibiotic use is inappropriate, particularly in low- and middle-income countries, fueling the selection of resistant strains. Fluoroquinolones, which replaced the older drugs as first-line therapy in adults thanks to rapid bactericidal activity and excellent tissue penetration, are now failing too. According to WHO 2025 reports, global ciprofloxacin resistance in Shigella stands at 29.7 percent and levofloxacin resistance at 32.7 percent, with Southeast Asia reaching an alarming 75.5 percent for ciprofloxacin. A longitudinal study in Bangladesh traced the collapse in real time, documenting ciprofloxacin resistance rising from 0 percent in 2004 to 43 percent by 2012. Fluoroquinolone-resistant Shigella is now classified as high-priority on the WHO bacterial priority pathogen list, ranked eighth in 2024. Resistance to macrolides, including azithromycin—the preferred option for pediatric patients, pregnant women, and those with fluoroquinolone contraindications—is also climbing, surpassing 60 percent in some endemic areas.

This cascade of failure has left third-generation cephalosporins as the critical fallback for severe, hospitalized, and pediatric cases. Cephalosporins are β-lactam antibiotics that kill bacteria by binding penicillin-binding proteins (PBPs) and disrupting the cross-linking of peptidoglycan, the essential structural polymer that maintains cell wall integrity and protects the bacterium from osmotic lysis. When peptidoglycan synthesis is inhibited, the compromised cell wall loses its structural integrity, and the bacterium swells and bursts under osmotic stress. Later generations of cephalosporins, including ceftriaxone and cefotaxime, offer enhanced stability against β-lactamase hydrolysis and strong activity against Gram-negative organisms such as Shigella, which explains their centrality in treating invasive disease. A striking illustration of their past efficacy comes from Israel, where in 2000 a three-day intramuscular ceftriaxone regimen achieved 99 percent clinical cure in acute invasive diarrhea among children—a population in which the country reported approximately 600 cases per 100,000 children aged one to four years.

That success story, however, has a grim sequel. By 2026, only 36 percent of Israeli isolates remained susceptible to ceftriaxone, compared with 77 percent susceptibility to azithromycin and 76 percent to ciprofloxacin. The mechanism behind this decline is the spread of extended-spectrum beta-lactamases (ESBLs), enzymes that hydrolyze the β-lactam ring at the heart of cephalosporin chemistry. The review identifies CTX-M-type ESBLs as the most common globally, alongside TEM and SHV variants. The regional data assembled in the study are sobering: in Jiangsu, China, 34.4 percent of S. flexneri isolates were resistant to cefotaxime and 24.1 percent to ceftazidime between 2013 and 2015; a national Chinese survey covering 2004 to 2016 found ceftriaxone resistance of 30.49 percent; and in Negev, southern Israel, between January 2020 and July 2024, ceftriaxone resistance among S. sonnei isolates reached 64 percent, with azithromycin resistance at 23 percent and ciprofloxacin resistance at 24 percent. In Iran, ampicillin resistance has been documented as high as 88.2 to 95.1 percent in recent surveillance studies, alongside substantial azithromycin resistance of 56.47 percent among southwestern Iranian isolates.

Perhaps most alarming is the emergence of multidrug-resistant (MDR) strains—those resistant to three or more antibiotic classes—and, at the extreme end, extensively drug-resistant (XDR) Shigella resistant to nearly all oral antibiotics. A case of XDR S. sonnei infection reported in Temple, Texas, in January 2023 underscores that this threat is no longer confined to resource-limited settings. The review also notes that in Africa, the pooled prevalence of ESBL and carbapenem-resistant Shigella is estimated at 41.2 percent, with S. flexneri the most prevalent species at 34.5 percent. The most common ESBL genes detected are blaTEM (25.9 percent), blaOXA-1 (25.7 percent), and blaCTX-M (10.8 percent), while carbapenemase genes such as blaNDM, blaKPC, and blaIMP remain rare—a narrow but critical window before even last-resort carbapenems are threatened. Dissemination pathways vary regionally: South Asia reports some of the world’s highest fluoroquinolone resistance, whereas parts of Africa show comparatively lower rates, underscoring the review’s argument that surveillance and prescribing guidance must be tailored to local resistance patterns rather than applied globally as one-size-fits-all protocols.

The authors highlight a structural weakness in the therapeutic arsenal that is easy to overlook: the absence of an effective oral cephalosporin. Ceftriaxone and cefotaxime must be administered parenterally, which constrains outpatient management and is especially problematic in resource-limited settings where hospital beds, trained staff, and cold chains are scarce. This forces clinicians into a dilemma—reserve intravenous cephalosporins for the sickest patients, or rely on oral agents such as azithromycin whose own efficacy is eroding. The review’s synthesis, which adapted Joanna Briggs Institute checklists for quality appraisal and prioritized high-quality evidence while integrating observational and in vitro studies to contextualize resistance mechanisms, makes clear that cephalosporin use should be guided by susceptibility testing wherever possible and embedded within antimicrobial stewardship programs to preserve what clinical utility remains.

The implications reach well beyond the pharmacy. Current management of shigellosis is stratified by severity: mild cases typically require only oral rehydration therapy, while moderate to severe infections warrant antibiotics to shorten symptom duration, prevent complications, and limit transmission—a dual clinical and public health purpose, since even shortening bacterial shedding slows outbreaks. As the drug options narrow, the review calls urgently for structured surveillance systems, evidence-based treatment protocols tailored to regional resistance profiles, and investment in alternatives including vaccines and phage therapy. The authors also flag a practical gap in the evidence base itself: the heterogeneity of study designs, populations, and outcome measures across the 105 included studies prevented formal meta-analysis, meaning that even the global picture of cephalosporin resistance in Shigella is assembled from fragments rather than a unified dataset.

What emerges from this exhaustive synthesis is a field at an inflection point. A pathogen that infects on a dose of a hundred cells, spreads through contaminated water and human contact, and hides inside the very cells meant to destroy it is now outpacing the drugs built to kill it, generation by generation. First ampicillin and trimethoprim-sulfamethoxazole fell, then fluoroquinolones stumbled, and now the cephalosporins—the last reliable line for children hospitalized with bloody diarrhea—are visibly eroding under the pressure of ESBL enzymes like CTX-M. Without swift investment in stewardship, surveillance, and entirely new therapeutic modalities, the review warns, clinicians may soon face the unthinkable: children with severe shigellosis and no effective antibiotic left to give.