RARE DISEASE
Necrotizing soft tissue infection
Necrotizing soft tissue infection
Necrotizing soft tissue infection
Synonyms: NSTI
Synonyms: NSTI
Synonyms: NSTI
Drug discovery
2
drugs
With orphan designations
Overview
Necrotizing soft tissue infection (NSTI) is a rapidly progressive, life-threatening bacterial or fungal infection causing tissue necrosis, systemic toxicity, and high mortality (6–76%) [1][4][7]. It primarily affects subcutaneous fat, fascia, or muscle, often arising from polymicrobial (70–80%) or monomicrobial (β-hemolytic streptococci, S. aureus) pathogens [1][3][10]. Diagnosis requires prompt surgical exploration due to nonspecific early symptoms (e.g., disproportionate pain, erythema) [6][16].
Categories: rare infectious diseases
Research Papers
1,001 drug discovery papers about Necrotizing soft tissue infection, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,001 drug discovery papers about Necrotizing soft tissue infection, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-09 | Conservative Management of Invasive Group A Streptococcal Infection With Cervical Necrotizing Fasciitis-Spectrum Disease and Pneumonia in a Healthy Young Adult.
Invasive Group A streptococcal (iGAS) infections are life-threatening conditions classically manifesting as necrotizing fasciitis or severe pneumonia, but their simultaneous occurrence in a previously healthy adult is extremely rare. While necrotizing fasciitis typically mandates urgent surgery, this report highlights a case of concurrent cervical necrotizing fasciitis-spectrum disease and pneumonia successfully managed through a conservative, non-surgical approach. A 29-year-old previously healthy Japanese male presented with a two-day history of fever, sore throat, and a maculopapular rash, with a throat swab positive for GAS. On Day 2, he acutely developed progressive dyspnea, hypoxemia, and extensive cervical subcutaneous emphysema. Computed tomography confirmed diffuse fascial edema and bilateral pulmonary infiltrates without signs of gas-forming abscess or irreversible tissue necrosis. Despite early amoxicillin administration, blood cultures remained negative, suggesting toxin-mediated clinical deterioration. Based on the imaging findings and close clinical monitoring, a non-operative strategy was selected. This was achieved by immediate medical escalation to broad-spectrum antimicrobials, including clindamycin to suppress toxin production, alongside meropenem and high-dose penicillin G. The patient recovered fully without surgical intervention. This case highlights that iGAS can cause rapid, concurrent soft-tissue and pulmonary involvement even in healthy individuals. In select cases of necrotizing fasciitis-spectrum disease where irreversible tissue necrosis is absent on prompt imaging and close clinical monitoring is maintained, aggressive multi-drug medical escalation incorporating antitoxin therapy can lead to successful outcomes without the need for morbid surgical procedures.
2026-07-29 | Synergistic activity of mitomycin C in combination with ciprofloxacin against severe Vibrio vulnificus infection.
Vibrio vulnificus is a highly virulent pathogen associated with rapidly progressive sepsis and necrotising soft-tissue infection, particularly among patients with diabetes or chronic liver disease. Effective treatment options remain limited, especially in the setting of high bacterial burden or immunocompromis. We performed an integrated preclinical assessment of mitomycin C (MMC) alone and in combination with ciprofloxacin (CIP) using in vitro susceptibility testing and a neutropenic murine model challenged with increasing inocula of V. vulnificus. Myelotoxicity, organ-specific toxicity, and the development of resistance under subinhibitory MMC exposure were evaluated through haematological profiling and histopathology. MMC demonstrated potent in vitro activity and conferred complete protection in mice challenged with low bacterial inocula (103-104 colony-forming units (CFU)/mL). Although efficacy declined with increasing bacterial burden, combination therapy with MMC and ciprofloxacin significantly improved survival across all inoculum levels, achieving complete protection at concentrations up to 1.4 ⨯ 107 CFU/mL and partial protection at 4.3 ⨯ 107 CFU/mL. The combination regimen was not associated with dose-dependent myelosuppression, and no hepatotoxicity or nephrotoxicity was observed. Exposure to subinhibitory concentrations of MMC did not result in increased minimum inhibitory concentrations over time. MMC-CIP combination therapy demonstrated synergistic efficacy against severe V. vulnificus infection in a neutropenic mouse model and may represent a promising therapeutic option. Dose-limiting myelotoxicity and the potential for resistance necessitate cautious dosing and further clinical investigation. This study addresses a critical therapeutic gap in severe V. vulnificus infection by proposing a mechanistically rational, dose-optimized adjunctive strategy supported by robust preclinical evidence.
2026-07-08 | Neorectal Perforation and Necrotizing Soft Tissue Infection of the Lower Limb Following Pelvic Reirradiation for Recurrent Rectal Cancer: A Case Report.
Neorectal perforation is a rare but serious complication following treatment for rectal cancer, and may lead to catastrophic sequelae if diagnosis and management are delayed. We report the case of a 54-year-old woman with locally recurrent rectal cancer who developed neorectal perforation and necrotizing soft tissue infection of the lower limb following chemoradiotherapy. Initial symptoms were attributed to sciatic nerve inflammation, and surgical consultation was delayed. The patient subsequently developed septic shock and was found to have extraperitoneal perforation extending through the greater sciatic foramen, with extensive necrotizing fasciitis of the gluteal and thigh compartments. Management required urgent laparotomy with resection of the colonic J pouch, omentoplasty, feeding gastrostomy, and extraperitoneal end colostomy, followed by multiple surgical debridements. The patient experienced prolonged critical illness, including multiorgan failure and colonization of wounds with multidrug-resistant organisms. Successful recovery was achieved through aggressive multidisciplinary care, including novel use of negative pressure wound therapy with acetic acid instillation. This case highlights the need for caution when re-irradiating the neorectum in the presence of a neorectal ulcer, and the importance of early surgical involvement in complex post-treatment complications.
2026-06-27 | Gram-negative-dominated polymicrobial microbiome of necrotizing soft tissue infections from North India: an integrated culture and 16S rRNA metagenomics prospective cohort study
ABSTRACT Necrotizing soft tissue infections (NSTIs) carry 10 to 30% mortality. Current empirical antimicrobial guidance derives almost entirely from Western cohorts dominated by Streptococcus pyogenes and aerobic-anaerobic consortia, yet whether this microbial paradigm applies to tropical, high-antimicrobial-pressure settings has not been tested with culture-independent methods. We did a prospective cohort study of 169 patients with intraoperatively confirmed NSTI at a North Indian tertiary center (2021 to 2024). Wound tissue underwent aerobic and anaerobic culture, QIIME2-based 16S rRNA gene amplicon sequencing (V3-V4), and targeted SYBR Green quantitative PCR (qPCR) for Acinetobacter baumannii and S. pyogenes . The wound microbiota was overwhelmingly Gram-negative and polymicrobial, anchored by A. baumannii (culture, 33.7%; metagenomics, 49.1%; qPCR, 37.9%), Escherichia coli (32.0%), and Klebsiella pneumoniae (20.7%); S. pyogenes contributed only 4.7% of culture-positive cases. Polymicrobial wounds had higher Shannon diversity (2.59 versus 2.33; P = 0.048) and discrete community composition (PERMANOVA R 2 = 0.511; P = 0.010). Culture-metagenomics agreement ranged from almost perfect for Escherichia (κ = 0.849) to slight for Streptococcus (κ = 0.131). North Indian NSTIs present a microbial picture distinct from the Western paradigm, with implications for empirical therapy. IMPORTANCE Necrotizing soft tissue infections kill rapidly, and physicians must choose antibiotics before laboratory results are available. Globally, treatment guidelines assume the dominant pathogen is Streptococcus pyogenes , a Gram-positive organism, because nearly all molecular evidence comes from Western countries. We show that in a large Indian cohort, the infection is instead dominated by Gram-negative bacteria, especially Acinetobacter baumannii , with S. pyogenes rarely present. Polymicrobial status, not wound location or injury mechanism, most strongly determines community composition. These findings challenge the one-size-fits-all antibiotic approach and argue for region-specific empirical regimens prioritizing Gram-negative coverage in tropical, high-antimicrobial-pressure settings.
2026-06-17 | The effect of Staphylococcus aureus targeting ROS-dependent mitochondrial damage activating NLRP10 in inducing skin and soft tissue infection.
Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation are central to the pathogenesis of Staphylococcus aureus-induced skin and soft tissue infections (SSTIs). NLRP10 has recently been identified as a key regulator of mitochondrial homeostasis and ROS dynamics. To investigate its regulatory role, we established an in vivo model of methicillin-resistant Staphylococcus aureus (MRSA)-induced SSTIs, which demonstrated significant skin lesions, necrosis, inflammatory infiltration, elevated ROS and LDH levels, decreased NAD+/NADH ratio and ATP content, enhanced apoptosis, and upregulated expression of Cleaved caspase-3, Bax, NLRP10, Cleaved caspase-1, ASC, and phosphorylated NF-κB p65. In vitro, using human primary keratinocytes, NLRP10 knockdown was found to exacerbate MRSA-induced mitochondrial ROS increase, loss of membrane potential, and apoptosis, while attenuating LDH release, ATP depletion, and the secretion of IL-1β/IL-18, as well as reducing the expression of Cleaved caspase-1, ASC, and phosphorylated NF-κB p65. Conversely, NLRP10 overexpression combined with the mitochondrial antioxidant MitoQ alleviated mitochondrial damage and apoptosis but significantly enhanced inflammasome activation and NF-κB pathway signaling. These findings collectively demonstrate that NLRP10 mediates its regulatory effects on Staphylococcus aureus-induced SSTIs through targeting ROS-driven mitochondrial dysfunction.
proteins
2026-02-18 | Necrotizing soft tissue infection of the fingertips secondary to paronychia in a leukemic child: a case report and warning.
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, for which chemotherapy remains the cornerstone of treatment. Skin toxicity is a frequent adverse reaction to chemotherapy; however, progression from paronychia to necrotizing soft tissue infection of the fingertips is uncommon. This report describes the case of a 7-year-old child with ALL who developed paronychia following combination chemotherapy with vincristine and daunorubicin. The infection progressed to involve multiple fingertips as necrotizing soft tissue infection, a course facilitated by the patient's underlying severe neutropenia. Raoultella ornithinolytica was identified on blood culture. A structured, multistep nursing protocol was implemented, including local disinfection, ethacridine lactate compresses, topical application of recombinant human epidermal growth factor solution and mupirocin ointment, and local oxygen insufflation. This regimen resulted in significant improvement of the lesions. Within 7 days, pain subsided, edema reduced by more than 50%, and joint mobility was largely restored, with complete clinical resolution achieved within 14 days. This case highlights the importance of early recognition of chemotherapy-induced skin toxicity and the value of standardized stepwise wound management in improving functional outcomes. It provides a practical reference for managing this rare yet severe cutaneous adverse reaction in children and underscores the critical role of specialized nursing in supportive oncology care.
2025-05-03 | Nutritional Support for Necrotizing Soft Tissue Infection Patients: From ICU to Outpatient Care
Although nutrition recommendations for patients with necrotizing soft tissue infections (NSTIs) often parallel those for patients with burn injuries, differences in the metabolic response to stress indicate that NSTIs require a unique approach. The sepsis and wound management associated with NSTIs trigger a metabolic response, driven by inflammatory and neuroendocrine changes, that leads to high circulating levels of cortisol, catecholamines, insulin, and pro-inflammatory cytokines. This metabolic response follows four phases of recovery (Early Acute; Late Acute; Persistent Inflammation, Immunosuppression, and Catabolism Syndrome; Recovery) that require a thoughtful approach to nutrition by risk screening, malnutrition assessment, and micronutrient deficiency assessment. Close monitoring of energy expenditure and protein needs is required for appropriate nutrition management. Nutrition intake after transfer from the intensive care unit and hospital discharge is often inadequate. Ongoing monitoring of nutrition intake at all outpatient follow-up appointments is necessary, regardless of the route of delivery, until the nutrition status stabilizes and any nutritional decline experienced during hospitalization has been corrected.
2025-03-12 | Structural basis for collagen recognition by the Streptococcus pyogenes M3 protein and its involvement in biofilm
Abstract The M protein is an essential virulence factor of Streptococcus pyogenes, or group A streptococci (GAS), one of the most common and dangerous human pathogens. Molecular and functional characterization of M protein variants and their interactions with host components is crucial for understanding streptococcal pathogenesis and vaccine development. The M3 protein is produced by the prevalent emm3 GAS serotype, which is frequently associated with severe invasive diseases. Here we characterize the interaction of M3 with human collagens through detailed structural and biochemical binding analysis. High-resolution structures of the N-terminal M3 domain in the free state as well as bound to a collagen peptide derived from the Collagen Ligands Collection reveal a novel T-shaped protein fold that presents binding sites complementing the characteristic topology of collagen triple helices. The structure of the M3/collagen peptide complex explains how emm3 GAS and related streptococci, such as the emerging human pathogen Streptococcus dysgalactiae subsp. equisimilis, can target collagens to enable colonization of various tissues. In line with this, we demonstrate that the M3/collagen interaction promotes enhanced biofilm formation of emm3 GAS in an emm type specific manner, which can be inhibited with the recombinant M3 N-terminal domain fragment. Further, emm3 GAS, but not an emm1 strain, are shown to colocalize with collagen in tissue biopsies from patients with necrotizing soft tissue infections, where GAS biofilms are common. This observation is reproduced in organotypic skin models. Together, these data provide detailed molecular insights into an important streptococcal virulence mechanism with implications for the understanding of invasive infections, strategies for treating biofilm and M-protein based vaccine design.
2024-10-26 | Subduing the Inflammatory Cytokine Storm.
The inflammatory cytokine response is essential for protective immunity, yet bacterial and viral pathogens often elicit an exaggerated response ("cytokine storm") harmful to the host that can cause multi-organ damage and lethality. Much has been published recently on the cytokine storm within the context of the coronavirus pandemic, yet bacterial sepsis, severe wound infections and toxic shock provide other prominent examples. The problem of the cytokine storm is compounded by the increasing incidence of multidrug-resistant bacterial strains. We created an incisive molecular tool for analyzing the role of the B7/CD28 costimulatory axis in the human inflammatory response. To attenuate the cytokine storm underlying infection pathology, yet preserve host defenses, we uniquely targeted the engagement of CD28 with its B7 co-ligands by means of short peptide mimetics of the human CD28 and B7 receptor homodimer interfaces. These peptides are not only effective tools for dissecting mechanism but also serve to attenuate the inflammatory response as a broad host-oriented therapeutic strategy against the cytokine storm. Indeed, such peptides protect mice from lethal Gram-positive bacterial superantigen-induced toxic shock even when dosed in molar amounts well below that of the superantigen and show promise in protecting humans from the severe inflammatory disease necrotizing soft tissue infections ('flesh-eating' bacterial sepsis) following traumatic wound injuries.
2024-07-29 | Fournier’s gangrene with abdominal wall cellulitis probably caused by animal microbiota after insulin injection
Fournier's gangrene (FG) is a rare, acute, life-threatening, necrotizing soft tissue infection of
cell therapies
2026-07-02 | Hemipelvectomy for Clostridium septicum necrotizing soft tissue infection with extensive pelvic organ destruction: a case report.
Clostridium septicum is a highly virulent, gas-forming, anaerobic Gram-positive bacillus known to cause rapidly progressive necrotizing soft tissue infection that is often associated with gastrointestinal malignancy or immunocompromised states. Mortality remains extremely high, with many patients dying within the first 24 h of onset. Although aggressive surgical debridement is the cornerstone of treatment, cases requiring hemipelvectomy are exceedingly rare, and postoperative management of exposed pelvic organs has not been described in the relevant literature. A 73-year-old woman with ascending colon cancer developed sudden severe left leg pain and paralysis, and computed tomography revealed extensive gas from the left thigh to the pelvis. Upon arrival at our tertiary center, she was in septic shock with gas rapidly progressing to the high retroperitoneum. Emergent hip disarticulation was performed, and Clostridium septicum was isolated. Despite early source control, ongoing toxin-mediated necrosis extending beyond the limits of limb amputation necessitated left hemipelvectomy on Day 4. Following radical debridement, postoperative management became extremely challenging because multiple pelvic organs were exposed, with necrosis of the bladder and perforation of ureter, rectum and vaginal wall. Serial debridement and staged repairs were required over a prolonged course. Granulation of the pelvic wound gradually progressed, allowing split-thickness skin grafting on Day 88, after which wound healing stabilized. She was ultimately stable enough to return to the referring hospital on Day 187. This is an extremely rare case of Clostridium septicum necrotizing soft tissue infection requiring hemipelvectomy, demonstrating that aggressive and timely radical debridement can be life-saving, even in cases with massive pelvic involvement. Furthermore, we present the first documented example of stepwise management of exposed pelvic organs after hemipelvectomy performed for necrotizing soft tissue infection, providing valuable insights for clinicians facing similar catastrophic presentations.
2026-06-29 | Pedicled Supraclavicular Flap Reconstruction Following Cervicofacial Necrotizing Fasciitis: A Case Report.
Cervicofacial necrotizing fasciitis is a life-threatening surgical emergency associated with significant morbidity and mortality, requiring early diagnosis and aggressive multimodal management. Reconstruction of the resulting soft tissue defects represents an additional challenge, particularly in resource-limited settings where microsurgical infrastructure may not be available. We report the case of a 42-year-old man who developed cervicofacial necrotizing fasciitis secondary to an odontogenic infection. Management consisted of broad-spectrum antibiotic therapy, early surgical debridement, and negative pressure wound therapy as a bridge to reconstruction. Once infection was controlled and a viable granulation tissue bed was established, definitive reconstruction was performed using a pedicled supraclavicular fasciocutaneous flap. The procedure was completed without complications, with satisfactory flap integration, cervicofacial contour restoration, and minimal donor site morbidity documented at outpatient follow-up. The pedicled supraclavicular flap proved to be a safe, reliable, and technically reproducible reconstructive option in this postinfectious context, offering an intrinsic vascular supply independent of the compromised recipient bed, a wide arc of rotation, and excellent color and texture match to cervicofacial skin. Its applicability in settings without microsurgical resources further supports its role as a first-line reconstructive strategy. This case contributes to the limited evidence on supraclavicular flap reconstruction following cervicofacial necrotizing fasciitis and underscores the value of a sequential, protocol-driven approach in achieving favorable outcomes.
2026-06-08 | Flap-to-flap neovascularization for extended soft-tissue reconstruction of the upper-limb.
Extensive upper-limb soft-tissue defects may exceed the surface area achievable with conventional free flaps, making reconstruction challenging when durable coverage and functional preservation are required. We describe a novel reconstructive strategy to extend soft-tissue coverage based on secondary flap-to-flap neovascularization in which a pedicled flap achieves secondary vascular independence through neovascularization from the free flap skin paddle via the subdermal vascular plexus, thereby enabling delayed division without additional microsurgical anastomoses. A 64-year-old man developed necrotizing fasciitis of the right upper limb following an insect bite. After repeated surgical debridements, a massive circumferential forearm defect extending to the elbow was associated with extensive tissue loss of the dorsal hand, first web space, and palm. A 45 × 11 cm chimeric anterolateral thigh-tensor fascia latae (ALT-TFL) free flap was harvested and anastomosed to the radial vessels, providing stable coverage of exposed extensor tendons and neurovascular structures. An ipsilateral pedicled 20 × 15 cm groin flap was inset onto the ALT skin paddle and subsequently divided, defatted, and wrapped around the thumb to recreate the first web space and resurface the palm. At 18-month follow-up, soft-tissue coverage remained stable, with complete flap survival, no recurrence of infection, and good functional recovery. Unlike sequential or conventional free-flap reconstruction, this approach does not require additional arterial inflow or flow-through anastomoses, relying instead on secondary flap-to-flap neovascularization. It may therefore represent a relevant strategy to extend reconstructive coverage beyond conventional flap dimensions in extensive upper-limb defects.
2026-05-15 | Utilizing Free Skin Grafts With the Preserved Subdermal Vascular Plexus for Repairing Facial and Cervical Skin and Soft Tissue Defects.
The reconstruction of facial and cervical skin and soft-tissue defects presents significant aesthetic challenges. While conventional skin grafting techniques offer reliable coverage, they often yield suboptimal outcomes, including pigmentary changes, contour irregularities, and scar contracture. This study evaluates the clinical efficacy of free skin grafts with a preserved subdermal vascular plexus for the repair of facial and cervical skin and soft tissue defects. A total of 25 patients presenting with facial and cervical skin and soft tissue defects between June 2022 and February 2025 were enrolled. According to the size of the defects, subdermal vascular network skin grafts were transplanted from their own bodies to repair the tissue defects. All skin grafts survived postoperatively, with no instances of poor healing, infection, or necrosis. During a follow-up period ranging from 6 months to 2 years, the repaired areas exhibited favorable aesthetic contours, soft and elastic texture, and a good color match with the surrounding skin. No significant pigmentation or cicatricial contracture was observed. Patient satisfaction with the outcomes was high. The application of free skin grafts preserving the subdermal vascular plexus for repairing facial and cervical skin and soft tissue defects is characterized by a straightforward surgical procedure, minimal donor site morbidity, and aesthetically pleasing results. This technique warrants clinical promotion.
2026-05-14 | Necrotizing Fasciitis of the Forearm in a 68-Year-Old Patient Treated with Split-Thickness Skin Graft: A Case Report.
Necrotizing fasciitis (NF) is a rare, rapidly progressive soft-tissue infection requiring emergent surgical intervention. Upper extremity involvement poses unique reconstructive challenges due to a thin, soft-tissue coverage and risk of tendon exposure. We present the case of a 68-year-old female with NF of the left forearm and hand, treated with three debridements followed by split-thickness skin grafting on hospital day 6. A combination of meshed and unmeshed grafts was used, with the unmeshed graft placed over the dorsum of the hand for improved cosmesis. The patient demonstrated excellent graft uptake and preserved hand function at long-term follow-up. This case highlights the feasibility of early grafting in sensitive areas with NF when adequate source control is achieved. Early skin grafting, when carefully timed, can result in favorable functional and esthetic outcomes in complex upper extremity infections.
antibodies
2026-07-17 | A fully human streptolysin O-neutralizing monoclonal antibody improves survival in a murine model of group A streptococcus necrotizing soft tissue infection.
Necrotizing soft tissue infections (NSTIs) caused by Streptococcus pyogenes (group A streptococcus [GAS]) are rapidly progressive, toxin-driven infections for which no targeted antitoxin therapies exist. Streptolysin O (SLO), a cholesterol-dependent cytolysin, is a key mediator of tissue injury, vascular occlusion, and immune dysfunction and, thus, represents a promising therapeutic target. Here, we isolated and characterized three fully human monoclonal antibodies (huMAbs) against SLO (C11, G4, and L17) from the memory B cells of a naturally immunized donor using antigen-specific B-cell enrichment. All three huMAbs bound SLO with high affinity and potently neutralized SLO-induced hemolysis in vitro. Mechanistic studies revealed that C11 and G4 inhibited SLO-membrane binding, whereas L17 protected host cells without blocking membrane binding. Despite similar neutralizing potency in vitro, only L17 significantly improved disease outcomes in vivo. In a murine model of GAS-NSTI, L17 reduced clinical disease severity and prolonged survival by approximately 130%. Together, these findings demonstrate that antibody-mediated neutralization of SLO can alter disease outcomes during GAS-necrotizing infection and support the potential of L17 as a clinically relevant antitoxin therapeutic candidate for GAS-NSTI.
2025-12-03 | Advances in Necrotizing Fasciitis Animal Models: Current Trends and Future Perspectives.
Necrotizing fasciitis (NF) is a rapidly progressive soft tissue infection with high morbidity and mortality, yet its pathophysiology remains incompletely understood. Animal models are indispensable for dissecting disease mechanisms and testing therapeutic interventions, yet their translational relevance varies across species and experimental approaches. This review critically evaluates NF models in rodents, zebrafish, rabbits, pigs, and non-human primates, highlighting their relative strengths in replicating immunopathology, systemic dissemination, and biofilm-driven persistence. We examine methodological strategies including bacterial inoculation, trauma-induced infection, immunosuppression-enhanced infection, genetic engineering, and optical imaging, and discuss how these frameworks capture discrete aspects of NF pathogenesis. Emerging technologies, including CRISPR-mediated host factor engineering, multi-omics profiling, intravital and high-resolution imaging, organ-on-chip platforms, and artificial intelligence, are integrated into next-generation models to enhance predictive power, mechanistic insight, and translational fidelity. We also outline innovative therapeutic strategies validated in preclinical models, from precision-targeted monoclonal antibodies and immunotherapies to advanced drug delivery systems and AI-guided predictive modeling. Finally, we discuss practical and ethical considerations for NF modeling, emphasizing reproducibility, standardization, and the 3Rs principle, and propose a forward-looking framework for integrating in vivo, in vitro, and in silico platforms. Collectively, these insights provide a roadmap for refining NF animal models, accelerating mechanistic discovery, and informing clinically relevant interventions.
2025-10-24 | Monoclonal Antibodies Can Aid in the Culture-Based Detection and Differentiation of Mucorales Fungi-The Flesh-Eating Pathogens Apophysomyces and Saksenaea as an Exemplar.
The frequency of necrotising cutaneous and soft tissue infections caused by the Mucorales fungi Apophysomyces and Sakasenaea is increasing. The absence of sophisticated diagnostic technologies in low- and middle-income countries (LMICs) means that detection of cutaneous mucormycosis continues to rely on culture of the infecting pathogens from biopsy and their differentiation based on morphological characteristics. However, Apophysomyces and Sakasenaea are notorious for their failure to sporulate on standard mycological media used for the identification of human pathogenic fungi. Differentiation of these pathogens and their discrimination from Aspergillus fumigatus, the most common mould pathogen of humans, is essential due to their differing sensitivities to the antifungal drugs used to treat mucormycosis. A murine IgG1 monoclonal antibody, JD4, has been developed that is specific to Apophysomyces species. In Western blotting and enzyme-linked immunosorbent assay (ELISA), mAb JD4 is shown to bind to an extracellular 15 kDa protein, readily detectable in crude antigen extracts from non-sporulating cultures of Apophysomyces. When combined with a Mucorales-specific lateral-flow immunoassay (LFIA), mAb JD4 allows the differentiation of Apophysomyces from Saksenaea species and discrimination from Aspergillus fumigatus. Monoclonal antibody JD4 enables the detection and differentiation of Apophysomyces species from other fungal pathogens that cause rapidly progressive cutaneous and soft tissue mycoses in humans. When this is combined with a rapid LFIA, improvements are offered in the sensitivity and specificity of Mucorales detection based on mycological culture, which remains a gold-standard procedure for mucormycosis detection in LMICs lacking access to more sophisticated diagnostic procedures.
2024-02-14 | Haemolysin Ahh1 secreted from Aeromonas dhakensis activates the NLRP3 inflammasome in macrophages and mediates severe soft tissue infection.
Severe soft tissue infections caused by Aeromonas dhakensis, such as necrotizing fasciitis or cellulitis, are prevalent in southern Taiwan and around the world. However, the mechanism by which A. dhakensis causes tissue damage remains unclear. Here, we found that the haemolysin Ahh1, which is the major virulence factor of A. dhakensis, causes cellular damage and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathway. Deletion of ahh1 significantly downregulated caspase-1, the proinflammatory cytokine interleukin 1β (IL-1β) and gasdermin D (GSDMD) and further decreased the damage caused by A. dhakensis in THP-1 cells. In addition, we found that knockdown of the NLRP3 inflammasome confers resistance to A. dhakensis infection in both THP-1 NLRP3-/- cells and C57BL/6 NLRP3-/- mice. In addition, we demonstrated that severe soft-tissue infections treated with antibiotics combined with a neutralizing antibody targeting IL-1β significantly increased the survival rate and alleviated the degree of tissue damage in model mice compared control mice. These findings show that antibiotics combined with therapies targeting IL-1β are potential strategies to treat severe tissue infections caused by toxin-producing bacteria.
2023-07-10 | Neutrophil-derived reactive agents induce a transient SpeB negative phenotype in Streptococcus pyogenes
Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection. A key driving force for this process is the bacterial Sda1 DNase.Bacterial infiltration, immune cell influx, tissue necrosis and inflammation in patient´s biopsies were determined using immunohistochemistry. SpeB secretion and activity by GAS post infections or challenges with reactive agents were determined via Western blot or casein agar and proteolytic activity assays, respectively. Proteome of GAS single colonies and neutrophil secretome were profiled, using mass spectrometry.Here, we identify another strategy resulting in SpeB-negative variants, namely reversible abrogation of SpeB secretion triggered by neutrophil effector molecules. Analysis of NSTI patient tissue biopsies revealed that tissue inflammation, neutrophil influx, and degranulation positively correlate with increasing frequency of SpeB-negative GAS clones. Using single colony proteomics, we show that GAS isolated directly from tissue express but do not secrete SpeB. Once the tissue pressure is lifted, GAS regain SpeB secreting function. Neutrophils were identified as the main immune cells responsible for the observed phenotype. Subsequent analyses identified hydrogen peroxide and hypochlorous acid as reactive agents driving this phenotypic GAS adaptation to the tissue environment. SpeB-negative GAS show improved survival within neutrophils and induce increased degranulation.Our findings provide new information about GAS fitness and heterogeneity in the soft tissue milieu and provide new potential targets for therapeutic intervention in NSTIs.
other
2026-05-12 | Identification of immunostimulatory antigens in Group A Streptococcus-derived vesicles.
An effective vaccine against Streptococcus pyogenes (Group A Streptococcus, GAS) is urgently needed. Bacteria-derived extracellular vesicles (EVs) are emerging as promising vaccine platforms. In this study, we evaluated the immunostimulatory properties of GAS-derived EVs when administered intranasally in mice. Immunization induced a strong humoral response, including pathogen-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies. Additionally, we observed local and systemic T cell responses, specifically a robust Th17 response along with a modest but statistically significant Th1 response. Through immunoprecipitation coupled with mass spectrometry and western blotting, we identified seven immunogenic proteins, including the lipoproteins MtsA, BMP, PrsA1, PrsA2, MetQ, MalX, and the glutamine transporter GlnP. These antigens were recognized by human sera from both healthy individuals and patients with necrotizing soft tissue infection. Finally, we demonstrate that these antigens stimulate production and secretion of IL-17A by lung cells and splenocytes and that they are highly conserved across diverse GAS M-types, highlighting their potential as broadly protective vaccine candidates.
2023-11-11 | Necrotizing fascitis: A case report
Background. Necrotizing soft tissue infections are actually the diseases with a severe outcome characterized by the progression of soft tissue inflammation with a catastrophic prognosis and the risk of major functional consequences. Only prompt diagnosis and prompt care, including prompt administration of appropriate antibiotic therapy and surgical treatment, can improve the outcome. Case report. A female patient, aged 66 years, came due to swelling and pain in the perineum. Before admission, the pains were of low intensity, and immediately before admission, their intensity increased. An incision was made in the perineal region and the abdominal region on the left. During the preparation, we came across a necrotic tissue from which a dark-gray liquid flew that had a strong smell. From the tenth postoperative day, secondary sutures were partly placed. Conclusion. Mortality and morbidity in this disease are high. A potential new treatment for this disease may be an antigen-inhibiting vaccine.
2019-04-11 | Protection against Staphylococcus aureus Colonization and Infection by B- and T-Cell-Mediated Mechanisms.
Staphylococcus aureus is a major cause of morbidity and mortality worldwide. S. aureus colonizes 20 to 80% of humans at any one time and causes a variety of illnesses. Strains that are resistant to common antibiotics further complicate management. S. aureus vaccine development has been unsuccessful so far, largely due to the incomplete understanding of the mechanisms of protection against this pathogen. Here, we studied the role of different aspects of adaptive immunity induced by an S. aureus vaccine in protection against S. aureus bacteremia, dermonecrosis, skin abscess, and gastrointestinal (GI) colonization. We show that, depending on the challenge model, the contributions of vaccine-induced S. aureus-specific antibody and Th1 and Th17 responses to protection are different: antibodies play a major role in reducing mortality during S. aureus bacteremia, whereas Th1 or Th17 responses are essential for prevention of S. aureus skin abscesses and the clearance of bacteria from the GI tract. Both antibody- and T-cell-mediated mechanisms contribute to prevention of S. aureus dermonecrosis. Engagement of all three immune pathways results in the most robust protection under each pathological condition. Therefore, our results suggest that eliciting multipronged humoral and cellular responses to S. aureus antigens may be critical to achieve effective and comprehensive immune defense against this pathogen.IMPORTANCES. aureus is a leading cause of healthcare- and community-associated bacterial infections. S. aureus causes various illnesses, including bacteremia, meningitis, endocarditis, pneumonia, osteomyelitis, sepsis, and skin and soft tissue infections. S. aureus colonizes between 20 and 80% of humans; carriers are at increased risk for infection and transmission to others. The spread of multidrug-resistant strains limits antibiotic treatment options. Vaccine development against S. aureus has been unsuccessful to date, likely due to an inadequate understanding about the mechanisms of immune defense against this pathogen. The significance of our work is in illustrating the necessity of generating multipronged B-cell, Th1-, and Th17-mediated responses to S. aureus antigens in conferring enhanced and broad protection against S. aureus invasive infection, skin and soft tissue infection, and mucosal colonization. Our work thus, provides important insights for future vaccine development against this pathogen.
small molecules
2026-08-09 | Conservative Management of Invasive Group A Streptococcal Infection With Cervical Necrotizing Fasciitis-Spectrum Disease and Pneumonia in a Healthy Young Adult.
Invasive Group A streptococcal (iGAS) infections are life-threatening conditions classically manifesting as necrotizing fasciitis or severe pneumonia, but their simultaneous occurrence in a previously healthy adult is extremely rare. While necrotizing fasciitis typically mandates urgent surgery, this report highlights a case of concurrent cervical necrotizing fasciitis-spectrum disease and pneumonia successfully managed through a conservative, non-surgical approach. A 29-year-old previously healthy Japanese male presented with a two-day history of fever, sore throat, and a maculopapular rash, with a throat swab positive for GAS. On Day 2, he acutely developed progressive dyspnea, hypoxemia, and extensive cervical subcutaneous emphysema. Computed tomography confirmed diffuse fascial edema and bilateral pulmonary infiltrates without signs of gas-forming abscess or irreversible tissue necrosis. Despite early amoxicillin administration, blood cultures remained negative, suggesting toxin-mediated clinical deterioration. Based on the imaging findings and close clinical monitoring, a non-operative strategy was selected. This was achieved by immediate medical escalation to broad-spectrum antimicrobials, including clindamycin to suppress toxin production, alongside meropenem and high-dose penicillin G. The patient recovered fully without surgical intervention. This case highlights that iGAS can cause rapid, concurrent soft-tissue and pulmonary involvement even in healthy individuals. In select cases of necrotizing fasciitis-spectrum disease where irreversible tissue necrosis is absent on prompt imaging and close clinical monitoring is maintained, aggressive multi-drug medical escalation incorporating antitoxin therapy can lead to successful outcomes without the need for morbid surgical procedures.
2026-07-29 | Synergistic activity of mitomycin C in combination with ciprofloxacin against severe Vibrio vulnificus infection.
Vibrio vulnificus is a highly virulent pathogen associated with rapidly progressive sepsis and necrotising soft-tissue infection, particularly among patients with diabetes or chronic liver disease. Effective treatment options remain limited, especially in the setting of high bacterial burden or immunocompromis. We performed an integrated preclinical assessment of mitomycin C (MMC) alone and in combination with ciprofloxacin (CIP) using in vitro susceptibility testing and a neutropenic murine model challenged with increasing inocula of V. vulnificus. Myelotoxicity, organ-specific toxicity, and the development of resistance under subinhibitory MMC exposure were evaluated through haematological profiling and histopathology. MMC demonstrated potent in vitro activity and conferred complete protection in mice challenged with low bacterial inocula (103-104 colony-forming units (CFU)/mL). Although efficacy declined with increasing bacterial burden, combination therapy with MMC and ciprofloxacin significantly improved survival across all inoculum levels, achieving complete protection at concentrations up to 1.4 ⨯ 107 CFU/mL and partial protection at 4.3 ⨯ 107 CFU/mL. The combination regimen was not associated with dose-dependent myelosuppression, and no hepatotoxicity or nephrotoxicity was observed. Exposure to subinhibitory concentrations of MMC did not result in increased minimum inhibitory concentrations over time. MMC-CIP combination therapy demonstrated synergistic efficacy against severe V. vulnificus infection in a neutropenic mouse model and may represent a promising therapeutic option. Dose-limiting myelotoxicity and the potential for resistance necessitate cautious dosing and further clinical investigation. This study addresses a critical therapeutic gap in severe V. vulnificus infection by proposing a mechanistically rational, dose-optimized adjunctive strategy supported by robust preclinical evidence.
2026-07-08 | Neorectal Perforation and Necrotizing Soft Tissue Infection of the Lower Limb Following Pelvic Reirradiation for Recurrent Rectal Cancer: A Case Report.
Neorectal perforation is a rare but serious complication following treatment for rectal cancer, and may lead to catastrophic sequelae if diagnosis and management are delayed. We report the case of a 54-year-old woman with locally recurrent rectal cancer who developed neorectal perforation and necrotizing soft tissue infection of the lower limb following chemoradiotherapy. Initial symptoms were attributed to sciatic nerve inflammation, and surgical consultation was delayed. The patient subsequently developed septic shock and was found to have extraperitoneal perforation extending through the greater sciatic foramen, with extensive necrotizing fasciitis of the gluteal and thigh compartments. Management required urgent laparotomy with resection of the colonic J pouch, omentoplasty, feeding gastrostomy, and extraperitoneal end colostomy, followed by multiple surgical debridements. The patient experienced prolonged critical illness, including multiorgan failure and colonization of wounds with multidrug-resistant organisms. Successful recovery was achieved through aggressive multidisciplinary care, including novel use of negative pressure wound therapy with acetic acid instillation. This case highlights the need for caution when re-irradiating the neorectum in the presence of a neorectal ulcer, and the importance of early surgical involvement in complex post-treatment complications.
2026-06-27 | Gram-negative-dominated polymicrobial microbiome of necrotizing soft tissue infections from North India: an integrated culture and 16S rRNA metagenomics prospective cohort study
ABSTRACT Necrotizing soft tissue infections (NSTIs) carry 10 to 30% mortality. Current empirical antimicrobial guidance derives almost entirely from Western cohorts dominated by Streptococcus pyogenes and aerobic-anaerobic consortia, yet whether this microbial paradigm applies to tropical, high-antimicrobial-pressure settings has not been tested with culture-independent methods. We did a prospective cohort study of 169 patients with intraoperatively confirmed NSTI at a North Indian tertiary center (2021 to 2024). Wound tissue underwent aerobic and anaerobic culture, QIIME2-based 16S rRNA gene amplicon sequencing (V3-V4), and targeted SYBR Green quantitative PCR (qPCR) for Acinetobacter baumannii and S. pyogenes . The wound microbiota was overwhelmingly Gram-negative and polymicrobial, anchored by A. baumannii (culture, 33.7%; metagenomics, 49.1%; qPCR, 37.9%), Escherichia coli (32.0%), and Klebsiella pneumoniae (20.7%); S. pyogenes contributed only 4.7% of culture-positive cases. Polymicrobial wounds had higher Shannon diversity (2.59 versus 2.33; P = 0.048) and discrete community composition (PERMANOVA R 2 = 0.511; P = 0.010). Culture-metagenomics agreement ranged from almost perfect for Escherichia (κ = 0.849) to slight for Streptococcus (κ = 0.131). North Indian NSTIs present a microbial picture distinct from the Western paradigm, with implications for empirical therapy. IMPORTANCE Necrotizing soft tissue infections kill rapidly, and physicians must choose antibiotics before laboratory results are available. Globally, treatment guidelines assume the dominant pathogen is Streptococcus pyogenes , a Gram-positive organism, because nearly all molecular evidence comes from Western countries. We show that in a large Indian cohort, the infection is instead dominated by Gram-negative bacteria, especially Acinetobacter baumannii , with S. pyogenes rarely present. Polymicrobial status, not wound location or injury mechanism, most strongly determines community composition. These findings challenge the one-size-fits-all antibiotic approach and argue for region-specific empirical regimens prioritizing Gram-negative coverage in tropical, high-antimicrobial-pressure settings.
2026-06-17 | The effect of Staphylococcus aureus targeting ROS-dependent mitochondrial damage activating NLRP10 in inducing skin and soft tissue infection.
Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation are central to the pathogenesis of Staphylococcus aureus-induced skin and soft tissue infections (SSTIs). NLRP10 has recently been identified as a key regulator of mitochondrial homeostasis and ROS dynamics. To investigate its regulatory role, we established an in vivo model of methicillin-resistant Staphylococcus aureus (MRSA)-induced SSTIs, which demonstrated significant skin lesions, necrosis, inflammatory infiltration, elevated ROS and LDH levels, decreased NAD+/NADH ratio and ATP content, enhanced apoptosis, and upregulated expression of Cleaved caspase-3, Bax, NLRP10, Cleaved caspase-1, ASC, and phosphorylated NF-κB p65. In vitro, using human primary keratinocytes, NLRP10 knockdown was found to exacerbate MRSA-induced mitochondrial ROS increase, loss of membrane potential, and apoptosis, while attenuating LDH release, ATP depletion, and the secretion of IL-1β/IL-18, as well as reducing the expression of Cleaved caspase-1, ASC, and phosphorylated NF-κB p65. Conversely, NLRP10 overexpression combined with the mitochondrial antioxidant MitoQ alleviated mitochondrial damage and apoptosis but significantly enhanced inflammasome activation and NF-κB pathway signaling. These findings collectively demonstrate that NLRP10 mediates its regulatory effects on Staphylococcus aureus-induced SSTIs through targeting ROS-driven mitochondrial dysfunction.
proteins
2026-02-18 | Necrotizing soft tissue infection of the fingertips secondary to paronychia in a leukemic child: a case report and warning.
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, for which chemotherapy remains the cornerstone of treatment. Skin toxicity is a frequent adverse reaction to chemotherapy; however, progression from paronychia to necrotizing soft tissue infection of the fingertips is uncommon. This report describes the case of a 7-year-old child with ALL who developed paronychia following combination chemotherapy with vincristine and daunorubicin. The infection progressed to involve multiple fingertips as necrotizing soft tissue infection, a course facilitated by the patient's underlying severe neutropenia. Raoultella ornithinolytica was identified on blood culture. A structured, multistep nursing protocol was implemented, including local disinfection, ethacridine lactate compresses, topical application of recombinant human epidermal growth factor solution and mupirocin ointment, and local oxygen insufflation. This regimen resulted in significant improvement of the lesions. Within 7 days, pain subsided, edema reduced by more than 50%, and joint mobility was largely restored, with complete clinical resolution achieved within 14 days. This case highlights the importance of early recognition of chemotherapy-induced skin toxicity and the value of standardized stepwise wound management in improving functional outcomes. It provides a practical reference for managing this rare yet severe cutaneous adverse reaction in children and underscores the critical role of specialized nursing in supportive oncology care.
2025-05-03 | Nutritional Support for Necrotizing Soft Tissue Infection Patients: From ICU to Outpatient Care
Although nutrition recommendations for patients with necrotizing soft tissue infections (NSTIs) often parallel those for patients with burn injuries, differences in the metabolic response to stress indicate that NSTIs require a unique approach. The sepsis and wound management associated with NSTIs trigger a metabolic response, driven by inflammatory and neuroendocrine changes, that leads to high circulating levels of cortisol, catecholamines, insulin, and pro-inflammatory cytokines. This metabolic response follows four phases of recovery (Early Acute; Late Acute; Persistent Inflammation, Immunosuppression, and Catabolism Syndrome; Recovery) that require a thoughtful approach to nutrition by risk screening, malnutrition assessment, and micronutrient deficiency assessment. Close monitoring of energy expenditure and protein needs is required for appropriate nutrition management. Nutrition intake after transfer from the intensive care unit and hospital discharge is often inadequate. Ongoing monitoring of nutrition intake at all outpatient follow-up appointments is necessary, regardless of the route of delivery, until the nutrition status stabilizes and any nutritional decline experienced during hospitalization has been corrected.
2025-03-12 | Structural basis for collagen recognition by the Streptococcus pyogenes M3 protein and its involvement in biofilm
Abstract The M protein is an essential virulence factor of Streptococcus pyogenes, or group A streptococci (GAS), one of the most common and dangerous human pathogens. Molecular and functional characterization of M protein variants and their interactions with host components is crucial for understanding streptococcal pathogenesis and vaccine development. The M3 protein is produced by the prevalent emm3 GAS serotype, which is frequently associated with severe invasive diseases. Here we characterize the interaction of M3 with human collagens through detailed structural and biochemical binding analysis. High-resolution structures of the N-terminal M3 domain in the free state as well as bound to a collagen peptide derived from the Collagen Ligands Collection reveal a novel T-shaped protein fold that presents binding sites complementing the characteristic topology of collagen triple helices. The structure of the M3/collagen peptide complex explains how emm3 GAS and related streptococci, such as the emerging human pathogen Streptococcus dysgalactiae subsp. equisimilis, can target collagens to enable colonization of various tissues. In line with this, we demonstrate that the M3/collagen interaction promotes enhanced biofilm formation of emm3 GAS in an emm type specific manner, which can be inhibited with the recombinant M3 N-terminal domain fragment. Further, emm3 GAS, but not an emm1 strain, are shown to colocalize with collagen in tissue biopsies from patients with necrotizing soft tissue infections, where GAS biofilms are common. This observation is reproduced in organotypic skin models. Together, these data provide detailed molecular insights into an important streptococcal virulence mechanism with implications for the understanding of invasive infections, strategies for treating biofilm and M-protein based vaccine design.
2024-10-26 | Subduing the Inflammatory Cytokine Storm.
The inflammatory cytokine response is essential for protective immunity, yet bacterial and viral pathogens often elicit an exaggerated response ("cytokine storm") harmful to the host that can cause multi-organ damage and lethality. Much has been published recently on the cytokine storm within the context of the coronavirus pandemic, yet bacterial sepsis, severe wound infections and toxic shock provide other prominent examples. The problem of the cytokine storm is compounded by the increasing incidence of multidrug-resistant bacterial strains. We created an incisive molecular tool for analyzing the role of the B7/CD28 costimulatory axis in the human inflammatory response. To attenuate the cytokine storm underlying infection pathology, yet preserve host defenses, we uniquely targeted the engagement of CD28 with its B7 co-ligands by means of short peptide mimetics of the human CD28 and B7 receptor homodimer interfaces. These peptides are not only effective tools for dissecting mechanism but also serve to attenuate the inflammatory response as a broad host-oriented therapeutic strategy against the cytokine storm. Indeed, such peptides protect mice from lethal Gram-positive bacterial superantigen-induced toxic shock even when dosed in molar amounts well below that of the superantigen and show promise in protecting humans from the severe inflammatory disease necrotizing soft tissue infections ('flesh-eating' bacterial sepsis) following traumatic wound injuries.
2024-07-29 | Fournier’s gangrene with abdominal wall cellulitis probably caused by animal microbiota after insulin injection
Fournier's gangrene (FG) is a rare, acute, life-threatening, necrotizing soft tissue infection of
cell therapies
2026-07-02 | Hemipelvectomy for Clostridium septicum necrotizing soft tissue infection with extensive pelvic organ destruction: a case report.
Clostridium septicum is a highly virulent, gas-forming, anaerobic Gram-positive bacillus known to cause rapidly progressive necrotizing soft tissue infection that is often associated with gastrointestinal malignancy or immunocompromised states. Mortality remains extremely high, with many patients dying within the first 24 h of onset. Although aggressive surgical debridement is the cornerstone of treatment, cases requiring hemipelvectomy are exceedingly rare, and postoperative management of exposed pelvic organs has not been described in the relevant literature. A 73-year-old woman with ascending colon cancer developed sudden severe left leg pain and paralysis, and computed tomography revealed extensive gas from the left thigh to the pelvis. Upon arrival at our tertiary center, she was in septic shock with gas rapidly progressing to the high retroperitoneum. Emergent hip disarticulation was performed, and Clostridium septicum was isolated. Despite early source control, ongoing toxin-mediated necrosis extending beyond the limits of limb amputation necessitated left hemipelvectomy on Day 4. Following radical debridement, postoperative management became extremely challenging because multiple pelvic organs were exposed, with necrosis of the bladder and perforation of ureter, rectum and vaginal wall. Serial debridement and staged repairs were required over a prolonged course. Granulation of the pelvic wound gradually progressed, allowing split-thickness skin grafting on Day 88, after which wound healing stabilized. She was ultimately stable enough to return to the referring hospital on Day 187. This is an extremely rare case of Clostridium septicum necrotizing soft tissue infection requiring hemipelvectomy, demonstrating that aggressive and timely radical debridement can be life-saving, even in cases with massive pelvic involvement. Furthermore, we present the first documented example of stepwise management of exposed pelvic organs after hemipelvectomy performed for necrotizing soft tissue infection, providing valuable insights for clinicians facing similar catastrophic presentations.
2026-06-29 | Pedicled Supraclavicular Flap Reconstruction Following Cervicofacial Necrotizing Fasciitis: A Case Report.
Cervicofacial necrotizing fasciitis is a life-threatening surgical emergency associated with significant morbidity and mortality, requiring early diagnosis and aggressive multimodal management. Reconstruction of the resulting soft tissue defects represents an additional challenge, particularly in resource-limited settings where microsurgical infrastructure may not be available. We report the case of a 42-year-old man who developed cervicofacial necrotizing fasciitis secondary to an odontogenic infection. Management consisted of broad-spectrum antibiotic therapy, early surgical debridement, and negative pressure wound therapy as a bridge to reconstruction. Once infection was controlled and a viable granulation tissue bed was established, definitive reconstruction was performed using a pedicled supraclavicular fasciocutaneous flap. The procedure was completed without complications, with satisfactory flap integration, cervicofacial contour restoration, and minimal donor site morbidity documented at outpatient follow-up. The pedicled supraclavicular flap proved to be a safe, reliable, and technically reproducible reconstructive option in this postinfectious context, offering an intrinsic vascular supply independent of the compromised recipient bed, a wide arc of rotation, and excellent color and texture match to cervicofacial skin. Its applicability in settings without microsurgical resources further supports its role as a first-line reconstructive strategy. This case contributes to the limited evidence on supraclavicular flap reconstruction following cervicofacial necrotizing fasciitis and underscores the value of a sequential, protocol-driven approach in achieving favorable outcomes.
2026-06-08 | Flap-to-flap neovascularization for extended soft-tissue reconstruction of the upper-limb.
Extensive upper-limb soft-tissue defects may exceed the surface area achievable with conventional free flaps, making reconstruction challenging when durable coverage and functional preservation are required. We describe a novel reconstructive strategy to extend soft-tissue coverage based on secondary flap-to-flap neovascularization in which a pedicled flap achieves secondary vascular independence through neovascularization from the free flap skin paddle via the subdermal vascular plexus, thereby enabling delayed division without additional microsurgical anastomoses. A 64-year-old man developed necrotizing fasciitis of the right upper limb following an insect bite. After repeated surgical debridements, a massive circumferential forearm defect extending to the elbow was associated with extensive tissue loss of the dorsal hand, first web space, and palm. A 45 × 11 cm chimeric anterolateral thigh-tensor fascia latae (ALT-TFL) free flap was harvested and anastomosed to the radial vessels, providing stable coverage of exposed extensor tendons and neurovascular structures. An ipsilateral pedicled 20 × 15 cm groin flap was inset onto the ALT skin paddle and subsequently divided, defatted, and wrapped around the thumb to recreate the first web space and resurface the palm. At 18-month follow-up, soft-tissue coverage remained stable, with complete flap survival, no recurrence of infection, and good functional recovery. Unlike sequential or conventional free-flap reconstruction, this approach does not require additional arterial inflow or flow-through anastomoses, relying instead on secondary flap-to-flap neovascularization. It may therefore represent a relevant strategy to extend reconstructive coverage beyond conventional flap dimensions in extensive upper-limb defects.
2026-05-15 | Utilizing Free Skin Grafts With the Preserved Subdermal Vascular Plexus for Repairing Facial and Cervical Skin and Soft Tissue Defects.
The reconstruction of facial and cervical skin and soft-tissue defects presents significant aesthetic challenges. While conventional skin grafting techniques offer reliable coverage, they often yield suboptimal outcomes, including pigmentary changes, contour irregularities, and scar contracture. This study evaluates the clinical efficacy of free skin grafts with a preserved subdermal vascular plexus for the repair of facial and cervical skin and soft tissue defects. A total of 25 patients presenting with facial and cervical skin and soft tissue defects between June 2022 and February 2025 were enrolled. According to the size of the defects, subdermal vascular network skin grafts were transplanted from their own bodies to repair the tissue defects. All skin grafts survived postoperatively, with no instances of poor healing, infection, or necrosis. During a follow-up period ranging from 6 months to 2 years, the repaired areas exhibited favorable aesthetic contours, soft and elastic texture, and a good color match with the surrounding skin. No significant pigmentation or cicatricial contracture was observed. Patient satisfaction with the outcomes was high. The application of free skin grafts preserving the subdermal vascular plexus for repairing facial and cervical skin and soft tissue defects is characterized by a straightforward surgical procedure, minimal donor site morbidity, and aesthetically pleasing results. This technique warrants clinical promotion.
2026-05-14 | Necrotizing Fasciitis of the Forearm in a 68-Year-Old Patient Treated with Split-Thickness Skin Graft: A Case Report.
Necrotizing fasciitis (NF) is a rare, rapidly progressive soft-tissue infection requiring emergent surgical intervention. Upper extremity involvement poses unique reconstructive challenges due to a thin, soft-tissue coverage and risk of tendon exposure. We present the case of a 68-year-old female with NF of the left forearm and hand, treated with three debridements followed by split-thickness skin grafting on hospital day 6. A combination of meshed and unmeshed grafts was used, with the unmeshed graft placed over the dorsum of the hand for improved cosmesis. The patient demonstrated excellent graft uptake and preserved hand function at long-term follow-up. This case highlights the feasibility of early grafting in sensitive areas with NF when adequate source control is achieved. Early skin grafting, when carefully timed, can result in favorable functional and esthetic outcomes in complex upper extremity infections.
antibodies
2026-07-17 | A fully human streptolysin O-neutralizing monoclonal antibody improves survival in a murine model of group A streptococcus necrotizing soft tissue infection.
Necrotizing soft tissue infections (NSTIs) caused by Streptococcus pyogenes (group A streptococcus [GAS]) are rapidly progressive, toxin-driven infections for which no targeted antitoxin therapies exist. Streptolysin O (SLO), a cholesterol-dependent cytolysin, is a key mediator of tissue injury, vascular occlusion, and immune dysfunction and, thus, represents a promising therapeutic target. Here, we isolated and characterized three fully human monoclonal antibodies (huMAbs) against SLO (C11, G4, and L17) from the memory B cells of a naturally immunized donor using antigen-specific B-cell enrichment. All three huMAbs bound SLO with high affinity and potently neutralized SLO-induced hemolysis in vitro. Mechanistic studies revealed that C11 and G4 inhibited SLO-membrane binding, whereas L17 protected host cells without blocking membrane binding. Despite similar neutralizing potency in vitro, only L17 significantly improved disease outcomes in vivo. In a murine model of GAS-NSTI, L17 reduced clinical disease severity and prolonged survival by approximately 130%. Together, these findings demonstrate that antibody-mediated neutralization of SLO can alter disease outcomes during GAS-necrotizing infection and support the potential of L17 as a clinically relevant antitoxin therapeutic candidate for GAS-NSTI.
2025-12-03 | Advances in Necrotizing Fasciitis Animal Models: Current Trends and Future Perspectives.
Necrotizing fasciitis (NF) is a rapidly progressive soft tissue infection with high morbidity and mortality, yet its pathophysiology remains incompletely understood. Animal models are indispensable for dissecting disease mechanisms and testing therapeutic interventions, yet their translational relevance varies across species and experimental approaches. This review critically evaluates NF models in rodents, zebrafish, rabbits, pigs, and non-human primates, highlighting their relative strengths in replicating immunopathology, systemic dissemination, and biofilm-driven persistence. We examine methodological strategies including bacterial inoculation, trauma-induced infection, immunosuppression-enhanced infection, genetic engineering, and optical imaging, and discuss how these frameworks capture discrete aspects of NF pathogenesis. Emerging technologies, including CRISPR-mediated host factor engineering, multi-omics profiling, intravital and high-resolution imaging, organ-on-chip platforms, and artificial intelligence, are integrated into next-generation models to enhance predictive power, mechanistic insight, and translational fidelity. We also outline innovative therapeutic strategies validated in preclinical models, from precision-targeted monoclonal antibodies and immunotherapies to advanced drug delivery systems and AI-guided predictive modeling. Finally, we discuss practical and ethical considerations for NF modeling, emphasizing reproducibility, standardization, and the 3Rs principle, and propose a forward-looking framework for integrating in vivo, in vitro, and in silico platforms. Collectively, these insights provide a roadmap for refining NF animal models, accelerating mechanistic discovery, and informing clinically relevant interventions.
2025-10-24 | Monoclonal Antibodies Can Aid in the Culture-Based Detection and Differentiation of Mucorales Fungi-The Flesh-Eating Pathogens Apophysomyces and Saksenaea as an Exemplar.
The frequency of necrotising cutaneous and soft tissue infections caused by the Mucorales fungi Apophysomyces and Sakasenaea is increasing. The absence of sophisticated diagnostic technologies in low- and middle-income countries (LMICs) means that detection of cutaneous mucormycosis continues to rely on culture of the infecting pathogens from biopsy and their differentiation based on morphological characteristics. However, Apophysomyces and Sakasenaea are notorious for their failure to sporulate on standard mycological media used for the identification of human pathogenic fungi. Differentiation of these pathogens and their discrimination from Aspergillus fumigatus, the most common mould pathogen of humans, is essential due to their differing sensitivities to the antifungal drugs used to treat mucormycosis. A murine IgG1 monoclonal antibody, JD4, has been developed that is specific to Apophysomyces species. In Western blotting and enzyme-linked immunosorbent assay (ELISA), mAb JD4 is shown to bind to an extracellular 15 kDa protein, readily detectable in crude antigen extracts from non-sporulating cultures of Apophysomyces. When combined with a Mucorales-specific lateral-flow immunoassay (LFIA), mAb JD4 allows the differentiation of Apophysomyces from Saksenaea species and discrimination from Aspergillus fumigatus. Monoclonal antibody JD4 enables the detection and differentiation of Apophysomyces species from other fungal pathogens that cause rapidly progressive cutaneous and soft tissue mycoses in humans. When this is combined with a rapid LFIA, improvements are offered in the sensitivity and specificity of Mucorales detection based on mycological culture, which remains a gold-standard procedure for mucormycosis detection in LMICs lacking access to more sophisticated diagnostic procedures.
2024-02-14 | Haemolysin Ahh1 secreted from Aeromonas dhakensis activates the NLRP3 inflammasome in macrophages and mediates severe soft tissue infection.
Severe soft tissue infections caused by Aeromonas dhakensis, such as necrotizing fasciitis or cellulitis, are prevalent in southern Taiwan and around the world. However, the mechanism by which A. dhakensis causes tissue damage remains unclear. Here, we found that the haemolysin Ahh1, which is the major virulence factor of A. dhakensis, causes cellular damage and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathway. Deletion of ahh1 significantly downregulated caspase-1, the proinflammatory cytokine interleukin 1β (IL-1β) and gasdermin D (GSDMD) and further decreased the damage caused by A. dhakensis in THP-1 cells. In addition, we found that knockdown of the NLRP3 inflammasome confers resistance to A. dhakensis infection in both THP-1 NLRP3-/- cells and C57BL/6 NLRP3-/- mice. In addition, we demonstrated that severe soft-tissue infections treated with antibiotics combined with a neutralizing antibody targeting IL-1β significantly increased the survival rate and alleviated the degree of tissue damage in model mice compared control mice. These findings show that antibiotics combined with therapies targeting IL-1β are potential strategies to treat severe tissue infections caused by toxin-producing bacteria.
2023-07-10 | Neutrophil-derived reactive agents induce a transient SpeB negative phenotype in Streptococcus pyogenes
Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection. A key driving force for this process is the bacterial Sda1 DNase.Bacterial infiltration, immune cell influx, tissue necrosis and inflammation in patient´s biopsies were determined using immunohistochemistry. SpeB secretion and activity by GAS post infections or challenges with reactive agents were determined via Western blot or casein agar and proteolytic activity assays, respectively. Proteome of GAS single colonies and neutrophil secretome were profiled, using mass spectrometry.Here, we identify another strategy resulting in SpeB-negative variants, namely reversible abrogation of SpeB secretion triggered by neutrophil effector molecules. Analysis of NSTI patient tissue biopsies revealed that tissue inflammation, neutrophil influx, and degranulation positively correlate with increasing frequency of SpeB-negative GAS clones. Using single colony proteomics, we show that GAS isolated directly from tissue express but do not secrete SpeB. Once the tissue pressure is lifted, GAS regain SpeB secreting function. Neutrophils were identified as the main immune cells responsible for the observed phenotype. Subsequent analyses identified hydrogen peroxide and hypochlorous acid as reactive agents driving this phenotypic GAS adaptation to the tissue environment. SpeB-negative GAS show improved survival within neutrophils and induce increased degranulation.Our findings provide new information about GAS fitness and heterogeneity in the soft tissue milieu and provide new potential targets for therapeutic intervention in NSTIs.
other
2026-05-12 | Identification of immunostimulatory antigens in Group A Streptococcus-derived vesicles.
An effective vaccine against Streptococcus pyogenes (Group A Streptococcus, GAS) is urgently needed. Bacteria-derived extracellular vesicles (EVs) are emerging as promising vaccine platforms. In this study, we evaluated the immunostimulatory properties of GAS-derived EVs when administered intranasally in mice. Immunization induced a strong humoral response, including pathogen-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies. Additionally, we observed local and systemic T cell responses, specifically a robust Th17 response along with a modest but statistically significant Th1 response. Through immunoprecipitation coupled with mass spectrometry and western blotting, we identified seven immunogenic proteins, including the lipoproteins MtsA, BMP, PrsA1, PrsA2, MetQ, MalX, and the glutamine transporter GlnP. These antigens were recognized by human sera from both healthy individuals and patients with necrotizing soft tissue infection. Finally, we demonstrate that these antigens stimulate production and secretion of IL-17A by lung cells and splenocytes and that they are highly conserved across diverse GAS M-types, highlighting their potential as broadly protective vaccine candidates.
2023-11-11 | Necrotizing fascitis: A case report
Background. Necrotizing soft tissue infections are actually the diseases with a severe outcome characterized by the progression of soft tissue inflammation with a catastrophic prognosis and the risk of major functional consequences. Only prompt diagnosis and prompt care, including prompt administration of appropriate antibiotic therapy and surgical treatment, can improve the outcome. Case report. A female patient, aged 66 years, came due to swelling and pain in the perineum. Before admission, the pains were of low intensity, and immediately before admission, their intensity increased. An incision was made in the perineal region and the abdominal region on the left. During the preparation, we came across a necrotic tissue from which a dark-gray liquid flew that had a strong smell. From the tenth postoperative day, secondary sutures were partly placed. Conclusion. Mortality and morbidity in this disease are high. A potential new treatment for this disease may be an antigen-inhibiting vaccine.
2019-04-11 | Protection against Staphylococcus aureus Colonization and Infection by B- and T-Cell-Mediated Mechanisms.
Staphylococcus aureus is a major cause of morbidity and mortality worldwide. S. aureus colonizes 20 to 80% of humans at any one time and causes a variety of illnesses. Strains that are resistant to common antibiotics further complicate management. S. aureus vaccine development has been unsuccessful so far, largely due to the incomplete understanding of the mechanisms of protection against this pathogen. Here, we studied the role of different aspects of adaptive immunity induced by an S. aureus vaccine in protection against S. aureus bacteremia, dermonecrosis, skin abscess, and gastrointestinal (GI) colonization. We show that, depending on the challenge model, the contributions of vaccine-induced S. aureus-specific antibody and Th1 and Th17 responses to protection are different: antibodies play a major role in reducing mortality during S. aureus bacteremia, whereas Th1 or Th17 responses are essential for prevention of S. aureus skin abscesses and the clearance of bacteria from the GI tract. Both antibody- and T-cell-mediated mechanisms contribute to prevention of S. aureus dermonecrosis. Engagement of all three immune pathways results in the most robust protection under each pathological condition. Therefore, our results suggest that eliciting multipronged humoral and cellular responses to S. aureus antigens may be critical to achieve effective and comprehensive immune defense against this pathogen.IMPORTANCES. aureus is a leading cause of healthcare- and community-associated bacterial infections. S. aureus causes various illnesses, including bacteremia, meningitis, endocarditis, pneumonia, osteomyelitis, sepsis, and skin and soft tissue infections. S. aureus colonizes between 20 and 80% of humans; carriers are at increased risk for infection and transmission to others. The spread of multidrug-resistant strains limits antibiotic treatment options. Vaccine development against S. aureus has been unsuccessful to date, likely due to an inadequate understanding about the mechanisms of immune defense against this pathogen. The significance of our work is in illustrating the necessity of generating multipronged B-cell, Th1-, and Th17-mediated responses to S. aureus antigens in conferring enhanced and broad protection against S. aureus invasive infection, skin and soft tissue infection, and mucosal colonization. Our work thus, provides important insights for future vaccine development against this pathogen.
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Drug Discovery Landscape
2 orphan drug designations for Necrotizing soft tissue infection.
2 orphan drug designations for Necrotizing soft tissue infection.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium acetate salt of the synthetic peptide H-D-Ala-Ser-Pro-Met-Leu-Val-Ala-Tyr-Asp-D-Ala-OH | peptides | EMA | 2014-07-29 | — | FGK Representative Service GmbH |
reltecimod | peptides | FDA | 2011-10-12 | — | Atox Bio, Inc. |
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