Human Leukocyte Antigens and Sulfamethoxazole/Cotrimoxazole-Induced Severe Cutaneous Adverse Reactions: A Systematic Review and Meta-Analysis.

Importance: Sulfamethoxazole (SMX) and cotrimoxazole (CTX), a fixed-dose combination of SMX and trimethoprim in a 5:1 ratio, are antibacterial sulfonamides commonly used for treating various diseases. A substantial prevalence of severe cutaneous adverse reactions (SCARs) following the administration of these drugs has been reported. However, the association between human leukocyte antigen (HLA) genotypes and SMX/CTX-induced SCARs has remained unclear. Objective: To investigate the association between HLA genotypes and SMX/CTX-induced SCARs. Data sources: A comprehensive search was conducted in CENTRAL (Cochrane Library), MEDLINE, and Embase from inception to January 17, 2023. Study Selection: Case-control studies that recruited patients who had experienced SCARs following SMX or CTX were included, and HLA alleles were analyzed. Data Extraction and Synthesis: Two independent authors extracted data on study characteristics and outcome data. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. The Newcastle-Ottawa Scale for case-control studies was used to assess study quality. Odds ratios (ORs) were calculated using a random-effects model for meta-analysis. Main Outcomes and Measures: The prespecified outcome was the OR comparing SMX/CTX-induced SCARs with healthy or SMX/CTX-tolerant controls based on different HLA alleles. Results: Six studies involving 322 patients with SCAR were included, including 236 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 86 with drug reaction with eosinophilia and systemic symptoms, 8448 healthy controls, and 229 tolerant controls. Significant associations were found in HLA-A*11:01 (OR, 2.10; 95% CI, 1.11-4.00), HLA-B*13:01 (OR, 5.96; 95% CI, 1.58-22.56), HLA-B*15:02 (OR, 2.23; 95% CI, 1.20-4.14), HLA-B*38:02 (OR, 3.47; 95% CI, 1.42-8.48), and HLA-C*08:01 (OR, 2.63; 95% CI, 1.07-6.44) compared with tolerant controls. In the Stevens-Johnson syndrome/toxic epidermal necrolysis subgroup, significant associations were found in HLA-B*15:02 (OR, 3.01; 95% CI, 1.56-5.80) and HLA-B*38:02 (OR, 5.13; 95% CI, 1.96-13.47). In the drug reaction with eosinophilia and systemic symptoms subgroup, significant associations were found in HLA-A*68:01 (OR, 12.86; 95% CI, 1.09-151.34), HLA-B*13:01 (OR, 23.09; 95% CI, 3.31-161.00), HLA-B*39:01 (OR, 4.56; 95% CI, 1.31-15.82). Conclusions and Relevance: The results of this systematic review and meta-analysis suggest that multiple HLA alleles (HLA-A*11:01, HLA-B*13:01, HLA-B*15:02, HLA-B*38:02, and HLA-C*0801) are associated with SMX/CTX-induced SCARs.

Drug Hypersensitivity Reactions in Patients with Cystic Fibrosis: Potential Value of the Lymphocyte Toxicity Assay to Assess Risk.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease characterized by multi-system dysfunction resulting in recurrent lung infections and progressive pulmonary disease. CF patients are at a higher risk for drug hypersensitivity reactions (DHRs) compared to the general population, which has been attributed to the recurrent need for antibiotics and the inflammation associated with CF disease. In vitro toxicity tests such as the lymphocyte toxicity assay (LTA) offer the potential for risk assessment for DHRs. In the current study, we investigated the utility of the LTA test for diagnosis of DHRs in a cohort of CF patients. METHOD: Twenty CF patients with suspected DHRs to sulfamethoxazole, penicillins, cephalosporins, meropenem, vancomycin, rifampicin, and tobramycin were recruited to this study and tested using the LTA test along with 20 healthy control volunteers. Demographic data of the patients, including age, sex, and medical history, were obtained. Blood samples were withdrawn from patients and healthy volunteers, and the LTA test was performed on isolated peripheral blood monocytes (PBMCs) from those individuals. RESULTS: Cells from CF patients with DHRs displayed a significant (p < 0.0001) concentration-dependent enhanced cell death upon incubation with the culprit drug compared to cells from healthy volunteers. The positivity rate of the LTA test was over 80% in patients with a medical history and clinical presentation consistent with DHRs. CONCLUSION: This study is the first to evaluate the use of the LTA test for diagnosis of DHRs in CF patients. According to our results, the LTA test may be a useful tool for diagnosis and management of DHRs in CF patients. Identifying the culprit drug is essential for optimal healthcare for CF patients in the setting of a suspected DHR. The data also provide evidence that accumulation of toxic reactive metabolites could be an important component in the cascade of events leading to the development of DHRs in CF patients. A larger-scale study is needed to confirm the data.

Medicine-Induced Acute Kidney Injury Findings from Spontaneous Reporting Systems, Sequence Symmetry Analysis and a Case-Control Study with a Focus on Medicines Used in Primary Care.

INTRODUCTION: Primary care provides an opportunity to prevent community acquired, medicine or drug-induced acute kidney injury. One of the barriers to proactive prevention of medicine-induced kidney injury in primary care is the lack of a list of nephrotoxic medicines that are most problematic in primary care, particularly one that provides a comparison of risks across medicines. OBJECTIVE: The aim of this study was to consolidate evidence on the risks associated with medicines and acute kidney injury, with a focus on medicines used in primary care. METHOD: We searched the MEDLINE and EMBASE databases to identify published studies of all medicines associated with acute kidney injury identified from spontaneous report data. For each medicine positively associated with acute kidney injury, as identified from spontaneous reports, we implemented a sequence symmetry analysis (SSA) and a case-control design to determine the association between the medicine and hospital admission with a primary diagnosis of acute kidney injury (representing community-acquired acute kidney injury). Administrative claims data held by the Australian Government Department of Veterans' Affairs for the study period 2005-2019 were used. RESULTS: We identified 89 medicines suspected of causing acute kidney injury based on spontaneous report data and a reporting odds ratio above 2, from Japan, France and the US. Spironolactone had risk estimates of 3 or more based on spontaneous reports, SSA and case-control methods, while furosemide and trimethoprim with sulfamethoxazole had risk estimates of 1.5 or more. Positive association with SSA and spontaneous reports, but not case control, showed zoledronic acid had risk estimates above 2, while candesartan telmisartan, simvastatin, naproxen and ibuprofen all had risk estimates in SSA between 1.5 and 2. Positive associations with case-control and spontaneous reports, but not SSA, were found for amphotericin B, omeprazole, metformin, amlodipine, ramipril, olmesartan, ciprofloxacin, valaciclovir, mycophenolate and diclofenac. All with the exception of metformin and omeprazole had risk estimates above 2. CONCLUSION: This research highlights a number of medicines that may contribute to acute injury; however, we had an insufficient sample to confirm associations of some medicines. Spironolactone, furosemide, and trimethoprim with sulfamethoxazole are medicines that, in particular, need to be used carefully and monitored closely in patients in the community at risk of acute kidney injury.

Sulfamethoxazole-induced sulfamethoxazole urolithiasis: a case report.

BACKGROUND: Drug-induced urolithiasis falls into two categories: drug-induced and metabolically-induced. Certain antimicrobials are associated with each; sulfonamides are associated with drug- or metabolite-containing calculi when taken in large doses over a long period of time. Trimethoprim-sulfamethoxazole, a member of the sulfonamide family, is a rare cause of drug-induced calculi. Cases of sulfonamide urolithiasis occurring in patients with known stone disease have rarely been reported. CASE PRESENTATION: We report a case of a patient with a brief history of recurrent calcium oxalate nephrolithiasis requiring 2 ureteroscopic procedures whose existing 6 mm lower pole renal stone more than quadrupled in size to form a 4 cm renal staghorn after 4 months of high-dose treatment for Nocardia pneumonia with trimethoprim-sulfamethoxazole. After ureteroscopy with laser lithotripsy and basketing of fragments, the stone was found to be predominantly composed of N4-acetyl-sulfamethoxazole, a metabolite of sulfamethoxazole. CONCLUSION: Stones composed of sulfamethoxazole or its metabolites are rare but have known associated risk factors that should be considered when prescribing this antibiotic. This case report illustrates additional risk factors for consideration, including pre-existing urinary calculi that may serve as a nidus for sulfamethoxazole deposition, and reviews treatment and prevention methods.

Environmental concentrations of sulfamethoxazole increase crayfish Pacifastacus leniusculus susceptibility to White Spot Syndrome Virus.

Antibiotics used for humans and livestock are emerging as pollutants in aquatic environments. However, little is known about their effect on aquatic organisms, especially in crustaceans. In the present study, the freshwater crayfish Pacifastacus leniusculus was exposed during 21 days to environmental concentrations of sulfamethoxazole (SMX) (100 ng/L and 1 µg/L). Subsequently, the crayfish susceptibility to infection was evaluated by using White Spot Syndrome Virus (WSSV) challenge, a well-known crustacean pathogen. The median survival time of the infected crayfish exposed to 100 ng/L SMX was one day, whereas the control and the group exposed to 1 µg/L SMX survived for two and three days, respectively. In order to elucidate the effect of SMX upon the crayfish immune response, new sets of crayfish were exposed to the same SMX treatments to evaluate mRNA levels of immune-related genes which are expressed and present in hemocytes and intestine, and to perform total and differential hemocyte counts. These results show a significant down-regulation of the antimicrobial peptide (AMP) Crustin 3 in hemocytes from the 100 ng/L SMX group, as well as a significant up-regulation of the AMP Crustin 1 in intestines from the 1 µg/L SMX group. Semigranular and total hemocyte cell number were observed to be significantly lower after exposure to 100 ng/L SMX in comparison with the control group. The present study demonstrates that environmentally relevant SMX concentrations in the water at 100 ng/L led to an increased WSSV susceptibility, that may have been caused by a reduction of circulating hemocytes. Nevertheless, SMX concentrations of 1 µg/L could marginally and for a few days have an immunostimulatory effect.

In Vitro Protective Effect of Ascorbic Acid Against Antibiotic-Induced Hepatotoxicity.

BACKGROUND: Although antibiotic-induced hepatotoxicity is recoverable with mild impairment, and some cases were reported to cause morbidity. However, an adjuvant is essential in reducing such incidences. OBJECTIVE: The aim of this study is to evaluate the protective effect of ascorbic acid on antibiotic induced liver toxicity using liver slices. METHOD: Fresh liver slices were incubated with different concentrations of sulfamethoxazole tetracycline and clavulanic acid along with ascorbic acid (200µg/ml) for 2 hours. The liver homogenate was assessed for markers like ALT, AST, MDA and CAT levels. Cytotoxicity assessment was performed using MTT assay. RESULTS: Incubating liver slices with all three antibiotics shows elevated levels of aminotransferases, MDA and CAT enzyme when compared to the control groups which indicates the level of hepatotoxicity. In the presence of ascorbic acid, the elevated levels of TBARS, ALT and AST were significantly reduced which showcases the protective effect of ascorbic acid. The percentage survival of cell was also shown to have improved while accessed using cell viability assay. CONCLUSION: Obtained data suggests that consuming vitamin C or vitamin C containing food like citrus fruits or green leafy vegetables equivalent to 3g/day during antibiotic treatment, perhaps put down the risk of liver toxicity to a greater extent.

Role of Oxidative Stress in Hypersensitivity Reactions to Sulfonamides.

Antimicrobial sulfonamides are important medications. However, their use is associated with major immune-mediated drug hypersensitivity reactions with a rate that ranges from 3% to 4% in the general population. The pathophysiology of sulfa-induced drug hypersensitivity reactions is not well understood, but accumulation of reactive metabolites (sulfamethoxazole [SMX] hydroxylamine [SMX-HA] and SMX N-nitrosamine [SMX-NO]) is thought to be a major factor. These reactive metabolites contribute to the formation of reactive oxygen species (ROS) known to cause cellular damage and induce cell death through apoptosis and necroptosis. ROS can also serve as "danger signals," priming immune cells to mount an immunological reaction. We recruited 26 sulfa-hypersensitive (HS) patients, 19 healthy control subjects, and 6 sulfa-tolerant patients to this study. Peripheral blood monocytes and platelets were isolated from blood samples and analyzed for in vitro cytotoxicity, ROS and carbonyl protein formation, lipid peroxidation, and GSH (glutathione) content after challenge with SMX-HA. When challenged with SMX-HA, cells isolated from sulfa-HS patients exhibited significantly (P ≤ .05) higher cell death, ROS and carbonyl protein formation, and lipid peroxidation. In addition, there was a high correlation between cell death in PBMCs and ROS levels. There was also depletion of GSH and lower GSH/GSSG ratios in peripheral blood mononuclear cells from sulfa-HS patients. The amount of ROS formed was negatively correlated with intracellular GSH content. The data demonstrate a major role for oxidative stress in in vitro cytotoxicity of SMX reactive metabolites and indicate increased vulnerability of cells from sulfa-HS patients to the in vitro challenge.

Loss of tolerance 5 days after discontinuing sulphonamide introduced via desensitization in delayed reaction.

The fixed drug eruption is a non-immediate hypersensitivity reaction to drug, characterized by recurrent erythematous or violaceous, rounded, well-defined border plaques, which always appear in the same location every time the culprit drug is administered. The usual practice is to avoid the drug involved and to use a structurally different drug. However, there are situations in which there is no safe and effective therapy. In such situations, desensitization is the only option. We describe the case of a patient who presented fixed eruption due to sulfamethoxazole-trimethoprim, who underwent successful desensitization, but required a repeat procedure twice due to relapse after inadvertent full-dose reintroduction. In non-immediate hypersensitivity reaction to drug, the indication is controversial and there is no technical standardization. Furthermore, the time at which such tolerance is lost after discontinuing the drug involved is unknown. In severe non-immediate reactions of types II and III, desensitization is contraindicated. The patient underwent desensitisation to sulfamethoxazole-trimethoprim three times - the first with recurrence of lesions and the second and third without manifestations, all concluded successfully and with no premedication.

Loss of tolerance 5 days after discontinuing sulphonamide introduced via desensitization in delayed reaction / Perda da tolerância 5 dias após suspensão de sulfonamida introduzida através de dessensibilização por reação tardia

ABSTRACT The fixed drug eruption is a non-immediate hypersensitivity reaction to drug, characterized by recurrent erythematous or violaceous, rounded, well-defined border plaques, which always appear in the same location every time the culprit drug is administered. The usual practice is to avoid the drug involved and to use a structurally different drug. However, there are situations in which there is no safe and effective therapy. In such situations, desensitization is the only option. We describe the case of a patient who presented fixed eruption due to sulfamethoxazole-trimethoprim, who underwent successful desensitization, but required a repeat procedure twice due to relapse after inadvertent full-dose reintroduction. In non-immediate hypersensitivity reaction to drug, the indication is controversial and there is no technical standardization. Furthermore, the time at which such tolerance is lost after discontinuing the drug involved is unknown. In severe non-immediate reactions of types II and III, desensitization is contraindicated. The patient underwent desensitisation to sulfamethoxazole-trimethoprim three times − the first with recurrence of lesions and the second and third without manifestations, all concluded successfully and with no premedication.

RESUMO A erupção fixa por drogas é uma reação de hipersensibilidade a medicamento não imediata, caracterizada por placas eritematosas ou violáceas, arredondadas, recorrentes, de bordas bem definidas e que aparecem sempre na mesma localização cada vez que o medicamento culpado é administrado. A prática habitual é evitar a droga envolvida e utilizar um medicamento estruturalmente diferente. Contudo, há situações em que não há terapêutica segura e eficaz. Em tais situações, a dessensibilização é a única opção. Descrevemos o caso de um paciente que apresentou erupção fixa por drogas por sulfametoxazol-trimetoprim, tendo sido submetido à dessensibilização com sucesso, mas necessitou repetição do procedimento duas vezes, por recidiva da reação após reintrodução inadvertida em dose plena. Em reação de hipersensibilidade a medicamento não imediata, a indicação é controversa e não há padronização técnica. Além disso, não se conhece o tempo durante o qual essa tolerância é perdida após a suspensão da droga envolvida. Nas reações não imediatas graves e dos tipos II e III, a dessensibilização está contraindicada. O paciente foi submetido a dessensibilização ao sulfametoxazol-trimetoprim por três vezes − a primeira com recorrência de lesões, e a segunda e terceira sem manifestações, sendo todas concluídas com sucesso e sem uso de pré-medicação.

Trimethyl Chitosan/Siloxane-Hybrid Coated Fe3O4 Nanoparticles for the Uptake of Sulfamethoxazole from Water.

The presence of several organic contaminants in the environment and aquatic compartments has been a matter of great concern in the recent years. To tackle this problem, new sustainable and cost-effective technologies are needed. Herein we describe magnetic biosorbents prepared from trimethyl chitosan (TMC), which is a quaternary chitosan scarcely studied for environmental applications. Core@shell particles comprising a core of magnetite (Fe3O4) coated with TMC/siloxane hybrid shells (Fe3O4@SiO2/SiTMC) were successfully prepared using a simple one-step coating procedure. Adsorption tests were conducted to investigate the potential of the coated particles for the magnetically assisted removal of the antibiotic sulfamethoxazole (SMX) from aqueous solutions. It was found that TMC-based particles provide higher SMX adsorption capacity than the counterparts prepared using pristine chitosan. Therefore, the type of chemical modification introduced in the chitosan type precursors used in the surface coatings has a dominant effect on the sorption efficiency of the respective final magnetic nanosorbents.

A pilot study of safety of sulfamethoxazole, trimethoprim and guaifenesin in pediatric and adult patients with acute bronchitis.

OBJECTIVE: This exploratory study assessed the safety of the combination of sulfamethoxazole, trimethoprim and guaifenesin (STG) in adult and pediatric patients with acute bronchitis according to local labelling in Peru. RESULTS: We enrolled 51 pediatric and 52 adult participants diagnosed with acute bronchitis and indication of STG. The mean ages were 7.6 years (SD ± 3.2 years) and 42.8 years (SD ± 16.1) and the proportion of female patients were 51% and 65%, respectively. The duration of treatment in pediatric patients was < 5 days in 2% of patients, 5 days in 13.7%, 6-7 days, in 82.4% and > 7 days in 2% while in adults patients it was < 5 days in 17%, 5 days in 69.2%; 6-7 days in 28.8% of patients. Adverse events (AEs) were registered in 9.6% and 19.2% of pediatric and adult patients, respectively. These AEs had definite relation of causality with the study drugs in 2 adults (20% of AEs) and possible causality with the study drugs in 4 pediatric (80% of AEs) and 2 adult cases (20% of AEs). Our results provide valuable data to develop trials of pharmacovigilance where different statistical parameters should be considered to calculate an adequate sample size in studies evaluating STG in pediatric or adult patients. Trial registration NCT02879981 and NCT02902640.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A Multicenter Retrospective Study of 377 Adult Patients from the United States.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare, severe mucocutaneous reaction with few large cohorts reported. This multicenter retrospective study included patients with SJS/TEN seen by inpatient consultative dermatologists at 18 academic medical centers in the United States. A total of 377 adult patients with SJS/TEN between January 1, 2000 and June 1, 2015 were entered, including 260 of 377 (69%) from 2010 onward. The most frequent cause of SJS/TEN was medication reaction in 338 of 377 (89.7%), most often to trimethoprim/sulfamethoxazole (89/338; 26.3%). Most patients were managed in an intensive care (100/368; 27.2%) or burn unit (151/368; 41.0%). Most received pharmacologic therapy (266/376; 70.7%) versus supportive care alone (110/376; 29.3%)-typically corticosteroids (113/266; 42.5%), intravenous immunoglobulin (94/266; 35.3%), or both therapies (54/266; 20.3%). Based on day 1 SCORTEN predicted mortality, approximately 78 in-hospital deaths were expected (77.7/368; 21%), but the observed mortality of 54 patients (54/368; 14.7%) was significantly lower (standardized mortality ratio = 0.70; 95% confidence interval = 0.58-0.79). Stratified by therapy received, the standardized mortality ratio was lowest among those receiving both steroids and intravenous immunoglobulin (standardized mortality ratio = 0.52; 95% confidence interval 0.21-0.79). This large cohort provides contemporary information regarding US patients with SJS/TEN. Mortality, although substantial, was significantly lower than predicted. Although the precise role of pharmacotherapy remains unclear, co-administration of corticosteroids and intravenous immunoglobulin, among other therapies, may warrant further study.

Influence of Long-Term Feeding Antibiotics on the Gut Health of Zebrafish.

The use of antibiotics for anti-infection and growth promotion has caused the overuse of antibiotics in aquaculture. However, the benefit or risk of the long-term use of antibiotics on fish growth or health has not been fully addressed. In the present study, zebrafish were fed with sulfamethoxazole (SMX) or oxytetracycline (OTC) at the therapeutic concentrations (100 and 80 mg/kg body weight per day, respectively) for 6 weeks to mimic the long-term use of antibiotics. The digestive enzyme activities were higher in both antibiotic treatments, and higher oxygen consumption rate was found in OTC treated group. As a result, SMX increased the weight gain of zebrafish, and OTC treatment did not show significant prompting effect on growth. The mortality was higher in SMX or OTC treated group on 2nd-4th day after exposure to Aeromonas hydrophila. Lower alkaline phosphatase (AKP) and acid phosphatase (ACP) activities were found in OTC treated group, while higher malondialdehyde (MDA) content was found in the intestine of both SMX and OTC treated zebrafish. Furthermore, feeding OTC decreased the intestinal microbial richness. This study revealed that long-term use of legal aquaculture concentrations of antibiotics caused systemic adverse effects on fish gut health; stringent policy for use of antibiotics in fish is urgent.

Application of in Vitro T Cell Assay Using Human Leukocyte Antigen-Typed Healthy Donors for the Assessment of Drug Immunogenicity.

It is unclear whether priming of naïve T cells to drugs is detectable in healthy human donors expressing different human leukocyte antigen (HLA) alleles. Thus, we examined T cell priming with drugs associated with HLA risk alleles and control compounds in 14 HLA-typed donors. Nitroso sulfamethoxazole and piperacillin activated T cells from all donors, whereas responses to carbamazepine and oxypurinol were only seen in donors expressing HLA-B*15:02 and HLA-B*58:01, respectively. Weak flucloxacillin-specific T cell responses were detected in donors expressing HLA-B*57:01 and HLA-B*58:01. These data show that the priming of T cells with certain drugs is skewed toward donors expressing specific HLA alleles.