Drug-induced liver injury is an important cause of clinically significant liver disease. In Western countries, antibiotics are the leading cause of DILI, with amoxicillin-clavulanate and trimethoprim-sulfamethoxazole most frequently implicated. Herbal and dietary supplements (HDS) are increasingly implicated as a cause of DILI worldwide, including ashwagandha, turmeric, and green tea extract in the United States. Advances in DILI diagnosis include the development of the Revised Electronic Causality Assessment Method (RECAM) instrument and the creation of the LiverTox website with drug and HDS likelihood scores. Newer causes of DILI include kinase inhibitors for cancer and autoimmune conditions, various immunomodulatory agents, and medications to treat liver disease. Immune-mediated liver injury from checkpoint inhibitors (ILICI) typically presents within the first 6 months of treatment with asymptomatic laboratory abnormalities. Treatment of DILI remains primarily supportive by withholding the offending agent and close monitoring, with corticosteroids only showing benefit in highly selected patients. Over 80% of DILI patients will fully recover within 6 months of drug discontinuation with supportive care, but recent outcomes for DILI-related ALF due to HDS have been worsening. Prognostic models can help identify hospitalized DILI patients in need of transplant and others who are at increased risk for 6-month mortality. Whole-exome sequencing to identify new genetic risk factors, development of in vitro diagnostic assays, and further studies of the host adaptive immune response in DILI pathogenesis will hopefully lead to further improvements in DILI diagnosis and treatment.

Children with severe acute malnutrition (SAM) are at high risk of invasive infection. In sub-Saharan Africa, invasive non-typhoidal Salmonella enterica (iNTS) serovars are a leading cause of paediatric bloodstream infection. However, low-resource settings lack genomic data linking intestinal carriage with concurrent BSI in children presenting with SAM.We conducted a longitudinal cohort study among children aged 0-59 months admitted for inpatient management of complicated SAM at the Madarounfa Intensive Nutritional Rehabilitation Centre, Maradi, Niger (2016-2017). Blood cultures and rectal swabs were obtained on admission (and during hospitalization if symptoms worsened). Genomic population structure of S. enterica serovars Enteritidis and Typhimurium was compared using phylogeny and clustering approaches. Among 1,371 enrolled children, 87 Salmonella isolates were recovered from 83 BSI episodes in 80 children. Invasive isolates belonged to a few globally circulating lineages, whereas carriage-only isolates demonstrated more heterogeneous genotypes. Minimum inhibitory concentrations were determined for 58 viable BSI isolates: susceptibility was retained to third-generation cephalosporins and carbapenems, while resistance to ampicillin (95%) and amoxicillin/clavulanate (90%) was common.A nested case-control analysis of rectal swabs from 232 children (58 iNTS BSI cases; 174 non-BSI controls) was performed to test the association between gut carriage and BSI. Salmonella was detected in 44/58 (76%) cases vs. 7/174 (4%) controls, yielding a relative risk of 18.86 (CI 95% 9.00-39.53; χ[2]=126.7; P<0.0001). Clustering analyses confirmed close genomic relatedness within patient pairs and indicated circulation of a limited number of endemic clones. Among controls with faecal Salmonella, serovars were diverse and distinct from invasive lineages.

Shigella is the pathogen of bacterial dysentery. With the widespread use of antibiotics, the burden of antibiotic resistance in Shigella has become increasingly pronounced. In this study, the cfa gene of ampicillin-resistant strain (Res) was knocked out and back-complemented strains were constructed. The susceptibility of Res and Δcfa strains to ampicillin was compared, and the molecular regulatory mechanisms of cfa gene on antibiotic resistance in Shigella were explored by screening the differentially expressed mRNAs, proteins, and metabolites of the two groups. In addition, we examined differences between the two groups in growth, biofilm formation, environmental stress (including temperature, pH, salt, oxidative stress, and carbon and nitrogen sources), and cytotoxicity. The sensitivity of Δcfa to ampicillin was increased 32-fold compared to the Res strain (64 µg/mL vs. 2 µg/mL). Compared to the Res strain, the Δcfa mutant exhibited a 16-fold increase in susceptibility to amoxicillin, a 16-fold increase in susceptibility to both penicillin and aztreonam, a 4-fold increase in susceptibility to cefotaxime, and a 2-fold increase in susceptibility to cefazolin, ceftazidime, ceftriaxone and tetracycline. The MICs of Δcfa-pcfa complemented strain was elevated to 4, 32, and 16 µg/mL for ampicillin, penicillin, and amoxicillin, respectively. The differential metabolites of the two groups were significantly enriched in the cysteine and methionine metabolic pathways (P < 0.05). Under no antibiotic stress, Δcfa grew faster than the Res strain and had greater biofilm formation capacity and environmental stress adaptation, but there was no significant difference in the virulence effect of the culture supernatant on Vero cell between the two groups. The cfa gene orchestrates sulfur metabolism and coordinates the cysteine-methionine biosynthetic pathway in bacteria. The cfa gene not only mediates penicillin antibiotics resistance mechanisms in Shigella sonnei but also modulates critical physiological processes.

Bovine mastitis is a major health and economic problem in dairy animals, primarily caused by bacterial pathogens such as Staphylococcus aureus, Streptococcus spp. and Escherichia coli. The rise of antimicrobial resistance has reduced the effectiveness of conventional antibiotics, emphasizing the need for alternative or adjunct treatment strategies. The present study evaluated the in vitro synergistic antimicrobial activity of amoxicillin in combination with N-acetylcysteine (NAC) against virulent isolates of S. aureus and E. coli recovered from clinical bovine mastitis cases. Antimicrobial susceptibility test was conducted using disc diffusion test, and the interaction between amoxicillin and NAC was assessed through a qualitative minimum inhibitory concentration test strip method and quantitative checkerboard assay. The combination of amoxicillin and NAC exhibited enhanced antibacterial activity compared to amoxicillin alone, indicating a synergistic effect against the virulent S. aureus and E. coli. Qualitative analysis revealed an increased zone of inhibition with the combination treatment relative to individual agents. Quantitative findings showed a 32-fold reduction in MIC for S. aureus and E. coli. The improved antimicrobial efficacy attributed to the antibiofilm and mucolytic properties of NAC, which can disrupt biofilm architecture and enhance antibiotic penetration. Overall, the findings suggest that NAC serve as a potential adjuvant to conventional antibiotic therapy for improved management of mastitis caused by resistant bacterial pathogens.

Ticks harbour diverse microbial communities, but opportunistic and environmentally associated bacteria within these systems remain poorly understood. During attempts to establish primary cell cultures from surface-sterilized embryos of the dog tick Rhipicephalus linnaei, we detected the presence of Stenotrophomonas maltophilia, a multidrug-resistant environmental bacterium and emerging opportunistic pathogen. Microscopic examination of Giemsa-stained smears showed abundant extracellular rod-shaped bacteria closely associated with degenerating tick cells, with no evidence of intracellular infection. Molecular identification based on 16S and 23S rRNA gene sequencing confirmed the bacteria as S. maltophilia, and antibiotic susceptibility testing revealed resistance to amoxicillin-clavulanic acid, imipenem, cefoxitin, and nitrofurantoin, but susceptibility to meropenem. Multi-locus sequence typing (MLST) identified the isolate as sequence type 948 (ST948), which is a single-locus variant of ST408 and a double-locus variant of ST144, both of which are representatives of environmental and clinical S. maltophilia strains from diverse geographic origins. These findings provide the first evidence of S. maltophilia occurring in a tick-derived cell culture system and highlight the need to consider opportunistic bacteria when interpreting tick microbiome and cell culture-based studies, particularly those involving veterinary-relevant tick species.

Amoxicillin is the most commonly used antibiotic globally. However, there is a relatively poor understanding of its pharmacokinetics, pharmacodynamics, and clinical pharmacology. We constructed a physiology-based pharmacokinetic (PBPK) model of amoxicillin to gain deeper insights into the adequacy of amoxicillin regimens for the treatment of infections relevant to global health. We constructed an amoxicillin PBPK model in PK-Sim using known ADME and physicochemical parameters, in vitro characterized transporter kinetics of amoxicillin with OAT3, and time-concentration data from the published literature. Unknown parameters were fitted using a subset of available clinical pharmacokinetic data for training, before final validation with a holdout data set. Population simulations were performed using the final model for a range of amoxicillin regimens and contexts. The final amoxicillin PBPK model was high performing by fold-error metrics for both plasma and urinary concentrations. Simulations demonstrated all regimens achieved the 40%T>minimum inhibitory concentration (MIC) target for Streptococcus pneumoniae up to 1 mg/L and all except p.o. 500 mg amoxicillin q8h for the wild-type Haemophilus influenzae MIC distribution. The simulations also demonstrated high urinary amoxicillin exposures and evaluated the effects of inadequate active ingredient content, missed doses, and probenecid co-administration. This PBPK model gives the following insights into amoxicillin pharmacokinetics: i) the adequacy of amoxicillin for infections caused by S. pneumoniae and H. influenzae; ii) the impact of non-compliance and loss of active ingredients on antimicrobial coverage; iii) the effect of probenecid co-administration to improve coverage; and iv) the characterization of high urinary amoxicillin exposure with consequences for use in urinary tract infections.

We report the case of a 23-year-old woman with a pre-existing penicillin allergy label from childhood who presented with severe bilateral conjunctivitis and oral mucositis following a prodromal respiratory illness. Her symptoms worsened shortly after receiving doxycycline, raising concern for a drug reaction. Her condition progressed with significant ocular involvement requiring bilateral amniotic membrane grafting and subsequent immunosuppressive therapy. Investigations confirmed Mycoplasma pneumoniae infection, supporting a diagnosis most consistent with Mycoplasma-induced rash and mucositis (MIRM), although Stevens-Johnson syndrome (SJS) could not be fully excluded. Following recovery, a structured allergy work-up was undertaken, including patch testing, intradermal testing and graded oral provocation in accordance with established guidance. All tests were negative, and the patient successfully tolerated amoxicillin, doxycycline and ibuprofen without adverse reactions. This case demonstrates how a structured, multidisciplinary approach to drug allergy evaluation can facilitate de-labelling in patients with complex mucocutaneous presentations, restore access to first-line therapies and improve patient care.