This study investigates the complexation of selected 3d transition metals (Co(II), Ni(II), Cu(II)) and lanthanide(III) ions (Nd(III), Eu(III), Tb(III)) with cloxacillin (Clox) and dicloxacillin (Diclox) in aqueous solution. The investigation combines potentiometric titrations and spectroscopic methods to provide insight into the coordination behavior of these isoxazolylpenicillins. The results show that complex stability follows the order Co(II) ≈ Ni(II) < Cu(II) and increases along the lanthanide series (Nd(III) < Eu(III) < Tb(III)). Dicloxacillin, containing two chlorine substituents in the isoxazolyl ring, forms consistently more stable complexes than cloxacillin, indicating a noticeable effect of ligand substitution on metal binding. Speciation analysis indicates the formation of mono- and bis-ligand species at near-neutral pH and hydroxo-ligand complexes at higher pH. Spectroscopic data confirm coordination mainly via the deprotonated carboxylate group, with additional involvement of amide functionalities. The observed spectral changes are consistent with potentiometric models and indicate stronger interactions in dicloxacillin systems. These findings demonstrate that small structural differences between the ligands significantly affect metal binding and speciation, providing new insight into β-lactam-metal interactions.

The rapid emergence of methicillin-resistant and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) represents a major global health challenge, necessitating the development of new antibacterial scaffolds with improved efficacy and safety.

Impetigo is a superficial skin infection that most commonly affects children 2 to 5 years of age. In the United States, more than 3 million cases of impetigo occur annually. Impetigo can be nonbullous (70%) or bullous (30%) and is most commonly caused by group A streptococcus and Staphylococcus aureus. Diagnosis of impetigo is based primarily on clinical examination and should be suspected in individuals with erythematous papules that progress to ruptured vesicles or bullae over 4 to 6 days, forming honey-colored crusts. Risk factors for impetigo include disruptions to the skin barrier, poor hygiene, crowded living environments, living in hot and humid climates, malnutrition, and diabetes. Topical mupirocin 2% ointment or retapamulin 1% ointment are the recommended initial treatments for mild, nonbullous and bullous impetigo. Oral antibiotics, such as dicloxacillin or cephalexin, should be targeted to group A streptococci and S. aureus and are recommended for outbreaks to decrease infection transmission or for severe, multilesional disease that does not respond to topical therapy within 3 to 5 days. Reducing the spread and recurrence of impetigo includes good hand hygiene, thoroughly washing objects used by people with impetigo, and refraining from returning to work or school until 12 to 24 hours after initiating antibiotic treatment or clinical improvement occurs.

Recent years have seen a notable increase in the number of publications concerning pharmacokinetic drug-drug interactions involving the isoxazolyl penicillins cloxacillin, dicloxacillin, flucloxacillin and oxacillin. Given that the findings predominantly rely on clinical observations, the interaction mechanisms and their clinical relevance remain insufficiently elucidated, thereby posing challenges for clinicians in managing these interactions. The aim of this literature review was to provide an overview of all reported pharmacokinetic drug-drug interactions involving isoxazolyl penicillins and to evaluate the plausible interaction mechanisms. We systematically searched articles reporting potential pharmacokinetic drug-drug interactions involving isoxazolyl penicillins in humans up to November 2025 in Pubmed and Embase. The quality of the articles was assessed using a self-developed risk of bias assessment tool. A modified drug-drug interaction probability assessment tool was used to objectively evaluate the probability of the reported potential interactions. A total of 33 potential victim drugs were identified across 51 articles, comprising 24 case reports or case series, 16 retrospective cohort studies and 11 prospective or crossover studies. Most of the included studies report a decreased exposure and/or efficacy of drugs during concomitant treatment with isoxazolyl penicillins. Although pointing towards induction of cytochrome P450 enzymes, diphosphate-glucuronosyltransferase enzymes and P-glycoprotein as most plausible mechanism for most interactions, the exact interaction mechanisms could not be fully elucidated due to the quality of the study designs and heterogeneity in endpoints. Clinicians should be aware of a potential clinically relevant interaction when combining isoxazolyl penicillins with drugs with a small therapeutic window that undergo extensive metabolism.

Dicloxacillin and flucloxacillin are β-lactamase-resistant penicillin antibiotics that have been in clinical use for over 50 years. While both antibiotics are known to induce cytochrome P450 enzymes, there is limited information available regarding their interactions with drug transporters. Here, we investigated the in vitro transport and inhibition of hepatic organic anion transporting polypeptides (OATPs) and renal organic anion transporters (OATs) by these antibiotics in recombinant transporter overexpressing HEK293 cells. We also investigated the transport of these antibiotics by efflux transporters, as well as their inhibition of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) using a HEK293 membrane vesicle transport assay. Dicloxacillin and flucloxacillin inhibited rosuvastatin transport by OATP1B1, OATP1B3, and OATP2B1, and the inhibition was strongest for OATP1Bs with IC50 values of 3.9 and 31 μM (OATP1B1) and 6.7 and 21 μM (OATP1B3) for dicloxacillin and flucloxacillin, respectively. Both antibiotics also inhibited BCRP-mediated rosuvastatin transport with IC50 values of 166 μM (dicloxacillin) and 379 μM (flucloxacillin), while P-gp-mediated transport of N-methyl-quinidine was inhibited to a lesser extent. All OATPs and OATs transported dicloxacillin and flucloxacillin. Static model predictions indicated that the inhibition of OATPs, BCRP, and P-glycoprotein by both compounds may be clinically relevant. We further developed and verified physiologically based pharmacokinetic (PBPK) models for dicloxacillin and flucloxacillin. PBPK model simulations predicted no major change in rosuvastatin, a substrate for OATPs and BCRP, pharmacokinetics when co-administered with dicloxacillin or flucloxacillin. Simulations with dicloxacillin and P-gp substrates dabigatran or digoxin also predicted limited inhibition of P-gp transport.

The predominant resistance mechanism observed in Gram-negative bacteria involves the production of β-lactamases, which catalyse the hydrolysis of β-lactam antibiotics, thereby rendering them ineffective. Although Isoxazolyl Penicillins have been available since the 1970s, there are currently no structures in complex with class-A β-lactamases available. Here we have analysed the structure of the clinically relevant β-lactamase CTX-M-14 from Klebsiella pneumoniae near physiological temperatures, via serial synchrotron crystallography. We demonstrate the acyl-enzyme intermediates of the catalytically impaired CTX-M-14 mutant E166A in complex with three Isoxazolyl-Penicillins: Oxacillin, Cloxacillin and Dicloxacillin. Structural comparisons of CTX-M-Penicillin complexes show that, while conserved active-site interactions are maintained, each Isoxazolyl-Penicillin adopts a distinct conformation. While the three derivatives differ only by one and two chlorine atoms, respectively, their conformational heterogeneity appears to be increased by chlorination of the phenyl ring.

Dicloxacillin and flucloxacillin are β-lactamase-resistant penicillin antibiotics that have been in clinical use for over 50 years. While both antibiotics are known to induce cytochrome P450 enzymes, there is limited information available regarding their interactions with drug transporters. Here, we investigated the in vitro transport and inhibition of hepatic organic anion transporting polypeptides (OATPs) and renal organic anion transporters (OATs) by these antibiotics in recombinant transporter overexpressing HEK293 cells. We also investigated the transport of these antibiotics by efflux transporters, as well as their inhibition of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) using a HEK293 membrane vesicle transport assay. Dicloxacillin and flucloxacillin inhibited rosuvastatin transport by OATP1B1, OATP1B3 and OATP2B1, and the inhibition was strongest for OATP1Bs with IC50 values of 3.9 μM and 31 μM (OATP1B1) and 6.7 μM and 21 μM (OATP1B3) for dicloxacillin and flucloxacillin, respectively. Both antibiotics also inhibited BCRP-mediated rosuvastatin transport with IC50 values of 166 μM (dicloxacillin) and 379 μM (flucloxacillin), while P-gp-mediated transport of N-methyl-quinidine was inhibited to a lesser extent. All OATPs and OATs transported dicloxacillin and flucloxacillin. Static model predictions indicated that the inhibition of OATPs, BCRP and P-glycoprotein by both compounds may be clinically relevant. We further developed and verified physiologically based pharmacokinetic (PBPK) models for dicloxacillin and flucloxacillin. PBPK model simulations predicted no major change in rosuvastatin, a substrate for OATPs and BCRP, pharmacokinetics, when co-administered with dicloxacillin or flucloxacillin. Simulations with dicloxacillin and P-gp substrates dabigatran or digoxin also predicted limited inhibition of P-gp transport.

The Tepetitlán reservoir is the fourth largest in the State of Mexico and represents about 7 % of the national territory. This body of water suffers from contamination by sewage, agricultural waste, solid waste, and mining activities, in addition to the effects of deforestation. The objective of this study was to characterize the main contaminants present in the water of the Tepetitlán reservoir and to evaluate the toxicity produced on the oocytes and larvae of Danio rerio. In this study, six sites were selected; for each site, a physicochemical analysis was performed, and the concentrations of heavy metals and pharmaceuticals present were determined. Zebrafish embryos were exposed to the reservoir water, and embryonic development and malformations resulting from this exposure were analyzed at 12, 24, 48, 72, and 96 h post fertilization (hpf). Additionally, the oxidative damage generated at 96 hpf in all sampling sites and the expression of genes involved in the response to oxidative stress (sod, cat, nfe2l2a, nfe2l2b, cyp1a, baxa, casp3, casp6, casp7, and casp9) were evaluated. The physicochemical parameters were within Mexican regulation for all sampling sites, except true color and conductivity. The contaminants present in the reservoir included heavy metals such as arsenic (As), cadmium (Cd), copper (Cu), chromium (Cr), lead (Pb), and zinc (Zn), and pharmaceuticals such as dicloxacillin (DCX), sulfamethoxazole (SMX), metformin (MET), carbamazepine (CBZ), naproxen (NPX), paracetamol (PCT), and 17α-ethinylestradiol (EE2), at concentrations of μg L[-1]. The main malformations observed were the following: head malformation (13), body bleeding (20), general malformation (5), spinal deformation (65), yolk sac deformation (35), tail deformation (15), pericardial edema (20), developmental delay (108), and yolk sac edema (72). Lipid and protein damage, a decrease in antioxidant activity, and an increase in the expression of genes involved in antioxidant processes, detoxification, and apoptosis were also observed. The study reveals that this body of water poses a risk to aquatic organisms.

Inappropriate use of antibiotics plays a key role in increasing bacterial resistance. The aim was to determine the prescription patterns and approved and unapproved indications for the use of penicillins in a group of patients from Colombia. This was a cross-sectional study on the use of penicillins in outpatients. The subjects were identified from a population-based drug dispensing database. Approved and unapproved indications were determined from records of the Food and Drug Administration (FDA) of the United States and the National Institute of Food and Drug Surveillance (INVIMA) of Colombia. Descriptive and multivariate analyses were performed. A total of 137,070 patients were identified; the average age was 35.8 ± 23.5 years, and 56.2 % were women. Amoxicillin (73.4 %), dicloxacillin (11.7 %) and sultamicillin (6.0 %) were the most prescribed penicillins, mainly for upper respiratory tract infections (43.0 %). In 68.9 % cases, penicillins were used for approved indications, especially to treat Helicobacter pylori (17.3 %). In 31.1 % of cases, penicillin prescriptions were used for unapproved indications (acute rhinopharyngitis: 8.1 %). Patients with skin and soft tissue infections (aOR = 2.82; 95 % CI 2.57‒3.09), with lower respiratory tract infections (aOR = 2.02; 95 % CI 1.89‒2.16), and those treated with dicloxacillin (aOR = 2.84; 95 % CI 2.07‒3.89) were more likely to be prescribed penicillins for unapproved indications. Amoxicillin was the most widely used penicillin in outpatients. Penicillins were frequently used for unapproved indications not recommended by drug regulatory agencies.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous reactions with mortality rates strongly correlated with disease severity. We report the case of a 47-year-old Mestizo man in Nicaragua with penicillin-induced SJS/TEN overlap syndrome (body surface area involvement: 10%-30%, score of toxic epidermal necrolysis, SCORTEN: 4, and predicted mortality: 58%). The patient developed mucosal erosions, hemorrhagic crusting, and disseminated erythematous plaques following exposure to amoxicillin and dicloxacillin (penicillin-class antibiotics). Initial misdiagnoses delayed care, but hospitalization prompted early intravenous dexamethasone, fluid resuscitation, topical corticosteroids, and immediate discontinuation of the offending agents. Epidermal detachment halted within 72 hours, with complete reepithelialization by day 10. Transient hyperglycemia resolved spontaneously, and the patient survived without infections or sequelae, contrasting with the SCORTEN-predicted mortality. This outcome supports early immunomodulation to mitigate cytokine-driven necroptosis, challenging historical concerns about corticosteroid risks. Limitations include the single-case design, absence of histopathology, and lack of human leukocyte antigen allele screening for pharmacogenomic insights. The case underscores the efficacy of prompt corticosteroids in high-risk SJS/TEN linked to penicillin-class drugs, emphasizing drug-specific vigilance and discontinuation. It highlights the need for population-specific SCORTEN calibration, pharmacogenomic integration, and publication of rare cases to enhance regional epidemiological understanding.

This research work comprises the computational analysis of natural compounds from Calotropis procera analyzed on the basis of their wound healing properties. 3D Quantitative structure activity relationship (QSAR) models were generated with statistical validation which was followed by leading compound candidates. This analytical technique was carried out for the evaluation of active compounds by correlation of structural parameters. Previously isolated natural compounds were selected on the basis of their in-vivo and in-vitro studies. After 3D-QSAR analysis, molecular docking procedure was performed on the active compounds against wound healing proteins (PDB: 6SMA, 5A8Y) and their binding scores were analyzed for the evaluation of binding interaction of Protein-Ligand complexes. Comparative analysis was also carried out by comparing the docking results of natural compounds and FDA approved antibiotics Cephalexin, Dicloxacillin, and Levofloxacin. After docking, Re-docking was also performed as an additional cross analysis technique for validation of the docking results. DFT study was carried out to reveal molecular activity by evaluation of quantum molecular properties. Hence, results revealed that Stigmasterol (12) is hit compound with better results than standard drugs Cephalexin and Levofloxacin. These derived results in this study provide significant information for wound healer drug-designing by using Stigmtasterol as natural compound having better wound healing property. The analysis suggested that the proposed hit compound exhibits the potential drug attribute, which indicates the suitability for future investigation to help treat the serious wounds or injuries.