Skin and soft tissues infections (SSTIs) are common conditions, affecting millions worldwide. SSTIs range from uncomplicated cellulitis to necrotizing fasciitis and can be divided into non-purulent and purulent forms. Non-purulent SSTI is most commonly associated with beta-haemolytic streptococci, while purulent SSTI is typically associated with Staphylococcus aureus Cellulitis most commonly presents with acute warmth, pain, tenderness to palpation, erythema, and oedema. Skin abscess typically presents with a fluctuant tender area with erythema. Laboratory testing is of limited use in most patients. Point-of-care ultrasound is useful for distinguishing cellulitis from abscess if the diagnosis is unclear. Management of SSTI includes antibiotics such as penicillin VK, dicloxacillin, or a cephalosporin, while treatment for skin abscess includes incision and drainage, with antibiotics recommended in select patients. Patients should elevate the affected extremity when possible, and non-steroidal anti-inflammatory drugs may reduce pain and inflammation. The effectiveness of decolonization for patients with recurrent cellulitis or skin abscess is controversial. While most patients with cellulitis or skin abscess are appropriate for discharge with follow-up, patients with sepsis and those with challenges adhering to therapy, immunosuppression, or failed outpatient therapy should be referred to the emergency department. Novel antibiotics such as tedizolid, delafloxacin, omadacycline, and ceftaroline may be considered in select cases.

Dicloxacillin is an oral, second generation penicillin antibiotic that is used to treat bacterial infections caused by penicillinase-resistant staphylococci. Dicloxacillin has been linked to rare instances of clinically apparent, idiosyncratic liver injury.

Three major penicillinase-resistant penicillins are available in the United States: dicloxacillin (dye klox" a sil' in), oxacillin (ox" a sil' in) and nafcillin (naf sil' in). Dicloxacillin is orally available; oxacillin and nafcillin have both oral and parenteral formulations, the latter being given by the intramuscular or intravenous route. Other formulations available abroad or in the past include methicillin, cloxacillin and flucloxacillin, which have been associated with a higher frequency of side effects including hepatic injury. The major indications for dicloxacillin, oxacillin and nafcillin are moderate-to-serious infections with susceptible penicillinase-producing staphylococci; these agents are also active against organisms susceptible to natural penicillins, but are less active than the natural penicillins.

Dicloxacillin is a penicillinase-resistant beta-lactam antibiotic and potent activator of the Pregnane X receptor (PXR), known to induce CYP2C9, CYP2C19, and CYP3A4 activity. Clinical data suggest it reduces anticoagulation in warfarin-treated patients and increases the risk of thromboembolic events. This open-label, sequential drug-drug interaction study quantitatively evaluated the effect of dicloxacillin on the pharmacokinetics of warfarin and phenytoin, two prototype CYP2C9 substrates with narrow therapeutic indices, and possible impact of CYP2C9 polymorphisms on the extent of this interaction. Twenty-eight healthy non-smoker subjects, 15 carriers of CYP2C9*1/*1, and 13 carriers of a single CYP2C9*2 or CYP2C9*3 allele, received single doses of warfarin (20 mg) and 1 week later, phenytoin (300 mg) before and during a 21-day course of dicloxacillin 500 mg four times daily. Plasma concentration of warfarin enantiomers and phenytoin and urine concentration of p-HPPH were measured using validated HPLC methods. Warfarin pharmacodynamics was monitored via serial INR measurements for up to 120 hours. Dicloxacillin increased oral clearance of (S)-warfarin and (R)-warfarin by 53.2% and 63.2%, respectively (P < 0.001). The area under the INR-time curve decreased by 15.5% (P < 0.001). Phenytoin oral clearance and p-HPPH formation clearance increased by 42.4% and 40.5%, respectively (P < 0.001). CYP2C9 induction was significantly greater in carriers of CYP2C9*1/*1 genotype and INR reduction was more pronounced among VKORC1 AA haplotype carriers. Dicloxacillin substantially induces the metabolism of warfarin and phenytoin. Whenever dicloxacillin is initiated, the dose of CYP2C9 substrates characterized by a narrow therapeutic window should be increased and drug levels and/or pharmacodynamic response should be closely monitored.

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.

In February, 2023, an outbreak of Enterobacter hormaechei ST79 carrying blaNDM-5 and blaOXA-48 was linked to contaminated dicloxacillin capsules administered to approximately 79 000 individuals in Denmark. Initial clonal outbreak investigations identified 11 patients with the E hormaechei ST79 outbreak strain, which carried blaNDM-5 on a distinct IncX3 plasmid, and in nine cases, blaOXA-48 was on a distinct IncL plasmid. Interspecies plasmid transfer was observed in one patient, suggesting a potential plasmid-mediated outbreak involving other Enterobacterales. However, no studies have characterised the progression of a clonal outbreak originating from a contaminated medicine into plasmid-mediated dissemination of carbapenemase genes. Hence, we aimed to characterise the clonal and plasmid-mediated spread of carbapenemase genes in this outbreak.

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.