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Based on in vitro synergy studies, the addition of nafcillin to daptomycin was used to treat refractory methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Daptomycin is a de facto cationic antimicrobial peptide in vivo, with antistaphylococcal mechanisms reminiscent of innate host defense peptides (HDPs). In this study, the effects of nafcillin on HDP activity against MRSA were examined in vitro and in vivo. Exposures to β-lactam antimicrobials in general, and nafcillin in particular, significantly increased killing of S. aureus by selected HDPs from keratinocytes, neutrophils, and platelets. This finding correlated with enhanced killing of MRSA by whole blood, neutrophils, and keratinocytes after growth in nafcillin. Finally, nafcillin pretreatment ex vivo reduced MRSA virulence in a murine subcutaneous infection model. Despite the lack of direct activity against MRSA, these studies show potent, consistent, and generalized nafcillin-mediated “sensitization” to increased killing of MRSA by various components of the innate host response. The use of nafcillin as adjunctive therapy in MRSA bacteremia merits further study and should be considered in cases refractory to standard therapy. Key messages Nafcillin has been used as adjunctive therapy to clear persistent MRSA bacteremia. Nafcillin enhances killing of MRSA by a cadre of innate host defense peptides. Nafcillin increases binding of human cathelicidin LL-37 to the MRSA membrane. Nafcillin enhances killing of MRSA by neutrophils. Nafcillin reduces virulence of MRSA in a murine subcutaneous infection model.

Infection leading to necrosis of any bone can lead to chronic osteomyelitis (CO), sometimes resulting in permanent orthopedic sequelae. There are no published guidelines on the optimal management of adult or pediatric CO The objective of this study was to analyze published evidence for the epidemiology and management of pediatric CO. Inclusion criteria were studies of any design (minimum 2 patients) in any language that included patients with CO up to 17 years of age and described the epidemiology or management of CO. Ovid Medline(R) ALL, Embase (via Ovid), CINAHL Plus with Full Text (via EBSCOhost) and Scopus were screened Jan 1, 1989 to Feb 13, 2025. Quality assessment was based on the degree of bias if one were to use that study to make decisions about management of CO. Studies were divided into those from middle-high and high-income countries versus studies from lower income countries. Data were extracted on demographics, biomarkers, pathogens, treatments offered, recurrences and orthopedic sequelae. There were 41 included studies - 26 from middle-high- and high-income countries (904 cases total) and 15 from lower income countries (975 cases total). All were observational and only 19 of the 41 studies reported 7 or 8 of the 8 items deemed essential to make decisions about management of CO. Definitions of CO varied markedly. Analyzing the 17 studies that included a minimum of 10 consecutive cases, 627 of 1073 cases (58%) occurred in males. In these 17 studies, the tibia or femur accounted for 630 of 934 cases (67%). In 212 of 287 cases (74%) with a single pathogen reported, that pathogen was Staphylococcus aureus. There were no apparent differences in sex, bones involved or pathogens by country income level. Most cases (with the notable exception of those in recent case series from the United States) were managed with debridement. This was typically followed by sequential intravenous/per os (IV/ PO) antibiotics with almost no patients managed with PO antibiotics alone. Twelve case series reported use of local antibiotic delivery in addition to systemic antibiotics, but none of these studies had a control group. Studies were too heterogeneous in design to allow for data to be directly compared or combined. However, there was no obvious relationship between the route or duration of antimicrobials and the incidence of recurrences or orthopedic sequalae. There is a great need for high quality studies of all aspects of diagnosis and treatment of CO. Empiric coverage should target S. aureus. The evidence is poor quality, but there is no evidence that prolonged courses of antibiotics prevent recurrences.

Infection leading to necrosis of any bone can lead to chronic osteomyelitis (CO), sometimes resulting in permanent orthopedic sequelae. There are no published guidelines on the optimal management of adult or pediatric CO The objective of this study was to analyze published evidence for the epidemiology and management of pediatric CO. Inclusion criteria were studies of any design (minimum 2 patients) in any language that included patients with CO up to 17 years of age and described the epidemiology or management of CO. Ovid Medline(R) ALL, Embase (via Ovid), CINAHL Plus with Full Text (via EBSCOhost) and Scopus were screened Jan 1, 1989 to Feb 13, 2025. Quality assessment was based on the degree of bias if one were to use that study to make decisions about management of CO. Studies were divided into those from middle-high and high-income countries versus studies from lower income countries. Data were extracted on demographics, biomarkers, pathogens, treatments offered, recurrences and orthopedic sequelae. There were 41 included studies - 26 from middle-high- and high-income countries (904 cases total) and 15 from lower income countries (975 cases total). All were observational and only 19 of the 41 studies reported 7 or 8 of the 8 items deemed essential to make decisions about management of CO. Definitions of CO varied markedly. Analyzing the 17 studies that included a minimum of 10 consecutive cases, 627 of 1073 cases (58%) occurred in males. In these 17 studies, the tibia or femur accounted for 630 of 934 cases (67%). In 212 of 287 cases (74%) with a single pathogen reported, that pathogen was Staphylococcus aureus. There were no apparent differences in sex, bones involved or pathogens by country income level. Most cases (with the notable exception of those in recent case series from the United States) were managed with debridement. This was typically followed by sequential intravenous/per os (IV/ PO) antibiotics with almost no patients managed with PO antibiotics alone. Twelve case series reported use of local antibiotic delivery in addition to systemic antibiotics, but none of these studies had a control group. Studies were too heterogeneous in design to allow for data to be directly compared or combined. However, there was no obvious relationship between the route or duration of antimicrobials and the incidence of recurrences or orthopedic sequalae. There is a great need for high quality studies of all aspects of diagnosis and treatment of CO. Empiric coverage should target S. aureus. The evidence is poor quality, but there is no evidence that prolonged courses of antibiotics prevent recurrences.

Salmonella Typhimurium is an invasive intracellular pathogen that employs various factors for its survival within host cells. To mitigate S . Typhimurium survival, it is crucial to identify factors that influence bacterial survival and to develop drugs that inhibit these factors. In this study, we investigated the effects of nafcillin and diosmin, both of which have been identified as inhibitors of Lon protease, on the intracellular survival of S . Typhimurium and its survival under various stress conditions. Additionally, we examined the expression of genes associated with the type II toxin-antitoxin system to enhance our understanding of the impact of these systems on the bacterium’s survival. Our findings indicate that while nafcillin and diosmin did not affect S . Typhimurium attachment, they significantly reduced bacterial intracellular survival, particularly in Hep2 cells after 16 h. These inhibitors were also effective in decreasing bacterial survival under oxidative and acidic stress conditions. Furthermore, gene expression analysis revealed that although there were variations in the expression of TA system genes in S . Typhimurium across different cell lines, the relEB system emerged as the most effective among those studied, exhibiting the highest increase in expression. This study highlights the efficacy of nafcillin and diosmin in reducing the intracellular survival of S . Typhimurium as well as its survival under stress conditions. These findings suggest potential new strategies for developing therapies aimed at preventing S . Typhimurium infections.

Background. Nafcillin and cefazolin are considered first-line therapy for most infections with methicillin-susceptible Staphylococcus aureus (MSSA), and recent studies have suggested similar clinical efficacy. Limited data are available on the comparative tolerability of these agents. Methods. In this retrospective cohort analysis of patients treated with either nafcillin or cefazolin for MSSA infection in the outpatient parenteral antimicrobial therapy clinic at Massachusetts General Hospital from 2007 to 2011, the frequency of premature antimicrobial discontinuation (PAD) and drug-emergent events (DEEs) was calculated. Results. Three hundred sixty-six and 119 patients were treated with nafcillin or cefazolin, respectively. The median anticipated duration of therapy was comparable at 28 (interquartile range [IQR], 16–37) and 29 (IQR, 24–39) days, respectively, for those treated with nafcillin and cefazolin. Fewer patients completed the prespecified treatment course with nafcillin than with cefazolin (PAD rate, 33.8% vs 6.7%; P < .0001). The hazard ratio for PAD in the nafcillin vs cefazolin groups was 2.81 (95% confidence interval [CI], 1.26–3.68). More patients in the nafcillin group developed rash (13.9% vs 4.2%; P = .002), renal dysfunction (11.4% vs 3.3%; P = .006), and liver function abnormalities (8.1% vs 1.6%; P = .01). Overall rates of DEEs per 1000 patient-days were 16.9 (95% CI, 10.4–27.3) and 4.8 (95% CI, 1.1–10.2), respectively. In 9 cases of nafcillin discontinuation, treatment was changed to cefazolin; all 9 completed treatment with no further observed DEEs. Conclusions. Nafcillin treatment was associated with higher rates of both PAD as well as DEEs compared with cefazolin treatment. This difference in tolerability, in addition to efficacy and cost, should be considered when decisions for outpatient parenteral MSSA treatment are made.

Background The high prevalence of methicillin-resistant S. aureus (MRSA) has led clinicians to select antibiotics that have coverage against MRSA, usually vancomycin, for empiric therapy for suspected staphylococcal infections. Clinicians often continue vancomycin started empirically even when methicillin-susceptible S. aureus (MSSA) strains are identified by culture. However, vancomycin has been associated with poor outcomes such as nephrotoxicity, persistent bacteremia and treatment failure. The objective of this study was to compare the effectiveness of vancomycin versus the beta-lactam antibiotics nafcillin and cefazolin among patients with MSSA bacteremia. The outcome of interest for this study was 30-day in-hospital mortality. Methods This retrospective cohort study included all adult in-patients admitted to a tertiary-care facility between January 1, 2003 and June 30, 2007 who had a positive blood culture for MSSA and received nafcillin, cefazolin or vancomycin. Cox proportional hazard models were used to assess independent mortality hazards comparing nafcillin or cefazolin versus vancomycin. Similar methods were used to estimate the survival benefits of switching from vancomycin to nafcillin or cefazolin versus leaving patients on vancomycin. Each model included statistical adjustment using propensity scores which contained variables associated with an increased propensity to receive vancomycin. Results 267 patients were included; 14% (38/267) received nafcillin or cefazolin, 51% (135/267) received both vancomycin and either nafcillin or cefazolin, and 35% (94/267) received vancomycin. Thirty (11%) died within 30 days. Those receiving nafcillin or cefazolin had 79% lower mortality hazards compared with those who received vancomycin alone (adjusted hazard ratio (HR): 0.21; 95% confidence interval (CI): 0.09, 0.47). Among the 122 patients who initially received vancomycin empirically, those who were switched to nafcillin or cefazolin (66/122) had 69% lower mortality hazards (adjusted HR: 0.31; 95% CI: 0.10, 0.95) compared to those who remained on vancomycin. Conclusions Receipt of nafcillin or cefazolin was protective against mortality compared to vancomycin even when therapy was altered after culture results identified MSSA. Convenience of vancomycin dosing may not outweigh the potential benefits of nafcillin or cefazolin in the treatment of MSSA bacteremia.

Objective The foodborne pathogen Salmonella enterica serovar Typhimurium causes self-limiting gastroenteritis in humans and is difficult to eliminate due to its ability to adhere to surfaces and form biofilms that exhibit high resistance to antimicrobial agents. To explore alternative strategies for biofilm treatment, it is essential to investigate novel agents that inhibit Salmonella biofilms. Method In this study, we investigated the minimum biofilm inhibitory concentrations (MBICs) and minimum biofilm eradication concentrations (MBECs) of nafcillin and diosmin, both previously identified as Lon protease inhibitors, against biofilms formed by S . Typhimurium. Furthermore, we examined the expression of genes associated with the type II toxin-antitoxin system to enhance our understanding of the impact of these inhibitors. Results The findings indicated a strong antibiofilm effect of nafcillin, with MBIC and MBEC values of 8 µg/mL and 32 µg/mL, respectively. These results were confirmed by field emission scanning electron microscopy (FE-SEM), which showed that biofilm formation was reduced in the presence of nafcillin. Additionally, it revealed morphological changes in the bacteria within the nafcillin-treated biofilms. Furthermore, gene expression analyses demonstrated a significant reduction in the expression of type II TA system genes following treatment with nafcillin and diosmin. Conclusion This study highlights the effectiveness of nafcillin in disrupting the biofilms of S . Typhimurium. These results suggest promising avenues for the development of novel therapeutic strategies targeting biofilms associated with S . Typhimurium.

The foodborne pathogen Salmonella enterica serovar Typhimurium causes self-limiting gastroenteritis in humans and is difficult to eliminate due to its ability to adhere to surfaces and form biofilms that exhibit high resistance to antimicrobial agents. To explore alternative strategies for biofilm treatment, it is essential to investigate novel agents that inhibit Salmonella biofilms. In this study, we investigated the minimum biofilm inhibitory concentrations (MBICs) and minimum biofilm eradication concentrations (MBECs) of nafcillin and diosmin, both previously identified as Lon protease inhibitors, against biofilms formed by S. Typhimurium. Furthermore, we examined the expression of genes associated with the type II toxin-antitoxin system to enhance our understanding of the impact of these inhibitors. The findings indicated a strong antibiofilm effect of nafcillin, with MBIC and MBEC values of 8 µg/mL and 32 µg/mL, respectively. These results were confirmed by field emission scanning electron microscopy (FE-SEM), which showed that biofilm formation was reduced in the presence of nafcillin. Additionally, it revealed morphological changes in the bacteria within the nafcillin-treated biofilms. Furthermore, gene expression analyses demonstrated a significant reduction in the expression of type II TA system genes following treatment with nafcillin and diosmin. This study highlights the effectiveness of nafcillin in disrupting the biofilms of S. Typhimurium. These results suggest promising avenues for the development of novel therapeutic strategies targeting biofilms associated with S. Typhimurium.