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Although widely used, cefazolin efficacy for the treatment of meticillin-susceptible Staphylococcus aureus (MSSA) bacteraemia has not thus far been investigated in a clinical trial. In this study, we aimed to compare the efficacy and safety of cefazolin with that of cloxacillin in patients with MSSA bacteraemia. We conducted an open-label, non-inferiority, randomised clinical trial in 21 university and non-university hospitals in France in adults (aged ≥18 years) with MSSA bacteraemia, without intravascular implant or suspicion of CNS infection. Participants were randomly assigned (1:1) to receive intravenously cefazolin (25–50 mg/kg every 8 h) or cloxacillin (25–50 mg/kg every 4–6 h) for the first 7 days of therapy using computer-generated blocks of various sizes and stratification on vascular-access associated bacteraemia and centre. Subsequent treatment was left to the choice of the investigator (total duration ≥14 days). The primary endpoint was a composite of sterile blood cultures at day 3 (day 5 for endocarditis) without relapse of bacteraemia, survival, and clinical success at day 90, and was assessed in the intention-to-treat population. A non-inferiority margin of 12% was chosen. This trial is registered on ClinicalTrials.gov (NCT03248063) and is complete. Between Sept 5, 2018, and Nov 16, 2023, 315 participants were enrolled and assigned to cefazolin (n=158) or cloxacillin (n=157); 12 participants were excluded from analysis in the cefazolin group, and 11 in the cloxacillin group (final population of 146 in each group). Mean age was 62·7 years (SD 16·4), 215 (74%) participants were male, and race or ethnicity data were not collected. Median Pitt score was 0 (IQR 0–0). The primary endpoint was met in 109 (75%) of 146 participants in the cefazolin group versus 108 (74%) of 146 participants in the cloxacillin group (treatment difference –1%; 95% CI –11 to 9; p=0·012). At the end of study treatment, 22 (15%) of 146 participants assigned to cefazolin and 40 (27%) of 146 participants assigned to cloxacillin had had a serious adverse event (p=0·010). Acute kidney injury occurred more frequently in participants assigned to cloxacillin (15 [12%] of 128) than in those assigned to cefazolin (one [1%] of 134; p=0·0002). Cefazolin constitutes an alternative to cloxacillin for the treatment of MSSA bacteraemia, offering non-inferior clinical efficacy and potentially enhanced tolerability. French Ministry of Health.

In this work, applications of nanohybrid composites based on titanium dioxide (TiO[sub.2]) with anatase crystallin phase and single-walled carbon nanohorns (SWCNHs) as promising catalysts for the photodegradation of amoxicillin (AMOX) are reported. In this order, TiO[sub.2]/SWCNH composites were prepared by the solid-state interaction of the two chemical compounds. The increase in the SWCNH concentration in the TiO[sub.2]/SWCNH composite mass, from 1 wt.% to 5 wt.% and 10 wt.% induces (i) a change in the relative intensity ratio of the Raman lines located at 145 and 1595 cm[sup.−1], which are attributed to the E[sub.g](1) vibrational mode of TiO[sub.2] and the graphitic structure of SWCNHs; and (ii) a gradual increase in the IR band absorbance at 1735 cm[sup.−1] because of the formation of new carboxylic groups on the SWCNHs’ surface. The best photocatalytic properties were obtained for the TiO[sub.2]/SWCNH composite with a SWCNH concentration of 5 wt.%, when approx. 92.4% of AMOX removal was achieved after 90 min of UV irradiation. The TiO[sub.2]/SWCNH composite is a more efficient catalyst in AMOX photodegradation than TiO[sub.2] as a consequence of the SWCNHs’ presence, which acts as a capture agent for the photogenerated electrons of TiO[sub.2] hindering the electron–hole recombination. The high stability of the TiO[sub.2]/SWCNH composite with a SWCNH concentration of 5 wt.% is proved by the reusing of the catalyst in six photodegradation cycles of the 98.5 μM AMOX solution, when the efficiency decreases from 92.4% up to 78%.

A method was developed for the isolation of geranyl acetate from the crude essential oil (EO) of Melaleuca armillaris (Sol. ex Gaertn.) Sm. leaves, and the purity of the isolated compound was analyzed by GC/MS spectral and NMR analysis and was found to have high purity (98.9%). In addition, the EO isolated presented 0.907 g/cm[sup.3], 1.474 and [α][sub.D] [sup.20]=−17.6 of density, refraction index and optical rotation, respectively. The chemical composition of the EO obtained for steam distillation from M. armillaris was analyzed by gas chromatographic and spectroscopic techniques (GC/MS and GC/FID). Thirty-eight compounds were identified, representing 99.92% of the total EO analyzed on a DB-5 ms (5% phenylmethylpolysiloxane) capillary column. This analysis showed that the EO consisted mainly of oxygenated monoterpenes (77.01%), followed by monoterpene hydrocarbons (21.31%) and sesquiterpene hydrocarbons (1.31%). Furthermore, the essential oil of M. armillaris was rich in 1,8-cineol (67 ± 2%), followed by limonene (10 ± 1%), α-Terpineol (9 ± 1%) and α-Pinene (5 ± 1%). Finally, the results suggest that the geranyl acetate isolated with high purity from crude essential oil is recommended to be explored as a component in medicinal or industrial use.

Background The evidence supporting rifampin combination therapy in prosthetic joint infections (PJI) is limited due to the lack of controlled studies. The aim of this study is to evaluate the effect of adding rifampin to conventional antimicrobial therapy in early staphylococcal PJIs treated with debridement and retention of the implant (DAIR). Methods In this multicenter randomized controlled trial, 99 patients with PJI after hip and knee arthroplasties were enrolled. They were randomly assigned to receive rifampin or not in addition to standard antimicrobial treatment with cloxacillin or vancomycin in case of methicillin resistance. The primary endpoint was no signs of infection after 2 years of follow-up. Results Forty-eight patients were included in the final analyses. There were no differences in patient characteristics or comorbidities between the two groups. There was no significant difference in remission rate between the rifampin combination group (17 of 23 (74%)) and the monotherapy group (18 of 25 (72%), relative risk 1.03, 95% confidence interval 0.73 to 1.45, p = 0.88). Conclusion This trial has not proven a statistically significant advantage by adding rifampin to standard antibiotic treatment in acute staphylococcal PJIs. Trial registration The Regional Ethics Committee and the Norwegian Medicines Agency approved the study (EudraCT 2005-005494-29), and the study was registered at ClinicalTrials.gov at Jan 18, 2007 ( NCT00423982 ).

Background Mastitis is one of the most costly diseases in Mediterranean buffalo (MB). At present, just a few specific antibiotics registered for this dairy specie have been synthetized. Efficacy of an antibiotic dry buffalo therapy (aDBT) against Staphylococcus aureus ( S. aureus ) mastitis, based on intra-quarter administration of 600 mg of benzathine cloxacillin, have been evaluated for the first time. Eighty MB’s quarters received a drying-off therapy (aDBT-group) and 80 were left untreated (no-aDBT-group). They were sampled at drying-off (pre-treatment) and at the resumption of milking [< 10 days in milk (DIM)]. Fresh calver mastitis rate , dry period new mastitis rate , dry period cure rate , and persistent mastitis rate were calculated for clinical monitoring. Overall proportion of positive quarters/animals, quarters affected by mastitis or intramammary infections (IMI), effects on somatic cell count (SCC) and milk yield were also assessed. Results An inter-group difference (aDBT vs. no-aDBT) was recorded for all the indexes considered. An intra-group (drying-off vs. < 10 DIM) difference was detected in aDBT-group regarding the proportion of positive-cultured quarters and animals. Concerning the latter, an inter-groups difference was also recorded at second sampling. No clinical mastitis due to the S. aureus was observed. Regarding the subclinical ones, a higher intra-group difference was observed in aDBT than no-aDBT group, while an inter-group difference was recorded at second sampling. No protective effect was observed against IMI. SCC showed an inter-group difference at second sampling, while none difference was instead detected for milk yield. Conclusions The effects against S. aureus mastitis of benzathine cloxacillin administration at drying-off were assessed for the first time in MB. Its use shows encouraging results in reducing the proportion of mastitis and positive animals at the resumption of the lactation.

PurposeTo compare the effectiveness and safety of cefazolin versus cloxacillin for the treatment of infective endocarditis (IE) due to methicillin-sensitive Staphylococci (MSS).MethodsData were retrospectively collected on patients treated for a definite MSS endocarditis who received cefazolin or cloxacillin for at least 10 consecutive days in six French hospitals between January-1 2014 and December-31 2020. The primary endpoint was treatment failure defined as a composite of death within 90 days of starting antibiotherapy, or embolic event during antibiotherapy, or relapse of IE within 90 days of stopping antibiotherapy. We used Cox regression adjusted for the inverse probability of treatment weighting of receiving cefazolin.Results192 patients were included (median age 67.8 years). IE was caused by S.aureus in 175 (91.1%) and by coagulase-negative staphylococci in 17 (8.9%). Ninety-four patients (48.9%) received cefazolin, and 98 (51%) received cloxacillin. 34 patients (34.7%) with cefazolin and 26 (27.7%) with cloxacillin met the composite primary endpoint, with no significant differences between groups (adjusted HR = 1.13, 95% CI 0.63 to 2.03). There were no significant differences in secondary efficacy endpoints or biological safety events.ConclusionThe effectiveness of cefazolin did not significantly differ from cloxacillin for the treatment of MSS endocarditis.

Treatment failure occurs in about 25% of patients with methicillin-susceptible Staphylococcus   aureus (MSSA) bacteremia. We assessed whether cloxacillin plus fosfomycin achieves better treatment success than cloxacillin alone in hospitalized adults with MSSA bacteremia. We conducted a multicenter, open-label, phase III–IV superiority randomized clinical trial. We randomly assigned patients (1:1) to receive 2 g of intravenous cloxacillin alone every 4 h or with 3 g of intravenous fosfomycin every 6 h for the initial 7 days. The primary endpoint was treatment success at day 7, a composite endpoint with the following criteria: patient alive, stable or with improved quick Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA, adjudicated by an independent committee blinded to treatment allocation. We randomized 215 patients, of whom 105 received cloxacillin plus fosfomycin and 110 received cloxacillin alone. We analyzed the primary endpoint with the intention-to-treat approach in 214 patients who received at least 1 day of treatment. Treatment success at day 7 after randomization was achieved in 83 (79.8%) of 104 patients receiving combination treatment versus 82 (74.5%) of 110 patients receiving monotherapy (risk difference 5.3%; 95% confidence interval (CI), –5.95–16.48). Secondary endpoints, including mortality and adverse events, were similar in the two groups except for persistent bacteremia at day 3, which was less common in the combination arm. In a prespecified interim analysis, the independent committee recommended stopping recruitment for futility prior to meeting the planned randomization of 366 patients. Cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in MSSA bacteremia. Further trials should consider the intrinsic heterogeneity of the infection by using a more personalized approach. ClinicalTrials.gov registration: NCT03959345 . New treatments are essential for methicillin-susceptible Staphylococcus   aureus bacteremia, but progress is slow. In this phase III–IV trial, cloxacillin plus fosfomycin failed to show superiority over cloxacillin alone, underscoring the challenges to improving patient outcomes.

Introduction The co-existence of malaria with bacterial infections is common in the tropics, hence the concurrent use of antimalarials and antibiotics. Objective This study aimed to investigate the effect on pharmacokinetics and antimicrobial activity of co-administration of quinine and combined ampicillin–cloxacillin. Methods In total, 14 healthy adults received single oral doses of ampicillin–cloxacillin combination alone and with quinine in a randomized crossover manner. Urine samples collected at predetermined intervals over 48 h were analysed. The effect of quinine on minimum inhibitory concentrations (MICs) of ampicillin and cloxacillin were determined against Staphylococcus aureus by agar diffusion, agar dilution, and broth dilution. Results Quinine significantly reduced the rate and extent of excretion of ampicillin and cloxacillin ( p  < 0.0002). The total amounts of ampicillin and cloxacillin excreted unchanged (Du ∞ ) alone were 217.10 ± 53.82 and 199.0 ± 64.29 mg versus 126.40 ± 50.63 and 135.20 ± 52.24 mg, respectively, with quinine. Respective maximum excretion rates (dDu/d t max ) for ampicillin and cloxacillin were 43.55 ± 19.41 and 77.64 ± 29.65 mg/h alone versus 18.01 ± 8.52 and 53.16 ± 20.72 mg/h with quinine. This indicates a significant reduction in Du ∞ and dDu/d t max by 41.78 and 58.65 % for ampicillin and 32.06 and 31.53 % for cloxacillin. Conversely, the disposition of quinine was unaffected by ampicillin–cloxacillin ( p  > 0.1). The MIC of antibiotics alone versus with quinine, respectively, were 0.11 ± 0.04 and 0.78 ± 0.1 µg/ml for ampicillin, and 0.18 ± 0.1 and 0.92 ± 0.4 µg/ml for cloxacillin, with a five- to sevenfold increase ( p  > 0.01); indicating a decrease in antimicrobial activity by quinine. Conclusions Quinine therefore, reduced the bioavailability and the antimicrobial activity of ampicillin–cloxacillin upon co-administration, which may have therapeutic implications. Caution is required with the co-administration of these medicines.

Staphylococcus epidermidis is a widely prevalent microorganism whose key virulence factors include a high ability to adhere to synthetic surfaces and the capacity to form biofilms. The widespread distribution of multidrug-resistant strains (e.g., MRSE—methycillin-resistant Staphylococcus epidermidis) compels researchers to explore new therapeutic approaches. Cinnamic acid and its derivatives are common plant-derived compounds known for their broad range of biological activities, including antimicrobial properties. The phenotypic assays conducted in this study revealed a strong anti-biofilm activity of the investigated compounds. Confocal laser scanning microscopy allowed for the visualization of structural changes within the biofilm and facilitated the assessment of bacterial cell viability in relation to the concentration of the tested substances.

Streptococcus uberis frequently causes bovine mastitis, an infectious udder disease with significant economic implications for dairy cows. Conventional antibiotics, such as cloxacillin, sometimes have limited success in eliminating S. uberis as a stand-alone therapy. To address this challenge, the study objective was to investigate the VersaTile engineered endolysin NC5 as a supplemental therapy to cloxacillin in a mouse model of bovine S. uberis mastitis. NC5 was previously selected based on its intracellular killing and biofilm eradicating activity. To deliver preclinical proof-of-concept of this supplemental strategy, lactating mice were intramammarily infected with a bovine S. uberis field isolate and subsequently treated with cloxacillin (30.0 μg) combined with either a low (23.5 μg) or high (235.0 μg) dose of NC5. An antibiotic monotherapy group, as well as placebo treatment, was included as controls. Two types of responders were identified: fast ( n = 17), showing response after 4-h treatment, and slow ( n = 10), exhibiting no clear response at 4 h post-treatment across all groups. The high-dose combination therapy in comparison with placebo treatment impacted the hallmarks of mastitis in the fast responders by reducing (i) the bacterial load 13,000-fold (4.11 ± 0.78 Δlog 10 ; p < 0.001), (ii) neutrophil infiltration 5.7-fold ( p > 0.05), and (iii) the key pro-inflammatory chemokine IL-8 13-fold ( p < 0.01). These mastitis hallmarks typically followed a dose response dependent on the amount of endolysin added. The current in vivo study complements our in vitro data and provides preclinical proof-of-concept of NC5 as an adjunct to intramammary cloxacillin treatment. Key points • Engineered endolysin NC5 was preclinically evaluated as add-on to cloxacillin treatment. • Two types of mice (slow and fast responding) were observed. • The add-on treatment decreased bacterial load, neutrophil influx, and pro-inflammatory mediators.