Clindamycin Research Articles

Sub-Inhibitory Concentrations of Oxacillin, but Not Clindamycin, Linezolid, or Tigecycline, Decrease Staphylococcal Phenol-Soluble Modulin Expression in Community-Acquired Methicillin-Resistant Staphylococcus aureus.

ABSTRACTStaphylococcus aureus (SA) is a major human pathogen producing virulence factors, such as Panton-Valentine-leucocidin (PVL), alpha-hemolysin (Hla), and phenol-soluble-modulins alpha (PSMα), including delta-hemolysin (Hld). Unlike oxacillin, clindamycin and linezolid subinhibitory concentrations (sub-MIC) display an anti-toxin effect on PVL and Hla expression. Few studies have investigated PSMα and Hld expression modulation by antibiotics. Herein, we assessed the effect of antibiotic sub-MIC on PSMα1 and Hld expression for 4 community-acquired methicillin-resistant SA (CA-MRSA), 2 strains belonging to USASA300 and 2 strains belonging to ST80 European clone. SA were grown under oxacillin, clindamycin, linezolid, or tigecycline. After incubation, culture pellets were used for the determination of psmα1, pmtB, pmtR mRNA, and RNAIII levels by relative quantitative RT-PCR. PSMα1 and Hld expressions were measured in supernatant using high-performance-liquid-chromatography coupled to mass-spectrometry (HPLC-MS). Oxacillin sub-MIC reduced PSMα1 and Hld production, partially related to mRNA variations. For other antibiotics, effects on toxin expression were strain or clone dependent. Antibiotic effect on mRNA did not always reflect protein expression modulation. Variations of pmtB, pmtR mRNA, and RNAIII levels were insufficient to explain toxin expression modulation. Altogether, these data indicate that PSMα and Hld expressions are modulated by antibiotics (potential anti-toxin effect of oxacillin) differently compared to PVL and Hla.IMPORTANCE Staphylococcal toxins play an important role in the physiopathology of staphylococcal infections. Subinhibitory concentrations (sub-MIC) of antibiotics modulate in vitro toxins expression in S. aureus: clindamycin (CLI) and linezolid (LIN) display an anti-toxin effect on Panton-Valentine leucocidin and alpha-hemolysin production, while oxacillin (OXA) has an inducing effect. Few studies have focused on the modulation of phenol-soluble modulins alpha (PSMα) including delta-hemolysin expression by sub-MIC antibiotics. The aim of the present study was to investigate the effects of sub-MIC antibiotics on the expression of PSMα toxins for 4 community-acquired methicillin-resistant S. aureus (CA-MRSA) clinical isolates. The data presented herein confirm that OXA sub-MICs constantly inhibit PSMα production for CA-MRSA. Certain strains of S. aureus are highly sensitive to sub-MICs of protein synthesis inhibitory agents, resulting in an important increase of mRNA levels to overcome the intrinsic ribosome blockage ability of these antibiotics, eventually translating in increased expression of toxins.

Engineering of Injectable Antibiotic-laden Fibrous Microparticles Gelatin Methacryloyl Hydrogel for Endodontic Infection Ablation.

This study aimed at engineering cytocompatible and injectable antibiotic-laden fibrous microparticles gelatin methacryloyl (GelMA) hydrogels for endodontic infection ablation. Clindamycin (CLIN) or metronidazole (MET) was added to a polymer solution and electrospun into fibrous mats, which were processed via cryomilling to obtain CLIN- or MET-laden fibrous microparticles. Then, GelMA was modified with CLIN- or MET-laden microparticles or by using equal amounts of each set of fibrous microparticles. Morphological characterization of electrospun fibers and cryomilled particles was performed via scanning electron microscopy (SEM). The experimental hydrogels were further examined for swelling, degradation, and toxicity to dental stem cells, as well as antimicrobial action against endodontic pathogens (agar diffusion) and biofilm inhibition, evaluated both quantitatively (CFU/mL) and qualitatively via confocal laser scanning microscopy (CLSM) and SEM. Data were analyzed using ANOVA and Tukey’s test (α = 0.05). The modification of GelMA with antibiotic-laden fibrous microparticles increased the hydrogel swelling ratio and degradation rate. Cell viability was slightly reduced, although without any significant toxicity (cell viability > 50%). All hydrogels containing antibiotic-laden fibrous microparticles displayed antibiofilm effects, with the dentin substrate showing nearly complete elimination of viable bacteria. Altogether, our findings suggest that the engineered injectable antibiotic-laden fibrous microparticles hydrogels hold clinical prospects for endodontic infection ablation.

Influence of Bile Acids in Hydrogel Pharmaceutical Formulations on Dissolution Rate and Permeation of Clindamycin Hydrochloride

Clindamycin hydrochloride is a widely used antibiotic for topical use, but its main disadvantage is poor skin penetration. Therefore, new approaches in the development of clindamycin topical formulations are of great importance. We aimed to investigate the effects of the type of gelling agent (carbomer and sodium carmellose), and the type and concentration of bile acids as penetration enhancers (0.1% and 0.5% of cholic and deoxycholic acid), on clindamycin release rate and permeation in a cellulose membrane in vitro model. Eight clindamycin hydrogel formulations were prepared using a 23 full factorial design, and they were evaluated for physical appearance, pH, drug content, drug release, and permeability parameters. Although formulations with carbomer as the gelling agent exerted optimal sensory properties, carmellose sodium hydrogels had significantly higher release rates and permeation of clindamycin hydrochloride. The bile acid enhancement factors were higher in carbomer gels, and cholic acid exerted more pronounced permeation-enhancing effects. Since the differences in the permeation parameters of hydrogels containing cholic acid in different concentrations were insignificant, its addition in a lower concentration is more favorable. The hydrogel containing carmellose sodium as a gelling agent and 0.1% cholic acid as a penetration enhancer can be considered as the formulation of choice.

Antibiotic Susceptibility and Differential expression of virulence genes in Staphylococcus aureus

Staphylococcus aureus is one of the most common pathogens in biofilm-associated chronic infections. S. aureus that live within biofilms avoid the host's immune response and are more resistant to antibiotics than planktonic bacteria. The current study was conducted to evaluate the antibacterial, antibiofilm and antivirulence of seven antibiotics (Ciprofloxacin (CP), Gentamicin (GEN), Tetracycline (TET), Amikacin (AMK), Clindamycin (CLI), Erythromycin (Ery) and Vancomycin (VAN) against S. aureus. The effects of seven antibiotics (CP, AMK, VAN, TET GEN, Ery and CLI) on S. aureus planktonic and biofilm were determined via Antibiotic susceptibility test, Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), disruption of microcolony, biofilm inhibition and degradation (crystal violet staining) and RT-qPCR. Antibiotic susceptibility test showed that CP, AMK, VAN, TET GEN, Ery and CLI has antibacterial activity against S. aureus with an inhibition zone of 28 mm, 21 mm, 27 mm, 20 mm, 25 mm, 27 mm and 19 mm respectively. The results showed that CP and AMK possessed the lowest MIC value against S. aureus with 0.125 µg/mL and 0.25 µg/mL for VAN, TET and GEN and 1.0 for Ery and CLI. The recorded values for MBCs were 0.25 μg for CP and AMK for S. aureus, 0.5 μg for vancomycin, tetracycline and gentamicin for S. aureus and 1.0 μg for Ery and CLI for S. aureus. Notably, CP and AMK demonstrated considerable efficacy, as shown by the low values for MIC; 0.125 μg and MBC; 0.25 μg for S. aureus. All antibiotics were found to disrupt microcolony formation in S. aureus at MIC of each antibiotics. At 0.25 μg concentration to 8 μg concentration of each antibiotic were significantly found to degrade and inhibit biofilm formation of S. aureus. The RT-qPCR showed that four genes including argF, purC, adh, and fabG were downregulated, whilst, three genes including scdA, pykA and menB were upregulated after exposure to CP, AMK, VAN, TET GEN, Ery and CLI. This study showed the efficacy of seven antibiotics against planktonic, biofilm, gene expression and that different concentrations of antibiotics have different degrees of potential effect on established biofilm. In addition, a decreased expression of virulence genes in S. aureus will impact their pathogenicity. These results provide the theoretical parameters for the selection of effective antimicrobial in clinical therapy and demonstrate how to correctly use antibiotics at MIC and sub-MIC as preventive drugs.

Online search interest in the use of antibiotics for dental pain: an infodemiology study

Objective: The objective of this study was to evaluate the online search interest pertaining to queries regardingantibiotics for dental pain. Material and Methods: Google Trends™ was used to identify the online searchinterest. Previously, a literature search was performed on the most frequently used antibiotics in dentistryin Brazil. Accordingly, the search terms used were Amoxicillin (AM), Clindamycin (CD), Azithromycin (AZ)and Metronidazole (MD), with the phrase “for toothache” in Portuguese and English. A time-series coveredthe last 240 weeks (from 2015 to 2020), and the results of each term were compared to their respectiveannual value. Geographic regions were also evaluated. To obtain a relative search volume (RSV), the resultingGoogle Trends™ numbers were then scaled to a range from 0 to 100 based on the ratio of searches on atopic to searches across all topics. Results: We observed an upward trend in all antibiotics search termsover the 5 years analyzed, with a peak of greater interest in 2019. The antibiotic of most interest related totoothache was ‘AM’, followed by ‘AZ’, ‘MD’, and ‘CD’. The annual RSV of toothache searches rose steadilyfrom 2015 to 2020. Variations were observed between Brazilian geographic regions, and the Northeastregion presented with the greatest interest in the topic. Conclusion: Although there were variations inannual and regional trends, an expressive and persistent increase in collective interest regarding the use ofantibiotics related to toothache, mainly amoxicillin, was observed. Our findings provide insights for publichealth promotion programs. KEYWORDSAntibiotics; Internet; Community pharmacies; Oral health; Public health.

Application of Factorial Design and Response Surface Methodology in the Optimization of Clindamycin Nanocomposites

This study is aimed at achieving the optimized preparation of a new extended‐release formulation of clindamycin (CLD) via loading of the CLD onto chitosan‐chondroitin sulfate (CS‐Chondro). The CS‐Chondro‐CLD nanocomposites were prepared by mixing different masses of CS (50, 100, and 200 mg) with Chondro (50, 100, and 200 mg) and different masses of CLD (75, 150, and 300 mg). The prepared nanocomposites were characterized by different techniques including loading efficiency (LE), X‐ray powder diffraction (XRD), scanning electron microscopy (SEM), Fourier‐transform infrared spectroscopy (FTIR), and release study. The XRD spectra of CS‐Chondro‐CLD nanocomposites showed two peaks at 2θ = 22.5° and 40.7°, indicating amorphous forms. The FTIR data shows incorporation of CLD into the CS‐Chondro polymers. An in vitro release study of CLD from nanocomposites was carried out using PBS at pH 7.4. The result showed that the release rate was completed after 25 hours. This study showed that the CS‐Chondro‐CLD nanocomposites have promising applications in the delivery of CLD drug.

Dependence of the dynamics of changes in the quality of life of patients with bacterial vaginosis on local levels of TNF-α and IL-1β.

Background and aim:Bacterial vaginosis is among serious health problem for women of reproductive age commonly associated with aberrant changes in the vaginal microbiome that influences on their local changes in inflammatory mediators and quality of life. The aim was to assess the dependence of the dynamics of changes in the quality of life of patients with bacterial vaginosis on local levels of TNF-α and IL-1β.Methods:In the prospective study 37 women aged 19-40 years with bacterial vaginosis were treated according to the Centres for Disease Control and Prevention. Patients received vaginal suppositories of clindamycin phosphate (100 mg) once daily for 3 days before bedtime. TNF-α, IL-1β levels in vaginal secretions by means of ELISA test), as well as the quality of life according to the RAND 36-Item Health Survey 1.0 were studied as in control group (once - to determine the reference values) and in the dynamics (the 1st day – before treatment, on the 7th day – after treatment) in the main group.Results:After the treatment microscopy of smears-imprints of vaginal secretions showed the complete absence of pathological microflora. The treatment was well tolerated by all patients. In the result there was proved the role of bacterial vaginosis in a violation of the quality of life of patients mainly due to the mental component of health, even after clinical and laboratory recovery.Conclusions:There was proved the relation of vaginal TNF-α and IL-1β with physical and mental health in patients with bacterial vaginosis which can have a prognostic significance of the disease. (www.actabiomedica.it)

Severe and delayed-onset acneiform eruptions as an adverse reaction to regorafenib.

Regorafenib is an oral multikinase inhibitor targeting several tyrosine kinase receptors including BRAF and epidermal growth factor receptor (EGFR) and is approved as a third-line treatment for metastatic gastrointestinal stromal tumor (GIST). While acneiform eruptions have been observed in patients receiving other BRAF and EGFR inhibitors, the commonly reported adverse reactions to regorafenib are fatigue and palmar-plantar erythrodysesthesia. Herein, we report, to the best of our knowledge, the first case who presented with a severe acneiform eruption 24 months after beginning regorafenib for the treatment of GIST. A 61-year-old woman developed GIST with multiple liver metastases, and she was treated with imatinib and sunitinib. However, these therapies were discontinued, and regorafenib was administered. Twenty-four months after beginning regorafenib, she developed an acneiform eruption on her back. Histopathologic analysis of a skin biopsy from the back revealed neutrophilic suppurative folliculitis. Therefore, she postponed regorafenib administration for 2 months and was treated with topical application of clindamycin phosphate hydrate, which was effective. Consistent with reported evidence that the presence of acneiform eruption and the efficacy of EGFR inhibitors are positively associated, regorafenib had good anticancer activity in our patient. Ultimately, we found that although regorafenib- associated skin toxicities usually appear within 1 month of treatment, patients potentially can present with delayed-onset acneiform eruptions even 24 months later.

Leaky gut biomarkers in casein- and gluten-rich diet fed rat model of autism.

It is proposed that gluten- and casein-rich diets (GRD and CRD) can synergistically exacerbate dysbiosis as comorbidity in autism by worsening leaky gut that affects the brain through the gut–brain axis. In this study, 35 young male rats were divided into 7 groups, Group 1 serves as control; Group 2, clindamycin (CL)-treated; and Group 3, propionic acid (PPA)-induced rodent model of autism. These three groups were fed standard diet until the end of the experiment. Groups 4–7 are rats treated similarly with CL and PPA, then fed on CRD or GRD until the end of the experiment. Serum zonulin, glutathione (GSH), lipid peroxides, and gut microbial composition were measured in the seven studied groups. Data demonstrate the significant increase in serum zonulin as marker of leaky gut in the CL-treated groups fed on CRD or GRD. Lipid peroxides were significantly higher in the serum of GRD-fed rats compared to CRD-fed or normal diet-fed rats. GSH was much lower in CL-treated groups fed on CRD or GRD compared to PPA-treated rats fed on both diets. Both diets differentially affected the diversity of the gut microbiota. This study demonstrates that CRD and GRD exacerbates leaky gut, according to serum zonulin, which was used as marker for increased gut permeability.

Composite Nanocellulose Fibers-Based Hydrogels Loading Clindamycin HCl with Ca2+ and Citric Acid as Crosslinking Agents for Pharmaceutical Applications.

Biocomposite hydrogels based on nanocellulose fibers (CNFs), low methoxy pectin (LMP), and sodium alginate (SA) were fabricated via the chemical crosslinking technique. The selected CNFs-based hydrogels were loaded with clindamycin hydrochloride (CM), an effective antibiotic as a model drug. The properties of the selected CNFs-based hydrogels loaded CM were characterized. The results showed that CNFs-based hydrogels composed of CNFs/LMP/SA at 1:1:1 and 2:0.5:0.5 mass ratios exhibited high drug content, suitable gel content, and high maximum swelling degree. In vitro assessment of cell viability revealed that the CM-incorporated composite CNFs-based hydrogels using calcium ion and citric acid as crosslinking agents exhibited high cytocompatibility with human keratinocytes cells. In vitro drug release experiment showed the prolonged release of CM and the hydrogel which has a greater CNFs portion (C2P0.5A0.5/Ca + Ci/CM) demonstrated lower drug release than the hydrogel having a lesser CNFs portion (C1P1A1/Ca + Ci/CM). The proportion of hydrophilic materials which were low methoxy pectin and sodium alginate in the matrix system influences drug release. In conclusion, biocomposite CNFs-based hydrogels composed of CNFs/LMP/SA at 1:1:1 and 2:0.5:0.5 mass ratios, loading CM with calcium ion and citric acid as crosslinking agents were successfully developed for the first time, suggesting their potential for pharmaceutical applications, such as a drug delivery system for healing infected wounds.

1240. Ceftobiprole Activity against Drug-Resistant Staphylococcus aureus Clinical Isolates Collected in the United States from 2016 through 2020

BackgroundMultidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) present significant treatment challenges and can cause serious morbidity and mortality. Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced cephalosporin approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Ceftobiprole is currently in phase 3 clinical development to support a New Drug Application in the United States for acute bacterial skin and skin structure infections and S. aureus bacteremia. Here, the activity of ceftobiprole and comparators was evaluated against recent MDR S. aureus and MRSA clinical isolates.Methods13,868 S. aureus isolates were collected from patients with various infection types at 34 US medical centers from 2016–2020. Susceptibility to ceftobiprole and comparator agents was tested by CLSI methods. Current CLSI and EUCAST interpretive criteria were applied (Table). Isolates were categorized as MDR if they were non-susceptible (NS; CLSI criteria) to ≥3 of the following antimicrobials: clindamycin (CM), daptomycin (DAP), erythromycin (ERY), gentamicin (GM), levofloxacin (LEV), linezolid (LZD), tetracycline (TET), tigecycline (TGC), trimethoprim-sulfamethoxazole (TMP-SMX), or vancomycin (VAN). Isolates displaying oxacillin MIC values ≥4 mg/L were categorized as MRSA.ResultsCeftobiprole was more active than ceftaroline (CPT) against MRSA (99.2% susceptible [S] versus 94.0% S, respectively) (Table). Ceftobiprole maintained activity against 88.0% of the CPT-NS isolates, but CPT was only active against 6.5% of the ceftobiprole-NS isolates. Ceftobiprole was also highly active (97.7–100.0% S) against isolates NS to CM, DAP, ERY, GM, LEV, LZD, TET, TGC, or TMP-SMX. No VAN-NS isolates were detected. Importantly, ceftobiprole was more active (97.7% S) than CPT (83.0% S) against the subset of MDR-MRSA isolates.Conclusion Conclusions: Ceftobiprole was highly active in vitro against MRSA and MDR S. aureus collected at US medical centers during 2016–2020. These results support the further development of ceftobiprole to treat S. aureus infections in the US. Disclosures Leonard R. Duncan, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Shionogi (Research Grant or Support) Kamal Hamed, MD, MPH, Basilea Pharmaceutica International, Ltd (Employee)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C) Jennifer Smart, PhD, Basilea Pharmaceutica International, Ltd. (Employee)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C) Michael A Pfaller, MD, Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Pfizer, Inc. (Research Grant or Support) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)

Optimization of entrapment efficiency and release of clindamycin in microsponge based gel

The aim of the present study was to formulate clindamycin (CLN) as a microsponge based gel to release the drug in a controlled manner and reduce the side effects in the treatment of acne. Since this method requires poor water solubility of the drug to be loaded in particles, therefore, conversion of the hydrochloride salt to free base was done. By using an emulsion solvent diffusion method, we made six different formulations of microsponges containing CLN-free base by changing the proportions of polymer, emulsifier and the pH of the external phase. These formulations were studied for physical characterization and for drug- polymer interactions. The physical characterization showed that microsponge formulations coded by C5, C6 resulted in a better loading efficiency and production yield and their particle size was less than 30 µm. Scanning electron microscopy images showed the microsponges porous and spherical. C5, C6 microsponge formulation was prepared as gel in Carbopol and in vitro evaluated. The microsponge formulation gel C8 was found to be optimized. C8 released 90.38% of drug over 12 h and showed viscosity 20,157 ± 38 cp, pH of 6.3 ± 0.09 and drug content of 99.64 ± 0.04%. Fourier transform infrared spectroscopy and differential scanning calorimetry confirmed no significant interactions between excipients and drug.

Preparation of Stable Clindamycin Phosphate Niosomes by Combination of Sorbitan Esters and their Ethoxylaed Derivatives

Preparation of Stable Clindamycin Phosphate Niosomes by Combination of Sorbitan Esters and their Ethoxylaed Derivatives

Glycyrrhetinic acid reverses antibiotic-induced intestinal epithelial injury through RNA-binding protein human antigen R (HuR)

BackgroundThe application/abuse of antibiotics can cause antibiotic-induced intestinal injury (AIJ), a typical clinical issue that disturbs intestinal homeostasis. However, the underlying post-transcriptional mechanism of AIJ remains unknown. Glycyrrhetinic acid (GA) is one of the main components of Glycyrrhiza uralensis Fisch. and Glycyrrhiza inflata Batalin (Fabaceae), and findings of our previous study showed that GA can maintain intestinal homeostasis post-transcriptionally through the RNA-binding protein human antigen R (HuR). PurposeThis study aimed to elucidate the role of HuR in AIJ and the protective effects of GA on AIJ. Study design and methodsClindamycin hydrochloride was used to clarify the effect of the antibiotic on the intestinal epithelium. Intestinal epithelium cell-6 (IEC-6) and Caco2 cells were used to demonstrate the in vitro effects of the antibiotic and GA on intestinal cells. HuR plasmid and siRNA were used to overexpress or silence HuR in vitro. SD rats were induced by using clindamycin hydrochloride capsules (250 mg/kg i.g.) for 7 consecutive days to construct the in vivo AIJ model. Rats of the AIJ model group were administrated GA (10 and 20 mg/kg i.g.) for 7 days, and subsequently, the protective effect of GA on the intestinal epithelium was evaluated. ResultsIn vitro results showed that the antibiotic (150–500 μM) suppressed proliferation, induced a delay in restitution after wounding, and caused cell cycle arrest at the G0/G1 phase in IEC-6 and Caco-2 cells. Moreover, the expression levels of HuR and its downstream gene, occludin and cyclin D1, decreased after treatment with the antibiotic (500 μM). Overexpression of HuR and GA (10 and 20 μM) reversed the antibiotic-induced inhibition of proliferation and G0/G1 phase arrest, and the antibiotic-induced decrease in HuR, occludin, and cyclin D1 expression was reversed after GA treatment (10 and 20 μM) in IEC-6 cells. In vivo results revealed the antibiotic-induced epithelial injury of both the small intestines (shortened and spared mucosa) and the large intestines (injured/deformed glands, reduced number of cup cells, and evident inflammatory cell infiltration), all of which were ameliorated after GA treatment (10 and 20 μM). ConclusionAntibiotics induce intestinal epithelial injury through HuR, and GA can exert a protective effect on AIJ by restoring HuR levels.

Severe and delayed-onset acneiform eruptions as an adverse reaction to regorafenib

Regorafenib is an oral multikinase inhibitor targeting several tyrosine kinase receptors including BRAF and epidermal growth factor receptor (EGFR), and is approved as a third-line treatment for metastatic gastrointestinal stromal tumor (GIST). While acneiform eruptions have been observed in patients receiving other BRAF and EGFR inhibitors, the commonly reported adverse reactions to regorafenib are fatigue and palmar-plantar erythrodysesthesia. Herein, we report, to the best of our knowledge, the first case who presented with a severe acneiform eruption 24 months after beginning regorafenib for the treatment of GIST. A 61-year-old woman developed GIST with multiple liver metastases, and she was treated with imatinib and sunitinib. However, these therapies were discontinued, and regorafenib was administered. Twenty-four months after beginning regorafenib, she developed an acneiform eruption on her back. Histopathologic analysis of a skin biopsy from the back revealed neutrophilic suppurative folliculitis. Therefore, she postponed regorafenib administration for 2 months and was treated with topical application of clindamycin phosphate hydrate, which was effective. Consistent with reported evidence that the presence of acneiform eruption and the efficacy of EGFR inhibitors are positively associated, regorafenib had good anticancer activity in our patient. Ultimately, we found that although regorafenib-associated skin toxicities usually appear within 1 month of treatment, patients potentially can present with delayed-onset acneiform eruptions even 24 months later.

Formulation and characterization of propolis and tea tree oil nanoemulsion loaded with clindamycin hydrochloride for wound healing: In-vitro and in-vivo wound healing assessment

This study aimed to develop propolis and tea tree oil nanoemulsion loaded with clindamycin hydrochloride to heal wound effectively. Nanoemulsion formulae were prepared and characterized by droplet size analysis, zeta potential, viscosity, ex-vivo permeation, and skin deposition. The optimal formula was evaluated in terms of morphology, cytotoxicity, and in-vitro wound healing assay. Also, the efficacy of the optimal formula was evaluated by in-vivo wound healing and histopathological studies. The optimal formula (F3) was composed of 9% tea tree oil and 0.4% propolis extracts with mean droplet size 19.42 ± 1.7 nm, zeta potential value −24.5 ± 0.2 mV, and viscosity 69.4 ± 1.8 mP. Furthermore, the optimal formula showed the highest skin deposition value 550.00 ± 4.9 µg/cm2 compared to other formulae. The TEM micrograph of the optimal formula showed that the nanoemulsion droplet has an almost spherical shape. Also, the optimal formula did not show noticeable toxicity to the human skin fibroblast cells. The in-vitro and in-vivo wound healing assay showed unexpected results that the un-loaded drug nanoemulsion formula had a comparable wound healing efficacy to the drug-loaded nanoemulsion formula. These results were confirmed with histopathological studies. Our results showed that the propolis and tea tree oil nanoemulsion, whether loaded or unloaded with an antibiotic, is an efficient local therapy for wound healing.

Formulation and Toxicity Evaluation of Nanostructured Lipid Carriers for the Treatment of Acne

Background: Acne vulgarise is an inflammatory disease involving the pathological alteration of the sebaceous glands of the body. It is not a life-threatening disease but has a great influence on lifestyle. Topical combination therapy of vitamin A and antibacterial drugs is an effective treatment for acne.
 Materials and Methods: The current work investigates the nanostructure lipid colloidal carrier system of Tretinoin and Clindamycin phosphate. Nanostructured lipid carriers (NLCs) were prepared by highspeed homogenization-sonication technique and characterized for physicochemical properties, permeation, in vivo anti-acne and toxicity (acute 2000 mg/Kg, repeat 1000 mg/kg) in Wistar rats. 
 Results: The prepared system was found to be stable, homogenous with more site retention of drugs having non-irritation and toxicity potential. The formulation showed a size of 283 nm, polydispersity index (PDI) 0.43 and Zeta potential (ZP) -37.9 mV with drug entrapment 92.0% and 66.15% for tretinoin and clindamycin respectively. Observed permeation was 18 % and 45% for Tretinoin and Clindamycin less than marketed formulation which is more focused on dermal retention of drug. No significant abnormalities and toxicological symptoms were observed for acute and repeat dose toxicity study for histopathology and haematological examinations of organs.
 Conclusion: Prepared NLC formulation was aimed at epidermal targeting. Based on obtained results it is concluded that developed lipid-based nanocarrier system of selected drugs showed the targeting potential for effective acne treatment.

EVALUATION OF THE IN VITRO ACTIVITY OF CEFTAROLINE AND COMPARATORS AGAINST STREPTOCOCCUS PNEUMONIAE ISOLATES FROM THE UNITED STATES: RESULTS FROM 10 YEARS OF THE AWARE SURVEILLANCE PROGRAM (2011-2020)

TOPIC: Chest Infections TYPE: Original Investigations PURPOSE: Ceftaroline (CPT) is a broad-spectrum cephalosporin with activity against S. pneumoniae (SPN), including ceftriaxone-resistant and multidrug-resistant (MDR) strains. CPT fosamil is approved for clinical use in the United States (US) to treat community-acquired bacterial pneumonia (CABP). We evaluated trends in SPN antimicrobial susceptibility in US hospitals during 2011-2020. METHODS: 7,901 isolates were consecutively collected (1 per patient) from 28 medical centers and tested for susceptibility to CPT and comparator agents using CLSI broth microdilution methods. Resistant subgroups included isolates that were nonsusceptible (NS) to penicillin (PEN), ceftriaxone (CRO), amoxicillin-clavulanate (AMX-CLA), erythromycin (ERY), clindamycin (CLI), tetracycline (TET), and levofloxacin (LEV) as well as MDR (NS to ≥3 classes of agents) and extensively drug resistant (XDR; NS to ≥5 classes). Selected isolates were serotyped. RESULTS: CPT inhibited 99.99% of SPN isolates at ≤0.5 mg/L (only 1 isolate had a CPT MIC of 1 mg/L) and remained active against all SPN-resistant subgroups, including AMX-CLA-NS (8.9% at ≥4 mg/L), PEN-NS (6.2% at ≥4 mg/L), and CRO-NS (5.1% at ≥2 mg/L). CPT activity remained stable against all R subgroups each year. In general, susceptibility to PEN, CRO, AMX-CLA, CLI, trimethoprim-sulfamethoxazole, and tetracycline (TET) increased from 2011 to 2015 and remained relatively stable from 2016 to 2020. Similarly, MDR and XDR rates decreased from 2011 to 2015 and remained stable in 2016-2020. Susceptibility to ERY oscillated from 52.2% (2014) to 56.4% (2011) and LEV was very active during the study period (98.9-100.0%S). MDR rates varied from 23.7% in 2011 to 16.2% in 2020 (19.7% overall), and XDR rates varied from 13.3% in 2011 to 1.8% in 2019 (6.1% overall). Against MDR isolates (n=1,555), CPT (MIC50/90, 0.06/0.25 mg/L; 99.9%S), LEV (MIC50/90, 1/1 mg/L 98.1%S), linezolid (LZD; MIC50/90, 1/1 mg/L; 100.0%S), and vancomycin (VAN; MIC50/90, 0.25/0.5 mg/L, 100.0%S) were the most active agents. All XDR isolates were susceptible to CPT (MIC50/90, 0.12/0.25 mg/L), LZD (MIC50/90, 0.5/1 mg/L), and VAN (MIC50/90, 0.25/0.5 mg/L), and 97.5% were susceptible to TIG (MIC50/90, ≤0.03/0.06 mg/L). The CPT-NS isolate was isolated in 2014 and had multiple substitutions in the penicillin binding proteins (PBP), mainly PBP2x, when compared with reference sequences. The CPT-NS isolate also showed 31 amino acid alterations in MurM. CONCLUSIONS: CPT demonstrated potent and consistent (2010-2020) activity against SPN, including several resistant phenotypes and the less susceptible serotypes. SPN susceptibility to many antibiotics increased from 2011 to 2015 but remained stable in 2016-2020. CLINICAL IMPLICATIONS: Increases in susceptibility rates could be related to the anti-pneumococcal vaccine PVC-13 introduced in 2010. Continued surveillance is crucial since resistance clones not covered by the vaccine may expand. DISCLOSURES: my employer received research support relationship with AbbVie Please note: 2020-2022 Added 04/20/2021 by Cecilia Carvalhaes, source=Web Response, value=Grant/Research Support No relevant relationships by Mariana Castanheira, source=Web Response no disclosure on file for Rodrigo Mendes;Research Contractor relationship with Allergan Please note: $1001 - $5000 by Helio Sader, source=Web Response, value=Grant/Research Support Research Contractor relationship with AbbVIe (formerly Allergan) Please note: Ongoing Added 04/15/2021 by Helio Sader, source=Web Response, value=Grant/Research Supportemployer received grant/research support relationship with Allergan/ Abbvie Please note: 2020-2022 Added 04/20/2021 by Dee Shortridge, source=Web Response, value=Grant/Research Support No relevant relationships by Streit Streit, source=Web Response

Genotypic and phenotypic characteristics of Streptococcus pneumoniae from community-acquired pneumonia patients and healthy asymptomatic participants in Sichuan province, China

BackgroundStreptococcus pneumoniae (S. pneumoniae) is the common cause of community-acquired pneumonia (CAP) and is also found in the upper respiratory tract of healthy people. Hence, the study aimed to compare the serotypes, virulence/pili genes, and antibiotic susceptibility of S. pneumoniae from healthy asymptomatic participants and CAP patients.MethodsStreptococcus pneumoniae were retrospectively collected from health asymptomatic participants and CAP patients in Sichuan, China. The serotypes were tested by multiplex polymerase chain reaction (PCR) or Quellung reaction. Antibiotic susceptibility testing was performed using the broth microdilution method. The molecular epidemiology of S. pneumoniae was analyzed by multilocus sequence typing (MLST). Additionally, the presence of virulence/pili genes were detected using PCR.ResultsA total of 83 pneumococcal isolates were collected in the current study. Of these, 52 and 31 isolates were from healthy asymptomatic participants and CAP patients, respectively. Most of S. pneumoniae were resistant to erythromycin (ERY), clindamycin (CLI), tetracycline (TET) and trimethoprim-sulfamethoxazole (SXT). 90.4% isolates were classified as multidrug resistant (MDR). The predominant serotypes were 3, 19F and 19A in the CAP carriers, whereas 3, 6 and 19F were the main serotypes among the asymptomatic carriers. The overall coverage rates of pneumococcal conjugate vaccine (PCV) 10 and PCV13 serotypes were 34.9% and 66.3%, respectively. The predominant sequence types (STs) were ST271, ST320, and ST3397. There were significant differences in some resistance and virulence characteristics between CAP patients and asymptomatic carriers. Additionally, clonal complex (CC) 271 strains had higher percentage in resistance to cefuroxime (CXM) and cefotaxime (CEF), meropenem (MER) and cefepime (CFP), which mainly carried the rlrA and sipA genes.ConclusionsHigh coverage rate of PCV13 and high prevalence of MDR indicated the necessity to expand immunization with PCV13 and rationally use the antibiotics in Sichuan, China. Importantly, long-term surveillance should be conducted to assess effectiveness brought by vaccines. Our findings may supply new guidance for developing new pneumococcal vaccines.

Antibacterial and osteogenic activities of clindamycin-releasing mesoporous silica/carboxymethyl chitosan composite hydrogels.

Conventional treatment of jaw bone infection is often ineffective at controlling bacterial infection and enhancing bone regeneration. Biodegradable composite hydrogels comprised of carboxymethyl chitosan (CMCS) and clindamycin (CDM)-loaded mesoporous silica nanoparticles (MCM-41), possessing dual antibacterial activity and osteogenic potency, were developed in the present study. CDM was successfully loaded into both untreated and plasma-treated MCM-41 nanoparticles, denoted as (p)-MCM-41, followed by the incorporation of each of CDM-loaded (p)-MCM-41 into CMCS. The resulting CDM-loaded composite hydrogels, (p)-MCM-41-CDM-CMCS, demonstrated slow degradation rates (about 70% remaining weight after 14-day immersion), while the CDM-free composite hydrogel entirely disintegrated after 4-day immersion. The plasma treatment was found to improve drug loading capacity and slow down initial drug burst effect. The prolonged releases of CDM from both (p)-MCM-41-CDM-CMCS retained their antibacterial effect against Streptococcus sanguinis for at least 14 days in vitro. In vitro assessment of osteogenic activity showed that the CDM-incorporated composite hydrogel was cytocompatible to human mesenchymal stem cells (hMSCs) and induced hMSC mineralization via p38-dependent upregulated alkaline phosphatase activity. In conclusion, novel (p)-MCM-41-CDM-CMCS hydrogels with combined controlled release of CDM and osteogenic potency were successfully developed for the first time, suggesting their potential clinical benefit for treatment of intraoral bone infection.