Search

Dalbavancin is a novel glycopeptide antibiotic approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). It is characterized by a potent activity against numerous Gram-positive pathogens, a long elimination half-life and a favorable safety profile. Most recently, its application for the treatment of periprosthetic joint infections (PJIs) was introduced. The aim of this study was to proof our hypothesis, that dalbavancin shows superior efficacy against staphylococcal biofilms on polyethylene (PE) disk devices compared with vancomycin and additive behavior in combination with rifampicin. Staphylococcus aureus biofilms were formed on PE disk devices for 96 h and subsequently treated with dalbavancin, vancomycin, rifampicin and dalbavancin-rifampicin combination at different concentrations. Quantification of antibacterial activity was determined by counting colony forming units (CFU/ml) after sonification of the PE, serial dilution of the bacterial suspension and plating on agar-plates. Biofilms were additionally life/dead-stained and visualized using fluorescence microscopy. Dalbavancin presented superior anti-biofilm activity compared to vancomycin. Additive effects of the combination dalbavancin and rifampicin were registered. Dalbavancin combined with rifampicin presents promising anti-biofilm activity characteristics in vitro. Further in vivo studies are necessary to establish recommendations for the general use of dalbavancin in the treatment of PJIs.

Gram-negative bacteria possess intrinsic resistance to glycopeptide antibiotics so these important antibacterial medications are only suitable for the treatment of Gram-positive bacterial infections. At the same time, polymyxins are peptide antibiotics, structurally related to glycopeptides, with remarkable activity against Gram-negative bacteria. With the aim of breaking the intrinsic resistance of Gram-negative bacteria against glycopeptides, a polycationic vancomycin aglycone derivative carrying an n-decanoyl side chain and five aminoethyl groups, which resembles the structure of polymyxins, was prepared. Although the compound by itself was not active against the Gram-negative bacteria tested, it synergized with teicoplanin against Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii, and it was able to potentiate vancomycin against these Gram-negative strains. Moreover, it proved to be active against vancomycin- and teicoplanin-resistant Gram-positive bacteria.

Antibacterial bone biomaterial coatings appeal to orthopaedics, dentistry and veterinary medicine. Achieving the successful, stable conjugation of suitable compounds to biomaterial surfaces is a major challenge. A pragmatic starting point is to make use of existing, approved antibiotics which are known to remain functional in a stationary, immobilised state. This includes the macrocyclic glycopeptide, teicoplanin, following the discovery, in the 1990’s, that it could be used as a chiral selector in chromatographic enantiomeric separations. Importantly teicoplanin works at the level of the bacterial cell wall making it a potential candidate for biomaterial functionalisations. We initially sought to functionalise titanium (Ti) with polydopamine and use this platform to capture teicoplanin, however we were unable to avoid the natural affinity of the antibiotic to the oxide surface of the metal. Whilst the interaction between teicoplanin and Ti was robust, we found that phosphate resulted in antibiotic loss. Before contemplating the covalent attachment of teicoplanin to Ti we examined whether a commercial teicoplanin stationary phase could kill staphylococci. Whilst this commercially available material could bind N-Acetyl-L-Lys-D-Ala-D-Ala it was unable to kill bacteria. We therefore strongly discourage attempts at covalently immobilising teicoplanin and/or other glycopeptide antibiotics in the pursuit of novel antibacterial bone biomaterials.

The glycopeptide A40926, produced by the actinomycete Nonomuraea gerenzanensis, is the precursor of dalbavancin, a second-generation glycopeptide antibiotic approved for clinical use in the USA and Europe in 2014 and 2015, respectively. The final product of the biosynthetic pathway is an O-acetylated form of A40926 (acA40926). Glycopeptide biosynthesis in N. gerenzanensis is dependent upon the dbv gene cluster that encodes, in addition to the two essential positive regulators Dbv3 and Dbv4, the putative members of a two-component signal transduction system, specifically the response regulator Dbv6 and the sensor kinase Dbv22. The aim of this work was to assign a role to these two genes. Our results demonstrate that deletion of dbv22 leads to an increased antibiotic production with a concomitant reduction in glycopeptide resistance. Deletion of dbv6 results in a similar phenotype, although the effects are not as strong as in the Δdbv22 mutant. Consistently, quantitative RT-PCR analysis showed that Dbv6 and Dbv22 negatively regulate the regulatory genes (dbv3 and dbv4), as well as some dbv biosynthetic genes (dbv23 and dbv24), whereas Dbv6 and Dbv22 positively regulate transcription of the single, cluster-associated resistance gene. Finally, we demonstrate that exogenously added acA40926 and its precursor A40926 can modulate transcription of dbv genes but with an opposite extent: A40926 strongly stimulates transcription of the Dbv6/Dbv22 target genes while acA40926 has a neutral or negative effect on transcription of those genes. We propose a model in which glycopeptide biosynthesis in N. gerenzanensis is modulated through a positive feedback by the biosynthetic precursor A40926 and a negative feedback by the final product acA40926. In addition to previously reported control systems, this sophisticated control loop might help the producing strain cope with the toxicity of its own product. This work, besides leading to improved glycopeptide producing strains, enlarges our knowledge on the regulation of glycopeptide biosynthesis in actinomycetes, setting N. gerenzanensis and its two-component system Dbv6-Dbv22 apart from other glycopeptide producers.

Methicillin-resistant Staphylococcus aureus (MRSA) are a major cause of healthcare and community- associated infections due to their ability to express a variety of virulence factors. We investigated 209 MRSA isolates obtained from 1 January to 31 December 2016 using a combination of phenotypic and genotypic methods to understand the genetic backgrounds of MRSA strains obtained in a General hospital in Kuwait. Antibiotics susceptibility was performed with disk diffusion, and MIC was measured with Etest strips. Molecular typing was performed using SCCmec typing, spa typing, and DNA microarray for antibiotic resistance and virulence genes. The isolates were susceptible to vancomycin, teicoplanin, rifampicin, ceftaroline, and linezolid but were resistant to gentamicin, tetracycline, erythromycin, fusidic acid, chloramphenicol and ciprofloxacin. Molecular typing revealed six SCCmec types, 56 spa types and 16 clonal complexes (CC). The common SCCmec types were type IV (39.5%), type III (34.4%), type V (25.8%) and type VI (3.8%). The dominant spa types were t860 (23.9%), t945 (8.6%), t127 (6.7%), t688 (6.7%), t304 (6.2) and t044 (5.7%). The other spa types occurred sporadically. Genes for PVL was detected in 59 (28.2%) of the isolates. CC8-ST239-MRSA-III + SCCmer (23.3%) was the most prevalent clone, followed by CC6-MRSA-IV (8.3%), CC80-MRSA-IV [PVL+] (5.8%), CC5-MRSA-VI + SCCfus (5.0%), CC30-MRSA-IV[PVL+] (4.1%), CC1-MRSA-V + SCCfus [PVL+] (4.1%), CC5-MRSA-V + SCCfus (4.1%) and CC22-MRSA-IV[PVL+] (4.1%). The study revealed that despite the emergence of MRSA with diverse genetic backgrounds over the years, ST239-MRSA-III remained the dominant clone in the hospital. This warrants reassessment of infection prevention and control procedures at this hospital.

The study was aimed to investigate the pathogens distribution and risk factors for PICC-related bloodstream infection in intensive care unit (ICU) patients. 402 patients placed with PICC in ICU were recruited in the study. The microbiological characteristics of PICC-related infection were investigated by Vitek 2 Compact automated microbial system. Antibiotics sensitivity was performed with disk diffusion and minimum inhibitory concentration (MIC) methods. Multivariate logistic and cox analyses were performed to identify the risk factors for PICC-related infection in ICU patients. 38 PICC-related infection cases were observed, and its morbidity was 9.45%. The morbidity was significantly higher in power PICC cases than that in common PICC cases. Gram-positive bacteria might be responsible for the major infection cases, followed by gram-negative bacteria, and fungi. Drug sensitivity analyses indicated that gram-negative bacteria showed low resistance to carbapenems antibiotics, and Cefperazone/sulbactam. The gram-positive bacterial exhibited sensitive to Teicoplanin and Vancomycin. The isolated fungi showed low resistance to the commonly used antifungal antibiotics. Multivariate analyses demonstrated that power PICC, high Charison scores, diabetes mellitus, double lumens triple lumens were risk factors for PICC-related infections among ICU patients. Power PICC, high Charison scores, diabetes mellitus, multi-lumens are risk factors for PICC-related bloodstream infection in ICU patients.

In contrast to the widely accepted consensus of the existence of a single RNA polymerase in bacteria, several actinomycetes have been recently shown to possess two forms of RNA polymerases due the to co-existence of two rpoB paralogs in their genome. However, the biological significance of the rpoB duplication is obscure. In this study we have determined the genome sequence of the lipoglycopeptide antibiotic A40926 producer Nonomuraea gerenzanensis ATCC 39727, an actinomycete with a large genome and two rpoB genes, i.e. rpoB(S) (the wild-type gene) and rpoB(R) (the mutant-type gene). We next analyzed the transcriptional and metabolite profiles in the wild-type gene and in two derivative strains over-expressing either rpoB(R) or a mutated form of this gene to explore the physiological role and biotechnological potential of the “mutant-type” RNA polymerase. We show that rpoB(R) controls antibiotic production and a wide range of metabolic adaptive behaviors in response to environmental pH. This may give interesting perspectives also with regard to biotechnological applications.

Staphylococcus epidermidis infections are a common occurrence in hospitals, particularly in catheter-related bloodstream and surgical site infections and infective endocarditis. Higher daptomycin minimum inhibitory concentration (MIC) values may be associated with daptomycin treatment failure among patients with S. epidermidis infections. We therefore conducted a retrospective cohort study to determine the predictive value of daptomycin susceptibility. A retrospective study was undertaken in 1,337 patients with S. epidermidis infections. Data were collected from 1 January 2013 to 31 December 2016 at Ehime University Hospital, and included the following clinicopathological factors for evaluation: age, sex, resistance to vancomycin or teicoplanin, and history of antimicrobial therapy. Multiple analysis was performed using logistic regression to identify factors that independently and significantly affected the daptomycin resistance. Daptomycin-resistant S. epidermidis was identified in 38 (2.8%) patients. According to the multiple analysis, only higher MIC values (≥16 mg/L) for teicoplanin (P S. epidermidis infections.

Dalbavancin is a new semisynthetic lipoglycopeptide with improved antimicrobial activity against various gram-positive pathogens. It demonstrates an extensive plasma half-life which permits outpatient parenteral antimicrobial therapy with weekly intervals and might therefore be an excellent treatment alternative for patients requiring prolonged antimicrobial therapy. The present study investigated dalbavancin monotherapy in an experimental implant-related methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis model. A clinical MRSA isolate and a Kirschner-wire were inserted into the proximal tibia of anaesthetized Sprague-Dawley rats. Four weeks after infection 34 animals were treated over 4 weeks with either dalbavancin (20 mg/kg loading-dose; 10 mg/kg daily), vancomycin (50 mg/kg twice daily) or left untreated. Twenty-four hours after the last treatment dose tibial bones and Kirschner-wires were harvested for microbiological examination. Based on quantitative bacterial cultures of osseous tissue, dalbavancin was as effective as vancomycin and both were superior to no treatment. No emergence of an induced glycopeptide-/lipoglycopeptide- resistance was observed after a treatment period of four weeks with either dalbavancin or vancomycin. In conclusion, monotherapy with dalbavancin was shown to be as effective as vancomycin for treatment of experimental implant-related MRSA osteomyelitis in rats, but both antimicrobials demonstrated only limited efficacy. Further studies are warranted to evaluate the clinical efficacy of dalbavancin for the treatment of periprosthetic S. aureus infections.

Bloodstream infections (BSIs) are a frequently observed complication in liver cirrhosis patients. This study aimed to investigate the microbiological characteristics and outcomes of BSIs in patients with liver cirrhosis. We retrospectively studied 852 patients with liver cirrhosis who developed a BSI. Patient outcome was evaluated using 30-day mortality and assessed using multivariate stepwise logistic regression analysis. Antibiotic sensitivity of the pathogens was tested. Gram-negative bacteria were responsible for 59.6% of BSIs, and Gram-positive bacteria caused 40.4% of the episodes among liver cirrhosis patients. The bacterial distribution significantly differed between hospital-acquired and community-acquired infections, especially in cases caused by Gram-negative pathogens. The results of the drug sensitivity test suggested that amikacin, cefoperazone/sulbactam, and piperacillin/tazobactam highly suppressed Gram-negative infections, while vancomycin and teicoplanin strongly inhibited Gram-positive BSIs. Liver failure, liver cancer, complications, Child-Pugh grade, septic shock, administration of appropriate antibiotics within 24 h, ICU admission, nosocomial infection, and Gram nature of the bacteria were independent risk factors for 30-day mortality (P

Eight heterogeneous vancomycin-intermediate S. aureus (h-VISA) and seven VISA clinical isolates confirmed by the population analysis profile/area under the curve ratio (PAP/AUC) were collected. We further performed the PAP/AUC, time-killing methods and MIC tests using vancomycin/teicoplanin alone or combination with susceptible breakpoint concentrations of cefazolin, cefmetazole, cefotaxime, and cefepime for these isolates. The PAP/AUC MIC curve shifted left after addition of cephalosporins with vancomycin or teicoplanin for both h-VISA and VISA isolates. With the combination of different cephalosporins with vancomycin or teicoplanin, the AUC/Mu3 AUC ratio decreased to S. aureus. These decreases ranged between 1.81–2.02 and 2.37–2.85-fold for h-VISA treated with cephalosporins and vancomycin or teicoplanin, and 2.05–4.59, and 2.93–4,89-fold for VISA treated with cephalosporins with vancomycin or teicoplanin. As measured by time-killing assays, the combinations of different cephalosporins with vancomycin concentrations at 1/2 and 1/4 MIC, exhibited a bactericidal and bacteriostatic effect in VISA. The mean fold of MIC decline for vancomycin base combinations ranged from 1.81–3.83 and 2.71–9.33 for h-VISA and VISA, respectively. Overall, this study demonstrated the enhanced antibacterial activity of vancomycin/teicoplanin after adding cephalosporins against clinical h-VISA/VISA isolates.