Search Results (11)

Vancomycin, a cornerstone antibiotic against severe Gram-positive infections, is increasingly challenged by resistance in Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin Enterococcus spp. (VRE), necessitating the development of novel therapeutic strategies. This review examines how structural modifications to vancomycin can enhance its antibacterial activity and explores the critical role of computational approaches in designing the next generation of analogs. By analyzing the existing literature, we highlight how strategic alterations, such as the introduction of lipophilic side chains, substitutions on the sugar moieties, and modifications to the aglycone core, have yielded derivatives with improved antibacterial potency. Notably, certain analogs (e.g., Vanc-83, Dipi-Van-Zn) have demonstrated expanded activity against Gram-negative bacteria and exhibited enhanced pharmacokinetic profiles, including prolonged half-lives and improved tissue penetration, crucial for effective treatment. Semisynthetic glycopeptides like telavancin, dalbavancin, and oritavancin exemplify successful translation of structural modifications, offering sustained plasma concentrations and simplified dosing regimens that improve patient compliance. Complementing these experimental efforts, computational methods, including molecular docking and molecular dynamics simulations, provide valuable insights into drug–target interactions, guiding the rational design of more effective analogs. Furthermore, physiologically based pharmacokinetic modeling aids in predicting the in vivo behavior and optimizing the pharmacokinetic properties of these novel compounds. This review highlights a critical path forward in the fight against multidrug-resistant infections. By meticulously examining the previously carried out structural refinement of vancomycin, guided by computational predictions and validated through rigorous experimental testing, we underscore its immense potential. Full article

Background: Vancomycin is a first-line drug for the treatment of MRSA infection. However, overuse of vancomycin can cause bacteria to become resistant, forming resistant strains and making infections more difficult to treat. This study aimed to evaluate the efficacy and safety of different antibiotics in the treatment of MRSA infections and to compare them, mainly with vancomycin, to find better vancomycin alternatives. Methods: All studies were obtained from the PubMed and Embase databases from inception to 13 April 2023. The three comprehensive indicators of clinical cure success rate, clinical microbiological success rate, and adverse reactions were evaluated, and the clinical cure success rates of three disease types, complex skin and skin structure infections (cSSSIs), complex skin and soft tissue infections (cSSTIs), and pneumonia, were analyzed in subgroups. All statistical analyses were performed using R and STATA 14.0 software for network meta-analysis. Results: A total of 38 trials with 6281 patients were included, and 13 drug treatments were evaluated. For MRSA infections, the results of network meta-analysis showed that the clinical success rates of linezolid, the combination of vancomycin and rifampin, and the combination of minocycline and rifampin were better than that of vancomycin (RR 1.71; 95%-CI 1.45–2.02), (RR 2.46; 95%-CI 1.10–5.49) (RR, 2.77; 95%-CI 1.06–7.21). The success rate of clinical microbiological treatment with vancomycin was inferior to that with telavancin (RR 0.74; 95%-CI 0.55–0.99). Linezolid had a higher rate of adverse reactions than teicoplanin (RR 5.35; 95%-CI 1.10–25.98). Subgroup analysis showed that vancomycin had a lower clinical success rate than linezolid in the treatment of MRSA-induced cSSSIs, cSSTIs, and pneumonia (RR 0.59; 95%-CI 0.44–0.80) (RR 0.55; 95%-CI 0.35–0.89) (RR 0.55; 95%-CI 0.32–0.93). Conclusions: This systematic review and NMA provide a new comparison framework for the clinical treatment of MRSA infection. The NMA suggests that linezolid may be the antibiotic of choice for the treatment of MRSA infections, with the ability to improve clinical and microbiological success rates despite its disadvantage in terms of adverse effects. At the same time, the combination of minocycline and rifampicin may be the most effective drug to treat MRSA-induced cSSSIs, tedizolid may be the best drug to treat MRSA-induced cSSTIs, and the combination of vancomycin and rifampicin may be the most effective treatment for MRSA-induced pneumonia. More high-quality studies are still needed in the future to further identify alternatives to vancomycin. Trial registration: PROSPERO registration number CRD42023416788. Full article

Daptomycin is one of the last therapeutic resources for multidrug-resistant gram-positive bacteria. Despite its structural similarities with glycopeptides, its mechanisms of action and resistance are different and in some respects are not completely understood. Mutations in several genes have been associated with daptomycin resistance, especially in mprF, walkR, rpoB and rpoC, but their role and importance remain to be elucidated. We have studied mutations in 11 genes, which have been previously associated with daptomycin non-susceptibility, in nine daptomycin-non-susceptible Staphylococcus aureus clinical isolates (daptomycin MIC: >1 mg/L). Susceptibility to daptomycin, vancomycin, linezolid, oxacillin, telavancin and dalbavancin was studied. walkR, agrA, cls1, cls2, fakA, pnpA, clpP, prs, rpoB, rpoC and mprF were amplified by PCR and sequenced. The sequences were compared with the S. aureus ATCC 25923 complete genome (GenBank gi: 685631213) by using BLAST^® software. We did not find any changes in walkR, pnpA, prs and clpP. All isolates excepting isolate MSa5 showed a high number of significant mutations (between 13 and 25 amino acid changes) in mprF. Most isolates also showed mutations in the rpo genes, the cls genes and fakA. Daptomycin non-susceptibility in S. aureus clinical isolates seems to be reached through different mutation combinations when compared to S. aureus ATCC 25293. Especially mprF and cls1 showed very high polymorphism in most isolates. Meanwhile, one isolate, MSa5, showed only single mutation in mprF (P314T). Full article

Nosocomial central nervous system (CNS) infections with carbapenem- and colistin-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria are an increasing therapeutic challenge. Here, we review pharmacokinetic and pharmacodynamic data and clinical experiences with new antibiotics administered intravenously for the treatment of CNS infections by multi-resistant bacteria. Cefiderocol, a new siderophore extended-spectrum cephalosporin, pharmacokinetically behaves similar to established cephalosporins and at high doses will probably be a valuable addition in our therapeutic armamentarium for CNS infections. The new glycopeptides dalbavancin, telavancin, and oritavancin are highly bound to plasma proteins. Although effective in animal models of meningitis, it is unlikely that they reach effective cerebrospinal fluid (CSF) concentrations after intravenous administration alone. The β-lactam/β-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the β-lactamase inhibitor tends to be too low to achieve adequate CSF concentrations. The oxazolidinone tedizolid has a broader spectrum but a less suitable pharmacokinetic profile than linezolid. The halogenated tetracycline eravacycline does not reach CSF concentrations sufficient to treat colistin-resistant Gram-negative bacteria with usual intravenous dosing. Generally, treatment of CNS infections should be intravenous, whenever possible, to avoid adverse effects of intraventricular therapy (IVT). An additional IVT can overcome the limited penetration of many new antibiotics into CSF. It should be considered for patients in which the CNS infection responds poorly to systemic antimicrobial therapy alone. Full article

Vancomycin and daptomycin are first-line drugs for the treatment of complicated methicillin-resistant Staphylococcus aureus (MRSA) infections, including bacteremia. However, their effectiveness is limited not only by their resistance to each antibiotic but also by their associated resistance to both drugs. It is unknown whether novel lipoglycopeptides can overcome this associated resistance. Resistant derivatives from five S. aureus strains were obtained during adaptive laboratory evolution with vancomycin and daptomycin. Both parental and derivative strains were subjected to susceptibility testing, population analysis profiles, measurements of growth rate and autolytic activity, and whole-genome sequencing. Regardless of whether vancomycin or daptomycin was selected, most of the derivatives were characterized by a reduced susceptibility to daptomycin, vancomycin, telavancin, dalbavancin, and oritavancin. Resistance to induced autolysis was observed in all derivatives. Daptomycin resistance was associated with a significant reduction in growth rate. Resistance to vancomycin was mainly associated with mutations in the genes responsible for cell wall biosynthesis, and resistance to daptomycin was associated with mutations in the genes responsible for phospholipid biosynthesis and glycerol metabolism. However, mutations in walK and mprF were detected in derivatives selected for both antibiotics. Full article

Atopic Dermatitis (AD) skin is susceptible to Staphylococcus aureus (SA) infection, potentially exposing it to a plethora of toxins and virulent determinants, including Panton-Valentine leukocidin (PVL) (α-hemolysin (Hla) and phenol-soluble modulins (PSMs)), and superantigens. Depending on the degree of infection (superficial or invasive), clinical treatments may encompass permanganate (aq) and bleach solutions coupled with intravenous/oral antibiotics such as amoxicillin, vancomycin, doxycycline, clindamycin, daptomycin, telavancin, linezolid, or tigecycline. However, when the skin is significantly traumatized (sheathing of epidermal sections), an SA infection can rapidly ensue, impairing the immune system, and inducing local and systemic AD presentations in susceptible areas. Furthermore, when AD presents systemically, desensitization can be long (years) and intertwined with periods of relapse. In such circumstances, the identification of triggers (stress or infection) and severity of the flare need careful monitoring (preferably in real-time) so that tailored treatments targeting the underlying pathological mechanisms (SA toxins, elevated immunoglobulins, impaired healing) can be modified, permitting rapid resolution of symptoms. Full article

Staphylococcal infections represent a challenge in companion animals and hospitalized patients. This study aimed to assess the resistance of Staphylococcus pseudintermedius isolates, against a broad panel of antibacterials, including exclusive to human medicine. A total of 40 S. pseudintermedius were collected from clinical specimens of dogs (n = 31) and cats (n = 5). All strains were tested for 20 antibacterials, namely 14 Critical Important and eight Highly Important Antibacterials (CIA and HIA, respectively), indicative for 18 antimicrobial classes. All strains were susceptible to seven antibiotics (daptomycin, fosfomycin, fusidic acid, linezolid, quinupristin-dalfopristin, teicoplanin/vancomycin, tigecycline). The highest resistance was against penicillin (97.5% Confidence Interval [CI]: 83.8–100.0), whereas the lowest against telavancin (2.5%, CI: 0.0–16.2). Resistance versus Highest Priority CIA was observed, namely against macrolides (70.0, CI: 52.1–84.3), quinolones (62.5, CI: 44.5–78.3), 5th generation cephalosporins (7.5, CI: 1.3–21.6), and glycopeptides (2.5%, CI: 0.0–14.2). Among High Priority CIA, strains were resistant only to aminoglycosides (65.0, CI: 47.0–80.4) and ansamycins (12.5, CI: 3.8–28.1). We observed the highest resistance against veterinary medicine antibacterials, but there was also resistance against antibacterials exclusive to human medicine, namely ceftaroline (7.5, CI: 1.0–23.8) and telavancin. S. pseudintermedius zoonotic potential and its rate of acquisition of new resistance should encourage surveillance on a broad spectrum of antibacterials. Full article

Infective endocarditis, osteomyelitis, and osteosynthesis-associated infections are mostly caused by Gram-positive bacteria. They are often difficult to treat and are associated with a poor prognosis. In the past 20 years, nine antibiotic drugs with predominant activity against Gram-positive bacteria have been introduced and approved by the Food and Drug Administration or the European Medicines Agency: ceftaroline, daptomycin, telavancin, dalbavancin, oritavancin, linezolid, tedizolid, delafloxacin, and omadacycline. This narrative review aims to provide an overview on these antibiotics with a special focus on their use in infective endocarditis, osteomyelitis, and osteosynthesis-associated infections. Although some of these approved antibiotics are promising, they should not be used as first- or second-line therapy, awaiting more clinical data. Full article

Nosocomial pneumonia (NP), including hospital-acquired pneumonia in non-intubated patients and ventilator-associated pneumonia, is one of the most frequent hospital-acquired infections, especially in the intensive care unit. NP has a significant impact on morbidity, mortality and health care costs, especially when the implicated pathogens are multidrug-resistant ones. This narrative review aims to critically review what is new in the field of NP, specifically, diagnosis and antibiotic treatment. Regarding novel imaging modalities, the current role of lung ultrasound and low radiation computed tomography are discussed, while regarding etiological diagnosis, recent developments in rapid microbiological confirmation, such as syndromic rapid multiplex Polymerase Chain Reaction panels are presented and compared with conventional cultures. Additionally, the volatile compounds/electronic nose, a promising diagnostic tool for the future is briefly presented. With respect to NP management, antibiotics approved for the indication of NP during the last decade are discussed, namely, ceftobiprole medocaril, telavancin, ceftolozane/tazobactam, ceftazidime/avibactam, and meropenem/vaborbactam. Full article

Glycopeptides, such as vancomycin and teicoplanin, are primarily used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, such as cellulitis, endocarditis, meningitis, pneumonia, and septicemia, and are some of the most commonly prescribed parenteral antimicrobials. Parenteral glycopeptides are first-line therapy for severe MRSA infections; however, oral vancomycin is used as a first-line treatment of Clostridioides difficile infections. Also, we currently have the longer-acting lipoglycopeptides, such as dalbavancin, oritavancin, and telavancin to our armamentarium for the treatment of MRSA infections. Lastly, vancomycin is often used as an alternative treatment for patients with β-lactam hypersensitivity. Common adverse effects associated with glycopeptide use include nephrotoxicity, ototoxicity, and Redman Syndrome (RMS). The RMS is often mistaken for a true allergy; however, it is a histamine-related infusion reaction rather than a true immunoglobulin E (IgE)-mediated allergic reaction. Although hypersensitivity to glycopeptides is rare, both immune-mediated and delayed reactions have been reported in the literature. We describe the various types of glycopeptide hypersensitivity reactions associated with glycopeptides and lipoglycopeptides, including IgE-mediated reactions, RMS, and linear immunoglobulin A bullous dermatosis, as well as describe cross-reactivity with other glycopeptides. Full article

Increasing multidrug-resistance to Gram-positive pathogens, particularly to staphylococci, enterococci and streptococci, is a major problem, resulting in significant morbidity, mortality and healthcare costs. In recent years, only a small number of novel antibiotics effective against Gram-positive bacteria has been approved. This review will discuss the current evidence for novel branded antibiotics that are highly effective in the treatment of multidrug-resistant infections by Gram-positive pathogens, namely ceftobiprole, ceftaroline, telavancin, oritavancin, dalbavancin, tedizolid, besifloxacin, delafloxacin, ozenoxacin, and omadacycline. The mechanism of action, pharmacokinetics, microbiological spectrum, efficacy and safety profile will be concisely presented. As for any emerging antibiotic agent, resistance is likely to develop against these highly effective antibiotics. Only through appropriate dosing, utilization and careful resistance development monitoring will these novel antibiotics continue to treat Gram-positive pathogens in the future. Full article