Dalbavancin and telavancin: novel lipoglycopeptides for the treatment of Gram-positive infections

Two glycopeptide analogues of vancomycin and teicoplanin have been developed with improved pharmacokinetic/pharmacodynamic parameters. Dalbavancin was derived from teicoplanin, and telavancin is a derivative of vancomycin. The half-life of dalbavancin in humans is 147-258 h (6-11 days) allowing for weekly administration. Dalbavancin possesses more potent in vitro activity than vancomycin or teicoplanin. Dalbavancin has been investigated in uncomplicated and complicated skin and skin structure infections (SSSIs) in clinical trials and has demonstrated equivalent or superior (versus vancomycin only) efficacy versus comparators. Telavancin exhibits a dual mechanism of action, low potential for resistance development and is active against resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Clinical trials involving SSSIs have demonstrated equivalent or superior (versus vancomycin for MRSA) efficacy compared with a standard therapy. Both telavancin and dalbavancin show promise as alternative treatments for patients with serious infections caused by resistant Gram-positive pathogens.     

Dalbavancin: an investigational glycopeptide

Glycopeptide antimicrobials have been a component of our therapeutic armamentarium for nearly 50 years. Although vancomycin, and more recently teicoplanin, have performed yeoman service over the years, the specter of bacterial resistance among Gram-positive aerobes has created doubts concerning how long they will continue to be useful antimicrobial agents. In an attempt to prolong the utility of the glycopeptides, efforts are underway to create new derivatives with improved pharmacologic and pharmacokinetic properties. One example of an improved glycopeptide from the pharmacokinetic perspective is dalbavancin (BI397)--a teicoplanin analog currently undergoing human testing. Elimination of this compound from the body occurs extremely slowly, with terminal disposition half-lifes of up to 200 h in healthy volunteers, thus allowing once-weekly dosing. Although not generally considered to be a potential alternative for the treatment of infections due to glycopeptide-resistant Gram-positive pathogens, dalbavancin may still be considered an advance on existing agents based on its patient-convenient once-weekly dosing regimen.     

新糖肽类抗生素dalbavancin

糖肽类抗生素常用于耐药革兰阳性菌感染的治疗。近年来，随着耐甲氧西林葡萄球菌（MRS）感染率不断升高和传播社区化，以及青霉素耐药肺炎链球菌分离率的逐渐上升，糖肽类抗生素等抗耐药革兰阳性菌药物的重要性进一步凸现，此类药物的研发已成为热点。dalbavancin为Vicuron Pharmaceuticals开发的新糖肽类抗生素，目前已完成了Ⅲ期临床试验，本文将就该药的抗菌作用、药动学及临床应用等方面作综述如下。     

Dalbavancin: a new option for the treatment of gram-positive infections

OBJECTIVE: To review the pharmacology, microbiology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of dalbavancin, a new semisynthetic lipoglycopeptide. DATA SOURCES: A MEDLINE search, restricted to the English language, was conducted from 1966 through January 2006. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, and the Infectious Diseases Society of America from 2000 to 2005 and information available from the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION: In vitro and preclinical studies, as well as Phase I, II, and III clinical trials, were evaluated to summarize the microbiology, pharmacology, clinical efficacy, and safety of dalbavancin. All published trials and abstracts citing dalbavancin were selected. DATA SYNTHESIS: Dalbavancin, a novel lipoglycopeptide, has a mechanism of action similar to that of other glycopeptides. It has in vitro activity against a variety of gram-positive organisms, but no activity against gram-negative or vancomycin-resistant enterococci that possess VanA gene. Due to its prolonged half-life (6-10 days), dalbavancin can be administered intravenously once weekly. In Phase II and III clinical trials, dalbavancin was effective and well tolerated for the treatment of skin and soft-tissue infections, catheter-related bloodstream infections, and skin and skin-structure infections. To date, adverse events are mild and limited; the most common include pyrexia, headache, nausea, oral candidiasis, diarrhea, and constipation. CONCLUSIONS: Dalbavancin appears to be a promising antimicrobial agent for the treatment of gram-positive infections. A new drug application was filed with the Food and Drug Administration (FDA) in December 2004. The FDA issued an approvable letter in 2005 for dalbavancin. If approved, dalbavancin is expected to be launched in the first quarter of 2006.     

In-vitro studies with ramoplanin (MDL 62,198): a novel lipoglycopeptide antimicrobial

Ramoplanin is a novel lipoglycopeptide antimicrobial complex, isolated from the fermentation products of a strain of Actinoplanes sp. (ATCC 33076), which comprises three closely related polypeptides, each containing chlorinated phenyl moieties and D-mannose. The in-vitro activity of ramoplanin was compared with those of vancomycin and teicoplanin. Ramoplanin was very active against Staphylococcus spp., irrespective of methicillin susceptibility, with all isolates inhibited by 1 mg/l or less. Concentrations of vancomycin and teicoplanin required to inhibit the same population of bacteria were 4 and 16 mg/l, respectively. Ramoplanin was also very active against Streptococcus spp. (alpha- and beta-haemolytic species, Str. pneumoniae and Enterococcus faecalis, Corynebacterium spp. (including Cory. jeikeium), Listeria monocytogenes, Gardnerella vaginalis, Propionibacterium acnes and Gram-positive anaerobic bacteria, with all isolates inhibited by 2 mg/l, or less. In general, the activity of ramoplanin against these species was either equal to or only slightly less than teicoplanin and equal to or somewhat greater than vancomycin. With the exception of Bacteroides melaninogenicus and Bact. bivius, ramoplanin was not active against Gram-negative bacteria.     

Identification of RNase 8 as a novel human antimicrobial protein

The antimicrobial activity of the human RNase A superfamily member RNase 8 was evaluated. Recombinant RNase 8 exhibited broad-spectrum microbicidal activity against potential pathogenic microorganisms (including multidrug-resistant strains) at micro- to nanomolar concentrations. Thus, RNase 8 was identified as a novel antimicrobial protein and may contribute to host defense.     

Evaluation of Dalbavancin in Vancomycin Allergic Patients: A Case Series

PurposeThere is a paucity of data regarding dalbavancin use in patients with a vancomycin allergy because of potential cross-reactivity between the 2 glycopeptide antibiotics.MethodsA retrospective medical record review was performed between February 2016 and February 2021 in patients with a listed vancomycin allergy who received dalbavancin as an outpatient infusion and had a listed vancomycin allergy in the electronic health record.FindingsThere were 559 unique patients during the study period who received dalbavancin as an outpatient infusion, 10 of whom had a documented vancomycin allergy in the electronic health record. Four of the 10 patients had a history of a type I IgE-mediated reaction to vancomycin, 1 patient reported delayed rash, 2 patients reported a vancomycin infusion reaction, 2 patients reported acute kidney injury, and 1 patient reported intolerance with general malaise. All 10 patients received at least 1 dose of dalbavancin with no reported adverse events.ImplicationsThis case series displays that all patients who received dalbavancin tolerated the infusion well with no adverse events reported. Dalbavancin may be a viable option for patients with a listed vancomycin allergy.     

Dalbavancin, a long-acting lipoglycopeptide for the treatment of multidrug-resistant Gram-positive bacteria

Dalbavancin is a new lipoglycopeptide antibiotic in late-stage clinical development as a once-weekly treatment for serious infections including skin and skin structure infections. Its in vitro potency is greater than that of vancomycin, with a MIC(90) of 0.06 mg/l for Staphylococcus aureus and coagulase-negative staphylococci (irrespective of oxacillin susceptibility), 0.06-0.12 mg/l for vancomycin-susceptible Enterococcus spp. and 0.003 mg/l or less for Streptococcus pneumoniae or beta-hemolytic streptococci. Dalbavancin has dual routes of elimination. The results of Phase II/III studies show clinical efficiency in complicated skin and skin structure infection. During clinical trials, dalbavancin was as effective as linezolid or vancomycin in the treatment of patients with complicated skin and skin structure infection, including those with methicillin-resistant S. aureus. An additional Phase II study demonstrated efficacy in catheter-related bacteremia. Other preliminary in vitro and in vivo data have identified putative interest of dalbavancin in endocarditis, osteitis, diabetic foot, respiratory tract or joint infection.     

Dalbavancin for the management of gram-positive osteomyelitis: Effectiveness and potential utility

Dalbavancin is approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections. It has promising pharmacokinetic/pharmacodynamic profiles in treating bone infections and safety data after multiple weekly dosing. The primary objective of this study is to describe the effectiveness and tolerability of dalbavancin in the treatment of osteomyelitis in adults. This study is a multicenter retrospective review, designed to identify patients with osteomyelitis who were treated with dalbavancin. Thirty-six patients with confirmed diagnosis of osteomyelitis who received dalbavancin were identified. Thirty-one patients met inclusion criteria for evaluation of clinical success at the end of the antibiotic course and 3?months after the completion of therapy. Twenty-eight (90%) patients achieved clinical success and there were no adverse events noted. Dalbavancin appears to be safe and effective in the treatment of osteomyelitis. More studies are needed to validate these findings.     

CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria

CEM-101 is a novel fluoroketolide with reported high potency against diverse groups of Gram-positive (Micrococcus spp., viridans group streptococci, Corynebacterium spp. Listeria monocytogenes, Clostridium spp., etc.) and Gram-negative bacteria (Neisseria gonorrhoeae, Campylobacter jejuni, Helicobacter pylori, Bacteroides fragilis, Shigella spp., etc.), including mycoplasma and ureaplasma, as well as bacteria commonly associated with community-acquired respiratory tract infections and skin and skin structure infections. In this study, CEM-101 and comparator antimicrobials were tested against a collection of very low prevalence aerobic and anaerobic bacteria collected via the SENTRY Antimicrobial Surveillance Program platform. CEM-101 was highly active against all Gram-positive organisms (MIC₅₀, 0.015 μg/mL) as compared with telithromycin (MIC₅₀, 0.06 μg/mL), clarithromycin (MIC₅₀, 0.12 μg/mL), and erythromycin (MIC₅₀, 0.25 μg/mL). Among Gram-negative pathogens, CEM-101 also displayed a high potency against most strains (MIC₅₀, 4 μg/mL) but was found to be equivalent or less active when compared with other antimicrobials tested with MIC₅₀ values ranging from ≤0.12 μg/mL for levofloxacin to 8 μg/mL for telithromycin. Among the strict anaerobic species, CEM-101 activity mirrored that of the aerobic species: high activity against the Gram-positive anaerobes (MIC₅₀ results ranging from ≤0.03 μg/mL to 0.12 μg/mL) and equivalent or less susceptible against Gram-negative anaerobes. Our in vitro antimicrobial susceptibility results for CEM-101 demonstrate better activity compared with other MLS_B class agents among a diverse group of uncommonly isolated bacterial pathogens; these results provide an impetus for possible expanded indications during Phase 2 and 3 clinical trials.     

In vitro antimicrobial activity of CP-99,219, a novel azabicyclo-naphthyridone.

CP-99,219 is a trifluoronaphthyridone with significant antibacterial activity that includes the family Enterobacteriaceae (MICs for 90% of the strains tested [MIC90s], < or = 0.015 to 0.5 micrograms/ml), Moraxella catarrhalis, Haemophilus influenzae, and gonococci (MICs, < or = 0.015 micrograms/ml). Legionella spp. were also CP-99,219 susceptible, with MICs of 0.008 to 0.12 micrograms/ml. CP-99,219 demonstrated activity greater than that of ciprofloxacin, ofloxacin, or enoxacin against Pseudomonas aeruginosa (MIC90, 1 microgram/ml), Xanthomonas maltophilia (MIC90, 2 micrograms/ml), Staphylococcus haemolyticus (MIC90, 0.5 micrograms/ml), Enterococcus faecalis (MIC90, 1 microgram/ml), and pneumococci (MIC90, 0.12 micrograms/ml). Numerous ciprofloxacin-resistant isolates were susceptible to CP-99,219, a new compound showing potential value for further in vivo trials.     

Comparative in vitro efficacies and antimicrobial durabilities of novel antimicrobial central venous catheters

We investigated the efficacies and durability of novel antimicrobial central venous catheters (CVCs) in preventing the adherence of microbial organisms to the surfaces of the CVCs. Novel antimicrobial CVCs investigated in this in vitro study were impregnated with antibiotics (minocycline and rifampin), with Oligon agent (silver, platinum, and carbon black), with approved antiseptics (chlorhexidine and silver sulfadiazine), or with a novel antiseptic agent, gendine, which contains gentian violet and chlorhexidine. When tested against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, gendine-coated CVC segments provided protection against bacterial adherence significantly more than all other types of tested CVCs (P < 0.05). Gendine-coated CVCs also provided better protection against Candida albicans and Candida parapsilosis than CVCs impregnated with antibiotics or with silver, platinum, and carbon (P < 0.02). After 28 days of being soaked in serum, the CVCs impregnated with chlorhexidine and silver sulfadiazine and the CVCs impregnated with silver, platinum, and carbon had lost antimicrobial activity against MRSA, P. aeruginosa, and C. parapsilosis, and the CVCs impregnated with minocycline and rifampin had lost activity against P. aeruginosa and C. parapsilosis. The CVCs impregnated with gendine maintained antimicrobial activities against MRSA, P. aeruginosa, and C. parapsilosis after 28 days of being soaked in serum. Central venous catheters impregnated with the novel investigational antiseptic gendine showed in vitro efficacy and provided protection against bacterial adherence more than other approved novel antimicrobial-coated CVCs.     

Dalbavancin activity against selected populations of antimicrobial-resistant Gram-positive pathogens

Dalbavancin, a dimethylaminepropyl amide derivative of the lipoglycopeptide A40926, was tested against 375 antimicrobial-resistant Gram-positive pathogens collected worldwide during 2001-2003. The isolates were tested by reference and Clinical Laboratory Standards Institute broth microdilution susceptibility methods, and dalbavancin was compared with over 20 other antimicrobials. Vancomycin resistance determinants among enterococci were identified using PCR primer sets for vanA and vanB. Dalbavancin was generally more potent than vancomycin or teicoplanin. Dalbavancin was highly active against penicillin- and ceftriaxone-resistant Streptococcus pneumoniae strains (MIC(90), < or = 0.016 microg/mL). Dalbavancin was also very active against teicoplanin-nonsusceptible coagulase-negative staphylococci (CoNS; MIC range, 0.03-0.25 microg/mL), but dalbavancin MIC results were slightly elevated compared with wild type strains. Dalbavancin inhibited vanB enterococci (MIC range, 0.03-0.12 microg/mL) and was active against other resistant, non-vanA enterococcal species. However, vanA enterococcal strains were not as susceptible to dalbavancin (MIC50, 16 microg/mL). In summary, dalbavancin was very active against a wide spectrum of resistant Gram-positive isolates and demonstrated greater potency than vancomycin or teicoplanin.     

In Vitro Activity of Dalbavancin against Drug-Resistant Staphylococcus aureus Isolates from a Global Surveillance Program

In over a decade (2002 to 2012) of Staphylococcus aureus surveillance testing on 62,195 isolates, dalbavancin was demonstrated to be active against isolates that were either susceptible or nonsusceptible to daptomycin, linezolid, or tigecycline. Nearly all (99.8%) multidrug-resistant methicillin-resistant S. aureus isolates were inhibited by dalbavancin at ≤0.12 μg/ml (MIC_50/90, 0.06/0.06 μg/ml), the current U.S. Food and Drug Administration (U.S. FDA) breakpoint. Overall, only 0.35% of the monitored S. aureus isolates had a dalbavancin MIC of either 0.25 or 0.5 μg/ml (i.e., were nonsusceptible).     

Ramoplanin: a novel antimicrobial agent with the potential to prevent vancomycin-resistant enterococcal infection in high-risk patients

The prevention of vancomycin-resistant Enterococcus (VRE) colonization and infection continues to be a high priority for clinicians. An oral antimicrobial agent that reduces or eliminates VRE gastrointestinal colonization could be useful for preventing VRE infection in selected patients. Ramoplanin, a glycolipodepsipeptide, is the first in a new class of antimicrobials. It has excellent in vitro activity against vancomycin-resistant Enterococcus faecium and Enterococcus faecalis. It is orally administered, and not absorbed systemically. In clinical trials, VRE gastrointestinal colonization was reduced to undetectable levels in 80-90% of patients during receipt of ramoplanin. A randomized, double-blinded, placebo-controlled multicentre study is currently being conducted to determine whether ramoplanin will prevent VRE bloodstream infection in oncology patients who are neutropenic due to treatment for a haematological malignancy or a bone marrow/stem cell transplant.     

Tigecycline: a glycylcycline antimicrobial agent

BACKGROUND: Tigecycline, the first glycylcycline to be approved by the US Food and Drug Administration, is a structural analogue of minocycline that was designed to avoid tetracycline resistance mediated by ribosomal protection and drug efflux. It is indicated for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections and is available for intravenous administration only. OBJECTIVE: This article summarizes the in vitro and in vivo activities and pharmacologic and pharmacokinetic properties of tigecycline, and reviews its clinical efficacy and tolerability profile. METHODS: Relevant information was identified through a search of MEDLINE (1966-April 2006), Iowa Drug Information Service (1966-April 2006), and International Pharmaceutical Abstracts (1970-April 2006) using the terms tigecycline, GAR-936, and glycylcycline. Also consulted were abstracts and posters from meetings of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2006) and documents provided for formulary consideration by the US manufacturer of tigecycline. RESULTS: Like the tetracyclines, tigecycline binds to the 30S subunit of bacterial ribosomes and inhibits protein synthesis by preventing the incorporation of amino acid residues into elongating peptide chains. In vitro, tigecycline exhibits activity against a wide range of clinically significant gram-positive and gram-negative bacteria, including multidrug-resistant strains (eg, oxacillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Enterobacteriaceae), and anaerobes (eg, Bacteroides spp). In pharmacokinetic studies in human adults, tigecycline had a large Vd (7-9 L/kg), was moderately bound to plasma protein (71%-89%), had an elimination t(1/2) of 42.4 hours, and was eliminated primarily by biliary/fecal (59%) and renal (33%) excretion. Dose adjustment did not appear to be necessary based on age, sex, renal function, or mild to moderate hepatic impairment (Child-Pugh class A-B). In patients with severe hepatic impairment (Child-Pugh class C), the maintenance dose should be reduced by 50%. In 4 Phase III clinical trials in patients with complicated skin and skin-structure infections and complicated intra-abdominal infections, tigecycline was reported to be noninferior to its comparators (vancomycin + aztreonam in 2 studies and imipenem/cilastatin in 2 studies), with clinical cure rates among clinically evaluable patients of >80% (P < 0.001 for noninferiority). The most frequently reported (> or =5 %) adverse events with tigecycline were nausea (28.5%), vomiting (19.4%), diarrhea (11.6%), local IV-site reaction (8.2%), infection (6.7%), fever (6.3%), abdominal pain (6.0%), and headache (5.6%). The recommended dosage of tigecycline is 100 mg IV given as a loading dose, followed by 50 mg IV g12h for 5 to 14 days. CONCLUSIONS: In clinical trials, tigecycline was effective for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections. With the exception of gastrointestinal adverse events, tigecycline was generally well tolerated. With a broad spectrum of activity that includes multidrug-resistant gram-positive and gram-negative pathogens, tigecycline may be useful in the treatment of conditions caused by these pathogens.     

Tigecycline: a new glycylcycline antimicrobial

Tigecycline is a new glycyclcycline antimicrobial recently approved for use in the USA, Europe and elsewhere. While related to the tetracyclines, tigecycline overcomes many of the mechanisms responsible for resistance to this class. It demonstrates favourable in vitro potency against a variety of aerobic and anaerobic Gram-positive and Gram-negative pathogens, including those frequently demonstrating resistance to multiple classes of antimicrobials. This includes methicillin-resistant Staphylococcus aureus, penicillin-resistant S. pneumoniae, vancomycin-resistant enterococci, Acinetobacter baumannii, beta-lactamase producing strains of Haemophilis influenzae and Moraxella catarrhalis, and extended-spectrum beta-lactamase producing strains of Escherichia coli and Klebsiella pneumoniae. In contrast, minimum inhibitory concentrations for Pseudomonas and Proteus spp. are markedly elevated. Tigecycline is administered parenterally twice daily. Randomised, controlled trials have demonstrated that tigecycline is non-inferior to the comparators for the treatment of complicated skin and skin structure infections, as well as complicated intra-abdominal infections. The most frequent and problematic side effect associated with its administration to date has been nausea and/or vomiting.     

Evaluation of the E test, a novel method of quantifying antimicrobial activity

The 'E test' is a method for measuring MICs of antimicrobial agents against bacteria and is based on diffusion of a pre-formed antibiotic gradient from a plastic strip. The performance of the E test was evaluated by comparison with a conventional agar dilution MIC method in tests with ten agents and a variety of organisms. Correlation between MICs by the agar dilution and E test methods was good, 98.85% results were within 2 log2 dilution steps in a total of 1304 tests. The E test is technically straightforward as tests are set up in the same way as the disc diffusion method. The versatility and ease of use of the E test make the method an attractive alternative to conventional dilution tests.