ABSTRACT Bacillus anthracis , the causative agent of anthrax, can produce fatal disease when it is inhaled or ingested by humans. Dalbavancin, a novel, semisynthetic lipoglycopeptide, has potent activity, greater than that of vancomycin, against Gram-positive bacteria and a half-life in humans that supports once-weekly dosing. Dalbavancin demonstrated potent in vitro activity against B. anthracis (MIC range, ≤0.03 to 0.5 mg/liter; MIC 50 and MIC 90 , 0.06 and 0.25 mg/liter, respectively), which led us to test its efficacy in a murine inhalation anthrax model. The peak concentrations of dalbavancin in mouse plasma after the administration of single intraperitoneal doses of 5 and 20 mg/kg of body weight were 15 and 71 mg/kg, respectively. At 20 mg/kg, the dalbavancin activity was detectable for 6 days after administration (terminal half-life, 53 h), indicating that long intervals between doses were feasible. The mice were challenged with 50 to 100 times the median lethal dose of the Ames strain of B. anthracis , an inoculum that kills untreated animals within 4 days. The efficacy of dalbavancin was 80 to 100%, as determined by the rate of survival at 42 days, when treatment was initiated 24 h postchallenge with regimens of 15 to 120 mg/kg every 36 h (q36h) or 30 to 240 mg/kg every 72 h (q72h). A regimen of ciprofloxacin known to protect 100% of animals was tested in parallel. Delayed dalbavancin treatment (beginning 36 or 48 h postchallenge) with 60 mg/kg q36h or 120 mg/kg q72h still provided 70 to 100% survival. The low MICs and long duration of efficacy in vivo suggest that dalbavancin may have potential as an alternative treatment or for the prophylaxis of B. anthracis infections.

Background: Azole-refractory mucosal candidiasis is a debilitating disease frequently seen in patients who are immunosuppressed as a result of HIV, malignancy, posttransplant immunosuppressive therapy, persistent neutropenia, steroid use, or diabetes. Anidulafungin has potent activity against a broad spectrum of Candida species, including strains resistant to azoles and amphotericin B. We performed an open-label, noncomparative study to examine efficacy and safety of anidulafungin in patients with azole-refractory oropharyngeal and esophageal candidiasis. Methods: Patients enrolled met diagnostic criteria for azole-refractory mucosal candidiasis. They received intravenous anidulafungin 100 mg on day 1 followed by daily 50-mg doses on day 2 through day 14 or for a maximum of 21 days. Primary efficacy variables were clinical response (for oropharyngeal candidiasis) and endoscopic and clinical response (for esophageal candidiasis) at the end of therapy. Results: Nineteen patients were enrolled; 89% had advanced HIV infection. Clinical success was observed in 95% of patients at end of therapy, and endoscopic success was observed in 92% of patients with esophageal candidiasis. At follow-up, clinical success was maintained in 47% of patients. The most common adverse event, experienced by 4 patients, was nausea and/or vomiting. Conclusions: Anidulafungin was well tolerated and efficacious in the treatment of patients with azole-refractory esophageal and oropharyngeal candidiasis.

ABSTRACT Dalbavancin, a semisynthetic lipoglycopeptide being developed for the treatment of skin and skin structure infections (SSSIs), has a half-life of 5 to 7 days in humans and offers promise for a convenient weekly dosing regimen. We studied the in vitro bactericidal activity of dalbavancin against target organisms, using the concentrations that are maintained in human blood with the proposed dosage regimen. Dalbavancin minimal bactericidal concentrations (MBCs) were ≤0.5 μg/ml for eight staphylococcal isolates; and for six of these strains, including one vancomycin-intermediate Staphylococcus aureus (VISA) isolate, the MBCs were equal to or within 1 doubling dilution of the MIC. Dalbavancin MICs for all three Streptococcus pyogenes strains were 0.008 μg/ml, as were the MBCs for two of the isolates. In time-kill studies conducted with a different set of seven strains (two methicillin-susceptible S. aureus isolates, three methicillin-resistant S. aureus isolates, one VISA isolate, and one S. pyogenes isolate), all strains exhibited a ≥3-log 10 decrease in their viable counts when they were exposed to ≥1 μg/ml of dalbavancin for 24 h. Resistance development studies by both direct selection (resistance frequency, <10 −10 ) and serial passage failed to produce stable mutants with decreased susceptibility to dalbavancin. These observations suggest that dalbavancin will be an effective choice for the management of patients with SSSIs.

ABSTRACT Performance of antimicrobial susceptibility tests with new agents requires careful consideration of the properties of the antimicrobial to ensure that the tests are standardized, reproducible, and reflect the true potency of the drug. Dalbavancin is a new glycopeptide with potent activity against gram-positive bacterial species. The investigations described here demonstrated that methodologic modifications of procedures are necessary to ensure consistent test results, both for quality control and for routine testing of clinical isolates. Dimethyl sulfoxide is the preferred primary solvent. The addition of 0.002% polysorbate-80 (a surfactant) to dalbavancin-containing wells in the reference broth microdilution assay resulted in consistent and reproducible MIC results for three quality control strains: Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, and Streptococcus pneumoniae ATCC 49619. The same degree of consistency was observed among clinical isolates of gram-positive bacterial species tested in several clinical laboratories. These results indicate that the addition of 0.002% (final concentration) of the surfactant in broth microdilution tests produces optimal dalbavancin MICs required for accurate and reproducible clinical laboratory tests, without untoward influences of substrate binding or media constituents.

BACKGROUNDAnidulafungin, a new echinocandin, has potent activity against candida species. We compared anidulafungin with fluconazole in a randomized, double-blind, noninferiority trial of treatment for invasive candidiasis.METHODSAdults with invasive candidiasis were randomly assigned to receive either intravenous anidulafungin or intravenous fluconazole. All patients could receive oral fluconazole after 10 days of intravenous therapy. The primary efficacy analysis assessed the global response (clinical and microbiologic) at the end of intravenous therapy in patients who had a positive baseline culture. Efficacy was also assessed at other time points.RESULTSEighty-nine percent of the 245 patients in the primary analysis had candidemia only. Candida albicans was isolated in 62% of the 245 patients. In vitro fluconazole resistance was infrequent. Most of the patients (97%) did not have neutropenia. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole (difference, 15.4 percentage points; 95% confidence interval [CI], 3.9 to 27.0). The results were similar for other efficacy end points. The statistical analyses failed to show a "center effect"; when data from the site enrolling the largest number of patients were removed, success rates at the end of intravenous therapy were 73.2% in the anidulafungin group and 61.1% in the fluconazole group (difference, 12.1 percentage points; 95% CI, -1.1 to 25.3). The frequency and types of adverse events were similar in the two groups. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P=0.13).CONCLUSIONSAnidulafungin was shown to be noninferior to fluconazole in the treatment of invasive candidiasis. (ClinicalTrials.gov number, NCT00056368 [ClinicalTrials.gov]).

Dalbavancin is an injectable, next generation lipoglycopeptide with an extended serum elimination half-life. Once-weekly dosing has been successful for treatment of skin and skin structure (SSSI) and catheter-related bloodstream infections (CR-BSI). Concurrent with clinical trails, dalbavancin resistance surveillance was initiated in 2003, and results are reported here for the 2004 United States (USA) component. A total of 3322 Gram-positive cocci were tested by reference broth microdilution methods. Organism species tested included: Staphylococcus aureus (2102; 49% oxacillin-resistant), coagulase-negative staphylococci (CoNS; 255, 82% oxacillin-resistant), β-hemolytic streptococci (241), viridans group streptococci (46), and Streptococcus pneumoniae (678). Dalbavancin (MIC90,0.06–0.12 μg/mL) was comparable in spectrum, but superior in potency to vancomycin (MIC90,1–2 μg/mL) against staphylococci. Dalbavancin MIC90 values against the tested streptococci was 0.03 μg/mL. Dalbavancin was more active against tested SSTI pathogens than comparator agents having complete susceptibility rates (100.0%) similar to vancomycin. Vancomycin, (16- to 32-fold), linezolid (8- to 32-fold), daptomycin (4- to 32-fold), and quinupristin/dalfopristin (4- to 32-fold) were less active than dalbavancin. In conclusion, dalbavancin exhibited greater potency than comparison glycopeptides or lipopeptides, streptogramin combinations, and oxazolidinones against Gram-positive pathogens associated with SSSI or CR-BSI. Dalbavancin wild-type MIC distributions remain unchanged compared with prior sampled years (2002–2003) in the USA.

ABSTRACT While standardized microdilution testing methodologies and quality control ranges exist for the novel glycolipopeptide dalbavancin, no testing methods have been described that are immediately available for routine use in clinical laboratories. In this study, we found that the dalbavancin Etest (AB BIODISK, Solna, Sweden) procedure demonstrated a high degree of agreement (100% within ±2 log 2 dilution steps) with the standardized broth microdilution method, validating the use of the Etest as an alternative test for investigational or clinical purposes following regulatory approval.

Dalbavancin, a new-generation semisynthetic lipoglycopeptide in phase 3 clinical development, has been documented to be more active than vancomycin or teicoplanin against Gram-positive bacteria, including multidrug-resistant strains, by in vitro testing and in animal models. The human pharmacokinetics of dalbavancin predicts efficacy at weekly dosing intervals. In a phase 2 open-label clinical trial, dalbavancin exhibited superiority when compared with vancomycin against catheter-related bloodstream infection (CR-BSI). The majority of pathogens identified in this study as in clinical practice were coagulase-negative staphylococci (CoNS), necessitating rigorous characterization of duplicate isolates to rule out contaminants and to validate cases for study evaluations. At follow-up for the intent-to-treat population, overall pathogen eradication was 92.3% for dalbavancin and 75.9% for vancomycin. We describe the details of organisms isolated, their epidemiologic/genetic characterization, susceptibility patterns against glycopeptides, and the eradication rates by organism group. In conclusion, dalbavancin was active against all isolated pathogens associated with CR-BSI (CoNS, Staphylococcus aureus and Enterococcus faecalis; all MIC results, < or = 0.25 microg/mL) and achieved significant (P < 0.05) clinical success when compared with vancomycin.

Anidulafungin, an echinocandin, is in late stage development for the treatment of fungal infections. We investigated the activity of anidulafungin in combination with other antifungal agents (fluconazole, itraconazole, ketoconazole, amphotericin B and 5-fluorocytosine) against four isolates each of Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis, and two isolates of Candida krusei using a macrobroth chequerboard method with interactions evaluated by fractional inhibitory concentration indices (FICIs). Additive activity (FICI>0.5 to 1) or indifference (FICI>1 to <4) was observed in 85 of 90 interactions of anidulafungin with another antifungal agent. Synergy with itraconazole (FICI≤0.5) was observed for one strain of C. glabrata, and antagonism with ketoconazole (FICI≥4), a drug rarely used systemically, was noted for four strains of C. tropicalis. The combination of anidulafungin and amphotericin B demonstrated additive activity for each of the 18 isolates of Candida tested. These results suggest additional studies are warranted, for example in animal models, to evaluate further the potential of combination antifungal therapy with anidulafungin for Candida infections.

Dalbavancin is a novel semi-synthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin. Chemical modification of natural glycopeptides has produced compounds with more potent antimicrobial activity and longer t(1/2), while maintaining an excellent safety profile. Dalbavancin, prepared from a teicoplanin-like glycopeptide, has better activity, in vitro and in animal infection models, than vancomycin and teicoplanin. In particular, dalbavancin has excellent activity against staphylococci, including coagulase-negatives. A unique feature of dalbavancin is its pharmacokinetics, characterized by a long elimination t(1/2) in humans which makes a once-weekly dosing regimen feasible. Dalbavancin recently completed Phase 3 clinical trials in skin and skin structure infection.

Dalbavancin is a bactericidal dimethylaminopropyl amide glycopeptide derivative possessing an extended serum elimination half-life in humans that allows once-weekly dosing for the therapy of Gram-positive infections. Strains from this baseline surveillance protocol in North America (NA; USA and Canada) and Europe (EU, 14 countries) were sampled in 2003. A total of 7,765 Gram-positive isolates (3,695 from NA and 4,070 from EU) were tested by reference broth microdilution methods against dalbavancin and 10 comparator agents. Species were analyzed separately by resistance phenotypes such as methicillin- (oxacillin-) resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. Dalbavancin and other glycopeptides were very active against staphylococci (n=4648) with dalbavancin being 16- to 32-fold more potent than vancomycin (MIC90, 0.06 versus 2 mg/L). MRSA rates were greater (31.6%) in NA than in EU (26.1%). Quinupristin/dalfopristin resistance (MIC, >= 2 mg/L; 0.1 - 0.5%) was documented more often in EU compared to NA. Dalbavancin (MIC50, 0.03 - 0.06 mg/L) was active against enterococci, except VanA resistance phenotypes. VRE rates were lower in EU (8.3%) then in NA (35.9%) from this resistance-enhanced enterococcal collection. Streptococci (dalbavancin MIC90, 0.016 - 0.03 mg/L) were generally most susceptible to glycopeptides (100.0%), quinupristin/dalfopristin (98.6 - 100.0%) and linezolid (100.0%); but dalbavancin was 16-fold more active than comparators. All vancomycin-susceptible enterococci and > 90% of vanB VRE had dalbavancin MIC values at <= 1 mg/L, but vanA VRE strains had dalbavancin MIC results ranging from 0.06 to > 8 mg/L (median MIC, 8 mg/L). Dalbavancin MIC values were not adversely influenced by geographic region or resistance phenotype (except vanA VRE). Infrequently isolated Gram-positive organisms such as Bacillus spp. (MIC90, 0.12 mg/L), Corynebacterium spp. (MIC90, 0.12 mg/L), Listeria monocytogenes (MIC90, 0.25 mg/L) and Micrococcus spp. (MIC90, 0.03 mg/L) were very susceptible to dalbavancin. In conclusion, these 2003 baseline resistance surveillance findings confirm the potent dalbavancin activity compared to several comparator agents against important Gram-positive pathogens. This high volume international survey indicates potential therapeutic roles for dalbavancin against many troublesome resistant Gram-positive phenotypes.

OBJECTIVES Dalbavancin is a novel, semi-synthetic glycopeptide antibiotic. The aim of this study was to further explore its activity against staphylococci. METHODS The bactericidal activity of dalbavancin was studied using MBC and time-kill methods. The potential for resistance to dalbavancin was examined using single-step and serial-passage experiments. RESULTS Dalbavancin was bactericidal against methicillin-susceptible and -resistant Staphylococcus aureus, in both the presence and absence of human serum. No resistance was seen with any isolate tested. After serial passage, bacterial populations were more homogeneous in their susceptibility to dalbavancin than to vancomycin or teicoplanin. CONCLUSION Dalbavancin is bactericidal for staphylococci. Resistance to this semi-synthetic glycopeptide is not readily developed in vitro.

BACKGROUNDCatheter-related bloodstream infections (CR-BSIs) are associated with substantial mortality, prolongation of hospital stay, and increased cost of care. Dalbavancin, a new glycopeptide antibiotic with unique pharmacokinetic properties that have allowed clinical development of a weekly dosing regimen, possesses excellent activity against clinically important gram-positive bacteria, suggesting utility in the treatment of patients with CR-BSIs.METHODSA phase 2, open-label, randomized, controlled, multicenter study of 75 adult patients with CR-BSIs compared treatment with intravenous dalbavancin, administered as a single 1000-mg dose followed by a 500-mg dose 1 week later, with intravenous vancomycin, administered twice daily for 14 days. Gram-positive bacteria isolated in this study included coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA).RESULTSInfected patients who received weekly dalbavancin (n=33) had an overall success rate (87.0%; 95% confidence interval [CI], 73.2%-100.0%) that was significantly higher than that of those who received vancomycin (n=34) (50.0%; 95% CI, 31.5%-68.5%). Adverse events and laboratory abnormalities were generally mild and were comparable for the 2 drugs.CONCLUSIONSDalbavancin thus appears to be an effective and well-tolerated treatment option for adult patients with CR-BSIs caused by CoNS and S. aureus, including MRSA.

Nisin is a cationic peptide produced by Lactococcus lactis. Its activity against clinical isolates of Clostridium difficile was compared to that of vancomycin and metronidazole by minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time-kill studies. Nisin was more active than the other agents, with a MIC90 of 0.256 mg/L and strong bactericidal activity. Nisin may be a promising agent for the management of C. difficile associated diarrhea.

ABSTRACT The rabbit model of endocarditis was used to test the effectiveness of vancomycin and two different lysostaphin dosing regimens for the treatment of infections caused by a Staphylococcus aureusstrain with reduced susceptibility to vancomycin (glycopeptide-intermediate susceptible S. aureus [GISA]). Vancomycin was ineffective, with no evidence of sterilization of aortic valve vegetations. However, rates of sterilization of aortic valve vegetations were significantly better for animals treated with either a single dose of lysostaphin (43%) or lysostaphin given twice daily for 3 days (83%) than for animals treated with vancomycin. Rabbits given a single dose of lysostaphin followed by a 3-day drug-free period had mean reductions in aortic valve vegetation bacterial counts of 7.27 and 6.63 log10 CFU/g compared with those for untreated control rabbits and the vancomycin-treated group, respectively. We conclude that lysostaphin is an effective alternative for the treatment of experimental aortic valve endocarditis caused by a clinical VISA strain.

ABSTRACT The emergence of clinical isolates of methicillin-resistantStaphylococcus aureus with reduced susceptibility to vancomycin has prompted a search for new and novel therapeutic agents active against S. aureus. Lysostaphin, a peptidase produced by Staphylococcus simulans, specifically cleaves the glycine-glycine bonds unique to the interpeptide cross-bridge of theS. aureus cell wall. The effectiveness of various regimens of dosing with intravenous lysostaphin was compared to that of vancomycin in the rabbit model of aortic valve endocarditis caused by a clinical methicillin-resistant S. aureus isolate. All animals were treated for a total of 3 days. The most active regimen, lysostaphin given three times daily, produced sterile vegetations in 10 of 11 treated rabbits, with a mean reduction in vegetation bacterial counts of 8.5 log10 CFU/g compared to the counts in the untreated controls. In contrast, vancomycin given twice daily sterilized no vegetations and reduced vegetation bacterial counts by only 4.8 log10 CFU/g. Lysostaphin given once daily was less effective, reducing mean vegetation bacterial counts by only 3.6 log10 CFU/g, but the combination of lysostaphin once daily and vancomycin twice daily reduced the mean vegetation bacterial density by 7.5 log10 CFU/g, a result that was significantly better than that for either regimen alone (P < 0.05). Lysostaphin was well tolerated by the rabbits, with no evidence of immunological reactions following up to 9 weeks of intravenous administration. We conclude that lysostaphin given alone or in combination with vancomycin is more effective in the treatment of experimental methicillin-resistant S. aureus aortic valve endocarditis than vancomycin alone.