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•In 2016–2020, MBL producers were 1.6% of Enterobacterales on a global scale.•MBL-producing Enterobacterales are increasing on a global scale.•NDM was the most prevalent MBL (global: 83.3%; across regions: 59.1%–93.8%).•ATM-AVI exhibited activity against MBL producers (99.4% inhibited at ≤8 mg/L).•ATM-AVI exhibited activity against NDM variants (98.1% inhibited at ≤8 mg/L).

Technological advancement is redefining supply chains (SCs) processes and soon traditional ways of managing SCs will no more be feasible and effective. Due to recent advancement in technology, digitalization has become an emerging topic among decision-makers and researchers. To cope-up with this emerging trend in customer behavior and remain competitive, organizations must move from their traditional ways of managing their SCs to digital supply chains (DSCs) for improved organizational performance. Therefore, the purpose of this article is in two folds: First, to identify critical factors of DSCs that are essential for transitioning traditional SCs to DSCs to improve organizational performance. Second, interpretive structural modeling is used to establish the relationship among critical factors and (matriced’ impacts croise´s multiplication applique´e a´un classement used to identify the driving and dependency power of the critical factors. Thus, this article identified fifteen DSC critical factors and established their direct and indirect effect on DSCs. The results show that “SC resilience”, and “proactive prevention” have the highest dependency power factors whilst “integration” and “advanced operational models” have the highest driving power factors. This article can help SC managers and decision-makers to understand the critical factors essential in adopting DSCs for improving organizational performance.

•Gram-negative respiratory isolates showed high susceptibility (>91%) to CAZ-AVI.•Except P. aeruginosa,MDR isolates showed >88% susceptibility to CAZ-AVI.•Prevalence of XDR P. aeruginosaand XDR K. pneumoniaewas high (>22%).•Only colistin showed high susceptibility across all the organisms (>81%).

•Global study on ATM-AVI and comparators against 2019 Enterobacterales isolates.•Active comparators included amikacin, colistin, carbapenems, and tigecycline.•ATM-AVI was active (>99.0% inhibited at ≤8 mg/L) globally and across regions.•Potent activity against MDR, ESBL, and CRE isolates (>99.0% inhibited at ≤8 mg/L).•Potent activity against MBL producers (>99.0% inhibited at ≤8 mg/L).

•WGS queried resistance mechanisms for aztreonam-avibactam in Enterobacterales.•Insertions in PBP3 found in E. coliisolates with aztreonam-avibactam MIC ≥ 2 μg/mL.•Avibactam-insensitive PER in some isolates with aztreonam-avibactam MIC ≥ 8 μg/mL.

ABSTRACTAntibacterial agents that kill nondividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides that are approved for acute bacterial skin and skin structure infections in adults caused by susceptible Gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin exerts bactericidal activity against methicillin-resistant Staphylococcus aureus(MRSA) isolates that are maintained in a nondividing state in vitro, whereas dalbavancin and the glycopeptide vancomycin do not.

ABSTRACTMeasurement of vancomycin susceptibility has been shown to be highly predictive as a surrogate measure of oritavancin susceptibility among clinically indicated Gram-positive species. Results of studying over 30,000 pathogens (from 2011 to 2014) by cross-susceptibility analysis and determining the poor reproducibility of oritavancin-nonsusceptible results showed nearly perfect surrogate testing accuracy (99.86 to 99.94%). Any isolate of an indicated organism species with locally reproducible oritavancin-nonsusceptible results (extremely rare) should be referred to a reference laboratory for confirmation of the results and determination of the resistance mechanism.

ABSTRACTOritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 μg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 μg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints.

ABSTRACTThe safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitropharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus(MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC0-24), 48 h (AUBKC0-48), and 72 h (AUBKC0-72). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC0-24s for the three MRSA strains than with vancomycin (P< 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC0-48and AUBKC0-72against one MRSA strain and a lower AUBKC0-48for another strain than did vancomycin exposure (P< 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC0-48and AUBKC0-72for one of the MRSA isolates than did vancomycin exposure (P< 0.05). Lower AUBKC0-24s for two of the MRSA strains (P< 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitropharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.

ABSTRACTOritavancin activity was tested against 15,764 gram-positive isolates collected from 246 hospital centers in 25 countries between 2005 and 2008. Organisms were Staphylococcus aureus(n= 9,075), coagulase-negative staphylococci (n= 1,664), Enterococcus faecalis(n= 1,738), Enterococcus faecium(n= 819), Streptococcus pyogenes(n= 959), Streptococcus agalactiae(n= 415), group C, G, and F streptococci (n= 84), and Streptococcus pneumoniae(n= 1,010). Among the evaluated staphylococci, 56.7% were resistant to oxacillin. The vancomycin resistance rate among enterococci was 21.2%. Penicillin-resistant and -intermediate rates were 14.7% and 21.4%, respectively, among S. pneumoniaeisolates. Among nonpneumococcal streptococci, 18.5% were nonsusceptible to erythromycin. Oritavancin showed substantial in vitro activity against all organisms tested, regardless of resistance profile. The maximum oritavancin MIC against all staphylococci tested (n= 10,739) was 4 μg/ml; the MIC90against S. aureuswas 0.12 μg/ml. Against E. faecalisand E. faecium, oritavancin MIC90s were 0.06 and 0.12, respectively. Oritavancin was active against glycopeptide-resistant enterococci, including VanA strains (n= 486), with MIC90s of 0.25 and 1 μg/ml against VanA E. faeciumand E. faecalis, respectively. Oritavancin showed potent activity against streptococci (n= 2,468); MIC90s for the different streptococcal species were between 0.008 and 1 μg/ml. These data are consistent with previous studies with respect to resistance rates of gram-positive isolates and demonstrate the spectrum and in vitro activity of oritavancin against a wide variety of contemporary gram-positive pathogens, regardless of resistance to currently used drugs. The data provide a foundation for interpreting oritavancin activity and potential changes in susceptibility over time once oritavancin enters into clinical use.

ABSTRACTSlow-growing bacteria and biofilms are notoriously tolerant to antibiotics. Oritavancin is a lipoglycopeptide with multiple mechanisms of action that contribute to its bactericidal action against exponentially growing gram-positive pathogens, including the inhibition of cell wall synthesis and perturbation of membrane barrier function. We sought to determine whether oritavancin could eradicate cells known to be tolerant to many antimicrobial agents, that is, stationary-phase and biofilm cultures of Staphylococcus aureusin vitro. Oritavancin exhibited concentration-dependent bactericidal activity against stationary-phase inocula of methicillin-susceptible S. aureus(MSSA) ATCC 29213, methicillin-resistant S. aureus(MRSA) ATCC 33591, and vancomycin-resistant S. aureus(VRSA) VRS5 inoculated into nutrient-depleted cation-adjusted Mueller-Hinton broth. As has been described for exponential-phase cells, oritavancin induced membrane depolarization, increased membrane permeability, and caused ultrastructural defects including a loss of nascent septal cross walls in stationary-phase MSSA. Furthermore, oritavancin sterilized biofilms of MSSA, MRSA, and VRSA at minimal biofilm eradication concentrations (MBECs) of between 0.5 and 8 μg/ml. Importantly, MBECs for oritavancin were within 1 doubling dilution of their respective planktonic broth MICs, highlighting the potency of oritavancin against biofilms. These results demonstrate a significant activity of oritavancin against S. aureusin phases of growth that exhibit tolerance to other antimicrobial agents.

ABSTRACTOritavancin, a semisynthetic lipoglycopeptide with activity against gram-positive bacteria, has multiple mechanisms of action, including the inhibition of cell wall synthesis and the perturbation of the membrane potential. Approved guidelines for broth microdilution MIC assays with dalbavancin, another lipoglycopeptide, require inclusion of 0.002% polysorbate 80. To investigate the potential impact of polysorbate 80 on oritavancin susceptibility assays, we quantified the recovery of [14C]oritavancin from susceptibility assay plates with and without polysorbate 80 and examined the effect of the presence of polysorbate 80 on the oritavancin MICs for 301 clinical isolates from the genera Staphylococcus, Enterococcus, and Streptococcus. In the absence of polysorbate 80, [14C]oritavancin was rapidly lost from solution in susceptibility assay test plates: 9% of the input drug was recovered in broth at 1 h when [14C]oritavancin was tested at 1 μg/ml. Furthermore, proportionately greater losses were observed at lower oritavancin concentrations, suggesting saturable binding of oritavancin to surfaces. The inclusion of 0.002% polysorbate 80 or 2% lysed horse blood permitted the recovery of 80 to 100% [14C]oritavancin at 24 h for all drug concentrations tested. Concordantly, oritavancin MIC90s for streptococcal isolates, as determined in medium containing 2% lysed horse blood, were identical with and without polysorbate 80. In stark contrast, polysorbate 80 reduced the oritavancin MIC90s by 16- to 32-fold for clinical isolates of enterococci and staphylococci, which are typically cultured without blood. The results presented here provide evidence that the MIC data for oritavancin in the current literature significantly underestimate the potency of oritavancin in vitro. Moreover, the combination of data from MIC and [14C]oritavancin recovery studies supports the revision of the oritavancin broth microdilution method to include polysorbate 80 throughout the assay.

Abstract.: The currently practiced protocol for routine serosubtyping of Neisseria meningitidis relies on reactivity of whole cells to monoclonal antibodies against the class 1 outer membrane protein (OMP) in ELISAs or dot-blots. This procedure, however, failed to yield serosubtyping information in 28% (48/174) of clinical isolates (1993–1994) in the province of Québec, Canada. These 48 strains were characterized by OMP profiles and ELISAs with outer membrane vesicles (OMVs). Forty out of the 48 strains expressed class 1 OMP, indicating that the inability to assign a serosubtype was not owing to the absence of the class 1 OMP. Of these, 15 (38%) were serosubtypable in ELISAs with outer membrane vesicles. Thus, 81% (141/174) of all meningococcal strains were serosubtypable with ELISAs using whole-cells or OMVs. Because the routinely used procedure for serosubtyping of meningococci is limited in providing serosubtype information, alternate procedures are proposed to obtain comprehensive information for epidemiological identification of this bacterium.

ABSTRACTOritavancin is an investigational lipoglycopeptide in clinical development for the treatment of acute bacterial skin and skin structure infections. In this study, we demonstrate that oritavancin causes bacterial membrane depolarization and permeabilization leading to cell death of Gram-positive pathogens and that these effects are attributable to the 4′-chlorobiphenylmethyl group of the molecule.

ABSTRACTBiophysical methods to study the binding of oritavancin, a lipoglycopeptide, to serum protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed oritavancin binding to serum from mouse, rat, dog, and human by a microbiological growth-based method under conditions that allow near-quantitative drug recovery. Protein binding was similar across species, ranging from 81.9% in human serum to 87.1% in dog serum. These estimates support the translation of oritavancin exposure from nonclinical studies to humans.

ABSTRACTOritavancin is a lipoglycopeptide with activity against gram-positive pathogens including vancomycin-resistant enterococci. The impact of human serum albumin (HSA) on oritavancin activity against enterococci was compared to those of vancomycin, daptomycin, teicoplanin, and linezolid in vitro using MIC and time-kill methods. Oritavancin MICs increased between 0- and 8-fold in the presence of HSA. In time-kill assays with HSA, oritavancin retained activity, killing or inhibiting enterococci more rapidly than did comparators when peak concentrations were simulated.

ABSTRACTOritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive infections. This study describes the synergistic activity of oritavancin in combination with gentamicin, linezolid, moxifloxacin, or rifampin in time-kill studies against methicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus.

ABSTRACTThe clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium(VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitroactivity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitropharmacokinetic/pharmacodynamic model.

ABSTRACTThere are limited therapeutic options to treat infections caused by vancomycin-resistant Enterococcus faecium(VREfm). The lipoglycopeptide oritavancin exhibits in vitroactivity against this pathogen, although its utility against infections caused by VREfm has not been clinically established. In this study, the pharmacodynamic activity of free-drug levels associated with 12 mg/kg/day of daptomycin and a single 1,200-mg dose of oritavancin were determined against three VanA VREfm isolates in an in vitropharmacokinetic/pharmacodynamic model.

The increasing incidence of antibiotic resistance in human pathogens is of significant concern. Resistance to the widely‐used and highly effective glycopeptide antibacterial agent vancomycin, which has been in clinical use for over half a century, has emerged in staphylococci and enterococci. This has spurred the development of newer glycopeptide agents, some of which show activity against vancomycin‐resistant organisms. The newer agents currently being developed contain lipophilic side‐chains, which distinguish them from vancomycin; as such, they are categorized as lipoglycopeptides. Oritavancin, telavancin, and dalbavancin are lipoglycopeptides in late‐stage development to combat Gram‐positive bacteria including methicillin‐resistant Staphylococcus aureus(MRSA) and vancomycin‐resistant enterococci. This unit describes methods that may be used to assess the in vitro activities of lipoglycopeptides. The methods include susceptibility assays, time‐kill and time‐kill‐synergy assays, inhibition of synthesis of macromolecules, membrane perturbation assays, and measurement of activity against biofilms. Curr. Protoc. Microbiol. 16:17.1.1‐17.1.22. © 2010 by John Wiley & Sons, Inc.