Glycopeptide

Dalbavancin is a semisynthetic lipoglycopeptide that is administered intravenously and was created to treat infections brought on by pathogens that are resistant to antibiotics. Strong in vitro bactericidal activity is demonstrated by dalapancin against gram-positive pathogens such as non-VanA strains of VRE, VISA, and S. aureus (MRSA). Dalbavancin has demonstrated greater potency against MRSA and β-hemolytic streptococci than other glycopeptide therapeutic agents, making it an excellent treatment for complicated skin and skin structure infections (cSSSIs)[1][2].

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Dalbavancin susceptibility of B. anthracis strains. [1]
Dalbavancin demonstrated potent in vitro activity. The MICs for the 30 strains of B. anthracis ranged from ≤0.03 to 0.5 μg/ml (Fig. 1), with the MIC50 being 0.06 μg/ml and the MIC90 being 0.25 μg/ml. In comparison, the vancomycin MICs ranged from 1 to 4 μg/ml. For the three MIC determinations, the MICs for the individual strains never varied by more than a single dilution.

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Antimicrobial susceptibility testing (AST) is performed to assess the in vitro activity of antimicrobial agents against various bacteria. The AST results, which are expressed as minimum inhibitory concentrations (MICs) are used in research for antimicrobial development and monitoring of resistance development and in the clinical setting for antimicrobial therapy guidance. Dalbavancin is a semi-synthetic lipoglycopeptide antimicrobial agent that was approved in May 2014 by the Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections caused by Gram-positive organisms. The advantage of dalbavancin over current anti-staphylococcal therapies is its long half-life, which allows for once-weekly dosing. Dalbavancin has activity against Staphylococcus aureus (including both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]), coagulase-negative staphylococci, Streptococcus pneumoniae, Streptococcus anginosus group, β-hemolytic streptococci and vancomycin susceptible enterococci. Similar to other recent lipoglycopeptide agents, optimization of CLSI and ISO broth susceptibility test methods includes the use of dimethyl sulfoxide (DMSO) as a solvent when preparing stock solutions and polysorbate 80 (P80) to alleviate adherence of the agent to plastic. Prior to the clinical studies and during the initial development of dalbavancin, susceptibility studies were not performed with the use of P-80 and MIC results tended to be 2-4 fold higher and similarly higher MIC results were obtained with the agar dilution susceptibility method. Dalbavancin was first included in CLSI broth microdilution methodology tables in 2005 and amended in 2006 to clarify use of DMSO and P-80. The broth microdilution (BMD) procedure shown here is specific to dalbavancin and is in accordance with the CLSI and ISO methods, with step-by-step detail and focus on the critical steps added for clarity [6].

Treatment with dalapancin (15–240 mg/kg; intraperitoneal injection; every 36 or 72 hours; for 14 days; female BALB/c mice) results in an 80%–100% survival rate across all dose regimens[1]. 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, < or =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.[1]

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Efficacy of Dalbavancin in the mouse inhalation anthrax model. (i) Postexposure prophylaxis model.[1]
Dalbavancin, administered i.p. q36h (at ≥15 mg/kg) or q72h (at ≥30 mg/kg) for 14 days starting at 24 h postchallenge, provided significant protection (P < 0.001). Whereas all control mice died within 4 days postchallenge, 80 to 100% of the mice treated with dalbavancin survived with all dose regimens (Fig. 3). There was no indication of a dose-response relationship with the regimens of dalbavancin utilized. In comparison, as observed previously, 100% survival was obtained with a regimen of 30 mg/kg of ciprofloxacin twice daily for 14 days. (ii) Postexposure treatment model.[1]
By 36 to 42 h postchallenge, clinical signs and deaths due to inhalational anthrax become evident in the mouse model. The efficacies of therapeutic agents, including ciprofloxacin and doxycycline, are significantly reduced when they are administered after that time. Delayed treatment with Dalbavancin provided 70 to 100% protection with i.p. administration of 60 mg/kg q36h or 120 mg/kg q72h starting at 36 or 48 h postchallenge (Fig. 4). In comparison, ciprofloxacin, administered at 30 mg/kg i.p. twice daily for 14 days beginning at 48 h postchallenge, protected 100% of the mice. Thus, intermittent dalbavancin treatment provided significant protection (P < 0.001 compared to the results for the controls), even when therapy was delayed until 36 or 48 h postchallenge, and its efficacy was at least comparable to that of ciprofloxacin administered twice daily (P > 0.05). The differences in survival obtained with ciprofloxacin treatment in this study and those obtained in previous studies are most likely due to variations in the final spore challenge dose within and between experiments that are inherent to the aerosol system. Due to this variation, the number of deaths prior to the initiation of the treatment at 48 h give different numbers of animals between groups at the initiation of treatment.

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The in vivo virulence of the S. aureus isolates was similar in the untreated control mice, based on the increase in thigh burden over the treatment period, i.e., 2.30 ± 0.14 log10 CFU/thigh. Two hours after infection, Dalbavancin was administered via the intraperitoneal route, with one of seven 2-fold-escalating doses of Dalbavancin (2.5, 5, 10, 20, 40, 80, and 160 mg/kg) being administered every 12 h for a 6-day treatment period. Untreated control groups were sampled at the start of therapy and at the end of the study. The thighs were removed from the animals and immediately processed for CFU determination. The results of these studies were analyzed by using a sigmoidal dose-effect model. The magnitude of the PK/PD index associated with each endpoint dose was calculated with the following equation: log10 D = log10 [E/(Emax − E)]/(N + log10 ED50), where E is the control growth for the static dose (D), E is the control growth − 1 log unit for D for 1-log kill, and E is the control growth − 2 log units for D for 2-log kill.
Results of 1-log kill and 2-log kill were achieved against seven and six of the isolates, respectively (Fig. 2A and Table 2). The Dalbavancin in vivo exposure-response data were also considered relative to the PK/PD-linked driver AUC/MIC, using concentrations of free drug. Drug accumulation was calculated and included in AUC estimates. Using a sigmoidal Emax model, the data fit was strong for the seven-strain data set (R2 = 0.86), as shown in Fig. 2B. The numerical AUC/MIC values associated with each of the three treatment endpoints are also shown in Table 2. Net stasis was observed with a dalbavancin free-drug AUC (fAUC)/MIC value near 25. fAUC/MIC values near 50 and 100 were associated with 1-log and 2-log reductions, respectively, in organism burdens in the neutropenic mice. [5]

Susceptibility to Dalbavancin. [1]
MICs were determined in triplicate by the broth microdilution method in cation-adjusted Mueller-Hinton broth (CAMHB), according to the methodology of the Clinical and Laboratory Standards Institute (CLSI) (11, 12). The final antibiotic concentrations were 0.03 to 64 μg/ml. After 18 to 24 h of incubation at 35°C, the MICs were determined both visually and spectrophotometrically (600 nm). The quality control strain Staphylococcus aureus ATCC 29213 was tested in parallel

Protocol [6]
Note: Refer to CLSI documents M7-A10 and M100-S25 and/or ISO/FDIS 20776-1 for full details of the reference broth microdilution method for antimicrobial susceptibility. The reference methods allow for options in some of the procedures specific to inoculum preparation and MIC panel production to achieve the same end result. The method detailed here relates to one antimicrobial agent, Dalbavancin, and some of the steps represent one of potentially several ways the reference procedure can be done. Appropriate safety precautions (consistent with biosafety level 2) should be utilized10. The MIC panel format used for the purpose of this video publication is shown in Table 1.

1. Store Dalbavancin Powder [6]
Upon receipt of diagnostic grade dalbavancin powder, store at -20 oC in a desiccated environment in a non-defrosting freezer. Prior to use, the powder should equilibrate to reach RT before opening.

2. Prepare MIC Panel Dilutions [6]
Prepare a stock solution no higher than 1,600 µg/ml of dalbavancin in neat (pure) DMSO in sterile glass or plastic tubes, and use on the same day of preparation or store at -20 to -60 oC or below for future use in a non-defrosting freezer. Take into consideration the potency of dalbavancin as provided on the documentation received with the powder, when weighing the powder (see Equation 1 for example 800 µg/ml stock preparation).
Dilute the stock dilution similar to the scheme as is shown in column 1 (“Source Concentration”) in Table 2 with neat DMSO in sterile glass or plastic tubes. Use one pipet for measuring diluent and another pipet for adding the initial dalbavancin stock to the first tube. For each subsequent dalbavancin stock concentration use a new pipet.
Prepare 100X final MIC panel concentration dilutions (intermediate concentrations) with neat DMSO. As is shown in columns 2-4 of Table 2, combine appropriate volumes of source and DMSO to achieve desired intermediate concentration (volumes to be used will depend on number of MIC panels to be made).
Prepare 0.004% P80: Prepare a fresh working stock solution of 2% P80 by adding 0.1 ml P80 to 4.9 ml dH2O. Sterilize by passing through a 0.22 micron filter and use solution on the same day of preparation. Prepare 0.004% P80 diluent by making a 1:500 dilution of 2% P80 (e.g., 0.3 ml of 2% P80 to 149.7 ml of CAMHB).
Further dilute the intermediate concentrations prepared in Step 2.2 1:100 in cation adjusted Mueller Hinton broth (CAMHB) supplemented with 0.004% (v/v) polysorbate-80 (P-80) P-80 and/or LHB (for streptococci) added at double the final concentration because addition of inoculum (step 4.3) will result in a 1:2 dilution. See columns 6 and 7 in Table 2.

3. Prepare MIC Panels [6]
Dispense 50 µl of each dalbavancin solution prepared in step 2.3 into appropriate wells of the MIC panel and include media only in one well (growth control well). A multi-channel pipet with sterile tips can be used for this step.
Use panels immediately or seal with plastic film, place in plastic bags and immediately place in a non-defrosting freezer at ≤-20 oC (preferably at ≤-60 oC) until needed. If frozen panels are used, remove seals and place individual panels on lab bench for 15-30 min (until well contents are thawed) before proceeding to panel inoculation.

4. Inoculate MIC Panels, Perform Purity and Setup Colony Count [6]
Select several well-isolated colonies from an 18-24 hr blood agar or other non-selective agar plate. Touch the top of each colony with a sterile loop or swab and transfer to 1-5 ml CAMHB or saline until turbidity is equivalent to a 0.5 McFarland standard. Assess turbidity by visual comparison to the 0.5 McFarland or with a photometric device.
Within 15-30 min of preparation, dilute the inoculum 1:100 in CAMHB (100 µl into 10 ml CAMHB). For most bacteria tested against dalbavancin, with the exception of S. pneumoniae, this dilution will provide a final well concentration of 5 x 105 CFU/ml (acceptable range is 2-8 x 105 CFU/ml). For S. pneumoniae, bacterial concentration based on comparison of turbidity to a 0.5 McFarland is typically considerably less, therefore, dilute the inoculum 1:25 (400 µl into 10 ml CAMHB+10% +LHB).
Within 15 min after inoculum preparation, transfer 50 µl of the final inoculum to each well (with exception of the sterility control well) of the MIC panel prepared in step 3. A multi-channel pipet using sterile tips can be used for this step.
Perform a purity check by transferring and spreading a 1-10 µl aliquot from the positive growth control well using a sterile loop to a nonselective agar (e.g., trypticase soy agar with 5% sheep blood).
Setup colony count by removing 10 µl from the growth control well with a single channel pipet and sterile tip and transfer to 10 ml of saline (1:1,000 dilution). Mix and transfer 100 µl with a single channel pipet and sterile tip to a suitable, nonselective agar medium (e.g., trypticase soy agar with 5% sheep blood) and spread over the entire agar surface with a sterile loop, repeating two times in different directions to assure even distribution of the inoculum (1:10 dilution).

5. Incubate MIC Panels, Colony Count and Purity Plates [6]
Seal each MIC panel or stack of no more than 4 panels in a plastic bag, with plastic tape or with a tight-fitting plastic cover before incubating. Alternatively, place empty MIC panel on the top of stack of no more than 4 MIC panels, place a damp paper towel in a plastic container, place MIC panels in the plastic container and close container securely with lid.
Incubate MIC panels in an ambient air incubator at 35 °C ± 2 °C for 16-20 hr (staphylococci and enterococci) and 20-24 hr (streptococci) within 30 min of inoculation. Incubate the colony count and purity plates under same conditions except incubate streptococci in a 5% CO2 incubator.

6. Read the MIC and Colony Count Plates; Check Purity Plate [6]
Read the MIC as the lowest concentration that completely inhibits bacterial growth in the wells as detected by the unaided eye.
Count colonies on the colony count plate. Multiply each colony by dilution factor (1:10,000) (e.g., 50 colonies is equivalent to 5 x 105 CFU/ml). An acceptable range is 20-80 colonies (2-8 x 105 CFU/ml) and is used as an approximate guideline.
Check purity plate. If all colonies are similar to the colonies used in step 4.1, then the inoculum can be considered pure. If there are any other colonies present, then there is potential for a contaminant to be present in the MIC panel and the test should be repeated.

Animal/Disease Models: Female balb/c (Bagg ALBino) mouse: (6-8 weeks) challenged with Ames strain of B. anthracis[1]
Doses: 15 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg, 240 mg/kg
Route of Administration: intraperitoneal (ip)injection; every 36 h or 72 h; for 14 days
Experimental Results: The efficacy 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 or 30 to 240 mg/kg every 72 h.

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Pharmacokinetics.[1]
Female ICR mice weighing 23 to 27 g were utilized. Single Dalbavancin doses of 5 and 20 mg/kg of body weight were administered i.p. or i.v. (via the tail vein) in 5% glucose solution. Blood samples were collected by cardiac puncture, while the mice were under halothane anesthesia, at 0.08, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 144 h after dosing. Three animals per route, dose, and time point were utilized. The blood was collected in heparinized tubes, which were centrifuged to prepare the plasma. The plasma samples were stored at −20°C until analysis. Dalbavancin concentrations were determined by a microbiological agar diffusion assay that measures the total drug concentration, as described previously. The values of the PK parameters were determined by noncompartmental analysis.Efficacy studies.[1]
Female BALB/c mice (age, 6 to 8 weeks) were challenged by aerosol with between 50 and 100 times the established 50% lethal dose (3.4 × 104 CFU) of a spore preparation of the Ames strain of B. anthracis. In the postexposure prophylaxis model, antibiotic treatment (administered in 0.2 ml i.p.) was initiated 24 h after challenge. Treatment groups (10 mice per group) received Dalbavancin once every 36 h (q36h) at doses ranging from 15 to 120 mg/kg or every 72 h (q72h) at doses ranging from 30 to 240 mg/kg for 14 days. A regimen of ciprofloxacin known to protect 100% of animals (30 mg/kg twice daily for 14 days) was tested in parallel. In the postexposure treatment experiments, the administration of Dalbavancin at 60 mg/kg q36h or 120 mg/kg q72h was initiated at later times (36 or 48 h) after challenge, when symptoms of infection could have appeared. Control mice received phosphate-buffered saline (PBS). The mice were monitored for survival for 42 days, at which time the surviving animals were killed and their organs were harvested to determine the tissue bacterial burden. For animals that died or that were moribund at earlier times, their organs were harvested at those times. Lungs, spleens, and the mediastinum region (lymph nodes) were aseptically removed, weighed, and homogenized in 1 ml of sterile water. Homogenates were serially diluted 10-fold in water, and 100-μl aliquots were plated on sheep blood agar. To determine the numbers of CFU of the anthrax spores, homogenates were heat shocked for 15 min at 65°C to kill vegetative cells, serially diluted, and plated as described above.

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The current studies were designed to define the pharmacodynamic (PD) target for Dalbavancin against S. aureus strains with dalbavancin MICs at or above the current FDA breakpoint (≥0.12 μg/ml), some of which were vancomycin-intermediate S. aureus (VISA) strains. The results from these studies provide a pharmacodynamic rationale in support of the current clinical dosing regimens. Furthermore, the data provide a starting point for the development of revised susceptibility breakpoints for this new compound.Seven strains of Staphylococcus aureus (including four vancomycin-intermediate S. aureus [VISA] strains) were studied (Table 1). The Dalbavancin and vancomycin MIC values were determined in triplicate using CLSI reference broth microdilution methods, in the presence of polysorbate 80. The Dalbavancin MIC range for the S. aureus isolates was 0.12 to 0.50 μg/ml. The neutropenic murine thigh infection model was used for all studies. Mice were inoculated with 107 CFU/ml of each strain. Single-dose plasma pharmacokinetic studies were performed with thigh-infected mice given intraperitoneal doses (0.2 ml/dose) of dalbavancin (2.5, 10, 40, 80, or 160 mg/kg). Dalbavancin plasma concentrations were measured with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay (Fig. 1); the lower limit of quantification for the assay was 0.05 μg/ml. Sample analysis precision (coefficient of variation [CV]) ranged from 5% to 6.4%, and accuracy (bias) ranged from −3.5% to −10.0%. Peak levels were observed by 2 to 6 h. Dalbavancin exhibited relatively linear pharmacokinetics, based on the dose-area under the concentration-time curve (AUC) relationship. The half-life was long and varied from 4.1 to 9.31 h. A protein binding value of 98.4%, based on prior studies in this model, was used. [5]

Absorption, Distribution and Excretion
In healthy subjects, following a single intravenous injection of dapavancin (dose range 140 mg to 1500 mg), both the AUC_0-24h and C_max of dapavancin increased proportionally with the dose, indicating linear pharmacokinetics. In healthy adults with normal renal function, no significant accumulation of dapavancin was observed with weekly intravenous infusions for up to eight weeks (1000 mg on day 1, followed by weekly infusions of 500 mg for up to seven weeks). In healthy subjects, following a single 1000 mg dose of dapavancin, an average of 33% of the administered dose was excreted unchanged in the urine, and approximately 12% was excreted as the metabolite hydroxydapavancin, with excretion occurring 42 days after administration. Within 70 days of administration, approximately 20% of the administered dose was excreted in the feces. Steady-state clearance and volume of distribution were comparable in healthy subjects and infected patients. The steady-state volume of distribution was similar to the extracellular fluid volume. 0.0513 L/h. Metabolites/Metabolites: Dapavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. Therefore, no significant amounts of metabolites were observed in human plasma. The metabolites hydroxydapavancin and mannoside ligand were detected in urine (<25% of the administered dose). The metabolic pathways producing these metabolites have not been determined; however, given the relatively small contribution of metabolism to the overall elimination of dapavancin, no drug interactions resulting from inhibition or induction of dapavancin metabolism are expected. Hydroxydapavancin and mannoside ligand exhibit significantly reduced antibacterial activity compared to dapavancin. Biological Half-Life: The terminal half-life is 346 hours. Pharmacokinetics of Dapavancin in Mouse Plasma. [1] Figure 2 shows the plasma concentrations of dapavancin (bound and free forms) at different sampling time points after intraperitoneal injection. Table 1 lists the pharmacokinetic and pharmacodynamic (PD) parameters for the 5 mg/kg and 20 mg/kg dose groups. Two hours after intraperitoneal injection, the peak plasma concentrations (Cmax) of dapavancin in the 5 mg/kg and 20 mg/kg dose groups were 15.2 μg/ml and 71.3 μg/ml, respectively. The terminal half-life of the 20 mg/kg dose group was 53 hours. Dapavancin was detectable in plasma (≥0.4 μg/ml) for 6 days after intraperitoneal injection of the 20 mg/kg dose. From 2 hours after administration, the plasma drug concentrations were closely correlated with the pharmacokinetic curves of the same dose administered intravenously (Figure 2). However, the area under the concentration-time curve (AUC; calculated to infinity) after intraperitoneal administration (176 and 848 mg·h/L for the 5 mg/kg and 20 mg/kg dose groups, respectively) was slightly lower than that after intravenous administration (200 and 1071 mg·h/L, respectively; data not shown). As observed in other animal and human studies (6, 16, 27, 33, 34), the pharmacokinetics of dapavancin in mice is dose-dependent, based on a comparison of the AUCs achieved at 5 mg/kg and 20 mg/kg doses. Following a single infusion of dapavancin, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased proportionally from 500 mg to 1000 mg (Cmax: 157 μg/ml and 299 μg/ml, respectively, at the 500 mg regimen; AUClast: 10,850 μg·h/ml and 22,679 μg·h/ml, respectively, at the 500 mg regimen), with low inter-subject variability. The mean terminal half-life (t_sub>1/2) after the 500 mg and 1000 mg doses were 204 hours and 193 hours, respectively. Clearance and volume of distribution were similar at both dose concentrations. All reported adverse events during treatment were considered mild. Laboratory values and vital signs did not change significantly over time in either treatment group. Conclusion: Overall, single 30-minute infusions of 500 mg and 1000 mg dapavancin were well tolerated in this study population, and plasma exposure was similar to that in non-Asian populations. [3]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Dapavancin has a plasma protein binding rate of 93% and is poorly absorbed orally, therefore it is unlikely to enter the infant's bloodstream and will not have any adverse effects on breastfed infants. If the mother needs to use dapavancin, there is no need to stop breastfeeding. Monitor the infant for possible gastrointestinal reactions such as diarrhea, vomiting, and candidiasis (e.g., thrush, diaper rash).
◉ Effects on Breastfed Infants
No relevant published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date.

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Protein Binding
Dapavancin reversibly binds to human plasma proteins, primarily albumin. Dapavancin has a plasma protein binding rate of 93% and is unaffected by drug concentration, renal insufficiency, or hepatic insufficiency.

[1]Antimicrob Agents Chemother. 2010 Mar;54(3):991-6.;

[2]Ther Clin Risk Manag. 2008 Feb;4(1):31-40.

[3]Clin Drug Investig. 2015 Dec;35(12):785-93.

[4]J Antimicrob Chemother. 2016 Jan;71(1):276-8.

[5]Antimicrob Agents Chemother. 2015 Dec;59(12):7833-6.

[6]J Vis Exp. 2015 Sep 9:(103):53028.

Pharmacodynamics
Based on animal infection models, the antibacterial activity of dapavancin appears to be most strongly correlated with the area under the concentration-time curve (AUC/MIC) of Staphylococcus aureus. An exposure-response analysis from a single study in patients with complicated skin and soft tissue infections supports a two-dose regimen for dapavancin injection. Therefore, for patients with normal renal function, the recommended dosing regimen for dapavancin is a single 1500 mg dose, or a 1000 mg dose followed by a 500 mg dose one week later [FDA label, F2356]. Dapavancin should be administered via intravenous infusion over 30 minutes. Furthermore, in a randomized, positive-controlled, placebo-controlled, full-scale QT/QTc study, 200 healthy subjects received either 1000 mg of dapavancin intravenously, 1500 mg of dapavancin intravenously, 400 mg of moxifloxacin orally, or placebo. Neither dapavancin 1000 mg nor dapavancin 1500 mg produced any clinically significant adverse effects on cardiac repolarization. Dapavancin is a semi-synthetic glycopeptide antibiotic used to treat acute bacterial skin and soft tissue infections caused or suspected of being caused by susceptible strains of specified Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus [MRSA]. It has both antimicrobial and antimicrobial action. It is a carbohydrate acid derivative, monosaccharide derivative, glycopeptide, and semi-synthetic derivative. Dapavancin is a second-generation lipoglycopeptide antibiotic designed to improve upon currently available natural glycopeptide antibiotics such as vancomycin and teicoplanin. Modifications to these older glycoprotein antibiotics have given dapavancin a similar mechanism of action, but with higher activity and requiring only once-weekly dosing. This product is indicated for the treatment of acute bacterial skin and soft tissue infections (ABSSSI) caused by the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus atypicalis, Streptococcus pharyngitis (including Streptococcus pharyngitis, Streptococcus intermedius, and Streptococcus constellations), and Enterococcus faecalis (vancomycin-sensitive strains). Dapavanc's mechanism of action is to interfere with bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of the peptidoglycan in the nascent cell wall, thereby preventing cross-linking. Dapavanc is a second-generation semi-synthetic lipopeptide antibiotic with bactericidal activity against a variety of Gram-positive bacteria. Unlike penicillins and cephalosporins, after administration of dapavanc, it binds tightly to the D-alanyl-D-alanine moiety of the peptidoglycan chain, thereby preventing peptidoglycan elongation and interfering with bacterial cell wall synthesis. This leads to the activation of bacterial autolysins and induces cell wall lysis.
Dapavancin is an unknown drug, with its clinical trial phase up to Phase IV (covering all indications). It was first approved in 2014 and currently has 3 approved indications and 7 investigational indications.

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Drug Indications
Dapavancin for injection is indicated for the treatment of acute bacterial skin and soft tissue infections (ABSSSI) in adults caused by susceptible strains of the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, atypical streptococci, streptococci of the pharynx (including Streptococcus pharynx, Streptococcus intermedius, and Streptococcus constellations), and Enterococcus faecalis (vancomycin-susceptible strains). Dapavancin is ineffective against Gram-negative bacteria; therefore, if acute bacterial skin and soft tissue infections (ABSSSI) are multimicrobial infections and involve suspected or confirmed Gram-negative pathogens, combination therapy may be necessary clinically. To reduce the emergence of drug-resistant bacteria and maintain the efficacy of dapavancin and other antimicrobial agents, dapavancin should only be used to treat infections confirmed or highly suspected to be caused by susceptible bacteria. When bacterial culture and drug susceptibility test results are available, they should be used as the basis for selecting or adjusting the antimicrobial treatment regimen. In the absence of such data, empirical treatment can be based on local epidemiological and drug susceptibility patterns. Anthrax is the pathogen of anthrax, which can cause fatal disease upon inhalation or ingestion. Dapavancin is a novel semi-synthetic lipopeptide antibiotic with potent antimicrobial activity against Gram-positive bacteria, superior to vancomycin, and has a long half-life in humans, supporting once-weekly dosing. In vitro studies of dapavancin have shown potent antimicrobial activity against Bacillus anthrax (MIC range ≤0.03–0.5 mg/L; MIC50 and MIC90 are 0.06 mg/L and 0.25 mg/L, respectively), therefore we tested its efficacy using a mouse inhalation anthrax model. Following a single intraperitoneal injection of 5 mg/kg and 20 mg/kg body weight, peak plasma concentrations in mice were 15 mg/kg and 71 mg/kg, respectively. At the 20 mg/kg dose, dapavancin activity persisted for 6 days (terminal half-life of 53 h), indicating that dosing intervals could be extended. Mice inoculated with a bacterial suspension equivalent to 50 to 100 times the median lethal dose of Bacillus anthracis Ames strain, which killed untreated animals within 4 days. Dapavancin efficacy was 80% to 100% when treatment was initiated 24 hours after inoculation, based on survival rates at 42 days. Dapavancin was administered at a dose of 15 to 120 mg/kg every 36 hours (q36h) or 30 to 240 mg/kg every 72 hours (q72h). Ciprofloxacin, known to provide 100% protection in animals, was also tested concurrently. Delayed dapavancin treatment (starting 36 or 48 hours after inoculation) at a dose of 60 mg/kg every 36 hours or 120 mg/kg every 72 hours still provides 70% to 100% survival. Dapavancin has a low MIC value and a long duration of efficacy, suggesting its potential as an alternative drug [1]

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The increasing resistance of streptococcal, staphylococcal and enterococcal strains to antimicrobial agents has been widely confirmed. At least 50% of nosocomial Staphylococcus aureus infections in intensive care units in the United States and the United Kingdom are caused by methicillin-resistant Staphylococcus aureus (MRSA). Resistance is not limited to hospitals; community-acquired MRSA (CA-MRSA) strains are now a common cause of complicated skin and soft tissue infections (cSSTI) in many areas. Dapavancin is a novel parenteral semi-synthetic lipoglycopeptide antibiotic, similar to the natural glycopeptide antibiotics vancomycin and teicoplanin. Dapavancin has multiple mechanisms of action, inhibiting bacterial cell wall formation through two different mechanisms, thereby enhancing its activity against a variety of Gram-positive bacteria, including Staphylococcus, Streptococcus, Enterococcus, and certain anaerobic bacteria. In addition, dapavancin has unique pharmacokinetic properties, most notably its long terminal half-life, which allows it to be administered once a week. This property may bring clinical and cost benefits. Overall, clinical trials have shown that dapavancin is a safe, well-tolerated, and effective antimicrobial agent. In the largest study evaluating dapavancin for the treatment of complicated skin and soft tissue infections (cSSTIs), its efficacy was comparable to linezolid. Dapavancin is expected to receive FDA approval in 2008 and is expected to become a novel antimicrobial agent for the treatment of cSSTIs. [2] Dapavancin is a novel lipopeptide antibiotic that is active against Staphylococcus aureus, including glycopeptide-resistant strains. The in vivo studies reported in this paper tested the antibacterial effect of the antibiotic against seven Staphylococcus aureus isolates with high MIC values (including several vancomycin-intermediate strains). The results showed that dapavancin achieved a 1-log bactericidal effect against seven of the isolates and a 2-log bactericidal effect against six of the isolates. The mean free drug concentration-time area under the curve (fAUC)/MIC values for net inhibition, 1-log bactericidal effect and 2-log bactericidal effect were 27.1, 53.3 and 111.1, respectively. [5] Animal models are essential for the development of active drugs against biothreat pathogens such as Bacillus anthracis. The mouse anthrax inhalation model is the first step to meet the FDA's Animal Rule (46). The results obtained by dapavancin in this model indicate the need for further studies in mice and strongly suggest the need for non-human primate models of Bacillus anthracis infection. [1]

C88H101CL3N10O28

1853.15

1850.585

C, 57.04; H, 5.49; Cl, 5.74; N, 7.56; O, 24.17

2227366-51-8

Dalbavancin;171500-79-1

Typically exists as White to light yellow solid at room temperature

22

30

22

129

3740

18

CC(C)CCCCCCCCC(=O)N[C@@H]1[C@H]([C@@H]([C@H](O[C@H]1OC2=C3C=C4C=C2OC5=C(C=C(C=C5)[C@H]([C@H]6C(=O)N[C@@H](C7=C(C(=CC(=C7)O)O[C@@H]8[C@H]([C@H]([C@@H]([C@H](O8)CO)O)O)O)C9=C(C=CC(=C9)[C@H](C(=O)N6)NC(=O)[C@@H]4NC(=O)[C@@H]1C2=C(C(=CC(=C2)OC2=C(C=CC(=C2)[C@H](C(=O)N[C@H](CC2=CC=C(O3)C=C2)C(=O)N1)NC)O)O)Cl)O)C(=O)NCCCN(C)C)O)Cl)C(=O)O)O)O.Cl

PEXPCJWLNBNBNT-AXKGEONOSA-N

InChI=1S/C88H100Cl2N10O28.ClH/c1-38(2)13-10-8-6-7-9-11-14-61(106)94-70-73(109)75(111)78(86(120)121)128-87(70)127-77-58-31-43-32-59(77)124-55-24-19-42(29-50(55)89)71(107)69-85(119)98-67(80(114)92-25-12-26-100(4)5)48-33-44(102)34-57(125-88-76(112)74(110)72(108)60(37-101)126-88)62(48)47-28-40(17-22-52(47)103)65(82(116)99-69)95-83(117)66(43)96-84(118)68-49-35-46(36-54(105)63(49)90)123-56-30-41(18-23-53(56)104)64(91-3)81(115)93-51(79(113)97-68)27-39-15-20-45(122-58)21-16-39;/h15-24,28-36,38,51,60,64-76,78,87-88,91,101-105,107-112H,6-14,25-27,37H2,1-5H3,(H,92,114)(H,93,115)(H,94,106)(H,95,117)(H,96,118)(H,97,113)(H,98,119)(H,99,116)(H,120,121);1H/t51-,60-,64-,65-,66-,67+,68+,69+,70-,71-,72-,73-,74+,75+,76+,78+,87-,88+;/m1./s1

(2S,3S,4R,5R,6S)-6-[[(1S,2R,19R,22R,34S,37R,40R,52S)-5,32-dichloro-52-[3-(dimethylamino)propylcarbamoyl]-2,26,31,44,49-pentahydroxy-22-(methylamino)-21,35,38,54,56,59-hexaoxo-47-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-7,13,28-trioxa-20,36,39,53,55,58-hexazaundecacyclo[38.14.2.23,6.214,17.219,34.18,12.123,27.129,33.141,45.010,37.046,51]hexahexaconta-3,5,8,10,12(64),14(63),15,17(62),23(61),24,26,29(60),30,32,41(57),42,44,46(51),47,49,65-henicosaen-64-yl]oxy]-3,4-dihydroxy-5-(10-methylundecanoylamino)oxane-2-carboxylic acid;hydrochloride

Dalbavancin (hydrochloride); CHEMBL3301650; Dalbavancin hydrochloride (5:8);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 250 mg/mL (134.91 mM)
H2O : 50 mg/mL (26.98 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (1.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (1.12 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (1.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)