ABSTRACT
Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C55PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C55PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-C55PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure-activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As for the natural product, these next-generation bacitracins were found to form stable complexes with C55PP. The structure-activity insights thus obtained serve to inform the design of C55PP-targeting antibiotics, a key and underexploited antibacterial strategy.
Subject(s)
Anti-Bacterial Agents , Bacitracin , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Bacitracin/pharmacology , Bacitracin/chemistry , Structure-Activity Relationship , Drug Resistance, Bacterial/drug effects , Vancomycin/pharmacology , Vancomycin/chemistry , Vancomycin/analogs & derivatives , Drug Design , Polyisoprenyl Phosphates/metabolism , Polyisoprenyl Phosphates/chemistry , Polyisoprenyl Phosphates/pharmacologySubject(s)
Anti-Bacterial Agents , Lipoglycopeptides , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Lipoglycopeptides/therapeutic use , Anti-Bacterial Agents/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Male , Female , Middle Aged , Recurrence , Aged , Drug Monitoring , Microbial Sensitivity Tests , Adult , Osteomyelitis/drug therapy , Osteomyelitis/microbiology , Vancomycin/analogs & derivativesABSTRACT
BACKGROUND: Oritavancin and dalbavancin are long-acting lipoglycopeptide antibiotics approved for the treatment of skin and skin structure infections. Recently, they have been used for outpatient antimicrobial therapy for complicated infections. No head-to-head studies exist for this purpose. OBJECTIVE: To compare outcomes of patients treated with multiple doses of oritavancin or dalbavancin for complicated infections. PATIENTS AND METHODS: This was a single-centre, retrospective cohort study evaluating adult patients who received two or more doses of lipoglycopeptides for complicated infections from February 2019 through December 2022. Patients receiving oritavancin were compared to dalbavancin after propensity score-matching. The primary endpoint was clinical success at 90 days. Other endpoints included: 30-day re-admission, 30-day mortality, adverse drug reactions (ADRs), and changes in white blood cell count and inflammatory markers after the first dose. RESULTS: After exclusions and propensity score-matching, 131 matched pairs (N = 262) were included in the analysis. Most patients were receiving lipoglycopeptide therapy for osteomyelitis. There was no significant difference in clinical success at 90 days in patients who received oritavancin compared to those who received dalbavancin (99 [76%] vs. 103 [79%], respectively; P = 0.556). There was no significant difference in secondary endpoints, however, there was a trend towards higher incidence of ADRs oritavancin compared to dalbavancin (9 [7%] vs. 2 [2%], respectively; P = 0.060) which led to more treatment discontinuation. CONCLUSION: There was no significant difference in efficacy between multi-dose oritavancin and dalbavancin for the treatment of complicated infections. Both agents were generally well tolerated; however, dalbavancin may be better tolerated when long-term treatment is warranted.
Subject(s)
Anti-Bacterial Agents , Lipoglycopeptides , Propensity Score , Teicoplanin , Humans , Teicoplanin/analogs & derivatives , Teicoplanin/therapeutic use , Teicoplanin/adverse effects , Teicoplanin/administration & dosage , Male , Female , Retrospective Studies , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/administration & dosage , Lipoglycopeptides/therapeutic use , Middle Aged , Aged , Adult , Treatment Outcome , Osteomyelitis/drug therapy , Aged, 80 and over , Vancomycin/analogs & derivativesSubject(s)
Endocarditis, Bacterial , Endocarditis , Enterococcus faecium , Gram-Positive Bacterial Infections , Substance-Related Disorders , Vancomycin/analogs & derivatives , Humans , Lipoglycopeptides/therapeutic use , Anti-Bacterial Agents/therapeutic use , Endocarditis, Bacterial/complications , Endocarditis, Bacterial/drug therapy , Substance-Related Disorders/drug therapy , Gram-Positive Bacterial Infections/complications , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Endocarditis/drug therapyABSTRACT
BACKGROUND: Oritavancin, a long-acting lipoglycopeptide approved for use in acute bacterial skin and skin structure infections, has limited data evaluating use in serious infections due to Gram-positive organisms. We aimed to assess the effectiveness and safety of oritavancin for consolidative treatment of Gram-positive bloodstream infections (BSI), including infective endocarditis (IE). METHODS: We conducted a retrospective cohort study evaluating adult patients admitted to University of Colorado Hospital from March 2016 to January 2022 who received ≥ 1 oritavancin dose for treatment of Gram-positive BSI. Patients were excluded if the index culture was drawn at an outside facility or were > 89 years of age. The primary outcome was a 90-day composite failure (clinical or microbiological failure) in those with 90-day follow-up. Secondary outcomes included individual components of the primary outcome, acute kidney injury (AKI), infusion-related reactions (IRR), and institutional cost avoidance. RESULTS: Overall, 72 patients were included. Mean ± SD age was 54 ± 16 years, 61% were male, and 10% had IE. Organisms most commonly causing BSI were Staphylococcus aureus (68%, 17% methicillin-resistant), followed by Streptococcus spp. (26%), and Enterococcus spp. (10%). Patients received standard-of-care antibiotics before oritavancin for a median (IQR) of 11 (5-17) days. Composite failure in the clinically evaluable population (n = 64) at 90-days occurred in 14% and was composed of clinical and microbiological failure, which occurred in 14% and 5% of patients, respectively. Three patients (4%) experienced AKI after oritavancin, and two (3%) experienced an IRR. Oritavancin utilization resulted in earlier discharge for 94% of patients corresponding to an institutional cost-avoidance of $3,055,804 (mean $44,938/patient) from 1,102 hospital days saved (mean 16 days/patient). CONCLUSIONS: The use of oritavancin may be an effective sequential therapy for Gram-positive BSI to facilitate early discharge resulting in institutional cost avoidance.
Subject(s)
Acute Kidney Injury , Drug-Related Side Effects and Adverse Reactions , Endocarditis, Bacterial , Endocarditis , Vancomycin/analogs & derivatives , Adult , Humans , Male , Middle Aged , Aged , Female , Lipoglycopeptides/therapeutic use , Retrospective StudiesABSTRACT
PURPOSE: Vancomycin-Resistant Enterococci (VREs) have emerged and become a problem that threatens the health of hospitalized patients. VRE can cause different serious infections of the urinary tract, the bloodstream, wound and other body sites. VREs are resistant to multiple antibiotics and treatment options are very limited. We aimed to investigate the efficacy of oritavancin and nisin alone and their combination against VRE strains. METHODS: VRE isolates from rectal swabs of hospitalized patients were identified by conventional and commercial methods. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of oritavancin and nisin against VRE strains were determined. The synergistic effect of both agent combinations was examined by the Checkerboard test. RESULTS: All VRE strains were identifined as Enterococcus faecium. The MIC value of oritavancin was found in the range of 0.015-0.24 âµg/mL; in which 48 strains were susceptible (≤0.12 âµg/mL) and two strains were resistant (>0.12 âµg/mL). The MBC of oritavancin was determined in the range of 0.06-3.84 âµg/mL. The MIC of nisin was found in the range of 12.5-100 âµg/mL; in which 32 strains were susceptible (≤50 âµg/mL) and 18 strains were resistant (>50 âµg/mL). MBC of nisin was determined in the range of 25-800 âµg/mL. Two oritavancin resistant strains were displayed indifference effect, whereas from 18 nisin resistant strains, 11 showed indifference, and seven displayed synergistic effect. Thirty-eight out of 48 strains which were sensitive to oritavancin showed indifference and 10 revealed synergistic effect, whereas 29 of 32 strains which were sensitive to nisin showed indifference and three had synergistic effect. CONCLUSIONS: A synergistic combination of oritavansin and nisin was detected in 20 strains (40%), Our study is the first study in Turkiye.
Subject(s)
Gram-Positive Bacterial Infections , Lipoglycopeptides , Nisin , Vancomycin-Resistant Enterococci , Vancomycin/analogs & derivatives , Humans , Nisin/pharmacology , Turkey , Gram-Positive Bacterial Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Microbial Sensitivity TestsSubject(s)
Skin Diseases, Bacterial , Soft Tissue Infections , Anti-Bacterial Agents/therapeutic use , Emergency Service, Hospital , Glycopeptides , Humans , Lipoglycopeptides/therapeutic use , Skin Diseases, Bacterial/drug therapy , Soft Tissue Infections/drug therapy , Vancomycin/analogs & derivativesABSTRACT
Combined intravenous and intrathecal administration of norvancomycin (NVCM) is routinely employed in treating methicillin-resistant Staphylococcus aureus (MRSA) ventriculitis in patients following craniotomy. However, the optimal dosing regimen, the pharmacokinetics (PK) of NVCM in cerebrospinal fluid (CSF), and the clinical outcome are yet to be elucidated. Herein, a single-center randomized controlled trial was conducted in the Neurosurgery Department of the Second Hospital of Hebei Medical University (Shijiazhuang, China). Patients with MRSA ventriculitis after craniotomy were randomly assigned to two groups. The control group received 800 mg NVCM intravenously every 12 h, and the experimental group received 800 mg NVCM intravenously every 12 h and 16 mg NVCM intrathecal administration every 24 h. The primary outcome was the length of therapy, while the secondary outcomes included the area under the concentration-time curve in 0-24 h/minimum inhibitory concentration ratio (AUC0-24h/MIC) of NVCM in CSF. A total of 29 patients (14 in the experimental group and 15 in the control group) were included in this study. Of these, 24 constituted the final analysis population, with 12 in each group. The average length of therapy in the experimental group was markedly shorter than that of the control group (11.2 ± 2.6 days vs. 16.6 ± 5.2 days, P = 0.005), while the AUC0-24h/MIC in the experimental group was significantly higher than that in the control group (2306.57 ± 928.58 vs. 46.83 ± 27.48, P < 0.001) with no increase in adverse reactions. Combined intravenous and intrathecal administration can shorten the treatment time of intracranial infection without higher adverse reaction risks in our research. Further studies with larger sample size are warranted to verify its safety and efficacy.
Subject(s)
Cerebral Ventriculitis , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Anti-Bacterial Agents , Central Nervous System , Cerebral Ventriculitis/drug therapy , Humans , Staphylococcal Infections/drug therapy , Vancomycin/analogs & derivativesABSTRACT
BACKGROUND: Vancomycin and norvancomycin, as potent antibacterial retention drugs, were used illegally on animals bred for food, which directly affected the quality and safety of animal-derived food, and even harmed human health. OBJECTIVE: A fast analysis method, which was adopted to detect residues of vancomycin and norvancomycin in milk, was implemented on a chromatographic system containing online solid-phase extraction (SPE) device that combined with high-resolution mass spectrometer (HRMS). METHOD: First, the analytes were added to the blank milk sample were extracted with water [containing 0.1% trifluoroacetic acid (TFA)]-acetonitrile (ACN) (8:2, v/v), and then were purified and enriched on a C18-XL column, whereafter eluted from the purification column onto the analytical column (Shiseido Capcell Pak ADME column) for chromatographic separation prior to hybrid quadrupole-Orbitrap (Q-Orbitrap) detection. RESULTS: The results showed that the limit of detection (LOD) for each analyte and the limit of quantitation (LOQ) were 0.15 and 0.5 µg/kg, respectively. The correlation coefficient(s) of vancomycin and norvancomycin ranged from 0 to 200 ng/mL were greater than 0.9983. CONCLUSIONS: These validations reflected that it was suitable for the established method to rapidly analyze vancomycin and norvancomycin residues in milk. HIGHLIGHTS: The method for detecting vancomycin and norvancomycin residues in milk by online SPE combined with LC-HRMS. Online SPE technology realized automation, and the application of HRMS greatly improved the reliability of qualitative and quantitative analyses. The developed method is fast, simple, and reliable; each methodological index can meet requirements of trace analyses of vancomycin and norvancomycin in milk.
Subject(s)
Milk , Vancomycin , Animals , Anti-Bacterial Agents/analysis , Chromatography, High Pressure Liquid , Chromatography, Liquid/methods , Milk/chemistry , Reproducibility of Results , Solid Phase Extraction/methods , Tandem Mass Spectrometry/methods , Vancomycin/analogs & derivativesABSTRACT
BACKGROUND: Vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib are five commonly used drugs which are all recommended to therapeutic drug monitoring in clinical settings. However, the blood concentration monitoring of these drugs and the interpretations of the test results are limited to some extent due to the differences of testing instruments and testing methods. METHODS: We established an ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantification of vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib in human plasma. The method was validated according to the guideline for bioanalytical method validation and applied in clinical therapy. RESULTS: The calibration ranges of vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib were 0.5-100 µg/mL, 0.5-100 µg/mL, 5-1000 ng/mL, 10-2000 ng/mL, and 5-500 ng/mL, respectively. Inaccuracy and imprecision of every drug were less than 15%. The internal standard normalized recovery rates of vancomycin and norvancomycin were about 45%, while which of methotrexate, paclitaxel, and imatinib were almost 100%. No obvious carryover effect was observed. Samples were stable for at least 24 h in the automatic sampler, 72 h at 4°C, and 1 week in -80°C. There were no differences of concentrations between plasma and serum for the five drugs. Moreover, there were positive correlations between methotrexate and vancomycin concentrations and creatinine, as well as positive correlation between imatinib concentration and age of the patient. CONCLUSIONS: The UPLC-MS/MS method was competent for the simultaneous monitoring of vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib because of its short analysis time, high specificity, and accuracy.
Subject(s)
Tandem Mass Spectrometry , Vancomycin , Chromatography, High Pressure Liquid/methods , Chromatography, Liquid/methods , Humans , Imatinib Mesylate , Methotrexate , Paclitaxel , Reproducibility of Results , Tandem Mass Spectrometry/methods , Vancomycin/analogs & derivativesABSTRACT
BACKGROUND: Early discharge (ED) from hospital and outpatient parenteral antibiotic therapy (OPAT) are effective approaches for the management of a range of infections, including acute bacterial skin and skin structure infections (ABSSSI). Strategies that facilitate ED, thereby reducing complications such as healthcare-acquired infection whilst enhancing patient quality of life, are being increasingly adopted in line with good antimicrobial stewardship practice. This study presents a cost-minimisation analysis for the use of oritavancin at ED versus relevant comparators from a National Health Service (NHS) and personal and social services United Kingdom perspective. METHODS: A cost-minimisation model considering adult patients with ABSSSI with suspected or confirmed methicillin-resistant Staphylococcus aureus (MRSA) infection, was developed based on publicly available NHS costs, practice guidelines for ABSSSI and clinical expert's opinion. Cost of treatment and treatment days were compared for oritavancin at ED to dalbavancin, teicoplanin, daptomycin and linezolid. RESULTS: Following the empiric use of either flucloxacillin or vancomycin in the inpatient setting, oritavancin was compared to OPAT with dalbavancin, teicoplanin and daptomycin, and oral linezolid from day 4 of treatment. Oritavancin at ED reduced treatment duration by 0.8 days and led to cost savings of £281 in comparison to dalbavancin. In comparison to teicoplanin, daptomycin and linezolid, oritavancin reduced treatment duration by 5 days, with marginally higher costs (£446, £137, and £1,434, respectively). CONCLUSION: Oritavancin, used to support ED, is associated with lower costs compared with dalbavancin and reduced treatment duration relative to all comparators. Its use would support an ED approach in MRSA ABSSSI management.
Subject(s)
Daptomycin , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/therapeutic use , Floxacillin , Glycopeptides/therapeutic use , Humans , Linezolid/therapeutic use , Lipoglycopeptides , Quality of Life , State Medicine , Teicoplanin/therapeutic use , Vancomycin/analogs & derivatives , Vancomycin/therapeutic useABSTRACT
A simple and sensitive method based on surface molecularly imprinted solid-phase extraction (SMISPE) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to determine the residues of vancomycin (VCM) and norvancomycin (NVCM) in milk samples. The imprinted polymer prepared with teicoplanin as a virtual template can specifically recognize VCM and NVCM. The samples were purified with SMISPE and analyzed by LC-MS/MS in positive ionization mode. The results showed that the VCM and NVCM had a good linear correlation in the range of 0.5 µg/kg to 50 µg/kg. The recoveries of target analytes were from 83.3% to 92.1%, and the limits of quantification were both 1.0 µg/kg. The matrix effects of VCM and NVCM were -11.0% and -3.43%, respectively. The proposed method can efficiently eliminate the interference from matrix compounds and reduce baseline noise, which is useful for the monitoring of the residues of VCM and NVCM in milk samples.
Subject(s)
Molecular Imprinting , Tandem Mass Spectrometry , Animals , Chromatography, High Pressure Liquid , Chromatography, Liquid , Milk , Solid Phase Extraction , Vancomycin/analogs & derivativesABSTRACT
Microbial keratitis occurs from the infection of the cornea by fungi and or bacteria. It remains one of the most common global causes of irreversible blindness accounting for 3.5% (36 million) of blind people as of 2015. This paper looks at the use of a bacteria binding polymer designed to bind Staphylococcus aureus and remove it from the corneal surface. Mechanical unbinding measurements were used to probe the interactions of a thermo-active bacteria-binding polymer, highly-branched poly(N-isopropyl acrylamide), functionalised with modified vancomycin end groups (HB-PNIPAM-Van) to bacteria placed on rabbit corneal surfaces studied ex-vivo. This was conducted during sequential temperature phase transitions of HB-PNIPAM-Van-S. aureus below, above and below the lower critical solution temperature (LCST) in 3 stages, in-vitro, using a novel micro-bead force spectroscopy (MBFS) approach via atomic force microscopy (AFM). The effect of temperature on the functionality of HB-PNIPAM-Van-S. aureus showed that the polymer-bacteria complex reduced the work done in removing bacterial aggregates at T > LCST (p < 0.05), exhibiting reversibility at T < LCST (p < 0.05). At T < LCST, the breaking force, number of unbinding events, percentage fitted segments in the short and long range, and the percentage of unbinding events occurring in the long range (> 2.5 µm) increased (p < 0.05). Furthermore, the LCST phase transition temperature showed 100 × more unbinding events in the long-range z-length (> 2.5 µm) compared to S. aureus aggregates only. Here, we present the first study using AFM to assess the reversible mechanical impact of a thermo-active polymer-binding bacteria on a natural corneal surface.
Subject(s)
Acrylic Resins/chemistry , Cornea/microbiology , Microscopy, Atomic Force/methods , Staphylococcus aureus/isolation & purification , Vancomycin/analogs & derivatives , Animals , Phase Transition , Rabbits , TemperatureABSTRACT
BACKGROUND: Norvancomycin has been widely used in clinic to treat against MRSA (Methicillin-resistant Staphylococcus aureus) and MRSE (Methicillin-resistant Staphylococcus epidermidis) infections in China. Amycolatopsis orientalis NCPC 2-48, a high yield strain derived from A. orientalis CPCC 200066, has been applied in industrial large-scale production of norvancomycin by North China Pharmaceutical Group. However, the potential high-yield and regulatory mechanism involved in norvancomycin biosynthetic pathway has not yet been addressed. RESULTS: Here we sequenced and compared the genomes and transcriptomes of A. orientalis CPCC 200066 and NCPC 2-48. These two genomes are extremely similar with an identity of more than 99.9%, and no duplication and structural variation was found in the norvancomycin biosynthetic gene cluster. Comparative transcriptomic analysis indicated that biosynthetic genes of norvancomycin, as well as some primary metabolite pathways for the biosynthetic precursors of norvancomycin were generally upregulated. AoStrR1 and AoLuxR1, two cluster-situated regulatory genes in norvancomycin cluster, were 23.3-fold and 5.8-fold upregulated in the high yield strain at 48 h, respectively. Over-expression of AoStrR1 and AoLuxR1 in CPCC 200066 resulted in an increase of norvancomycin production, indicating their positive roles in norvancomycin biosynthesis. Furthermore, AoStrR1 can regulate the production of norvancomycin by directly interacting with at least 8 promoters of norvancomycin biosynthetic genes or operons. CONCLUSION: Our results suggested that the high yield of NCPC 2-48 can be ascribed to increased expression level of norvancomycin biosynthetic genes in its cluster as well as the genes responsible for the supply of its precursors. The norvancomycin biosynthetic genes are presumably regulated by AoStrR1 and AoLuxR1, of them AoStrR1 is possibly the ultimate pathway-specific regulator for the norvancomycin production. These results are helpful for further clarification of the holistic and pathway-specific regulatory mechanism of norvancomycin biosynthesis in the industrial production strain.
Subject(s)
Genomics , Transcriptome/genetics , Vancomycin/analogs & derivatives , Amycolatopsis/genetics , Bacterial Proteins/metabolism , Base Sequence , Biosynthetic Pathways , Multigene Family , Promoter Regions, Genetic/genetics , Protein Binding , Vancomycin/biosynthesis , Vancomycin/chemistryABSTRACT
PURPOSE: Efficacy of norvancomycin (NVCM) through continuous topical ocular instillation drug delivery (CTOIDD) system for treating severe acute bacterial keratitis infection with Staphylococcus aureus was investigated. METHODS: Rabbits with bacterial keratitis were treated using CTOIDD with NVCM (n=13), topical NVCM eye drops (n=11), and CTOIDD with saline (n=8). Clinical signs of keratitis in all groups were assessed consecutively for a week. Bacterial quantification of excised corneas was counted on the fourth and eighth days. Histopathologic examinations were performed to assess inflammatory cell infiltration on the eighth day. RESULTS: All signs of bacterial keratitis were alleviated in CTOIDD with NVCM according to criteria, and the CTOIDD-NVCM group had significantly less inflammation than CTOIDD-saline (p<0.05), and eye drop-NVCM (p<0.05). Two eyes in the eye drop-NVCM group, four eyes in the CTOIDD-saline group had corneal perforation (CP), while none of the rabbits showed CP in the CTOIDD-NVCM group. Bacterial counts were significantly less in the CTOIDD with NVCM group in comparison to the eye drop-NVCM (p<0.05), and CTOIDD-saline (p<0.05) groups. Severe inflammation and marked inflammatory cell infiltration were found in histopathologic examinations in the CTOIDD-saline and eye drop-NVCM groups, while significantly less inflammation was documented in the CTOIDD-NVCM (p<0.05) group. CONCLUSION: CTOIDD with NVCM effectively reduced the severity and treated acute bacterial S. aureus keratitis infection in a rabbit model. The presented approach of CTOIDD with NVCM appears to be a promising therapeutic approach for severe acute bacterial keratitis.
Subject(s)
Anti-Bacterial Agents/pharmacology , Eye Infections, Bacterial/drug therapy , Keratitis/drug therapy , Ophthalmic Solutions/pharmacology , Staphylococcus aureus/drug effects , Vancomycin/analogs & derivatives , Acute Disease , Administration, Ophthalmic , Animals , Anti-Bacterial Agents/administration & dosage , Dose-Response Relationship, Drug , Eye Infections, Bacterial/microbiology , Female , Keratitis/microbiology , Microbial Sensitivity Tests , Molecular Structure , Ophthalmic Solutions/administration & dosage , Rabbits , Structure-Activity Relationship , Vancomycin/administration & dosage , Vancomycin/pharmacologyABSTRACT
OBJECTIVES: To determine the epidemiological cut-off values (ECOFFs) of norvancomycin for Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus hominis. METHODS: We collected 1199 clinical isolates of Staphylococcus species from five laboratories located in four cities in China. MICs and inhibitory zone diameters of norvancomycin were determined by broth microdilution and the disc diffusion method, separately. ECOFFs of norvancomycin for four species were calculated by ECOFFinder software following EUCAST principles. Methicillin and vancomycin resistance genes (mecA/mecC and vanA/vanB/vanC/vanD/vanE) were screened for by PCR in all isolates. Pearson correlation and χ2 test were used to calculate the correlation of MICs and inhibition zone diameters, and MICs and resistance genes, respectively. RESULTS: MICs of norvancomycin for all strains from five laboratories fell in the range of 0.12-2 mg/L. ECOFFs of norvancomycin were determined to be 2 mg/L for S. epidermidis and S. haemolyticus and 1 mg/L for S. aureus and S. hominis. A weak correlation was observed between MIC values and zone diameters for S. haemolyticus (r = -0.36) and S. hominis (r = -0.26), while no correlation was found for S. epidermidis and S. aureus. The mecA gene was detected in 63.1% of Staphylococcus, whereas no isolate carried mecC, vanA, vanB, vanC, vanD or vanE. ECOFFs of norvancomycin were not correlated with mecA gene carriage in Staphylococcus species. CONCLUSIONS: ECOFFs of norvancomycin for four Staphylococcus species were determined, which will be helpful to differentiate WT strains. The correlation of MICs and zone diameters of norvancomycin was weak in Staphylococcus species.
Subject(s)
Staphylococcal Infections , Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , China/epidemiology , Humans , Microbial Sensitivity Tests , Staphylococcal Infections/epidemiology , Staphylococcus epidermidis/genetics , Staphylococcus haemolyticus/genetics , Staphylococcus hominis/genetics , Vancomycin/analogs & derivativesABSTRACT
Vancomycin and norvancomycin are glycopeptide antibiotics for gram-positive bacteria infection, but indiscriminately used in aquaculture. In this study, a QuEChERS (quick, easy, cheap, effective, rugged, and safe)/96-well solid-phase extraction (SPE) plate method was used to extract vancomycin and norvancomycin in fish meat samples, and the drugs were further analyzed by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The parameters, such as the sorbent of cation exchange resin, the proportion of acetonitrile (15%) in extractant, the mobile phase of water (0.1% formic acid)/acetonitrile, were optimized. The method was validated in terms of linearity (0.9990-0.9994), LOD (0.51 µg·kg-1), LOQ (1.73 µg·kg-1), intra-dayprecision (<5.19%), inter-day precision (<6.30%), and recovery (86.7-98.6%). Finally, the method was successfully applied to contaminated and randomly collected samples. The results indicated that the proposed method meet the daily monitoring requirements for vancomycin and norvancomycin.
Subject(s)
Costs and Cost Analysis , Fishes , Safety , Solid Phase Extraction/economics , Solid Phase Extraction/methods , Vancomycin/analogs & derivatives , Vancomycin/isolation & purification , Animals , Chromatography, High Pressure Liquid , Limit of Detection , Seafood/analysis , Tandem Mass Spectrometry , Time Factors , Water/chemistryABSTRACT
Since its discovery, vancomycin has been used in the clinic for >60 years. Because of their durability, vancomycin and related glycopeptides serve as the antibiotics of last resort for the treatment of protracted bacterial infections of resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant (MDR) Streptococcus pneumoniae. After 30 years of use, vancomycin resistance was first observed and is now widespread in enterococci and more recently in S. aureus. The widespread prevalence of vancomycin-resistant enterococci (VRE) and the emergence of vancomycin-resistant S. aureus (VRSA) represent a call to focus on the challenge of resistance, highlight the need for new therapeutics, and provide the inspiration for the design of more durable antibiotics less prone to bacterial resistance than even vancomycin.Herein we summarize progress on efforts to overcome vancomycin resistance, first addressing recovery of its original durable mechanism of action and then introducing additional independent mechanisms of action intended to increase the potency and durability beyond that of vancomycin itself. The knowledge of the origin of vancomycin resistance and an understanding of the molecular basis of the loss of binding affinity between vancomycin and the altered target ligand d-Ala-d-Lac provided the basis for the subtle and rational redesign of the vancomycin binding pocket to remove the destabilizing lone-pair repulsion or reintroduce a lost H-bond while not impeding binding to the unaltered ligand d-Ala-d-Ala. Preparation of the modified glycopeptide core structure was conducted by total synthesis, providing binding pocket-modified vancomycin aglycons with dual d-Ala-d-Ala/d-Lac binding properties that directly address the intrinsic mechanism of resistance to vancomycin. Fully glycosylated pocket-modified vancomycin analogues were generated through a subsequent two-step enzymatic glycosylation, providing a starting point for peripheral modifications used to introduce additional mechanisms of action. A well-established vancosamine N-(4-chlorobiphenyl)methyl (CBP) modification as well as newly discovered C-terminal trimethylammonium cation (C1) or guanidine modifications were introduced, providing two additional synergistic mechanisms of action independent of d-Ala-d-Ala/d-Lac binding. The CBP modification provides an additional stage for inhibition of cell wall synthesis that results from direct competitive inhibition of transglycosylase, whereas the C1/guanidine modification induces bacteria cell permeablization. The synergistic behavior of the three independent mechanisms of action combined in a single molecule provides ultrapotent antibiotics (MIC = 0.01-0.005 µg/mL against VanA VRE). Beyond the remarkable antimicrobial activity, the multiple mechanisms of action suppress the rate at which resistance may be selected, where any single mechanism of action is protected by the action of others. The results detailed herein show that rational targeting of durable vancomycin-derived antibiotics has generated compounds with a "resistance against resistance", provided new candidate antibiotics, and may serve as a generalizable strategy to combat antibacterial resistance.
Subject(s)
Anti-Bacterial Agents/chemistry , Drug Design , Vancomycin/analogs & derivatives , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Binding Sites , Dipeptides/chemistry , Dipeptides/metabolism , Glycopeptides/chemistry , Glycopeptides/metabolism , Guanidine/chemistry , Half-Life , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Vancomycin/chemical synthesis , Vancomycin/metabolism , Vancomycin/pharmacology , Vancomycin Resistance/drug effectsABSTRACT
Knowledge of pharmacokinetic (PK) behavior of norvancomycin (NVCM) in pediatric patients is lacking, which leads to empirical therapy in clinical practice. This study developed a population PK model of children aged 0-15 years; 112 opportunistic samples in total from 90 children were analyzed. The stability and prediction of the final model were evaluated by goodness-of-fit plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. The PKs of NVCM in children was described by a 2-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates on clearance. The population typical values of the PK parameters were as follows: clearance 0.12 L/kg/h, central compartment distribution volume 0.17 L/kg, peripheral compartment distribution volume 0.38 L/kg, and intercompartmental clearance 0.35 L/kg/h. Logistic analysis showed that the ratio of area under the concentration-time curve over 24 hours (AUC0-24 ) to minimum inhibitory concentration (MIC) had the strongest correlation with clinical efficacy, and at least 80% clinical efficiency could be achieved when AUC0-24 /MIC ≥ 221.06 was defined as the target. Monte Carlo simulation results suggested that a higher dose was required for this pediatric population in order to reach the target. The dosing regimen was optimized based on the final model. A population PK model of NVCM was first characterized in children with hematologic malignancy, and an evidence-based approach for NVCM dosage individualization was provided.