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OBJECTIVES: We evaluated the efficacies of human-simulated regimens (HSRs) of two clinically utilized sulbactam regimens: 1 g q6h 0.5 h infusion (maximum FDA-approved dosage) and 3 g q8h 4 h infusion (high-dose, prolonged-infusion regimen), against Acinetobacter baumannii in a translational murine model. METHODS: Thirty-two clinical A. baumannii isolates were investigated, of which 16 were sulbactam resistant (MICâ≥â16 mg/L), 6 were sulbactam intermediate (MICâ=â8 mg/L) and 10 were sulbactam susceptible (MICâ≤â4 mg/L). Efficacies of the two sulbactam HSRs were assessed in the neutropenic murine pneumonia model. Changes in log10 cfu/lungs at 24 h compared with 0 h controls were measured, and efficacy was defined as achieving 1 log kill relative to baseline. WGS of the isolates and bioinformatics analysis were performed to explore potential associations between the genomic backgrounds and the in vivo responses. RESULTS: Eleven isolates harboured blaOXA-23, of which 10 were sulbactam resistant, 1 was sulbactam intermediate while none was sulbactam susceptible. Both sulbactam HSRs achieved >1 log kill against sulbactam-susceptible isolates. Against sulbactam-intermediate and sulbactam-resistant isolates, lack of efficacy correlated with the presence of the blaOXA-23 gene; sulbactam 1 g HSR and 3 g HSR did not show efficacy against 11/11 and 9/11 blaOXA-23-positive isolates, respectively, while efficacy was observed against all 11 blaOXA-23-negative sulbactam-intermediate and sulbactam-resistant isolates (i.e. harbouring other resistance genes). CONCLUSIONS: A sulbactam high-dose prolonged-infusion regimen provides comparable activity to the standard dose against isolates currently considered sulbactam susceptible. However, the activity against isolates with intermediate and resistant susceptibility could be predicted by the detection of blaOXA-23. Enhancing detection capabilities of common diagnostic modalities to include OXA-23 can improve patient outcome.
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BACKGROUND: Sulbactam dosing for Acinetobacter baumannii infections has not been standardized due to limited available pharmacokinetics/pharmacodynamics (PK/PD) data. Herein, we report a comprehensive PK/PD analysis of ampicillin-sulbactam against A. baumannii pneumonia. METHODS: Twenty-one A. baumannii clinical isolates were tested in the neutropenic murine pneumonia model. For dose-ranging studies, groups of mice were administered escalating doses of ampicillin-sulbactam. Changes in log10cfu/lungs relative to 0 h were assessed. Dose-fractionation studies were performed. Estimates of the percentage of of time during which the unbound plasma sulbactam concentrations exceeded the MIC (%fTâ>âMIC) required for different efficacy endpoints were calculated. The probabilities of target attainment (PTA) for the 1-log kill plasma targets were estimated following clinically utilized sulbactam regimens. RESULTS: Dose-fractionation studies demonstrated time-dependent kill. Isolates resistant to both sulbactam and meropenem required three times the exposures to achieve 1-log kill; median [IQR] %fTâ>âMIC of 60.37% [51.6-66.8] compared with other phenotypes (21.17 [16.0-32.9] %fTâ>âMIC). Sulbactam standard dose (1 g q6h, 0.5 h infusion) provided >90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h, 4 h inf provided greater PTA for isolates with sulbactam-intermediate susceptibility (8 mg/L, 100% versus 86% following the standard dose). Despite the higher exposure following 3 g q8h, 4 h inf, PTA was ≤57% among sulbactam-resistant/meropenem-resistant isolates. CONCLUSION: Sulbactam standard dose is a valuable regimen across sulbactam-susceptible isolates while the high-dose extended-infusion provides additional benefit against sulbactam-intermediate isolates. Given that most of the sulbactam-resistant A. baumannii isolates are meropenem-resistant, high-dose prolonged-infusion regimens are not expected to be effective as monotherapy against infections due to these isolates.
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OBJECTIVES: We evaluated the in vivo efficacy of human-simulated regimens (HSRs) of cefiderocol, ceftazidime/avibactam, meropenem and ceftazidime/avibactam/meropenem combination against Guiana-extended spectrum (GES)-producing Pseudomonas aeruginosa isolates. METHODS: Eighteen P. aeruginosa isolates producing GES-1 (nâ=â5), GES-5 (nâ=â5) or miscellaneous GESs (combinations of GES-19, GES-20 and/or GES-26; nâ=â8) were evaluated. In vitro MIC testing was determined using broth microdilution. In a validated murine thigh infection model, HSRs of cefiderocol 2 g q8h as a 3 h IV infusion, ceftazidime/avibactam 2.5 g q8h as a 2 h IV infusion, meropenem 2 g q8h as a 3 h IV infusion or ceftazidime/avibactam/meropenem were administered. Change in bacterial burden relative to baseline and the proportion of isolates in each genotypic group meeting 1-log10 kill endpoint were assessed. RESULTS: Modal MICs (mg/L) ranged from 0.125 to 1 for cefiderocol, 4 to >64 for ceftazidime/avibactam and 2 to >64 for meropenem. Cefiderocol produced >1-log10 of kill against all 18 tested isolates. Meropenem was active against all GES-1 isolates whereas activity against GES-5 and miscellaneous GESs was lacking, consistent with the MICs. Ceftazidime/avibactam was active against all GES-1 and GES-5 isolates and retained activity against 62.5% of miscellaneous GESs including isolates with elevated MICs. For isolates where ceftazidime/avibactam failed, the addition of meropenem restored the in vivo efficacy. CONCLUSIONS: As monotherapy, cefiderocol was active in vivo against all tested isolates. The activities of meropenem or ceftazidime/avibactam alone were variable; however, a combination of both was active against all isolates. Cefiderocol and ceftazidime/avibactam/meropenem could be valuable therapeutic options for GES-producing P. aeruginosa infections. Clinical confirmatory data are warranted.
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Antibacterianos , Ceftazidima , Animales , Humanos , Ratones , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Ceftazidima/farmacología , Ceftazidima/uso terapéutico , Pseudomonas aeruginosa , Meropenem , Pseudomonas , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , beta-Lactamasas , Combinación de Medicamentos , Pruebas de Sensibilidad Microbiana , CefiderocolRESUMEN
OBJECTIVE: Tebipenem pivoxil hydrobromide is a novel oral carbapenem prodrug of tebipenem, the active moiety. We assessed tebipenem steady-state pharmacokinetics in the skin and soft tissue in healthy subjects and infected patients with diabetes using in vivo microdialysis. METHODS: Six healthy subjects and six patients with an ongoing diabetic foot infection (DFI) received tebipenem pivoxil hydrobromide 600â mg orally every 8â h for three doses. A microdialysis probe was inserted in the thigh of healthy subjects or by the wound margin in patients. Plasma and dialysate samples were obtained immediately prior to the third dose and sampled over 8â h. RESULTS: Tebipenem plasma protein binding (meanâ±âSD) was 50.2%â±â2.4% in healthy subjects and 53.5%â±â5.6% in infected patients. Meanâ±âSD tebipenem pharmacokinetic parameters in plasma for healthy subjects and infected patients were: maximum free concentration (fCmax), 3.74â±â2.35 and 3.40â±â2.86â mg/L, respectively; half-life, 0.88â±â0.11 and 2.02â±â1.32â h; fAUC0-8, 5.61â±â1.64 and 10.01â±â4.81â mg·h/L. Tebipenem tissue AUC0-8 was 5.99â±â3.07 and 8.60â±â2.88â mg·h/L for healthy subjects and patients, respectively. The interstitial concentration-time profile largely mirrored the free plasma profile within both populations, resulting in a penetration ratio of 107% in healthy subjects and 90% in infected patients. CONCLUSIONS: Tebipenem demonstrated excellent distribution into skin and soft tissue of healthy subjects and patients with DFI following oral administration of 600â mg of tebipenem pivoxil hydrobromide.
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Enfermedades Transmisibles , Diabetes Mellitus , Pie Diabético , Humanos , Pie Diabético/tratamiento farmacológico , Distribución Tisular , Voluntarios Sanos , Microdiálisis , MonobactamasRESUMEN
BACKGROUND: To date, no real-world data are available to describe cefiderocol use in carbapenem-resistant Acinetobacter baumannii (CRAB) meningitis. Furthermore, cefiderocol pharmacokinetic (PK) data to support CNS penetration in human subjects are limited. These gaps pose a significant concern for clinicians who are faced with treating such infections when considering cefiderocol use. OBJECTIVES: To describe cefiderocol CSF and plasma PK and pharmacodynamic (PD) data from two different dosing regimens [2â g IV q6h (regimen 1) and 2â g IV q8h (regimen 2)] during treatment of CRAB meningitis. PATIENTS AND METHODS: A 61-year-old woman with CRAB meningitis was treated with cefiderocol and intraventricular gentamicin. Steady-state plasma and CSF cefiderocol concentrations were evaluated on Day 19 (regimen 1) and Day 24 (regimen 2) during the cefiderocol treatment course. RESULTS: CSF AUC was 146.49 and 118.28â mg·h/L, as determined by the linear-log trapezoidal method for regimens 1 and 2, respectively. Penetration into CSF estimated as the AUCCSF/AUCfree plasma ratio was 68% and 60% for regimens 1 and 2, respectively. Estimated free plasma and CSF concentrations exceeded the MIC of the isolate for 100% of the dosing interval. Microbiological and clinical cure were achieved, and no cefiderocol-associated adverse effects were observed. CONCLUSIONS: Cefiderocol, when given as 2â g q8h and 2â g q6h, attained CSF concentrations that exceeded the organism-specific MIC and the CLSI susceptible breakpoint (≤4â mg/L) for 100% of the dosing interval.
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Acinetobacter baumannii , Meningitis , Antibacterianos/farmacología , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Cefalosporinas/uso terapéutico , Femenino , Gentamicinas , Humanos , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , CefiderocolRESUMEN
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are correlated with high mortality rates worldwide. Thus, the administration of antibiotic therapy with appropriate dosing regimen is critical. An efficient antibiotic is needed to maintain an adequate concentration at the infection site, for a sufficient period of time, to achieve the best therapeutic outcome. It can, however, be challenging for antibiotics to penetrate the pulmonary system due to the complexity of its structure. Crossing the blood alveolar barrier is a difficult process determined by multiple factors that are either drug related or infection related. Thus, the understanding of pharmacokinetics/pharmacodynamics (PK/PD) of antibiotics identifies the optimum dosing regimens to achieve drug penetration into the epithelial lining fluid at adequate therapeutic concentrations. Critically ill patients in the ICU can express augmented renal clearance (ARC), characterized by enhanced renal function, or may have renal dysfunction necessitating supportive care such as continuous renal replacement therapy (CRRT). Both ARC and CRRT can alter drug elimination, thus affecting drug concentrations. PK of critically ill patients is less clear due to the multiple variabilities associated with their condition. Therefore, conventional dosing regimens often lead to therapeutic failure. Another major hurdle faced in optimizing treatment for HAP/VAP is the reduction of the in vitro potency. Therapeutic drug monitoring (TDM), if available, may allow health care providers to personalize treatment to maximize efficacy of the drug exposures while minimizing toxicity. TDM can be of significant importance in populations whom PK are less defined and for resistant infections to achieve the best therapeutic outcome.
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Neumonía Asociada al Ventilador , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Enfermedad Crítica/terapia , Monitoreo de Drogas , Hospitales , Humanos , Neumonía Asociada al Ventilador/tratamiento farmacológicoRESUMEN
Bacterial biofilms are surface-attached communities of slow-growing and non-replicating persister cells that demonstrate high levels of antibiotic tolerance. Biofilms occur in nearly 80 % of infections and present unique challenges to our current arsenal of antibiotic therapies, all of which were initially discovered for their abilities to target rapidly dividing, free-floating planktonic bacteria. Bacterial biofilms are credited as the underlying cause of chronic and recurring bacterial infections. Innovative approaches are required to identify new small molecules that operate through bacterial growth-independent mechanisms to effectively eradicate biofilms. One source of inspiration comes from within the lungs of young cystic fibrosis (CF) patients, who often endure persistent Staphylococcus aureus infections. As these CF patients age, Pseudomonas aeruginosa co-infects the lungs and utilizes phenazine antibiotics to eradicate the established S.â aureus infection. Our group has taken a special interest in this microbial competition strategy and we are investigating the potential of phenazine antibiotic-inspired compounds and synthetic analogues thereof to eradicate persistent bacterial biofilms. To discover new biofilm-eradicating agents, we have established an interdisciplinary research program involving synthetic medicinal chemistry, microbiology and molecular biology. From these efforts, we have identified a series of halogenated phenazines (HPs) that potently eradicate bacterial biofilms, and future work aims to translate these preliminary findings into ground-breaking clinical advances for the treatment of persistent biofilm infections.
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Antibacterianos/farmacología , Fenómenos Fisiológicos Bacterianos/efectos de los fármacos , Biopelículas/efectos de los fármacos , Descubrimiento de Drogas , Fenazinas/farmacología , Animales , Antibacterianos/síntesis química , Células HeLa , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Fenazinas/síntesis químicaRESUMEN
Bacterial biofilms are surface-attached communities of non-replicating bacteria innately tolerant to antibiotics. Biofilms display differential gene expression profiles and physiologies as compared to their planktonic counterparts; however, their biology remains largely unknown. In this study, we used a halogenated phenazine (HP) biofilm eradicator in transcript profiling experiments (RNA-seq) to define cellular targets and pathways critical to biofilm viability. WoPPER analysis with time-course validation (RT-qPCR) revealed that HP-14 induces rapid iron starvation in MRSA biofilms, as evident by the activation of iron-acquisition gene clusters in 1â hour. Serine proteases and oligopeptide transporters were also found to be up-regulated, whereas glycolysis, arginine deiminase, and urease gene clusters were down-regulated. KEGG analysis revealed that HP-14 impacts metabolic and ABC transporter functional pathways. These findings suggest that MRSA biofilm viability relies on iron homeostasis.
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Biopelículas , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/fisiología , Transcriptoma , Antibacterianos/química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Halogenación , Humanos , Hierro/metabolismo , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Fenazinas/química , Fenazinas/farmacología , Transducción de Señal/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Transcriptoma/efectos de los fármacosRESUMEN
Bacterial biofilms housing dormant persister cells are innately tolerant to antibiotics and disinfectants, yet several membrane-active agents are known to eradicate tolerant bacterial cells. NH125, a membrane-active persister killer and starting point for development, led to the identification of two N-arylated analogues (1 and 2) that displayed improved biofilm eradication potencies compared to the parent compound and rapid persister-cell-killing activities in stationary cultures of methicillin-resistant Staphylococcus aureus (MRSA). We found 1 and 2 to be superior to other membrane-active agents in biofilm eradication assays, with 1 demonstrating minimum biofilm eradication concentrations (MBEC) of 23.5, 11.7, and 2.35â µm against MRSA, methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococcus faecium (VRE) biofilms, respectively. We tested our panel of membrane-active agents against MRSA stationary cultures and found 1 to rapidly eradicate MRSA stationary cells by 4â log units (99.99 %) in 30â min. The potent biofilm eradication and rapid persister-cell-killing activities exhibited by N-arylated NH125 analogues could have significant impact in addressing biofilm-associated problems.
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Biopelículas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Acetamidas/química , Antibacterianos/química , Antibacterianos/farmacología , Eritrocitos/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piridinas/químicaRESUMEN
During microbial infection, antimicrobial peptides are utilized by the immune response to rapidly eradicate microbial pathogens through the destruction of cellular membranes. Inspired by antimicrobial peptides, quaternary ammonium cationic (QAC) compounds have emerged as agents capable of destroying bacterial membranes leading to rapid bacterial death, including the eradication of persistent, surface-attached bacterial biofilms. NH125, an imidazolium cation with a sixteen membered fatty tail, was recently reported to eradicate persister cells and was our starting point for the development of novel antimicrobial agents. Here, we describe the design, chemical synthesis and biological investigations of a collection of 30 diverse NH125 analogues which provided critical insights into structural features that are important for antimicrobial activities in this class. From these studies, multiple NH125 analogues were identified to possess potent antibacterial and antifungal activities, eradicate both bacterial and fungal biofilms and rapidly eradicate MRSA persister cells in stationary phase. NH125 analogues also demonstrated more rapid persister cell killing activities against MRSA when tested alongside a panel of diverse membrane-active agents, including BAC-16 and daptomycin. NH125 analogues could have a significant impact on persister- and biofilm-related problems in numerous biomedical applications.
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Antibacterianos/farmacología , Antifúngicos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Biopelículas/efectos de los fármacos , Imidazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Péptidos Catiónicos Antimicrobianos/síntesis química , Péptidos Catiónicos Antimicrobianos/química , Bacterias/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hongos/efectos de los fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Agents capable of eradicating bacterial biofilms are of great importance to human health as biofilm-associated infections are tolerant to our current antibiotic therapies. We have recently discovered that halogenated quinoline (HQ) small molecules are: 1)â capable of eradicating methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin-resistant Enterococcus faecium (VRE) biofilms, and 2)â synthetic tuning of the 2-position of the HQ scaffold has a significant impact on antibacterial and antibiofilm activities. Here, we report the chemical synthesis and biological evaluation of 39 HQ analogues that have a high degree of structural diversity at the 2-position. We identified diverse analogues that are alkylated and aminated at the 2-position of the HQ scaffold and demonstrate potent antibacterial (MIC≤0.39â µm) and biofilm eradication (MBEC 1.0-93.8â µm) activities against drug-resistant Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium strains while demonstrating <5 % haemolysis activity against human red blood cells (RBCs) at 200â µm. In addition, these HQs demonstrated low cytotoxicity against HeLa cells. Halogenated quinolines are a promising class of antibiofilm agents against Gram-positive pathogens that could lead to useful treatments against persistent bacterial infections.
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Antibacterianos/síntesis química , Quinolinas/química , Alquilación , Aminación , Antibacterianos/farmacología , Antibacterianos/toxicidad , Biopelículas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Enterococcus faecium/efectos de los fármacos , Enterococcus faecium/fisiología , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Halogenación , Células HeLa , Hemólisis/efectos de los fármacos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/fisiología , Quinolinas/farmacología , Quinolinas/toxicidad , Staphylococcus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Small molecules capable of eradicating non-replicating bacterial biofilms are of great importance to human health as conventional antibiotics are ineffective against these surface-attached bacterial communities. Here, we report the discovery of several halogenated quinolines (HQs) identified through a reductive amination reaction that demonstrated potent eradication of MRSA (HQ-6; MBEC = 125 µM), MRSE (HQ-3; MBEC = 3.0 µM) and VRE (HQ-4, HQ-5 and HQ-6; MBEC = 1.0 µM) biofilms. HQs were evaluated using the Calgary Biofilm Device (CBD) and demonstrated near equipotent killing activities against planktonic and biofilm cells based on MBC and MBEC values. When tested against red blood cells, these HQ analogues demonstrated low haemolytic activity (3 to 21% at 200 µM) thus we conclude that these HQ analogues do not operate primarily through the destruction of bacterial membranes, typical of other biofilm-eradicating agents (i.e., antimicrobial peptides). HQ antibacterial agents are potent biofilm-eradicating compounds and could lead to useful treatments for biofilm-associated bacterial infections.
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Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Enterococcus faecium/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Quinolinas/farmacología , Staphylococcus epidermidis/efectos de los fármacos , Resistencia a la Vancomicina , Aminación , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Halogenación , Humanos , Resistencia a la Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxidación-Reducción , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad , Resistencia a la Vancomicina/efectos de los fármacosRESUMEN
Conventional antibiotics are ineffective against non-replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1, that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC = 0.2-12.5â µM), as well as the effective killing of MRSA persister cells in non-biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non-biofilm persisters alongside 14. HP 13 displayed potent antibacterial activity against slow-growing M.â tuberculosis (MIC = 3.13â µM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non-toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.
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Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/citología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Fenazinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/crecimiento & desarrollo , Fenazinas/síntesis química , Fenazinas/química , Relación Estructura-ActividadRESUMEN
Staphylococcus aureus and Staphylococcus epidermidis are recognized as the most frequent cause of biofilm-associated nosocomial and indwelling medical device infections. Biofilm-associated infections are known to be highly resistant to our current arsenal of clinically used antibiotics and antibacterial agents. To exacerbate this problem, no therapeutic option exists that targets biofilm-dependent machinery critical to Staphylococcal biofilm formation and maintenance. Here, we describe the discovery of a series of quinoline small molecules that demonstrate potent biofilm dispersal activity against methicillin-resistant S. aureus and S. epidermidis using a scaffold hopping strategy. This interesting class of quinolines also has select synthetic analogues that demonstrate potent antibacterial activity and biofilm inhibition against S. aureus and S. epidermidis.
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Antibacterianos/química , Biopelículas/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Staphylococcus epidermidis/efectos de los fármacos , Antibacterianos/farmacología , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
PURPOSE: Sulbactam/durlobactam is a combination antibiotic designed to target Acinetobacter baumannii, including carbapenem-resistant and multidrug-resistant strains. The objective of this study was to determine the physical compatibility of sulbactam/durlobactam solution during simulated Y-site administration with 95 intravenous (IV) drugs. METHODS: Vials of sulbactam/durlobactam solution were diluted in 0.9% sodium chloride injection to a volume of 100 mL (the final concentration of both drugs was 15 mg/mL). All other IV drugs were reconstituted according to the manufacturer's recommendations and diluted with 0.9% sodium chloride injection to the upper range of concentrations used clinically or tested undiluted as intended for administration. Y-site conditions were simulated by mixing 5 mL of sulbactam/durlobactam with 5 mL of the tested drug solutions in a 1:1 ratio. Solutions were inspected for physical characteristics (clarity, color, and Tyndall effect), turbidity, and pH changes before admixture, immediately post admixture, and over 4 hours. Incompatibility was defined as any observed precipitation, significant color change, positive Tyndall test, or turbidity change of ≥0.5 nephelometric turbidity unit during the observation period. RESULTS: Sulbactam/durlobactam was physically compatible with 38 out of 42 antimicrobials tested (90.5%) and compatible overall with 86 of 95 drugs tested (90.5%). Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, ciprofloxacin, daptomycin, levofloxacin, phenytoin sodium, vecuronium, and propofol. CONCLUSION: The Y-site compatibility of sulbactam/durlobactam with 95 IV drugs was described. These compatibility data will assist pharmacists and nurses to safely coordinate administration of IV medications with sulbactam/durlobactam.
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Cloruro de Sodio , Sulbactam , Humanos , Infusiones Intravenosas , Antibacterianos , Incompatibilidad de MedicamentosRESUMEN
Antimicrobial treatments for extensively drug-resistant Acinetobacter baumannii (XDR-AB) infections have proven lackluster, while dosing challenges in patients receiving continuous renal replacement therapy continue. We describe a patient receiving cefiderocol, ampicillin/sulbactam, and tigecycline for XDR-AB while undergoing continuous venovenous hemodiafiltration. The clinical course, cefiderocol and sulbactam pharmacokinetics, and synergy assessments are described.
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Bacterial biofilms are surface-attached communities of slow- or non-replicating cells embedded within a protective matrix of biomolecules. Unlike free-floating planktonic bacteria, biofilms are innately tolerant to conventional antibiotics and are prevalent in recurring and chronic infections. Nitroxoline, a broad-spectrum biofilm-eradicating agent, was used to probe biofilm viability. Transcript profiling (RNA-seq) showed that 452 of 2594 genes (17.4%) in methicillin-resistant Staphylococcus aureus (MRSA) biofilms were differentially expressed after a 2 h treatment of nitroxoline. WoPPER analysis and time-course validation (RT-qPCR) revealed that gene clusters involved in iron acquisition (sbn, isd, MW2101, MW0695, fhu, and feo) were rapidly up-regulated following nitroxoline treatment, which is indicative of iron starvation in MRSA biofilms. In addition, genes related to oligopeptide transporters and riboflavin biosynthesis were found to be up-regulated, while genes related to carotenoid biosynthesis and nitrate assimilation were down-regulated. RT-qPCR experiments revealed that iron uptake transcripts were also up-regulated in established Staphylococcus epidermidis and Acinetobacter baumannii biofilms following nitroxoline treatment. Overall, we show RNA-seq to be an ideal platform to define cellular pathways critical for biofilm survival, in addition to demonstrating the need these bacterial communities have for iron.
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Staphylococcus aureus Resistente a Meticilina , Bacterias/genética , Biopelículas , Hierro , Staphylococcus aureus Resistente a Meticilina/genética , Familia de Multigenes , Nitroquinolinas , Regulación hacia ArribaRESUMEN
Pathogenic bacteria demonstrate incredible abilities to evade conventional antibiotics through the development of resistance and formation of dormant, surface-attached biofilms. Therefore, agents that target and eradicate planktonic and biofilm bacteria are of significant interest. We explored a new series of halogenated phenazines (HP) through the use of N-aryl-2-nitrosoaniline synthetic intermediates that enabled functionalization of the 3-position of this scaffold. Several HPs demonstrated potent antibacterial and biofilm-killing activities (e.g., HP 29, against methicillin-resistant Staphylococcus aureus: MIC = 0.075 µM; MBEC = 2.35 µM), and transcriptional analysis revealed that HPs 3, 28, and 29 induce rapid iron starvation in MRSA biofilms. Several HPs demonstrated excellent activities against Mycobacterium tuberculosis (HP 34, MIC = 0.80 µM against CDC1551). This work established new SAR insights, and HP 29 demonstrated efficacy in dorsal wound infection models in mice. Encouraged by these findings, we believe that HPs could lead to significant advances in the treatment of challenging infections.
Asunto(s)
Compuestos de Anilina/química , Antibacterianos/síntesis química , Fenazinas/química , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Biopelículas/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Diseño de Fármacos , Femenino , Halogenación , Humanos , Hierro/química , Deficiencias de Hierro , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/fisiología , Ratones , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/efectos de los fármacos , Fenazinas/farmacología , Fenazinas/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Relación Estructura-Actividad , Cicatrización de Heridas/efectos de los fármacosRESUMEN
While a number of disinfection techniques are employed in healthcare units, the eradication of drug-resistant microorganisms remains a challenge. We recently reported N-arylated NH125 analogue 1, which demonstrated potent biofilm eradication and antibacterial activities against a panel of drug-resistant pathogens. The broad-spectrum activities observed for 1 along with its rapid eradication of MRSA persister cells suggested that this agent, and related analogues, can serve as disinfectants for antibiotic resistant pathogens in healthcare settings. Here, we report the rapid bactericidal activities of 1 against a panel of exponentially-growing, drug-resistant pathogens. Against MRSA, MRSE, VRE and MDR A. baumannii, 1 eradicated bacterial cells after five minutes when tested at 50 µM (3- to 6-log reduction of CFU per mL). We highlighted the rapid killing activities by demonstrating that 1 eradicates 99.99% of viable MRSA 1707 cells in one minute (50 µM, 4-log reduction of CFU per mL). In addition, 1 rapidly eradicated fungal pathogen C. neoformans in kill kinetic experiments. A solution of 1 demonstrated similar shelf stability to known disinfectant BAC-16 when tested up to 111 days after being stored. Collectively, our data highlights the potential of 1 to be used as a disinfecting agent to prevent healthcare-associated, drug-resistant infections.
RESUMEN
Bacteria utilize multiple mechanisms that enable them to gain or acquire resistance to antibiotic therapies during the treatment of infections. In addition, bacteria form biofilms which are surface-attached communities of enriched populations containing persister cells encased within a protective extracellular matrix of biomolecules, leading to chronic and recurring antibiotic-tolerant infections. Antibiotic resistance and tolerance are major global problems that require innovative therapeutic strategies to address the challenges associated with pathogenic bacteria. Historically, natural products have played a critical role in bringing new therapies to the clinic to treat life-threatening bacterial infections. This Perspective provides an overview of antibiotic resistance and tolerance and highlights recent advances (chemistry, biology, drug discovery, and development) from various research programs involved in the discovery of new antibacterial agents inspired by a diverse series of natural product antibiotics.