RESUMEN

PURPOSE: Infection by carbapenem-resistant Klebsiella pneumoniae (CRKP) has high mortality. There is no clear optimal therapeutic choice for pneumonia caused by CRKP. The aim of this study was to compare the clinical outcomes and safety of the standard doses of polymyxin B-based regimens vs tigecycline-based regimens and to identify risk factors for mortality. METHODS: This retrospective cohort study included patients with pneumonia caused by CRKP between January 1, 2020 and December 31, 2022. The primary outcomes were 7-day bacterial eradication rate and 14- and 28-day all-cause mortality. The secondary outcome was incidence of acute kidney injury. RESULTS: Seventy-three patients were included in this study, 29 in the polymyxin B-based combination therapy group and 44 in tigecycline-based combination therapy group. There were no significant differences between the two groups in terms of the 7-day bacterial eradication rate (31.03% vs 20.45%, p = 0.409), the 14-day all-cause mortality (37.93% vs 22.73%, p = 0.160), and the incidence of acute kidney injury (14.29% vs 6.82%, p = 0.526). The 28-day all-cause mortality in the polymyxin B-based therapy group was higher than in the tigecycline-based group (75.86% vs 45.45%, p = 0.010). Binary logistic regression analysis revealed that male and previous use of carbapenems were independent factors associated with 28-day all-cause mortality for patients treated with polymyxin B (p < 0.05). CONCLUSIONS: Polymyxin B-based combination therapy at the standard dose should be used with caution for patients with CRKP-induced pneumonia, especially for men who used carbapenems prior to CRKP detection.

Asunto(s)

Antibacterianos , Quimioterapia Combinada , Infecciones por Klebsiella , Klebsiella pneumoniae , Polimixina B , Tigeciclina , Humanos , Polimixina B/administración & dosificación , Polimixina B/uso terapéutico , Polimixina B/efectos adversos , Masculino , Estudios Retrospectivos , Tigeciclina/administración & dosificación , Tigeciclina/uso terapéutico , Tigeciclina/efectos adversos , Femenino , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/mortalidad , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Anciano , Klebsiella pneumoniae/efectos de los fármacos , Persona de Mediana Edad , Carbapenémicos/uso terapéutico , Carbapenémicos/efectos adversos , Carbapenémicos/administración & dosificación , Resultado del Tratamiento , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/mortalidad

RESUMEN

Escherichia coli, a rod-shaped Gram-negative bacterium, is a significant causative agent of severe clinical bacterial infections. This study aimed to analyze the epidemiology of extended-spectrum ß-lactamase (ESBL)-producing mcr-1 -positive E. coli in Shandong, China. We collected 668 non-duplicate ESBL-producing E. coli strains from clinical samples at Shandong Provincial Hospital between January and December 2018, and estimated their minimum inhibitory concentrations (MICs) using a VITEK® 2 compact system and broth microdilution. Next-generation sequencing and bioinformatic analyses identified the mcr-1 gene and other resistance genes in the polymyxin B-resistant strains. The conjugation experiment assessed the horizontal transfer capacity of the mcr-1 gene. Of the strains collected, 24 polymyxin B-resistant strains were isolated with a positivity rate of 3.59% and among the 668 strains, 19 clinical strains carried the mobile colistin resistance gene mcr-1, with a positivity rate of approximately 2.8%. All 19 clinical strains were resistant to ampicillin, cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, and polymyxin B. Seventeen strains successfully transferred the mcr-1 gene into E. coli J53. All transconjugants were resistant to polymyxin B, and carried the drug resistance gene mcr-1. The 19 clinical strains had 14 sequence types (STs), with ST155 (n = 4) being the most common. The whole-genome sequencing results of pECO-POL-29_mcr1 revealed that no ISApl1 insertion sequences were found on either side of the mcr-1 gene. Our study uncovered the molecular epidemiology of mcr-1-carrying ESBL-producing E. coli in the region and suggested horizontal transmission mediated by plasmids as the main mode of mcr-1 transmission.

Asunto(s)

Antibacterianos , Infecciones por Escherichia coli , Proteínas de Escherichia coli , Escherichia coli , Pruebas de Sensibilidad Microbiana , Epidemiología Molecular , Polimixina B , Centros de Atención Terciaria , beta-Lactamasas , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Polimixina B/farmacología , Humanos , China/epidemiología , beta-Lactamasas/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Antibacterianos/farmacología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/epidemiología , Farmacorresistencia Bacteriana/genética , Plásmidos/genética , Farmacorresistencia Bacteriana Múltiple/genética

RESUMEN

We compared clinical outcomes of patients who received monotherapy and combination therapy for treatment of MDR A. baumannii VAP. 170 patients were included. Vasopressor use and mortality rate were higher for combination therapy (69.3% versus 28.6%, p=0.024; 67.5% versus 14.3%, p=0.007; respectively). Majority received polymyxin B-based combination therapy, with higher mortality than those without polymyxin B (80.2% versus 19.8%, p=0.043). After adjusting for vasopressor use, monotherapy, dual combination, and triple combination therapy were not associated with mortality (aHR 0.24, 95% CI 0.03 to 1.79, p=0.169; aHR 1.26, 95% CI 0.79 to 2.00, p=0.367; aHR 0.93, 95% CI 0.57 to 1.49, p=0.744; respectively). There was no difference in adverse effects and length of stay between the two groups. Mortality from MDR A. baumannii VAP was high and not associated with monotherapy or combination therapy after adjustment for vasopressor use. Antibiotic regimens other than those containing polymyxin are urgently needed for the treatment of these infections.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Quimioterapia Combinada , Neumonía Asociada al Ventilador , Centros de Atención Terciaria , Humanos , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/uso terapéutico , Femenino , Masculino , Neumonía Asociada al Ventilador/tratamiento farmacológico , Neumonía Asociada al Ventilador/microbiología , Persona de Mediana Edad , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/mortalidad , Infecciones por Acinetobacter/microbiología , Anciano , Resultado del Tratamiento , Adulto , Polimixina B/uso terapéutico , Polimixina B/administración & dosificación , Estudios Retrospectivos

RESUMEN

BACKGROUND: The study aimed to compare polymyxin B with colistimethate sodium (CMS) regarding neurotoxicity, nephrotoxicity and 30-day mortality in patients with MDR Gram-negatives. METHODS: All adult patients who received polymyxin B or CMS for at least 24 h for the treatment of MDR microorganisms were evaluated retrospectively. RESULTS: Among 413 initially screened patients, 147 patients who were conscious and able to express their symptoms were included in the neurotoxicity analysis. 13 of 77 patients with polymyxin B and 1 of 70 with CMS had neurotoxic adverse events, mainly paresthesias. All events were reversible after drug discontinuation. Among 290 patients included in nephrotoxicity analysis, the incidence of acute kidney injury (AKI) was 44.7% and 40.0% for polymyxin B and CMS, respectively (p = 0.425). AKI occurred two days earlier with colistin than polymyxin B without statistical significance (median (IQR): 5 (3-11) vs. 7 (3-12), respectively, p = 0.701). Polymyxin therapy was withdrawn in 41.1% of patients after AKI occurred and CMS was more frequently withdrawn than polymyxin B (p = 0.025). AKI was reversible in 91.6% of patients with CMS and 79% with polymyxin B after the drug withdrawal. Older age, higher baseline serum creatinine and the use of at least two nephrotoxic drugs were independent factors associated with AKI (OR 1.05, p < 0.001; OR 2.99, p = 0.022 and OR 2.45, p = 0.006, respectively). Septic shock, mechanical ventilation, presence of a central venous catheter and Charlson comorbidity index (OR 2.13, p = 0.004; OR 3.37, p < 0.001; OR 2.47, p = 0.004 and OR 1.21, p p < 0.001, respectively) were the independent predictors of mortality. The type of polymyxin was not related to mortality. CONCLUSIONS: Neurotoxicity is a relatively common adverse event that leads to drug withdrawal during polymyxins, particularly polymyxin B. Nephrotoxicity is very common during polymyxin therapy and the two polymyxins display similar nephrotoxic events with high reversibility rates after drug withdrawal. Close monitoring of AKI is crucial during polymyxin therapy, particularly, for elderly patients, patients who have high baseline creatinine, and using other nephrotoxic drugs.

Asunto(s)

Lesión Renal Aguda , Antibacterianos , Colistina , Polimixina B , Humanos , Colistina/efectos adversos , Colistina/análogos & derivados , Polimixina B/efectos adversos , Polimixina B/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Antibacterianos/efectos adversos , Lesión Renal Aguda/inducido químicamente , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Adulto , Farmacorresistencia Bacteriana Múltiple , Anciano de 80 o más Años , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/epidemiología

RESUMEN

Polymyxin B (PB) and Polymyxin E (PE, also called colistin) are used as the last treatment resort for multidrug-resistant Gram-negative bacterial infections. The nephrotoxicity and neurotoxicity of polymyxins limit their clinical use, and guidelines recommend therapeutic drug monitoring (TDM) to optimize efficacy and reduce toxicity. However, there are limited analytical methods available for the determination of PB and PE. This study aimed to develop a simple and robust liquid chromatography with tandem mass spectrometry (LC-MS/MS) analytical method for determining the main compounds of PB and PE, namely PB1, PB2, ile-PB1, PE1, and PE2, in human plasma and to investigate of their pharmacokinetics in critically ill patients with the use of PB and PE, respectively. Plasma PB1, PB2, ile-PB1, PE1, and PE2 were chromatographically separated on a Welch LP-C18 column and detected using electrospray ionization mode coupled with multiple reaction monitoring. The calibration curve showed acceptable linearity over 20-10,000 ng/mL for PB1, PE1, and PE2 and 10-5000 ng/mL for PB2 and ile-PB1 in the plasma, respectively. After validation following approved guidelines, this method was successfully applied for PB and PE pharmacokinetic analysis and TDM in critically ill patients. Additionally, the composition of PB1, PB2, ile-PB1, PE1, and PE2 remains unchanged from 0 to 12 h after entering the patient's body.

Asunto(s)

Antibacterianos , Monitoreo de Drogas , Polimixina B , Espectrometría de Masas en Tándem , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antibacterianos/farmacocinética , Antibacterianos/sangre , Calibración , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Colistina/farmacocinética , Colistina/sangre , Colistina/análogos & derivados , Enfermedad Crítica , Monitoreo de Drogas/métodos , Límite de Detección , Polimixina B/farmacocinética , Polimixina B/sangre , Polimixinas/farmacocinética , Polimixinas/sangre , Polimixinas/análogos & derivados , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos

RESUMEN

OBJECTIVES: The emergence of polymyxin-resistant Klebsiella pneumoniae (KPN) in clinical settings necessitates an analysis of its antibiotic resistance characteristics, epidemiological features, and risk factors for its development. This study aims to provide insights for the prevention and control of polymyxin-resistant KPN infections. METHODS: Thirty clinical isolates of polymyxin-resistant KPN were collected from the Third Xiangya Hospital of Central South University. Their antibiotic resistance profiles were analyzed. The presence of carbapenemase KPC, OXA-48, VIM, IMP, and NDM was detected using colloidal gold immunochromatography. Hypervirulent KPN was initially screened using the string test. Biofilm formation capacity was assessed using crystal violet staining. Combination drug susceptibility tests (polymyxin B with meropenem, tigecycline, cefoperazone/sulbactam) were conducted using the checkerboard method. Polymyxin-related resistance genes were detected by PCR. Multi-locus sequence typing (MLST) was performed for genotyping and phylogenetic tree construction. The study also involved collecting data from carbapenem-resistant (CR)-KPN polymyxin-resistant strains (23 strains, experimental group) and CR-KPN polymyxin-sensitive strains (57 strains, control group) to analyze potential risk factors for polymyxin-resistant KPN infection through univariate analysis and multivariate Logistic regression. The induction of resistance by continuous exposure to polymyxin B and colistin E was also tested. RESULTS: Among the 30 polymyxin-resistant KPN isolates, 28 were CR-KPN, all producing KPC enzyme. Four isolates were positive in the string test. Most isolates showed strong biofilm formation capabilities. Combination therapy showed additive or synergistic effects. All isolates carried the pmrA and phoP genes, while no mcr-1 or mcr-2 genes were detected. MLST results indicated that ST11 was the predominant type. The phylogenetic tree suggested that polymyxin-resistant KPN had not caused a hospital outbreak in the institution. The use of two or more different classes of antibiotics and the use of polymyxin were identified as independent risk factors for the development of polymyxin-resistant strains. Continuous use of polymyxin induced drug resistance. CONCLUSIONS: Polymyxin-resistant KPN is resistant to nearly all commonly used antibiotics, making polymyxin-based combination therapy a viable option. No plasmid-mediated polymyxin-resistant KPN has been isolated in the hospital. Polymyxin can induce resistance in KPN, highlighting the need for rational antibiotic use in clinical settings to delay the emergence of resistance.

Asunto(s)

Antibacterianos , Infecciones por Klebsiella , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Polimixinas , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/aislamiento & purificación , Antibacterianos/farmacología , Humanos , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Polimixinas/farmacología , beta-Lactamasas/genética , Proteínas Bacterianas/genética , Tipificación de Secuencias Multilocus , Farmacorresistencia Bacteriana Múltiple/genética , Polimixina B/farmacología , Farmacorresistencia Bacteriana , Biopelículas/efectos de los fármacos , Factores de Riesgo , Carbapenémicos/farmacología

RESUMEN

The persistent emergence of multidrug-resistant bacterial pathogens is leading to a decline in the therapeutic efficacy of antibiotics, with Pseudomonas aeruginosa (P. aeruginosa) emerging as a notable threat. We investigated the antibiotic resistance and quorum sensing (QS) system of P. aeruginosa, with a particular focused on outer membrane vesicles (OMVs) and polymyxin B as the last line of antibiotic defense. Our findings indicate that OMVs increase the resistance of P. aeruginosa to polymyxin B. The overall gene transcription levels within P. aeruginosa also reveal that OMVs can reduce the efficacy of polymyxin B. However, both OMVs and sublethal concentrations of polymyxin B suppressed the transcription levels of genes associated with the QS system. Furthermore, OMVs and polymyxin B acted in concert on the QS system of P. aeruginosa to produce a more potent inhibitory effect. This suppression was evidenced by a decrease in the secretion of virulence factors, impaired bacterial motility, and a notable decline in the ability to form biofilms. These results reveal that OMVs enhance the resistance of P. aeruginosa to polymyxin B, yet they collaborate with polymyxin B to inhibit the QS system. Our research contribute to a deeper understanding of the resistance mechanisms of P. aeruginosa in the environment, and provide new insights into the reduction of bacterial infections caused by P. aeruginosa through the QS system.

Asunto(s)

Antibacterianos , Farmacorresistencia Bacteriana , Polimixina B , Pseudomonas aeruginosa , Percepción de Quorum , Pseudomonas aeruginosa/efectos de los fármacos , Percepción de Quorum/efectos de los fármacos , Antibacterianos/farmacología , Polimixina B/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Biopelículas/efectos de los fármacos , Membrana Externa Bacteriana/efectos de los fármacos , Membrana Externa Bacteriana/metabolismo , Pruebas de Sensibilidad Microbiana

RESUMEN

BACKGROUND: Polymyxins have re-emerged as a last-resort therapeutic option for infections caused by carbapenem-resistant gram-negative bacteria. Nephrotoxicity induced by polymyxins is a significant limitation of its use in the clinic. Polymyxin B and colistin sulfate are two widely used active formulations of polymyxins. However, there is a lack of studies conducting a comparative assessment of nephrotoxicity between the two formulations. This study aimed to compare the nephrotoxicity of polymyxin B and colistin sulfate in critically ill patients. METHODS: We conducted a retrospective cohort study among critically ill patients who received intravenous polymyxin B or colistin sulfate for over 48 h from January 2017 to January 2024. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, and the secondary outcome was 30-day all-cause mortality. Additionally, the risk factors of polymyxins-induced AKI and 30-day all-cause mortality were identified by Cox proportional hazard regression analysis. RESULTS: A total of 473 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received polymyxin B compared to those who received colistin sulfate in the unmatched cohort (20.8% vs. 9.0%, p = 0.002) and in the propensity score matching cohort (21.1% vs. 7.0%, p = 0.004), respectively. However, there was no significant difference in 30-day all-cause mortality between the two groups. Polymyxin type, septic shock, and concomitant use of vasopressors were identified as independent risk factors for polymyxin-induced AKI. CONCLUSIONS: The prevalence of AKI was higher among patients who received polymyxin B compared to those treated with colistin sulfate. However, there was no significant difference in 30-day all-cause mortality between the two groups. Further prospective, multicenter studies with larger sample sizes are needed to validate these findings.

Asunto(s)

Lesión Renal Aguda , Antibacterianos , Colistina , Enfermedad Crítica , Polimixina B , Humanos , Colistina/efectos adversos , Colistina/administración & dosificación , Polimixina B/efectos adversos , Polimixina B/administración & dosificación , Polimixina B/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Anciano , Estudios de Cohortes , Administración Intravenosa , Incidencia , Factores de Riesgo

RESUMEN

OBJECTIVES: A Salmonella enterica subsp. diarizonae (hereafter S. diarizonae) clinical strain S499 demonstrated unique genomic features. The strain S499 was treated with polymyxin B in vitro to investigate the mechanism of resistance. METHODS: S499 was treated with polymyxin B by increasing concentration gradually to obtain a resistant mutant S499V. Whole genomes of the two strains were sequenced using Illumina HiSeq X-10 and PacBio RS II platforms. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to compare the gene expression. RESULTS: The chromosome of strain S499 contained a 40-kb DNA region that was replicated after treatment with polymyxin B and generated a triple tandem DNA repeat region in the chromosome of mutant strain S499V. This repeat region in S499V was flanked by IS1 and contained pmrD, pmrG, and arnBCADTEF operon. In comparison to the homologous 40-kb DNA region of strain S499, a few genes in the repeat DNA region of strain S499V contained truncating mutations that generate two open reading frames (ORFs). The expression of pmrD, pmrG, and arnT was significantly upregulated in S499V. CONCLUSION: The duplication and overexpression of pmrD, pmrG, and arnT operon may be responsible for the polymyxin B resistance of mutant strain S499V.

Asunto(s)

Antibacterianos , Farmacorresistencia Bacteriana , Mutación , Polimixina B , Polimixina B/farmacología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/genética , Pruebas de Sensibilidad Microbiana , Secuenciación Completa del Genoma , Salmonella enterica/genética , Salmonella enterica/efectos de los fármacos , Humanos , Mutagénesis Insercional , Genoma Bacteriano , Salmonella/genética , Salmonella/efectos de los fármacos , Proteínas Bacterianas/genética , Operón , Regulación Bacteriana de la Expresión Génica , Infecciones por Salmonella/microbiología

RESUMEN

Acinetobacter baumannii is a bacteria associated with nosocomial infections and outbreaks, difficult to control due to its antibiotic resistance, ability to survive in adverse conditions, and biofilm formation adhering to biotic and abiotic surfaces. Therefore, this study aimed to evaluate the antibiofilm activity of biogenic silver nanoparticle (Bio-AgNP) and polymyxin B alone and combined in biofilms formed by isolates of carbapenem-resistant A. baumannii (CR-Ab). In the biofilm formation inhibition assay, CR-Ab strains were exposed to different concentrations of the treatments before inducing biofilm formation, to determine the ability to inhibit/prevent bacterial biofilm formation. While in the biofilm rupture assay, the bacterial biofilm formation step was previously carried out and the adhered cells were exposed to different concentrations of the treatments to evaluate their ability to destroy the bacterial biofilm formed. All CR-Ab isolates and ATCC® 19606™ used in this study are strong biofilm formers. The antibiofilm activity of Bio-AgNP and polymyxin B against CR-Ab and ATCC® 19606™ demonstrated inhibitory and biofilm-disrupting activity. When used in combination, Bio-AgNP and polymyxin B inhibited 4.9-100% of biofilm formation in the CR-Ab isolates and ATCC® 19606™. Meanwhile, when Bio-AgNP and polymyxin B were combined, disruption of 6.8-77.8% of biofilm formed was observed. Thus, antibiofilm activity against CR-Ab was demonstrated when Bio-AgNP was used alone or in combination with polymyxin B, emerging as an alternative in the control of CR-Ab strains.

Asunto(s)

Acinetobacter baumannii , Antibacterianos , Biopelículas , Carbapenémicos , Nanopartículas del Metal , Pruebas de Sensibilidad Microbiana , Polimixina B , Plata , Biopelículas/efectos de los fármacos , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/fisiología , Polimixina B/farmacología , Plata/farmacología , Plata/química , Antibacterianos/farmacología , Nanopartículas del Metal/química , Carbapenémicos/farmacología , Infecciones por Acinetobacter/microbiología , Infecciones por Acinetobacter/tratamiento farmacológico , Humanos , Sinergismo Farmacológico , Farmacorresistencia Bacteriana

RESUMEN

BACKGROUND: Gram-negative bacteria (GNB) are becoming increasingly resistant to a wide variety of antibiotics. There are currently limited treatments for GNB, and the combination of antibiotics with complementary mechanisms has been reported to be a feasible strategy for treating GNB infection. The inability to cross the GNB outer membrane (OM) is an important reason that a broad spectrum of Gram-positive only class of antibiotics (GPOAs) is lacking. Polymyxins may help GPOAs to permeate by disrupting OM of GNB. OBJECTIVE: To identify what kind of GPOAs can be aided to broaden their anti-GNB spectrum by polymyxins, we systematically investigated the synergy of eight GPOAs in combination with colistin (COL) and polymyxin B (PMB) against GNB in vitro. METHODS: The synergistic effect of COL or PMB and GPOAs combinations against GNB reference strains and clinical isolates were determined by checkerboard tests. The killing kinetics of the combinations were assessed using time-kill assays. RESULTS: In the checkerboard tests, polymyxins-GPOAs combinations exert synergistic effects characterized by species and strain specificity. The synergistic interactions on P. aeruginosa strains are significantly lower than those on strains of A. baumannii, K. pneumoniae and E. coli. Among all the combinations, COL has shown the best synergistic effect in combination with dalbavancin (DAL) or oritavancin (ORI) versus almost all of the strains tested, with FICIs from 0.16 to 0.50 and 0.13 to < 0.28, respectively. In addition, the time-kill assays demonstrated that COL/DAL and COL/ORI had sustained bactericidal activity. CONCLUSIONS: Our results indicated that polymyxins could help GPOAs to permeate the OM of specific GNB, thus showed synergistic effects and bactericidal effects in the in vitro assays. In vivo combination studies should be further conducted to validate the results of this study.

Asunto(s)

Antibacterianos , Colistina , Sinergismo Farmacológico , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Polimixina B , Polimixinas , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Polimixinas/farmacología , Polimixina B/farmacología , Humanos , Colistina/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Pseudomonas aeruginosa/efectos de los fármacos

RESUMEN

INTRODUCTION: The aim of this study was to compare the efficacy and safety of colistin sulfate (CS) with polymyxin B sulfate (PMB) in the treatment of pneumonia induced by carbapenem-resistant Gram-negative bacteria (CR-GNB). METHODOLOGY: Patients diagnosed with pneumonia caused by CR-GNB and admitted to the intensive care unit (ICU) from January 2020 to September 2022 were enrolled in this study. The patients were divided into the CS group and the PMB group according to their medication regimens. Group-wise demographic data, clinical efficacy, prognosis, and adverse events were analyzed and compared. RESULTS: A total of 120 patients (68 in the CS group and 52 in the PMB group) with pneumonia were included in the study. The majority of the pathogens were CR-Acinetobacter baumannii, followed by CR-Klebsiella pneumoniae, and CR-Pseudomonas aeruginosa. The clinical response rates in the CS and PMB groups after treatment were 62.0% and 65.4%, bacterial clearances were 44.0% and 36.5%, 28-day mortality rates were 16.0% and 13.5%, respectively; no significant differences between the two treatments were found. Nevertheless, the adverse effects were significantly less common in the CS group than in the PMB group, especially when treatments were administered intravenously. CONCLUSIONS: CS, a novel polymyxin E formulation, is as effective as PMB in treating pneumonia induced by CR-GNB while causing less side effects.

Asunto(s)

Antibacterianos , Colistina , Neumonía Bacteriana , Polimixina B , Humanos , Polimixina B/uso terapéutico , Polimixina B/administración & dosificación , Masculino , Colistina/uso terapéutico , Colistina/efectos adversos , Colistina/administración & dosificación , Femenino , Antibacterianos/uso terapéutico , Persona de Mediana Edad , Anciano , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Estudios Retrospectivos , Acinetobacter baumannii/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Resultado del Tratamiento , Adulto , Bacterias Gramnegativas/efectos de los fármacos , Unidades de Cuidados Intensivos , Pseudomonas aeruginosa/efectos de los fármacos , Anciano de 80 o más Años , Klebsiella pneumoniae/efectos de los fármacos

RESUMEN

OBJECTIVES: Polymyxin-induced nephrotoxicity (PIN) is a major safety concern and challenge in clinical practice, which limits the clinical use of polymyxins. This study aims to investigate the risk factors and to develop a scoring tool for the early prediction of PIN. METHODS: Data on critically ill patients who received intravenous polymyxin B or colistin sulfate for over 24 h were collected. Logistic regression with the least absolute shrinkage and selection operator (LASSO) was used to identify variables that are associated with outcomes. The eXtreme Gradient Boosting (XGB) classifier algorithm was used to further visualize factors with significant differences. A prediction model for PIN was developed through binary logistic regression analysis and the model was assessed by temporal validation and external validation. Finally, a risk-scoring system was developed based on the prediction model. RESULTS: Of 508 patients, 161 (31.6%) patients developed PIN. Polymyxin type, loading dose, septic shock, concomitant vasopressors and baseline blood urea nitrogen (BUN) level were identified as significant predictors of PIN. All validation exhibited great discrimination, with the AUC of 0.742 (95% CI: 0.696-0.787) for internal validation, of 0.708 (95% CI: 0.605-0.810) for temporal validation and of 0.874 (95% CI: 0.759-0.989) for external validation, respectively. A simple risk-scoring tool was developed with a total risk score ranging from -3 to 4, corresponding to a risk of PIN from 0.79% to 81.24%. CONCLUSIONS: This study established a prediction model for PIN. Before using polymyxins, the simple risk-scoring tool can effectively identify patients at risk of developing PIN within a range of 7% to 65%.

Asunto(s)

Antibacterianos , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Antibacterianos/efectos adversos , Anciano , Factores de Riesgo , Polimixina B/efectos adversos , Polimixina B/administración & dosificación , Proyectos Piloto , Enfermedad Crítica , Medición de Riesgo/métodos , Polimixinas/efectos adversos , Colistina/efectos adversos , Colistina/administración & dosificación , Modelos Logísticos , Adulto , Enfermedades Renales/inducido químicamente

RESUMEN

In recent years, polymyxin has been used as a last-resort therapy for carbapenem-resistant bacterial infections. The emergence of heteroresistance (HR) to polymyxin hampers the efficacy of polymyxin treatment by amplifying resistant subpopulation. However, the mechanisms behind polymyxin HR remain unclear. Small noncoding RNAs (sRNAs) play an important role in regulating drug resistance. The purpose of this study was to investigate the effects and mechanisms of sRNA on polymyxin B (PB)-HR in carbapenem-resistant Klebsiella pneumoniae. In this study, a novel sRNA PhaS was identified by transcriptome sequencing. PhaS expression was elevated in the PB heteroresistant subpopulation. Overexpression and deletion of PhaS were constructed in three carbapenem-resistant K. pneumoniae strains. Population analysis profiling, growth curve, and time-killing curve analysis showed that PhaS enhanced PB-HR. In addition, we verified that PhaS directly targeted phoP through the green fluorescent protein reporter system. PhaS promoted the expression of phoP, thereby encouraging the expression of downstream genes pmrD and arnT. This upregulation of arnT promoted the 4-amino-4-deoxyL-arabinosaccharide (L-Ara4N) modification of lipid A in PhaS overexpressing strains, thus enhancing PB-HR. Further, within the promoter region of PhaS, specific PhoP recognition sites were identified. ONPG assays and RT-qPCR analysis confirmed that PhaS expression was positively modulated by PhoP and thus up-regulated by PB stimulation. To sum up, a novel sRNA enhancing PB-HR was identified and a positive feedback regulatory pathway of sRNA-PhoP/Q was demonstrated in the study. This helps to provide a more comprehensive and clear understanding of the underlying mechanisms behind polymyxin HR in carbapenem-resistant K. pneumoniae.

Asunto(s)

Antibacterianos , Proteínas Bacterianas , Carbapenémicos , Regulación Bacteriana de la Expresión Génica , Klebsiella pneumoniae , Polimixina B , ARN Pequeño no Traducido , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efectos de los fármacos , Polimixina B/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Carbapenémicos/farmacología , ARN Pequeño no Traducido/genética , Pruebas de Sensibilidad Microbiana , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/tratamiento farmacológico , Humanos , ARN Bacteriano/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Farmacorresistencia Bacteriana/genética

RESUMEN

Biofilms, particularly those formed by multiple bacterial species, pose significant economic and environmental challenges, especially in the context of medical implants. Addressing the urgent need for effective treatment strategies that do not exacerbate drug resistance, we developed a novel nanoformulation, Ce6&PMb@BPN, based on black phosphorus nanosheets (BPN) for targeted treatment of mixed-species biofilms formed by Acinetobacter baumannii (A. baumannii) and methicillin-resistant Staphylococcus aureus (MRSA).The formulation leverages polymyxin B (PMb) for bacterial targeting and chlorin e6 (Ce6) for photodynamic action. Upon near-infrared (NIR) irradiation, Ce6&PMb@BPN efficiently eliminates biofilms by combining chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), reducing biofilm biomass significantly within 30 min. In vivo studies on mice infected with mixed-species biofilm-coated catheters demonstrated the formulation's potent antibacterial and biofilm ablation effects. Moreover, comprehensive biosafety evaluations confirmed the excellent biocompatibility of Ce6&PMb@BPN. Taken together, this intelligently designed nanoformulation holds potential for effectively treating biofilm-associated infections, addressing the urgent need for strategies to combat antibiotic-resistant biofilms, particularly mixed-species biofilm, in medical settings.

Asunto(s)

Acinetobacter baumannii , Antibacterianos , Biopelículas , Staphylococcus aureus Resistente a Meticilina , Nanoestructuras , Fósforo , Fotoquimioterapia , Polimixina B , Porfirinas , Animales , Biopelículas/efectos de los fármacos , Polimixina B/administración & dosificación , Polimixina B/farmacología , Fósforo/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/química , Fotoquimioterapia/métodos , Acinetobacter baumannii/efectos de los fármacos , Nanoestructuras/química , Porfirinas/administración & dosificación , Porfirinas/química , Porfirinas/farmacología , Clorofilidas , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Ratones , Femenino , Terapia Fototérmica/métodos , Ratones Endogámicos BALB C , Farmacorresistencia Bacteriana , Infecciones Estafilocócicas/tratamiento farmacológico

RESUMEN

PURPOSE: Polymyxin B, with its unique structure and mechanism of action, has emerged as a key therapeutic agent against Gram-negative bacteria. The study aims to explore potential factors to influence its effectiveness and safety. METHODS: A model-based meta-analysis of 96 articles was conducted, focusing on factors like dosage, bacterial species, and combined antibiotic therapy. The analysis evaluated mortality rates and incidence rate of renal dysfunction, also employing parametric survival models to assess 30-d survival rates. RESULTS: In the study involving 96 articles and 9716 patients, polymyxin B's daily dose showed minimal effect on overall mortality, with high-dose group mortality at 33.57% (95% confidence intervals [CI]: 29.15-38.00) compared to the low-dose group at 35.44% (95% CI: 28.99-41.88), P = 0.64. Mortality significantly varied by bacterial species, with Pseudomonas aeruginosa infections at 58.50% (95% CI: 55.42-63.58). Monotherapy exhibited the highest mortality at 40.25% (95% CI: 34.75-45.76), P < 0.01. Renal dysfunction was more common in high-dose patients at 29.75% (95% CI: 28.52-30.98), with no significant difference across antibiotic regimens, P = 0.54. The 30-d overall survival rate for monotherapy therapy was 63.6% (95% CI: 59.3-67.5) and 70.2% (95% CI: 64.4-76.2) for association therapy with ß-lactam drugs. CONCLUSIONS: The dosage of polymyxin B does not significantly change death rates, but its effectiveness varies based on the bacterial infection. Certain bacteria like P. aeruginosa are associated with higher mortality. Combining polymyxin B with other antibiotics, especially ß-lactam drugs, improves survival rates. Side effects depend on the dose, with lower doses being safer. These findings emphasize the importance of customizing treatment to balance effectiveness and safety.

Asunto(s)

Antibacterianos , Infecciones por Bacterias Gramnegativas , Polimixina B , Polimixina B/uso terapéutico , Polimixina B/efectos adversos , Polimixina B/administración & dosificación , Humanos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/mortalidad , Infecciones por Bacterias Gramnegativas/microbiología , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Bacterias Gramnegativas/efectos de los fármacos , Resultado del Tratamiento , Análisis de Supervivencia

RESUMEN

The increasing resistance to polymyxins in Acinetobacter baumannii has made it even more urgent to develop new treatments. Anti-virulence compounds have been researched as a new solution. Here, we evaluated the modification of virulence features of A. baumannii after acquiring resistance to polymyxin B. The results showed lineages attaining unstable resistance to polymyxin B, except for Ab7 (A. baumannii polymyxin B resistant lineage), which showed stable resistance without an associated fitness cost. Analysis of virulence by a murine sepsis model indicated diminished virulence in Ab7 (A. baumannii polymyxin B resistant lineage) compared with Ab0 (A. baumannii polymyxin B susceptible lineage). Similarly, downregulation of virulence genes was observed by qPCR at 1 and 3 h of growth. However, an increase in bauE, abaI, and pgAB expression was observed after 6 h of growth. Comparison analysis of Ab0, Ab7, and Pseudomonas aeruginosa suggested no biofilm formation by Ab7. In general, although a decrease in virulence was observed in Ab7 when compared with Ab0, some virulence feature that enables infection could be maintained. In light of this, virulence genes bauE, abaI, and pgAB showed a potential relevance in the maintenance of virulence in polymyxin B-resistant strains, making them promising anti-virulence targets.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Farmacorresistencia Bacteriana , Polimixina B , Polimixina B/farmacología , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/patogenicidad , Acinetobacter baumannii/genética , Animales , Antibacterianos/farmacología , Virulencia , Ratones , Infecciones por Acinetobacter/microbiología , Factores de Virulencia/genética , Pruebas de Sensibilidad Microbiana , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Modelos Animales de Enfermedad , Sepsis/microbiología , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo

RESUMEN

Polymyxins are gram-negative antibiotics that target lipid A, the conserved membrane anchor of lipopolysaccharide in the outer membrane. Despite their clinical importance, the molecular mechanisms underpinning polymyxin activity remain unresolved. Here, we use surface plasmon resonance to kinetically interrogate interactions between polymyxins and lipid A and derive a phenomenological model. Our analyses suggest a lipid A-catalyzed, three-state mechanism for polymyxins: transient binding, membrane insertion, and super-stoichiometric cluster accumulation with a long residence time. Accumulation also occurs for brevicidine, another lipid A-targeting antibacterial molecule. Lipid A modifications that impart polymyxin resistance and a non-bactericidal polymyxin derivative exhibit binding that does not evolve into long-lived species. We propose that transient binding to lipid A permeabilizes the outer membrane and cluster accumulation enables the bactericidal activity of polymyxins. These findings could establish a blueprint for discovery of lipid A-targeting antibiotics and provide a generalizable approach to study interactions with the gram-negative outer membrane.

Asunto(s)

Antibacterianos , Lípido A , Polimixina B , Resonancia por Plasmón de Superficie , Polimixina B/farmacología , Polimixina B/metabolismo , Lípido A/metabolismo , Lípido A/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/metabolismo , Pruebas de Sensibilidad Microbiana , Membrana Externa Bacteriana/metabolismo , Membrana Externa Bacteriana/efectos de los fármacos , Cinética

RESUMEN

The rapid expansion of antibiotic-resistant bacterial diseases is a global burden on public health. It makes sense to repurpose and reposition already-approved medications for use as supplementary agents in synergistic combinations with existing antibiotics. Here, we demonstrate that the anthelmintic drug nitazoxanide (NTZ) synergistically enhances the effectiveness of the lipopeptide antibiotic polymyxin B in inhibiting gram-negative bacteria, including those resistant to polymyxin B. Mechanistic investigations revealed that nitazoxanide inhibited calcium influx and cell membrane depolarization, enhanced the affinity between polymyxin B and the extracellular membrane, and promoted intracellular ATP depletion and an increase in reactive oxygen species (ROS), thus enhancing the penetration and disruption of the Escherichia coli cell membrane by polymyxin B. The transcriptomic analysis revealed that the combination resulted in energy depletion by inhibiting both aerobic and anaerobic respiration patterns in bacterial cells. The increased bactericidal effect of polymyxin B on the E. coli ∆nuoC strain further indicates that NuoC could be a promising target for nitazoxanide. Furthermore, the combination of nitazoxanide and polymyxin B showed promising therapeutic effects in a mouse infection model infected with E. coli. Taken together, these results demonstrate the potential of nitazoxanide as a novel adjuvant to polymyxin B, to overcome antibiotic resistance and improve therapeutic outcomes in refractory infections.IMPORTANCEThe rapid spread of antibiotic-resistant bacteria poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Here, the synergistic activity of the FDA-approved agent nitazoxanide (NTZ) combined with polymyxin B was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of the combination of nitazoxanide and polymyxin B were explored by fluorescent dye, transmission electron microscopy (TEM), and transcriptomic analysis. The synergistic efficacy was evaluated in vivo by the Escherichia coli and mouse sepsis models. These results suggested that nitazoxanide, as a promising antibiotic adjuvant, can effectively enhance polymyxin B activity, providing a potential strategy for treating multidrug-resistant bacteria.

Asunto(s)

Antibacterianos , Sinergismo Farmacológico , Infecciones por Escherichia coli , Escherichia coli , Nitrocompuestos , Polimixina B , Tiazoles , Nitrocompuestos/farmacología , Animales , Tiazoles/farmacología , Polimixina B/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Ratones , Antibacterianos/farmacología , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Pruebas de Sensibilidad Microbiana , Especies Reactivas de Oxígeno/metabolismo , Femenino

Asunto(s)

Antibacterianos , Polimixina B , Humanos , Polimixina B/farmacocinética , Polimixina B/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación