RESUMEN

BACKGROUND: Glycopeptides for ampicillin-susceptible Enterococcus faecalis/faecium bacteremia are readily prescribed depending on the severity of the condition. However, there is limited data on the outcomes of glycopeptide use compared to ampicillin-containing regimens for ampicillin-susceptible E. faecalis/faecium bacteremia. From an antibiotic stewardship perspective, it is important to determine whether the use of glycopeptides is associated with improved clinical outcomes in patients with ampicillin-susceptible E. faecalis/faecium bacteremia. METHODS: This retrospective cohort study was conducted at a university-affiliated hospital between January 2010 and September 2019. We collected data from patients with positive blood cultures for Enterococcus species isolates. The clinical data of patients who received ampicillin-containing regimens or glycopeptides as definitive therapy for ampicillin-susceptible E. faecalis/faecium bacteremia were reviewed. Multivariate logistic regression analysis was performed to identify risk factors for 28-day mortality. RESULTS: Ampicillin-susceptible E. faecalis/faecium accounted for 41.2% (557/1,353) of enterococcal bacteremia cases during the study period. A total of 127 patients who received ampicillin-containing regimens (N = 56) or glycopeptides (N = 71) as definitive therapy were included in the analysis. The 28-day mortality rate was higher in patients treated with glycopeptides (19.7%) than in those treated with ampicillin-containing regimens (3.6%) (p = 0.006). However, in the multivariate model, antibiotic choice was not an independent predictor of 28-day mortality (adjusted OR, 3.7; 95% CI, 0.6-23.6). CONCLUSIONS: Glycopeptide use was not associated with improved mortality in patients with ampicillin-susceptible E. faecalis/faecium bacteremia. This study provides insights to reduce the inappropriate use of glycopeptides in ampicillin-susceptible E. faecalis/faecium bacteremia treatment and promote antimicrobial stewardship.

Asunto(s)

Ampicilina , Antibacterianos , Bacteriemia , Enterococcus faecalis , Glicopéptidos , Infecciones por Bacterias Grampositivas , Sulbactam , Humanos , Estudios Retrospectivos , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Bacteriemia/mortalidad , Ampicilina/uso terapéutico , Ampicilina/farmacología , Masculino , Femenino , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Enterococcus faecalis/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Infecciones por Bacterias Grampositivas/mortalidad , Anciano , Persona de Mediana Edad , Glicopéptidos/uso terapéutico , Glicopéptidos/farmacología , Sulbactam/uso terapéutico , Sulbactam/farmacología , Resultado del Tratamiento , Pruebas de Sensibilidad Microbiana , Anciano de 80 o más Años

RESUMEN

We investigated the activity of cefiderocol/ß-lactamase inhibitor combinations against clinical strains with different susceptibility profiles to cefiderocol to explore the potentiality of antibiotic combinations as a strategy to contain the major public health problem of multidrug-resistant (MDR) pathogens. Specifically, we evaluated the synergistic activity of cefiderocol with avibactam, sulbactam, or tazobactam on three of the most "Critical Priority" group of MDR bacteria (carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii). Clinical isolates were genomically characterized by Illumina iSeq 100. The synergy test was conducted with time-kill curve assays. Specifically, cefiderocol/avibactam, /sulbactam, or /tazobactam combinations were analyzed. Synergism was assigned if bacterial grow reduction reached 2 log10 CFU/mL. We reported the high antimicrobial activity of the cefiderocol/sulbactam combination against carbapenem-resistant Enterobacterales, P. aeruginosa, and A. baumannii; of the cefiderocol/avibactam combination against carbapenem-resistant Enterobacterales; and of the cefiderocol/tazobactam combination against carbapenem-resistant Enterobacterales and P. aeruginosa. Our results demonstrate that all ß-lactamase inhibitors (BLIs) tested are able to enhance cefiderocol antimicrobial activity, also against cefiderocol-resistant isolates. The cefiderocol/sulbactam combination emerges as the most promising combination, proving to highly enhance cefiderocol activity in all the analyzed carbapenem-resistant Gram-negative isolates, whereas the Cefiderocol/tazobactam combination resulted in being active only against carbapenem-resistant Enterobacterales and P. aeruginosa, and cefiderocol/avibactam was only active against carbapenem-resistant Enterobacterales.

Asunto(s)

Antibacterianos , Compuestos de Azabiciclo , Cefiderocol , Cefalosporinas , Sinergismo Farmacológico , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Sulbactam , Tazobactam , Compuestos de Azabiciclo/farmacología , Tazobactam/farmacología , Sulbactam/farmacología , Cefalosporinas/farmacología , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Carbapenémicos/farmacología , Humanos , Acinetobacter baumannii/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Inhibidores de beta-Lactamasas/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Combinación de Medicamentos

RESUMEN

To evaluate the in vitro activity of ampicillin-sulbactam and cefoperazone-sulbactam against A. baumannii using the broth disk elution testing, a total of 150 A. baumannii isolates were collected from across China between January 2019 and January 2021, including 51 carbapenem-susceptible and 99 carbapenem-resistant isolates. Broth disk elution (BDE) and the broth microdilution (BMD) method were performed for all strains. The concentration range of the BDE was 10/10 µg/mL, 20/20 µg/mL, and 30/30 µg/mL for ampicillin-sulbactam, and 37.5/15 µg/mL, 75/30 µg/mL, 112.5/45 µg/mL, and 150/60 µg/mL for cefoperazone-sulbactam, respectively. Compared with BMD, the BDE results of ampicillin-sulbactam and cefoperazone-sulbactam showed a categorical agreement of 83.3% (125/150) and 95.3% (143/150), with minor errors of 16.7% (25/150) and 4.7% (7/150), respectively. No major error or very major errors were detected. The sensitivity differences by BDE of carbapenem-resistant A. baumannii (CRAb) to different concentrations of ampicillin-sulbactam showed statistically significant (p < 0.017), while those to cefoperazone-sulbactam at 37.5/15 µg/mL, 75/30 µg/mL, and 112.5/45 µg/mL were significant (p < 0.008). However, no significant difference in sensitivity was observed between 112.5/45 µg/mL and 150/60 µg/mL (p > 0.008). In conclusion, the BDE is a reliable and convenient method to detect the in vitro activity of cefoperazone-sulbactam against A. baumannii, and the results could serve as a clinical reference value when deciding whether or not to use high-dose sulbactam for the treatment of A. baumannii infections.

Asunto(s)

Acinetobacter baumannii , Ampicilina , Antibacterianos , Cefoperazona , Sulbactam , Acinetobacter baumannii/efectos de los fármacos , Sulbactam/farmacología , Cefoperazona/farmacología , Ampicilina/farmacología , Antibacterianos/farmacología , Humanos , Infecciones por Acinetobacter/microbiología , Pruebas de Sensibilidad Microbiana , China , Pruebas Antimicrobianas de Difusión por Disco/métodos

RESUMEN

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 (MIC ≥ 16 mg/L), 6 were sulbactam intermediate (MIC = 8 mg/L) and 10 were sulbactam susceptible (MIC ≤ 4 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.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Pruebas de Sensibilidad Microbiana , Sulbactam , beta-Lactamasas , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/genética , Sulbactam/administración & dosificación , Sulbactam/uso terapéutico , Sulbactam/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Ratones , beta-Lactamasas/genética , Humanos , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Modelos Animales de Enfermedad , Femenino , Resultado del Tratamiento , Farmacorresistencia Bacteriana

RESUMEN

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 (%fT > MIC) 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] %fT > MIC of 60.37% [51.6-66.8] compared with other phenotypes (21.17 [16.0-32.9] %fT > MIC). 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.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Ampicilina , Antibacterianos , Pruebas de Sensibilidad Microbiana , Sulbactam , Acinetobacter baumannii/efectos de los fármacos , Sulbactam/farmacocinética , Sulbactam/administración & dosificación , Sulbactam/farmacología , Sulbactam/uso terapéutico , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Animales , Ampicilina/farmacocinética , Ampicilina/administración & dosificación , Ampicilina/farmacología , Ratones , Femenino , Modelos Animales de Enfermedad , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Humanos

RESUMEN

Combinations of the ß-lactam/ß-lactamase inhibitor sulbactam-durlobactam and seventeen antimicrobial agents were tested against strains of Acinetobacter baumannii in checkerboard assays. Most combinations resulted in indifference with no instances of antagonism. These results suggest sulbactam-durlobactam antibacterial activity against A. baumannii is unlikely to be affected if co-dosed with other antimicrobial agents.

Asunto(s)

Acinetobacter baumannii , Antibacterianos , Compuestos de Azabiciclo , Pruebas de Sensibilidad Microbiana , Sulbactam , Sulbactam/farmacología , Acinetobacter baumannii/efectos de los fármacos , Compuestos de Azabiciclo/farmacología , Antibacterianos/farmacología , Humanos , Acinetobacter calcoaceticus/efectos de los fármacos , Inhibidores de beta-Lactamasas/farmacología , Infecciones por Acinetobacter/microbiología , Infecciones por Acinetobacter/tratamiento farmacológico , Combinación de Medicamentos

RESUMEN

BACKGROUND: To establish a method to induce Campylobacter jejuni colonization in the intestines of C57BL/6 mice through antibiotic-induced microbiome depletion. RESULTS: Fifty-four female C57BL/6 mice were divided into the normal, control, and experimental groups. The experimental group was administered intragastric cefoperazone sodium and sulbactam sodium (50 mg/mL) for 2 days; then, the experimental and control mice were intragastrically administered 200 µL C. jejuni, which was repeated once more after 2 days. Animal feces were collected, and the HipO gene of C. jejuni was detected using TaqMan qPCR from day 1 to day 14 after modeling completion. Immunofluorescence was used to detect intestinal C. jejuni colonization on day 14, and pathological changes were observed using hematoxylin and eosin staining. Additionally, 16S rDNA analyses of the intestinal contents were conducted on day 14. In the experimental group, C. jejuni was detected in the feces from days 1 to 14 on TaqMan qPCR, and immunofluorescence-labeled C. jejuni were visibly discernable in the intestinal lumen. The intestinal mucosa was generally intact and showed no significant inflammatory-cell infiltration. Diversity analysis of the colonic microbiota showed significant inter-group differences. In the experimental group, the composition of the colonic microbiota differed from that in the other 2 groups at the phylum level, and was characterized by a higher proportion of Bacteroidetes and a lower proportion of Firmicutes. CONCLUSIONS: Microbiome depletion induced by cefoperazone sodium and sulbactam sodium could promote long-term colonization of C. jejuni in the intestines of mice.

Asunto(s)

Antibacterianos , Infecciones por Campylobacter , Campylobacter jejuni , Cefoperazona , Heces , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , ARN Ribosómico 16S , Sulbactam , Animales , Campylobacter jejuni/efectos de los fármacos , Campylobacter jejuni/crecimiento & desarrollo , Femenino , Antibacterianos/farmacología , Cefoperazona/farmacología , Heces/microbiología , Infecciones por Campylobacter/microbiología , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Sulbactam/farmacología , ARN Ribosómico 16S/genética , Intestinos/microbiología , Colon/microbiología , Colon/patología , Modelos Animales de Enfermedad , Mucosa Intestinal/microbiología , Mucosa Intestinal/efectos de los fármacos , ADN Bacteriano/genética , ADN Ribosómico/genética

RESUMEN

We report the emergence of cefiderocol resistance in a blaOXA-72 carbapenem-resistant Acinetobacter baumannii isolate from a sacral decubitus ulcer. Cefiderocol was initially used; however, a newly approved sulbactam-durlobactam therapy with source control and flap coverage was successful in treating the infection. Laboratory investigation revealed cefiderocol resistance mediated by ISAba36 insertion into the siderophore receptor pirA.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Carbapenémicos , Cefiderocol , Cefalosporinas , Pruebas de Sensibilidad Microbiana , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/genética , Antibacterianos/farmacología , Humanos , Cefalosporinas/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Carbapenémicos/farmacología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Sulbactam/farmacología , Masculino , Farmacorresistencia Bacteriana Múltiple/genética , Compuestos de Azabiciclo/farmacología , Elementos Transponibles de ADN/genética , Proteínas de la Membrana Bacteriana Externa

RESUMEN

ß-Lactamases (EC 3.5.2.6) confer resistance against ß-lactam group-containing antibiotics in bacteria and higher eukaryotes, including humans. Pathogenic bacterial resistance against ß-lactam antibiotics is a primary concern for potential therapeutic developments and drug targets. Here, we report putative ß-lactamase activity, sulbactam binding (a ß-lactam analogue) in the low µM affinity range, and site-specific interaction studies of a 14 kDa UV- and dark-inducible protein (abbreviated as UVI31+, a BolA homologue) from Chlamydomonas reinhartii. Intriguingly, the solution NMR structure of UVI31 + bears no resemblance to other known ß-lactamases; however, the sulbactam binding is found at two sites rich in positively charged residues, mainly at the L2 loop regions and the N-terminus. Using NMR spectroscopy, ITC and MD simulations, we map the ligand binding sites in UVI31 + providing atomic-level insights into its ß-lactamase activity. Current study is the first report on ß-lactamase activity of UVI31+, a BolA analogue, from C. reinhartii. Furthermore, our mutation studies reveal that the active site serine-55 is crucial for ß-lactamase activity.

Asunto(s)

Chlamydomonas reinhardtii , beta-Lactamasas , Chlamydomonas reinhardtii/enzimología , beta-Lactamasas/química , beta-Lactamasas/metabolismo , Sitios de Unión , Resonancia Magnética Nuclear Biomolecular/métodos , Sulbactam/química , Sulbactam/farmacología , Espectroscopía de Resonancia Magnética/métodos , Simulación de Dinámica Molecular , Secuencia de Aminoácidos , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Unión Proteica

RESUMEN

Acinetobacter baumannii-calcoaceticus complex (ABC) causes severe, difficult-to-treat infections that are frequently antibiotic resistant. Sulbactam-durlobactam (SUL-DUR) is a targeted ß-lactam/ß-lactamase inhibitor combination antibiotic designed to treat ABC infections, including those caused by multidrug-resistant strains. In a global, pathogen-specific, randomized, controlled phase 3 trial (ATTACK), the efficacy and safety of SUL-DUR were compared to colistin, both dosed with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. Results from ATTACK showed that SUL-DUR met the criteria for non-inferiority to colistin for the primary efficacy endpoint of 28-day all-cause mortality with improved clinical and microbiological outcomes compared to colistin. This report describes the characterization of the baseline ABC isolates from patients enrolled in ATTACK, including an analysis of the correlation of microbiological outcomes with SUL-DUR MIC values and the molecular drivers of SUL-DUR resistance.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Colistina , Pruebas de Sensibilidad Microbiana , Sulbactam , Humanos , Masculino , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter calcoaceticus/efectos de los fármacos , Acinetobacter calcoaceticus/genética , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Combinación Cilastatina e Imipenem/uso terapéutico , Colistina/farmacología , Colistina/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Sulbactam/uso terapéutico , Sulbactam/farmacología

RESUMEN

We present our findings on interpatient transmission, epidemic control measures, and the outcomes of a series of ten critically ill burn patients who were either colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB). None of the five infected patients achieved clinical cure, and all experienced relapses. Microbiological failure was observed in 40% of the infected patients. The isolated CRAB strains were found to carry blaOXA-23 and armA resistance genes. Despite the lack of clinical cure, all five infected patients survived and were discharged from the Burn Intensive Care Unit.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Compuestos de Azabiciclo , Carbapenémicos , Ceftazidima , Brotes de Enfermedades , Combinación de Medicamentos , Unidades de Cuidados Intensivos , Sulbactam , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/genética , Acinetobacter baumannii/aislamiento & purificación , Humanos , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Infecciones por Acinetobacter/epidemiología , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Masculino , Compuestos de Azabiciclo/uso terapéutico , Compuestos de Azabiciclo/farmacología , Sulbactam/uso terapéutico , Sulbactam/farmacología , Femenino , Persona de Mediana Edad , Adulto , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Ceftazidima/uso terapéutico , Ceftazidima/farmacología , Quemaduras/complicaciones , Quemaduras/microbiología , Quimioterapia Combinada , Resultado del Tratamiento , Anciano , Infección Hospitalaria/microbiología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/epidemiología , Farmacorresistencia Bacteriana Múltiple/genética , beta-Lactamasas/genética , Unidades de Quemados

RESUMEN

OBJECTIVES: To evaluate the in vitro activity of the combination of apramycin with colistin, meropenem, minocycline or sulbactam, against some well-characterized XDR Acinetobacter baumannii clinical isolates from Greece, to understand how apramycin can be best incorporated into clinical practice and optimize effectiveness. METHODS: In vitro interactions of apramycin (0.5×, 1× and 2× the MIC value) with colistin (2 mg/L), meropenem (30 mg/L), minocycline (3.5 mg/L) or sulbactam (24 mg/L) were tested using time-kill methodology. Twenty-one clinical A. baumannii isolates were chosen, exhibiting apramycin MICs of 4-16 mg/L, which were at or below the apramycin preliminary epidemiological cut-off value of 16 mg/L. These isolates were selected for a range of colistin (4-32 mg/L), meropenem (16-256 mg/L), minocycline (8-32 mg/L) and sulbactam (8-32 mg/L) MICs across the resistant range. Synergy was defined as a ≥2 log10 cfu/mL reduction compared with the most active agent. RESULTS: The combination of apramycin with colistin, meropenem, minocycline or sulbactam was synergistic, at least at one of the concentrations of apramycin (0.5×, 1× or 2× MIC), against 83.3%, 90.5%, 90.9% or 92.3% of the tested isolates, respectively. Apramycin alone was bactericidal at 24 h against 9.5% and 33.3% of the tested isolates at concentrations equal to 1× and 2× MIC, while the combination of apramycin at 2× MIC with colistin, meropenem or sulbactam was bactericidal against all isolates tested (100%). The apramycin 2× MIC/minocycline combination had bactericidal activity against 90.9% of the tested isolates. CONCLUSIONS: Apramycin combinations may have potential as a treatment option for XDR/pandrug-resistant (PDR) A. baumannii infections and warrant validation in the clinical setting, when this new aminoglycoside is available for clinical use.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Pruebas de Sensibilidad Microbiana , Nebramicina , Nebramicina/análogos & derivados , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/aislamiento & purificación , Grecia , Antibacterianos/farmacología , Humanos , Infecciones por Acinetobacter/microbiología , Infecciones por Acinetobacter/tratamiento farmacológico , Nebramicina/farmacología , Sulbactam/farmacología , Sinergismo Farmacológico , Meropenem/farmacología , Colistina/farmacología , Farmacorresistencia Bacteriana Múltiple , Viabilidad Microbiana/efectos de los fármacos , Minociclina/farmacología

RESUMEN

Sulbactam-durlobactam is a pathogen-targeted ß-lactam/ß-lactamase inhibitor combination that has been approved by the US FDA for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC) in patients 18 years of age and older. Sulbactam is a penicillin derivative with antibacterial activity against Acinetobacter but is prone to hydrolysis by ß-lactamases encoded by contemporary isolates. Durlobactam is a diazabicyclooctane ß-lactamase inhibitor with activity against Ambler classes A, C and D serine ß-lactamases that restores sulbactam activity both in vitro and in vivo against multidrug-resistant ABC. Sulbactam-durlobactam is a promising alternative therapy for the treatment of serious Acinetobacter infections, which can have high rates of mortality.

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Sulbactam­durlobactam: a drug for treating lung infectionsAcinetobacter is a type of bacteria. One type, called CRAB, causes serious infections and can be fatal. CRAB is very hard to treat because most drugs no longer work. Sulbactam­durlobactam (SUL-DUR) is a drug that can kill CRAB. The US FDA approved SUL-DUR in May of 2023 for treating lung infections (pneumonia) caused by CRAB. This article explains how SUL-DUR works. Use of SUL-DUR and other drugs to treat these types of infections are discussed. In conclusion, SUL-DUR is a promising therapy for serious infections caused by CRAB.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Compuestos de Azabiciclo , Sulbactam , Inhibidores de beta-Lactamasas , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/enzimología , Sulbactam/farmacología , Humanos , Inhibidores de beta-Lactamasas/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Compuestos de Azabiciclo/farmacología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple , beta-Lactamasas/metabolismo , beta-Lactamasas/genética , beta-Lactamas/farmacología , Pruebas de Sensibilidad Microbiana , Combinación de Medicamentos , Animales

RESUMEN

BACKGROUND: The drug resistance of carbapenem-resistant Acinetobacter baumannii bloodstream infections (CRAB-BSI), especially hospital-acquired infections, has promoted their rapid and vast spread. It is necessary to use reliable methods to establish better prediction models. According to Cox proportional hazards regression, a nomogram was established. METHODS: A retrospective cohort study among patients who were diagnosed with CRAB-BSI was performed from January 2020 to December 2022. Univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors regarding CRAB-BSI. Then, nomograms were used to calculate the area under the curve (AUC), C-index, and calibration curve to determine the predictive accuracy and dis-criminability. Decision curve analysis (DCA) was employed to further confirm the clinical effectiveness of the nomogram. RESULTS: A total of 98 cases were included in the comparison between the 28-day mortality group consisting of 32 patients and the 28-day survival group with 66 patients. The use of cefoperazone-sulbactam was significantly higher among patients who survived than among those who died. Univariable analysis revealed that factors such as primary diagnosis, time to inadequate antimicrobial therapy, and high serum creatinine and procalcitonin (PCT) levels were more prevalent in the mortality group. However, only primary diagnosis, time to inadequate antimicrobial therapy, and high PCT levels emerged as statistically significant risk factors for death in multivariate analysis and were used to construct the nomogram. The nomogram validation exhibited excellent performance. CONCLUSIONS: The nomogram was sufficiently accurate to predict the risk and prognostic factors of CRAB-BSI, allowing for individualized clinical decisions for future clinical work. The cefoperazone-sulbactam did have an effect, but more studies are needed to interpret it.

Asunto(s)

Acinetobacter baumannii , Antiinfecciosos , Sepsis , Humanos , Nomogramas , Sulbactam/farmacología , Cefoperazona/farmacología , Cefoperazona/uso terapéutico , Estudios Retrospectivos , Antiinfecciosos/farmacología , Sepsis/tratamiento farmacológico , Pronóstico

RESUMEN

OBJECTIVES: This study aimed to appraise clinical practice guidelines (CPGs) for the treatment of carbapenem-resistant Gram-negative Bacilli (CRGNB) infections and to summarise the recommendations. METHODS: A systematic search of the literature published from January 2012 to March 2023 was undertaken to identify CPGs related to CRGNB infections treatment. The methodological and reporting quality of eligible CPGs were assessed using six domains of the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool and seven domains of the Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist. Basic information and recommendations of included CPGs were extracted and compared. RESULTS: A total of 21 CPGs from 7953 relevant articles were included. The mean overall AGREE II score was 62.7%, and was highest for "clarity of presentation" (90.2%) and lowest for "stakeholder involvement" (44.8%). The overall reporting quality of all of the CPGs was suboptimal, with the proportion of eligible items ranging from 45.7 to 85.7%. The treatment of CRGNB infections is related to the type of pathogen, the sensitivity of antimicrobial agents, and the site of infection. In general, the recommended options mainly included novel ß-lactam/ ß-lactamase inhibitors, cefiderocol, ampicillin-sulbactam (mainly for carbapenem-resistant Acinetobacter baumannii [CRAB]), and combination therapy, involving polymyxin B/colistin, tigecycline (except for carbapenem-resistant Pseudomonas aeruginosa), aminoglycosides, carbapenems, fosfomycin, and sulbactam (mainly for CRAB). CONCLUSIONS: The methodological and reporting quality of CPGs for the treatment of CRGNB infections are generally suboptimal and need further improvement. Both monotherapy with novel drugs and combination therapy play important roles in the treatment.

Asunto(s)

Antibacterianos , Carbapenémicos , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas , Guías de Práctica Clínica como Asunto , Humanos , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Carbapenémicos/uso terapéutico , Carbapenémicos/farmacología , Cefiderocol , Fosfomicina/uso terapéutico , Fosfomicina/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Pruebas de Sensibilidad Microbiana/normas , Sulbactam/uso terapéutico , Sulbactam/farmacología , Tigeciclina/uso terapéutico , Tigeciclina/farmacología

RESUMEN

The activity of a novel ß-lactamase inhibitor combination, sulbactam-durlobactam (SUL-DUR), was tested against 87 colistin-resistant and/or cefiderocol-non-susceptible carbapenem-resistant Acinetobacter baumannii clinical isolates collected from U.S. hospitals between 2017 and 2019. Among them, 89% and 97% were susceptible to SUL-DUR and imipenem plus SUL-DUR, with MIC50/MIC90 values of 2 µg/mL/8 µg/mL and 1 µg/mL/4 µg/mL, respectively. The presence of amino acid substitutions in penicillin-binding protein 3, including previously reported A515V or T526S, was associated with SUL-DUR non-susceptibility.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Compuestos de Azabiciclo , Humanos , Colistina/farmacología , Antibacterianos/farmacología , Cefiderocol , Infecciones por Acinetobacter/tratamiento farmacológico , Sulbactam/farmacología , Imipenem/farmacología , Hospitales , Pruebas de Sensibilidad Microbiana , Combinación de Medicamentos

RESUMEN

BACKGROUND: Sulbactam-durlobactam (SUL-DUR) has been tested in vitro for its ability to generate resistance in clinical isolates of Acinetobacter species. According to prior studies, combining durlobactam with sulbactam causes sulbactam-resistant isolates to become more active and revert to susceptibility. We aimed to conduct a systematic review of the in vitro activity of SUL-DUR on A. baumannii (Ab) isolates, including carbapenem-resistant A. baumannii (CRAb), to provide an overview for physicians dealing with Ab infections. METHODS: The following keywords were searched in the PubMed, Google Scholar, and EMBASE databases to look for eligible original works that have been published without restrictions till June 30, 2023: A. baumannii and sulbactam-durlobactam, SUL-DUR, durlobactam, and sulbactam-ETX2514. We also searched clinicaltrials.gov and the Clinical Trials Registry of India (CTRI) for clinical trials involving sulbactamdurlobactam and Acinetobacter. RESULTS: There were a total of 852 abstracts found. Among them, 633 articles with titles, abstracts, and keywords were reviewed, and 574 articles were removed after the initial screening. A total of 59 full-text eligible articles were evaluated, and 51 of them were eliminated because they did not satisfy the criteria set for inclusion. The full texts of the final 8 in vitro studies on A. baumanii and sulbactam/durlobactam were further evaluated. There were 5 trials on A. baumanii and sulbactam/durlobactam found on clinicaltrials.gov and the Clinical Trial Registry of India (CTRI). CONCLUSION: The findings from the studies show that SUL-DUR might be a successful therapeutic option for multidrug-resistant-Ab infections. Future clinical trials will be required to validate the possibility of using this combination to treat multidrug-resistant A. baumannii infections.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Compuestos de Azabiciclo , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Sulbactam , Acinetobacter baumannii/efectos de los fármacos , Sulbactam/uso terapéutico , Sulbactam/farmacología , Humanos , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Combinación de Medicamentos

RESUMEN

Multidrug-resistant Acinetobacter baumannii (MDRAB) is an important pathogen that causes nosocomial infections and is resistant to almost all antibiotics, including carbapenems. Cefiderocol is a novel siderophore cephalosporin active against a broad spectrum of gram-negative bacteria. However, the susceptibility of MDRAB to cefiderocol has not yet been reported in Japan. In this study, we measured the minimum inhibitory concentrations (MICs) of antibiotics including cefiderocol against MDRAB clinical isolates collected during a nosocomial outbreak between 2009 and 2010 at the Teikyo University Hospital in Japan. We found that all 10 MDRAB clinical isolates tested were susceptible to cefiderocol, with an MIC range of 0.12 to 1 µg/mL. All the isolates also exhibited resistance to ampicillin-sulbactam and an intermediate resistance to colistin, whereas nine of them were susceptible to tigecycline. DNA sequencing revealed that all strains harbored an OXA-51-like carbapenemase, a major cause of carbapenem resistance in A. baumannii in Japan. In conclusion, this study showed that the cefiderocol susceptibility of MDRAB clinical isolates in Japan was equivalent to that to colistin or tigecycline, and thus cefiderocol is a potential treatment option for MDRAB infections.

Asunto(s)

Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Cefiderocol , Cefalosporinas , Infección Hospitalaria , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/aislamiento & purificación , Humanos , Japón , Antibacterianos/farmacología , Cefalosporinas/farmacología , Infecciones por Acinetobacter/microbiología , Infecciones por Acinetobacter/tratamiento farmacológico , Infección Hospitalaria/microbiología , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Tigeciclina/farmacología , Colistina/farmacología , Análisis de Secuencia de ADN , Sulbactam/farmacología , Sideróforos/farmacología , Minociclina/análogos & derivados , Minociclina/farmacología , Proteínas Bacterianas/genética

RESUMEN

Sulbactam-durlobactam is a ß-lactam/ß-lactamase inhibitor combination developed to treat hospital-acquired and ventilator-associated bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Durlobactam is a diazabicyclooctane ß-lactamase inhibitor with potent activity against Ambler classes A, C, and D serine ß-lactamases and restores sulbactam activity against multidrug-resistant ABC. Studies were conducted to establish sulbactam-durlobactam antimicrobial susceptibility testing methods for both broth microdilution minimal inhibitory concentration (MIC) and disk diffusion tests as well as quality control (QC) ranges. To establish the MIC test method, combinations of sulbactam and durlobactam were evaluated using a panel of genetically characterized A. baumannii isolates which were categorized as predicted to be susceptible or resistant based on the spectrum of ß-lactamase inhibition by durlobactam. MIC testing with doubling dilutions of sulbactam with a fixed concentration of 4 µg/mL of durlobactam resulted in the greatest discrimination of the pre-defined susceptible and resistant strains. Similarly, the sulbactam/durlobactam 10/10 µg disk concentration showed the best discrimination as well as correlation with the MIC test. A. baumannii NCTC 13304 was selected for QC purposes because it assesses the activity of both sulbactam and durlobactam with clear endpoints. Multi-laboratory QC studies were conducted according to CLSI M23 Tier 2 criteria. A sulbactam-durlobactam broth MIC QC range of 0.5/4-2/4 µg/mL and a zone diameter QC range of 24-30 mm were determined for A. baumannii NCTC 13304 and have been approved by CLSI. These studies will enable clinical laboratories to perform susceptibility tests with accurate and reproducible methods.

Asunto(s)

Acinetobacter baumannii , Compuestos de Azabiciclo , Sulbactam , Humanos , Sulbactam/farmacología , Sulbactam/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Pruebas de Sensibilidad Microbiana , Control de Calidad , Combinación de Medicamentos

RESUMEN

Infections caused by Acinetobacter baumannii are increasingly multidrug resistant and associated with high rates of morbidity and mortality. Sulbactam is a ß-lactamase inhibitor with intrinsic antibacterial activity against A. baumannii. Durlobactam is a non-ß-lactam ß-lactamase inhibitor with an extended spectrum of activity compared to other inhibitors of its class. In vitro pharmacodynamic infection models were undertaken to establish the pharmacokinetic/pharmacodynamic (PK/PD) index and magnitudes associated with sulbactam and durlobactam efficacy and to simulate epithelial lining fluid (ELF) exposures at clinical doses to understand sulbactam-durlobactam activity with and without co-administration of a carbapenem. Hollow fiber infection models (HFIMs) and one-compartment systems were used to identify the PK/PD indices and exposure magnitudes associated of 1-log10 and 2-log10 colony-forming unit (CFU)/mL reductions. Sulbactam and durlobactam demonstrated PK/PD drivers of % time above the minimum inhibition concentration (%T > MIC) and area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24)/MIC, respectively. Against a sulbactam-susceptible strain, sulbactam %T > MIC of 71.5 and 82.0 were associated with 1-log10 and 2-log10 CFU/mL reductions, respectively, in the HFIM. Against a non-susceptible strain, durlobactam restored the activity of sulbactam with an AUC0-24/MICs of 34.0 and 46.8 using a polysulfone cartridge to achieve a 1-log10 and 2-log10 CFU/mL reduction. These magnitudes were reduced to 13.8 and 24.2, respectively, using a polyvinylidene fluoride cartridge with a membrane pore size of 0.1 µm. In the one-compartment model, durlobactam AUC0-24/MIC to achieve 1-log10 and 2-log10 CFU/mL reduction were 7.6 and 33.4, respectively. Simulations of clinical ELF exposures in the HFIM showed cidal activity at MICs ≤4 µg/mL. Penicillin binding protein 3 mutant strains with MICs of 8 µg/mL may benefit from the addition of a carbapenem at clinical exposures.

Asunto(s)

Acinetobacter baumannii , Sulbactam , Sulbactam/farmacología , Inhibidores de beta-Lactamasas/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/farmacología , Pruebas de Sensibilidad Microbiana