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1.
Antimicrob Agents Chemother ; 68(10): e0077024, 2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39287402

RESUMEN

Gram-negatives harboring metallo-ß-lactamases (MBLs) and extended-spectrum ß-lactamases (ESBLs) pose a substantial risk to the public health landscape. In ongoing efforts to combat these "superbugs," we explored the clinical combination of aztreonam and ceftazidime/avibactam together with varying dosages of polymyxin B and imipenem against Klebsiella pneumoniae (Kp CDC Nevada) in a 9-day hollow fiber infection model (HFIM). As previously reported by our group, although the base of aztreonam and ceftazidime/avibactam alone leads to 3.34 log10 fold reductions within 72 hours, addition of polymyxin B or imipenem to the base regimen caused maximal killing of 7.55 log10 and 7.4 log10 fold reduction, respectively, by the 72-hour time point. Although low-dose polymyxin B and imipenem enhanced the bactericidal activity as an adjuvant to aztreonam +ceftazidime/avibactam, regrowth to ~9 log10CFU/mL by 216 hours rendered these combinations ineffective. When aztreonam +ceftazidime/avibactam was supplemented with high-dose polymyxin B and or low-dose polymyxin B + imipenem, it resulted in effective long-term clearance of the bacterial population. Time lapse microscopy profiled the emergence of long filamentous cells in response to PBP3 binding due to aztreonam and ceftazidime. The emergence of spheroplasts via imipenem and damage to the outer membrane via polymyxin B was visualized as a mechanism of persister killing. Despite intrinsic mgrB and blaNDM-1 resistance, polymyxin B and ß-lactam combinations represent a promising strategy. Future studies using an integrated molecularly precise pharmacodynamic approach are warranted to unravel the mechanistic details to propose optimal antibiotic combinations to combat untreatable, pan-drug-resistant Gram-negatives.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Ceftazidima , Combinación de Medicamentos , Imipenem , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Polimixina B , beta-Lactamasas , Klebsiella pneumoniae/efectos de los fármacos , beta-Lactamasas/metabolismo , beta-Lactamasas/genética , Compuestos de Azabiciclo/farmacología , Antibacterianos/farmacología , Ceftazidima/farmacología , Aztreonam/farmacología , Polimixina B/farmacología , Imipenem/farmacología , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Farmacorresistencia Bacteriana Múltiple/genética , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Quimioterapia Combinada
2.
Microbiol Spectr ; 12(10): e0095324, 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39225487

RESUMEN

The combination of aztreonam with ceftazidime/avibactam is considered a potential therapeutic approach for the treatment of infections caused by metallo-ß-lactamase (MBL)-producing isolates. In this study, in vitro antibacterial activity of aztreonam with avibactam against 204 carbapenemase-producing Enterobacterales was determined by broth disk elution (BDE) method of two detection volumes (5- and 2-mL broth), with broth microdilution (BMD) method as a reference. For the BDE-5mL test, the categorical agreement (CA) of ATM+CZA-lo tube (aztreonam/ceftazidime/avibactam: 6/6/4 mg/L) was 99.5%, with 0.5% major error (ME) and 0% very major error (VME); the CA of 2ATM+CZA-lo tube (12/6/4 mg/L) was 100%, with no ME and VME. For the BDE-2mL test, the CA of ATM+2CZA-hi tube (15/10/4 mg/L) was 98.5%, with 0% ME and 37.5% VME; the CA of 2ATM+2CZA-hi tube (30/10/4 mg/L) was 97.1%, with 0% ME and 75% VME. The BDE-5 mL test is an economical and practical method for clinical microbiology laboratories to determine the antibacterial susceptibility of aztreonam with avibactam against Enterobacterales, especially the 2ATM+CZA-lo tube with a final concentration of 12/6/4 mg/L of aztreonam/ceftazidime/avibactam. IMPORTANCE: Infections caused by metallo-ß-lactamase (MBL)-producing Enterobacterales are increasingly reported worldwide, and it is a significant challenge for clinical infection treatment. MBLs are adept at hydrolyzing almost all traditional ß-lactam antibiotics except aztreonam, and the enzyme activity cannot be inhibited by traditional or novel ß-lactamase inhibitors. The good thing is that the combination of aztreonam with ceftazidime/avibactam has been proven to be one of the potential therapeutic approaches for treating infections related with MBL-producing isolates. Broth microdilution (BMD) method is recommended as a reference method for its accuracy, but it is too complex to perform in most routine laboratories. Finding a more convenient, practical, and accurate susceptibility testing method for aztreonam/avibactam in clinical microbiology laboratories is very necessary. Here, we evaluated the performance of broth disk elution (BDE) method for aztreonam in combination with ceftazidime/avibactam against Enterobacterales isolates, with BMD as a reference.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Ceftazidima , Combinación de Medicamentos , Enterobacteriaceae , Pruebas de Sensibilidad Microbiana , Aztreonam/farmacología , Compuestos de Azabiciclo/farmacología , Ceftazidima/farmacología , Antibacterianos/farmacología , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/aislamiento & purificación , Humanos , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/tratamiento farmacológico , beta-Lactamasas/metabolismo
4.
Antimicrob Agents Chemother ; 68(10): e0069324, 2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39158279

RESUMEN

Treatment options for carbapenem-resistant gram-negative bacilli (CR-GNB), especially metallo-ß-lactamase (MBL)-producing CR-GNB, are limited. Aztreonam (ATM) in combination with avibactam (AVI) has shown potential for treating MBL-producing carbapenem-resistant Enterobacterales (CREs) and Stenotrophomonas maltophilia. However, data on ATM in combination with other ß-lactamase inhibitors (BLIs) are limited. We performed a multicenter study to evaluate the in vitro activities of ATM in combination with AVI, vaborbactam (VAB), relebactam (REL), tazobactam (TAZ) as well as with their commercially available formulations against CREs and S. maltophilia using broth microdilution. AVI restored ATM activity for MBL-producing CREs (ATM: 9.8% vs ATM-AVI: 78.0%) and S. maltophilia (ATM: 0% vs ATM-AVI: 93.3%). REL also moderately restored activity of ATM in MBL-producing CREs (ATM: 9.8% vs ATM-REL: 42.7%) and S. maltophilia (ATM: 0% vs ATM-REL: 68.9%). VAB and TAZ demonstrated very limited effect on the activity of ATM against CR-GNB evaluated. The combination of ATM with ceftazidime-AVI (CAZ-AVI) demonstrated maximum activity against CREs. Although ATM-CAZ-AVI is the most potent regimen available for CREs and S. maltophilia, ATM-IMI-REL might be a reasonable alternative.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Ácidos Borónicos , Pruebas de Sensibilidad Microbiana , Inhibidores de beta-Lactamasas , beta-Lactamasas , Aztreonam/farmacología , Compuestos de Azabiciclo/farmacología , Antibacterianos/farmacología , beta-Lactamasas/metabolismo , Inhibidores de beta-Lactamasas/farmacología , Ácidos Borónicos/farmacología , Carbapenémicos/farmacología , Humanos , Bacterias Gramnegativas/efectos de los fármacos , Stenotrophomonas maltophilia/efectos de los fármacos , Tazobactam/farmacología
5.
J Antibiot (Tokyo) ; 77(10): 706-710, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38951709

RESUMEN

This study was aimed at understanding the distributions of the MICs (minimum inhibitory concentrations) of aztreonam-avibactam, ceftazidime-avibactam and meropenem with respect to Klebsiella pneumoniae isolates producing different types of carbapenemases and their combinations. K. pneumoniae isolates were collected between 2019 and 2022 from 37 hospitals. PCR was used to screen for blaKPC-, blaNDM- and blaOXA-48-like genes. MICs were determined by the broth microdilution method for meropenem, aztreonam-avibactam and ceftazidime-avibactam at a constant avibactam concentration of 4 mg l-1. MIC distributions were analyzed for groups of isolates based on the identified carbapenemases including their combinations. The AZT/AVI MIC50 and MIC90 for all NDM-positive isolates were 0.25 and 0.5, respectively, and for serine-carbapenemase-only producers, they were 0.25 and 1 mg l-1, respectively. The CZD/AVI MIC50 and MIC90 values for serine-carbapenemase-only producers were 1 and 4 mg l-1, respectively. The AZT/AVI MIC50 and MIC90 values for co-producers and single carbapenemase producers were the same (i.e., 0.25 and 1 mg l-1, respectively). The total proportion of meropenem-susceptible isolates (≤8 mg l-1) among all the carbapenemase producers was 25.1% (31.1% among single-carbapenemase producers and 9.2% among co-producers). The results support the use of aztreonam-avibactam for the empirical treatment of infections caused by any carbapenemase producers.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Proteínas Bacterianas , Ceftazidima , Combinación de Medicamentos , Klebsiella pneumoniae , Meropenem , Pruebas de Sensibilidad Microbiana , beta-Lactamasas , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Compuestos de Azabiciclo/farmacología , Antibacterianos/farmacología , Ceftazidima/farmacología , Aztreonam/farmacología , Meropenem/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Humanos , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/tratamiento farmacológico
6.
Int J Antimicrob Agents ; 64(3): 107256, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38925228

RESUMEN

This study was conducted to investigate decreased susceptibility (minimum inhibitory concentrations [MICs] 0.25-4 mg/L) and resistance (MICs > 4 mg/L) to aztreonam-avibactam (ATM-AVI). Contemporary non-replicate clinical isolates of carbapenemase-producing Escherichia coli (CP-EC) (n=90) and ESBL-producing E. coli (EP-EC) (n=12) were used. CP-EC belonged to 25 distinct sequence types (STs) and all EP-EC belonged to ST405. All strains were isolated from 2019 to 2022 at the Karolinska University Laboratory, Stockholm, Sweden. ATM-AVI MICs were determined using broth microdilution. The EUCAST epidemiological cut-off value of 0.125 mg/L was used to define the wild type (WT). Whole-genome sequences (Illumina) were analysed for detecting resistance determinants among WT vs. non-WT isolates. Among 102 isolates, 40 (39%) and 62 (61%) were WT and non-WT, respectively. Among non-WT isolates, resistance was noted for 20 and decreased susceptibility for 42. Resistance was observed among 14/47 New Delhi metallo-ß-lactamase (NDM)-producers, 5/43 OXA-48 group producers, and 1/12 EP-EC. Decreased susceptibility was observed among 29/47 NDM, 13/43 OXA-48 group, and 3/12 EP-EC. Resistant isolates predominantly belonged to ST405, followed by STs 410, 361, 167, 617, and 1284. Penicillin-binding protein 3 (PBP3) inserts (YRIK/YRIN) were observed in 20/20 and CMY-42 in 5/20 resistant isolates. Several mutations in the ftsI (encoding PBP3) and regulatory genes of outer membrane proteins (OmpC and OmpF) and efflux pumps (AcrAB-TolC) were detected. A ≥ 2-fold reduction in MICs was observed among 20/20 vs. 7/20 isolates tested in the presence of the membrane permeabiliser, polymyxin B nanopeptide (PMBN) and efflux inhibitor, phenylalanine arginine ß-naphthylamide (PAßN), respectively. In conclusion, resistance to ATM-AVI is a result of interplay of various determinants, including target alterations, deactivating enzymes, and decreased permeability.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Escherichia coli , Proteínas de Unión a las Penicilinas , beta-Lactamasas , Humanos , Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Aztreonam/farmacología , Proteínas Bacterianas , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/microbiología , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Pruebas de Sensibilidad Microbiana , Proteínas de Unión a las Penicilinas/genética , Proteínas de Unión a las Penicilinas/metabolismo , Suecia , Secuenciación Completa del Genoma
7.
Int J Antimicrob Agents ; 64(3): 107260, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38945177

RESUMEN

OBJECTIVES: The proliferation of metallo-ß-lactamase (MBL)-producing Pseudomonas aeruginosa represents a significant public health threat. P. aeruginosa undergoes significant phenotypic changes that drastically impair antibiotic efficacy. The objectives of this study were (1) to quantify the time-course of killing of VIM-2-producing P. aeruginosa in response to aztreonam-based therapies (including avibactam for coverage of AmpC), and (2) to document the capacity of P. aeruginosa to undergo morphological transformations that facilitate persistence. METHODS: A well-characterised, clinical VIM-2-producing P. aeruginosa was studied in the hollow fibre infection model (HFIM) over 9 days (7 days of active antibiotic therapy, 2 days of treatment withdrawal) at a 107.5 CFU/mL starting inoculum. HFIM treatment arms included: growth control, aztreonam, ceftazidime/avibactam, aztreonam/ceftazidime/avibactam, polymyxin B, and aztreonam/ceftazidime/avibactam/polymyxin B. In addition, real-time imaging studies were conducted under static conditions to determine the time course of the reversion of persister cells. RESULTS: There was a pronounced discrepancy between OD620 and bacterial counts obtained from plating methods (hereafter referred to as 'OD-count discrepancy'). For aztreonam monotherapy, observed counts were 0 CFU/mL by 120 h. Despite this, there was a significant OD-count discrepancy compared with the pre-treatment 0 h. Between therapy withdrawal at 168 h and 216 h, all arms with suppressed counts had regrown to the system-carrying capacity. Real-time imaging of the P. aeruginosa filaments after drug removal showed rapid reversion from a long, filamentous phenotype to many individual rods within 2 h. CONCLUSION: Managing MBL-producing P. aeruginosa requires a multifaceted approach, focused on maximising killing and minimising proliferation of resistant and persistent subpopulations, which will involve eliminating drug-induced phenotypic transformers.


Asunto(s)
Antibacterianos , Aztreonam , Pseudomonas aeruginosa , beta-Lactamasas , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Antibacterianos/farmacología , Aztreonam/farmacología , Humanos , Ceftazidima/farmacología , Compuestos de Azabiciclo/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pruebas de Sensibilidad Microbiana , Combinación de Medicamentos , Viabilidad Microbiana/efectos de los fármacos
8.
Ann Clin Microbiol Antimicrob ; 23(1): 47, 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38796461

RESUMEN

BACKGROUND: Aztreonam-avibactam (ATM-AVI) combination shows promising effectiveness on most carbapenemase-producing Gram-negatives, yet standardized antibiotic susceptibility testing (AST) methods for evaluating the combination in clinical laboratories is lacking. We aimed to evaluate different ATM-AVI AST approaches. METHODS: 96 characterized carbapenem-resistant clinical isolates belonging to 9 Enterobacterales (EB; n = 80) and P. aeruginosa (PA; n = 16) species, including 90 carbapenemase producers and 72 strains resistant to both CAZ-AVI and ATM, were tested. Paper disk elution (DE; Bio-Rad) and E-test gradient strips stacking (SS; bioMérieux) were performed for the ATM + CAZ-AVI combination. MIC Test Strip (MTS; Liofilchem) was evaluated for ATM-AVI MIC determination. Results were interpreted applying ATM clinical breakpoints of the EUCAST guidelines and compared to the broth microdilution method (Sensititre, Thermofisher). RESULTS: According to broth microdilution method, 93% of EB and 69% of PA were tested susceptible to ATM-AVI. The synergistic effect of ATM-AVI was of 95% for EB, but of only 17% for PA. The MTS method yielded higher categorical and essential agreement (CA/EA) rates for both EB (89%/91%) and PA (94%/94%) compared to SS, where the rates were 87%/83% for EB and 81%/81% for PA. MTS and SS yielded 2 and 3 major discrepancies, respectively, while 3 very major discrepancies each were observed for both methods. Concerning the DE method, CA reached 91% for EB and 81% for PA, but high number of very major discrepancies were observed for EB (n = 6; 8%) and for PA (n = 3; 19%). CONCLUSIONS: The ATM-AVI association displayed excellent in vitro activity against highly resistant clinical Enterobacterales strains. MTS method offers accurate ATM-AVI AST results, while the SS method might serve as better alternative then DE method in assessing the efficacy of ATM + CAZ-AVI combination. However, further investigation is needed to confirm the methods' ability to detect ATM-AVI resistance.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Aztreonam/farmacología , Compuestos de Azabiciclo/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Antibacterianos/farmacología , Humanos , Bacterias Gramnegativas/efectos de los fármacos , Combinación de Medicamentos , Pseudomonas aeruginosa/efectos de los fármacos , beta-Lactamasas/metabolismo , Enterobacteriaceae/efectos de los fármacos , Proteínas Bacterianas , Infecciones por Bacterias Gramnegativas/microbiología
9.
Eur J Clin Microbiol Infect Dis ; 43(7): 1309-1318, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38700663

RESUMEN

PURPOSE: Enterobacteriaceae carrying mcr-9, in particularly those also co-containing metallo-ß-lactamase (MBL) and TEM type ß-lactamase, present potential transmission risks and lack adequate clinical response methods, thereby posing a major threat to global public health. The aim of this study was to assess the antimicrobial efficacy of a combined ceftazidime/avibactam (CZA) and aztreonam (ATM) regimen against carbapenem-resistant Enterobacter cloacae complex (CRECC) co-producing mcr-9, MBL and TEM. METHODS: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model. RESULTS: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups. CONCLUSION: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Ceftazidima , Combinación de Medicamentos , Enterobacter cloacae , Infecciones por Enterobacteriaceae , Pruebas de Sensibilidad Microbiana , beta-Lactamasas , Aztreonam/farmacología , Aztreonam/uso terapéutico , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Infecciones por Enterobacteriaceae/microbiología , Animales , Enterobacter cloacae/efectos de los fármacos , Enterobacter cloacae/genética , Ceftazidima/farmacología , Ceftazidima/uso terapéutico , Humanos , beta-Lactamasas/metabolismo , beta-Lactamasas/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Quimioterapia Combinada , Mariposas Nocturnas/microbiología , Farmacorresistencia Bacteriana Múltiple/genética , Modelos Animales de Enfermedad
10.
Eur J Clin Microbiol Infect Dis ; 43(7): 1393-1405, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38722450

RESUMEN

PURPOSE: Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-ß-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate. METHODS: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L). RESULTS: Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints. CONCLUSION: The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Escherichia coli , Metabolómica , Aztreonam/farmacología , Compuestos de Azabiciclo/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Escherichia coli/genética , Antibacterianos/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/tratamiento farmacológico , Metaboloma/efectos de los fármacos
11.
Microb Pathog ; 192: 106668, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38697232

RESUMEN

OBJECTIVES: The emergence of carbapenem-resistant Pseudomonas putida (CRPP) has raised public awareness. This study investigated two strains from the Pseudomonas putida group that were resistant to carbapenem, tigecycline, and aztreonam-avibactam (ATM-AVI), with a focus on their microbial and genomic characteristics. METHODS: We assessed the antibiotic resistance profile using broth dilution, disk diffusion, and E-test methods. Efflux pump phenotype testing and real-time quantitative PCR were employed to evaluate efflux pump activity in tigecycline resistance, while polymerase chain reaction was utilized to detect common carbapenem genes. Additionally, whole-genome sequencing was performed to analyze genomic characteristics. The transferability of blaIMP-1 and blaAFM-4 was assessed through a conjugation experiment. Furthermore, growth kinetics and biofilm formation were examined using growth curves and crystal violet staining. RESULTS: Both strains demonstrated resistance to carbapenem, tigecycline, and ATM-AVI. Notably, NMP can restore sensitivity to tigecycline. Subsequent analysis revealed that they co-produced blaIMP-1, blaAFM-4, tmexCD-toprJ, and blaOXA-1041, belonging to a novel sequence type ST268. Although they were closely related on the phylogenetic tree, they exhibited different levels of virulence. Genetic environment analysis indicated variations compared to prior studies, particularly regarding the blaIMP-1 and blaAFM-4 genes, which showed limited horizontal transferability. Moreover, it was observed that temperature exerted a specific influence on their biological factors. CONCLUSION: We initially identified two P. putida ST268 strains co-producing blaIMP-1, blaAFM-4, blaOXA-1041, and tmexCD-toprJ. The resistance to tigecycline and ATM-AVI can be attributed to the presence of multiple drug resistance determinants. These findings underscore the significance of P. putida as a reservoir for novel antibiotic resistance genes. Therefore, it is imperative to develop alternative antibiotic therapies and establish effective monitoring of bacterial resistance.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Pruebas de Sensibilidad Microbiana , Pseudomonas putida , Tigeciclina , beta-Lactamasas , Pseudomonas putida/genética , Pseudomonas putida/efectos de los fármacos , Tigeciclina/farmacología , Antibacterianos/farmacología , China , Aztreonam/farmacología , Compuestos de Azabiciclo/farmacología , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Farmacorresistencia Bacteriana Múltiple/genética , Secuenciación Completa del Genoma , Humanos , Combinación de Medicamentos , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Infecciones por Pseudomonas/microbiología , Carbapenémicos/farmacología
12.
Eur J Clin Microbiol Infect Dis ; 43(8): 1579-1587, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38811482

RESUMEN

PURPOSE: Amongst all etiologic hospital-acquired infection factors, K. pneumoniae strains producing New Delhi metallo-ß-lactamase (KP-NDM) belong to pathogens with the most effective antibiotic resistance mechanisms. Clinical guidelines recommend using ceftazidime/avibactam with aztreonam (CZA + AT) as the preferred option for NDM-producing Enterobacterales. However, the number of observations on such treatment regimen is limited. This retrospective study reports the clinical and microbiological outcomes of 23 patients with KP-NDM hospital-acquired infection treated with CZA + AT at a single center in Poland. METHODS: The isolates were derived from the urine, lungs, blood, peritoneal cavity, wounds, and peritonsillar abscess. In microbiological analysis, mass spectrometry for pathogen identification, polymerase chain reaction, or an immunochromatographic assay for detection of carbapenemase, as well as VITEK-2 system, broth microdilution, and microdilution in agar method for antimicrobial susceptibility tests were used, depending of the pathogens' nature. CZA was administered intravenously (IV) at 2.5 g every eight hours in patients with normal kidney function, and aztreonam was administered at 2 g every eight hours IV. Such dosage was modified when renal function was reduced. RESULTS: KP-NDM was eradicated in all cases. Four patients (17.4%) died: three of them had a neoplastic disease, and one - a COVID-19 infection. CONCLUSION: The combination of CZA + AT is a safe and effective therapy for infections caused by KP-NDM, both at the clinical and microbiological levels. The synergistic action of all compounds resulted in a good agreement between the clinical efficacy of CZA + AT and the results of in vitro susceptibility testing.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Ceftazidima , Combinación de Medicamentos , Infecciones por Klebsiella , Klebsiella pneumoniae , beta-Lactamasas , Humanos , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Aztreonam/farmacología , Aztreonam/uso terapéutico , beta-Lactamasas/metabolismo , Masculino , Compuestos de Azabiciclo/uso terapéutico , Compuestos de Azabiciclo/farmacología , Femenino , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Ceftazidima/uso terapéutico , Ceftazidima/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Polonia , Pruebas de Sensibilidad Microbiana , Adulto , Anciano de 80 o más Años , Resultado del Tratamiento , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología
13.
Microbiol Spectr ; 12(6): e0010724, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38712934

RESUMEN

This study aimed to assess the in vitro efficacy of ceftazidime-avibactam (CZA) in combination with various antimicrobial agents against carbapenem-resistant Klebsiella pneumoniae (CRKP). We selected 59 clinical CRKP isolates containing distinct drug resistance mechanisms. The minimum inhibitory concentrations (MICs) of meropenem (MEM), colistin (COL), eravacycline (ERA), amikacin (AK), fosfomycin (FOS), and aztreonam (ATM), both individually and in combination with CZA, were tested using the checkerboard method. The interactions of antimicrobial agent combinations were assessed by fractional inhibitory concentration index (FICI) and susceptible breakpoint index (SBPI). The time-kill curve assay was employed to dynamically evaluate the effects of these drugs alone and in combination format. In the checkerboard assay, the combination of CZA+MEM showed the highest level of synergistic effect against both KPC-producing and carbapenemase-non-producing isolates, with synergy rates of 91.3% and 100%, respectively. Following closely was the combination of FOS+CZA . For metallo-beta-lactamases (MBLs) producing strains, ATM+CZA displayed complete synergy, while the combination of MEM+CZA showed a synergy rate of only 57.14% for NDM-producing strains and 91.67% for IMP-producing strains. In the time-kill assay, MEM+CZA also demonstrated significant synergistic effects against the two KPC-2-producing isolates (Y070 and L70), the two carbapenemase-non-producing isolates (Y083 and L093), and the NDM-1-producing strain L13, with reductions in log10 CFU/mL exceeding 10 compared to the control. Against the IMP-producing strain Y047, ATM+CZA exhibited the highest synergistic effect, resulting in a log10 CFU/mL reduction of 10.43 compared to the control. The combination of CZA and MEM exhibited good synergistic effects against KPC-producing and non-enzyme-producing strains, followed by the FOS+CZA combination. Among MBL-producing strains, ATM+CZA demonstrated the most pronounced synergistic effect. However, the combinations of CZA with ERA, AK, and COL show irrelevant effects against the tested clinical isolates. IMPORTANCE: Our study confirmed the efficacy of the combination CZA+MEM against KPC-producing and non-carbapenemase-producing strains. For metalloenzyme-producing strains, CZA+ATM demonstrated the most significant synergy. Additionally, CZA exhibited a notable synergy effect when combined with FOS. These combination therapies present promising new options for the treatment of CRKP infection.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Enterobacteriaceae Resistentes a los Carbapenémicos , Ceftazidima , Combinación de Medicamentos , Sinergismo Farmacológico , Infecciones por Klebsiella , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Compuestos de Azabiciclo/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Ceftazidima/farmacología , Humanos , Antibacterianos/farmacología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , beta-Lactamasas/metabolismo , beta-Lactamasas/genética , Carbapenémicos/farmacología , Farmacorresistencia Bacteriana Múltiple , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Fosfomicina/farmacología , Aztreonam/farmacología
14.
PLoS One ; 19(5): e0303753, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38758757

RESUMEN

NDM-producing carbapenem-resistant bacterial infections became a challenge for clinicians. Combination therapy of aztreonam and ceftazidime-avibactam is a prudent choice for these infections. However, there is still no recommendation of a practically feasible method for testing aztreonam and ceftazidime-avibactam synergy. We proposed a simple method for testing aztreonam and ceftazidime-avibactam synergy and compared it with reference broth micro-dilution and other methods. Carbapenem-resistant Enterobacterales clinical isolates were screened for the presence of the NDM gene by the Carba R test. NDM harbouring isolates were tested for aztreonam and ceftazidime-avibactam synergy by broth microdilution (reference method), E strip-disc diffusion, double disc diffusion, and disc replacement methods. In the newly proposed method, the MHA medium was supplemented with ceftazidime-avibactam (corresponding to an aztreonam concentration of 4µg/ml). The MHA medium was then inoculated with the standard inoculum (0.5 McFarland) of the test organism. An AZT disc (30 µg) was placed on the supplemented MHA medium, and the medium was incubated overnight at 37°C. Aztreonam zone diameter on the supplemented MHA medium (in the presence of ceftazidime-avibactam) was compared with that from a standard disc diffusion plate (without ceftazidime-avibactam), performed in parallel. Interpretation of synergy was based on the restoration of aztreonam zone diameter (in the presence of ceftazidime-avibactam) crossing the CLSI susceptibility breakpoint, i.e., ≥ 21 mm. Of 37 carbapenem-resistant NDM-producing isolates, 35 (94.6%) were resistant to aztreonam and tested synergy positive by the proposed method. Its sensitivity and specificity were 97.14% and 100%, respectively. Cohen's kappa value showed substantial agreement of the reference method with the proposed method (κ = 0.78) but no other methods. The proposed method is simple, easily interpretable, and showed excellent sensitivity, specificity, and agreement with the reference method. Therefore, the new method is feasible and reliable for testing aztreonam synergy with avibactam in NDM-producing Enterobacterales.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Ceftazidima , Combinación de Medicamentos , Enterobacteriaceae , Pruebas de Sensibilidad Microbiana , beta-Lactamasas , Ceftazidima/farmacología , Aztreonam/farmacología , Compuestos de Azabiciclo/farmacología , beta-Lactamasas/metabolismo , beta-Lactamasas/genética , Pruebas de Sensibilidad Microbiana/métodos , Antibacterianos/farmacología , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/enzimología , Enterobacteriaceae/genética , Humanos , Sinergismo Farmacológico , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/tratamiento farmacológico
15.
Clin Infect Dis ; 79(4): 834-837, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-38661186

RESUMEN

We report identification of 5 patients with infections caused by NDM-5-producing Escherichia coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane ß-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Infecciones por Escherichia coli , Escherichia coli , Pruebas de Sensibilidad Microbiana , Mutación , Proteínas de Unión a las Penicilinas , beta-Lactamasas , Humanos , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/tratamiento farmacológico , Proteínas de Unión a las Penicilinas/genética , Proteínas de Unión a las Penicilinas/metabolismo , Estados Unidos , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Masculino , Femenino , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Persona de Mediana Edad , Aztreonam/farmacología , Cefalosporinas/farmacología , Cefalosporinas/uso terapéutico , Combinación de Medicamentos , Anciano , Cefiderocol , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo
16.
Int J Antimicrob Agents ; 63(6): 107161, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38561094

RESUMEN

OBJECTIVE: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P. aeruginosa strains using the CDC dynamic in vitro biofilm reactor (CBR), mechanism-based mathematical modelling (MBM) and genomic studies. METHODS: Two CF multidrug-resistant strains were investigated in a 168 h CBR (n = 2 biological replicates). Regimens were inhaled aztreonam (75 mg 8-hourly) and tobramycin (300 mg 12-hourly) in monotherapies and combination. The simulated pharmacokinetic profiles of aztreonam and tobramycin (t1/2 = 3 h) were based on published lung fluid concentrations in patients with CF. Total viable and resistant counts were determined for planktonic and biofilm bacteria. MBM of total and resistant bacterial counts and whole genome sequencing were completed. RESULTS: Both isolates showed reproducible bacterial regrowth and resistance amplification for the monotherapies by 168 h. The combination performed synergistically, with minimal resistant subpopulations compared to the respective monotherapies at 168 h. Mechanistic synergy appropriately described the antibacterial effects of the combination regimen in the MBM. Genomic analysis of colonies recovered from monotherapy regimens indicated noncanonical resistance mechanisms were likely responsible for treatment failure. CONCLUSION: The combination of aztreonam and tobramycin was required to suppress the regrowth and resistance of planktonic and biofilm bacteria in all biological replicates of both hypermutable multidrug-resistant P. aeruginosa CF isolates. The developed MBM could be utilised for future investigations of this promising inhaled combination.


Asunto(s)
Antibacterianos , Aztreonam , Biopelículas , Fibrosis Quística , Sinergismo Farmacológico , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Tobramicina , Secuenciación Completa del Genoma , Tobramicina/administración & dosificación , Tobramicina/farmacología , Aztreonam/farmacología , Aztreonam/administración & dosificación , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Biopelículas/efectos de los fármacos , Fibrosis Quística/microbiología , Fibrosis Quística/complicaciones , Humanos , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Administración por Inhalación , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana Múltiple/genética , Modelos Teóricos , Quimioterapia Combinada
17.
Int J Antimicrob Agents ; 63(6): 107163, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38570018

RESUMEN

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses immense threats to the health of infected patients worldwide, especially children. This study reports the infection caused by CRKP in a paediatric intensive care unit (PICU) child and its drug-resistant mutation during the treatment. Twelve Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains were isolated from the child. Broth microdilution method, plasmid transformation assay, and whole genome sequencing (WGS) were performed to investigate the antimicrobial susceptibility, resistance mechanisms, and genetic structural features of CRKPs. The results showed that 12 strains were highly resistant to most available antimicrobial agents. Among them, K. pneumoniae FD11 and K. pneumoniae FD12 were resistant to ceftazidime-avibactam (CZA, MIC >64 mg/L) and restored the carbapenem susceptibility (Imipenem, MIC =0.25 mg/L; Meropenem, MIC =2 mg/L). The patient improved after treatment with CZA in combination with aztreonam. Plasmid transformation assay demonstrated that the blaKPC-33-positive transformant increased MICs of CZA by at least 33-fold and 8-fold compared with the recipient Escherichia coli DH5α and blaKPC-2-positive transformants. WGS analysis revealed that all strains belonged to the ST11-KL64 type and showed highly homologous (3-26 single nucleotide polymorphisms [SNPs]). A single base mutation (G532T) of blaKPC-2 resulted in a tyrosine to aspartic acid substitution at Ambler amino acid position 179 (D179Y), which conferred CZA resistance in K. pneumoniae. This is the first report of a drug-resistant mutation evolving into blaKPC-33 during the treatment of blaKPC-2-positive CRKP in paediatric-infected patients. It advises clinicians that routine sequential antimicrobial susceptibility testing and KPC genotyping are critical during CZA therapy in children infected with CRKP.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Proteínas Bacterianas , Ceftazidima , Combinación de Medicamentos , Infecciones por Klebsiella , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , beta-Lactamasas , Humanos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Klebsiella pneumoniae/aislamiento & purificación , Compuestos de Azabiciclo/farmacología , Ceftazidima/farmacología , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/tratamiento farmacológico , beta-Lactamasas/genética , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Secuenciación Completa del Genoma , Farmacorresistencia Bacteriana Múltiple/genética , Niño , Plásmidos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Masculino , Aztreonam/farmacología
18.
J Antimicrob Chemother ; 79(6): 1309-1312, 2024 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-38564262

RESUMEN

OBJECTIVES: To evaluate the performance of an in-house developed disk diffusion method for aztreonam in combination with avibactam against Enterobacteriales. METHODS: The in vitro antibacterial activity of aztreonam with avibactam against 204 carbapenemase-producing Enterobacteriales was determined by a disk diffusion method, with a broth microdilution method as a reference. RESULTS: The optimal S/R breakpoints for disk diffusion tests of 30/20 and 10/4 µg disks, calculated by the dBETs software using the model-based approaches, were ≥22/≤21 and ≥12/≤11 mm, respectively. On the basis of the estimated breakpoints, the CAs for disk diffusion tests of 30/20 and 10/4 µg aztreonam/avibactam disks were both 98.0%, with 0.5% major error and 37.5% very major error. CONCLUSIONS: The home-made disk diffusion method is an economical and practical method for clinical microbiology laboratories to determine the antibacterial susceptibility of aztreonam with avibactam against Enterobacteriales.


Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Aztreonam , Pruebas Antimicrobianas de Difusión por Disco , Enterobacteriaceae , Aztreonam/farmacología , Compuestos de Azabiciclo/farmacología , Antibacterianos/farmacología , Enterobacteriaceae/efectos de los fármacos , Pruebas Antimicrobianas de Difusión por Disco/métodos , Pruebas Antimicrobianas de Difusión por Disco/normas , Pruebas de Sensibilidad Microbiana/métodos , Pruebas de Sensibilidad Microbiana/normas , Humanos
19.
J Antimicrob Chemother ; 79(6): 1385-1396, 2024 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-38629469

RESUMEN

BACKGROUND: Riemerella anatipestifer encodes an iron acquisition system, but whether it encodes the iron efflux pump and its role in antibiotic resistance are largely unknown. OBJECTIVES: To screen and identify an iron efflux gene in R. anatipestifer and determine whether and how the iron efflux gene is involved in antibiotic resistance. METHODS: In this study, gene knockout, streptonigrin susceptibility assay and inductively coupled plasma mass spectrometry were used to screen for the iron efflux gene ietA. The MIC measurements, scanning electron microscopy and reactive oxygen species (ROS) detection were used to verify the role of IetA in aztreonam resistance and its mechanism. Mortality and colonization assay were used to investigate the role of IetA in virulence. RESULTS: The deletion mutant ΔietA showed heightened susceptibility to streptonigrin, and prominent intracellular iron accumulation was observed in ΔfurΔietA under excess iron conditions. Additionally, ΔietA exhibited increased sensitivity to H2O2-produced oxidative stress. Under aerobic conditions with abundant iron, ΔietA displayed increased susceptibility to the ß-lactam antibiotic aztreonam due to heightened ROS production. However, the killing efficacy of aztreonam was diminished in both WT and ΔietA under anaerobic or iron restriction conditions. Further experiments demonstrated that the efficiency of aztreonam against ΔietA was dependent on respiratory complexes Ⅰ and Ⅱ. Finally, in a duckling model, ΔietA had reduced virulence compared with the WT. CONCLUSION: Iron efflux is critical to alleviate oxidative stress damage and ß-lactam aztreonam killing in R. anatipestifer, which is linked by cellular respiration.


Asunto(s)
Antibacterianos , Aztreonam , Hierro , Pruebas de Sensibilidad Microbiana , Estrés Oxidativo , Riemerella , Estrés Oxidativo/efectos de los fármacos , Hierro/metabolismo , Animales , Antibacterianos/farmacología , Riemerella/efectos de los fármacos , Riemerella/genética , Riemerella/patogenicidad , Riemerella/metabolismo , Aztreonam/farmacología , Infecciones por Flavobacteriaceae/microbiología , Virulencia , Resistencia betalactámica , Patos , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Estreptonigrina/farmacología , Técnicas de Inactivación de Genes , Enfermedades de las Aves de Corral/microbiología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo
20.
Antimicrob Agents Chemother ; 68(5): e0147423, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38602418

RESUMEN

Pseudomonas aeruginosa harboring Verona Integron-encoded metallo-ß-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US, however, VIM-CRPA remain rare. Starting in December 2018, we identified a cluster of cases in our institution. Herein, we present our epidemiological investigation and strategies to control/manage these challenging infections. This study was conducted in a large academic healthcare system in Miami, FL, between December 2018 and January 2022. Patients were prospectively identified via rapid molecular diagnostics when cultures revealed carbapenem-resistant P. aeruginosa. Alerts were received in real time by the antimicrobial stewardship program and infection prevention teams. Upon alert recognition, a series of interventions were performed as a coordinated effort. A retrospective chart review was conducted to collect patient demographics, antimicrobial therapy, and clinical outcomes. Thirty-nine VIM-CRPA isolates led to infection in 21 patients. The majority were male (76.2%); the median age was 52 years. The majority were mechanically ventilated (n = 15/21; 71.4%); 47.6% (n = 10/21) received renal replacement therapy at the time of index culture. Respiratory (n = 20/39; 51.3%) or bloodstream (n = 13/39; 33.3%) were the most common sources. Most infections (n = 23/37; 62.2%) were treated with an aztreonam-avibactam regimen. Six patients (28.6%) expired within 30 days of index VIM-CRPA infection. Fourteen isolates were selected for whole genome sequencing. Most of them belonged to ST111 (12/14), and they all carried blaVIM-2 chromosomally. This report describes the clinical experience treating serious VIM-CRPA infections with either aztreonam-ceftazidime/avibactam or cefiderocol in combination with other agents. The importance of implementing infection prevention strategies to curb VIM-CRPA outbreaks is also demonstrated.


Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas , Pseudomonas aeruginosa , beta-Lactamasas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Programas de Optimización del Uso de los Antimicrobianos , Compuestos de Azabiciclo/uso terapéutico , Aztreonam/uso terapéutico , Aztreonam/farmacología , beta-Lactamasas/genética , Carbapenémicos/uso terapéutico , Carbapenémicos/farmacología , Ceftazidima/uso terapéutico , Ceftazidima/farmacología , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple/genética , Integrones/genética , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Estudios Retrospectivos
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