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Objective: Characterization of the multidrug resistance (MDR) region in P. aeruginosa strain PA59 revealed the presence of antibiotic resistance genes, including blaIMP-45 and blaVIM-2, within a complex genetic landscape of mobile genetic elements. Methods: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) strains were isolated from Shanghai Changhai Hospital. Polymerase chain reaction (PCR) was used to detect the ß-lactamase genes in the isolated strains. Strains carrying two or more genes were subjected to whole-genome sequencing (WGS) and in-depth bioinformatics analysis. Results: A total of 94 CRPA strains were isolated, among which PA59 was determined to carry blaIMP-45 and blaVIM-2 genes. Compared with single-gene positive or other blaIMP and blaVIM dual-gene positive strains reported, PA59 exhibited a broader range of drug resistance. We discovered a multidrug resistant (MDR)-related region composed of various mobile elements in the PA59 chromosome. This region carried many resistance genes, including the target genes blaIMP-45 and blaVIM-2. By further comparing the mobile elements GI13 and Ph08, we speculated that this integron structure carrying blaIMP-45 and blaVIM-2 was initially integrated into the genomic island or prophage, forming a more complex genetic structure, and then further integrated into the PA59 chromosome through plasmids. Phylogenetic tree analysis showed limited sequence similarity between PA59 and other CRPA strains. Conclusions: This study identified PA59 as the first reported P. aeruginosa strain carrying both blaIMP-45 and blaVIM-2 on the chromosome. The assembly and annotation of the PA59 genome provide valuable insights into the genomic diversity and gene content of this clinically important pathogen, aiding the development of effective strategies against antibiotic resistance.

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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.

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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

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The present study aimed to explore the genomic characteristics of eight New Delhi metallo-ß-lactamase-1 (NDM-1)-producing carbapenem-resistant Pseudomonas aeruginosa (CRPA) isolates from a Bulgarian tertiary hospital (2021-2023) in comparison to blaNDM-1-positive strains originating from the Balkans. Antimicrobial susceptibility testing, phenotypic assays for carbapenemase activity, PCR screening, whole-genome sequencing (WGS), and phylogenomic analysis were performed. Seven of the CRPA isolates investigated (Minimum inhibitory concentration values of imipenem and meropenem >32 mg L-1) were also resistant to piperacillin-tazobactam, ceftazidime, ceftazidime-avibactam, cefepime, ceftolozane-tazobactam, amikacin, tobramycin, ciprofloxacin, and levofloxacin, but were susceptible to colistin (0.5-2 mg L-1) and cefiderocol (0.25-1 mg L-1). The P. aeruginosa Pae57 isolate (designated Pae57) remained susceptible to aminoglycosides as well. WGS uncovered the co-existence of blaNDM-1 and blaGES-1. The isolates belonged to the ST654 high-risk clone, except for Pae57 (ST611). Alignment against reference sequences revealed the presence of a Tn21 transposon harboring bleMBL-blaNDM-1-ISAba125. It was similar to that found in the P. aeruginosa ST654 NDM1_1 strain (GCA_020404785.1) from Serbia. Phylogenomic analysis of our isolates indicated that seven of them (ST654) differed from each other in no more than 44 single-nucleotide polymorphisms (SNPs). Pae57 (ST611) was strikingly different (>21,700 SNPs) compared to all Balkan strains. In conclusion, to our knowledge this is the first report of blaNDM-1-positive P. aeruginosa ST611 isolation, which indicates the transmission dynamics of this determinant between high-risk and potentially high-risk P. aeruginosa clones. Obtained results unveil the dissemination of clonally related NDM-1-producing P. aeruginosa strains in the monitored hospital for approximately a 2-year period.

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Antibacterianos , Pruebas de Sensibilidad Microbiana , Filogenia , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Centros de Atención Terciaria , beta-Lactamasas , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/aislamiento & purificación , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Humanos , Bulgaria , Antibacterianos/farmacología , Infecciones por Pseudomonas/microbiología , Secuenciación Completa del Genoma , Genoma Bacteriano , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Farmacorresistencia Bacteriana Múltiple/genética

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INTRODUCTION: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a serious threat to public health. Globally, carbapenemases-producing CRPA isolates mainly belong to 'high-risk' clones; however, the molecular epidemiology of CRPA isolates circulating in Chile are scarce, where this pathogen is the main aetiological agent of ventilator-associated pneumonia. OBJECTIVES: To characterize the phylogenomics and molecular features of ST654 CRPA isolates collected in Chile between 2016 and 2022. METHODS: Eighty-nine CRPA isolates collected in different Chilean hospitals from clinical specimens between 2005 and 2022 were analysed. Antibiotic susceptibility tests and carbapenemases production were carried out on the CRPA ST654 isolates. Also, they were subjected to whole-genome sequencing, from which in silico analyses were performed. RESULTS: Thirty-four strains (38.2%) belonged to the ST654 high-risk clone, being the most predominant lineage of the collection. Most of these isolates belonged to a subclade including KPC producers that also clustered with strains from Argentina and the United States, whereas few VIM and NDM co-producers clustered in two different smaller subclades. The isolates exhibited a broad resistome encompassing genes mediating resistance to several other clinically relevant drugs. Additionally, all the 34 ST654 isolates were ExoS+ as a virulence factor and associated to the O4-serotype. CONCLUSIONS: Our report represents the most comprehensive phylogenomic study of a CRPA high-risk clone ST654 to date. Our analyses suggest that this lineage is undergoing a divergent evolutionary path in Chile, because most of the isolates were KPC producers and were O4 serotype, differing from previous descriptions, which underline the relevance of performing molecular surveillance on this pathogen.

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Proteínas Bacterianas , Carbapenémicos , Pruebas de Sensibilidad Microbiana , Filogenia , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Secuenciación Completa del Genoma , beta-Lactamasas , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Pseudomonas aeruginosa/clasificación , Chile/epidemiología , Humanos , Carbapenémicos/farmacología , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/epidemiología , beta-Lactamasas/genética , Proteínas Bacterianas/genética , Hospitales , Antibacterianos/farmacología , Epidemiología Molecular , Genoma Bacteriano , Femenino , Masculino , Persona de Mediana Edad , Neumonía Asociada al Ventilador/microbiología , Neumonía Asociada al Ventilador/epidemiología , Genómica , Anciano , Adulto , Farmacorresistencia Bacteriana Múltiple/genética

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Background: Carbapenem-resistant P. aeruginosa (CRPA) is a common hospital-acquired bacterium. It exhibits high resistance to many antibiotics, including ceftazidime/avibactam and cefteolozane/tazobactam. The presence of carbapenem-resistant genes and co-existence Klebsiella pneumoniae carbapenemase (KPC) and metallo-ß-lactamases (MBLs) further inactivated all ß-lactams. Understanding the resistance genes of CRPA can help in uncovering the resistance mechanism and guiding anti-infective treatment. Herein, we reported a case of perianal infection with hypervirulent ST463 Pseudomonas aeruginosa. Case Presentation: The case is a 32-year-old acute myeloid leukemia (AML) patient with fever and septic shock during hematopoietic stem cell transplantation (HSCT), and the pathogen was finally identified as a highly virulent sequence type 463 (ST463) P. aeruginosa harboring carbapenem-resistant genes blaAFM-1 and blaKPC-2, which was detected in the bloodstream and originated from a perianal infection. The strain was resistant to ceftazidime/avibactam but successfully treated with polymyxin B, surgical debridement, and granulocyte engraftment after HSCT. The AML was cured during the 19-month follow-up. Conclusion: This case emphasizes the importance of metagenomic next-generation sequencing (mNGS) and whole-genome sequencing (WGS) in identifying microbes with rare resistant genes, and managing CRPA, especially in immunocompromised patients. Polymyxin B may be the least resistant option.

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BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) infection has become a major public health concern. The recommendations for monotherapy and combination therapy in the current guidelines lack sufficient evidence to support them. The primary objective of this study is to determine the effectiveness of anti-Infective combination therapy compared to monotherapy in achieving clinical success in patients with CRPA infection and risk factors of clinical failure of monotherapy. METHODS: A retrospective study from Medical Information Mart for Intensive Care IV (MIMIC-IV) was conducted. We included adults with infections caused by CRPA. The outcomes of this study were clinical success, complete clinical success, and 28-day all-cause mortality. RESULTS: A total of 279 subjects were finally enrolled. The rate of clinical success for combination therapy was higher than that for monotherapy (73.1% versus 60.4%, p=0.028). Compared to clinical failure patients, patients in the clinical success group were more likely to die within 28 days after CRPA was found (48.3% versus 3.6%, p<0.001). In a multivariate logistic regression analysis, monotherapy was found to be significantly correlated with clinical success (OR, 0.559, 95% CI, 0.321-0.976; p = 0.041). CONCLUSION: Combination therapy is more effective for CRPA infection patients, especially those whose SOFA score is ≥ 2 or whose Charlson comorbidity index is ≥ 6.

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Antibacterianos , Infecciones por Pseudomonas , Adulto , Humanos , Estudios Retrospectivos , Antibacterianos/uso terapéutico , Carbapenémicos/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa

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PURPOSE: The emergence of carbapenem-resistant P. aeruginosa (CRPA) harbouring acquired carbapenemase genes (blaVIM, blaIMP and blaNDM) has become a global public health threat. Three CRPA isolates included in the study had an extensively drug-resistant phenotype with susceptibility to colistin only and were positive for the blaNDM-1 gene. The current study aimed to investigate the genomic epidemiology and molecular characteristics of the blaNDM-1-positive CRPA isolates collected from the Gauteng region, South Africa. METHODS: Short read whole genome sequencing (WGS) was performed to determine sequence types (STs), genetic relatedness, resistome, virulome and the genetic environment of the blaNDM-1 gene. RESULTS: The WGS and phylogenetic analyses revealed that the study isolates belonged to an international high-risk clone ST773 and belonged to the same clade with eight blaNDM-1-positive ST773 isolates from Hungary, India, Nigeria, South Korea and USA. The study isolates harboured a wide repertoire of intrinsic and acquired antibiotic resistance genes (ARGs) related with mobile genetic elements, porins and efflux pumps, as well as virulence factor genes. The clade-specific ARGs (blaNDM-1, floR2/cmlA9, rmtB4, tetG) were found in a putative integrative and conjugative element (ICE) region similar to ICE6660-like. CONCLUSION: As ICE carrying the blaNDM-1 gene can easily spread to other P. aeruginosa isolates and other Gram-negative bacteria, the findings in this study highlight the need for appropriate management strategies and active surveillance of CRPA isolates in the Gauteng region, South Africa.

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Antibacterianos , Pseudomonas aeruginosa , Humanos , Filogenia , Sudáfrica/epidemiología , Antibacterianos/farmacología , beta-Lactamasas/genética , Carbapenémicos/farmacología , Genómica , Pruebas de Sensibilidad Microbiana

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OBJECTIVES: Resistance against ceftazidime-avibactam (CZA) in carbapenem-resistant Pseudomonas aeruginosa (CRPA) is emerging. This study was aimed at detecting the prevalence and molecular characteristics of CZA-resistant CRPA clinical isolates in Guangdong Province, China. METHODS: The antimicrobial susceptibility profile of these strains was determined. A subset of 16 CZA-resistant CRPA isolates was analysed by whole-genome sequencing (WGS). Genetic surroundings of carbapenem resistance genes and pan-genome-wide association analysis were further studied. RESULTS: Of the 250 CRPA isolates, CZA resistance rate was 6.4% (16/250). The minimum inhibitory concentration (MIC) of CZA range was from 0.25 to >256 mg/L. MIC50 and MIC90 were 2/4 and 8/4 mg/L, respectively. Among the 16 CZA-resistant CRPA strains, 31.3% (5/16) of them carried class B carbapenem resistance genes, including blaIMP-4, blaIMP-45, and blaVIM-2, located on IncP-2 megaplasmids or chromosomes, respectively. Pan-genome-wide association analysis of accessory genes for CZA-susceptible or -resistant CRPA isolates showed that PA1874, a hypothetical protein containing BapA prefix-like domain, was enriched in CZA-resistant group significantly. CONCLUSIONS: Class B carbapenem resistance genes play important roles in CZA resistance. Meanwhile, the PA1874 gene may be a novel mechanism involving in CZA resistance. It is necessary to continually monitor CZA-resistant CRPA isolates.

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Antibacterianos , Compuestos de Azabiciclo , Ceftazidima , Infecciones por Pseudomonas , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Pseudomonas aeruginosa , Prevalencia , Estudio de Asociación del Genoma Completo , Infecciones por Pseudomonas/epidemiología , Infecciones por Pseudomonas/tratamiento farmacológico , Carbapenémicos/farmacología , Combinación de Medicamentos

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PURPOSE: To characterize the resistance mechanisms affecting the cefepime-taniborbactam combination in a collection of carbapenemase-producing Enterobacterales (CPE) and carbapenem-resistant Pseudomonas spp. (predominantly P. aeruginosa; CRPA) clinical isolates. METHODS: CPE (n = 247) and CRPA (n = 170) isolates were prospectively collected from patients admitted to 8 Spanish hospitals. Susceptibility to cefepime-taniborbactam and comparators was determined by broth microdilution. Cefepime-taniborbactam was the most active agent, inhibiting 97.6% of CPE and 67.1% of CRPA (MICs ≤ 8/4 mg/L). All isolates with cefepime-taniborbactam MIC > 8/4 mg/L (5 CPE and 52 CRPA) and a subset with MIC ≤ 8/4 mg/L (23 CPE and 24 CRPA) were characterized by whole genome sequencing. RESULTS: A reduced cefepime-taniborbactam activity was found in two KPC-ST307-Klebsiella pneumoniae isolates with altered porins [KPC-62-K. pneumoniae (OmpA, OmpR/EnvZ), KPC-150-K. pneumoniae (OmpK35, OmpK36)] and one each ST133-VIM-1-Enterobacter hormaechei with altered OmpD, OmpR, and OmpC; IMP-8-ST24-Enterobacter asburiae; and NDM-5-Escherichia coli with an YRIN-inserted PBP3 and a mutated PBP2. Among the P. aeruginosa (68/76), elevated cefepime-taniborbactam MICs were mostly associated with GES-5-ST235, OXA-2+VIM-2-ST235, and OXA-2+VIM-20-ST175 isolates also carrying mutations in PBP3, efflux pump (mexR, mexZ) and AmpC (mpl) regulators, and non-carbapenemase-ST175 isolates with AmpD-T139M and PBP3-R504C mutations. Overall, accumulation of these mutations was frequently detected among non-carbapenemase producers. CONCLUSIONS: The reduced cefepime-taniborbactam activity among the minority of isolates with elevated cefepime-taniborbactam MICs is not only due to IMP carbapenemases but also to the accumulation of multiple resistance mechanisms, including PBP and porin mutations in CPE and chromosomal mutations leading to efflux pumps up-regulation, AmpC overexpression, and PBP modifications in P. aeruginosa.

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Antibacterianos , Proteínas Bacterianas , Ácidos Borínicos , Carbapenémicos , Ácidos Carboxílicos , Humanos , Cefepima/farmacología , Carbapenémicos/farmacología , Antibacterianos/farmacología , Pseudomonas/genética , España/epidemiología , beta-Lactamasas/genética , Pseudomonas aeruginosa/genética , Pruebas de Sensibilidad Microbiana

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<b>Objective</b> To evaluate the effectiveness of multi-disciplinary team (MDT) mode in the prevention and control of multidrug resistant organism (MDRO) infection in lung transplant recipients. <b>Methods</b> Lung transplant recipients admitted to the hospital from 2019 to 2022 were enrolled. MDT expert group was established in January, 2020. A series of prevention and control measures were conducted. The implementation rate of MDRO prevention and control measures and the detection rate of MDRO on the environmental surface from 2020 to 2022, and the detection rate of MDRO in lung transplant recipients from 2019 to 2022 were analyzed. <b>Results</b> The overall implementation rate of MDRO prevention and control measures for medical staff was increased from 64.9% in 2020 to 91.6% in 2022, showing an increasing trend year by year (<i>P</i><0.05). The detection rate of MDRO on the environmental surface was decreased from 28% in 2020 to 9% in 2022, showing a downward trend year by year (<i>P</i><0.05). The detection rate of MDRO in lung transplant recipients was decreased from 66.7% in 2019 to 44.3% in 2022, showing a decreasing trend year by year (<i>P</i><0.001). <b>Conclusions</b> MDT mode management may enhance the implementation of MDRO prevention and control measures for medical staff, effectively reduce the infection rate of MDRO in lung transplant recipients and the detection rate of MDRO on the environmental surface, which is worthy of widespread application.

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Pseudomonas aeruginosa high-risk clones pose severe threats to public health. Here, we characterize the imipenem/relebactam (IR) resistance mechanisms in P. aeruginosa high-risk clones sequence type 235 (ST235) and ST463 in China. Minimum inhibitory concentrations (MICs) were determined, and Illumina short-read sequencing was performed for 1,168 clinical carbapenem-resistant P. aeruginosa (CRPA) isolates. The gene copy number and expression level were analyzed by Illumina sequencing depth and reverse transcription-quantitative PCR, respectively. Resistance conferred by bla GES-5 was evaluated by cloning experiments. ST463 and ST235 accounted for 9.8% (115/1,168) and 4.5% (53/1,168) of total isolates, respectively, and showed high frequencies of extensively drug-resistant and difficult-to-treat resistant phenotypes. The overall IR-resistant rate in CRPA was 21.0% (245/1,168). However, the IR resistance rate was 81.7% (94/115) in ST463-PA and 52.8% (28/53) in ST235-PA. Of the ST463 isolates, 92.2% (106/115) were Klebsiella pneumoniae carbapenemase-producing P. aeruginosa (KPC-PA), and all 94 IR-resistant ST463-PA produced KPC-2. Compared to IR-susceptible ST463 KPC-2-PA, IR-resistant ST463 KPC-2-PA exhibited significantly higher bla KPC-2 copy numbers and expression levels. In ST463 KPC-2-PA, 16 mg/L relebactam resulted in additional fourfold reductions in imipenem MIC50/90 values compared to 4 mg/L relebactam. In ST235, 1.9% (1/53) carried bla IMP carbapenemase and 54.7% (29/53) carried bla GES carbapenemase. Other than the IMP producer, all 27 IR-resistant ST235-PA produced GES-5. Cloning experiments revealed that imipenem resistance in bla GES-5-carrying PAO1 transformants was generally unaffected by relebactam. In conclusion, IR-resistant CRPA isolates in China were mainly distributed in P. aeruginosa high-risk clones ST463 and ST235. The major underlying IR resistance mechanisms were bla KPC-2 overexpression and bla GES-5 carriage.

Asunto(s)

Infecciones por Pseudomonas , Pseudomonas aeruginosa , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , beta-Lactamasas/metabolismo , Carbapenémicos/uso terapéutico , Células Clonales/metabolismo , Imipenem/farmacología , Imipenem/uso terapéutico , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Infecciones por Pseudomonas/tratamiento farmacológico

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The escalating prevalence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a significant threat to global public health through the spread of its 'high-risk' clones. Immediate and decisive research into antimicrobial agents against CRPA is crucial for the development of effective measures and interventions. Overexpression of the MexAB-OprM efflux pump is one of the major mechanisms of CRPA. Since the active efflux of antibacterial agents plays a significant role in mediating drug resistance in CRPA, the inhibition of efflux pumps has become a promising strategy to restore antibacterial potency. Piperine (PIP) has been proven to be a promising efflux pump inhibitor in some bacteria. However, there are no studies on whether PIP can act as a potential efflux pump inhibitor in CRPA. The present study aimed to identify the antibacterial activity of PIP against CRPA and to evaluate the effect on the MexAB-OprM efflux pump. Molecular docking was used to analyze the possible interaction of PIP with the proteins of the MexAB-OprM efflux pump in CRPA. The effect of PIP on the expression of the MexAB-OprM efflux pump was investigated by real-time quantitative PCR (qPCR) and ethidium bromide accumulation efflux assay. The effect of PIP on CRPA imipenem (IPM) resistance was investigated by the checkerboard dilution method. The results demonstrated that PIP exhibited the lowest binding affinity of -9.1 kcal towards efflux pump proteins. A synergistic effect between PIP and IPM on CRPA was observed. More importantly, PIP effectively hindered the efflux of ethidium bromide and IPM by up-regulating MexR gene expression while down-regulating MexA, MexB, and OprM gene expressions. In conclusion, PIP could enhance the antibacterial activity of IPM by inhibiting the MexAB-OprM efflux pump. Our work proved that PIP had the potential to be an efflux pump inhibitor of CRPA.

Asunto(s)

Imipenem , Pseudomonas aeruginosa , Imipenem/farmacología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Etidio/farmacología , Simulación del Acoplamiento Molecular , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Antibacterianos/farmacología , Antibacterianos/metabolismo , Pruebas de Sensibilidad Microbiana

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OBJECTIVE: To observe the clinical characteristics and impact on mortality of carbapenem-resistant Pseudomonas aeruginosa (CRPA) colonized or infected patients with hematological disorders in order to provide evidence for the prevention and treatment of CRPA. METHODS: The patients who were colonized or infected with CRPA in the Department of Hematology of The First Affiliated Hospital of Zhejiang Chinese Medical University from January 2020 to March 2021 were selected as the research subjects, the clinical data such as hospitalization time, primary disease treatment regimen, granulocyte count, previous infection and antibiotic regimen of these patients were analyzed, meanwhile, antibiotic regimen and efficacy during CRPA infection, 30-day and long-term survival were also analyzed. RESULTS: A total of 59 patients were included in this study, and divided into CRPA infection group (43 cases) and CRPA colonization group (16 cases). Univariate logistic regression analysis showed that ECOG score (P =0.003), agranulocytosis (P <0.001), and exposure to upper than 3rd generations of cephalosporins and tigecycline within 30 days (P =0.035, P =0.017) were the high-risk factors for CRPA infection. Multivariate logistic regression analysis showed that ECOG score of 3/4 ( OR=10.815, 95%CI: 1.260-92.820, P =0.030) and agranulocytosis ( OR=13.82, 95%CI: 2.243-85.176, P =0.005) were independent risk factors for CRPA infection. There was a statistically significant difference in cumulative survival rate between CRPA colonization group and CRPA infection group ( χ2=14.134, P < 0.001). Kaplan-Meier survival analysis showed that the influencing factors of 30-day survival in patients with CRPA infection were agranulocytosis (P =0.022), soft tissue infection (P =0.03), and time of hospitalization before CRPA infection (P =0.041). Cox regression analysis showed that agranulocytosis was an independent risk factor affecting 30-day survival of patients with CRPA infection (HR=3.229, 95%CI :1.093-3.548, P =0.034). CONCLUSIONS: Patients with hematological disorders have high mortality and poor prognosis after CRPA infection. Bloodstream infection and soft tissue infection are the main causes of death. Patients with high suspicion of CRPA infection and high-risk should be treated as soon as possible.

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Enfermedades Hematológicas , Infecciones de los Tejidos Blandos , Humanos , Carbapenémicos/uso terapéutico , Pseudomonas aeruginosa , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Antibacterianos/uso terapéutico , Análisis de Supervivencia

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Background: Infections caused by carbapenem-resistant Pseudomonas aeruginosa (CRPA) are related to higher mortality. The objective of this study was to explore clinical outcomes of CRPA bacteremia, identify risk factors and also, compare the efficacy of traditional and novel antibiotic regimens. Methods: This retrospective study was conducted at a blood diseases hospital in China. The study included hematological patients who were diagnosed with CRPA bacteremia between January 2014 and August 2022. The primary endpoint was all-cause mortality at day 30. Secondary endpoints included 7-day and 30-day clinical cure. Multivariable Cox regression analysis was employed to identify mortality-related risk factors. Results: 100 patients infected with CRPA bacteremia were included and 29 patients accepted allogenic-hematopoietic stem cell transplantation. 24 received ceftazidime-avibactam (CAZ-AVI)-based therapy and 76 received other traditional antibiotics. 30-day mortality was 21.0%. Multivariable cox regression analysis showed neutropenia >7 days after bloodstream infections (BSI) (P=0.030, HR: 4.068, 95%CI: 1.146~14.434), higher Pitt bacteremia score (P<0.001, HR:1.824, 95%CI: 1.322~2.517), higher Charlson comorbidity index (P=0.01, HR: 1.613, 95%CI: 1.124~2.315) and bacteremia due to multidrug-resistant Pseudomonas aeruginosa (MDR-PA) (P=0.024, HR:3.086, 95%CI: 1.163~8.197) were identified as independent risk factors of 30-day mortality. After controlling for confounders, an additional multivariable cox regression analysis revealed definitive regimens containing CAZ-AVI were associated with lower mortality in CRPA bacteremia (P=0.016, HR: 0.150, 95%CI: 0.032~0.702), as well as in MDR-PA bacteremia (P=0.019, HR: 0.119, 95%CI: 0.020~0.709). Conclusions: For patients with hematological diseases and CRPA bacteremia, 30-day mortality rate was 21.0% (21/100). Neutropenia >7 days after BSI, higher Pitt bacteremia score, higher Charlson comorbidity index and bacteremia due to MDR-PA increased 30-day mortality. CAZ-AVI-based regimens were effective alternatives for bacteremia due to CRPA or MDR-PA.

Asunto(s)

Bacteriemia , Enfermedades Hematológicas , Neutropenia , Infecciones por Pseudomonas , Humanos , Pseudomonas aeruginosa , Estudios Retrospectivos , Carbapenémicos/uso terapéutico , Carbapenémicos/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Antibacterianos/farmacología , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/tratamiento farmacológico , Factores de Riesgo , Bacteriemia/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana

RESUMEN

BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a life-threatening healthcare-associated infection affecting especially patients with immunosuppression and comorbidities. We investigated the association between the incidence of CRPA bacteremia, antibiotic consumption, and infection control measures in a hospital during 2013-2018. METHODS: We prospectively recorded the incidence of CRPA bacteremia, antibiotic consumption, use of hand-hygiene solutions, and isolation rates of multidrug-resistant (MDR) carrier patients. FINDINGS: The consumption of colistin, aminoglycosides, and third-generation cephalosporins decreased significantly in the total hospital and its divisions (p-value < 0.001 for all comparisons) while the consumption of carbapenems decreased significantly in the adults ICU (p-value = 0.025). In addition, the incidence of CRPA significantly decreased in the total hospital clinics and departments (p-values = 0.027 and 0.042, respectively) and in adults clinics and departments (p-values = 0.031 and 0.051, respectively), while in the adults ICU, the incidence remained unchanged. Increased isolation rates of MDR carrier patients, even two months before, significantly correlated with decreased incidence of CRPA bacteremia (IRR: 0.20, 95% CI: 0.05-0.73, p-value = 0.015) in the adults ICU. Interestingly, when the use of hand-hygiene solutions (alcohol and/or scrub) increased, the consumption of advanced, nonadvanced, and all antibiotics decreased significantly. CONCLUSION: In our hospital, multimodal infection control interventions resulted in a significant reduction of CRPA bacteremia, mostly due to the reduction of all classes of antibiotics.

RESUMEN

Delafloxacin (DLX) is a recently approved fluoroquinolone with broad activity against common cystic fibrosis (CF) pathogens, including multidrug-resistant Pseudomonas aeruginosa (MDR-Psa). Delafloxacin has been previously shown to have excellent lung and biofilm penetration and enhanced activity at lower pH environments, such as those that would be observed in the CF lung. We analyzed six Psa strains isolated from CF sputum and compared DLX to ciprofloxacin (CPX) and levofloxacin (LVX). Minimum inhibitory concentrations (MICs) were determined for DLX using standard culture media (pH 7.3) and artificial sputum media (ASM), a physiologic media recapitulating the CF lung microenvironment (pH 6.9). Delafloxacin activity was further compared to CPX and LVX in an in vitro CF sputum time-kill model at physiologically relevant drug concentrations (Cmax, Cmed, Cmin). Delafloxacin exhibited 2- to 4-fold MIC reductions in ASM, which corresponded with significant improvements in bacterial killing in the CF sputum time-kill model between DLX and LVX at Cmed (p = 0.033) and Cmin (p = 0.004). Compared to CPX, DLX demonstrated significantly greater killing at Cmin (p = 0.024). Overall, DLX demonstrated favorable in vitro activity compared to alternative fluoroquinolones against MDR-Psa. Delafloxacin may be considered as an option against MDR-Psa pulmonary infections in CF.

RESUMEN

BACKGROUND: Pseudomonas aeruginosa (P. aeruginosa) is an important cause of nosocomial infections, and contributes to high morbidity and mortality, especially in intensive care units. P. aeruginosa is considered a 'critical' category bacterial pathogen by the World Health Organization to encourage an urgent need for research and development of new antibiotics against its infections. AIM: To investigate the effectiveness of baicalin combined with tobramycin therapy as a potential treatment method for carbapenem-resistant P. aeruginosa (CRPA) infections. METHODS: Polymerase chain reaction (PCR) and RT-PCR were used to detect the expression levels of drug-resistant genes (including VIM, IMP and OprD2) and biofilm-related genes (including algD, pslA and lasR) in CRPA that confer resistance to tobramycin, baicalin and tobramycin combined with baicalin (0, 1/8, 1/4, 1/2 and 1MIC). RESULTS: There was a correlation between biofilm formation and the expression of biofilm-related genes. In addition, VIM, IMP, OprD2, algD, pslA and lasR that confer biofilm production under different concentrations in CRPA were significantly correlated. The synergistic effect of baicalin combined with tobramycin was a significant down-regulation of VIM, IMP, algD, pslA and lasR. CONCLUSION: Baicalin combined with tobramycin therapy can be an effective treatment method for patients with CRPA infection.

RESUMEN

Cefiderocol is an option for infections caused by multidrug-resistant Pseudomonas aeruginosa, but its in vitro activity against these isolates and its clinical effectiveness for isolates with MICs of >1 µg/mL is unclear. We investigated the in vitro activity of cefiderocol against P. aeruginosa isolates collected from patients treated with cefiderocol through the compassionate use program and assessed physician-reported clinical response and 28-day all-cause mortality by cefiderocol MIC values. P. aeruginosa isolates underwent susceptibility testing to cefiderocol and comparator agents by using reference broth microdilution. U.S. Food and Drug Administration (FDA; susceptible, ≤1 µg/mL) and Clinical and Laboratory Standards Institute (CLSI; susceptible, ≤4 µg/mL) cefiderocol breakpoints were applied. Additionally, molecular characterization of ß-lactamase genes was performed. Clinical response and vital status were reported by treating physicians. Forty-six patients with P. aeruginosa infections were evaluated. Twenty-nine (63%) and 42 (91%) isolates were susceptible to cefiderocol using FDA and CLSI breakpoints, respectively. Thirty-seven (80%) and 32 (70%) isolates were not susceptible to ceftolozane-tazobactam and ceftazidime-avibactam, respectively. The clinical response rate was 69% (20/29) with a cefiderocol MIC of ≤1 µg/mL, 69% (9/13) with a cefiderocol MIC of 2 to 4 µg/mL, and 100% (4/4) with an MIC of ≥8 µg/mL, while day 28 all-cause mortality rates were 23% (6/26; MIC ≤ 1 µg/mL), 33% (4/12; MIC, 2 to 4 µg/mL), and 0% (0/4; MIC ≥8 µg/mL), respectively. Cefiderocol was active in vitro against most P. aeruginosa isolated from patients with limited or no alternative therapies. Patients with cefiderocol MICs of 2 to 4 µg/mL did not have significantly worse outcomes than those with MICs of ≤1 µg/mL.

Asunto(s)

Antibacterianos , Infecciones por Pseudomonas , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Pseudomonas aeruginosa , Ensayos de Uso Compasivo , Infecciones por Pseudomonas/tratamiento farmacológico , Cefalosporinas/farmacología , Cefalosporinas/uso terapéutico , Ceftazidima/farmacología , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana Múltiple/genética , Cefiderocol

RESUMEN

The dissemination of carbapenem-resistant Gram-negative bacilli (CRGNB) is a global public health issue. CRGNB isolates are usually extensively drug-resistant or pandrug-resistant, resulting in limited antimicrobial treatment options and high mortality. A multidisciplinary guideline development group covering clinical infectious diseases, clinical microbiology, clinical pharmacology, infection control, and guideline methodology experts jointly developed the present clinical practice guidelines based on best available scientific evidence to address the clinical issues regarding laboratory testing, antimicrobial therapy, and prevention of CRGNB infections. This guideline focuses on carbapenem-resistant Enterobacteriales (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA). Sixteen clinical questions were proposed from the perspective of current clinical practice and translated into research questions using PICO (population, intervention, comparator, and outcomes) format to collect and synthesize relevant evidence to inform corresponding recommendations. The grading of recommendations, assessment, development and evaluation (GRADE) approach was used to evaluate the quality of evidence, benefit and risk profile of corresponding interventions and formulate recommendations or suggestions. Evidence extracted from systematic reviews and randomized controlled trials (RCTs) was considered preferentially for treatment-related clinical questions. Observational studies, non-controlled studies, and expert opinions were considered as supplementary evidence in the absence of RCTs. The strength of recommendations was classified as strong or conditional (weak). The evidence informing recommendations derives from studies worldwide, while the implementation suggestions combined the Chinese experience. The target audience of this guideline is clinician and related professionals involved in management of infectious diseases.

Asunto(s)

Carbapenémicos , Infecciones por Bacterias Gramnegativas , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas/diagnóstico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/prevención & control , Control de Infecciones

RESUMEN

Background and aims: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a major cause of healthcare-associated infections worldwide, but comprehensive study of clinical characteristics for CRPA infections among critically ill children remains limited in China. The objective of this study was to determine the epidemiology, risk factors, and clinical outcomes of CRPA infections among critically ill pediatric patients in a large tertiary pediatric hospital in China. Methods: A retrospective case-control study of patients with P. aeruginosa infections was conducted in the three intensive care units (ICUs) of Shanghai Children's Medical Center from January 2016 to December 2021. All patients with CRPA infection in the ICUs were enrolled as case patients. Patients with carbapenem-susceptible P. aeruginosa (CSPA) infection were randomly selected as control patients in a ratio of 1:1. Clinical characteristics of those inpatients were reviewed through the hospital information system. Univariate and multivariate analyses were performed to evaluate risk factors associated with the development of CRPA infections and mortality of P. aeruginosa infections. Results: A total of 528 cases of P. aeruginosa infection in the ICUs were enrolled in the 6-year study. The prevalence of CRPA and MDRPA (multidrug-resistance P. aeruginosa) was 18.4 and 25.6%, respectively. Significant risk factors related to CRPA infection were the length of hospitalization >28 days (OR = 3.241, 95% CI 1.622-6.473, p = 0.001), receiving invasive operations (OR = 2.393, 95% CI 1.196-4.788, p = 0.014) and a blood transfusion (OR = 7.003, 95% CI 2.416-20.297, p < 0.001) within 30 days before infection. Conversely, birth weight ≥2,500 g (OR = 0.278, 95% CI 0.122-0.635, p = 0.001) and breast nursing (OR = 0.362, 95% CI 0.168-0.777, p = 0.009) were significant protective factors against CRPA infections. The in-hospital mortality rate was 14.2%, and no difference in mortality was observed between patients with CRPA and CSPA infections. Platelet < 100 × 109/L (OR = 5.729, 95% CI 1.048-31.308, p = 0.044) and serum urea <3.2 mmol/L (OR = 5.173, 95% CI 1.215-22.023, p = 0.026) were independent predictors for the mortality due to P. aeruginosa infection. Conclusions: Our findings provide insights into CRPA infections among critically ill children in China. They provide guidance in identifying patients that may be at high risk for a resistant infection and emphasize the importance of antimicrobial stewardship and infection control in hospitals.

Asunto(s)

Antibacterianos , Infecciones por Pseudomonas , Humanos , Niño , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Pseudomonas aeruginosa , Estudios Retrospectivos , Estudios de Casos y Controles , Prevalencia , Infecciones por Pseudomonas/epidemiología , Enfermedad Crítica , Hospitales Pediátricos , Resistencia betalactámica , China/epidemiología , Carbapenémicos/farmacología , Factores de Riesgo