Multidrug-resistant Enterobacterales Research Articles

Efficacy of an inulin-based treatment on intestinal colonization by multidrug-resistant E. coli: insight into the mechanism of action

ABSTRACT Inulin, an increasingly studied dietary fiber, alters intestinal microbiota. The aim of this study was to assess whether inulin decreases intestinal colonization by multidrug resistant E. coli and to investigate its potential mechanisms of action. Mice with amoxicillin-induced intestinal dysbiosis mice were inoculated with extended spectrum beta-lactamase producing E. coli (ESBL-E. coli). The combination of inulin and pantoprazole (IP) significantly reduced ESBL-E. coli fecal titers, whereas pantoprazole alone did not and inulin had a delayed and limited effect. Fecal microbiome was assessed using shotgun metagenomic sequencing and qPCR. The efficacy of IP was predicted by increased abundance of 74 taxa, including two species of Adlercreutzia. Preventive treatments with A. caecimuris or A. muris also reduced ESBL-E. coli fecal titers. Fecal microbiota of mice effectively treated by IP was enriched in genes involved in inulin catabolism, production of propionate and expression of beta-lactamases. They also had increased beta-lactamase activity and decreased amoxicillin concentration. These results suggest that IP act through production of propionate and degradation of amoxicillin by the microbiota. The combination of pantoprazole and inulin is a potential treatment of intestinal colonization by multidrug-resistant E. coli. The ability of prebiotics to promote propionate and/or beta-lactamase producing bacteria may be used as a screening tool to identify potential treatments of intestinal colonization by multidrug resistant Enterobacterales.

High prevalence of multidrug-resistant Enterobacterales carrying extended-spectrum beta-lactamase and AmpC genes isolated from neonatal sepsis in Ahvaz, Iran

ObjectivesIn the recent years, multidrug resistant (MDR) neonatal septicemia-causing Enterobacterales has been dramatically increased due to the extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes. This study aimed to assess the antibiotic resistance pattern, prevalence of ESBLs/AmpC beta-lactamase genes, and Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) fingerprints in Enterobacterales isolated from neonatal sepsis.ResultsIn total, 59 Enterobacterales isolates including 41 (69.5%) Enterobacter species, 15 (25.4%) Klebsiella pneumoniae and 3 (5.1%) Escherichia coli were isolated respectively. Resistance to ceftazidime and cefotaxime was seen in all of isolates. Furthermore, all of them were multidrug-resistant (resistant to three different antibiotic categories). The phenotypic tests showed that 100% of isolates were ESBL-positive. Moreover, AmpC production was observed in 84.7% (n = 50/59) of isolates. Among 59 ESBL-positive isolates, the highest percentage belonged to blaCTX−M−15 gene (66.1%) followed by blaCTX−M (45.8%), blaCTX−M−14 (30.5%), blaSHV (28.8%), and blaTEM (13.6%). The frequency of blaDHA, blaEBC, blaMOX and blaCIT genes were 24%, 24%, 4%, and 2% respectively. ERIC-PCR analysis revealed that Enterobacterales isolates were genetically diverse. The remarkable prevalence of MDR Enterobacterales isolates carrying ESBL and AmpC beta-lactamase genes emphasizes that efficient surveillance measures are essential to avoid the more expansion of drug resistance amongst isolates.

Spread and evolution of blaKPC-plasmid between Serratia marcescens and Klebsiella pneumoniae

ObjectivesblaKPC-carrying Enterobacterales have post great challenges to global healthcare systems. In this study, we reported the evolution and spread of blaKPC between Serratia marcescens and Klebsiella pneumoniae. MethodsFour S. marcescens and one K. pneumoniae strains were isolated from the sputum samples of the patient. Antimicrobial susceptibility tests and whole genome sequencing were performed to investigate the phenotype & genotype of strains. Conjugation assays, cloning experiment and kinetic parameters measuring were performed to explore the spread and antimicrobial resistance mechanisms. ResultsThe evolution and transmission of blaKPC-2 occurred during the treatment of ceftazidime-avibactam and trimethoprim-sulfamethoxazole. Analysis of the antimicrobial susceptibility and genetic profiles of the clinical strains showed that blaKPC-2 evolved into blaKPC-71 and blaKPC-44, together with resistance to ceftazidime-avibactam and carbapenems susceptibility recovery under antimicrobial pressure. Cloning and expression of blaKPC-44 & blaKPC-71 in E. coli DH5α showed that KPC-44 and KPC-71 resulted in a 64∼128-fold increase in the MIC value for ceftazidime-avibactam. Meanwhile, the kinetic assays also showed that the enzyme activity of KPC-44 and KPC-71 towards carbapenems was destroyed and couldn't be inhibited by avibactam. Based on the conjugation assay and whole genome sequence analyses, we provided evolutionary insights into the transmission pathway trace of blaKPC-bearing plasmids between S. marcescens and K. pneumoniae. ConclusionsMixed-species co-infection is one of the risk factors leading to the spread of plasmids carrying carbapenem-resistant genes, and increased surveillance of multidrug-resistant Enterobacterales is urgently needed.

Occurrence and persistence of multidrug-resistant Enterobacterales isolated from urban, industrial and surface water in Monastir, Tunisia

The One Health approach of antimicrobial resistance highlighted the role of the aquatic environment as a reservoir and dissemination source of resistance genes and resistant bacteria, especially due to anthropogenic activities. Resistance to extended-spectrum cephalosporins (ESC) conferred by extended-spectrum beta-lactamases (ESBLs) in E. coli has been proposed as the major marker of the AMR burden in cross-sectoral approaches. In this study, we investigated wastewater, surface water and seawater that are subjected to official water quality monitoring in Monastir, Tunisia. While all but one sample were declared compliant according to the official tests, ESC-resistant bacteria were detected in 31 (19.1 %) samples. Thirty-nine isolates, coming from urban, industrial and surface water in Monastir, were collected and characterized using antibiograms and whole-genome sequencing. These isolates were identified as 27 Escherichia coli (69.3 %) belonging to 13 STs, 10 Klebsiella pneumoniae (25.6 %) belonging to six STs, and two Citrobacter freundii (5.1 %). We observed the persistence and dissemination of clones over time and in different sampling sites, and no typically human-associated pathogens could be identified apart from one ST131. All isolates presented a blaCTX-M gene – blaCTX-M-15 (n = 22) and blaCTX-M-55 (n = 8) being the most frequent variants – which were identified on plasmids (n = 20) or on the chromosome (n = 19). In conclusion, we observed ESC resistance in rather ubiquitous bacteria that are capable of surviving in the water environment. This suggests that including the total coliform count and the ESBL count as determined by bacterial growth on selective plates in the official monitoring would greatly improve water quality control in Tunisia.

Antibiotic Susceptibility Profiles of Bacterial Isolates Recovered from Abscesses in Cattle and Sheep at a Slaughterhouse in Algeria.

Abscesses represent the most prominent emerging problem in the red meat industry, leading to great economic constraints and public health hazards. Data on etiological agents present in these purulent lesions in Algeria are very scarce. The aim of this study was to identify the bacteria responsible for these abscesses and to determine their antibiotic susceptibility profiles. A total of 123 samples of abscesses from 100 slaughtered sheep and 23 slaughtered cattle were cultured in several media. A total of 114 bacterial isolates were cultured from 103 abscesses. Bacteria were identified using MALDI-TOF, and antibiotic susceptibility was determined by the disk diffusion method on Mueller-Hinton agar. A total of 73.6% (n = 84) corresponded to Enterobacterales, of which four were multidrug-resistant (MDR). These isolates, together with Staphylococcus aureus, coagulase negative Staphylococci, and seven randomly chosen susceptible Escherichia coli isolates, were further characterized using WGS. Resistome analysis of the four MDR Enterobacterales isolates revealed the presence of OXA-48 carbapenemase in two Klebsiella pneumoniae ST985 and one E. coli ST10 isolates and a CTX-M-15 ESBL in one E. coli isolate ST1706. Two coagulase-negative Staphylococci isolates were found to carry the mecA gene. WGS showed the presence of different resistance genes and virulence genes. Our study revealed 5% of MDR Enterobacterales (including ESBLs and carbapenemases) identified from abscesses, thus urging the need for abscess monitoring in slaughterhouses.

First Detection of International High-Risk blaKPC-2-Harbouring Escherichia coli Pandemic Lineage ST648 in Pet Food Packages

The continued worldwide increase in pet ownership has significantly boosted the growth of the pet food industry accompanied by new food safety risks and challenges. This study was designed to determine the occurrence and molecularly characterize multidrug-resistant (MDR) Enterobacterales in pet food. Eighty-six (86) packages of dry and wet pet food purchased in different retail stores were screened for carbapenem-resistant Enterobacterales (CRE). Antimicrobial susceptibility testing was performed by agar dilution technique using EUCAST/BrCAST recommendations. Blue-Carba test was further used to screen for carbapenemase-producing isolates. Isolated CRE strains were identified at the species level using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Detection of carbapenemase-encoding genes was carried out by PCR, Sanger sequencing, and whole genome sequencing (WGS). A total of 15 (17.4%) MDR-CRE (Escherichia coli (n = 2), Enterobacter cloacae (n = 10), Leclercia adecarboxylata (n = 2), and Cronobacter spp. (n = 1)) were isolated from 86 pet food samples. In addition to being resistant to beta-lactams, the Gram-negative bacterial isolates were also resistant to aminoglycosides, fluoroquinolones, and tigecycline. Interestingly, two carbapenem-resistant E. coli isolates harboured blaKPC-2 gene. WGS analysis of the two blaKPC-2-producing E. coli isolates revealed that they both belong to ST648 and serotype O153:H2 group. The genetic context of the blaKPC-2 showed that they were carried by an IncN plasmid on a Tn4401b transposon element. To the best of our knowledge, this is the first description of blaKPC-2-harbouring E. coli ST648 pathogens in pet food. The detection of blaKPC-2-harbouring E. coli ST648 pandemic high-risk lineage in pet food is worrisome and a serious “One Health” issue. Therefore, pet food should be considered as a potential vehicle for the transmission of MDR pathogens to companion animals, and a risk factor for the dissemination of these bacterial pathogens to pet animals and their human guardians.

Enhancing colistin efficacy against Salmonella infections with a quinazoline-based dual therapeutic strategy

Colistin remains one of the last-resort therapies for combating infections caused by multidrug-resistant (MDR) Enterobacterales, despite its adverse nephro- and neuro-toxic effects. This study elucidates the mechanism of action of a non-antibiotic 4-anilinoquinazoline-based compound that synergistically enhances the effectiveness of colistin against Salmonella enterica. The quinazoline sensitizes Salmonella by deactivating intrinsic, mutational, and transferable resistance mechanisms that enable Salmonella to counteract the antibiotic impact colistin, together with an induced disruption to the electrochemical balance of the bacterial membrane. The attenuation of colistin resistance via the combined treatment approach also proves efficacious against E. coli, Klebsiella, and Acinetobacter strains. The dual therapy reduces the mortality of Galleria mellonella larvae undergoing a systemic Salmonella infection when compared to individual drug treatments. Overall, our findings unveil the potential of the quinazoline-colistin combined therapy as an innovative strategy against MDR bacteria.

In vitro activity of ceftazidime-avibactam against gram-negative bacteria in patients with bacteremia and skin and soft-tissue infections in Colombia 2019–2021

ObjectivesCeftazidime-avibactam (CAZ-AVI) is an option for infections caused by MDR gram-negative bacilli. In this study, we aimed to analyze the in vitro antimicrobial activity of CAZ-AVI and other antimicrobial agents against gram-negative bacilli that were collected in Colombia between 2019 and 2021 from patients with bacteremia and skin and soft-tissue infections (SSTIs). MethodsA total of 600 Enterobacterales and 259 P. aeruginosa strains were analyzed. The phenotypic resistance of isolates, particularly non-susceptibility to meropenem, multidrug-resistant (MDR) isolates, and difficult-to-treat (DTR) P. aeruginosa, was evaluated according to CLSI breakpoints. ResultsEnterobacterales had the most susceptibility to CAZ-AVI (96.5 %) and tigecycline (95 %). Tigecycline and CAZ-AVI were the antimicrobial agents with the most in vitro activity against carbapenem-resistant Enterobacterales (CRE). CAZ-AVI was the antimicrobial treatment with the most activity against P. aeruginosa. ConclusionsTigecycline and CAZ-AVI were the antimicrobial agents with the most activity against CRE and MDR Enterobacterales. For P. aeruginosa, CAZ-AVI was the antimicrobial treatment with the most in vitro activity.

Effects of breastfeeding on children’s gut colonization with multidrug-resistant Enterobacterales in peri-urban Lima, Peru

ABSTRACT Children living in low-resource settings are frequently gut-colonized with multidrug-resistant bacteria. We explored whether breastfeeding may protect against children’s incident gut colonization with extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-Ec) and Klebsiella, Enterobacter, or Citrobacter spp. (ESBL-KEC). We screened 937 monthly stool samples collected from 112 children aged 1–16 months during a 2016–19 prospective cohort study of enteric infections in peri-urban Lima. We used 52,816 daily surveys to examine how exposures to breastfeeding in the 30 days prior to a stool sample were associated with children’s risks of incident gut-colonization, controlling for antibiotic use and other covariates. We sequenced 78 ESBL-Ec from 47 children to explore their diversity. Gut-colonization with ESBL-Ec was increasingly prevalent as children aged, approaching 75% by 16 months, while ESBL-KEC prevalence fluctuated between 18% and 36%. Through 6 months of age, exclusively providing human milk in the 30 days prior to a stool sample did not reduce children’s risk of incident gut-colonization with ESBL-Ec or ESBL-KEC. From 6 to 16 months of age, every 3 additional days of breastfeeding in the prior 30 days was associated with 6% lower risk of incident ESBL-Ec gut-colonization (95% CI: 0.90, 0.98, p = .003). No effects were observed on incident ESBL-KEC colonization. We detected highly diverse ESBL-Ec among children and few differences between children who were predominantly breastfed (mean age: 4.1 months) versus older children (10.8 months). Continued breastfeeding after 6 months conferred protection against children’s incident gut colonization with ESBL-Ec in this setting. Policies supporting continued breastfeeding should be considered in efforts to combat antibiotic resistance.

Ceftazidime-Avibactam Improves Outcomes in High-Risk Neutropenic Patients with Klebsiella pneumoniae Carbapenemase-Producing Enterobacterales Bacteremia.

Few studies have evaluated the efficacy of ceftazidime-avibactam (CA) for Klebsiella pneumoniae carbapenemase-producing Enterobacterales bacteremia (KPC-PEB) in high-risk neutropenic patients. This is a prospective multicenter observational study in high-risk neutropenic patients with multi-drug resistant Enterobacterales bacteremia. They were compared according to the resistance mechanism and definitive treatment provided: KPC-CPE treated with CA (G1), KPC-CPE treated with other antibiotics (G2), and patients with ESBL-producing Enterobacterales bacteremia who received appropriate definitive therapy (G3). Thirty-day mortality was evaluated using a logistic regression model, and survival was analyzed with Kaplan-Meier curves. A total of 238 patients were included: 18 (G1), 52 (G2), and 168 (G3). Klebsiella spp. (60.9%) and Escherichia coli (26.4%) were the Enterobacterales most frequently isolated, and 71% of the bacteremias had a clinical source. The resistance profile between G1 and G2 was colistin 35.3% vs. 36.5%, amikacin 16.7% vs. 40.4%, and tigeclycline 11.1% vs. 19.2%. The antibiotics prescribed in combination with G2 were carbapenems, colistin, amikacin, fosfomycin, tigecycline, and fluoroquinolones. Seven-day clinical response in G1 vs. G2 vs. G3 was 94.4% vs. 42.3% vs. 82.7%, respectively (p < 0.001). Thirty-day overall mortality in G1 vs. G2 vs. G3 was 22.2% vs. 53.8% vs. 11.9%, respectively (p < 0.001), and infection-related mortality was 5.5% vs. 51.9% vs. 7.7% (p < 0.001). The independent risk factors for mortality were Pitt score > 4: OR 3.63, 95% CI, 1.18-11.14 (p = 0.025) and KPC-PEB treated with other antibiotics: OR 8.85, 95% CI, 2.58-30.33 (p = 0.001), while 7-day clinical response was a protective factor for survival: OR 0.02, 95% CI, 0.01-0.08 (p < 0.001). High-risk neutropenic patients with KPC-CPE treated with CA had an outcome similar to those treated for ESBL-producing Enterobacterales, with higher 7-day clinical response and lower overall and infection-related mortality than those treated with other antibiotics. In view of these data, CA may be considered the preferred therapeutic option for KPC-PEB in high-risk neutropenic patients.

Characterization of VIM-29 and VIM-86, two VIM-1 variants isolated in multidrug-resistant Enterobacterales in France.

Characterization of VIM-29 and VIM-86, two VIM-1 variants isolated in multidrug-resistant Enterobacterales in France.

Clinical and epidemiological characteristics of multi-drug resistant Enterobacterales isolated from King Fahad Hospital of the University, AlKhobar, Saudi Arabia.

Multi-drug resistant (MDR) Enterobacterales remain a major clinical problem. Infections caused by carbapenem-resistant strains are particularly difficult to treat. This study aimed to assess the clinical and epidemiological characteristics of MDR Enterobacterales isolates. A total of 154 non-repetitive clinical isolates, including Escherichia coli (n = 66), Klebsiella pneumoniae (n = 70), and other Enterobacterales (n = 18), were collected from the Diagnostic Microbiology Laboratory at King Fahad Hospital of the University. Most E. coli isolates were collected from urine specimens (n = 50, 75.8%) and resistance against the third and fourth-generation cephalosporins (ceftriaxone, ceftazidime, cefixime, and cefepime) and fluoroquinolones (ciprofloxacin and levofloxacin) was assessed. Clonal relatedness analysis using enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) revealed two clones (E. coli A and B), each comprising two strains. Most K. pneumoniae samples were collected from respiratory specimens (27.1%, 20 samples), and the strains showed overall resistance to most of the antimicrobials tested (54%‒100%). Moreover, clonal-relatedness analysis using ERIC-PCR revealed seven major clones of K. pneumoniae. These findings suggest nosocomial transmission among some identical strains and emphasize the importance of strict compliance with infection prevention and control policies and regulations. Environmental reservoirs could facilitate this indirect transmission, which needs to be investigated.

Multidrug-resistant Gram-negative clinical isolates with reduced susceptibility/resistance to cefiderocol: which are the best present and future therapeutic alternatives?

PurposeTo evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa.MethodsMIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective β-lactam breakpoints according to EUCAST were used for BL/BLI combinations.ResultsFor Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs.ConclusionsZidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates.

An alarming prevalence of multidrug-resistant (MDR) ESKAPE pathogens and other drug-resistant bacteria isolated from patients with bloodstream infections hospitalized at Muhimbili National Hospital in Dar es Salaam, Tanzania

This study was conducted between April and May 2023 at the Muhimbili National Hospital in Tanzania to determine the prevalence of multidrug-resistant (MDR) ESKAPE, and other drug-resistant bacteria isolated from 856 patients with bloodstream infections (BSIs). The prevalence of BSIs was 37.3% (319/856), with 5% (17/319) of the patients having polymicrobial infections. The prevalence of BSIs was slightly greater among males (38.3%, 162/423) than females (36.3%, 157/433) (p= 0.585. Most of the infections occurred in children aged &lt;1 year (45.3%, 149/329) or adults aged ≥61 years (45.7%, 37/81) (p= 0.001). Patients admitted to the intensive care unit (ICU) had significantly greater BSIs (44%; 113/258) than those admitted to other wards (34.4%; 206/599) (p= 0.006). The ESKAPE pathogens accounted for 43.28% of all the isolates, predominantly Staphylococcus aureus (16.4%), followed by Klebsiella pneumoniae (9.25%), Acinetobacter spp. (6.86%), and Pseudomonas aeruginosa (4.77%). The overall proportion of MDR bacteria was 83.8%, and 63.64% were resistant to more than four classes of antibiotics. Among the remaining strains, 23.4% of the ESKAPE pathogens and 10% of the MDR Enterobacterales were resistant to eight different classes of the tested antibiotics and were regarded as extensively drug-resistant (XDR). Resistance to 3rd generation cephalosporins was observed in 91% of the Klebsiella pneumoniae isolates and all the Enterobacter spp. The proportion of methicillin-resistant S. aureus (MRSA) was 71.4%. Based on these results, we strongly discourage empiric treatment of BSIs and recommend that laboratory results guide all prescriptions. Immediate action is undoubtedly needed to introduce rapid drug resistance tests and review the existing management guidelines.

Prevalence of Multidrug-Resistant Enterobacterales Isolated from 2019 to 2020 in a Tertiary Hospital in Dakar-Senegal

Background: Multi-resistant bacteria have emerged as a global threat to human health. In Africa, there are few data on AMR. The objective of this study was to determine antibiotic resistance profile of enterobacteria strains and prevalence of multidrug-resistant bacteria isolated in a university hospital in the suburbs of Dakar.&#x0D; Methods: Enterobacterales were isolated from a wide range of clinical specimens (urine, pus, blood, catheter tip and bronchoalveolar fluid) from inpatients and outpatients at Medical Biology Laboratory of National University Hospital Center of Pikine from November 2019 to October 2020. Enterobacterales were identified using API 20E. Antimicrobial susceptibility testing was performed with ATB G-EU (08) (bio Mérieuxs®) on all enterobacterales in accordance with CA-SFM/EUCAST 2020 guidelines.&#x0D; Results: Of the 3422 different clinical specimens tested, 623 (17.1%) were culture positive. Enterobacteriaceae accounted for 57.6% (n=359) of the strains; Escherichia coli and Klebsiella pneumoniae were predominant isolates with 53.5% and 20.6% respectively. Seventy-four(%) strains of enterobacterales were ESBL. Antibiotic resistance patterns showed a prevalence of multidrug resistant strains of 32.6%. The most active antibiotics on isolates were imipenem (25%), followed by amikacin (15%), fosfomycin (12%) and piperacillin-tazobactam (10%).&#x0D; Conclusion: High rates of ESBL and multidrug-resistant strains were found in both outpatients and inpatients. These results indicate need for an active surveillance system for antimicrobial resistance. Also, the application of good hospital hygiene practices and antibiotic therapy adapted to local data must be adopted.

2782. In vitro activity of ceftazidime-avibactam against Gram-negative strains in patients with bacteremia and skin and soft-tissue infections in Colombia 2019-2021

Abstract Background In vitro activity of Ceftazidime-avibactam (CAZ-AVI) in patients with bacteremia and skin and soft tissue infections (SSTIs) is unknown. The study aimed to analyze the in vitro antimicrobial activity of CAZ-AVI and other antimicrobials against Gram-negative bacilli collected in hospitals in Colombia in patients with bacteremia and SSTIs. Methods Enterobacterales and P. aeruginosa from patients with bacteremia and SSTIs were analyzed. Strains were collected from four ATLAS-reporting hospitals in Colombia between 2019 and 2021. Results Enterobacterales: A total of 600 Enterobacterales were collected. The most susceptible antimicrobials to Enterobacterales were CAZ-AVI (96.5%), tigecycline (95%), and amikacin (92.17%). The incidence of carbapenem-resistant Enterobacterales (CRE) was 13.5% (n= 81), and the antimicrobials with the best activity were tigecycline (93.83%), CAZ-AVI (74.07%), and amikacin (50.62%) (Figure 1). Tigecycline, CAZ-AVI, and amikacin were the antimicrobials with the best in vitro activity against MDR Enterobacterales, extended-spectrum β-lactamase-producing (ESBL) Enterobacterales, and KPC-producing Enterobacterales (Figure 2). K. pneumoniae (n= 198), E. coli (n= 167), Enterobacter cloacae (n= 46), and Serratia marcescens (n= 41) were the strains most frequently isolated (Table 1). Tigecycline and CAZ-AVI had excellent in vitro activity against all four species, as well as for those ESBL-producers, MDR, and carbapenem-resistant (CR). P. aerugniosa: A total of 259 P. aeruginosa were analyzed. CAZ-AVI was the antimicrobial with the best in vitro activity against P. aeruginosa with a susceptibility of 83.4%, as well as against CR (S= 44%), MDR (S= 50.58%), and DTR Pseudomonas (S= 33.33%). Figure 1 Antimicrobial activity among isolates of Enterobacterales and Carbapenem-resistant Enterobacterales (CRE) collected in Colombia between 2019 - 2021 S: susceptible; NS: Not susceptible; Pip/taz: Piperacillin-tazobactam; CZA: Ceftazidime-Avibactam; S: susceptible; NS: Not susceptible; CRE: Carbapenem-resistant Enterobacterales Figura 2 Not susceptibility among isolates of Extended-spectrum β-lactamase Enterobacterales, Multidrug-resistant Enterobacterales, Klebsiella pneumoniae carbapenemase (KPC)-producing enterobacterales, and metallo β-lactamase producing enterobacterales in Colombia A. Not susceptibility among isolates of Extended-spectrum β-lactamase enterobacterales (green color) and Multidrug-resistant Enterobacterales (orange color) B. Not susceptibility among Klebsiella pneumoniae carbapenemase (KPC)-producing enterobacterales (green color) and metallo β-lactamase producing enterobacterales (orange color) Pip/taz: Piperacillin-tazobactam; CZA: Ceftazidime-Avibactam; MDR: Multidrug-resistant Conclusion Tigecycline and CAZ-AVI were the two antimicrobials with excellent in vitro activity against clinical specimens from patients with bacteremia and SSTIs caused by CRE, MDR Enterobacterales, and ESBL- and KPC-producing Enterobacterales. Against MDR, CR, and DTR P. aeruginosa, CAZ-AVI and amikacin were the antimicrobials with the best in vitro activity (Figure 3). Disclosures Elkin Lemos-Luengas, MD MSc PhD, Pfizer Colombia: Honoraria Sixta Romelia Rentería-Valoyes, Md, Pfizer: Senior Associate Medicines Business /Medical Scientific Liaison MD for Pfizer Colombia Diana Marcela Almario Muñoz, MD, MSc, Pfizer Colombia: Medical Scientific Liaison Carlos David Gamboa Orozco, Md, Pfizer: Medical Scientific Liaison for Pfizer Colombia Juan Camilo Olivella Gómez, n/a, Pfizer Colombia: Medical Student Jorge Ramos-Castaneda, PhD, Pfizer: Advisor/Consultant

2523. Outcomes by Resistance Phenotype and Genotype among Baseline Pathogen in Patients with Complicated Urinary Tract Infection (cUTI) in the Phase 3 CERTAIN-1 Study

Abstract Background Taniborbactam is an investigational β-lactamase inhibitor that restores cefepime (FEP) activity against FEP-, carbapenem-, and multidrug-resistant Enterobacterales and Pseudomonas aeruginosa producing serine- and metallo-β-lactamases. Cefepime-taniborbactam (FTB) was superior to meropenem (MEM) for the primary composite endpoint of microbiologic and clinical success at test of cure (TOC) in adults with cUTI in the CERTAIN-1 study (NCT03840148). We assessed outcomes in subsets defined by baseline pathogen resistance phenotype and genotype. Methods Composite, microbiologic and clinical responses at TOC were assessed in the extended microbiologic intent-to-treat (microITT) population (patients with Enterobacterales and/or P. aeruginosa at ≥105 CFU/mL in urine at study entry against which at least 1 study drug had activity [FTB MIC ≤16 µg/mL; MEM MIC ≤2 µg/mL (Enterobacterales) or ≤4 µg/mL (P. aeruginosa)]). Phenotypic subsets included FEP-, multidrug-, and/or carbapenem resistance. Genotypic subsets included carriage of ESBL, extended-spectrum AmpC, plasmidic AmpC, and/or carbapenemase genes. Results For patients in the FTB treatment group with Enterobacterales at baseline, composite, microbiologic, and clinical success rates in resistant subsets were similar to or higher than those overall (Table). FTB achieved composite success in 7/8 patients with carbapenem-resistant Enterobacterales and in 8/9 patients with Enterobacterales producing a carbapenemase (5 OXA-48-group; 2 KPC-3, 2 NDM-1). FTB achieved composite success in 8/16 patients (clinical success in 13/16 patients) with P. aeruginosa overall; from 1 to 5 patients in the FTB group had P. aeruginosa in defined resistance categories. Conclusion FTB demonstrated efficacy in cUTI patients infected with cefepime-, multidrug-, and carbapenem-resistant pathogens and pathogens carrying ESBL, AmpC, and carbapenemase genes. Rates of success at TOC in each resistance subset were similar to or higher than those overall. These results are consistent with the ability of taniborbactam to restore cefepime activity against cefepime-, multidrug-, and carbapenem-resistant gram-negative pathogens producing serine and metallo-β-lactamases in nonclinical studies. Disclosures Greg Moeck, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Leanne Gasink, MD, MSCE, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|CSL Behring: Advisor/Consultant|CSL Behring: Consulting fees|Everest Medicines: Grant/Research Support|Evopint Biosciences: Advisor/Consultant|Evopint Biosciences: Consulting fees|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|LBG Consulting, LLC: Principal|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees|Vera Therapeutics: Advisor/Consultant|Vera Therapeutics: Consulting fees Mary Beth Dorr, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Merck and Co.: Shareholder|Pfizer: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Hongzi Chen, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee|Venatorx Pharmaceuticals, Inc.: Stocks/Bonds Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Florian Wagenlehner, MD, Achaogen: Advisory Board member, study participation|Astellas: Honoraria|AstraZeneca: Honoraria|AstraZeneca: Advisory Board member|Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Bionorica: Honoraria|Bionorica: Meeting/travel support, study participation|Deutsches Zentrum für Infektionsforschung (DZIF): Study participation|Enteris BioPharma: Study participation|Everest Medicines: Grant/Research Support|German S3 guideline Urinary tract infections: Board Member|Glaxo Smith Kline: Advisor/Consultant|Glaxo Smith Kline: Honoraria|Glaxo Smith Kline: Consulting fees, meeting/travel support, advisory board member, principal investigator in a GSK-sponsored study|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Guidelines European Association of Urology: Infections in Urology: Board Member|Helperby Therapeutics: Study participation|Janssen: Honoraria|Janssen: Advisory Board member|Klosterfrau: Honoraria|LeoPharma: Advisory Board member|MerLion: Advisory Board member|MIP Pharma: Honoraria|MSD: Advisory Board member|OM Pharma/Vifor Pharma: Advisory Board member, study participation|OM-Pharma: Honoraria|Pfizer: Honoraria|Pfizer: Advisory Board member|RosenPharma: Advisory Board member|Shionogi: Advisory Board member, study participation|Speaker research group German research foundation (DFG) Bacterial Renal Infections and Defense (FOR 5427): Study participation|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|University Hospital Giessen and Marburg GmbH, and Justus Liebig University, Germany: Employee|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees, Advisory Board member Tim Henkel, MD, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Employee, consulting fees, shareholder Paul McGovern, MD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Paratek Pharmaceuticals: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder

2128. In Vitro Activity of Ceftibuten-Avibactam and Comparator Agents Against Resistant Enterobacterales from UTIs Collected Globally as Part of the ATLAS Surveillance Program, 2022

Abstract Background Increasing resistance among agents commonly prescribed to treat urinary tract infections (UTIs) indicate that new orally bioavailable agents are needed. Ceftibuten (CTB) is an orally administered third-generation cephalosporin and is in early clinical development being combined with an oral prodrug of avibactam (AVI). AVI is a non-β-lactam inhibitor of Ambler class A β-lactamases, including ESBLs and KPCs, class C (AmpC) β-lactamases, and some class D (OXA-48) β-lactamases. Ceftibuten-avibactam prodrug (CBA) is in early clinical development as a potential oral treatment for complicated urinary tract infections. This study evaluated the in vitro activity of CBA and oral comparators against Enterobacterales from UTIs with drug-resistant phenotypes collected globally as part of the 2022 Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Methods 4,265 non-duplicate clinical isolates from UTIs were collected in 2022 in 55 countries. Susceptibility testing with CBA tested at a fixed concentration of 4 µg/mL AVI and comparators was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. Nonsusceptible (NS)/resistant (R) phenotypes were based on 2023 CLSI breakpoints. MDR was defined as R to ≥1 agent from ≥3 drug classes. Results CBA was the most active compound tested against all Enterobacterales, with the MIC90 value decreasing from 32 µg/mL to 0.12 µg/mL. A total of 96% of all isolates were inhibited at a CBA MIC of ≤1 µg/mL. Percent susceptible of oral comparators ranged from 63.4% to 76.8%. CBA maintained activity against NS/R subsets of Enterobacterales (MIC90 range, 0.25 to 4 µg/mL; 85.0% to 93.2% inhibited at ≤1 µg/mL), including MDR isolates (MIC90, &amp;gt;64 µg/mL; 81.7% inhibited at ≤1 µg/mL). Conclusion Ceftibuten-avibactam demonstrated potent in vitro activity against multidrug-resistant Enterobacterales collected globally. Ceftibuten -avibactam prodrug could be an effective oral therapy for difficult-to-treat infections caused by multidrug-resistant Enterobacterales. Disclosures Meredith Hackel, PhD, Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck &amp; Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

2172. Activity of Cefiderocol and Comparator Agents Against Molecularly Characterized Multidrug-resistant Enterobacterales Clinical Isolates from United States Hospitals (2020–2022)

Abstract Background Cefiderocol (CFDC) is a siderophore cephalosporin that hijacks the iron transport system of Gram-negative bacteria to facilitate cell entry and reach its target. CFDC remains stable to hydrolysis in the presence of serine β-lactamases (ESBLs, KPC, and OXA-type carbapenemases) and metallo-β-lactamases (MBL). CFDC and comparator activities were analyzed against Enterobacterales (ENT), including molecularly characterized isolates, as part of the US SENTRY Antimicrobial Surveillance Program. Methods 11,884 ENT were collected from 33 sites in the USA in 2020–2022. Susceptibility (S) testing was performed by broth microdilution. CFDC testing utilized iron-depleted media. CLSI breakpoints were used. E. coli, K. pneumoniae, and P. mirabilis with ceftriaxone, ceftazidime, or aztreonam MIC ≥ 2 μg/mL plus any ENT displaying an MIC ≥ 2 μg/mL for imipenem (excluding P. mirabilis, P. penneri, and indole-positive Proteeae) or meropenem (MER) were subjected to genome sequencing and screening of β-lactamase genes. Results CFDC (99.8%S), imipenem-relebactam (IMR; 98.0%S), meropenem-vaborbactam (MEV; 100%S), and ceftazidime-avibactam (CZA; 100%S) were active against carbapenem-susceptible ENT that carried ESBL and/or AmpC genes (Table). CFDC (MIC50/90, 0.5/4 μg/mL; 97.6%S) and CZA (MIC50/90, 1/8 μg/mL; 91.5%S) were the most active agents against carbapenem-nonS isolates, whereas IMR (MIC50/90, 0.25/4 μg/mL; 81.2%S) and MEV (MIC50/90, 0.12/8 μg/mL; 87.9%S) had suboptimal activity. CFDC (MIC50/90, 0.5/4 μg/mL), IMR (MIC50/90, 0.12/0.5 μg/mL), MEV (MIC50/90, 0.03/1 μg/mL), and CZA (MIC50/90, 1/2 μg/mL) were active (98.7–100%S) against the KPC subset. CFDC (MIC, 2/4 μg/mL; 90.9%S) was also active against ENT carrying MBL genes, whereas CFDC (MIC, 0.5-2 μg/mL; 100%S) and CZA (0.5-4 μg/mL; 100%S) were active against isolates carrying blaOXA-48–like. Conclusion CFDC activity against ENT was consistent, regardless of isolate phenotypes or genotypes, including against isolates carrying carbapenemase genes other than blaKPC, where approved β-lactam/β-lactamase inhibitor combinations showed limited activity. These data emphasize CFDC as an important option for the treatment of infections caused by ENT and resistant subsets. Disclosures Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Dee Shortridge, PhD, Melinta: Grant/Research Support|Shionogi: Grant/Research Support Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

1449. Evaluation of Cloud-Based Automated Analytic Pipelines for Whole Genome Sequencing Analysis of Multidrug-Resistant Gram-Negative Organism Outbreaks

Abstract Background Clinical implementation of whole genome sequencing (WGS) has been identified as the optimal approach to identify transmission of multidrug-resistant (MDR) organisms in the healthcare setting. Although WGS capabilities are becoming more common in clinical laboratories, analysis and interpretation of results is still a barrier to implementation. The purpose of this study was to evaluate cloud-based automated analytic pipelines to aid with WGS analysis of MDR gram-negative organisms as part of outbreak investigations. Methods A convenience set of MDR Enterobacterales (n: 142), Acinetobacter baumannii complex (n: 14) and Pseudomonas aeruginosa (n:29) isolates were WGS on Illumina sequencing platforms. The FASTQ files were uploaded to AREScloud (Ares Genetics, an OpGen group company) and to EPISEQ CS (bioMérieux) for whole genome or core genome multi-locus sequence typing (wgMLST/cgMLST) with dendrogram creation. Results were compared to traditional 7 gene MLST schema. Ease-of-use and additional tools were compared between pipelines. Results AREScloud and EPISEQ CS generated similar dendrograms for all organisms evaluated (examples provided in Figures 1 &amp; 2). EPISEQ CS provided preset similarity thresholds based on percent relatedness to define clusters simplifying outbreak analysis, whereas AREScloud allowed users to define allelic difference cutoffs. Although the wgMLST/cgMLST clusters aligned with traditional MLST types, not all isolates assigned to a similar MLST were identified as part of a related cluster demonstrating increased resolution of wgMLST and cgMLST phylogenetic assessments. Table 1 compares the features between the two pipelines. Dendrogram generated for Escherichia coli (EPISEQ CS) Dendrogram generated for Escherichia coli (AREScloud) Comparison of features between EPISEQ CS and AREScloud for phylogenetic analysis Conclusion Both cloud-based tools perform comparably for assessing phylogenetic relatedness compared to traditional MLST. Preset similarity thresholds available with EPISEQ CS provide ease-of-use for cluster assessment. Additional features, such as resistome and virulome analysis, are available by both pipelines. Predictive WGS-AST is an additional asset available with AREScloud. Disclosures Karen C. Carroll, MD, Abbott Diagnostics: Board Member|Co-Diagnostics, Inc.: Board Member|Great Basin: Grant/Research Support|Meridian Diagnostics: Grant/Research Support|Pattern Diagnostics: Advisor/Consultant|Pattern Diagnostics: Stocks/Bonds|Qiagen, Inc.: Grant/Research Support|Scanogen: Advisor/Consultant|Scanogen: Grant/Research Support Patricia J. Simner, PhD, Affinity Biosensors: Grant/Research Support|BD Diagnostics: Advisor/Consultant|BD Diagnostics: Grant/Research Support|Entasis: Advisor/Consultant|GeneCapture: Stocks/Bonds|Merck: Advisor/Consultant|OpGen Inc: Board Member|OpGen Inc: Grant/Research Support|OpGen Inc: Honoraria|Qiagen Sciences Inc: Advisor/Consultant|Qiagen Sciences Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|T2 Biosystems: Grant/Research Support