Development processes and action on climate change are closely interlinked. This is recognised by the Intergovernmental Panel on Climate Change (IPCC) in its fifth assessment report, which reports on ...climate-resilient pathways, understood as development trajectories towards sustainable development which include adaptation and mitigation. The upcoming sixth assessment report dedicates a chapter to climate resilient development pathways. In this context, this paper asks what conceptual and empirical advances on climate resilient development pathways were made since the fifth assessment report. Through a literature review, this paper analyses goals and approaches for climate resilient development pathways, and discusses what conceptual advances have and could still be made. We find little evidence of dedicated concept development. Rather, we observe conceptual ambiguity. Literature showed four non-exclusive clusters of approaches: (a) climate action oriented, (b) social-learning and co-creation oriented, (c) mainstreaming oriented and (d) transformation oriented. We recommend operationalising climate resilient development pathways as the process of consolidating climate action and development decisions towards long-term sustainable development. This process requires explicit engagement with aspirations of actors, and connecting past developments with future aspirations and understandings of risk. Working with multiple pathways allows us to embed flexibility, anticipation and learning in planning. A greater focus is needed on issues linked to justice and equity as climate resilient development pathways will inevitably involve trade-offs. Substantiating the concept of climate resilient development pathways has the potential to bridge climate and development perspectives, which may otherwise remain separated in development and climate policy, practice and science.
•We find little evidence of dedicated concept development on climate resilient development pathways.•The use of the concept climate resilient development pathways in different domains has giving rise to conceptual ambiguity.•Climate resilient development pathways consolidate climate action and development towards long-term sustainable development.•Climate resilient development pathways will involve debate and struggle, resulting in winners and losers.•Lessons are engagement with justice and equity issues and imbedding flexibility, anticipation and learning in decision-making.
Abstract
Background
The β-lactamase inhibitor, avibactam, has potent inhibitory activity against Class A, Class C, and certain Class D serine β-lactamases. This study evaluated the in vitro activity ...of ceftazidime-avibactam (CZA) and comparators against respiratory tract infection (RTI)-associated Pseudomonas aeruginosa isolated from presumed community-acquired (CA; cultured < 48 hours after hospital admission) and hospital-acquired (HA; cultured ≥48 hours post-admission) infections collected from 2017-2021.
Methods
11,780 non-duplicate P. aeruginosa were collected from 246 sites in 54 countries as part of ATLAS 2017-2021 (excluding mainland China and North America) from respiratory tract infections for which the length of hospitalization was specified. Susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2023 breakpoints. Meropenem-nonsusceptible (MEM-NS) isolates were screened for the presence of β-lactamase genes. All MEM-NS isolates were screened in 2017-2020, whereas ∼25% of those collected in 2020 and 2021 were screened.
Results
CZA was the most active agent examined against the CA-infection isolates, inhibiting 92.3% of the population (Table). Against the HA isolates, 89.0% were susceptible to CZA, a percentage slightly lower than amikacin (89.4%). Removing MBL-producers increased the percentages susceptible to CZA for both groups by 2-3 percentage points. Approximately 68-70% of the meropenem-nonsusceptible isolates from both groups were susceptible to CZA, values similar to those demonstrated by amikacin and ceftolozane/tazobactam.
Conclusion
The percentage of CA and HA isolates from respiratory tract infections inhibited by CZA was approximately 15 and 20 percentage points higher, respectively, than the percentages inhibited by meropenem, and slightly higher (1-2 percentage points) than ceftolozane-tazobactam. The potent in vitro activity of CZA against HA isolates was exceeded only by amikacin, an agent discouraged as monotherapy for P. aeruginosa infections outside of the urinary tract by the CLSI. CZA remains an excellent therapeutic choice for use against P. aeruginosa, regardless of whether they’re CA or HA.
Disclosures
Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
Abstract
Background
Taniborbactam is a novel, investigational broad-spectrum β-lactamase inhibitor with direct inhibitory activity against both serine- and metallo-β-lactamases. Taniborbactam ...restores the activity of cefepime (FEP) against many difficult to treat organisms, including cephalosporin- and carbapenem-resistant Enterobacterales (EB) and Pseudomonas aeruginosa (PA). The activity of cefepime-taniborbactam (FTB) and comparator agents was evaluated against nonsusceptible (NS)/resistant (R) clinical isolates of EB and PA from the United States (US) collected in global surveillance.
Methods
MICs of FTB (taniborbactam fixed at 4 µg/mL) and comparators were determined using the CLSI reference method against EB (n=4,220) and PA (n=1,222) from the US collected in 2018-2021. NS/R phenotypes were based on 2023 CLSI breakpoints (EUCAST breakpoint for meropenem-vaborbactam MEV against PA). Multidrug R (MDR) was defined as R to ≥1 agent from ≥3 drug classes.
Results
Overall, 13.1% and 10.3% of EB isolates were NS to FEP and piperacillin-tazobactam (TZP), respectively (Table). FTB had potent activity against all EB (MIC50/90, 0.03/0.12 µg/mL; 99.9% inhibited at ≤16 µg/mL). FTB maintained activity against NS/R subsets of EB (MIC90 range, 1 to 8 µg/mL; 90.0% to 99.3% inhibited at ≤16 µg/mL) including MDR isolates (MIC90, 2 µg/mL; 98.4% inhibited at ≤16 µg/mL). FTB was the most active tested agent against PA overall (MIC50/90, 2/8 µg/mL; 97.7% inhibited at ≤16 µg/mL). Among meropenem (MEM)-NS isolates, 91.2% were inhibited by FTB at ≤16 µg/mL compared to 76.6% susceptible to ceftolozane-tazobactam (CT). FTB at ≤16 µg/mL inhibited 74.2% of CT NS isolates of PA whereas 47.2% of isolates of this phenotype were susceptible to ceftazidime-avibactam (CZA). Against MDR PA (13.4% of all PA), FTB (MIC50/90, 8/32 µg/mL) inhibited 85.4% of isolates at ≤16 µg/mL compared to 59.1% that were susceptible to CT.
Conclusion
Cefepime-taniborbactam had potent in vitro activity against recent EB and PA from the US, including MDR isolates and isolates NS to FEP, MEM, TZP, CZA, CT, and/or MEV. These data support continued development of cefepime-taniborbactam as a potential treatment option for challenging infections due to resistant Gram-negative pathogens.
Disclosures
Meredith Hackel, PhD, Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
Abstract
Background
Taniborbactam, a cyclic boronate-based β-lactamase inhibitor with activity against serine-, and NDM & VIM metallo-β-lactamases (MBLs), in combination with the fourth-generation ...cephalosporin, cefepime, is in development for treatment of complicated urinary tract infections. This study examined the in vitro activity of cefepime-taniborbactam against clinical isolates from the US, with a focus on carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA).
Methods
From 2018-2021, as part of the GEARS Antimicrobial Surveillance Program, 4,220 Enterobacterales and 1,222 P. aeruginosa were collected from 38 clinical sites in the US. MICs of cefepime with taniborbactam fixed at 4 µg/mL and comparators were determined by broth microdilution according to CLSI guidelines and interpreted using 2023 CLSI breakpoints. CRE was defined by resistance to meropenem; CRPA was defined by resistance to meropenem and/or imipenem. Isolates with cefepime-taniborbactam MIC ≥16 µg/mL were characterized by whole genome sequencing. Isolates resistant to meropenem were screened for acquired β-lactamases by multiplex PCR/Sanger sequencing.
Results
In total, 97.1% of the 68 CRE isolates were inhibited by ≤16 µg/mL of cefepime-taniborbactam. The majority of CRE (51/68; 75.0%) produced a carbapenemase (40 KPC, 9 MBLs, 2 OXA-48) and 98.0% were inhibited by ≤16 µg/mL cefepime-taniborbactam, a substantially greater percentage than the most active comparator, meropenem-vaborbactam (82.4% susceptible). Cefepime-taniborbactam at ≤16 µg/mL inhibited 92.9% of all CRPA (n=308), 88.7% of meropenem-resistant P. aeruginosa (n=177), and 90.6% of carbapenemase-negative, meropenem-resistant P. aeruginosa (n=170) whereas the most active comparator, ceftazidime-avibactam, covered 84.7%, 75.7%, and 77.6% of these resistant subsets, respectively.
Conclusion
Cefepime-taniborbactam inhibited ≥94.1% of CRE isolates from the US, regardless of carbapenemase carriage. Similarly potent activity was observed for cefepime-taniborbactam against CRPA, including meropenem-resistant strains without a detected carbapenemase. The continued development of cefepime-taniborbactam appears warranted.
Disclosures
Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Meredith Hackel, PhD, Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
Abstract
Background
The investigational β-lactam/non-β-lactam β-lactamase inhibitor combination aztreonam-avibactam (ATM-AVI) is active in vitro against CRE isolates, including MBL-producers, as well ...as those co-producing serine β-lactamases of Class A, C, and some class D types. This study evaluated the in vitro activity of ATM-AVI and comparators against carbapenemase- and non-carbapenemase-producing CRE collected globally from 2017−2021 as part of the ATLAS surveillance program.
Methods
85,990 non-duplicate, clinically relevant Enterobacterales isolates were collected from 258 medical centers located in 56 countries worldwide (excluding N. America and China). Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. ATM-AVI was tested at a fixed concentration of 4 mg/L avibactam. A tentative ATM-AVI pharmacokinetic/pharmacodynamic (PK/PD) susceptible MIC breakpoint of ≤ 8 mg/L was applied for comparison purposes. Organisms with meropenem MIC >1 mg/L and Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis with aztreonam or ceftazidime MIC >1 mg/L were screened for β-lactamase genes by PCR and Sanger sequencing.
Results
In total, 5,473 isolates were identified as CRE based on resistance to meropenem. ATM-AVI demonstrated potent in vitro activity against the CRE, with 99.3% of isolates (MIC90, 1 mg/L) inhibited at ≤8 mg/L (Table). ATM-AVI inhibited 99.5% of the carbapenemase-positive CRE, including 99.1% of the MBL-carriers (n=2,375) and 99.8% of serine-carbapenemase carriers (n=2,675) at ≤8 mg/L. Activity was somewhat reduced against the 441 CRE without detected carbapenemases as 96.3% (MIC90, 4 mg/L) of the isolates were inhibited at ≤8 mg/L aztreonam-avibactam. Amikacin was the most active comparator, although < 50% of each subgroup was susceptible at the CLSI breakpoint.
Conclusion
Based on MIC90 values and the preliminary PK/PD breakpoint, ATM-AVI demonstrated potent in vitro activity against CRE, including MBL- and serine carbapenemase-carrying isolates. As limited therapeutic options presently exist for treating infections caused by CRE, further development of this agent appears warranted.
Disclosures
Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
The DiversiLab system, which uses repetitive sequence-based PCR (rep-PCR) to genotype micro-organisms, was evaluated as a molecular typing tool for members of the genus Candida. Initially, 41 ...clinical Candida spp. (7 Candida krusei, 10 Candida parapsilosis, 7 Candida albicans, 10 Candida tropicalis and 7 Candida glabrata), previously identified at the species level by morphological and biochemical analysis, were analysed with the DiversiLab system. Species identification was confirmed by DNA sequence analysis of the contiguous internal transcribed spacer (ITS) region (ITS1-5.8S-ITS2). On the basis of an 80 % similarity threshold, rep-PCR consistently clustered like species and this set of isolates, along with five ATCC reference strains, was used to create a DNA fingerprint library with the DiversiLab software. Subsequently, an additional set of 115 clinical Candida isolates, identified biochemically as C. albicans (n=94), C. glabrata (n=8), C. parapsilosis (n=5), C. tropicalis (n=3), C. krusei (n=3) and Candida lusitaniae (n=2), isolated at a regional reference laboratory, were typed using DiversiLab. One hundred and six of these isolates clustered with members of the Candida library at >80 % similarity and thus could be assigned species identification, and initial calculations showed that identification via rep-PCR fingerprinting was 95 % concordant (101/106) with the biochemical/morphological identification. However, ITS region sequencing of the five discrepant samples, as well as the nine isolates that were <80 % similar to the database samples, showed that nine were misidentified with traditional biochemical/morphological methods. For the misidentified isolates, the sequence-based identification was in agreement with the DiversiLab clustering, yielding an actual correlation of >99 %. As traditional techniques can take several days to provide information about Candida at the genus/species level, genotyping with the DiversiLab system holds promise for more-rapid speciation of members of this genus. This system may also be useful for epidemiological studies such as source tracking that require Candida subspecies discrimination.
Avian paramyxovirus 1 (APMV-1), also referred to as Newcastle disease virus (NDV), variants of low virulence were isolated from chickens, ducks and other unidentified species found in live-bird ...markets of the northeastern United States. These isolates were characterized as APMV-1 by the hemagglutination-inhibition (HI) assay utilizing NDV-specific polyclonal antisera. However, the isolates failed to react with a monoclonal antibody that has specificity for a wide variety of APMV-1 isolates. Although only highly virulent isolates require reporting to international regulatory agencies, the ability to correctly identify APMV-1 types is important for control and regulatory purposes. Protein gel patterns of the purified isolates resembled previously reported APMV-1 and anti-NDV polyclonal sera recognized the viral proteins. For three isolates oligonucleotide primers specific for the nucleoprotein, fusion protein and polymerase genes of NDV were utilized to synthesize cDNA using viral RNA as a template. Approximately 12
kb of the genome was subsequently sequenced for the three isolates that included the nucleoprotein, phosphoprotein, matrix protein, fusion (F) protein, hemagglutinin-neuraminidase protein genes and a 5′ portion of the polymerase gene. The isolates had an F protein cleavage site sequence of ERQER/LVG indicating low-virulence viruses that phylogenetically separated with other unique NDV isolates designated as a lineage 6 genotype. Additionally, a four amino acid insert was detected in the predicted phosphoprotein which complies with the “rule of six” among paramyxoviruses. These APMV-1 genotypes have not been previously reported in North America and further substantiate the heterogeneous genetic nature of these commercially important pathogens found worldwide.
The susceptibility, immune response, and protection to challenge after vaccination in racing pigeons (Columbia livia) was assessed with the 2002–2003 exotic Newcastle disease (END) virus responsible ...for the most recent major outbreak in Southern California. Immunologically naïve pigeons appeared resistant to disease, regardless of dose, after a natural route of exposure. Twenty percent morbidity was observed in each group of birds receiving between 102.1 and 108.1 50% embryo infectious dose (EID50) per bird, with one bird succumbing to challenge in the 108.1 EID50/bird group at day 12 postinoculation. Although resistant to disease, birds in all groups continued to shed virus from either oral or cloacal route at the end of the 14-day sampling period, and seroconversion was only observed in birds receiving ≥106.1 EID50. Single or double vaccination of juvenile and adult birds with pigeon paramyxovirus virus type 1 (PPMV-1) vaccine followed by END challenge with 106.1 EID50/bird decreased the duration, incidence, and viral load. A positive correlation was observed between the presence of hemagglutination-inhibiting antibody titers at challenge and decreased viral shedding. Overt clinical signs of disease were not observed in any PPMV-1–vaccinated birds after challenge.
Abstract
Background
Increasing resistance among agents commonly prescribed to treat urinary tract infections indicate that new oral agents are urgently needed. Ceftibuten in combination with ...VNRX-7145 is under development as an oral treatment for complicated urinary tract infections caused by serine β-lactamase-producing Enterobacterales, including isolates carrying ESBLs and carbapenemases. In vivo, VNRX-7145 (VNRX-5236 etzadroxil) is cleaved into to the active inhibitor, VNRX-5236. This study assessed the in vitro activity of ceftibuten/VNRX-5236 against 592 isolates of Enterobacterales from urinary tract infections (UTIs) from a 2018-2020 global culture collection.
Methods
MICs of ceftibuten with VNRX-5236 fixed at 4 µg/mL and comparators were determined following CLSI M07-A11 guidelines against 592 Enterobacterales. Isolates were from community and hospital UTI infections collected from 133 sites in 31 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints.
Results
A substantial percentage of isolates were non-susceptible to extended-spectrum β-lactams, levofloxacin (LVX), trimethoprim-sulfamethoxazole (SXT), and amoxicillin-clavulanate (AMC) (Table). The addition of VNRX-5236 reduced ceftibuten MIC90 values by ≥8-fold to ≥128-fold, depending on the resistant subset. Ceftibuten/VNRX-5236 had potent activity against all Enterobacterales, with MIC50/90 values of 0.06/0.25 µg/mL and 98.3% inhibited at ≤2 µg/mL. Ceftibuten/VNRX-5236 maintained activity against resistant subsets (MIC90 range, 0.5 to 2 µg/mL; 91.5% to 97.1% inhibited at ≤2 µg/mL), including serine carbapenemase-positive isolates (MIC90 0.5 µg/mL; 100% inhibited at ≤1 µg/mL). Ceftibuten/VNRX-5236 in vitro potency was similar to that of newer parenteral and investigational oral therapies.
Results Table
Conclusion
Ceftibuten/VNRX-5236 exhibited promising in vitro activity against recent Enterobacterales from UTIs, and may have potential as an oral treatment option for complicated urinary tract infections, including those caused by serine β-lactamase-expressing Enterobacterales (ESBL, KPC, OXA-48/OXA-48-like) for which there are currently few oral treatment options available.
Disclosures
Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Mark G G. Wise, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
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