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• We identified multiple New Delhi metallo-beta-lactamase 1 Klebsiella pneumoniae isolates in Ukrainian patients. • We detected isolates co-carrying OXA-48 and New Delhi metallo-beta-lactamase-1 carbapenemases. • Treatment choices were limited by the occurrence of multiresistant co-infections. • Sequencing results suggest partial transmission during primary care in Ukraine. We analyzed consecutive clinical cases of infections due to carbapenemase-producing gram-negative bacteria detected in war-wounded patients from Ukraine who were treated at one university medical center in southwest Germany between June and December 2022. The isolates of multiresistant gram-negative bacteria were subjected to a thorough microbiological characterization and whole genome sequencing (WGS). We identified five war-wounded Ukrainian patients who developed infections with New Delhi metallo-β-lactamase 1-positive Klebsiella pneumoniae. Two isolates also carried OXA-48 carbapenemases. The bacteria were resistant to novel antibiotics, such as ceftazidime/avibactam and cefiderocol. The used treatment strategies included combinations of ceftazidime/avibactam + aztreonam, colistin, or tigecycline. WGS suggested transmission during primary care in Ukraine. We conclude that there is an urgent need for thorough surveillance of multiresistant pathogens in patients from war zones. [ABSTRACT FROM AUTHOR]

Limited data on clinical and microbiological efficacy, patient mortality, and other associated factors are available for ceftazidime/avibactam (CAZ/AVI)-based regimens for carbapenem-resistant Gram-negative bacteria (CR-GNB). This study aimed to assess these issues retrospectively using multicenter data. This multicenter study included CR-GNB infected patients treated with CAZ/AVI-based regimens for more than three days. Patient characteristics, bacterial culture reports, drug-sensitivity test results, and antibiotic use, including CAZ/AVI use, were extracted from the patient's clinical records. The clinical and microbiological efficacy of the combined drug regimen and patient mortality were evaluated according to corresponding definitions. Univariate and multivariate logistic regressions were performed to explore the efficacy and mortality-related factors. A total of 183 patients with CR-GNB infection were considered for the analysis according to the inclusion and exclusion criteria. After the treatment of CAZ/AVI-based regimens, the clinical efficacy was 75.4 %. The 7-day microbial efficacy and clearance rate after treatment were 43.7 % and 66.0 %, respectively. Moreover, 30-day all-cause and in-hospital mortality were 11.5 % and 14.2 %, respectively. Harboring renal dysfunction (creatinine clearance rate (CCR) of<20 mL/min), cardiovascular diseases, and digestive system diseases were independent risk factors for poor clinical efficacy of CAZ/AVI-based regimens. Bloodstream infection (BSI), patients with the adjusted doses of CAZ/AVI, and CAZ/AVI co-administration with carbapenem were independently associated factors of bacterial clearance by CAZ/AVI-based regimens. Age, total hospital stays, use of mechanical ventilation, and cumulative CAZ/AVI dose were independent factors associated with all-cause mortality. CAZ/AVI was an effective drug in treating CR-GNB infection. CAZ/AVI that is mostly excreted by the kidney and is accumulated in renal impairment should be renally adjusted. Renal dysfunction and the adjusted dose of CAZ/AVI were associated with efficacy. Clinicians should individualize CAZ/AVI regimen and dose by the level of renal function to achieve optimal efficacy and survival. The efficacy of CAZ/AVI in the treatment of CR-GNB infection, as well as the implementation of individualized precision drug administration of CAZ/AVI according to patients' different infection sites, renal function, bacterial types, bacterial resistance mechanisms, blood concentration monitoring and other conditions need to be further studied in multicenter. [ABSTRACT FROM AUTHOR]

With the increase in drug resistance rates of pathogens isolated from complicated intra-abdominal infections (cIAIs), ceftazidime/avibactam (CAZ-AVI) is increasingly used clinically. However, given the high drug cost and the fact that not yet covered by the health insurance payment, this study evaluated the cost-effectiveness of CAZ-AVI plus metronidazole versus meropenem as a first-line empiric treatment for cIAIs from the perspective of the Chinese healthcare system. A decision analytic model with a one-year time horizon was constructed to assess the cost-effectiveness based on the entire disease course. Model inputs were mainly obtained from clinical studies, published literature, and publicly available databases. Primary outcomes were cost, quality-adjusted life years (QALYs), life years (Lys), and incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analysis were also performed. In the base cases, compared to meropenem, CAZ-AVI plus metronidazole had a shorter mean hospital length of stay (–0.77 days per patient) and longer life expectancy (+0.05 LYs and +0.06 QALYs). CAZ-AVI plus metronidazole had an ICER of $25517/QALY, which is well below the threshold of $31509 per QALY in China. The one-way sensitivity analysis showed that the change of the treatment duration of CAZ-AVI plus metronidazole was the parameter that most influenced the results of the ICER. In probabilistic sensitivity analysis, CAZ-AVI plus metronidazole was the optimal strategy in 75% of simulations at $31510/QALY threshold. CAZ-AVI plus metronidazole could be considered as a cost-effective option for the empiric treatment of patients with cIAIs in China, and this benefit will be more evident when the price of CAZ-AVI decreases by 23.8%. [ABSTRACT FROM AUTHOR]

• Plasmid-encoded bla KPC-2 in ST463 P. aeruginosa can inserted into chromosome by IS 26. • bla KPC-2 multicopy and overexpression caused CZA resistance in ST463 P. aeruginosa. • bla KPC-14 was first identified in P. aeruginosa. • vfr D143N mutation rendered P. aeruginosa aflagellate. KPC-2-producing Pseudomonas aeruginosa high-risk sequence type (ST) 463 is increasingly prevalent in China and poses severe threats to public health. In this study, we aimed to investigate within-host adaptive evolution of this clone during therapy. Using nine serial respiratory isolates from a post-lung transplantation patient undergoing multiple antibiotic treatments, we conducted genomic, transcriptomic and phenotypic analyses to uncover the adaptive mechanisms of a KPC-2-producing ST463 P. aeruginosa strain. The early-course isolates exhibited low-level resistance to ceftazidime/avibactam (CZA), facilitated by the bla KPC-2 gene's presence on both chromosome and plasmid, and its overexpression. Comparative genomic analysis revealed that chromosomal integration of bla KPC-2 resulted from intracellular replicative transposition of the plasmid-derived IS 26-bla KPC-2 -IS 26 composite transposon. As the infection progressed, selective pressures, predominantly from antibiotic interventions and host immune response, led to significant genomic and phenotypic changes. The late-course isolates developed a Δ242-GT-243 deletion in plasmid-encoded bla KPC-2 (bla KPC-14) after sustained CZA exposure, conferring high-level CZA resistance. Increased expression of pili and extracellular polysaccharides boosted biofilm formation. A D143N mutation in the global regulator vfr rendered the strain aflagellate by abrogating the ability of fleQ to positively regulate flagellar gene expression. The enhancement of antibiotic resistance and immune evasion collaboratively facilitated the prolonged survival of ST463 P. aeruginosa within the host. Our findings highlight the remarkable capacity of ST463 P. aeruginosa in adapting to the dynamic host pressures, supporting its persistence and dissemination in healthcare. [Display omitted] [ABSTRACT FROM AUTHOR]

This study aimed to characterize three KPC variants (KPC-33, KPC-100, and KPC-201) obtained from a clinical isolate of Pseudomonas aeruginosa (#700), along with two induced strains C109 and C108. Genomic DNAs of #700 (ST235), C109 (ST463), and C108 (ST1076) were sequenced using Illumina and Oxford Nanopore technologies. The transferability and stability of the plasmid was assessed through conjugation experiments and plasmid stability experiments, respectively. Minimum inhibitory concentrations of bacterial strains were determined using broth microdilution methods. In vitro induction was performed using ceftazidime-avibactam (CZA) at concentrations of 6/4 µg/ml. Linear genomic alignments were visualized using Easyfig, and protein structure modeling of the novel KPC variant (KPC-201) was conducted using PyMol. The plasmids carrying the KPC variants in the three CZA-resistant strains (C109, C108, and #700) had sizes of 39,251 bp (KPC-100), 394,978 bp (KPC-201), and 48,994 bp (KPC-33). All three plasmids belonged to the IncP-like incompatibility (Inc) groups, and the plasmid exhibited relatively high plasmid stability, KPC-33 and KPC-201-harboring plasmids were successfully transferred to the recipient strain P. aeruginosa PAO1rifR. The genetic environments of the three bla KPC genes differed from each other. The mobile elements of the three bla KPC genes were as follows, Tn AS1 -IS 26 -ΔIS Kpn27 - bla KPC-33 -IS Kpn6 -IS 26 , IS 6 -ΔIS Kpn27 - bla KPC-100 -IS Kpn6 -IS 26- Tn 3- IS 26 , and IS 6100 -IS Kpn27-bla KPC- 201-IS Kpn6 -Tn AS1. Notably, the length of ΔIS Kpn27 upstream of the bla KPC-33 and bla KPC-100 genes were remarkably short, measuring 114 bp and 56 bp, respectively, deviating significantly from typical lengths associated with IS Kpn27 elements. Moreover, the novel KPC variant, KPC-201, featured a deletion of amino acids LDR at positions 161–163 in KPC-3, resulting in a looser pocket structure contributing to its avibactam resistance. KPC-201, identified as a novel KPC variant, exhibits resistance to CZA. The presence of multiple mobile elements surrounding the bla KPC-variant genes on stable plasmids is concerning. Urgent preventive measures are crucial to curb its dissemination in clinical settings. [ABSTRACT FROM AUTHOR]

• Mutated KPC variants were associated with high-level ceftazidime/avibactam resistance. • A significant fitness cost was shown in KPC-33-bearing and KPC-39-bearing strains. • Various KPC variants could potentially incur distinct fitness costs. Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is a global public health issue, and ceftazidime/avibactam is recommended by international guidelines as the preferred treatment for KPC- and OXA-48-producing CRKP. Since its introduction in Taiwan in 2019, ceftazidime/avibactam-resistant strains have emerged. Our aim is to investigate the mechanisms of ceftazidime/avibactam resistance in CRKP in Taiwan and study their associated fitness costs. Ceftazidime/avibactam-resistant CRKP strains with exposure to ceftazidime/avibactam isolated from clinical specimens were consecutively collected at Taipei Veterans General Hospital in 2020. The serial strains exhibiting ceftazidime/avibactam-susceptible and ceftazidime/avibactam-resistant phenotypes isolated from the same patient were characterized using whole-genome sequencing and tested for their growth rates and competitive abilities. A total of 35 ceftazidime/avibactam-resistant CRKP strains were identified, with 20 being metallo-β-lactamase producers. Ten strains harboured KPC variants, exhibiting MIC for ceftazidime/avibactam ranging from 64 to ≥256 mg/L. The 10 strains demonstrating high-level ceftazidime/avibactam resistance possessed mutated KPC variants: KPC-33 (n = 3), KPC-31 (n = 1), KPC-39 (n = 1), KPC-44 (n = 1), KPC-58 (n = 1), KPC-90 (n = 1), and two novel KPC variants. Ceftazidime/avibactam-resistant strains with KPC-33 and KPC-39 showed a significant fitness cost and lower growth rate compared to their parental strains. In contrast, ceftazidime/avibactam-resistant strains with KPC-58 and KPC-58 plus D179Y showed similar growth rates and competitive abilities compared to their parental strains. Mutated KPC variants conferred high-level ceftazidime/avibactam resistance in Taiwan. Significant fitness costs were observed in both the ceftazidime/avibactam-resistant KPC-33 and KPC-39 strains. Despite conferring a similar level of ceftazidime/avibactam resistance, different KPC variants could entail varying degrees of fitness costs. [Display omitted] [ABSTRACT FROM AUTHOR]

Enterobacterales with carbapenemase-independent resistance to carbapenems are sometimes selected during therapy and, on rare occasions, cause outbreaks. Most have extended-spectrum or AmpC β-lactamases, together with changes to permeability or penicillin-binding proteins (PBPs). Newer β-lactam–β-lactamase inhibitor combinations may present useful options for infections due to these organisms. Accordingly, Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing broth-microdilution was used to measure the minimum inhibitory concentrations (MICs) of ceftazidime/avibactam and aztreonam/avibactam for 51 carbapenemase-negative Enterobacterales with resistance or reduced susceptibility to carbapenems: genomic sequencing of the least-susceptible organisms was also undertaken. MICs of the two avibactam combinations cross-correlated closely, but with fewer MICs (2/51 vs. 10/51) exceeding 8+4 mg/L in the case of ceftazidime/avibactam. Raised MICs for Escherichia coli were associated with PBP3 inserts together with CMY-42 β-lactamase; correlates among Enterobacter cloacae complex isolates remain elusive, with AmpC and PBP3 sequences found to be species specific. In the case of Klebsiella spp., no MICs exceeding 2 mg/L were seen for either combination. It appears that these avibactam combinations have potential against Enterobacterales with carbapenemase-independent carbapenem resistance or reduced susceptibility, with ceftazidime/avibactam being more reliably active than aztreonam/avibactam. [ABSTRACT FROM AUTHOR]

• 360 P. aeruginosa from patients with SSTI from 47 hospitals were evaluated • The new BL/BLIs CAZ-AVI, TOL-TAZ, MEM-VAB, and IMI-REL were tested • These β-lactamase inhibitor combinations were active against 98.3-98.6% of isolates • Ceftazidime-avibactam was active against 92.6% of meropenem-nonsusceptible isolates The limited armamentarium against multidrug-resistant Gram-negative bacilli led to the development of a new generation of β-lactam/β-lactamase inhibitor combinations (BL/BLI). To evaluate the in vitro activity of ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from patients hospitalized with skin and soft tissue infections (SSTIs) in several countries around the world. A total of 360 P. aeruginosa isolates were consecutively collected from 47 medical centers located in Western Europe, Eastern Europe, the Asia-Pacific region, and Latin America. Susceptibility testing was performed by broth microdilution method at a monitoring laboratory. EUCAST breakpoints were applied. Ceftazidime/avibactam (98.3% susceptible), ceftolozane/tazobactam (98.6% susceptible), and imipenem/relebactam (98.3% susceptible) were the most active compounds after colistin (100.0% susceptible) and retained activity against isolates nonsusceptible to piperacillin/tazobactam, meropenem, imipenem, and/or ceftazidime. Meropenem-vaborbactam was active against 94.2% of isolates. Ceftazidime/avibactam was the most active BL/BLI against meropenem-nonsusceptible (92.6% susceptible) and imipenem-resistant (93.8% susceptible) isolates, whereas ceftolozane/tazobactam was the most active BL/BLI against piperacillin/tazobactam-resistant (91.1% susceptible) and ceftazidime-resistant (91.7% susceptible) isolates. The recently approved BL/BLIs demonstrated potent activity and broad coverage against contemporary P. aeruginosa isolates from patients with SSTIs. [ABSTRACT FROM AUTHOR]

Enterobacteriaceae are the most common pathogens in nosocomial and community infections. Carbapenems are widely used as the most effective antibacterial agents against Enterobacteriaceae. However, increasing use of carbapenems has accelerated the emergence of carbapenem-resistant Enterobacteriaceae. This was a systematic review of recently published data to compare the clinical efficacy and safety of ceftazidime/avibactam (CAZ-AVI) and carbapenems in the treatment of Enterobacteriaceae infections. Moreover, we also attempted to assess whether it is feasible to treat Enterobacteriaceae infections with CAZ-AVI instead of carbapenems. A comprehensive search was performed using Medline, Embase and Cochrane Library for randomised controlled trials (RCTs) comparing the efficacy and safety of CAZ-AVI and carbapenems for the treatment of Enterobacteriaceae infections. Clinical success, microbiological success, adverse events (AEs), serious adverse events (SAEs) and mortality were assessed as the main outcomes. Three RCTs (1186 patients) were included in the meta-analysis. The meta-analysis showed that there were no significant differences between CAZ-AVI and carbapenems in clinical success [risk difference (RD) = 0.00, 95% confidence interval (CI) –0.06 to 0.06; P = 0.99], microbiological success (RD = 0.07, 95% CI –0.04 to 0.18; P = 0.21) or AEs (RD = 0.00, 95% CI –0.02 to 0.03; P = 0.81). SAEs with CAZ-AVI were numerically higher than with carbapenems (RD = 0.02, 95% CI –0.00 to 0.04; P = 0.06). CAZ-AVI is comparable with carbapenems in efficacy and safety for Enterobacteriaceae infections. More high-quality and large-scale RCTs are needed to further confirm the safety of CAZ-AVI. [PROSPERO ID: CRD42019116685.] [ABSTRACT FROM AUTHOR]

• Ceftazidime/avibactam (CAZ/AVI) is a novel β-lactam/β-lactamase inhibitor combination. • CAZ/AVI displays in vitro activity against strains producing class A and D carbapenemases. • No conclusive data on whether CAZ/AVI can be used alone or in combination to treat carbapenem-resistant GNB. • Meta-analysis on the efficacy of CAZ/AVI monotherapy or combination therapy for carbapenem-resistant GNB. Clinicians may use ceftazidime/avibactam in combination with other active agents to treat infections due to carbapenem-resistant organisms, although no conclusive data support this practice. This meta-analysis compared the efficacy of ceftazidime/avibactam as monotherapy or combination therapy against infections due to carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPa). An online literature search was conducted to identify observational studies published as full papers and indexed up to February 2019 comparing the efficacy, in terms of mortality and microbiological cure rates, of ceftazidime/avibactam monotherapy or combination therapy with other active agents for infections due to CRE or CRPa. The relative risk (RR) of mortality and microbiological eradication was estimated based on pooled data from all eligible studies. Eleven studies were included in the meta-analysis accounting for 396 subjects, of whom 202 received combination therapy. The mortality rate was 38.1% for combination therapy and 30.9% for monotherapy (RR = 1.18, 95% CI 0.88–1.58; P = 0.259). Similarly, no difference was found between the two groups when analysing the rate of microbiological cure (64.9% for combination therapy vs. 63.4% for monotherapy; RR = 1.04, 95% CI 0.85–1.28, P = 0.705). Moreover, no difference was observed for both outcomes when patients infected with P. aeruginosa were excluded from the analysis. This meta-analysis suggests that use of ceftazidime/avibactam in monotherapy or combination therapy for infections due to CRE or CRPa could show a similar effect on mortality and microbiological cure rates. Studies on larger samples are needed to address this important issue. [ABSTRACT FROM AUTHOR]

• Loading dose is one of the primary strategies for CAZ/AVI treatment optimization. • Prolonged infusion was associated with significantly a higher clinical cure rate. • CAZ/AVI dose adjustment for renal dysfunction was a negative predictor factor. This retrospective study aimed to identify the effectiveness of ceftazidime/avibactam (CAZ/AVI) and its optimisation programs for severe hospital-acquired pulmonary infections (sHAPi) caused by carbapenem-resistant and difficult-to-treat Pseudomonas aeruginosa (CRPA and DTR –P. aeruginosa). We retrospectively analysed observational data on treatment and outcomes of CAZ/AVI for sHAPi caused by CRPA or DTR–P. aeruginosa. The primary study outcomes were to evaluate the clinical and microbiology efficacy of CAZ/AVI. The cohort consisted of 84 in-patients with sHAPi caused by CRPA (n = 39) and DTR- P. aeruginosa (n = 45) who received at least 72 h of CAZ/AVI therapy. The clinical cure rate was 63.1% in total. There was no significant difference in study outcomes between patients treated with CAZ/AVI monotherapy and those managed with combination regimens. CAZ/AVI as first-line therapy possessed prominent clinical benefits regarding infections caused by DTR– P. aeruginosa. The clinical cure rate was positively relevant with loading dose for CAZ/AVI (odds ratio [OR] 0.03; 95% confidence interval [CI] 0.004–0.19; P < 0.001) and with CAZ/AVI administration by prolonged infusion (odds ratio 0.15; 95% confidence interval 0.03–0.77; P = 0.002). APACHE II score>15 (P = 0.013), septic shock at infection onset (P = 0.001), and CAZ/AVI dose adjustment for renal dysfunction (P = 0.003) were negative predictors of clinical cure. CAZ/AVI is a valid alternative for sHAPi caused by CPRA and DTR– P. aeruginosa , even when used alone. Optimisations of the treatment with CAZ/AVI in critically ill patients, including loading dose, adequate maintenance dose and prolonged infusion, were positively associated with potential clinical benefits. [ABSTRACT FROM AUTHOR]

• 64.1% of multi-drug-resistant/extensively drug-resistant (MDR/XDR) Pseudomonas aeruginosa were susceptible to ceftazidime/avibactam. • Only one gradient diffusion test was acceptable as an alternative to broth microdilution for susceptibility testing. • Ceftazidime/avibactam-resistant MDR/XDR P. aeruginosa mainly belong to bla IMP - positive ST235. Ceftazidime/avibactam (CZA) is a new β-lactam/β-lactamase inhibitor combination with promising properties as avibactam can inhibit a broad range of β-lactamases (e.g. bla KPC , bla OXA-48). The objectives of this study were: (i) to assess CZA susceptibility rates; (ii) to compare gradient and disk diffusion tests with broth microdilution (BMD) for CZA susceptibility testing; and (iii) to study the clonal structure and antimicrobial resistance genes in multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa. Isolates (n =192) from routine diagnostics (Germany, 2013–2018) were tested by BMD reference method, gradient diffusion test (Etest, bioMérieux and MIC Test Strip, Liofilchem) and disk diffusion test (MAST and Oxoid). All isolates were whole-genome sequenced to screen for metallo-β-lactamases and to assess the clonal structure using core-genome multi-locus sequence typing. In total, 64.1% of isolates (n =123) were susceptible to CZA (minimum inhibitory concentration required to inhibit the growth of 50% of organisms 8 mg/L, minimum inhibitory concentration required to inhibit the growth of 90% of organisms >256 mg/L, range 0.5–>256 mg/L). Susceptibility rates were higher in MDR (85.0%) than in XDR (49.1%) P. aeruginosa. Among commercial susceptibility testing methods, Etest showed highest accuracy in comparison to BMD (essential agreement 94.8%, categorical agreement 94.3%). CZA-resistant isolates (n =69) mainly belonged to ST235 (n =29, bla IMP -positive). In conclusion, CZA is a promising treatment option for infections caused by MDR P. aeruginosa. CZA-resistant P. aeruginosa mainly belong to the pandemic ST235 high-risk clone. Etest can be considered as an alternative to BMD. [ABSTRACT FROM AUTHOR]

• Phylogenetic analysis of resistance in cystic fibrosis Pseudomonas aeruginosa. • AmpC variations are associated with high-level cloxacillin-insensitive ceftazidime resistance. • AmpD variations are associated with ceftolozane/tazobactam and ceftazidime/avibactam double resistance. • Mutational resistance emerged in phylogenetically separate lineages. • Mutation-driven evolution in the population structure of P. aeruginosa. Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/β-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa. [ABSTRACT FROM AUTHOR]

Highlights • Since 2010, very few new antibiotics have been approved to fight multidrug-resistant Gram-negative bacteria. • These include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, plazomicin, and eravacycline. • There are several more new and emerging antibiotics in development or undergoing clinical trials. • Alternative treatments for Gram-negative bacterial infections are being explored, including targeting quorum-sensing systems, lectin inhibition, bacteriophage-mediated endolysin delivery, and antibody immune therapy. Abstract The spread of multidrug-resistant bacteria is an ever-growing concern, particularly among Gram-negative bacteria because of their intrinsic resistance and how quickly they acquire and spread new resistance mechanisms. Treating infections caused by Gram-negative bacteria is a challenge for medical practitioners and increases patient mortality and cost of care globally. This vulnerability, along with strategies to tackle antimicrobial resistance development, prompts the development of new antibiotic agents and exploration of alternative treatment options. This article summarises the new antibiotics that have recently been approved for Gram-negative bacterial infections, looks down the pipeline at promising agents currently in phase I, II, or III clinical trials, and introduces new alternative avenues that show potential in combating multidrug-resistant Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

• Imipenem/relebactam and ceftazidime/avibactam resistance was evaluated in K. pneumoniae. • Resistance to imipenem/relebactam and ceftazidime/avibactam develops rapidly in all clones. • Imipenem/relebactam resistance involves OmpK36 disruption and KPC modification. • KPC variants selected with imipenem/relebactam show resistance to relebactam inhibition. • Development of imipenem/relebactam resistance imposes high fitness costs. In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development trajectories, differentially selected resistance mechanisms and their associated fitness cost using four representative high-risk K. pneumoniae clones. Mutant frequencies and mutant preventive concentrations were determined using agar plates containing incremental concentrations of β-lactam/β-lactamase inhibitor. Resistance dynamics were determined through incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic combination up to their 64 × baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing, whole genome sequencing and competitive growth assays (to determine in vitro fitness). KPC variants associated with imipenem/relebactam resistance were characterized by cloning and biochemical experiments, atomic models and molecular dynamics simulation studies. Imipenem/relebactam prevented the emergence of single-step resistance mutants at lower concentrations than ceftazidime/avibactam. In three of the four strains evaluated, imipenem/relebactam resistance development emerged more rapidly, and in the ST512/KPC-3 clone reached higher levels compared to baseline MICs than for ceftazidime/avibactam. Lineages evolved in the presence of ceftazidime/avibactam showed KPC substitutions associated with high-level ceftazidime/avibactam resistance, increased imipenem/relebactam susceptibility and low fitness costs. Lineages that evolved in the presence of imipenem/relebactam showed OmpK36 disruption, KPC modifications (S106L, N132S, L167R) and strain-specific substitutions associated with imipenem/relebactam resistance and high fitness costs. Imipenem/relebactam-selected KPC derivatives demonstrated enhanced relebactam resistance through important changes affecting relebactam recognition and positioning. Our findings anticipate potential resistance mechanisms affecting imipenem/relebactam during treatment of KPC-producing K. pneumoniae infections. [ABSTRACT FROM AUTHOR]

Highlights • Carbapenemase-producing Enterobacteriaceae may be extensively drug resistant. • Phenotypic drug-resistance profiles alone may not indicate viable therapies. • Gradient diffusion strip (GDS) methods may reveal appropriate combination therapy. • Phenotypic profiling with GDS may be valuable in the presence or absence of molecular assays. Abstract Ceftazidime/avibactam plus aztreonam (CZA+ATM) is an emerging option to combat carbapenemase-producing Enterobacteriaceae (CPE) expressing resistance via multiple β-lactamases within Ambler classes A, B, C, and D. The benefit of this combination is apparent when the pathogen-specific resistance genotype is characterized. However, rapid molecular diagnostic systems may be unavailable to allow this precision medicine-based approach. Using synergy tests with antibiotic gradient diffusion strips (GDSs), we aimed to prove that the defined phenotypic profile of CPE is reliably predicted by the genotype to confirm the utility of this method as a phenotypic profiling tool for use in the clinical setting. Synergy assessments for CPE (n =10) that co-produce serine- and metallo-β-lactamases were performed by crossing CZA and ATM antibiotic GDSs (Liofilchem® and Etest®). The minimum inhibitory concentration (MIC):MIC ratio method was also conducted for five CPE. All CPE were resistant to CZA and ATM when tested alone. Using classical fractional inhibitory concentration definitions, synergy (9/10) and additivity (1/10) was detected by at least one method for all isolates. As predicted by cross-coverage of genotypically defined serine- and metallo-β-lactamases, for all isolates CZA+ATM produced a phenotypic profile distinguished by sizeable zones of inhibited growth which we term the 'zone of hope'. In conclusion, simple procedures utilizing antibiotic GDSs were concordant with the known genotypic profile of the CPE selected for study. This approach appears to be a valuable tool for guiding therapy in the absence of molecular diagnostic systems. Furthermore, this study confirms potent in vitro activity of CZA+ATM against CPE expressing multiple β-lactamases. [ABSTRACT FROM AUTHOR]

Avibactam (AVI) is a novel β-lactamase inhibitor active against class A, class C and some class D β-lactamases. In combination with ceftazidime, AVI may be useful for the treatment of infections due to Gram-negative bacteria producing carbapenemases from these classes; however, susceptibility data for some of the less common carbapenemases are limited. To assess the in vitro activity of ceftazidime/avibactam (CZA), a panel of 50 diverse carbapenemase-producing Gram-negative bacteria collected from clinical samples in Victoria, Australia, containing KPC, GES, SME, OXA-23 and OXA-48-like carbapenemases were tested for susceptibility to CZA using the broth microdilution (BMD), Etest and disk diffusion methods. All isolates were susceptible to CZA. Etest correlated well with BMD, although Etest minimum inhibitory concentrations (MICs) were generally lower than BMD. Disk diffusion correlated moderately well with BMD, with two interpretive errors. This study confirms phenotypic CZA susceptibility in the carbapenemase groups tested, including the less common OXA-23-producing Escherichia coli , SME-producing Serratia marcescens and GES-5-producing Pseudomonas aeruginosa. [ABSTRACT FROM AUTHOR]

Background Ceftazidime/avibactam is a newly approved β-lactam/β-lactamase inhibitor combination with activity against antibiotic-resistant Gram-negative organisms, including many carbapenem-resistant strains. Although this agent may offer a promising treatment option for serious infections with limited alternatives available, clinical experience with ceftazidime/avibactam in treatment of infections caused by multidrug-resistant Gram-negative organisms other than Klebsiella pneumoniae is limited. Methods A retrospective case series was performed to evaluate patients treated with ceftazidime/avibactam for infections caused by organisms other than K. pneumoniae at our institution over a 1-year period. Patients aged at least 18 years who received at least one dose of ceftazidime/avibactam were eligible for inclusion. Clinical and microbiological data were collected, and investigators assessed adverse effects, microbiological cure, clinical success, and 30-day in-hospital mortality following completion of ceftazidime/avibactam therapy. Results Ten patients were included. The most common index infection was pneumonia (n = 6/13, 46%) and the most frequently isolated organism was Pseudomonas aeruginosa (n = 8/21, 38%). Fifty percent of patients received ceftazidime/avibactam as monotherapy. Microbiological cure was achieved in 67% (n = 6/9) of patients and 70% (n = 7/10) of patients met criteria for clinical success. The 30-day in-hospital mortality rate was 30%. No patients experienced adverse events because of ceftazidime/avibactam therapy. Conclusions For infections caused by antibiotic-resistant Gram-negative organisms other than K. pneumoniae, clinical and microbiological success rates for patients treated with ceftazidime/avibactam were similar to those that have been reported for K. pneumoniae . Ceftazidime/avibactam appears to be a promising treatment option for infections caused by a variety of resistant Gram-negative organisms when limited alternatives exist. [ABSTRACT FROM AUTHOR]

• The study investigated the ceftazidime/avibactam (CZA) resistance mechanisms in strains that had not been exposed to CZA previously. • Strains were collected from 43 hospitals in 18 provinces across China. • Phenotypic and genotypic analysis of CZA-resistant Enterobacterales was undertaken. In order to investigate ceftazidime/avibactam (CZA) resistance characteristics and mechanisms of bacteraemic Enterobacterales strains that had not been treated previously with CZA, 9708 strains were collected from 43 hospitals in 18 provinces across China from January 2019 to June 2020. The minimum inhibitory concentration (MIC) values of CZA in 165 (1.70%) strains were ≥8/4 mg/L. Ten (6.06%) CZA-resistant strains without metallo-β-lactamase production were obtained from the individuals without prior exposure to CZA, including six Escherichia coli isolates, three Klebsiella pneumoniae isolates and one Enterobacter cloacae isolate. Whole-genome sequencing revealed that ECB88611, ECB142593 and ECB144539 had encoded disrupted OmpF loss of function. OmpF of ECB126041 had a 2_9 MKRNILAV deletion; OmpK35 of three K. pneumoniae isolates harboured amino acid fragment deletions from positions 1 to 38; and ELB117287 had encoded disrupted OmpF. The G132D amino acid substitution of OmpC of ECB88611, ECB142593 and ECB144539, and the 134_135GD insertion of OmpK36 of three K. pneumoniae isolates were predicted to alter ceftazidime permeability. 333_334 YRIK or YRIN insertions occurred in PBP3 of six E. coli isolates. The relative expression of bla KPC-2 in KPB125108 was 4.527 ± 0.2166 times higher than the control strain, and the relative expression of acrF in six E. coli isolates was 2–3 times higher than the control strain. The addition of phenylalanine-arginine-β-naphthylamine at 100 mg/L decreased the MIC values of CZA against nine strains significantly. In conclusion, the antimicrobial resistance mechanisms in 10 isolates included increased expression of bla KPC-2 , non-functional OMPs, upregulation of efflux pump activity, and variants of PBP3. Most of these mechanisms affected the antimicrobial activity of CZA by impeding ceftazidime. [ABSTRACT FROM AUTHOR]

• Ceftazidime/avibactam (CAZ/AVI) and polymyxin B are the last resort for carbapenem-resistant Gram-negative bacteria (CRGNB) infections in some countries, but data comparing the effectiveness of the two antibiotics are limited. • CAZ/AVI therapy was associated with treatment success among patients with CRGNB infection, but did not improve 28-day in-hospital survival compared with polymyxin B. • CRGNB patients with a Charlson comorbidity index ≥ 5 and APACHE II score ≥ 15 had poor a prognosis. To compare the effectiveness of ceftazidime/avibactam (CAZ/AVI) and polymyxin B against carbapenem-resistant Gram-negative bacteria (CRGNB) infections in western China. The medical records of patients with CRGNB infections in this hospital from 2018–2022 were retrospectively reviewed. The data included demographic characteristics, laboratory results, antibiotic strategies and clinical outcomes. A total of 378 patients with CRGNB infections were enrolled, including 112 patients in the CAZ/AVI group and 266 patients in the polymyxin B group. The most common pathogen was carbapenem-resistant Klebsiella pneumoniae (44.44%). The rates of treatment failure at 28 days (65.04% vs. 45.54%; P = 0.000) and 28-day in-hospital mortality (20.30% vs. 9.82%; P = 0.014) in the polymyxin B group were higher than those in the CAZ/AVI group. Multivariable analysis revealed that multiple organ dysfunction syndrome (OR 2.730; P = 0.017), acute renal failure (OR 2.595; P = 0.020), higher Charlson comorbidity index (CCI) (OR 1.184; P = 0.011) and Acute Physiology And Chronic Health Evaluation (APACHE) Ⅱ scores (OR 1.149; P = 0.000) were independent risk factors for treatment failure, whereas CAZ/AVI therapy (OR 0.333; P = 0.002) had a protective effect. Multivariate Cox regression analysis revealed that CCI ≥ 5 and APACHE II score ≥ 15 were associated with a higher 28-day in-hospital mortality rate (P < 0.001). CAZ/AVI therapy was associated with treatment success among patients with CRGNB infection. However, CAZ/AVI therapy did not improve 28-day in-hospital survival compared with polymyxin B. The CCI ≥ 5 and APACHE II score ≥ 15 affected 28-day in-hospital mortality of CRGNB-infected patients. [ABSTRACT FROM AUTHOR]

• The efficacy of novel antibiotics for complicated urinary tract infections is unknown. • The clinical cure rate was higher in patients receiving novel antibiotics. • Novel antibiotics were associated with a higher microbiological eradication rate. • No significant difference was found in the risks of adverse events. • Novel antibiotics may be more effective than, and as safe as, conventional antibiotics. To assess the clinical efficacy and safety of novel antibiotics for complicated urinary tract infections (cUTIs). Three electronic databases (Medline, Embase and the Cochrane Library) were searched from inception until 20 October 2022 to identify randomized controlled trials (RCTs) investigating the efficacy and safety of novel antibiotics (novel β-lactam/β-lactamase inhibitor combinations, aminoglycosides, fluoroquinolones and cefiderocol) against cUTIs. The primary outcome was the clinical cure rate (CCR) at test of cure (TOC), while secondary outcomes included CCR at end of treatment (EOT), microbiological eradication rate, and the risk of adverse events (AEs). Trial sequential analysis (TSA) was used to examine the evidence. In total, 11 RCTs demonstrated a higher CCR [83.6% vs 80.3%, odds ratio (OR) 1.37, 95% confidence interval (CI) 1.08–1.74, P =0.01, I 2=35%, 11 RCTs, 3514 participants] and microbiological eradication rate (77.7% vs 67.2%, OR 1.79, 95% CI 1.46–2.20, P <0.00001, 11 RCTs, 4347 participants) at TOC in the intervention group compared with the control group. At EOT, there was no significant difference in CCR (OR 0.96, P =0.81, I 2=4%, nine RCTs, 3429 participants) or risk of treatment-emergent AEs (OR 0.95, P =0.57, I 2=51% , 11 RCTs, 5790 participants) between the intervention and control groups. TSA showed robust evidence regarding microbiological eradication rate and treatment-emergent AEs, while the CCR at TOC and EOT remained inconclusive. While showing similar safety, the investigated novel antibiotics may be more effective than the conventional antibiotics for patients with cUTIs. However, as the pooled evidence relating to CCR remained inconclusive, further studies are required to address this issue. [ABSTRACT FROM AUTHOR]

Background Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made. Aims This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms. Sources A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies. Content Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline. Implications The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-β-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa , but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development. [ABSTRACT FROM AUTHOR]

Ceftazidime/avibactam (CAZ/AVI) is the first antimicrobial agent with activity against carbapenem-resistant Enterobacteriaceae (CRE) approved by the US Food and Drug Administration (FDA). Notably, human clinical outcome data for this indication are limited. Therefore, a retrospective study was performed to evaluate the clinical outcomes and bacterial genomic characteristics of patients hospitalised at a tertiary medical centre with CRE infections treated for the first time with CAZ/AVI. From a total of 44 patients with CRE infections, 6 patients were treated with CAZ/AVI. The duration of CAZ/AVI treatment ranged from 7 days to 28 days. Five patients achieved clinical cure, however two relapsed with the same carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strain within 3 weeks of completion of CAZ/AVI treatment. In addition, one patient with CR-Kp pneumonia experienced clinical failure despite having a documented CAZ/AVI-susceptible CR-Kp strain [minimum inhibitory concentration (MIC) = 2 mg/L]. Consequently, the overall rate of unsuccessful outcome in this small cohort of patients was 50%. All strains carried KPC-3, OXA-9 and different TEM and SHV β-lactamases, but none carried the intrinsically avibactam-resistant class B metallo-β-lactamases. No obvious differences in antibiotic resistance genes were observed. This study provides an early glimpse of the clinical outcomes of patients with CR-Kp infections treated with CAZ/AVI. Findings of clinical failure and relapse in patients with no prior exposure to CAZ/AVI and with documented susceptibility to CAZ/AVI highlight the urgent need for well-designed clinical studies evaluating the effectiveness of CAZ/AVI in the treatment of CRE infections. [ABSTRACT FROM AUTHOR]

Ceftazidime/avibactam comprises the broad-spectrum cephalosporin ceftazidime and the non-β-lactam β-lactamase inhibitor avibactam. This phase 3, randomised, double-blind study (NCT01726023) assessed the efficacy and safety of ceftazidime/avibactam plus metronidazole compared with meropenem in patients with complicated intra-abdominal infection (cIAI) in Asian countries. Subjects aged 18–90 years and hospitalised with cIAI requiring surgical intervention were randomised 1:1 to receive every 8 h either: ceftazidime/avibactam (2000/500 mg, 2-h infusion) followed by metronidazole (500 mg, 60-min infusion); or meropenem (1000 mg, 30-min infusion). Non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was concluded if the lower limit of the 95% confidence interval (CI) for the between-group difference in clinical cure rate was greater than −12.5% at the test-of-cure (TOC) visit (28–35 days after randomisation) in the clinically evaluable (CE) population. Safety was also evaluated. Of 441 subjects randomised, 432 received at least one dose of study medication (ceftazidime/avibactam plus metronidazole, n  = 215; meropenem, n  = 217). In the CE population at the TOC visit, non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was demonstrated, with clinical cure reported for 93.8% (166/177) and 94.0% (173/184) of subjects, respectively (between-group difference, −0.2, 95% CI −5.53 to 4.97). The clinical cure rate with ceftazidime/avibactam plus metronidazole was comparable in subjects with ceftazidime-non-susceptible and ceftazidime-susceptible isolates (95.7% vs. 92.1%, respectively). Adverse events were similar between the study groups. Ceftazidime/avibactam plus metronidazole was non-inferior to meropenem in the treatment of cIAIs in Asian populations and was effective against ceftazidime-non-susceptible pathogens. No new safety concerns were identified. [ABSTRACT FROM AUTHOR]

The activities of the novel β-lactam/non-β-lactam β-lactamase inhibitor combination ceftazidime/avibactam and comparators were evaluated against isolates from pneumonia in hospitalised patients including ventilated patients (PHP, pneumonia not designated as VABP; VABP, pneumonia in ventilated patients). Isolates were from the European–Mediterranean region (EuM), China and the USA collected in the SENTRY Antimicrobial Surveillance Program between 2009 and 2011 inclusive. A total of 2393 organisms from PHP were from the EuM, 888 from China and 3213 from the USA; from VABP patients there were 918, 97 and 692 organisms collected, respectively. Among Enterobacteriaceae from PHP, ceftazidime/avibactam MIC 90 values against Escherichia coli ranged from 0.25–0.5 mg/L and Klebsiella spp. MIC 90 values were 0.5 mg/L in each region. Among VABP isolates, MIC 90 values for ceftazidime/avibactam against E. coli were 0.25 mg/L; for Klebsiella spp. from VABP patients, MIC 90 values were similar to those obtained against PHP isolates. The MIC of ceftazidime/avibactam was ≤8 mg/L against 92–96% of Pseudomonas aeruginosa isolated from PHP patients. Isolates of P. aeruginosa from VABP patients were of lower susceptibility to all antibacterial agents (e.g. depending on region, meropenem susceptibilities were 51.2–69.4% in contrast to 68.3–76.7% among PHP patients). However, ceftazidime/avibactam inhibited 79.2–95.4% of VABP isolates at an MIC of ≤8 mg/L. Acinetobacter spp. were resistant to many agents and only rates of susceptibility to colistin were >90% across all regions both for PHP and VABP isolates. Ceftazidime/avibactam was generally active against a high proportion of isolates resistant to ceftazidime from PHP and VAPB patients. [ABSTRACT FROM AUTHOR]

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Carbapenem-resistant Enterobacterales (CRE) are a growing threat to public health. This study was conducted to determine the prevalence of carbapenem-resistant Klebsiella pneumoniae (CR-KP) and the associated carbapenemase genes using data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2020. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method, and carbapenemase genes were detected using multiplex polymerase chain reaction (PCR). Clinical and Laboratory Standards Institute breakpoints were used for interpretation of susceptibility. A total of 6753 K. pneumoniae isolates were collected from 57 countries in six regions worldwide. Of these, 1118 (16.6%) were CR-KP isolates. Among 1079 of the tested CR-KP isolates, 1017 (94.3%) had at least one of the class A (41.0%, 417/1017), B (39.3%, 400/1017), and D (38.8%, 395/1017) carbapenemase genes. The resistance patterns and associated genes differed significantly between the participating countries. India, Greece, and Argentina had the highest rates of carbapenem resistance. Susceptibility to the β-lactamase inhibitor combination, ceftazidime/avibactam was greater than that to meropenem/vaborbactam in all K. pneumoniae (93.7% vs. 90.3%, P < 0.05), CR-KP (63.3% vs. 41.5%, P < 0.05), CR-KP with genes for Klebsiella pneumoniae carbapenemase-like carbapenemase (99.5% vs. 96.0%, P < 0.05), oxacillinase-like carbapenemase (98.7% vs. 4.6%, P < 0.05), and CR-KP without carbapenemase genes (93.5% vs. 79.0%, P < 0.05). CR-KP was the only exception with class B carbapenemase, with susceptibility rates of 1.4% and 9.4% to ceftazidime/avibactam and meropenem/vaborbactam, respectively (P < 0.05). Overall, surveillance results are important for guiding empirical antimicrobial therapy in different regions and for monitoring the global transmission of CR-KP with varying resistance mechanisms. [ABSTRACT FROM AUTHOR]

Ceftazidime/avibactam is a new combination of the antibiotic ceftazidime with the novel, non-β-lactam β-lactamase inhibitor avibactam. The purpose of the present study was to investigate the effect of ceftazidime/avibactam on the human intestinal microbiota following intravenous (i.v.) administration. Twelve healthy volunteers received ceftazidime/avibactam by i.v. infusion (2000 mg ceftazidime and 500 mg avibactam) given over 2 h every 8 h on Days 1–6 (inclusive) and a single dose on Day 7. Faecal samples were collected on Day–1 (pre-dose), during administration on Days 2, 5 and 7 and post-dose on Days 9, 14 and 21. Samples were cultured on non-selective and selective media. The number of Escherichia coli and other enterobacteria decreased significantly during administration of ceftazidime/avibactam, whereas the number of enterococci increased. Lactobacilli, bifidobacteria, clostridia and Bacteroides decreased significantly during ceftazidime/avibactam administration. The effects on lactobacilli, bifidobacteria and Bacteroides were similar in the 12 volunteers, whilst clostridia showed different ecological patterns among the volunteers. Toxigenic Clostridium difficile strains were detected in five volunteers during the study. In four of the volunteers, loose stools were reported as adverse events. Plasma samples were collected on Days −1, 2, 5 and 7. Ceftazidime and avibactam concentrations in plasma (ceftazidime 0–224.2 mg/L of plasma and avibactam 0–70.5 mg/L of plasma) and faeces (ceftazidime 0–468.2 mg/kg of faeces and avibactam 0–146.0 mg/kg of faeces) were found by bioassay. New colonising resistant clostridia were found in five volunteers and lactobacilli were found in three volunteers. [ABSTRACT FROM AUTHOR]

• Real-life clinical experience with ceftazidime/avibactam (C/A) therapy in the ICU setting. • C/A appears safe and effective for severe infections due to carbapenem-resistant GNB in critically ill patients. • Combination therapy of C/A with other antimicrobials was not associated with a higher clinical or microbiological response. • Mortality was mainly related to presence of bacteraemia, previous corticosteroids and need for life-supporting therapies. This study aimed to assess the efficacy of ceftazidime/avibactam (C/A) in the treatment of infections due to Gram-negative bacteria (GNB) in critically ill patients. A multicentre, retrospective, observational study was conducted in critically ill patients receiving C/A for GNB infections. We evaluated demographic data, localisation and severity of infection, clinical and microbiological outcomes, and mortality. A total of 68 patients received C/A for serious GNB infections. The main infections were respiratory (33.8%), intra-abdominal (22.1%) and urinary tract infections (10.3%); bacteraemia was found in 22 cases (32.4%). Most infections were complicated by septic shock (58.8%) or sepsis (36.8%) and most of them required life-supporting therapies. Enterobacterales (79.4%) and Pseudomonas aeruginosa (19.1%) were the most frequently isolated bacteria; 84.2% of isolates were carbapenem-resistant. Thirty-four patients (50.0%) received C/A in combination with other antimicrobials. Fifty patients (73.5%) presented a favourable clinical response. Microbiological eradication was documented in 25 cases (36.8%). No significant differences were found in clinical response between patients treated with monotherapy or combined therapy (79.4% vs. 67.6%; P = 0.27). Overall intensive care unit (ICU) mortality was 41.2%. Univariate analysis showed that 30-day all-cause mortality was significantly (P < 0.05) associated with bacteraemia, previous corticosteroid use and the need of life-supporting therapies. C/A appears to be an effective therapy for severe infections due to GNB, including carbapenem-resistant isolates, in critically ill patients. C/A combination therapy was not associated with a higher clinical response. Mortality correlated significantly with the presence of bacteraemia, previous corticosteroid use and the need for life-supporting therapies. [ABSTRACT FROM AUTHOR]

• Isolates recovered before treatment with ceftazidime/avibactam (CZA) were susceptible to CZA and produced KPC-3. • Resistance to CZA was related to bla KPC-3 mutations, including the new bla KPC-94 and bla KPC-95 alleles. • All Klebsiella pneumoniae isolates belonged to ST512. • All CZA-resistant isolates with bla KPC-3 variants had restoration of carbapenem susceptibility. Ceftazidime/avibactam (CZA) is used to treat infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp). Resistance to CZA is commonly related to point mutations in the bla KPC gene. Here we describe the in vivo emergence of CZA resistance in clinical isolates of KPC-Kp from four patients treated with this combination therapy. Four pre-therapy and five post-therapy KPC-Kp isolates were examined. Antibiogram (microdilution and gradient strips) and whole-genome sequencing were performed. The role of KPC mutations was validated by cloning bla KPC genes into competent Escherichia coli. All KPC-Kp isolates recovered before treatment with CZA were susceptible to CZA and produced KPC-3. Five KPC-Kp isolates recovered after treatment were resistant to this combination. Three post-therapy isolates from two patients produced KPC-31 (D179Y mutation). Additionally, we identified the novel substitution LN169–170H (KPC-94) in one isolate, and the combination of two independently described mutations, D179Y and A172T (KPC-95), in another isolate. All KPC-Kp isolates belonged to sequence type 512 (ST512). All CZA-resistant isolates with bla KPC variants had restoration of carbapenem susceptibility. In conclusion, resistance to CZA was related to bla KPC mutations, including the new KPC-94 and KPC-95 alleles, which do not cause carbapenem resistance. [ABSTRACT FROM AUTHOR]

• Multidrug-resistant Gram-negative infections affect mortality in haematological patients • Multidrug-resistant Gram-negative bacteria colonisation is a risk factor for blood stream infection • Ceftazidime/avibactam and ceftolozane/tazobactam are active against carbapenem-resistant bacteria • Empirical therapy of febrile neutropenia should be tailored according to the colonisation status • A de-escalation approach is mandatory to preserve the activity of these new antibiotics To evaluate ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) use in haematological patients with febrile neutropenia receiving high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT). A retrospective study was conducted to assess C/A and C/T efficacy through infection-related mortality (IRM) and bacteraemia clearance for carbapenem-resistant Gram-negative bacteria (CR-GNB) pre-engraftment blood-stream infections (PE-BSIs) between January–December 2018. Seventy patients underwent allogeneic HSCT: C/A and C/T were dispensed in 13% and 3%, respectively. C/A was administered as definite therapy for carbapenem-resistant Klebsiella pneumoniae (CR- Kp) PE-BSI in four carriers (bacteraemia clearance in 5 days), empirical therapy for a clinically documented infection in two patients (one carrier with pneumonia and one non-carrier with shock) and empirical therapy for fever of unknown origin in three CR- Kp carriers. C/T was administered as definite therapy for carbapenem-resistant Pseudomonas aeruginosa (CR- Pa) intra-abdominal infection in one carrier and empirical therapy for a clinically documented infection (pneumonia) in one non-carrier. Among patients without PE-BSIs and with Gram-positive bacteria PE-BSIs, IRM was 0% at +30 days; conversely, it was 30% in GNB PE-BSIs (two CR- Kp and one CR- Pa C/T-resistant). Thirty-nine patients underwent autologous HSCT: C/A and C/T were administered, respectively, as definite therapy for CR- Kp PE-BSI in one carrier (bacteraemia clearance in 3 days) and for Pa PE-BSI (three strains, one CR- Pa) in one non-carrier (bacteraemia clearance in 2 days). Overall, IRM at +30 days was 0%. Monitoring multidrug-resistant GNB colonisation enabled selection of carriers who benefit from prompt administration of new antibiotics, improving HSCT outcomes in a high-risk population. C/A and C/T were effective in bacteraemia clearance; unfortunately, multidrug-resistant GNB PE-BSIs were still a burden to IRM. [ABSTRACT FROM AUTHOR]

• 38.4% of Klebsiella pneumoniae and 28.3% of Klebsiella aerogenes were multidrug-resistant (MDR). • <5% of MDR K. pneumoniae and MDR K. aerogenes were resistant to ceftazidime/avibactam (CAZ/AVI). • >90% of MDR K. pneumoniae were resistant to cephalosporins. • 98.0% of MDR, metallo-β-lactamase (MBL)-positive K. pneumoniae were resistant to CAZ/AVI. • The tigecycline MIC 90 was 2 mg/L against all subsets of MDR K. pneumoniae. Infections caused by Klebsiella spp. are difficult to treat when these pathogens exhibit multidrug resistance (resistance to ≥3 drug classes). This study determined rates of multidrug-resistant (MDR) Klebsiella spp. among clinical isolates collected globally (Africa/Middle East, Asia, Oceania, Europe and Latin America, but not the USA) as part of the INFORM surveillance programme (2015–2017). In vitro antimicrobial activities of ceftazidime/avibactam (CAZ/AVI) and comparator antimicrobials against these MDR isolates were determined using CLSI broth microdilution methodology. MICs were interpreted using EUCAST 2019 breakpoints. By species, 38.4% (4555/11 864) of Klebsiella pneumoniae isolates were MDR, followed by 28.3% (452/1598) of Klebsiella aerogenes. The majority (69.5%) of MDR K. pneumoniae isolates were extended-spectrum β-lactamase (ESBL)-positive and carbapenemase-negative compared with 1.3% of MDR K. aerogenes. Globally, >92% of MDR K. pneumoniae isolates were resistant to amoxicillin/clavulanic acid, aztreonam, cefepime, ceftazidime or ceftriaxone. CAZ/AVI, colistin and tigecycline MIC 90 values were 1–2 mg/L against the global collection of MDR K. pneumoniae and MDR K. aerogenes. Approximately 5% (216/4555) of all MDR K. pneumoniae isolates and 1.1% (5/452) of all MDR K. aerogenes isolates were resistant to CAZ/AVI. Rates of resistance to CAZ/AVI and colistin were low for MDR, ESBL-positive, carbapenemase-negative K. pneumoniae (0.1% and 3.0%, respectively). Resistance to CAZ/AVI was highest among MDR, carbapenemase-positive, metallo-β-lactamase (MBL)-positive K. pneumoniae (98.0%), whereas colistin resistance was highest among MDR, carbapenemase-positive, MBL-negative isolates (30.2%). The results of this study suggest that CAZ/AVI, colistin and tigecycline are potential treatment options for nosocomial infections caused by MDR Klebsiella spp. isolates. [ABSTRACT FROM AUTHOR]

The aim was to investigate the activity of ceftazidime/avibactam (CAZ/AVI) against carbapenem-resistant Klebsiella pneumoniae (CRKP) and identify the resistance mechanisms before CAZ/AVI coming to Chinese market. Clinical CRKP isolates were continuously collected from 36 tertiary hospitals in China from 1 March 2017 to 31 July 2017. CAZ/AVI MICs were determined by agar dilution method. CAZ/AVI resistant isolates were submitted to whole genome sequencing. The copy number and relative expression of bla KPC were determined by quantitative PCR. A total of 872 CRKP isolates were collected, and MIC 50 and MIC 90 of CAZ/AVI were 4 and 8 mg/L. The resistant rate of CAZ/AVI was 3.7% (32/872). Among the resistant isolates, 53.1% (17/32) were metallo-β-lactamase-producing K. pneumoniae (MBL-KP), 40.6% (13/32) were Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) and 6.3% (2/32) produced both MBL and KPC. One of the KPC-KP with high level CAZ/AVI resistance (>128 mg/L) harboured mutated bla KPC-2 (D179Y). In 12 wild-type bla KPC-2 isolates, the relative copy number and expression of bla KPC-2 gene were 2.5-fold and 2.7-fold higher than that in the CAZ/AVI MIC ≤0.5 mg/L group (p < 0.05), and when added avibactam at a fixed concentration of 8 mg/L, 91.7% (11/12) isolates could restore susceptibility. Resistance against CAZ/AVI in CRKP emerged before clinical use of CAZ/AVI in China, although most of the CRKP isolates maintained the susceptibility. MBL production, bla KPC-2 point mutation and high KPC expression played an important role in CAZ/AVI resistance. [ABSTRACT FROM AUTHOR]