Atrial Arrhythmias in Patients With Pulmonary Hypertension.

TOPIC IMPORTANCE: Atrial arrhythmias (AA) are common in patients with pulmonary hypertension (PH) and contribute to morbidity and mortality. Given the growing PH population, understanding the pathophysiology, clinical impact, and management of AA in PH is important. REVIEW FINDINGS: AA occurs in PH with a 5-year incidence of 10% to 25%. AA confers a higher morbidity and mortality, and restoration of normal sinus rhythm improves survival and functionality. AA is thought to develop because of structural alterations of the right atrium caused by changes to the right ventricle (RV) due to elevated pulmonary artery pressures. AA can subsequently worsen RV function. Current guidelines do not provide comprehensive recommendations for the management of AA in PH. Robust evidence to favor a specific treatment approach is lacking. Although the role of medical rate or rhythm control, and the use of cardioversion and ablation, can be inferred from other populations, evidence is lacking in the PH population. Much remains to be determined regarding the optimal management strategy. We present here our institutional approach and discuss areas for future research. SUMMARY: This review highlights the epidemiology and pathophysiology of AA in patients with PH, describes the relationship between AA and RV dysfunction, and discusses current management practices. We outline our institutional approach and offer directions for future investigation.

In vitro activity of ceftazidime-avibactam and comparators against OXA-48-like Enterobacterales collected between 2016 and 2020.

Oxacillinases (OXA)-48-like ß-lactamases are one of the most common resistance determinants among carbapenem-resistant Enterobacterales reported globally. Moreover, there is no standard treatment available against organisms producing OXA-48-like enzymes, and they are sometimes difficult to detect, making treatment challenging. The objective of this study was to evaluate the distribution and antimicrobial susceptibility of blaOXA-48-like Enterobacterales isolates against ceftazidime-avibactam (CAZ-AVI) and a panel of comparators collected worldwide from 2016 to 2020 as a part of the Antimicrobial Testing Leadership and Surveillance program. Among all the Enterobacterales isolates collected, 1.8% (1,690/94,052) carried blaOXA-48-like, and a majority of those were identified as K. pneumoniae (86.5%, 1,462/1,690). Among all the blaOXA-48-like isolates, 88.9% (1,502/1,690) were extended-spectrum ß-lactamase (ESBL)-positive, 20.7% (350/1,690) were metallo-ß-lactamase (MBL)-positive, and 8.9% (150/1,690) were ESBL- and MBL-negative. There were 10 different variants of the OXA-48-like family of enzymes detected, with the major variant being blaOXA-48 (50.2%, 848/1,690), blaOXA-232 (29.3%, 496/1,690), and blaOXA-181 (18.0%, 304/1,690). Overall, all the blaOXA-48-like isolates showed a susceptibility of 78.6% to CAZ-AVI. Importantly, high susceptibility to CAZ-AVI was shown by all the blaOXA-48 type, MBL-negative isolates (n = 1,380, ≥99.0%), and all the MBL-negative isolates (n = 1,300, ≥97.6%) of the major variants (blaOXA-48, blaOXA-232, and blaOXA-181) studied. Among the comparator agents, all isolates showed good susceptibility to only tigecycline (>95.0%) and colistin (>78.6%). Considering the limited treatment options available, CAZ-AVI could be considered as a potential treatment option against blaOXA-48-like Enterobacterales. However, routine surveillance and appropriate stewardship strategies for these organisms may help identify emerging resistance mechanisms and effective treatment of infections. IMPORTANCE: Resistance to carbapenems among Enterobacterales is often due to the production of enzymes that are members of the oxacillinases (OXA)-48-like family. These organisms can also be resistant to other classes of drugs and are difficult to identify and treat. This study evaluated the activity of the drug ceftazidime-avibactam (CAZ-AVI) and other comparator agents against a global collection of Enterobacterales that produce OXA-48-like enzymes. CAZ-AVI was active against blaOXA-48-like Enterobacterales, and only colistin and tigecycline were similarly active among the comparator agents, highlighting the limited treatment options against these organisms. Continued surveillance of the distribution of these OXA 48-like producing Enterobacterales and monitoring of resistance patterns along with the implementation of antimicrobial stewardship measures to guide antibiotic use and appropriate treatment are necessary to avoid drug resistance among these organisms.

Systematic review of the effect of metabolic syndrome on outcomes due to acute respiratory distress syndrome: a protocol.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a life-threatening condition commonly seen in the intensive care unit. COVID-19 has dramatically increased the incidence of ARDS-with this rise in cases comes the ability to detect predisposing factors perhaps not recognised before, such as metabolic syndrome (MetS) and its associated conditions (hypertension, obesity, dyslipidaemia and type 2 diabetes mellitus). In this systematic review, we seek to describe the complex relationship between MetS, its associated conditions and ARDS (including COVID-19 ARDS). METHODS AND ANALYSIS: A systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL and Web of Science will be conducted. The population of interest is adults with ARDS and MetS (as defined according to the study author recognising that MetS definitions vary) or any MetS-associated condition. The control group will be adult patients with ARDS without MetS or any individual MetS-associated condition. We will search studies published in English, with a date restriction from the year 2000 to June 2023 and employ the search phrases 'metabolic syndrome', 'acute respiratory distress syndrome' and related terms. Search terms including 'dyslipidaemia', 'hypertension', 'diabetes mellitus' and 'obesity' will also be utilised. Outcomes of interest will include mortality (in-hospital, ICU, 28-day, 60-day and 90-day), days requiring mechanical ventilation and hospital and/or ICU length of stay. Study bias will be assessed using the NIH Bias Scale. ETHICS AND DISSEMINATION: Ethical approval is not required because this study includes previously published and publicly accessible data. Findings from this review will be disseminated via publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023405816.

Systematic review of ceftaroline fosamil in the management of patients with methicillin-resistant Staphylococcus aureus pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for an array of problematic community- and healthcare-acquired infections, including pneumonia, and is frequently associated with severe disease and high mortality rates. Standard recommended treatments for empiric and targeted coverage of suspected MRSA in patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), are vancomycin and linezolid. However, adverse events such as acute kidney injury and Clostridium difficile infection have been associated with these antibiotics. Ceftaroline fosamil is a ß-lactam/extended-spectrum cephalosporin approved for the treatment of adults and children with CAP and complicated skin and soft tissue infections. Ceftaroline has in vitro activity against a range of common Gram-positive bacteria and is distinct among the ß-lactams in retaining activity against MRSA. Due to the design of the pivotal randomised controlled trials of ceftaroline fosamil, outcomes in patients with MRSA CAP were not evaluated. However, various reports of real-world outcomes with ceftaroline fosamil for pneumonia caused by MRSA, including CAP and HAP/VAP, been published since its approval. A systematic literature review and qualitative analysis of relevant publications was undertaken to collate and summarise relevant published data on the efficacy and safety of ceftaroline fosamil in patients with MRSA pneumonia. While relatively few real-world outcomes studies are available, the available data suggest that ceftaroline fosamil is a possible alternative to linezolid and vancomycin for MRSA pneumonia. Specific scenarios in which ceftaroline fosamil might be considered include bacteraemia and complicating factors such as empyema.

Efficacy and safety of ceftazidime/avibactam in patients with infections caused by ß-lactamase-producing Gram-negative pathogens: a pooled analysis from the Phase 3 clinical trial programme.

OBJECTIVES: This post hoc pooled analysis evaluated clinical and microbiological outcomes and safety in patients with infections caused by ß-lactamase-producing Gram-negative pathogens across five Phase 3, randomized, controlled, multicentre trials of ceftazidime/avibactam in adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis and nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP). METHODS: In each trial, RECLAIM/RECLAIM 3 (cIAI), REPRISE (cIAI/cUTI), RECAPTURE (cUTI) and REPROVE (NP, including VAP) patients were randomized 1:1 to IV ceftazidime/avibactam (plus metronidazole for patients with cIAI) or comparators (carbapenems in >97% patients) for 5-21 days. Clinical and microbiological responses at the test-of-cure visit were assessed for patients with ESBLs, and/or plasmidic and/or overexpression of chromosomal AmpC, and/or serine carbapenemases without MBLs identified in baseline Gram-negative isolates by phenotypic screening and molecular characterization in the pooled microbiological modified ITT (mMITT) population. RESULTS: In total, 813 patients (ceftazidime/avibactam, n = 389; comparator, n = 424) had ≥1 ß-lactamase-producing baseline pathogen identified, amongst whom 792 patients (ceftazidime/avibactam, n = 379; comparator, n = 413) had no MBLs. The most frequent ß-lactamase-producing pathogens across treatment groups were Escherichia coli (n = 381), Klebsiella pneumoniae (n = 261) and Pseudomonas aeruginosa (n = 53). Clinical cure rates in the pooled non-MBL ß-lactamase-producing mMITT population were 88.1% (334/379) for ceftazidime/avibactam and 88.1% (364/413) for comparators; favourable microbiological response rates were 76.5% (290/379) and 68.8% (284/413), respectively. The safety profile of ceftazidime/avibactam was consistent with previous observations. CONCLUSIONS: This analysis provides supportive evidence of the efficacy and safety of ceftazidime/avibactam in patients with infections caused by ESBLs, AmpC and serine carbapenemase-producing Gram-negative pathogens. TRIAL REGISTRATION: NCT01499290; NCT01726023; NCT01644643; NCT01595438/NCT01599806; NCT01808092.

Ceftazidime-avibactam and comparators against Pseudomonas aeruginosa isolates collected globally and in each geographical region between 2017-2020.

OBJECTIVES: The objective of this study was to assess the distribution and antimicrobial susceptibility of Pseudomonas aeruginosa isolates against ceftazidime-avibactam (CAZ-AVI) and a panel of comparator agents collected globally and in each region from 2017-2020 from the Antimicrobial Testing Leadership and Surveillance program. METHODS: Susceptibility and minimum inhibitory concentration of all P. aeruginosa isolates were determined using broth microdilution methodology according to the Clinical and Laboratory Standards Institute guidelines. RESULTS: Of the total 29746 isolates of P. aeruginosa collected, 20.9% were multidrug resistant (MDR), 20.7% were extremely drug resistant (XDR), 8.4% were CAZ-AVI-resistant (CAZ-AVI-R), and 3.0% were MBL-positive. Amongst the MBL-positive isolates, the proportion of VIM-positive isolates was highest (77.8%). The highest proportion of MDR (25.5%), XDR (25.0%), MBL-positive (5.7%), and CAZ-AVI-R (12.3%) isolates were in Latin America. Amongst the sources, the highest proportion of isolates were from respiratory sources (43.0%), and the majority of isolates were from non-intensive care unit wards (71.2%). Overall, all P. aeruginosa isolates (90.9%) showed high susceptibility to CAZ-AVI. However, MDR and XDR isolates were less susceptible to CAZ-AVI (≤60.7). The only comparators to which all isolates of P. aeruginosa showed good overall susceptibility were colistin (99.1%) and amikacin (90.5%). However, only colistin was active (≥98.3%) against all the resistant isolates. CONCLUSION: CAZ-AVI presents a potential treatment option against P. aeruginosa infections. However, active monitoring and surveillance, especially of the resistant phenotypes, is warranted for effective treatment of infections caused by P. aeruginosa.

Determination of MIC Quality Control Ranges for Ceftibuten-Avibactam (Fixed 4 µg/mL), a Novel ß-Lactam/ß-Lactamase Inhibitor Combination.

Ceftibuten/ARX-1796 (avibactam prodrug) is a novel oral antibacterial combination in early clinical development for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis. ARX-1796 is the novel avibactam prodrug being combined with ceftibuten for oral dosing that is converted to active avibactam in vivo. A Clinical and Laboratory Standards Institute (CLSI) M23 (2018) tier 2 broth microdilution quality control (QC) study was conducted with ceftibuten-avibactam to establish MIC QC ranges. Ceftibuten-avibactam broth microdilution QC ranges were approved for Escherichia coli ATCC 25922 (0.016/4 to 0.12/4 µg/mL), E. coli NCTC 13353 (0.03/4 to 0.12/4 µg/mL), Klebsiella pneumoniae ATCC 700603 (0.06/4 to 0.25/4 µg/mL), K. pneumoniae ATCC BAA-1705 (0.03/4 to 0.25/4 µg/mL), and K. pneumoniae ATCC BAA-2814 (0.12/4 to 0.5/4 µg/mL) by the CLSI Subcommittee on Antimicrobial Susceptibility Testing in January 2022. Approved ceftibuten-avibactam QC ranges will support future clinical development, device manufacturers, and routine patient care.

Incidence of ESBLs and carbapenemases among Enterobacterales and carbapenemases in Pseudomonas aeruginosa isolates collected globally: results from ATLAS 2017-2019.

OBJECTIVES: To assess the global and regional distribution of ESBLs in Enterobacterales and carbapenemases in Enterobacterales and Pseudomonas aeruginosa. METHODS: Antimicrobial susceptibility of isolates collected from ATLAS (2017-2019) was determined per CLSI guidelines. Enterobacterales exhibiting meropenem MICs ≥2 mg/L and/or ceftazidime/avibactam and/or aztreonam/avibactam MICs ≥16 mg/L, Escherichia coli and Klebsiella pneumoniae with aztreonam and/or ceftazidime MICs ≥2 mg/L, and P. aeruginosa with meropenem MICs ≥4 mg/L were screened for ß-lactamases by PCR and sequencing. RESULTS: Globally, ESBL-positive E. coli (23.7%, 4750/20047) and K. pneumoniae (35.1%, 6055/17229) carried predominantly the CTX-M-15 variant (E. coli: 53.9%; K. pneumoniae: 80.0%) with highest incidence in Africa/Middle East (AfME). Among carbapenem-resistant (CR) E. coli (1.1%, 217/20047) and Enterobacter cloacae (3.8%, 259/6866), NDMs were predominant (E. coli in AfME: 62.5%; E. cloacae in Asia Pacific: 59.7%). CR K. pneumoniae (13.3%, 2299/17 229) and P. aeruginosa (20.3%, 4187/20 643) carried predominantly KPC (30.9%) and VIM (14.7%), respectively, with highest frequency in Latin America. Among ESBL-positive Enterobacterales, susceptibility to ceftazidime/avibactam (>90.0%) and amikacin (>85.0%) was higher than to piperacillin/tazobactam (>45.0%) and ciprofloxacin (>7.4%). In CR Enterobacterales, susceptibility to amikacin (>54.0%) and ceftazidime/avibactam (>31.0%) was higher than to ciprofloxacin (>2.7%) and piperacillin/tazobactam (>0.5%). CR P. aeruginosa similarly demonstrated higher susceptibility to amikacin (63.4%) and ceftazidime/avibactam (61.9%) than to ciprofloxacin (26.2%) and piperacillin/tazobactam (25.3%). CONCLUSIONS: Varied distribution of resistance genotypes across regions among ESBL-positive Enterobacterales and CR Enterobacterales and P. aeruginosa provide crucial insights on major resistance mechanisms and trends observed in recent years. Continued surveillance is warranted for monitoring global dissemination and resistance.

Epidemiology of Resistance Determinants Identified in Meropenem-Nonsusceptible Enterobacterales Collected as Part of a Global Surveillance Study, 2018 to 2019.

The objective of this study was to describe the frequency of resistance determinants in meropenem-nonsusceptible (MEM-NS) Enterobacterales isolates collected in 2018 and 2019 as a part of the ATLAS global surveillance program. Among a total of 39,368 Enterobacterales isolates collected in 2018 and 2019, 5.7% were MEM-NS (MIC ≥2 µg/mL). Among the different regions, the proportion of MEM-NS isolates ranged from 1.9% (North America) to 8.4% (Asia/Pacific). The majority of MEM-NS isolates collected were of the species Klebsiella pneumoniae (71.5%). Among the MEM-NS Enterobacterales isolates collected, metallo-ß-lactamases (MBL) were identified in 36.7%, KPC in 25.5%, and OXA-48-like in 24.1%. The predominance of resistance mechanisms among MEM-NS isolates varied by region: MBLs were dominant in isolates collected in Africa and Middle East (AfME, 49%) and Asia/Pacific (59.4%), OXA-48-like carbapenemases were predominant in Europe (30%), and KPC in Latin America (51.9%) and North America (53.6%). NDM ß-lactamases accounted for the majority of MBLs identified (88.4%). Of the 38 carbapenemase variants identified, NDM-1 (68.7%), KPC-2 (54.6%), OXA-48 (54.3%), and VIM-1 (76.1%) were the common variants within their respective families. Among the MEM-NS isolates, 7.9% co-carried two carbapenemases. Notably, the proportion of MEM-NS Enterobacterales increased from 4.9% in 2018 to 6.4% in 2019. The results of this study show a continuation of the trend of increasing carbapenem-resistance within clinical Enterobacterales with mechanisms of resistance varying across different regions. The existential threat to public health posed by the continued spread of nearly untreatable pathogens requires a multifaceted approach to prevent the collapse of modern medicine.

The primary pharmacology of ceftazidime/avibactam: microbiology from clinical studies, and development of resistance during treatment.

As one of a series of thematically linked reviews of the primary pharmacology of the ß-lactam/ß-lactamase inhibitor combination, ceftazidime/avibactam, this article reviews the microbiological findings in drug-exposed patients. Earlier articles in the series focused on basic in vitro and in vivo translational biology (J Antimicrob Chemother 2022; 77: 2321-40 and 2341-52) and the development and mechanisms of resistance in vitro (J Antimicrob Chemother 2023: Epub ahead of print. doi: 10.1093/jac/dkac449). In clinical trials of ceftazidime/avibactam, combined favourable microbiological responses for evaluable patients infected at baseline by susceptible Enterobacterales or Pseudomonas aeruginosa were 86.1% (851/988). The corresponding percent favourable among patients infected by ceftazidime/avibactam-resistant pathogens was 58.8% (10/17), noting that the majority (15/17) of the resistant examples were P. aeruginosa. Microbiological response rates to comparator treatments in the same clinical trials ranged between 64% and 95%, depending on the type of infection and the analysis population. Uncontrolled case studies over a wide range of patients infected by antibiotic multiresistant Gram-negative bacteria have demonstrated that ceftazidime/avibactam can elicit microbiological clearance of ceftazidime/avibactam-susceptible strains. In case studies where a matched cohort of patients had been treated with antibacterial agents other than ceftazidime/avibactam, microbiological outcomes were comparable between treatments, mostly being observationally more favourable for ceftazidime/avibactam (recognizing that numbers were too small for definitive superiority assessments). Development of resistance to ceftazidime/avibactam during therapy is reviewed. The phenomenon has been reported multiple times, mostly in difficult-to-treat patients infected by KPC-producing Enterobacterales. Molecular mechanisms, when determined, have frequently been observed previously in vitro, such as the 'Ω-loop' D179Y (Asp179Tyr) substitution found in KPC variant enzymes. In human volunteers exposed to therapeutic levels of ceftazidime/avibactam, faecal numbers of Escherichia coli, other enterobacteria, lactobacilli, bifidobacteria, clostridia and Bacteroides spp. decreased. Clostridioides difficile was detected in the faeces, but this was of uncertain significance, because no unexposed controls were studied.

The Use and Effectiveness of Ceftazidime-Avibactam in Real-World Clinical Practice: EZTEAM Study.

INTRODUCTION: Ceftazidime-avibactam has proven activity against multidrug-resistant (MDR) bacteria in clinical trials and real-world studies. This study was conducted to describe the patterns of use of ceftazidime-avibactam (including indications and associated antibiotics), and the effectiveness and safety of ceftazidime-avibactam in real-world clinical practice. METHODS: This non-interventional medical chart review study was conducted in 11 countries across the European and Latin American (LATAM) regions. Consecutive patients treated in clinical practice with at least one dose of ceftazidime-avibactam for an approved indication per country label since 01 January 2018 (or launch date in the country if posterior) were enrolled. Effectiveness analyses were conducted in patients treated with ceftazidime-avibactam for at least 72 h. RESULTS: Of the 569 eligible patients enrolled, 516 (90.7%) were treated for at least 72 h (354 patients from Europe and 162 patients from LATAM); 390 patients (75.7%) had switched from another antibiotic line for Gram-negative coverage. Infection sources were intra-abdominal, urinary, respiratory, bloodstream infections, and other infections (approximately 20% each). K. pneumoniae was the most common microorganism identified in the latest microbiological evaluation before starting ceftazidime-avibactam (59.3%). Two-thirds of microorganisms tested for susceptibility were MDR, of which 89.3% were carbapenem-resistant. The common MDR mechanisms for K. pneumoniae were carbapenemase (33.9%), oxacillinase 48 (25.2%), extended-spectrum beta-lactamase (21.5%), or metallo-beta-lactamase (14.2%) production. Without prior patient exposure, 17 isolates (mostly K. pneumoniae) were resistant to ceftazidime-avibactam. Treatment success was achieved in 77.3% of patients overall (88.3% among patients with urinary infection), regardless of first or second treatment line. In-hospital mortality rate was 23.1%. Adverse events were reported for six of the 569 patients enrolled. CONCLUSION: This study provides important real-world evidence on treatment patterns, effectiveness, and safety of ceftazidime-avibactam in clinical practice through its recruitment in the European and LATAM regions. Ceftazidime-avibactam is one of the antibiotics to consider for treatment of MDR bacteria. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03923426.

The primary pharmacology of ceftazidime/avibactam: resistance in vitro.

This article reviews resistance to ceftazidime/avibactam as an aspect of its primary pharmacology, linked thematically with recent reviews of the basic in vitro and in vivo translational biology of the combination (J Antimicrob Chemother 2022; 77: 2321-40 and 2341-52). In Enterobacterales or Pseudomonas aeruginosa, single-step exposures to 8×  MIC of ceftazidime/avibactam yielded frequencies of resistance from <∼0.5 × 10-9 to 2-8 × 10-9, depending on the host strain and the ß-lactamase harboured. ß-Lactamase structural gene mutations mostly affected the avibactam binding site through changes in the Ω-loop: e.g. Asp179Tyr (D179Y) in KPC-2. Other mutations included ones proposed to reduce the permeability to ceftazidime and/or avibactam through changes in outer membrane structure, up-regulated efflux, or both. The existence, or otherwise, of cross-resistance between ceftazidime/avibactam and other antibacterial agents was also reviewed as a key element of the preclinical primary pharmacology of the new agent. Cross-resistance between ceftazidime/avibactam and other ß-lactam-based antibacterial agents was caused by MBLs. Mechanism-based cross-resistance was not observed between ceftazidime/avibactam and fluoroquinolones, aminoglycosides or colistin. A low level of general co-resistance to ceftazidime/avibactam was observed in MDR Enterobacterales and P. aeruginosa. For example, among 2821 MDR Klebsiella spp., 3.4% were resistant to ceftazidime/avibactam, in contrast to 0.07% of 8177 non-MDR isolates. Much of this was caused by possession of MBLs. Among 1151 MDR, XDR and pandrug-resistant isolates of P. aeruginosa from the USA, 11.1% were resistant to ceftazidime/avibactam, in contrast to 3.0% of 7452 unselected isolates. In this case, the decreased proportion susceptible was not due to MBLs.

In Vitro Activity of Ceftibuten-Avibactam against ß-Lactamase-Positive Enterobacterales from the ATLAS Global Surveillance Program.

Ceftibuten is an established, oral, third-generation cephalosporin in early clinical development in combination with an oral prodrug of avibactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. We evaluated the in vitro activity of ceftibuten-avibactam against 1,165 Enterobacterales isolates selected from the 2016-2020 ATLAS global surveillance program based upon their ß-lactamase genotype, ß-lactam-susceptible phenotype, species identification, and specimen source (95.8% urine). MICs were determined by CLSI broth microdilution. Avibactam was tested at a fixed concentration of 4 µg/mL. Molecular methods were used to identify ß-lactamase genes. Ceftibuten-avibactam inhibited 90% (MIC90) of ESBL-producing (n = 645), KPC-producing (n = 60), chromosomal AmpC-positive (n = 100), OXA-48-like-producing (n = 50), and acquired AmpC-producing (n = 110) isolates at concentrations of 0.12, 0.5, 1, 2, and 4 µg/mL, respectively. At concentrations of ≤1 and ≤8 µg/mL, ceftibuten-avibactam inhibited 98.4 and 99.2% of ESBL-positive isolates; 96.7 and 100% of KPC-positive isolates; 91.0 and 99.0% of chromosomal AmpC-positive isolates; 86.0 and 96.0% of OXA-48-like-positive isolates; and 85.5 and 91.8% of acquired AmpC-positive isolates. Against ESBL-producing, KPC-producing, chromosomal AmpC-positive, OXA-48-like-producing, and acquired AmpC-producing isolates, ceftibuten-avibactam was 256-, 128-, >64-, >32-, and > 16-fold more potent than ceftibuten alone. The potency of ceftibuten-avibactam was 4-fold greater than ceftazidime-avibactam against ESBL-producing (ceftibuten-avibactam MIC90, 0.12 µg/mL; ceftazidime-avibactam MIC90, 0.5 µg/mL) and KPC-producing (0.5 µg/mL; 2 µg/mL) isolates, equivalent to ceftazidime-avibactam (MIC90, 2 µg/mL) against OXA-48-like-producing isolates, 2-fold less active than ceftazidime-avibactam (1 µg/mL; 0.5 µg/mL) against chromosomal AmpC-positive isolates, and 4-fold less active than ceftazidime-avibactam (4 µg/mL; 1 µg/mL) against acquired AmpC-producing isolates. Continued development of ceftibuten-avibactam appears justified.

Antimicrobial Activity of Ceftazidime-Avibactam and Comparators Against Fluoroquinolone-Resistant Klebsiella pneumoniae Collected Globally from Antimicrobial Testing Leadership and Surveillance: 2018-2019.

This study assessed the in vitro antimicrobial activity of ceftazidime-avibactam (CAZ-AVI) and a panel of comparator agents, including aztreonam, cefepime, ceftazidime, meropenem, imipenem, colistin, piperacillin-tazobactam, and tigecycline against isolates of fluoroquinolone-resistant (FQ-R) Klebsiella pneumoniae collected in 2018 and 2019 from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Susceptibility and minimum inhibitory concentration were determined using broth microdilution for all antimicrobial agents by a central reference laboratory according to the Clinical and Laboratory Standards Institute guidelines and European Committee on Antimicrobial Susceptibility Testing guidelines. Of all the K. pneumoniae isolates (n = 10,906), 44.1% (4,814/10,906) were FQ-R. Of these, 71.3% (3,432/4,814) were extended-spectrum ß-lactamase (ESBL)-positive, and 10.4% (499/4,814) were CAZ-AVI-resistant. CAZ-AVI showed high susceptibility (>87%) against all the FQ-R K. pneumoniae isolates. However, metallo- ß-lactamase-positive isolates showed low susceptibility (3.8%; 18/470) to CAZ-AVI. Among the different geographical regions, CAZ-AVI showed the highest activity against isolates collected from North America (98.2%, 216/220) and lowest against those collected from Asia Pacific (APAC) (81.7%; 882/1,079). Among comparator agents, carbapenems showed a relatively lower susceptibility (<71.5%), while only tigecycline and colistin were active (>85%) across all isolates. In conclusion, CAZ-AVI may be a potential treatment option for FQ-R K. pneumoniae isolates. However, increasing CAZ-AVI resistance among ESBL-positive and metallo-ß-lactamase-positive isolates and in isolates from APAC warrants continuous surveillance.

Ceftazidime-avibactam activity against Gram-negative respiratory isolates collected between 2018 and 2019.

OBJECTIVES: The objective of this study was to assess the in vitro activity of ceftazidime-avibactam (CAZ-AVI) and a panel of comparator agents against isolates of Enterobacter spp., Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa collected in 2018 and 2019 by different centres worldwide from patients with respiratory tract infections. METHODS: Susceptibility and minimum inhibitory concentration (MIC) of all organisms were determined using broth microdilution methodology for CAZ-AVI, and a panel of comparator antimicrobial agents by a central reference laboratory according to Clinical and Laboratory Standards Institute guidelines and European Committee on Antimicrobial Susceptibility Testing guidelines. RESULTS: CAZ-AVI demonstrated potent antimicrobial activity against isolates of Enterobacter spp. (97.6% susceptibility, MIC90, 1 µg/ml), E. coli (98.5% susceptibility, MIC90, 0.25 µg/ml), K. pneumoniae (94.7% susceptibility, MIC90 2 µg/ml), and P. aeruginosa (91.2% susceptibility, MIC90 8 µg/ml). CAZ-AVI was also active (susceptibility >85%) against MDR isolates for all organisms except P. aeruginosa. Only a small proportion (<10%) of all isolates of Enterobacter spp. and E. coli were identified as XDR compared to isolates of K. pneumoniae and P. aeruginosa isolates (>20%). Susceptibility to CAZ-AVI was high (>70%) among XDR isolates of Enterobacter spp., K. pneumoniae, and E. coli, compared to P. aeruginosa (<70%). Among the comparator agents, only colistin showed consistent activity across all the organisms (>85%). CONCLUSION: Gram-negative respiratory isolates collected in 2018-2019 showed high susceptibility to CAZ-AVI; CAZ-AVI represents a potential treatment option against infection caused by these organisms.

Pregnancy-Onset Ulcerative Colitis in a Pediatric Patient Presenting With Altered Mental Status and Severe Anemia.

Ulcerative colitis (UC) classically presents with abdominal pain, hematochezia, or diarrhea. However, it can present atypically in pediatric and pregnant patients, posing a diagnostic challenge. A healthy, 16-year-old primigravida presented at 18 weeks and six days of gestation with sudden-onset altered mental status and severe anemia. Hematochezia began about 12 hours after admission. She underwent extensive workup, leading to an endoscopic and histopathologic diagnosis of UC, and achieved prenatal remission with high-dose steroids and infliximab. Her pregnancy, however, was complicated by severe preeclampsia, and her child's post-delivery course was medically complex from an unrelated etiology. Pregnancy-onset inflammatory bowel disease (IBD) in the pediatric population is an uncommon but important consideration. Early diagnosis, treatment, and counseling are vital to achieve results comparable to those of patients without IBD.

Carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa causing infection in Africa and the Middle East: a surveillance study from the ATLAS programme (2018-20).

Objectives: To determine the in vitro susceptibility of Enterobacterales (n = 5457) and Pseudomonas aeruginosa (n = 1949) isolated from hospitalized patients in Africa (three countries) and the Middle East (five countries) in 2018-20 to a panel of 11 antimicrobials and to identify ß-lactamase/carbapenemase genes in isolates with meropenem-non-susceptible and/or ceftazidime/avibactam-resistant phenotypes. Methods: CLSI broth microdilution testing generated MICs that were interpreted using CLSI (2021) breakpoints. ß-Lactamase/carbapenemase genes were identified using multiplex PCR assays. Results: Enterobacterales isolates were highly susceptible to amikacin (96.7%), ceftazidime/avibactam (96.6%) and tigecycline (96.0%), and slightly less susceptible to meropenem (94.3%). In total, 337 Enterobacterales isolates (6.2% of all Enterobacterales isolates) carried one or more carbapenemase genes: 188 isolates carried a serine carbapenemase (178 OXA, 10 KPC) and 167 isolates carried an MBL (18 isolates carried both an MBL and an OXA). NDM-1 was the most common MBL identified (64.1% of NDM enzymes; 59.9% of all MBLs). OXA-48 (47.8%) and OXA-181 (38.8%) were the most common OXAs detected. P. aeruginosa isolates were most susceptible to ceftazidime/avibactam (89.1%) and amikacin (88.9%). Only 73.1% of P. aeruginosa isolates were meropenem susceptible. The majority (68.1%) of P. aeruginosa isolates tested for carbapenemase/ß-lactamase genes were negative. In total, 88 isolates (4.5% of all P. aeruginosa isolates) carried one or more carbapenemase genes: 81 isolates carried an MBL and 8 carried a GES carbapenemase (1 isolate carried genes for both). Conclusions: Carbapenemase detection was closely associated with meropenem-non-susceptible phenotypes for Enterobacterales (89.1%) but not for P. aeruginosa (24.2%). Wide geographic variation in carbapenemase type and frequency of detection was observed.

The primary pharmacology of ceftazidime/avibactam: in vitro translational biology.

Previous reviews of ceftazidime/avibactam have focused on in vitro molecular enzymology and microbiology or the clinically associated properties of the combination. Here we take a different approach. We initiate a series of linked reviews that analyse research on the combination that built the primary pharmacology data required to support the clinical and business risk decisions to perform randomized controlled Phase 3 clinical trials, and the additional microbiological research that was added to the above, and the safety and chemical manufacturing and controls data, that constituted successful regulatory licensing applications for ceftazidime/avibactam in multiple countries, including the USA and the EU. The aim of the series is to provide both a source of reference for clinicians and microbiologists to be able to use ceftazidime/avibactam to its best advantage for patients, but also a case study of bringing a novel ß-lactamase inhibitor (in combination with an established ß-lactam) through the microbiological aspects of clinical development and regulatory applications, updated finally with a review of resistance occurring in patients under treatment. This first article reviews the biochemistry, structural biology and basic microbiology of the combination, showing that avibactam inhibits the great majority of serine-dependent ß-lactamases in Enterobacterales and Pseudomonas aeruginosa to restore the in vitro antibacterial activity of ceftazidime. Translation to efficacy against infections in vivo is reviewed in the second co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2341-52).

The primary pharmacology of ceftazidime/avibactam: in vivo translational biology and pharmacokinetics/pharmacodynamics (PK/PD).

This review describes the translational in vivo and non-clinical pharmacokinetics/pharmacodynamics (PK/PD) research that supported clinical trialling and subsequently licensing approval of ceftazidime/avibactam, a new ß-lactam/ß-lactamase inhibitor combination aimed at the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. The review thematically follows on from the co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2321-40). Avibactam protected ceftazidime in animal models of infection with ceftazidime-resistant, ß-lactamase-producing bacteria. For example, a single subcutaneous dose of ceftazidime at 1024 mg/kg yielded little effect on the growth of ceftazidime-resistant, blaKPC-2-carrying Klebsiella pneumoniae in the thighs of neutropenic mice (final counts of 4 × 108 to 8 × 108 cfu/thigh). In contrast, co-administration of avibactam in a 4:1 ratio (ceftazidime:avibactam) was bactericidal in the same model (final counts of 2 × 104 to 3 × 104 cfu/thigh). In a rat abdominal abscess model, therapy with ceftazidime or ceftazidime/avibactam (4:1 w/w) against blaKPC-2-positive K. pneumoniae resulted in 9.3 versus 3.3 log cfu/abscess, respectively, after 52 h. With respect to PK/PD, in Monte Carlo simulations, attainment of unbound drug exposure targets (ceftazidime fT>8 mg/L and avibactam fT>1 mg/L, each for 50% of the dosing interval) for the labelled dose of ceftazidime/avibactam (2 and 0.5 g, respectively, q8h by 2 h IV infusion), including dose adjustments for patients with impaired renal function, ranged between 94.8% and 99.6% of patients, depending on the infection modelled.