{"id":27033,"date":"2024-12-29T04:42:00","date_gmt":"2024-12-28T20:42:00","guid":{"rendered":"http:\/\/csccm.org.cn\/?p=27033"},"modified":"2024-12-29T05:53:35","modified_gmt":"2024-12-28T21:53:35","slug":"lancet-infect-dis%e5%8f%91%e8%a1%a8%e8%bf%b0%e8%af%84%ef%bc%9a%e9%92%88%e5%af%b9%e9%87%91%e5%b1%9e%ce%b2-%e5%86%85%e9%85%b0%e8%83%ba%e9%85%b6%e7%9a%84%e6%b2%bb%e7%96%97","status":"publish","type":"post","link":"https:\/\/csccm.org.cn\/?p=27033","title":{"rendered":"[Lancet Infect Dis\u53d1\u8868\u8ff0\u8bc4]\uff1a\u9488\u5bf9\u91d1\u5c5e\u03b2-\u5185\u9170\u80fa\u9176\u7684\u6cbb\u7597"},"content":{"rendered":"\n

COMMENT<\/strong><\/p>\n\n\n\n

REVISITing treatment of metallo-\u03b2-lactamases<\/h1>\n\n\n\n

Emily L\u00a0Heil, Erin K\u00a0McCreary<\/h3>\n\n\n\n

Lancet Infect Dis 2024 Online first October 07, 2024<\/h3>\n\n\n\n

https:\/\/doi.org\/10.1016\/S1473-3099(24)00561-9<\/h3>\n\n\n\n

Metallo-\u03b2-lactamase enzymes, named because of the presence of one or two zinc ions at the catalytic site, are responsible for \u03b2-lactam antibiotic hydrolysis and are increasing in prevalence worldwide.1<\/sup><\/a> Despite the increase in antibiotic development over the past decade, a \u03b2-lactamase inhibitor that binds to metallo-\u03b2-lactamases is not commercially available. Treatment options for metallo-\u03b2-lactamases are restricted to non-\u03b2-lactam antibiotics, cefiderocol, or the combination of ceftazidime\u2013avibactam and aztreonam.2<\/sup><\/a>Aztreonam is stable against metallo-\u03b2-lactamase-mediated hydrolysis, and avibactam inhibits most other clinically relevant \u03b2-lactamase enzymes, making this an enticing combination.<\/p>\n\n\n\n

In The Lancet Infectious Diseases<\/em>, Yehuda Carmeli and colleagues present the results of the REVISIT study,3<\/sup><\/a> a prospective, multi-national, open-label, randomised trial in which patients who were admitted to the hospital with complicated intra-abdominal infection (cIAI) or hospital-acquired or ventilator-associated pneumonia (HAP\u2013VAP), suspected or confirmed to be caused by Gram-negative bacteria, were randomised in a 2:1 ratio to aztreonam\u2013avibactam or meropenem with or without colistin. Formal hypothesis testing was not planned for the study and there was no power calculation completed a priori. 422 patients were enrolled and randomly allocated, with 271 having at least one Gram-negative pathogen identified at baseline. Only 80 isolates were tested for carbapenemases, of which 19 were positive: nine (11%) for serine carbapenemases and ten (12%) for metallo-\u03b2-lactamases (including one patient with the intrinsically metallo-\u03b2-lactamase-positive Stenotrophomonas maltophilia<\/em>). Patients were excluded if they had received more than 24 h of any systemic antibiotic within 48 h before randomisation, unless the patient had a previous systemic antibiotic treatment failure based on worsening signs and symptoms of infection or lack of improvement despite a minimum of 48 h of treatment (which occurred in 75 patients [27%] of 282 in the aztreonam\u2013avibactam group and 30 [21%] of 140 in the meropenem group).<\/p>\n\n\n\n

Most patients were not critically ill, with approximately 60% of patients in both groups having an Acute Physiology and Chronic Health Evaluation II score of 10 or under and a primary diagnosis of cIAI. Overall, 26 (19%) patients in the meropenem group received concomitant colistin; only four (1%) patients in the entire cohort received a concomitant aminoglycoside, all in the aztreonam\u2013avibactam group. In the intention-to-treat analysis cohort, the clinical cure rate at the test-of-cure visit (day 28) was 68\u00b74% in the aztreonam\u2013avibactam group and 65\u00b77% in the meropenem group (treatment difference 2\u00b77% [95% CI \u201311\u00b74 to 17\u00b78]). While a primary endpoint of clinical cure might be scrutinised in an open-label study, clinical response was assessed by a masked independent adjudication committee, resulting in an unbiased adjudication of the primary objective. Consistent with other clinical trials, patients with HAP\u2013VAP had lower clinical cure rates and a higher proportion of previous treatment failure than patients with cIAI. 28-day all-cause mortality rates were low (five [3%] of 177 for aztreonam\u2013avibactam vs<\/em> six [6 %] of 94 for meropenem) in the microbiological intention-to-treat cohort (ie, those with at least one Gram-negative pathogen identified at baseline).<\/p>\n\n\n\n

In the microbiologically evaluable analysis set with metallo-\u03b2-lactamase-positive pathogens, clinical cure rates were 50\u00b70% (two of four) and 0% (zero of one) in the aztreonam\u2013avibactam and meropenem groups, respectively. One patient with clinical failure in the aztreonam\u2013avibactam group had S maltophilia<\/em> (metallo-\u03b2-lactamase subtype L1) with an aztreonam\u2013avibactam minimum inhibitory concentration (MIC) of 2 mg\/L and a non-metallo-\u03b2-lactamase-producing Pseudomonas aeruginosa<\/em> co-infection. Another patient with clinical failure in the aztreonam\u2013avibactam group had Verona integron-encoded metallo-\u03b2-lactamase-producing Klebsiella pneumoniae<\/em> with an aztreonam\u2013avibactam MIC of 2 mg\/L. All patient isolates were within the proposed susceptibility breakpoint for aztreonam\u2013avibactam (ie, \u22644\/4 \u03bcg\/mL for Enterobacterales and \u22648\/4 \u03bcg\/mL for P aeruginosa<\/em> and S maltophilia<\/em>).4<\/sup><\/a> Notably, patients with monomicrobial P aeruginosa<\/em> infection were excluded from the study; patients with polymicrobial infections including P aeruginosa<\/em> were excluded from the clinically evaluable group. The co-formulation of aztreonam and avibactam was given at a pharmacokinetically and pharmacodynamically optimised ratio of 3:1 (1500 mg aztreonam plus 500 mg avibactam every 6 h for patients with creatinine clearance >50 mL\/min) to optimise the pharmacokinetics and pharmacodynamics of both drugs, and therefore it is unlikely that failure to achieve appropriate drug exposure contributed to clinical failure.5<\/sup><\/a><\/p>\n\n\n\n

Adverse drug events in the study were common, including relatively high rates of Clostridioides difficile<\/em> infection (8% in the aztreonam\u2013avibactam group), hypersensitivity events (13% in the aztreonam\u2013avibactam group, although none were reported to be anaphylaxis or angioedema), and mild-to-moderate liver-related adverse events (18%). Encouragingly, hepatic aminotransferase elevations were similar between groups, potentially due to the lower dose of aztreonam used compared to previous reports.6<\/sup><\/a><\/p>\n\n\n\n

Can the co-formulation of aztreonam\u2013avibactam replace the use of ceftazidime\u2013avibactam plus aztreonam in practice? A co-formulation of aztreonam\u2013avibactam provides an optimised ratio of drugs and circumvents the administration challenges of simultaneous ceftazidime\u2013avibactam plus aztreonam.7<\/sup><\/a> However, aztreonam\u2013avibactam requires two loading doses, administered sequentially over 30 min and then 3 h, with the maintenance regimen starting 3 h after the end of the second loading dose. Additionally, there might be some benefit with the addition of ceftazidime, as demonstrated in hollow-fibre infection models comparing ceftazidime\u2013avibactam plus aztreonam with aztreonam\u2013avibactam against regrowth of New Delhi metallo-\u03b2-lactamase 1-producing Enterobacteriaceae.8<\/sup><\/a> Ultimately, the small number of patients with metallo-\u03b2-lactamases in the study restricts the ability to draw conclusions about the utility of aztreonam\u2013avibactam in eradicating these difficult-to-treat pathogens. However, years of experience with the combination of ceftazidime\u2013avibactam plus aztreonam suggest this combination reduces 30-day mortality compared with colistin-based regimens in patients with carbapenem-resistant Enterobacterales infections.9<\/sup><\/a> Importantly, the data evaluating ceftazidime\u2013avibactam plus aztreonam are all observational in nature, and dosing is not standardised across studies.<\/p>\n\n\n\n

Developing a \u03b2-lactamase inhibitor for metallo-\u03b2-lactamases is challenging for numerous reasons, including structural diversity and toxicity concerns related to their similarities to human enzymes.10<\/sup><\/a>\u00a0In the interim, aztreonam\u2013avibactam might be a single drug option for culture-confirmed metallo-\u03b2-lactamase-producing monomicrobial infections.<\/p>\n\n\n\n

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COMMENT REVISITing treatment of metallo-\u03b2-lactamases Em […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27033"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=27033"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27033\/revisions"}],"predecessor-version":[{"id":27034,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27033\/revisions\/27034"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=27033"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=27033"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=27033"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}