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

ABSTRACT Oxacillinases (OXA)-48-like β-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 β-lactamase (ESBL)-positive, 20.7% (350/1,690) were metallo-β-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.

Resistance to carbapenems can be mediated by production of carbapenemases belonging to Ambler class A (bla KPC and bla GES ), class B [metallo-β-lactamases (MBL)], or class D [oxacillinases (OXA)] β-lactamases (10,11).Among the resistance determinants of CREs, those carrying metallo-β-lactamases (MBLs, 36.7%),bla KPC (25.5%), and bla OXA-48- like (24.1%) have been shown to be most frequently identified as per a global study assessing distribution between 2018 and 2019 (8).Notably, the resistance mechanisms among CREs vary among the different regions, with predominance of bla NDM reported in Africa and the Middle East (AfME) and Asia Pacific (APAC), bla OXA-48-like in Europe, and bla KPC in Latin America (LATAM) and North America (8).Furthermore, CRE infections are associated with an increased risk of morbidity and mortality and higher cost (9,(12)(13)(14).Two studies assessing the cost associated with CRE infections reported a higher cost: an incidence of 15 per 100,000 costing USD 1.4 billion to the hospitals, USD 0.8 billion to third-party payers, and USD 2.8 billion in the United States (12); and a hospital-associated CRE incidence of 233 per 100,000 costed SGD 12.16 million annually based on direct costs in Singapore (13).
OXA, belonging to class D β-lactamases, are either plasmid-mediated or naturally occurring chromosomally encoded (15).There are several groups of carbapenemresistant OXA-type β-lactamases, including OXA-23-like, OXA-24/40-like, OXA-51-like, OXA-58-like, and OXA-48-like (16).The OXA-48 enzyme was first identified in Klebsiella pneumoniae in Turkey in 2001 (17).Following that, they were also reported in multiple countries in the Middle East and North Africa, which were important reservoirs for OXA-48-like Enterobacterales (18).Since then, they have been reported as the most common carbapenemases in several regions spreading to non-endemic areas, causing nosocomial outbreaks (19)(20)(21).There are currently no standard treatments against infections caused by isolates producing these carbapenemases (21,22).Furthermore, currently, these bacteria are sometimes difficult to detect due to their lower carbape nem-hydrolyzing ability as compared to other carbapenemases, and as a result, they often do not exceed the level for detection of phenotypic resistance.This delay in detection could lead to treatment errors and is possibly associated with treatment failure (21).
Although extended-spectrum cephalosporins are active against OXA-48-like enzymes, most OXA-48-like enzymes containing bacteria also carry ESBLs, making them resistant to treatment with these cephalosporins (21).Ceftazidime-avibactam (CAZ-AVI) is a combination of ceftazidime, a third-generation cephalosporin and avibactam, and a non-β-lactam β-lactamase inhibitor (23).CAZ-AVI has been shown to be active against bla OXA-48-like Enterobacterales, including those carrying ESBLs (20,21,24).However, CAZ-AVI is not active against organisms that produce MBLs (25).This activity of CAZ-AVI is attributed to the activity of avibactam against ambler class A, class C, and some class D β-lactamases but not class B (26).The addition of avibactam to ceftazidime expands the Gram-negative spectrum of activity to include multidrug-resistant (MDR) bacteria, those producing ESBLs and non-MBLs (26).
Due to the increasing incidence, limited treatment options, and challenges in detection of Enterobacterales producing OXA-48-like carbapenemases, it is important to continue monitoring the distribution and resistance patterns of these isolates to establish appropriate antibiotic stewardship strategies for the management of infections caused by these organisms.A previous study, which was a part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program, reported the distribution and susceptibility of bla OXA-48-like Enterobacterales isolates to CAZ-AVI, collected between 2012 and 2015 from Africa and the Middle East (AfME), Asia Pacific (APAC), Europe, and Latin America (LATAM).The study reported that CAZ-AVI demonstrated good activity (susceptibility 89.7%, MIC 90 >128 mg/L) against bla OXA-48-like isolates, with potent activity (susceptibility 100%, MIC 90 4 mg/L) against the MBL-negative isolates (25).The current study provides an update to the previous study and aims to evaluate the distribution and antimicrobial susceptibility of bla OXA-48-like Enterobacterales isolates collected worldwide (AfME, APAC, Europe, LATAM, and North America) in 2016-2020 from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program (27) against CAZ-AVI and a panel of comparator agents.
Our study demonstrated high susceptibility (>99.0%,Table 4) to CAZ-AVI against all the bla OXA-48-like , MBL (−), ESBL (±) and the ESBL (+), MBL (−) isolates, which was similar to the susceptibility (>99.2%)among those collected in 2012-2015 (25).In the current study, CAZ-AVI was active against all isolates of bla OXA-48-like Enterobacterales (78.6%,Table 4).Comparatively higher susceptibility to CAZ-AVI was reported in the INFORM study (89.3%-92.5%)(25).In the current study, CAZ-AVI showed very low activity (susceptibility, ≤0.3%; MIC 90 , >128 mg/L; Table S2) against bla OXA-48-like , MBL (+), ESBL (±) Enterobacterales isolates, which is expected as avibactam has no inhibitory activity against MBLs (24).However, to overcome the lack of activity of avibactam against MBL-positive Enterobacterales, the addition of aztreonam to CAZ-AVI has been proposed as a therapeutic combination (29).In line with our current finding that CAZ-AVI was active against MBL-negative isolates, the overall reduced susceptibility of all bla OXA-48-like Enterobacterales isolates to CAZ-AVI, as compared to the previous INFORM study, could be attributed to the increase in the proportion of bla OXA-48-like isolates co-carrying MBLs in the current study (25).Taken together, while CAZ-AVI still presents a potential treatment option against these isolates, the rise in the proportion of isolates co-carrying MBLs that trigger CAZ-AVI resistance is of serious concern.Among the major bla OXA-48-like variants, all isolates-carrying bla OXA-48 showed high susceptibility (91.9%) to CAZ-AVI as compared to those carrying bla OXA-232 (65.7%) and bla OXA-181 (60.2%).In the previous INFORM study, the overall susceptibility of bla OXA-48 type isolates to CAZ-AVI (92.5%) was in line with that reported in this study.However, all isolates of bla OXA-181 and 41.7% of bla OXA-232 were susceptible to CAZ-AVI in the previous study (25).Importantly, MBL-negative isolates of all the three major variants assessed in the current study showed high susceptibility (>97.6%) to CAZ-AVI.These data are corroborated by the previous INFORM study in which MBL-negative isolates of the three bla OXA-48-like variants showed high susceptibility (>99.2%) to CAZ-AVI.Notably, MBL co-carriage was high among bla OXA-232 (32.9%)-and bla OXA-181 (39.5%)-carrying isolates, indicating that the lower susceptibility to CAZ-AVI among these variants is likely due to the presence of MBL genes (Table S3).Among the comparator agents, only tigecycline (susceptibility, >94.0%;MIC 90 , 2 mg/L) and colistin (susceptibility, >78.7%;MIC 90 , ≤8 mg/L) were active against all the bla OXA-48-like isolates.These data are in agreement with those of the previous INFORM study where tigecycline (susceptibility, ≥92.5%;MIC 90 , 2 mg/L) and colistin (susceptibil ity, ≥78.7%;MIC 90 , ≤4 mg/L) were the only comparator agents active against all the bla OXA-48-like isolates (25).
In a clinical study by Caston et al., treatment with CAZ-AVI was shown to have a significantly higher clinical cure rate at 14 days than that with comparator agents (85.7% vs 34.8%) in patients infected with carbapenemase-producing Enterobacterales, where majority of the infections were associated with OXA-48 producers (30).Further more, for infections caused by OXA-48-producing Enterobacterales, salvage therapy with CAZ-AVI has been shown to have a 61.5% clinical cure rate (31).Colistin and tigecycline monotherapies and combination therapies have been used to treat infections caused by OXA-48-producing Enterobacterales (31).The 2023 Infectious Diseases Society of America (IDSA) guidance on treatment of resistant Gram-negative infections recom mends CAZ-AVI as the preferred treatment option for OXA-48-like-producing infections other than those of the urinary tract (32).Furthermore, the IDSA recommends tigecycline as an alternative treatment of infections caused by OXA-48-like-producing Enterobacter ales excluding bloodstream infections and urinary tract infections (32).On the other hand, colistin is not suggested for treatment of infections caused by CRE due to increased mortality and nephrotoxicity associated with polymyxin-based regimens (32).
This study had limitations.First, as a pre-defined number of isolates were collected from each site, the results of this study cannot be interpreted as prevalence or used for epidemiological data.Second, there was a variation in the number of participating centers between years as well as the distribution of centers in each region.Third, the β-lactamase screening criteria were altered in 2015 to exclude the characterization of isolates that tested as imipenem or doripenem non-susceptible but only merope nem-susceptible (25).Hence, some isolates that were non-susceptible to the other carbapenemases could have been excluded from the screening.Although the majority of bla OXA-48-like isolates co-carried an ESBL and isolates resistant to ceftazidime (MIC >8 µg/mL) were also screened for β-lactamase genes, some meropenem-susceptible isolates that did not co-carry ceftazidime-hydrolyzing β-lactamases could have been omitted from this analysis.
In this study, CAZ-AVI was highly active against all MBL-negative, bla OXA-48-like Enterobacterales isolates collected from 2016 to 2020 with sustained activity from the previous time period (2012)(2013)(2014)(2015).However, the overall increase in the geographic spread of bla OXA-48-like Enterobacterales and those co-carrying MBLs is concerning, especially with currently available limited treatment options.Considering the limited treatment options against OXA-48-like Enterobacterales and the challenges of toxicity and increasing resistance with tigecycline and colistin, CAZ-AVI could be considered as a potential treatment option.Routine surveillance of these clinically relevant isolates and appropriate stewardship strategies may help identify emerging resistance mechanisms and effective treatment of infections.

TABLE 2
Antimicrobial activity of CAZ-AVI and comparators against all bla OXA-48-like Enterobacterales isolates collected globally in 2016-2020 c a EUCAST breakpoints have been used.b FDA-approved breakpoints have been used.c

TABLE 4
Antimicrobial activity of CAZ-AVI and comparators against variants of bla OXA-48l-like Enterobac terales isolates collected globally in 2016-2020 c
a EUCAST breakpoints have been used.b