•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.
Clinical isolates were consecutively collected from 70 United States medical centers in 2017–2018 and susceptibility tested by reference broth microdilution methods at a central laboratory. The most ...active agents against Enterobacterales (n = 3269) were ceftazidime-avibactam (99.9% susceptible), amikacin (98.7% susceptible), meropenem (97.4% susceptible), and tigecycline (94.6% susceptible), but only ceftazidime-avibactam and tigecycline retained good activity (≥90% susceptible) against carbapenem-resistant Enterobacterales (97.5% and 92.4% susceptible, respectively). The most active agents against multidrug-resistant (MDR) Enterobacterales were ceftazidime-avibactam (99.2% susceptible) and amikacin (90.9% susceptible), whereas ceftolozane-tazobactam and meropenem were active against only 53.8% and 78.1% of these organisms, respectively. Among ESBL-producing Enterobacterales (excluding carbapenemase-producing), susceptibility rates for ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem were 100.0%, 84.1%, and 98.9%, respectively. Ceftazidime-avibactam and ceftolozane-tazobactam were very active against P. aeruginosa (n = 2215) and exhibited similar susceptibility rates (96.0% and 95.9% susceptible, respectively), including against meropenem-nonsusceptible (87.2% and 87.3% susceptible, respectively) and MDR (83.5% and 83.7% susceptible, respectively) isolates.
Abstract
Background
Zidebactam, a bicyclo-acyl hydrazide β-lactam ‘enhancer’ antibiotic, in combination with cefepime (WCK 5222) is under clinical development for the treatment of resistant ...Gram-negative infections.
Objectives
To evaluate the in vitro activity of cefepime/zidebactam and comparators against 24 220 Gram-negative bacteria.
Methods
Organisms were consecutively collected in 2018–19 from 137 medical centres located in the USA (n = 9140), Western Europe (W-EU; n = 5929), Eastern Europe (E-EU; n = 3036), the Asia-Pacific region (APAC; n = 3791) and Latin America (LATAM; n = 2324). The isolates were susceptibility tested using the broth microdilution method as part of the SENTRY Program. Cefepime/zidebactam was tested at a 1:1 ratio.
Results
Cefepime/zidebactam was highly active against Enterobacterales (MIC50/90 0.03/0.25 mg/L; 99.9% inhibited at ≤8 mg/L) and retained potent activity against carbapenem-resistant Enterobacterales (CRE) isolates (97.8% inhibited at ≤8 mg/L). CRE rates varied widely from 1.1% in the USA to 1.9% in W-EU, 3.6% in APAC and 14.6% in E-EU (3.9% overall). The most common carbapenemase genes observed overall were blaKPC (37.6% of CRE), blaOXA-48-like (30.0%) and blaNDM (23.8%). Resistance to ceftazidime/avibactam among CRE was elevated in APAC (64.8%), E-EU (25.5%) and LATAM (20.7%). Against Pseudomonas aeruginosa, cefepime/zidebactam inhibited 99.2% of isolates at ≤8 mg/L and susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam was lowest in E-EU (83.9% and 82.0%, respectively). Cefepime/zidebactam exhibited good activity against Stenotrophomonas maltophilia (80.0% inhibited at ≤8 mg/L) and Burkholderia cepacia (89.4% inhibited at ≤8 mg/L).
Conclusions
Cefepime/zidebactam demonstrated potent in vitro activity against a large worldwide collection of contemporary clinical isolates of Gram-negative bacteria.
Abstract
Objectives
To evaluate ceftazidime/avibactam resistance mechanisms among Pseudomonas aeruginosa clinical isolates and compare with isolates susceptible to this combination.
Methods
During ...2015, 2548 P. aeruginosa isolates were collected in 106 US hospitals and 46 (1.8%) were resistant to ceftazidime/avibactam. These isolates were matched with 109 ceftazidime/avibactam-susceptible isolates resistant to other antipseudomonal agents and were evaluated for the presence of β-lactam resistance mechanisms using WGS analysis and quantitative real-time PCR. Results were analysed using logistic regression comparing the isolate groups to understand the mechanisms of ceftazidime/avibactam resistance.
Results
Two isolates carried the MBLs blaVIM-1 and blaVIM-2 and another three had unique alterations or deletions in the chromosomal AmpC Ω-loop associated with ceftazidime/avibactam resistance. Overexpression of mexA (+27.4%), disruptions in ampP (+21.7%), mexR (+17.1%) and mexZ (+14.6%) and alterations in ctpA (+13.0%), dnaK (+17.8%) and ftsI (+20.8%) were significantly more prevalent among ceftazidime/avibactam-resistant isolates when compared with their susceptible counterparts independently or in combination. The combination of dnaK alterations and mexA overexpression was more common among ceftazidime/avibactam-resistant by 82×; mexR disruptions and mexA overexpression by 45×; and other two- or three-genotype interactions that included alterations/disruptions in dnaK, ftsI, nalD, mexR, mexZ and mexA overexpression by 6.5× to 34×.
Conclusions
Resistance to ceftazidime/avibactam among P. aeruginosa clinical isolates has been shown to be a complex interplay of resistance mechanisms that can affect ceftazidime and/or avibactam and some similar findings were reported in laboratory isolates exposed to ceftazidime ± avibactam.
The activities of ceftazidime-avibactam, ceftolozane-tazobactam, and comparators were evaluated for 733 isolates displaying resistance to broad-spectrum cephalosporins and carrying extended-spectrum ...β-lactamase (ESBL) genes detected by whole-genome sequencing analysis. Isolates were collected during 2017 in U.S. hospitals. The ESBL producers were 486
, 190
, and 42
isolates and isolates from 3 other species. The most common groups of ESBL-encoding genes were
-like (
= 491 isolates) and
alone (
= 168) or plus
(
= 260), followed by
-like (
162), which included
and
(104 and 51 isolates, respectively), and
and
(48 and 22 isolates, respectively). ESBL producers carried other β-lactamases, including 1
harboring
All ESBL-producing isolates were susceptible to ceftazidime-avibactam, and 90.2/83.9% (CLSI/EUCAST breakpoints) were susceptible to ceftolozane-tazobactam. Tigecycline (98.1/95.8% susceptible) and colistin (99.2%) were comparators that displayed the greatest activity against these isolates. Ceftolozane-tazobactam inhibited 91.4/83.9% of isolates carrying
-like and 97.5/95.1% of isolates carrying
-like, and its activity was more limited against the 91 isolates carrying
(66.7/61.1% susceptible). Ceftolozane-tazobactam inhibited 95.5% of the
isolates but only 83.0%, 64.3%, and 80.0% of
,
, and other species harboring ESBL-encoding genes (CLSI breakpoints), respectively. Outer membrane protein sequences for ceftolozane-tazobactam-nonsusceptible isolates did not exhibit significant differences compared to those in genetically related ceftolozane-tazobactam-susceptible isolates. Ceftazidime-avibactam was more active than other agents tested, including ceftolozane-tazobactam, and the activity of this combination was stable regardless of species or ESBL gene carried.
Lefamulin, the first semisynthetic pleuromutilin antibacterial for intravenous and oral treatment of community-acquired bacterial pneumonia (CABP), and comparators were evaluated for
activity against ...a global collection of pathogens commonly causing CABP (
= 8595) from the 2015 and 2016 SENTRY Antimicrobial Surveillance Program. Lefamulin was highly active against the pathogens
, including multidrug-resistant and extensively drug-resistant strains (MIC
for total and resistant subsets, 0.06/0.12 μg/ml; 100% inhibited at ≤1 μg/ml),
, including methicillin-resistant
(MRSA; both MIC
, 0.06/0.12 μg/ml; 99.8% and 99.6% inhibited at ≤1 μg/ml, respectively),
(MIC
, 0.5/1 μg/ml; 93.8% inhibited at ≤1 μg/ml), and
(MIC
, 0.06/0.12 μg/ml; 100% inhibited at ≤0.25 μg/ml), and its activity was unaffected by resistance to other antibacterial classes.
Among 15,588 Enterobacteriaceae isolates collected in 63 U.S. hospitals from 2012 to 2014, 2,129 (13.7%) displayed an extended-spectrum β-lactamase (ESBL) phenotype. These rates were similar over ...time (13.2 to 13.9%); however, differences among Escherichia coli (12.7 and 15.1% in 2012 and 2014; P = 0.007) and Klebsiella pneumoniae (18.9 and 15.5% in 2012 and 2014; P = 0.006) were noted when comparing 2014 and 2012. Carbapenem-resistant Enterobacteriaceae (CRE) (2.3 and 1.8%) and carbapenem-resistant K. pneumoniae (6.8 and 5.1%; P = 0.003) rates were lower in 2014 than in 2012. Isolates carrying blaCTX-M-15-like genes were stable (42.1 to 42.4%), but a decrease among E. coli isolates (59.1 and 49.7%; P = 0.008) and an increase among K. pneumoniae isolates (32.7 and 41.2%; P = 0.022) in 2014 were observed. Isolates carrying blaKPC (304) decreased over the years (16.5 and 10.9%; P = 0.008), mainly due to the decrease in K. pneumoniae isolates harboring blaKPC (n = 285; 35.6 and 28.4%; P = 0.041) in hospitals in the Mid-Atlantic and South Atlantic regions, where these isolates were highly prevalent during 2012 and 2013. Isolates carrying blaCMY-2-like and blaCTX-M-14-like genes increased (8.2 and 11.9% and 9.1 and 12.9%, respectively; P = 0.04 for both), and those producing blaSHV ESBL decreased (24.9 and 12.7%; P < 0.001) over the studied years, due to a decreased occurrence of the enzymes among K. pneumoniae isolates. Other enzymes were detected in smaller numbers of isolates, including four K. pneumoniae isolates carrying blaNDM-1 metallo-β-lactamase (two in 2012 and two in 2014). Ceftazidime-avibactam, a recently approved β-lactamase inhibitor combination, was very active against the ESBL phenotype isolates (MIC50/90, 0.12 and 1 μg/ml; 99.7% susceptible) and CRE strains (MIC50/90, 0.5 and 2 μg/ml; 98.5% susceptible) that displayed elevated MIC values for many comparator agents. In conclusion, significant changes were noted in the frequencies of isolates harboring various β-lactamases among U.S. hospitals between 2012 and 2014 that will require continued monitoring.
We evaluated trends in
antimicrobial susceptibility in U.S. hospitals in the 2010-2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth ...microdilution methods. Methicillin-resistant
(MRSA) rates decreased from 50.0% (in 2010) to 42.2% (in 2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim-sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against methicillin-susceptible
(MSSA) and MRSA (97.2% susceptible) with no marked variations.
Plazomicin was active against 97.0% of 8,783
isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all ...aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.
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