We evaluated the activity of meropenem-vaborbactam against contemporary nonfastidious Gram-negative clinical isolates, including
isolates with resistance phenotypes and carbapenemase genotypes. ...Meropenem-vaborbactam (inhibitor at 8 μg/ml) and comparators were susceptibility tested by reference broth microdilution methods against 14,304 Gram-negative clinical isolates collected worldwide during 2014. Carbapenemase-encoding genes were screened by PCR and sequencing. Meropenem-vaborbactam (MIC
, ≤0.015/0.06 μg/ml) inhibited 99.1 and 99.3% of the 10,426
isolates tested at ≤1 and ≤2 μg/ml, respectively. Meropenem inhibited 97.3 and 97.7% of these isolates at the same concentrations. Against
isolates displaying carbapenem-resistant
(CRE) (
= 265), multidrug-resistant (MDR) (
= 1,210), and extensively drug-resistant (XDR) (
= 161) phenotypes, meropenem-vaborbactam displayed MIC
values of 0.5/32, 0.03/1, and 0.5/32 μg/ml, respectively, whereas meropenem activities were 16/>32, 0.06/32, and 0.5/32 μg/ml, respectively. Among all geographic regions, the highest meropenem-vaborbactam activities were observed for CRE and MDR isolates from the United States (MIC
, 0.03/1 and 0.03/0.12 μg/ml, respectively). Meropenem-vaborbactam was very active against 135 KPC producers, and all isolates were inhibited by concentrations of ≤8 μg/ml (133 isolates by concentrations of ≤2 μg/ml). This combination had limited activity against isolates producing metallo-β-lactamases (including 25 NDM-1 and 16 VIM producers) and/or oxacillinases (27 OXA-48/OXA-163 producers) that were detected mainly in Asia-Pacific and some European countries. The activity of meropenem-vaborbactam was similar to that of meropenem alone against
,
spp., and
Meropenem-vaborbactam was active against contemporary
isolates collected worldwide, and this combination demonstrated enhanced activity compared to those of meropenem and most comparator agents against CRE isolates and KPC producers, the latter of which are often MDR.
represents a major cause of health care-associated infections, and inappropriate initial antimicrobial therapy is associated with increased morbidity and mortality. The International Network for ...Optimal Resistance Monitoring (INFORM) program monitors the
activity of ceftazidime-avibactam and many comparator agents. We evaluated the antimicrobial susceptibility of 7,452
isolates collected from 79 U.S. medical centers in 2012 to 2015. The isolates were collected and tested consecutively for susceptibility by broth microdilution method. Infection types included mainly pneumonia (50.5%), skin and skin structure (24.0%), urinary tract (7.8%), and bloodstream (7.7%) infections. The only compounds with >90% susceptibility rates were colistin (MIC
, 1/2 mg/liter, respectively; 99.4% susceptible), ceftazidime-avibactam (MIC
, 2/4 mg/liter, respectively; 97.0% susceptible), and amikacin (MIC
, 2/8 mg/liter, respectively; 97.0/93.0% susceptible CLSI/EUCAST, respectively). The addition of avibactam to ceftazidime increased the percentage of susceptible
isolates from 84.3% to 97.0%. Multidrug resistance (MDR) and extensive drug resistance (XDR) phenotypes were observed among 1,151 (15.4%) and 698 (9.4%) isolates, respectively, and ceftazidime-avibactam inhibited 82.1 and 75.8% of these isolates at ≤8 mg/liter, respectively. High rates of cross-resistance were observed with ceftazidime, meropenem, and piperacillin-tazobactam, whereas ceftazidime-avibactam retained activity against isolates nonsusceptible to ceftazidime (81.0% susceptible), meropenem (86.2% susceptible), and piperacillin-tazobactam (85.4% susceptible), as well as isolates nonsusceptible to these three β-lactams (71.2% susceptible). The only antimicrobial combinations that provided a better overall anti-
coverage than ceftazidime-avibactam (97.0% susceptibility rate) were those including amikacin (97.0 to 98.4% coverage). Susceptibility rates remained stable during the study period. The results of this investigation highlight the challenge of optimizing empirical antimicrobial therapy for
infections.
Omadacycline was tested against 21,000 bacterial isolates collected prospectively from medical centers in Europe and the United States during 2016. Omadacycline was active against
(MIC
/MIC
, ...0.12/0.25 mg/liter), including methicillin-resistant
(MRSA); streptococci (MIC
/MIC
, 0.06/0.12 mg/liter), including
, viridans group streptococci, and beta-hemolytic streptococci;
, including
(MIC
/MIC
, 0.5/2 mg/liter);
(MIC
/MIC
, 1/1 mg/liter); and
(MIC
/MIC
, 0.25/0.25 mg/liter). Omadacycline merits further study in serious infections where resistant pathogens may be encountered.
Omadacycline is a broad-spectrum aminomethylcycline in late-stage clinical development for the treatment of acute bacterial skin and skin structure infections and community-acquired pneumonia as an ...oral and an intravenous once-daily formulation. In this study, omadacycline and comparators were tested against 69,246 nonduplicate bacterial isolates collected prospectively during 2010 and 2011 from medical centers in Asia-Pacific (11,397 isolates), Europe (23,490 isolates), Latin America (8,038 isolates), and North America (26,321 isolates). Omadacycline was tested by broth microdilution following Clinical and Laboratory Standards Institute M07-A10 (2015) methods. A total of 99.9% of
isolates were inhibited by ≤2 μg/ml of omadacycline (MIC
, 0.12/0.25 μg/ml), including 100.0% of methicillin-susceptible
isolates and 99.8% of methicillin-resistant
isolates. Omadacycline potencies were comparable for
(MIC
, 0.06/0.06 μg/ml), viridans group streptococci (MIC
, 0.06/0.12 μg/ml), and beta-hemolytic streptococci (MIC
, 0.06/0.12 μg/ml) regardless of species and susceptibility to penicillin. Omadacycline was active against
and was most active against
(MIC
, 0.5/2 μg/ml),
(MIC
, 2/4 μg/ml),
(MIC
, 1/4 μg/ml), and
spp. (MIC
, 1/4 μg/ml). Omadacycline was active against
(MIC
, 1/1 μg/ml) regardless of β-lactamase status and against
(MIC
, 0.12/0.25 μg/ml). The potent activity of omadacycline against Gram-positive and Gram-negative bacteria indicates that omadacycline merits further study in serious infections in which multidrug resistance and mixed Gram-positive and Gram-negative infections may be a concern.
Omadacycline is a broad-spectrum aminomethylcycline approved in October 2018 by the U.S. Food and Drug Administration for treating acute bacterial skin and skin structure infections and ...community-acquired pneumonia as both an oral and intravenous once-daily formulation. In this report, the activities of omadacycline and comparators were tested against 49,000 nonduplicate bacterial isolates collected prospectively during 2016 to 2018 from medical centers in Europe (24,500 isolates, 40 medical centers 19 countries) and the United States (24,500 isolates, 33 medical centers 23 states and all 9 U.S. census divisions). Omadacycline was tested by broth microdilution following the methods in Clinical and Laboratory Standards Institute document M07 (
, 11th ed., 2018). Omadacycline (MIC
, 0.12/0.25 mg/liter) inhibited 98.6% of
isolates at ≤0.5 mg/liter, including 96.3% of methicillin-resistant
isolates and 99.8% of methicillin-susceptible
isolates. Omadacycline potency was comparable for
(MIC
, 0.06/0.12 mg/liter), viridans group streptococci (MIC
, 0.06/0.12 mg/liter), and beta-hemolytic streptococci (MIC
, 0.12/0.25 mg/liter), regardless of species and susceptibility to penicillin, macrolides, or tetracycline. Omadacycline was active against all
tested (MIC
, 1/8 mg/liter; 87.5% of isolates were inhibited at ≤4 mg/liter) except
(MIC
, 16/>32 mg/liter) and indole-positive
spp. (MIC
, 8/32 mg/liter) and was most active against
(MIC
, 0.5/2 mg/liter),
(MIC
, 1/2 mg/liter), and
spp. (MIC
, 1/4 mg/liter). Omadacycline inhibited 92.4% of
species complex and 88.5% of
isolates at ≤4 mg/liter. Omadacycline was active against
(MIC
, 0.5/1 mg/liter), regardless of β-lactamase status, and against
(MIC
, ≤0.12/0.25 mg/liter). The potent activity of omadacycline against Gram-positive and -negative bacteria indicates that omadacycline merits further study in serious infections in which multidrug resistance and mixed Gram-positive and Gram-negative bacterial infections may be a concern.
•Dissemination of carbapenem-resistant Enterobacteriaceae (CRE) is a matter of great concern worldwide.•CRE are often multidrug-resistant and few, sometimes suboptimal, therapeutic agents are ...effective against these isolates.•Meropenem/vaborbactam was recently approved by the FDA for treatment of adults with complicated urinary tract infection.•The current data demonstrate the activity of this combination against contemporary isolates.•Isolates tested include CRE that were characterised for the presence of carbapenemase genes.
The activity of meropenem/vaborbactam was evaluated against 11 559 Enterobacteriaceae isolates, including 330 carbapenem-resistant phenotypes (CRE) and carbapenemase genotypes collected worldwide during 2015. Antimicrobial susceptibility testing for meropenem/vaborbactam (inhibitor at 8 mg/L) and comparators was performed by the reference broth microdilution method. CRE isolates were screened for the presence of genes encoding carbapenemases, and 292 (88.5%) of the CRE isolates carried these resistance genes. A total of 209 isolates (63.3% of the CRE; 1.8% of the overall Enterobacteriaceae population) carried blaKPC, including genes encoding KPC-2 (90 isolates), KPC-3 (117 isolates) and KPC-17 (2 isolates). Overall, meropenem/vaborbactam (vaborbactam at 8 mg/L) inhibited 99.3% of all Enterobacteriaceae isolates at the US-FDA susceptibility breakpoint of ≤4/8 mg/L. Meropenem alone inhibited 96.9% of the isolates at the current CLSI susceptibility breakpoint of ≤2 mg/L. Susceptibility rates for comparator antimicrobial agents tested against Enterobacteriaceae isolates ranged from 82.1–98.2% applying the CLSI breakpoints. Against CRE isolates, meropenem/vaborbactam displayed MIC50/90 values at 0.5/32 mg/L, whereas meropenem MIC50/90 values were 16/>32 mg/L. Meropenem/vaborbactam was very active against KPC-producers, and 99.5% of these isolates were inhibited by ≤4/8 mg/L. The single resistant isolate was shown to harbour an outer membrane porin alteration. Meropenem/vaborbactam had limited activity against MBL-producing isolates (including 49 NDM-, 1 IMP-64- and 2 VIM-producers) and/or oxacillinases (47 OXA-48/-232) that were detected mainly in European countries. Meropenem/vaborbactam was active against contemporary CRE and wild-type Enterobacteriaceae collected worldwide and this combination demonstrated enhanced activity compared with meropenem and most comparator agents against CRE and KPC-producers.
Sulbactam is a class A β-lactamase inhibitor with intrinsic whole-cell activity against certain bacterial species, including Acinetobacter baumannii. The clinical use of sulbactam for A. baumannii ...infections is of interest due to increasing multidrug resistance in this pathogen. However, the molecular drivers of its antibacterial activity and resistance determinants have yet to be precisely defined. Here we show that the antibacterial activities of sulbactam vary widely across contemporary A. baumannii clinical isolates and are mediated through inhibition of the penicillin-binding proteins (PBPs) PBP1 and PBP3, with very low frequency of resistance; the rare pbp3 mutants with high levels of resistance to sulbactam are attenuated in fitness. These results support further investigation of the potential clinical utility of sulbactam.
•Manogepix is active against Candida spp., including Candida auris.•Manogepix is active against echinocandin-resistant Candida spp. isolates.•Manogepix is active against Aspergillus spp. ...isolates.•Manogepix is active against A. fumigatus isolates with elevated azole MICs and cyp mutations.•Manogepix is active against rare mould isolates, including Scedosporium spp.
: Manogepix, the active moiety of the prodrug fosmanogepix, is a novel antifungal with activity against major fungal pathogens including Candida (except Candida krusei), Aspergillus and difficult-to-treat/rare moulds. We tested manogepix and comparators against 2669 contemporary (2018–2019) fungal isolates collected from 82 medical centres in North America (42.3%), Europe (37.9%), Asia-Pacific (12.3%) and Latin America (7.6%). Of these, 70.7% were Candida spp., 3.6% were non-Candida yeasts including 49 Cryptococcus neoformans var. grubii, 21.7% were Aspergillus spp. and 4.1% were other moulds.
Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method.
Manogepix (MIC50/90, 0.008/0.06 mg/L) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, manogepix (MIC50/90, 0.5/2 mg/L) was ≥4-fold more active than anidulafungin, micafungin and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., manogepix (MEC50/90, 0.015/0.03 mg/L) had comparable activity to anidulafungin and micafungin. Low manogepix concentrations inhibited uncommon species of Candida, non-Candida yeasts, and rare moulds including Scedosporium spp. and Lomentospora (Scedosporium) prolificans.
Manogepix exhibited potent activity against contemporary fungal isolates, including echinocandin- and azole-resistant strains of Candida and Aspergillus spp., respectively. Although rare, Candida strains that were non-wild type for manogepix demonstrated resistance to fluconazole. However, the clinical relevance of this finding is unknown. The extended spectrum of manogepix is noteworthy for its activity against many less-common yet antifungal-resistant strains. Clinical studies are underway to evaluate the utility of fosmanogepix against difficult-to-treat resistant fungal infections.
Abstract
Background
The SENTRY Antimicrobial Surveillance Program was established in 1997 and encompasses over 750 000 bacterial isolates from ≥400 medical centers worldwide. Among the pathogens ...tested, Pseudomonas aeruginosa remains a common cause of multidrug-resistant (MDR) bloodstream infections and pneumonia in hospitalized patients. In the present study, we reviewed geographic and temporal trends in resistant phenotypes of P. aeruginosa over 20 years of the SENTRY Program.
Methods
From 1997 to 2016, 52 022 clinically significant consecutive isolates were submitted from ≥200 medical centers representing the Asia-Pacific region, Europe, Latin America, and North America. Only 1 isolate per patient per infection episode was submitted. Isolates were identified by standard algorithms and/or matrix-assisted laser desorption ionization-time of flight mass spectrometry. Susceptibility testing was performed by Clinical and Laboratory Standards Institute (CLSI) methods and interpreted using CLSI and European Committee on Antimicrobial Susceptibility Testing 2018 criteria at JMI Laboratories.
Results
The most common infection from which P. aeruginosa was isolated was pneumonia in hospitalized patients (44.6%) followed by bloodstream infection (27.9%), with pneumonia having a slightly higher rate of MDR (27.7%) than bloodstream infections (23.7%). The region with the highest percentage of MDR phenotypes was Latin America (41.1%), followed by Europe (28.4%). The MDR rates were highest in 2005–2008 and have decreased in the most recent period. Colistin was the most active drug tested (99.4% susceptible), followed by amikacin (90.5% susceptible).
Conclusions
Over the 20 years of SENTRY Program surveillance, the rate of MDR P. aeruginosa infections has decreased, particularly in Latin America. Whether the trend of decreasing resistance in P. aeruginosa is maintained will be documented in future SENTRY Program and other surveillance reports.
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
. 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.
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