In Vitro Potency and Spectrum of the Novel Polymyxin MRX-8 Tested against Clinical Isolates of Gram-Negative Bacteria.

The polymyxins display excellent in vitro antimicrobial activity against most Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates, but their clinical utility has been limited because of class-specific toxicity problems. Therefore, new polymyxin analogs with improved safety properties are needed to combat serious infections caused by resistant Gram-negative pathogens. MRX-8 is a novel polymyxin B analog that displays reduced toxicity in in vitro and animal assays and is currently being evaluated in a phase 1 clinical trial. In this nonclinical study, the in vitro potency and spectrum of MRX-8 and comparators were evaluated against a large set of Gram-negative clinical isolates collected in the United States in 2017 to 2020. MRX-8, colistin, and polymyxin B exhibited nearly identical antimicrobial activities against the Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii isolate sets. MRX-8 MIC50 and MIC90 values were 0.12 and 0.25 mg/L, respectively, for the set of Enterobacterales isolates not intrinsically resistant to colistin and 0.5 and 1 mg/L, respectively, against both the A. baumannii and P. aeruginosa isolate sets. All three polymyxin-class compounds retained activity against meropenem-resistant and multidrug-resistant isolate subsets but were inactive against isolates displaying acquired or intrinsic resistance to polymyxins. These results support the continued development of MRX-8 to treat serious Gram-negative infections.

Antimicrobial activity of cefepime/zidebactam (WCK 5222), a ß-lactam/ß-lactam enhancer combination, against clinical isolates of Gram-negative bacteria collected worldwide (2018-19).

BACKGROUND: Zidebactam, a bicyclo-acyl hydrazide ß-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.

In Vitro Activity and Potency of the Novel Oxazolidinone Contezolid (MRX-I) Tested against Gram-Positive Clinical Isolates from the United States and Europe.

Contezolid, a new oxazolidinone antibacterial agent currently in development for the treatment of skin and skin structure infections, was susceptibility tested against Gram-positive clinical isolates (n = 1,211). Contezolid demonstrated potent activity against Staphylococcus aureus (MIC50/90, 0.5/1 mg/liter), coagulase-negative Staphylococcus (MIC50/90, 0.25/0.5 mg/liter), Enterococcus spp. (MIC50/90, 0.5/1 mg/liter), and streptococci (MIC50/90, 1/1 mg/liter). Moreover, methicillin-resistant S. aureus and vancomycin-resistant Enterococcus faecium isolates were all inhibited by contezolid at ≤1 mg/liter. These results support the clinical development of contezolid.

Antimicrobial Activity of Ceftolozane-Tazobactam and Comparators against Clinical Isolates of Haemophilus influenzae from the United States and Europe.

Nine hundred Haemophilus influenzae clinical isolates from 83 U.S. and European medical centers were tested for susceptibility by reference broth microdilution methods against ceftolozane-tazobactam and comparators. Results were stratified by ß-lactamase production and infection type. Overall, ceftolozane-tazobactam MIC50/90 values were 0.12/0.25 mg/liter, and 99.0% of isolates were inhibited at the susceptible breakpoint of ≤0.5 mg/liter; the highest MIC value was only 2 mg/liter. Our results support using ceftolozane-tazobactam to treat H. influenzae infections.

Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents When Tested against a Large Collection of Contemporary Stenotrophomonas maltophilia Isolates from Medical Centers Worldwide.

Aztreonam-avibactam was tested against 1,839 Stenotrophomonas maltophilia isolates collected worldwide and demonstrated potent activity against isolates from all geographic regions and infection types (overall MIC50/90, 4/4 mg/liter; 97.8% inhibited at ≤8 mg/liter). Trimethoprim-sulfamethoxazole (TMP-SMX) (MIC50/90, ≤0.5/1 mg/liter; 95.4% susceptible) and minocycline (MIC50/90, 0.5/2 mg/liter; 99.5% susceptible) were also very active. Aztreonam-avibactam inhibited 84.7% of non-TMP-SMX-susceptible isolates at ≤8 mg/liter. Aztreonam-avibactam may represent a valuable option for the treatment of S. maltophilia infections, addressing a major unmet medical need.

Ceftobiprole Activity against Bacteria from Skin and Skin Structure Infections in the United States from 2016 through 2018.

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), beta-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC50/90, 0.5/1 mg/liter; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [MRSA]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum ß-lactamase [ESBL] phenotype). A total of 74.4% of P. aeruginosa, 100% of beta-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/liter. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016 to 2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for a potential ABSSSI indication.

Susceptibility trends of ceftolozane/tazobactam and comparators when tested against European Gram-negative bacterial surveillance isolates collected during 2012-18.

BACKGROUND: The Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) monitors the in vitro activity of ceftolozane/tazobactam and numerous antimicrobial agents against Gram-negative bacteria worldwide. OBJECTIVES: To evaluate the activity of ceftolozane/tazobactam and resistance trends among Pseudomonas aeruginosa and Enterobacterales isolates in Europe between 2012 and 2018. METHODS: P. aeruginosa (7503) and Enterobacterales (30 582) isolates were collected from 53 medical centres in 26 countries in Europe and the Mediterranean region and tested for susceptibility by reference broth microdilution method in a central laboratory. MIC results were interpreted using EUCAST criteria. RESULTS: Ceftolozane/tazobactam was the most active compound tested against P. aeruginosa isolates after colistin, with overall susceptibility rates of 94.1% in Western Europe and 80.9% in Eastern Europe. Moreover, ceftolozane/tazobactam retained activity against 75.2% and 59.2% of meropenem-non-susceptible P. aeruginosa isolates in Western and Eastern Europe, respectively. Tobramycin was the third most active compound tested against P. aeruginosa, with susceptibility rates of 88.6% and 70.9% in Western and Eastern Europe, respectively. Ceftolozane/tazobactam was active against 94.5% of all Enterobacterales and 96.1% of meropenem-susceptible isolates from Western Europe. In Eastern Europe, ceftolozane/tazobactam was active against 79.4% of Enterobacterales overall and 86.2% of meropenem-susceptible isolates. DISCUSSION: Antimicrobial susceptibility rates for agents commonly used to treat serious systemic infections varied widely among nations and geographic regions and were generally lower in Eastern Europe compared with Western Europe. Ceftolozane/tazobactam demonstrated potent activity against P. aeruginosa, including MDR strains, and retained activity against most meropenem-susceptible Enterobacterales causing infection in European medical centres.

Antimicrobial activity of POL7306 tested against clinical isolates of Gram-negative bacteria collected worldwide.

BACKGROUND: POL7306 belongs to a new class of peptidomimetic outer-membrane-protein-targeting antibiotics with a novel mechanism of action. POL7306 is in development for the treatment of infections caused by antimicrobial-resistant Gram-negative bacteria and has demonstrated low cytotoxicity and nephrotoxicity. METHODS: A total of 891 isolates were collected by the SENTRY Antimicrobial Surveillance Program from 134 medical centres in Europe (n = 424; 41 centres in 18 nations), the USA (n = 411 isolates from 67 centres), the Asia-Pacific region (n = 24; 15 centres in 6 nations) and Latin America (n = 32; 11 centres in 9 nations) and included 558 Enterobacterales, 310 non-fermenters and 23 fastidious organisms. Susceptibility testing was performed using the reference broth microdilution method and the medium was supplemented with 0.002% polysorbate-80 for testing POL7306. Resistant subsets were characterized by WGS. RESULTS: POL7306 demonstrated potent in vitro activity against Enterobacterales [including carbapenem-resistant (MIC50/90, 0.06/0.25 mg/L), ESBL-producing (MIC50/90, 0.06/0.12 mg/L), KPC-producing (MIC50/90, 0.12/0.25 mg/L), MBL-producing (MIC50/90, 0.06/0.25 mg/L), colistin-non-susceptible, mcr-negative (MIC50/90, 0.5/2 mg/L) and mcr-positive (MIC50/90, 0.12/0.25 mg/L) Enterobacterales], Pseudomonas aeruginosa (MIC50/90, 0.25/0.25 mg/L), Acinetobacter baumannii (MIC50/90, 0.06/0.12 mg/L) and Stenotrophomonas maltophilia (MIC50/90, 0.06/0.25 mg/L). CONCLUSIONS: POL7306 demonstrated potent activity against a large collection of Gram-negative organisms collected worldwide that included colistin-resistant, XDR and ESBL- and carbapenemase-producing isolates for which there are currently limited treatment options.

Ceftobiprole Activity against Gram-Positive and -Negative Pathogens Collected from the United States in 2006 and 2016.

Ceftobiprole is an advanced cephalosporin with potent activity against Gram-positive and Gram-negative bacteria that has been approved in many European and non-European countries to treat community- and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). This study reports on the activity of ceftobiprole against a large set of clinical isolates obtained from hospitalized patients in the United States in 2016 that caused serious infections, including pneumonia, bacteremia, and skin and skin structure infections. To assess any potential temporal changes in ceftobiprole activity, the 2016 results were compared to corresponding MIC data from a 2006 U.S. survey that included key target pathogens. Ceftobiprole exhibited potent activity against Staphylococcus aureus (including methicillin-resistant S. aureus isolates, which were 99.3% susceptible), coagulase-negative staphylococci (100% susceptible), Enterococcus faecalis (100% susceptible), Streptococcus pneumoniae (99.7% susceptible), and other tested streptococci. Similarly, ceftobiprole was highly active against Enterobacteriaceae isolates that did not exhibit an extended-spectrum ß-lactamase (ESBL) phenotype, including Escherichia coli (99.8% susceptible) and Klebsiella pneumoniae (99.6% susceptible). A total of 99.6% of all Haemophilus influenzae and Moraxella catarrhalis isolates were inhibited at ≤1 mg/liter ceftobiprole, and 72.7% of the Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. With the exception of decreased cephalosporin susceptibility among Enterobacteriaceae isolates, which correlates with an increased prevalence of ESBL-producing isolates, ceftobiprole had similar activities against the isolate sets collected in 2006 and 2016. Therefore, ceftobiprole remains highly active when tested in vitro against a large number of current Gram-positive or Gram-negative pathogens that cause serious infections.

Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015.

The activities of ceftolozane-tazobactam and comparator agents against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States during 2013 to 2015 were evaluated. Organisms included 1,576 Pseudomonas aeruginosa and 2,362 Enterobacteriaceae isolates susceptibility tested using reference broth microdilution methods. Ceftolozane-tazobactam, cefepime, ceftazidime, meropenem, and piperacillin-tazobactam inhibited 96.3%, 84.8%, 83.5%, 80.0%, and 78.6%, respectively, of the P. aeruginosa isolates. Ceftolozane-tazobactam inhibited 77.5 to 85.1% of isolates nonsusceptible to antipseudomonal ß-lactams and 86.6% and 71.0% of the 372 (23.6% overall) multidrug- and 155 (9.8%) extensively drug-resistant isolates tested. The activity of this combination was greater than those of other ß-lactams evaluated against P. aeruginosa groups across all U.S. census divisions. Ceftolozane-tazobactam was active against 90.6% of the Enterobacteriaceae, being less active than only meropenem (95.6% susceptible) among the ß-lactams evaluated. Against 145 Escherichia coli and Klebsiella pneumoniae isolates carrying extended-spectrum-ß-lactamase (ESBL)-encoding genes without carbapenemases, ceftolozane-tazobactam inhibited 82.8% of these isolates and was more active than cefepime and piperacillin-tazobactam (15.2% and 74.3% susceptible, respectively). ESBL genes included in this analysis were mainly blaCTX-M-15-like (89 isolates) and blaCTX-M-14-like (22) genes but also blaSHV (31) and blaTEM (3). Ceftolozane-tazobactam also displayed activity (84.6% susceptible) against 13 isolates harboring acquired AmpC genes. All ß-lactams displayed limited activity against blaKPC-carrying isolates. Ceftolozane-tazobactam was the most active ß-lactam tested against P. aeruginosa isolates from isolates that were the probable cause of pneumonia and displayed in vitro activity against Enterobacteriaceae, including isolates resistant to cephalosporins and carrying ESBL genes.

Antimicrobial Activity of Dalbavancin against Staphylococcus aureus with Decreased Susceptibility to Glycopeptides, Daptomycin, and/or Linezolid from U.S. Medical Centers.

Dalbavancin activity was assessed against a large collection of Staphylococcus aureus isolates (n = 59,903), including isolates with decreased susceptibility to vancomycin (MIC, ≥2 mg/liter; n = 1,141), daptomycin (MIC, ≥2 mg/liter; n = 48), telavancin (MIC, ≥0.12 mg/liter; n = 52), teicoplanin (MIC, ≥4 mg/liter; n = 143), and/or linezolid (MIC, ≥8 mg/liter; n = 25). Dalbavancin displayed susceptibility rates ranging from 90.4% (isolates with telavancin MIC ≥0.12 mg/liter) to 100.0% (linezolid-resistant isolates) and lower MIC values than the comparators against these resistant subsets.

In Vitro Activities of Ceftaroline and Comparators against Streptococcus pneumoniae Isolates from U.S. Hospitals: Results from Seven Years of the AWARE Surveillance Program (2010 to 2016).

We evaluated trends in Streptococcus pneumoniae antimicrobial susceptibility in United States hospitals in the 2010 to 2016 period. A total of 8,768 clinical isolates from 47 medical centers were tested for susceptibility by broth microdilution methods. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) rates decreased from 25.7% and 12.4%, respectively, in 2010 to 17.7% and 3.6%, respectively, in 2016. The susceptibilities to most comparator antimicrobial agents increased, whereas the susceptibilities to ceftaroline, levofloxacin, linezolid, and tigecycline remained stable. Ceftaroline retained potent activity against S. pneumoniae (>99.9%) with no marked variations.

Activity of dalbavancin and comparator agents against Gram-positive cocci from clinical infections in the USA and Europe 2015-16.

Background: Many infections due to Gram-positive cocci (GPC; staphylococci, streptococci and enterococci) regularly involve prolonged systemic antibiotic use. Dalbavancin has demonstrated activity against GPC isolates and has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. Objectives: To evaluate the activity of dalbavancin against GPC isolated from a variety of infection types in the USA and Europe. Methods: A total of 14 319 Staphylococcus aureus, 1992 CoNS, 3269 ß-haemolytic streptococci (BHS), 2071 Enterococcus faecalis, 936 Enterococcus faecium, 71 Enterococcus gallinarum/casseliflavus and other Enterococcus spp., 3487 Streptococcus pneumoniae and 1063 viridans group streptococci (VGS) causing clinical infections were consecutively collected (2015-16) and tested for susceptibility by broth microdilution methods. Results: All S. aureus (36.4% MRSA) isolates were susceptible to dalbavancin, teicoplanin and vancomycin, while daptomycin and linezolid showed susceptibility rates of >99.9% (according to CLSI criteria). Dalbavancin MIC results were at least 16-fold lower than these comparators against all S. aureus. Dalbavancin was the most potent agent against CoNS [62.2%/59.6% methicillin-resistant (CLSI/EUCAST)], followed by daptomycin, linezolid and vancomycin. All vancomycin-susceptible E. faecalis isolates were inhibited by dalbavancin at ≤0.25 mg/L (FDA susceptible breakpoint). Dalbavancin was very active against BHS (MIC90 0.03 mg/L) and the most active agent against S. pneumoniae and VGS (highest MIC 0.25 mg/L). Ceftriaxone, daptomycin, levofloxacin and vancomycin were also active (93.5%-100.0% susceptible) against VGS, whereas clindamycin, erythromycin, penicillin and tetracycline had lower activity. Conclusions: Dalbavancin appears to be a viable candidate for treating serious infections caused by GPC.

Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing urinary tract and intraabdominal infections in Europe: report from an antimicrobial surveillance programme (2012-15).

Objectives: To evaluate the in vitro activity of ceftolozane/tazobactam and comparators tested against European isolates of Enterobacteriaceae and Pseudomonas aeruginosa from hospitalized patients with urinary tract infection or intraabdominal infections. Methods: A total of 6553 Gram-negative organisms (603 P. aeruginosa and 5950 Enterobacteriaceae) were consecutively collected from 41 hospitals located in 17 European countries plus Israel and Turkey. The organisms were tested for susceptibility by broth microdilution methods and the results interpreted according to EUCAST and CLSI breakpoint criteria. Results: Ceftolozane/tazobactam [MIC 50/90 0.25/1 mg/L; 93.5%/91.3% susceptible (S) (CLSI/EUCAST criteria)] and meropenem [MIC 50/90 ≤0.06/≤0.06 mg/L; 98.1%/98.3% S (CLSI/EUCAST)] were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates, 1.9% were carbapenem resistant (CRE), 15.2% exhibited an ESBL non-CRE phenotype, 14.6% were MDR, 2.2% were XDR and <0.1% were pan-drug resistant (PDR). Whereas ceftolozane/tazobactam showed activity against ESBL non-CRE phenotype isolates (MIC 50/90 0.5/8 mg/L), it lacked useful activity against strains with a CRE (MIC 50/90 >32/>32 mg/L; 3.6% S) or PDR (MIC 50 >32 mg/L; 0.0% S) phenotype. Ceftolozane/tazobactam was the most potent (MIC 50/90 0.5/4 mg/L) ß-lactam agent tested against P. aeruginosa isolates, inhibiting 91.7% at an MIC of ≤4 mg/L. P. aeruginosa exhibited high rates of resistance to cefepime (20.6%), ceftazidime (23.1%), meropenem (9.0%) and piperacillin/tazobactam (26.9%) (EUCAST criteria). Among these four P. aeruginosa resistant phenotypes, 61.3%-70.4% were susceptible to ceftolozane/tazobactam. Conclusions: Ceftolozane/tazobactam was the most active ß-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than currently available cephalosporins and piperacillin/tazobactam when tested against Enterobacteriaceae.

Update on the in vitro activity of ceftaroline against Staphylococcus aureus from United States (US) medical centers stratified by infection type (2018-2020).

Ceftaroline and comparators were tested against 9,268 Staphylococcus aureus isolates from 33 United States hospitals (2018-2020). Ceftaroline (MIC50/90, 0.25/1 mg/L) susceptibility ranged from 95.4% (pneumonia) to 98.5% (skin and skin structure) and was 97.2% overall. Ceftaroline retained potent and broad-spectrum activity against methicillin-resistant isolates, with a 93.4% overall susceptibility.

Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library.

The continuing emergence of antibiotic-resistant microbes highlights the need for the identification of new chemotypes with antimicrobial activity. One of the most prolific sources of antimicrobial molecules has been the systematic screening of natural product samples. The National Institute of Allergy and Infectious Diseases and the National Cancer Institute here report a large screen of 326,656 partially purified natural product fractions against a panel of four microbial pathogens, resulting in the identification of >3000 fractions with antifungal and/or antibacterial activity. A small sample of these active fractions was further purified and the chemical structures responsible for the antimicrobial activity were elucidated. The proof-of-concept study identified many different chemotypes, several of which have not previously been reported to have antimicrobial activity. The results show that there remain many unidentified antibiotic compounds from nature.

Ceftobiprole activity against Gram-positive and Gram-negative pathogens causing bone and joint infections in the United States from 2016 to 2020.

Bone and joint infections (BJIs) present significant treatment challenges. Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus, is approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. In this study, the in vitro activity of ceftobiprole and comparators was evaluated against clinical isolates collected from BJIs in the USA from 2016 to 2020. Gram-positive pathogens made up 70.6% of all BJI isolates and included S. aureus (47.4% of all isolates), ß-hemolytic streptococci, coagulase-negative staphylococci, and Enterococcus faecalis. Ceftobiprole was highly active against S. aureus (MIC50/90 values, 0.5/1 mg/L; 99.6% susceptible using the European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoint of ≤2 mg/L for the treatment of pneumonia patients) and exhibited potent activity against the other Gram-positive cocci and the predominant BJI Gram-negative groups. These results support the further evaluation of ceftobiprole for this potential indication.

In Vitro and In Vivo Antimicrobial Activity of the Novel Peptide OMN6 against Multidrug-Resistant Acinetobacter baumannii.

The rapid worldwide spread of antimicrobial resistance highlights the significant need for the development of innovative treatments to fight multidrug-resistant bacteria. This study describes the potent antimicrobial activity of the novel peptide OMN6 against a wide array of drug-resistant Acinetobacter baumannii clinical isolates. OMN6 prevented the growth of all tested isolates, regardless of any pre-existing resistance mechanisms. Moreover, in vitro serial-passaging studies demonstrated that no resistance developed against OMN6. Importantly, OMN6 was highly efficacious in treating animal models of lung and blood infections caused by multidrug-resistant A. baumannii. Taken together, these results point to OMN6 as a novel antimicrobial agent with the potential to treat life-threatening infections caused by multidrug-resistant A. baumannii avoiding resistance.

Antimicrobial activities of ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, meropenem/vaborbactam, and comparators against Pseudomonas aeruginosa from patients with skin and soft tissue infections.

BACKGROUND: The limited armamentarium against multidrug-resistant Gram-negative bacilli led to the development of a new generation of ß-lactam/ß-lactamase inhibitor combinations (BL/BLI). OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The recently approved BL/BLIs demonstrated potent activity and broad coverage against contemporary P. aeruginosa isolates from patients with SSTIs.

Antimicrobial activity of ceftazidime/avibactam, ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa from cystic fibrosis patients.

OBJECTIVES: To evaluate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa isolates collected from the lower respiratory tract of cystic fibrosis (CF) patients. METHODS: We susceptibility tested 273 contemporary P. aeruginosa isolates from 39 hospitals worldwide (17 countries) by the reference broth microdilution method. RESULTS: Ceftazidime/avibactam [MIC50/90, 2/8 mg/L; 96.0% susceptible (S)] was the most active agent, followed by ceftolozane/tazobactam (MIC50/90, 1/4 mg/L; 90.5% S), ceftazidime (MIC50/90, 2/>32 mg/L; 80.6% S), piperacillin/tazobactam (MIC50/90, 4/128 mg/L; 80.2% S) and tobramycin (MIC50/90, 2/>16 mg/L; 76.6% S). Ceftazidime/avibactam retained activity against P. aeruginosa isolates non-susceptible to meropenem (86.5% S to ceftazidime/avibactam), piperacillin/tazobactam (85.2% S to ceftazidime/avibactam) or ceftazidime (79.2% S to ceftazidime/avibactam). MDR phenotype was observed among 36.3% of isolates, and 88.9% and 73.7% of MDR isolates were susceptible to ceftazidime/avibactam and ceftolozane/tazobactam, respectively. Against isolates non-susceptible to meropenem, piperacillin/tazobactam and ceftazidime, susceptibility rates were 78.9% for ceftazidime/avibactam and 47.4% for ceftolozane/tazobactam. Ceftazidime/avibactam was active against 65.4% of ceftolozane/tazobactam-non-susceptible isolates and ceftolozane/tazobactam was active against 18.2% of ceftazidime/avibactam-non-susceptible isolates. CONCLUSIONS: Ceftazidime/avibactam and ceftolozane/tazobactam exhibited potent and broad-spectrum activity against P. aeruginosa isolated from CF patients worldwide, but higher susceptibility rates for ceftazidime/avibactam compared with ceftolozane/tazobactam were observed among the resistant subsets. Ceftazidime/avibactam and ceftolozane/tazobactam represent valuable options to treat CF pulmonary exacerbations caused by P. aeruginosa.