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.

Surveillance of omadacycline activity tested against clinical isolates from the USA: report from the SENTRY Antimicrobial Surveillance Program, 2019.

OBJECTIVES: Omadacycline was tested against 7000 bacterial isolates collected prospectively from medical centres in the USA during 2019. METHODS: Antimicrobial susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: Omadacycline was active against: Staphylococcus aureus (MIC50/90, 0.12/0.25 mg/L; 98.3% susceptible), including methicillin-resistant S. aureus (MRSA); Enterococcus faecalis (MIC50/90, 0.06/0.25 mg/L; 100.0% susceptible), including vancomycin-resistant enterococci (VRE); Streptococcus pneumoniae (MIC50/90, 0.06/0.06 mg/L; 99.8% susceptible); viridans group streptococci, including Streptococcus anginosus group (MIC50/90, 0.03/0.06 mg/L; 100.0% susceptible); ß-haemolytic streptococci, including Streptococcus pyogenes (MIC50/90, 0.06/0.12 mg/L; 99.2% susceptible); Enterobacterales (MIC50/90, 1/8 mg/L; 86.9% inhibited at ≤4 mg/L), including Escherichia coli (MIC50/90, 0.5/2 mg/L; 99.6% inhibited at ≤4 mg/L); Enterobacter cloacae (MIC50/90, 2/4 mg/L; 98.5% susceptible); Klebsiella pneumoniae (MIC50/90, 1/4 mg/L; 93.2% susceptible); Acinetobacter baumannii (MIC50/90, 0.5/4 mg/L; 90.8% inhibited at ≤4 mg/L); Haemophilus influenzae (MIC50/90, 0.5/1 mg/L; 100.0% susceptible); and Moraxella catarrhalis (MIC50/90, ≤0.12/0.25 mg/L). CONCLUSION: The 2019 in vitro activity of omadacycline against key Gram-positive and Gram-negative pathogens has not changed compared with the prior 3 years of surveillance in the SENTRY Antimicrobial Surveillance Program. Omadacycline merits further study in serious infections where resistant pathogens may be encountered.

Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018-2019).

OBJECTIVES: 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. METHODS: Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method. RESULTS: 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. CONCLUSION: 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.

In vitro activity of iclaprim and comparator agents against Listeria monocytogenes clinical isolates from 2012 to 2018.

OBJECTIVES: This study examined the in vitro activity of iclaprim and comparators against 40 Listeria monocytogenes clinical isolates mostly (95%) from patients with bloodstream infection (BSI) from the USA, Australia/New Zealand, Latin America and Europe collected between 2012-2018. METHODS: Antimicrobial susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria. RESULTS: The iclaprim MIC90 value for all L. monocytogenes was 0.015 µg/mL. The MIC50/90 values for iclaprim were 4-fold lower than trimethoprim, the only FDA-approved dihydrofolate reductase inhibitor, against all L. monocytogenes. CONCLUSION: Iclaprim demonstrated lower MIC values than trimethoprim against a collection (2012-2018) of L. monocytogenes clinical isolates mostly from patients with BSI from the USA, Australia/New Zealand, Latin America and Europe.

Susceptibility trends of ceftolozane/tazobactam and comparators when tested against U.S. gram-negative bacterial surveillance isolates (2012-2018).

Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a ß-lactamase inhibitor. Ceftolozane/tazobactam has been approved in >60 countries for treating complicated urinary tract infections, acute pyelonephritis, complicated intra-abdominal infections (with metronidazole), and hospital-acquired pneumonia, including ventilator-associated pneumonia in adults. We analyzed susceptibilities for 35,882 gram-negative isolates collected from patients in 35 US medical centers from 2012 to 2018. The rate of multi-drug resistant Enterobacterales was stable (9.5%-10.1%), while the P. aeruginosa multi-drug resistance rate increased from 15.5% in 2012 to 22.9% in 2018. The carbapenem-resistant Enterobacterales rates varied from 0.9% to 2.2% and extended-spectrum ß-lactamase phenotypes increased from 10.5% to 16.8%. The most active drugs against P. aeruginosa were ceftolozane/tazobactam (95.8%-97.5% susceptible) and amikacin (93.9%-98.0%); against Enterobacterales, amikacin (97.9%-98.8%), meropenem (97.7%-98.8%), and ceftolozane/tazobactam (93.3%-95.6%) were the most active. These data suggest that ceftolozane/tazobactam has effective in vitro activity against organisms causing serious gram-negative infections.

Update on the activity of delafloxacin against acute bacterial skin and skin-structure infection isolates from European hospitals (2014-2019).

OBJECTIVES: Delafloxacin is a broad-spectrum anionic fluoroquinolone with activity against Gram-positive and Gram-negative organisms, including methicillin-resistant Staphylococcus aureus. Both oral and intravenous formulations were approved for use in the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) due to Gram-positive and Gram-negative organisms by the US Food and Drug Administration (2017) and European Medicines Agency (2019), and for community-acquired bacterial pneumonia by the FDA (2019). The SENTRY Antimicrobial Surveillance Program has monitored the susceptibility of delafloxacin in the USA and Europe since 2014. The purpose of this study is to provide an update on delafloxacin activity against ABSSSI isolates primarily collected from hospitalised patients in Europe. METHODS: A total of 11,866 non-duplicate ABSSSI isolates were collected from 2014 to 2019 from 46 European medical centres in 24 countries. Susceptibilities were determined by broth microdilution. Results were interpreted using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (2020). RESULTS: The most common isolate wasS. aureus (37.8%; n = 4484), followed by Escherichia coli (11.0%) and Streptococcus spp. (10.0%). Delafloxacin susceptibility for S. aureus was 92.4% (MIC50/90, ≤0.004/0.25 mg/L), streptococci 98.4% and E. coli 58.1%. Delafloxacin was more active against S. aureus than levofloxacin (84.0% intermediate; MIC50/90, 0.25/>4 mg/L) and moxifloxacin (84.3% susceptible; MIC50/90, ≤0.06/2 mg/L). Susceptibility of E. coli was similar for the three quinolones. CONCLUSIONS: Delafloxacin had broad-spectrum activity and improved potency against Gram-positive pathogens compared with levofloxacin and moxifloxacin. These data suggest that delafloxacin may be a useful therapeutic choice for the most common causes of ABSSSI.

In vitro activity of KHP-3757 (a novel LpxC inhibitor) and comparator agents against recent and molecularly characterized Pseudomonas aeruginosa isolates from a global surveillance program (2017-2018).

This study evaluated the in vitro activity of KHP-3757 (a novel LpxC inhibitor) and comparator agents against recent, geographically diverse, Pseudomonas aeruginosa isolates from a global surveillance program as well as molecularly characterized extended-spectrum-ß-lactamase-positive, metallo-ß-lactamase-positive, and colistin-resistant strains. KHP-3757 (MIC50/90, 0.25/0.5 mg/L; 97.4% inhibited at ≤0.5 mg/L) demonstrated potent in vitro activity based on MIC90 values against P. aeruginosa isolates including extended-spectrum-ß-lactamase-positive, metallo-ß-lactamase-positive, and colistin-resistant strains outperforming other comparator agents.

Comparison of minimum inhibitory concentration results for gepotidacin obtained using agar dilution and broth microdilution methods.

Gepotidacin (GSK2140944) is a first in class, novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in Phase 3 clinical development for the treatment of gonorrhea and uncomplicated urinary tract infections (acute cystitis). This study tested the equivalency of minimal inhibitory concentrations (MICs) obtained by two reference susceptibility testing methods, agar dilution and broth microdilution, for gepotidacin when tested against various gram-positive and gram-negative organisms. Equivalency, measured as the essential agreement >89.9%, was established between the two methods for determining gepotidacin susceptibility results against Staphylococcus spp., Streptococcus spp., and Escherichia coli. However, for Neisseria gonorrhoeae and Haemophilus influenzae, equivalency was not established. Agar dilution remains the sole dilution reference method for determining gepotidacin MICs against N. gonorrhoeae.

Activity of ceftolozane-tazobactam and comparators when tested against bacterial surveillance isolates collected from patients at risk of infections caused by resistant gram-negative pathogens.

Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a ß-lactamase inhibitor. Ceftolozane-tazobactam has been approved for treatment of complicated urinary tract infections and acute pyelonephritis, for complicated intra-abdominal infections (with metronidazole) in adults, and for hospital-acquired bacterial pneumonia including ventilator-associated bacterial pneumonia. This study analyzed gram-negative pathogen susceptibility in US and European patients who are considered at risk for infections caused by pathogens resistant to commonly used antimicrobials: patients in the intensive care unit (ICU), patients on the hematology/oncology or transplant service who may be immunocompromised, and patients >65 years old (yo). ICU patients had the lowest susceptibility for Enterobacterales and PSA. The susceptibility for isolates from the immunocompromised and >65 yo groups was similar. Ceftolozane-tazobactam was the most active agent against PSA, with ≥90%S for >65 yo and immunocompromised, and >80%S for ICU. Meropenem and ceftolozane-tazobactam were the most active agents against Enterobacterales.

Old In Vitro Antimicrobial Breakpoints Are Misleading Stewardship Efforts, Delaying Adoption of Innovative Therapies, and Harming Patients.

The current antimicrobial market and old (pre-2000) in vitro antimicrobial susceptibility test interpretative criteria (STIC) are not working properly. Malfunctioning susceptibility breakpoints and antimicrobial markets have serious implications for both patients (ie, from a safety and efficacy perspective) and antibiotic-focused pharmaceutical and biotechnology company economic viability. Poorly functioning STIC fail both patients and clinicians since they do not discriminate between likely effective and ineffective antimicrobial regimens. Poor economic viability fails patients and clinicians as it decreases the industry's ability to develop antimicrobial agents that clinicians and patients urgently require now and in the future. Herein, we review how STIC for older antimicrobial agents were determined and how their correction can impact the perceived utility of old relative to new antimicrobial agents. Moreover, we describe the data and analysis needs to systematically reevaluate older STIC values. We call for professional infectious diseases societies, government agencies, and other consensus bodies interested in the appropriate use of antimicrobial agents to join an effort to systematically evaluate and, where warranted, correct STIC for all relevant antimicrobial agents. This effort will amplify the effects of other measures designed to increase appropriate antimicrobial use (ie, good antimicrobial stewardship), development, and regulation.

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.

Omadacycline invitro activity against a molecularly characterized collection of clinical isolates with known acquired tetracycline resistance mechanisms.

Omadacycline and tigecycline MIC90 values were 2 µg/mL and 0.25 µg/mL, respectively, against Staphylococcus aureus carrying tet(M), whereas the minocycline, tetracycline, and doxycycline values were > 8 µg/mL. Similarly, omadacycline and tigecycline remained active against Enterococcus faecalis and Streptococcus pneumoniae harboring tet(L)and/or tet(M)(MIC90, 0.06-0.25 µg/mL), whereas other tetracyclines were inactive (MIC90, >8 µg/mL). Omadacycline and tigecycline remained more potent than minocycline, tetracycline, and doxycycline against Enterobacteriaceae carrying tet. This study demonstrates the effectiveness of modern tetracyclines, omadacycline, and tigecycline against isolates with tetracycline resistance genes.

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.

Assessment of Tedizolid In Vitro Activity and Resistance Mechanisms against a Collection of Enterococcus spp. Causing Invasive Infections, Including Isolates Requiring an Optimized Dosing Strategy for Daptomycin from U.S. and European Medical Centers, 2016 to 2018.

High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium isolates. Only 3.3% and 2.1% of E. faecalis isolates had elevated daptomycin MIC (≥2 mg/liter) and vancomycin resistance, respectively. In contrast, 37.4% to 40.3% of E. faecium isolates exhibited these phenotypes. Tedizolid inhibited 98.9% to 100.0% of enterococci causing serious invasive infections, including resistant subsets. Oxazolidinone resistance was mainly driven by G2576T; however, optrA and poxtA genes were also detected, including poxtA in the United States and Turkey.

Antimicrobial Activity of Telavancin Tested In Vitro Against a Global Collection of Gram-Positive Pathogens, Including Multidrug-Resistant Isolates (2015-2017).

This study evaluated the in vitro antimicrobial activity of telavancin against a large collection of Gram-positive pathogens of clinical importance, which were collected worldwide from 2015 through 2017, including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, Enterococcus spp., ß-hemolytic streptococci (BHS), Streptococcus pneumoniae, and viridans group streptococci (VGS). This report completes 7 years of continuous surveillance data for telavancin using the approved reference method for in vitro testing methodology that includes the addition of polysorbate 80. For isolates collected from 2015 through 2017, telavancin exhibited potent activity against the following species and groups that have Clinical and Laboratory Standards Institute (CLSI)-approved interpretive criteria: MRSA (MIC90 value, 0.06 µg/mL; 100% susceptible), vancomycin-susceptible Enterococcus faecalis (MIC90 value, 0.25 µg/mL; 99.9% susceptible), BHS (MIC90 value, 0.03 µg/mL; 100% susceptible), and VGS (MIC90 value, 0.03 µg/mL; 99.0% susceptible). Importantly, telavancin maintained excellent antimicrobial activity against multidrug-resistant subsets of these pathogen groups and against ceftaroline-nonsusceptible (telavancin MIC90 value, 0.06 µg/mL; 100% susceptible) and ceftaroline-resistant (telavancin MIC90 value, 0.12 µg/mL; 100% susceptible) S. aureus isolates.

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.

In Vitro Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates.

KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-ß-lactamase (ESBL)- and metallo-ß-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.

Surveillance of Omadacycline Activity Tested against Clinical Isolates from the United States and Europe: Report from the SENTRY Antimicrobial Surveillance Program, 2016 to 2018.

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 (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard, 11th ed., 2018). Omadacycline (MIC50/90, 0.12/0.25 mg/liter) inhibited 98.6% of Staphylococcus aureus isolates at ≤0.5 mg/liter, including 96.3% of methicillin-resistant S. aureus isolates and 99.8% of methicillin-susceptible S. aureus isolates. Omadacycline potency was comparable for Streptococcus pneumoniae (MIC50/90, 0.06/0.12 mg/liter), viridans group streptococci (MIC50/90, 0.06/0.12 mg/liter), and beta-hemolytic streptococci (MIC50/90, 0.12/0.25 mg/liter), regardless of species and susceptibility to penicillin, macrolides, or tetracycline. Omadacycline was active against all Enterobacterales tested (MIC50/90, 1/8 mg/liter; 87.5% of isolates were inhibited at ≤4 mg/liter) except Proteus mirabilis (MIC50/90, 16/>32 mg/liter) and indole-positive Proteus spp. (MIC50/90, 8/32 mg/liter) and was most active against Escherichia coli (MIC50/90, 0.5/2 mg/liter), Klebsiella oxytoca (MIC50/90, 1/2 mg/liter), and Citrobacter spp. (MIC50/90, 1/4 mg/liter). Omadacycline inhibited 92.4% of Enterobacter cloacae species complex and 88.5% of Klebsiella pneumoniae isolates at ≤4 mg/liter. Omadacycline was active against Haemophilus influenzae (MIC50/90, 0.5/1 mg/liter), regardless of ß-lactamase status, and against Moraxella catarrhalis (MIC50/90, ≤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.

Comparison of ceftazidime-avibactam and ceftolozane-tazobactam in vitro activities when tested against gram-negative bacteria isolated from patients hospitalized with pneumonia in United States medical centers (2017-2018).

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.

Antimicrobial activity of ceftolozane/tazobactam tested against contemporary (2015-2017) Pseudomonas aeruginosa isolates from a global surveillance programme.

OBJECTIVES: Ceftolozane/tazobactam (C-T) is an antimicrobial combination of an antipseudomonal cephalosporin and a ß-lactamase inhibitor. C-T has been approved in >60 countries for complicated urinary tract infections, acute pyelonephritis, complicated intra-abdominal infections in combination with metronidazole, and was recently approved for hospital-acquired bacterial pneumonia. In this study, data for Pseudomonas aeruginosa isolates consecutively collected from various infection types in hospitalised patients from 2015 to 2017 were analysed. METHODS: A total of 6836 P. aeruginosa isolates were collected from 104 hospitals in four continents and were tested for susceptibility to C-T by CLSI broth microdilution methodology at JMI Laboratories using CLSI (2018) breakpoints. Other agents tested included amikacin, ceftazidime (CAZ), colistin (COL), levofloxacin (LVX), meropenem (MEM) and piperacillin/tazobactam (TZP). Resistance phenotypes analysed included CAZ-non-susceptible (CAZ-NS), COL-NS, MEM-NS, LVX-NS, TZP-NS and ß-lactam-NS. Multidrug resistance (MDR) was defined as NS to ≥1 drug in ≥3 drug classes, and extensively drug-resistant (XDR) was defined as NS to ≥1 agent in all but 2 or fewer antimicrobial classes. RESULTS: The most common infection from which P. aeruginosa was isolated was pneumonia (51.6%), followed by skin and skin-structure infection (22.2%) and bloodstream infection (15.3%). Percentage susceptibility to C-T varied by region: 98.2% in North America; 94.8% in Asia-Pacific; 90.8% in Latin America; and 89.1% in Europe. CONCLUSION: C-T had potent activity against P. aeruginosa isolated from patients in hospitals in four continents. C-T was more active than all comparators, except COL, and maintained activity against MDR and XDR isolates and isolates NS to all four tested ß-lactams. C-T was active against 13/16 COL-NS isolates.