scholarly journals In Vitro Activity of Lefamulin Against a Global Collection of Bacterial Pathogens Commonly Causing Community-Acquired Bacterial Pneumonia (CABP, SENTRY 2015)

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S373-S373 ◽  
Author(s):  
Susanne Paukner ◽  
Helio S Sader ◽  
Jennifer M Streit ◽  
Robert K Flamm ◽  
Steven P Gelone
Keyword(s):  
Respiratory Tract ◽  
Bacterial Pathogens ◽  
Bloodstream Infections ◽  
Vitro Activity ◽  
Asia Pacific ◽  
Respiratory Pathogens ◽  
In Vitro Activity ◽  
Tract Infections ◽  
Research Grant

Abstract Background CABP is the number one reason for death by infectious diseases worldwide and emerging resistance complicates its treatment. Lefamulin is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans. It is currently in Phase 3 trials for the treatment of CABP in adults. Lefamulin effectively and selectively inhibits bacterial translation by binding to the peptidyl transferase center (PTC) via four H-bonds and other interactions at the A- and P-site resulting in an “induced fit.” This study investigated the activity of lefamulin and comparators against a contemporary set of bacterial pathogens associated with community-acquired respiratory infections collected worldwide. Methods Unique patients’ isolates (n = 2817) were collected globally in US (19.7%), Europe (36.9%), Latin America (5.7%) and Asia-Pacific region (37.6%) (30 countries, 116 sites) from adult and pediatric patients with respiratory tract infection (88.0%), bloodstream infections (5.5%) and other infections (2.4%). Lefamulin and comparators were tested by CLSI broth microdilution and susceptibility was determined using the CLSI (2017) breakpoints. Results LEF was the most potent compound tested, with 99.7% of all S. pneumoniae isolates being inhibited at a concentration of ≤0.25 mg/L (MIC50/90 values of 0.06/0.12 mg/L) and its activity was not affected by resistance to other antibiotic classes. S. pneumoniae isolates were largely susceptible to levofloxacin (99.1%) and ceftriaxone (96.5%), while 34.5%, 23.3% and 16.8% of isolates were resistant to macrolides, tetracycline and clindamycin, respectively. Lefamulin also showed potent activity against H. influenzae (MIC50/90 of 0.5/1 mg/L), including 22.0% of ß-lactamase producing strains, and M. catarrhalis (0.06/0.12 mg/L). Conclusion Lefamulin demonstrated potent in vitro activity against this global collection of contemporary respiratory pathogens and its activity was unchanged regardless of resistance phenotype to the other antibiotic classes including macrolides, ß-lactams, tetracyclines or fluoroquinolones. These data support the continued clinical development of lefamulin for the treatment of respiratory tract infections, including CABP. Disclosures S. Paukner, Nabriva Therapeutics: Employee and Shareholder, Salary; H. S. Sader, Nabriva Therapeutics: Research Contractor, Research grant; J. M. Streit, Nabriva Therapeutics: Research Contractor, Research grant; R. K. Flamm, Nabriva Therapeutics: Research Contractor, Research grant; S. P. Gelone, Nabriva Therapeutics: Employee and Shareholder, Salary

scholarly journals Cefepime-Zidebactam (WCK 5222) Activity Tested against Gram-negative Organisms Causing Bloodstream Infections Worldwide

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S374-S375 ◽  
Author(s):  
Helio S Sader ◽  
Mariana Castanheira ◽  
Jennifer M Streit ◽  
Leonard R Duncan ◽  
Robert K Flamm
Keyword(s):  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Vitro Activity ◽  
Asia Pacific ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Research Grant

Abstract Background Zidebactam (ZID), a bicyclo-acyl hydrazide, is a β-lactam enhancer with a dual mechanism of action involving selective and high binding affinity to Gram-negative (GN) PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of cefepime (FEP) combined with ZID against GN organisms causing bloodstream infections (BSI) in hospitals worldwide. Methods A total of 2,094 isolates from 105 medical centers were evaluated. Isolates were collected from Europe (1,050), USA (331), Latin America (LA; 200) and the Asia-Pacific region (AP; 393) in 2015, and China (120) in 2013 by the SENTRY Program. Susceptibility (S) testing was performed by reference broth microdilution method against FEP-ZID (1:1 ratio) and comparators. The collection included 1,809 Enterobacteriaceae (ENT), 170 P. aeruginosa (PSA) and 115 Acinetobacter spp. (ASP). Results FEP-ZID was very active against ENT (MIC50/90 of ≤0.03/0.12 μg/mL) with 99.9 and 100.0% of isolates inhibited at ≤4/4 and ≤8/8 μg/mL, respectively, and retained potent activity against carbapenem-resistant (CRE; n = 44; MIC50/90, 1/4 μg/mL), multidrug-resistant (MDR), and extensively drug-resistant (XDR) isolates (Table). Amikacin (AMK; MIC50/90, 2/4 μg/mL; 97.7% S) was also very active against ENT, and colistin (COL; MIC50/90, 0.12/>8 μg/mL) inhibited only 87.3% of isolates at ≤2 μg/mL. FEP-ZID was highly active against PSA, including isolates resistant to other antipseudomonal β-lactams, MDR (MIC50/90, 4/8 μg/mL) and XDR (MIC50/90, 4/8 μg/mL) isolates. Among the comparators, COL (MIC50/90 of ≤0.5/1 μg/mL; 100.0% S) and AMK (MIC50/90, 4/16 μg/mL; 91.2% S) were the most active agents against PSA. FEP-ZID (MIC50/90, 16/32 μg/mL) was 4-fold more active than FEP against ASP. Conclusion FEP-ZID (WCK 5222) exhibited potent in vitro activity against a large worldwide collection of GN isolates from BSI, including MDR and XDR isolates. These results support further clinical development of WCK 5222 for treating BSI. Disclosures H. S. Sader, Wockhardt Bio Ag: Research Contractor, Research grant; M. Castanheira, Wockhardt Bio Ag: Research Contractor, Research grant; J. M. Streit, Wockhardt Bio Ag: Research Contractor, Research grant; L. R. Duncan, Wockhardt Bio Ag: Research Contractor, Research grant; R. K. Flamm, Wock: Research Contractor, Research support

scholarly journals 703. In Vitro Activity of Lefamulin Against Bacterial Pathogens Causing Community-Acquired Bacterial Pneumonia (CABP): SENTRY Surveillance 2017–2018 Results From the United States (US)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S317-S318
Author(s):  
Helio S Sader ◽  
Susanne Paukner ◽  
S J Ryan Arends ◽  
Steven P Gelone
Keyword(s):  
United States ◽  
Bacterial Pathogens ◽  
The United States ◽  
Vitro Activity ◽  
Protein Synthesis Inhibitor ◽  
Respiratory Pathogens ◽  
In Vitro Activity ◽  
Synthesis Inhibitor ◽  
Tract Infections

Abstract Background Lefamulin (LEF), a novel pleuromutilin protein synthesis inhibitor in development for use as an empiric IV and oral monotherapy for CABP, recently demonstrated safety and efficacy in two phase 3 trials in adults with CABP (PORT II–V). LEF IV or IV/oral (5–7 days; 10 days for methicillin-resistant Staphylococcus aureus [MRSA]) and LEF oral (5 days) were noninferior to MOX IV or IV/oral (7 days; 10 days for MRSA) and MOX oral (7 days) in patients with CABP caused by the most prevalent typical and atypical bacterial pathogens. This study investigated the in vitro activity of LEF and comparators against bacterial respiratory pathogens collected in the United States in 2017 and 2018. Methods As part of the SENTRY Surveillance Programme, isolates (n = 2299, 1/patient) were collected from 39 medical centers in the United States from patients with community-acquired respiratory tract infections (1812/2299 [78.8%]) and pneumonia in hospitalized patients (487/2299 [21.2%]). LEF and comparators were tested by broth microdilution and CLSI (2019) breakpoints were applied. Results LEF demonstrated potent antibacterial activity against all pathogens tested and was unaffected by resistance to other antibiotic classes (table). Streptococcus pneumoniae isolates were largely susceptible ( >80%) to most comparators; however, 45.6% and 20.4% were resistant (R) to macrolides and tetracycline, respectively. LEF exhibited a MIC50/90 of 0.12/0.25 mg/L for S. pneumoniae, including all R subsets. Among S. aureus isolates, and particularly MRSA, resistance to macrolides was high (48.5% and 81.2% R, respectively). LEF showed a MIC50/90 of 0.06/0.12 mg/L for S. aureus, including all R subsets. Haemophilus influenzae isolates were susceptible to all comparators except for ampicillin (31.4% R) and trimethoprim-sulfamethoxazole (35.3% R). LEF displayed a MIC50/90 of 0.5/2 mg/L for H. influenzae isolates. Moraxella catarrhalis isolates, which were largely β-lactamase positive (98%), were susceptible to all comparators. Conclusion LEF displayed potent in vitro activity against contemporary CABP pathogens collected in the United States. LEF activity was unaffected by resistance to other antibiotic classes, including fluoroquinolones, macrolides, β-lactams, and tetracyclines. Disclosures All authors: No reported disclosures.

scholarly journals 1041. In vitro activity of tebipenem against a recent collection of fastidious organisms recovered from respiratory tract infections

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S611-S611
Author(s):  
S J Ryan Arends ◽  
Abby L Klauer ◽  
Nicole Cotroneo ◽  
Ian A Critchley ◽  
Rodrigo E Mendes
Keyword(s):  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Oral Treatment ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Haemophilus Parainfluenzae ◽  
Recent Collection ◽  
Tract Infections ◽  
Research Grant

Abstract Background Tebipenem is under development as an oral treatment option for complicated urinary tract infections and acute pyelonephritis. This study further evaluated the in vitro activity of tebipenem against various fastidious organisms recovered from community-acquired respiratory tract infections (CARTIs). Methods The study included a total of 2,476 fastidious organisms: Haemophilus influenzae (692 isolates, including fluoroquinolone-resistant, β-lactamase-positive, and β-lactamase-negative ampicillin-resistant [BLNAR]), Haemophilus parainfluenzae (30 isolates, including β-lactamase-positive and BLNAR), Moraxella catarrhalis (490 isolates), and Streptococcus pneumoniae (1,264 isolates, including penicillin-resistant). The isolates were collected primarily from CARTIs (90.8%) and pneumonia in hospitalized patients (PIHPs, 9.2%). Organisms were tested using reference broth microdilution methods in a central laboratory. Results Tebipenem had MIC90 values of 0.5 mg/L against H. influenzae and 1 mg/L against H. parainfluenzae isolates. All 18 BLNAR isolates from these two species were inhibited at ≤1 mg/L of tebipenem. The MIC90 values observed for ertapenem and meropenem was 0.25 mg/L for these organisms. Tebipenem displayed good activity against M. catarrhalis (MIC90, 0.03 mg/L). Tebipenem inhibited 100% of S. pneumoniae isolates at ≤1 mg/L. Tebipenem activity (MIC90, 0.12 mg/L) was 8-fold greater than ertapenem (MIC90, 1 mg/L) against S. pneumoniae isolates. Conclusion Tebipenem displayed potent activity against fastidious organisms causing respiratory tract infections. Greater than 99.7% of all Haemophilus isolates, including all BLNAR, were inhibited at ≤1 mg/L. All M. catarrhalis isolates were inhibited at ≤0.03 mg/L. Although tebipenem activity correlated with penicillin resistance, all S. pneumoniae isolates were inhibited at ≤1 mg/L. Tebipenem in vitro activity was greater than ertapenem when tested against S. pneumoniae isolates. This data supports the possible development of tebipenem as an oral option for combating CARTIs caused by these organisms. Table Disclosures S J Ryan Arends, PhD, AbbVie (formerly Allergan) (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Abby L. Klauer, n/a, Cidara Therapeutics, Inc. (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Nicole Cotroneo, Spero Therapeutics (Employee, Shareholder) Ian A. Critchley, Ph.D., Spero Therapeutics (Employee, Shareholder) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)

scholarly journals 1226. In Vitro Activity of Tebipenem and Comparators Against Enterobacterales Collected from Patients with Bloodstream Infections as Part of the 2019 Global STEWARD Surveillance Program

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S702-S702
Author(s):  
Ian A Critchley ◽  
Nicole Cotroneo ◽  
Rodrigo E Mendes ◽  
Michael J Pucci
Keyword(s):  
Bloodstream Infections ◽  
Clinical Development ◽  
Asia Pacific ◽  
Surveillance Program ◽  
In Vitro Activity ◽  
Medical Centers ◽  
Oral Agents ◽  
The Us ◽  
Research Grant

Abstract Background Bloodstream infections (BSI) are a significant cause of morbidity and mortality. Enterobacterales (ENT) are frequently implicated in BSI with an increase in organisms producing extended-spectrum β-lactamase (ESBL). This challenges a possible transition to current oral agents due to co-resistance. Carbapenems are active against ESBL-ENT and tebipenem (TBP) is a new oral carbapenem in clinical development. The aim of the study was to assess resistance (R) among BSI isolates and activity of TBP and comparators against ENT collected in a 2019 surveillance study. Methods 2612 ENT from BSI were centrally tested by reference broth microdilution. Isolates were from medical centers in the US, Europe (EU), Latin America (LA) and Asia Pacific (AP). MIC results were interpreted according to CLSI, including ESBL assignment. CRE were sequenced to identify carbapenemase genes. Results Among the ENT, non-susceptibility (NS) rates to ceftazidime, levofloxacin were 20.4 and 27.0%, respectively, and R to trimethoprim-sulfamethoxazole was 31.1%. NS rates for ertapenem (ETP) and MER were 4.9 and 2.7%, respectively. MIC90s for TBP, ETP and MER were 0.12, 0.12 and 0.06 µg/mL, respectively. The MIC90 for TBP was 0.06 µg/mL for ENT from the US and 0.12 µg/mL for isolates from EU, LA and AP. Escherichia coli (EC) was the most prevalent (52% of ENT isolates) and the MIC90 for TBP ranged from 0.015 µg/mL for isolates in the US/EU to 0.03 µg/mL for isolates in LA/AP. ESBL-EC ranged from 15.7% in US to 34.3% in LA. TBP was active against ESBL-EC with an MIC90 of 0.03 µg/mL. Klebsiella pneumoniae (KP) accounted for 22.7% of BSI caused by ENT and TBP MIC90 ranged from 0.06 µg/mL for KP in US to >8 µg/mL in EU, LA and AP. MER-R KP ranged from 2.4% in US to 14.9% in LA. KPC-2, -3 and NDM were the most prevalent carbapenemases. TBP MIC90 values for MER-S ESBL KP in EU, LA and AP were ≤0.12 µg/mL. Conclusion TBP activity was similar to ETP and MER against ENT responsible for BSI. R to oral agents was compromised by ESBL co-resistance. TBP was among the most active agents against EC isolates and ESBL phenotypes. Among KP, TBP was more active against isolates from US where prevalence of CRE was lower than EU, LA and AP. TBP may be considered as an alternative oral option for BSI caused by non-CRE ESBL-producing ENT. Disclosures Ian A. Critchley, Ph.D., Spero Therapeutics (Employee, Shareholder) Nicole Cotroneo, Spero Therapeutics (Employee, Shareholder) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)

scholarly journals 693. In Vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against Enterobacteriaceae and Pseudomonas aeruginosa Collected From Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2014–2017

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S314-S314
Author(s):  
Krystyna Kazmierczak ◽  
Gregory Stone ◽  
Daniel F Sahm
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Therapeutic Option ◽  
Bloodstream Infections ◽  
The United States ◽  
Vitro Activity ◽  
Asia Pacific ◽  
Surveillance Program ◽  
In Vitro Activity ◽  
Susceptibility Data

Abstract Background Avibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The combination of ceftazidime (CAZ) with AVI has been approved in Europe and in the United States for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacteriaceae (Eba) and Pseudomonas aeruginosa (Pae) isolates collected from patients with bloodstream infections as part of the ATLAS surveillance program in 2014–2017. Methods A total of 53416 Eba and 15050 Pae nonduplicate clinically significant isolates, including 5155 Eba and 845 Pae isolated from bloodstream infections, were collected by 167 hospital laboratories in 36 countries in Europe, Latin America, Asia/Pacific (excluding China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. CAZ-AVI was tested at a fixed concentration of 4 µg/mL AVI. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes. Results Susceptibility data are shown in the Table. Percentages of susceptibility (% S) to the tested agents were 0.2–2.8% lower among Eba and Pae from bloodstream infections compared with isolates from combined sources in most cases. CAZ-AVI showed potent in vitro activity against all Eba bloodstream isolates and subsets of CAZ-NS and colistin-resistant (CST-R) isolates (MIC90, 0.5–2 µg/mL, 96.0–100% S). Reduced activity against MEM-NS Eba was attributable to carriage of class B metallo-β-lactamases (MBLs) because all MEM-NS MBL-negative isolates were susceptible to CAZ-AVI. CAZ-AVI also showed good in vitro activity against the majority of Pae bloodstream isolates (MIC90, 16 µg/mL, 89.5% S). Activity was reduced against CAZ-NS, MEM-NS and CST-R subsets (53.7–85.0% S), which included isolates carrying MBLs, but exceeded the activity of CAZ and MEM against these subsets by 15–65%. CST and amikacin were the only tested comparators that demonstrated comparable or greater activity against Pae bloodstream isolates. Conclusion CAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by MBL-negative Eba and Pae isolates. Disclosures All authors: No reported disclosures.

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