In-vitro activity of cefepime against bacterial pathogens from hospitalized patients

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

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In Vitro Activity of Lefamulin against S. aureus Collected Worldwide from Hospitalized Patients with Bacterial Pneumonia

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.914 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S372-S372 ◽

Cited By ~ 2

Author(s):

Susanne Paukner ◽

Robert K Flamm ◽

Jason Schuchert ◽

Steven P Gelone ◽

Helio S Sader

Keyword(s):

Bacterial Pneumonia ◽

Methicillin Resistance ◽

Hospitalized Patients ◽

Vitro Activity ◽

Surveillance Program ◽

Invasive Infection ◽

In Vitro Activity ◽

Broth Microdilution Method ◽

Research Grant

Abstract Background S. aureus (SA) is a well-recognized cause of pneumonia from both the community and hospital settings. The clinical management of SA pneumonia is complicated by the invasive infection it can cause and the high prevalence of methicillin-resistance (MR). Lefamulin (LEF) is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans. LEF is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans and it specifically inhibits bacterial protein synthesis. LEF is currently in Phase 3 trials for the treatment of community-acquired bacterial pneumonia (CABP). This study investigated the in vitro activity of LEF and comparators against SA strains collected from patients hospitalized with pneumonia in 2015. Methods 1273 unique SA isolates were collected from hospitalized patients with pneumonia worldwide in 28 countries (33 sites) in 2015 as part of the SENTRY surveillance program. Isolates included 401 hospital-acquired (HA) SA (259 from ICU, 152 from ventilator associated pneumonia, VAP). Susceptibility testing was conducted using the CLSI broth microdilution method and susceptibility was interpreted per CLSI 2017 breakpoint criteria. Results LEF was the most potent compound tested, with 99.7% of all SA isolates being inhibited at a concentration of ≤0.25 mg/L (MIC50/90 values of 0.06/0.12 mg/L) and irrespective of the collection source (ICU/non-ICU, VAP/non-VAP). 31.6% of isolates (n = 402) were MRSA of which 99.3% were inhibited at a LEF concentration of ≤0.25 µg/mL (MIC50/90, 0.06/0.12 mg/L). Susceptibility rates for all SA isolates were >90% for ceftaroline, vancomycin, linezolid and doxycycline. Susceptibility to azithromycin, levofloxacin and clindamycin was limited, particularly among MRSA (see Table). Conclusion SA strains collected from patients hospitalized with pneumonia including HAP and VAP were highly susceptible to LEF regardless of the resistance phenotype to the other antibiotics tested. Due to its potent activity against resistant SA and the most prevalent typical and atypical respiratory pathogens, as well as the availability of IV and oral formulations, LEF has the potential to play a role in the empiric treatment of CABP and supports evaluation in HAP and VAP caused by SA. Disclosures S. Paukner, Nabriva Therapeutics: Employee and Shareholder, Salary; R. K. Flamm, Nabriva Therapeutics: Research Contractor, Research grant; J. Schuchert, Nabriva Therapeutics: Research Contractor, Research grant; S. P. Gelone, Nabriva Therapeutics: Employee and Shareholder, Salary; H. S. Sader, The Medicines Company: Research Contractor, Research grant

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