scholarly journals In Vitro Activity of Iclaprim against Isolates in Two Phase 3 Clinical Trials (REVIVE-1 and -2) for Acute Bacterial Skin and Skin Structure Infections

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Stephanie Noviello ◽  
Sophie Magnet ◽  
Stephen Hawser ◽  
David B. Huang
Keyword(s):  
Susceptibility Testing ◽  
In Vitro Activity ◽  
Phase 3 ◽  
Gram Positive ◽  
Two Phase ◽  
Content Type ◽  
Skin Structure ◽  
Streptococcus Anginosus ◽  
Antibacterial Susceptibility

ABSTRACT Iclaprim, a selective bacterial dihydrofolate reductase inhibitor, and other antibiotics were tested against Gram-positive isolates from two phase 3 studies of acute bacterial skin and skin structure infections (ABSSSIs) (REVIVE-1 and -2). Seven hundred ninety baseline isolates, including Staphylococcus aureus, β-hemolytic streptococci, and Streptococcus anginosus group, underwent antibacterial susceptibility testing. Iclaprim had an MIC90 of 0.12 μg/ml for S. aureus (0.12 μg/ml for methicillin susceptible, 0.25 μg/ml for methicillin resistant), 0.25 μg/ml for β-hemolytic streptococci, and 0.008 μg/ml for S. anginosus group. Iclaprim demonstrated potent activity against these Gram-positive ABSSSI isolates.

scholarly journals In VitroActivities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia

2015 ◽  
Vol 59 (10) ◽  
pp. 6262-6265 ◽  
Author(s):  
Ko-Hung Chen ◽  
Yu-Tsung Huang ◽  
Chun-Hsing Liao ◽  
Wang-Hui Sheng ◽  
Po-Ren Hsueh
Keyword(s):  
Staphylococcus Aureus ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Streptococcus Anginosus ◽  
Wide Range ◽  
Gram Positive Cocci

ABSTRACTTedizolid is a novel, expanded-spectrum oxazolidinone with potent activity against a wide range of Gram-positive pathogens. A total of 425 isolates of Gram-positive bacteria were obtained consecutively from patients with acute bacterial skin and skin structure infections (ABSSSIs) or pneumonia. These isolates included methicillin-susceptibleStaphylococcus aureus(MSSA) (n= 100), methicillin-resistantStaphylococcus aureus(MRSA) (n= 100),Streptococcus pyogenes(n= 50),Streptococcus agalactiae(n= 50),Streptococcus anginosusgroup (n= 75),Enterococcus faecalis(n= 50), and vancomycin-resistant enterococci (VRE) (Enterococcus faecium) (n= 50). The MICs of tedizolid and linezolid were determined by the agar dilution method. Tedizolid exhibited betterin vitroactivities than linezolid against MSSA (MIC90s, 0.5 versus 2 μg/ml), MRSA (MIC90s, 0.5 versus 2 μg/ml),S. pyogenes(MIC90s, 0.5 versus 2 μg/ml),S. agalactiae(MIC90s, 0.5 versus 2 μg/ml),Streptococcus anginosusgroup (MIC90s, 0.5 versus 2 μg/ml),E. faecalis(MIC90s, 0.5 versus 2 μg/ml), and VRE (MIC90s, 0.5 versus 2 μg/ml). The tedizolid MICs againstE. faecalis(n= 3) and VRE (n= 2) intermediate to linezolid (MICs, 4 μg/ml) were 1 μg/ml and 0.5 μg/ml, respectively. The tedizolid MIC90s against S. anginosus,S. constellatus, andS. intermediuswere 0.5, 1, and 0.5 μg/ml, respectively, and the rates of susceptibility based on the U.S. FDA MIC interpretive breakpoints to the isolates were 16%, 28%, and 72%, respectively. Tedizolid exhibited 2- to 4-fold betterin vitroactivities than linezolid against a variety of Gram-positive cocci associated with ABSSSIs and pneumonia. The lower susceptibilities of tedizolid against isolates ofS. anginosusandS. constellatusthan against those ofS. intermediusin Taiwan were noted.

scholarly journals In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Nicole E. Scangarella-Oman ◽  
Karen A. Ingraham ◽  
Courtney A. Tiffany ◽  
Lynn Tomsho ◽  
Stephanie F. Van Horn ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Phase 2 ◽  
Topoisomerase Inhibitors ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Phase 2 Study ◽  
Secondary Endpoints ◽  
Dose Ranging

ABSTRACT A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12 h [q12h], 1,000 mg q12h, and 1,000 mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines. Staphylococcus aureus accounted for 78/102 (76%) of Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA), and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the gepotidacin 750-mg q12h group, 89% for the 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5 μg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N, both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial agent. (This study has been registered at ClinicalTrials.gov under identifier NCT02045797.)

scholarly journals In Vitro Activity of Ceftobiprole against Pathogens from Two Phase 3 Clinical Trials of Complicated Skin and Skin Structure Infections

2008 ◽  
Vol 52 (9) ◽  
pp. 3418-3423 ◽  
Author(s):  
Karen M. Amsler ◽  
Todd A. Davies ◽  
Wenchi Shang ◽  
Michael R. Jacobs ◽  
Karen Bush
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Trials ◽  
In Vitro Activity ◽  
Phase 3 ◽  
Two Phase ◽  
Gram Negative ◽  
Skin Structure ◽  
Complicated Skin ◽  
Resistant Strains

ABSTRACT In phase 3 clinical trials for ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of ≤4 μg/ml. Against Enterobacteriaceae and Pseudomonas aeruginosa isolates, the potency of ceftobiprole was similar to that of cefepime.

scholarly journals In Vitro Activity of Delafloxacin and Microbiological Response against Fluoroquinolone-Susceptible and Nonsusceptible Staphylococcus aureus Isolates from Two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
S. McCurdy ◽  
L. Lawrence ◽  
M. Quintas ◽  
L. Woosley ◽  
R. Flamm ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
The United States ◽  
Phase 3 ◽  
Two Phase ◽  
Content Type ◽  
Skin Structure ◽  
Fluoroquinolone Antibiotics ◽  
Gram Negative Organisms ◽  
Intent To Treat

ABSTRACT Delafloxacin is an investigational anionic fluoroquinolone antibiotic with broad-spectrum in vitro activity, including activity against Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The in vitro activity of delafloxacin and the percent microbiological response in subjects infected with fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus isolates were determined from two global phase 3 studies of delafloxacin versus vancomycin plus aztreonam in patients with acute bacterial skin and skin structure infections (ABSSSI). Patients from 23 countries, predominately the United States but also Europe, South America, and Asia, were enrolled. The microbiological intent-to-treat (MITT) population included 1,042 patients from which 685 S. aureus isolates were submitted for identification and susceptibility testing per CLSI guidelines at the central laboratory (JMI Laboratories, North Liberty, IA). The comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Nonsusceptibility to these antibiotics was determined using CLSI breakpoints. S. aureus isolates were 33.7% levofloxacin nonsusceptible (LVX-NS). The delafloxacin MIC90 values against levofloxacin-nonsusceptible S. aureus, methicillin-resistant S. aureus (MRSA), and methicillin-susceptible S. aureus isolates were all 0.25 μg/ml. Delafloxacin demonstrated high rates of microbiological response against LVX-NS isolates as well as isolates with documented mutations in the quinolone resistance-determining region (QRDR). S. aureus was eradicated or presumed eradicated in 98.4% (245/249) of delafloxacin-treated patients. Similar eradication rates were observed for delafloxacin-treated subjects with levofloxacin-nonsusceptible S. aureus isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%). Microbiological response rates of 98.6% were observed with delafloxacin-treated subjects with S. aureus isolates with the S84L mutation in gyrA and the S80Y mutation in parC, the most commonly observed mutations in global phase 3 studies. The data suggest that delafloxacin could be a good option for the treatment of infections caused by S. aureus isolates causing ABSSSI, including MRSA isolates, where high rates of ciprofloxacin and levofloxacin nonsusceptibility are observed. (The phase 3 studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT01984684 and NCT01811732.)

scholarly journals A pooled analysis of patients with wound infections in the Phase 3 REVIVE trials: randomized, double-blind studies to evaluate the safety and efficacy of iclaprim versus vancomycin for treatment of acute bacterial skin and skin structure infections

2020 ◽  
Vol 69 (4) ◽  
pp. 625-630
Author(s):  
Stephanie Noviello ◽  
G. Ralph Corey ◽  
Thomas L. Holland ◽  
Thomas Lodise ◽  
William O’Riordan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Safety Profile ◽  
Wound Infections ◽  
Phase 3 ◽  
Gram Positive ◽  
Two Phase ◽  
Double Blind ◽  
Skin Structure ◽  
Treatment Difference ◽  
Vancomycin Treatment

Introduction. Iclaprim is a diaminopyrimidine antibiotic for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to Gram-positive pathogens. Aim. This analysis evaluates patients with wound infections from two Phase 3 trials of ABSSSI. Methodology. Six-hundred-two patients with wound infections from two Phase 3, double-blinded, randomized, multicenter, active controlled trials (REVIVE-1/–2) were evaluated in a post hoc analysis of iclaprim 80 mg compared with vancomycin 15 mg kg–1 administered intravenously every 12 h for 5–14 days. The primary endpoint was to determine whether iclaprim was non-inferior (10 % margin) to vancomycin in achieving a ≥20 % reduction from baseline in lesion size 48–72 h after starting study drug (early clinical response [ECR]). Safety was assessed. Results. In REVIVE-1, ECR was 83.5 % with iclaprim versus 79.7 % with vancomycin (treatment difference 3.77%, 95 % CI −4.50%, 12.04%). In REVIVE-2, ECR was 82.7 % with iclaprim versus 76.3 % with vancomycin (treatment difference 6.38%, 95 % CI −3.35%, 16.12%). In the pooled dataset, iclaprim had similar ECR rates compared with vancomycin among wound infection patients (83.2 % vs 78.2 %) with a treatment difference of 5.01 % (95 % CI −1.29%, 11.32%). The safety profile was similar in iclaprim- and vancomycin-treated patients, except for a higher incidence of diarrhea with vancomycin (n=17) compared with iclaprim (n=6) and fatigue with iclaprim (n=17) compared with vancomycin (n=8). Conclusion. Based on early clinical response, iclaprim achieved non-inferiority to vancomycin with a similar safety profile in patients with wound infections suspected or confirmed as caused by Gram-positive pathogens. Iclaprim may be a valuable treatment option for wound infections.

scholarly journals In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Gregory G. Stone ◽  
Patricia A. Bradford ◽  
Margaret Tawadrous ◽  
Dianna Taylor ◽  
Mary Jane Cadatal ◽  
...  
Keyword(s):  
Nosocomial Pneumonia ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
Ventilator Associated Pneumonia ◽  
Phase 3 ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active

ABSTRACT Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

scholarly journals 686. Evaluation of Contezolid Activity to Anaerobic and Gram-positive-cocci Isolates from a Phase 3 Acute Bacterial Skin and Skin Structure Infection Clinical Trial (MRX-I-06)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S312-S312
Author(s):  
Yang Yang ◽  
Demei Zhu
Keyword(s):  
Dilution Method ◽  
Phase 3 ◽  
Gram Positive ◽  
In Vitro Susceptibility ◽  
Skin Structure ◽  
Prevotella Bivia ◽  
In Vitro Antibacterial Activity ◽  
Agar Dilution ◽  
Leuconostoc Lactis

Abstract Background Contezolid (MRX-I) is an oxazolidinone in development for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). In this study, in vitro susceptibility (S) for Contezolid and comparator agents for Gram-positive (GP) and anaerobic isolates from Phase 3 ABSSSI clinical trials were determined. Methods 313 isolates were collected from 65 participated sites and sent to a central laboratory for MIC testing. Clinical isolates included 34 anaerobes (15 Finegoldia magna, 8 Actinomyces spp., 4 Prevotella spp., 3 Propionibacterium avidum, 2 Peptostreptococcus spp., 1 Veillonella spp. and 1 Bacteroides fragilis), 187 S. aureus (59.7%). 12 S. pyogenes, 5 Enterococcus, and 75 other Gram-positive organisms. Broth micro-dilution method was used to determine the MIC of contezolid, linezolid, and other comparators to facultative isolates. Agar dilution was carried out for the anaerobes. Results For both 33 MRSA and 154 MSSA MIC50/90 values of contezolid and linezolid were 2 mg/L. One E. faecalis showed decreased susceptibility to oxazolidinones (both MIC = 4). 1 mg/L contezolid and linezolid could inhibit 12 S. pyogenes. 2 mg/L contezolid and linezolid could inhibit 15 Finegoldia magna. 0.5 mg/L contezolid and linezolid could inhibit 8 Actinomyces spp. To one Bacteroides fragili, two Prevotella bivia and one Leuconostoc lactis (Intrinsic resistant to vancomycin) the MIC of contezolid were 4 or 8 mg/L. In general, Contezolid had lower or equal MIC50/90 values against both GP and ANA species compared with linezolid for all organisms. Conclusion Contezolid demonstrated potent in vitro antibacterial activity against Gram-positive and anaerobic isolates tested. These data suggest that contezolid might be a beneficial supplement to the arena against MDR Gram-positive infection. Disclosures All authors: No reported disclosures.

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