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

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Michael D. Huband ◽  
Rodrigo E. Mendes ◽  
Michael A. Pfaller ◽  
Jill M. Lindley ◽  
Gregory J. Strand ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Species Complex ◽  
Phase 1 ◽  
The United States ◽  
Clinical Development ◽  
Asia Pacific ◽  
Third Generation ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT 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-β-lactamase (ESBL)- and metallo-β-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.

scholarly journals Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
Debora Rubio-Aparicio ◽  
Thomas G. Nolan ◽  
Jonathan Parkinson ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Hollow Fiber ◽  
Phase 1 ◽  
Phase 3 ◽  
Fiber Model ◽  
Content Type ◽  
Development Of Resistance ◽  
Carbapenem Resistant ◽  
Dosage Regimens

ABSTRACT The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.

scholarly journals Semimechanistic Pharmacokinetic/Pharmacodynamic Modeling of Fosfomycin and Sulbactam Combination against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Sazlyna Mohd Sazlly Lim ◽  
Aaron J. Heffernan ◽  
Jason A. Roberts ◽  
Fekade B. Sime
Keyword(s):  
Acinetobacter Baumannii ◽  
Treatment Options ◽  
Pharmacodynamic Modeling ◽  
Synergistic Activity ◽  
Bacterial Burden ◽  
Target Attainment ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Time Kill

ABSTRACT Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates. Synergism of FOS/SUL against 50 clinical CR-AB isolates was screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill, and 2-log kill after 24 h of combination therapy. The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased 4- to 8-fold, compared to the monotherapy MIC50 and MIC90. In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro. Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam at 4 g every 8 h demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69 to 76%, compared to ∼15 to 30% with monotherapy regimens at the highest doses. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

Aztreonam/avibactam activity against clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019

2020 ◽  
Author(s):  
Helio S Sader ◽  
Cecilia G Carvalhaes ◽  
S J Ryan Arends ◽  
Mariana Castanheira ◽  
Rodrigo E Mendes
Keyword(s):  
Latin America ◽  
Western Europe ◽  
Multidrug Resistant ◽  
Clinical Development ◽  
Asia Pacific ◽  
Asia Pacific Region ◽  
Carbapenem Resistant ◽  
Serious Infections ◽  
Susceptibility Tests

Abstract Background Aztreonam is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs) and avibactam is a non-β-lactam β-lactamase inhibitor that effectively inhibits serine carbapenemases (CPs). Aztreonam/avibactam is under clinical development for treatment of serious infections caused by Gram-negative bacteria, including MBL-producers. Objectives To evaluate the in vitro activity of aztreonam/avibactam against clinical Enterobacterales isolates. Methods 8787 Enterobacterales were collected consecutively from 64 medical centres located in Western Europe (W-EU; n = 4616; 26 centres in 10 nations), Eastern Europe (E-EU; n = 1554; 11 centres in 9 nations), the Asia-Pacific region (APAC; n = 1456; 17 centres in 9 nations), and Latin America (LATAM; n = 1161; 10 centres in 6 nations). Susceptibility tests were performed by reference broth microdilution methods and interpreted according to EUCAST criteria. Results 99.9% of isolates were inhibited at aztreonam/avibactam MIC of ≤8 mg/L (MIC50/90, ≤0.03/0.12 mg/L), including 99.7% of carbapenem-resistant (CRE; n = 396; MIC50/90, 0.25/0.5 mg/L) and 99.7% of multidrug-resistant isolates (n = 1706; MIC50/90, 0.06/0.5 mg/L). CRE rates were 1.2%, 12.9%, 5.2%, and 5.8% in W-EU, E-EU, APAC, and LATAM, respectively (4.5% overall). A CP was identified in 90.2% of CRE isolates. The most common CPs were variants of KPC (35.9% of CRE), NDM (29.0%), and OXA-48 (26.8%). The highest aztreonam/avibactam MIC value among MBL-producers (n = 110; MIC50/90, 0.12/0.5 mg/L) was 2 mg/L. Susceptibility rates for ceftriaxone, meropenem, levofloxacin, and amikacin were highest in W-EU (80.9%, 99.0%, 80.7% and 97.9%, respectively) and lowest in E-EU (52.0%, 88.9%, 54.1%, and 84.2%, respectively). Conclusions Our results support clinical development of aztreonam/avibactam to treat infections caused by Enterobacterales, including MBL-producers.

scholarly journals ARGONAUT II Study of the In Vitro Activity of Plazomicin against Carbapenemase-Producing Klebsiella pneumoniae

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Michael R. Jacobs ◽  
Caryn E. Good ◽  
Andrea M. Hujer ◽  
Ayman M. Abdelhamed ◽  
Daniel D. Rhoads ◽  
...  
Keyword(s):  
United States ◽  
16S Rrna ◽  
Klebsiella Pneumoniae ◽  
Great Lakes ◽  
The United States ◽  
Great Lakes Region ◽  
In Vitro Activity ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT Plazomicin was tested against 697 recently acquired carbapenem-resistant Klebsiella pneumoniae isolates from the Great Lakes region of the United States. Plazomicin MIC50 and MIC90 values were 0.25 and 1 mg/liter, respectively; 680 isolates (97.6%) were susceptible (MICs of ≤2 mg/liter), 9 (1.3%) intermediate (MICs of 4 mg/liter), and 8 (1.1%) resistant (MICs of >32 mg/liter). Resistance was associated with rmtF-, rmtB-, or armA-encoded 16S rRNA methyltransferases in all except 1 isolate.

scholarly journals Global Dissemination ofblaKPCinto Bacterial Species beyond Klebsiella pneumoniae andIn VitroSusceptibility to Ceftazidime-Avibactam and Aztreonam-Avibactam

2016 ◽  
Vol 60 (8) ◽  
pp. 4490-4500 ◽  
Author(s):  
Krystyna M. Kazmierczak ◽  
Douglas J. Biedenbach ◽  
Meredith Hackel ◽  
Sharon Rabine ◽  
Boudewijn L. M. de Jonge ◽  
...  
Keyword(s):  
United States ◽  
Klebsiella Pneumoniae ◽  
Molecular Mechanisms ◽  
Bacterial Species ◽  
The United States ◽  
Asia Pacific ◽  
Gram Negative ◽  
Content Type ◽  
Global Problem

ABSTRACTTheKlebsiella pneumoniaecarbapenemase (KPC), first described in the United States in 1996, is now a widespread global problem in several Gram-negative species. A worldwide surveillance study collected Gram-negative pathogens from 202 global sites in 40 countries during 2012 to 2014 and determined susceptibility to β-lactams and other class agents by broth microdilution testing. Molecular mechanisms of β-lactam resistance among carbapenem-nonsusceptibleEnterobacteriaceaeandPseudomonas aeruginosawere determined using PCR and sequencing. Genes encoding KPC enzymes were found in 586 isolates from 22 countries (76 medical centers), including countries in the Asia-Pacific region (32 isolates), Europe (264 isolates), Latin America (210 isolates), and the Middle East (19 isolates, Israel only) and the United States (61 isolates). The majority of isolates wereK. pneumoniae(83.4%); however, KPC was detected in 13 additional species. KPC-2 (69.6%) was more common than KPC-3 (29.5%), with regional variation observed. A novel KPC variant, KPC-18 (KPC-3[V8I]), was identified during the study. Few antimicrobial agents tested remained effectivein vitroagainst KPC-producing isolates, with ceftazidime-avibactam (MIC90, 4 μg/ml), aztreonam-avibactam (MIC90, 0.5 μg/ml), and tigecycline (MIC90, 2 μg/ml) retaining the greatest activity againstEnterobacteriaceaecocarrying KPC and other β-lactamases, whereas colistin (MIC90, 2 μg/ml) demonstrated the greatestin vitroactivity against KPC-positiveP. aeruginosa. This analysis of surveillance data demonstrated that KPC is widely disseminated. KPC was found in multiple species ofEnterobacteriaceaeandP. aeruginosaand has now become a global problem.

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

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Cecilia G. Carvalhaes ◽  
Leonard R. Duncan ◽  
Wen Wang ◽  
Helio S. Sader
Keyword(s):  
Antibacterial Agent ◽  
The United States ◽  
Clinical Development ◽  
Clinical Isolates ◽  
The Novel ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Content Type ◽  
Vancomycin Resistant

ABSTRACT 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.

scholarly journals In VitroBactericidal Activity of Trimethoprim-Sulfamethoxazole Alone and in Combination with Colistin against Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

2016 ◽  
Vol 60 (11) ◽  
pp. 6903-6906 ◽  
Author(s):  
Martha Nepka ◽  
Efstathia Perivolioti ◽  
Eleni Kraniotaki ◽  
Lida Politi ◽  
Athanasios Tsakris ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Effective Therapy ◽  
Clinical Isolates ◽  
Serum Concentrations ◽  
Content Type ◽  
Clinical Strains ◽  
Carbapenem Resistant

ABSTRACTTrimethoprim-sulfamethoxazole alone and combined with colistin was testedin vitroagainst six carbapenem-resistantAcinetobacter baumannii(CRAB) clinical strains. After 24 h, at achievable serum concentrations, trimethoprim-sulfamethoxazole effectively killed all strains, while colistin killed only one strain. Trimethoprim-sulfamethoxazole plus colistin rapidly killed all strains after 6 h and for up to 24 h. Trimethoprim-sulfamethoxazole, one of the few remaining antimicrobials that still has a degree of activity, particularly combined with colistin, might represent an effective therapy for severe CRAB infections.

scholarly journals Worldwide Appraisal and Update (2010) of Telavancin Activity Tested against a Collection of Gram-Positive Clinical Pathogens from Five Continents

2012 ◽  
Vol 56 (7) ◽  
pp. 3999-4004 ◽  
Author(s):  
Rodrigo E. Mendes ◽  
Helio S. Sader ◽  
David J. Farrell ◽  
Ronald N. Jones
Keyword(s):  
Staphylococcus Aureus ◽  
The United States ◽  
Asia Pacific ◽  
Pacific Region ◽  
Asia Pacific Region ◽  
Gram Positive ◽  
Content Type ◽  
Viridans Group Streptococcus ◽  
Clinical Pathogens

ABSTRACTA total of 15,480 Gram-positive pathogens were collected from 89 sites in the United States, Europe, the Asia-Pacific region, and Latin America in 2010. Telavancin was active against indicatedStaphylococcus aureus(MIC50/90, 0.12/0.25 μg/ml), vancomycin-susceptibleEnterococcus faecalis(MIC50/90, 0.5/0.5 μg/ml), and beta-hemolytic (MIC50/90, 0.06/0.12 μg/ml) and viridans group streptococcus (MIC50/90, 0.03/0.06 μg/ml) isolates. These MIC results showed potency for telavancin equal to or greater than that of comparators. Thesein vitrodata confirm a continued potent activity of telavancin when tested against contemporary Gram-positive clinical isolates.

scholarly journals Results from the Solithromycin International Surveillance Program (2014)

2016 ◽  
Vol 60 (6) ◽  
pp. 3662-3668 ◽  
Author(s):  
David J. Farrell ◽  
Robert K. Flamm ◽  
Helio S. Sader ◽  
Ronald N. Jones
Keyword(s):  
The United States ◽  
Geographic Region ◽  
Clinical Development ◽  
Asia Pacific ◽  
Fourth Generation ◽  
Resistant Bacteria ◽  
Surveillance Program ◽  
Asia Pacific Region ◽  
Content Type ◽  
Important Indication

Solithromycin, a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide, was tested against a 2014 collection of 6,115 isolates, includingStreptococcus pneumoniae(1,713 isolates),Haemophilus influenzae(1,308),Moraxella catarrhalis(577),Staphylococcus aureus(1,024), and beta-hemolytic streptococci (1,493), by reference broth microdilution methods. The geographic samples included 2,748 isolates from the United States, 2,536 from Europe, 386 from Latin America, and 445 from the Asia-Pacific region. Solithromycin was observed to be very active againstS. pneumoniae(MIC50/90, 0.008/0.12 μg/ml), demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 μg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 μg/ml), with all strains being inhibited at a solithromycin MIC of ≤1 μg/ml. AgainstH. influenzae, solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 μg/ml), and both of these compounds were 2-fold less active than azithromycin (MIC50/90, 0.5/1 μg/ml). All but one of theM. catarrhalisisolates were inhibited by solithromycin at ≤0.25 μg/ml. Solithromycin inhibited 85.3% ofS. aureusisolates at ≤1 μg/ml, and its activity was lower against methicillin-resistant (MIC50/90, 0.06/>32 μg/ml) than against methicillin-susceptible (MIC50/90, 0.06/0.06 μg/ml) isolates. Little variation in solithromycin activity was observed by geographic region for the species tested. Solithromycin was very active against beta-hemolytic streptococci (MIC50/90, 0.015/0.03 μg/ml), and all isolates were inhibited at MIC values of ≤0.5 μg/ml. In conclusion, solithromycin demonstrated potent activity against global and contemporary (2014) pathogens that represent the major causes of community-acquired bacterial pneumonia. These data support the continued clinical development of solithromycin for the treatment of this important indication.

scholarly journals Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Juan Carlos Vázquez-Ucha ◽  
Marta Martínez-Guitián ◽  
María Maneiro ◽  
Kelly Conde-Pérez ◽  
Laura Álvarez-Fraga ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Combined Therapy ◽  
Severe Infection ◽  
Carbapenem Resistance ◽  
Antibacterial Treatment ◽  
Bacterial Burden ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D

ABSTRACT The carbapenem-hydrolyzing class D β-lactamases (CHDLs) are the main mechanism of carbapenem resistance in Acinetobacter baumannii. CHDLs are not effectively inactivated by clinically available β-lactam-type inhibitors. We have previously described the in vitro efficacy of the inhibitor LN-1-255 in combination with carbapenems. The aim of this study was to compare the efficacy of LN-1-255 with that of imipenem in murine pneumonia using A. baumannii strains carrying their most extended carbapenemases, OXA-23 and OXA-24/40. The blaOXA-23 and blaOXA-24/40 genes were cloned into the carbapenem-susceptible A. baumannii ATCC 17978 strain. Clinical isolates Ab1 and JC12/04, producing the enzymes OXA-23 and OXA-24/40, respectively, were used in the study. Pharmacokinetic (PK) parameters were determined. An experimental pneumonia model was used to evaluate the efficacy of the combined imipenem–LN-1-255 therapy. MICs of imipenem decreased between 32- and 128-fold in the presence of LN-1-255. Intramuscular treatment with imipenem–LN-1-255 (30/50 mg/kg) decreased the bacterial burden by (i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and Ab1 strains, respectively, and by (ii) 2.5 and 4.5 log10 CFU/g lung in the infection produced by the ATCC 17978-OXA-24/40 and the JC12/04 strains, respectively. In all assays, combined therapy offered higher protection against pneumonia than that provided by monotherapy. No toxicity was observed in treated mice. Imipenem treatment combined with LN-1-255 treatment significantly reduced the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclinical assays demonstrated the potential of LN-1-255 and imipenem therapy as a new antibacterial treatment.

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