scholarly journals Ceftolozane–tazobactam for the treatment of osteomyelitis caused by multidrug-resistant pathogens: a case series

2019 ◽  
Vol 11 ◽  
pp. 204209861986208 ◽  
Author(s):  
Xing Tan ◽  
Ryan P. Moenster
Keyword(s):  
Case Reports ◽  
Case Series ◽  
Complicated Urinary Tract Infection ◽  
Multidrug Resistant ◽  
High Dose ◽  
Gram Negative ◽  
The Us ◽  
Attractive Option ◽  
Gram Negative Organisms

Ceftolozane–tazobactam (CT) is a recently approved novel cephalosporin and β-lactamase inhibitor combination agent with in vitro activity against various Gram-positive and Gram-negative pathogens, including several multidrug-resistant (MDR) Gram-negative organisms. CT is currently approved by the US Food and Drug Administration for the treatment of complicated intrabdominal infection and complicated urinary tract infection at a dose of 1.5 g intravenously every 8 h. This agent is an attractive option for MDR osteomyelitis (OM) treatment, but clinical data is limited to case reports and series. Here we report a series of five patients with MDR OM who were treated with CT. Pathogens involved in these infections were MDR Acinetobacter baumannii (two isolates) and MDR Pseudomonas aeruginosa (four isolates). Two patients were disease free 6 months after therapy was discontinued, one required an additional curative surgical procedure, and two (both on high-dose therapy) developed adverse reactions likely related to CT that necessitated early antibiotic discontinuation.

In Vitro Activity of Imipenem/Relebactam and Ceftolozane/Tazobactam Against Clinical Isolates of Gram-negative Bacilli With Difficult-to-Treat Resistance and Multidrug-resistant Phenotypes—Study for Monitoring Antimicrobial Resistance Trends, United States 2015–2017

2020 ◽  
Author(s):  
James A Karlowsky ◽  
Sibylle H Lob ◽  
Janet Raddatz ◽  
Daryl D DePestel ◽  
Katherine Young ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
First Line ◽  
Clin Microbiol Infect ◽  
Gram Negative ◽  
Novel Approach ◽  
The Us ◽  
Urinary Isolates

Abstract Background Multidrug-resistant (MDR) bacteria are frequently defined using the criteria established by Magiorakos et al [Clin Microbiol Infect 2012;18:268–81]. Difficult-to-treat resistance (DTR) [Kadri et al, Clin Infect Dis 2018;67:1803–14] is a novel approach to defining resistance in gram-negative bacilli focusing on treatment-limiting resistance to first-line agents (all β-lactams and fluoroquinolones). Methods Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MICs) were determined for imipenem/relebactam, ceftolozane/tazobactam, and comparators against respiratory, intraabdominal, and urinary isolates of Enterobacterales (n = 10 516) and Pseudomonas aeruginosa (n = 2732) collected in 26 US hospitals in 2015–2017. Results Among all Enterobacterales, 1.0% of isolates were DTR and 15.6% were MDR; 8.4% of P. aeruginosa isolates were DTR and 32.4% were MDR. MDR rates for Enterobacterales and DTR and MDR rates for P. aeruginosa were significantly higher (P < .05) in isolates collected in intensive care units (ICUs) than in non-ICUs and in respiratory tract isolates than in intraabdominal or urinary tract isolates. In addition, 82.4% of DTR and 92.1% of MDR Enterobacterales and 62.2% of DTR and 82.2% of MDR P. aeruginosa were imipenem/relebactam-susceptible, and 1.5% of DTR and 65.8% of MDR Enterobacterales and 67.5% of DTR and 84.0% of MDR P. aeruginosa were ceftolozane/tazobactam-susceptible. Conclusions MDR phenotypes defined using the Magiorakos criteria may overcall treatment-limiting resistance in gram-negative bacilli. In the US, DTR Enterobacterales were infrequent, while MDR Enterobacterales isolates and DTR and MDR P. aeruginosa were common. Imipenem/relebactam (Enterobacterales, P. aeruginosa) and ceftolozane/tazobactam (P. aeruginosa) retained in vitro activity against most DTR and MDR isolates.

scholarly journals 2214. Comparison of Cefepime–Zidebactam (WCK 5222), Ceftazidime–Avibactam, and Ceftolozane–Tazobactam Tested Against Gram-Negative Organisms Causing Pneumonia in United States Hospitals in 2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S755-S755 ◽  
Author(s):  
Helio S Sader ◽  
Cecilia G Carvalhaes ◽  
Rodrigo E Mendes ◽  
Mariana Castanheira ◽  
Robert K Flamm
Keyword(s):  
Therapeutic Option ◽  
High Dose ◽  
Gram Negative ◽  
E Coli ◽  
Highly Active ◽  
Medical Centers ◽  
Carbapenem Resistant ◽  
Gram Negative Organisms ◽  
Dual Mechanism

Abstract Background Zidebactam (ZID) is a bicyclo-acyl hydrazide antibiotic with a dual mechanism of action: selective Gram-negative PBP2 binding and β-lactamase inhibition. We evaluated the frequency and antimicrobial susceptibility (S) of Gram-negative bacilli (GNB) isolated from patients with pneumonia in US hospitals. Methods All 3,086 clinical isolates were consecutively collected from patients hospitalized with pneumonia (1/patient) in 29 US medical centers in 2018, and the GNB (n = 2,171) were S tested against cefepime (FEP)-ZID (1:1 ratio) and comparators by reference broth microdilution methods. The FEP S breakpoint of ≤8 mg/L (CLSI, high dose) was applied to FEP-ZID for comparison purposes. An FEP-ZID S breakpoint of ≤64 mg/L has been proposed for non-fermentative GNB based on pharmacokinetic/pharmacodynamic target attainment and was applied. Enterobacterales (ENT) isolateswere screened for β-lactamase genes by whole-genome sequencing. Results GNB represented 70.3% of the collection, and the most common GNB were P. aeruginosa (PSA; 34.9% of GNB), K. pneumoniae (10.9%), E. coli (9.7%), S. marcescens (7.7%), and S. maltophilia (XM; 6.4%). FEP-ZID was highly active against PSA (MIC50/90, 2/8 mg/L; 98.8% and 99.9% inhibited at ≤8 and ≤16 mg/L, respectively; highest MIC, 32 mg/L), including resistant subsets (table). Among comparators, colistin (99.6%S), ceftazidime–avibactam (CAZ-AVI; 95.2%S), and ceftolozane–tazobactam (C-T; 94.5%S) were the most active compounds against PSA. FEP-ZID inhibited all ENT at ≤4 mg/L, including ESBL-producers (MIC90, 0.25 mg/L) and carbapenem-resistant ENT (MIC90, 4 mg/L). The most active comparators against ENT were CAZ-AVI (99.9%S), amikacin (98.5%S), and meropenem (MEM; 98.3%S). FEP-ZID inhibited 75.0% and 97.9% of XM isolates at ≤8 and ≤16 mg/L, respectively (highest MIC, 64 mg/L). The only other compounds active against XM were co-trimoxazole (MIC50/90, ≤0.12/2 mg/L; 95.7%S) and levofloxacin (MIC50/90, 1/2 mg/L; 70.7%S). FEP-ZID inhibited 71.0% and 98.9% of A. baumannii isolates at ≤8 and ≤64 mg/L,, respectively. Conclusion FEP-ZID showed potent in vitro activity against GNB causing pneumonia in US hospitals and may represent a valuable therapeutic option for these difficult-to-treat infections Disclosures All authors: No reported disclosures.

scholarly journals Prolonged Use of Oritavancin for Vancomycin-Resistant Enterococcus faecium Prosthetic Valve Endocarditis

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Jennifer A. Johnson ◽  
Eoin R. Feeney ◽  
David W. Kubiak ◽  
G. Ralph Corey
Keyword(s):  
Prosthetic Valve ◽  
Case Reports ◽  
Treatment Options ◽  
Prosthetic Valve Endocarditis ◽  
Additional Treatment ◽  
High Dose ◽  
Vancomycin Resistant Enterococci ◽  
The Us ◽  
Vancomycin Resistant

Abstract Oritavancin is a novel lipoglycopeptide with activity against Gram-positive organisms including streptococci, methicillin-resistant Staphylococcus aureus, vancomycin-resistant S aureus (VRSA), and vancomycin-resistant enterococci (VRE) [1–3]. The US Food and Drug Administration approved oritavancin as a single intravenous dose of 1200 mg for the treatment of acute bacterial skin and skin structure infections on the basis of 2 clinical trials demonstrating noninferiority compared with vancomycin [4, 5]. There are limited options for treatment of serious VRE infections. Monotherapy with daptomycin or tigecycline or linezolid may be sufficient in some cases, but combination therapy is often indicated for severe or complicated infections such as endocarditis. Several antibiotic combinations have been used in isolated case reports with some efficacy, including the following: high-dose ampicillin with an aminoglycoside [6], ampicillin with ceftriaxone or imipenem [7, 8], high-dose daptomycin with ampicillin and gentamicin [9] or with gentamicin and rifampin [10], daptomycin with tigecycline [11, 12], quinupristin-dalfopristin with high-dose ampicillin [13] or doxycycline and rifampin [14], and linezolid with tigecycline [15]. The limited efficacy, limited susceptibility, and extensive toxicities with many of these agents and combinations present barriers to effective treatment. Additional treatment options for VRE endocarditis would be valuable. Although oritavancin has been shown to have in vitro activity against some isolates of VRE, clinical data are lacking. We describe the first use of a prolonged course of oritavancin in the treatment of a serious VRE infection, prosthetic valve endocarditis.

scholarly journals In Vitro Activity of the Histatin Derivative P-113 against Multidrug-Resistant Pathogens Responsible for Pneumonia in Immunocompromised Patients

2005 ◽  
Vol 49 (3) ◽  
pp. 1249-1252 ◽  
Author(s):  
Andrea Giacometti ◽  
Oscar Cirioni ◽  
Wojciech Kamysz ◽  
Giuseppina D'Amato ◽  
Carmela Silvestri ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Vitro Activity ◽  
Immunocompromised Patients ◽  
In Vitro Activity ◽  
Beta Lactams ◽  
Gram Negative ◽  
Resistant Strains ◽  
Multidrug Resistant Pathogens ◽  
Gram Negative Organisms

ABSTRACT The in vitro activity of the histatin derivative P-113, alone or combined with eight antibiotics, was investigated against multidrug-resistant strains isolated from clinical specimens of immunocompromised patients with pneumonia. The gram-negative isolates were susceptible to P-113. S. aureus showed less susceptibility. Synergy was demonstrated when P-113 was combined with beta-lactams against gram-negative organisms.

scholarly journals 698. In vitro Activity of a New Generation Oxopyrazole Antibiotic Against Multidrug-Resistant Gram-Negative Bacilli

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S315-S316
Author(s):  
Joel Goldberg ◽  
Christopher Bethel ◽  
Andrea M Hujer ◽  
Kristine Hujer ◽  
Steven Marshall ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
E Coli ◽  
New Class ◽  
Resistant Strains ◽  
Gram Negative Organisms ◽  
New Generation ◽  
Hospital Acquired

Abstract Background Multidrug-resistant Gram-negative bacilli (MDRGNB) are emerging as a challenging cause of hospital-acquired infections and represent a critical need for innovative antibacterial development. New oxopyrazole agents targeting penicillin-binding proteins (PBPs) based on a non-β-lactam core and incorporating a siderophore moiety (Figure 1) which facilitates transport to the periplasm are being developed that show promise against Gram-negative organisms including multidrug-resistant strains of E. coli, K. pneumoniae and P. aeruginosa. Methods YU253434, an example of this new class of antibacterials, was investigated in vitro. Minimum inhibitory concentrations (MICs) were determined by broth microdilution against a representative panel comprising 15 strains each of E. coli, K. pneumoniae and P. aeruginosa, which contain extended-spectrum β-lactamase (ESBL) and/or carbapenemases genes.All studies were performed according to current Clinical & Laboratory Standards Institute (CLSI) guidelines using iron-depleted media. Ceftazidime breakpoints were arbitrability chosen as a reference for YU253434 (susceptibilities ≤4 μg/mL for Enterobacteriaceae and ≤8 μg/mL for P. aeruginosa). Results MIC testing (Figures 2–4) against E. coli showed 11 strains were YU253434 susceptible (compared with 6 for ceftazidime, and 3 for imipenem); against K. pneumoniae 13 strains were YU253434 susceptible (compared with 2 for ceftazidime and 6 for imipenem); against P. aeruginosa 10 strains were YU253434 susceptible (compared with 0 for both ceftazidime and imipenem). There appeared to be no correlation between YU253434 resistance and the presence of specific lactamase genes. Conclusion YU253434, a new generation oxopyrazole antibiotic, demonstrated promising in vitro potency against a panel of E. coli, K. pneumonia, and P. aeruginosa strains which contain ESBL and/or carbapenemases genes. Disclosures All authors: No reported disclosures.

scholarly journals In Vivo Efficacy of Simulated Human Dosing Regimens of Prolonged-Infusion Doripenem against Carbapenemase- Producing Klebsiella pneumoniae

2010 ◽  
Vol 54 (10) ◽  
pp. 4112-4115 ◽  
Author(s):  
Catharine C. Bulik ◽  
David P. Nicolau
Keyword(s):  
Klebsiella Pneumoniae ◽  
White Blood Cells ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Wide Range ◽  
Dosing Regimens ◽  
Gram Negative Organisms ◽  
Immunocompromised Mice

ABSTRACT Carbapenemase-producing Klebsiella pneumoniae (KPC) bacteria are rapidly becoming one of the most detrimental drug-resistant Gram-negative pathogens. Doripenem is the newest FDA-approved carbapenem that has the greatest in vitro potency against a wide range of Gram-negative organisms, including multidrug-resistant organisms. Previous work in an animal model has shown efficacy against Pseudomonas aeruginosa with MICs above the current breakpoints of susceptibility. The purpose of this study is to evaluate the efficacy of 1-g and 2-g dose prolonged infusions of doripenem against KPC isolates in both an immunocompetent and neutropenic murine thigh model. Seven clinical KPC isolates (broth microdilution [BMD] MIC range, 4 to 32 μg/ml; Etest MIC range, 3 to >32 μg/ml) were used. After infection, groups of mice were administered doripenem doses previously shown to simulate the exposures observed in humans after the administration of 1 or 2 g every 8 h as a 4-h infusion. In immunocompromised mice, 1- and 2-g doses of doripenem achieved bacteriostasis against isolates with MICs up to and including 8 μg/ml and 16 μg/ml, respectively. In immunocompetent animals, statistically significant reductions in the number of CFU were observed with overall decreases of approximately 1 log (P < 0.05). While carbapenemase-producing Klebsiella pneumoniae continues to decrease our meager supply of active agents, the ability of doripenem to produce CFU reductions in the presence of white blood cells (WBCs) using humanized exposures suggests the potential utility of this agent in combination against this increasingly problematic pathogen.

scholarly journals In Vitro Activities of the Rx-01 Oxazolidinones against Hospital and Community Pathogens

2008 ◽  
Vol 52 (5) ◽  
pp. 1653-1662 ◽  
Author(s):  
Laura Lawrence ◽  
Paul Danese ◽  
Joe DeVito ◽  
Francois Franceschi ◽  
Joyce Sutcliffe
Keyword(s):  
Staphylococcus Aureus ◽  
Moraxella Catarrhalis ◽  
Multidrug Resistant ◽  
Gram Positive ◽  
Gram Negative ◽  
Vancomycin Resistant Enterococci ◽  
The Family ◽  
Vancomycin Resistant ◽  
Gram Negative Organisms

ABSTRACT Rx-01_423 and Rx-01_667 are two members of the family of oxazolidinones that were designed using a combination of computational and medicinal chemistry and conventional biological techniques. The compounds have a two- to eightfold-improved potency over linezolid against serious gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant streptococci, and vancomycin-resistant enterococci. This enhanced potency extends to the coverage of linezolid-resistant gram-positive microbes, especially multidrug-resistant enterococci and pneumococci. Compounds from this series expand the spectrum compared with linezolid to include fastidious gram-negative organisms like Haemophilus influenzae and Moraxella catarrhalis. Like linezolid, the Rx-01 compounds are bacteriostatic against MRSA and enterococci but are generally bactericidal against S. pneumoniae and H. influenzae.

scholarly journals 708. In Vitro Activity of Plazomicin vs. Clinical Isolates of Gram-Negative Bacilli, Including Aminoglycoside Nonsusceptible and Multidrug-Resistant Subsets, Recovered from Patients Across Canada as Part of the CANWARD study, 2011–2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S319-S319
Author(s):  
Andrew Walkty ◽  
Heather Adam ◽  
Melanie Baxter ◽  
Philippe Lagace-Wiens ◽  
James Karlowsky ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Gram Negative ◽  
E Coli ◽  
The Us ◽  
Us Fda ◽  
Tract Infections

Abstract Background Plazomicin (PLZ) is a next-generation aminoglycoside currently approved by the US FDA for the treatment of complicated urinary tract infections, including pyelonephritis. The purpose of this study was to evaluate the in vitro activity of PLZ against a large collection of Gram-negative bacilli obtained from patients attending Canadian hospitals. Methods Annually from 2011 to 2018, sentinel hospitals across Canada submitted blood, respiratory, urine, and wound isolates from patients attending ERs, medical and surgical wards, hospital clinics, and ICUs (CANWARD). Susceptibility testing was performed using broth microdilution (and breakpoints) as described by CLSI (FDA breakpoints used for PLZ). Results See table. S, susceptible; NS, nonsusceptible; ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant (NS to antimicrobials from three or more classes); n.d., not defined. Conclusion PLZ demonstrated excellent in vitro activity vs. E. coli and K. pneumoniae clinical isolates, including aminoglycoside NS, ESBL-positive, and MDR subsets. Disclosures All authors: No reported disclosures.

scholarly journals Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Iris H. Chen ◽  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Multidrug Resistant ◽  
Bacterial Reduction ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type ◽  
Log Reduction ◽  
Gram Negative Organisms

ABSTRACT Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of β-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (20-g, 3-h infusion every 8 h [Q8H]) and ceftazidime (2-g, 2-h infusion Q8H) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/ml, and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10 CFU/thigh at 24 h compared to 0-h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; the mean bacterial reduction at 24 h was −2.67 ± 0.68 log10 CFU/thigh with ≥2-log reduction achieved in 21 isolates (87.5%) and a ≥1-log reduction achieved in the remaining 3 isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced a mean bacterial reduction of −1.38 ± 1.49 log10 CFU/thigh among 10 ceftazidime-susceptible isolates and a mean bacterial growth of 0.64 ± 0.79 log10 CFU/thigh among 14 ceftazidime-nonsusceptible isolates. Although ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-nonsusceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.

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