A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales

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.

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Cefiderocol: A Siderophore Cephalosporin

Annals of Pharmacotherapy ◽

10.1177/1060028020929988 ◽

2020 ◽

Vol 54 (12) ◽

pp. 1215-1231

Author(s):

Rania M. El-Lababidi ◽

John George Rizk

Keyword(s):

Nosocomial Pneumonia ◽

Data Extraction ◽

Multidrug Resistant ◽

Phase Iii ◽

Gram Negative ◽

Carbapenem Resistant ◽

Study Selection ◽

Serious Infections ◽

Wide Range ◽

Tract Infections

Objective: This article reviews the available data on the chemistry, spectrum of activity, pharmacokinetic and pharmacodynamic properties, clinical efficacy, and potential place in therapy of cefiderocol. Data Sources: A literature search through PubMed, Google Scholar, and ClinicalTrials.gov was conducted (2009 to March 2020) using the search terms cefiderocol and S-649266. Abstracts presented at recent conferences, prescribing information, and information from the US Food and Drug Administration (FDA) and the manufacturer’s website were reviewed. Study Selection and Data Extraction: All relevant published articles, package inserts, and unpublished meeting abstracts on cefiderocol were reviewed. Data Synthesis: Cefiderocol is the first siderophore antibiotic to be approved by the FDA. It was shown to be active against a wide range of resistant Gram-negative pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae, and Stenotrophomonas maltophilia. Cefiderocol was studied in the treatment of adult patients with complicated urinary tract infections (cUTIs) and nosocomial pneumonia and was well tolerated. In a recently completed prospective study, higher mortality was observed with cefiderocol in the treatment of serious infections caused by carbapenem-resistant (CR) Gram-negative pathogens. Relevance to Patient Care and Clinical Practice: The approval of cefiderocol provides a new option in the treatment of cUTIs and potentially treatment of nosocomial pneumonia caused by resistant Gram-negative pathogens. Given the higher mortality observed with cefiderocol, its use in the treatment of CR Gram-negative infections should be carefully considered. Conclusion: Cefiderocol shows promising activity against MDR Gram-negative pathogens. Its use in the treatment of serious infections caused by CR Gram-negative bacteria needs further evaluation in phase III clinical studies.

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Implementation of vancomycin dosing nomogram in an electronic prescribing system: an innovative tool in antibiotic stewardship

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502014000300016 ◽

2014 ◽

Vol 50 (3) ◽

pp. 567-572 ◽

Cited By ~ 2

Author(s):

Tácio de Mendonça Lima ◽

Sabrina Calil Elias ◽

Rita de Cássia Elias Estrela ◽

Fernando Luiz Lopes Cardoso

Keyword(s):

Electronic Prescribing ◽

Pharmacokinetics And Pharmacodynamics ◽

Trough Serum ◽

Serious Infections ◽

Serum Trough ◽

Dosing Regimens ◽

Basic Parameters ◽

Innovative Tool ◽

Computer Based ◽

Dosing Nomogram

Vancomycin (VAN) is the gold standard therapy for Methicillin-resistant Staphylococcus aureus(MRSA) infections such as bacteremia and endocarditis. However, VAN suboptimal dosing for serious infections caused by S. aureus isolates that have elevated minimum inhibitory concentration (MIC), could be associated with poor outcome. Better understanding of VAN pharmacokinetics and pharmacodynamics (PK/PD) has led to the creation of new recommendations with optimized dosing regimens for the treatment of MRSA infections. For severe infectious, such as pneumonia and endocarditis, a VAN serum trough concentration of 15-20 mg/L at the steady state should be targeted. The aim of this study was to show how a nomogram with updated VAN dosing was devised and how it was implemented in the electronic prescribing (e-prescribing) system of a teaching hospital. VAN loading dose and maintenance doses were calculated from a pharmacokinetic equation using basic parameters: weight, estimated creatinine clearance, as well as peak and trough serum concentrations. The implementation of the VAN dosing nomogram in the hospital e-prescribing system definitively changed the long-standing medical prescription fallacy of "same dose fits all". Finally, this computer-based electronic program has allowed a wide-ranging intervention and should be recognized as a powerful tool for implementation in antimicrobial stewardship programs.

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165. Cefiderocol Treatment for Serious Infections Caused by Carbapenem-resistant Bacteria: Post-hoc Analysis of Outcomes by Pathogen in the CREDIBLE-CR Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.475 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S212-S212

Author(s):

Yuko Matsunaga ◽

Mari Ariyasu ◽

Miki Takemura ◽

Yoshinori Yamano ◽

Kiichiro Toyoizumi ◽

...

Keyword(s):

Clinical Cure ◽

Carbapenem Resistance ◽

Bloodstream Infections ◽

Resistant Bacteria ◽

Open Label ◽

Gram Negative ◽

Mitt Population ◽

Carbapenem Resistant ◽

Serious Infections ◽

Tract Infections

Abstract Background The efficacy and safety of cefiderocol (CFDC), a novel siderophore cephalosporin, for the treatment of serious infections due to carbapenem-resistant (CR) Gram-negative pathogens was assessed in the CREDIBLE-CR study. The current analysis evaluated clinical and microbiological outcomes by baseline CR pathogen. Methods An open-label, prospective, randomised 2:1, Phase 3 study (CREDIBLE-CR; NCT02714595) was conducted in adult patients with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia, bloodstream infections or sepsis, and complicated urinary tract infections caused by CR Gram-negative pathogens. Patients received either intravenous (IV) CFDC 2g, q8h, 3-h infusion, or IV best available therapy (BAT: up to 3 drugs in combination), for 7–14 days (extendable to 21 days). Clinical and microbiological outcomes were assessed in the CR microbiological intent-to-treat (CR-MITT) population by CR pathogen, baseline MIC and by mechanism of carbapenem resistance at test of cure (TOC). Only summary statistics were collected. Results In the CR-MITT population (CFDC N=80; BAT N=38), Acinetobacter baumannii (46.3% and 44.7%), Klebsiella pneumoniae (33.8% and 31.5%), and Pseudomonas aeruginosa (15% and 26%) were the most frequent pathogens in CFDC and BAT arms, respectively. For all CR pathogens, clinical cure rates were achieved in 52.5% in the CFDC arm and 50.0% in the BAT arm at TOC; rates were similar between treatment arms by baseline CR pathogen (Table 1). Numerically higher clinical cure and microbiological outcomes were observed with CFDC for Enterobacterales (Table 1), especially against NDM-producing bacteria or those with porin-channel mutations (Table 1). CFDC MIC values ranged between ≤0.03 and 4 μg/mL, except for one pathogen (Table 2). Microbiological outcomes for CR A. baumannii, CR K. pneumoniae, and CR P. aeruginosa at TOC by baseline MICs of ≤4 μg/mL ranged between 0–40%, 0–100%, and 0–100%, respectively; at MIC ≤4 μg/mL, clinical and microbiological outcomes were equal (Table 2). Conclusion CFDC, via a novel mechanism of entry and its stability against β-lactamases, was effective against serious infections caused by CR pathogens with various resistance mechanisms or baseline MIC values. Disclosures Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Masahiro Kinoshita, MPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

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Association Between Carbapenem Resistance and Mortality Among Adult, Hospitalized Patients With Serious Infections Due to Enterobacteriaceae: Results of a Systematic Literature Review and Meta-analysis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy150 ◽

2018 ◽

Vol 5 (7) ◽

Cited By ~ 40

Author(s):

Amber Martin ◽

Kyle Fahrbach ◽

Qi Zhao ◽

Thomas Lodise

Keyword(s):

Literature Review ◽

Systematic Literature Review ◽

Meta Analysis ◽

Carbapenem Resistance ◽

Hospitalized Patients ◽

Mortality Data ◽

Carbapenem Resistant ◽

Serious Infections ◽

New Antibiotics ◽

Appropriate Therapy

Abstract This study quantified mortality associated with serious infections caused by carbapenem-resistant (CRE) and carbapenem-susceptible Enterobacteriaceae (CSE). A systematic literature review was conducted, evaluating outcomes in hospitalized patients with CRE infections from a blood, urinary, pulmonary, or intra-abdominal source. A meta-analysis (MA) calculating odds ratios (ORs) for mortality was performed. Twenty-two studies met the criteria for inclusion in the MA: 12 included mortality data for CRE vs CSE populations. Compared with CSE, CRE was associated with a significantly higher risk of overall mortality (OR, 3.39; 95% confidence interval [CI], 2.35–4.89), as was monotherapy (vs combination therapy) treatment of patients with CRE infections (OR, 2.19; 95% CI, 1.00–4.80). These results document the increased mortality associated with serious CRE infections compared with CSE infections among hospitalized adults. It will be important to reevaluate the mortality in CRE and CSE populations, especially among patients who receive early appropriate therapy, as new antibiotics become available.

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Antibiotic combinations for serious infections caused by carbapenem-resistant Acinetobacter baumannii in a mouse pneumonia model

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkh485 ◽

2004 ◽

Vol 54 (6) ◽

pp. 1085-1091 ◽

Cited By ~ 93

Author(s):

Abelardo Montero ◽

Javier Ariza ◽

Xavier Corbella ◽

Alejandro Doménech ◽

Carmen Cabellos ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Carbapenem Resistant ◽

Serious Infections

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Impact of Two Antibiotic Therapies on Clinical Outcome and Gut Microbiota Profile in Liver Transplant Paediatric Candidates Colonized by Carbapenem-Resistant Klebsiella pneumoniae CR-KP

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.730904 ◽

2021 ◽

Vol 11 ◽

Author(s):

Sabrina Cardile ◽

Federica Del Chierico ◽

Manila Candusso ◽

Sofia Reddel ◽

Paola Bernaschi ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Gut Microbiota ◽

Liver Transplant ◽

Short Chain Fatty Acids ◽

Multidrug Resistant ◽

Transplant Patients ◽

Carbapenem Resistant ◽

Serious Infections ◽

One Year ◽

The Impact

Colonization by multidrug-resistant (MDR) organisms in liver transplant (LT) candidates significantly affects the LT outcome. To date, consensus about patient management is lacking, including microbiological screening indications. This pilot study aimed to evaluate the impact of carbapenem-resistant Klebsiella pneumoniae (CR-KP) colonization in LT paediatric candidates to enable optimal prevention and therapeutic strategies that exploit both clinical and microbiological approaches. Seven paediatric patients colonized by CR-KP were evaluated before and until one-year post LT. At the time of the transplant, patients were stratified based on antibiotic (ATB) prophylaxis into two groups: ‘standard ATB’ (standard ATB prophylaxis), and ‘targeted ATB’ (MDR antibiogram-based ATB prophylaxis). Twenty-eight faecal samples were collected during follow-up and used for MDR screening and gut microbiota 16S rRNA-based profiling. Post-transplant hospitalization duration was comparable for both groups. With the exception of one patient, no serious infections and/or complications, nor deaths were recorded. A progressive MDR decontamination was registered. In the ‘standard ATB’ group, overall bacterial richness increased. Moreover, 6 months after LT, Lactobacillus and Bulleidia were increased and Enterobacteriaceae and Klebsiella spp. were reduced. In the ‘targeted ATB’ group Klebsiella spp., Ruminococcus gnavus, Erysipelotrichaceae, and Bifidobacterium spp. were increased 12 months after LT. In conclusion, both antibiotics prophylaxis do not affect nor LT outcomes or the risk of intestinal bacterial translocation. However, in the ‘standard ATB’ group, gut microbiota richness after LT was increased, with an increase of beneficial lactic acid- and short-chain fatty acids (SCFA)-producing bacteria and the reduction of harmful Enterobacteriaceae and Klebsiella spp. It could therefore be appropriate to administer standard prophylaxis, reserving the use of ATB-based molecules only in case of complications.

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Novel Specific Metallo-ß-lactamase Inhibitor, ANT2681, Restores Meropenem Activity to Clinically Effective Levels Against NDM-Positive Enterobacterales

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00203-21 ◽

2021 ◽

Author(s):

Magdalena Zalacain ◽

Clarisse Lozano ◽

Agustina Llanos ◽

Nicolas Sprynski ◽

Thomas Valmont ◽

...

Keyword(s):

Therapeutic Option ◽

Treatment Options ◽

Competitive Inhibitor ◽

Health Concern ◽

New Delhi ◽

E Coli ◽

Carbapenem Resistant ◽

Serious Infections ◽

High Incidence ◽

Additional Resistance

The global dissemination of metallo-ß-lactamase (MBL)-producing carbapenem resistant Enterobacterales (CRE) is a serious public health concern. Specifically, NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, particularly as effective treatments for serine-ß-lactamase (SBL)-producing Enterobacterales are now commercially available. Since the NDM gene is carried on promiscuous plasmids encoding multiple additional resistance determinants, a large proportion of NDM-CREs are also resistant to many commonly used antibiotics, resulting in limited and sub-optimal treatment options. ANT2681 is a specific, competitive inhibitor of MBLs with potent activity against NDM enzymes, progressing to clinical development in combination with meropenem (MEM). Susceptibility studies have been performed with MEM-ANT2681 against 1,687 MBL-positive Enterobacterales, including 1,108 NDM-CRE. Addition of ANT2681 at 8 μg/ml reduced MEM MIC50/MIC90 from >32/>32 μg/ml to 0.25/8 μg/ml. Moreover, the combination of 8 μg/ml of both MEM and ANT2681 inhibited 74.9% of the VIM-positive and 85.7% of the IMP-positive Enterobacterales tested. The antibacterial activity of MEM-ANT2681 against NDM-CRE compared very favourably to that of cefiderocol (FDC) and cefepime (FEP)-taniborbactam, which displayed MIC90 values of 8 μg/ml and 32 μg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had an MIC90 of 0.5 μg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive E. coli (MIC90 1 μg/ml), in contrast to ATM-AVI (MIC90 4 μg/ml), FDC (MIC90 >32 μg/ml) and FEP-taniborbactam (MIC90 >32 μg/ml) which were less effective due to the high incidence of resistant PBP3-insertion mutants. MEM-ANT2681 offers a potential new therapeutic option to treat serious infections caused by NDM-CRE.

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