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Pharmacotherapy Aug 2023Intravenous β-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability....
International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases,...
Intravenous β-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. β-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PIs) can be applied during the administration of intravenous β-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of PI β-lactams developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug-monitoring considerations, and the use of PI β-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of β-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).
Topics: Adult; Humans; Child; Pharmacists; Cystic Fibrosis; Anti-Infective Agents; Monobactams; Communicable Diseases; Anti-Bacterial Agents; Pharmacy
PubMed: 37615245
DOI: 10.1002/phar.2842 -
Medizinische Klinik, Intensivmedizin... Mar 2023Infections due to antibiotic-resistant bacteria are threatening modern healthcare, and antibacterial resistance has become one of the greatest threats to public health.... (Review)
Review
BACKGROUND
Infections due to antibiotic-resistant bacteria are threatening modern healthcare, and antibacterial resistance has become one of the greatest threats to public health. In Germany 54,500 patients become infected with antibiotic-resistant bacteria per year, causing about 2400 attributable deaths. Rising resistance in Gram-negative bacteria especially carbapenem-resistant pathogens is of particular concern due to the lack of effective and safe alternative treatment options.
OBJECTIVE
The results from trials and compassionate-use programs with the new antibiotic cefiderocol, which was approved by the European Medicines Agency (EMA) in April 2020 for the treatment of adults with infections caused by aerobic Gram-negative bacteria, are summarized.
RESULTS
The new β‑lactam antibiotic cefiderocol is the first siderophore cephalosporin indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options. Its chemical structure and its unique mechanism of action confer enhanced stability against β‑lactamases including all classes of clinically relevant carbapenemases. In vitro data show high antibacterial activity against multidrug resistant Gram-negative bacteria, Enterobacterales and nonfermenters, including carbapenem-resistant strains. In clinical trials, cefiderocol showed superiority in complicated urinary tract infection in comparison to imipenem and non-inferiority versus meropenem in hospital-acquired/ventilator-associated pneumonia patients and severe infections caused by carbapenem-resistant pathogens.
CONCLUSION
Clinical trial data and case reports identified in the literature search show that cefiderocol is a promising treatment option for severe infections caused by drug-resistant Gram-negative bacteria, particularly carbapenem-resistant bacteria.
Topics: Adult; Humans; Cephalosporins; Anti-Bacterial Agents; Monobactams; Carbapenems; Cefiderocol
PubMed: 35913604
DOI: 10.1007/s00063-022-00925-5 -
Current Opinion in Infectious Diseases Dec 2023In the present narrative review, we discuss the characteristics and differences between the Infectious Diseases Society of America (IDSA) and European Society of... (Review)
Review
PURPOSE OF REVIEW
In the present narrative review, we discuss the characteristics and differences between the Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines in terms on their recommendations/suggestions for the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii infections.
RECENT FINDINGS
Treatment of severe infections caused by nonfermenting gram-negative bacteria (NF-GNB) is posing both novel hopes and novel challenges to physicians worldwide, and both the IDSA and the ESCMID have recently updated/released their guidelines or guidance documents, based on different philosophies and providing recommendations for the treatment of NF-GNB infections. In order to correctly exploit recent advances in the treatment of such infections, IDSA and ESCMID approaches should be viewed as complementary and evolving, and should not preclude further revision based on accumulating evidence on the use of novel β-lactams and β-lactam/β-lactamase inhibitor combinations.
SUMMARY
A joint consideration of both philosophies should leave the door opened for the wise use of novel agents, ultimately building precious experience on their use that could favorably influence future guidelines revisions.
Topics: Humans; Anti-Bacterial Agents; Gram-Negative Bacteria; beta-Lactamase Inhibitors; beta-Lactams; Acinetobacter Infections; Monobactams; Communicable Diseases
PubMed: 37769165
DOI: 10.1097/QCO.0000000000000982 -
JAMA Cardiology Sep 2023Fluoroquinolone use has been associated with increased hospitalization with aortic aneurysm or dissection in noninterventional studies, but the reason for this observed... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Fluoroquinolone use has been associated with increased hospitalization with aortic aneurysm or dissection in noninterventional studies, but the reason for this observed association is unclear.
OBJECTIVE
To determine the association between fluoroquinolone use and aortic aneurysm or dissection using multiple study designs and multiple databases to increase the robustness of findings.
DESIGN, SETTING, AND PARTICIPANTS
Cohort and case-crossover studies were conducted separately in 2 databases of UK primary care records. Clinical Practice Research Datalink Aurum and GOLD primary care records were linked to hospital admissions data. Adults with a systemic fluoroquinolone or cephalosporin prescription between April 1997 and December 2019 were included in the cohort study. Adults hospitalized with aortic aneurysm or dissection within the eligibility period were included in the case-crossover study. Individuals meeting inclusion criteria in the case-crossover study were matched 1:3 to control individuals on age, sex, index date, and clinical practice to adjust for calendar trends in prescribing. Data were analyzed from January to July 2022.
EXPOSURES
Systemic fluoroquinolone or comparator antibiotic.
MAIN OUTCOMES AND MEASURES
Hazard ratios (HRs) were estimated in the cohort study for the association between prescription of fluoroquinolones and hospitalization with aortic aneurysm or dissection using stabilized inverse probability of treatment-weighted Cox regression. Odds ratios (OR) were estimated in the case-crossover study for the association between systemic fluoroquinolone use and hospitalization with aortic aneurysm or dissection using a conditional logistic regression model. Estimates were pooled across databases using fixed-effects meta-analysis.
RESULTS
In the cohort study, we identified 3 134 121 adults in Aurum (mean [SD] age, 52.5 [20.3] years; 1 969 257 [62.8%] female) and 452 086 in GOLD (mean [SD] age, 53.9 [20.2] years; 286 502 [63.4%] female) who were prescribed fluoroquinolones or cephalosporins. In crude analyses, fluoroquinolone relative to cephalosporin use was associated with increased hospitalization with aortic aneurysm or dissection (pooled HR, 1.28; 95% CI, 1.13-1.44; P < .001) but after adjustment for potential confounders, this association disappeared (pooled adjusted HR, 1.03; 95% CI, 0.91-1.17; P = .65). In the case-crossover study, we identified 84 841 individuals hospitalized with aortic aneurysm or dissection in Aurum (mean [SD] age, 75.5 [10.9]; 23 551 [27.8%] female) and 10 357 in GOLD (mean [SD] age, 75.6 [10.5]; 2809 [27.1%] female). Relative to nonuse, fluoroquinolone use was associated with an increase in hospitalization with aortic aneurysm or dissection, but no association was found relative to other antibiotics (vs cephalosporin pooled OR, 1.05; 95% CI, 0.87-1.27; vs trimethoprim, 0.89; 95% CI, 0.75-1.06; vs co-amoxiclav, 0.98; 95% CI, 0.82-1.18).
CONCLUSIONS AND RELEVANCE
The results in this study suggest that estimates of association of fluoroquinolones with aortic aneurysm or dissection may be affected by confounding. When such confounding is accounted for, no association was evident, providing reassurance on the safety of fluoroquinolones with respect to aortic aneurysm or dissection.
Topics: Adult; Humans; Female; Middle Aged; Aged; Male; Fluoroquinolones; Cohort Studies; Cross-Over Studies; Anti-Bacterial Agents; Aortic Aneurysm; Aortic Dissection; Cephalosporins; Monobactams; Hospitalization
PubMed: 37585175
DOI: 10.1001/jamacardio.2023.2418 -
Applied Microbiology and Biotechnology Dec 2022Antibiotics are antibacterial compounds that interfere with bacterial growth, without harming the infected eukaryotic host. Among the clinical agents, beta-lactams play... (Review)
Review
Antibiotics are antibacterial compounds that interfere with bacterial growth, without harming the infected eukaryotic host. Among the clinical agents, beta-lactams play a major role in treating infected humans and animals. However, the ever-increasing antibiotic resistance crisis is forcing the pharmaceutical industry to search for new antibacterial drugs to combat a range of current and potential multi-resistant bacterial pathogens. In this review, we provide an overview of the development, innovation, and current status of therapeutic applications for beta-lactams with a focus on semi-synthetic cephalosporins. Cephalosporin C (CPC), which is a natural secondary metabolite from the filamentous fungus Acremonium chrysogenum, plays a major and demanding role in both producing modern antibiotics and developing new ones. CPC serves as a core compound for producing semi-synthetic cephalosporins that can control infections with different resistance mechanisms. We therefore summarize our latest knowledge about the CPC biosynthetic pathway and its regulation in the fungal host. Finally, we describe how CPC serves as a key lead generation source for the in vitro and better, in vivo synthesis of 7-aminocephalosporanic acid (7-ACA), the major core compound for the pharmaceutical synthesis of current and future semi-synthetic cephalosporins. KEY POINTS: • Latest literature on cephalosporin generations • Biotechnical production of cephalosporins • In vivo production of 7-ACA.
Topics: Animals; Humans; Monobactams; Cephalosporins; Anti-Bacterial Agents; Drug Industry
PubMed: 36401643
DOI: 10.1007/s00253-022-12272-8 -
Frontiers in Microbiology 2021Tularemia, caused by , is endemic to the northern hemisphere. This zoonotic organism has historically been developed into a biological weapon. For this Tier 1, Category... (Review)
Review
Tularemia, caused by , is endemic to the northern hemisphere. This zoonotic organism has historically been developed into a biological weapon. For this Tier 1, Category A select agent, it is important to expand our understanding of its mechanisms of antibiotic resistance (AMR). is unlike many Gram-negative organisms in that it does not have significant plasmid mobility, and does not express AMR mechanisms on plasmids; thus plasmid-mediated resistance does not occur naturally. It is possible to artificially introduce plasmids with AMR markers for cloning and gene expression purposes. In this review, we survey both the experimental research on AMR in and bioinformatic databases which contain genomic and proteomic data. We explore both the genetic determinants of intrinsic AMR and naturally acquired or engineered antimicrobial resistance as well as phenotypic resistance in . Herein we survey resistance to beta-lactams, monobactams, carbapenems, aminoglycosides, tetracycline, polymyxins, macrolides, rifampin, fosmidomycin, and fluoroquinolones. We also highlight research about the phenotypic AMR difference between planktonic and biofilm We discuss newly developed methods of testing antibiotics against which involve the intracellular nature of infection and may better reflect the eventual clinical outcomes for new antibiotic compounds. Understanding the genetically encoded determinants of AMR in is key to optimizing the treatment of patients and potentially developing new antimicrobials for this dangerous intracellular pathogen.
PubMed: 34054749
DOI: 10.3389/fmicb.2021.644855 -
Microbiology Spectrum Jun 2023Cefiderocol and aztreonam-avibactam (ATM-AVI) both had activity against carbapenem-resistant Gram-negative bacilli, including those that produce metallo-β-lactamases...
Cefiderocol and aztreonam-avibactam (ATM-AVI) both had activity against carbapenem-resistant Gram-negative bacilli, including those that produce metallo-β-lactamases (MBLs). We compared the activities and inoculum effects of these antibiotics against carbapenemase-producing (CPE), especially MBL-producing isolates. The MICs of cefiderocol and ATM-AVI were determined using broth microdilution method for a 2016 to 2021 collection of isolates which produced MBL, KPC, or OXA-48-like carbapenemases. MICs with high bacteria inoculum were also evaluated for susceptible isolates. A total of 195 CPE were tested, including 143 MBL- (74 NDM, 42 IMP, and 27 VIM), 38 KPC-, and 14 OXA-48-like-producing isolates. The susceptible rates of MBL-, KPC-, and OXA-48-like producers to cefiderocol were 86.0%, 92.1%, and 92.9%, respectively, and that to ATM-AVI were 95.8%, 100%, and 100%, respectively. NDM producers displayed lower susceptibility and higher MICs/MICs of cefiderocol (78.4%, 2/16 mg/L) than IMP (92.9%, 0.375/4 mg/L) and VIM (96.3%, 1/4 mg/L) producers. NDM- and VIM-producing Escherichia coli showed lower susceptibility to ATM-AVI (77.3% and 75.0%, respectively) compared to MBL-CPE of other species (100% susceptible). Inoculum effects for cefiderocol and ATM-AVI were observed among 95.9% and 95.2% of susceptible CPE, respectively. A switch from susceptible to resistant category was observed in 83.6% (143/171) of isolates for cefiderocol and 94.7% (179/189) for ATM-AVI. Our results revealed that NDM-producing had lower susceptibility to cefiderocol and ATM-AVI. Prominent inoculum effects on both antibiotics were observed for CPE, which suggested a risk of microbiological failure when they were used for CPE infections with high bacteria burden. The prevalence of infections caused by carbapenem-resistant is increasing worldwide. Currently, therapeutic options for metallo-β-lactamase (MBL)-producing remain limited. We demonstrated that clinical metallo-β-lactamase (MBL)-producing isolates were highly susceptible to cefiderocol (86.0%) and aztreonam-avibactam (ATM-AVI) (95.8%). However, inoculum effects on cefiderocol and ATM-AVI were observed for over 90% of susceptible carbapenemase-producing (CPE) isolates. Our findings highlight a potential risk of microbiological failure when using monotherapy with cefiderocol or ATM-AVI to treat severe CPE infection.
Topics: Humans; Aztreonam; Enterobacteriaceae; Anti-Bacterial Agents; beta-Lactamases; Enterobacteriaceae Infections; Carbapenem-Resistant Enterobacteriaceae; Escherichia coli; Microbial Sensitivity Tests; Cefiderocol
PubMed: 37154758
DOI: 10.1128/spectrum.00569-23 -
International Immunopharmacology Sep 2023Beta-lactam (BLM) antibiotics, including amino-penicillin and cephalosporins, are typically the first-choice treatment for bacterial infections. However, adverse... (Review)
Review
Beta-lactam (BLM) antibiotics, including amino-penicillin and cephalosporins, are typically the first-choice treatment for bacterial infections. However, adverse reactions to these antibiotics are frequently reported, causing non-allergist physicians to select alternative broad-spectrum antibiotics that can have harmful consequences. Patients with unclear histories of hypersensitivity reactions to BLMs should undergo an allergy workup to establish a firm diagnosis, particularly when different drugs are prescribed simultaneously. However, finding the safest, most precise, and cost-effective methods for confirming BLMs hypersensitivity and selecting the most appropriate alternative BLM is uncertain, particularly in severe delayed reactions. This review aims to provide data and recommendations on the availability and validity of skin tests (STs), drug provocation test (DPT) protocols, based on the latest published literature and guideline. To make the process more practical, we focused on cross-reactivity between BLMs and diagnostic tests. There are two main novel aspects of this document: 1) For T-cell-mediated reactions, patient stratification into high, moderate, and low-risk groups based on the mortality and morbidity of adverse drug reactions. 2) For IgE-mediated reactions, stratification of individuals with isolated limited urticarial without anaphylaxis in a low-risk group and removal of the extensive limitation.
Topics: Humans; Anti-Bacterial Agents; beta-Lactams; Drug Hypersensitivity; Penicillins; Skin Tests; Monobactams; Anaphylaxis; Cross Reactions
PubMed: 37413935
DOI: 10.1016/j.intimp.2023.110573 -
Journal of Medicinal Chemistry Mar 2020Infections caused by resistant bacteria are nowadays too common, and some pathogens have even become resistant to multiple types of antibiotics, in which case few or... (Review)
Review
Infections caused by resistant bacteria are nowadays too common, and some pathogens have even become resistant to multiple types of antibiotics, in which case few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy "antibiotic + inhibitor of resistance". These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clinical use. Three main types of compounds have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; (iii) efflux pump inhibitors. This Perspective is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-negative bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems, and monobactams), by the production of β-lactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.
Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Microbial; Humans; Protein Structure, Secondary; Protein Structure, Tertiary; Treatment Outcome; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 31663735
DOI: 10.1021/acs.jmedchem.9b01279 -
American Journal of TherapeuticsAztreonam is not a preferred empiric antibiotic because of variable susceptibilities compared with alternative agents. In addition, it has no Gram-positive activity,...
BACKGROUND
Aztreonam is not a preferred empiric antibiotic because of variable susceptibilities compared with alternative agents. In addition, it has no Gram-positive activity, necessitating coadministration with vancomycin when used empirically, and is more costly when compared with other Gram-negative active agents. Aztreonam is often given to patients with a reported penicillin allergy without further investigation into the reaction or other relevant allergy information.
STUDY QUESTION
How frequently is aztreonam being used inappropriately?
STUDY DESIGN
We conducted a retrospective chart review at an academic medical center to assess the appropriateness of our aztreonam use.
MEASURES AND OUTCOMES
Our primary outcome was frequency of appropriate aztreonam use, based on a true IgE-mediated allergy reported for each patient. We evaluated whether the patients had tolerated a beta-lactam in the past, and what the reported allergic reaction was.
RESULTS
We included 165 patients and found that 46.7% of our aztreonam use was inappropriate, based on previous use of a beta-lactam, or no documentation of an IgE-mediated response. Of the patients with a documented beta-lactam allergy, 63 (38.2%) patients had no allergy manifestation listed, and 37 (22.4%) patients had a non-IgE-mediated allergy manifestation. Of the total population, 61 (37%) patients had tolerated a beta-lactam in the past.
CONCLUSIONS
Aztreonam should be avoided, except in the case of a true IgE-mediated allergic reaction. Our goal was to reduce the inappropriate use of aztreonam at our institution by one or more of the following: educating providers, reviewing aztreonam orders, requiring answering of order questions, or requiring an indication for use. Penicillin skin testing and desensitization are options as well.
Topics: Anti-Bacterial Agents; Aztreonam; Drug Hypersensitivity; Humans; Penicillins; Retrospective Studies; beta-Lactams
PubMed: 31714256
DOI: 10.1097/MJT.0000000000001058