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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 -
Journal of Pharmacy Practice Dec 2014Penicillin is the most frequently reported cause of drug allergy, and cross-reactivity of penicillins with other beta-lactam antibiotics is an area of debate. This... (Review)
Review
Penicillin is the most frequently reported cause of drug allergy, and cross-reactivity of penicillins with other beta-lactam antibiotics is an area of debate. This review evaluates the available data on immunoglobulin E-mediated penicillin hypersensitivity and cross-reactivity with cephalosporin, carbapenem, and monobactam antibiotics. A MEDLINE search was conducted from 1950 to October 2013, and selected references from review articles were also evaluated. There is a wide variety in reported incidences of cross-reactivity between penicillins and cephalosporins or carbapenems, with early retrospective studies suggesting up to 41.7% and 47.4% cross-reactivity, respectively. Conversely, the use of monobactam antibiotics is frequently employed in the case of a penicillin allergy, as prescribers believe that there is no cross-reactivity between the 2 drug classes. More recent prospective studies suggest that the rates of cross-reactivity with cephalosporins and carbapenems are <5% and <1%, respectively. Similarities in penicillin and cephalosporin side chains may play a role in cross-reactivity between these classes. Cross-reactivity with monobactams is essentially negligible; however, there are some clinical data to support an interaction between ceftazidime and aztreonam, due to the similarity of their side chains. The data reviewed suggest that avoidance of other beta-lactams in patients with type 1 hypersensitivity to penicillins should be reconsidered.
Topics: Anti-Bacterial Agents; Carbapenems; Cephalosporins; Cross Reactions; Drug Hypersensitivity; Humans; Monobactams; Penicillins
PubMed: 25124380
DOI: 10.1177/0897190014546109 -
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 -
Medicinal Research Reviews Mar 2018Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged.... (Review)
Review
Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic β-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial β-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their β-lactamase stability. In that respect, our review covers the updates in the field of monocyclic β-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic β-lactams, classified according to their N-substituent, and the associated antibacterial or β-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic β-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic β-lactams.
Topics: Anti-Bacterial Agents; Monobactams; Siderophores; Structure-Activity Relationship; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 28815732
DOI: 10.1002/med.21443 -
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 -
Therapeutic Drug Monitoring Oct 2023Recently, several studies have assessed the effects of therapeutic drug monitoring of frequently prescribed beta-lactam antibiotics, for which they were quantified in...
BACKGROUND
Recently, several studies have assessed the effects of therapeutic drug monitoring of frequently prescribed beta-lactam antibiotics, for which they were quantified in human plasma samples. Beta-lactams are considered unstable, leading to extra challenges in quantification. Therefore, to ensure sample stability and minimize sample degradation before analysis, stability studies are crucial. This study investigated the stability of 10 frequently used beta-lactam antibiotics in human plasma at relevant storage conditions for clinical use.
METHODS
Amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, imipenem, meropenem, and piperacillin were analyzed using ultraperformance convergence chromatography tandem mass spectrometry and liquid chromatography tandem mass spectrometry. Their short-term and long-term stabilities were investigated by measuring quality control samples at low and high concentrations against freshly prepared calibration standards. Measured concentrations at each time point were compared with the concentrations at T = 0. Antibiotics were considered stable if recovery results were between 85% and 115%.
RESULTS
Short-term stability results indicated ceftriaxone, cefuroxime, and meropenem to be stable up to 24 hours at room temperature. All evaluated antibiotics, except imipenem, were stable on ice in a cool box for 24 hours. Amoxicillin, benzylpenicillin, and piperacillin were stable for 24 hours at 4-6°C. Cefotaxime, ceftazidime, cefuroxime, and meropenem were stable at 4-6°C up to 72 hours. Ceftriaxone and flucloxacillin were stable for 1 week at 4-6°C. Long-term stability results showed that all antibiotics were stable up to 1 year at -80°C, except imipenem and piperacillin, which were stable for 6 months at -80°C.
CONCLUSIONS
Plasma samples for amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, flucloxacillin, and piperacillin may be stored for a maximum of 24 hours in a cool box. Refrigeration is suitable for plasma samples of amoxicillin, benzylpenicillin, meropenem, and piperacillin for up to 24 hours and cefotaxime, ceftriaxone, ceftazidime and cefuroxime for 72 hours. Plasma samples for imipenem should be frozen directly at -80°C. For long-term storage, plasma samples can be stored at -80°C for a maximum of 6 months for imipenem and piperacillin and 12 months for all other evaluated antibiotics.
Topics: Humans; Meropenem; Ceftazidime; Floxacillin; Cefuroxime; Ceftriaxone; Anti-Bacterial Agents; Piperacillin; Monobactams; Tandem Mass Spectrometry; Imipenem; Cefotaxime; Amoxicillin
PubMed: 37199408
DOI: 10.1097/FTD.0000000000001100 -
Current Medicinal Chemistry 2023β-lactam antibiotics treat bacterial infections very effectively, but overuse and misuse have led to resistance. β-lactamase enzymes hydrolyze β-lactam antibiotics... (Review)
Review
β-lactam antibiotics treat bacterial infections very effectively, but overuse and misuse have led to resistance. β-lactamase enzymes hydrolyze β-lactam antibiotics and are the primary cause of resistance in bacteria. Bacteria evolve and clinically mutate to produce such β -lactamase enzymes, which could hydrolyze newly discovered antibiotics. Therefore, carbapenems are considered to be the last resort for antimicrobial treatment. Further, different inhibitors have been discovered to fight these evolving and mutating β- lactamase enzyme resistance. These inhibitors are given in combination with the β-lactam antibiotics to treat bacterial infections effectively. But in due course of time, it has been observed that bacteria develop resistance against this combination. This is an extensive review that discusses different classes of β-lactamase enzymes, their mechanism of action, and the role of critical structural elements like loops and catalytically relevant mutations. Such mutations and structural modifications result in expanding the spectrum of activity, making these β-lactamase enzymes resistant to the newly discovered β-lactam antibiotics and their inhibitors. Detailed knowledge of such mutations, catalytically relevant structural modifications, related kinetics, and action mechanisms could help develop new inhibitors effectively. Further, a detailed discussion of available inhibitors against each class of β-lactamase enzymes is also present.
Topics: Humans; beta-Lactamases; beta-Lactamase Inhibitors; Anti-Bacterial Agents; Monobactams; Bacteria; Bacterial Infections
PubMed: 35726414
DOI: 10.2174/0929867329666220620165429 -
European Journal of Medicinal Chemistry Nov 2022The effectiveness of β-lactam antibiotics is increasingly influenced by serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), which can hydrolyze β-lactam... (Review)
Review
The effectiveness of β-lactam antibiotics is increasingly influenced by serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), which can hydrolyze β-lactam antibiotics. The development of effective β-lactamase inhibitors is an important direction to extend use of β-lactam antibiotics. Although six SBL inhibitors have been approved for clinical use, but no MBL inhibitors or MBL/SBL dual-action inhibitors are available so far. Broad-spectrum targeting clinically relevant MBLs and SBLs is currently desirable, while it is not easy to achieve such a purpose owing to structural and mechanistic differences between MBLs and SBLs. In this review, we summarized recent advances of inhibitor chemotypes targeting MBLs and SBLs and their inhibition mechanisms, particularly including lead discovery and structural optimization strategies, with the aim to provide useful information for future efforts to develop new MBL and SBL inhibitors.
Topics: Anti-Bacterial Agents; Monobactams; Serine; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35988449
DOI: 10.1016/j.ejmech.2022.114677 -
Antimicrobial Agents and Chemotherapy Oct 2022Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required...
Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required for beta-lactamase inhibition, xeruborbactam has direct antibacterial activity against some Gram-negative bacteria, with MIC/MIC values of 16/32 μg/mL and 16/64 μg/mL against carbapenem-resistant and carbapenem-resistant Acinetobacter baumannii, respectively (the MIC/MIC values against Pseudomonas aeruginosa are >64 μg/mL). In Klebsiella pneumoniae, inactivation of OmpK36 alone or in combination with OmpK35 resulted in 2- to 4-fold increases in the xeruborbactam MIC. In A. baumannii and P. aeruginosa, AdeIJK and MexAB-OprM, respectively, affected xeruborbactam's antibacterial potency (the MICs were 4- to 16-fold higher in efflux-proficient strains). In Escherichia coli and K. pneumoniae, the 50% inhibitory concentrations (ICs) of xeruborbactam's binding to penicillin-binding proteins (PBPs) PBP1a/PBP1b, PBP2, and PBP3 were in the 40 to 70 μM range; in A. baumannii, xeruborbactam bound to PBP1a, PBP2, and PBP3 with ICs of 1.4 μM, 23 μM, and 140 μM, respectively. Treating K. pneumoniae and P. aeruginosa with xeruborbactam at 1× and 2× MIC resulted in changes of cellular morphology similar to those observed with meropenem; the morphological changes observed after treatment of A. baumannii were consistent with inhibition of multiple PBPs but were unique to xeruborbactam compared to the results for control beta-lactams. No single-step xeruborbactam resistance mutants were obtained after selection at 4× MIC of xeruborbactam using wild-type strains of E. coli, K. pneumoniae, and A. baumannii; mutations selected at 2× MIC in K. pneumoniae did not affect antibiotic potentiation by xeruborbactam through beta-lactamase inhibition. Consistent with inhibition of PBPs, xeruborbactam enhanced the potencies of beta-lactam antibiotics even against strains that lacked beta-lactamase. In a large panel of KPC-producing clinical isolates, the MIC values of meropenem tested with xeruborbactam (8 μg/mL) were at least 4-fold lower than those in combination with vaborbactam at 64 μg/mL, the concentration of vaborbactam that is associated with complete inhibition of KPC. The additional enhancement of the potency of beta-lactam antibiotics beyond beta-lactamase inhibition may contribute to the potentiation of beta-lactam antibiotics by xeruborbactam.
Topics: Meropenem; Penicillin-Binding Proteins; Escherichia coli; Anti-Bacterial Agents; beta-Lactamases; beta-Lactams; Microbial Sensitivity Tests; Klebsiella pneumoniae; Carbapenems; Monobactams; Pseudomonas aeruginosa; Serine
PubMed: 36102663
DOI: 10.1128/aac.00879-22