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Antibiotics (Basel, Switzerland) Jun 2023Several studies have reported an increased frequency of colonization and/or infection with antibiotic-resistant bacteria (ARB) during the COVID-19 pandemic.... (Review)
Review
Several studies have reported an increased frequency of colonization and/or infection with antibiotic-resistant bacteria (ARB) during the COVID-19 pandemic. Extended-spectrum beta-lactamase-producing (ESBL-PE) are a group of bacteria with intrinsic resistance to multiple antibiotics, including penicillins, cephalosporins, and monobactams. These pathogens are easy to spread and can cause difficult-to-treat infections. Here, we summarize the available evidence on the impact of the COVID-19 pandemic on infections caused by ESBL-PE. Using specific criteria and keywords, we searched PubMed, MEDLINE, and EMBASE for articles published up to 30 March 2023 on potential changes in the epidemiology of ESBL-E since the beginning of the COVID-19 pandemic. We identified eight studies that documented the impact of COVID-19 on ESBL-E. Five studies were focused on assessing the frequency of ESBL-PE in patient-derived specimens, and three studies investigated the epidemiological aspects of ESBL-PE infections in the context of the COVID-19 pandemic. Some of the studies that were focused on patient specimens reported a decrease in ESBL-PE positivity during the pandemic, whereas the three studies that involved patient data (1829 patients in total) reported a higher incidence of ESBL-PE infections in patients hospitalized for COVID-19 compared with those with other conditions. There are limited data on the real impact of the COVID-19 pandemic on the epidemiology of ESBL-PE infections; however, patient-derived data suggest that the pandemic has exacerbated the spread of these pathogens.
PubMed: 37370383
DOI: 10.3390/antibiotics12061064 -
The Journal of Allergy and Clinical... Aug 2023A guideline identifying when inpatients with penicillin or cephalosporin antibiotic allergy labels (PCAAL) can receive β-lactam antibiotics increased β-lactam receipt...
BACKGROUND
A guideline identifying when inpatients with penicillin or cephalosporin antibiotic allergy labels (PCAAL) can receive β-lactam antibiotics increased β-lactam receipt at a large northeastern US health care system.
OBJECTIVE
To report outcomes of implementing a similar guideline and electronic order set (OS) at an independent academic health care system.
METHODS
Penicillin/cephalosporin receipt (percentage of inpatients receiving full doses) and alternative antibiotic use (days of therapy per 1000 patient-days [DOT/1000PD]) were compared over 3 periods before (February 1, 2017, to January 31, 2018) and after guideline implementation (February 1, 2018, to January 31, 2019), and after OS implementation (February 1, 2019, to January 31, 2020) among inpatients with PCAAL admitted on medical services with access to guideline/OS and education (Medical-PCAAL, n = 8721), surgical services with access to guideline/OS without education (Surgical-PCAAL, n = 5069), and obstetrics/gynecology services without interventions (Ob/Gyn-PCAAL, n = 798) and inpatients without PCAAL admitted on the same services (Medical-No-PCAAL, n = 50,840; Surgical-No-PCAAL, n = 29,845; Ob/Gyn-No-PCAAL, n = 6109). χ tests were used to compare categorical variables, and analysis of variance was used to compare continuous and interrupted time series analyses (ITSA) to investigate the guideline/OS implementation effect on penicillin/cephalosporin receipt.
RESULTS
In the Medical-PCAAL group, penicillin/cephalosporin receipt increased (58%-68%, P < .001), specifically for cefazolin (8%-11%, P = .02) and third- to fifth-generation cephalosporins (43%-48%, P = .04), and aztreonam use decreased (12 DOT/1000PD, P = .03). In the Medical-No-PCAAL group, penicillin/cephalosporin receipt increased (88%-90%, P = .004), specifically for penicillin (40%-44%, P < .001), without changes in aztreonam use. Significant changes were not observed in these outcomes on surgical or obstetrics/gynecology services. Per ITSA, guideline/OS implementation was associated with increased penicillin/cephalosporin receipt in the Medical-PCAAL group only.
CONCLUSION
Guideline and OS implementation was associated with improved antibiotic stewardship on inpatient services that also received allergy education.
Topics: Humans; Anti-Bacterial Agents; beta-Lactams; Inpatients; Aztreonam; Penicillins; Cephalosporins; Drug Hypersensitivity; Hypersensitivity; Retrospective Studies
PubMed: 37182569
DOI: 10.1016/j.jaip.2023.04.051 -
The Journal of Antimicrobial... Jul 2023To assess the global and regional distribution of ESBLs in Enterobacterales and carbapenemases in Enterobacterales and Pseudomonas aeruginosa.
OBJECTIVES
To assess the global and regional distribution of ESBLs in Enterobacterales and carbapenemases in Enterobacterales and Pseudomonas aeruginosa.
METHODS
Antimicrobial susceptibility of isolates collected from ATLAS (2017-2019) was determined per CLSI guidelines. Enterobacterales exhibiting meropenem MICs ≥2 mg/L and/or ceftazidime/avibactam and/or aztreonam/avibactam MICs ≥16 mg/L, Escherichia coli and Klebsiella pneumoniae with aztreonam and/or ceftazidime MICs ≥2 mg/L, and P. aeruginosa with meropenem MICs ≥4 mg/L were screened for β-lactamases by PCR and sequencing.
RESULTS
Globally, ESBL-positive E. coli (23.7%, 4750/20047) and K. pneumoniae (35.1%, 6055/17229) carried predominantly the CTX-M-15 variant (E. coli: 53.9%; K. pneumoniae: 80.0%) with highest incidence in Africa/Middle East (AfME). Among carbapenem-resistant (CR) E. coli (1.1%, 217/20047) and Enterobacter cloacae (3.8%, 259/6866), NDMs were predominant (E. coli in AfME: 62.5%; E. cloacae in Asia Pacific: 59.7%). CR K. pneumoniae (13.3%, 2299/17 229) and P. aeruginosa (20.3%, 4187/20 643) carried predominantly KPC (30.9%) and VIM (14.7%), respectively, with highest frequency in Latin America. Among ESBL-positive Enterobacterales, susceptibility to ceftazidime/avibactam (>90.0%) and amikacin (>85.0%) was higher than to piperacillin/tazobactam (>45.0%) and ciprofloxacin (>7.4%). In CR Enterobacterales, susceptibility to amikacin (>54.0%) and ceftazidime/avibactam (>31.0%) was higher than to ciprofloxacin (>2.7%) and piperacillin/tazobactam (>0.5%). CR P. aeruginosa similarly demonstrated higher susceptibility to amikacin (63.4%) and ceftazidime/avibactam (61.9%) than to ciprofloxacin (26.2%) and piperacillin/tazobactam (25.3%).
CONCLUSIONS
Varied distribution of resistance genotypes across regions among ESBL-positive Enterobacterales and CR Enterobacterales and P. aeruginosa provide crucial insights on major resistance mechanisms and trends observed in recent years. Continued surveillance is warranted for monitoring global dissemination and resistance.
Topics: Ceftazidime; Pseudomonas aeruginosa; Anti-Bacterial Agents; Amikacin; Aztreonam; Meropenem; Escherichia coli; Incidence; Azabicyclo Compounds; beta-Lactamases; Piperacillin, Tazobactam Drug Combination; Klebsiella pneumoniae; Drug Combinations; Ciprofloxacin; Microbial Sensitivity Tests
PubMed: 37161662
DOI: 10.1093/jac/dkad127 -
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 -
Antimicrobial Agents and Chemotherapy Jul 2023The impact of broad-spectrum β-lactamases on the susceptibility to novel β-lactamase/β-lactamase inhibitor combinations was evaluated both in Pseudomonas aeruginosa...
Impact of Acquired Broad Spectrum β-Lactamases on Susceptibility to Novel Combinations Made of β-Lactams (Aztreonam, Cefepime, Meropenem, and Imipenem) and Novel β-Lactamase Inhibitors in Escherichia coli and Pseudomonas aeruginosa.
The impact of broad-spectrum β-lactamases on the susceptibility to novel β-lactamase/β-lactamase inhibitor combinations was evaluated both in Pseudomonas aeruginosa and Escherichia coli using isogenic backgrounds. Cefepime-zidebactam displayed low MICs, mainly due to the significant intrinsic antibacterial activity of zidebactam. Cefepime-taniborbactam showed excellent activity against recombinant E. coli strains, including metallo-β-lactamase producers, whereas aztreonam-avibactam remained the best therapeutic option against class B β-lactamase-producing P. aeruginosa.
Topics: Cefepime; beta-Lactamase Inhibitors; Meropenem; beta-Lactams; Aztreonam; Imipenem; Pseudomonas aeruginosa; Escherichia coli; beta-Lactamases; Anti-Bacterial Agents; Azabicyclo Compounds; Microbial Sensitivity Tests
PubMed: 37255469
DOI: 10.1128/aac.00339-23 -
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 -
RSC Advances Aug 2022SME-1 is a carbapenemase, produced by organism and causes nosocomial infections such as in bloodstream, wounds, urinary tract, or respiratory tract infections....
SME-1 is a carbapenemase, produced by organism and causes nosocomial infections such as in bloodstream, wounds, urinary tract, or respiratory tract infections. Treatment of such infections becomes very complex due its resistance towards penicillins, cephalosporins, monobactams, and carbapenems. Resistance to such antibiotics is of great medical concern. The misuse and overuse of these antibiotics result in the clinical mutation and production of novel β-lactamase enzymes such as SME-1, which show resistance to carbapenems. Class A contains most of the clinically significant extended spectrum of β-lactamase enzymes and carbapenemases. In this study, class A β-lactamase SME-1 sequence, structure, and binding were compared with naturally mutated class A β-lactamase enzymes and a wild-type TEM-1. This study was performed for revealing mutations, which could be responsible for the carbapenemase activity of SME-1. The dynamic characteristics of SME-1 enzymes manifest a different degree of conservation and variability, which confers them to possess carbapenemase activities. Met69Cys, Glu104Tyr, Tyr105His, Ala237Ser, and Gly238Cys mutations occur in SME-1 as compared to wild-type TEM-1. These mutated residues are present close to active site residues such as Ser70, Lys73, Ser130, Asn132, Glu166, and Asn170, which participate in the hydrolytic reaction of β-lactam antibiotics. Furthermore, these mutated residues demonstrate altered interactions with the β-lactam antibiotics (results in altered binding) and within themselves (results in active site structure alterations), which results in expanding the spectrum of activity of these enzymes. This study provides important insights into the structure and activity relationship of SME-1 enzymes. This is evident from the Ω-loop structure modification, which forms the wall of the active site and repositioning of residues involved in hydrolytic reactions, when present in the complex with meropenem in a stable state of MD simulation at 50 ns. Hence, Met69Cys, Glu104Tyr, Tyr105His, Ala237Ser, and Gly238Cys mutations could result in an altered active site structure, binding, and activity of SME-1 with meropenem and thus become resistantant against meropenem, which is a carbapenem.
PubMed: 36105999
DOI: 10.1039/d2ra02849b -
The Journal of Antimicrobial... Oct 2023Critically ill patients have increased variability in beta-lactam antibiotic (beta-lactam) exposure due to alterations in their volume of distribution and elimination.... (Review)
Review
Critically ill patients have increased variability in beta-lactam antibiotic (beta-lactam) exposure due to alterations in their volume of distribution and elimination. Therapeutic drug monitoring (TDM) of beta-lactams, as a dose optimization and individualization tool, has been recommended to overcome this variability in exposure. Despite its potential benefit, only a few centres worldwide perform beta-lactam TDM. An important reason for the low uptake is that the evidence for clinical benefits of beta-lactam TDM is not well established. TDM also requires the availability of specific infrastructure, knowledge and expertise. Observational studies and systematic reviews have demonstrated that TDM leads to an improvement in achieving target concentrations, a reduction in potentially toxic concentrations and improvement of clinical and microbiological outcomes. However, a small number of randomized controlled trials have not shown a mortality benefit. Opportunities for improved study design are apparent, as existing studies are limited by their inclusion of heterogeneous patient populations, including patients that may not even have infection, small sample size, variability in the types of beta-lactams included, infections caused by highly susceptible bacteria, and varied sampling, analytical and dosing algorithm methods. Here we review the fundamentals of beta-lactam TDM in critically ill patients, the existing clinical evidence and the practical aspects involved in beta-lactam TDM implementation.
Topics: Humans; Anti-Bacterial Agents; Drug Monitoring; Critical Illness; beta-Lactams; Critical Care; Monobactams
PubMed: 37466209
DOI: 10.1093/jac/dkad223 -
The Journal of Antimicrobial... Nov 2023The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For...
BACKGROUND
The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable β-lactams, standard and high dosages have been proposed for short-infusion regimens only.
OBJECTIVES
To evaluate dosages for β-lactams administered by prolonged infusion (PI) and continuous infusion (CI).
METHODS
Monte Carlo simulations were performed for seven injectable β-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable.
RESULTS
Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam.
CONCLUSIONS
These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.
Topics: Humans; Cefepime; Aztreonam; Anti-Bacterial Agents; Ceftazidime; Piperacillin; Microbial Sensitivity Tests; Monte Carlo Method
PubMed: 37796958
DOI: 10.1093/jac/dkad300 -
Antibiotics (Basel, Switzerland) Sep 2021Beta-lactam antibiotics are often the backbone of treatment for Gram-negative infections in the critically ill. Beta-lactams exhibit time-dependent killing, and their... (Review)
Review
Beta-lactam antibiotics are often the backbone of treatment for Gram-negative infections in the critically ill. Beta-lactams exhibit time-dependent killing, and their efficacy depends on the percentage of dosing interval that the concentration remains above the minimum inhibitory concentration. The Gram-negative resistance rates of pathogens are increasing in the intensive care unit (ICU), and critically ill patients often possess physiology that makes dosing more challenging. The volume of distribution is usually increased, and drug clearance is variable. Augmented renal clearance and hypermetabolic states increase the clearance of beta-lactams, while acute kidney injury reduces the clearance. To overcome the factors affecting ICU patients and decreasing susceptibilities, dosing strategies involving higher doses, and extended or continuous infusions may be required. In this review, we specifically examined pharmacokinetic models in ICU patients, to determine the desired beta-lactam regimens for clinical breakpoints of and as determined by the European Committee on Antimicrobial Susceptibility Testing. The beta-lactams evaluated included penicillins, cephalosporins, carbapenems, and monobactams. We found that when treating less-susceptible pathogens, especially , continuous infusions are frequently needed to achieve the desired pharmacokinetic/pharmacodynamic targets. More studies are needed to determine optimal dosing strategies in the novel beta-lactams.
PubMed: 34680734
DOI: 10.3390/antibiotics10101154