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Cold Spring Harbor Perspectives in... Aug 2016β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related... (Review)
Review
β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum β-lactamase inhibitors that work against many problematic β-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.
Topics: Carbapenems; Cephalosporins; History, 20th Century; History, 21st Century; Humans; Monobactams; Penicillins; beta-Lactam Resistance; beta-Lactamase Inhibitors
PubMed: 27329032
DOI: 10.1101/cshperspect.a025247 -
Journal of Molecular Biology Aug 2019The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the... (Review)
Review
The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa). β-Lactamases divide into four classes; the active-site serine β-lactamases (classes A, C and D) and the zinc-dependent or metallo-β-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for β-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of β-lactam breakdown. A second focus is β-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of β-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of β-lactams with diazabicyclooctanone and cyclic boronate serine β-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of β-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new β-lactam:inhibitor combinations and the continuing clinical importance of β-lactams mean that this remains a rewarding research area.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Catalytic Domain; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Humans; Interspersed Repetitive Sequences; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 30959050
DOI: 10.1016/j.jmb.2019.04.002 -
Revista Argentina de Microbiologia 2022The aim of this review is to present an update on the susceptibility of viridans group streptococci (VGS) to β-lactam antimicrobials, with emphasis on the Argentinean... (Review)
Review
The aim of this review is to present an update on the susceptibility of viridans group streptococci (VGS) to β-lactam antimicrobials, with emphasis on the Argentinean scenario. VGS are a heterogeneous group including five groups of species, each one exhibiting peculiar susceptibility patterns to penicillin (PEN). Species of the Streptococcus mitis group are frequently nonsusceptible to PEN. PEN resistance is associated with changes in PEN-binding proteins. In Argentina, one to two thirds of VGS are nonsusceptible to PEN. Third generation cephalosporins and carbapenems are currently more effective in vitro than PEN against VGS. Mortality was associated to nonsusceptibility to PEN in at least two studies involving patients with bacteremia caused by VGS. Treatment of endocarditis due to VGS should be adjusted/to the PEN susceptibility of the isolates. Vancomycin may be an alternative choice for treating endocarditis caused by PEN-resistant isolates (MIC≥4μg/ml).
Topics: Humans; Microbial Sensitivity Tests; Streptococcal Infections; Viridans Streptococci; Penicillins; Monobactams; beta-Lactams; Anti-Bacterial Agents; Endocarditis
PubMed: 36266147
DOI: 10.1016/j.ram.2022.06.004 -
Antimicrobial Agents and Chemotherapy Oct 2018β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of... (Review)
Review
β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years ago. These well-studied enzymes, currently numbering almost 2,800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally occurring β-lactams. Their ancestors were presumably penicillin-binding proteins that share sequence homology with β-lactamases possessing an active-site serine. Metallo-β-lactamases also exist, with one or two catalytically functional zinc ions. Although penicillinases in Gram-positive bacteria were reported shortly after penicillin was introduced clinically, transmissible β-lactamases that could hydrolyze recently approved cephalosporins, monobactams, and carbapenems later became important in Gram-negative pathogens. Nomenclature is based on one of two major systems. Originally, functional classifications were used, based on substrate and inhibitor profiles. A later scheme classifies β-lactamases according to amino acid sequences, resulting in class A, B, C, and D enzymes. A more recent nomenclature combines the molecular and biochemical classifications into 17 functional groups that describe most β-lactamases. Some of the most problematic enzymes in the clinical community include extended-spectrum β-lactamases (ESBLs) and the serine and metallo-carbapenemases, all of which are at least partially addressed with new β-lactamase inhibitor combinations. New enzyme variants continue to be described, partly because of the ease of obtaining sequence data from whole-genome sequencing studies. Often, these new enzymes are devoid of any phenotypic descriptions, making it more difficult for clinicians and antibiotic researchers to address new challenges that may be posed by unusual β-lactamases.
Topics: Bacterial Proteins; Cephalosporins; Gram-Negative Bacteria; Gram-Positive Bacteria; Penicillinase; beta-Lactamases; beta-Lactams
PubMed: 30061284
DOI: 10.1128/AAC.01076-18 -
Frontiers in Cellular and Infection... 2022Infections by Gram-negative multi-drug resistant (MDR) bacterial species are difficult to treat using available antibiotics. Overuse of carbapenems has contributed to... (Review)
Review
Infections by Gram-negative multi-drug resistant (MDR) bacterial species are difficult to treat using available antibiotics. Overuse of carbapenems has contributed to widespread resistance to these antibiotics; as a result, carbapenem-resistant Enterobacterales (CRE), (CRAB), and (CRPA) have become common causes of healthcare-associated infections. Carbapenems, tigecycline, and colistin are the last resource antibiotics currently used; however, multiple reports of resistance to these antimicrobial agents have been documented worldwide. Recently, new antibiotics have been evaluated against Gram-negatives, including plazomicin (a new aminoglycoside) to treat CRE infection, eravacycline (a novel tetracycline) with activity against CRAB, and cefiderocol (a synthetic conjugate) for the treatment of nosocomial pneumonia by carbapenem-non-susceptible Gram-negative isolates. Furthermore, combinations of known β-lactams with recently developed β-lactam inhibitors, such as ceftazidime-avibactam, ceftolozane-tazobactam, ceftazidime-tazobactam, and meropenem-vaborbactam, has been suggested for the treatment of infections by extended-spectrum β-lactamases, carbapenemases, and AmpC producer bacteria. Nonetheless, they are not active against all carbapenemases, and there are reports of resistance to these combinations in clinical isolates.This review summarizes and discusses the and clinical evidence of the recently approved antibiotics, β-lactam inhibitors, and those in advanced phases of development for treating MDR infections caused by Gram-negative multi-drug resistant (MDR) bacterial species.
Topics: Anti-Bacterial Agents; Carbapenems; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Tazobactam
PubMed: 35669117
DOI: 10.3389/fcimb.2022.884365 -
Revista Espanola de Quimioterapia :... Apr 2022Cefiderocol is a new siderophore cephalosporin with potent in vitro activity against gram-negative bacilli including Enterobacterales that produce all kinds of... (Review)
Review
Cefiderocol is a new siderophore cephalosporin with potent in vitro activity against gram-negative bacilli including Enterobacterales that produce all kinds of carbapenemases and non-fermenting Gram-negative with difficult-to-treat resistance. As a β-lactam, its efficacy is optimized in extended-perfusion and requires dose adjustment in renal dysfunction and hyperclearance. Its efficacy has been validated in three clinical trials, one of them in the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia. The clinical trial aimed at difficult-to-treat gram-negatives achieved the clinical and microbiological target, but the increase in mortality observed in the cefiderocol arm makes it necessary to demonstrate efficacy in real clinical practice. Cefiderocol is a good option among the new β-lactams for the treatment of pneumonia caused by Gram-negative bacilli carbapenem-resistant.
Topics: Anti-Bacterial Agents; Carbapenems; Cephalosporins; Gram-Negative Bacteria; Humans; Cefiderocol
PubMed: 35488822
DOI: 10.37201/req/s01.07.2022 -
Critical Care (London, England) Sep 2018Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients and beta-lactams are the most common antibiotic... (Review)
Review
Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients and beta-lactams are the most common antibiotic class used. Critically ill patient's pathophysiological factors lead to altered pharmacokinetics and pharmacodynamics of beta-lactams.A comprehensive bibliographic search in PubMed database of all English language articles published from January 2000 to December 2017 was performed, allowing the selection of articles addressing the pharmacokinetics or pharmacodynamics of beta-lactam antibiotics in critically ill patients.In critically ill patients, several factors may increase volume of distribution and enhance renal clearance, inducing high intra- and inter-patient variability in beta-lactam concentration and promoting the risk of antibiotic underdosing. The duration of infusion of beta-lactams has been shown to influence the fT > minimal inhibitory concentration and an improved beta-lactam pharmacodynamics profile may be obtained by longer exposure with more frequent dosing, extended infusions, or continuous infusions.The use of extracorporeal support techniques in the critically ill may further contribute to this problem and we recommend not reducing standard antibiotic dosage since no drug accumulation was found in the available literature and to maintain continuous or prolonged infusion, especially for the treatment of infections caused by multidrug-resistant bacteria.Prediction of outcome based on concentrations in plasma results in overestimation of antimicrobial activity at the site of infection, namely in cerebrospinal fluid and the lung. Therefore, although no studies have assessed clinical outcome, we recommend using higher than standard dosing, preferably with continuous or prolonged infusions, especially when treating less susceptible bacterial strains at these sites, as the pharmacodynamics profile may improve with no apparent increase in toxicity.A therapeutic drug monitoring-guided approach could be particularly useful in critically ill patients in whom achieving target concentrations is more difficult, such as obese patients, immunocompromised patients, those infected by highly resistant bacterial strains, patients with augmented renal clearance, and those undergoing extracorporeal support techniques.
Topics: Anti-Bacterial Agents; Critical Illness; Drug Monitoring; Drug Utilization Review; Humans; Infusions, Intravenous; beta-Lactams
PubMed: 30244674
DOI: 10.1186/s13054-018-2155-1 -
Intensive Care Medicine Dec 2022Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.
METHODS
This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.
RESULTS
In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.
CONCLUSIONS
We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.
Topics: Humans; Middle Aged; Critical Illness; beta-Lactams; Ciprofloxacin; Intensive Care Units; Anti-Bacterial Agents; Monobactams
PubMed: 36350354
DOI: 10.1007/s00134-022-06921-9 -
Clinical Infectious Diseases : An... Nov 2022Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is recommended to address the variability in exposure observed in critical illness. However, the impact of... (Meta-Analysis)
Meta-Analysis
Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is recommended to address the variability in exposure observed in critical illness. However, the impact of TDM-guided dosing on clinical outcomes remains unknown. We conducted a systematic review and meta-analysis on TDM-guided dosing and clinical outcomes (all-cause mortality, clinical cure, microbiological cure, treatment failure, hospital and intensive care unit length of stay, target attainment, antibiotic-related adverse events, and emergence of resistance) in critically ill patients with suspected or proven sepsis. Eleven studies (n = 1463 participants) were included. TDM-guided dosing was associated with improved clinical cure (relative risk, 1.17; 95% confidence interval [CI], 1.04 to 1.31), microbiological cure (RR, 1.14; 95% CI, 1.03 to 1.27), treatment failure (RR, 0.79; 95% CI, .66 to .94), and target attainment (RR, 1.85; 95% CI, 1.08 to 3.16). No associations with mortality and length of stay were found. TDM-guided dosing improved clinical and microbiological cure and treatment response. Larger, prospective, randomized trials are required to better assess the utility of beta-lactam TDM in critically ill patients.
Topics: Humans; Critical Illness; Drug Monitoring; Prospective Studies; beta-Lactams; Anti-Bacterial Agents; Monobactams
PubMed: 35731853
DOI: 10.1093/cid/ciac506 -
Marine Drugs Jan 2023The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics-including penicillins, cephalosporins, and carbapenems-as... (Review)
Review
The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics-including penicillins, cephalosporins, and carbapenems-as largely (if not exclusively) secondary metabolites of terrestrial fungi and bacteria, transformed modern medicine. The antibiotic β-lactams inactivate essential enzymes of bacterial cell-wall biosynthesis. Moreover, the ability of the β-lactams to function as enzyme inhibitors is of such great medical value, that inhibitors of the enzymes which degrade hydrolytically the β-lactams, the β-lactamases, have equal value. Given this privileged status for the β-lactam ring, it is therefore a disappointment that the exemplification of this ring in marine secondary metabolites is sparse. It may be that biologically active marine β-lactams are there, and simply have yet to be encountered. In this report, we posit a second explanation: that the value of the β-lactam to secure an ecological advantage in the marine environment might be compromised by its close structural similarity to the β-lactones of quorum sensing. The steric and reactivity similarities between the β-lactams and the β-lactones represent an outside-of-the-box opportunity for correlating new structures and new enzyme targets for the discovery of compelling biological activities.
Topics: beta-Lactams; Anti-Bacterial Agents; Penicillins; beta-Lactamases; Bacteria; Lactones; Oceans and Seas
PubMed: 36827127
DOI: 10.3390/md21020086