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Annals of Medicine Dec 2023Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for...
Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for difficult-to-treat resistance, since carbapenem-resistant organisms are often resistant to many classes of antibiotics. Carbapenem resistance in the Gram-negative pathogen is mostly due to the production of carbapenemases, enzymes able to hydrolyze carbapenems, and carbapenemase (KPC)-type enzymes are overall the most prevalent carbapenemases in . In the last decade, the management of severe infections due to KPC-producing (KPC-Kp) in humans has presented many peculiar challenges to clinicians worldwide. In this perspective, we discuss how the treatment of severe KPC-Kp infections has evolved over the last decades, guided by the accumulating evidence from clinical studies, and how recent advances in diagnostics have allowed to anticipate identification of KPC-Kp in infected patients.KEY MESSAGESIn the last decade, the management of severe infections due to KPC-Kp has presented many peculiar challenges to clinicians worldwideFollowing the introduction in clinical practice of novel β-lactam/β-lactamase inhibitor combinations and novel β-lactams active against KPC-producing bacteria, the management of severe KPC-Kp infections has witnessed a remarkable evolutionTreatment of severe KPC-Kp infections is a highly dynamic process, in which the wise use of novel antimicrobials should be accompanied by a continuous refinement based on evolving clinical evidence and laboratory diagnostics.
Topics: Humans; Klebsiella pneumoniae; Carbapenems; Monobactams; Anti-Bacterial Agents; Lactams
PubMed: 36856521
DOI: 10.1080/07853890.2022.2152484 -
Mini Reviews in Medicinal Chemistry Dec 2009CXCR4 and CCR5 constitute the two major coreceptors for HIV-1 entry into host cells. In the course of an HIV-infection, a coreceptor switch takes place in approximately... (Review)
Review
CXCR4 and CCR5 constitute the two major coreceptors for HIV-1 entry into host cells. In the course of an HIV-infection, a coreceptor switch takes place in approximately half of the patients - from R5 HIV-1 (CCR5 utilizing) strains to X4 HIV-1 (CXCR4 utilizing) strains. Treatment of HIV-infected individuals with CXCR4 antagonists delays the onset of AIDS by preventing the CCR5 to CXCR4 coreceptor switch. In addition to the endogenous CXCR4 and CCR5 ligands, other chemokines, for example the human herpesvirus 8 encoded CC-chemokine, vCCL2, and modifications hereof, have proven efficient HIV-1 cell-entry inhibition through chemokine receptor interaction. However, pharmacokinetic and immunogenic drawbacks of chemokines and peptidic/peptoid compounds have brought the attention towards small-molecule antagonists, such as AMD3100, that displays high specificity and affinity towards CXCR4, but unfortunately no oral bioavailability. The hunt for orally active small-molecule CXCR4 antagonists led to the development of monocyclam-based compounds, and recently to the non-cyclam antagonist AMD070, which is orally active and currently in Phase II clinical trial as anti-HIV treatment. Current review provides an overview of the drug discovery within the field of anti-HIV treatment targeting CXCR4 spanning from natural occurring and modified chemokines, to HIV-mimicking peptides and peptoids ending at the non-peptide antagonists.
Topics: Amino Acid Sequence; Anti-HIV Agents; CCR5 Receptor Antagonists; Chemokines; HIV Fusion Inhibitors; HIV Infections; Humans; Molecular Sequence Data; Monobactams; Receptors, CCR5; Receptors, CXCR4
PubMed: 20088780
DOI: 10.2174/138955709791012265 -
The Journal of Allergy and Clinical... Jan 2024
Topics: Humans; Cephalosporins; Monobactams
PubMed: 38185495
DOI: 10.1016/j.jaip.2023.10.051 -
Clinical Pharmacy 1985The chemistry, in vitro activity, pharmacokinetics, adverse reactions, and clinical use of the monobactam antimicrobial aztreonam are reviewed. Aztreonam, an... (Review)
Review
The chemistry, in vitro activity, pharmacokinetics, adverse reactions, and clinical use of the monobactam antimicrobial aztreonam are reviewed. Aztreonam, an investigational agent nearing approval in the United States and Canada, is the first in a class of monobactam antimicrobials to be evaluated extensively in vitro and in vivo. It has a narrow spectrum of activity, encompassing only aerobic gram-negative microorganisms including Pseudomonas aeruginosa and most multiply resistant Enterobacteriaceae. Aztreonam has no useful activity against gram-positive or anaerobic microorganisms. In preliminary studies, aztreonam achieved high tissue concentrations and was usually well tolerated. Approximately 65-75% of an administered dose is excreted unchanged into the urine, and the elimination half-life is 1.6-2.2 hours in subjects with normal renal function. Dosage should be adjusted in patients with renal impairment. Aztreonam was shown equivalent to gentamicin and cefamandole for treating serious urinary-tract infections and produced cure rates greater than 85% in gonococcal, lower respiratory tract, orthopedic, serious urinary tract, acute uncomplicated lower urinary-tract, gynecologic, and intraabdominal infections. Development of resistance during therapy may be less likely with aztreonam than with other new cephalosporins. Aztreonam will probably have an important role in antimicrobial therapy, but much further study is necessary to assess clinical efficacy and toxicity. The clinical importance of aztreonam's superior activity under anaerobic conditions compared with aminoglycosides and the theoretical reduced alteration in GI colonization resistance must be assessed in controlled trials. Evaluation of aztreonam versus ceftazidime, the carbapenems, and the carboxyquinolones is needed, and the likelihood of gram-positive superinfection, especially with enterococci, must be further assessed.
Topics: Animals; Aztreonam; Bacteria; Chemical Phenomena; Chemistry; Drug Compounding; Drug Interactions; Formularies as Topic; Humans; Kinetics; Structure-Activity Relationship
PubMed: 3902330
DOI: No ID Found -
Gastroenterology Clinics of North... Sep 2001This article presents a review of causes, presentation, and diagnosis of traveler's diarrhea. Treatment and prevention of this common problem is described in some... (Review)
Review
This article presents a review of causes, presentation, and diagnosis of traveler's diarrhea. Treatment and prevention of this common problem is described in some detail. Finally, a practical and cost-effective approach to evaluating and treating a returning traveler is presented.
Topics: Adolescent; Adult; Antidiarrheals; Aztreonam; Benzimidazoles; Diarrhea; Humans; Infant; Loperamide; Monobactams; Travel
PubMed: 11586551
DOI: 10.1016/s0889-8553(05)70204-1 -
Mayo Clinic Proceedings Sep 1987Cephalosporin and related antibiotics are highly effective bactericidal agents of relatively low toxicity. The spectrum of activity varies with the drug but is usually... (Comparative Study)
Comparative Study Review
Cephalosporin and related antibiotics are highly effective bactericidal agents of relatively low toxicity. The spectrum of activity varies with the drug but is usually broad. The first-generation cephalosporins, and especially cefazolin, are most active against sensitive staphylococci and streptococci. Most second-generation (except cefoxitin) and third-generation cephalosporins show substantial activity against Haemophilus influenzae. All cephalosporins (except cefsulodin) are active against Klebsiella, Escherichia coli, and Proteus mirabilis, whereas only the third-generation agents have pronounced activity against the other Enterobacteriaceae. Imipenem (a carbapenem) is active against essentially all pathogenic organisms, but aztreonam (a monobactam) is active against only aerobic gram-negative bacilli. Advantages associated with some of the new cephalosporins are once-daily administration and high cerebrospinal fluid levels. With the development of new cephalosporins, however, new toxicities have become apparent, and superinfections and induction of resistance have become greater problems. The cephalosporins are among the most expensive antibiotics in use today; thus, use of these expensive agents must be justified by lower toxicity, greater efficacy, or both in comparison with drugs of more reasonable cost.
Topics: Bacteria; Bacterial Infections; Cephalosporins; Drug Resistance, Microbial; Humans; Monobactams; Thienamycins
PubMed: 3306182
DOI: 10.1016/s0025-6196(12)62336-2 -
European Journal of Neurology Dec 2023Evidence-based recommendations for treatment of Lyme neuroborreliosis (LNB) should rely on the available literature. As new data emerges, close review and evaluation of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Evidence-based recommendations for treatment of Lyme neuroborreliosis (LNB) should rely on the available literature. As new data emerges, close review and evaluation of the recent literature is needed to build evidence-based recommendations to inform clinical practice and management of LNB. We performed an update of a previous systematic review on treatment of LNB.
METHODS
A systematic literature search of Medline and CENTRAL was performed for published studies from 2015 to 2023 to update a previous systematic review. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were evaluated. Risk of bias was assessed using the Cochrane risk of bias tools for RCTs; NRS were assessed using the ROBINS-I-tool. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Data were integrated into an existing meta-analysis of the available literature.
RESULTS
After screening 1530 records, two RCTs and five NRS with new and relevant data were additionally identified. Meta-analysis showed no statistically significant difference between doxycycline and beta-lactam antibiotics regarding residual neurological symptoms after 12 months. Meta-analysis showed no benefit of extended antibiotic treatment of LNB. Three NRS show no benefit for additional steroid use in LNB with facial palsy.
DISCUSSION
Additional incorporated recent research corroborates existing guideline recommendations for treatment of LNB. New RCTs add to the certainty of previous analysis showing similar efficacy for doxycycline and beta-lactam antibiotics in LNB. Available evidence shows no benefit for extended antibiotic treatment in LNB. NRS do not suggest a role for steroids in facial palsy due to LNB.
Topics: Humans; Lyme Neuroborreliosis; Doxycycline; Facial Paralysis; Anti-Bacterial Agents; Monobactams
PubMed: 37565386
DOI: 10.1111/ene.16034 -
The American Journal of Medicine Mar 1990Aztreonam, the first monobactam, has been used extensively in the treatment of a variety of infections caused by gram-negative pathogens. It has been shown to be highly... (Review)
Review
Aztreonam, the first monobactam, has been used extensively in the treatment of a variety of infections caused by gram-negative pathogens. It has been shown to be highly effective against susceptible bacteria without causing serious adverse reactions. Its pharmacologic profile can be attributed to its unique chemical properties and mechanisms of action, which differ substantially from those of the bicyclic beta-lactams, such as the penicillins and cephalosporins. Administered parenterally, aztreonam provides peak serum concentrations for most Enterobacteriaceae and Pseudomonas aeruginosa. It is widely distributed throughout the body. Excretion is largely dependent on renal mechanisms, so dosage can be adjusted in the presence of renal impairment. The clinical uses of aztreonam include treatment of urinary tract, lower respiratory tract, and intraabdominal infections, as well as septicemia, endometritis, pelvic cellulitis, and skin and skin structure infections due to aerobic gram-negative organisms. It is concluded that aztreonam can be used with confidence in the single-drug treatment of susceptible aerobic, gram-negative pathogens. In the treatment of mixed infections, or those of unknown etiology, however, combination therapy is recommended to ensure coverage of gram-positive and anaerobic bacteria.
Topics: Aztreonam; Bacteria; Bacterial Infections; Humans; Microbial Sensitivity Tests
PubMed: 2180293
DOI: 10.1016/0002-9343(90)90079-s -
Expert Opinion on Therapeutic Patents Mar 2021Monocyclic beta-lactams are four-membered cyclic amides with various structural modifications of the nucleus that determine their chemical reactivity and target... (Review)
Review
INTRODUCTION
Monocyclic beta-lactams are four-membered cyclic amides with various structural modifications of the nucleus that determine their chemical reactivity and target specificity. Their historical use is based on their antibacterial activity, but they have recently appeared in other areas as well.
AREAS COVERED
This review summarizes the relevant patent development on monocyclic beta-lactams in various therapeutic areas over the last 10 years. The majority of patents describe compounds with antibacterial activity, while there are some recent patents describing the neuroprotective, anti-inflammatory, anti-cancer, anticoagulant and antihyperlipidemic effects of 2-azetidinones.
EXPERT OPINION
Monocyclic beta-lactams can be considered safe and nontoxic drugs, as they have been used in the clinic for almost half of the century. Recently, monocyclic beta-lactams have been increasingly recognized for their non-antibiotic activity, which has led to some promising new clinical candidates in the field of neurodegenerative diseases and coagulation therapy. With regard to their antibacterial activity, there is still room for improvement of their activity and broadening of their spectrum of action, especially in Gram-positive bacteria and on drug-insensitive penicillin-binding proteins, and in increasing their beta-lactamase stability.
Topics: Animals; Anti-Bacterial Agents; Anticoagulants; Drug Development; Humans; Monobactams; Neurodegenerative Diseases; Patents as Topic; Structure-Activity Relationship
PubMed: 33327805
DOI: 10.1080/13543776.2021.1865919 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2002A theoretical study of the water-assisted alkaline hydrolysis of 2-azetidinone, 3-formylamino-2-azetidinone and 3-formylamino-2-azetidine-1-sulfonate ion is carried out...
A theoretical study of the water-assisted alkaline hydrolysis of 2-azetidinone, 3-formylamino-2-azetidinone and 3-formylamino-2-azetidine-1-sulfonate ion is carried out at the B3LYP/6-31+G* level. The effect of bulk solvent is taken into account using the PCM solvation model while specific solvent effects are represented by the inclusion of an ancillary water molecule along the reaction profile. The calculated free energy barriers in solution are in reasonable agreement with experimental values. The observed substituent effects due to the presence of the 3-formylamino and the SO(3) groups attached to the beta-lactam ring are crucial factors determining the hydrolysis of monobactam antibiotics.
Topics: Azetidines; Hydrolysis; Hydroxides; Models, Chemical; Molecular Structure; Monobactams; Solvents; Structure-Activity Relationship; Thermodynamics; Water
PubMed: 11857700
DOI: 10.1002/1521-3765(20020215)8:4<859::aid-chem859>3.0.co;2-i