Mechanisms of Action: Physiological Effects
- Mechanisms of Action: Physiological EffectsLeishmania donovani Parasites Are Inhibited by the Benzoxaborole AN2690 Targeting Leucyl-tRNA Synthetase
Visceral leishmaniasis is an important public health threat in parts of India. It is caused by a protozoan parasite, Leishmania donovani.
- Mechanisms of Action: Physiological EffectsSynergy between Circular Bacteriocin AS-48 and Ethambutol against Mycobacterium tuberculosis
The increasing incidence of multidrug-resistant Mycobacterium tuberculosis strains and the very few drugs available for treatment are promoting the discovery and development of new molecules that could help in the control of this disease. Bacteriocin AS-48 is an antibacterial peptide produced by ...
- Mechanisms of Action: Physiological EffectsThailandamide, a Fatty Acid Synthesis Antibiotic That Is Coexpressed with a Resistant Target Gene
Microbes encode many uncharacterized gene clusters that may produce antibiotics and other bioactive small molecules. Methods for activating these genes are needed to explore their biosynthetic potential.
- Mechanisms of Action: Physiological EffectsCrystal Structures of Penicillin-Binding Protein D2 from Listeria monocytogenes and Structural Basis for Antibiotic Specificity
β-Lactam antibiotics that inhibit penicillin-binding proteins (PBPs) have been widely used in the treatment of bacterial infections. However, the molecular basis underlying the different inhibitory potencies of β-lactams against specific PBPs is not fully understood.
- Mechanisms of Action: Physiological EffectsPharmacological Inhibition of the Vacuolar ATPase in Bloodstream-Form Trypanosoma brucei Rescues Genetic Knockdown of Mitochondrial Gene Expression
Trypanosomatid parasites cause diseases in humans and livestock. It was reported that partial inhibition of the vacuolar ATPase (V-ATPase) affects the dependence of Trypanosoma brucei on its mitochondrial genome (kinetoplast DNA [kDNA]), a target of the antitrypanosomatid drug isometamidium.
Mechanisms of Resistance
- Mechanisms of ResistanceMolecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar
A total of 301 Candida bloodstream isolates collected from 289 patients over 5 years at a tertiary hospital in Qatar were evaluated. Out of all Candida infections, 53% were diagnosed in patients admitted to the intensive care units.
- Mechanisms of ResistanceCombination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination
Single amino acid substitutions in the Ω loop of KPC β-lactamases are known to lead to resistance to the ceftazidime-avibactam combination. Here, we investigate this mechanism of resistance in CTX-M enzymes, which are the most widely spread extended-spectrum β-lactamases worldwide.
- Mechanisms of ResistanceMolecular Insights into Functional Differences between mcr-3- and mcr-1-Mediated Colistin Resistance
The global emergence of plasmid-mediated colistin resistance genes mcr-1 and mcr-3 has threatened the role of the “last-resort” drug colistin in the defense against infections caused by multidrug-resistant Gram-negative bacteria. However, functional differences between these two genes in mediating colistin resistance remain poorly understood.
- Mechanisms of ResistanceCeftaroline Resistance by Clone-Specific Polymorphism in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus
A total of 281 nonduplicated Staphylococcus aureus blood isolates were collected from January to May 2017 from eight hospitals in South Korea to investigate the epidemiological traits of ceftaroline resistance in methicillin-resistant S. aureus (MRSA). Cefoxitin-disk diffusion tests and the mecA...
- Mechanisms of ResistanceMutations in gyrA and gyrB in Moxifloxacin-Resistant Mycobacterium avium Complex and Mycobacterium abscessus Complex Clinical Isolates
Data on the frequency of gyrA and gyrB mutations in fluoroquinolone-resistant isolates of the Mycobacterium avium complex (MAC) and the Mycobacterium abscessus complex (MABC) are limited. In our analysis, we did not find any resistance-associated mutations in gyrA or ...
- Mechanisms of ResistanceFitness Costs and the Rapid Spread of kelch13-C580Y Substitutions Conferring Artemisinin Resistance
Fitness costs are key determinants of whether drug resistance alleles establish and how fast they spread within populations. More than 125 different kelch13 alleles, each containing a different amino acid substitution, have arisen in Southeast Asian malaria parasite (Plasmodium falciparum) populations under artemisinin selection over the past 15 years in a...
- Mechanisms of ResistanceTEM-184, a Novel TEM-Derived Extended-Spectrum β-Lactamase with Enhanced Activity against Aztreonam
TEM-184, a novel TEM-derived extended-spectrum β-lactamase (ESBL), was isolated from an Escherichia coli ST354 clinical strain. Compared to TEM-1, TEM-184 contains the mutations Q6K, E104K, I127V, R164S, and M182T.
- Mechanisms of ResistanceColistin Heteroresistance and Involvement of the PmrAB Regulatory System in Acinetobacter baumannii
Multidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem, and colistin is increasingly being used as a last-resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described.
- Mechanisms of ResistanceGenes and Proteins Involved in qnrS1 Induction
Expression of the quinolone resistance gene qnrS1 is increased by quinolones, but unlike induction of some other qnr genes, the bacterial SOS system is not involved and no lexA box is found upstream. Nonetheless, at least 205 bp of upstream sequence is required for induction to take place.
- Mechanisms of ResistanceBroad-Spectrum Adaptive Antibiotic Resistance Associated with Pseudomonas aeruginosa Mucin-Dependent Surfing Motility
Surfing motility is a novel form of surface adaptation exhibited by the nosocomial pathogen Pseudomonas aeruginosa in the presence of the glycoprotein mucin, which is found in high abundance at mucosal surfaces, especially those of the lungs of cystic fibrosis and bronchiectasis patients. Here, we investigated the adaptive antibiotic resistance of...
- Mechanisms of ResistanceCharacterization of a Novel SXT/R391 Integrative and Conjugative Element Carrying cfr, blaCTX-M-65, fosA3, and aac(6′)-Ib-cr in Proteus mirabilis
A novel 139,487-bp SXT/R391 integrative and conjugative element, ICEPmiChnBCP11, was characterized in Proteus mirabilis of swine origin in China. ICEPmiChnBCP11 harbors 20 different antimicrobial resistance genes, including the clinically important rRNA methyltransferase gene cfr, the extended-spectrum β-lactamase gene blaCTX-M...
- Mechanisms of ResistanceContribution of Novel Amino Acid Alterations in PmrA or PmrB to Colistin Resistance in mcr-Negative Escherichia coli Clinical Isolates, Including Major Multidrug-Resistant Lineages O25b:H4-ST131-H30Rx and Non-x
Colistin is a last-line drug for multidrug-resistant Gram-negative bacteria. We previously reported four plasmid-mediated colistin resistance (mcr) gene-negative colistin-resistant Escherichia coli clinical isolates, including the major pathogenic and fluoroquinolone-resistant strains O25b:H4-ST131-H30Rx (isolates SRE34 and SRE44; MIC for colistin =...
- Mechanisms of ResistanceCRISPR/Cas9 Genome Editing To Demonstrate the Contribution of Cyp51A Gly138Ser to Azole Resistance in Aspergillus fumigatus...
A pan-azole-resistant Aspergillus fumigatus strain with the cyp51A mutations Gly138Ser and Asn248Lys was isolated from a patient receiving long-term voriconazole treatment. PCR fragments containing cyp51A with the mutations were introduced along with the Cas9 protein and single guide RNA into the azole-resistant/susceptible strains.
- Mechanisms of ResistanceFunctional Characterization of AbaQ, a Novel Efflux Pump Mediating Quinolone Resistance in Acinetobacter baumannii
Acinetobacter baumannii has emerged as an important multidrug-resistant nosocomial pathogen. In previous work, we identified a putative MFS transporter, AU097_RS17040, involved in the pathogenicity of A. baumannii (M.
- Mechanisms of ResistanceEfficiency of Target Larvicides Is Conditioned by ABC-Mediated Transport in the Zoonotic Nematode Anisakis pegreffii
Anisakiasis is among the most significant emerging foodborne parasitoses contracted through consumption of thermally unprocessed seafood harboring infective Anisakis species larvae. The efficacy of the currently applied anthelminthic therapy in humans and in model organisms has not proven sufficient, so alternative solutions employing natural compounds combined with...
- Mechanisms of ResistanceScreening and Characterization of Multidrug-Resistant Gram-Negative Bacteria from a Remote African Area, São Tomé and Príncipe
The occurrence of resistance to last-resort antibiotics was evaluated among Enterobacteriaceae isolates recovered from hospitalized children in a remote African archipelago, São Tomé and Príncipe, where there is limited access to those antibiotics. Fifty patients were screened for colonization by carbapenem-, pan-aminoglycoside-, or polymyxin-resistant...
Susceptibility
- SusceptibilityValidating a 14-Drug Microtiter Plate Containing Bedaquiline and Delamanid for Large-Scale Research Susceptibility Testing of Mycobacterium tuberculosis
The UKMYC5 plate is a 96-well microtiter plate designed by the CRyPTIC Consortium (Comprehensive Resistance Prediction for Tuberculosis: an International Consortium) to enable the measurement of MICs of 14 different antituberculosis (anti-TB) compounds for >30,000 clinical Mycobacterium tuberculosis isolates. Unlike the MYCOTB plate, on which the UKMYC5 plate is...
- SusceptibilityMolecular Identification and Susceptibility Testing of Molds Isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 Study)
Antifungal resistance is increasing by the emergence of intrinsically resistant species and by the development of secondary resistance in susceptible species. A previous study performed in Spain revealed levels of azole resistance in molds of between 10 and 12.7%, but secondary resistance in Aspergillus fumigatus was not detected.
- SusceptibilityIn Vitro Susceptibility of Burkholderia cepacia Complex Isolated from Cystic Fibrosis Patients to Ceftazidime-Avibactam and Ceftolozane-Tazobactam
We tested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. The highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole.
- SusceptibilityIn Vitro Activity of Ceftolozane-Tazobactam against Enterobacter cloacae Complex Clinical Isolates with Different β-Lactam Resistance Phenotypes
The study evaluated the in vitro activity of ceftolozane-tazobactam (C/T) against 94 unique clinical isolates of Enterobacter cloacae complex (ECC). No difference was observed according to the ECC cluster.
- SusceptibilityVariability of Daptomycin MIC Values for Enterococcus faecium When Measured by Reference Broth Microdilution and Gradient Diffusion Tests
Daptomycin has become a mainstay therapy for the treatment of serious vancomycin-resistant Enterococcus faecium infections. However, concern exists that current testing methods do not accurately predict the clinical success of daptomycin therapy.
- SusceptibilityActivity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients
Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a...
Analytical Procedures
- Analytical ProceduresQuantification of Cefepime, Meropenem, Piperacillin, and Tazobactam in Human Plasma Using a Sensitive and Robust Liquid Chromatography-Tandem Mass Spectrometry Method, Part 1: Assay Development and Validation
The highly variable pharmacokinetics of β-lactam antibiotics and β-lactamase inhibitors poses a significant challenge to clinicians in ensuring appropriate antibiotic doses in critically ill patients. Therefore, routine monitoring of plasma concentrations is important for individualization of antimicrobial therapy.
- Analytical ProceduresQuantification of Cefepime, Meropenem, Piperacillin, and Tazobactam in Human Plasma Using a Sensitive and Robust Liquid Chromatography-Tandem Mass Spectrometry Method, Part 2: Stability Evaluation
Although the stability of β-lactam antibiotics is a known issue, none of the previously reported bioanalytical methods had an adequate evaluation of the stability of these drugs. In the current study, the stability of cefepime, meropenem, piperacillin, and tazobactam under various conditions was comprehensively evaluated.
Epidemiology and Surveillance
- Epidemiology and SurveillanceNeisseria meningitidis Antimicrobial Resistance in Italy, 2006 to 2016
The aim of this study was to evaluate the antimicrobial susceptibilities of 866 Neisseria meningitidis invasive strains during 11 years of surveillance in Italy. Two and six strains were resistant to ciprofloxacin and rifampin, respectively.
- Epidemiology and SurveillancePrevalence and Genetic Analysis of mcr-3-Positive Aeromonas Species from Humans, Retail Meat, and Environmental Water Samples
The mobile colistin resistance gene mcr-3 is globally disseminated in both Enterobacteriaceae and Aeromonas species, with the latter potentially serving as a reservoir for this gene. Here, we investigated the prevalence of mcr-3 in rectal swabs from humans, in food-producing...
- Epidemiology and SurveillanceSpread of blaCTX-M-15-Producing Enterobacteriaceae and OXA-23-Producing Acinetobacter baumannii Sequence Type 2 in Tunisian Seafood
Bivalves are filter-feeding animals and markers of bacterial pollution. We report a massive spread of blaCTX-M-15 through dominant Escherichia coli and Klebsiella pneumoniae lineages and/or plasmid subtypes (F31:A4:B1) as well as the presence of OXA-23-producing...
- Epidemiology and SurveillanceMolecular Characterization of Nasal Methicillin-Resistant Staphylococcus aureus Isolates Showing Increasing Prevalence of Mupirocin Resistance and Associated Multidrug Resistance following Attempted Decolonization
Sequential methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients following attempted mupirocin nasal decolonization showed an increase in mupirocin resistance (MR) from 6.6% to 20%. MR isolates from patients who failed decolonization yielded indistinguishable spa types and carried multiple antimicrobial and antiseptic resistance genes,...
- Epidemiology and SurveillanceAcquisition of Beta-Lactamase by Neisseria meningitidis through Possible Horizontal Gene Transfer
We report the detection in France of a beta-lactamase-producing invasive meningococcal isolate. Whole-genome sequencing of the isolate revealed a ROB-1-type beta-lactamase gene that is frequently encountered in Haemophilus influenzae, suggesting horizontal transfer between isolates of these bacterial species.
- Epidemiology and SurveillanceMulticlonal Expansion and High Prevalence of β-Lactamase-Negative Haemophilus influenzae with High-Level Ampicillin Resistance in Japan and Susceptibility to Quinolones
β-Lactam-resistant Haemophilus influenzae is a clinical concern. A high prevalence (>40%) of β-lactamase-negative high-level ampicillin-resistant H. influenzae (high-BLNAR) isolates in Japan has been reported.
- Epidemiology and SurveillanceSurveillance of Genetic Variations Associated with Antimalarial Resistance of Plasmodium falciparum Isolates from Returned Migrant Workers in Wuhan, Central China
Antimalarial drug resistance developed in Plasmodium falciparum has become a problem for malaria control. Evaluation of drug resistance is the first step for effective malaria control.
Experimental Therapeutics
- Experimental TherapeuticsPharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits
Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant Enterobacteriaceae. We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the...
- Experimental TherapeuticsSuperior Pyronaridine Single-Dose Pharmacodynamics Compared to Artesunate, Chloroquine, and Amodiaquine in a Murine Malaria Luciferase Model
Many previous in vitro and in vivo preclinical malaria drug studies have relied on low-parasite-number drug inhibition numerically compared to the untreated controls. In contrast, human malaria drug studies measure the high-parasite-density killing near 100 million/ml.
- Experimental TherapeuticsGenistein and Ascorbic Acid Reduce Oxidative Stress-Derived DNA Damage Induced by the Antileishmanial Meglumine Antimoniate
Meglumine antimoniate (Glucantime) is a pentavalent antimonial used to treat leishmaniasis, despite its acknowledged toxic effects, such as its ability to cause oxidative damage to lipids and proteins. Recently, our group demonstrated that meglumine antimoniate causes oxidative stress-derived DNA damage.
- Experimental TherapeuticsPharmacokinetics, Tolerability, and Safety of Murepavadin, a Novel Antipseudomonal Antibiotic, in Subjects with Mild, Moderate, or Severe Renal Function Impairment
This open-label, nonrandomized, single-dose, phase 1 study evaluated the pharmacokinetics and safety of murepavadin, a novel peptide antibiotic for the treatment of serious Pseudomonas aeruginosa infections. The study was conducted in 32 subjects of either sex in 4 groups (up to 8 per group) with mild (group 1), moderate (group 2), and severe (group 3) renal function...
- Experimental TherapeuticsBenefits of Ascorbic Acid in Association with Low-Dose Benznidazole in Treatment of Chagas Disease
The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD.
- Experimental TherapeuticsReversal of Chloroquine Resistance of Plasmodium vivax in Aotus Monkeys
Chloroquine-resistant (CQR) vivax malaria has emerged as a threat to the malaria elimination agenda. The objective of this study was to assess if a combination of chloroquine (CQ) and prochlorperazine was able to reverse CQ resistance of the Plasmodium vivax AMRU-1 strain from Papua New Guinea in infected ...
- Experimental TherapeuticsGold Nanoparticle-Conjugated Cinnamic Acid Exhibits Antiacanthamoebic and Antibacterial Properties
trans-Cinnamic acid (CA) is a natural organic compound. Using amoebicidal assays, for the first time we showed that CA affected the viability of the protist pathogen Acanthamoeba castellanii.
- Experimental TherapeuticsScreening of Preselected Libraries Targeting Mycobacterium abscessus for Drug Discovery
Mycobacterium abscessus is intrinsically resistant to many antimycobacterial antibiotics, which presents serious problems in therapy. Here, we describe the development of a novel phenotype-based microscopic and computerized imaging drug screening approach.
- Experimental TherapeuticsRepurposing Strategy of Atorvastatin against Trypanosoma cruzi: In Vitro Monotherapy and Combined Therapy with Benznidazole Exhibit Synergistic Trypanocidal Activity
Statins are inhibitors of cholesterol synthesis, but other biological properties, such as antimicrobial effects, have also been assigned to them, leading to their designation as pleiotropic agents. Our goal was to investigate the activity and selectivity of atorvastatin (AVA) against Trypanosoma cruzi by using in vitro models, aiming for more effective and...
- Experimental TherapeuticsThe Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis
Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activities of olorofim against Coccidioides species.
- Experimental TherapeuticsIn Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes.
- Experimental TherapeuticsAmbroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity
Host-directed therapy in tuberculosis is a potential adjunct to antibiotic chemotherapy directed at Mycobacterium tuberculosis. Ambroxol, a lead compound, emerged from a screen for autophagy-inducing drugs.
- Experimental TherapeuticsIn Vivo Pharmacodynamic Characterization of a Novel Odilorhabdin Antibiotic, NOSO-502, against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model
NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae. The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude best correlated with efficacy in the murine thigh infection model.
- Experimental TherapeuticsThe Fungal Cyp51 Inhibitor VT-1129 Is Efficacious in an Experimental Model of Cryptococcal Meningitis
Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungus-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species.
- Experimental TherapeuticsAssessment of the Additional Value of Verapamil to a Moxifloxacin and Linezolid Combination Regimen in a Murine Tuberculosis Model
The favorable treatment outcome rate for multidrug-resistant tuberculosis (MDR-TB) is only 54%, and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the value of the addition of the efflux pump inhibitor verapamil to this backbone.
- Experimental TherapeuticsEfficacy and Pharmacokinetics Evaluation of a Single Oral Dose of Afoxolaner against Sarcoptes scabiei in the Porcine Scabies Model for Human Infestation
Scabies is a major and potentially growing public health problem worldwide with an unmet need for acaricidal agents with greater efficacy and improved pharmacological properties for its treatment. The objective of the present study was to assess the efficacy and describe the pharmacokinetics profile of a novel acaricide, afoxolaner (AFX), in a relevant experimental porcine model.
- Experimental TherapeuticsIn Vivo Efficacy of Meropenem with a Novel Non-β-Lactam–β-Lactamase Inhibitor, Nacubactam, against Gram-Negative Organisms Exhibiting Various Resistance Mechanisms in a Murine Complicated Urinary Tract Infection Model
Urinary tract infections (UTIs) are a tremendous burden on the health care system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multidrug-resistant (MDR) organisms, limiting the availability of effective antimicrobials.
Clinical Therapeutics
- Clinical TherapeuticsRapid Antibiotic Combination Testing for Carbapenem-Resistant Gram-Negative Bacteria within Six Hours Using ATP Bioluminescence
To guide the timely selection of antibiotic combinations against carbapenem-resistant Gram-negative bacteria (CR-GNB), an in vitro test with a short turnaround time is essential. We developed an in vitro ATP bioluminescence assay to determine effective antibiotic combinations against CR-GNB within 6 h.
- Clinical TherapeuticsTen-Day Quadruple Therapy Comprising Low-Dose Rabeprazole, Bismuth, Amoxicillin, and Tetracycline Is an Effective and Safe First-Line Treatment for Helicobacter pylori Infection in a Population with High Antibiotic Resistance: a Prospective, Multicenter, Randomized, Parallel-Controlled Clinical Trial in China
The objective of this study was to investigate the efficacy and safety of 10-day bismuth quadruple therapy with amoxicillin, tetracycline, or clarithromycin and different doses of rabeprazole for first-line treatment of Helicobacter pylori infection. This multicenter, randomized, parallel-controlled clinical trial was conducted between March 2013 and August 2014....
- Clinical TherapeuticsPopulation Pharmacokinetic Study of Amoxicillin-Treated Burn Patients Hospitalized at a Swiss Tertiary-Care Center
The objective of this study was to investigate the population pharmacokinetics (PK) of amoxicillin in ICU burn patients and the optimal dosage regimens. This was a prospective study involving 21 consecutive burn patients receiving amoxicillin.
- Clinical TherapeuticsEffect of Cumulative Intravenous Voriconazole Dose on Renal Function in Hematological Patients
Intravenous voriconazole (VRC) is formulated by the incorporation of sulfobutylether-β-cyclodextrin (SBECD), which may accumulate to adversely affect renal function. However, the effect of long-term use of intravenous VRC on renal function is unclear.
- Clinical TherapeuticsPharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis
Over the past decade, the prevalence of infections involving methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile.
- Clinical TherapeuticsRole of Lock Therapy for Long-Term Catheter-Related Infections by Multidrug-Resistant Bacteria
The management of long-term central venous catheter (LTCVC) infections by multidrug-resistant (MDR) bacteria in cancer patient is a challenge. The objectives of this study were to analyze outcomes in cancer patients with LTCVC-associated infection, identify risks for unfavorable outcomes, and determine the impact of MDR bacteria and antibiotic lock therapy (ALT) in managing such infections.
- Clinical TherapeuticsSystematic Review and Meta-analysis of the Efficacy of Short-Course Antibiotic Treatments for Community-Acquired Pneumonia in Adults
The duration of therapy for community-acquired pneumonia (CAP) remains undefined. We sought to investigate whether short-course antibiotic treatment for CAP is associated with favorable clinical outcomes in adult patients.
- Clinical TherapeuticsIs It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?
Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring to optimize therapy. We report two cases of central nervous system aspergillosis treated with voriconazole.
- Clinical TherapeuticsRandomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia
New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia.
- Clinical TherapeuticsEchinocandin Treatment of Candida albicans Biofilms Enhances Neutrophil Extracellular Trap Formation
The nosocomial pathogen Candida albicans forms biofilms on medical devices that persist in the face of antifungals and host defenses. Echinocandins, the most effective antibiofilm drugs, have recently been shown to augment the activity of neutrophils against biofilms through an unknown mechanism.
- Clinical TherapeuticsPredictors of Peripherally Inserted Central Catheter Occlusion in the Outpatient Parenteral Antimicrobial Therapy Setting
In this retrospective study of 285 patients receiving outpatient parenteral antibiotic therapy (OPAT), the duration of antibiotic, use of double-lumen catheters, and receipt of penicillin G and cloxacillin appeared to increase the risk of peripherally inserted central catheter (PICC) occlusion. Physicians should consider these factors when prescribing long-term antibiotic therapy.
- Clinical TherapeuticsPharmacokinetics of a Pediatric Tribendimidine Dose-Finding Study To Treat Hookworm Infection in African Children
Tribendimidine is a broad-spectrum anthelminthic available in China, which is currently being pursued for U.S. Food and Drug Administration approval for soil-transmitted helminth infections.
- Clinical TherapeuticsPharmacodynamic Target Attainment for Cefepime, Meropenem, and Piperacillin-Tazobactam Using a Pharmacokinetic/Pharmacodynamic-Based Dosing Calculator in Critically Ill Patients
This was a prospective study to determine if pharmacokinetic/pharmacodynamic (PK/PD)-based antibiotic dosing software aids in achieving concentration targets in critically ill patients receiving cefepime (n = 10), meropenem (n = 20), or piperacillin-tazobactam (n = 19). Antibiotic calculator doses targeting a >90% probability of target attainment (PTA) differed from package insert doses for 22.4% (11/49) of...
- Clinical Therapeuticsβ-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance...
Augmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance.
Pharmacology
- PharmacologyEvaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations
Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children.
- PharmacologyUCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle,...
- PharmacologyPharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants
Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg)...
- PharmacologyComprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro
The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, using...
- PharmacologyResults of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection
Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections.
- PharmacologyExternal Evaluation of a Gentamicin Infant Population Pharmacokinetic Model Using Data from a National Electronic Health Record Database
Gentamicin is a common antibiotic used in neonates and infants. A recently published population pharmacokinetic (PK) model was developed using data from multiple studies, and the objective of our analyses was to evaluate the feasibility of using a national electronic health record (EHR) database for further external evaluation of this model.
- PharmacologyPopulation Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia
Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data.
- PharmacologyAzithromycin in Combination with Ceftriaxone Reduces Systemic Inflammation and Provides Survival Benefit in a Murine Model of Polymicrobial Sepsis
Sepsis is a life-threatening systemic inflammatory condition triggered as a result of an excessive host immune response to infection. In the past, immunomodulators have demonstrated a protective effect in sepsis.
- PharmacologyPopulation Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis
Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known.
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