Chemistry; Biosynthesis
Chemistry; BiosynthesisExploring Ubiquinone Biosynthesis Inhibition as a Strategy for Improving Atovaquone Efficacy in MalariaAtovaquone (AV) acts on the malaria parasite by competing with ubiquinol (UQH2) for its union to the mitochondrial bc1 complex, preventing the ubiquinone-8 and ubiquinone-9 (UQ-8 and UQ-9) redox recycling, which is a necessary step in pyrimidine biosynthesis. This study focused on UQ biosynthesis in Plasmodium falciparum and adopted proof-of-...
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsSynergistic Quinolone Sensitization by Targeting the recA SOS Response Gene and Oxidative StressSuppression of the recA SOS response gene and reactive oxygen species (ROS) overproduction have been shown, separately, to enhance fluoroquinolone activity and lethality. Their putative synergistic impact as a strategy to potentiate the efficacy of bactericidal antimicrobial agents such as fluoroquinolones is unknown.
Mechanisms of Action: Physiological EffectsMetabolic Survival Adaptations of Plasmodium falciparum Exposed to Sublethal Doses of FosmidomycinThe malaria parasite Plasmodium falciparum contains the apicoplast organelle that synthesizes isoprenoids, which are metabolites necessary for posttranslational modification of Plasmodium proteins. We used fosmidomycin, an antibiotic that inhibits isoprenoid biosynthesis, to identify mechanisms that underlie the development of the parasite’s adaptation to the...
Mechanisms of Action: Physiological EffectsInduction of Native c-di-GMP Phosphodiesterases Leads to Dispersal of Pseudomonas aeruginosa BiofilmsA decade of research has shown that the molecule c-di-GMP functions as a central second messenger in many bacteria. A high level of c-di-GMP is associated with biofilm formation, whereas a low level of c-di-GMP is associated with a planktonic single-cell bacterial lifestyle. c-di-GMP is formed by diguanylate cyclases and is degraded by specific phosphodiesterases.
Mechanisms of Action: Physiological EffectsEthylzingerone, a Novel Compound with Antifungal ActivityPreservatives increase the shelf life of cosmetic products by preventing growth of contaminating microbes, including bacteria and fungi. In recent years, the Scientific Committee on Consumer Safety (SCCS) has recommended the ban or restricted use of a number of preservatives due to safety concerns.
Mechanisms of Resistance
Mechanisms of ResistanceDaptomycin Resistance in Enterococcus faecium Can Be Delayed by Disruption of the LiaFSR Stress Response PathwayLiaFSR signaling plays a major role in mediating daptomycin (DAP) resistance in enterococci, and the lack of a functional LiaFSR pathway leads to DAP hypersusceptibility. Using in vitro experimental evolution, we evaluated how Enterococcus faecium with a liaR response regulator gene deletion evolved DAP resistance.
Mechanisms of ResistanceCarbapenem Use Is Driving the Evolution of Imipenemase 1 VariantsMetallo-β-lactamases (MBLs) are a growing clinical threat because they inactivate nearly all β-lactam-containing antibiotics, and there are no clinically available inhibitors. A significant number of variants have already emerged for each MBL subfamily.
Mechanisms of ResistanceLimited Multidrug Resistance Efflux Pump Overexpression among Multidrug-Resistant Escherichia coli Strains of ST131Gram-negative bacteria partly rely on efflux pumps to facilitate growth under stressful conditions and to increase resistance to a wide variety of commonly used drugs. In recent years, Escherichia coli sequence type 131 (ST131) has emerged as a major cause of extraintestinal infection frequently exhibiting a multidrug resistance (MDR) phenotype.
Mechanisms of ResistanceStructural and Biochemical Characterization of the Novel CTX-M-151 Extended-Spectrum β-Lactamase and Its Inhibition by AvibactamThe diazabicyclooctane (DBO) inhibitor avibactam (AVI) reversibly inactivates most serine β-lactamases, including the CTX-M β-lactamases. Currently, more than 230 unique CTX-M members distributed in five clusters with less than 5% amino acid sequence divergence within each group have been described.
Mechanisms of ResistanceThe C2H2 Transcription Factor SltA Contributes to Azole Resistance by Coregulating the Expression of the Drug Target Erg11A and the Drug Efflux Pump Mdr1 in Aspergillus fumigatusThe emergence of azole-resistant fungal pathogens has posed a great threat to public health worldwide. Although the molecular mechanism of azole resistance has been extensively investigated, the potential regulators of azole resistance remain largely unexplored.
Mechanisms of ResistanceThe Pup-Proteasome System Protects Mycobacteria from Antimicrobial AntifolatesProtein turnover via the Pup-proteasome system (PPS) is essential for nitric oxide resistance and virulence of Mycobacterium tuberculosis, the causative agent of tuberculosis. Our study revealed components of PPS as novel determinants of intrinsic antifolate resistance in both M. tuberculosis and...
Editor's Pick Mechanisms of ResistanceAdaptive Processes Change as Multiple Functions EvolveEpistasis influences the gene-environment interactions that shape bacterial fitness through antibiotic exposure, which can ultimately affect the availability of certain resistance phenotypes to bacteria. The substitutions present within blaTEM-50 confer both cephalosporin and β-lactamase inhibitor resistance.
Mechanisms of ResistanceModulation of Human Beta-Defensin 2 Expression by Pathogenic Neisseria meningitidis and Commensal LactobacilliAntimicrobial peptides (AMPs) play an important role in the defense against pathogens by targeting and killing invading microbes. Some pathogenic bacteria have been shown to negatively regulate AMP expression, while several commensals may induce AMP expression.
Mechanisms of ResistanceA Novel Transferable Resistance-Nodulation-Division Pump Gene Cluster, tmexCD2-toprJ2, Confers Tigecycline Resistance in Raoultella ornithinolyticaWe recently identified a novel plasmid-mediated resistance-nodulation-division (RND)-type efflux pump gene cluster, tmexCD1-toprJ1, in Klebsiella pneumoniae that conferred resistance to multiple antimicrobials, including tigecycline. While homologs of tmexCD1-toprJ1 were found encoded in many other bacterial species in GenBank, their functions and...
Mechanisms of ResistanceInteraction of Staphylococcus aureus and Acinetobacter baumannii during In Vitro β-Lactam ExposureWe sought to determine if Acinetobacter baumannii is capable of altering the pharmacodynamics of an antistaphylococcal β-lactam. Two strains of methicillin-susceptible Staphylococcus aureus (MSSA) and two A. baumannii isolates...
Mechanisms of ResistanceTetracycline Resistance Mediated by tet(M) Has Variable Integrative Conjugative Element Composition in Mycoplasma hominis Strains Isolated in the United Kingdom from 2005 to 2015A minimal genome and absent bacterial cell wall render Mycoplasma hominis inherently resistant to most antimicrobials except lincosamides, tetracyclines, and fluoroquinolones. Often dismissed as a commensal (except where linked to preterm birth), it causes septic arthritis in immunodeficient patients and is increasingly associated with transplant failure (particularly...
Susceptibility
SusceptibilityThe Role of New Posaconazole Formulations in the Treatment of Candida albicans Infections: Data from an In Vitro Pharmacokinetic-Pharmacodynamic ModelPosaconazole is more active than fluconazole against Candida albicans in vitro and is approved for the treatment of oropharyngeal candidiasis but not for that of invasive candidiasis (IC). Here, we explored the efficacy of posaconazole against C. albicans in an in vitro...
SusceptibilityIdentification of Antifungal Compounds against Multidrug-Resistant Candida auris Utilizing a High-Throughput Drug-Repurposing ScreenCandida auris is an emerging fatal fungal infection that has resulted in several outbreaks in hospitals and care facilities. Current treatment options are limited by the development of drug resistance.
SusceptibilityHeterologous Expression of ethA and katG in Mycobacterium marinum Enables the Rapid Identification of New Prodrugs Active against Mycobacterium tuberculosisScreening strategies for antituberculosis compounds using Mycobacterium tuberculosis are time consuming and require biosafety level 3 (BSL3) facilities, which makes the development of high-throughput assays difficult and expensive. Mycobacterium marinum, a close genetic relative of...
SusceptibilityMonitoring the Epidemiology and Antifungal Resistance of Yeasts Causing Fungemia in a Tertiary Care Hospital in Madrid, Spain: Any Relevant Changes in the Last 13 Years?We conducted an updated analysis on yeast isolates causing fungemia in patients admitted to a tertiary hospital in Madrid, Spain, over a 13-year period. We studied 896 isolates associated with 872 episodes of fungemia in 857 hospitalized patients between January 2007 and December 2019.
SusceptibilityPhysicochemical and Structural Parameters Contributing to the Antibacterial Activity and Efflux Susceptibility of Small-Molecule Inhibitors of Escherichia coliDiscovering new Gram-negative antibiotics has been a challenge for decades. This has been largely attributed to a limited understanding of the molecular descriptors governing Gram-negative permeation and efflux evasion.
SusceptibilityEvaluation of Synergistic Activity of Isavuconazole or Voriconazole plus Anidulafungin and the Occurrence and Genetic Characterization of Candida auris Detected in a Surveillance ProgramA total of 15 Candida auris isolates from the SENTRY antimicrobial surveillance program between 2006 and 2019 were combined with 21 isolates from other collections for the evaluation of antifungal susceptibility and synergy against anidulafungin plus voriconazole or isavuconazole using the checkerboard method. Surveillance isolates were analyzed for genetic...
SusceptibilityIn Vitro and In Vivo Activities of TP0480066, a Novel Topoisomerase Inhibitor, against Neisseria gonorrhoeaeGonorrhea is a common, sexually transmitted disease caused by Neisseria gonorrhoeae. Multidrug-resistant N. gonorrhoeae is an urgent threat, and the development of a new antimicrobial agent that functions via a new mechanism is strongly desired.
SusceptibilitySynergistic Rifabutin and Colistin Reduce Emergence of Resistance When Treating Acinetobacter baumanniiRecently, we reported rifabutin hyperactivity against Acinetobacter baumannii. We sought to characterize potential interactions between rifabutin and colistin, the last-resort drug for carbapenem-resistant infections. Rifabutin and colistin were synergistic in vitro and in vivo, and low-dose colistin significantly suppressed emergence of resistance...
SusceptibilityAssessment of Piperacillin-Tazobactam-Meropenem Synergy against Serine Carbapenemase-Producing Enterobacterales Using Time-Kill AssaysSynergy between piperacillin-tazobactam and meropenem against KPC-producing Klebsiella pneumoniae was recently demonstrated. We sought to test the combination against a broader range of serine carbapenemase producers.
SusceptibilityIn Vitro Resistance and Evolution of Resistance to Tavaborole in Trichophyton rubrumTavaborole is currently used in the topical treatment of onychomycosis. In this study, we analyzed the in vitro emergence/evolution of resistance against tavaborole in Trichophyton rubrum.
SusceptibilityActivity of Cefepime in Combination with the Novel β-Lactamase Inhibitor Taniborbactam (VNRX-5133) against Extended-Spectrum-β-Lactamase-Producing Isolates in In Vitro Checkerboard AssaysExtended-spectrum-β-lactamase (ESBL)-producing strains are increasing worldwide, limiting therapeutic options. Taniborbactam (VNRX-5133) is a newly developed β-lactamase inhibitor with a wide spectrum of activity covering both serine and metallo enzymes.
Antiviral Agents
Antiviral AgentsInhibition of Arenaviruses by Combinations of Orally Available Approved DrugsNeglected diseases caused by arenaviruses such as Lassa virus (LASV) and filoviruses like Ebola virus (EBOV) primarily afflict resource-limited countries, where antiviral drug development is often minimal. Previous studies have shown that many approved drugs developed for other clinical indications inhibit EBOV and LASV and that combinations of these drugs provide synergistic suppression of EBOV, often by blocking discrete steps in...
Antiviral AgentsIn Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficileOPS-2071 is a novel quinolone antibacterial agent characterized by low oral absorption that reduces the risk of adverse events typical of fluoroquinolone class antibiotics. The in vitro and in vivo antibacterial activities of OPS-2071 against Clostridioides difficile were evaluated in comparison to vancomycin and fidaxomicin.
Antiviral AgentsDiazadispiroalkane Derivatives Are New Viral Entry InhibitorsHerpesviruses are widespread and can cause serious illness. Many currently available antiviral drugs have limited effects, result in rapid development of resistance, and often exhibit dose-dependent toxicity.
Antiviral AgentsA Concept Evaluation Study of a New Combination Bictegravir plus Tenofovir Alafenamide Nanoformulation with Prolonged Sustained-Drug-Release Potency for HIV-1 Preexposure ProphylaxisThe antiretroviral treatment (ART) approach is the best-prescribed approach to date for preexposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination antiretroviral (cARV) regimen has become cumbersome for healthy individuals, leading to nonadherence.
Antiviral AgentsAT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment.
Antiviral AgentsKinetic Characterization and Inhibitor Screening for the Proteases Leading to Identification of Drugs against SARS-CoV-2Coronavirus (CoV) disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has claimed many lives worldwide and is still spreading since December 2019. The 3C-like protease (3CLpro) and papain-like protease (PLpro) are essential for maturation of viral polyproteins in SARS-CoV-2 life cycle and thus regarded as key drug targets for the disease.
Antiviral AgentsEnisamium Reduces Influenza Virus Shedding and Improves Patient Recovery by Inhibiting Viral RNA Polymerase ActivityInfections with respiratory viruses constitute a huge burden on our health and economy. Antivirals against some respiratory viruses are available, but further options are urgently needed. Enisamium iodide (laboratory code FAV00A, trade name Amizon) is an antiviral marketed in countries of the Commonwealth of Independent States for the treatment of viral respiratory infections, but its clinical efficacy and mode of action are not well...
Epidemiology and Surveillance
Epidemiology and SurveillanceMultidrug-Resistant Plasmodium falciparum Parasites in the Central Highlands of Vietnam Jeopardize Malaria Control and Elimination StrategiesPlasmodium falciparum resistance to dihydroartemisinin-piperaquine has spread through the Greater Mekong Subregion to southwestern Vietnam. In 2018 to 2019, we collected 127 P. falciparum isolates from Dak Nong (36), Dak Lak (55), Gia Lai (13), and Kon Tum (23) provinces in Vietnam’s Central...
Epidemiology and SurveillanceEpidemic Territorial Spread of IncP-2-Type VIM-2 Carbapenemase-Encoding Megaplasmids in Nosocomial Pseudomonas aeruginosa PopulationsIn 2003 to 2004, the first five VIM-2 metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa (MPPA) isolates with an In4-like integron, In461 (aadB-blaVIM-2-aadA6), on conjugative plasmids were identified in three hospitals in Poland. In 2005 to 2015, MPPA expanded much in the country, and as many as 80 isolates in a...
Editor's Pick Epidemiology and SurveillanceAnalysis of Multidrug Resistance in Staphylococcus aureus with a Machine Learning-Generated AntibiogramMultidrug resistance (MDR) surveillance consists of reporting MDR prevalence and MDR phenotypes. Detailed knowledge of the specific associations underlying MDR patterns can allow antimicrobial stewardship programs to accurately identify clinically relevant resistance patterns.
Epidemiology and SurveillancePolyclonal Dissemination of NDM-1- and NDM-9-Producing Escherichia coli and Klebsiella pneumoniae in French PolynesiaThe whole-genome sequencing analysis revealed a polyclonal dissemination of NDM-1 and NDM-9 variants in Escherichia coli (n = 20) and Klebsiella pneumoniae (n = 2) in Tahiti since 2015 via interspecies transfer of three different blaNDM-carrying plasmids (IncR,...
Experimental Therapeutics
Experimental TherapeuticsThe Antibiotic Negamycin Crosses the Bacterial Cytoplasmic Membrane by Multiple RoutesNegamycin is a natural pseudodipeptide antibiotic with promising activity against Gram-negative and Gram-positive bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus, and good efficacy in infection models. It binds to ribosomes with a novel binding mode...
Experimental TherapeuticsBoromycin Has Potent Anti-Toxoplasma and Anti-Cryptosporidium ActivityToxoplasma gondii and Cryptosporidium parvum, members of the phylum Apicomplexa, are significant pathogens of both humans and animals worldwide for which new and effective therapeutics are needed. Here, we describe the activity of the antibiotic boromycin against Toxoplasma and ...
Experimental TherapeuticsIn Vitro Activity and In Vivo Efficacy of Cefiderocol against Stenotrophomonas maltophiliaCefiderocol is a novel siderophore cephalosporin antibiotic with broad coverage against difficult-to-treat Gram-negative bacteria, including those resistant to carbapenems. Its activity against Stenotrophomonas maltophilia was investigated in vitro against clinical isolates and in lung infection models using strains either resistant (SR202006) or susceptible...
Experimental TherapeuticsComparative Pharmacodynamics of Echinocandins against Aspergillus fumigatus Using an In Vitro Pharmacokinetic/Pharmacodynamic Model That Correlates with Clinical Response to Caspofungin Therapy: Is There a Place for Dose Optimization?Echinocandins have been used as primary therapy of invasive aspergillosis (IA), with suboptimal results at standard dosing. Here, we explored the efficacy of dose escalation in a validated in vitro pharmacokinetic/pharmacodynamic (PK/PD) model.
Experimental TherapeuticsDevelopment and Characterization of Monoolein-Based Liposomes of Carvacrol, Cinnamaldehyde, Citral, or Thymol with Anti-Candida ActivitiesThere is an increasing need for novel drugs and new strategies for the therapy of invasive candidiasis. This study aimed to develop and characterize liposome-based nanoparticles of carvacrol, cinnamaldehyde, citral, and thymol with anti-Candida activities.
Experimental TherapeuticsIn Vitro Study of the Synergistic Effect of an Enzyme Cocktail and Antibiotics against Biofilms in a Prosthetic Joint Infection ModelProsthetic joint infections (PJI) are frequent complications of arthroplasties. Their treatment is made complex by the rapid formation of bacterial biofilms, limiting the effectiveness of antibiotic therapy.
Experimental TherapeuticsIn Vivo Antibacterial Activity of AcetazolamideVancomycin-resistant enterococci (VRE) represent a major public health threat that requires the development of new therapeutics. In the present study, acetazolamide (AZM) was evaluated against enterococci.
Experimental TherapeuticsA Hyaluronic Acid Hydrogel Loaded with Gentamicin and Vancomycin Successfully Eradicates Chronic Methicillin-Resistant Staphylococcus aureus Orthopedic Infection in a Sheep ModelImplantable orthopedic devices have had an enormously positive impact on human health; however, despite best practice, patients are prone to developing orthopedic device-related infections (ODRI) that have high treatment failure rates. One barrier to the development of improved treatment options is the lack of an animal model that may serve as a robust preclinical assessment of efficacy.
Experimental TherapeuticsDeletion of pknG Abates Reactivation of Latent Mycobacterium tuberculosis in MiceEradication of tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has been a challenge due to its uncanny ability to survive in a dormant state inside host granulomas for decades. Mtb rewires its metabolic and redox regulatory networks to survive in the hostile hypoxic and nutrient-limiting environment, facilitating the formation of drug-...
Experimental TherapeuticsEfficient Treatment of Experimental Cerebral Malaria by an Artemisone-SMEDDS System: Impact of Application Route and Dosing FrequencyArtemisone (ART) has been successfully tested in vitro and in animal models against several diseases. However, its poor aqueous solubility and limited chemical stability are serious challenges.
Experimental TherapeuticsActivity of Clofazimine and TBI-166 against Mycobacterium tuberculosis in Different Administration Intervals in Mouse Tuberculosis ModelsClofazimine (CLO) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising antituberculosis activity in vitro and in animal models and is currently under phase I clinical development for the treatment of tuberculosis in China.
Experimental TherapeuticsElectrostatic-Mediated Affinity Tuning of Lysostaphin Accelerates Bacterial Lysis Kinetics and Enhances In Vivo EfficacyDrug-resistant bacterial pathogens are a serious threat to global health, and antibacterial lysins are at the forefront of innovative treatments for these life-threatening infections. While lysins’ general mechanism of action is well understood, the design principles that might enable engineering of performance-enhanced variants are still being formulated.
Experimental TherapeuticsIn Vivo Targeting of Escherichia coli with Vancomycin-ArginineThe ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to Gram-negative bacteria was investigated. Its MIC toward Escherichia coli, including β-lactamase expressing Ambler classes A, B, and D, was 8 to 16 μg/ml.
Experimental TherapeuticsComparative Efficacy of the Novel Diarylquinoline TBAJ-587 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of TuberculosisSince its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis.
Experimental TherapeuticsThe Benzimidazole SPR719 Shows Promising Concentration-Dependent Activity and Synergy against Nontuberculous MycobacteriaNontuberculous mycobacterial pulmonary disease (NTM-PD) is emerging worldwide. Currently recommended multidrug treatment regimens yield poor outcomes, and new drugs and regimens are direly needed.
Experimental TherapeuticsDose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance SuppressionThe repurposed agent moxifloxacin has become an important addition to the physician’s armamentarium for the therapy of Mycobacterium tuberculosis. When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for Mycobacterium tuberculosis...
Experimental Therapeuticsβ-Lactam Combinations That Exhibit Synergy against Mycobacteroides abscessus Clinical IsolatesMycobacteroides abscessus (Mab) is an opportunistic environmental pathogen that can cause chronic pulmonary disease in the setting of structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. These infections are often incurable and associated with rapid lung function decline. Mab is naturally...
Clinical Therapeutics
Clinical TherapeuticsPoor Correlation between Meropenem and Piperacillin Plasma Concentrations and Delivered Dose of Continuous Renal Replacement TherapyThere is insufficient data on the relationship between antibiotic dosing and plasma concentrations in patients treated with continuous renal replacement therapy (CRRT). In this prospective observational study, we explored the variability in plasma concentrations of meropenem and piperacillin in critically ill patients treated with CRRT and the correlation between concentrations and CRRT intensity.
Clinical TherapeuticsPopulation Pharmacokinetic Model of Oxfendazole and Metabolites in Healthy Adults following Single Ascending DosesOxfendazole is a potent veterinary benzimidazole anthelmintic under transition to humans for the treatment of multiple parasitic infectious diseases. The first-in-human study evaluating the disposition of oxfendazole and its metabolites in healthy adults following single ascending oral doses from 0.5 to 60 mg/kg of body weight shows that oxfendazole pharmacokinetics is substantially nonlinear, which complicates correlating oxfendazole...
Clinical TherapeuticsDrug-Drug Interaction Study of Benznidazole and E1224 in Healthy Male VolunteersE1224 is a prodrug of ravuconazole (RVZ), an antifungal drug with promising anti-Trypanosoma cruzi activity, the causative organism of Chagas disease (CD). This study was designed to assess the pharmacokinetics (PK) and safety interactions of benznidazole (BNZ), the drug of choice for treatment of CD, and E1224 in healthy volunteers.
Clinical TherapeuticsLimited Utility of Procalcitonin in Identifying Community-Associated Bacterial Infections in Patients Presenting with Coronavirus Disease 2019The role of procalcitonin in identifying community-associated bacterial infections among patients with coronavirus disease 2019 is not yet established. In 2,443 patients with 148 bacterial coinfections, mean procalcitonin levels were significantly higher with any bacterial infection (13.16 ± 51.19 ng/ml; P = 0.0091) and with bacteremia (34.25 ± 85.01 ng/ml; P = 0.0125) than without infection (2.00 ± 15.26 ng/ml).
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Clinical TherapeuticsHigher Dosing of Rifamycins Does Not Increase Activity against Mycobacterium tuberculosis in the Hollow-Fiber Infection ModelImprovements in the translational value of preclinical models can allow more-successful and more-focused research on shortening the duration of tuberculosis treatment. Although the hollow-fiber infection model (HFIM) is considered a valuable addition to the drug development pipeline, its exact role has not been fully determined yet.
Clinical TherapeuticsVariability of Hydroxy-Itraconazole in Relation to Itraconazole Bloodstream ConcentrationsWe analyzed the relationship between itraconazole (ITZ) and hydroxy-itraconazole (OH-ITZ) levels in 1,223 human samples. Overall, there was a statistically significant correlation between ITZ and OH-ITZ levels (Pearson’s r, 0.7838), and OH-ITZ levels were generally higher than ITZ levels (median OH-ITZ:ITZ ratio, 1.73; range, 0.13 to 8.96).
Clinical TherapeuticsRandomized Controlled Trial of the Electrocardiographic Effects of Four Antimalarials for Pregnant Women with Uncomplicated Malaria on the Thailand-Myanmar BorderQuinoline antimalarials cause drug-induced electrocardiograph QT prolongation, a potential risk factor for torsade de pointes. The effects of currently used antimalarials on the electrocardiogram (ECG) were assessed in pregnant women with malaria.
Clinical TherapeuticsHigh-Dose Micafungin in Neonates and Young Infants with Invasive Candidiasis: Results of a Phase 2 StudyLimited data are available on the most appropriate dosing, efficacy, and safety of micafungin in neonates with invasive candidiasis (IC). This study evaluated plasma levels, efficacy, and safety of micafungin at a dose of 8 mg/kg daily for a mean of 13.3 days (±5.2 days) in 35 neonates and young infants with IC.
Clinical TherapeuticsOptimizing Aminoglycoside Dosing Regimens for Critically Ill Pediatric Patients with Augmented Renal Clearance: a Convergence of Parametric and Nonparametric Population ApproachesAugmented renal clearance (ARC) can occur in critically ill pediatric patients receiving aminoglycosides such as gentamicin and tobramycin, yet optimal dosing strategies for ARC are undefined. We evaluated the probability of achieving efficacious or toxic exposures in pediatrics. Parallel population modeling of concentration strategies were pursued using Pmetrics v1.5.2 (nonparametric) and Monolix v2019R2 (parametric).
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Pharmacology
PharmacologyParasite-Host Dynamics throughout Antimalarial Drug Development Stages Complicate the Translation of Parasite ClearanceEnsuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy.
PharmacologySemimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage MalariaDihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for Plasmodium falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies.
PharmacologyPopulation Pharmacokinetic and Pharmacodynamic Target Attainment Analysis of Cefazolin in the Serum and Hip Joint Capsule of Patients Undergoing Total Hip ArthroplastyThe objectives of this study were to evaluate the population pharmacokinetics of prophylactic cefazolin (CFZ) from its serum and hip joint capsule concentrations in patients undergoing total hip arthroplasty and to establish the pharmacodynamic target concentration exceeding the MIC for designing an effective dosing regimen for serum and the hip joint capsule. We analyzed 249 serum samples and 125 hip joint capsule samples from 125...
PharmacologyArtemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification PathwayArtemisinin (ART)-based antimalarial drugs are believed to exert lethal effects on malarial parasites by alkylating a variety of intracellular molecular targets. Recent work with live parasites has shown that one of the alkylated targets is free heme within the parasite digestive vacuole, which is liberated upon hemoglobin catabolism by the intraerythrocytic parasite, and that reduced levels of heme alkylation occur in artemisinin-...
PharmacologyAlteration in Acute Kidney Injury Potential with the Combination of Vancomycin and Imipenem-Cilastatin/Relebactam or Piperacillin/Tazobactam in a Preclinical ModelThe risk of vancomycin (VAN)-associated acute kidney injury (AKI) may be altered with combination regimens. The specific AKI risk when VAN is combined with imipenem-cilastatin/relebactam (IMP-C/REL) or piperacillin/tazobactam (TZP) has not been clearly defined.
PharmacologyIn Vivo Activity of WCK 4282 (High-Dose Cefepime/Tazobactam) against Serine-β-Lactamase-Producing Enterobacterales and Pseudomonas aeruginosa in the Neutropenic Murine Lung Infection ModelWCK 4282 (cefepime 2 g-tazobactam 2 g) maximizes systemic exposure of tazobactam and restores cefepime activity against various extended-spectrum β-lactamase (ESBL)- and cephalosporinase-producing strains in vitro. We describe clinical WCK 4282 exposure efficacies against various serine β-lactamase-producing Enterobacterales and...
PharmacologyPharmacokinetic Study of Rectal Artesunate in Children with Severe Malaria in AfricaWhen severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, crossover clinical trial in 83 Congolese children with severe falciparum malaria to characterize the pharmacokinetics of rectal artesunate.
PharmacologyTherapeutic Potential of Fosmanogepix (APX001) for Intra-abdominal Candidiasis: from Lesion Penetration to Efficacy in a Mouse ModelIntra-abdominal candidiasis (IAC) is one of the most common yet underappreciated forms of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug-resistant breakthrough infections are common in some institutions despite the use of echinocandins as first-line agents.
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Antimicrobial Agents and Chemotherapy® (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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Commentary
Finding antivirals to reduce coronavirus disease 2019 (COVID-19) morbidity and mortality has been challenging. Large randomized clinical trials that aimed to test four repurposed drugs, hydroxychloroquine, lopinavir-ritonavir, interferon beta 1a, and remdesivir, have shown that these compounds lack an impact on the COVID-19 course.