Table of Contents
Minireview
MinireviewCetylpyridinium Chloride: Mechanism of Action, Antimicrobial Efficacy in Biofilms, and Potential Risks of ResistanceAntimicrobial resistance is a serious issue for public health care all over the world. While resistance toward antibiotics has attracted strong interest among researchers and the general public over the last 2 decades, the directly related problem of resistance toward antiseptics and biocides has been somewhat left untended. In the field of dentistry, antiseptics are routinely used in professional care, but they are also included in...
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsChemokine CCL28 Is a Potent Therapeutic Agent for Oropharyngeal CandidiasisCandida albicans is a commensal organism that causes life-threatening or life-altering opportunistic infections. Treatment of Candida infections is limited by the paucity of antifungal drug classes. Naturally occurring antimicrobial peptides are promising agents for drug development. CCL28 is a CC chemokine that is abundant in saliva and has in vitro...
Mechanisms of Action: Physiological EffectsTranscriptional Inhibition of the F1F0-Type ATP Synthase Has Bactericidal Consequences on the Viability of MycobacteriaBedaquiline, an inhibitor of the mycobacterial ATP synthase, has revolutionized the treatment of Mycobacterium tuberculosis infection. Although a potent inhibitor, it is characterized by poorly understood delayed time-dependent bactericidal activity. Here, we demonstrate that in contrast to bedaquiline, the transcriptional inhibition of the ATP synthase in...
Mechanisms of Resistance
Mechanisms of ResistanceInsights into the l,d-Transpeptidases and d,d-Carboxypeptidase of Mycobacterium abscessus: Ceftaroline, Imipenem, and Novel Diazabicyclooctane InhibitorsMycobacterium abscessus is a highly drug-resistant nontuberculous mycobacterium (NTM). Efforts to discover new treatments for M. abscessus infections are accelerating, with a focus on cell wall synthesis proteins (M. abscessus...
Mechanisms of ResistanceFitness Cost and Compensatory Evolution in Levofloxacin-Resistant Mycobacterium aurumWe isolated spontaneous levofloxacin-resistant strains of Mycobacterium aurum to study the fitness cost and compensatory evolution of fluoroquinolone resistance in mycobacteria. Five of six mutant strains with substantial growth defects showed restored fitness after being serially passaged for 18 growth cycles, along with increased cellular ATP level. Whole-genome...
Mechanisms of ResistanceKPC-50 Confers Resistance to Ceftazidime-Avibactam Associated with Reduced Carbapenemase ActivityKPC-50 is a KPC-3 variant identified from a Klebsiella pneumoniae clinical isolate recovered in Switzerland in 2019. Compared to KPC-3, KPC-50 shows (i) a three-amino-acid insertion (Glu-Ala-Val) between amino acids 276 and 277, (ii) an increased affinity to ceftazidime, (iii) a decreased sensitivity to avibactam, explaining the ceftazidime-avibactam resistance, and (...
Editor's Pick Mechanisms of ResistanceChromosomal Resistance to Metronidazole in Clostridioides difficile Can Be Mediated by Epistasis between Iron Homeostasis and OxidoreductasesChromosomal resistance to metronidazole has emerged in clinical Clostridioides difficile isolates, but the genetic mechanisms remain unclear. This is further hindered by the inability to generate spontaneous metronidazole-resistant mutants in the lab to interpret genetic variations in clinical isolates. We therefore constructed a mismatch repair mutator in...
Mechanisms of ResistanceAntibiotic Substrate Selectivity of Pseudomonas aeruginosa MexY and MexB Efflux Systems Is Determined by a Goldilocks AffinityResistance-nodulation-division (RND) efflux pumps are important contributors to bacterial antibiotic resistance. In this study, we combined evolutionary sequence analyses, computational structural modeling, and ligand docking to develop a framework that can explain the known antibiotic substrate selectivity differences between two Pseudomonas aeruginosa RND...
Mechanisms of ResistanceSimulating the Influence of Conjugative-Plasmid Kinetic Values on the Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing ModelBacterial plasmids harboring antibiotic resistance genes are critical in the spread of antibiotic resistance. It is known that plasmids differ in their kinetic values, i.e., conjugation rate, segregation rate by copy number incompatibility with related plasmids, and rate of stochastic loss during replication. They also differ in cost to the cell in terms of reducing fitness and in the frequency of compensatory mutations compensating...
Editor's Pick Mechanisms of ResistanceIn Vitro Activity of the Ultrabroad-Spectrum-Beta-Lactamase Inhibitor QPX7728 against Carbapenem-Resistant Enterobacterales with Varying Intrinsic and Acquired Resistance MechanismsQPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 μg/ml) was tested against 598...
Mechanisms of ResistanceAntimicrobial Susceptibility and Clonality of Vaginally Derived Multidrug-Resistant Mobiluncus Isolates in ChinaHere, the antimicrobial susceptibility, resistance mechanisms, and clonality of Mobiluncus sp. isolates recovered from gynecological outpatients in China were investigated. Compared to M. mulieris, M. curtisii exhibited higher antimicrobial resistance to metronidazole, clindamycin, and...
Mechanisms of ResistanceProteomic Investigation of the Signal Transduction Pathways Controlling Colistin Resistance in Klebsiella pneumoniaeColistin resistance in Klebsiella pneumoniae is predominantly caused by mutations that increase expression of the arn (also known as pbg or pmrF) operon. Expression is activated by the PhoPQ and PmrAB two-component systems. Constitutive PhoPQ activation occurs directly by mutation or following loss of MgrB. PhoPQ may also cross-activate...
Mechanisms of ResistancePersistence Dynamics of Antimicrobial-Resistant Neisseria in the Pharynx of Rhesus MacaquesPharyngeal infections by Neisseria gonorrhoeae are often asymptomatic, making them difficult to treat. However, in vivo animal modeling of human pharyngeal infections by pathogenic Neisseria species is challenging due to numerous host tropism barriers. We have relied on rhesus macaques to investigate pharyngeal persistence of naturally occurring ...
Editor's Pick Mechanisms of ResistanceA Novel Combination of CYP51A Mutations Confers Pan-Azole Resistance in Aspergillus fumigatusThe treatment of invasive and chronic aspergillosis involves triazole drugs. Its intensive use has resulted in the selection of resistant isolates, and at present, azole resistance in Aspergillus fumigatus is considered an emerging threat to public health worldwide. The aim of this work is to uncover the molecular mechanism implicated in the azole resistance phenotype...
Mechanisms of ResistancePlasmodium falciparum Isolates Carrying pfk13 Polymorphisms Harbor the SVMNT Allele of pfcrt in Northwestern IndonesiaArtemisinin-based combination therapy (ACT) is the first-line antimalarial regimen in Indonesia. Susceptibility of Plasmodium falciparum to artemisinin is falling in the Greater Mekong subregion, but it is not known whether the efficacy of current combinations is also threatened in nearby Sumatera. We evaluated the genetic loci pfcrt, pfmdr1, and pfk13...
Susceptibility
SusceptibilityAR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessusTherapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo. Antimicrobial...
SusceptibilityIn Vitro Activities of Eravacycline and Other Antimicrobial Agents against Human Mycoplasmas and UreaplasmasWe performed in vitro susceptibility testing for eravacycline in comparison to 4 other antimicrobials against 10 Mycoplasma genitalium, 40 Mycoplasma hominis, 44 Mycoplasma pneumoniae, 20...
Editor's Pick SusceptibilityIn Vitro Activity of Manogepix (APX001A) and Comparators against Contemporary Molds: MEC Comparison and Preliminary Experience with Colorimetric MIC DeterminationManogepix (APX001A) is the active moiety of the drug candidate fosmanogepix (APX001), currently in clinical development for the treatment of invasive fungal infections. We compared manogepix EUCAST minimum effective concentrations (MECs) to MICs of five comparators and CLSI MECs and MICs by a colorimetric method against contemporary molds. EUCAST susceptibility testing was performed for 161 isolates. Interlaboratory and intermethod...
Antiviral Agents
Antiviral AgentsFilovirus Antiviral Activity of Cationic Amphiphilic Drugs Is Associated with Lipophilicity and Ability To Induce PhospholipidosisSeveral cationic amphiphilic drugs (CADs) have been found to inhibit cell entry of filoviruses and other enveloped viruses. Structurally unrelated CADs may have antiviral activity, yet the underlying common mechanism and structure-activity relationship are incompletely understood. We aimed to understand how widespread antiviral activity is among CADs and which structural and physico-chemical properties are linked to entry inhibition. We...
Antiviral AgentsIdentification of Estrogen Receptor Modulators as Inhibitors of Flavivirus InfectionFlaviviruses such as Zika virus (ZIKV), dengue virus (DENV), and West Nile virus (WNV) are major global pathogens for which safe and effective antiviral therapies are not currently available. To identify antiviral small molecules with well-characterized safety and bioavailability profiles, we screened a library of 2,907 approved drugs and pharmacologically active compounds for inhibitors of ZIKV infection using a high-throughput cell-...
Antiviral AgentsStructure-Activity Relationship Analysis of Benzotriazine Analogues as HIV-1 Latency-Reversing Agents“Shock and kill” therapeutic strategies toward HIV eradication are based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) and the consequent killing of the reactivated cell by either the cytopathic effect of HIV or an arm of the immune system. We have recently found several benzotriazole and benzotriazine analogues that have the ability to reactivate latent HIV by inhibiting signal transducer and...
Antiviral AgentsSuramin Inhibits SARS-CoV-2 Infection in Cell Culture by Interfering with Early Steps of the Replication CycleThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that originated in Wuhan, China, in December 2019 has impacted public health, society, the global economy, and the daily lives of billions of people in an unprecedented manner. There are currently no specific registered antiviral drugs to treat or prevent SARS-CoV-2 infections. Therefore, drug repurposing would be the fastest route to provide at least a temporary...
Epidemiology and Surveillance
Editor's Pick Epidemiology and SurveillanceA Propensity Score Matched Study of the Positive Impact of Infectious Diseases Consultation on Antimicrobial Appropriateness in Hospitalized Patients with Antimicrobial Stewardship OversightHospital-based antibiotic stewardship (AS) programs provide oversight and guidance for appropriate antimicrobial use in acute care settings. Infectious disease expertise is beneficial in the care of hospitalized patients with infections. The impact of infectious diseases consultation (IDC) on antimicrobial appropriateness in a large tertiary hospital with an established AS program was investigated. This was a cross-sectional study from...
Epidemiology and SurveillanceAntimicrobial Susceptibility and Cross-Resistance Patterns among Common Complicated Urinary Tract Infections in U.S. Hospitals, 2013 to 2018In the face of increasing rates of antimicrobial resistance in complicated urinary tract infections (cUTIs), clinicians need to understand cross-resistance patterns among commonly encountered pathogens. We performed a multicenter, retrospective cohort study in the Premier database of approximately 180 hospitals, from 2013 to 2018. Using an ICD-9/10-based algorithm, we identified all adult patients hospitalized with cUTIs and included...
Epidemiology and SurveillanceGenomic Study of blaIMI-Positive Enterobacter cloacae Complex in Singapore over a Five-Year Study PeriodThe blaIMI gene is rarely detected outside the Enterobacter genus. Genomic characterization of 87 blaIMI-positive Enterobacter cloacae complex members revealed that the largest phylogenomic clade was made up of E. cloacae subsp. cloacae (71.3...
Epidemiology and SurveillanceIn Vitro Activity of Omadacycline, a New Tetracycline Analog, and Comparators against Clostridioides difficileOmadacycline is a potent aminomethylcycline with in vitro activity against Gram-positive, Gram-negative, and anaerobic bacteria. Preliminary data demonstrated that omadacycline has in vitro activity against Clostridioides difficile; however, large-scale in vitro studies have not been done. The purpose of this study was to assess the in...
Epidemiology and SurveillanceThe mcr-9 Gene of Salmonella and Escherichia coli Is Not Associated with Colistin Resistance in the United StatesReports of transmissible colistin resistance show the importance of comprehensive colistin resistance surveillance. Recently, a new allele of the mobile colistin resistance (mcr) gene family designated mcr-9, which shows variation in genetic context and colistin susceptibility, was reported. We tested over 100 Salmonella enterica and...
Epidemiology and SurveillanceExtended-Spectrum-β-Lactamase- and Plasmid AmpC-Producing Escherichia coli Causing Community-Onset Bloodstream Infection: Association of Bacterial Clones and Virulence Genes with Septic Shock, Source of Infection, and RecurrenceInvasive infections due to extended-spectrum-β-lactamase- and pAmpC-producing Escherichia coli (ESBL/pAmpC-EC) are an important cause of morbidity, often caused by the high-risk clone sequence type (ST131) and isolates classified as extraintestinal pathogenic E. coli (ExPEC). The relative influence...
Experimental Therapeutics
Experimental TherapeuticsNovel Antiparasitic Activity of the Antifungal Lead OccidiofunginNovel antiparasitic activity was observed for the antifungal occidiofungin. It efficaciously and irreversibly inhibited the zoonotic enteric parasite Cryptosporidium parvum in vitro with limited cytotoxicity (50% effective concentration [EC50] = 120 nM versus 50% cytotoxic concentration [TC50] = 988 nM), and its application disrupted the...
Editor's Pick Experimental TherapeuticsPreserving Vascular Integrity Protects Mice against Multidrug-Resistant Gram-Negative Bacterial InfectionThe rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including Acinetobacter baumannii,...
Experimental TherapeuticsIn Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar EchinococcosisAlveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is a lethal disease in humans. Novel therapeutic options are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. In this study, we assessed the in vitro and in vivo effects of the epidermal growth factor...
Experimental TherapeuticsInhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic MeningoencephalitisPrimary amoebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living amoeba Naegleria fowleri. The amoeba migrates along the olfactory nerve to the brain, resulting in seizures, coma, and, eventually, death. Previous research has shown that Naegleria gruberi, a close...
Experimental TherapeuticsChitosan Ameliorates Candida auris Virulence in a Galleria mellonella Infection ModelCandida auris has emerged as a multidrug-resistant nosocomial pathogen over the last decade. Outbreaks of the organism in health care facilities have resulted in life-threatening invasive candidiasis in over 40 countries worldwide. Resistance by C. auris to conventional antifungal drugs such as...
Experimental TherapeuticsTCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovaniT-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins, such as actin and tubulin. In Leishmania donovani, the γ subunit of TCP1 (LdTCP1γ) has been cloned and characterized. It forms a high-molecular-weight homo-oligomeric complex that performs ATP-dependent protein folding. In the present study, we evaluated the...
Experimental TherapeuticsAnalysis of Paradoxical Efficacy of Carbapenems against Carbapenemase-Producing Escherichia coli in a Murine Model of Lethal PeritonitisThe clinical benefit of carbapenems against carbapenemase-producing Enterobacteriaceae (CPE) remains in question. MICs of imipenem (IMP) and ertapenem (ERT) against isogenic derivatives of the wild-type strain Escherichia coli CFT073 producing KPC-3, OXA-48, or NDM-1 were 0.25, 2, 16, and 64 mg/liter for IMP and 0.008, 0.5, 8, and 64 mg/liter for ERT,...
Experimental TherapeuticsSimvastatin Improves Cardiac Function through Notch 1 Activation in BALB/c Mice with Chronic Chagas CardiomyopathyChagas disease, caused by the protozoan Trypanosoma cruzi, endemic in Latin America but distributed worldwide because of migration. Without appropriate treatment, the disease progresses from an acute asymptomatic phase to a chronic, progressive inflammatory cardiomyopathy causing heart failure and death. Despite specific trypanocidal therapy, heart damage progression...
Experimental TherapeuticsAmlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi InfectionMining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed...
Clinical Therapeutics
Clinical TherapeuticsOpen-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Conventional Itraconazole Capsules in Healthy AdultsSuper bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two...
Clinical TherapeuticsIn Vitro and In Vivo Characterization of Tebipenem, an Oral CarbapenemThe continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability...
Pharmacology
PharmacologyPredicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic ModellingLong-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-...
PharmacologyPolymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniaeResistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae. Monotherapies and double- and triple-combination...
PharmacologyHuman-Simulated Antimicrobial Regimens in Animal Models: Transparency and Validation Are ImperativeAnimal infection models are invaluable in optimizing antimicrobial dosage in humans. Utilization of human-simulated regimens (HSRs) in animal models helps to evaluate antimicrobial efficacy at clinically achievable drug concentrations. To that end, pharmacokinetic studies in infected animals and confirmation of the HSR pharmacokinetic profile are essential in evaluating observed versus expected drug concentrations. We present and...
PharmacologyReappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic AnalysisData of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for...
PharmacologySequential Time-Kill, a Simple Experimental Trick To Discriminate between Pharmacokinetics/Pharmacodynamics Models with Distinct Heterogeneous Subpopulations versus Homogenous Population with Adaptive ResistanceExperiments were conducted with polymyxin B and two Klebsiella pneumonia isogenic strains (the wild type, KP_WT, and its transconjugant carrying the mobile colistin resistance gene, KP_MCR-1) to demonstrate that conducting two consecutive time-kill experiments (sequential TK) represents a simple approach to discriminate between pharmacokinetics/pharmacodynamics models...
PharmacologyTime above the MIC of Piperacillin-Tazobactam as a Predictor of Outcome in Pseudomonas aeruginosa BacteremiaPseudomonas aeruginosa bacteremia is an infection associated with a high mortality rate. Piperacillin-tazobactam is a β-lactam–β-lactamase inhibitor combination that is frequently used for the management of Pseudomonas aeruginosa infections. The pharmacokinetic-pharmacodynamic index associated with...
Letters to the Editor
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