Minireview
MinireviewThe Future of Antifungal Drug Therapy: Novel Compounds and TargetsFungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans.
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsCefiderocol Retains Antibiofilm Activity in Multidrug-Resistant Gram-Negative PathogensCefiderocol is a siderophore cephalosporin with potent antibacterial activity against a broad range of Gram-negative pathogens, including multidrug-resistant strains. Siderophore antibiotics bind ferric iron and utilize iron transporters to cross the cell membrane.
Mechanisms of Action: Physiological EffectsEfg1 and Cas5 Orchestrate Cell Wall Damage Response to Caspofungin in Candida albicansEchinocandins are recommended as the first-line drugs for the treatment of systemic candidiasis. Cas5 is a key transcription factor involved in the response to cell wall damage induced by echinocandins.
Mechanisms of Action: Physiological EffectsStructural and Cellular Insights into the l,d-Transpeptidase YcbB as a Therapeutic Target in Citrobacter rodentium, Salmonella Typhimurium, and Salmonella Typhi InfectionsThe bacterial cell wall plays a key role in viability and is an important drug target. The cell wall is made of elongated polymers that are cross-linked to one another to form a load-bearing mesh. An alternative cell wall cross-linking mechanism used by the l,d-transpeptidase YcbB has been implicated in the stress-regulated roles of β-lactam resistance, outer membrane defect rescue, and...
Mechanisms of Resistance
Mechanisms of ResistanceAtypical Mutation in Neisseria gonorrhoeae 23S rRNA Associated with High-Level Azithromycin ResistanceA2059G mutation in the 23S rRNA gene is the only reported mechanism conferring high-level azithromycin resistance (HL-AZMR) in Neisseria gonorrhoeae. Through U.S. gonococcal antimicrobial resistance surveillance projects, we identified four HL-AZMR gonococcal isolates lacking this mutational genotype. Genetic analysis revealed an A2058G mutation of 23S rRNA alleles in...
Mechanisms of ResistanceA GC-Rich Prophage-Like Genomic Region of Mycoplasma bovirhinis HAZ141_2 Carries a Gene Cluster Encoding Resistance to Kanamycin and NeomycinRecently, a complete genome sequence of Mycoplasma bovirhinis HAZ141_2 was published showing the presence of a 54-kB prophage-like region. Bioinformatic analysis revealed that this region has a more than 40% GC content and a chimeric organization with three structural elements—a prophage continuous region, a restriction-modification cassette, and a highly...
Mechanisms of ResistanceMechanisms of Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa: Results of the GERPA Multicenter StudyResistance mechanisms of Pseudomonas aeruginosa to ceftolozane/tazobactam (C/T) were assessed on a collection of 420 nonredundant strains nonsusceptible to ceftazidime (MIC > 8 μg/ml) and/or imipenem (>4 μg/ml), collected by 36 French hospital laboratories over a one-month period (the GERPA study). Rates of C/T resistance (MIC > 4/4 μg/ml) were equal to 10%...
Mechanisms of ResistanceFungal Zn(II)2Cys6 Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole StressAntifungal azoles are the most widely used antifungal drugs in clinical and agricultural practice. Fungi can mount adaptive responses to azole stress by modifying the transcript levels of many genes, and the responsive mechanisms to azoles are the basis for fungi to develop azole resistance.
Mechanisms of ResistancefosM, a New Family of Fosfomycin Resistance Genes Identified in Bacterial Species Isolated from Human MicrobiotaFosfomycin is a decades-old antibiotic, currently reused because of its activity against multidrug-resistant bacteria. Here, we used a combined in vitro/in silico approach to search for fosfomycin resistance determinants in 25 new bacterial species isolated from the human microbiota.
Mechanisms of ResistancePotential Mobilization of mcr-10 by an Integrative Mobile Element via Site-Specific Recombination in Cronobacter sakazakiimcr-10 is a newly identified plasmid-borne colistin resistance gene, but its mobilization mechanism remains unclear. In this study, mcr-10 was found on an IncFIB plasmid carrying virulence genes mrkABCDFJ, iucABCD/iutA, and eitCBAD in a Cronobacter sakazakii isolate.
Mechanisms of ResistanceNew Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate NatureInactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the...
Mechanisms of ResistancePseudomonas aeruginosa Polynucleotide Phosphorylase Controls Tolerance to Aminoglycoside Antibiotics by Regulating the MexXY Multidrug Efflux PumpPseudomonas aeruginosa is an opportunistic pathogen that shows high intrinsic resistance to a variety of antibiotics. The MexX-MexY-OprM efflux pump plays an important role in bacterial resistance to aminoglycoside antibiotics.
Mechanisms of ResistanceStructural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanesβ-Lactam antibiotics are presently the most important treatments for infections by pathogenic Escherichia coli, but their use is increasingly compromised by β-lactamases, including the chromosomally encoded class C AmpC serine-β-lactamases (SBLs). The diazabicyclooctane (DBO) avibactam is a potent AmpC inhibitor; the clinical success of avibactam combined with...
Susceptibility
SusceptibilityBurkholderia pseudomallei Clinical Isolates Are Highly Susceptible In Vitro to Cefiderocol, a Siderophore CephalosporinCefiderocol is a cephalosporin designed to treat multidrug-resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater in vitro activity against many Gram-negative...
SusceptibilityEmergence of Resistance in Klebsiella aerogenes to Piperacillin-Tazobactam and CeftriaxoneWe examined the effects of piperacillin-tazobactam (TZP) concentration and bacterial inoculum on in vitro killing and the emergence of resistance in Klebsiella aerogenes. The MICs for 15 clinical respiratory isolates were determined by broth microdilution for TZP and by Etest for ceftriaxone (CRO) and cefepime (FEP). The presence of resistance in TZP-...
SusceptibilityRifampin, Rifapentine, and Rifabutin Are Active against Intracellular Periprosthetic Joint Infection-Associated Staphylococcus epidermidisStaphylococcus epidermidis is a major cause of periprosthetic joint infection (PJI); its intracellular persistence within osteoblasts may compromise therapy if that therapy is not intracellularly active. The intracellular activity of rifampin, rifapentine, and rifabutin was assessed against five rifampin-susceptible and two rifampin-resistant...
Antiviral Agents
Antiviral AgentsBroad-Spectrum Antiviral Activity of 3′-Deoxy-3′-Fluoroadenosine against Emerging FlavivirusesEmerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties.
Antiviral AgentsOff-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral AgentRemdesivir (RDV, GS-5734), the first FDA-approved antiviral for the treatment of COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. It is intracellularly metabolized into the active triphosphate form, which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases.
Antiviral AgentsA Valid Warning or Clinical Lore: an Evaluation of Safety Outcomes of Remdesivir in Patients with Impaired Renal Function from a Multicenter Matched CohortPer prescribing guidance, remdesivir is not recommended for SARS-CoV-2 in patients with renal disease given the absence of safety data in this patient population. This study was a multicenter, retrospective chart review of hospitalized patients with SARS-CoV-2 who received remdesivir.
Epidemiology and Surveillance
Epidemiology and SurveillanceICEHpsaHPS7, a Novel Multiple Drug Resistance Integrative Conjugative Element in Glaesserella parasuisIntegrative conjugative elements (ICEs) are a kind of novel self-transmissible mobile genetic element. In this study, a novel ICE was identified in Glaesserella (Haemophilus) parasuis.
Epidemiology and SurveillanceContinued Low Efficacy of Artemether-Lumefantrine in Angola in 2019Biennial therapeutic efficacy monitoring is a crucial activity for ensuring the efficacy of currently used artemisinin-based combination therapy in Angola. Children with acute uncomplicated Plasmodium falciparum infection in sentinel sites in the Benguela, Zaire, and Lunda Sul Provinces were treated with artemether-lumefantrine (AL) or artesunate-amodiaquine (ASAQ)...
Epidemiology and SurveillanceCharacterization of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump in Klebsiella pneumoniae and Klebsiella quasipneumoniae from Patients in ChinaTwo multidrug-resistant (MDR) mcr-1-harboring Klebsiella pneumoniae isolates from patients with urinary tract infections and one MDR Klebsiella quasipneumoniae isolate from a patient with bloodstream infection were identified to carry tmexCD1-toprJ1. The addition of the efflux pump...
Experimental Therapeutics
Experimental TherapeuticsSodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection LoadNeisseria meningitidis and Neisseria gonorrhoeae, two highly related species that might have emerged from a common commensal ancestor, constitute major human threats. Vaccines are available to prevent N. meningitidis infection,...
Experimental TherapeuticsPharmacokinetics of Benznidazole in Experimental Chronic Chagas Disease Using the Swiss Mouse–Berenice-78 Trypanosoma cruzi Strain ModelChronic Chagas disease might have an impact on benznidazole pharmacokinetics with potential alterations in the therapeutic dosing regimen. This study aims to investigate the influence of chronic Trypanosoma cruzi infection on the pharmacokinetics and biodistribution of benznidazole in mice.
Experimental TherapeuticsDiscovery of Amoebicidal Compounds by Combining Computational and Experimental ApproachesPathogenic and opportunistic free-living amoebae such as Acanthamoeba spp. can cause keratitis (Acanthamoeba keratitis [AK]), which may ultimately lead to permanent visual impairment or blindness. Acanthamoeba can also cause rare but usually fatal granulomatous amoebic encephalitis (GAE). Current therapeutic options for AK require a lengthy treatment with nonspecific drugs that are often associated with...
Experimental TherapeuticsThe Antifungal and Synergistic Effect of Bisphosphonates in CryptococcusNew treatment strategies are required for cryptococcosis, a leading mycosis in HIV-AIDS patients. Following the identification of Cryptococcus proteins differentially expressed in response to fluconazole, we targeted farnesyl pryrophosphate synthetase (FPPS), an enzyme in the squalene biosynthesis pathway, using nitrogenous bisphosphonates. We hypothesized that these would disrupt squalene synthesis and thereby produce synergy...
Experimental TherapeuticsShort-Term Effects of Appropriate Empirical Antimicrobial Treatment with Ceftolozane/Tazobactam in a Swine Model of Nosocomial PneumoniaThe rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in...
Experimental TherapeuticsDifferential In Vitro Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved Mycobacterium abscessusCurrent treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net nonreplicating...
Clinical Therapeutics
Clinical TherapeuticsPharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm InfectionsIn the treatment of hookworm infections, pharmacotherapy has been only moderately successful and drug resistance is a threat. Therefore, novel treatment options including combination therapies should be considered, in which tribendimidine could play a role. Our aims were to (i) characterize the pharmacokinetics of tribendimidine’s metabolites in adolescents receiving tribendimidine monotherapy or in combination with ivermectin or...
Clinical TherapeuticsLiquid Chromatography Mass Spectrometry Detection of Antibiotic Agents in Sputum from Persons with Cystic FibrosisAntibiotic therapy is expected to impact host microbial communities considerably, yet many studies focused on microbiome and health are often confounded by limited information about antibiotic exposure. Given that antibiotics have diverse pharmacokinetic and antimicrobial properties, investigating the type and concentration of these agents in specific host specimens would provide much needed insight into their impact on the microbes...
Clinical TherapeuticsAdverse Events Associated with Nifurtimox Treatment for Chagas Disease in Children and AdultsNifurtimox (NF) is one of the only two drugs currently available for Chagas disease (ChD) treatment. However, data on NF safety are scarce, and many physicians defer or refuse NF treatment because of concerns about drug tolerance.
Clinical TherapeuticsDefining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparumThe spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum.
Clinical TherapeuticsValidation of a Community-Acquired Pneumonia Score To Improve Empiric Antibiotic Selection at an Academic Medical CenterThe 2019 American Thoracic Society and the Infectious Diseases Society of America community-acquired pneumonia (CAP) guidelines recommend that drug-resistant pathogens (DRP) be empirically covered if locally validated risk factors are present. This retrospective case-control validation study evaluated the performance of the drug resistance in pneumonia (DRIP) clinical prediction score.
Clinical TherapeuticsEffects of Antibiotic Treatment with Piperacillin/Tazobactam versus Ceftriaxone on the Composition of the Murine Gut MicrobiotaEffective antimicrobial stewardship requires a better understanding of the impact of different antibiotics on the gut microflora. Studies with humans are confounded by large interindividual variability and difficulty in identifying control cohorts.
Clinical TherapeuticsPharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal EfficacyAspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of...
Clinical TherapeuticsEvaluation of Linezolid Pharmacokinetics in Critically Ill Obese Patients with Severe Skin and Soft Tissue InfectionsLinezolid standard dosing is fixed at 600 mg every 12 h (q12h) for adults. Literature suggests critically ill, obese patients require higher doses.
Clinical TherapeuticsPopulation Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm InfectionTribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine’s primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii)...
Clinical TherapeuticsComparing the Population Pharmacokinetics of and Acute Kidney Injury Due to Polymyxin B in Chinese Patients with or without Renal InsufficiencyDespite excellent bactericidal effect, dosing adjustment of polymyxin B for patients with renal insufficiency and polymyxin B-related nephrotoxicity is still a major concern to clinicians. The aim of this study was to compare the population pharmacokinetics (PK) properties of polymyxin B in Chinese patients with different renal functions and to investigate the relationship between PK parameters and polymyxin B-related acute kidney...
Clinical TherapeuticsProspective Cohort Study of Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Adults on Extracorporeal Membrane OxygenationThe aim of this study was to develop a population pharmacokinetics (PK) model for vancomycin and to evaluate its pharmacodynamic target attainment (TA) in adults on extracorporeal membrane oxygenation (ECMO). After a single 1,000-mg dose of vancomycin, samples were collected 9 times per patient prospectively.
Pharmacology
PharmacologyPretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with TuberculosisShorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid.
PharmacologyPopulation Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Pediatric PatientsThis study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM.
PharmacologyIn Vivo Efficacy and Metabolism of the Antimalarial Cycleanine and Improved In Vitro Antiplasmodial Activity of Semisynthetic AnaloguesBisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine [compound 1], isochondodendrine [compound 2], and 2′-norcocsuline [compound 3]) isolated from the Triclisia subcordata Oliv. medicinal plant...
PharmacologyThe Funnel: a Screening Technique for Identifying Optimal Two-Drug Combination Chemotherapy RegimensThe Mycobacterium tuberculosis drug discovery effort has generated a substantial number of new/repurposed drugs for therapy for this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged.
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