Challenging Clinical Case in Antimicrobial Resistance
Challenging Clinical Case in Antimicrobial ResistanceTreatment of Multidrug-Resistant Vancomycin-Resistant Enterococcus faecium Hardware-Associated Vertebral Osteomyelitis with Oritavancin plus AmpicillinWeekly oritavancin plus ampicillin continuous infusion combination therapy was used to successfully treat a deep spine vancomycin-resistant Enterococcus faecium infection associated with hardware. Checkerboard and time-kill assays confirmed synergy between these two antibiotics.
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsSpontaneously Arising Streptococcus mutans Variants with Reduced Susceptibility to Chlorhexidine Display Genetic Defects and Diminished FitnessChlorhexidine (CHX) has been used to control dental caries caused by acid-tolerant bacteria such as Streptococcus mutans since the 1970s. Repeat CHX exposure for other bacterial species results in the development of variants with reduced susceptibility that also become more resistant to other antimicrobials.
Mechanisms of Action: Physiological EffectsAntibiotic Killing of Diversely Generated Populations of Nonreplicating BacteriaNonreplicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to killing by bactericidal antibiotics of three classes of nonreplicating populations of planktonic bacteria: (i) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (ii) persisters, minority...
Mechanisms of Resistance
Mechanisms of ResistanceIsoniazid Resistance in Mycobacterium tuberculosis Is a Heterogeneous Phenotype Composed of Overlapping MIC Distributions with Different Underlying Resistance MechanismsMIC testing using the Bactec mycobacteria growth indicator tube system 960 of 70 phylogenetically diverse, isoniazid-resistant clinical strains of Mycobacterium tuberculosis revealed a complex pattern of overlapping MIC distributions. Whole-genome sequencing explained most of the levels of resistance observed.
Mechanisms of ResistanceApplication of CRISPR/Cas9-Based Genome Editing in Studying the Mechanism of Pandrug Resistance in Klebsiella pneumoniaeIn this study, a CRISPR/Cas9-mediated genome editing method was used to study the functions of the mgrB, tetA, and ramR genes in mediating colistin and tigecycline resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP). Inactivation of the tetA or ramR gene or the mgrB gene by CRISPR/Cas9 affected...
Mechanisms of ResistanceEmerging erm(B)-Mediated Macrolide Resistance Associated with Novel Multidrug Resistance Genomic Islands in CampylobacterThe rapid dissemination of the macrolide resistance gene erm(B) will likely compromise the efficacy of macrolides as the treatment of choice for campylobacteriosis. More importantly, erm(B) is always associated with several multidrug resistance genomic islands (MDRGIs), which confer resistance to multiple other antimicrobials.
Mechanisms of ResistanceLink between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatusAspergillus fumigatus is an opportunistic mold responsible for invasive aspergillosis. Triazoles (e.g., voriconazole) represent the first-line treatment, but emerging resistance is of concern.
Mechanisms of ResistanceThe Combination Rifampin-Nitazoxanide, but Not Rifampin-Isoniazid-Pyrazinamide-Ethambutol, Kills Dormant Mycobacterium tuberculosis in Hypoxia at Neutral pHThe activities of rifampin, nitazoxanide, PA-824, and sutezolid were tested against dormant Mycobacterium tuberculosis under conditions mimicking caseous granulomas (hypoxia at pH 7.3) in comparison with those of the combination rifampin-isoniazid-pyrazinamide-ethambutol (R-I-Z-E), which is used for human therapy. Mycobacterial viability was monitored by CFU and...
Mechanisms of ResistanceTwo Hypervirulent Klebsiella pneumoniae Isolates Producing a blaKPC-2 Carbapenemase from a Canadian PatientThis report describes two hypervirulent Klebsiella pneumoniae isolates that produced K. pneumoniae carbapenemase (KPC), which were identified from a rectal swab and a urine culture upon hospital admission. The patient had recently traveled to Greece, where he was hospitalized.
Mechanisms of ResistanceIdentification of a Carbapenemase-Producing Hypervirulent Klebsiella pneumoniae Isolate in the United StatesWe report on a carbapenemase-producing hypervirulent Klebsiella pneumoniae (CP-hvKP) isolate collected from a U.S. patient at an outpatient clinic.
Mechanisms of ResistanceNew Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section NigriInvasive aspergillosis (IA) is a severe condition mainly caused by Aspergillus fumigatus, although other species of the genus, such as section Nigri members, can also be involved. Voriconazole (VRC) is the recommended treatment for IA; however, the prevalence of azole-resistant Aspergillus isolates has alarmingly increased in recent years, and the...
Mechanisms of ResistanceFunctional Characterization of a Miniature Inverted Transposable Element at the Origin of mcr-5 Gene Acquisition in Escherichia coliPlasmid-mediated colistin resistance of the mobile colistin resistance (MCR) type is a growing concern in Enterobacteriaceae since it has been described worldwide in humans and animals. Here, we identified a series of MCR-producing Escherichia coli isolates corresponding to two different clones (...
Mechanisms of ResistanceThe Essential Role of Hypermutation in Rapid Adaptation to Antibiotic StressA common outcome of antibiotic exposure in patients and in vitro is the evolution of a hypermutator phenotype that enables rapid adaptation by pathogens. While hypermutation is a robust mechanism for rapid adaptation, it requires trade-offs between the adaptive mutations and the more common “hitchhiker” mutations that accumulate from the increased mutation rate.
Mechanisms of ResistanceDefects in Efflux (oprM), β-Lactamase (ampC), and Lipopolysaccharide Transport (lptE) Genes Mediate Antibiotic Hypersusceptibility of Pseudomonas aeruginosa Strain Z61Antibiotic hypersensitive bacterial mutants (e.g., Escherichia coli imp) are used to investigate intrinsic resistance and are exploited in antibacterial discovery to track weak antibacterial activity of novel inhibitor compounds. Pseudomonas aeruginosa Z61 is one such drug-hypersusceptible...
Mechanisms of ResistanceLow Level of Antifungal Resistance in Iranian Isolates of Candida glabrata Recovered from Blood Samples in a Multicenter Study from 2015 to 2018 and Potential Prognostic Values of Genotyping and Sequencing of PDR1Establishing an effective empirical antifungal therapy requires that national surveillance studies be conducted. Herein, we report the clinical outcome of infections with and the microbiological features of Iranian isolates of Candida glabrata derived from patients suffering from candidemia.
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Mechanisms of ResistancePhylogenomic Investigation of IncI1-Iγ Plasmids Harboring blaCMY-2 and blaSHV-12 in Salmonella enterica and Escherichia coli in Multiple CountriesThe objective of this study was to elucidate the genetic and evolutionary relatedness of blaCMY-2- and blaSHV-12-carrying IncI1-Iγ plasmids. Phylogenomic analysis based on core genome alignments and gene presence/absence was performed for different IncI1-Iγ sequence types (STs).
Susceptibility
SusceptibilityU.S.-Based National Surveillance for Fidaxomicin Susceptibility of Clostridioides difficile-Associated Diarrheal Isolates from 2013 to 2016In 2011, we initiated a sentinel surveillance network to assess changes in Clostridioides (formerly Clostridium) difficile antimicrobial susceptibility to fidaxomicin from 6 geographically dispersed medical centers in the United States. This report summarizes data from 2013 to 2016. C. difficile isolates or toxin-positive stools from...
Editor's Pick SusceptibilityBicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam AntibioticsEndovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as “resistant” to β-lactams, often leading to the use of costly and/or toxic treatment regimens. In this investigation, five prototype...
SusceptibilityNatamycin and Voriconazole Exhibit Synergistic Interactions with Nonantifungal Ophthalmic Agents against Fusarium Species Ocular IsolatesThe in vitro activities of two antifungal drugs in combination with four nonantifungal ophthalmic agents were evaluated using a broth microdilution method and a collection of eight Fusarium ocular isolates that exhibited resistance to both natamycin (MICs, 14 to 32 μg/ml) and voriconazole (MICs, 4 to >128 μg/ml). Synergistic and indifferent interactions were observed for natamycin and 5-fluorouracil and natamycin...
SusceptibilityComparing Antimicrobial Susceptibilities among Mycoplasma pneumoniae Isolates from Pediatric Patients in Japan between Two Recent Epidemic PeriodsWe compared the antimicrobial susceptibility of Mycoplasma pneumoniae isolates from pediatric patients in Japan in 2011–2012 and 2015–2016, when epidemics occurred. The antimicrobial activity of macrolides and tetracyclines against M. pneumoniae infection tended to be restored in 2015–2016.
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SusceptibilityIn Vitro Activity of Fenticonazole against Candida and Bacterial Vaginitis Isolates Determined by Mono- or Dual-Species Testing AssaysWe determined the in vitro activity of fenticonazole against 318 vaginitis isolates of Candida and bacterial species and selected 28 isolates for time-kill studies. At concentrations equal to 4× MIC, fenticonazole reached the 99.9% killing endpoint by ∼10 h for Staphylococcus aureus, ...
Biologic Response Modifiers
Biologic Response ModifiersMycobacterium abscessus Cells Have Altered Antibiotic Tolerance and Surface Glycolipids in Artificial Cystic Fibrosis Sputum MediumMycobacterium abscessus is a biofilm-forming, multidrug-resistant nontuberculous mycobacterial (NTM) pathogen increasingly found in cystic fibrosis patients. Antibiotic treatment for these infections is often unsuccessful, partly due to M. abscessus’s high intrinsic antibiotic resistance.
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Analytical Procedures
Analytical ProceduresEfficient Inactivation of Clinically Relevant Antimicrobial Drug Concentrations by BacT/Alert or Bactec Resin-Containing Media in Simulated Adult Blood CulturesWe assessed the antimicrobial-inactivation capability of BacT/Alert (FA Plus and FN Plus) or Bactec (Plus Aerobic/F and Plus Anaerobic/F) media for 40 antibiotic-bacterium combinations in simulated adult blood cultures. Aside from high recovery rates (93.2% and 88.4%, respectively), we showed that at the lowest but clinically relevant antibiotic concentrations, both BacT/Alert and Bactec media recovered all the organisms tested with...
Analytical ProceduresSimplified Testing Method for Direct Detection of Carbapenemase-Producing Organisms from Positive Blood Cultures Using the NG-Test Carba 5 AssayWe directly tested 484 organisms from clinical (n = 310) and simulated (n = 174) positive blood cultures using the NG-Test Carba 5 assay for carbapenemase-producing Enterobacterales detection. The assay identified all but 4 of the KPC (170/171), OXA-48-like (22/22), VIM (19/21), and NDM (14/15) producers with no false positives.
Antiviral Agents
Antiviral AgentsNucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis VirusesDengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridae family. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas.
Antiviral AgentsNovel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS ComplicationsThere is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF...
Epidemiology and Surveillance
Epidemiology and SurveillanceComparative Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Enterobacteriaceae Isolates Producing Extended-Spectrum β-Lactamases from U.S. HospitalsThe activities of ceftazidime-avibactam, ceftolozane-tazobactam, and comparators were evaluated for 733 isolates displaying resistance to broad-spectrum cephalosporins and carrying extended-spectrum β-lactamase (ESBL) genes detected by whole-genome sequencing analysis. Isolates were collected during 2017 in U.S.
Epidemiology and SurveillanceTrends in and Predictors of Carbapenem Consumption across North American Hospitals: Results from a Multicenter Survey by the MAD-ID Research NetworkWe sought to define trends in and predictors of carbapenem consumption across community, teaching, and university-affiliated hospitals in the United States and Canada. We conducted a retrospective multicenter survey of carbapenem and broad-spectrum noncarbapenem beta-lactam consumption between January 2011 and December 2013.
Epidemiology and SurveillanceThe Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance ProgramBloodstream infection (BSI) organisms were consecutively collected from >200 medical centers in 45 nations between 1997 and 2016. Species identification and susceptibility testing followed Clinical and Laboratory Standards Institute broth microdilution methods at a central laboratory.
Epidemiology and SurveillanceIndependent Host Factors and Bacterial Genetic Determinants of the Emergence and Dominance of Escherichia coli Sequence Type 131 CTX-M-27 in a Community Pediatric Cohort StudyThe recent emergence and diffusion in the community of Escherichia coli isolates belonging to the multidrug-resistant and CTX-M-27-producing sequence type 131 (ST131) C1-M27 cluster makes this cluster potentially as epidemic as the worldwide E. coli ST131 subclade C2 composed of multidrug-resistant...
Epidemiology and SurveillanceIn Vitro Activity of Cefepime-Enmetazobactam against Gram-Negative Isolates Collected from U.S. and European Hospitals during 2014–2015Enmetazobactam, formerly AAI101, is a novel penicillanic acid sulfone extended-spectrum β-lactamase (ESBL) inhibitor. The combination of enmetazobactam with cefepime has entered clinical trials to assess safety and efficacy in patients with complicated urinary tract infections.
Epidemiology and SurveillancePolymorphisms in Plasmodium falciparum Kelch 13 and P. vivax Kelch 12 Genes in Parasites Collected from Three South Pacific Countries Prior to Extensive Exposure to Artemisinin Combination TherapiesThe South Pacific countries Solomon Islands, Vanuatu, and Papua New Guinea (PNG) adopted artemisinin-based combination therapies (ACTs) in 2008. We examined Kelch 13 and Kelch 12 genes in parasites originating from these countries before or at ACT introduction.
Epidemiology and SurveillanceJoint Modeling of Resistance to Six Antimicrobials in Urinary Escherichia coli Isolates in Quebec, CanadaEmpirical treatment of urinary tract infections should be based on susceptibility profiles specific to the locale and patient population. Additionally, these susceptibility profiles should account for correlations between resistance to different types of antimicrobials.
Experimental Therapeutics
Experimental TherapeuticsIsolation of Phage Lysins That Effectively Kill Pseudomonas aeruginosa in Mouse Models of Lung and Skin InfectionMultidrug resistance (MDR) is rapidly increasing in prevalence among isolates of the opportunistic pathogen Pseudomonas aeruginosa, leaving few treatment options. Phage lysins are cell wall hydrolases that have a demonstrated therapeutic potential against Gram-positive pathogens; however, the outer membrane of Gram-negative bacteria prevents most lysins from reaching...
Experimental TherapeuticsEfficacy of Human Exposures of Gepotidacin (GSK2140944) against Escherichia coli in a Rat Pyelonephritis ModelGepotidacin is a first-in-class triazaacenaphthylene antibacterial that inhibits bacterial type II topoisomerases and has in vitro activity against a range of bacterial pathogens, including Escherichia coli. Urinary tract infections often progress to pyelonephritis and are a worldwide problem due to the prevalence of multidrug-resistant...
Experimental TherapeuticsCombining Ceftriaxone with Doxycycline and Daptomycin Reduces Mortality, Neuroinflammation, Brain Damage, and Hearing Loss in Infant Rat Pneumococcal MeningitisDespite appropriate antibiotic therapy, pneumococcal meningitis (PM) is associated with a case fatality rate of up to 30% in high-income countries. Survivors often suffer from severe lifelong disabilities.
Experimental TherapeuticsSynergistic Effect of Colistin Combined with PFK-158 against Colistin-Resistant EnterobacteriaceaeAs increasing numbers of colistin-resistant bacteria emerge, new therapies are urgently needed to treat infections caused by these pathogens. The discovery of new combination therapies is one important way to solve such problems.
Experimental TherapeuticsNitroglycerin-Citrate-Ethanol Catheter Lock Solution Is Highly Effective for In Vitro Eradication of Candida auris BiofilmCandida auris poses emerging risks for causing severe central line-associated bloodstream infections. We tested in vitro the ability of antifungal lock solutions to rapidly eradicate C. auris biofilms.
Experimental TherapeuticsAdvancing the Therapeutic Potential of Indoleamides for TuberculosisIndole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis. In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation.
Experimental TherapeuticsShortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene DecayBuruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients.
Experimental TherapeuticsIn Vivo Pharmacodynamics of Omadacycline against Staphylococcus aureus in the Neutropenic Murine Thigh Infection ModelOmadacycline is a novel aminomethylcycline antibiotic with potent activity against Staphylococcus aureus, including methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). We investigated the...
Experimental TherapeuticsEfficacy of Aerosolized Rifaximin versus Tobramycin for Treatment of Pseudomonas aeruginosa Pneumonia in MicePseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that can cause chronic lung infections in patients with cystic fibrosis (CF). The current preferred treatment for CF lung infections includes inhaled tobramycin (TOB); however, studies suggest TOB cannot effectively inhibit biofilm formation.
Experimental TherapeuticsIdentifying Regimens Containing TBI-166, a New Drug Candidate against Mycobacterium tuberculosis In Vitro and In VivoTBI-166, derived from riminophenazine analogues, is under development in a phase I clinical trial in China. TBI-166 showed more potent anti-tuberculosis (anti-TB) activity than did clofazimine in in vitro and animal experiments.
Experimental TherapeuticsTreatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during PregnancyPrevious studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory...
Clinical Therapeutics
Clinical TherapeuticsModified Mouse Model of Clostridioides difficile Infection as a Platform for Probiotic Efficacy StudiesProbiotics may represent a promising approach for reducing Clostridioides (Clostridium) difficile infections (CDIs). A clinical trial conducted by our group demonstrated that CDI patients undergoing adjunctive treatment with Lactobacillus and Bifidobacterium probiotics had a reduction in diarrheal duration and compositional changes in their stool microbiomes.
Clinical TherapeuticsMolecular Testing of Serial Blood Specimens from Patients with Early Lyme Disease during Treatment Reveals Changing Coinfection with Mixtures of Borrelia burgdorferi GenotypesBorrelia burgdorferi is the etiological agent of Lyme disease. In the current study, we used direct-detection PCR and electrospray ionization mass spectrometry to monitor and genotype B. burgdorferi isolates from serially collected whole-blood specimens from patients clinically diagnosed with early...
Clinical TherapeuticsFluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose SelectionFluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers.
Editor's Pick Clinical TherapeuticsProspective Observational Study of the Clinical Prognoses of Patients with Bloodstream Infections Caused by Ampicillin-Susceptible but Penicillin-Resistant Enterococcus faecalisThe purpose of this study was to evaluate the clinical impacts of ampicillin-susceptible but penicillin-resistant (ASPR) phenotypes of Enterococcus faecalis on clinical outcomes in patients with bloodstream infection (BSI). A total of 295 patients with an E. faecalis BSI from six sentinel hospitals...
Clinical TherapeuticsPopulation Pharmacokinetics of Anidulafungin in Critically Ill PatientsA two-compartment pharmacokinetic (PK) population model of anidulafungin was fitted to PK data from 23 critically ill patients (age, 65 years [range, 28 to 81 years]; total body weight [TBW], 75 kg [range, 54 to 168 kg]). TBW was associated with clearance and incorporated into a final population PK model.
Clinical TherapeuticsLimited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis PatientsTherapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve the response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest, the area under the concentration-time curve.
Clinical TherapeuticsComparable Efficacy and Better Safety of Double β-Lactam Combination Therapy versus β‑Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled TrialsThere is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined.
Clinical TherapeuticsEfficacy and Safety of Tedizolid Phosphate versus Linezolid in a Randomized Phase 3 Trial in Patients with Acute Bacterial Skin and Skin Structure InfectionTedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infection (ABSSSI) caused by Gram-positive bacteria in the United States, Europe, and other countries. In this multicenter, double-blind, phase 3 study, 598 adult ABSSSI patients in China, Taiwan, the Philippines, and the United States were randomized to receive 200 mg of tedizolid, intravenously (i.v.)/orally (p.o.), once daily for 6 days or...
Clinical TherapeuticsA First-in-Human Study To Assess the Safety and Pharmacokinetics of LYS228, a Novel Intravenous Monobactam Antibiotic in Healthy VolunteersInfections caused by antibiotic-resistant Gram-negative bacteria expressing extended-spectrum β-lactamases and carbapenemases are a growing global problem resulting in increased morbidity and mortality with limited treatment options. LYS228 is a novel intravenous monobactam antibiotic targeting penicillin binding protein 3 with potent activity against Enterobacteriaceae...
Pharmacology
PharmacologyUsing Mycobacterium tuberculosis Single-Nucleotide Polymorphisms To Predict Fluoroquinolone Treatment ResponseClinical phenotypic fluoroquinolone susceptibility testing of Mycobacterium tuberculosis is currently based on M. tuberculosis growth at a single critical concentration, which provides limited information for a nuanced clinical response. We propose using specific resistance-conferring...
PharmacologyComparative Performance of Urinary Biomarkers for Vancomycin-Induced Kidney Injury According to Timeline of InjuryUrinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage.
PharmacologyIn Vitro Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against EnterobacteriaceaeA novel antibiotic combination of the oral cephalosporin ceftibuten (CTB) and the β-lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those caused by extended-spectrum-β-lactamase (ESBL)-producing organisms. This study aimed to identify the pharmacodynamic index and magnitude of this index for CLA, when combined with a fixed CTB exposure (∼59% free time above the CTB-CLA MIC)...
PharmacologyIn Vivo Pharmacodynamic Profile of Ceftibuten-Clavulanate Combination against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae in the Murine Thigh Infection ModelCeftibuten-clavulanate (CTB-CLA) is a novel β-lactam–β-lactamase combination with potential utility for the management of urinary tract infections caused by extended-spectrum-β-lactamase (ESBL)-producing organisms. We examined the pharmacodynamics of the combination against 25 Enterobacteriaceae expressing β-lactamases (CTX-M, TEM, and SHV wild types and SHV-ESBL) in...
Editor's Pick PharmacologyIn Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection ModelWe describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against multidrug-resistant Pseudomonas aeruginosa (meropenem MICs 8 to >256 μg/ml) in a neutropenic murine thigh infection model. WCK 5222 MICs ranged from 4 to 32 μg/ml.
PharmacologyBody Surface Area-Based Dosing Regimen of Caspofungin in Children: a Population Pharmacokinetics Confirmatory StudyWe evaluated the population pharmacokinetics of caspofungin in children (2 to 12 years of age). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination.
PharmacologyValidation and Application of an HPLC-DAD Method for Routine Therapeutic Drug Monitoring of CeftobiproleCeftobiprole is a fifth-generation cephalosporin approved for the treatment of pneumonia, with a broad antibacterial spectrum, including potent activity against methicillin-resistant Staphylococcus aureus. As for the other cephalosporins, high pharmacokinetic variability and concentration-dependent neurotoxicity are expected.
PharmacologyActivity of Antibiotics against Staphylococcus aureus in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture MediumStaphylococcus aureus is a highly prevalent pathogen in the respiratory tract of young patients with cystic fibrosis (CF) and causes biofilm-related infections. Here, we set up an in vitro model of a biofilm grown in Trypticase soy broth supplemented with glucose and NaCl (TGN) or in artificial sputum medium (ASM) and used it to evaluate on a pharmacodynamic...
PharmacologySystematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through ImmunomodulationHost immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, and it has been hypothesized that the antileishmanial drug miltefosine is capable of immunomodulation and induction of Th1...
PharmacologyPreclinical Pharmacokinetic and Pharmacodynamic Data To Support Cefoxitin Nebulization for the Treatment of Mycobacterium abscessusMycobacterium abscessus is responsible for difficult-to-treat chronic pulmonary infections in humans. Current regimens, including parenteral administrations of cefoxitin (FOX) in combination with amikacin and clarithromycin, raise compliance problems and are frequently associated with high failure and development of resistance.
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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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