Minireviews
MinireviewEchinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to BedsideEchinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA).
MinireviewA Guide to Understanding Antimicrobial Drug Dosing in Critically Ill Patients on Renal Replacement Therapy...A careful management of antimicrobials is essential in the critically ill with acute kidney injury, especially if renal replacement therapy is required. Acute kidney injury may lead per se to clinically significant modifications of drugs’ pharmacokinetic parameters, and the need for renal replacement therapy represents a further variable that should be considered to avoid inappropriate antimicrobial therapy.
Challenging Clinical Cases in Antimicrobial Resistance
Challenging Clinical Case in Antimicrobial ResistanceManaging All the Genotypic Knowledge: Approach to a Septic Patient Colonized by Different Enterobacteriales with Unique CarbapenemasesThe recent development of new antimicrobials active against carbapenemase-producing Enterobacteriales (CPE) has brought new hope for the treatment of infections due to these organisms. However, the evolving epidemiology of bacteria with carbapenemases may complicate management, as providers are faced with treating patients colonized by bacteria producing multiple carbapenemases.
Challenging Clinical Case in Antimicrobial ResistanceAmphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS-Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and OsteomyelitisWe report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of...
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsThe Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain ComplexesThe novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function.
Editor's Pick Mechanisms of Action: Physiological EffectsUtilization of CRISPR Interference To Validate MmpL3 as a Drug Target in Mycobacterium tuberculosisThere is an urgent need for novel therapeutics to treat Mycobacterium tuberculosis infections. Genetic strategies for validating novel targets are available, yet their time-consuming nature limits their utility. Here, using MmpL3 as a model target, we report on the application of mycobacterial CRISPR interference for the rapid validation of target essentiality and...
Editor's Pick Mechanisms of Action: Physiological EffectsBedaquiline Eliminates Bactericidal Activity of β-Lactams against Mycobacterium abscessusThe β-lactams imipenem and cefoxitin are used for the treatment of Mycobacterium abscessus lung infections. Here, we show that these cell wall synthesis inhibitors trigger a lethal bacterial ATP burst by increasing oxidative phosphorylation. Cotreatment of M. abscessus with the antimycobacterial ATP...
Mechanisms of Resistance
Mechanisms of ResistanceIn Vitro Study of Stepwise Acquisition of rv0678 and atpE Mutations Conferring Bedaquiline ResistanceBedaquiline resistance within Mycobacterium tuberculosis may arise through efflux-based (rv0678) or target-based (atpE) pathway mutations. M. tuberculosis mutant populations from each of five sequential steps in a passaging approach, using a pyrazinamide-resistant ATCC strain, were...
Editor's Pick Mechanisms of ResistanceIntercellular Transfer of Chromosomal Antimicrobial Resistance Genes between Acinetobacter baumannii Strains Mediated by ProphagesThe spread of antimicrobial resistance genes (ARGs) among Gram-negative pathogens, including Acinetobacter baumannii, is primarily mediated by transferable plasmids; however, ARGs are frequently integrated into its chromosome. How ARG gets horizontally incorporated into the chromosome of A. baumannii...
Mechanisms of ResistanceThe blaNDM-1-Carrying IncA/C2 Plasmid Underlies Structural Alterations and Cointegrate Formation In VivoIn 2012, a carbapenemase-producing Salmonella enterica serovar Corvallis isolate carrying a blaNDM-1 multiresistance IncA/C2 plasmid, apart from IncHI2 and ColE-like plasmids, was detected in a wild bird in Germany. In a recent broiler chicken infection study, we observed transfer of this blaNDM-1-carrying IncA/C...
Mechanisms of ResistanceNacubactam Enhances Meropenem Activity against Carbapenem-Resistant Klebsiella pneumoniae Producing KPCCarbapenem-resistant Enterobacteriaceae (CRE) are resistant to most antibiotics, making CRE infections extremely difficult to treat with available agents. Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) are predominant carbapenemases in CRE in the United States. Nacubactam is a bridged...
Mechanisms of ResistanceEmergence of Oxacillin Resistance in Stealth Methicillin-Resistant Staphylococcus aureus Due to mecA Sequence InstabilityStaphylococcus aureus strains that possess a mecA gene but are phenotypically susceptible to oxacillin and cefoxitin (OS-MRSA) have been recognized for over a decade and are a challenge for diagnostic laboratories. The mechanisms underlying the discrepancy vary from isolate to isolate.
Mechanisms of ResistanceRapid Increase in Carbapenemase-Producing Enterobacteriaceae in Retail Meat Driven by the Spread of the blaNDM-5-Carrying IncX3 Plasmid in China from 2016 to 2018The presence and molecular characteristics of carbapenemase-producing Enterobacteriaceae (CPE) among meat products in China were investigated. A total of 110 carbapenem-resistant Enterobacteriaceae (CRE) isolates, including 94 ...
Mechanisms of ResistanceMultiple Copies of qnrA1 on an IncA/C2 Plasmid Explain Enhanced Quinolone Resistance in an Escherichia coli MutantIn a previous study, mutants with enhanced ciprofloxacin resistance (Cipr) were selected from Escherichia coli J53/pMG252 carrying qnrA1. Strain J53 Cipr 8-2 showed an increase in the copy number and transcription level of qnrA1. We sequenced the plasmids on Illumina and MinION platforms.
Mechanisms of ResistanceReactive Oxygen Species Production Is a Major Factor Directing the Postantibiotic Effect of Fluoroquinolones in Streptococcus pneumoniaeWe studied the molecular mechanisms involved in the postantibiotic effect of the fluoroquinolones levofloxacin and moxifloxacin in Streptococcus pneumoniae. Wild-type strain R6 had postantibiotic effects of 2.05 ± 0.10 h (mean ± standard deviation [SD]) and 3.23 ± 0.45 h at 2.5× and 10× MIC of levofloxacin, respectively. Moxifloxacin exhibited lower effects of 0.87 ±...
Mechanisms of ResistanceChemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma bruceiThe arsenal of drugs used to treat leishmaniasis, caused by Leishmania spp., is limited and beset by toxicity and emergent resistance. Furthermore, our understanding of drug mode of action and potential routes to resistance is limited. Forward genetic approaches have revolutionized our understanding of drug mode of action in the related kinetoplastid parasite ...
Mechanisms of ResistanceEssential Role for the Phosphatidylinositol 3,5-Bisphosphate Synthesis Complex in Caspofungin Tolerance and Virulence in Candida glabrataIncreasing resistance of the human opportunistic fungal pathogen Candida glabrata toward the echinocandin antifungals, which target the cell wall, is a matter of grave clinical concern. Echinocandin resistance in C. glabrata has primarily been associated with mutations in the β-glucan synthase-...
Susceptibility
SusceptibilityIn Vitro Activities of Bedaquiline and Delamanid against Nontuberculous Mycobacteria Isolated in Beijing, ChinaDue to the natural resistance of nontuberculous mycobacteria (NTM) against multiple antibiotics, treatment of infections caused by them is often long-course and less successful. The main objective of our study was the evaluation of in vitro susceptibility of 209 isolates consisting of different NTM species against bedaquiline and delamanid. Furthermore, reference strains of 33 rapidly growing mycobacterium (RGM) species and 19...
SusceptibilityIvermectin Impairs the Development of Sexual and Asexual Stages of Plasmodium falciparum In VitroIvermectin is the drug of choice for many parasitic infections, with more than one billion doses being distributed in onchocerciasis programs. The drug has been put into focus recently by the malaria community because of its potential to kill blood-sucking mosquitoes, thereby reducing malaria transmission.
SusceptibilityFluconazole Resistance in Isolates of Uncommon Pathogenic Yeast Species from the United KingdomThe triazole drug fluconazole remains one of the most commonly prescribed antifungal drugs, both for prophylaxis in high-risk patients and also as a second-line treatment option for invasive Candida infections. Established susceptibility profiles and clinical interpretive breakpoints are available for fluconazole with...
SusceptibilityImpact of Species Diversity on the Design of RNA-Based Diagnostics for Antibiotic Resistance in Neisseria gonorrhoeaeQuantitative assessment of antibiotic-responsive RNA transcripts holds promise for a rapid point-of-care (POC) diagnostic tool for antimicrobial susceptibility testing. These assays aim to distinguish susceptible and resistant isolates by transcriptional differences upon drug exposure. However, an often-overlooked dimension of designing these tests is that the genetic diversity within a species may yield differential transcriptional...
SusceptibilityThe Repurposed Drug Disulfiram Inhibits Urease and Aldehyde Dehydrogenase and Prevents In Vitro Growth of the Oomycete Pythium insidiosumPythium insidiosum is an oomycete microorganism that causes a life-threatening infectious disease, called pythiosis, in humans and animals. The disease has been increasingly reported worldwide.
SusceptibilitySynergistic Efficacy of β-Lactam Combinations against Mycobacterium abscessus Pulmonary Infection in MiceMycobacterium abscessus is an emerging pathogen capable of causing invasive pulmonary infections in patients with chronic lung diseases. These infections are difficult to treat, necessitating prolonged multidrug therapy, which is further complicated by extensive intrinsic and acquired resistance exhibited by clinical...
SusceptibilityA Revised Species Concept for Opportunistic Mucor Species Reveals Species-Specific Antifungal Susceptibility ProfilesRecently, the species concept of opportunistic Mucor circinelloides and its relatives has been revised, resulting in the recognition of its classical formae as independent species and the description of new species. In this study, we used isolates of all clinically relevant Mucor species and performed susceptibility testing using the EUCAST reference method...
SusceptibilityIn Vitro Activity of Bedaquiline and Delamanid against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical IsolatesWe evaluated the in vitro activities of the antimicrobial drugs bedaquiline and delamanid against the major pathogenic nontuberculous mycobacteria (NTM). Delamanid showed high MIC values for all NTM except Mycobacterium kansasii. However, bedaquiline showed low MIC values for the major pathogenic NTM, including...
SusceptibilityIn Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during...
SusceptibilityIn Vitro Activity of Chlorhexidine Compared with Seven Antifungal Agents against 98 Fusarium Isolates Recovered from Fungal Keratitis Patients...Fungal keratitis is a common but severe eye infection in tropical and subtropical areas of the world. In regions with a temperate climate, the frequency of infection is rising in patients with contact lenses and following trauma. Early and adequate therapy is important to prevent disease progression and loss of vision. The management of Fusarium keratitis is complex, and the optimal treatment is not well defined.
Antiviral Agents
Antiviral AgentsMultiple Drug Transporters Contribute to the Placental Transfer of EmtricitabineEmtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were...
Antiviral AgentsNovel Protease Inhibitors Containing C-5-Modified bis-Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2′ Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug ResistanceCombination antiretroviral therapy has achieved dramatic reductions in the mortality and morbidity in people with HIV-1 infection. Darunavir (DRV) represents a most efficacious and well-tolerated protease inhibitor (PI) with a high genetic barrier to the emergence of drug-resistant HIV-1. However, highly DRV-resistant variants have been reported in patients receiving long-term DRV-containing regimens.
Antiviral AgentsIntravenous Immunoglobulin Administration Significantly Increases BKPyV Genotype-Specific Neutralizing Antibody Titers in Kidney Transplant RecipientsBK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is one of the major causes of kidney graft dysfunction, and there are no BKPyV-specific antiviral therapies available. BKPyV neutralizing antibodies (NAbs) play key roles in protecting against BKPyV replication and represent a potential therapeutic or preventive strategy. In this study, we evaluated NAb titers in intravenous immunoglobulin (i.v. Ig) preparations and in kidney...
Antiviral AgentsAn Evolutionary Model-Based Approach To Quantify the Genetic Barrier to Drug Resistance in Fast-Evolving Viruses and Its Application to HIV-1 Subtypes and Integrase InhibitorsViral pathogens causing global disease burdens are often characterized by high rates of evolutionary changes. The extensive viral diversity at baseline can shorten the time to escape from therapeutic or immune selective pressure and alter mutational pathways. The impact of genotypic background on the barrier to resistance can be difficult to capture, particularly for agents in experimental stages or that are recently approved or...
Antiviral AgentsLethal Mutagenesis of Rift Valley Fever Virus Induced by FavipiravirRift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections...
Antiviral AgentsNonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse TranscriptaseSubstitutions at residue Y181 in HIV-1 reverse transcriptase (RT), in particular, Y181C, Y181I, and Y181V, are associated with nonnucleoside RT inhibitor (NNRTI) cross-resistance. In this study, we used kinetic and thermodynamic approaches, in addition to molecular modeling, to gain insight into the mechanisms by which these substitutions confer resistance to nevirapine (NVP), efavirenz (EFV), and rilpivirine (RPV).
Epidemiology and Surveillance
Epidemiology and SurveillancePatient-to-Patient Transmission of Acinetobacter baumannii Gastrointestinal Colonization in the Intensive Care UnitAcinetobacter baumannii is an important nosocomial pathogen. The objective of this study was to determine the proportion of A. baumannii infections due to patient-to-patient transmission by analyzing the molecular epidemiology of patients who acquired...
Epidemiology and SurveillanceEmergence of Carbapenem-Resistant Pseudomonas asiatica Producing NDM-1 and VIM-2 Metallo-β-Lactamases in MyanmarPseudomonas asiatica is a recently proposed species of the genus Pseudomonas. This study describes eight isolates of carbapenem-resistant P. asiatica harboring blaNDM-1 and blaVIM-2, genes encoding metallo-β-lactamase (MBL). These isolates were obtained from urine samples of patients hospitalized in Myanmar....
Epidemiology and SurveillanceThe Arginine Deiminase Operon Is Responsible for a Fitness Trade-Off in Extended-Spectrum-β-Lactamase-Producing Strains of Escherichia coliWe previously identified an operon involved in an arginine deiminase (ADI) pathway (arc operon) on a CTX-M-producing plasmid from an O102-ST405 strain of Escherichia coli. As the ADI pathway was shown to be involved in the virulence of various Gram-positive bacteria, we tested whether the ADI pathway could be involved in the epidemiological success of...
Epidemiology and SurveillanceThe Likelihood of Developing a Carbapenem-Resistant Enterobacteriaceae Infection during a Hospital StayOf 1,455 unique patients in U.S. intensive care units (ICUs), 4% were rectally colonized with CRE on admission. A total of 297 patients were initially negative for carbapenem-resistant Enterobacteriaceae (CRE) and remained in the ICU long enough to contribute additional swabs; 22% of these patients had a subsequent CRE-positive swab, with a median time to CRE...
Editor's Pick Epidemiology and SurveillanceRepeated Detection of Carbapenemase-Producing Escherichia coli in Gulls Inhabiting AlaskaHere, we report the first detection of carbapenemase-producing Escherichia coli in Alaska and in wildlife in the United States. Wild bird (gull) feces sampled at three locations in Southcentral Alaska yielded isolates that harbored plasmid-encoded blaKPC-2 or chromosomally encoded blaOXA-48 and genes associated with...
Epidemiology and SurveillanceEvolution and Genetic Diversity of the k13 Gene Associated with Artemisinin Delayed Parasite Clearance in Plasmodium falciparumMutations in the Plasmodium falciparum k13 (Pfk13) gene are linked to delayed parasite clearance in response to artemisinin-based combination therapies (ACTs) in Southeast Asia. To explore the evolutionary rate and constraints acting on this gene, k13 orthologs from species sharing a recent common ancestor with...
Experimental Therapeutics
Experimental TherapeuticsEfficacy of a Multimechanistic Monoclonal Antibody Combination against Staphylococcus aureus Surgical Site Infections in MiceSurgical site infections (SSIs) are commonly caused by Staphylococcus aureus. We report that a combination of three monoclonal antibodies (MEDI6389) that neutralize S. aureus alpha-toxin, clumping factor A, and four leukocidins (LukSF, LukED, HlgAB, and HlgCB) plus vancomycin had enhanced efficacy...
Experimental TherapeuticsRandomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in the Lung Epithelial Lining Fluid of Healthy VolunteersASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-...
Experimental TherapeuticsPhage Therapy of Pneumonia Is Not Associated with an Overstimulation of the Inflammatory Response Compared to Antibiotic Treatment in MiceSupported by years of clinical use in some countries and more recently by literature on experimental models, as well as its compassionate use in Europe and in the United States, bacteriophage (phage) therapy is providing a solution for difficult-to-treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce.
Experimental TherapeuticsPharmacodynamics of Ceftazidime plus Avibactam against KPC-2-Bearing Isolates of Klebsiella pneumoniae in a Hollow Fiber Infection ModelCeftazidime-avibactam (CAZ/AVI) combines ceftazidime with a diazabicyclooctane non-β-lactam β-lactamase inhibitor. This has potent inhibitory activity against KPC-type enzymes. We studied activity of clinically relevant regimens of CAZ/AVI against two KPC-2-bearing Klebsiella pneumoniae isolates (sequence type 258 recovered sequentially from the same patient) with and...
Experimental TherapeuticsEndocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based RegimensOptimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo.
Experimental TherapeuticsTreatment Efficacy of MEDI3902 in Pseudomonas aeruginosa Bloodstream Infection and Acute Pneumonia Rabbit ModelsPseudomonas aeruginosa is a challenge for clinicians due to increasing drug resistance and dwindling treatment options. We report on the activity of MEDI3902, an antibody targeting type 3 secretion protein PcrV and Psl exopolysaccharide, in rabbit bloodstream and lung infection models. MEDI3902 prophylaxis or treatment was protective in both acute models and exhibited...
Experimental TherapeuticsUnexpected Activity of Oral Fosfomycin against Resistant Strains of Escherichia coli in Murine PyelonephritisFosfomycin tromethamine activity is well established for oral treatment of uncomplicated lower urinary tract infections, but little is known about its potential efficacy in pyelonephritis. Ascending pyelonephritis was induced in mice infected with 6 strains of Escherichia coli (fosfomycin MICs, 1 μg/ml to 256 μg/ml). The urine pH was 4.5 before infection and 5.5 to 6....
Experimental TherapeuticsIn Vivo Pharmacokinetic/Pharmacodynamic Targets of Levonadifloxacin against Staphylococcus aureus in a Neutropenic Murine Lung Infection ModelLevonadifloxacin is a novel benzoquinolizine subclass of fluoroquinolone, active against quinolone-resistant Staphylococcus aureus. A phase 3 trial for levonadifloxacin and its oral prodrug was recently completed. The present study identified area under the concentration-time curve for the free, unbound fraction of a drug divided by the MIC (fAUC/MIC) as an...
Experimental TherapeuticsLichtheimia corymbifera Colonization Leading to Pulmonary Infection Can Be Prevented with Liposomal Amphotericin B in a New Murine ModelThe incidence of pulmonary mucormycosis is constantly increasing, especially in hematological patients staying in high-efficiency particulate air-filtered rooms. Pulmonary inhalation of spores may occur outside the hospital, leading to invasive disease once patients received chemotherapies.
Experimental TherapeuticsAmino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during InfectionThe emergence of multidrug-resistant Klebsiella pneumoniae has rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required for K. pneumoniae survival in the lung, amino acid biosynthesis genes were critical for infection in both immunosuppressed...
Clinical Therapeutics
Clinical TherapeuticsRandomized Noninferiority Trial of Cefoperazone-Sulbactam versus Cefepime in the Treatment of Hospital-Acquired and Healthcare-Associated PneumoniaCefoperazone, a third-generation cephamycin with broad-spectrum antibacterial activity and the ability to permeate bacterial cell membranes, is active against commonly encountered multidrug-resistant pathogens for hospital-acquired pneumonia (HAP) and health care-associated pneumonia (HCAP).
Editor's Pick Clinical TherapeuticsFirst-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis TreatmentThis first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily.
Clinical TherapeuticsLarger Dose Reductions of Vancomycin Required in Neonates with Patent Ductus Arteriosus Receiving Indomethacin versus IbuprofenIbuprofen and indomethacin are commonly used to induce ductus arteriosus closure in preterm neonates. Our group previously reported that ibuprofen decreased vancomycin clearance by 16%. In this study, we quantified the impact of indomethacin coadministration on vancomycin clearance by extending our vancomycin population pharmacokinetic model with a data set containing vancomycin concentrations measured in preterm neonates comedicated...
Pharmacology
PharmacologySequential Open-Label Study of the Safety, Tolerability, and Pharmacokinetic Interactions between Dihydroartemisinin-Piperaquine and Mefloquine in Healthy Thai AdultsArtemisinin-based combination therapies (ACTs) have contributed substantially to the global decline in Plasmodium falciparum morbidity and mortality, but resistance to artemisinins and their partner drugs is increasing in Southeast Asia, threatening malaria control. New antimalarial compounds will not be generally available soon.
PharmacologyPopulation Pharmacokinetic Analyses for Arbekacin after Administration of ME1100 Inhalation SolutionME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration.
PharmacologyTenofovir Plasma Concentration from Preexposure Prophylaxis at the Time of Potential HIV Exposure: a Population Pharmacokinetic Modeling and Simulation Study Involving Serodiscordant Couples in East AfricaThe Partners Demonstration Project was a prospective, open-label, implementation science-driven study of preexposure prophylaxis (PrEP) among heterosexual HIV serodiscordant couples in Kenya and Uganda. Adherence data were collected using the Medication Event Monitoring System (MEMS), and time of sexual activity was collected using the mobile phone short message service (SMS). Two plasma samples were collected at a single study visit....
PharmacologyPharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative InfectionsTebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract...
PharmacologyReappraisal of Linezolid Dosing in Renal Impairment To Improve SafetyLinezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy.
PharmacologyEvaluation of a Library of FDA-Approved Drugs for Their Ability To Potentiate Antibiotics against Multidrug-Resistant Gram-Negative PathogensThe Prestwick library was screened for antibacterial activity or “antibiotic resistance breaker” (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, the screen identified very few ARB hits, which were strain/drug specific.
PharmacologyEvaluation of the Synergy of Ceftazidime-Avibactam in Combination with Meropenem, Amikacin, Aztreonam, Colistin, or Fosfomycin against Well-Characterized Multidrug-Resistant Klebsiella pneumoniae and Pseudomonas aeruginosaMultidrug-resistant (MDR) Gram-negative organisms are a major health concern due to lack of effective therapy. Emergence of resistance to newer agents like ceftazidime-avibactam (CZA) further magnifies the problem. In this context, combination therapy of CZA with other antimicrobials may have potential in treating these pathogens. Unfortunately, there are limited data regarding these combinations.
PharmacologyPharmacokinetic/Pharmacodynamic Evaluation of Solithromycin against Streptococcus pneumoniae Using Data from a Neutropenic Murine Lung Infection ModelSolithromycin (CEM-101) is a novel fluoroketolide antimicrobial agent with activity against typical and atypical pathogens associated with community-acquired bacterial pneumonia. Using a neutropenic murine lung infection model, the objectives of this study were to identify the pharmacokinetic/pharmacodynamic (PK/PD) index most closely associated with efficacy and the magnitude of such indices associated with solithromycin efficacy...
PharmacologyGenomewide Association Study Confirming the Association of NAT2 with Susceptibility to Antituberculosis Drug-Induced Liver Injury in Thai PatientsAntituberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genomewide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients. This study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in...
Letters to the Editor
Letter to the EditorIn Vitro Activity of Levonadifloxacin (WCK 771) against Chlamydia pneumoniae
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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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Dr. Louis B. Rice, Editor in Chief
Commentary
Wild animals foraging in the human-influenced environment are colonized by bacteria with clinically important antibiotic resistance. The occurrence of such bacteria in wildlife is influenced by various biological, ecological, and geographical factors which have not yet been fully understood.