Editorial
Challenging Clinical Cases in Antimicrobial Resistance
Editor's Pick Challenging Clinical Case in Antimicrobial ResistanceBacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosaWe documented the adjunctive bacteriophage therapy to treat a chronic relapsing periprosthetic joint infection of the knee and chronic osteomyelitis of the femur caused by multidrug-resistant Pseudomonas aeruginosa. The combined antibiotic-phage treatment eradicated the infection, and no side effects to phages were observed.
Editor's Pick Challenging Clinical Case in Antimicrobial ResistanceSuccessful Systemic and Topical Treatment of Mycobacterium abscessus OtomastoiditisMycobacterium abscessus is an extensively drug-resistant opportunistic pathogen that can cause chronic otomastoiditis. There are no evidence-based treatment regimens for this severe infection. We treated four children with M. abscessus otomastoiditis with a structured regimen of topical imipenem and...
Editor's Pick Challenging Clinical Case in Antimicrobial ResistanceA Dutch Case Report of Successful Treatment of Chronic Relapsing Urinary Tract Infection with Bacteriophages in a Renal Transplant PatientWe report a case of a 58-year-old renal transplant patient who developed a recurrent urinary tract infection with an extended-spectrum β-lactamase (ESBL)-positive Klebsiella pneumoniae strain in the first month posttransplant. Even though it tested susceptible to carbapenems and despite repeated meropenem treatment, his infection recurred. The infection eventually...
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsDAV131A Protects Hamsters from Lethal Clostridioides difficile Infection Induced by FluoroquinolonesFluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone...
Mechanisms of Action: Physiological EffectsInfluence of the α-Methoxy Group on the Reaction of Temocillin with Pseudomonas aeruginosa PBP3 and CTX-M-14 β-LactamaseThe prevalence of multidrug-resistant Pseudomonas aeruginosa has led to the reexamination of older “forgotten” drugs, such as temocillin, for their ability to combat resistant microbes. Temocillin is the 6-α-methoxy analogue of ticarcillin, a carboxypenicillin with well-characterized antipseudomonal properties. The α-methoxy modification confers resistance to serine β...
Mechanisms of Action: Physiological EffectsMetabolomics Study of the Synergistic Killing of Polymyxin B in Combination with Amikacin against Polymyxin-Susceptible and -Resistant Pseudomonas aeruginosaIn the present study, we employed untargeted metabolomics to investigate the synergistic killing mechanism of polymyxin B in combination with an aminoglycoside, amikacin, against a polymyxin-susceptible isolate of Pseudomonas aeruginosa, FADDI-PA111 (MIC = 2 mg/liter for both polymyxin B and amikacin), and a polymyxin-resistant Liverpool epidemic strain (LES), LESB58...
Mechanisms of Action: Physiological EffectsAntifungal Activity of Mammalian Serum Amyloid A1 against Candida albicansMammalian serum amyloid A (SAA) is a major acute phase protein that shows a massive increase in plasma concentration during inflammation. In the present study, we demonstrate that the expression of mouse SAA1 in serum was increased when infected with Candida albicans, a major human fungal pathogen, in a systemic infection model. We then set out to investigate the...
Mechanisms of Resistance
Mechanisms of ResistanceGenomic and Metabolomic Polymorphism among Experimentally Selected Paromomycin-Resistant Leishmania donovani StrainsUnderstanding the mechanism(s) underpinning drug resistance could lead to novel treatments to reverse the increased tolerance of a pathogen. In this study, paromomycin (PMM) resistance (PMMr) was induced in three Nepalese clinical strains of Leishmania donovani with different inherent susceptibilities to antimony (Sb) drugs by stepwise exposure of...
Mechanisms of Resistancecfr(B), cfr(C), and a New cfr-Like Gene, cfr(E), in Clostridium difficile Strains Recovered across Latin AmericaCfr is a radical S-adenosyl-l-methionine (SAM) enzyme that confers cross-resistance to antibiotics targeting the 23S rRNA through hypermethylation of nucleotide A2503. Three cfr-like genes implicated in antibiotic resistance have been described, two of which, cfr(B) and cfr(C), have been sporadically detected in ...
Editor's Pick Mechanisms of ResistanceCapturing the Resistome: a Targeted Capture Method To Reveal Antibiotic Resistance Determinants in MetagenomesIdentification of the nucleotide sequences encoding antibiotic resistance elements and determination of their association with antibiotic resistance are critical to improve surveillance and monitor trends in antibiotic resistance. Current methods to study antibiotic resistance in various environments rely on extensive deep sequencing or laborious culturing of fastidious organisms, both of which are heavily time-consuming operations....
Mechanisms of ResistanceNovel Plasmid-Mediated tet(X5) Gene Conferring Resistance to Tigecycline, Eravacycline, and Omadacycline in a Clinical Acinetobacter baumannii IsolateA novel, plasmid-mediated, high-level tigecycline resistance tet(X) gene variant, tet(X5), was detected in a clinical Acinetobacter baumannii isolate from China in 2017. Tet(X5) shows 84.5% and 90.5% amino acid identity to Tet(X3) and Tet(X4), respectively, with similar binding sites and a comparable affinity for tetracyclines. The tet(X5)-...
Mechanisms of ResistanceHigh-Level Carbapenem Resistance in OXA-232-Producing Raoultella ornithinolytica Triggered by Ertapenem TherapyOXA-232 is an OXA-48-group class D β-lactamase that hydrolyzes expanded-spectrum cephalosporins and carbapenems at low levels. Clinical strains producing OXA-232 are sometimes susceptible to carbapenems, making it difficult to identify them in the clinical microbiology laboratory.
Mechanisms of ResistanceEvaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in Candida SpeciesManogepix (MGX) targets the conserved fungal Gwt1 enzyme required for acylation of inositol early in the glycosylphosphatidylinositol biosynthesis pathway. The prodrug fosmanogepix is currently in clinical development for the treatment of invasive fungal infections.
Editor's Pick Mechanisms of ResistanceMutations Reducing In Vitro Susceptibility to Novel LpxC Inhibitors in Pseudomonas aeruginosa and Interplay of Efflux and Nonefflux MechanismsUpregulated expression of efflux pumps, lpxC target mutations, LpxC protein overexpression, and mutations in fabG were previously shown to mediate single-step resistance to the LpxC inhibitor CHIR-090 in P. aeruginosa. Single-step selection experiments using three recently described LpxC inhibitors (compounds 2, 3, and 4) and mutant characterization...
Mechanisms of ResistanceRegulation and Anaerobic Function of the Clostridioides difficile β-LactamaseClostridioides difficile causes severe antibiotic-associated diarrhea and colitis. C. difficile is an anaerobic, Gram-positive sporeformer that is highly resistant to β-lactams, the most commonly prescribed antibiotics. The resistance of...
Mechanisms of ResistanceModification of pfap2μ and pfubp1 Markedly Reduces Ring-Stage Susceptibility of Plasmodium falciparum to Artemisinin In VitroManagement of uncomplicated malaria worldwide is threatened by the emergence in Asia of Plasmodium falciparum carrying variants of the pfk13 locus and exhibiting reduced susceptibility to artemisinin. Mutations in two other genes, ubp1 and ap2μ, are associated with artemisinin resistance in rodent malaria and with clinical failure of...
Mechanisms of ResistanceA Loop-Mediated Isothermal Amplification Assay Targeting Neisseria gonorrhoeae penA-60.001Ceftriaxone (CRO) is widely used as the first-line treatment for gonococcal infections. However, CRO-resistant Neisseria gonorrhoeae strains carrying mosaic penA-60.001 have emerged recently and disseminated worldwide. To meet the urgent need to detect these strains, we report here a loop-mediated isothermal amplification (LAMP) assay system that targets...
Mechanisms of ResistanceThe Transcriptional Repressor SmvR Is Important for Decreased Chlorhexidine Susceptibility in Enterobacter cloacae ComplexMajor facilitator superfamily (MFS) efflux pumps have been shown to be important for bacterial cells to cope with biocides such as chlorhexidine (CHX), a widely used molecule in hospital settings. In this work, we evaluated the role of two genes, smvA and smvR, in CHX resistance in Enterobacter cloacae complex (ECC). smvA encodes an MFS pump...
Mechanisms of ResistanceThe Sle1 Cell Wall Amidase Is Essential for β-Lactam Resistance in Community-Acquired Methicillin-Resistant Staphylococcus aureus USA300Most clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) strains have become resistant to β-lactams antibiotics through horizontal acquisition of the mecA gene encoding PBP2a, a peptidoglycan transpeptidase with low affinity for β-lactams. The level of resistance conferred by mecA is, however, strain dependent, and the mechanisms...
Mechanisms of ResistanceImprovement of the Immunochromatographic NG-Test Carba 5 Assay for the Detection of IMP Variants Previously UndetectedHere, we evaluated the immunochromatographic assay NG-Test Carba 5v2 (NG-Biotech), with improved IMP variant detection on 31 IMP producers, representing the different branches of the IMP phylogeny, including 32 OXA-48, 19 KPC, 12 VIM, 14 NDM, and 13 multiple carbapenemase producers (CPs), 13 CPs that were not targeted, and 13 carbapenemase-negative isolates. All tested IMP variants were accurately detected without impairing detection of...
Susceptibility
SusceptibilityNew Antifungal Susceptibility Test Based on Chitin Detection by Image CytometryThe antifungal susceptibility tests used in clinical laboratories have several limitations. We developed a new test, SensiFONG, based on the detection of chitin levels after exposure to antifungal drugs. The optimal culture conditions were 30°C for 6 h for yeast strains and 26°C for 16 h for molds. The strains were exposed to a range of echinocandin or azole concentrations. Chitin was stained with calcofluor white.
SusceptibilitySusceptibility of Methicillin-Resistant Staphylococcus aureus to Five Quinazolinone AntibacterialsThe in vitro activities of five quinazolinone antibacterials, compounds Q1 to Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (in μg/ml) were as follows: Q1, 0.5/2; Q2, 1/4; Q3, 2/4; Q4, 0.06/0.25; and Q5, 0.125/0.5.
SusceptibilityPyomelanin Secretion in Madurella mycetomatis Interferes with Spectrophotometric Endpoint Reading Using the Sensititre YeastOne alamarBlue Assay but Not with Visual Endpoint ReadingThe use of the Sensititre YeastOne YO10 alamarBlue assay for the in vitro susceptibility testing of Madurella mycetomatis was evaluated in M. mycetomatis isolates with and without pyomelanin secretion. Pyomelanin secretion did not influence visual endpoint reading; however, it caused a shift in peak absorbance from 570 nm to 620 nm when read...
SusceptibilityActivity of Meropenem with a Novel Broader-Spectrum β-Lactamase Inhibitor, WCK 4234, against Gram-Negative Pathogens Endemic to New York CityWCK 4234 is a novel diazabicyclooctane with potent inhibitory activity against class A and D carbapenemases and class C enzymes. We examined the in vitro activity of meropenem plus WCK 4234 (4 or 8 μg/ml) against Gram-negative pathogens from New York City. Three groups of isolates were analyzed: a contemporary collection of isolates, a collection of known carbapenem-resistant isolates, and a collection of isolates with defined...
SusceptibilityComparable In Vitro Activities of Second-Generation HIV-1 Integrase Strand Transfer Inhibitors (INSTIs) on HIV-1 Clinical Isolates with INSTI Resistance MutationsSecond-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG).
Biologic Response Modifiers
Biologic Response ModifiersQuinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction SystemThe rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that...
Antiviral Agents
Antiviral AgentsAnti-inflammatory Compound Shows Therapeutic Safety and Efficacy against Flavivirus InfectionFlaviviruses comprise several medically important viruses, including Japanese encephalitis virus, West Nile virus, dengue virus (DENV), yellow fever virus, and Zika virus (ZIKV). A large outbreak of DENV and ZIKV occurred recently, leading to many cases of illness and death. However, despite decades of effort, we have no clinically specific therapeutic drugs against DENV and ZIKV. Previous studies showed that inflammatory responses play...
Antiviral AgentsGriffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126Griffithsin (Grft) is an antiviral lectin that has been shown to potently inhibit HIV-1 by binding high-mannose N-linked glycosylation sites on HIV-1 gp120. A key factor for Grft potency is glycosylation at N295 of gp120, which is directly adjacent to N332, a target glycan for an entire class of broadly neutralizing antibodies (bNAbs).
Antiviral AgentsA New Role for Capsid Assembly Modulators To Target Mature Hepatitis B Virus Capsids and Prevent Virus InfectionHepatitis B virus (HBV) is a major human pathogen, killing an estimated 887,000 people per year. Therefore, potentially curative therapies are of high importance. Following infection, HBV deposits a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that serves as a transcription template and is not affected by current therapies. HBV core protein allosteric modulators (CpAMs) prevent correct capsid assembly but may...
Antiviral AgentsPolymerase Activity, Protein-Protein Interaction, and Cellular Localization of the Usutu Virus NS5 ProteinUsutu virus (USUV) has become increasingly relevant in recent years, with large outbreaks that sporadically have affected humans being reported in wildlife. Similarly to the rest of flaviviruses, USUV contains a positive-sense single-stranded RNA genome which is replicated by the activity of nonstructural protein 5 (NS5). USUV NS5 shows high sequence identity with the remaining viruses in this genus.
Antiviral AgentsA First-in-Human Trial of GLS4, a Novel Inhibitor of Hepatitis B Virus Capsid Assembly, following Single- and Multiple-Ascending-Oral-Dose Studies with or without Ritonavir in Healthy Adult VolunteersGLS4 is a novel inhibitor of the hepatitis B virus (HBV) capsid assembly with inhibitory activities against nucleot(s)ide-resistant HBV strains. This study investigated the pharmacokinetics, safety, and tolerability of GLS4 and the effects of food and ritonavir in healthy adults. GLS4 was administered in a single-ascending-dose study over 1 to 240 mg and multiple-ascending-dose study that ranged from 30 mg once daily to 180 mg three...
Antiviral AgentsReciprocal Modulation of Antiretroviral Drug and Steroid Receptor Function In VitroMillions of women are exposed simultaneously to antiretroviral drugs (ARVs) and progestin-based hormonal contraceptives. Yet the reciprocal modulation by ARVs and progestins of their intracellular functions is relatively unexplored.
Epidemiology and Surveillance
Epidemiology and SurveillanceImproved Antibiotic Prescribing within a Veterans Affairs Primary Care System through a Multifaceted Intervention Centered on Peer Comparison of Overall Antibiotic Prescribing RatesReducing inappropriate outpatient antibiotic use is an important national goal. Limited data exist on targeted education and peer comparison of overall antibiotic prescribing rates as an antimicrobial stewardship strategy. Primary care professionals (PCPs) from all seven clinics within our health care system were offered an education session, followed by monthly e-mails with their antibiotic prescribing rate, peer prescribing rates, and...
Epidemiology and SurveillanceA Prospective Cohort Study of Durations of Staphylococcus aureus Bacteremia According to Different Phenotypes and a New Concept of Persistent BacteremiaThe purpose of this study was to describe and compare the duration of Staphylococcus aureus bacteremia (SAB) according to methicillin resistance and the primary foci of infection. We also aimed to newly define persistent SAB considering these results. Nonduplicated episodes of SAB in patients aged ≥15 years from 14 hospitals in the Republic of Korea were analyzed...
Epidemiology and SurveillanceEmergence of an NDM-5-Producing Hypervirulent Klebsiella pneumoniae Sequence Type 35 Strain with Chromosomal Integration of an Integrative and Conjugative Element, ICEKp1Here, we report an NDM-5-producing sequence type 35 (ST35) hypervirulent Klebsiella pneumoniae strain, isolated from the blood of a male patient. It showed a remarkable resistance to serum killing and neutrophil phagocytosis and high virulence in a mouse peritonitis infection model.
Epidemiology and SurveillanceA Systematic Review and Meta-analysis of the Prevalence of Community-Onset Bloodstream Infections among Hospitalized Patients in Africa and AsiaCommunity-onset bloodstream infections (CO-BSI) are major causes of severe febrile illness and death worldwide. In light of new data and the growing problem of antimicrobial resistance (AMR) among pathogens causing BSI, we undertook a systematic review of hospital-based studies of CO-BSI among patients hospitalized with fever.
Experimental Therapeutics
Experimental TherapeuticsMultiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut MicrobiotaCRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial.
Experimental TherapeuticsPharmacodynamics of ClpP-Activating Antibiotic Combinations against Gram-Positive PathogensIt is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides (ADEPs) are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including staphylococci, streptococci, and...
Experimental TherapeuticsTHP-1 and Dictyostelium Infection Models for Screening and Characterization of Anti-Mycobacterium abscessus Hit Compounds!!NCR1!! presents a great challenge to antimycobacterial therapy due to its innate resistance against most antibiotics. M. abscessus is able to grow intracellularly in human macrophages, suggesting that intracellular models can facilitate drug discovery. Thus, we have developed two host cell models: human macrophages for use in a new high-content screening...
Experimental TherapeuticsNitroxide Functionalized Antibiotics Are Promising Eradication Agents against Staphylococcus aureus BiofilmsTreatment of biofilm-related Staphylococcus aureus infections represents an important medical challenge worldwide, as biofilms, even those involving drug-susceptible S. aureus strains, are highly refractory to conventional antibiotic therapy. Nitroxides were recently shown to induce the dispersal of...
Experimental TherapeuticsCarbapenem-Containing Combination Antibiotic Therapy against Carbapenem-Resistant Uropathogenic EnterobacteriaceaeThe increasing global prevalence of carbapenem-resistant Enterobacteriaceae (CRE) combined with the decline in effective therapies is a public health care crisis. After respiratory tract infections, urinary tract infections and associated urosepsis are the second most affected by CRE pathogens.
Experimental TherapeuticsGalactomannan Is a Biomarker of Fosmanogepix (APX001) Efficacy in Treating Experimental Invasive Pulmonary AspergillosisGalactomannan (GM) detection in biological samples has been shown to predict therapeutic response by azoles and polyenes. In a murine invasive pulmonary aspergillosis model, fosmanogepix or posaconazole treatment resulted in an ∼6- to 7-log reduction in conidial equivalents (CE)/g lung tissue after 96 h versus placebo.
Clinical Therapeutics
Clinical TherapeuticsIntracellular Pharmacodynamic Modeling Is Predictive of the Clinical Activity of Fluoroquinolones against TuberculosisClinical studies of new antitubercular drugs are costly and time-consuming. Owing to the extensive tuberculosis (TB) treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of preclinical models in predicting the activity of fluoroquinolones underline the importance of developing new and more robust predictive tools that...
Clinical TherapeuticsActivity of Hospital Disinfectants against Vegetative Cells and Spores of Clostridioides difficile Embedded in BiofilmsClostridioides difficile spores can survive in the environment in either mono- or mixed-species biofilms. However, no previous studies have investigated chemical disinfection of C. difficile spores embedded in biofilms. Thus, the purpose of this study was to assess the in vitro...
Clinical TherapeuticsMinimal Cerebrospinal Fluid Concentration of Miltefosine despite Therapeutic Plasma Levels during the Treatment of Amebic EncephalitisMiltefosine is an alkylphosphocholine compound that is used primarily for treatment of leishmaniasis and demonstrates in vitro and in vivo antiamebic activity against Acanthamoeba species. Recommendations for treatment of amebic encephalitis generally include miltefosine therapy. Data indicate that treatment with an amebicidal concentration of at least 16 μg/ml of miltefosine is required for most ...
Clinical TherapeuticsA Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy VolunteersArtefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum...
Clinical TherapeuticsTarget-Controlled Infusion of Cefepime in Critically Ill PatientsAttainment of appropriate pharmacokinetic-pharmacodynamic (PK-PD) targets for antimicrobial treatment is challenging in critically ill patients, particularly for cefepime, which exhibits a relative narrow therapeutic-toxic window compared to other beta-lactam antibiotics. Target-controlled infusion (TCI) systems, which deliver drugs to achieve specific target drug concentrations, have successfully been implemented for improved dosing of...
Clinical TherapeuticsIn Vitro Activities of β-Lactam–β-Lactamase Inhibitor Antimicrobial Agents against Cystic Fibrosis Respiratory PathogensWe tested the in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, piperacillin-tazobactam, and 11 other antimicrobial agents against 420 Burkholderia, Achromobacter, Stenotrophomonas, and Pandoraea strains, 89% of which were cultured from respiratory specimens from persons with cystic fibrosis.
Clinical TherapeuticsIntermittent Treatment with Azithromycin and Ethambutol for Noncavitary Mycobacterium avium Complex Pulmonary DiseaseWe evaluated the efficacy of intermittent azithromycin and ethambutol therapy for noncavitary Mycobacterium avium complex pulmonary disease (MAC-PD). Twenty-nine (76%) of 38 patients achieved sputum culture conversion after 12 months of treatment, and sputum smear positivity was an independent factor for failure to achieve culture conversion (adjusted odds ratio, 26.7...
Pharmacology
PharmacologyAntiretroviral Penetration across Three Preclinical Animal Models and Humans in Eight Putative HIV Viral ReservoirsFor HIV cure strategies like “kick and kill” to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of six ARVs in three preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some, but not all, ARVs.
PharmacologyA Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous HemodiafiltrationThe aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and...
PharmacologyMeropenem-Tobramycin Combination Regimens Combat Carbapenem-Resistant Pseudomonas aeruginosa in the Hollow-Fiber Infection Model Simulating Augmented Renal Clearance in Critically Ill PatientsAugmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance amplification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates...
PharmacologyEfficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection ModelCefiderocol is a siderophore-cephalosporin conjugate with greater in vitro potency under iron-depleted conditions. During infection, iron is scarce in host tissue; however, it is not known whether iron overload in the host, such as in cases of hereditary hemochromatosis, alters the efficacy of cefiderocol. We compared cefiderocol efficacy between iron-overloaded and standard murine thigh infection models.
PharmacologyPharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary ExacerbationAdults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in...
PharmacologyDevelopment of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic ConjugatesSiderophore-antibiotic conjugates have increased in vitro activity in low-iron environments where bacteria express siderophores and associated transporters. The host immune hypoferremic response reduces iron availability to bacteria; however, patients with iron overload or deficiency may have altered ability to restrict iron, which may affect the efficacy of siderophore-antibiotic conjugates. In vivo models of...
Letters to the Editor
Letter to the EditorAzithromycin Phenotypic versus Clinical Resistance
Letter to the EditorReply to Edelstein, “Azithromycin Phenotypic versus Clinical 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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Commentaries
We highlight features associated with bacteriophage therapy that make it an attractive treatment option for multidrug-resistant infections and also discuss some of the challenges that need to be considered in the design and execution of clinical trials directed at evaluating the efficacy of bacteriophage therapy in humans.
Pediatric otomastoiditis due to Mycobacterium abscessus can be a devastating infection that presents multiple treatment challenges. Van Wijk et al. report the use of a structured approach with a standardized regimen of intravenous (i.v.), topical, and oral antibiotics and surgical intervention for four pediatric patients with multidrug-resistant...
While resistance to antibacterial drugs is increasing globally, it is unevenly distributed. The number of cases that are truly difficult to treat remain below the number required to drive an adequate market for needed new therapies. Without a sufficient market, companies pursuing these drugs risk financial failure. Here, I explore, at least briefly, the current situation and the financial risks to companies. I provide potential...