Minireview
MinireviewRole of Rifampin against Staphylococcal Biofilm Infections In Vitro, in Animal Models, and in Orthopedic-Device-Related InfectionsRifampin has been used as an agent in combination therapy in orthopedic device-related infections (ODRI) for almost three decades. The aim of this review is to provide data regarding the role of rifampin against biofilm infection in vitro, in animal models, and in clinical ODRI.
Chemistry; Biosynthesis
Chemistry; BiosynthesisLeishmanicidal Activity of Isoselenocyanate DerivativesConventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon.
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsInhibition of Protein Secretion in Escherichia coli and Sub-MIC Effects of Arylomycin AntibioticsAt sufficient concentrations, antibiotics effectively eradicate many bacterial infections. However, during therapy, bacteria are unavoidably exposed to lower antibiotic concentrations, and sub-MIC exposure can result in a wide variety of other effects, including the induction of virulence, which can complicate therapy, or horizontal gene transfer (HGT), which can accelerate the spread of resistance genes.
Mechanisms of Action: Physiological EffectsGenome Location Dictates the Transcriptional Response to PolC Inhibition in Clostridium difficileClostridium difficile is a potentially lethal gut pathogen that causes nosocomial and community-acquired infections. Limited treatment options and reports of reduced susceptibility to current treatment emphasize the necessity for novel antimicrobials.
Mechanisms of Action: Physiological EffectsExamination of Fluconazole-Induced Alopecia in an Animal Model and Human CohortFluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms.
Mechanisms of Action: Physiological EffectsThe Antibiotic Trimethoprim Displays Strong Mutagenic Synergy with 2-AminopurineWe show that trimethoprim (TMP), an antibiotic in current use, displays a strong synergistic effect on mutagenesis in Escherichia coli when paired with the base analog 2-aminopurine (2AP), resulting in a 35-fold increase in mutation frequencies in the rpoB-Rifr system. Combination therapies are often employed both as antibiotic treatments and in...
Mechanisms of Action: Physiological EffectsHost Cell Metabolism Contributes to Delayed-Death Kinetics of Apicoplast Inhibitors in Toxoplasma gondiiToxoplasma gondii and related human parasites contain an essential plastid organelle called the apicoplast. Clinically used antibiotics and other inhibitors that disrupt apicoplast biogenesis cause a mysterious “delayed-death” phenotype in which parasite growth is unaffected during the first lytic cycle of inhibitor treatment but is severely inhibited in the second...
Mechanisms of Resistance
Mechanisms of ResistanceIdentification of a Novel Gene Associated with High-Level β-Lactam Resistance in Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Strain Mu3 and Methicillin-Resistant S. aureus Strain N315β-Lactam resistance levels vary among methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, mediated by chromosomal mutations and exogenous resistance gene mecA. However, MRSA resistance mechanisms are incompletely understood.
Mechanisms of ResistanceMutations in cdsA and pgsA Correlate with Daptomycin Resistance in Streptococcus mitis and S. oralisWe investigated the ability of several recent clinical viridans group streptococci (VGS) bloodstream isolates (Streptococcus mitis/S. oralis subgroup) from daptomycin (DAP)-naive patients to develop DAP resistance in vitro. All strains rapidly developed high-level and stable DAP resistance...
Mechanisms of ResistanceMicrosatellite Typing and Resistance Mechanism Analysis of Voriconazole-Resistant Aspergillus flavus Isolates in South Korean HospitalsA recent surveillance study in South Korea revealed that 14% (7/50) of Aspergillus flavus clinical isolates had a voriconazole minimum inhibitory concentration of ≥4 μg/ml. Of seven non-wild-type (non-WT) isolates, six ear isolates from four hospitals shared the same microsatellite genotype.
Mechanisms of ResistanceComparative Genomics of Serial Candida glabrata Isolates and the Rapid Acquisition of Echinocandin Resistance during TherapyThe opportunistic pathogen Candida glabrata shows a concerning increase in drug resistance. Here, we present the analysis of two serial bloodstream isolates, obtained 12 days apart.
Mechanisms of ResistanceGenetic Mechanisms behind the Spread of Reduced Susceptibility to Azithromycin in Shigella Strains Isolated from Men Who Have Sex with Men in Québec, CanadaWe analyzed 254 Shigella species isolates collected in Québec, Canada, during 2013 and 2014. Overall, 23.6% of isolates showed reduced susceptibility to azithromycin (RSA) encoded by mphA (11.6%), ermB (1.7%), or both genes (86.7%).
Mechanisms of ResistanceTarget (MexB)- and Efflux-Based Mechanisms Decreasing the Effectiveness of the Efflux Pump Inhibitor D13-9001 in Pseudomonas aeruginosa PAO1: Uncovering a New Role for MexMN-OprM in Efflux of β-Lactams and a Novel Regulatory Circuit (MmnRS) Controlling MexMN ExpressionEfflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance.
Mechanisms of ResistanceMolecular Analysis of Linezolid-Resistant Clinical Isolates of Mycobacterium abscessusA total of 194 Mycobacterium abscessus isolates were collected from patients, and the whole genomes were sequenced. Eighty-five (43.8%) isolates showed linezolid (LZD) resistance.
Mechanisms of ResistanceERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in KuwaitCandida glabrata is intrinsically less susceptible to azoles, and resistance to echinocandins and reduced susceptibility (RS) to amphotericin B (AMB) have also been detected. The molecular mechanisms of RS to AMB were investigated in C. glabrata strains in Kuwait by sequence analyses of genes...
Editor's Pick Mechanisms of ResistanceGenetic and Transcriptomic Analyses of Ciprofloxacin-Tolerant Staphylococcus aureus Isolated by the Replica Plating Tolerance Isolation System (REPTIS)We developed a simple, efficient, and cost-effective method, named the replica plating tolerance isolation system (REPTIS), to detect the antibiotic tolerance potential of a bacterial strain. This method can also be used to quantify the antibiotic-tolerant subpopulation in a...
Mechanisms of ResistanceRole of the Hydrophobic Bridge in the Carbapenemase Activity of Class D β-LactamasesClass D carbapenemases are enzymes of the utmost clinical importance due to their ability to confer resistance to the last-resort carbapenem antibiotics. We investigated the role of the conserved hydrophobic bridge in the carbapenemase activity of OXA-23, the major carbapenemase of the important pathogen Acinetobacter baumannii.
Mechanisms of ResistanceRole of TEM-1 β-Lactamase in the Predominance of Ampicillin-Sulbactam-Nonsusceptible Escherichia coli in JapanWe investigated the epidemiology and resistance mechanisms of ampicillin-sulbactam-nonsusceptible Escherichia coli, focusing on the role of the TEM-1 β-lactamase. We collected all nonduplicate E. coli clinical isolates at 10 Japanese hospitals during December 2014 and examined their antimicrobial...
Susceptibility
SusceptibilityA Diagnostic Algorithm To Investigate Pyrazinamide and Ethambutol Resistance in Rifampin-Resistant Mycobacterium tuberculosis Isolates in a Low-Incidence SettingPhenotypic drug susceptibility testing (DST) for the two first-line tuberculosis drugs ethambutol and pyrazinamide is known to yield unreliable and inaccurate results. In this prospective study, we propose a diagnostic algorithm combining phenotypic DST with Sanger sequencing to inform clinical decision-making for drug-resistant Mycobacterium tuberculosis complex...
SusceptibilityIn Vivo Gentamicin Susceptibility Test for Prevention of Bacterial Biofilms in Bone Tissue and on ImplantsThe objective of this study was to set up an in vivo gentamicin susceptibility test for biofilm prevention in bone tissue and on implants. Twenty-five pigs were allocated to six groups.
SusceptibilityIn Vitro Activity of Omadacycline against Chlamydia pneumoniaeThe in vitro activities of omadacycline, azithromycin, doxycycline, moxifloxacin, and levofloxacin were tested against 15 isolates of Chlamydia pneumoniae. The minimum inhibitory concentration at which 90% of the isolates of C. pneumoniae were inhibited by omadacycline was 0.25 μg/ml (range...
SusceptibilityIn Vitro Susceptibility Testing of Bedaquiline against Mycobacterium abscessus ComplexWe performed bedaquiline broth microdilution susceptibility testing using Clinical and Laboratory Standards Institute (CLSI) guidelines on 104 nonduplicate isolates of Mycobacterium abscessus complex [M. abscessus subsp. abscessus...
Analytical Procedures
Analytical ProceduresUsefulness of Serial Blood Sampling and PCR Replicates for Treatment Monitoring of Patients with Chronic Chagas DiseaseThis work evaluated a serial blood sampling procedure to enhance the sensitivity of duplex real-time quantitative PCR (qPCR) for baseline detection and quantification of parasitic loads and posttreatment identification of failure in the context of clinical trials for treatment of chronic Chagas disease, namely, DNDi-CH-E1224-001 (ClinicalTrials.gov registration no. NCT01489228) and the MSF-DNDi PCR Sampling Optimization Study (...
Antiviral Agents
Antiviral AgentsDrug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-AmodiaquineAcross sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and...
Antiviral AgentsBeyond Members of the Flaviviridae Family, Sofosbuvir Also Inhibits Chikungunya Virus ReplicationChikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed.
Editor's Pick Antiviral AgentsInhibitors of Signaling Pathways That Block Reversal of HIV-1 LatencySignaling pathways play a key role in HIV-1 latency. In this study, we used the 24ST1NLESG cell line of HIV-1 latency to screen a library of structurally diverse, medicinally active, cell permeable kinase inhibitors, which target a wide range of signaling pathways, to identify inhibitors of HIV-1 latency reversal.
Epidemiology and Surveillance
Editor's Pick Epidemiology and SurveillancePatients at Risk for Aortic Rupture Often Exposed to Fluoroquinolones during HospitalizationSeveral studies have indicated that fluoroquinolone use may be associated with an increased risk of aortic aneurysm or dissection (AAD). Because patients with AAD or Marfan syndrome are at increased risk for aortic rupture, we performed a retrospective cohort study to determine the prevalence of systemic fluoroquinolone exposure and predictors of fluoroquinolone use in these patients.
Epidemiology and SurveillanceEmergence of Resistance to Quinolones and β-Lactam Antibiotics in Enteroaggregative and Enterotoxigenic Escherichia coli Causing Traveler’s DiarrheaThe objective of this study was to assess the antimicrobial resistance of enteroaggregative Escherichia coli (EAEC) and enterotoxigenic E. coli (ETEC) strains causing traveler’s diarrhea (TD) and to investigate the molecular characterization of antimicrobial resistance genes to third-generation...
Epidemiology and SurveillanceAntibiotic Resistance of Campylobacter Species in a Pediatric Cohort StudyThe objective of this study was to determine the phenotypic patterns of antibiotic resistance and the epidemiology of drug-resistant Campylobacter spp. from a low-resource setting.
Epidemiology and SurveillanceDiverse Vectors and Mechanisms Spread New Delhi Metallo-β-Lactamases among Carbapenem-Resistant Enterobacteriaceae in the Greater Boston AreaNew Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized.
Experimental Therapeutics
Experimental TherapeuticsHigh-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model of Mycobacterium ulcerans DiseaseBuruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR).
Experimental TherapeuticsMonitoring of Fluconazole and Caspofungin Activity against In Vivo Candida glabrata Biofilms by Bioluminescence ImagingCandida glabrata can attach to various medical implants and forms thick biofilms despite its inability to switch from yeast to hyphae. The current in vivo C. glabrata biofilm models only provide limited information about colonization and infection and usually require animal sacrifice.
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Experimental TherapeuticsAPX001 Is Effective in the Treatment of Murine Invasive Pulmonary AspergillosisInvasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high, and new treatments are needed.
Experimental TherapeuticsAPX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis PneumoniaCoccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis and C. posadasii, that are endemic in the southwestern United States and other areas in the Western Hemisphere. Chronic cavitary...
Experimental TherapeuticsIn Vivo Applicability of Neosartorya fischeri Antifungal Protein 2 (NFAP2) in Treatment of Vulvovaginal CandidiasisAs a consequence of emerging numbers of vulvovaginitis cases caused by azole-resistant and biofilm-forming Candida species, fast and efficient treatment of this infection has become challenging. The problem is further exacerbated by the severe side effects of azoles as long-term-use medications in the recurrent form.
Experimental TherapeuticsA Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosisMycobacterium tuberculosis, the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug-resistant strains has become a major challenge for health care systems and, in some cases, has rendered TB untreatable.
Experimental TherapeuticsOptimal Piperacillin-Tazobactam Dosing Strategies against Extended-Spectrum-β-Lactamase-Producing EnterobacteriaceaePiperacillin-tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae. However, limited understanding of optimal dosing strategies for this combination may curtail its utility.
Experimental TherapeuticsImpact of Antifungal Compounds on Viability and Anti-Aspergillus Activity of Human Natural Killer CellsDespite the availability of new antifungal compounds, invasive aspergillosis carries high morbidity and mortality in hematopoietic stem cell transplant recipients. In vitro studies and animal models suggest that the adoptive transfer of natural killer (NK) cells might be a promising immunotherapeutic option in this setting.
Clinical Therapeutics
Clinical TherapeuticsModeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in UgandaDihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing.
Clinical TherapeuticsAntibiotics Stimulate Formation of Vesicles in Staphylococcus aureus in both Phage-Dependent and -Independent Fashions and via Different RoutesBacterial membrane vesicle research has so far focused mainly on Gram-negative bacteria. Only recently have Gram-positive bacteria been demonstrated to produce and release extracellular membrane vesicles (MVs) that contribute to bacterial virulence.
Editor's Pick Clinical TherapeuticsA Hypothesis-Generating Study of the Combination of Aspirin plus Macrolides in Patients with Severe Community-Acquired PneumoniaWhile the inflammatory response to severe pneumonia is paramount in limiting and resolving the infection, excessive inflammation can lead to deleterious effects. We theorized that patients with severe community-acquired pneumonia (CAP) who were treated with macrolides and aspirin would receive benefit beyond that of conventional antibiotic therapy.
Clinical TherapeuticsOmadacycline Gut Microbiome Exposure Does Not Induce Clostridium difficile Proliferation or Toxin Production in a Model That Simulates the Proximal, Medial, and Distal Human ColonA clinically reflective model of the human colon was used to investigate the effects of the broad-spectrum antibiotic omadacycline on the gut microbiome and the subsequent potential to induce simulated Clostridium difficile infection (CDI). Triple-stage chemostat gut models were inoculated with pooled human fecal slurry from healthy volunteers (age, ≥60 years).
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Clinical TherapeuticsCarbapenem versus Cefepime or Piperacillin-Tazobactam for Empiric Treatment of Bacteremia Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli in Patients with Hematologic MalignancyInfections with extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli are common in patients with hematologic malignancy. The utility of cefepime and piperacillin-tazobactam as empiric therapy for ESBL-producing E. coli bacteremia in patients with hematologic malignancy is largely unknown...
Clinical TherapeuticsPreexposure to Isavuconazole Increases the Virulence of Mucorales but Not Aspergillus fumigatus in a Drosophila melanogaster Infection ModelBreakthrough mucormycosis in patients receiving isavuconazole prophylaxis or therapy has been reported. We compared the impact of isavuconazole and voriconazole exposure on the virulence of clinical isolates of Aspergillus fumigatus and different Mucorales species in a Drosophila melanogaster...
Clinical TherapeuticsPopulation Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile InfectionThe fully human monoclonal antibody bezlotoxumab is indicated for preventing the recurrence of Clostridioides difficile (formerly Clostridium difficile) infection (CDI) in adults who receive antibacterial treatment for CDI and who are at high risk for a CDI recurrence. The efficacy and safety of 10-...
Editor's Pick Clinical TherapeuticsComparative Activity of Ceftriaxone, Ciprofloxacin, and Gentamicin as a Function of Bacterial Growth Rate Probed by Escherichia coli Chromosome Replication in the Mouse Peritonitis ModelCommonly used antibiotics exert their effects predominantly on rapidly growing bacterial cells; yet, the growth dynamics taking place during infection in a complex host environment remain largely unknown. Hence, a means to measure in situ bacterial growth rate is essential to predict the outcome of antibacterial treatment.
Clinical TherapeuticsA Case-Control Study of Real-Life Experience with Ceftolozane-Tazobactam in Patients with Hematologic Malignancy and Pseudomonas aeruginosa InfectionWe present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam. We performed a single-center case-control study comparing patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (...
Pharmacology
PharmacologyEfficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection ModelHerein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and...
PharmacologyPopulation Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in GabonMefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and the metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women.
PharmacologyEvaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosisMulti- and extensively drug-resistant tuberculosis (M/XDR-TB) has become an increasing threat not only in countries where the TB burden is high but also in affluent regions, due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of Mycobacterium tuberculosis.
PharmacologyPharmacodynamics of Minocycline against Acinetobacter baumannii in a Rat Pneumonia ModelMinocycline is currently approved in the United States for the treatment of infections caused by susceptible isolates of Acinetobacter spp. The objective of these studies was to determine the minocycline exposures associated with an antibacterial effect against Acinetobacter baumannii in a rat pneumonia model.
PharmacologyPopulation Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffeiAmphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment of talaromycosis. However, little is known about the population pharmacokinetics and pharmacodynamics of DAmB for talaromycosis.
PharmacologyHigh-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus VentriculitisA patient received continuous infusion of cefazolin 10 g then 8 g daily for an external ventricular drainage-related methicillin-susceptible Staphylococcus aureus (MSSA) ventriculitis. Median free concentrations in the cerebrospinal fluid were 11.9 and 6.1 mg/liter after 10- and 8-g doses, respectively.
PharmacologyIs One Sample Enough? β-Lactam Target Attainment and Penetration into Epithelial Lining Fluid Based on Multiple Bronchoalveolar Lavage Sampling Time Points in a Swine Pneumonia ModelDescribing the disposition of antimicrobial agents at the site of infection is crucial to guide optimal dosing for investigational agents. For antibiotics in development for the treatment of nosocomial pneumonia, concentrations in the epithelial lining fluid (ELF) of the lung are frequently determined from a bronchoscopy at a single time point.
PharmacologyMulticenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement TherapyIntravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear.
![SCY-078, a Novel Fungicidal Agent, Demonstrates Distribution to Tissues Associated with Fungal Infections during Mass Balance Studies with Intravenous and Oral [<sup>14</sup>C]SCY-078 in Albino and Pigmented Rats](https://aac.asm.org/sites/default/files/styles/thumbnail/public/externals/61555423f7506be51698d50d6ddc1042.jpg?itok=9mDuLQb_)
PharmacologySCY-078, a Novel Fungicidal Agent, Demonstrates Distribution to Tissues Associated with Fungal Infections during Mass Balance Studies with Intravenous and Oral [14C]SCY-078 in Albino and Pigmented RatsSCY-078, a fungicidal β-1,3-glucan synthesis inhibitor administered as intravenous or oral [14C]SCY-078 to rats, was distributed primarily into tissues associated with invasive fungal disease (kidney, lung, liver, spleen, bone marrow, muscle, vaginal tissue, and skin) to levels exceeding those in plasma. Oral fraction absorbed was ∼40%.
PharmacologyPopulation Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young InfantsAmoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice.
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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