Minireviews
MinireviewDrug Development against Smallpox: Present and FutureForty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years, the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus de novo,...
MinireviewConsiderations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-AvibactamAn extensive clinical development program (comprising two phase 2 and five phase 3 trials) has demonstrated the efficacy and safety of ceftazidime-avibactam in the treatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). During the phase 3 clinical program, updated population pharmacokinetic (...
Challenging Clinical Cases in Antimicrobial Resistance
Challenging Clinical Case in Antimicrobial ResistanceCase Commentary: the Need for Cefiderocol Is Clear, but Are the Supporting Clinical Data?Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded in vitro activity against multidrug-resistant Gram-negative bacteria. In two challenging cases reported here, cefiderocol shows potential utility as salvage therapy against difficult-to-treat pathogens with limited or no treatment options; however, two multicenter, randomized clinical trials have yielded mixed results among cefiderocol-treated...
Challenging Clinical Case in Antimicrobial ResistanceCoinfections of Two Strains of NDM-1- and OXA-232-Coproducing Klebsiella pneumoniae in a Kidney Transplant PatientWe report here a fatal case of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in a renal transplant patient without a travel history in the prior year, from whom 2 genetically different CRKP (sequence type 14 [ST14] and ST2497) strains carrying the same plasmids and antimicrobial resistance genes, including blaNDM-1, bla...
Challenging Clinical Case in Antimicrobial ResistanceLong-Term Compassionate Use of Cefiderocol To Treat Chronic Osteomyelitis Caused by Extensively Drug-Resistant Pseudomonas aeruginosa and Extended-Spectrum-β-Lactamase-Producing Klebsiella pneumoniae in a Pediatric PatientWe report a 15 year-old Nigerian adolescent male with chronic osteomyelitis caused by an extensively drug-resistant (XDR) Pseudomonas aeruginosa strain of sequence type 773 (ST773) carrying blaNDM-1 and an extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae...
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsNew Evidence and Insights on Dalbavancin and Wound Healing in a Mouse Model of Skin InfectionDalbavancin is an effective antibiotic that is widely used to treat skin infection. Our aim was to determine the effect of dalbavancin administration on wound healing compared to that of vancomycin and to elucidate if epidermal growth factor receptor (EGFR), matrix metalloproteinase 1 (MMP-1), MMP-9, and vascular endothelial growth factor (VEGF) could be involved in its therapeutic mechanism. A mouse model of methicillin-resistant...
Mechanisms of Resistance
Editor's Pick Mechanisms of ResistanceSuppression of β-Lactam Resistance by Aspergillomarasmine A Is Influenced by both the Metallo-β-Lactamase Target and the Antibiotic PartnerThe rise of Gram-negative pathogens expressing metallo-β-lactamases (MBLs) is a growing concern, threatening the efficacy of β-lactam antibiotics, in particular, the carbapenems. There are no inhibitors of MBLs in current clinical use. Aspergillomarasmine A (AMA) is an MBL inhibitor isolated from Aspergillus versicolor with the ability to rescue meropenem activity in...
Mechanisms of ResistanceFirst Occurrence of the OXA-198 Carbapenemase in EnterobacteralesA carbapenem-resistant Citrobacter sp. was recovered from routine screening of multidrug-resistant bacteria. This isolate coproduced OXA-48 and OXA-198. OXA-48 was carried by the prototypical IncL plasmid, whereas OXA-198 was carried by a peculiar IncHI-type plasmid. This carbapenemase gene was inserted within a class 1 integron located on a conjugative plasmid. This report describes the first occurrence of OXA-198 in ...
Mechanisms of ResistanceMechanisms of Acquired In Vivo and In Vitro Resistance to Voriconazole by Candida krusei following Exposure to Suboptimal Drug ConcentrationFive Candida krusei isolates (susceptible and resistant) recovered from the urine of a kidney transplant patient treated with voriconazole (VRC) 200 mg twice daily for 20 days were studied. Eight unrelated clinical isolates of C. krusei were exposed in vitro to VRC 0.001 μg/ml for 30 days....
Mechanisms of ResistanceCeftazidime-Avibactam Resistance Associated with Increased blaKPC-3 Gene Copy Number Mediated by pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella pneumoniaeThis study reports on the characterization of two ceftazidime-avibactam (CZA)-resistant KPC-producing Klebsiella pneumoniae strains (KP-14159 and KP-8788) sequentially isolated from infections occurred in a patient never treated with CZA. Whole-genome sequencing characterization using a combined short- and long-read sequencing approach showed that both isolates...
Editor's Pick Mechanisms of ResistancePotency of Vaborbactam Is Less Affected than That of Avibactam in Strains Producing KPC-2 Mutations That Confer Resistance to Ceftazidime-AvibactamResistance to ceftazidime-avibactam due to mutations in KPC genes has been reported both in vitro and in clinical settings. The most frequently reported mutation leads to the amino acid substitution D179Y in the Ω loop of the enzyme. Bacterial cells that carry mutant KPC acquire a higher level of ceftazidime resistance, become more sensitive to other cephalosporins, and almost completely lose resistance to carbapenems. In this...
Mechanisms of ResistanceThe Efflux Pump MexXY/OprM Contributes to the Tolerance and Acquired Resistance of Pseudomonas aeruginosa to ColistinThe intrinsic resistance of Pseudomonas aeruginosa to polymyxins in part relies on the addition of 4-amino-4-deoxy-l-arabinose (Ara4N) molecules to the lipid A of lipopolysaccharide (LPS), through induction of operon arnBCADTEF-ugd (arn) expression. As demonstrated previously, at least three two-component regulatory systems (...
Mechanisms of ResistanceAdaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosaColistin (polymyxin E) is a last-resort antibiotic against multidrug-resistant isolates of Pseudomonas aeruginosa. However, the nephro-toxicity of colistin limits its use, spurring the interest in novel antimicrobial peptides (AMP). Here, we show that the synthetic AMP-dendrimer G3KL (MW 4,531.38 Da, 15 positive charges, MIC = 8 mg/liter) showed faster killing than...
Mechanisms of ResistanceCharacterization of FosL1, a Plasmid-Encoded Fosfomycin Resistance Protein Identified in Escherichia coliFosfomycin is gaining renewed interest for treating urinary tract infections. Monitoring fosfomycin resistance is therefore important in order to detect the emergence of novel resistance mechanisms. Here, we used the Rapid Fosfomycin NP test to screen a collection of extended-spectrum-β-lactamase-producing Escherichia coli isolates from Switzerland and found a...
Editor's Pick Mechanisms of ResistanceMultiple Low-Reactivity Class B Penicillin-Binding Proteins Are Required for Cephalosporin Resistance in EnterococciEnterococcus faecalis and Enterococcus faecium are commensals of the gastrointestinal tract of most terrestrial organisms, including humans, and are major causes of health care-associated infections. Such infections are difficult or impossible to treat, as the enterococcal strains responsible are...
Mechanisms of ResistanceOXA-181-Producing Extraintestinal Pathogenic Escherichia coli Sequence Type 410 Isolated from a Dog in PortugalTwo multidrug-resistant and carbapenemase-producing Escherichia coli clones of sequence type 410 were isolated from fecal samples of a dog with skin infection on admission to an animal hospital in Portugal and 1 month after discharge. Whole-genome sequencing revealed a 126,409-bp Col156/IncFIA/IncFII multidrug resistance plasmid and a 51,479-bp IncX3 bla...
Mechanisms of ResistanceA Multispecies Cluster of VIM-1 Carbapenemase-Producing Enterobacterales Linked by a Novel, Highly Conjugative, and Broad-Host-Range IncA Plasmid Forebodes the Reemergence of VIM-1In this study, we investigated VIM-1-producing Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Citrobacter freundii, and...
Mechanisms of ResistanceOverexpression of RamA, Which Regulates Production of the Multidrug Resistance Efflux Pump AcrAB-TolC, Increases Mutation Rate and Influences Drug Resistance PhenotypeIn Enterobacteriales, the AcrAB-TolC efflux pump exports substrates, including antimicrobials, from the cell. Overexpression of AcrAB-TolC can occur after exposure to fluoroquinolones, leading to multidrug resistance. The expression of AcrAB-TolC in Salmonella is primarily regulated by the transcriptional activator RamA. However, other transcriptional activators, such as MarA, SoxRS, and Rob, can influence AcrAB-TolC...
Susceptibility
SusceptibilityActivity of a Long-Acting Echinocandin, Rezafungin, and Comparator Antifungal Agents Tested against Contemporary Invasive Fungal Isolates (SENTRY Program, 2016 to 2018)We evaluated the activity of rezafungin and comparators, using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, against a worldwide collection of 2,205 invasive fungal isolates recovered from 2016 to 2018. Candida (n = 1,904 isolates; 6 species), Cryptococcus neoformans (n = 73),...
SusceptibilityAntagonistic Effect of Colistin on Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus in In Vitro and In Vivo StudiesAs concerns arise that the vancomycin MIC of methicillin-resistant Staphylococcus aureus (MRSA) could be increased by concurrent colistin administration, we evaluated the effect of colistin on vancomycin efficacy against MRSA via in vitro and in vivo studies. Among MRSA blood isolates collected in a tertiary-care hospital, we selected representative...
SusceptibilityMIC and Upper Limit of Wild-Type Distribution for 13 Antifungal Agents against a Trichophyton mentagrophytes-Trichophyton interdigitale Complex of Indian OriginDermatophytosis due to the Trichophyton mentagrophytes-Trichophyton interdigitale complex is being increasingly reported across India. Reports of therapeutic failure have surfaced recently, but there are no clinical break points (CBP) or epidemiological cutoffs (ECVs) available to guide the treatment of dermatophytosis. In this study, a total of 498 isolates of the...
SusceptibilityIn Vitro Susceptibility of Thai Pythium insidiosum Isolates to Antibacterial AgentsHuman pythiosis is a life-threatening human disease caused by Pythium insidiosum. In Thailand, vascular pythiosis is the most common form and carries a mortality rate of 10 to 40%, despite aggressive treatment with radical surgery, antifungal agents, and immunotherapy. Itraconazole and terbinafine have been the mainstay of treatment, until recently, based on case...
Editor's Pick SusceptibilityIn Vitro Evaluation of Antifungal Drug Combinations against Multidrug-Resistant Candida auris Isolates from New York OutbreakSince 2016, New York hospitals and health care facilities have faced an unprecedented outbreak of the pathogenic yeast Candida auris. We tested over 1,000 C. auris isolates from affected facilities and found high resistance to fluconazole (MIC > 256 mg/liter) and variable resistance to other...
SusceptibilityComparison of MIC Test Strip and Sensititre YeastOne with the CLSI and EUCAST Broth Microdilution Reference Methods for In Vitro Antifungal Susceptibility Testing of Cryptococcus neoformansWe compared MIC test strip (MTS) and Sensititre YeastOne (SYO) methods with EUCAST and CLSI methods for amphotericin B, 5-fluocytosine, fluconazole, voriconazole, and isavuconazole against 106 Cryptococcus neoformans isolates. The overall essential agreement between the EUCAST and CLSI methods was >72% and >94% at ±1 and ±2 dilutions, respectively. The essential...
Editor's Pick SusceptibilityRezafungin In Vitro Activity against Contemporary Nordic Clinical Candida Isolates and Candida auris Determined by the EUCAST Reference MethodRezafungin (formerly CD101) is a novel echinocandin in clinical development. EUCAST epidemiological cutoff values (ECOFFs) have not yet been established. We determined the in vitro activity of rezafungin and comparators against 1,293 Nordic yeast isolates and 122 Indian Candida auris isolates and established single-center wild-type upper limits (WT-UL). The...
Analytical Procedures
Analytical ProceduresA Simple Method To Detect Point Mutations in Aspergillus fumigatus cyp51A Gene Using a Surveyor Nuclease AssayOne of the main mechanisms of azole resistance of Aspergillus fumigatus is thought to be a reduction in the drug’s affinity for the target molecule, Cyp51A, due to its amino acid mutation(s). It is known that the azole resistance pattern is closely related to the mutation site(s) of the molecule. In this study, we tried to develop a simple and rapid detection method...
Antiviral Agents
Antiviral AgentsHypersusceptibility of Human Cytomegalovirus to Foscarnet Induced by Mutations in Helices K and P of the Viral DNA PolymeraseHerein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of cytomegalovirus DNA polymerase for susceptibility to foscarnet. Q579I and K805Q recombinant viruses were hypersusceptible to foscarnet (respective mean 50% effective concentrations [EC50] of 0.12- and 0.19-fold that of the wild type). Three-dimensional modeling...
Antiviral AgentsCase Report of Increased Exposure to Antiretrovirals following Sleeve GastrectomyBariatric surgery is increasingly performed in morbidly obese HIV patients. Limited data exist regarding antiretroviral drug exposure after bariatric surgery. We report a case of a morbidly obese HIV patient who underwent sleeve gastrectomy. Abacavir, lamivudine, and dolutegravir therapeutic drug monitoring was performed at several time points pre- and postsurgery. Significantly increased levels were measured, particularly for abacavir...
Antiviral AgentsPhase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell TransplantationHuman cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled...
Antiviral Agents6′-β-Fluoro-Homoaristeromycin and 6′-Fluoro-Homoneplanocin A Are Potent Inhibitors of Chikungunya Virus Replication through Their Direct Effect on Viral Nonstructural Protein 1Alphaviruses are arthropod-borne, positive-stranded RNA viruses capable of causing severe disease with high morbidity. Chikungunya virus (CHIKV) is an alphavirus that causes a febrile illness which can progress into chronic arthralgia. The current lack of vaccines and specific treatment for CHIKV infection underscores the need to develop new therapeutic interventions. To discover new antiviral agents, we performed a compound screen in...
Antiviral AgentsAntiviral Activity of Tenofovir Alafenamide against HIV-1 with Thymidine Analog-Associated Mutations and M184VTenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are prodrugs of the HIV-1 nucleotide reverse transcriptase inhibitor tenofovir (TFV). In vivo, TAF achieves >4-fold-higher intracellular levels of TFV diphosphate (TFV-DP) compared to TDF. Since thymidine analog-associated mutations (TAMs) in HIV-1 confer reduced TFV susceptibility, patients with TAM-containing HIV-1 may benefit from higher TFV-DP levels...
Epidemiology and Surveillance
Epidemiology and SurveillanceAssessment of Tedizolid In Vitro Activity and Resistance Mechanisms against a Collection of Enterococcus spp. Causing Invasive Infections, Including Isolates Requiring an Optimized Dosing Strategy for Daptomycin from U.S. and European Medical Centers, 2016 to 2018High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium isolates. Only 3.3% and 2.1% of E. faecalis isolates had elevated daptomycin MIC (≥2 mg/liter) and vancomycin...
Epidemiology and SurveillanceAntimalarial Drug Resistance Profiling of Plasmodium falciparum Infections in Ghana Using Molecular Inversion Probes and Next-Generation SequencingA key drawback to monitoring the emergence and spread of antimalarial drug resistance in sub-Saharan Africa is early detection and containment. Next-generation sequencing methods offer the resolution, sensitivity, and scale required to fill this gap by surveilling for molecular markers of drug resistance. We performed targeted sequencing using molecular inversion probes to interrogate five...
Epidemiology and SurveillanceA Computer Modelling Approach To Evaluate the Accuracy of Microsatellite Markers for Classification of Recurrent Infections during Routine Monitoring of Antimalarial Drug EfficacyAntimalarial drugs have long half-lives, so clinical trials to monitor their efficacy require long periods of follow-up to capture drug failure that may become patent only weeks after treatment. Reinfections often occur during follow-up, so robust methods of distinguishing drug failures (recrudescence) from emerging new infections are needed to produce accurate failure rate estimates. Molecular correction aims to achieve this by...
Epidemiology and SurveillanceAntibiotic Exposure and Risk for Hospital-Associated Clostridioides difficile InfectionClostridioides difficile infection (CDI) is a health care-associated infection associated with significant morbidity and cost, with highly varied risk across populations. More effective, risk-based prevention strategies are needed. Here, we investigate risk factors for hospital-associated CDI in a large integrated health system. In a retrospective cohort of all adult...
Epidemiology and SurveillanceDevelopment of a Multiplex Real-Time PCR Assay for Rapid Detection of Tigecycline Resistance Gene tet(X) Variants from Bacterial, Fecal, and Environmental SamplesWe developed a multiplex real-time SYBR green-based PCR assay for rapid detection of tet(X) and its variants, including tet(X1) and tet(X2) and high-level tigecycline resistance genes tet(X3), tet(X4), and tet(X5). We showed that the real-time PCR assay developed had high linearity (R2 ≥ 0.996), sensitivity (low detection limit), and specificity (only the target...
Epidemiology and SurveillanceA Pilot Study of Chicago Waterways as Reservoirs of Multidrug-Resistant Enterobacteriaceae (MDR-Ent) in a High-Risk Region for Community-Acquired MDR-Ent Infection in ChildrenCommunity-acquired multidrug resistant Enterobacteriaceae (MDR-Ent) infections continue to increase in the United States. In prior studies, we identified neighboring regions in Chicago, Illinois, where children have 5 to 6 times greater odds of MDR-Ent infections. To prevent community spread of MDR-Ent, we need to identify the MDR-Ent reservoirs. A pilot study of 4 Chicago waterways for MDR-Ent and associated antibiotic...
Epidemiology and SurveillanceClinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosaWe aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa...
Epidemiology and SurveillanceIn Vitro Activity of Sulbactam-Durlobactam against Acinetobacter baumannii-calcoaceticus Complex Isolates Collected Globally in 2016 and 2017Acinetobacter baumannii-calcoaceticus complex (ABC) organisms cause severe infections that are difficult to treat due to preexisting antibiotic resistance. Sulbactam-durlobactam (formerly sulbactam-ETX2514) (SUL-DUR) is a β-lactam–β-lactamase inhibitor combination antibiotic designed to treat serious infections caused by ABC organisms, including multidrug-...
Experimental Therapeutics
Experimental TherapeuticsActivation of Heme Oxygenase Expression by Cobalt Protoporphyrin Treatment Prevents Pneumonic Plague Caused by Inhalation of Yersinia pestisPneumonic plague, caused by the Gram-negative bacteria Yersinia pestis, is an invasive, rapidly progressing disease with poor survival rates. Following inhalation of Y. pestis, bacterial invasion of the lungs and a tissue-damaging inflammatory response allows vascular spread of the infection....
Experimental TherapeuticsIdentification of Off-Patent Drugs That Show Synergism with Amphotericin B or That Present Antifungal Action against Cryptococcus neoformans and Candida spp.Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some lipidic and liposomal formulations that present reduced toxicity are available, their price limits their application in developing countries. Flucytosine (5FC) has shown synergistic effect with AmB for treatment of some fungal infections, such as cryptococcosis, but again...
Experimental TherapeuticsLychnopholide in Poly(d,l-Lactide)-Block-Polyethylene Glycol Nanocapsules Cures Infection with a Drug-Resistant Trypanosoma cruzi Strain at Acute and Chronic PhasesChagas disease remains neglected, and current chemotherapeutics present severe limitations. Lychnopholide (LYC) at low doses loaded in polymeric poly(d,l-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules (LYC-PLA-PEG-NC) exhibits anti-Trypanosoma cruzi efficacy in mice infected with a partially drug-...
Experimental TherapeuticsPaenipeptin Analogues Potentiate Clarithromycin and Rifampin against mcr-1-Mediated Polymyxin-Resistant Escherichia coli In VivoPolymyxin resistance mediated by the mcr-1 gene threatens the last-resort antibiotics. Linear lipopeptide paenipeptin analogues 1 and 15 disrupted the outer membrane of Gram-negative pathogens and potentiated clarithromycin and rifampin against mcr-1-positive Escherichia coli from the FDA-CDC Antimicrobial Resistance Isolate Bank. In the presence of...
Experimental TherapeuticsMinocycline-EDTA-Ethanol Antimicrobial Catheter Lock Solution Is Highly Effective In Vitro for Eradication of Candida auris BiofilmsCandida auris is an emerging pathogen that can cause virulent central-line-associated bloodstream infections. Catheter salvage through the eradication of biofilms is a desirable therapeutic option. We compared taurolidine and minocycline-EDTA-ethanol (MEE) catheter lock solutions in vitro for the eradication of biofilms of 10...
Experimental TherapeuticsPharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic RabbitsKlebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC-...
Experimental TherapeuticsIdentification of Antibiotics That Diminish Disease in a Murine Model of Enterohemorrhagic Escherichia coli InfectionInfections with enterohemorrhagic Escherichia coli (EHEC) cause disease ranging from mild diarrhea to hemolytic-uremic syndrome (HUS) and are the most common cause of renal failure in children in high-income countries. The severity of the disease derives from the release of Shiga toxins (Stx). The use of antibiotics to treat EHEC infections is generally avoided, as it...
Experimental TherapeuticsAntibody Binding to the O-Specific Antigen of Pseudomonas aeruginosa O6 Inhibits Cell GrowthPseudomonas aeruginosa is an opportunistic pathogen that is inherently resistant to many antibiotics and represents an increasing threat due to the emergence of drug-resistant strains. There is a pressing need to develop innovative antimicrobials against this pathogen. In this study, we identified the O-specific antigen (OSA) of...
Experimental TherapeuticsPreclinical Antimalarial Combination Study of M5717, a Plasmodium falciparum Elongation Factor 2 Inhibitor, and Pyronaridine, a Hemozoin Formation InhibitorAntimalarial drug resistance in the Plasmodium falciparum parasite poses a constant challenge for drug development. To mitigate this risk, new antimalarial medicines should be developed as fixed-dose combinations. Assessing the pharmacodynamic interactions of potential antimalarial drug combination partners during early phases of development is essential in developing...
Experimental TherapeuticsActivity of Imipenem-Relebactam and Meropenem-Vaborbactam against Carbapenem-Resistant, SME-Producing Serratia marcescensThe Serratia marcescens enzyme (SME) is a chromosomally encoded carbapenemase with no known optimal treatment. Various β-lactam/β-lactamase inhibitors and comparators were evaluated against 8 SME producers via broth microdilution. Four isolates were subsequently tested via time-kill analyses. All isolates were resistant to imipenem, imipenem-relebactam, and meropenem...
Experimental TherapeuticsHydrogen Peroxide-Generating Electrochemical Scaffold Activity against Trispecies BiofilmsThe antibiofilm activity of a hydrogen peroxide-generating electrochemical scaffold (e-scaffold) was determined against mono- and trispecies biofilms of methicillin-resistant Staphylococcus aureus, multidrug-resistant Pseudomonas aeruginosa, and...
Experimental TherapeuticsTBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessusLung disease caused by Mycobacterium abscessus is very difficult to cure, and treatment failure rates are high. The antituberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays a long terminal half-life, and presents a cardiotoxicity liability associated with QT interval prolongation....
Experimental TherapeuticsEfficacy of Ceftolozane-Tazobactam in Combination with Colistin against Extensively Drug-Resistant Pseudomonas aeruginosa, Including High-Risk Clones, in an In Vitro Pharmacodynamic ModelCombination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. Colistin has been the only treatment available for these infections for many years, but its results are suboptimal. Ceftolozane-tazobactam (C/T) is a newly available therapeutic option that has shown good antipseudomonal activity, even...
Clinical Therapeutics
Clinical TherapeuticsClostridioides difficile-Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent MechanismsA clinically relevant risk factor for Clostridioides difficile-associated disease (CDAD) is recent antibiotic treatment. Although broad-spectrum antibiotics have been shown to disrupt the structure of the gut microbiota, some antibiotics appear to increase CDAD risk without being highly active against intestinal anaerobes, suggesting direct nonantimicrobial effects....
Clinical TherapeuticsSafety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy VolunteersMMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed....
Editor's Pick Clinical TherapeuticsFourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary TuberculosisLinezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg...
Clinical TherapeuticsUtility of Methicillin-Resistant Staphylococcus aureus Nares Screening for Patients with a Diabetic Foot InfectionTreatment of suspected methicillin-resistant Staphylococcus aureus (MRSA) is a cornerstone of severe diabetic foot infections; however, antibiotics can be associated with toxicity. The objective of this study was to determine the negative predictive value (NPV) of MRSA nares screening in the determination of subsequent MRSA in patients with a diabetic foot infection....
Clinical TherapeuticsReal-World Experience with Ceftolozane-Tazobactam for Multidrug-Resistant Gram-Negative Bacterial InfectionsOur objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary...
Pharmacology
PharmacologyLead Optimization of Dehydroemetine for Repositioned Use in MalariaDrug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM...
PharmacologyPopulation Pharmacokinetics of Teicoplanin in Preterm and Term Neonates: Is It Time for a New Dosing Regimen?Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations...
PharmacologyExtension of Pharmacokinetic/Pharmacodynamic Time-Kill Studies To Include Lipopolysaccharide/Endotoxin Release from Escherichia coli Exposed to CefuroximeThe release of inflammatory bacterial products, such as lipopolysaccharide (LPS)/endotoxin, may be increased upon the administration of antibiotics. An improved quantitative understanding of endotoxin release and its relation to antibiotic exposure and bacterial growth/killing may be gained by an integrated analysis of these processes. The aim of this work was to establish a mathematical model that relates...
PharmacologyPopulation Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound TherapyThe aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the...
PharmacologyActivity of Antibiotics against Pseudomonas aeruginosa in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture MediumPseudomonas aeruginosa is a major cause of respiratory biofilm-related infections in patients with cystic fibrosis. We developed an in vitro pharmacodynamic model to study the activity of antipseudomonal antibiotics against PAO1 biofilms grown in artificial sputum medium with agar [ASM(+)] versus that against biofilms grown in Trypticase soy broth...
PharmacologyFosamprenavir with Ritonavir Pharmacokinetics during PregnancyThe purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography....
PharmacologyN-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and N-Acetyl-Isoniazid Pharmacokinetics during Antituberculosis TreatmentThe distribution of N-acetyltransferase 2 gene (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in the South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics (PK) in Zulu black HIV-infected South Africans in Durban, South Africa. HIV-infected participants with...
PharmacologyPharmacodynamics of Meropenem against Acinetobacter baumannii in a Neutropenic Mouse Thigh Infection ModelAcinetobacter baumannii infections are difficult to treat and have limited treatment options. Carbapenems, including meropenem, are currently considered the first-line agents for the treatment of infections caused by Acinetobacter spp. The percentage of a 24-hour period that the concentration of...
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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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