Pharmacodynamic assessment of apramycin against Mycobacterium abscessus in a hollow fibre infection model.

Background: Mycobacterium abscessus is an important cause of pulmonary infections, particularly among people with cystic fibrosis. Current treatment options for M. abscessus are suboptimal.

Ceftazidime/avibactam alone or in combination with an aminoglycoside for treatment of carbapenem-resistant Enterobacterales infections: A retrospective cohort study.

Background: Ceftazidime/avibactam is one of the preferred treatment options for carbapenem-resistant Enterobacterales (CRE). However, the benefit of combining ceftazidime/avibactam with another antibiotic remains unclear.

Objectives: To identify variables associated with treatment failure during the use of ceftazidime/avibactam for CRE infections and assess the effect of combining an aminoglycoside with ceftazidime/avibactam.

Interaction of sp. RIT 592 induces the production of broad-spectrum antibiotics in sp. RIT 594.

Antimicrobial resistance (AMR) is one of the most alarming global public health challenges of the 21st century. Over 3 million antimicrobial-resistant infections occur in the United States annually, with nearly 50,000 cases being fatal. Innovations in drug discovery methods and platforms are crucial to identify novel antibiotics to combat AMR.

Optimization of an in vitro Pseudomonas aeruginosa Biofilm Model to Examine Antibiotic Pharmacodynamics at the Air-Liquid Interface.

Pseudomonas aeruginosa is an important cause of lower respiratory tract infections, such as ventilator-associated bacterial pneumonia (VABP). Using inhaled antibiotics to treat VABP can achieve high drug concentrations at the infection site while minimizing systemic toxicities. Despite the theoretical advantages, clinical trials have failed to show a benefit for inhaled antibiotic therapy in treating VABP.

Assessment of antibiotic release and antibacterial efficacy from pendant glutathione hydrogels using ex vivo porcine skin.

Acute bacterial skin and skin structure infections (ABSSSIs) confer a substantial burden on the healthcare system. Local antibiotic delivery systems can provide controlled drug release directly to the site of infection to maximize efficacy and minimize systemic toxicity. The purpose of this study was to examine the antibacterial activity of antibiotic-loaded glutathione-conjugated poly(ethylene glycol) hydrogels (GSH-PEG) against ABSSSIs utilizing an ex vivo porcine dermal explant model.

Klebsiella pneumoniae clinical isolates with features of both multidrug-resistance and hypervirulence have unexpectedly low virulence.

Klebsiella pneumoniae has been classified into two types, classical K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP).

Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A.

The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria.

Pharmacokinetics and dialytic clearance of baricitinib during in vivo continuous venovenous haemodialysis in a patient with COVID-19.

Objectives: To date, there are no published pharmacokinetic (PK) data for baricitinib in critically ill patients requiring continuous renal replacement therapy. This paper describes in detail the plasma PK and dialytic clearance of baricitinib in a patient infected with coronavirus disease 2019 (COVID-19) requiring continuous renal replacement therapy in order to suggest dosing strategies in this population.

Methods: Baricitinib 2 mg daily was used for the treatment of COVID-19 in a critically ill patient on continuous venovenous haemodialysis (CVVHD).

Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity.

Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM).

Combatting Planktonic and Biofilm Populations of Carbapenem-Resistant with Polymyxin-Based Combinations.

Carbapenem-resistant (CRAB) can cause serious infections that are associated with high mortality rates. During the course of an infection, many CRAB isolates are able to form biofilms, which are recalcitrant to several antibiotics and can be difficult to treat. Polymyxin-based regimens are a first-line treatment option for CRAB infections, but they have not been optimized against both planktonic and biofilm phases of growth.

Research priorities towards precision antibiotic therapy to improve patient care.

Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections.

Antibiotic susceptibility patterns of viridans group streptococci isolates in the United States from 2010 to 2020.

Background: Viridans group streptococci (VGS) are typically part of the commensal flora but can also cause severe invasive diseases such as infective endocarditis. There are limited data available showing antibiotic susceptibility over time for VGS.

Objectives: To evaluate antibiotic susceptibility trends in VGS over time.

Aminoglycoside-resistance gene signatures are predictive of aminoglycoside MICs for carbapenem-resistant Klebsiella pneumoniae.

Background: Aminoglycoside-containing regimens may be an effective treatment option for infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp), but aminoglycoside-resistance genes are common in these strains. The relationship between the aminoglycoside-resistance genes and aminoglycoside MICs remains poorly defined.

Objectives: To identify genotypic signatures capable of predicting aminoglycoside MICs for CR-Kp.

Genomic Features Associated with the Degree of Phenotypic Resistance to Carbapenems in Carbapenem-Resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae strains cause severe infections that are difficult to treat. The production of carbapenemases such as the K. pneumoniae carbapenemase (KPC) is a common mechanism by which these strains resist killing by the carbapenems.

Capability of Enterococcus faecalis to shield Gram-negative pathogens from aminoglycoside exposure.

Background: Enterococcus faecalis commonly produce aminoglycoside-modifying enzymes (AMEs) and are implicated in polymicrobial infections.

Objectives: To determine if AME-producing E. faecalis is capable of protecting Enterobacteriaceae and Pseudomonas aeruginosa from gentamicin exposure.

Generating Genotype-Specific Aminoglycoside Combinations with Ceftazidime/Avibactam for KPC-Producing .

Antibiotic combinations, including ceftazidime/avibactam (CAZ/AVI), are frequently employed to combat KPC-producing Klebsiella pneumoniae (KPC-Kp), though such combinations have not been rationally optimized. Clinical KPC-Kp isolates with common genes encoding aminoglycoside-modifying enzymes (AMEs), or , were used in static time-kill assays ( = 4 isolates) and the hollow-fiber infection model (HFIM;  = 2 isolates) to evaluate the activity of gentamicin, amikacin, and CAZ/AVI alone and in combinations. A short course, one-time aminoglycoside dose was also evaluated.

Optimization of Ceftazidime/Avibactam for KPC-Producing .

Ceftazidime/avibactam is an important treatment option for infections caused by carbapenemase-producing (KPC-Kp), however, resistance can emerge during treatment. The objective of the study was to define the ceftazidime/avibactam concentrations required to suppress bacterial regrowth in ceftazidime/avibactam susceptible isolates and identify active therapies against ceftazidime/avibactam-resistant KPC-Kp. Time-kill assays were performed against twelve ST258 KPC-Kp isolates that harbored or .

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales.

The spread of metallo-β-lactamase (MBL)-producing Enterobacterales worldwide without the simultaneous increase in active antibiotics makes these organisms an urgent public health threat. This review summarizes recent advancements in diagnostic and treatment strategies for infections caused by MBL-producing Enterobacterales. Adequate treatment of patients infected with MBL-producing Enterobacterales relies on detection of the β-lactamase in the clinic.

Optimizing aminoglycoside selection for KPC-producing Klebsiella pneumoniae with the aminoglycoside-modifying enzyme (AME) gene aac(6')-Ib.

Objectives: KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates commonly co-harbour the aminoglycoside-modifying enzyme (AME) gene aac(6')-Ib, which encodes an AME that can confer resistance to some of the commercially available aminoglycosides. We sought to determine the influence of AAC(6')-Ib in KPC-Kp on the pharmacodynamic activity of aminoglycosides.

Methods: Six KPC-Kp clinical isolates, three with and three without aac(6')-Ib, were analysed.

A coup d'état by NDM-producing Klebsiella pneumoniae overthrows the major bacterial population during KPC-directed therapy.

The objective of this study was to utilize a co-culture hollow-fiber infection model (HFIM) to characterize the interplay between a small, difficult-to-detect, New Delhi metallo-β-lactamase-producing Klebsiella pneumoniae (NDM-Kp) minor population and a larger K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae population in the presence of KPC-directed antibacterial therapy.

Unraveling the Gentamicin Drug Product Complexity Reveals Variation in Microbiological Activities and Nephrotoxicity.

The gentamicin drug product is a complex mixture of numerous components, many of which have not individually undergone safety and efficacy assessments. This is in contrast to the majority of medicines that require rigorous characterizations of trace impurities and are dosed as single components. In gentamicin, four components, known as gentamicin congeners C1, C1a, C2, and C2a, comprise the majority of the mixture.

In Vitro Pharmacodynamic Analyses Help Guide the Treatment of Multidrug-Resistant and Carbapenem-Resistant Bacteremia in a Liver Transplant Patient.

Background: Infections due to multidrug-resistant pathogens are particularly deadly and difficult to treat in immunocompromised patients, where few data exist to guide optimal antimicrobial therapy. In the absence of adequate clinical data, in vitro pharmacokinetic (PK)/pharmacodynamic (PD) analyses can help to design treatment regimens that are bactericidal and may be clinically effective.

Methods: We report a case in which in vitro pharmacodynamic analyses were utilized to guide the treatment of complex, recurrent bacteremias due to vancomycin-, daptomycin-, and linezolid-resistant and carbapenem-resistant complex in a liver transplant patient.

Multidrug Resistant Acinetobacter baumannii: Resistance by Any Other Name Would Still be Hard to Treat.

Purpose Of Review: Acinetobacter baumannii (AB) is an infamous nosocomial pathogen with a seemingly limitless capacity for antimicrobial resistance, leading to few treatment options and poor clinical outcomes. The debatably low pathogenicity and virulence of AB are juxtaposed by its exceptionally high rate of infection-related mortality, likely due to delays in time to effective antimicrobial therapy secondary to its predilection for resistance to first-line agents. Recent studies of AB and its infections have led to a burgeoning understanding of this critical microbial threat and provided clinicians with new ammunition for which to target this elusive pathogen.