How do I manage Difficult-to-Treat Pseudomonas aeruginosa infections?: Key Questions for Today's Clinicians.

Background: Pseudomonas aeruginosa has a remarkable ability to develop resistance to antimicrobials in vivo, often leaving very limited therapeutic options and making treatment particularly challenging. In fact, P. aeruginosa infections with "difficult-to-treat resistance" are one of the most concerning contemporary bacterial infections.

New Perspectives on Antimicrobial Agents: Sulbactam-durlobactam.

Infections due to Carbapenem-resistant (CRAB) are a significant burden and are associated with devastating outcomes. Subsequently, CRAB is recognized as an urgent threat to human health by the United States (US) Centers for Disease Control and Prevention and is designated a critical pathogen, with the highest priority for research and development of novel treatment options, by the World Health Organization. Sulbactam-durlobactam was approved by the US Food and Drug Administration in 2023 for the treatment of Hospital Acquired and Ventilator Associated Bacterial Pneumonia caused by susceptible strains of , and as of 2024, is the Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections preferred treatment strategy, in combination with a carbapenem, for infections due to CRAB.

Longitudinal surveillance and transmission of using whole genome sequencing-a tale of two hospitals.

Objective: is known to cause global outbreaks and routine surveillance to prevent nosocomial transmission has historically been limited. A longitudinal surveillance study of isolates using whole genome sequencing (WGS) and whole genome multilocus sequence typing (wgMLST) was performed to map the distribution of sequence types (STs) and intrahospital transmission.

Methods: All clinical isolates were collected in two hospitals (H1, H2) from fifteen units between 2017 and 2021 in Southeast Michigan and analyzed.

Effectiveness of piperacillin/tazobactam loading dose for extended infusion dosing among patients with Gram-negative bacteraemia.

Objective: To examine the effect of a loading dose (LD) for extended infusion piperacillin/tazobactam on clinical outcomes.

Methods: This single-centre, retrospective cohort study evaluated adult patients with Gram-negative bacteraemia who received extended infusion piperacillin/tazobactam for ≥48 hours between 2015 and 2022. In December 2019, the study institution developed a policy that automatically ordered a piperacillin/tazobactam LD whenever piperacillin/tazobactam was prescribed.

A network analysis of carbapenem-resistant Klebsiella pneumoniae among healthcare facilities.

With limited treatments for carbapenem-resistant Klebsiella pneumoniae (CRKp), curtailing transmission is critical. We applied a network analysis using epidemiological admission data and bacterial genetics to characterize CRKp spread among patients in 16 acute care hospitals linked to 217 other healthcare facilities in the United States. Patients with diagnosed CRKp infection were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a prospective, observational study conducted from 12/2011 to 6/2016.

The Impact of Synergistic Therapy Between Colistin and Meropenem on Outcomes of Patients With Pneumonia or Bloodstream Infection Due to Carbapenem-Resistant Gram-Negative Pathogens.

Background: Colistin, a last-line treatment for carbapenem-resistant Gram-negative bacilli (CRGNB), is frequently used in combination with meropenem because these agents often demonstrate in vitro synergy. Using data from the OVERCOME trial comparing colistin + meropenem to colistin + placebo for treatment of pneumonia or bloodstream infection due to CRGNB, we evaluated the impact of synergistic therapy on outcomes.

Methods: In vitro synergy testing between colistin and meropenem was conducted using 24-hour time-kill analysis; synergy was defined as >2-log reduction in colony-forming units/ml compared to the most active single agent.

Pivmecillinam for Treatment of Uncomplicated Urinary Tract Infection: New Efficacy Analysis.

Background: In April 2024-over 40 years after its first approval in Europe-pivmecillinam received approval from the United States Food and Drug Administration (FDA) for the treatment of uncomplicated urinary tract infection (uUTI) in women aged ≥18 years, caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus. Herein, we describe the reanalysis from previously published clinical trials, conducted in accordance with current FDA efficacy criteria, which formed the basis for this regulatory approval.

Methods: Of 14 studies reviewed, 3 randomized, controlled trials offered suitable subject-level data from patients with uUTI treated with 185 mg pivmecillinam 3 times daily for 3-7 days.

Population Pharmacokinetic/Toxicodynamic Model for Polymyxin B in Critically Ill Patients to Identify the Risk of Nephrotoxicity.

Polymyxins are used against highly resistant Gram-negative pathogens, and nephrotoxicity (acute kidney injury, AKI) is the major dose-limiting adverse effect. We aimed to develop a well-informed population pharmacokinetic/toxicodynamic (PK/TD) model using the largest polymyxin B-treated critically ill patient population studied to inform polymyxin B dosing strategies. Critically ill patients receiving intravenous polymyxin B for at least 48 hours were enrolled in an observational study.

Power considerations for the win ratio: A rank-based simulation approach.

Background: The win ratio is an innovative statistical method for evaluating efficacy in clinical trials. The underlying distributions of outcomes, along with potential censoring, ties, and correlations, add complexity to specifying a win ratio for study design purposes. As successful study planning hinges on thorough consideration of sample size and statistical power, we developed a flexible approach to support the use of the win ratio in clinical trials.

The association between undetected heteroresistance and antibiotic treatment failure in complicated urinary tract infection.

Background: Antibiotic resistance is a worsening public health threat. One poorly understood aspect of this problem is unexpected antibiotic treatment failure; when an infecting isolate is deemed susceptible to a given antibiotic, yet treatment with that drug fails. It has been proposed that heteroresistance may be an explanation for at least some unexplained treatment failures.

Cefepime-enmetazobactam: first approved cefepime-β- lactamase inhibitor combination for multi-drug resistant Enterobacterales.

Cefepime-enmetazobactam is a β-lactam/β-lactamase inhibitor (BL/BLI) combination that has demonstrated potent activity against extended spectrum beta-lactamase (ESBL)-producing Enterobacterales, recently approved by the US FDA for the treatment of complicated urinary tract infections (cUTI) and by the European Medicines Agency and the UK Healthcare products Regulatory Agency for the treatment of cUTI, hospital-acquired pneumonia including ventilator-associated pneumonia and bacteremia in adults. Cefepime is a 4th generation cephalosporin with a broad spectrum bactericidal activity and enhanced stability to degradation by chromosomal and plasmid-mediated AmpC cephalosporinases as well as carbapenemase OXA-48 like enzymes. Enmetazobactam is a novel penicillanic acid sulfone β-lactamase inhibitor structurally similar to tazobactam with activity against CTX-M, TEM, and SHV ESBL, and other class A β-lactamases, that restores cefepime activity in vitro and in vivo against ESBLs-producing Enterobacterales.

Safety and Tolerability of Pivmecillinam During More Than Four Decades of Clinical Experience: A Systematic Review.

The recent US Food and Drug Administration approval of pivmecillinam-an oral prodrug of the amidinopenicillin antibiotic mecillinam-presents a valuable opportunity to address the need for new treatments for uncomplicated urinary tract infection (uUTI). We report findings of a systematic literature review of the safety profile of pivmecillinam/mecillinam based on more than 40 years' experience, mainly in Europe and Canada, to describe its tolerability profile and identify any important safety signals. In total, 110 eligible publications were identified describing use of pivmecillinam/mecillinam as monotherapy or in combination, for treatment of uUTI or other infectious conditions.

Effectiveness of ceftazidime-avibactam versus ceftolozane-tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the USA (CACTUS): a multicentre, retrospective, observational study.

Background: Ceftolozane-tazobactam and ceftazidime-avibactam are preferred treatment options for multidrug-resistant Pseudomonas aeruginosa infections; however, real-world comparative effectiveness studies are scarce. Pharmacokinetic and pharmacodynamic differences between the agents might affect clinical response rates. We aimed to compare the effectiveness of ceftolozane-tazobactam and ceftazidime-avibactam for treatment of invasive multidrug-resistant P aeruginosa infections.

Disseminated histoplasmosis with oral involvement and co-infection with Pneumocystis in a patient with HIV: A case report.

Oral manifestations of disseminated histoplasmosis are rare but can present in immunocompromised individuals. We report a case of disseminated Histoplasmosis presenting with presumed oral involvement and pneumonia in a seropositive HIV individual. A 32-year-old male with HIV presented to the emergency department for a two-week history of abdominal pain and a tongue ulcer in the setting of significant weight loss, blood-tinged sputum, and non-adherence with antiretroviral therapy for three years.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Risk Assessment, Diagnostic Imaging, and Microbiological Evaluation in Adults, Children, and Pregnant People.

As the first part of an update to the clinical practice guideline on the diagnosis and management of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America, the panel presents 21 updated recommendations. These recommendations span risk assessment, diagnostic imaging, and microbiological evaluation. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Appendicitis in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America (IDSA). In this paper, the panel provides recommendations for diagnostic imaging of suspected acute appendicitis. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Utility of Blood Cultures in Adults, Children, and Pregnant People.

This article is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this guideline, the panel provides recommendations for obtaining blood cultures in patients with known or suspected intra-abdominal infection. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Utility of Intra-abdominal Fluid Cultures in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for obtaining cultures of intra-abdominal fluid in patients with known or suspected intra-abdominal infection. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Intra-abdominal Abscess in Adults, Children, and Pregnant People.

This article is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this article, the panel provides recommendations for diagnostic imaging of suspected acute intra-abdominal abscess. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Risk Assessment in Adults and Children.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides a recommendation for risk stratification according to severity of illness score. The panel's recommendation is based on evidence derived from systematic literature reviews and adheres to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Diverticulitis in Adults and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for diagnostic imaging of suspected acute diverticulitis. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

Review of the In Vitro Microbiological Activity of Mecillinam Against Common Uropathogens in Uncomplicated Urinary Tract Infection: Focus on Resistant Pathogens.

Antimicrobial resistance in uropathogens commonly causing urinary tract infections (UTIs) is a growing problem internationally. Pivmecillinam, the oral prodrug of mecillinam, has been used for over 40 years, primarily in Northern Europe and Canada. It is recommended in several countries as a first-line agent for the treatment of uncomplicated UTIs (uUTIs) and is now approved in the United States.

Clinical outcomes in patients infected with ertapenem-only-resistant Enterobacterales versus multi-carbapenem-resistant Enterobacterales.

Background: Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE).

Objectives: To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents.

Methods: Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included.