The emergence of cefiderocol resistance in Pseudomonas aeruginosa from a heteroresistant isolate during prolonged therapy.

Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant P. aeruginosa that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance.

Infectious Diseases Management in Wound Care Settings: Common Causative Organisms and Frequently Prescribed Antibiotics.

GENERAL PURPOSE: To provide information about the management of infected wounds in wound care settings. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Identify a host factor that may predispose a patient to a wound infection as well as characteristics of each stage of wound infection.2. Distinguish a common organism that causes early, acute wound infections and explain the preferred method for obtaining a wound specimen for culture.3. Apply knowledge of commonly prescribed antibiotics in wound care settings.

Although all chronic wounds are colonized by microbes and not all wounds are infected, antibiotics are widely prescribed in wound care settings. Antibiotic misuse in wound care occurs for many reasons, including diagnostic uncertainty regarding the presence of a bacterial infection, insufficient clinician knowledge about when antibiotics are necessary, clinicians' fear of achieving unfavorable patient outcomes, and patient demand. Understanding wound infection stages and proper wound assessment are essential to differentiate infected wounds from colonized wounds. Adequate knowledge of microbiology and commonly prescribed antibiotics in wound care settings is critical to optimize antimicrobial management. In this article, the authors review wound infection stages, host resistant factors, and microbial virulence factors that affect the progression of wound infection, specimen collection, common causative organisms, and commonly prescribed antibiotics in wound care settings.

Optimizing Pharmacokinetics-Pharmacodynamics of Antimicrobial Management in Patients with Sepsis: A Review.

Critically ill patients with sepsis or septic shock are at an increased risk of death. Early and aggressive interventions are essential for improving clinical outcomes. There are a number of therapeutic and practical challenges in the management of antimicrobials in patients with sepsis. These include the timely selection and administration of appropriate antimicrobials, significant physiological alterations that can influence antimicrobial pharmacokinetics, and significant interpatient variability of antimicrobial concentrations using standard dosing approaches. Understanding the impact of these factors on the probability of attaining pharmacokinetic-pharmacodynamic target goals is essential to guide optimal therapy. Using rapid diagnostic technology could facilitate timely selection of antimicrobials, and therapeutic drug monitoring would provide a more individualized dosing approach. Using an interdisciplinary sepsis team would also be beneficial in coordinating efforts to overcome the challenges encountered during this critical period to ensure optimal care.

Determining ß-lactam exposure threshold to suppress resistance development in Gram-negative bacteria.

Objectives: ß-Lactams are commonly used for nosocomial infections and resistance to these agents among Gram-negative bacteria is increasing rapidly. Optimized dosing is expected to reduce the likelihood of resistance development during antimicrobial therapy, but the target for clinical dose adjustment is not well established. We examined the likelihood that various dosing exposures would suppress resistance development in an in vitro hollow-fibre infection model. Methods: Two strains of Klebsiella pneumoniae and two strains of Pseudomonas aeruginosa (baseline inocula of ∼10 8  cfu/mL) were examined. Various dosing exposures of cefepime, ceftazidime and meropenem were simulated in the hollow-fibre infection model. Serial samples were obtained to ascertain the pharmacokinetic simulations and viable bacterial burden for up to 120 h. Drug concentrations were determined by a validated LC-MS/MS assay and the simulated exposures were expressed as C min /MIC ratios. Resistance development was detected by quantitative culture on drug-supplemented media plates (at 3× the corresponding baseline MIC). The C min /MIC breakpoint threshold to prevent bacterial regrowth was identified by classification and regression tree (CART) analysis. Results: For all strains, the bacterial burden declined initially with the simulated exposures, but regrowth was observed in 9 out of 31 experiments. CART analysis revealed that a C min /MIC ratio ≥3.8 was significantly associated with regrowth prevention (100% versus 44%, P = 0.001). Conclusions: The development of ß-lactam resistance during therapy could be suppressed by an optimized dosing exposure. Validation of the proposed target in a well-designed clinical study is warranted.

Predicting the risk of nephrotoxicity in patients receiving colistimethate sodium: a multicentre, retrospective, cohort study.

OBJECTIVES: With increasing rates of infections caused by MDR Gram-negative organisms, clinicians resort to older agents such as colistimethate sodium (CMS) despite a significant risk of nephrotoxicity. Several risk factors for CMS-associated nephrotoxicity have been reported, but they have yet to be validated. We compared the performance of published mathematical models in predicting the risk of CMS-associated nephrotoxicity. METHODS: In a multicentre, retrospective, cohort study, adult patients (≥18 years of age) were evaluated from five large academic medical centres in the USA. Patients with normal renal function (baseline serum creatinine ≤1.5 mg/dL) who received intravenous CMS for ≥72 h were followed for up to 30 days. The development of nephrotoxicity was as defined by the RIFLE criteria. Each published model was conditioned using patient-specific variables to predict the risk of nephrotoxicity. The predictive performance of the models was evaluated using the observed-to-expected (O/E) ratio. The most significant cut-off threshold for stratifying patients into high and low risk of nephrotoxicity was identified using classification and regression tree analysis. RESULTS: A total of 106 patients were examined (mean age 53.3 ±â€Š14.9 years, 66% male); the overall observed nephrotoxicity rate was 52.8%. We identified a simple model demonstrating reasonable overall nephrotoxicity risk assessment [O/E ratio of 1.07 (95% CI = 0.81-1.39)] and high sensitivity (92.9%) in predicting nephrotoxicity development in patients on CMS therapy. CONCLUSIONS: We identified a model that could be incorporated into patient management strategies to reduce the risk of nephrotoxicity in patients requiring CMS therapy.

Validation of a model to predict the risk of nephrotoxicity in patients receiving colistin.

Despite concerns about its nephrotoxicity, colistin often remains the only effective agent for treating multidrug-resistant Gram-negative infections. Published studies have reported a wide range of nephrotoxicity risk factors. To assess the clinical utility of various models, we compared their performances for predicting the risk of nephrotoxicity. We identified a model demonstrating reasonable overall risk assessment, with an observed/expected ratio of 1.29 (95% confidence interval [CI], 0.68 to 1.90) and a positive predictive value of 87.5% for identifying patients at high risk of developing nephrotoxicity.

In vitro assessment and multicenter cohort study of comparative nephrotoxicity rates associated with colistimethate versus polymyxin B therapy.

Despite concerns of nephrotoxicity, polymyxin antibiotics often remain the only susceptible agents for multidrug-resistant (MDR) Gram-negative bacteria. Colistin has been more commonly used clinically due to a perceived safety benefit. We compared the nephrotoxicity of colistin to polymyxin B. The in vitro cytotoxicity of colistin was compared to polymyxin B in two mammalian renal cell lines. To validate the clinical relevance of the findings, we evaluated adult patients with normal renal function who received a minimum of 72 h of polymyxin therapy in a multicenter study. The primary outcome was the prevalence of nephrotoxicity, as defined by the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. Colistin exhibited an in vitro cytotoxicity profile similar to polymyxin B. A total of 225 patients (121 receiving colistimethate, 104 receiving polymyxin B) were evaluated. Independent risk factors for colistimethate-associated nephrotoxicity included age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00 to 1.07; P = 0.03), duration of therapy (OR 1.08; 95% CI, 1.02 to 1.15; P = 0.02), and daily dose by ideal body weight (OR 1.40; 95% CI, 1.05 to 1.88; P = 0.02). In contrast, cystic fibrosis was found to be a protective factor in patients who received colistimethate (OR, 0.03; 95% CI, 0.001 to 0.79; P = 0.04). In a matched analysis based on the risk factors identified (n = 76), the prevalence of nephrotoxicity was higher with colistimethate than with polymyxin B (55.3% versus 21.1%; P = 0.004). Polymyxin B was not found to be more nephrotoxic than colistin and may be the preferred polymyxin for MDR infections. A prospective study comparing the two polymyxins directly is warranted.

An integrated approach to evaluate different tetracycline derivatives for formulary decisions.

PURPOSE: Stenotrophomonas maltophilia has emerged as a critical opportunistic pathogen associated with significant morbidity and mortality. Tetracycline derivatives have been recognized as alternative treatment options, but they have varied pharmacokinetic properties. An integrated approach to different tetracycline derivatives for formulary decisions is reported. METHODS: The minimum inhibitory concentration (MIC) data from clonally diverse bloodstream S. maltophilia isolates were examined, along with the pharmacokinetic profiles of 4 tetracycline derivatives, to predict achievable pharmacodynamic exposures with standard intravenous dosing regimens. Antimicrobial therapy was assessed using the ratio of daily drug acquisition cost relative to the ratio of the free-drug area under the time-concentration curve (fAUC) to minimum inhibitory concentration (MIC) for 90% of isolates (fAUC/MIC90). RESULTS: In our analysis, minocycline had the greatest fAUC/MIC90. Doxycycline was the most financially preferred agent, as calculated using 2020 average wholesale price for base-case estimates of drug acquisition cost. CONCLUSION: An integrated evaluation for antimicrobial formulary decision-making addressed local susceptibility data, pharmacokinetics, pharmacodynamics, dosing regimens, and drug acquisition costs. This comprehensive method is more objective than the conventional approach and warrants validation.

Using clinical decision support to improve urine culture diagnostic stewardship, antimicrobial stewardship, and financial cost: A multicenter experience.

OBJECTIVE: Despite evidence to the contrary, many practitioners continue to inappropriately screen for and treat bacteria in the urine of clinically asymptomatic patients. The purpose of this study was to evaluate the impact of a new order set on the number of urine culture performed, antibiotic days of therapy (DOT), catheter-associated urinary tract infections (CAUTI), and associated financial impact. DESIGN: A quasi-experimental before-and-after intervention. SETTING: We conducted this study at 5 Catholic Health Initiative (CHI) hospitals in Texas that use the same electronic health record (EHR) system. PATIENTS: The study populations included adult patients who had urine culture performed from June 2017 to June 2019. INTERVENTION: The intervention (implemented June 25, 2018) was the addition of a new order set in the electronic health record that required practitioners to choose an indication for the type of urine study. The primary outcome was number of urine cultures performed adjusted for the number of total patient days. RESULTS: Following implementation of the new order set, the number of urine cultures performed among the 5 sites decreased from 1,175.8 tests per 10,000 patient days before the intervention to 701.4 after the intervention (40.4% reduction; P < .01). Antibiotic DOT for patients with a urinary tract infection indication decreased from 102.5 to 86.9 per 1,000 patient days (15.2% reduction; P < .01). The CAUTI standardized infection ratio was 1.0 before the intervention and 0.8 after the intervention (P = .23). The estimated yearly savings following the intervention was US$535,181. CONCLUSIONS: The addition of a new order set resulted in decreases in the number of urine cultures performed and the antibiotic DOT, as well as substantial financial savings.

Outcomes of empiric aminoglycoside monotherapy for Pseudomonas aeruginosa bacteremia.

We evaluated 30-day mortality in patients with Pseudomonas aeruginosa bacteremia. There was no significant difference in mortality among patients who received functional aminoglycoside monotherapy versus inappropriate empiric therapy. Among patients given appropriate empiric therapy, functional aminoglycoside monotherapy was associated with less favorable outcomes compared to beta-lactam monotherapy.

Significant Publications on Infectious Diseases Pharmacotherapy in 2018.

PURPOSE: To summarize the top 10 most influential peer-reviewed infectious diseases (ID) pharmacotherapy articles published in the year 2018. SUMMARY: Members of the Houston Infectious Diseases Network (HIDN) nominated articles that were thought to have most notably contributed to ID pharmacotherapy in 2018, including those related to human immunodeficiency virus (HIV). A total of 26 articles were nominated: 22 articles pertaining to general ID pharmacotherapy and 4 articles involving HIV/AIDS. To select the most significant articles of 2018, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) asking members to vote on their top 10 general ID publications and 1 HIV publication. Of the 462 members surveyed, 213 (46%) and 108 (23%) voted for general ID pharmacotherapy- and HIV-related articles, respectively. The top article(s) for both categories are summarized. CONCLUSION: With the increased emphasis on antimicrobial stewardship initiatives and the growing problem of multidrug-resistant (MDR) organisms, the amount of ID literature centered on stewardship, appropriate treatment durations, and newly approved antimicrobial agents continues to expand, making it challenging for clinicians to stay informed on the most relevant publications. This review summarizes significant ID-related publications in 2018 with the goal of aiding clinicians in staying up to date on the most noteworthy publications in ID pharmacotherapy.

Significant Publications on Infectious Diseases Pharmacotherapy in 2017.

PURPOSE: The most significant peer-reviewed articles pertaining to infectious diseases (ID) pharmacotherapy, as selected by panels of ID pharmacists, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network (HIDN) were asked to nominate peer-reviewed articles that they believed most contributed to the practice of ID pharmacotherapy in 2017, including the areas of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 33 articles related to general ID pharmacotherapy and 4 articles related to HIV/AIDS was compiled. A survey was distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) for the purpose of selecting 10 articles believed to have made the most significant impact on general ID pharmacotherapy and the single significant publication related to HIV/AIDS. Of 524 SIDP members who responded, 221 (42%) and 95 (18%) members voted for general pharmacotherapy- and HIV/AIDS-related articles, respectively. The highest ranked articles are summarized below. CONCLUSION: Remaining informed on the most significant ID-related publications is a challenge when considering the large number of ID-related articles published annually. This review of significant publications in 2017 may aid in that effort.

Significant Publications on Infectious Diseases Pharmacotherapy in 2016.

PURPOSE: This is a summary of the most important articles on infectious diseases (ID) pharmacotherapy published in peer-reviewed literature in 2016 as selected by clinical pharmacists with ID expertise. SUMMARY: The Houston Infectious Diseases Network (HIDN) was asked to identify articles published in peer-reviewed literature in 2016 that were believed to contribute significantly to ID pharmacotherapy, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 46 articles on general ID pharmacotherapy and 8 articles on HIV/AIDS were nominated. Members of the Society of Infectious Diseases Pharmacists (SIDP) were surveyed to select 10 general ID articles believed to have made a significant impact on general ID pharmacotherapy and 1 article most significant to HIV/AIDS pharmacotherapy. Of 445 SIDP members surveyed, 212 (47.6%) and 95 (21.3%) members voted for general ID pharmacotherapy- and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the large number of ID-related articles published each year, it can be challenging to stay current with the most relevant ID publications. This review of significant publications in 2016 may provide a starting point for that process.

An institutional review of antimicrobial stewardship interventions.

In order to combat increasing rates of bacterial resistance, many institutions have implemented antimicrobial stewardship programmes (ASPs) to improve antibiotic use. To ascertain the potential impact of our stewardship programme at Baylor St Luke's Medical Center (Houston, TX), antimicrobial-related interventions were analysed over a 4-year period. ASP recommendations related to antimicrobial therapy from 2009 to 2012 were retrieved from the hospital electronic database and were retrospectively reviewed. The number of interventions for each time period was adjusted to the hospital census data. The interventions were randomly assessed and categorised for clinical significance based on established institutional guidelines. In total, 14654 non-duplicate antimicrobial therapy interventions were retrieved, of which 11874 (81.0%) were audited for accuracy. Approximately 13 interventions were made per 1000 patient-days, but there were no significant patterns observed regarding the number of interventions performed from month to month (range 8-21). The most frequent types of interventions were related to inappropriate dosing (39.0%), antimicrobial selection (20.5%) and drug allergy (13.0%). Serious adverse drug events (ADEs) were potentially avoided in 20.7% of all interventions. Cumulative potential cost avoidance was more than US$6.5 million. In our institution, proper drug and dose selection were the major components of the ASP. Without focusing solely on reduction of drug acquisition costs, implementation of an ASP could still be cost effective by improving the quality of patient care and avoiding ADEs with serious consequences.

Significant publications on infectious diseases pharmacotherapy in 2014.

PURPOSE: The most important articles on infectious diseases (ID) pharmacotherapy published in the peer-reviewed literature in 2014, as nominated and selected by panels of pharmacists and others with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles published in 2014 from prominent peer-reviewed journals that were felt to have a major impact in the field of ID pharmacotherapy. A list of 19 nominated articles on general ID-related topics and 9 articles specifically related to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a national online survey, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles believed to have made a significant contribution to the field of ID pharmacotherapy and 1 article contributing to HIV/AIDS pharmacotherapy. Of the 291 SIDP members surveyed, 134 (46%) and 56 (19%) participated in the selection of general ID-related articles and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles, 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the vast number of articles published each year, it is difficult to remain up-to-date on current, significant ID pharmacotherapy publications. This review of significant publications in 2014 may be helpful by lessening this burden.