CNS Aspergillosis and Cryptococcosis with Cytomegalovirus Pneumonia in a Patient with Chronic Lymphocytic Leukemia Treated with Acalabrutinib.

Bruton's tyrosine kinase inhibitors (BTKis) are the preferred treatment for chronic lymphocytic leukemia (CLL). Despite their therapeutic benefits, these targeted agents have been associated with an increased risk of invasive infections. We describe a 68-year-old male who developed multiple bacterial, fungal and viral infections while on treatment with acalabrutinib. To our knowledge, this is the first reported case of concomitant CNS infections with Cryptococcus neoformans and Aspergillus fumigatus, along with cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) pneumonia while on acalabrutinib. This case adds to the scarce literature of fungal and bacterial infections associated with acalabrutinib, raising the suspicion that infection risk is a medication class effect for BTKis.

Candidemia in Adult Patients in the ICU: A Reappraisal of Susceptibility Testing and Antifungal Therapy.

OBJECTIVE: To provide updates on the epidemiology and recommendations for management of candidemia in patients with critical illness. DATA SOURCES: A literature search using the PubMed database (inception to March 2023) was conducted using the search terms "invasive candidiasis," "candidemia," "critically ill," "azoles," "echinocandin," "antifungal agents," "rapid diagnostics," "antifungal susceptibility testing," "therapeutic drug monitoring," "antifungal dosing," "persistent candidemia," and "Candida biofilm." STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Ongoing trials were identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 109 articles were reviewed including 25 pharmacokinetic/pharmacodynamic studies and 30 studies including patient data, 13 of which were randomized controlled clinical trials. The remaining 54 articles included fungal surveillance data, in vitro studies, review articles, and survey data. The current 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Management of Candidiasis provides recommendations for selecting empiric and definitive antifungal therapies for candidemia, but data are limited regarding optimized dosing strategies in critically ill patients with dynamic pharmacokinetic changes or persistent candidemia complicated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Outcomes due to candidemia remain poor despite improved diagnostic platforms, antifungal susceptibility testing, and antifungal therapy selection for candidemia in critically ill patients. Earlier detection and identification of the species causing candidemia combined with recognition of patient-specific factors leading to dosing discrepancies are crucial to improving outcomes in critically ill patients with candidemia. CONCLUSIONS: Treatment of candidemia in critically ill patients must account for the incidence of non-albicans Candida species and trends in antifungal resistance as well as overcome the complex pathophysiologic changes to avoid suboptimal antifungal exposure.

Impact of Fluoroquinolone Susceptibility Suppression on Discharge Prescribing for Acute Uncomplicated Cystitis.

Background: Fluoroquinolones (FQs) are associated with adverse effects and increasing resistance. However, uncomplicated cystitis remains a frequent reason for FQ use. Selective reporting involves withholding susceptibilities for select antimicrobial agents on microbiology reports, in hopes of dissuading use by providers. The purpose of this study was to investigate the impact of FQ susceptibility suppression on discharge prescribing for hospitalized patients with uncomplicated cystitis. Methods: This retrospective quasi-experimental analysis was conducted among adult patients at a 350-bed academic medical center. Its aim was to compare the incidence of FQ prescribing for cystitis at hospital discharge, one year before and after implementation (1 March 2017-31 March 2019) of a policy to suppress FQ urinary susceptibility results for pansusceptible Klebsiella spp and Escherichia coli. FQ appropriateness and risk factors for FQ use were also examined. Results: There was a relative risk reduction of 39% in discharge FQ prescribing when adjusted for discharge team (adjusted risk ratio, 0.61; 95% CI, .40-.93). Almost all FQ use was inappropriate, largely due to organisms' susceptibility to a guideline-preferred agent (n = 61). In multivariate analysis, odds ratios of discharge FQ prescribing were 0.22 (95% CI, .12-.39) for insured patients, 0.43 (95% CI, .21-.86) for patients with antibiotic allergy, and 57.8 (95% CI, 13.7-244) for those receiving inpatient FQ. Discharge from a medicine team was protective against discharge FQ prescribing. Conclusions: With multidisciplinary inpatient medicine services and avoidance of inpatient FQ use, suppression of FQ susceptibilities on pansusceptible urine isolates for Klebsiella spp and E coli may represent an attractive strategy for antibiotic stewardship at hospital discharge.

Comparison of dosing strategies in obese patients prescribed intravenous acyclovir and evaluation of rate of acute kidney injury.

INTRODUCTION: There is limited guidance on the most appropriate dosing strategy for intravenous (IV) acyclovir in obese patients. The manufacturer's labelling suggests using ideal body weight (IBW); however, previous pharmacokinetic studies of obese patients have shown more rapid systemic clearance and lower area under the curve and peak concentrations compared with patients with a body mass index (BMI) < 30 kg/m2. Although pharmacokinetic data suggest that plasma concentrations of acyclovir are best predicted when using adjusted body weight (AdjBW) doses, there is concern about higher rates of acute kidney injury (AKI). METHODS: This was a retrospective cohort review of adult patients with a BMI ≥ 30 kg/m2 prescribed IV acyclovir ≥ 48 hours between 1 January 2014 and 31 August 2021 at a 511-bed academic medical centre. The primary objective was to compare AdjBW with IBW dosing in obese patients who had been prescribed IV acyclovir and to determine whether AdjBW dosing results in higher rates of AKI. RESULTS: Ninety-four patients were included: 61 were in the IBW cohort and 33 were in the AdjBW cohort. The median BMI [IQR] for all patients was 34.7 kg/m2 [31.8-40.6]. Patients in the AdjBW cohort received a significantly higher median acyclovir dose of 800 mg/dose [IQR 700-850] compared with 600 mg/dose [IQR 500-700] for the IBW cohort (P ≤ 0.0001). No patients dosed using AdjBW developed AKI compared with eight (13.1%) in the IBW group. CONCLUSION: In this study, 8.5% of all obese patients receiving acyclovir developed AKI. Further studies are needed to confirm dosing recommendations.

Treatment decisions in VRE bacteraemia: a survey of infectious diseases pharmacists.

Background: VRE infections increased in 2020. High-dose daptomycin (≥10 mg/kg) has shown mortality benefit over other regimens, though daptomycin resistance is increasing. Limited data exist on the practice patterns of ID pharmacists for VRE bloodstream infections (VRE BSIs). Objectives: To describe practice patterns for VRE BSI in ID pharmacists. Methods: A 22-question REDCap survey was distributed to ID pharmacist members of the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (ID PRN) via e-mail listserv. The survey was distributed on 7 April 2022 and remained open for 4 weeks. Results: Sixty-eight pharmacists responded. All pharmacists completed additional training or certification in infectious diseases past their PharmD, and most (70.5%) had been practising for 10 years or less. Pharmacists at academic medical centres (80.0%) were more likely (P = 0.001) to have implemented the updated CLSI breakpoints than pharmacists at other types of institutions (55.2%). Daptomycin was the preferred drug for VRE BSI (92.6%), with 10 mg/kg (72.1%) being the preferred dose. Adjusted body weight was the most common weight (61.2%) used for obese patients. Fourteen days (76.1%) was the most common treatment duration for VRE BSI. Pharmacists defined persistent VRE BSI as 5 days (68.7%) after first blood culture. Conclusions: ID pharmacists overwhelmingly selected high-dose daptomycin for VRE BSI. There were variations in practice and response rate when selecting combination therapy, managing persistent bacteraemia, and treating patients with high daptomycin MICs or previous exposure to daptomycin.

Therapeutic Options for Adult Patients With Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Narrative Review.

OBJECTIVE: To compare the efficacy of antimicrobial therapies used in the management of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. DATA SOURCES: A literature search using the PubMed database (inception to December 2022) was conducted using the search terms "Staphylococcus aureus bacteremia," "methicillin-susceptible Staphylococcus aureus bacteremia," "persistent methicillin-susceptible Staphylococcus aureus bacteremia," and "refractory methicillin-susceptible Staphylococcus aureus bacteremia ." In addition, therapeutic agents which could be used as treatment for MSSA including "nafcillin," "oxacillin," "cefazolin," "ceftaroline," "gentamicin," "rifampin," and "daptomycin" were also combined with the aforementioned search terms to capture data using these agents. STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Articles and abstracts were considered for inclusion in addition to ongoing trials identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 78 articles were reviewed including 17 in vitro or animal model studies and 39 studies including patient data. The remaining 22 articles included guidelines, review articles, and editorials. Recent data evaluating use of dual ß-lactam regimens for persistent MSSA bacteremia were limited to 8 case reports or case series. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: At present, there is little guidance on how to best manage patients with persistent MSSA bacteremia. This narrative review collates the available data to assist clinicians in selecting the best possible antimicrobial regimen when facing this clinical conundrum. CONCLUSIONS: Modification of antimicrobial therapy, in conjunction with source control and infectious diseases consultation, may all be necessary to sterilize blood cultures in patients with persistent MSSA bacteremia.

Impact of a Pharmacist-Managed Outpatient Parenteral Antimicrobial Therapy (OPAT) Service on Cost Savings and Clinical Outcomes at an Academic Medical Center.

Background: Outpatient antimicrobial therapy (OPAT) is managed by a variety of teams, but primarily through an infectious disease clinic. At our medical center, OPAT monitoring is performed telephonically by pharmacists through a collaborative practice agreement under the supervision of an infectious disease physician. The effect of telephonic monitoring of OPAT by pharmacists on patient outcomes is unknown. Methods: This retrospective cohort study was conducted between July 2017 and July 2018 at a 350-bed academic medical center and included adult patients discharged home on IV antibiotics or oral linezolid. The experimental group comprised patients discharged with a consultation for the OPAT management program, whereas the control group comprised patients discharged home without a consultation. The primary outcome was 30-day readmission. Results: In total, 399 patients were included: 243 patients in the OPAT management program group and 156 patients in the control group. The 30-day readmission rates were similar in each cohort (20% vs 19%; P = .8193); however, the 30-day readmission rates were lower in the OPAT management program for patients discharged on vancomycin (19.4% vs 39.1%; P = .004). Conclusions: We did not find a difference in 30-day readmissions between patients receiving pharmacy-driven OPAT management services and those who did not. Patients receiving vancomycin via OPAT had lower 30-day readmissions when included in the pharmacist-driven OPAT management program. Institutions with limited resources may consider reserving OPAT management services for patients receiving antimicrobials that require pharmacokinetic dosing and/or close monitoring.

Variation Among Infectious Diseases Pharmacists for the Treatment of Staphylococcus aureus Bacteremia.

Introduction: Staphylococcus aureus bacteremia (SAB) remains complex, in that optimal treatment for patients, including complicated or persistent infection, remains unclear. Two recent surveys have demonstrated practice variations in SAB among infectious diseases (ID) physicians. Objectives: The purpose of this survey was to examine practice variations in SAB among ID pharmacists. Methods: A thirty-five-question survey was electronically distributed to the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (IDPRN) in Fall 2019 to determine differences in SAB management. Data were analyzed utilizing Pearson's Chi-Square or Fisher's Exact Test. Results: A total of 106 ID pharmacists responded. Only 28% of pharmacists practiced at hospitals with mandatory ID consultation for SAB. A majority (75%) had rapid diagnostic technology (RDT) for identifying SABSI, but 32% of those facilities with RDT did not notify pharmacy with results. Anti-staphylococcal penicillins were preferred for MSSA blood stream infections (BSI) in patients with central nervous system infection and endocarditis, whereas cefazolin was favored for other MSSA BSI. For persistent MRSA BSI, 34% selected daptomycin alone while 38% elected to combine daptomycin and ceftaroline. Pharmacists at hospitals less than 500 beds were more likely to use daptomycin, while those at larger hospitals were more likely to use daptomycin and ceftaroline for persistent MRSA BSI (P < .05). Conclusions: A survey of ID pharmacists showed variation in the management of SABs, as well as the definition and treatment of persistent SAB. Mandatory ID consultation and RDT use to improve SAB management have not been optimized.

Keeping Up With the Literature: New Solutions for an Old Problem.

Pharmacists utilize medical literature to provide evidence-based care to patients. However, staying up to date with current literature can be challenging, especially with the increasing number of publications produced in a growing number of journals. While evaluating literature is a standard in pharmacy education and training, the specific skill of keeping up with the literature is often not included. We explore the following 5 strategies to help pharmacists stay up to date with the literature: medical journals, social media, podcasts, teaching/precepting, and continuing education/board certification. Pharmacists are encouraged to evaluate which tactics fit best into their practice and incorporate them into their workflow, as well as routinely reflect on the system they create and continue to modify as needed.

Evaluation of Ceftazidime Use in the Neonatal Intensive Care Unit and Association With Cephalosporin-Resistant Gram-Negative Bacteria.

BACKGROUND: Cefotaxime shortage in 2015 led to increased ceftazidime use in the neonatal intensive care unit (NICU). OBJECTIVE: The purpose was to explore whether ceftazidime increases risk for development of resistant gram-negative organisms. METHODS: Retrospective evaluation of NICU patients with cultures positive for Escherichia coli, Pseudomonas aeruginosa, Klebsiella species, or Stenotrophomonas maltophilia between January1, 2015 and August 31, 2020. Isolates were excluded if obtained from same patient and source within 90 days or if patient ≤7 days of life or admitted from a referring hospital. Data collection included demographics and clinical parameters, and culture/susceptibility data. The primary objective was comparison of pathogens and clinical parameters in those with and without third-generation cephalosporin resistance. The secondary objectives included a comparison between those with and without ceftazidime exposure and identification of factors associated with resistance. Comparisons were made using χ2, Fisher exact tests, or Wilcoxon tests. A logistic regression was used to identify risk factors for resistance. RESULTS: Overall, 349 isolates, representing 215 patients, were included. The most common source was endotracheal (n = 192, 55.0%) and pathogens were E coli (31.8%) and P aeruginosa (29.2%). Overall, 12.3% (n = 43) were resistant and these were obtained after longer parenteral nutrition (PN), central line access, and antibiotic days versus susceptible isolates. Higher resistance was noted after ceftazidime exposure versus no exposure, 19.1% versus 6.6%. Each day of ceftazidime was associated with 13% greater odds of P aeruginosa resistance (adjusted odds ratio: 1.13 [95% confidence interval: 1.03-1.23]). CONCLUSION AND RELEVANCE: Ceftazidime duration was associated with increased risk for P aeruginosa resistance. Additional studies are needed to confirm these findings.

Review of Ceftazidime-Avibactam, Meropenem-Vaborbactam, and Imipenem/Cilastatin-Relebactam to Target Klebsiella pneumoniae Carbapenemase-Producing Enterobacterales.

Objective: To provide a review of 3 novel antimicrobial agents-ceftazidime-avibactam, meropenem-vaborbactam, and imipenem/cilastatin-relebactam-regarding treatment of Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC). Data Sources: A literature search of PubMed and OVID (MEDLINE) was performed up to March 2020 using the following search terms: Vabomere, meropenem-vaborbactam, vaborbactam, RPX7009, Klebsiella pneumoniae carbapenemase, KPC, carbapenem-resistant Enterobacteriaceae, CRE, relebactam, imipenem-relebactam, MK-7655, ceftazidime-avibactam. Abstracts from conferences, article bibliographies, and product information were also reviewed. Study Selection and Data Extraction: Articles were first screened by English language, then title, then abstract, and finally by review of the full article. Fifty-five clinical and preclinical studies were included. Data Synthesis: These 3 novel ß-lactam/ß-lactamase inhibitor combinations have shown considerable improvement in safety and efficacy as compared with traditional polymyxin-based combination therapy for the treatment of KPC infections. While meropenem-vaborbactam has not shown improved activity against Pseudomonas aeruginosa, it has shown decreased rates of resistance to KPC versus ceftazidime-avibactam. Conclusions: With increasing incidence of KPC infections on a global scale, pharmacists should be aware of the notable similarities and differences between these 3 agents, and the current data supporting their use. Pharmacists may want to consider meropenem-vaborbactam over ceftazidime-avibactam for KPC infections due to decreased likelihood of resistance.

Daptomycin dosing in obese patients: analysis of the use of adjusted body weight versus actual body weight.

BACKGROUND: Food and Drug Administration-approved daptomycin dosing uses actual body weight, despite limited dosing information for obese patients. Studies report alterations in daptomycin pharmacokinetics and creatine phosphokinase elevations associated with higher weight-based doses required for obese patients. Limited information regarding clinical outcomes with alternative daptomycin dosing strategies in obesity exists. OBJECTIVE: This study evaluates equivalency of clinical and safety outcomes in obese patients with daptomycin dosed on adjusted body weight versus a historical cohort using actual body weight. METHODS: This retrospective, single center study compared equivalency of outcomes with two one-sided tests in patients with body mass index ⩾30 kg/m2 who received daptomycin dosed on actual body weight versus adjusted body weight. The primary outcome was clinical failure. Secondary outcomes included 90-day readmission and 90-day mortality. A combined safety endpoint included creatine phosphokinase elevation, patient-reported myopathy, and rhabdomyolysis. RESULTS: A total of 667 patients were screened for inclusion; 101 patients were analyzed with 50 in the actual body weight cohort and 51 in the adjusted body weight cohort. The two regimens were statistically equivalent for clinical failure (2% actual body weight versus 4% adjusted body weight; p < 0.001 for equivalency). The two regimens were also statistically equivalent for 90-day mortality (6% actual body weight versus 4% adjusted body weight; p = 0.0014 for equivalency). Limitations include single center, retrospective design, and sample size. Daptomycin dosing intensified throughout the study period. CONCLUSION: The two daptomycin dosing cohorts were statistically equivalent for both clinical failure and 90-day mortality. More data are needed to assess outcomes with higher (⩾8 mg/kg/day) daptomycin doses in this patient population.

Adding double carbapenem therapy to the armamentarium against carbapenem-resistant Enterobacteriaceae bloodstream infections.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) constitute a threat, since they cause infections with high mortality rates. Historically, polymyxin-based therapies have been the regimens of choice for CRE bloodstream infection (BSI). Recent studies have shown improved outcomes with ß-lactam-based therapies, including double carbapenem regimens for CRE BSIs compared to polymyxin-based regimens. The purpose of this report was to review the data supporting double carbapenem therapy for CRE BSI and provide recommendations regarding their use. METHODS: A systematic literature search through 31 January 2018 was performed. RESULTS: Multiple in vitro studies have described synergistic activity with ertapenem-based double carbapenem regimens for KPC-producing Enterobacteriaceae. Additionally, efficacy has been observed with double carbapenem regimens in multiple case reports and case series. A prospective multi-centre observational study of double carbapenem therapies in patients with CRE BSIs showed lower mortality compared to standard therapy. CONCLUSIONS: Clinicians should consider double carbapenem therapy as an option for treating CRE infections.

Impact of Ceftazidime Use on Susceptibility Patterns in the Neonatal Intensive Care Unit.

BACKGROUND: Ceftazidime use in the neonatal intensive care unit (NICU) has increased after a cefotaxime shortage. The impact of this change is unknown. The purpose was to assess the effect of increased ceftazidime use on susceptibilities of Gram-negative organisms in the NICU. METHODS: Retrospective study of Gram-negative isolates identified in blood, urine, cerebrospinal fluid, tracheostomy, abdominal fluid and pleural fluid cultures from a single-center NICU over a 5-year period. Duplicate cultures that occurred within 90 days were noted. Pre- and postshortage periods were defined based on cessation of cefotaxime. Third- and fourth-generation cephalosporin susceptibility rates were compared between periods, as well as rates of extended-spectrum beta-lactamase (ESBL) Escherichia coli and Klebsiella species. RESULTS: Analysis included 666 isolates. Twelve (1.8%) were duplicate isolates that occurred after a 90-day period. The preshortage period included 464 (69.7%) isolates, and the postshortage included 202 (30.3%). No significant differences in susceptibility rates were noted when excluding duplicates. No difference in ESBL rates for E. coli were noted between periods (3.8% vs. 4.9%, P =1.000). No ESBL-positive Klebsiella species were identified. A post-hoc analysis of duplicate isolates demonstrated significant lower susceptibility rates for Pseudomonas aeruginosa to ceftazidime (risk ratio 0.58; 95% CI: 0.43-0.79) and cefepime (risk ratio 0.66; 95% CI: 0.51-0.86). CONCLUSIONS: Ceftazidime use did not appear to affect susceptibility rates for third- and fourth-generation cephalosporins for most Gram-negative organisms in the short-term of 1.5 years. However, susceptibility rates for P. aeruginosa decreased when evaluating duplicate isolates. Long-term monitoring is needed to assess the true impact.

Risk Factors for Failure in Complicated Intraabdominal Infections.

OBJECTIVES: Approximately 20% of patients with complicated intraabdominal infections (cIAIs) fail therapy. The purpose of this study was to identify risk factors for clinical failure in patients with cIAIs. METHODS: International Classification of Diseases, Ninth Revision codes for cIAIs were obtained to identify patients. Adult patients who received at least 48 hours of intravenous antibiotics were included. Patients were chronologically matched for age, sex, and comorbidities. The primary outcome was clinical failure. Statistical analysis included bivariate tests and multivariable logistic regression. RESULTS: A total of 1405 patients were screened; 139 patients were included. The median (interquartile range) age and Charlson Comorbidity Index were 54 (37-62) years and 0 (0-1), respectively. Clinical failure was observed in 47 patients (34%), with 5 deaths (3.6%). Multivariate analysis of the unmatched population showed older age was protective (odds ratio [OR] 0.967, 95% confidence interval [CI] 0.944-0.991). In the matched population elevated serum creatinine (OR 2.2168, 95% CI 1.091-4.308) and increased time to source control (OR 1.015, 95% CI 1.000-1.030) were predictive of clinical failure. CONCLUSIONS: In a low comorbid cIAI population with and without surgical intervention, serum creatinine was an independent risk factor for clinical failure. In the matched case-control of patients, time to source-control procedure was an independent predictor of clinical failure.