Pharmacotherapeutic Considerations in the Treatment of Nontuberculous Mycobacterial Infections: A Primer for Clinicians.

Nontuberculous mycobacteria (NTM) can cause a variety of infections, including serious pulmonary disease. Treatment encompasses polypharmacy, with a targeted regimen of 2-5 active medications, depending on site of infection, species, and clinical characteristics. Medications may include oral, intravenous, and inhalational routes. Medication acquisition can be challenging for numerous reasons, including investigational status, limited distribution models, and insurance prior authorization. Additionally, monitoring and managing adverse reactions and drug interactions is a unique skill set. While NTM is primarily medically managed, clinicians may not be familiar with the intricacies of medication selection, procurement, and monitoring. This review offers insights into the pharmacotherapeutic considerations of this highly complex disease state, including regimen design, medication acquisition, safety monitoring, relevant drug-drug interactions, and adverse drug reactions.

The prevalence of gram-negative bacteria with difficult-to-treat resistance and utilization of novel ß-lactam antibiotics in the southeastern United States.

Objective: To evaluate temporal trends in the prevalence of gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) in the southeastern United States. Secondary objective was to examine the use of novel ß-lactams for GNB with DTR by both antimicrobial use (AU) and a novel metric of adjusted AU by microbiological burden (am-AU). Design: Retrospective, multicenter, cohort. Setting: Ten hospitals in the southeastern United States. Methods: GNB with DTR including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. from 2015 to 2020 were tracked at each institution. Cumulative AU of novel ß-lactams including ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, and cefiderocol in days of therapy (DOT) per 1,000 patient-days was calculated. Linear regression was utilized to examine temporal trends in the prevalence of GNB with DTR and cumulative AU of novel ß-lactams. Results: The overall prevalence of GNB with DTR was 0.85% (1,223/143,638) with numerical increase from 0.77% to 1.00% between 2015 and 2020 (P = .06). There was a statistically significant increase in DTR Enterobacterales (0.11% to 0.28%, P = .023) and DTR Acinetobacter spp. (4.2% to 18.8%, P = .002). Cumulative AU of novel ß-lactams was 1.91 ± 1.95 DOT per 1,000 patient-days. When comparing cumulative mean AU and am-AU, there was an increase from 1.91 to 2.36 DOT/1,000 patient-days, with more than half of the hospitals shifting in ranking after adjustment for microbiological burden. Conclusions: The overall prevalence of GNB with DTR and the use of novel ß-lactams remain low. However, the uptrend in the use of novel ß-lactams after adjusting for microbiological burden suggests a higher utilization relative to the prevalence of GNB with DTR.

A Baker's Dozen of Top Antimicrobial Stewardship Intervention Publications in 2022.

Keeping abreast of the antimicrobial stewardship-related articles published each year is challenging. The Southeastern Research Group Endeavor identified antimicrobial stewardship-related, peer-reviewed literature that detailed an actionable intervention during 2022. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight actionable interventions used by antimicrobial stewardship programs to capture potentially effective strategies for local implementation.

Serratia endocarditis: antimicrobial management strategies and clinical outcomes.

OBJECTIVES: The incidence of Serratia endocarditis is increasing, yet optimal treatment has not been defined. Our objective was to investigate the outcomes of patients with Serratia endocarditis by treatment strategy. METHODS: We reviewed adult patients with definitive Serratia endocarditis at two independent health systems between July 2001 and April 2023. Combination therapy was defined as receipt of ≥2 in vitro active agents for ≥72 h. RESULTS: Seventy-five patients were included; 64% (48/75) were male and 85% (64/75) were people who inject drugs. Compared with monotherapy, receipt of combination therapy was associated with lower rates of microbiological failure (0% versus 15%, P = 0.026) and 90 day all-cause mortality (11% versus 31%, P = 0.049). Antimicrobial discontinuation due to an adverse event was more common among patients receiving combination therapy compared with monotherapy (36% versus 8%, P = 0.058). CONCLUSIONS: In the largest series of Serratia endocarditis to date, combination antibiotic treatment was associated with improved outcomes. However, larger, prospective studies are warranted.

Impact of clinical pharmacist discharge prescription review on the appropriateness of antibiotic therapy: a retrospective comparison.

BACKGROUND: Inappropriate antibiotic prescribing upon hospital discharge has been identified as a significant problem. Despite high rates of antibiotic prescription errors, there is no widely accepted antimicrobial stewardship initiative to prevent such errors. AIM: The primary objective of this study was to determine the impact of hospital-based clinical pharmacist discharge prescription review on the appropriateness of antibiotic prescriptions. METHOD: This was an observational study comparing the appropriateness of hospital discharge antibiotic prescriptions between two similar internal medicine services. One cohort of patients was admitted to medicine services where rounding clinical pharmacists performed routine antibiotic discharge assessment, and the comparator cohort was admitted to hospitalist services without routine pharmacist discharge antibiotic review. RESULTS: Our study included 150 cases per cohort. Baseline characteristics were similar between groups, except for increased age (p = 0.025) and fewer cases of acute bacterial skin & skin structure infections (p = 0.001) in the hospitalist cohort. Antibiotic appropriateness was considerably greater in the medicine (pharmacist) group versus hospitalist group [(83% versus 54%, respectively (p < 0.00001)]. The difference in appropriateness was mainly driven by pneumonia and urinary tract infection prescriptions. CONCLUSION: Appropriateness of antibiotic prescriptions significantly improved in the setting of pharmacist discharge review. This initiative highlights the important role of clinical pharmacists in outpatient antimicrobial stewardship.

Adapting the layered learning model to a virtual international exchange program.

INTRODUCTION: The layered learning model (LLM) is a well-established teaching approach designed for attending preceptors to train post-graduate learners and to precept students. The adaptation of a LLM to a virtual exchange program has not been previously described. The purpose of this study was to evaluate the effectiveness of the longitudinal virtual international exchange program in applying principles of the LLM to multiple levels of learners and instructors at West Virginia University (WVU) School of Pharmacy and Kitasato University (KU) School of Pharmacy. METHODS: The online survey piloted the impact of applying the LLM to virtual international exchange sessions on improving participant knowledge in pharmacy practice, pharmacy education, cultural practices, and cultural awareness. The survey questions assessed the program's structure and effectiveness in achieving learning outcomes related to pharmacy residency topics and cultural competency using a five-point Likert scale. RESULTS: Median scores of the effectiveness of the virtual international exchange program structure were high (≥ 4.0). Two questions evaluating the use of the LLM had median scores of 4.0. All nine residency-related questions were rated ≥3.0. The median scores for three questions evaluating small group discussions and the use of the LLM were rated significantly higher by WVU participants than KU participants. There were no significant differences in program structure and learning outcome ratings between participant groups (student vs. resident/fellow vs. preceptor/faculty). CONCLUSIONS: Application of the LLM to the virtual international exchange program was positively received by participants, particularly by United States participants.

Evaluating the Medication Regimen Complexity Score as a Predictor of Clinical Outcomes in the Critically Ill.

Background: Medication Regimen Complexity (MRC) refers to the combination of medication classes, dosages, and frequencies. The objective of this study was to examine the relationship between the scores of different MRC tools and the clinical outcomes. Methods: We conducted a retrospective cohort study at Roger William Medical Center, Providence, Rhode Island, which included 317 adult patients admitted to the intensive care unit (ICU) between 1 February 2020 and 30 August 2020. MRC was assessed using the MRC Index (MRCI) and MRC for the Intensive Care Unit (MRC-ICU). A multivariable logistic regression model was used to identify associations among MRC scores, clinical outcomes, and a logistic classifier to predict clinical outcomes. Results: Higher MRC scores were associated with increased mortality, a longer ICU length of stay (LOS), and the need for mechanical ventilation (MV). MRC-ICU scores at 24 h were significantly (p < 0.001) associated with increased ICU mortality, LOS, and MV, with ORs of 1.12 (95% CI: 1.06−1.19), 1.17 (1.1−1.24), and 1.21 (1.14−1.29), respectively. Mortality prediction was similar using both scoring tools (AUC: 0.88 [0.75−0.97] vs. 0.88 [0.76−0.97]. The model with 15 medication classes outperformed others in predicting the ICU LOS and the need for MV with AUCs of 0.82 (0.71−0.93) and 0.87 (0.77−0.96), respectively. Conclusion: Our results demonstrated that both MRC scores were associated with poorer clinical outcomes. The incorporation of MRC scores in real-time therapeutic decision making can aid clinicians to prescribe safer alternatives.

A Baker's Dozen of Top Antimicrobial Stewardship Intervention Publications in 2020.

The number of articles related to antimicrobial stewardship published each year has increased significantly over the last decade. Keeping up with the literature, particularly the most innovative, well-designed, or applicable to one's own practice area, can be challenging. The Southeastern Research Group Endeavor (SERGE-45) network reviewed antimicrobial stewardship-related, peer-reviewed literature from 2020 that detailed actionable interventions. The top 13 publications were summarized following identification using a modified Delphi technique. This article highlights the selected interventions and may serve as a key resource for teaching and training, and to identify novel or optimized stewardship opportunities within one's institution.

Impact of anti-anaerobic antibiotic activity on graft-versus-host disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients at an institution that utilizes antibiotic cycling.

BACKGROUND: At our institution, antibiotic cycling for febrile neutropenia is utilized to increase heterogeneity of antibiotic exposure in patients who have undergone an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Development of acute graft-versus-host disease (aGVHD) has been associated with low diversity within stool microbiota. To date, discordant outcomes have been reported implicating anti-anaerobic antibiotic use with the development of aGVHD, and there is currently a lack of published data available in an antibiotic cycled environment. The objective of this study was to determine if there is a difference in the rate of aGVHD in patients who receive anti-anaerobic cycled antibiotics compared with other cycled antibiotics. METHODS: This was a retrospective, observational study evaluating rates of aGVHD in patients who received antibiotics with anaerobic vs non-anaerobic coverage post-allo-HSCT from January 2008 to January 2018. Univariate and multivariable analyses were performed to assess associations with aGVHD. Secondary outcomes include rate of all stages of aGVHD, progression-free survival, overall survival, 100-day treatment-related mortality (TRM), and 1-year TRM. RESULTS: A total of 273 patients were included in the study. Baseline characteristics were similar between groups, except patients who received anti-anaerobic antibiotics had more unrelated donors (P = .002), were more likely to get myeloablative preparatory regimens (P = .009), had less subtherapeutic calcineurin inhibitor serum concentrations (P = .001), and more often received T-cell depletion (P = .004). The incidence of grades II-IV aGVHD post-HSCT in patients who received anti-anaerobic antibiotics was 32.6% compared with 18.8% in patients who received other antibiotics (P = .015). Multivariable analysis showed that the occurrence of grades II-IV aGVHD was associated with cytomegalovirus reactivation (OR = 2.1, 95% CI = 1.0-4.5, P = .047), unrelated donors (OR = 6.1, 95% CI = 2.3-16.6, P < .001), and use of anti-anaerobic antibiotics (OR = 2.3, 95% CI = 1.1-4.8, P = .021). A 100-day TRM in patients who received anti-anaerobic antibiotics was 9.6% compared with 3.6% in patients who received other antibiotics (P = .046). One-year TRM in patients who received anti-anaerobic antibiotics was 25.2% compared with 13.8% in patients who received other antibiotics (P = .017). There was no statistically significant difference seen between groups in progression free survival or overall survival. CONCLUSION: Variability in baseline characteristics limits ability to make strong conclusions, but patients who received antibiotics with anaerobic coverage during the first 30 days after an allogeneic HSCT appeared to be at an increased risk of developing aGVHD and TRM. Larger well-controlled trials are warranted to further clarify these relationships.

Intravenous Zanamivir: A Viable Option for Critically Ill Patients With Influenza.

OBJECTIVE: To review the pharmacology, clinical trial data, and clinical implications for the intravenous formulation of zanamivir. DATA SOURCES: MEDLINE, PubMed, EMBASE, and Google Scholar were searched during November 2019 to July 2020. Search terms zanamivir and neuraminidase inhibitor were used. STUDY SELECTION AND DATA EXTRACTION: All human trials and major reports from compassionate use programs with the intravenous zanamivir (IVZ) formulation were assessed and reviewed here. DATA SYNTHESIS: IVZ was found to be similar but not superior to oral oseltamivir in hospitalized patients when studied in populations with very low baseline oseltamivir resistance. IVZ provides an effective alternative for critically ill patients when oral antiviral therapy is not preferred or when oseltamivir resistance is increased. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: IVZ was recently authorized for use by the European Medicines Agency, and it is eligible for consideration in emergency use protocols and US stockpile inclusion. It will be of particular interest in critically ill patients especially during influenza seasons with appreciable oseltamivir and peramivir resistance. CONCLUSIONS: The available information suggests that the intravenous formulation of zanamivir offers a viable alternative treatment for critically ill patients with influenza, especially when resistance to other agents is present.

Impact of an automatic hospital probiotic protocol on Clostridioides (Clostridium) difficile infection (CDI) rates and CDI antibiotic usage in a community hospital setting.

The aim of the present study was to see how widespread preventative use of the probiotic Saccharomyces boulardii via automatic protocol in hospitalised patients receiving antibacterials affected rates of hospital-associated Clostridioides (Clostridium) difficile infection (HA-CDI). Rates of HA-CDI appeared to be similar between the pre-protocol and protocol periods. Use of CDI treatment antibiotics (oral metronidazole and oral vancomycin) was also similar. Laboratory-confirmed isolation of S. boulardii from sterile body sites was identified in five patients during the protocol versus only one case in the pre-protocol years.

The 2016 ACCP Pharmacotherapy Didactic Curriculum Toolkit.

The 2016 American College of Clinical Pharmacy (ACCP) Educational Affairs Committee was charged with updating and contemporizing ACCP's 2009 Pharmacotherapy Didactic Curriculum Toolkit. The toolkit has been designed to guide schools and colleges of pharmacy in developing, maintaining, and modifying their curricula. The 2016 committee reviewed the recent medical literature and other documents to identify disease states that are responsive to drug therapy. Diseases and content topics were organized by organ system, when feasible, and grouped into tiers as defined by practice competency. Tier 1 topics should be taught in a manner that prepares all students to provide collaborative, patient-centered care upon graduation and licensure. Tier 2 topics are generally taught in the professional curriculum, but students may require additional knowledge or skills after graduation (e.g., residency training) to achieve competency in providing direct patient care. Tier 3 topics may not be taught in the professional curriculum; thus, graduates will be required to obtain the necessary knowledge and skills on their own to provide direct patient care, if required in their practice. The 2016 toolkit contains 276 diseases and content topics, of which 87 (32%) are categorized as tier 1, 133 (48%) as tier 2, and 56 (20%) as tier 3. The large number of tier 1 topics will require schools and colleges to use creative pedagogical strategies to achieve the necessary practice competencies. Almost half of the topics (48%) are tier 2, highlighting the importance of postgraduate residency training or equivalent practice experience to competently care for patients with these disorders. The Pharmacotherapy Didactic Curriculum Toolkit will continue to be updated to provide guidance to faculty at schools and colleges of pharmacy as these academic pharmacy institutions regularly evaluate and modify their curricula to keep abreast of scientific advances and associated practice changes. Access the current Pharmacotherapy Didactic Curriculum Toolkit at http://www.accp.com/docs/positions/misc/Toolkit_final.pdf.

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients.

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m(2), respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h; P = 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter; P = 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter; P = 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.).

Evaluation of a bedside scoring system for predicting clinical cure and recurrence of Clostridium difficile infections.

PURPOSE: The accuracy of a bedside scoring system, ATLAS, for predicting clinical cure and recurrence of Clostridium difficile infections (CDIs) was evaluated. METHODS: A single-center retrospective medical record review was performed for symptomatic adult patients with stool assay-diagnosed CDI treated with metronidazole or vancomycin or both. Multiple logistic regression analysis was performed to assess the potential association of the ATLAS score and other potential factors on achieving cure and 90-day CDI recurrence. ATLAS scores were calculated, and risk factors for severe CDI, severe-complicated CDI, decreased cure rates, and recurrence were recorded. RESULTS: Data from 245 adult patients were assessed. ATLAS scores showed a significant inverse association with the cure rate (p = 0.009) but not with the 90-day recurrence rate (p = 0.901). The only ATLAS component to be independently associated (inversely) with cure was the concomitant use of antibiotics (p = 0.022). Metronidazole was initiated in 97% of patients, with 32% switching to oral vancomycin. Longer courses of vancomycin were associated with a higher cure rate (p = 0.0009) but not with recurrence (p = 0.170). Complicated cases were less likely to be cured (p = 0.027) and more likely to recur within 90 days (p = 0.002). Antibiotics continued after CDI treatment was associated with recurrence (p = 0.055). CONCLUSION: A low ATLAS score was found to correlate with higher cure rates in patients with CDI receiving metronidazole, oral vancomycin, or both. However, the score could not predict CDI recurrence.

Review of the new delayed-release oral tablet and intravenous dosage forms of posaconazole.

The triazole antifungal posaconazole was first approved as an oral suspension formulation. Despite pharmacokinetic target attainment and clinical efficacy in premarketing trials, postmarketing analyses indicated unpredictable bioavailability resulting in subtherapeutic concentrations and reports of breakthrough fungal infections. The newly approved posaconazole delayed-release tablet and intravenous formulations display more consistent bioavailability in the presence of concomitant disease states, medications, and dietary considerations that classically alter drug concentrations of the oral suspension. Both the delayed-release tablet and intravenous formulation display a similar adverse-effect profile to the oral suspension. The posaconazole delayed-release oral tablet is not significantly affected by gastric acid suppression therapy, and the intravenous dosage form provides an option for patients who are intubated or unable to tolerate oral medications. Pharmacoeconomic considerations, particularly with intravenous posaconazole, will likely play a role in dosage form selection and frequency of use. Due to sustained, higher drug concentrations, the new posaconazole formulations hold promise for greater efficacy in antifungal prophylaxis and bring opportunity for further study in the treatment of invasive mycoses.

Role of doxycycline in Clostridium difficile infection acquisition.

OBJECTIVE: To evaluate and review the literature surrounding the potential protective benefit of tetracyclines, particularly doxycycline, in reducing Clostridium difficile infection (CDI) acquisition. DATA SOURCES: MEDLINE/PubMed, Google Scholar, and International Pharmaceutical Abstracts were searched through January 2014 using the search terms doxycycline, tetracycline, and Clostridium difficile. STUDY SELECTION AND DATA EXTRACTION: Relevant studies, case reports, and review articles were screened for inclusion. Bibliographies of articles were extensively reviewed for additional sources. DATA SYNTHESIS: Doxycycline is a second-generation tetracycline antibiotic indicated for use in a variety of clinical syndromes and has activity against aerobic Gram-positive and -negative, anaerobic, and atypical bacteria as well as protozoan parasites. Although not used therapeutically to treat CDI, doxycycline may prevent or attenuate the virulence factors of toxigenic C difficile. Current literature does not indicate an increased risk of development of CDI with doxycycline use. In 3 retrospective studies, the use of doxycycline was associated with a protective effect. CONCLUSIONS: Doxycycline has been shown to have potential protective effects against the development of CDI. Although further randomized placebo-controlled studies are needed, available data suggest that the use of doxycycline in place of alternative antimicrobials, when appropriate, may be a useful antimicrobial stewardship strategy aimed at reducing the incidence of CDI.