Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy.

BACKGROUND: Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients. OBJECTIVE: To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin. METHODS: This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile-associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications. RESULTS: Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 ± 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007). CONCLUSION: Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed.

Pharmacy students' perceptions and attitudes toward face-to-face vs. virtual team-based learning (TBL) in the didactic curriculum: A mixed-methods study.

INTRODUCTION: Virtual TBL is an online adaptation of the team-based learning (TBL) instructional strategy, emphasizing collaborative learning and problem-solving. The emergency shift to virtual TBL during the COVID-19 pandemic presented unique challenges. This study aims to 1) compare overall pharmacy students' perceptions and attitudes toward face-to-face (FTF) TBL vs. virtual TBL in the didactic curriculum and stratify their perceptions and attitudes by various students' characteristics; 2) evaluate students' perceptions of the strengths and weaknesses of virtual TBL. METHODS: This mixed-methods, pre-post, cross-sectional study utilized an anonymous survey to collect the data. Pharmacy students completed a survey to compare their perceptions and attitudes toward learning, class experience, learning outcomes achieved, and satisfaction with FTF TBL vs. virtual TBL using a 5-point Likert-type scale. Additionally, the survey included two open-ended questions to gather students' perceptions of the strengths and weaknesses of virtual TBL. Quantitative survey data were analyzed using the Wilcoxon matched-pairs signed rank exact test, while qualitative survey data were analyzed using thematic analysis. RESULTS: A total of 117 students (response rate of 59.4%) completed the study survey. Pharmacy students perceived FTF TBL to be superior to virtual TBL in their attitudes toward learning, class experience, learning outcomes achieved, and overall satisfaction across various students' characteristics. While the students identified some unique strengths of using virtual TBL, they also highlighted several weaknesses of using this learning modality compared to FTF TBL. CONCLUSIONS: Pharmacy students perceived FTF TBL to be superior to virtual TBL across various students' characteristics. These findings can be helpful to pharmacy programs considering the implementation of virtual TBL in their didactic curricula. Future research should explore whether a purposefully designed virtual TBL environment, as opposed to the pandemic-driven emergency TBL planning, can influence students' perceptions and attitudes toward virtual TBL.

Impact of a Rapid Blood Culture Diagnostic Panel on Time to Optimal Antimicrobial Therapy at a Veterans Affairs Medical Center.

PURPOSE: Utilization of rapid diagnostic testing alongside intensive antimicrobial stewardship interventions improves patient outcomes. We sought to determine the clinical impact of a rapid blood culture identification (BCID) panel in an established Antimicrobial Stewardship Program (ASP) with limited personnel resources. METHODS: A single center retrospective pre- and post-intervention cohort study was performed following the implementation of a BCID panel on patients admitted with at least 1 positive blood culture during the study period. The primary outcome was time to optimal therapy from blood culture collection. Secondary outcomes included days of therapy (DOT), length of stay, and 30-day mortality and readmission rates. RESULTS: 277 patients were screened with 180 patients included, with 82 patients in the pre-BCID and 98 in the post-BCID arms. Median time to optimal therapy was 73.8 hours (IQR; 1.1-79.6) in the pre-BCID arm and 34.7 hours (IQR; 10.9-71.6) in the post-BCID arm (p ≤ 0.001). Median DOT for vancomycin was 4 and 3 days (p ≤ 0.001), and for piperacillin-tazobactam was 3.5 and 2 days (p ≤ 0.007), for the pre-BCID and post-BCID arms, respectively. Median length of hospitalization was decreased from 11 to 9 days (p = 0.031). No significant change in 30-day readmission rate was noted, with a trend toward lower mortality (12% vs 5%; p = 0.086). CONCLUSION: Introduction of BCID into the daily workflow resulted in a significant reduction in time to optimal therapy for bloodstream infections and DOT for select broad-spectrum antibiotics, highlighting the potential benefits of rapid diagnostics even in settings with limited personnel resources.

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.

An evaluation of tedizolid for the treatment of MRSA infections.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA)is a common pathogen in acute bacterial skin and soft tissue infections (ABSSSIs), nosocomial pneumonia, bacteremia, endocarditis, as well as diabetic foot, bone, and joint infections. Areas covered: This review summarizes the randomized controlled trials that evaluated the clinical efficacy of tedizolid in ABSSSIs, which is currently the only United States Food and Drug Administration-labeled indication for tedizolid. Expert opinion: Tedizolid has several potential advantages over linezolid including once-daily dosing, shorter duration of therapy, and increased tolerability. However, its cost will likely limit its adoption for ABSSSIs with MRSA because other oxazolidinone antibiotics are available in less costly generic versions. Tedizolid is also currently being investigated for its use in other MRSA infections including nosocomial pneumonia as well as diabetic foot, bone, and joint infections and tedizolid's use in these disease states appears more promising. Potential indications for future clinical investigation of tedizolid's efficacy and safety include bacteremia and meningitis.

Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation.

PURPOSE: Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. METHODS: This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. FINDINGS: A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). IMPLICATIONS: Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.

Fosfomycin for the treatment of resistant gram-negative bacterial infections. Insights from the Society of Infectious Diseases Pharmacists.

The antimicrobial agent fosfomycin was discovered in 1969, at a time when bacteria had not yet developed extended-spectrum ß-lactamases or carbapenemases. Decades later, it is not uncommon for gram-negative organisms to be multidrug-resistant and even pan-resistant to available antibiotic regimens, leaving clinicians with few therapeutic alternatives. Because fosfomycin has been shown to retain activity against these virulent pathogens, there is renewed interest in its use as a therapeutic agent. Fosfomycin formulations including fosfomycin disodium and the newer tromethamine salt are less toxic than other alternatives and are attractive options for resistant gram-negative and gram-positive infections. Oral fosfomycin tromethamine is approved for urinary tract infections in the United States, and an intravenous formulation is also available outside of the United States for systemic disease. The bactericidal action of fosfomycin occurs at an earlier step in cell wall synthesis than that of ß-lactam antibiotics. From an in vitro standpoint, fosfomycin generally has high activity against ESBL- and carbapenemase-producing Enterobacteriaceae; multidrug-resistant Pseudomonas aeruginosa susceptibility appears to be more dependent on the local antibiogram. Fosfomycin formulations have a large volume of distribution, penetrate biofilms, and concentrate in the urine. Both oral and intravenous fosfomycin formulations are effective for a wide range of gram-negative infections and disease severities; however, clinical studies are limited. Fosfomycin formulations are well-tolerated, and mild gastrointestinal distress is the most common adverse effect. The primary limitations of fosfomycin are the lack of established regimens for complicated infections and the lack of availability of the intravenous formulation in the United States. Further study of this promising agent seems warranted in the current climate of antibiotic resistance.

Interprofessional pharmacy observation activity for third-year dental students.

Interprofessional learning is a key component of today's health sciences education. Within a two-course series in dental pharmacology and therapeutics, a dental curriculum was revised to provide an interprofessional activity to expose dental students to a community pharmacy setting. The objectives of this activity were to augment students' learning about drug laws and prescription writing, as well as to foster interprofessional relationships and collaboration between pharmacists and dentists. Dental students were scheduled for one-hour observations at community pharmacies on campus. Learning objectives to guide this activity focused on demonstrating community pharmacy operating procedures, identifying ways to minimize prescribing and dosing errors, and understanding how pharmacists can assist dentists in prescribing. Following the observation, students were required to submit a written assignment, which accounted for 14 percent of their course grade. All 119 dental students (100 percent) enrolled in the course for the summers of 2012 and 2013 completed the activity. The average grade on the written assignment was 96.2 out of 100. At the end of the course, students were asked to participate in an online course evaluation survey, for which response rates were 37 percent and 43 percent for 2012 and 2013, respectively. The students rated the pharmacy observation activity favorably on this course evaluation. The pharmacy observation activity provided a successful interprofessional component to the didactic pharmacy course and was well received by the dental students as well as the community pharmacists.

Telavancin for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA).

Telavancin is a bactericidal lipoglycopeptide antibiotic that is structurally related to vancomycin. It demonstrates in vitro activity against a variety of Gram-positive pathogens including, but not limited to, methicillin-resistant Staphylococcus aureus (MRSA). Telavancin is currently FDA-approved for the treatment of complicated skin and skin-structure infections. Recently, two randomized clinical trials demonstrated the efficacy and safety of telavancin compared to vancomycin for the treatment of nosocomial pneumonia. Overall, telavancin has a favorable safety profile. However, mild gastrointestinal disturbances and reversible increases in serum creatinine were observed in clinical studies. Additional clinical studies are needed to evaluate telavancin's efficacy and safety in comparison to other antistaphylococcal agents for the treatment of infections such as bacteremia and endocarditis.

Integration of an introductory pharmacy practice experience with an advanced pharmacy practice experience in adult internal medicine.

OBJECTIVE: To describe the development, implementation, and assessment of an internal medicine introductory pharmacy practice experience (IPPE) that was integrated with an existing advanced pharmacy practice experience (APPE) in internal medicine. DESIGN: A structured IPPE was designed for first-, second-, and third-year pharmacy (P1, P2, and P3) students. Activities for the IPPE were based on the established APPE and the individual learner's educational level. ASSESSMENT: Students reported a greater understanding of clinical pharmacists' roles, increased confidence in their clinical skills, and better preparation for APPEs. Peers viewed the approach as innovative and transferable to other practice settings. Participating faculty members provided a greater number of contact hours compared to traditional one-time site visits. CONCLUSIONS: Integrating an IPPE with an existing APPE is an effective and efficient way to provide patient care experiences for students in the P1-P3 years in accordance with accreditation standards.

Trimethoprim-sulfamethoxazole-induced hyponatremia.

An 86-year-old Caucasian male developed hyponatremia while on trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 mg, one tablet by mouth twice daily. Upon discontinuation of therapy, his serum sodium and symptoms improved. He was inadvertently rechallenged several months later with TMP-SMX and had similar symptoms and laboratory abnormalities. TMP-SMX-induced hyponatremia is a rare occurrence. Previous publications have most often reported this phenomenon in combination with hyperkalemia. However, this patient represents a case of TMP-SMX-induced hyponatremia independent of hyperkalemia and provides a rare opportunity to observe a challenge and rechallenge with the offending medication. Although the mechanism behind this adverse drug reaction remains unclear, a score of 7 on the Naranjo probability scale indicates a probable likelihood that TMP-SMX was the cause of the hyponatremia in this patient. This case demonstrates that TMP-SMX can result in the development of hyponatremia independent of hyperkalemia. Health care providers should be aware of the potential for hyponatremia associated with TMP-SMX and consider monitoring electrolytes and renal function during therapy.

Stevens-Johnson syndrome associated with furosemide: a case report.

PURPOSE: To report a probable association of Stevens-Johnson Syndrome (SJS) with furosemide and suspected cross-sensitivity with lincomycin and silver sulfadiazine cream. SUMMARY: A 28-year-old Hispanic male was admitted for SJS, with a prolonged hospital course and unclear etiology throughout the majority of the stay. Patient's medications prior to development of SJS symptoms were stable for 3 months and with the exception of furosemide, all were continued throughout the hospitalization while the SJS resolved. During hospitalization, the patient was unintentionally rechallenged with furosemide, after which the rash reappeared and then worsened further with use of silver sulfadiazine cream. At this point in the hospitalization, the prolonged course of the rash prior to admission and the administration of lincomycin 3 days prior to admission were revealed. This suggests the SJS was initially caused by furosemide, a nonaromatic sulfonamide diuretic, with slow progression prior to hospital admission over approximately 7 weeks, followed by an acute worsening caused by lincomycin, a sulfide antibiotic. CONCLUSION: Use of the Naranjo ADR Probability Scale indicates a probable relationship between SJS and furosemide in this patient. Clinicians should be aware of this rare potential adverse effect, even months after the initiation of therapy.

Telavancin: a new lipoglycopeptide for gram-positive infections.

Telavancin is a lipoglycopeptide derivative of vancomycin. Similar to vancomycin, it demonstrates activity in vitro against a variety of Gram-positive pathogens, including but not limited to methicillin-resistant Staphylococccus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). Modifications to vancomycin's structure expanded telavancin's spectrum of activity in vitro to include organisms such as glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant S. aureus (VRSA) and vancomycin-resistant enterococci (VRE). However, the clinical implications of this are currently unknown. Similar to other glycopeptides, televancin binds to the D-alanyl-D-alanine (D-Ala-D-Ala) terminus in Gram-positive organisms, resulting in inhibition of bacterial cell wall synthesis. In addition, telavancin causes depolarization of the bacterial cell membrane and increased membrane permeability. The resulting activity in vitro is rapidly bactericidal and concentration dependent, with the ratio of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) as the best predictor of activity in animal models to date. In humans, telavancin exhibits a pharmacokinetic profile that permits once-daily intravenous administration. Doses of 7.5 and 10 mg/kg/day have been studied in clinical trials. The need for dosage adjustments based on age, gender and obesity appear unnecessary. In addition, moderate hepatic impairment does not appreciably alter the pharmacokinetics of the drug. Because telavancin is extensively cleared by the kidneys, dosage adjustments will be required in patients with moderate to severe renal impairment. Published phase II and III clinical trials have shown telavancin to be comparable to standard therapy for the treatment of complicated skin and soft tissue infections. Clinical trials in the treatment of S. aureus bacteremia and hospital-acquired pneumonia are under way. Adverse effects overall appear to be mild and reversible, with taste disturbance, foamy urine, headache, procedural site pain, nausea and vomiting being the most commonly reported. However, renal toxicity was reported more frequently with telavancin than with vancomycin in two phase III clinical trials (3% versus 1%). Prolongation of the corrected QT (QTc) interval has been more common with telavancin than comparator agents, but no clinically significant electrocardiogram (ECG) changes or cardiac abnormalities have been observed to date. Although human pregnancy data is not currently available, animal data revealed limb malformations that were possibly related to telavancin therapy. Therefore, the potential teratogenicity of this agent must be considered in women who are pregnant or may become pregnant.

Posaconazole's impact on prophylaxis and treatment of invasive fungal infections: an update.

Owing to the morbidity and mortality associated with invasive fungal infections, particularly in the immunocompromised host, development of new agents for both prevention and treatment is essential. Posaconazole is a recently approved extended-spectrum triazole available as an oral suspension. It exhibits fungistatic activity against a variety of fungal pathogens. Pharmacokinetic data in special patient populations (such as neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome, allogeneic hematopoietic stem cell transplant recipients, febrile neutropenic patients and pediatric patients) have been published recently. Controlled clinical trials establish posaconazole's safety and efficacy in infections, such as oropharyngeal candidiasis and prophylaxis against invasive fungal infections. Data are also emerging in the treatment of zygomycosis and selected cases of aspergillosis. Posaconazole is well tolerated during short- and long-term use, with the most commonly reported adverse events being mild-to-moderate gastrointestinal disturbances. Data suggest a relationship between posaconazole plasma concentrations and prophylactic efficacy; however, the role of therapeutic drug monitoring has yet to be completely defined. Since posaconazole is available only as an oral formulation, its use may be limited in critically ill patient populations.