Isavuconazole Is as Effective as and Better Tolerated Than Voriconazole for Antifungal Prophylaxis in Lung Transplant Recipients.

BACKGROUND: Invasive fungal infections (IFIs) are common following lung transplantation. Isavuconazole is unstudied as prophylaxis in organ transplant recipients. We compared effectiveness and tolerability of isavuconazole and voriconazole prophylaxis in lung transplant recipients. METHODS: A single-center, retrospective study of patients who received isavuconazole (September 2015-February 2018) or voriconazole (September 2013-September 2015) for antifungal prophylaxis. IFIs were defined by EORTC/MSG criteria. RESULTS: Patients received isavuconazole (n = 144) or voriconazole (n = 156) for median 3.4 and 3.1 months, respectively. Adjunctive inhaled amphotericin B (iAmB) was administered to 100% and 41% of patients in the respective groups. At 1 year, 8% of patients receiving isavuconazole or voriconazole developed IFIs. For both groups, 70% and 30% of IFIs were caused by molds and yeasts, respectively, and breakthrough IFI (bIFI) rate was 3%. Outcomes did not significantly differ for patients receiving or not receiving iAmB. Independent risk factors for bIFI and breakthrough invasive mold infection (bIMI) were mold-positive respiratory culture and red blood cell transfusion >7 units at transplant. Bronchial necrosis >2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI. Isavuconazole and voriconazole were discontinued prematurely due to adverse events in 11% and 36% of patients, respectively (P = .0001). Most common causes of voriconazole and isavuconazole discontinuation were hepatotoxicity and lack of oral intake, respectively. Patients receiving ≥90 days prophylaxis had fewer IFIs at 1 year (3% vs 9%, P = .02). IFIs were associated with increased mortality (P = .0001) and longer hospitalizations (P = .0005). CONCLUSIONS: Isavuconazole was effective and well tolerated as antifungal prophylaxis following lung transplantation.

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients.

We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring.

Adverse Events Lead to Drug Discontinuation More Commonly among Patients Who Receive Nafcillin than among Those Who Receive Oxacillin.

Nafcillin and oxacillin are used interchangeably in clinical practice, yet few studies have evaluated the safety of these two agents. Our objective was to compare the differential tolerabilities of nafcillin and oxacillin among hospitalized patients. We conducted a retrospective cohort study of all patients who received 12 g/day of nafcillin or oxacillin for at least 24 h. Two hundred twenty-four patients were included. Baseline characteristics and comorbidities were similar among patients receiving nafcillin (n = 160) and those receiving oxacillin (n = 64). Hypokalemia, defined as a potassium level of ≤3.3 mmol/liter or ≤2.9 mmol/liter or as a ≥0.5-mmol/liter decrease from the baseline level, occurred more frequently among patients who received nafcillin (51%, 20%, and 56%, respectively) than among those who received oxacillin (17%, 3%, and 34%, respectively; P < 0.0001, P = 0.0008, and P = 0.005, respectively). By multivariate logistic regression analysis, receipt of nafcillin was an independent predictor of severe hypokalemia (odds ratio [OR] = 6.74; 95% confidence interval [CI], 1.46 to 31.2; P = 0.02). Rates of hepatotoxicity did not differ between groups; however, acute kidney injury occurred more commonly with nafcillin than with oxacillin (18% versus 6%; P = 0.03). Overall, 18% of patients who received nafcillin discontinued therapy prematurely due to adverse events, compared to 2% of patients who received oxacillin (P = 0.0004). Nafcillin treatment is associated with higher rates of adverse events and treatment discontinuation than oxacillin among hospitalized adult patients. These findings have important implications for patients in both inpatient and outpatient settings, particularly patients who require long-term therapy and cannot be monitored routinely. Future randomized controlled studies evaluating the efficacy, costs, and tolerability of nafcillin versus oxacillin are warranted.

Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis.

OBJECTIVES: The optimum trough concentration of voriconazole for clinical response and safety is controversial. The objective of this review was to determine the optimum trough concentration of voriconazole and evaluate its relationship with efficacy and safety. METHODS: MEDLINE, EMBASE, ClinicalTrials.gov, the Cochrane Library and three Chinese literature databases were searched. Observational studies that compared clinical outcomes below and above the trough concentration cut-off value were included. We set the trough concentration cut-off value for efficacy as 0.5, 1.0, 1.5, 2.0 and 3.0 mg/L and for safety as 3.0, 4.0, 5.0, 5.5 and 6.0 mg/L. The efficacy outcomes were invasive fungal infection-related mortality, all-cause mortality, rate of successful treatment and rate of prophylaxis failure. The safety outcomes included incidents of hepatotoxicity, neurotoxicity and visual disorders. RESULTS: A total of 21 studies involving 1158 patients were included. Compared with voriconazole trough concentrations of >0.5 mg/L, levels of <0.5 mg/L significantly decreased the rate of treatment success (risk ratio = 0.46, 95% CI 0.29-0.74). The incidence of hepatotoxicity was significantly increased with trough concentrations >3.0, >4.0, >5.5 and >6.0 mg/L. The incidence of neurotoxicity was significantly increased with trough concentrations >4.0 and >5.5 mg/L. CONCLUSIONS: A voriconazole level of 0.5 mg/L should be considered the lower threshold associated with efficacy. A trough concentration >3.0 mg/L is associated with increased hepatotoxicity, particularly for the Asian population, and >4.0 mg/L is associated with increased neurotoxicity.

Immunosuppressive aspects of analgesics and sedatives used in mechanically ventilated patients: an underappreciated risk factor for the development of ventilator-associated pneumonia in critically ill patients.

OBJECTIVE: To evaluate the evidence describing the immunosuppressive and pharmacokinetic properties of commonly used analgesic and sedation agents in critically ill patients. DATA SOURCES: MEDLINE (January 1980-September 2013) was searched. STUDY SELECTION AND DATA EXTRACTION: All in vitro and in vivo studies that evaluated the immune-modulating properties of analgesic and sedation agents commonly used in the critically ill were included. Full-text and abstract-only articles (noted) were included in this review. Inclusion criteria were met by 46 studies and were evaluated. DATA SYNTHESIS: Analgesic and sedation agents have been shown to be immunosuppressive in a variety of models. In vitro models use a variety of immune cells to demonstrate the immunosuppressive properties of opioids, benzodiazepines, and to a lesser extent, propofol. In each case, animal studies provide more robust data supporting the concept that opioids, benzodiazepines, and propofol exhibit immunosuppressive activities ranging from innate to adaptive immune alterations. Human studies, though more limited, provide further support that these agents inhibit the immune response. In contrast, data have shown that dexmedetomidine may attenuate the immune system. Clinical trial data evaluating the immunosuppressive properties of these agents is limited. CONCLUSIONS: Analgesic and sedation agents have clearly been shown to alter cellular function and other mediators of the immune system; yet the clinical impact remains to be fully elucidated. The mechanism by which sedation interruption reduces ventilator-associated pneumonia may in fact be a reduction in immunosuppressive effects. Studies linking the immune-modulating effects of analgesic and sedation agents in critically ill patients are needed.

Clindamycin Plus Vancomycin Versus Linezolid for Treatment of Necrotizing Soft Tissue Infection.

Background: Necrotizing soft tissue infections (NSTIs) are life-threatening infections. The aim of this study is to evaluate the safety of clindamycin plus vancomycin versus linezolid as empiric treatment of NSTIs. Methods: This was a retrospective, single-center, quasi-experimental study of patients admitted from 1 June 2018 to 30 June 2019 (preintervention) and 1 May 2020 to 15 October 2021 (postintervention). Patients who received surgical management within 24 hours of NSTI diagnosis and at least 1 dose of linezolid or clindamycin were included. The primary endpoint was death at 30 days. The secondary outcomes included rates of acute kidney injury (AKI) and Clostridioides difficile infection (CDI). Results: A total of 274 patients were identified by admission diagnosis code for NSTI or Fournier gangrene; 164 patients met the inclusion criteria. Sixty-two matched pairs were evaluated. There was no difference in rates of 30-day mortality (8.06% vs 6.45%; hazard ratio [HR], 1.67 [95% confidence interval {CI}, .32-10.73]; P = .65). There was no difference in CDI (6.45% vs 1.61%; HR, Infinite [Inf], [95% CI, .66-Inf]; P = .07) but more AKI in the preintervention group (9.68% vs 1.61%; HR, 6 [95% CI, .73-276]; P = .05). Conclusions: In this small, retrospective, single-center, quasi-experimental study, there was no difference in 30-day mortality in patients receiving treatment with clindamycin plus vancomycin versus linezolid in combination with standard gram-negative and anaerobic therapy and surgical debridement for the treatment of NSTIs. A composite outcome of death, AKI, or CDI within 30 days was more common in the clindamycin plus vancomycin group.

Stewardship-Guided T2Candida Testing Shortens Time to Antifungal Treatment and Reduces Antifungal Usage Among Medical Intensive Care Unit Patients With Septic Shock.

Background: Diagnosis of invasive candidiasis (IC) is limited by insensitivity and slow turnaround of cultures. Our objectives were to define the performance of T2Candida, a nonculture test, under guidance of a diagnostic stewardship program, and evaluate impact on time to antifungal initiation and antifungal utilization. Methods: This was a retrospective study of adult medical intensive care unit (MICU) patients with septic shock for whom T2Candida testing was performed from March 2017 to March 2020. Patients with positive T2Candida results during this period were compared to MICU patients who did not undergo T2Candida testing but had septic shock and blood cultures positive for Candida from January 2016 through March 2020. Results: Overall, 155 T2Candida tests from 143 patients were included. Nine percent of T2Candida tests were positive compared to 4.5% of blood cultures. Sensitivity, specificity, positive predictive value, and negative predictive value of T2Candida for proven and probable IC were 78%, 95%, 50%, and 99%, respectively. Patients who tested positive for T2Candida (n = 14) were diagnosed earlier and initiated on antifungal therapy sooner than patients with IC (n = 14) diagnosed by blood culture alone (median, 5.6 vs 60 hours; P < .0001). Median antifungal days of therapy/1000 patient-days were 23.3/month preimplementation and 15/month postimplementation (P  = .007). Following a negative T2Candida result, empiric antifungals were either not administered in 58% or discontinued within 72 hours in 96% of patients. Conclusions: Diagnostic stewardship guided T2Candida testing resulted in reduced time to IC diagnosis, faster initiation of antifungal therapy, and lower antifungal usage among MICU patients with septic shock.

Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings.

BACKGROUND: Computerized provider order entry with decision support software offers an opportunity to identify and prevent medication-related errors, including drug-drug interactions (DDIs), through alerting mechanisms. However, the number of alerts generated can overwhelm and lead to "alert fatigue." A DDI alert system based on severity rankings has been shown to reduce alert fatigue; however, the best method to populate this type of database is unclear. OBJECTIVE: To compare the severity ranking of proprietary databases to clinician assessment for DDIs occurring in critically ill patients. METHODS: This observational, prospective study was conducted over 8 weeks in the cardiac and cardiothoracic intensive care unit. Medication profiles of patients were screened for the presence of DDIs and a severity evaluation was conducted using rankings of proprietary databases and clinician opinion using a DDI severity assessment tool. The primary outcome measure was the number of DDIs considered severe by both evaluation methods. RESULTS: A total of 1150 DDIs were identified after 400 patient medication profiles were evaluated. Of these, 458 were unique drug pairs. Overall, 7.4% (34/458) were considered a severe interaction based upon proprietary database ratings. The assessment by clinicians ranked 6.6% (30/458) of the unique DDIs as severe. Only 3 interactions, atazanavir-simvastatin, atazanavir-tenofovir, and aspirin-warfarin, were considered severe by both evaluation methods. CONCLUSIONS: Since proprietary databases and clinician assessment of severe DDIs do not agree, developing a knowledge base for a DDI alert system likely requires proprietary database information in conjunction with clinical opinion.

Neuroleptic malignant syndrome in traumatic brain injury patients treated with haloperidol.

BACKGROUND: Haloperidol, which is commonly used to treat agitation in critically ill patients, has been associated with the development of neuroleptic malignant syndrome (NMS). The purpose of this manuscript was to review the literature describing NMS and haloperidol use in patients sustaining a traumatic brain injury (TBI) since these patients may be at greater risk for NMS. METHODS: A computerized search of MEDLINE was conducted (1966-May 2008) to identify all publications in which haloperidol was related to NMS in patients with a TBI. The references of these manuscripts were reviewed for additional literature. RESULTS: Nine case reports describe the development of NMS in patients with TBI treated with haloperidol for agitation. Cumulative haloperidol doses before the onset of NMS ranged from 10 mg to at least 210 mg. Most of these patients received high dose (> or =30 mg) haloperidol. Four patients received haloperidol parenterally. On diagnosis, of NMS, haloperidol was discontinued in five cases, and all were given supportive care and pharmacologic treatment. Patients were discharged with improved, but diminished functional capacity. CONCLUSION: Development of NMS in TBI patients treated with haloperidol should be a concern for clinicians since these patients may be at greater risk for this adverse event; especially if the patient is receiving haloperidol at high doses parenterally. Future studies are needed to evaluate the incidence and increased risk of adverse events in patients sustaining a TBI and receiving haloperidol especially since haloperidol is being used more frequently in the critically ill patients.

Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury.

OBJECT: Current standard of care for patients with severe traumatic brain injury (TBI) is prophylactic treatment with phenytoin for 7 days to decrease the risk of early posttraumatic seizures. Phenytoin alters drug metabolism, induces fever, and requires therapeutic-level monitoring. Alternatively, levetiracetam (Keppra) does not require serum monitoring or have significant pharmacokinetic interactions. In the current study, the authors compare the EEG findings in patients receiving phenytoin with those receiving levetiracetam monotherapy for seizure prophylaxis following severe TBI. METHODS: Data were prospectively collected in 32 cases in which patients received levetiracetam for the first 7 days after severe TBI and compared with data from a historical cohort of 41 cases in which patients received phenytoin monotherapy. Patients underwent 1-hour electroencephalographic (EEG) monitoring if they displayed persistent coma, decreased mental status, or clinical signs of seizures. The EEG results were grouped into normal and abnormal findings, with abnormal EEG findings further categorized as seizure activity or seizure tendency. RESULTS: Fifteen of 32 patients in the levetiracetam group warranted EEG monitoring. In 7 of these 15 cases the results were normal and in 8 abnormal; 1 patient had seizure activity, whereas 7 had seizure tendency. Twelve of 41 patients in the phenytoin group received EEG monitoring, with all results being normal. Patients treated with levetiracetam and phenytoin had equivalent incidence of seizure activity (p = 0.556). Patients receiving levetiracetam had a higher incidence of abnormal EEG findings (p = 0.003). CONCLUSIONS: Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG analysis.

Predictors of resistant alcohol withdrawal (RAW): A retrospective case-control study.

BACKGROUND: Benzodiazepine-resistant alcohol withdrawal (RAW), defined by a requirement of ≥ 40 mg of diazepam in 1 h, represents a severe form of withdrawal without predictive parameters. This study was designed to identify risk factors associated with RAW versus withdrawal without benzodiazepine resistance (nRAW). METHODS: A retrospective cohort of adults with severe alcohol withdrawal were screened. Demographic and clinical variables, collected through chart review, underwent logistic regression to select the subset that predicst RAW. RESULTS: 736 patients (515 nRAW, 221 RAW) were analyzed. RAW patients were younger (P < 0.001), male (P = 0.008) Caucasians (P = 0.037) with histories of psychiatric illness (P < 0.001), higher serum ethanol concentrations (P < 0.007), and abnormal liver enzymes (P = 0.01). RAW patients had significantly lower platelets (P < 0.001), chloride (P = 0.02), and potassium (P = 0.01) levels; severity of illness (SAPSII) (P < 0.001) and comorbidity scores (P < 0.001). Caucasian race and male gender were found to be 3.6 and 2.6 times more likely to be RAW. For every 1-unit increase in comorbidity and severity of illness scores, patients were 22% [OR(95% CI) 0.78 (0.66-0.90)] and 4% [0.96 (0.93-0.98)] less likely to be RAW. Patients with a psychiatric history or thrombocytopenia were 2 times more likely [2.02 (1.24-3.30); 2.13 (1.31-3.50), respectively] to be RAW. CONCLUSION: These data demonstrate the predictive ability of a history of psychiatric illness, thrombocytopenia, gender, race, baseline severity of illness and comorbidity scores for developing RAW. Considering these characteristics in early withdrawal management may prevent progression to RAW outcomes.

Management and Novel Adjuncts of Necrotizing Soft Tissue Infections.

Necrotizing soft tissue infections (NSTI) have been recognized for millennia and continue to impose considerable burden on both patient and society in terms of morbidity, death, and the allocation of resources. With improvements in the delivery of critical care, outcomes have improved, although disease-specific therapies are lacking. The basic principles of early diagnosis, of prompt and broad antimicrobial therapy, and of aggressive debridement have remained unchanged. Clearly novel and new therapeutics are needed to combat this persistently lethal disease. This review emphasizes the pillars of NSTI management and then summarizes the contemporary evidence supporting the incorporation of novel adjuncts to the pharmacologic and operative foundations of managing this disease.

Diagnostic Modalities for Invasive Mould Infections among Hematopoietic Stem Cell Transplant and Solid Organ Recipients: Performance Characteristics and Practical Roles in the Clinic.

The morbidity and mortality of hematopoietic stem cell and solid organ transplant patients with invasive fungal infections (IFIs) remain high despite an increase in the number of effective antifungal agents. Early diagnosis leading to timely administration of antifungal therapy has been linked to better outcomes. Unfortunately, the diagnosis of IFIs remains challenging. The current gold standard for diagnosis is a combination of histopathology and culture, for which the sensitivity is <50%. Over the past two decades, a plethora of non-culture-based antigen and molecular assays have been developed and clinically validated. In this article, we will review the performance of the current commercially available non-cultural diagnostics and discuss their practical roles in the clinic.

Development of an antimicrobial stewardship-based infectious diseases elective that incorporates human patient simulation technology.

OBJECTIVE: To design an elective for pharmacy students that facilitates antimicrobial stewardship awareness, knowledge, and skill development by solving clinical cases, using human patient simulation technology. DESIGN: The elective was designed for PharmD students to describe principles and functions of stewardship programs, select, evaluate, refine, or redesign patient-specific plans for infectious diseases in the context of antimicrobial stewardship, and propose criteria and stewardship management strategies for an antimicrobial class at a health care institution. Teaching methods included active learning and lectures. Cases of bacterial endocarditis and cryptococcal meningitis were developed that incorporated human patient simulation technology. ASSESSMENT: Forty-five pharmacy students completed an antimicrobial stewardship elective between 2010 and 2013. Outcomes were assessed using student perceptions of and performance on rubric-graded assignments. CONCLUSION: A PharmD elective using active learning, including novel cases conducted with human patient simulation technology, enabled outcomes consistent with those desired of pharmacists assisting in antimicrobial stewardship programs.

Validation of the effectiveness of a vancomycin nomogram in achieving target trough concentrations of 15-20 mg/L suggested by the vancomycin consensus guidelines.

STUDY OBJECTIVE: To assess and validate the effectiveness of a newly constructed vancomycin dosing nomogram in achieving target trough serum concentrations of 15-20 mg/L. DESIGN: Prospective multicenter study. SETTING: Five tertiary care teaching hospitals. PATIENTS: A total of 200 adults who required vancomycin dosages targeted to attain recommended trough vancomycin serum concentrations of 15-20 mg/L. INTERVENTION: The new nomogram, which based dosing on weight and renal function, was used to calculate patients' initial vancomycin dosages. Serum trough concentrations were measured before the fourth or fifth dose, and dosages were adjusted as needed. MEASUREMENTS AND MAIN RESULTS: Median patient age was 56 years (interquartile range [IQR] 49-65 yrs), median weight was 71.2 kg (IQR 63-85 kg), and median creatinine clearance was 66.5 ml/minute (IQR 52-82 ml/min). The median initial vancomycin trough concentration achieved was 17.5 mg/L (IQR 15.0-20.0 mg/L), with 116 patients (58%) achieving the initial target trough of 15-20 mg/L. The median percent error was 13.6%, and the mean ± SD error for predicted versus actual serum trough concentrations was -0.50 ± 0.021 mg/L. One hundred fifty-four patients (77%) eventually achieved the trough target concentration within a median of 2 days. One hundred forty patients (70%) achieved initial troughs of 14-21 mg/L and 160 (80%) achieved troughs of 13-22 mg/L. Nine patients (4.5%) experienced nephrotoxicity while receiving vancomycin, which occurred after a median of 8 days of therapy. The median initial vancomycin trough concentration for these patients was 18.5 mg/L (IQR 15.3-19.3 mg/L), with eight of the nine patients having trough concentrations of 15 mg/L or greater. CONCLUSION: Fifty-eight percent of patients achieved the target trough of 15-20 mg/L (median 17.5 mg/L). The performance of the nomogram improved to 80% when the trough range was adjusted to 13-22 mg/L. Caution should be applied when using this nomogram. The nomogram should not replace clinical judgment, and dosage adjustments should be based on pharmacokinetic-pharmacodynamic targets and clinical response.