Safety and efficacy of weight-based ganciclovir dosing strategies in overweight/obese patients.

BACKGROUND: The management of cytomegalovirus (CMV) is particularly challenging as both CMV and its usual first-line treatment, ganciclovir, are associated with neutropenia. Ganciclovir dosing is weight-based, most commonly utilizing total body weight (TBW). The subsequent high doses of ganciclovir in overweight/obese patients may increase the risk of toxicity. Utilizing adjusted body weight (AdjBW) dosing may help mitigate this risk. Therefore, the objective of this study was to evaluate the difference in toxicity and efficacy between TBW and AdjBW ganciclovir dosing strategies in overweight/obese patients. METHODS: This retrospective study conducted safety and efficacy analyses of ganciclovir courses (≥72 h) used as CMV treatment. The primary safety outcome was the incidence of neutropenia (absolute neutrophil count <1000 cells/µL), and the primary efficacy outcome was a 2-log decrease in CMV polymerase chain reaction within 4 weeks following ganciclovir initiation. In both analyses, courses were excluded in which ganciclovir was dosed outside of specified renal dosing parameters for >20% of the course. RESULTS: Among the 253 courses in the safety cohort, there was no difference in the incidence of neutropenia (17.4% vs. 13.5%, p = .50) in AdjBW compared to TBW dosing. In the 62 courses evaluating efficacy, there was no statistical difference between AdjBW and TBW dosing (60.0% vs. 45.2%, p = .28). No subgroups were identified in which AdjBW dosing was advantageous. CONCLUSION: Utilization of AdjBW ganciclovir dosing did not result in decreased neutropenia or treatment efficacy as compared to TBW dosing. Further studies with larger patient populations would be beneficial to confirm these findings.

Invasive fungal sinusitis risk factors among immunosuppressed hematopoietic stem cell transplant recipients.

KEY POINTS: Invasive fungal sinusitis (IFS) rate and risk factors in transplant recipients were explored IFS rate is higher in allogeneic recipients with prior transplants and worse comorbidity scores The at-risk timeframes for IFS development were identified.

Cytomegalovirus Infections of the Stem Cell Transplant Recipient and Hematologic Malignancy Patient.

Cytomegalovirus (CMV) may no longer be the menace that plagues stem cell transplant outcomes, owing to marked improvements in transplantation techniques and methods of prophylaxis. However, it still remains a common and morbid problem for recipients of stem cell transplant and patients with certain hematologic malignancies. This article discusses the epidemiology and risk factors of CMV infection and disease, associated morbidity and mortality, diagnosis, and clinical features of clinical syndromes associated with CMV and the principles of management of CMV, with special attention to resistant CMV as it pertains to infectious disease specialists.

Prevalence, Underlying Causes, and Preventability of Sepsis-Associated Mortality in US Acute Care Hospitals.

Importance: Sepsis is present in many hospitalizations that culminate in death. The contribution of sepsis to these deaths, and the extent to which they are preventable, is unknown. Objective: To estimate the prevalence, underlying causes, and preventability of sepsis-associated mortality in acute care hospitals. Design, Setting, and Participants: Cohort study in which a retrospective medical record review was conducted of 568 randomly selected adults admitted to 6 US academic and community hospitals from January 1, 2014, to December 31, 2015, who died in the hospital or were discharged to hospice and not readmitted. Medical records were reviewed from January 1, 2017, to March 31, 2018. Main Outcomes and Measures: Clinicians reviewed cases for sepsis during hospitalization using Sepsis-3 criteria, hospice-qualifying criteria on admission, immediate and underlying causes of death, and suboptimal sepsis-related care such as inappropriate or delayed antibiotics, inadequate source control, or other medical errors. The preventability of each sepsis-associated death was rated on a 6-point Likert scale. Results: The study cohort included 568 patients (289 [50.9%] men; mean [SD] age, 70.5 [16.1] years) who died in the hospital or were discharged to hospice. Sepsis was present in 300 hospitalizations (52.8%; 95% CI, 48.6%-57.0%) and was the immediate cause of death in 198 cases (34.9%; 95% CI, 30.9%-38.9%). The next most common immediate causes of death were progressive cancer (92 [16.2%]) and heart failure (39 [6.9%]). The most common underlying causes of death in patients with sepsis were solid cancer (63 of 300 [21.0%]), chronic heart disease (46 of 300 [15.3%]), hematologic cancer (31 of 300 [10.3%]), dementia (29 of 300 [9.7%]), and chronic lung disease (27 of 300 [9.0%]). Hospice-qualifying conditions were present on admission in 121 of 300 sepsis-associated deaths (40.3%; 95% CI 34.7%-46.1%), most commonly end-stage cancer. Suboptimal care, most commonly delays in antibiotics, was identified in 68 of 300 sepsis-associated deaths (22.7%). However, only 11 sepsis-associated deaths (3.7%) were judged definitely or moderately likely preventable; another 25 sepsis-associated deaths (8.3%) were considered possibly preventable. Conclusions and Relevance: In this cohort from 6 US hospitals, sepsis was the most common immediate cause of death. However, most underlying causes of death were related to severe chronic comorbidities and most sepsis-associated deaths were unlikely to be preventable through better hospital-based care. Further innovations in the prevention and care of underlying conditions may be necessary before a major reduction in sepsis-associated deaths can be achieved.

Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study.

OBJECTIVES: Many septic patients receive care that fails the Centers for Medicare and Medicaid Services' SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the "all-or-nothing" measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented. DESIGN: Retrospective cohort study. SETTING: Seven U.S. hospitals. PATIENTS: Adult patients included in SEP-1 reporting between October 2015 and September 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19-2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85-2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04-3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70-1.72; p = 0.674). CONCLUSIONS: Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.

Variability in determining sepsis time zero and bundle compliance rates for the centers for medicare and medicaid services SEP-1 measure.

We compared sepsis "time zero" and Centers for Medicare and Medicaid Services (CMS) SEP-1 pass rates among 3 abstractors in 3 hospitals. Abstractors agreed on time zero in 29 of 80 (36%) cases. Perceived pass rates ranged from 9 of 80 cases (11%) to 19 of 80 cases (23%). Variability in time zero and perceived pass rates limits the utility of SEP-1 for measuring quality.

Pseudozyma and other non-Candida opportunistic yeast bloodstream infections in a large stem cell transplant center.

Non-Candida opportunistic yeasts are emerging causes of bloodstream infection (BSI) in immunocompromised hosts. However, their clinical presentation, management, and outcomes in stem cell transplant (SCT) recipients are not well described. We report the first case to our knowledge of Pseudozyma BSI in a SCT recipient. He had evidence of cutaneous involvement, which has not been previously described in the literature. He became infected while neutropenic and receiving empiric micafungin, which is notable because Pseudozyma is reported to be resistant to echinocandins. He was successfully treated with the sequential use of liposomal amphotericin B and voriconazole. A review of the literature revealed nine reported instances of Pseudozyma fungemia. We performed a retrospective review of 3557 SCT recipients at our institution from January 2000 to June 2015 and identified four additional cases of non-Candida yeast BSIs. These include two with Cryptococcus, one with Trichosporon, and one with Saccharomyces. Pseudozyma and other non-Candida yeasts are emerging pathogens that can cause severe and disseminated infections in SCT recipients and other immunocompromised hosts. Clinicians should have a high degree of suspicion for echinocandin-resistant yeasts, if patients develop breakthrough yeast BSIs while receiving echinocandin therapy.

Delayed infection with Parvimonas micra following spinal instrumentation.

BACKGROUND CONTEXT: Delayed-onset surgical site infections following spinal instrumentation are uncommon and often present with chronic pain and implant failure. Anaerobic organisms are rarely implicated and identified with difficulty in these infections. PURPOSE: We report a case of vertebral osteomyelitis and epidural abscess due to Parvimonas micra, an anaerobic bacterium, six months following spinal instrumentation. STUDY DESIGN/SETTING: Case Report. RESULTS: P. micra was identified from multiple intraoperative tissue and hardware specimens. With hardware explant and antibiotic therapy, the patient had a successful outcome. CONCLUSIONS: To our knowledge, this is the first report of a P. micra hardware-associated spinal infection.

High-dose caspofungin as a component of combination antifungal therapy in 91 patients with neoplastic diseases and hematopoietic stem cell transplantation: a critical review of short-term and long-term adverse events.

The antifungal activity of echinocandins is concentration dependent. Previously, we demonstrated that high-dose caspofungin (HD-CSP; 100 mg daily) was well tolerated in 34 immunosuppressed patients with cancer and may have favorably influenced outcomes. We retrospectively assessed all 91 patients in whom HD-CSP was given for the treatment of invasive fungal disease (IFD). The median number of doses was 18.5 ± 21.5, and in 8 (9%) patients more than 40 doses were given. Most (62%) of the patients had leukemia. A total of 45 (49%) patients had undergone stem cell transplantation; 80% received allogeneic grafts and 47% had graft-versus-host disease. High-dose corticosteroids were given during antifungal therapy in 26 (29%) patients. In all, 8 (9%) patients had new elevation in serum bilirubin during HD-CSP therapy; normalization occurred after voriconazole and HD-CSP were discontinued in 4 patients each. No other short-term or delayed adverse events were observed. In all, 40 (44%) patients died of IFD. High-dose corticosteroids during HD-CSP (odds ratio [OR] 8, 95% confidence interval [CI] 2.1-30.4; P < .002) and starting HD-CSP in the critical care unit (OR 67.5, 95% CI 5.25-868.9; P < .001) were associated with death from fungal disease. Prolonged HD-CSP therapy was well tolerated. Drug-induced hyperbilirubinemia may pose a potential limitation for continued HD-CSP use in highly susceptible patients with hematologic neoplasms and stem cell transplantation.

Use of healthy-donor granulocyte transfusions to treat infections in neutropenic patients with myeloid or lymphoid neoplasms: experience in 74 patients treated with 373 granulocyte transfusions.

BACKGROUND/AIMS: Despite limited evidence for efficacy, granulocyte transfusions (GTX) are used to prevent and treat opportunistic infections in patients with neutropenia. METHODS: Three hundred and seventy-three GTX given to 74 patients were assessed retrospectively. RESULTS: GTX were discontinued because of clinical improvement more often in patients with severe infections than in patients without severe infections (27 vs. 12%; p ≤ 0.002), whereas deaths resulted in discontinuation of GTX therapy less often in patients with severe infections than without (8 vs. 39%; p ≤ 0.002). Patients who died by 12 weeks after GTX initiation were more likely to have leukemia (p = 0.03), not to have recovery of neutrophil counts (p < 0.0001), and to have started GTX during a critical care unit stay (p < 0.001). Uses of granulocyte colony-stimulating factor (p ≤ 0.02) and interferon-γ (p ≤ 0.04) were more common in patients who survived. In patients with comorbidities (31%; odds ratio, OR, 12.6; 95% confidence interval, CI, 2.4-65.7; p ≤ 0.003), GTX was started in the critical care unit (OR 8.8; 95% CI 2.5-30.9; p < 0.001), and a high total bilirubin level at the end of GTX (OR 2.1; 95% CI 1.1-4.2; p = 0.03) had a higher probability of death 12 weeks after GTX therapy commenced. CONCLUSIONS: The possibility that a niche population may benefit from GTX requires further assessment.

Granulocyte macrophage colony-stimulating factor in 66 patients with myeloid or lymphoid neoplasms and recipients of hematopoietic stem cell transplantation with invasive fungal disease.

BACKGROUND/AIMS: Adding granulocyte macrophage colony-stimulating factor (GM-CSF) may improve the response to antifungal therapy in immunosuppressed patients with invasive fungal disease (IFD). METHODS: We retrospectively assessed 66 patients in whom GM-CSF was given during antifungal therapy. RESULTS: Severe neutropenia (77%) and refractory/relapsed cancer (65%) were common in the group. Prior to GM-CSF therapy, 15% of patients received high-dose corticosteroids for a median of 30 ± 16 days [median cumulative dose (c.d.) 1,184 ± 1,019 mg], and 9 received steroids during GM-CSF therapy for a median of 16 ± 12 days (median c.d. 230 ± 1,314 mg). Mild toxic effects were noted in 9% of patients; there were no cases of cardiopulmonary toxicity. All-cause deaths were observed in 68% of patients and 48% died of progressive IFD. High-dose corticosteroids prior to GM-CSF (OR 24; 95% CI 2.21-264.9; p ≤ 0.009), GM-CSF started in the intensive care unit (OR 10; 95% CI 1.66-63.8; p ≤ 0.01), concurrent granulocyte transfusions (OR 5; 95% CI 1.27-16.8; p ≤ 0.02) and proven/probable IFD (OR 4; 95% CI 1-16.2; p ≤ 0.05) predicted antifungal treatment failure. CONCLUSIONS: GM-CSF adjuvant therapy was tolerated without serous toxicity and antifungal treatment failure remained a challenge in patients treated with high-dose systemic corticosteroids.

The incidence of necrotizing changes in adults with pneumococcal pneumonia.

BACKGROUND: Necrotizing pneumonia is generally considered a rare complication of pneumococcal infection in adults. We systematically studied the incidence of necrotizing changes in adult patients with pneumococcal pneumonia and examined the severity of infection, role of causative serotypes, and association with bacteremia. METHODS: We used a database of all pneumococcal infections identified at our medical center between 2000 and 2010. Original readings of chest X-rays (CXR) and computerized tomography (CT) were noted. Images were then independently reevaluated by 2 radiologists. The severity of disease at admission was assessed using SMART-COP and Pneumonia Outcomes Research Team (PORT) scoring systems. RESULTS: In 351 cases of pneumococcal pneumonia, necrosis was reported in no (0%) original CXR readings and in 6 of 136 (4.4%) CTs. With rereading, 8 of 351 (2.3%) CXR and 15 of 136 (11.0%) CT had necrotizing changes. Overall, these changes were identified in 23 of 351 (6.6%) patients. The incidence of bacteremia and the admitting SMART-COP and PORT scores were similar in patients with and without necrosis (P = 1.00, P = .32, and P = .54, respectively). Type 3 pneumococcus was more commonly isolated from patients with necrosis than from patients without necrosis (P = .05), but 10 other serotypes were also implicated in 16 cases for which the organism was available for typing. CONCLUSIONS: Necrotizing changes in the lungs were seen in 6.6% of a large series of adults with pneumococcal pneumonia but were often overlooked on initial readings. Patients with necrosis were not more likely to have bacteremia or more severe disease. Type 3 pneumococcus was the most commonly identified serotype.