Clinical manifestations and treatment outcomes for patients with Pseudomonas endocarditis.

OBJECTIVES: To investigate clinical outcomes of patients with Pseudomonas endocarditis and identify factors associated with treatment failure. METHODS: Adult patients meeting definitive Duke's criteria for Pseudomonas endocarditis at 11 hospitals were identified between May 2000 and February 2024. Failure was defined as death or microbiological failure by day 42. First-line therapy consisted of cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam alone or in combination. RESULTS: Forty-eight patients met inclusion criteria; 29% were persons who inject drugs and 13% were organ transplant recipients. Pseudomonas aeruginosa was the causative species in 98% of cases. Patients who experienced 42 day cure were more likely to be initially managed with first-line ß-lactam agents compared with those who experienced clinical failure (97% versus 62%, P = 0.004). Treatment with first-line ß-lactams was associated with shorter time to treatment initiation and a lower likelihood of infection due to MDR Pseudomonas spp. In the univariate model, patients who experienced 90 day mortality were more likely to have prosthetic valve endocarditis (57% versus 24%, P = 0.02), an intracardiac complication (36% versus 9%, P = 0.04) and a higher median (IQR) Pitt bacteraemia score [2.5 (2-3.8) versus 1 (0-2), P = 0.048]. Combination therapy did not improve clinical outcomes but did increase the rate of adverse effects resulting in drug discontinuation compared with monotherapy, (21% versus 0%, P = 0.08). CONCLUSIONS: This is the largest study of Pseudomonas endocarditis to date. We identified improved clinical outcomes when cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam were used for initial treatment. We did not identify a clinical benefit for combination treatment.

Clinical outcomes of baloxavir versus oseltamivir in immunocompromised patients.

BACKGROUND: Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear. METHODS: We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality. RESULTS: Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes. CONCLUSION: Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.

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.

Outcomes of pregnant women exposed to Sotrovimab for the treatment of COVID-19 in the BA.1 Omicron predominant era (PRESTO).

BACKGROUND: Sotrovimab, a monoclonal antibody with efficacy against SARS-CoV-2 including certain Omicron variants, has been used in treatment of mild-moderate COVID-19. Limited data exists regarding its use in pregnant women. METHODS: Electronic medical record review of pregnant COVID-19 patients treated with sotrovimab from 12/30/21 - 1/31/22 (Yale New Haven Health Hospital System [YNHHS]) was performed. Included were pregnant individuals ≥ 12 years, weighing ≥ 40 kg, with positive SARS-CoV-2 test (within 10 days). Those receiving care outside YNHHS or receiving other SARS-CoV-2 treatment were excluded. We assessed demographics, medical history, and Monoclonal Antibody Screening Score (MASS). The primary composite clinical outcome assessed included emergency department (ED) visit < 24 h, hospitalization, intensive care unit (ICU) admission, and/or death within 29 days of sotrovimab. Secondarily, adverse feto-maternal outcomes and events for neonates were assessed at birth or through the end of the study period, which was 8/15/22. RESULTS: Among 22 subjects, median age was 32 years and body mass index was 27 kg/m2. 63% were Caucasian, 9% Hispanic, 14% African-American, and 9% Asian. 9% had diabetes and sickle cell disease. 5% had well-controlled HIV. 18%, 46%, and 36% received sotrovimab in trimester 1, 2, and 3, respectively. No infusion/allergic reactions occurred. MASS values were < 4. Only 12/22 (55%) received complete primary vaccination (46% mRNA-1273; 46% BNT162b2; 8% JNJ-78,436,735); none received a booster. CONCLUSIONS: Pregnant COVID-19 patients receiving sotrovimab at our center tolerated it well with good clinical outcomes. Pregnancy and neonatal complications did not appear sotrovimab-related. Though a limited sample, our data helps elucidate the safety and tolerability of sotrovimab in pregnant women.

Genetic and Epidemiologic Analyses of an Outbreak of Pneumocystis jirovecii Pneumonia Among Kidney Transplant Recipients in the United States.

BACKGROUND: Pneumocystis jirovecii is an opportunistic fungus that causes Pneumocystis pneumonia (PCP) in immunocompromised hosts. Over an 11-month period, we observed a rise in cases of PCP among kidney-transplant recipients (KTR), prompting an outbreak investigation. METHODS: Clinical and epidemiologic data were collected for KTR diagnosed with PCP between July 2019 and May 2020. Pneumocystis strain typing was performed using restriction fragment length polymorphism analyses and multilocus sequence typing in combination with next-generation sequencing. A transmission map was drawn, and a case-control analysis was performed to determine risk factors associated with PCP. RESULTS: Nineteen cases of PCP in KTR were diagnosed at a median of 79 months post-transplantation; 8 received monthly belatacept infusions. Baseline characteristics were similar for KTR on belatacept versus other regimens; the number of clinic visits was numerically higher for the belatacept group during the study period (median 7.5 vs 3). Molecular typing of respiratory specimens from 9 patients revealed coinfection with up to 7 P. jirovecii strains per patient. A transmission map suggested multiple clusters of interhuman transmission. In a case-control univariate analysis, belatacept, lower absolute lymphocyte count, non-White race, and more transplant clinic visits were associated with an increased risk of PCP. In multivariate and prediction power estimate analyses, frequent clinic visits was the strongest risk factor for PCP. CONCLUSIONS: Increased clinic exposure appeared to facilitate multiple clusters of nosocomial PCP transmission among KTR. Belatacept was a risk factor for PCP, possibly by increasing clinic exposure through the need for frequent visits for monthly infusions.

Rectal screening for azole non-susceptible Candida species in patients undergoing liver transplantation.

INTRODUCTION: Candidiasis is the most common invasive fungal infection in solid organ transplant recipients, and liver transplant (LT) recipients are at heightened risk. We hypothesized that pre-transplant screening for azole non-susceptible Candida (ANSC) allows for tailored antifungal prophylaxis to reduce the incidence of post-LT ANSC infection. METHODS: We performed a retrospective chart review of adult (age ≥18 years) patients who underwent LT at Yale New Haven Hospital from April 2019 to March 2021. Screening for ANSC, defined as Candida glabrata or Candida krusei, was performed using a rectal swab prior to or at the time of LT. RESULTS: During the study period, ANSC screening was performed in 47 patients who underwent a total of 48 LTs, with 46/48 (96%) primary LTs and two re-transplantations. Ten of 48 screened cases (21%) had ANSC-positive rectal swabs. Only seven of 10 ANSC-colonized patients received appropriate antifungal prophylaxis (i.e., anidulafungin), and one of these seven patients developed candidemia within 30 days of LT. The median number of candidiasis risk factors was one, and 29% of the cohort had two or more risk factors. DISCUSSION: Routine ANSC screening of LT candidates may assist in selecting appropriate antifungal prophylaxis but may be insufficient to prevent infection in those with multiple risk factors for Candida infection.

An outbreak of SARS-CoV-2 on a transplant unit in the early vaccination era.

BACKGROUND: Solid organ transplant recipients are at increased risk of COVID-19-associated morbidity and mortality. AIMS: We describe a nosocomial outbreak investigation on an immunocompromised inpatient unit. METHODS: Patients positive for SARS-CoV-2 were identified. An epidemiologic investigation was assisted with whole genome sequencing of positive samples. RESULTS: Two patients were identified as potential index cases; one presented with diarrhea and was initially not isolated, and the other developed hypoxemia on hospital day 18 before testing positive. Following identification of a SARS-CoV-2 cluster, the unit was closed and all patients and staff received surveillance testing revealing eight additional positive patients and staff members. Whole genome sequencing confirmed an outbreak. Enhanced infection prevention practices mitigated further spread. Asymptomatic patients with COVID-19 were successfully treated with bamlanivimab. DISCUSSION: Preventing SARS-CoV-2 outbreaks in transplant units poses unique challenges as patients may have atypical presentations of COVID-19. Immunocompromised patients who test positive for SARS-CoV-2 while asymptomatic may benefit from monoclonal antibody therapy to prevent disease progression. All hospital staff members working with immunocompromised patients should be promptly encouraged to follow infection prevention behaviors and receive SARS-CoV-2 vaccination. CONCLUSION: SARS-CoV-2 outbreaks on immunocompromised units can be mitigated through prompt identification of cases and robust infection prevention practices.

Combination Therapy of Chloramphenicol and Daptomycin for the Treatment of Infective Endocarditis Secondary to Multidrug Resistant Enterococcus faecium.

A 38-years-old female with an aortic valve replacement presented to an outside hospital (OSH) with fevers and malaise. Blood cultures revealed VRE which was resistant to linezolid, resistant to ampicillin, non-susceptible to daptomycin (MIC of 8 mcg/mL), and exhibited susceptibility to gentamicin. The patient was therefore initiated on intravenous (IV) daptomycin 6 mg/kg q24h and gentamicin IV 1 mg/kg q8h. However, after 14 days of therapy with daptomycin and gentamicin, the patient was transferred to our institution for the management of cardiogenic shock and hypoxemic respiratory failure. Given the concern for treatment failure, her antimicrobial regimen was changed to IV chloramphenicol 12.5 mg/kg every 6 hours with IV daptomycin 10 mg/kg every 48 hours given an estimated creatinine clearance of 30 mL/minutes. In vitro susceptibilities for chloramphenicol were performed which confirmed susceptibility. A transesophageal echocardiogram revealed a possible abscess at the left coronary cusp and aortic valve dehiscence. The patient underwent aortic valve replacement with aortic root reconstruction. The aortic valve culture grew VRE susceptible to linezolid but resistant to ampicillin and doxycycline. The patient was deemed clinically cured after 42 days of combination therapy with daptomycin and chloramphenicol. After 6 years of follow-up, the patient has not had a recurrent VRE infection. To our knowledge, this is the first case of endocarditis secondary to VRE that was successfully managed with the combination of daptomycin and chloramphenicol.

Renal and Hepatic Toxicity Analysis of Remdesivir Formulations: Does What Is on the Inside Really Count?

It has been postulated that the injectable solution formulation of remdesivir could be more nephrotoxic than the lyophilized powder since it contains twice as much sulfobutylether-ß-cyclodextrin (SBECD). Therefore, we evaluated 1,000 hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who received remdesivir lyophilized powder or solution. A logistic regression model accounting for baseline confounders identified that neither the use of the injectable solution (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.49 to 2.29; P = 0.901) nor a creatinine clearance of <30 ml/min at the time of remdesivir initiation (OR, 1.39; 95% CI, 0.51 to 3.5; P = 0.499) was significantly associated with acute kidney injury. Regarding hepatoxicity, there was no significant difference in early discontinuation of remdesivir due to abnormal liver function tests between patients who received the lyophilized powder versus those who received solution (0.9% versus 2.3%, P = 0.09).

A Valid Warning or Clinical Lore: an Evaluation of Safety Outcomes of Remdesivir in Patients with Impaired Renal Function from a Multicenter Matched Cohort.

Per prescribing guidance, remdesivir is not recommended for SARS-CoV-2 in patients with renal disease given the absence of safety data in this patient population. This study was a multicenter, retrospective chart review of hospitalized patients with SARS-CoV-2 who received remdesivir. Safety outcomes were compared between patients with an estimated creatinine clearance (eCrCl) of <30 ml/min and an eCrCl of ≥30 ml/min. The primary endpoint was acute kidney injury (AKI) at the end of treatment (EOT). Of 359 patients who received remdesivir, 347 met inclusion criteria. Patients with an eCrCl of <30 ml/min were older {median, 80 years (interquartile range [IQR], 63.8 to 89) versus 62 (IQR, 54 to 74); P < 0.001}, were more likely to be on vasopressors on the day of remdesivir administration (30% versus 12.7%; P = 0.003), and were more likely to be mechanically ventilated during remdesivir therapy (27.5% versus 12.4%; P = 0.01) than those with an eCrCl of ≥30 ml/min. Despite these confounders, there was no significant difference in the frequency of EOT AKI (5% versus 2.3%; P = 0.283) or early discontinuation due to abnormal liver function tests (LFTs) (0% versus 3.9%; P = 0.374). Of the 5% of patients who developed EOT AKI on remdesivir with an eCrCl <30 ml/min, no cases were attributable to remdesivir administration per the treating physician. Comparable safety outcomes were observed when 1:1 nearest neighbor matching was applied to account for baseline confounders. In conclusion, remdesivir administration was not significantly associated with increased EOT AKI in patients with an eCrCl of <30 ml/min compared to patients with an eCrCl of ≥30 ml/min.

Cytokine Profiles Before and After Immune Modulation in Hospitalized Patients with COVID-19.

We describe the cytokine profiles of a large cohort of hospitalized patients with moderate to critical COVID-19, focusing on IL-6, sIL2R, and IL-10 levels before and after receiving immune modulating therapies, namely, tocilizumab and glucocorticoids. We also discuss the possible roles of sIL2R and IL-10 as markers of ongoing immune dysregulation after IL-6 inhibition. We performed a retrospective chart review of adult patients admitted to a tertiary care center with moderate to critical SARS-CoV-2 infection. Disease severity was based on maximum oxygen requirement during hospital stay to maintain SpO2 > 93% (moderate, 0-3 L NC; severe, 4-6 L NC or non-rebreather; critical, HFNC, NIPPV, or MV). All patients were treated using the institution's treatment algorithm, which included consideration of tocilizumab for severe and critical disease. The most common cytokine elevations among all patients included IL-6, sIL2R, IFN-γ, and IL-10; patients who received tocilizumab had higher incidence of IL-6 and sIL2R elevations. Pre-tocilizumab IL-6 levels increased with disease severity (p = .0151). Both IL-6 and sIL2R levels significantly increased after administration of tocilizumab in all severity groups; IL-10 levels decreased in severe (p = .0203), but not moderate or critical, patients after they received tocilizumab. Cluster analysis revealed association between higher admission IL-6, sIL2R, and CRP levels and disease severity. Mean IL-6, sIL2R, and D-dimer were associated with mortality, and tocilizumab-treated patients with elevated IL-6, IL-10, and D-dimer were more likely to also receive glucocorticoids. Accessible clinical cytokine panels may be useful for monitoring response to treatment in COVID-19. The increase in sIL2R post-tocilizumab, despite administration of glucocorticoids, may indicate the need for combination therapy in order to modulate more than one hyperinflammatory pathway in COVID-19. We also discuss the role of cytokines as potential biomarkers for use of adjunct glucocorticoid therapy.

Education needed to improve antimicrobial use during end-of-life care of older adults with advanced cancer: A cross-sectional survey.

BACKGROUND: Antimicrobial use during end-of-life care of older adults with advanced cancer is prevalent. Factors influencing the decision to prescribe antimicrobials during end-of-life care are not well defined. AIM: To evaluate factors influencing medicine subspecialists to prescribe intravenous and oral antimicrobials during end-of-life care of older adults with advanced cancer to guide an educational intervention. DESIGN: 18-item single-center cross-sectional survey. SETTING/PARTICIPANTS: Inpatient medicine subspecialists in 2018. RESULTS: Of 186 subspecialists surveyed, 67 (36%) responded. Most considered withholding antimicrobials at the time of clinical deterioration during hospitalization (n = 54/67, 81%), viewed the initiation of additional intravenous antimicrobials as escalation of care (n = 44/67, 66%), and believed decision-making should involve patients or surrogates and providers (n = 64/67, 96%). Fifty-one percent (n = 30/59) of respondents who conducted advance care planning did not discuss antimicrobials. Barriers to discussing end-of-life antimicrobials included the potential to overwhelm patients or families, challenges of withdrawing antimicrobials, and insufficient training. CONCLUSIONS: Although the initiation of additional intravenous antimicrobials was viewed as escalation of care, antimicrobials were not routinely discussed during advance care planning. Educational interventions that promote recognition of antimicrobial-associated adverse events, incorporate antimicrobial use into advance care plans, and offer communication simulation training around the role of antimicrobials during end-of-life care are warranted.

Three is a crowd: Clinical outcomes of a twice daily versus a thrice daily metronidazole dosing strategy from a multicenter study.

This was a multicenter, retrospective study of patients with anaerobic bacteremia comparing metronidazole 500 mg every 8 h versus 500 mg every 12 h. Of 782 patients reviewed, 85 met inclusion criteria. There was no significant difference in mortality, length of stay, or escalation of therapy between dosing strategies.

Orally Administered Human Immunoglobulin Therapy for Norovirus Enteritis in Solid Organ Transplant Recipients: A Case Series at a Single Academic Transplant Center.

Norovirus enteritis can cause intractable diarrhea in solid organ transplant (SOT) recipients, for which there are no established treatments. We reviewed medical records of 9 SOT recipients at our center who received orally administered human immunoglobulin for norovirus enteritis, and it appeared to be an effective treatment modality.

High Agreement Between an Ultrasensitive Clostridioides difficile Toxin Assay and a C. difficile Laboratory Algorithm Utilizing GDH-and-Toxin Enzyme Immunoassays and Cytotoxin Testing.

The Singulex Clarity C. diff toxins A/B (Clarity) assay is an automated, ultrasensitive immunoassay for the detection of Clostridioides difficile toxins in stool. In this study, the performance of the Clarity assay was compared to that of a multistep algorithm using an enzyme immunoassay (EIA) for detection of glutamate dehydrogenase (GDH) and toxins A and B arbitrated by a semiquantitative cell cytotoxicity neutralization assay (CCNA). The performance of the assay was evaluated using 211 residual deidentified stool samples tested with a GDH-and-toxin EIA (C. Diff Quik Chek Complete; Techlab), with GDH-and-toxin discordant samples tested with CCNA. The stool samples were stored at -80°C before being tested with the Clarity assay. For samples discordant between Clarity and the standard-of-care algorithm, the samples were tested with PCR (Xpert C. difficile; Cepheid), and chart review was performed. The testing algorithm resulted in 34 GDH+/toxin+, 53 GDH-/toxin-, and 124 GDH+/toxin- samples, of which 39 were CCNA+ and 85 were CCNA- Clarity had 96.2% negative agreement with GDH-/toxin- samples, 100% positive agreement with GDH+/toxin+ samples, and 95.3% agreement with GDH+/toxin-/CCNA- samples. The Clarity result was invalid for one sample. Clarity agreed with 61.5% of GDH+/toxin-/CCNA+ samples, 90.0% of GDH+/toxin-/CCNA+ (high-positive) samples, and 31.6% of GDH+/toxin-/CCNA+ (low-positive) samples. The Singulex Clarity C. diff toxins A/B assay demonstrated high agreement with a testing algorithm utilizing a GDH-and-toxin EIA and CCNA. This novel automated assay may offer an accurate, stand-alone solution for C. difficile infection (CDI) diagnostics, and further prospective clinical studies are merited.

Clinical outcomes of baloxavir versus oseltamivir in patients hospitalized with influenza A.

OBJECTIVES: To date, clinical trials evaluating baloxavir have excluded patients hospitalized with influenza infection and therefore this study sought to evaluate the efficacy of baloxavir in inpatients with influenza A. METHODS: This study was a multicentre, retrospective chart review of adult patients admitted to the hospital within the Yale New Haven Health System who received oseltamivir or baloxavir for the treatment of influenza A. Patients were screened for inclusion between January 2018 and April 2018 in the oseltamivir group, while patients in the baloxavir group were screened for inclusion between January 2019 and April 2019. Influenza A diagnosis was confirmed by RT-PCR using a nasopharyngeal swab specimen. RESULTS: Of the 2392 patients assessed, 790 met the inclusion criteria. There were 359 patients who received baloxavir and 431 patients who received oseltamivir. Patients who received baloxavir were younger compared with those who received oseltamivir [median = 69 (IQR = 57-81) years versus 77 (IQR = 62-86) years; P < 0.001]. Patients who received baloxavir had no significant difference in hospital length of stay [median = 4 (IQR = 3-6) days versus 5 (IQR = 3-6) days; P = 0.45] or 30 day all-cause mortality [12 (3.3%) versus 26 (6%); P = 0.079] compared with those who received oseltamivir. However, patients who received baloxavir had a significantly faster time to hypoxia resolution [median = 51.7 (IQR = 25.3-89.3) h versus 72 (IQR = 37.5-123) h; P < 0.001]. CONCLUSIONS: The results of this study support the use of baloxavir for the treatment of influenza A in hospitalized patients with the potential benefit of a faster time to resolution of hypoxia.

The impact of a multimodal approach to vancomycin discontinuation in hematopoietic stem cell transplant recipients (HSCT) with febrile neutropenia (FN).

BACKGROUND: Current guidelines recommend adding vancomycin to empiric treatment of FN in patients who meet specific criteria. After 48 hours, the guidelines recommend discontinuing vancomycin if resistant Gram-positive organisms are not identified. Based on these recommendations, a vancomycin stewardship team defined criteria for discontinuation of vancomycin at 48 hours and increased surveillance of vancomycin usage through a multimodal approach. The purpose of this retrospective analysis is to assess the impact of this multimodal approach on the discontinuation of empiric vancomycin at 48 hours in FN. METHODS: This retrospective analysis included a pre- and post-intervention cohort of 200 HSCT recipients with FN from 2015 to 2018. Criteria for continued vancomycin use beyond 48 hours included culture-documented resistant Gram-positive infection, positive Methicillin-Resistant S aureus (MRSA) nasal swab with evidence of pneumonia, or hemodynamic instability with concern for sepsis. The following patient characteristics were collected: previous MRSA infection, MRSA nasal swab collection and results, culture results, duration of vancomycin use, rationale for continuation of vancomycin beyond 48 hours, and re-initiation of vancomycin. RESULTS: In the post-intervention cohort, vancomycin discontinuation at 48 hours increased from 31% (95% CI 21.94-40.05) to 70% (95% CI 61.02-78.97; P < 0.0001). An additional 23% of vancomycin orders were discontinued at 72 hours. Off criteria vancomycin use decreased from 33% in pre to 1% in the post-implementation cohort. CONCLUSION: Establishing define criteria for vancomycin use in FN patients with a multimodal approach of physicians from hematology and infectious diseases, clinical pharmacists and the antibiotic stewardship team significantly improved vancomycin discontinuation.

Evaluating a voriconazole dose modification guideline to optimize dosing in patients with hematologic malignancies.

BACKGROUND: Voriconazole is an azole antifungal utilized for prophylaxis and treatment of invasive fungal infections in hematologic patients. Previous studies have revealed decreased efficacy and increased toxicity with subtherapeutic <1 mcg/mL and supratherapeutic > 4 mcg/mL levels. A voriconazole dose modification guideline was introduced in July 2014 based on a retrospective analysis. OBJECTIVE: The primary objective was to evaluate the voriconazole dose modification guideline. Secondary objectives were to identify patient-specific characteristics that contribute to inadequate levels, adverse effects, and breakthrough invasive fungal infections. METHODS: This prospective study included 128 patients with 250 admissions who received voriconazole from July 2014 to February 2016. Eligible adult patients receiving voriconazole for prophylaxis or treatment with at least one trough level, drawn appropriately, were included. Demographics, adverse effects, and breakthrough invasive fungal infections were documented. RESULTS: Voriconazole use was categorized as: new start, new start with loading dose, or continuation of home therapy. The median initial levels were 1.5, 3.5, and 1.7 mcg/mL with 62% (73/119), 55% (6/11), and 60% (72/120) within the therapeutic range, respectively. Using the voriconazole dose modification guideline, 80% were within goal by the second dose adjustment. Age ≤ 30 and BMI ≤ 25 kg/m2 had higher rates of subtherapeutic levels in the new start cohorts (p = 0.024 and p = 0.009). Approximately 7.6% of patients experienced an adverse effect with neurologic/psychological being the most common. A total of 8.5% of patients had a possible, probable or proven breakthrough invasive fungal infections while on voriconazole. CONCLUSION: Using the voriconazole dose modification guideline, the number of patients that reached therapeutic range improved from 36% to 80% by the second dose adjustment (p = 0.007). This voriconazole dose modification guideline can be utilized to help dose and adjust voriconazole in order to achieve therapeutic levels.

Telavancin for refractory MRSA bacteraemia in intermittent haemodialysis recipients.

Background: Patients with end-stage renal disease (ESRD) requiring intermittent haemodialysis (IHD) are at high risk of MRSA bacteraemia (MRSA-B) and often fail first-line therapy. The safety, effectiveness and optimal dosing of telavancin for MRSA-B in this patient population are unclear. Objectives: We aimed to describe clinical outcomes of telavancin in the treatment of refractory MRSA-B in patients with ESRD requiring IHD. Patients and methods: This was a retrospective study of hospitalized patients at two tertiary care academic medical centres with recurrent or persistent (≥3 days) MRSA-B treated with telavancin monotherapy. Outcomes included duration of MRSA-B (pre-telavancin versus post-telavancin) and microbiological failure (duration of MRSA-B ≥3 days after initiation of telavancin). Results: Telavancin dosed 10 mg/kg three times weekly post-IHD or 10 mg/kg every 48 h resulted in microbiological cure in 7/8 (87.5%) refractory MRSA-B cases. Telavancin monotherapy was associated with a significant reduction in median duration of bacteraemia [16 days pre-telavancin (IQR 8-19 days) versus 1 day post-telavancin (IQR 0-2 days); P = 0.018]. Telavancin was well tolerated by all patients and no adverse events were reported. Conclusions: Telavancin was very safe and highly effective in the treatment of refractory MRSA-B in a cohort of patients with ESRD requiring IHD. These data support the utility of telavancin in the armamentarium against refractory MRSA-B, particularly in the high-risk IHD-dependent population.