Farnaz Foolad

Association of daptomycin dosing regimen and mortality in patients with VRE bacteraemia: a review

VRE are associated with ∼1300 deaths per year in the USA. Recent literature suggests that daptomycin, a cyclic lipopeptide antibiotic with concentration-dependent bactericidal activity, is the preferred treatment option for VRE bacteraemia, yet the optimal dosing strategy for this indication has not been established. In vitro evidence suggests that higher-than-labelled doses of daptomycin are required to optimally treat VRE bacteraemia and to inhibit the development of resistance. However, concern of dose-dependent toxicities, notably increases in creatine phosphokinase and the development of rhabdomyolysis, are a barrier to initiating high-dose schemes in clinical practice. Thus, the effectiveness and safety of high-dose daptomycin regimens in clinical practice have remained unclear. While early studies failed to identify differences in mortality, newer, larger investigations suggest high-dose (≥9u2009mg/kg) daptomycin is associated with reduced mortality in patients with VRE bacteraemia compared with standard (6u2009mg/kg) dosing regimens. Additionally, the high-dose regimens appear to be safe and may be associated with improved microbiological outcomes. The purpose of this review is to examine the published evidence on the effectiveness and safety of high-dose daptomycin compared with standard dosing regimens for VRE bacteraemia.

A multicentre stewardship initiative to decrease excessive duration of antibiotic therapy for the treatment of community-acquired pneumonia

BackgroundnThe increased emphasis on pneumonia-related performance measures and patient outcomes has led hospitals to implement multifaceted approaches to quickly identify patients with community-acquired pneumonia (CAP), start timely therapy and reduce readmission. However, there has been minimal focus on duration of therapy (DOT) and patients often receive prolonged antibiotic courses. The IDSA and American Thoracic Society (IDSA/ATS) CAP guidelines recommend 5u2009days of therapy for clinically stable patients that quickly defervesce and stewardship teams are well positioned to influence prescribing practices.nnnObjectivesnDetermine the impact of a prospective stewardship intervention on total antibiotic DOT and associated clinical outcomes in hospitalized patients with CAP.nnnMethodsnThis multicentre, quasi-experimental study evaluated three concurrent interventions over a 6u2009month period to promote appropriate DOT. All centres updated institutional CAP guidelines to promote IDSA/ATS-concordant DOT, provided education and conducted daily audit and feedback with intervention to provide patient-specific DOT recommendations.nnnResultsnA total of 600 patients with CAP were included (307 in the historical control group and 293 in the stewardship intervention group). The stewardship intervention increased compliance with DOT recommendations (42% versus 5.6%, Pu2009<u20090.001) and reduced the median DOT per patient (6 versus 9u2009days, Pu2009<u20090.001). Clinical outcomes, including mortality, readmission with pneumonia, presentation to the emergency centre/clinic with pneumonia and incidence of Clostridium difficile infection within 30u2009days of discharge, were not different between groups.nnnConclusionsnThis multicentre evaluation of a stewardship intervention in hospitalized CAP patients reduced the total antibiotic DOT and increased guideline-concordant DOT without adversely affecting patient outcomes.

Letermovir for the prevention of cytomegalovirus infection in adult cytomegalovirus-seropositive hematopoietic stem cell transplant recipients

ABSTRACT Introduction: Allogeneic hematopoietic cell transplants (allo-HCT) recipients are at the high-risk of reactivation of cytomegalovirus (CMV), and reactivation is associated with significant morbidity and mortality. Although available anti-CMV therapies may be effective for the prevention of CMV, they are plagued by unacceptable toxicities that prohibit their use in the post-transplant period. Recently studied CMV-active agents, such as maribavir and brincidofovir, failed to reduce the incidence of CMV infection in HCT recipients. Letermovir represents the first agent in the non-nucleoside 3,4 dihydro-quinazoline class of CMV viral terminase complex inhibitors, with activity solely against CMV. The positive results from the recently published Phase III study of letermovir for prevention of CMV infection in CMV-seropositive allo-HCT recipients led to its approval as a prophylactic agent for CMV in multiple countries. Areas covered: In this review, we will evaluate this novel agent with a focus on letermovir mechanism of action, pharmacokinetics and metabolism, clinical efficacy, and safety and toxicities. Expert commentary: With the introduction of letermovir, prevention of CMV infection in allo-HCT recipients may shift considerably, from a predominantly preemptive strategy to one that utilizes this novel therapy for prophylaxis.

Oral Versus Aerosolized Ribavirin for the Treatment of Respiratory Syncytial Virus Infections in Hematopoietic Cell Transplant Recipients

Abstract Background The use of oral ribavirin (RBV) for respiratory syncytial virus (RSV) infections is not well studied. With the drastic increase in the cost of aerosolized RBV, we aimed to compare outcomes of hematopoietic cell transplant (HCT) recipients treated with oral or aerosolized RBV for RSV infections. Methods We reviewed the records of 124 HCT recipients with RSV infections treated with oral or aerosolized RBV from September 2014 through April 2017. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. Results Seventy patients (56%) received aerosolized RBV and 54 (44%) oral RBV. Both groups had a 27% rate of progression to LRI (P = 1.00). Mortality rates did not significantly differ between groups (30-day: aerosolized 10%, oral 9%, P = 1.00; 90-day: aerosolized 23%, oral 11%, P = .10). Classification and regression tree analysis identified ISI ≥7 as an independent predictor of 30-day mortality. For patients with ISI ≥7, 30-day mortality was significantly increased overall, yet remained similar between the aerosolized and oral therapy groups (33% for both). After propensity score adjustment, Cox proportional hazards models showed similar mortality rates between oral and aerosolized therapy groups (30-day: hazard ratio [HR], 1.12 [95% confidence interval {CI}, .345–3.65, P = .845). Conclusions HCT recipients with RSV infections had similar outcomes when treated with aerosolized or oral RBV. Oral ribavirin may be an effective alternative to aerosolized RBV, with potential significant cost savings.

Nivolumab–induced encephalitis post allogeneic stem cell transplant in a patient with Hodgkin’s disease

Immune check-point inhibitors (CPI) represent a novel therapeutic strategy for the treatment of solid and haematologic malignancies [1]. Tumour cells are able to evade immune surveillance and CPIs act by blocking negative regulatory components on T-cells, thus enhancing their activity against tumour cells [2]. Nivolumab, a humanised IgG4 kappa monoclonal antibody that acts against the programmed cell death 1 (PD-1) receptor in T-cells, was approved in 2016 for relapsed or refractory Hodgkin lymphoma (HL) after haematopoietic stem cell transplantation (HCT) [3]. Neurologic immune-related adverse reactions (IRARs) after treatment with CPI have previously been reported, most commonly with the CTLA-4 inhibitor ipilimumab [4]. Here, we report the first detailed description of nivolumab associated autoimmune encephalitis in a patient with relapsed Hodgkin lymphoma after allogenic HCT. A 28-year-old female was admitted with 2 weeks of worsening headaches. She had a medical history of HL with infiltration of the spleen, bones and lung diagnosed in 2014. She failed multiple rounds of chemotherapy prior to autologous HCT in October 2015 with complete remission until 2016, then she relapsed again and received 4 cycles of brentuximab vedotin, achieving complete remission, followed by matched unrelated allogeneic HCT in June 2016 with a preparative regimen of clofarabine, busulfan, and gemcitabine. Her post-transplant course was complicated by GVHD of the liver treated with prednisone from February through May 2017. She relapsed 9 months after the allogeneic HCT and achieved complete clinical remission after 8 cycles of brentuximab vedotin, only to relapse again in December 2017. She then started therapy with escalating doses of nivolumab 80 mg on day 1 in February 2018, followed by a second dose of 120 mg (2 mg/kg) on day 14. She was not on any other immunosuppressants at this time. The patient reported that a few days following the first dose of nivolumab she started experiencing headaches that resembled migraines but were relieved with aspirin. After the second dose of nivolumab, the headaches worsened and were associated with nausea and dizziness. On day 22, the patient presented to clinic with severe frontal headaches and was referred to the emergency department for concern of possible meningitis. On admission, she was afebrile, alert but apathetic with mild clouding of consciousness. Physical examination was positive for photophobia but negative for nuchal rigidity, Kernig and Brudzinsky signs. No oral lesions, systemic skin lesions, heart murmur or abdominal tenderness were observed. A brain MRI done on day 22 showed no abnormalities and a lumbar puncture was performed with the following findings (normal ranges indicated in parenthesis): WBC: 136 cells/ml, 90% lymphocytes (0-5 cells/ml), protein: 60mg/dl (20-40mg/ dl), glucose: 53mg/dl (serum glucose 89 mg/dl) (45–80mg/ dl). A Meningitis/Encephalitis Panel (BioFire FilmArray® BioFire Diagnostics, LLC, Salt Lake City, Utah, USA) of the CSF was negative for Escherichia coli, Haemophilus influenza, Listeria monocytogenes, Neisseria meningitides, Streptococcus agalactiae, Streptococcus pneumoniae, Cytomegalovirus (CMV) Cryptococcus neoformans/gattii, These authors contributed equally: Alejandro De la Hoz, Farnaz Foolad

Disease-based antimicrobial stewardship: a review of active and passive approaches to patient management

Although new antimicrobial stewardship programmes (ASPs) often begin by targeting the reduction of antimicrobial use, an increasing focus of ASPs is to improve the management of specific infectious diseases. Disease-based antimicrobial stewardship emphasizes improving patient outcomes by optimizing antimicrobial use and increasing compliance with performance measures. Directing efforts towards the comprehensive management of specific infections allows ASPs to promote the shift in healthcare towards improving quality, safety and patient outcome metrics for specific diseases. This review evaluates published active and passive disease-based antimicrobial stewardship interventions and their impact on antimicrobial use and associated patient outcomes for patients with pneumonia, acute bacterial skin and skin structure infections, bloodstream infections, urinary tract infections, asymptomatic bacteriuria, Clostridium difficile infection and intra-abdominal infections. Current literature suggests that disease-based antimicrobial stewardship effects on medical management and patient outcomes vary based on infectious disease syndrome, resource availability and intervention type.