Onc and Transplant ID: September 2018

Doubling the dose of the inactivated seasonal influenza vaccine in solid organ transplant patients is safe and provides greater immunogenicity than standard dosing. The authors performed a randomized controlled trial of administering 30ug (double dose) versus 15ug (standard dose) of inactivated trivalent influenza vaccine to kidney and liver transplant recipients. Seventy-nine patients were enrolled, 40 in the doubled dose arm and 39 in the standard dose arm. More patients in the double-dose arm achieved seroprotective antibody titers to all vaccine strains after immunization (88% vs 69%; p=0.048). That said, while all of the differences between geometric mean titers to individual strains were higher in the double dose recipients, none of the differences reached statistical significance. Adverse events were mild in both groups and no vaccine-related severe adverse events occurred. 30181045

So here’s a question: why not just use the high-dose trivalent inactivated flu vaccine, which contains about 4 times the antigen load of the standard vaccine? Good news: CID published a randomized controlled trial asking that very question this past May. In that study comparing the high-dose vaccine (Sanofi’s Fluzone) to a standard dose vaccine (GSK’s Fluviral) in 172 solid organ transplant recipients, seroconversion to at least one vaccine strain was higher in the high-dose vaccine recipients (79% versus 56%; p<0.001), as were seroconversions to the H1N1, H3N2, and B strains individually (p<0.05 for all). Also, geometric mean titers were significantly higher in the high-dose vaccine recipients. So, while data suggests both the double-dose and high-dose vaccine strategies are superior to giving the standard-dose inactivated seasonal influenza vaccine for SOT patients, I think the data for the high-dose vaccine looks a little bit stronger. 29253089

Good news for your transplant center’s pharmacy budget: oral ribavirin works as well as the aerosolized form for RSV infections in stem cell transplant recipients. First, a disclaimer: this paper was published by my colleagues at the MD Anderson Cancer Center, so I’m biased to think it’s important.

The pricing of aerosolized ribavirin is absurd. UpToDate cites an average wholesale cost of $30,000 a day: to put that into perspective, for the cost of the usual 5-day course of aerosolized ribavirin I could send my daughter to my alma mater, UT-Austin, for a 4-year Bachelor’s degree followed by 4 years of medical school, and I would still have enough money left over to buy her a new car for graduation. The equivalent course of oral ribavirin, at a price of a couple dollars per tablet, costs about as much as dinner for two and margaritas at my favorite Mexican restaurant. So isn’t it nice to know the two formulations have equal efficacy for RSV?

Foolad et al reviewed cases of RSV infection (both URI and LRI) in HSCT recipients who developed RSV infection and received at least 48 hours of treatment with either inhaled or oral ribavirin at MDACC over a three year period. RSV infections were diagnosed using the BioFire respiratory panel. The primary outcome of interest was 30-day mortality; other measured outcomes included need for ICU admission and mechanical ventilation.

The cohort included a total 124 patients (70 in the inhaled group and 54 in the oral group). Half the cohort had URI and half LRI. Lymphopenia was more common in the inhaled ribavirin recipients that those given oral ribavirin; otherwise, the two groups were similar. Predictors of 30-day mortality included receipt of corticosteroids (83% vs 50%; p=0.03), lymphopenia (50% vs 16%, p=0.012), nosocomial infection (50% vs 8%; p=0.0001), and a high-risk immunodeficiency scoring index (50% vs 11%; p=0.002). Survivors and non-survivors were equally likely to have received oral ribavirin (44% vs 42%). In multivariable analysis, nosocomial infection (aHR 4.8), LRI at diagnosis (aHR 8.7), and haploidentical transplant (aHR 10.3) predicted 30-day mortality, whereas receipt of oral ribavirin did not (aHR 0.93; p=0.845). 30202920

Antibiotic lock therapy may improve treatment success and survival in cancer patients with long-term catheter-related bloodstream infections.  Freire et al reviewed all bloodstream infections related to long-term central venous catheters (LTCVCs) in patients at a Brazilian cancer center between 2009 and 2016. The variable of interest was whether antibiotic lock therapy (ALT) was used in managing the infections, and the primary outcomes of interest were 30-day mortality and treatment failure, defined as persistence or recurrence of infection within 30 days of completing the initial treatment course.

At this center, systemic antibiotics are prescribed for bloodstream infection using a standardized protocol recommending 1 week of therapy for coagulase-negative staph infections, two weeks for gram-negative bacilli and Candida, and up to 4 weeks for infections due to S. aureus. The protocol recommends ALT for gram-negative bacilli and coagulase-negative staph infections, but only in the absence of complicating factors (e.g. sepsis, septic thrombophlebitis, endocarditis, etc). This is where I think the study’s conclusions are up for interpretation: basically, ALT wasn’t given for infections due to S. aureus or Candida or infections with other known predictors of a poor outcome, which is sort of setting up ALT for success as an alternative or adjunct to systemic antibiotics. To their credit, the authors point this out as a likely source of bias in the discussion.

Moving on: a total 296 LTCVC-related infections occurred in 275 patients during the study period (0.25 infectious per 1000 catheter-days); S. aureus was the most commonly identified pathogen, followed by coagulase-negative staph and gram-negative bacilli. ALT alone was used in 62 patients and was part of the initial treatment regimen in 57 patients. The LTCVC was removed in 36% of cases managed with ALT.

Treatment failure in the ALT group was 24% versus 35% in the overall cohort. In a multivariate analysis, risk factors for failure included being in palliative care (OR 3.1; p = 0.003) and having a high SOFA score (OR 1.19; p = 0.002), whereas use of ALT was protective (OR 0.44; p =0.03). The 30-day infection-related mortality rate was 24%, and in multivariate analysis the risk factors for death included being in palliative care (OR 2.7; p = 0.002), having an MDR organism (OR 2.1, p = 0.02), and having a high SOFA score (OR 1.38; p<0.0001), whereas protective factors included having a hematologic malignancy (OR 0.5; p = 0.04), adherence to the institutional protocol for LTCVC-BSIs (OR 0.51; p = 0.02), and use of ALT (OR 0.29; p = 0.04). So, maybe ALT added to systemic antimicrobial therapy improves the outcome of LTCVC-related bloodstream infections? Perhaps we need a randomized controlled trial. 29987150

Oral vancomycin prophylaxis effectively prevents C. difficile infection (CDI) in allogenic hematopoietic stem cell transplantation. This retrospective cohort study out of the Abramson Cancer Center at UPenn examined the effectiveness of oral vancomycin prophylaxis (125mg twice daily for the full duration of hospitalization) in 145 patients with allogenic HSCT. The outcomes of interest were incidence of CDI, graft versus host disease (GHVD), and relapse of the patient’s underlying disease by 6 months after transplantation.

No cases of CDI occurred in the 90 patients given vancomycin prophylaxis, whereas the incidence of CDI in the remaining 55 patients was 20% (p<0.001). Vancomycin was not associated with higher risk of gastrointestinal GVHD of any grade, nor was it associated with disease relapse. My primary reaction to this paper that I’d like to know the incidence of colonization and/or infection with vancomycin-resistant enterococci between the two groups. Fidaxomycin, which has no activity against enterococcus and ought not select for VRE, might be a more appropriate agent for this indication (if CDI prophylaxis needs to be given at all, as judicious antibiotic use should be the first-line strategy to deal with a high prevalence of CDI). 30256954

Fungal endocarditis is a bad disease to have. Congratulations to this team of Brazilian researchers, who pooled every case from five hospitals to produce a decent-sized cohort of a rare disease. Of 78 patients with fungal endocarditis, the median age was 50 years and the most common risk factors were antibiotic exposure in the previous 30 days (73%), presence of a central line (55%), and cardiac surgery in the preceding two months (27%). Most cases involved the aortic and/or mitral valves and had large vegetations (median 15mm; range 5-40mm). Most cases involved Candida species (85%), with the rest due to Aspergillus, Trichosporon, Fusarium, and a smattering of endemic mycoses and rarer fungi. Blood cultures were positive in 98% of cases and valve cultures in 49%; four cases also had positive cultures from sites of embolic disease.

Median duration of antifungal therapy was 31 days and valve replacement was performed in 58%. In-hospital mortality was 54% and among survivors the rate of relapse was 27%. Among the patients with Candida endocarditis, predictors of in-hospital mortality included acute heart failure (OR 5; p=0.027) and nonsurgical treatment (OR 11.1; p=0.004), whereas having isolated right-sided endocarditis was protective (OR 0.13; p=0.023). I found it interesting that the authors did not mention how often suppressive antifungal therapy was given after the initial treatment course, or what drugs were used for that; particularly in cases involving prosthetic cardiac valves or vascular grafts, I would be inclined to leave patients on some sort of azole for life. 30248465