Weekly Articles: 12/27/2020

George R Thompson, III, Alex Soriano, Athanasios Skoutelis, Jose A Vazquez, Patrick M Honore, Juan P Horcajada, Herbert Spapen, Matteo Bassetti, Luis Ostrosky-Zeichner, Anita F Das, Rolando M Viani, Taylor Sandison, Peter G Pappas, Rezafungin versus Caspofungin in a Phase 2, Randomized, Double-Blind Study for the Treatment of Candidemia and Invasive Candidiasis- The STRIVE Trial, Clinical Infectious Diseases, , ciaa1380, https://doi.org/10.1093/cid/ciaa1380

This is a phase 2, randomized, double-blind, double-dummy, multicenter trial evaluating caspofungin compared to its newer, younger brother rezafungin, a next-generation echinocandin. Notably, it achieves high plasma drug concentrations early on and has a prolonged half-life of around 133 hours, allowing weekly dosing. Here, there were 2 parts for the randomization process:

• Part 1: randomization in a 1:1:1 fashion to rezafungin 400mg weekly for 2-4 weeks OR rezafungin 400mg on week one followed by 200mg weekly thereafter OR caspofungin 70mg loading -> 50mg daily with option to step down to PO therapy (fluconazole)
• Part 2: randomization 2:1 to receive rezafugnin weekly or caspofungin daily. Initially it was dose for 400mg weekly but changed to 400mg loading then 200mg weekly thereafter. Notably, those who were randomized to receive 400mg weekly at the start of part 2 remained on the dose

Blinding was preserved as needed with IV or oral components. Primary endpoint was clinical resolution of symptoms + mycological eradication at day 14 (2 neg blood cultures at least 12 hours apart). 207 patients were randomized.

While groups were fairly well balanced, a higher percentage in both rezafungin groups had an APACHE II score >20 (21% and 25% vs 13%). Notably, a higher proportion of patients in the rezafungin group 400mg/200mg had C. glabrata (30% vs 16% in the caspofungin group). Overall cure rates were comparable between groups:

A higher proportion of patients in the rezafungin group had some sort of adverse events, 87.7% in the rezafungin 400mg, 92.5% in the rezafungin 400/200, and 80.9% in the caspofungin group. Severe adverse events were comparable between groups, however, and serious adverse events were reported in 43%, 52% and 42% of the rezafungin 400, rezafungin 400/200, and caspofungin groups. 

Of course, this study was not powered to show non-inferiority between rezafungin and caspofungin, and a lot of the exclusion criteria involved patients with endocarditis and neutropenia. Despite this, I am hopeful we will be able to obtain a drug that can be dose once a week and circumvent a PICC line and all the issues that go along with it. In terms of logistics as outpatient, however, that is another topic in and of itself (do ID clinics need to start preparing infusion centers similar to rheumatology? Especially with the advent of long half-life drugs such as oritavancin and cabotegravir). 

Kozal M, Aberg J, Pialoux G, Cahn P, Thompson M, Molina JM, Grinsztejn B, Diaz R, Castagna A, Kumar P, Latiff G, DeJesus E, Gummel M, Gartland M, Pierce A, Ackerman P, Llamoso C, Lataillade M; BRIGHTE Trial Team. Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2020 Mar 26;382(13):1232-1243. doi: 10.1056/NEJMoa1902493. PMID: 32212519.

This one is from earlier in the year but I still find it interesting. This is a 48-week analysis of an ongoing phase 3 BRIGHTE trial evaluating fostemsavir in patients with multidrug-resistant HIV-1 infection. Fostemsavir is the prodrug of temsavir, an attachment inhibitor that binds to glycoprotein 120 (gp120) close to the CD4+ binding site, which locks the gp120 into a closed state and prevents attachment and entry into T-cell. Think of it as an entry inhibitor different from the other classes:

Enrolled patients had failed their ART (viral load >400) and resistance to at least 4 of the 6 ART classes. There were 2 cohorts. In the first cohort, patients who had at least one active ART  were randomized in a 3:1 ratio to receive fostemsavir 600mg BID from day 1-8 or placebo. After 8 days, all patients received open label fostemsavir. In the second cohort, patients who had no active ART received open-label fostemsavir (i.e. these patients had no other options so “hey, let’s just give them his drug and hopefully it works for them”):

Primary end point was mean change in log10 of viral load from day 1 to day 8. 371 patients were enrolled, of which 272 underwent randomization. Mean reduction at day 8 in the fostemsavir group was 0.79 +/- 0.05 log₁₀ copies/mL compared to 0.17 +/- 0.08 log₁₀ copies/mL in the placebo group (difference -0.63 log₁₀ copies/mL, 95% CI -0.81 to-0.44). In those whose viral load was >1000 copies/mL, reduction at day 9 in the experimental group was 0.86 log₁₀ copies/mL vs 0.20 log₁₀ copies/mL in the placebo group. A reduction of greater than 0.5 log₁₀ copies/mL occurred in 68% in the experimental group vs 19% in the placebo group. Increase in CD4 T-cells was 139 cells/mL in the experimental group vs 64 cells/mL in the placebo group. Response rate (VL <40 copies/mL) in the randomized control group was 54% at week 48. Notably response rates were lower in those with viral load >100,000 and low baseline CD4 T-cells <20 cells/mL. 49 patients in the randomized group met criteria for virological failure and of 47 who had phenotypes, 20 of these had S375N and M426L mutations which confer resistance to this drug.

Studies regarding MDR HIV are difficult to conduct, as they have little options. It would be incredibly difficult to have a more robust trial in the future, so this will have to do. Either way, this drug offers some hope for those who are running out of options, however we will need to wait for the completion of the trial to see the percentage of resistance that manifests here, as these regimens tend to only have one or 2 active components, at best.

Batra, P., Soni, K.D. & Mathur, P. Efficacy of probiotics in the prevention of VAP in critically ill ICU patients: an updated systematic review and meta-analysis of randomized control trials. j intensive care 8, 81 (2020). https://doi.org/10.1186/s40560-020-00487-8

This was a meta-analysis of 9 randomized trials evaluating the utility of probiotics in preventing VAP in mechanically ventilated patients. The idea behind probiotics as a preventative method for VAP is due to the fact they can inhibit the growth of pathogenic micro-organisms and stimulate the proliferation of normal epithelium, which maintains the mucosal defense barriers. All 9 studies were placebo controlled, though the definition of VAP varied among these studies, though most of them required a positive CXR and another clinical finding and/or microbiological diagnosis. A total of 1127 patients were randomized. VAP in the probiotic group was lower in comparison to the control group (OR 0.70, 95% CI 0.56 to 0.88, I² = 37%):

The incidence of VAP was statistically significant in studies with high risk of bias (RR 0.59, 95% CI 0.38 to 0.92, I² =47) which disappeared when taking into account studies with lower bias (0.76, 95% CI 0.57 to 1.02, I²=40), though the trend was towards lower rates of VAP. Duration of mechanical ventilation was also lower in the probiotic group:

And those in the probiotic group also had lower length of ICU stay:

There was also decreased mortality in the probiotic group (OR 0.73, 95% CI 0.54 to 0.98). I think this is a fairly interesting study and probiotics are harmless enough to proceed with it in ventilated patients. Most of the probiotics were a mix of bacteria, administered within 48-72hrs of admission for anywhere between 14-28 days. 

Mohamed ZU, Prasannan P, Moni M, et al. Vitamin C Therapy for Routine Care in Septic Shock (ViCTOR) Trial: Effect of Intravenous Vitamin C, Thiamine, and Hydrocortisone Administration on Inpatient Mortality among Patients with Septic Shock. Indian J Crit Care Med. 2020;24(8):653-661. doi:10.5005/jp-journals-10071-23517

The issue of vitamin C in septic shock contains to rear its head. This was a single-center, open-label, prospective randomized controlled trial that randomized patients in a 1:1 ratio to hydrocortisone 50mg q6h + vitamin C 1.5g q6h, and thiamine 200mg q12h and to standard of care. Patients were started on this regimen within 6 hours of admission/onset of septic shock. Primary come was inpatient all-cause mortality between HAT and standard of care. 90 patients were randomized, an primary end point of mortality was 53% in the routine care group and 57% in the HAT group:

While the primary endpoint was negative, the secondary endpoints are interesting. The time to shock reversal was significantly lower in the HAT group, even after adjusting for steroid use. Change SOFA score was also greater in the HAT group, though this did not reach statistical significance. Length of stay was longer in the HAT group. 

What to make of this? Going back to the CITRIS-ALI trial (which is cited in this paper), the primary endpoint was change in SOFA score. This did not reach statistical significance, however mortality was statistically different between groups. Notably, the mortality between groups the first 96 hours was 23% in the placebo group vs 4% in the experimental group. Despite this, the only study that demonstrated mortality benefit was the CITRIS-ALI trial, which again, was a secondary outcome. The ORANGES and HYVCTTSSS trials did show faster shock reversal but no mortality benefit. Either way, this was a single-center study so that hurts its external validity. I do not see this issue going away, especially with data suggesting faster shock reversal. 

Takuji Komeda, Takahiro Takazono, Naoki Hosogaya, Taiga Miyazaki, Eriko Ogura, Shinpei Iwata, Hideyuki Miyauchi, Keiichi Honda, Masakazu Fujiwara, Yoshikazu Ajisawa, Hideaki Watanabe, Yoshitake Kitanishi, Kanae Hara, Hiroshi Mukae, Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study, Clinical Infectious Diseases, , ciaa1870, https://doi.org/10.1093/cid/ciaa1870

This is a retrospective observational cohort comparing baloxavir with neuraminidase inhibitors (mainly oseltamivir but also include zanamivir and laninamivir) in outpatients with confirmed influenza. Primary end point was incidence of hospitalization anywhere from day 2-14 (day 1 being day of enrollment and first day of therapy). Secondary endpoints included administration of antibiotics, diagnosis of pneumonia, or any other flu medication. Propensity scores and inverse probability of treatment weighting were used to compare the groups. 339,007 patients were included, of which 146,192 received baloxavir and 92,700 received oseltamivir. 81,438 received laninamivir and 18677 received zanamivir. 

Patients treated with both oseltamivir and zanamivir were more likely to be admitted when compared to those treated with baloxavir (RR 1.41, 95% CI 1.00-2.00 for oseltamivir, RR 1.85, 95% CI 1.23-2.78 for zanamivir):

Patients in the oseltamivir group were less likely to get antibiotics, but were more likely to have other influenza drugs:

For zanamivir and lanimavir, baloxavir tends to do better here as well:

This is a fairly interesting study, given that baloxavir resistance is an issue. Overall, this is encouraging for single-dose baloxavir and increased adherence when compared to oseltamivir.

Verboom DM, van de Groep K, Boel CHE, Haas PJA, Derde LPG, Cremer OL, Bonten MJM. The Diagnostic Yield of Routine Admission Blood Cultures in Critically Ill Patients. Crit Care Med. 2021 Jan 1;49(1):60-69. doi: 10.1097/CCM.0000000000004717. PMID: 33165029.

I do not know how to feel about this one. This is a prospective study that evaluated the utility of an automatic order set that included a single set of blood cultures to all patients admitted to the ICU, regardless of clinical suspicion of infection. This was a before-after analysis in a single center from the Netherlands. 1775 patients were admitted before the intervention and 1871 were admitted afterwards. The patients were matched between groups, though more patient in the before period had immunodeficiency (18.3% vs 13.6%) and those in the after period were transferred in (12.3% vs 16..4%). ICU and 30-day mortality did not differ between periods. Overall, 95 bacteremias were detected in the before period (5.4%) vs 154 in the after period (8.2%), RR 1.5 (95% CI 1.2-2.0). 40 contaminated blood cultures were seen in the before period compared to 180 in the after period, RR 4.3 (95% CI 3.0-6.0). In those with suspected infection, the patients in the after period were more likely to be diagnosed with bacteremia compared to the before period (RR 1.5, 95% CI 1.1-1.9). In those with no suspected infection, RR for detecting bacteremias was 5.6 (95% CI 1.3-25.1) while the RR for contamination was 7.4 (95% CI 4.2-13.1).

The calculated number needed to culture to get an additional bacteremia was 17. Notably, despite higher incidence of contamination in the after period, the rates of vancomycin administration did not differ between time periods (gives me hope people are still judicious with their antibiotic use).

Given all the other tools we have for suspected infection, I do not think the increase risk of contamination is worth it here. While length of hospital stay was actually shorter in the after period, there was no clear benefit seen in terms of mortality here. I can see this leading to higher instances of repeat blood cultures and perhaps unnecessary antibiotic administration.