Weekly Articles 8/15/2021

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Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, Stowe J, Tessier E, Groves N, Dabrera G, Myers R, Campbell CNJ, Amirthalingam G, Edmunds M, Zambon M, Brown KE, Hopkins S, Chand M, Ramsay M. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021 Aug 12;385(7):585-594. doi: 10.1056/NEJMoa2108891. Epub 2021 Jul 21. PMID: 34289274; PMCID: PMC8314739.

This was a study evaluating the efficacy of the Pfizer vaccine and the AstraZeneca vaccine on the delta variant. A test-negative case control design was used to estimate the vaccine effectiveness against symptomatic disease caused by the delta variant compared to the alpha variant. Data was adjusted based on age, sex, race, ethinic group, care home residence, foreing travel, ehealth and social care worker status. 19109 cases were included in the analysis. Of these, the delta variant was seen in 4272 samples. Those who had the delta variant were more likely to have had foreign travel, had more recent case positivity, and be of Indian, or Pakistani descent. Vaccine efficacy was notably lower after the first dose for those who had the delta variant compared to the alpha variant (36% vs 49%), but it increased after the second dose:

The Pfiezer vaccine seemed to be more efficacious against the delta variant compared to the AstraZeneca vaccine. At the time of writing this, there was no data available for hospitalizations, which I think is a very important data point to consider.

Debes AK, Xiao S, Colantuoni E, Egbert ER, Caturegli P, Gadala A, Milstone AM. Association of Vaccine Type and Prior SARS-CoV-2 Infection With Symptoms and Antibody Measurements Following Vaccination Among Health Care Workers. JAMA Intern Med. 2021 Aug 16. doi: 10.1001/jamainternmed.2021.4580. Epub ahead of print. PMID: 34398173.

Small paper on symptoms after vaccination in a cohort of healthcare workers. Here 954 healthcare workers were evaluated, of which 52 (5%) had symptoms after shot 1 and 407 (43%) had them after the second dose. After adjustment, those who got the Moderna vaccine were more likely to have some sort of symptoms (after dose 1 OR 1.83, 95% CI 0.96-3.5, dose 2OR 2.43, 95% CI 1.73-3.40). Prior SARS-CoV exposure was also associated with symptoms.

Regardless, the vast majority (99%) developed IgG against the spike protein 14 days after dose 2.

Oldenburg CE, Pinsky BA, Brogdon J, Chen C, Ruder K, Zhong L, Nyatigo F, Cook CA, Hinterwirth A, Lebas E, Redd T, Porco TC, Lietman TM, Arnold BF, Doan T. Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA. 2021 Aug 10;326(6):490-498. doi: 10.1001/jama.2021.11517. PMID: 34269813; PMCID: PMC8285753.

This was a randomized clinical trial comparing the efficacy of a single dose of 1.2mg of azithromycin vs placebo on self-reported COVID-19 symptoms in an outpatient population. Patients with a documented positive RT PCR within 7 days of enrollment were eligible, and those who were taking HCQ, greater than 55, or had a prolonged QTc were excluded (as to avoid worsening QTc prolongation). Patients were randomized in a 2:1 fashion to a single dose of azithromycin or placebo. Primary outcome was the self-reported absence of COVID-19 symptoms at day 14, with online surveys used to measure the outcome. The original primary outcome was hospitalizations, but this was changed due to the lower rate of hospitalizations seen. Further, the trial was stopped early after an initial interim analysis found that recruitment was taking longer than anticipated and due to futility. 263 patients were enrolled, of which 171 were randomized to either group. Both groups were fairly well balanced in terms of baseline characteristics. At day 14, there was no significant difference between groups in terms of self-reported COVID-19 symptoms:

This held true for both symptomatic and asymptomatic patients. In the secondary outcomes, more patients in the azithromycin group ended up going to an urgent care of ED, though I would not put too much weight on it.

More patients in the azithromycin group had diarrhea, nausea, or abdominal pain when compared to the placebo cohort. I am not terribly surprised about these results, as azithromycin was given relatively late into the disease course and these patients were likely to do well anyways. I do not know if a lower, but more prolonged dose would work given the anti-inflammatory effects azithromycin tends to have. Either way, another potentially effective oral drug therapy strikes out. 

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, Spiga F, Savovic J, Tierney J, Baron G, Benbenishty JS, Berry LR, Broman N, Cavalcanti AB, Colman R, De Buyser SL, Derde LPG, Domingo P, Omar SF, Fernandez-Cruz A, Feuth T, Garcia F, Garcia-Vicuna R, Gonzalez-Alvaro I, Gordon AC, Haynes R, Hermine O, Horby PW, Horick NK, Kumar K, Lambrecht BN, Landray MJ, Leal L, Lederer DJ, Lorenzi E, Mariette X, Merchante N, Misnan NA, Mohan SV, Nivens MC, Oksi J, Perez-Molina JA, Pizov R, Porcher R, Postma S, Rajasuriar R, Ramanan AV, Ravaud P, Reid PD, Rutgers A, Sancho-Lopez A, Seto TB, Sivapalasingam S, Soin AS, Staplin N, Stone JH, Strohbehn GW, Sunden-Cullberg J, Torre-Cisneros J, Tsai LW, van Hoogstraten H, van Meerten T, Veiga VC, Westerweel PE, Murthy S, Diaz JV, Marshall JC, Sterne JAC. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA. 2021 Aug 10;326(6):499-518. doi: 10.1001/jama.2021.11330. PMID: 34228774; PMCID: PMC8261689.

What about IL-6 inhibitors? This was a meta-analysis of prospective randomized trials comparing the administration of IL-6 antagonist with usual care or placebo and all-cause mortality at 28 days in those hospitalized with COVID-19. Multiple subgroup analysis were performed, including those who received respiratory support (at all levels), receipt of steroids, those who required organ support, age/gender, and CRP at baseline. 27 trials were included, with tocilizumab accounting for 19 of these trail, sarilumab for 89, and siltuximab in one. More patients in the sarilumab trials were on mechanical ventilation and a lower proportion received corticosteroids. For the primary outcome, using fixed effects meta-analysis, the summary OR was 0.86 (95% CI 0.79-0.95), for a 22% mortality risk reduction compared to usual care of placebo. This seems to have been driven by tocilizumab trial, as the sarilumab trials tended to veer towards a higher mortality though this was not statistically significant:

In looking at those who use steroids vs those who didn’t, the use of IL-6 inhibitors was associated with improved mortality benefit when steroids were given:

There was no increase risk of infections when IL-6 inhibitors were used (OR 0.99, 95% CI 0.85-1.16) and in terms of secondary outcomes, the use of corticosteroids with IL-6 inhibitors was associated with reduced risk of progression to mechanical ventilation, though this was only seen for tocilizumab.

The primary outcome suggests that IL-6 inhibitors, especially tocilizumab, are associated with improved all-cause mortality with minimal risk of infections. The secondary outcomes suggest that steroids may be somewhat responsible for this effect, though that is conjecture on my part. All that said, if IL-6 is available and you need it, it does not seem unreasonable to use it. 

Pavord S, Scully M, Hunt BJ, Lester W, Bagot C, Craven B, Rampotas A, Ambler G, Makris M. Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis. N Engl J Med. 2021 Aug 11. doi: 10.1056/NEJMoa2109908. Epub ahead of print. PMID: 34379914.

Speaking of vaccines, this study described 220 cases of definitive or probable vaccine induced immune thrombocytopenia and thrombocytosis. I discussed how this syndrome, described following the AstraZeneca vaccine, was similar to HIT, in which there is a high proportion of antibodies against PF-4.  Cases were defined as definitive (based on all 5 criteria below), probable, and possible:

The authors also evaluated the time from vaccination to presentation, as well as the site of thrombosis. At the time of the study, ~16 million doses of the vaccine had been administered, with rates of VITT being 1:50,000 in those under the age of 50 and 1:100,000 in those over 50. 97% presented within 5-30 days after the vaccination and none had been exposed to heparin. Median platelet count was 47,000 and anti-PF4-antibodies were present in 198/200 tested. 

The most common site of thrombosis was the cerebral veins, followed by pulmonary arteries, and DVTs. There were also a significant proportion of intracranial hemorrhage, which was more common in patients with lower platelet counts (median 34,000). IVIG was used in 72% of patients and 17 patients with severe disease underwent PLEX. 

Steroids were used in 26% of cases, of which 50% had <30k platelets. Mortality rate in this cohort was 22%, with cerebral venous thrombosis (OR 2.7, 95% CI 1.4 to 5.2), lower platelet count (OR 1.7, 95% CI 1.3 to 2.3), increase in D-dimer (OR 1.2, 95% CI 1 to 1.3) and decrease in baseline fibrinogen (OR 1.7, 95% CI 1.1 to 2.5). 

While rare, this complication is quite devastating. This, on top of the lower efficacy of the AstraZeneca vaccine against the delta variant, may lead me to recommend the mRNA vaccines over this one. Though from a public health perspective, it is still a fairly good vaccine, given the available options, I can see more people gravitating towards the Pfizer and Moderna vaccines. 

Burke RM, Rickman HM, Singh V, Corbett EL, Ayles H, Jahn A, Hosseinipour MC, Wilkinson RJ, MacPherson P. What is the optimum time to start antiretroviral therapy in people with HIV and tuberculosis coinfection? A systematic review and meta-analysis. J Int AIDS Soc. 2021 Jul;24(7):e25772. doi: 10.1002/jia2.25772. PMID: 34289243; PMCID: PMC8294654.

When should you start HIV medications when someone also has tuberculosis? This is a meta-analysis of 10 trials comparing an early initiation of ART therapy (within 2 weeks of starting TB therapy) or a delayed strategy (after 8 weeks of TB therapy). The authors also compared a more general definition, usually before 4 weeks or after 4 weeks, as there was a lot of heterogeneity in the studies. Further, 4 trials allowed clinically diagnosed tuberculosis (i.e. no need for micro diagnosis), 3 studies only allowed pulmonary TB and 6 allowed extrapulmonary TB patients to be enrolled. Comparing ART within 2 weeks vs after 2 weeks of TB initiation, there was no difference in the primary outcome of death:

This was true when comparing outcomes at a 4 week timeframe:

Patient’s whose CD4 was <50 had no difference in mortality when comparing a strategy of <2 weeks or more than 2 weeks, though when comparing the 4 week timeframe, there was a benefit towards early ART:

There was no difference between either strategy when CD4 >50. For IRIS, when comparing the 4 week strategy, there was a benefit towards less cases of IRIS when starting ART after 4 weeks of therapy:

What to make of this? It is difficult to say, as there were so many variables that differed between trials. I think the main takeaway here is that overall, starting ART early seems to be a reasonable thing as long as there is no suspicion of TB meningitis (as I have discussed in the past). I think in the long-term, it may even benefit someone. The one caveat here is that there is a higher chance of IRIS when starting ART early, but this does not seem to translate towards higher mortality. 

Suárez-García I, Alejos B, Ruiz-Algueró M, García Yubero C, Moreno C, Bernal E, Pérez-Is L, Zubero Z, de Zárraga Fernández MA, Samperiz Abad G, Jarrín I; Cohort of the Spanish HIV/AIDS Research Network (CoRIS). Effectiveness and tolerability of dolutegravir and abacavir/lamivudine administered as two separate pills compared to their equivalent single-tablet regimen in a multicentre cohort in Spain. J Int AIDS Soc. 2021 Jul;24(7):e25758. doi: 10.1002/jia2.25758. PMID: 34291580; PMCID: PMC8295592.

If you have practiced HIV medicine in the states, I think you will know folks are transitioning towards a single-tablet regimen. Most of the time, it is Biktarvy (TAF/FTC/BIC) but regimens such as triumeq (ABC/3TC/DTG) are still widely prescribed (though triumeq is a huge pill). Certain combinations, however, are not available due to patents (ever wondered why there is no such thing as FTC/TAF/DTG?). This Spanish, multicenter cohort compared the combination of dolutegravir, abacavir, and lamivudine as either 2 separate pills or as a single combination, in terms of effectiveness and tolerability. All patients who were naive were included. Patients who were given Triumeq, DTG + ABC/3TC (generic) or DTG+ ABC/3TC (brand) were included, but these were not randomized. A total of 944 patients were included, of which 88% were on Triumeq. Patients across all 3 groups were fairly similar, though the ones in the Triumeq group had lower VL. At 24 weeks, 86% of the Triumeq group and 87% of the DTG + ABC/3TC had achieved viral suppression:

Within the DTG + ABC/3TG brand group, 86% changed to the single pill, mostly due to simplification. So these therapies, as long as the components are the same, will be equally effective. 

Bosch DE, Mathias PC, Krumm N, Bryan A, Fang FC, Greninger AL. Elevated white blood cell count does not predict Clostridium difficile nucleic acid testing results. Clin Infect Dis. 2021 Feb 10:ciab106. doi: 10.1093/cid/ciab106. Epub ahead of print. PMID: 33564820.

This study evaluated the predictive value of leukocytosis for C. diff colitis. This prospective cohort study divided patients who had a leukocytosis above or below 15K and a NAAT result. 16568 patients were included, of which 1681 tested positive for C. diff. WBC distribution between positive and negative patients was similar:

While outpatients and ED patients had a higher WBC, the ROC AUC was 0.59, so not very predictive. Further, the difference in WBC from 3 days prior to testing positive was not very different compared to C. diff negative patients (median change 200 vs 0). It should be noted, however, that the rate of death and length of stay were both correlated with the degree of leukocytosis (i.e. higher WBC = more death and longer stay):

Unless you tested positive, in which case, the rate of death and hospitalization were better! It should be noted, however, that higher WBC lead to higher rates of dual therapy with vancomycin and MTZ:

I think this may contradict the notion that a leukemoid reaction should be followed by C. diff testing in the absence of symptoms. 

Harris GR, Karmarkar EN, Quenelle R, Chaille L, Madhok J, Tien V, Gupta J, Jain S, Liu M, Roy S, Narasimhan S, Kimura A, Cope JR, Ali IKM. Death From Primary Amebic Meningoencephalitis After Recreational Water Exposure During Recent Travel to India-Santa Clara County, California, 2020. Open Forum Infect Dis. 2021 Jul 27;8(8):ofab322. doi: 10.1093/ofid/ofab322. PMID: 34395708; PMCID: PMC8360241.

An interesting case study. A man in his mid-40s had returned to the US from India 3 days prior with a sore throat and cough. He became encephalopathic and was admitted to the hospital with sighs of fever, tachycardia, and significant hypertension. He was lethargic and was intubated for airway protection. He had an LP which revealed a RBC of 49, 2083 WBC (91% neutrophils), protein 477. Gram stain was negative, and was started on empirical therapy for meningitis. He had 4 serial LPs with high opening pressures >55cm H2O. During this time, WBC counts increased to 15k and glucose dropped to <2 while protein increased to 1023. He was started on dexamethasone, had an EVD placed, but pathology revealed vacuolated cells with pale, eosinophilic nuclei. He was found to have amebic trophozoites in the CSF; he was started on IV amphoB, CTX, rifampin, and fluconazole but he ultimately succumbed on hospital day 5. N. folweri was confirmed by rtPCR. Notably, his only exposure was swimming in an indoor pool at a privately owned short-term vacation rental in India. 

Stewart AG, Paterson DL, Young B, Lye DC, Davis JS, Schneider K, Yilmaz M, Dinleyici R, Runnegar N, Henderson A, Archuleta S, Kalimuddin S, Forde BM, Chatfield MD, Bauer MJ, Lipman J, Harris-Brown T, Harris PNA; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC β-Lactamase-Producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp, or Serratia marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2). Open Forum Infect Dis. 2021 Aug 2;8(8):ofab387. doi: 10.1093/ofid/ofab387. PMID: 34395716; PMCID: PMC8361238.

This is the pilot of the MERINO trial, which attempts to compare pip-tazo and carbapenems in bacteremia caused by gram-negatives that are known to be ampC producers. This was a international, multicenter, open-label trial that enrolled patients who tested positive for Klebsiella aerogenes, serratia marcescens, providencia spp, morganella morganii or Citrobacter freundii that had susceptibility to cephalosporins, pip-tazo, or carbapenems. Patients were randomized within 72 hours to either meropenem or pip-tazo in a 1:1 fashion. Primary outcome was a composite of all cause mortality at 30 days, ongoing fever or leukocytosis at day 5 post randomization, microbiological failure on days 3-5, or microbiological relapse at days 5-30. 79 patients were randomized, and 72 were included in the primary analysis. Both groups were fairly well balanced, though 73% of those in the pip-tazo group had surgery within 14 days compared to 12% in the meropenem group. Further, those in the pip-tazo group took 7 hours for appropriate antibiotics compared to 1.5hours in the meropenem group. Primary outcome was met in 29% of the patients in the pip-tazo group compared to 21% in the meropenem group (risk difference 8%, 95% CI -12 to 28%). The results were similar in the per protocol group (risk difference 6%, 95% -14 to 24). Notably, more patients in the Pip-tazo group had microbiological failure and microbiological relapse:

Susceptibility to pip-tazo was seen in 96.5% of isolates, while to meropenem was seen in 100%. No ESBL, OXA, or carbapenamese genes were identified. We will have to wait and see for the more robust results from the larger trial, but I think this give a bit of insight as to where things will go. 

Kendall MA, Lalloo U, Fletcher CV, Wu X, Podany AT, Cardoso SW, Ive P, Benson CA. Safety and Pharmacokinetics of Double-Dose Lopinavir/Ritonavir + Rifampin Versus Lopinavir/Ritonavir + Daily Rifabutin for Treatment of Human Immunodeficiency Virus-Tuberculosis Coinfection. Clin Infect Dis. 2021 Aug 16;73(4):706-715. doi: 10.1093/cid/ciab097. PMID: 34398956; PMCID: PMC8366816.

This is more of a pharmacology study. Rifampin and rifabutin tend to decrease the plasma concentrations of PIs, including lopinavir/ritonavir (Kaletra). In high-TB burden countries, they do not have access to integrase inhibitors so a lot of the regimens have to work around this fact. Further, PIs increase rifabutin concentrations and increase the risk of adverse events. Raltegravir has been found to increase the activity of the kaletra-based regimen. This was a prospective, randomized, open label trial that compared 3 LPV/r based regimen combined with TB treatment that had either rifampin or rifapentine. Patients with TB and failure of initial ART regimen requiring PI-based regimens were included. Patients were randomized in a 1:1:1 fashion to either LPV/r 400/100 BID + 2 NRTIs + IPE + rifabutin 300mg daily and then 150mg/day when ART is starged 2) LPV/r 800/200 + 2 NRTs + RIPE (standard), 3) same as A + RAL 400mg BID. Primary PK outcomes were max concentration and trough for LPV and RAL, AUC 12 of AUC 24 for both, and oral clearance. Primary HIV outcome was viral suppression at 48 weeks. 71 patients were enrolled, Viral suppression occurred in 58% of group A, 67% in group B, and 61% in group C (when defining viral suppression to <400 copies/mL). IF using the <50 copies/mL, then the percentages were 46% in group A, 54% in group B, and 57% in group C. 

Sputum TB conversion was achieved in 88% of group A, 82% in group B, and 70% in group C. As far as the PK parameters were concerned, there was no difference in the PK parameters for LPV in either arm. The rifabutin parameters were all higher without the addition of raltegravir:

Notably, 3 of the patients in group 1 suffered from uveitis while none in group 3 did so, suggesting the interaction between RAL and rifabutin. 

Suzuki H, Perencevich EN, Diekema DJ, Livorsi DJ, Nair R, Kralovic SM, Roselle GA, Goto M. Temporal Trends of Candidemia Incidence Rates and Potential Contributions of Infection Control Initiatives over 18 Years within the US Veteran Health Administration System: A Joinpoint Time-Series Analysis. Clin Infect Dis. 2021 Feb 10:ciab105. doi: 10.1093/cid/ciab105. Epub ahead of print. PMID: 33564858.

This study evaluated the national VA data to evaluate the rates of candidemia between 2000 and 2017. They also attempted to evaluate the impact of the catheter-related blood stream infection recommendations from the IDA (2001) and CDC (2002). 17661 unique candidemia cases were included, most of which occurred while inpatient (85%). Median monthly rates were 2.75 episodes/10,000 patient days while inpatient compared to 0.46 episodes/10,000 patient days outpatients. The rate of candidemia while in-patient increased early in the 2000s, but interestingly decreased after catheter-related blood stream infections had to be reported, and also at around the same time as the IDSA candidemia guidelines started:

This translates to a 77.1% reduction in incidence rates of hospital related candidemia from 8/2004 to 12/2017. Inpatient prescription fates of triazoles decreased along with an increase in triazoles in the outpatient setting:

This suggests that implementation of bundles and guidelines does lead to a system-wide reduction in cases of candidemia, which means these actually work as annoying as they may be. 

Blanco JL, Fuertes I, Bosch J, De Lazzari E, Gonzalez-Cordón A, Vergara A, Blanco-Arevalo A, Mayans J, Inciarte A, Estrach T, Martinez E, Cranston RD, Gatell JM, Alsina-Gibert M. Effective treatment of Lymphogranuloma venereum proctitis with Azithromycin. Clin Infect Dis. 2021 Jan 19:ciab044. doi: 10.1093/cid/ciab044. Epub ahead of print. PMID: 33462582.

This is a prospective, non-randomized, open trial comparing treatment of lymphogranuloma venereum proctitis with either extended azithromycin (1g oncer per week for 3 weeks ) or doxycycline 100mg BID for 21 days. Patients were recruited 7 days after empirical STI therapy was initiated and if they had a positive rectal LGV PCR test. After the first 7 days, if patients were given doxycycline as part of their empiric therapy, they would keep it for another 14 days. Those who got one dose of azithromycin would get an additional 2 doses. It should be noted the initial therapy was at the discretion of the treating physician. Primary endpoint was LGV cure, defined as a clinical cure  (at least 6 weeks out) or microbiological cure (repeat testing at least 4 weeks out). 125 patients were enrolled, of which 120 had underlying HIV. Most patients were in the azithromycin group (82 vs 43), though there were no other differences between the groups. In the mITT population, primary endpoint was achieved in 80/82 patients in teh azithromycin group (98%) compared to 41/43 in the doxycycline group (95%) for a treatment difference of 2.2 (95% CI -3.2 to 13.2). By day 21, in those who had repeat testing, LGV-PCR negativity was 96.5% in the azithromycin group vs 97.2% in the doxycycline group:

There are of course, issues with this study, the major one being the lack of randomization and how the preference played a role in terms of which therapy was chosen (the less cumbersome azithromycin or the daily doxycycline). In the absence of further data, I think there is a compelling argument to be made for the once weekly azithromycin to be given, if the patient prefers this type of therapy. 

Torrico F, Gascón J, Barreira F, Blum B, Almeida IC, Alonso-Vega C, Barboza T, Bilbe G, Correia E, Garcia W, Ortiz L, Parrado R, Ramirez JC, Ribeiro I, Strub-Wourgaft N, Vaillant M, Sosa-Estani S; BENDITA study group. New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial. Lancet Infect Dis. 2021 Aug;21(8):1129-1140. doi: 10.1016/S1473-3099(20)30844-6. Epub 2021 Apr 6. Erratum in: Lancet Infect Dis. 2021 Aug;21(8):e208. PMID: 33836161.

And now a disease no one ever sees, Chagas disease. This was a double-blind, double-dummy, phase 2 multicenter, randomized trial comparing benznidazole monotherapy and combination of benzidazole and fosravuconazole in different doses. Patients were randomized in a 1:1:1:1:1:1:1 (so seven groups) to 300mg of daily benzindazole daily for 8 weeks, 300mg benznidazole daily for 4weeks, 300mg benzindazole daily for 2 weeks, 150mg benzindazole daily for 4 weeks, 150mg benzindazole daily for 4 weeks + fosravuconazole, and 300mg benzindazole 300mg weekly for 8 weeks plus fosravuconazole and a placebo group.  Primary endpoint was parasitological clearance at 6 months of follow up. 210 patients were enrolled (none of them who had GI or cardiac forms of the disease), with each group being fairly well balanced. In the ITT population, 85% of all experimental groups and 3% of the placebo group achieved sustained parasitological clearance at 6 months:

As seen above, there was no difference within each of the experimental group. Notably, time to clearance was shorter in the benznidazole 300mg daily x 8 weeks group and the 150mg daily for four weeks and fosravauconazole group. Most adverse events were related to the nervous system, skin and SQ disorder, and GI disorders. Severe adverse events were seen only in the max dose group. 

This is more of a proof-of-concept trial to attempt to get a different therapeutic approach for Chagas disease, as 300mg daily benzindazole for 8 weeks (the standard) leads to multiple adverse events resulting in discontinuation of therapy. 

Rupawala AH, Gachette D, Bakhit M, Jimoh L, Kelly CR. Management of Severe and Severe/Complicated Clostridoides difficile Infection using Sequential Fecal Microbiota Transplant by Retention Enema. Clin Infect Dis. 2021 Jan 21:ciab041. doi: 10.1093/cid/ciab041. Epub ahead of print. PMID: 33476379.

This was a single-center prospective study of 15 patients with severe or complicated CDI. Patients were enrolled if they had failed at least 48hrs of conventional CDI (IV flagyl, PO vancomycin or rectal vancomycin) with worsening labs or clinical parameters. From here, FMT was performed via retention enema up to 3 between days 1 through 5. Primary endpoint was clinical response by day 7 (improvement in diarrhea, WBC count, and CRP). 87% of patients had a clinical response by day 7, with 73% having a resolution of leukocytosis by day of discharge. 5 patients died, of which 2 was related to CID. 5 of the patients who underwent FMT had sustained clinical response at day 30 while four had recurrence. I do not know how far up the colon a retention enema goes, but this would be a much easier way to administer FMT (besides crapsules). Not a lot to comment on given the small number of patients and the single center nature of it, but interesting nonetheless. 

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