Weekly Articles 5/30/2021

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Quite a few here. A brief word on the new vancomycin dosing guidelines, dual therapy for enterococcal IE and MRSA bacteremia, and several updates on COVID-19.

Anna Poston-Blahnik, Ryan Moenster, Association Between Vancomycin Area Under the Curve and Nephrotoxicity: a single center, retrospective cohort study in a veteran population, Open Forum Infectious Diseases, Volume 8, Issue 5, May 2021, ofab094, https://doi.org/10.1093/ofid/ofab094

This was a retrospective study evaluating the relationship between AUC for vancomycin and its relationship with acute renal injury, as defined by a rise in creatinine of 0.3mg/dL or 50% increase from baseline. The AUC cut-off used was >550 and patients needed to have been treated for at least 4 days. 200 patients were included, 100 with >550 AUC and 100 <500 AUC. The overall rate of AKI was 22%, with the rate being 42% if AUC was >550 while only 2% if AUC was <550:

Not surprisingly, the vancomycin dose was higher in the high AUC cohort (1722 mg vs 2361) as was the creatinine (1.48 vs 1.22). Length of stay was similar between the 2 groups. Multivariate analysis found that AUC >550, age >70, and low CrCl were associated with acute kidney injury:

One thing to note is the AUC was calculated using a different method, the Moise-Broder equation, as opposed to a Bayesian model. Of course, using creatinine as a marker for acute kidney injury has issues as it does not explore more relevant outcomes such as dialysis and mortality. Furthermore, whether or not AUC is directly related to AKI is unknown, as the higher dose is inherently associated with a higher creatinine (duh). 

As some of you may know, the guidelines for vancomycin dosing from 2020 have changed the recommendation on how to monitor and now recommend using AUC as opposed to trough. If you recall, the AUC/MIC is how vancomycin exerts its antibacterial activity, however we use the goal trough of 15-20 because it guarantees you get an adequate trough (400) at minimum but it fails at telling you how high it could go. So for one person, a trough of 15 will get them at that 400 AUC but for another, the same trough would mean an AUC of 1500. As a result, measuring the AUC would yield less chances of overdosing and avoid complications, namely acute renal injury. This past issue of CID had a point and counterpoint about the new AUC guidelines, which I think are interesting reads.

Thomas P Lodise, George Drusano, Vancomycin Area Under the Curve–Guided Dosing and Monitoring for Adult and Pediatric Patients With Suspected or Documented Serious Methicillin-Resistant Staphylococcus aureus Infections: Putting the Safety of Our Patients First, Clinical Infectious Diseases, Volume 72, Issue 9, 1 May 2021, Pages 1497–1501, https://doi.org/10.1093/cid/ciaa1744

Sarah C J Jorgensen, Brad Spellberg, Andrew F Shorr, William F Wright, Should Therapeutic Drug Monitoring Based on the Vancomycin Area Under the Concentration-Time Curve Be Standard for Serious Methicillin-Resistant Staphylococcus aureus Infections?—No, Clinical Infectious Diseases, Volume 72, Issue 9, 1 May 2021, Pages 1502–1506, https://doi.org/10.1093/cid/ciaa1743

Niyati H Shah, Kathleen A Shutt, Yohei Doi, Ampicillin-Ceftriaxone vs Ampicillin-Gentamicin for Definitive Therapy of Enterococcus faecalis Infective Endocarditis: A Propensity Score–Matched, Retrospective Cohort Analysis, Open Forum Infectious Diseases, Volume 8, Issue 4, April 2021, ofab102, https://doi.org/10.1093/ofid/ofab102

This was a retrospective cohort study comparing ampicillin-ceftriaxone vs ampicillin-gentamicin in the treatment of enterococcal infective endocarditis in 3 centers. Primary outcome was 90-day all-cause mortality, with propensity score matching performed to control for several variables. 190 patients were included, with patients in the ampicillin-gentamicin group more likely to have a prosthetic valve and receiving surgical intervention, while more patients in the ampicillin-ceftriaxone group having higher incidence of high-level aminoglycoside resistance (HLAR). There was no statistical difference in terms of primary outcomes at 90 days:

Secondary outcomes, including in-hospital mortality, hospital readmission, and length of hospital stay, were not statistically different. One thing to note is the difference in duration of bacteremia, being significantly shorter in that of the gentamicin group, however, a higher number of patients in that group required change in antibiotics due to adverse events:

One thing to note about these results is that, despite matching, the gentamicin group had more complications (including a higher rate of annular abscesses), which may have influenced the results. The other thing to note is the interesting difference in the length of bacteremia and rate of chance between both groups. Given that mortality here was not statistically different, it begs the question as to if ceftriaxone, with less adverse events and longer duration of bacteremia, is the better option. I would assume the dose was 2g q12h rather than q24h but what do I know. 

Pujol M, Miró JM, Shaw E, Aguado JM, San-Juan R, Puig-Asensio M, Pigrau C, Calbo E, Montejo M, Rodriguez-Álvarez R, Garcia-Pais MJ, Pintado V, Escudero-Sánchez R, Lopez-Contreras J, Morata L, Montero M, Andrés M, Pasquau J, Arenas MD, Padilla B, Murillas J, Jover-Sáenz A, López-Cortes LE, García-Pardo G, Gasch O, Videla S, Hereu P, Tebé C, Pallarès N, Sanllorente M, Domínguez MÁ, Càmara J, Ferrer A, Padullés A, Cuervo G, Carratalà J; MRSA Bacteremia (BACSARM) Trial Investigators. Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial. Clin Infect Dis. 2021 May 4;72(9):1517-1525. doi: 10.1093/cid/ciaa1081. PMID: 32725216; PMCID: PMC8096235.

From dual therapy in one type of endocarditis to another one, this case MRSA. As highlighted previously, dual therapy with vancomycin and a beta-lactam has not been effective for therapy of MRSA bacteremia. This trial was a multicenter, randomized, open label trail evaluating daptomycin 10mg/kg with daptomycin 10mg/kg plus fosfomycin 2g q6h for 2 weeks or 4-6 weeks, depending on whether the bacteremia was uncomplicated or complicated/IE. Patients were randomized in a 1:1 fashion, with the primary endpoint being treatment success at 6 weeks after the end of therapy (test of cure, TOC). 167 patients were randomized, with patients in the daptomycin group more likely to have diabetes, heart failure, but no difference in rate of endocarditis or Pitt bacteremia score. In the mITT analysis, treatment success at TOC was achieved in 54% of the dual therapy group compared to 42% in the daptomycin alone group (RR 1.29, 95% CI 0.93-1.8). The patients in the dual therapy group were more likely to clear blood cultures faster, with all clearing their cultures at day 7:

There was also a higher rate of complicated bacteremia in the daptomycin alone group. In subgroup analysis, dual therapy was associated with better outcomes in those <73yo, those with Pitt score >1, and a trend towards bacteremia without endocarditis:

Unfortunately, there was a higher rate of treatment discontinuation for the dual therapy group:

This equates to a 12% higher rate of treatment success for the dual therapy group. I am still hesitant about dual therapy in MRSA (including rifampin and ceftaroline), however I can see this being something you pull out for severe complicated bacteremia. The other question going forward would be how long to keep fosfomycin on board; for the duration of therapy or until blood culture clearance? 

Schumacher AC, Elbadawi LI, DeSalvo T, Straily A, Ajzenberg D, Letzer D, Moldenhauer E, Handly TL, Hill D, Dardé ML, Pomares C, Passebosc-Faure K, Bisgard K, Gomez CA, Press C, Smiley S, Montoya JG, Kazmierczak JJ. Toxoplasmosis Outbreak Associated With Toxoplasma gondii-Contaminated Venison-High Attack Rate, Unusual Clinical Presentation, and Atypical Genotype. Clin Infect Dis. 2021 May 4;72(9):1557-1565. doi: 10.1093/cid/ciaa285. PMID: 32412062.

This is a cool case series of Toxoplamsosis. An outbreak was identified in September 2017 in Wisconsin. The outbreak occurred when a group of 12 men attended a retreat where they ate undercooked venison from a white-tailed deer that was “locally harvested and self-processed” the week before consumption (I assume they hunted it). 11 of the 12 attendees were infected with toxoplasmosis, the one who did not get infected did not eat the meat. 9 of the patients presented with symptoms including headache, muscle aches, fatigue, fever, sweats, and chills, and one reported arthralgias, dark urine and lymphadenopathy. Frozen venison was collected and showed toxo cysts on pathology:

This likely reflected a high parasitic load, which would manifest with the high attack rate and severity of the symptoms the patients presented with. 

Lin Y, Rong J, Zhang Z. Silent existence of eosinopenia in sepsis: a systematic review and meta-analysis. BMC Infect Dis. 2021 May 24;21(1):471. doi: 10.1186/s12879-021-06150-3. PMID: 34030641; PMCID: PMC8142617.

This was a meta-analysis evaluating the utility of eosinopenia as a biomarker for sepsis. Remember that the administration of steroids leads to eosinopenia, while adrenal insufficiency is associated with relative eosinophilia. Given that sepsis is due to dysregulation of the immune system (and increased in endogenous cortisol), it would stand to reason that people with sepsis would present with eosinopenia. 12 trials were evaluated in this meta-analysis, which included 3842 patients. The pooled sensitivity and specificity for eosinopenia as a predictor of sepsis was 66% and 68%, respectively:

The diagnostic OR was 4.23 (95% CI 2.15-8.31), with an AUC of 0.73. Using cut-off values of 50, 40, <25, and 100, the sensitivity was 0.61, 0.79, 0.57, and 0.54 while specificity was 0.61, 0.75, 0.83, and 0.51, respectively. Within each trial, the sensitivity ranged from 29% to 91%. I’ll stick to SIRS-criteria, thank you very much. 

Toine Mercier, Ellen Guldentops, Katrien Lagrou, Johan Maertens, Prospective Evaluation of the Turbidimetric β-D-Glucan Assay and 2 Lateral Flow Assays on Serum in Invasive Aspergillosis, Clinical Infectious Diseases, Volume 72, Issue 9, 1 May 2021, Pages 1577–1584, https://doi.org/10.1093/cid/ciaa295

I wrote in the past about the fungitell assay, which detects BD glucan using horseshoe crab blood. It essentially measures the clotting activity by activation of the horseshoe crab coagulation system by BD glucan and spits out a number, which is the optical density. When positive, the color of the assay changes to yellow (a colorimetric reaction), which can result in a false positive in the presence of lipemia or hemolysis. Recently, the Wako assay was approved in Europe, which uses turbidity rather than color, and a different assay. This was a prospective study of patients with hematological malignancies at risk of developing invasive fungal disease. The Wako assay as well as 2 lateral flow assays for aspergillus were compared for the diagnosis of IFD with the EORTC/MSG criteria as standard. 239 patients were included, and overall serum galactomannan and one of the lateral assays, LFA, had the overall best performance:

The Wako assay had a better performance when the cut-off of 2.359 was used as opposed to the manufacturers cut-off of 11.

Combining the Wako assay with LFA or LFD did not result in improved sensitivity but had a higher specificity than either alone. Both LFA and LFD tended to stay positive after therapy, with 94% of patients having a positive LFA after one week of therapy, and 61% still being positive after 2 weeks. BD glucan was still positive in 53% of patients after 2 weeks of therapy. Nothing groundbreaking here, just interesting to keep in mind we may be getting a new BD glucan assay. 

Salisch NC, Stephenson KE, Williams K, Cox F, van der Fits L, Heerwegh D, Truyers C, Habets MN, Kanjilal DG, Larocca RA, Abbink P, Liu J, Peter L, Fierro C, De La Barrera RA, Modjarrad K, Zahn RC, Hendriks J, Cahill CP, Leyssen M, Douoguih M, van Hoof J, Schuitemaker H, Barouch DH. A Double-Blind, Randomized, Placebo-Controlled Phase 1 Study of Ad26.ZIKV.001, an Ad26-Vectored Anti-Zika Virus Vaccine. Ann Intern Med. 2021 May;174(5):585-594. doi: 10.7326/M20-5306. Epub 2021 Feb 16. PMID: 33587687.

This is one topic I do not cover in these summaries. This was a phase 1, two-center, randomized double blind trial evaluating the safety and immunogenicity of the Zika vaccine, D26.ZIK.001 at 2 different doses (5×1010, low dose and 1 x1011, high dose) as one or 2 doses, 56 days apart. Patients were randomized in a 1:1:1:1:1 fashion, low dose/low dose, low dose/placebo, high dose/high dose, high dose/placebo, placebo/placebo. End point was safety and reactogenicity. Further, IgG from patients were transferred to a nonlethal mouse zika challenge model. 100 patients were randomized, all being fairly healthy. 75% of patients who got the low dose reported adverse events, compared to 88% who got any of the high dose and 45% who got placebo. Most common side effects were pain/tenderness at the site, swelling, nausea, myalgia, headache, arthralgia, fatigue, and chills. There were 8 grade 3 or 4 adverse events. In terms of immunogenicity, 90% of patients who got the vaccine seroconverted at 28 days after the first vaccine: 88% for the lower dose group combined and 94% for the higher dose combined. Durability was higher for the HD/PL group compared to the LD/PL group:

IgG was received from 25 patients, with mice being infused with either 6mg or 1mg of IgG and then being challenged with IV Zika virus. Transfer of 6mg IgG from vaccine recipients conferred complete protection from viremia in most animals, with 1mg of IgG conferring partial protection from viremia. 

Early study, but it is cool.

RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0. PMID: 33933206; PMCID: PMC8084355.

Recovery time! This was part of the larger RECOVERY trial, which was a multi-center UK trial that evaluated multiple therapies for COVID. This one deals with tocilizumab, a recombinant anti-IL-6 monoclonal antibody. This was a randomized, open-label trial that evaluated the use of one or 2 doses of tocilizumab (weight based, a second dose could be given if the patient had not improved) with standard of care. Notably, all patients in this trial had been enrolled in other arms of the main RECOVERY trial and were included if they had progressed in their disease states 21 days after the original allocation (O2 saturation <92% and CRP >75mg/dL). Patients were randomized in a 1:1 ratio, with the primary outcome being all-cause mortality at 28 days. 4116 patients were randomized, with both groups being fairly well balanced. 82% of patients in both groups received some sort of corticosteroids, while 13% required mechanical ventilation. 28-day all cause mortality was 31% in the tocilizumab group compared to 35% in the usual care group, suggesting a statistical reduction in mortality (RR 0.85, 95% CI 0.76-0.94):

As noted above, rate of discharge within 28 days and receipt of mechanical ventilation favored tocilizumab as well. Subgroup analysis, notably, revealed that the use of corticosteroids was associated with favorable tocilizumab results. Meta-analysis that included 8 additional trials further suggested that tocilizumab was associated with improved mortality, though this was only shown after the inclusion of the much larger recovery trial:

I think this was a fairly well designed trial, though the time after the initial randomization was a bit much for my liking (3 weeks). Having said that, pulling out an immunosuppressant 3 weeks in makes sense, and the large numbers gives me a bit of hope that this could be one of those drugs we pull out when nothing else is working. 

Glans H, Gredmark-Russ S, Olausson M, Falck-Jones S, Varnaite R, Christ W, Maleki KT, Karlberg ML, Broddesson S, Falck-Jones R, Bell M, Johansson N, Färnert A, Smed-Sörensen A, Klingström J, Bråve A. Shedding of infectious SARS-CoV-2 by hospitalized COVID-19 patients in relation to serum antibody responses. BMC Infect Dis. 2021 May 27;21(1):494. doi: 10.1186/s12879-021-06202-8. PMID: 34044758.

This was a cool one. This was a retrospective study evaluating the ability to culture infectious SARS-CoV2 from a cohort of patients hospitalized and how the amount of neutralizing antibody plays a role here. 36 patients were included, with 33 receiving some sort of supplemental oxygen. Patients had both nasopharyngeal/pharyngeal PCR  and sputum culture done 8 days after their admission.  64% of patients were PCR positive when including all samples. Notably, 39% of nasopharyngeal samples were PCR positive but only 4 were noted to be infectious, compared to 60% of sputum samples and only 1 being infectious:

This represented 17% of all COVID positive patients, suggesting that detection of virus in PCR does not mean that it is an infectious sample. Neutralizing antibodies were detected in 33 out of 36 patients, with three of the infectious patients having no neutralizing antibodies and one having low titers of one (1:10). There was a strong correlation between amount of neutralizing antibodies and PCR positivity:

I guess this kinda muddies the water as to when to take someone off isolation, as it was seen here that isolation off COVID from PCR does not mean one is shedding the virus. Nevertheless, I think this gives some reassurance about taking patients off isolation in the grand scheme of things. 

Manabe T, Kambayashi D, Akatsu H, Kudo K. Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis. BMC Infect Dis. 2021 May 27;21(1):489. doi: 10.1186/s12879-021-06164-x. PMID: 34044777.

Favipiravir is a RNA polymerase inhibitor that is used to treat Ebola and influenza infections and it has been evaluated in COVID-19 infections. This is a meta-analysis of 11 studies, 3 of which were RTCs. Multiple comparators were used, including standard of care, baloxavir, Kletra, HCQ, azithromycin, and umifenovir along with standard of care. Dose was 1600mg twice daily on the first day followed by 600mg twice daily. Favipiravir was associated with improved viral clearance on day 7 but not day 14:

Favipiravir was also associated with better clinical outcomes at both days 7 and 14, though the definitions for clinical improvement varied on studies (ranging from resolution of fever, respiratory fate, O2 saturation, improvement on the NEWS, or CT chest improvement). One thing to note is that, while the text mentions improvement, the forest plots seem to have it backwards, so flip the x-axis for it to make sense:

I am not sure how to feel about this; I think there is some sort of data here but this meta-analysis is difficult to interpret as there was a lot of heterogeneity in terms of comparators and how the clinical recovery (the main outcome of interest) was measured. Reassuringly, 4 studies included patients with severe COVID or requiring mechanical ventilation/ICU admission. 

Al-Samkari H, Gupta S, Leaf RK, Wang W, Rosovsky RP, Brenner SK, Hayek SS, Berlin H, Kapoor R, Shaefi S, Melamed ML, Sutherland A, Radbel J, Green A, Garibaldi BT, Srivastava A, Leonberg-Yoo A, Shehata AM, Flythe JE, Rashidi A, Goyal N, Chan L, Mathews KS, Hedayati SS, Dy R, Toth-Manikowski SM, Zhang J, Mallappallil M, Redfern RE, Bansal AD, Short SAP, Vangel MG, Admon AJ, Semler MW, Bauer KA, Hernán MA, Leaf DE, Al-Samkari H; STOP-COVID Investigators. Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19. Ann Intern Med. 2021 May;174(5):622-632. doi: 10.7326/M20-6739. Epub 2021 Jan 26. PMID: 33493012; PMCID: PMC7863679.

This was a multicenter cohort study of patients with COVID-19 admitted to an ICU evaluating the incidence of DVT and major bleeding, as well as to identify the risk factors for VTE and effect of early therapeutic anticoagulation on survival. Multivariate logistic regression was used to evaluate the predictors of VTE. The investigators also used the observational data to emulate a hypothetical trial comparing patients who received therapeutic anticoagulation within 2 days of ICU admission with those who did not, with primary endpoint being survival. To accomplish this, inverse probability weighting was used to adjust for confounding (among other statistical wizardry). 3239 patients were evaluated, with 204 patients having radiographically confirmed VTE, for a 6.3% incidence. Notably, only routine screening occurred in 3 out of the 67 sites. Major bleeding occurred in 90 patients (2.8%), mostly in the GI tract (32%) and intracranially (14%). Of these, 60 were receiving therapeutic anticoagulation at the time of the bleed. Multiavriate analysis revealed that male sex (OR 1.6, 95% CI 1.13 to 2.27), and high D-dimer on day 1 (OR 1.79, 95% CI 1.14 to 2.81 if 1001 to 2500 ng/mL vs 1000: OR 2.70, 95% CI 1.31 to 5.53 for 2501 to 10000 vs 1000, OR 4.71 95% CI 1.57 to 14.13 for >10,000 vs 1000) were associated with increased risk of VTE. 

In terms of therapeutic anticoagulation, those who received it were more likely to be mechanically ventilated, have a high SOFA score. All patients received at least prophylactic anticoagulation, with 8 centers (12%) transitioning from prophylactic to higher than standard doses in some or all patients with COVID based on a risk-adapted approach. 1412 patients received therapeutic anticoagulation within 14 days. In the target trial, 2809 patients were included, of which 384 were treated with early therapeutic anticoagulation. After IPW adjustment, 47% of patients in the early therapeutic anticoagulation group died compared to 37% not treated with therapeutic anticoagulation, HR 1.12, 95% CI 0.92 to 1.35):

Subgroup analysis did not find any difference either. Oddly, in all subgroups, there was a trend towards worsened mortality with therapeutic anticoagulation. Whether this is due to a higher risk of bleeding or other factors at play, it is unclear, but it makes it more and more clear that therapeutic anticoagulation without evidence of VTE may not be a good idea. Unfortunately, the fact this was not an RCT does hinder its applicability as even with IPW matching, one cannot really control for all variables but this was an otherwise fairly good study. The question now is, given the risk of VTE with higher D-dimer, would one have to go hunting for a clot once a D-dimer threshold is reached? I do not know the answer to this. 

Kaka AS, MacDonald R, Greer N, Vela K, Duan-Porter W, Obley A, Wilt TJ. Major Update: Remdesivir for Adults With COVID-19 : A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points. Ann Intern Med. 2021 May;174(5):663-672. doi: 10.7326/M20-8148. Epub 2021 Feb 9. Erratum in: Ann Intern Med. 2021 Mar 16;: PMID: 33560863; PMCID: PMC7901604.

This is an update on the review and meta-analysis for Remdesivir in COVID-19. They evaluated 5 RCTs, where remdesivir was given as a 200mg one time dose followed by 100mg daily for 5-10 days. Four studies compared remdesivir with placebo while the last one compared a 5 day dose vs 10 day dose. In this review, they added the results of the ACCT-1 trial (where remdesivir was associated with shorter time to recovery) and Solidarity (where remdesivir did not find reduction in 28 day mortality). Overall, it seems that remdesivir was associated with decreased mortality (10d course) when compared to control in those who got supplemental oxygen but not on the vent:

10 day remdesivir dose was associated with a higher proportion of patients who recovered (ARD 6.5%, 95% CI 2.4 to 10.7), higher proportion of clinical improvement based on a 6-point ordinal scale (ARD 7.2% to 7.5%), reduction in median hospital length of stay (mean difference 5 days), and a small reduction in patients who ended up receiving mechanical ventilation or ECMO. 

Post hoc analysis found that patients who worsened on a 5 day course of Remdesivir (meaning they subsequently needed mechanical ventilation or ECMO) continuing remdesivir through 10 days resulted in a lower mortality rate (ARD 23%, 95% Ci 1 to 45%). 

There is nothing new here. Give remdesivir to those who need some sort of oxygen (not mechanical ventilation), and do a 5 day course. If someone goes from supplemental oxygen to mechanical ventilation while on Remdesivir, then keep it for 10 days total. A subsequent editorial summarizes the guidelines as follows:

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