Weekly Articles 11/28/2021

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I stop writing about COVID on the regular and now Omicron is here to terrorize us.

Dan Ilges, David J Ritchie, Tamara Krekel, Elizabeth A Neuner, Nicholas Hampton, Marin H Kollef, Scott Micek, Assessment of Antibiotic De-escalation by Spectrum Score in Patients With Nosocomial Pneumonia: A Single-Center, Retrospective Cohort Study, Open Forum Infectious Diseases, Volume 8, Issue 11, November 2021, ofab508, https://doi.org/10.1093/ofid/ofab508

This was a retrospective cohort study evaluating the impact of antibiotic de-escalation based on a modified antibiotic spectrum index (ASI) in terms of outcomes in patients with HAP/VAP. Patients were divided into two groups, de-escalation or no de-escalation. This was defined as a reduction in ASI at day 3. Primary outcome was composite of all-cause mortality or readmission for pneumonia within 30 days of pneumonia diagnosis. 1812 patients were evaluated in the cohort, of which 786 had antibiotic de-escalation. Interestingly, those who had de-escalation had higher APACHE II scores, while those who did not de-escalate were more likely to have cystic fibrosis and bone marrow transplant. Furthermore, more patients in the de-escalation cohort were diagnosed with VAP. Overall, there was no difference between groups when it came to the primary outcome:

Not surprisingly, those in the de-escalation cohort had lower antibiotic days as well as lower rates of C.diff and hospital days. 

David W McCormick, Julika Kaplan, Cliff Whigham, Michael Coburn, Stephen B Greenberg, The Changing Epidemiology and Microbiology of Patients With Prostate Abscess: Increase in Staphylococcal Infection, Open Forum Infectious Diseases, Volume 8, Issue 11, November 2021, ofab503, https://doi.org/10.1093/ofid/ofab503

Prostate abscesses tend to grow gram negatives as these are the type of organisms that hang around the GU/GI tract. This retrospective cohort study evaluated 32 cases of prostatic abscesses to figure out the microbiology of said abscesses. Within this cohort, 18 were found to be due to Staph aureus. Patients who had Staph aureus abscess tended to be younger and have longer hospital length of stays, but abscess volume was generally lower (7.3 cm3 vs 16 cm3). Kleb pneumo (13%) and E. coli (9%) were the next most common causative organisms. Notably, 72% of patients who had S. aureus prostatic abscess also had extraprostatic disease, with 6 patients having bacteremia and 7 having a distal focus of infection. This is largely a descriptive study, but I think it seriously begs a few questions. First, should you cover gram positives when you find prostatitis? I do not think I can make that decision based on one single study, but this is something worth considering especially in cases of relapse. Second, and I think the biggest one, if you find staph aureus in the urine or somewhere else, start looking for a primary focus of infection. In this small cohort, the vast majority of patients had an additional focus of Staph aureus infection which is not surprising but again, makes you a bit concerned. Moral of the story: find S. aureus in urine = look for bacteremia. 

Apostolopoulou A, Clancy CJ, Skeel A, Nguyen MH. Invasive Pulmonary Aspergillosis Complicating Noninfluenza Respiratory Viral Infections in Solid Organ Transplant Recipients. Open Forum Infect Dis. 2021 Oct 2;8(11):ofab478. doi: 10.1093/ofid/ofab478. PMID: 34805426; PMCID: PMC8600160.

I think a lot of people know about the relationship between influenza infection and invasive fungal disease. This was a retrospective study evaluating the association between respiratory syncytial virus (RSV), parainfluenza (PIV), and adenovirus (ADV) infections and IPA in solid organ transplant patients. Patients were divided into asymptomatic, upper respiratory infections, or pneumonia. Cases of IPA were identified within 90 days of respiratory infection. A total of 2986 patients were included, of which 221 were diagnosed with a total of 255 respiratory infections. There were no major differences in terms of baseline characteristics between the type of respiratory infections. 43 patients (17%) had isolation of aspergillus from the lower respiratory tract within 90 days of viral infection, of which only 11 had either proven/probable disease, leading to a case incidence of 4%. 91% of those who had IPA were either lung or heart-lung transplant patients. Major risk factors included a cumulative dose of >140mg of prednisone within 7 days of viral infection (OR 22.6, 95% CI 4.5-112) and lung involvement of any virus (OR 7.2, 95% CI 1.6-31.7). Not surprisingly, mortality was higher in those who had IPA:

This suggests that more than anything, steroids seem to be the major driver of IPA. There is very little to suggest that any of the viruses played a major role in the IPA pathogenesis, though the type of organ transplant may also have played a role here.  

Shah AA, Donovan K, Seeley C, Dickson EA, Palmer AJR, Doree C, Brunskill S, Reid J, Acheson AG, Sugavanam A, Litton E, Stanworth SJ. Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021 Nov 1;4(11):e2133935. doi: 10.1001/jamanetworkopen.2021.33935. PMID: 34767026; PMCID: PMC8590171.

Does IV iron therapy lead to higher risk of infection. This meta-analysis evaluated 154 studies to evaluate if IV iron therapy, compared to placebo or oral iron, was associated with higher risk of infection. There was an overall high risk of bias in 106 RCTs and low in 31RCTs. Overall, IV iron was associated with increased risk of infection when compared to oral iron or no iron:

This outcome held true when a sensitivity analysis that excluded high risk of bias studies, RR 1.15 (95% CI 0.98-1.35), though this did not reach statistical significance. The most common site of infection reported in 24 RCTs was the lung. Of course, one of the issues of the study was the variation and inconsistency with the description of infection and how it was reported, meaning that these results should be taken into consideration. Furthermore, short and long term mortality was not different between cohorts so overall, it seems IV iron is a reasonable thing to do despite the concern for infection. 

Petersen KJ, Metcalf N, Cooley S, Tomov D, Vaida F, Paul R, Ances BM. Accelerated Brain Aging and Cerebral Blood Flow Reduction in Persons With Human Immunodeficiency Virus. Clin Infect Dis. 2021 Nov 16;73(10):1813-1821. doi: 10.1093/cid/ciab169. PMID: 33621317; PMCID: PMC8599198.

This was an interesting study. This cohort study applied structural and perfusion neuroimaging to model brain health across the lifespan of a group of patients with HIV and HIV negative controls. The idea here was that cerebral blood flow tends to decrease in those with HIV. Patients who were HIV positive but suppressed were compared with negative controls and patients with HIV who were not suppressed (cutoff here was 50 copies/mL). 206 HIV negative controls were compared with 230 suppressed load HIV patients and 93 non-suppressed HIV patients. These patients underwent brain MRIs as well as neuropsychological testing. HIV negative patients were significantly younger, were less likely to be african american, and more likely to be female compared to the HIV cohort. This was controlled for in subsequent modelling. CBF, which decreased with age, was more negatively impacted in those who were detectable compared to the control or the controlled (undetectable) HIV cohort:

Furthermore, structural aging was greeted for HIV patients than for controls, but not different between the detectable and undetectable cohorts:

Several cognitive functions were also decreased in all HIV patients, namely executive function, psychomotor, language, and global. When looking at detectable vs undetectable, psychomotor, language, and global function was also decreased more in the detectable cohort. 

I think how HIV status affects rates of dementia as these folks end up living longer. 

Higgs ES, Gayedyu-Dennis D, Fischer Ii WA, Nason M, Reilly C, Beavogui AH, Aboulhab J, Nordwall J, Lobbo P, Wachekwa I, Cao H, Cihlar T, Hensley L, Lane HC. PREVAIL IV: A Randomized, Double-Blind, 2-Phase, Phase 2 Trial of Remdesivir vs Placebo for Reduction of Ebola Virus RNA in the Semen of Male Survivors. Clin Infect Dis. 2021 Nov 16;73(10):1849-1856. doi: 10.1093/cid/ciab215. PMID: 33709142.

So Ebola tends to live in men’s semen after they become infected. This randomized control trial evaluated the utility of a 5-day course of IV remdesivir in residual seminal Ebola virus RNA atr both a short-term and long-term follow up. 38 patients were randomized, which was significantly lower than the planned enrollment of 60-120. There was no significant difference between baseline characteristics in both groups. There was no statistical difference during the treatment period, but there was a statistical difference at the long-term follow up:

van den Berg P, Schechter-Perkins EM, Jack RS, Epshtein I, Nelson R, Oster E, Branch-Elliman W. Effectiveness of 3 Versus 6 ft of Physical Distancing for Controlling Spread of Coronavirus Disease 2019 Among Primary and Secondary Students and Staff: A Retrospective, Statewide Cohort Study. Clin Infect Dis. 2021 Nov 16;73(10):1871-1878. doi: 10.1093/cid/ciab230. PMID: 33704422; PMCID: PMC7989511.

This retrospective cohort study evaluated the effectiveness of different physical distancing policies (>3 vs >6ft) on the incidence of SARS-CoV2 infections in students/staff in different Massachusetts school districts. Those who had a minimum of 3ft of distancing, even if they recommended greater distances, were in the 3ft cohort. Those who allowed >3ft of distancing in full reopening, but opened in a hybrid learning model with >6ft requirements in the hybrid model were classified as >6ft distancing. High campus enrollment was defined as >80% in person attendance. 242 districts were analyzed, leaving 537,336 students and 99,390 staff to analyze. 4226 cases in students and 2382 in staff were reported during the study period. 100% of districts with any type of in-person training adopted universal masking for students grade 2 and above, with ~70% of districts requiring it for younger students. The rate of COVID per district reflected the community rates, despite the distancing protocols:

Unadjusted rates of COVID-19 was not statistically different between different distancing protocols (0.891, 95% CI 0.594-1.335 for students, 0.989, 95% CI 0.733-1.334 for staff). This held true after adjustment:

Of course, it should be noted that all these districts had a mask mandate for older students and there is variability between what was recommended and what was enforced, but this suggests that as long as masks are used, distancing can be reduced. 

Chiang HY, Chen TC, Lin CC, Ho LC, Kuo CC, Chi CY. Trend and Predictors of Short-term Mortality of Adult Bacteremia at Emergency Departments: A 14-Year Cohort Study of 14 625 Patients. Open Forum Infect Dis. 2021 Oct 6;8(11):ofab485. doi: 10.1093/ofid/ofab485. PMID: 34805430; PMCID: PMC8598924.

This was a 14-year retrospective study evaluating an ED algorithm to predict 7-day mortality for bacteremia. A multivariate model was performed on a derivation model to obtain each variable, which included age, temperature, hypotension, mechanical ventilation, cardiac arrest, mental status, cancer, cirrhosis, source of infection, steroid use, eGFR, platelets, RDW, BUN, K, and hemoglobin. 14625 patients were included, with 80% being randomly placed in the derivation cohort. 7 day mortality was 8.53%.  Age, hypotension, cardiac arrest, platelets <100, reduced eGFR, anemia, and cancer were significant predictors of mortality:

AUC for the derivation cohort was 0.909 and 0.903 for the validation cohort.This model also predicted mortality better than other scores such as the Pitt-Bacteremia score. FUrthermore, at 14- and 28-day mortality, it also outperformed the Pitt Bacteremia score and bloodstream infection mortality risk score:

So I do not know how to feel about this. It’s neat, but if someone comes in after a cardiac arrest, then yeah, they’re not going to do well. 

Palin V, Welfare W, Ashcroft DM, van Staa TP. Shorter and Longer Courses of Antibiotics for Common Infections and the Association With Reductions of Infection-Related Complications Including Hospital Admissions. Clin Infect Dis. 2021 Nov 16;73(10):1805-1812. doi: 10.1093/cid/ciab159. PMID: 33623985; PMCID: PMC8599204.

I am all about shortening antibiotic courses, but what are the outcomes when you do this? This population-based cohort study evaluated systemic antibiotic prescriptions for URTIs, UTIs, or LRTIs in acute infections only. Primary outcome was infection related complications (hospital admission) within 30 days after initial visit. Over 4 million acute infection-related visits wer  recorded. The overall incidence of infection-related hospitalizations was 0.15%, with the majority occurring in those who got 8-15 days of antibiotics total. Age and sex adjusted HR demonstrated that, overall longer duration of antibiotic therapy was associated with higher infection-related hospitalization, which held true for all infections, except for UTIs in the immediate 3 day follow up period:

Patients with increased comorbidities were also more likely to experience an infection-related hospitalization (HR 1.42, 95% CI 1.26-1.6 for moderate CCI, which increased with higher CCI). Comparing HR for the first 5 days versus remaining follow-up showed that longer antibiotic courses were no more effective than shorter courses:

I think, at minimum, this demonstrates that short course of antibiotics are just as  effective as longer courses for things like pneumonia or UTI, though bacteremias, still need to watch out for those. 

Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL, Hebner CM, Sager J, Mogalian E, Tipple C, Peppercorn A, Alexander E, Pang PS, Free A, Brinson C, Aldinger M, Shapiro AE; COMET-ICE Investigators. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941-1950. doi: 10.1056/NEJMoa2107934. Epub 2021 Oct 27. PMID: 34706189.

Another day, another monoclonal antibody for COVID. Compared to most out in the market which targets the ACE-receptor, Sotrovimab targets a conserved epitope, allowing it to be used for several other variants (in other words, its target is something that does not mutate as fast as the ACE receptor). This phase 3, multicenter, randomized, double-blind trial evaluated a single dose of sotrovimab 500mg in patients with mild-to-moderate COVID-19 in high-risk, non-hospitalized patients. Primary outcome was percentage of patients who were hospitalized for more than 24 hours or who had died from any cause through day 29 after randomization. 583 patients were randomized in a 1:1 fashion for the ITT interim analysis while 868 patients were randomized in the safety interim analysis (weird, I know, but this is an ongoing trial). In both populations, the characteristics were well balanced. 1% in the experimental group and 7% in the placebo group had disease progression (RR 85%, 95% CI 44 to 96%). 

Both groups had similar rates of adverse events

More tools for battling COVID, but only time will tell if this will be something that is widely available.

D Podzamczer, R Micán, J Tiraboschi, J Portilla, P Domingo, J M Llibre, E Ribera, M J Vivancos, L Morano, M Masiá, C Gómez, F Fanjul, A Payeras, A Inciarte, V Estrada, A Rivero, Á Castro, E Bernal, D Vinuesa, H Knobel, J Troya, J Macías, M Montero, J Sanz, A Navarro-Alcaraz, A Caicedo, G Fernández, E Martínez, S Moreno, SYMTRI study investigators, Darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus dolutegravir /abacavir/lamivudine in antiretroviral-naïve adults (SYMTRI): a multicenter randomized open-label study (PReEC/RIS-57), Open Forum Infectious Diseases, 2021;, ofab595, https://doi.org/10.1093/ofid/ofab595

Integrase inhibitor based ART is first line therapy for treatment naive HIV patients, with PI-based regimen being an alternative. This study compared two single-pill regimens, darunavir/cobicistat/emtricitabine/TAF (it should be noted this combo as a single pill is new, but has been given as Descovy + Prezcobix) versus Triumeq aka dolutegravir/abacavir/lamivudine. This was a randomized, parallel, open-label, multicenter non-inferiority trial where patients who were newly diagnosed were randomized in a 1:1 fashion to either drug. Primary endpoint was proportion of patients who were virally suppressed at week 48. 316 patients were randomized, with both being fairly well balanced. 40% of the patients had VL >100,000 copies/mL. In the ITT analysis, 79% in the PI group and 82% of the INTI group had achieved viral suppression by week 48 (adjusted treatment difference -2.4%, 95% CI -11.3 to 6.6). 

Notably, more patients in the PI group had increases in the LDL and total cholesterol, while patients in the INTI group had higher increases in serum creatinine and glucose, which is a bit interesting considering conventional wisdom with regards to ART. Either way, this suggest that both types of therapy are efficacious, though later outcomes such as renal function and bone health may persuade you one way or the other. 

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