Weekly Articles 2/22/2021

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Albin OR, Henig O, Patel TS, Valley TS, Pogue JM, Petty LA, Mills JP, Brancaccio A, Martin ET, Kaye KS. Clinical Implications of Microbiologic Treatment Failure in the Setting of Clinical Cure of Bacterial Pneumonia. Clin Infect Dis. 2020 Dec 15;71(12):3033-3041. doi: 10.1093/cid/ciz1187. PMID: 31832641; PMCID: PMC7819508.

This is a retrospective study of 441 patients with pneumonia in a single center to evaluate the association between microbiological treatment failure and subsequent recurrence and death. Patients have to have a diagnosis of pneumonia as well as repeat respiratory culture at the end of therapy. Outcomes were obtained after therapy, at day 30, and at day 90. Of these, 237 patients had microbiological cure while 204 had microbiological failure. Patients with microbiological failure were more likely to have a tracheostomy (30% vs 15%), have renal disease (44% vs 33%), and less likely to be white (73 vs 83%). MRSA and Pseudomonas were more likely to have microbiological failure. Patients with microbiological failure were more likely to have 30 day and 90 day primary outcomes:

Multivariate analysis found microbiological failure to be associated with 90 day primary outcome (aOR 1.58, 95% CI 1.06-2.35). Staph aureus and non-fermenter gram negatives were also associated with higher rates of recurrence in those with microbiological failure:

It shouldn’t be surprising that lack of microbiological eradication is associated with recurrence, however this was mostly driven by the 90 day endpoint. Mortality was not affected (early end point was statistically significant, but just barely). How applicable these results are is difficult, as a lot of these patients are critically ill. Plus, it is not standard of care to obtain follow up sputum cultures (remember, these are hard enough to get right) so I do not see this as practice changing. Though you can extrapolate to those who tend to be heavily colonized with bacteria (i.e. cystic fibrosis and tracheostomy patients) and figure these will have recurrent pneumonia. 

Hojat LS, Bessesen MT, Huang M, Reid M, Knepper BC, Miller MA, Shihadeh KC, Fugit RV, Jenkins TC. Effectiveness of Shorter Versus Longer Durations of Therapy for Common Inpatient Infections Associated With Bacteremia: A Multicenter, Propensity-Weighted Cohort Study. Clin Infect Dis. 2020 Dec 15;71(12):3071-3078. doi: 10.1093/cid/ciz1197. PMID: 31858136.

This was a cohort study evaluating shorter (5-9 day) vs longer (10-15 day) antibiotic therapy in common infections associated with bacteremia in the hospital setting (pneumonia, UTI, and acute skin and soft tissue infections). Patients with MSSA/MRSA, Staph lugdnunenis, fungemia, and contaminant blood cultures were excluded. Primary outcome was clinical failure (composite of rehospitalization or resumption of antibiotics for the original infection or all cause 30 day mortality). 408 patients were included, of which 123 received short duration antibiotics and 285 got long duration antibiotics. More patients in the longer course tended to be former smokers, have diabetes, or a solid tumor malignancy:

Primary outcome occurred in 12.2% of patients in the short duration group compared to 12.3% in the long duration group. After propensity score matching, there was no difference in primary outcomes:

Despite this, there was a higher incidence of resuming antibiotics for the same infection in teh short course group (OR 1.62, 95% CI 1.01-2.61). Notably, beta-lactams were more likely to have a higher rate of treatment failure in the shorter duration group:

It is difficult to tease out what to make of the higher rate of recurrence in the short antibiotic group given the retrospective nature. Plus, those in the shorter group seem to be more predisposed to C. diff which makes no sense. Most patients got a predominantly PO regimen in both groups, which is reassuring. Despite this, with uncomplicated bacteremia it seems that shorter is a reasonable option for most infections. 

Huhn GD, Crofoot G, Ramgopal M, Gathe J, Bolan R, Luo D, Simonson RB, Nettles RE, Benson C, Dunn K. Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in a Rapid-Initiation Model of Care for Human Immunodeficiency Virus Type 1 Infection: Primary Analysis of the DIAMOND Study. Clin Infect Dis. 2020 Dec 15;71(12):3110-3117. doi: 10.1093/cid/ciz1213. PMID: 31879782; PMCID: PMC7819515.

This is the phase 3, open-label, single-arm, prospective multicenter study evaluating the rapid initiation of Symtuza (emtracitabine, TAF, darunavir/cobicistat) within 2 weeks of diagnosis. Primary endpoint was the proportion of patients with virologic response at week 48 defined as viral load <50 copies/mL. 109 patients were enrolled in the stuy, of which 92/109 (84%) achieved the primary end point. 8 patients had no viral load at the end of the study, 5 discontinued the drug early and 4 had viral load <200 copies/mL:

Symtuza was overall well tolerated:

This was a fairly good proof-of-concept study, which suggest early initiation of ART is a reasonable option even when not all data is available on first follow up. The reason for this regimen is as follows: it avoids abacavir, which negates HLA-B5701 testing, it has a high barrier to resistance, and it can be used with M184V mutation. While not a randomized trial, it is nevertheless useful for implementing early ART therapy. 

Kobayashi M, McGee L, Chochua S, Apostol M, Alden NB, Farley MM, Harrison LH, Lynfield R, Vagnone PS, Smelser C, Muse A, Thomas AR, Deng L, Metcalf BJ, Beall BW, Schrag SJ. Low but Increasing Prevalence of Reduced Beta-lactam Susceptibility Among Invasive Group B Streptococcal Isolates, US Population-Based Surveillance, 1998-2018. Open Forum Infect Dis. 2020 Dec 21;8(2):ofaa634. doi: 10.1093/ofid/ofaa634. PMID: 33553474; PMCID: PMC7850125.

This was a population and laboratory based surveillance of invasive group B streptococcus in 10 states. Reduced beta lactam susceptibility (RBLS) and non-susceptibility (NS) were calculated using MIC as well as whole genome sequencing. A total of 28,269 patients were evaluated, with the most common syndrome in adults being bacteremia (37.8%), usually occurring in patients with diabetes (48.6%). Overall, 137 isolates (0.5%) met RBLS criteria and 28 (0.1%) met NS criteria. The proportion of RBLS increased from 1998 to 2018 (OR 1.10, 95% CI 1.06-1.14). Notably, those with bacteremia had lower proportion of RBLS (0.12%) compared to those with meningitis (0.95%) or osteomyelitis (3.70%):

It is reassuring the susceptibility for group B strep is still favorable. I have seen more cases of group B strep bacteremia so having a good beta lactam to treat invasive infections is clutch. Keep it in the back of your mind in the next 10-20 years, as susceptibilities change for this organism and we see it more often in our elderly population.

Dinh A, Hallouin-Bernard MC, Davido B, Lemaignen A, Bouchand F, Duran C, Even A, Denys P, Perrouin-Verbe B, Sotto A, Lavigne JP, Bruyère F, Grall N, Tavernier E, Bernard L. Weekly Sequential Antibioprophylaxis for Recurrent Urinary Tract Infections Among Patients With Neurogenic Bladder: A Randomized Controlled Trial. Clin Infect Dis. 2020 Dec 15;71(12):3128-3135. doi: 10.1093/cid/ciz1207. PMID: 31867616.

Here is a patient population that is difficult to treat. This is a multicenter, open-label, randomized superiority controlled trial comparing weekly oral cyclic antibiotic therapy vs no prophylaxis in patients with neurogenic bladder who use clean, intermittent self-cath. Notably, patients who use other drainage methods were excluded (so indwelling cath patients were excluded) and patients needed to have at least 4 symptomatic UTIs. Patients were randomized in a 1:1 fashion to receive antibiotics or no antibiotics. Patients alternated 2 antibiotics based on their tolerance and resistance profiles over a period of 6 months. Primary endpoint was the number of symptomatic UTIs (defined as >103 CFUs/mL in combination with a clinical sign which included hyperreflexivity, spasticity, and contractures along with typical UTI symptoms). The initial goal was a total of 90 patients but enrollment was slow and there was a significant efficacy in the prophylaxis regimen, so the trial was stopped at 45 patients. Patients in the prophylaxis group were more likely to have a higher number of UTIs compared to the no prophylaxis group (12 vs 9.5):

There was a lower median number of UTIs at 6 months in the prophylaxis group compared to the no prophylaxis group (1 vs 2.5 respectively, p-value 0.024) as well as lower febrile UTIs (0 vs 9, p <0.001). The most common antibiotics used were fosfomycin-trometamol and cefixim followed by fosfomycin-trometamol/amox-clav:

There was no difference in the emergence of ESBL and MRSA between groups, which is reassuring, though this was based on MRSA nasal swab and ESBL rectal swab. This is an interesting study, which may be useful down the line. I would like to have a larger study prior to implementing this strategy in the future, especially as these patients tend to come in and out of the hospital with questionable UTIs. 

Matthew A Miller, Kyle C Molina, Jonathan A Gutman, Sias Scherger, Jessica M Lum, Sherif B Mossad, Mary Burgess, Matthew P Cheng, Sally T Chuang, Samantha E Jacobs, Dante P Melendez, Dimpy P Shah, Andrea Zimmer, M Rizwan Sohail, Sadia Syed, Randall C Walker, Eric M Poeschla, Maheen Z Abidi, Mucormycosis in Hematopoietic Cell Transplant Recipients and in Patients With Hematological Malignancies in the Era of New Antifungal Agents, Open Forum Infectious Diseases, Volume 8, Issue 2, February 2021, ofaa646, https://doi.org/10.1093/ofid/ofaa646

This retrospective multicenter study evaluated the characteristics and survival outcomes for patients with hematopoietic stem cell transplant and heme malignancies and invasive mucormycosis. In the past few years, prophylaxis has shifted from echinocandins to mould active triazoles, and therapy has transitioned to liposomal amphotericin B and, in some cases, combination with posaconazole and isavuconazole. 64 patients were included in the study, with mortality at 30 days being 36% and 63% within one year:

91% of patients received prophylaxis with voriconazole. Furthermore, posaconazole is combined with AmB in 58% of patients, followed by isavuconazole with 16%. Treatment failure was 64% in the Amb-treated group compared to 43% to the combination group (p-value 0.136). All cause mortality was higher for the amphotericin monotherapy group than for the  combination group, but this was not statistically significant:

Huerga H, Mathabire Rucker SC, Bastard M, Mpunga J, Amoros Quiles I, Kabaghe C, Sannino L, Szumilin E. Urine Lipoarabinomannan Testing for All HIV Patients Hospitalized in Medical Wards Identifies a Large Proportion of Patients With Tuberculosis at Risk of Death. Open Forum Infect Dis. 2020 Dec 23;8(2):ofaa639. doi: 10.1093/ofid/ofaa639. PMID: 33575422; PMCID: PMC7863865.

Lipoarabinomannan, a glycolipid and virulence factor associated with tuberculosis, has been used as a point of care testing method for patients with suspected tuberculosis in HIV patients. The sensitivity depends on immunosuppression, with WHO guidelines recommending the use of LAM for HIV positive patients with signs and symptoms of TB or with advanced HIV disease or if CD4 <200. This propsective observational study evaluated the use of urine LAM in adult patients with HIV admitted to a medical ward during 2 periods: from 8/2015-7/2016 where LAM tests were not used for clinical management and after 7/2016, where they could be used for management. All patients had sputum microscopy, sputum GeneXpert, CXR, and CD4 count. 387 patients were evaluated, with 64% having presumptive tuberculosis. 26% of patients tested positive for LAM, 13.2% (100/383) were positive for sputum microscopy and 14% (33/236) were positive for sputum geneXpert. 119/387 patients had at least one positive TB test, with LAM being positive in 84% compared to sputum microscopy (27%) and Xpert (28%). Among the 119 patients with a positive result, LAM was the only test positive in 67.2% of patients. LAM positivity was associated with immunosuppression (CD4 <200), presumptive tuberculosis and illness severity, though the latter did not reach statistical significance:

In-hospital mortality was higher in LAM-positive patients compared to LAM-negative patients (19.8% vs 9.6%, p-0.008). 

Multivariate analysis found that risk of mortality was higher in patients with LAM-positive tests (aOR 2.5, 95% CI 1.1-5.8) and in those with CD4 <200 (aOR 2.7, 95% CI 1.5-4.8). While LAM certainly has a prognostic value, its use was not associated with improved mortality when used to guide therapy. 

Hogan CA, Yang S, Garner OB, Green DA, Gomez CA, Dien Bard J, Pinsky BA, Banaei N. Clinical Impact of Metagenomic Next-Generation Sequencing of Plasma Cell-Free DNA for the Diagnosis of Infectious Diseases: A Multicenter Retrospective Cohort Study. Clin Infect Dis. 2020 Jan 14:ciaa035. doi: 10.1093/cid/ciaa035. Epub ahead of print. PMID: 31942944.

I wrote about the Karius test in the past. This relies on cell-free DNA, essentially DNA out in the wild within the bloodstream, and amplifying this for diagnostics. The Karius test allows you to detect around 1200 species of bacteria, fungi, and parasite. This was a multicenter, retrospective study of 5 institutions that attempted to examine the impact of the Karius test in clinical decisions. 82 tests were performed, with positivity rate being 50 of 82 (61%). Karius test lead to a clinical impact in 9 patients (11%), with positive clinical impact in only 6 of these. This suggest that the Karius test may not have a significant impact in certain clinical situations, especially as this tests may be way more expensive than traditional tests.

Bruun T, Rath E, Madsen MB, Oppegaard O, Nekludov M, Arnell P, Karlsson Y, Babbar A, Bergey F, Itzek A, Hyldegaard O, Norrby-Teglund A, Skrede S; INFECT Study Group. Risk Factors and Predictors of Mortality in Streptococcal Necrotizing Soft-tissue Infections: A Multicenter Prospective Study. Clin Infect Dis. 2021 Jan 27;72(2):293-300. doi: 10.1093/cid/ciaa027. PMID: 31923305; PMCID: PMC7840107.

This was a multicenter, prospective observational cohort study that evaluated the risk factors for mortality in patients presenting with necrotizing fasciitis from group A and group D strep. 409 patients with necrotizing fasciitis were evaluated, of which 126 cases were due to GAS and 27 were due to GDS. Elevated creatinine was more common in GAS than GDS and more patients with GAS presented with septic shock (65% vs 41%). There was no difference in LRINEC score between groups. Risk factors for necrotizing fasciitis with streptococcus included male sex, blunt trauma, or chronic wound or skin disease:

Risk factors for mortality include age, male sex, septic shock, and lack of hyperbaric oxygen, though the last one was analyzed to control for confounders:

It is interesting to note that group D strep is also associated with some cases of necrotizing fasciitis, despite GAS outnumbering GDS by a factor of 4.7. While IVIG was not statistically significantly associated with increased mortality, there was a notable trend (75% of GAS and 59% of GDS received IVIG). Another interesting thing to highlight is that 60% of patients with GAS had no significant comorbidities, suggesting the high virulence of this disease.

Erikstrup C, Hother CE, Pedersen OBV, Mølbak K, Skov RL, Holm DK, Sækmose SG, Nilsson AC, Brooks PT, Boldsen JK, Mikkelsen C, Gybel-Brask M, Sørensen E, Dinh KM, Mikkelsen S, Møller BK, Haunstrup T, Harritshøj L, Jensen BA, Hjalgrim H, Lillevang ST, Ullum H. Estimation of SARS-CoV-2 infection fatality rate by real-time antibody screening of blood donors. Clin Infect Dis. 2020 Jun 25:ciaa849. doi: 10.1093/cid/ciaa849. Epub ahead of print. PMID: 32584966.

This was a prospective screening of all blood donations to Denmark for SARS-CoV2 antibodies. 20640 blood donations were obtained, with overall unadjusted seroprevalence of 2.0% for positive SARS-CoV2 antibodies (95% CI 1.8-2.2%), adjusted to 1.9% (95% CI 0.8-2.3%). IFR was noted to be 0.089% in this population. 

This suggest that social distancing measures (which were implemented around March) seem to help in terms of infection spread and mortality.

Murai IH, Fernandes AL, Sales LP, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA. Published online February 17, 2021. doi:10.1001/jama.2020.26848

I have written in the past about vitamin D deficiency’s association with worse outcomes in viral respiratory diseases as well as its association with increased mortality in COVID. This was a multicenter, double-blind, parallel-group, randomized placebo controlled trial evaluating a single dose of 200,000 IU of vitamin D3 in COVID-19 patients with moderate to severe disease. Primary outcome was hospital length of stay. 240 patients were randomized in a 1:1 fashion. For the most part, patients were well balanced in terms of characteristics. Hospital length of stay was not significantly different between vitamin D3 group and placebo (7 days vs 7 days, aHR 0.99, 95% CI 0.71-1.37)

There was no difference in terms of admission to ICU or mechanical ventilation requirement for all patients, though there was a trend benefiting the vitamin D group. Vitamin D supplementation did not improve mortality, in-hospital mortality, or mechanical ventilation requirements when only those with vitamin D deficiency are analyzed.

It is unfortunate that vitamin D supplementation did not work here, however you could argue low patient numbers or giving it too late could have contributed to the lack of positive outcome. Certainly different doses could be used and for a longer period of time. Whether vitamin D supplementation as outpatient in at risk patients remains to be seen, but this seems to be a reasonable option. As far as it being a therapeutic option for in-patients, it is unlikely to provide any benefit. 

Thomas S, Patel D, Bittel B, et al. Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial. JAMA Netw Open. 2021;4(2):e210369. doi:10.1001/jamanetworkopen.2021.0369

This is a prospective, randomized, open-label trial multicenter trial in 2 states (Ohio and Florida) evaluating the use of vitamin C and zinc in outpatients with COVID-19. Patients were allocated in a 1:1:1:1 strategy to receive either (1) 8000mg vitamin C, (2) 50mg of zinc gluconate at bedtime, (3) both therapies, and (4) usual care. Patients were evaluated based on both a 4-symptom score (for patients enrolled through July 16, 2020) and on the 12-symptom score (for those enrolled after July 16). Primary endpoint was the number of days required to achieve a 50% reduction in symptom severity score from peak symptom score. There was a plan to enroll 420 patients, but the trial was stopped early due to futility at the interim analysis done at 40% of enrollment. 214 patients were evaluated. There were some imbalances between the groups, including more patients in the dual therapy group having diabetes, hypertension, and hyperlipidemia, but everything else was fairly balanced. There was no significant difference in the primary outcome for either the 4-symptom of 12-symptom scores:

This one is a doozy for zinc-enthusiast. It is known that zinc plays a role in immune function and may have antiviral effects in vitro. While people will mention the lack of ionophore, it should be noted that biological plausibility does not translate well into clinical outcomes (i.e. even if in vitro something works, it may not work in the real world). Until data suggesting that HCQ + Zinc comes out suggesting improvement in outcomes, I think we can hold off zinc and vitamin C for now. 

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