Weekly Articles 2/7/2021

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Well hello there. I took too long of a break but I am back for some more articles to report on. Up up and away!

Prior to writing about these articles, let’s take a step back and figure out what cefiderocol is. This is a new cephalosporin (a siderophore, if you will) that has broad gram negative coverage but no gram positive or anaerobic coverage. You can think of it as the opposite of ceftaroline to an extent). This week’s issue of the Lancet Infectious Disease reports on 2 studies comparing Cefiderocol with either an extended-infusion carbapenem or best-available therapy. 

Wunderink RG, Matsunaga Y, Ariyasu M, Clevenbergh P, Echols R, Kaye KS, Kollef M, Menon A, Pogue JM, Shorr AF, Timsit JF, Zeitlinger M, Nagata TD. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021 Feb;21(2):213-225. doi: 10.1016/S1473-3099(20)30731-3. Epub 2020 Oct 12. PMID: 33058798.

This was a rouble-blind, parallel group, phase 3, randomized multicenter trial that evaluated Cefiderocol in a 1:1 fashion with extended infusion meropenem in patients who presented with HAP, VAP, or HCAP. Notably, this study excluded those with known carbapenem resistant organisms as well as those with APACHE scores >35. Patients were treated for 7-14 days and were not allowed to have inhaled or PO step down antibiotics during the trial. Primary end point was all-cause mortality at day 14, and the study was designed for non-inferiority. 300 patients were recruited and were fairly well matched at baseline, though more patients in the cefiderocol group had carabepenmase producing enterobacterales (13% vs 4%). There was no difference in all-cause mortality between either group (12% vs 12%, difference 0.8, 95% CI -6.7 to 8.2). There was also no difference in clinical cure or microbiological eradication:

Seems that cefiderocol works as well as carbapenems, though the exclusion of the group where this would be used makes its applicability a bit of an issue. Furthermore, the pharmaceutical company played a role in the study design and protocol. Take that as you will. I do not see Cefiderocol being used outside of ID physicians and it will likely not be used in this specific situations (read: this will likely be used in cystic fibrosis patients with flares, complicated bladder infections in paralyzed patients, etc. Think of a situation where patients will need to have several courses of antibiotics for “flares” and this is where it can be useful). Speaking of excluding Carbapenamase-producing organisms…

Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R, Lodise TP, Naas T, Niki Y, Paterson DL, Portsmouth S, Torre-Cisneros J, Toyoizumi K, Wunderink RG, Nagata TD. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021 Feb;21(2):226-240. doi: 10.1016/S1473-3099(20)30796-9. Epub 2020 Oct 12. PMID: 33058795.

This was an open-label, parallel group, phase 3 multicenter trial that enrolled patients with VAP/HAP, bacteremia, or complicated UTI with evidence of a carbapenem-resistant gram negative infection. Patients were randomized in a 2:1 fashion to either cefiderocol or best-available therapy. Cefiderocol could be used in combination with another antibiotic that was not a polymixin, cephalosporins, or carbapenems. Escalation of antibiotics was considered a protocol violation. There were 2 primary end-points, depending on the type of infection. For those who had a complicated UTI, the primary endpoint was microbiological eradication at test of cure. For everyone else, the primary endpoint was clinical cure. 150 patients were randomized, with more patients over 65 being assigned to the cefiderocol group and more patients in the alternate therapy having sepsis. As seen in the table below, there is no difference in the primary outcomes, though there are a few things to discuss:

First, more patients in the nosocomial and bacteremia cefiderocol group had sustained cure on follow up. In terms of microbiological outcomes, those in the cefiderocol bacteremia group had a better rate of eradication at end of treatment, while at the test of cure, complicated UTIs microbiological eradication was better in the cefiderocol. All cause mortality, based on microorganism, was about the same for all organisms except for acinetobacter, where it favored best available therapy:

So this is a better study, though there are some questions about the efficacy for acinetobacter. 

Kadri SS, Lai YL, Warner S, et al. Inappropriate empirical antibiotic therapy for bloodstream infections based on discordant in-vitro susceptibilities: a retrospective cohort analysis of prevalence, predictors, and mortality risk in US hospitals. The Lancet. Infectious Diseases. 2021 Feb;21(2):241-251. DOI: 10.1016/s1473-3099(20)30477-1.

Now on to a not very surprising study. This is a multicenter retrospective study of patients with bacteremia (monomicrobial) assessing the prevalence, predictors, and mortality risk of discordant empirical antibiotic therapy (i.e. empiric therapy does not match susceptibilities of organism grown). Only patients who had antibiotics given after blood cultures on the same day were evaluated. Over 26000 patients were evaluated and 4195 (19%) patients had discordant empiric antibiotic therapy. Vancomycin was the most commonly concordant antibiotic given compared to levofloxacin which was the most common discordant antibiotic given. Obviously, things like bug being resistant to the antibiotic was a risk factor for discordant antibiotic (OR 9.09, 95% CI 7.68-10.76), though the most common species with enterobacteriaceae being a reference, was Enterococcus (OR 4.73, 95% CI 3.91-5.71) followed by acinetobacter. Staph aureus, pneumococcus were less likely to be associated with discordant therapy.

Notable factors associated with increased risk of discordant antibiotic include black race, previous infection with same pathogen, broad spectrum or multidrug therapy, presumed abdominal, multisite, respiratory, or SST infection:

Mortality rate was higher in those receiving discordant therapy (aOR 1.46, 95% CI 1.28-1.66). Mortality was much higher in those with Staph aureus who got discordant therapy (aOR 1.85, 95% CI 1.43-2.40). FUrther, delayed antibiotic therapy was also associated with higher risk of mortality (aOR 1.21, 95% CI 1.06-1.38) but this was only seen in those with septic shock but not those who were not in shock. Again, this is not surprising, but does have some important information as to when to cast a broad net in terms of therapy and how quickly to escalate or switch. Also, it will change as we transition to more BioFire results which can show us some resistance patterns prior to cultures coming back. 

A few studies on a new-drug for RSV. These 2 studies evaluate the utility of presatovir for the treatment of upper and lower respiratory tract infections in patients with HCT. This is an oral RSV fusion inhibitor with anti-RSV activity in vitro and a half life of 34 hours.

Roy F Chemaly, Sanjeet S Dadwal, Anne Bergeron, Per Ljungman, Yae-Jean Kim, Guang-Shing Cheng, Sudhakar N Pipavath, Ajit P Limaye, Elodie Blanchard, Drew J Winston, Patrick J Stiff, Tsila Zuckerman, Silvy Lachance, Galia Rahav, Catherine B Small, Kathleen M Mullane, Roberto L Patron, Dong-Gun Lee, Hans H Hirsch, Alpana Waghmare, Matt McKevitt, Robert Jordan, Ying Guo, Polina German, Danielle P Porter, David L Gossage, Timothy R Watkins, Francisco M Marty, Jason W Chien, Michael Boeckh, A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients, Clinical Infectious Diseases, Volume 71, Issue 11, 1 December 2020, Pages 2777–2786, https://doi.org/10.1093/cid/ciz1166

This is a phase II, randomized, double blind, placebo controlled, multicenter study in patients with HCT and positive local RSV within 7 days of symptoms. Patients were randomized to 1:1 stratified by lymphopenia to either presatovir or placebo. Primary end points were change in RSV viral load between days 1 and 9 and patients who developed lower respiratory tract infections (LRTCs). 189 patients were randomized, short of their goal of 200 as interim analysis revealed there was not going to be a difference in results even if more patients were recruited. There was no difference in the change from baseline to day 9 in RSV viral load between groups:

There was also no statistical difference in LRTC in either group (19.5% in placebo vs 11.2% in presatovir), though there was a trend to favor presatovir:

Looking at table 2, there was a difference in LRTCs in patients with lymphs <200, and those who were hospitalized on day 1, suggesting that early administration of presatovir may be beneficial:

There was also a trend towards lower complications in those who did not receive ribavirin. 

Francisco M Marty, Roy F Chemaly, Kathleen M Mullane, Dong-Gun Lee, Hans H Hirsch, Catherine B Small, Anne Bergeron, Shmuel Shoham, Per Ljungman, Alpana Waghmare, Elodie Blanchard, Yae-Jean Kim, Matt McKevitt, Danielle P Porter, Robert Jordan, Ying Guo, Polina German, Michael Boeckh, Timothy R Watkins, Jason W Chien, Sanjeet S Dadwal, A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract, Clinical Infectious Diseases, Volume 71, Issue 11, 1 December 2020, Pages 2787–2795, https://doi.org/10.1093/cid/ciz1167

This trial is similar to the above one, but evaluates lower respiratory tract infections with RSV rather than just URTI. These patients needed to have imaging with pulmonary infiltrates. This was a phase 2, randomized, double-blind, placebo-controlled trial, where patients were randomized in a 1:1 fashion to presatovir and placebo stratified to oxygen and ribavirin use. Endpoint was change in RSV viral load from day 1 to day 9, with oxygen-free days being a secondary outcome. 60 patients were randomized, and there was no difference in change of RSV viral load between groups:

There was also no change in patients requiring oxygen at day 28 (p-value 0.84). 

It doesn’t look great for presatovir. There were no serious adverse events in either study, which is reassuring especially when the alternative is ribavirin. I do have issues with the primary outcome being change in viral load, but given the difficulty with recruiting it may be an understandable endpoint as you may need more patients to prove a difference in mortality (which there was a trend in the first study). Either way, stay tuned. 

Michal Landes, Yasmin Maor, Diego Mercer, Zohar Habot-Wilner, Efraim Bilavsky, Bibiana Chazan, Regev Cohen, Daniel Glikman, Jacob Strahilevitz, Michal Katzir, Vladislav Litachevsky, Rimma Melamed, Alex Guri, Hila Shaked, Odelya Perets, Yonit Wiener-Well, Anat Stren, Michal Paul, Oren Zimhony, Isaac Srugo, Galia Rahav, Jihad Bishara, Amir A Kuperman, Ronen Ben-Ami, Moshe Ephros, Michael Giladi, Cat Scratch Disease Presenting as Fever of Unknown Origin Is a Unique Clinical Syndrome, Clinical Infectious Diseases, Volume 71, Issue 11, 1 December 2020, Pages 2818–2824, https://doi.org/10.1093/cid/ciz1137

This is a super interesting one. Cat scratch disease, caused by Bartonella henselae, presents with lymphadenitis and fever. One atypical presentation is fever of unknown origin. Here, the authors described CSD-associated FUO. During a 14 year period, 60 patients were determined to have CSD-FUO. Most patients (over 80%) had contact with a cat, with older patients and patients requiring hospitalization for investigation more likely to have CSD-FUO as opposed to typical CSD:

There is an entire table of manifestations, but I will highlight those that were present in over 50% of patients. Shaking chills, fatigue/weakness, weight loss and night sweats were the most common symptoms. Interestingly, 51.7% of patients had a relapsing fever pattern, with a median duration of 3 days per febrile episode followed by 5 days of afebrile episode. The mean number of episodes such as these were 6. This may be a differential diagnosis for relapsing fever along with borrelia recurrentis and Bartonella quintana (aka trench fever, named after its description in the trenches of WWI). 

Philip W Lam, Payam Tarighi, Marion Elligsen, Avery B Nathens, Daniel Riegert, Jordan Tarshis, Jerome A Leis, Impact of the Allergy Clarification for Cefazolin Evidence-based Prescribing Tool on Receipt of Preferred Perioperative Prophylaxis: An Interrupted Time Series Study, Clinical Infectious Diseases, Volume 71, Issue 11, 1 December 2020, Pages 2955–2957, https://doi.org/10.1093/cid/ciaa516

Penicillin allergy is a lie. Or maybe overblown. This is an intervention study evaluating the Allergy Clarification for Cefazolin Evidence-based Prescribing Tool (ACCEPT) used to identify who can get cefazolin. 

This was a 16-month interrupted time series study. Primary outcome was the monthly proportion of patients with a beta-lactam allergy who underwent elective surgery and received perioperative prophylaxis. Secondary outcome was perioperative allergic reactions. Not surprisingly, the number of cefazolin use increased with implementation of the ACCEPT tool, though there was only 2 perioperative allergic reactions in the intervention period in those with reported allergy, which was attributed to blue dye and likely a hypersensitivity reaction. 

Cannot say I am surprised; not all beta-lactams have the same side chain, which is what causes allergic reactions. So penicillin does not have the same side chain as cefazolin or even amoxicillin. Ceftazidime and aztreonam, however, is a different ordeal as aztreonam’s side chain is a “mirror” of that of ceftazidime. 

And now to COVID. 

Mahesh C Patel, Lelia H Chaisson, Scott Borgetti, Deborah Burdsall, Rashmi K Chugh, Christopher R Hoff, Elizabeth B Murphy, Emily A Murskyj, Shannon Wilson, Joe Ramos, Lynn Akker, Debra Bryars, Evonda Thomas-Smith, Susan C Bleasdale, Ngozi O Ezike, Asymptomatic SARS-CoV-2 Infection and COVID-19 Mortality During an Outbreak Investigation in a Skilled Nursing Facility, Clinical Infectious Diseases, Volume 71, Issue 11, 1 December 2020, Pages 2920–2926, https://doi.org/10.1093/cid/ciaa763

This was a descriptive study of a cluster of COVID infections in a SNF in Illinois. The SNF offered testing to all residents on one day and followed them for 30 days to evaluate the presymptomatic and asymptomatic infection. 127 patients were evaluated, with 116 sharing a room. From March 11-15, 8 residents were tested and 6 were positive. Starting March 15, 118 residents were tested, of which 27 were positive, for a total of 33 infections (26%). Of these, 13 had symptoms at testing while 14 did not have symptoms (only 1 of these eventually developed symptoms). Of the 91 who did not have COVID, 35 developed symptoms after testing, with 3 being retested and 2 being found positive. 10/35 were hospitalized, and 71% of all positive patients survived at day 30 (95% CI 52-83). I would have liked to have seen testing in the other 32 patients, though I would assume these were all positive, essentially doubling the infection rate. Yeah, close quarters is not an ideal scenario. 

Keith Sigel, Talia Swartz, Eddye Golden, Ishan Paranjpe, Sulaiman Somani, Felix Richter, Jessica K De Freitas, Riccardo Miotto, Shan Zhao, Paz Polak, Tinaye Mutetwa, Stephanie Factor, Saurabh Mehandru, Michael Mullen, Francesca Cossarini, Erwin Bottinger, Zahi Fayad, Miriam Merad, Sacha Gnjatic, Judith Aberg, Alexander Charney, Girish Nadkarni, Benjamin S Glicksberg, Coronavirus 2019 and People Living With Human Immunodeficiency Virus: Outcomes for Hospitalized Patients in New York City, Clinical Infectious Diseases, Volume 71, Issue 11, 1 December 2020, Pages 2933–2938, https://doi.org/10.1093/cid/ciaa880

This was a study that assessed outcomes of COVID infected HIV patients compared to a hospitalized cohort of COVID patients without HIV. 88 patients with co-infections were compared to 405 patients with COVID and no HIV. There were no differences between groups, although patients with HIV had higher rates of cancer, COPD, and smokers. Furthermore, ferritin levels were lower in those with HIV. Overall, there was no difference in mortality, ICU admission, or mechanical ventilation:

When comparing COVID-HIV patients who died compared to those who survived, the only differences include higher rate of organ transplant (17 vs 1%), lower use of NRTIs (89 vs 99%), higher CRP (209 vs 101), higher PCT (0.74 vs 0.19), and higher IL-6 (131 vs 57).

Seems reasonable that those who are well controlled in terms of their HIV have similar outcomes to that of non-HIV infected folks. 

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