Weekly Articles 11/14/2021

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Look, I know I have been absent but I have really good reason for that. No COVID-related articles today.

Mark Beldman, Claudia Löwik, Alex Soriano, Laila Albiach, Wierd P Zijlstra, Bas A S Knobben, Paul Jutte, Ricardo Sousa, André Carvalho, Karan Goswami, Javad Parvizi, Katherine A Belden, Marjan Wouthuyzen-Bakker, If, When, and How to Use Rifampin in Acute Staphylococcal Periprosthetic Joint Infections, a Multicentre Observational Study, Clinical Infectious Diseases, Volume 73, Issue 9, 1 November 2021, Pages 1634–1641, https://doi.org/10.1093/cid/ciab426

This retrospective study evaluated the use of rifampin adjunctive therapy in prosthetic joint infection. Primary outcome was treatment failure within a year of debridement and irrigation  and retention of prosthetics. 669 patients were included, of which 61% were treated with rifampin. Patients who did not get rifampin were more likely to be obese, have a late acute PJI, and mless likely to have cemented implant. Treatment failure occurred less often in the rifampin cohort (32.2% vs 54.2%), with most prominent effect being in the knee cohort. 

In multivariate analysis, rifampin and infected primary arthroplasties were associated with treatment success:

Timing of rifampin also had some impact on success. Starting within 5 days of surgical debridement was associated with higher failure rates (40.8%) compared to starting between days 5 and 9 (20.9%) and after 10 days (21.4%). In multivariate analysis, starting rifampin within 5 days of surgery had an OR of 1.96 (95% CI 1.08 to 3.56) for treatment failure. Moreover, the use of antibiotics other than FQs or clindamycin was associated with higher rate of treatment failure (OR 10.1, 95% CI 5.56-18.2). I gotta say, I am still confused about when to use rifampin for PJI, but this seems to suggest that there is a benefit overall. 

Gandhi AM, Shah MD, Donohue LE, Cox HL, Eby JC. Tolerability of Cefazolin in Nafcillin-Intolerant Patients for the Treatment of Methicillin-Susceptible Staphylococcus aureus Infections. Clin Infect Dis. 2021 Nov 2;73(9):1650-1655. doi: 10.1093/cid/ciab368. PMID: 33905485.

Can you use cefazolin if you are intolerant to nafcillin? This was a retrospective case series that sought to identify the percentage of patients who completed cefazolin after having a non-IgE mediated hypersensitivity reaction to nafcillin (i.e. they did not have anaphylaxis). The criteria the authors used were as follows:

183 patients who switched were evaluated, of which 80 were ultimately included. Of these, 71 patients (89%) tolerated the switch to cefazolin and completed therapy. Using the Naranjo Scale to determine the likelihood of suspected HSR due to nafcillin, none were definite while 44 (64$) were probable, and 31 (36%) were possible. Something that really grinds my gears is having “penicillin-allergy” listed as a true allergy when it most likely wasn’t a real allergy. I think this supports that idea to a certain degree, though it obviously excluded the IgE mediated reactions. 

Tumbarello M, Raffaelli F, Giannella M, Mantengoli E, Mularoni A, Venditti M, De Rosa FG, Sarmati L, Bassetti M, Brindicci G, Rossi M, Luzzati R, Grossi PA, Corona A, Capone A, Falcone M, Mussini C, Trecarichi EM, Cascio A, Guffanti E, Russo A, De Pascale G, Tascini C, Gentile I, Losito AR, Bussini L, Corti G, Ceccarelli G, Corcione S, Compagno M, Giacobbe DR, Saracino A, Fantoni M, Antinori S, Peghin M, Bonfanti P, Oliva A, De Gasperi A, Tiseo G, Rovelli C, Meschiari M, Shbaklo N, Spanu T, Cauda R, Viale P. Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study. Clin Infect Dis. 2021 Nov 2;73(9):1664-1676. doi: 10.1093/cid/ciab176. PMID: 33618353.

This retrospective study evaluated inpatients in 22 Italian hospitals who received ceftazidime-avibactam for KPC-Kleb pneumo infections. Primary outcome was all-cause mortality 30 days after infection onset, which was obtained by using multivariate logistic regression analysis. 577 patients who received at least 72 hours of therapy were included. 70% cases were managed with combination therapy, which included another drug such as fosfomycin, tigecycline, gentamicin, or meropenem. 30-day mortality rate was 25%, with no significant difference in those who were managed with Avycaz alone or in combination (26.1% vs 25%). Univariate analysis found that patients who died tended to be older, have hospital acquired infection, have pre-existing cardio or cerebrovascular disease and/or neutropenia. Multivariate analysis found that septic shock, neutropenia, lower respiratory tract infection, and avycaz dose adjustment due to renal function were all independently associated with higher mortality:

Interestingly, prolonged infusino of Avycaz was associated with lower mortality rate as seen above:

Not surprised about things like being sicker is associated with higher mortality, however the extended infusion is a bit of an interesting one. I think it has to do with the way beta-lactams tend to work, namely their activity tends to be correlated with time above MIC, which is why you dose it so frequently. 

Senchyna F, Hogan CA, Murugesan K, Moreno A, Ho DY, Subramanian A, Schwenk HT, Budvytiene I, Costa HA, Gombar S, Banaei N. Clinical Accuracy and Impact of Plasma Cell-Free DNA Fungal Polymerase Chain Reaction Panel for Noninvasive Diagnosis of Fungal Infection. Clin Infect Dis. 2021 Nov 2;73(9):1677-1684. doi: 10.1093/cid/ciab158. PMID: 33606010.

I’ve talked about cell-free DNA and its utility in diagnosing several types of deep seated infections, especially in immunocompromised individuals. This was a retrospective study evaluating a novel fungal cfDNA PCR in patients with confirmed and suspected IFI. 104 patients were evaluated, which comprised 115 episodes of IFI. The sensitivity and specificity of the fungal cfDNA was 56.5% and 99.5%, respectively. This increased with the optimal plasma volume, with a sensitivity of 69.6%. When looking at different species, the sensitivity was overall higher for mucorales agents, followed by C. albicans:

Using additional data for 226 patients, the impact of a positive test was evaluated. Overall, 42.6% of patients had a positive clinical impact with the use of the assay:

While the sensitivity is relatively low, I think this overall beats having to get a deep tissue biopsy for diagnosis. I think this will be the next generation of diagnostic studies. 

Schoepf IC, Thorball CW, Ledergerber B, Engel T, Raffenberg M, Kootstra NA, Reiss P, Hasse B, Marzolini C, Thurnheer C, Seneghini M, Bernasconi E, Cavassini M, Buvelot H, Kouyos R, Günthard HF, Fellay J, Tarr PE; Swiss HIV Cohort Study. Coronary Artery Disease-Associated and Longevity-Associated Polygenic Risk Scores for Prediction of Coronary Artery Disease Events in Persons Living With Human Immunodeficiency Virus: The Swiss HIV Cohort Study. Clin Infect Dis. 2021 Nov 2;73(9):1597-1604. doi: 10.1093/cid/ciab521. PMID: 34091660.

Ah, HIV. Apparently associated with higher risk of coronary artery disease. This study evaluated the CAD event prediction in the well known Swiss HIV cohort based on traditional, HIV-related, and genetic risk factors (the latter of which included polygenic risk scores that consisted of nearly 2 million SNPs). 269 cases were compared with 567 controls. Cases included MIs, stenting/angiography, CABG, and fatal CAD. Case patients tended to be on ART for a lot longer (10.9 years vs 6.0, median), as well as having lower CD4 counts. They also tended to be more likely to have traditional CAD risk factors such as T2DM, HLD, and tobacco abuse. Both traditional CAD risk factors and PRSs were independently associated with coronary artery disease events:

As you can see from the graph, more cases tended to have higher risk factors by either PRSs or clinical risk factors. Similarly, Adjusted ORs for CAD tended to be worse with higher numbers of PRSs:

The highest OR for unfavorable genetic background was 3.17 (95% CI 1.74-5.79) as seen in the above table. CAD events were associated with age, dyslipidemia, diabetes, CMV seropositivity, current use of abacavir, cumulative exposure to darunavir, stavudine, and indinavir. I think this highlights the importance of a genetic component for CAD that HIV patients have to content, and why (overall) we see folks who “do everything wrong” yet have no CAD events. 

Dagher MM, Eichenberger EM, Addae-Konadu KL, Dotters-Katz SK, Kohler CL, Fowler VG, Federspiel JJ. Maternal and Fetal Outcomes Associated With Infective Endocarditis in Pregnancy. Clin Infect Dis. 2021 Nov 2;73(9):1571-1579. doi: 10.1093/cid/ciab533. PMID: 34111290; PMCID: PMC8563217.

So I tend to avoid talking abut pregnant women because their physiology baffles me (honestly, everything in medicine baffles me, but this moreso). Its almost as if you could make an entire specialty about complications in pregnant women. Anyway, this was a retrospective study that used a national cohort to evaluate the outcomes in maternity-associated infective endocarditis. This included: in hospital mortality, valve repair and replacement, intubation/ventilation, thromboembolic events, length of stay, and total in patient cost.  382 maternity associated IE were included. These cases were matched with non-maternity associated IE, on which propensity score matching was performed. There was no statistical difference in in-hospital mortality in the maternity-associated (8.1%) and non-maternity associated (10.6%) cohorts. From the highlighted outcomes, only thromboembolic events was lower in the maternity subgroup after adjustment:

When comparing delivery in IE and non-IE groups, this is where the biggest difference was seen. Notably, those who had IE and delivered were more likely to be in lower median household income areas (43.3% living in the lowest quartile if with IE compared to 27.7% without IE). The patients with IE also had higher rates of co-morbidities (38.3% vs 0.2%), as well as congenital heart disease (7.3% vs 0.1%) and CHF (9% vs <0.1%). Further, deliveries in patients with IE were associated with higher morbidity (77% vs 1.6%, aRR 47, 95% CI 38-58). 

Sipilä, P.N., Heikkilä, N., Lindbohm, J.V., Hakulinen, C., Vahtera, J., Elovainio, M., Suominen, S., Väänänen, A., Koskinen, A., Nyberg, S.T., Pentti, J., Strandberg, T.E., & Kivimäki, M. (2021). Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort. The Lancet. Infectious diseases.

Are infections associated with dementia? Perhaps. This was a multicohort, observational study that evaluated the association based on pathogen and type of infection as well as severity with subsequent dementia diagnosis. 260490 patients were included in the primary cohort, with 485,708 patients being included in the replication cohort. Adjusted HR for admission to the hospital for an infection was 1.48 (95% CI 1.37-1.60). These associations held true for any bacterial or viral infection:

Furthermore, it should be noted the association between infection and diagnosis of dementia did not hold near the time of diagnosis of dementia. Further, the associatino between infection and dementia was stronger for non-Alzheimer’s type of dementia:

Which considering infection = inflammation = higher risk of clots, this should make physiological sense. The association was stronger when a patient had at least three infections (aHR 1.68, 95% CI 1.25-2.25 for three or more infections). 

Glynn, Judith R. and Dube, Albert and Fielding, Katherine and Crampin, Amelia C. and Group, Karonga Prevention Trial and Kanjala, Chifundo and Fine, Paul, The Effect of BCG on Mortality Beyond Infancy: 30-Year Follow-Up of a Double-Blind Randomised Placebo-Controlled Trial of BCG Re-Vaccination in Malawi. Available at SSRN: https://ssrn.com/abstract=3684476 or http://dx.doi.org/10.2139/ssrn.3684476

I think I’ll discuss the BCG vaccine at some point, but this double-blind, randomised control trial evaluated the effects of BCG vaccination with or without killed M. leprae on the incidence of leprosy and tuberculosis. Patients who had a BCG vaccination scar were randomized to repeat BCG vaccine alone, BCG with M. leprae, and placebo. The initial study evaluated the outcome of leprosy and TB however, this analysis focused on the all-cause mortality in those who received either injection or placebo. Statistical analysis were performed in a ITT for different age groups. A total of 33,788 had follow up, with no statistical difference seen between either BCG group or placebo for both Northern and southern areas, as well as based on age at vaccination:

Margaret M Cooper, Candice R Preslaski, Katherine C Shihadeh, Kellie L Hawkins, Timothy C Jenkins, Multiple-Dose Dalbavancin Regimens as the Predominant Treatment of Deep-Seated or Endovascular Infections: A Scoping Review, Open Forum Infectious Diseases, Volume 8, Issue 11, November 2021, ofab486, https://doi.org/10.1093/ofid/ofab486

Ah, Dalvabancin, you single-dose antibiotic. This one is approved for Skin and soft tissue infections from gram positive bacteria and has a half-life of around 346 hours, allowing you to give two doses, separated by one week. Further, it seems that giving two 1.5g doses split one week apart allows therapeutic concentration in bone and joint tissue for up to 8 weeks. This was a review evaluating the use of Dalvabancin for deep seated or endovascular infections caused by gram positive bacteria. 144 cases were evaluated, with 65% involving bone and joint infections. Success occurred in 133 (92%) of patients, with complicated bacteremia having the lowest success rate:

Most indications received at least 2 doses of the antibiotic, with IE receiving a median of 3:

I think this is a reassuring review on the utility of Dalvabancin to treat some of these infections. I would like to see more data on its utility for multi-drug resistant organisms (i.e. those where you cannot use linezolid/Dapto), but I’ll take what I can get. 

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