Weekly Articles 7/4/2021

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A bit late on this one but I have some info on the delta variant.

Lustig Y, Zuckerman N, Nemet I, Atari N, Kliker L, Regev-Yochay G, Sapir E, Mor O, Alroy-Preis S, Mendelson E, Mandelboim M. Neutralising capacity against Delta (B.1.617.2) and other variants of concern following Comirnaty (BNT162b2, BioNTech/Pfizer) vaccination in health care workers, Israel. Euro Surveill. 2021 Jul;26(26). doi: 10.2807/1560-7917.ES.2021.26.26.2100557. PMID: 34212838.

A pair of reports on immunization and the delta variant (B.1.617.2) which popped up in India initially. This is a report on the neutralizing response of the serum of healthcare workers immunized with the Pfizer vaccine. Multiple isolates were evaluated, which included 2 delta samples, an alpha and beta variant as well. As highlighted below, the authors measured the neutralizing antibodies against all variants and not surprisingly, found that the geometric mean titers were higher to the original strain when compared to other variants:

Wall EC, Wu M, Harvey R, Kelly G, Warchal S, Sawyer C, Daniels R, Hobson P, Hatipoglu E, Ngai Y, Hussain S, Nicod J, Goldstone R, Ambrose K, Hindmarsh S, Beale R, Riddell A, Gamblin S, Howell M, Kassiotis G, Libri V, Williams B, Swanton C, Gandhi S, Bauer DL. Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet. 2021 Jun 19;397(10292):2331-2333. doi: 10.1016/S0140-6736(21)01290-3. Epub 2021 Jun 3. PMID: 34090624; PMCID: PMC8175044.

Similarly, in another report, 250 patients vaccinated with the Pfizer vaccine also had their neutralizing antibody titers measured either after one dose or 2 doses against 5 different strains. Overall, 2 doses of the vaccine elicited a neutralizing antibody response in all patients in all variants with the exception of 6 (3%) and nine (5%) of 159 patients against B.1.167.2 and B.1.351 respectively:

While this was true, as noted above, the GMT against certain variants was significantly lower. Furthermore, while one dose conferread a reasonable response against the original strain, the degree of response varied depending on the strain:

Compared to other strains, the delta variant has 12 mutations in its spike protein, however it lacks any mutations on its ACE-2 receptor binding domain that is associated with other variants. I had previously commented on several vaccine studies and how, while vaccine efficacy decreases with each variant, there seems to be few cases of severe COVID reported, which I think is reassuring. 

Shinde V, Bhikha S, Hoosain Z, Archary M, Bhorat Q, Fairlie L, Lalloo U, Masilela MSL, Moodley D, Hanley S, Fouche L, Louw C, Tameris M, Singh N, Goga A, Dheda K, Grobbelaar C, Kruger G, Carrim-Ganey N, Baillie V, de Oliveira T, Lombard Koen A, Lombaard JJ, Mngqibisa R, Bhorat AE, Benadé G, Lalloo N, Pitsi A, Vollgraaff PL, Luabeya A, Esmail A, Petrick FG, Oommen-Jose A, Foulkes S, Ahmed K, Thombrayil A, Fries L, Cloney-Clark S, Zhu M, Bennett C, Albert G, Faust E, Plested JS, Robertson A, Neal S, Cho I, Glenn GM, Dubovsky F, Madhi SA; 2019nCoV-501 Study Group. Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021 May 20;384(20):1899-1909. doi: 10.1056/NEJMoa2103055. Epub 2021 May 5. PMID: 33951374; PMCID: PMC8091623.

Speaking of vaccines, this was a phase-3 randomized, observer-blinded, placebo controlled trial evaluating the efficacy of the Novavax vaccine. Patients were randomized in a 1:1 ratio to receive 2 doses of the vaccine or placebo administered 21 days apart. Primary endpoint was the efficacy of the vaccine against the first occurrence of any confirmed symptomatic COVID vaccine at least 7 days after the first dose. This was analyzed in a per-protocol population as well as in an ITT fashion. 15139 patients received at least one dose of the vaccine or placebo. Both groups were fairly well balanced, as expected based on a trial of this size. Not surprisingly, more patients in the vaccine group experienced adverse events, though there were little, if any, grade 4 adverse events reported:

Overall, there were more local side effects in the vaccine group after the first dose (58% vs 18%) and second dose (80% vs 16%). Systemic adverse events followed a similar pattern (46% vs 36% for first dose and 64% vs 30% for the second dose). Only 3 recipients experienced grade 4 adverse events. There was one case of myocarditis that occurred 3 days after the second dose that may be immune-mediated. In the primary end point, 10 patients in the vaccine group received a diagnosis of COVID-19 (6.53 per 1000 person-years) compared to 96 in the placebo group (63.43 per 1000 person years), for a VE of 89.7% (95% CI 80 to 94.6%). Of the 10 cases in the vaccine group, 8 were caused by the B.1.1.7 variant, and 1 by a non-B.1.1.7 variant. 5 cases of severe covid occurred in the placebo group. Efficacy was 86.3% (95% CI 71 to  93.5%) for the B.1.1.7 variant and 96.4% (95% CI 73.8 to 99.4) against non-B.1.1.7 variants.

So overall good results from this new vaccine. 

Zachary A Yetmar, Elena Beam, John C O’Horo, Ravindra Ganesh, Dennis M Bierle, Lisa Brumble, Maria Teresa Seville, Raymund R Razonable, Monoclonal Antibody Therapy for COVID-19 in Solid Organ Transplant Recipients, Open Forum Infectious Diseases, Volume 8, Issue 6, June 2021, ofab255, https://doi.org/10.1093/ofid/ofab255

This is a cohort of COVID outpatients with solid organ transplant who received monoclonal antibodies, either bamlanivimab or the combination of casirivimab-imdevimab and its impact to prevent clinical progression of mild to moderate COVID-19. Patients were enrolled if they had mild to moderate COVID-19 and are within 10 days of symptom onset. Outcomes included ED visit, hospital admission, ICU admission, mortality, and allograft rejection at 28 days after MAB administration. 73 patients were evaluated, and 75% received bam-bam. Within this cohort, 9 patients were hospitalized, and 11 being seen in the ED within 28 days of MAB administration. Of the 9 patients admitted, 7 were attributed to COVID-19:

Those who were admitted had a longer time from symptom onset to administration of MABs (6 days vs 4 days), were more likely to receive casirivimab-imdevimab (26.6% vs 11.1%), and were more likely to have HTN (100% vs 61%).

Only 10 adverse events occurred in this cohort, with no cases of anaphylaxis or allograft rejection. It is difficult to draw any meaningful conclusions here, but it seems that MAB administration to this population is a safe deal. 

Angel Y, Spitzer A, Henig O, Saiag E, Sprecher E, Padova H, Ben-Ami R. Association Between Vaccination With BNT162b2 and Incidence of Symptomatic and Asymptomatic SARS-CoV-2 Infections Among Health Care Workers. JAMA. 2021 Jun 22;325(24):2457-2465. doi: 10.1001/jama.2021.7152. PMID: 33956048; PMCID: PMC8220476.

This is a retrospective cohort study that evaluated the association between the Pfizer vaccine and SARS-CoV2 infections among Israeli healthcare workers. Primary outcome was the incidence of infection amongst vaccinated HCW compared to those who were not vaccinated. 6710 participants were evaluated, of which 5517 (82.2%) received the 2 doses of the vaccine, while 757 were not vaccinated. Vaccinated HCW were older and more frequently male. 64 vaccinated HCW were infected (incidence rate of 19.4 per 100,000 person-days) compared to 85 non-vaccinated (IR 186.1 per 100,000 person days). For symptomatic COVID, the IR was 4.7 vs 149.8 per 100,000 person days for an adjusted IRR of 0.03 (95% CI 0.01 to 0.06). The incidence rate for asymptomatic SARS-CoV2 was 11.3 vs 67 per 100,000 person days, for an adjusted IRR of 0.14 (95% CI 0.07-0.31):

As noted above, the results were similar in the propensity matched cohort. Asymptomatic infection was not reduced with partial vaccination, but symptomatic infection was still reduced. Please kids, get your vaccines. 


And now, non-COVID stuff

Lau A, Kong FYS, Fairley CK, Templeton DJ, Amin J, Phillips S, Law M, Chen MY, Bradshaw CS, Donovan B, McNulty A, Boyd MA, Timms P, Chow EPF, Regan DG, Khaw C, Lewis DA, Kaldor J, Ratnayake M, Carvalho N, Hocking JS. Azithromycin or Doxycycline for Asymptomatic Rectal Chlamydia trachomatis. N Engl J Med. 2021 Jun 24;384(25):2418-2427. doi: 10.1056/NEJMoa2031631. PMID: 34161706.

Now for non-COVID stuff. This is a double-blind, randomized, control trial comparing 7 days of doxycycline 100mg BID and 1g of azithromycin once in MSM for the treatment of asymptomatic rectal chlamydia. Men who were diagnosed with either gonorrhea or mycoplasma, concurrent syphilis, or asymptomatic LGV were excluded. Patients were randomized in a 1:1 fashion, with the azithromycin group receiving matching placebos to complete the 7 day course. Patients were evaluated at 4 weeks for a test of cure assessment by NAAT. Primary endpoint was a negative result at week 4 (test of cure), which was evaluated in a modified ITT after excluding patients who ended up being diagnosed with LGV. Notably, due to unseen circumstances (COVID), they were unable to check re-infection or viral loads/CD4. 625 patients were randomized, which were fairly well balanced with the exception of a higher rate of HIV infection in the doxycycline group (14% vs 8.4%), higher rate of prior chlamydia infection in the doxy group (54% vs 44%) and douching prior anal sex (66% vs 57%). NAAT positivity was similar between groups (87% in the doxycycline group and 81% in the azithromycin group). Microbiologic cure was observed in 97% of the doxycycline group and 76.4% of the azithromycin group (adjusted Risk difference, 19.9%, 95% CI 14.6 to 25.3%). This was similarly seen in the per-protocol analysis:

A higher percentage of patients in the azithromycin group had adverse event, with diarrhea driving this difference:

Why such a difference was seen is difficult to say. The authors do postulate that the MIC for azithromycin is much higher in colorectal cell lines compared to endocervical cell lines, something not seen for doxycycline. Further, it seems that azithromycin, while lipid soluble, may need transportation by inflammatory cells for it to work. One thing to note is that in those who failed azithromycin therapy, their baseline chlamydial load was higher. I do not see this as clinically relevant, as you are most likely treating without this information, so it seems that doxycycline is the way to go.

Park Y, Park YE, Jhun BW, Park J, Kwak N, Jo KW, Yim JJ, Shim TS, Kang YA. Impact of Susceptibility to Injectable Antibiotics on the Treatment Outcomes of Mycobacterium abscessus Pulmonary Disease. Open Forum Infect Dis. 2021 May 12;8(6):ofab215. doi: 10.1093/ofid/ofab215. PMID: 34189168; PMCID: PMC8231371.

I have a feeling everytime I do a general post, I see articles related to that. This was a multicenter retrospective cohort study that evaluated the impact of in vitro testing of susceptibility to IV antibiotics on outcomes for patients with M. abscessus pulmonary disease. Patients were treated with at least 4 weeks of combination of IV therapy, usually amikacin and a beta-lactam (cefoxitin and imipenem). Primary outcome was culture conversion and microbiological cure according to susceptibility to IV antibiotics. 127 patients were initially enrolled, of which 82 were included in the final analysis. 65 of these had inducible clarithromycin resistance (seen after incubation at day 14). There was no statistical difference between the patients with clarithromycin inducible resistance or susceptibility. Overall, sputum conversion rate and microbiological cure rate were similar regardless of susceptibility:

When looking at patients with cavitary lesions and those with positive smears and cavitary lesions, antibiotic susceptibility seemed to be related to treatment outcomes, and those who were treated for >1 year, microbiological cure was related to cefoxitin susceptibility, but this did not reach statistical significance:

I do not think we will ever know the answer to this question. The one thing we do know is that susceptibility to macrolides may have an impact on outcomes. 

Elvstam O, Marrone G, Medstrand P, Treutiger CJ, Sönnerborg A, Gisslén M, Björkman P. All-Cause Mortality and Serious Non-AIDS Events in Adults With Low-level Human Immunodeficiency Virus Viremia During Combination Antiretroviral Therapy: Results From a Swedish Nationwide Observational Study. Clin Infect Dis. 2021 Jun 15;72(12):2079-2086. doi: 10.1093/cid/ciaa413. PMID: 32271361; PMCID: PMC8204776.

This is a nationwide, observational cohort study that evaluated the impact of low level viremia (either 50-199 copies/mL or 200-900 copies/mL) on all-cause mortality, AIDS-defining conditions, and serious non-AIDS events. This cohort used data from the Sweedish HIV registry, and patients had to have been on ART. 6956 patients were included, with patients achieving viral suppression being more likely to have been included at a later point in time and less likely to be on a PI-based regimen. 953 patients met criteria for low level viremia, of which 508 had 200-999 copies/mL. During 49,986 person-years follow up, 459 deaths were reported, with the most common cause of death being due to HIV/AIDS (31%). After adjustment, patients with low level viremia had higher mortality rate compared to those with viral suppression, which was similar between the 2 subgroups:

Low level viremia was also associated with higher all-cause mortality in patients who started cART after January 2005 (aHR 3.2, 95% CI 1.5-6.7), which was not impacted by the type of regimen. Further, older age, male sex, higher pre-ART CD4 cell counts, and treatment interrputions were associated with higher all-cause mortality. Non-sustained viremia was also associated with an increase risk of AIDS, which was not seen in low-level viremia:

Which was seen also when looking at serious non-AIDS events (typically CV events or non-AIDS malignancy). Whether these results are due to ongoing inflammation or something the virus is doing is unclear, though I am willing to say the former rather than the latter. Strategies to achieve suppression are still beyond me, especially when it comes to treating experienced patients but it seems the goal should be to achieve viral suppression as much as possible. 

Fourman LT, Stanley TL, Zheng I, Pan CS, Feldpausch MN, Purdy J, Aepfelbacher J, Buckless C, Tsao A, Corey KE, Chung RT, Torriani M, Kleiner DE, Hadigan CM, Grinspoon SK. Clinical Predictors of Liver Fibrosis Presence and Progression in Human Immunodeficiency Virus-Associated Nonalcoholic Fatty Liver Disease. Clin Infect Dis. 2021 Jun 15;72(12):2087-2094. doi: 10.1093/cid/ciaa382. PMID: 32270862; PMCID: PMC8204775.

This was part of a randomized, double-blind trial where patients received tesamorelin, a GHRH analogue to reduce liver fat and prevent progression of liver fibrosis. 61 patients with HIV and no other risk factors for liver disease were enrolled. This study actually included liver biopsy samples that were obtained at the time of enrollment and at the end, and use this data along with visceral fat and other clinical characteristics, to evaluate the progression of this cohort of patients who were on the placebo end of the trial. Of the 58 patients who were evaluated, 62% were on an integrase-based regimen, and 24 had paired liver biopsy specimens 12 months apart. At baseline, 25 patients had liver fibrosis and these tended to be on NNRTI, more likely to have NASH, have higher NASH activity scores, more likely to have lobular inflammation and hepatocellular ballooning, and have higher Transaminitis and visceral fat:

38% of patients had progression of liver fibrosis, with baseline visceral adipose tissue being higher in those who progressed (306 vs 212). Overall, in multivariate analysis, VAT was associated with progression of liver fibrosis:

Histological characteristics at baseline had no association with this. I think the study was a bit small to see if the type of ART had any impact, as it has been seen that integrase inhibitors leads to higher fatty liver rates. The percentage of liver fat was not associated with an increased rate of fibrosis in this study, though there was a trend towards that being the case. Interestingly, a decrease in inflammation and lower A1c was seen in those who did not progress, though how much this matters is unclear:

Daneman N, Cheng Y, Gomes T, Guan J, Mamdani MM, Saxena FE, Juurlink DN. Metronidazole-associated Neurologic Events: A Nested Case-control Study. Clin Infect Dis. 2021 Jun 15;72(12):2095-2100. doi: 10.1093/cid/ciaa395. PMID: 32303736; PMCID: PMC8204771.

This is a cool one. This was a case-control study of older adults from Ontario that compared the rate of central or peripheral nervous system events within 100 days of the receipt of metronidazole or clindamycin (the latter chosen as it is used in most of the same conditions one would give MTZ). All outpatient prescriptions in those who were 65 years or older were evaluated. The authors also calculated the total mass of metronidazole (in grams) dispensed. Of over 78,000 patients who had an event, 1212 had exposure to either MTZ or clinda, but not both. These were matched with up to 10 event-free controls for a total of 12098. Those who had neurological events were more likely to be in lower-income neighborhoods, have higher healthcare utilization rates, and have higher rates of co-morbidities. After adjustment, rate of neurologic adverse events were haver in the MTZ group (aOR 1.43, 95% CI 1.26-1.63), which was seen in both CNS and PNS events:

When looking at the total dose administered, there seems to be no clear dose-response effect seen:

What does this mean and what is the mechanism behind this? I do not know, but I think the rate here is significant to think about MTZ the next time a neurological event occurs in older patients. 

Karlowsky JA, Lob SH, Raddatz J, DePestel DD, Young K, Motyl MR, Sahm DF. In Vitro Activity of Imipenem/Relebactam and Ceftolozane/Tazobactam Against Clinical Isolates of Gram-negative Bacilli With Difficult-to-Treat Resistance and Multidrug-resistant Phenotypes-Study for Monitoring Antimicrobial Resistance Trends, United States 2015-2017. Clin Infect Dis. 2021 Jun 15;72(12):2112-2120. doi: 10.1093/cid/ciaa381. PMID: 32246147.

One thing I didn’t know (and most likely will write a post on this in the future) is there were different definitions for drug-resistant gram negative bacteria. There is the MDR, which is defined as not susceptible to one or more agents in at least 3 antimicrobial categories. Then, there is DTR )or difficult-to-treat resistance), which is an isolate that is not susceptible to all beta-lactams, as well as carbapenems and quinolones. Why the difference? Its because with MDR, the implication is that even if you have resistance to one type of antibiotic, you can use another one without any implications to its toxicity or efficacy (i.e. each antibiotic is interchangeable). With DTR, since you knock out your first line agents, the implication is that you can only use more toxic agents. So it tells you a bit more. The only reason I speak of this right now is because this study compared the definition of DTR and MDR against gram-negative bacilli and the in vitro activities of ceftolozane/tazobactam and imipenem/relebactam. 10516 Enterobacteriaceae and 2732 pseudomonas organisms were evaluated. 1% of enterobacteriaceae were DTR while 15.6% were MDR; 8.2% of Pseudomonas were DTR while 32.4% were MDR:

Within each gram negative, the rates differ with the highest rate of DTR being in K. pneumoniae. Rates of resistance were similar in ICU and non-ICU isolates as were depending on where in the body the organism was isolated, with the exception of pseudomonas having higher resistance when isolated from the respiratory tract:

The susceptibility of imipenem/relebactam was 95% for all isolates (82% for DTR and 92% for MDR isolates) of enterobacteriaceae, while for ceftolozane/tazobactam, the numbers were 94%, 1.5% (DTR) and 66% (MDR). Only colistin and amikacin had higher susceptibility numbers. Similar numbers were seen for pseudomonas, though the susceptibility was lower for DTR:

So what was going on with ceftolozane/tazobactam? Well, it is likely these isolates were carbapanemases which have no susceptibility either way. 

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