Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Lukash UV, Vlasova AV, Gorev VV, Tiganova OA, Bystrova AA, Kamenev MM, Khasanova KA, Denisenko NP, Sychev DA

The ECMM EQUAL Scores tool was proposed in 2018 as a way to improve the quality of treatment of invasive mycoses and assess compliance with the diagnostic algorithm. Currently, there are no reports of its practical application in pediatrics. This study aimed to assess the prevalence of invasive mycosis in a pediatric hospital, the attributed mortality in children with invasive mycosis, and to analyze the dynamics of consumption of antifungal drugs. By design, the study was multidirectional observational, and spanned two years, with retrospective part over the period from 01.01.2022 to 31.12.2022, and prospective part — from 01.01.2023 to 31.08.2024. We used ECMM EQUAL Scores to evaluate the conformity of the fungal infection prevention measures and the empirical therapy to the established risk tier the patients were allocated to, and calculated the ATC/DDD index to measure the consumption of antifungal drugs. During the 20-month follow-up period, 78 children survived, 20 died; supervision continues. The attributed mortality rate was 25.6%. The weighted average absolute ECMM EQUAL Scores were as follows: for candidiasis — 8.4 (38%), for aspergillosis — 6.6 (24%), and for mucormycosis — 9.85 (31%). With the help of the ATC/DDD index, we assessed the dynamics of consumption of antifungal drugs in 2022 and 2023, the "before" and "after" periods. It was concluded that introduction of the ECMM tool into the invasive mycosis diagnostic routine significantly raised the number of detected cases (from 5 to 98 per year), and pushed down the attributed mortality from 60% to 25.6%. With ECMM EQUAL Scores, the NNT index was 2.9. Before introduction of the ECMM tool, in 2022, antifungal drugs were given for 30.3 DDD per 100 bed-days, after the introduction in 2023 — 54.7 DDD per 100 bed-days.

Received: 2024-11-15

Published online: 2024-12-26

DOI: 10.24075/brsmu.2024.067

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Kornienko MA, Kuzin VV, Abdraimova NK, Gorodnichev RB, Shitikov EA

Staphylococcus aureus is the causative agent of a wide range of infections, including severe systemic diseases, which is often multidrug resistant. Given the growing overall antibiotic resistance, a promising approach to treating staphylococcal infections is administration of bacteriophages, especially in combination with antibiotics. This study aimed to evaluate the synergistic effect of linezolid and bacteriophage vB_SauM-515A1 in combating a systemic infection in BALB/c mice. Using 36 animals, we established the optimal way of administration and the infecting dose of the microorganism (5 × 108 CFU/mouse intravenously), and identified the threshold concentrations of antimicrobial agents for monotherapy. The evaluation was based on the revealed contamination of internal organs (kidneys, spleen) and blood. To learn the etiotropic effect of linezolid (10 mg/kg animal weight) combined with the phage (2 × 107 PFU/mouse), we worked with a control group and a test group, 12 mice in each; 2, 8, 18, and 24 hours after infection, the former received the drug only, the latter — the investigated combination. Combined therapy had a more pronounced effect, decreasing the bacterial load in the kidneys by two to three orders of magnitude compared with monotherapy on the first day of treatment. Thus, the combined use of linezolid and bacteriophages is promising for the treatment of infections caused by S. aureus, and may increase the effectiveness of treatment and reduce the risk of side effects of high-dose antibiotics.

Received: 2024-11-06

Published online: 2024-12-25

DOI: 10.24075/brsmu.2024.062

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Abdraimova NK, Shitikov EA, Malakhova MV, Gorodnichev RB, Kornienko MA

Staphylococcus aureus causes a broad range of infections and is often characterized by multidrug resistance (MDR). Treatment of staphylococcal infections is further complicated by the ability of bacterium to form biofilms protecting it against antimicrobial agents and the immune system. The use of bacteriophages is one of the promising strategies for combating the bacteria showing MDR and biofilm formation activity. The study aimed to assess the effects of the lytic phages vB_SauM515A1 (genus Kayvirus, family Herelleviridae) and vB_SauP-436A (genus Rosenblumvirus, family Rountreeviridae) on biofilms of the S. aureus clinical strains. The study involved 20 strains of eight sequence types, among which 45% (9/20) belonged to MRSA, and 35% (7/20) showed MDR. All the strains demonstrated the ability to form biofilms, and 65% (13/20) were strong biofilm producers. Genes of the icaADBC operon responsible for synthesis of polysaccharide intercellular adhesin were found in genomes of all samples. The exposure of planktonic bacterial cells to bacteriophages showed that 70% (14/20) of strains were sensitive to phage vB_SauM-515A1 and 50% (10/20) were sensitive to phage vB_SauP-436A. Furthermore, the 24-h treatment of biofilms of sensitive strains with phage vB_SauM-515A1 led to the biofilm biomass increase in 64.3% (9/14) of cases, while phage vB_SauP-436A, on the contrary, significantly reduced the quantity of biofilm in 40% (4/10) of strains. The results obtained highlight the ambiguity of interaction between bacteriophages and S. aureus biofilms and suggest the need for further research aimed at optimizing phage therapy targeting the biofilm-forming strains.

Received: 2024-11-14

Published online: 2024-12-24

DOI: 10.24075/brsmu.2024.061

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VIEWS 343

Zagoskin AA, Avakova RA, Rezvykh LF, Zakharova MV, Mubarakshina EK, Ivanov RA, Nagornykh MO

The widespread use of antibiotics in medicine and agriculture has significantly accelerated the emergence rate of bacterial infections showing multiple antibiotic resistance. Since resistance to conventional antibiotics is developed rather quickly, designing alternative antimicrobial drugs with other mechanisms underlying their effects on bacteria is a promising. The enzymes possessing bactericidal activity may be one option for such antibacterial agents. The study aimed to produce the combination recombinant protein-based products active against bacteria and their biofilms. Soluble forms of five recombinant proteins were produced using the genetic engineering approaches. Two of these have a bacteriolytic effect (endolysins LysK and PM9 from the Staphylococcus aureus bacteriophages), the other are capable of disrupting extracellular DNA matrix in biofilms (two nonspecific nucleases NucA, as well as the DNA-specific deoxyribonuclease I). It has been shown that natural endolysin PM9 with the truncated catalytic domain shows 4 times lower bacteriolytic efficacy compared to the full-size LysK version. Comparative analysis revealed 1.5–2 timed higher efficacy of nonspecific nucleases in terms of bacterial biofilm disruption compared to the DNA-specific deoxyribonuclease I. It has been shown that simultaneous use of endolysins and nucleases has a synergistic antibacterial effect and disrupts biofilms of the pathogenic bacterium Staphylococcus aureus. The findings show the prospects of developing the recombinant protein-based antibacterial drugs.

Received: 2024-11-25

Published online: 2024-12-23

DOI: 10.24075/brsmu.2024.064

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Osikov MV, Efros LA, Zhuravleva LYu, Fedosov AA

Diabetes mellitus (DM) is one of the major factors contributing to the development and aggravation of chronic kidney disease (CKD). The accurate and convenient markers for early detection, estimation of progression, and adequate control of CKD therapy in individuals with DM are limited to glomerular filtration rate (GFR) and albuminuria. Given the role of chronic inflammation in the pathogenesis of DM and CKD, the study aimed to assess indicators of inflammation and the correlation of those with GFR in patients with type 1 DM (T1D) and early stage CKD. The study involved healthy individuals (n = 14), patients with T1D showing no signs of CKD (n = 30), as well as patients with T1D and stage 1 CKD (n = 60), stage 2 CKD (n = 38), and stage 3 CKD (n = 31). GFR was calculated using the formula СКD-ЕРI (eGFR); serum levels of IL1β and TNFα, C-reactive protein (CRP), and ceruloplasmin (CP) were determined by enzyme immunoassay; the neutrophil-to-lymphocyte index and the leukocyte intoxication index (LII) were calculated. It has been found that serum concentrations of IL1β, TNFα, CRP, and CP are elevated; LII and the neutrophil-to-lymphocyte index are increased. The inflammation and acute phase response severity progresses and reaches its maximum in stage 3b CKD, when the serum concentration of IL1β is increased 2.4-fold (р = 0.042), TNFα concentration by 34% (р = 0.005), CRP concentration 33-fold (р < 0.000), CP concentration by 73% (р = 0.008), LII 8.4-fold (р < 0.000), neutrophil-to-lymphocyte index 5-fold (р = 0.013). The integral kidney function indicator, eGFR, decreases with increasing serum levels of the above indicators. Thus, IL1β, TNFα, CRP, CP, LII, and the neutrophil-to-lymphocyte index can be considered as affordable and informative indicators for estimation of inflammation, the levels of which increase with progression of early stage CKD in patients with T1D.

Received: 2024-10-24

Published online: 2024-12-23

DOI: 10.24075/brsmu.2024.060

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VIEWS 413

Sinitsyn MV, Voskresenskaya AA, Pozdeyeva NA

Calculation of toric intraocular lenses (tIOLs) in patients after penetrating keratoplasty (PK) is challenging. The study aimed to perform comparative retrospective analysis of various methods for calculation of tIOL during phacoemulsification in patients after PK. We analyzed case reports of 36 eyes (36 patients) after PK, which underwent phacoemulsification with tIOL implantation. All tIOLs were recalculated using four different methods. In group 1, tIOL calculation was performed using keratometry data of the anterior surface of the corneal graft measured using a corneal topographer, and the posterior surface of the corneal graft measured using optical coherence tomography of the cornea or the Scheimpflug keratotopographer. In group 2, keratometry of both corneal graft surfaces was measured using the Scheimpflug keratotopographer, in group 3 — using OCT of the cornea, in group 4 — using the keratotopographer. The online Barrett True — K Toric Calculator was used to calculate tIOLs in groups 1–3, and The Kane Formula was used in group 4. There were significant differences in the values of the spherical and cylindrical components of refraction between the studied groups (p < 0.05). The highest predictability of tIOL calculation was reported for group 1: the ensured postoperative refraction for the spherical component was within ±0.5 D in 58% of eyes, within ±1.0 D in 67% of eyes; postoperative refraction for the cylindrical component was within –0.5 D in 56% of eyes, within ‒1.0 D in 89% of eyes. Thus, the highest predictability of tIOL calculation is observed in patients of group 1.

Received: 2024-11-11

Published online: 2024-12-22

DOI: 10.24075/brsmu.2024.063

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Burmenskaya OV, Trofimov DYu, Kometova VV, Rodionova MV, Rodionov VV

Today, preoperative hormone therapy is a standard procedure in the context of treatment of ESR+/HER2-negative early-stage breast cancer. Transcription profiles of genes helps make assessment of effectiveness of this therapy more accurate. This study aimed to investigate the changes in gene expression caused by the preoperative aromatase inhibitor response test in postmenopausal women with ESR+/HER2-negative breast cancer. The participants were 100 breast cancer patients treated at the Department of Breast Pathology of Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology. We did a pathomorphological study of FFPE blocks (trephine biopsied before the hormone response test was prescribed) and intraoperative samples, and immunohistochemical (Ki67, ER, PR, HER2/neu) and molecular genetic studies of 45 target genes (quantitative RT-PCR). Aromatase inhibitors in the preoperative hormone response test caused significant changes in the mRNA expression of 37 genes in breast tumors: for 35 of them (ESR1, PGR, AR, ERBB2, FGFR4, MKI67, MYBL2, CCNB1, AURKA, BIRC5, CCND1, CCNE1, CDKN2A, KIF14, PPP2R2A, PTTG1, TMEM45B, TPX2, ANLN, MMP11, CTSL2, EMSY, PAK1, BCL2, BAG1, PTEN, TYMS, EXO1, UBE2T, NAT1, SCGB2A2, GATA3, FOXA1, ZNF703, CD274/PD-L1) the level was decreased, and for 2 genes it increased (SFRP1, KRT5). The results of this study can be used in the development of a hormone sensitivity test and personification of adjuvant systemic treatment for breast cancer patients.

Received: 2024-11-08

Published online: 2024-12-21

DOI: 10.24075/brsmu.2024.059

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Andreevskaya SN, Smirnova TG, Chernousova LN, Larionova EE, Sevastyanova EV, Ustinova VV, Kiseleva EA, Ergeshov A

As M. tuberculosis strains develop resistance to fluoroquinolones, pools of M. tuberculosis sensitive to drugs of this group and pools of M. tuberculosis with different resistance determinants can simultaneously coexist in the host organism. The goal of this research was to run an in vitro investigation of growth characteristics of M. tuberculosis strains which have different genetic determinants of resistance to fluoroquinolones, in the setting of competition for nutrients. The research used five clinical strains of multidrug-resistant M. tuberculosis differing in gyrA structure. Strains were cultured in pairs and individually under optimal conditions (Middlebrook 7H9 medium) and under conditions of multistress (50% Middlebrook 7H9 medium, 2 mM KNO2, 0.02% H2O2). The experiment took 21 days. The number of cells of each co-cultured strain was estimated from calibration curves. These curves showed the dependence of the threshold cycle of the polymerase chain reaction — respective to the channel targeted by the mutation — on the concentration of M. tuberculosis cells. The competitive fitness value and specific growth rate were calculated from the number of cells of each strain when co-cultured. M. tuberculosis strains with mutations in gyrA were found to be inferior in growth rate to the wild-type gyrA strain, which was particularly pronounced under multistress conditions. The strain with the most common gyrA_D94G mutation had the lowest growth rate of all strains examined. It has been hypothesised that the slow growth of M. tuberculosis with this mutation may lead to tolerance to anti-tuberculosis drugs, and as a result, the strain gains an advantage under chemotherapy conditions compared to other gyrA mutant variants.

Received: 2024-11-05

Published online: 2024-12-19

DOI: 10.24075/brsmu.2024.058

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VIEWS 366