Long-term Combination Therapy Research Articles

The synergistic effect between phages and Ceftolozane/Tazobactam in Pseudomonas aeruginosa endotracheal tube biofilm Applying phages to control endotracheal tube biofilm

ABSTRACT Although an increased effectiveness has been suggested when phages and antibiotics are combined, this approach has not been tested against a mature biofilm on an endotracheal tube (ETT) surface. This study evaluated the effect of short- and long-term combined phage-antibiotic therapy in a control of a mature biofilm on an ETT surface. Pseudomonas aeruginosa strains, including susceptible and resistant clinical samples, were used to develop the ETT biofilm. Biofilm was treated with 108PFU/mL of phage_2, phage_18 or 5 μg/mL of ceftolozane/tazobactam, alone or in combination with phages. The sequential combination of the two different phages and ceftolozane/tazobactam was also tested. Biofilm viability was assessed after short (2, 4, 24 h) and long-(48, 72 h) term treatment exposure using colony forming unit measurement. For long-term exposition, a new treatment shot was added every 24 h. In the sequential combination, the phage type was switched at 24 h of treatment. Regarding the susceptible strains, the treatments had limited antibiofilm effect after 2, 4 and 24 h. After 48 and 72 h, administering phages alone had no effect on biofilm viability, indicating the emergence of phage-resistant phenotypes. Nonetheless, the combined phage-antibiotic treatment reduced the biofilm viability in about 5-log, whilst antibiotic alone reduced in about 3-log. The sequential combination of phages and antibiotic reduced the biofilm viability in about 6-log. With respect to the resistant strains, no antibiofilm activity was observed regarding the treatment arms. The combination of phages and ceftolozane/tazobactam showed a synergism strain-dependent, being more apparent in susceptible strains.

Comparative effects of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors on heart failure with preserved ejection fraction in diabetic patients: a meta-analysis

BackgroundHeart failure with preserved ejection fraction (HFpEF) is common in type 2 diabetes mellitus (T2D), leading to high morbidity and mortality. Managing HFpEF in diabetic patients is challenging with limited treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown potential cardiovascular benefits. This meta-analysis compares the effects of GLP1-RA and SGLT2 inhibitors on HFpEF in T2D patients.MethodsWe conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating GLP1-RA and SGLT2 inhibitors’ impact on HFpEF in T2D patients. Databases searched included PubMed, MEDLINE, and Cochrane Library up to July 2024. Primary outcomes were changes in left ventricular ejection fraction (LVEF), myocardial fibrosis (extracellular volume fraction, ECV), and functional capacity (6-minute walk test, 6MWT). Secondary outcomes included HbA1c, body weight, and systolic blood pressure (SBP). ResultsTwelve studies with 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774) were included. Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo (GLP1-RA: mean difference [MD] 2.8%, 95% confidence interval [CI] 1.5 to 4.1, p < 0.001; SGLT2 inhibitors: MD 3.2%, 95% CI 2.0 to 4.4, p < 0.001). SGLT2 inhibitors significantly reduced myocardial fibrosis (MD -3.5%, 95% CI -4.2 to -2.8, p < 0.001) more than GLP1-RA (MD -2.3%, 95% CI -3.0 to -1.6, p < 0.001). Functional capacity improved significantly with both treatments (GLP1-RA: MD 45 m, 95% CI 30 to 60, p < 0.001; SGLT2 inhibitors: MD 50 m, 95% CI 35 to 65, p < 0.001). Secondary outcomes showed reductions in HbA1c (GLP1-RA: MD -1.1%, 95% CI -1.4 to -0.8, p < 0.001; SGLT2 inhibitors: MD -1.0%, 95% CI -1.3 to -0.7, p < 0.001) and body weight (GLP1-RA: MD -2.5 kg, 95% CI -3.1 to -1.9, p < 0.001; SGLT2 inhibitors: MD -2.0 kg, 95% CI -2.6 to -1.4, p < 0.001). Both treatments significantly lowered SBP (GLP1-RA: MD -5.2 mmHg, 95% CI -6.5 to -3.9, p < 0.001; SGLT2 inhibitors: MD -4.8 mmHg, 95% CI -6.0 to -3.6, p < 0.001).ConclusionsGLP1-RA and SGLT2 inhibitors significantly benefit HFpEF management in T2D patients. SGLT2 inhibitors reduce myocardial fibrosis more effectively, while both improve LVEF, functional capacity, and metabolic parameters. These therapies should be integral to HFpEF management in diabetic patients. Further research is needed on long-term outcomes and potential combined therapy effects.

Pharmacotherapy with alpha-1 adrenergic blockers and lipid spectrum correction in patients with urinary disorders

The study was based on treatment outcomes in a group of 130 patients aged 18–81 years. Subgroups were formed according to gender and age criteria, which included 56 men and 74 women, and were also divided into subgroups under 65 years of age and after 65. Treatment lasting continuously from 11 to 18 months was carried out in the form of combination therapy with the prescription of α1‑blockers (terazosin, doxazosin) in combination with vitamin-like drugs (levocarnitine, alpha-lipoic acid) in dosages according to the official instructions for the drug. The work involved systems for tabular assessment of the clinical symptoms of urinary disorders, as well as instrumental, laboratory, and statistical methods (Mann — Whitney test, Spearman's rank correlation coefficient).Results. Against the background of the prescribed treatment, HDL levels significantly changed from 1.3 to 1.38 mmol/L, as well as VLDL from 0.88 to 0.72 mmol/L in the general observation group. In some indicators, particularly total cholesterol, low-density lipoprotein, and triglycerides, no dynamics were noted. In the men subgroup, the indicators of both HDL and VLDL changed significantly and reliably from 1.2 to 1.29 mmol/L and, accordingly, from 0.79 to 0.65 mmol/L. In the 65-yearold subgroup, VLDL levels significantly decreased from 0.88 to 0.76 mmol/L and triglyceride levels from 1.9 to 1.65 mmol/L, respectively. In the subgroup of patients aged &gt;65 years, there was a significant increase in HDL from 1.29 to 1.46 mmol/L.Conclusion. Long-term combination therapy over 11 months, including alpha1 inhibitors in combination with vitamin-like drugs, significantly changed the lipid spectrum. The best outcomes of pharmacotherapy were observed in the male subgroup and in patients aged &gt;65 years.

Mycobacterium abscessus Corneal Ulcer with Conjunctival Toxicity due to Topical Amikacin

Purpose: This report presents a case of repeated toxic conjunctival necrosis caused by amikacin eye drops in a patient with a corneal ulcer induced by Mycobacterium abscessus (M. abscessus).Case summary: During treatment for herpetic keratitis with complaints of conjunctival hyperemia and eye pain in the right eye for 1 month. Slit-lamp microscopy revealed a circular corneal epithelial defect and stromal infiltration of her right eye. Gram staining and culture were performed, and eye drops were prescribed for empirical treatment. The bacterial culture grew M. abscessus. Antibiotic susceptibility tests showed resistance to quinolone. The patient was prescribed amikacin eye drops and the corneal epithelial defects improved. Two weeks later, circular conjunctival epithelial defects and hyperemia were observed on the inferior conjunctiva. Conjunctival necrosis caused by amikacin was suspected. The amikacin eye drops were discontinued and the conjunctival lesion improved. However, the patient’s corneal ulcer recurred. The amikacin eye drops were restarted, but conjunctival toxicity recurred, so she was treated with topical clarithromycin and moxifloxacin. The eye drops were gradually reduced and the lesion healed leaving mild corneal opacity.Conclusions: M. abscessus-induced keratitis resistant to quinolone antibiotics requires long-term combined therapy with multiple drugs. Amikacin eye drops should be used carefully as conjunctival toxicity may occur.

Long-term combination therapy with metformin and oxymetholone in a Fanconi anemia mouse model.

Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3weeks to 18months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=.01) and hemoglobin levels (p<.05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [Lin-Sca+c-Kit+]) was significantly increased (p=.001) by long-term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials. HIGHLIGHTS: Long-term coadministration of metformin in combination with oxymetholone is well tolerated by Fancd2-/- mice. Hematopoietic stem cell quiescence in mutant mice was enhanced by treatment with metformin alone. Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.

Long-term combined antiplatelet therapy for secondary prevention of noncardioembolic stroke

Introduction. The high risk of recurrent ischemic events after non-cardioembolic ischemic stroke(IS), the prevalence of which is 25% of all strokes in the Russian Federation, determines the need to search for effective and safe secondary prevention strategies.Аim. The study was to evaluate the efficacy and safety of a combination of ADP receptor inhibitors (dipyridamole) with acetylsalicylic acid in patients with ischemic stroke (IS) in the secondary prevention of noncardioembolic stroke.Materials and methods. 229 patients in the early recovery period of noncardioembolic IS (139 women, 90 men), with an average age of 59.0 ± 5.7 years were included in the study. The duration of IS was 54.4 ± 6.1 days. All patients received a multimodal medical rehabilitation (MMR) program. Long-term double antiplatelet therapy with acetylsalicylic acid (ASA) 75 mg per day and dipyridamole at a daily dose of 225 mg divided into 3 doses were prescribed to all the patients. The neurological and neuropsychological status of the patient, quality of life and hemorheological parameters were assessed initially (T0), after MMR (T1, 6 weeks) and 12 months after IS(T2).Results. Motor and coordination indicators of patients as well as the cognitive and emotional parameters were significantly (p &lt; 0,05) improved due to MMR technology. These were confirmed by the dynamics of the corresponding scales. The prescribed double antiplatelet therapy did not cause significant adverse events and worsening of the patients’ well-being both during the MMR process and during the observation period. The combination of ASA with dipyridamole was well tolerated. At the end of the study, recurrent IS, myocardial infarctions, and fatal bleeding were not recorded. In 5.2% patients with severe risks of cardiovascular complications there was occurred TIA. The effectiveness of the dual antiplatelet therapy was confirmed by a decrease in the level of platelet aggregation (p &lt; 0,05).Conclusions. The high effectiveness of secondary prevention of IS with a combination of ASA and dipyridamole with good tolerability and safety in patients after IS has been shown.

Atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia (using the aripiprazole model)

The review discusses aspects of the use of atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia using the model of aripiprazole, a partial agonist of dopamine receptors. According to numerous studies, aripiprazole is the drug of choice for augmentative therapy of major depressive disorder, as well as for relieving and long-term maintenance monotherapy and combination therapy of various affective episodes of bipolar affective disorder and depression in schizophrenia.

A prospective observational study on efficacy and tolerability of the drugs used in treating rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is an autoimmune disorder requiring long-term combination therapy with disease-modifying antirheumatic drugs (DMARDs), non-steroidal anti-inflammatory agents (NSAIDS), low-dose steroids, proton pump inhibitors, calcium, and folic acid and these drugs cause multitude of side effects. This study on the efficacy and tolerability of drugs used in RA among South Indian patients can guide in tailoring a treatment regimen more suited for South Indian population. Aims and Objectives: The main objective of this study was to evaluate the efficacy and tolerability of drugs used in the treatment of RA among South Indian patients. Materials and Methods: In this prospective observational study, 120 newly diagnosed RA patients attending rheumatology outpatient department in a tertiary care center in South India were recruited after obtaining Institutional Ethics Committee approval and informed consent. Sociodemographic details and baseline investigations were done. Each patient was followed up for a period of 6 months wherein, response to treatment was evaluated and adverse drug reactions (ADRs) reported were collected, analyzed and appropriate treatment was instituted. Data analysis was done using SPSS software. Results: One hundred patients completed the study. There was female preponderance (85%) and 38% were rheumatoid factor positive. Efficacy of combination therapy was evidenced falling erythrocyte sedimentation rate (P &lt; 0.001), modified health assessment questionnaire,and disease activity score 28 scorings after 1st, 3rd, and 6th month of therapy (P &lt; 0.001) and improvement in hemoglobin count (P &lt; 0.001). The number of swollen joints was also significantly reduced (P &lt; 0.001). Common ADRs reported were gastritis (29%), mucosal ulcers (10%), macrocytic anemia (3%), chloroquine-related ocular toxicity (2%). Conclusion: NSAIDS and steroids helped to achieve early remission and caused most of adverse effects. Methotrexate and chloroquine had good tolerability and were preferred DMARDs in our center. Thus, we conclude that the combination therapy used in our center is efficacious and well tolerated by South Indian population.

Combined pathogenetic therapy of erectile dysfunction

Introduction. Erectile dysfunction (ED) is a common condition that reduces the quality of life of numerous men. Therefore, optimising treatment protocols is always a challenge.Objective. To evaluate the efficacy of "Edelim®" for pathogenetic therapy for erectile dysfunction.Materials and methods. The study included 67 men (40 – 65 years old) with ED. The patients were divided into two treatment groups: the main group received tadalafil 5 mg PO o.d. + “Edelim®”, the control group received tadalafil 5 mg PO o.d. only. As effectiveness criteria anthropometric studies were used, IIEF-5 scale, metabolic profile blood tests, and systemic endothelial function was assessed.Results. Over 12 months of therapy, the IIEF-5 score increased by 28.2% in the main group and by 10.3% in the control group. After 12 months in the main group total cholesterol, LDL, triglycerides decreased by 14.8%, 10.7% and 13.9% respectively. The reactive hyperaemia index after 3, 6 and 12 months increased by 6.6%, 10.9% and 22.0%, respectively. In the control group these indices did not change significantly. The main group showed a stable decrease in body mass and waist circumference by an average of 2.6% and 3.8% respectively after 12 months. In the control group, body mass did not change significantly.Conclusion. Some patients require combination therapy to address metabolic risk factors and disorders, despite the high efficacy of PDE-5 inhibitors in improving erection quality. “Edelim®” is the first product created specifically for long-term combined pathogenetic therapy of ED with metabolic disorders.

A plain language summary of the long-term relugolix combination therapy study for uterine fibroids.

What is this summary about? This is a summary of a research study (known as a clinical trial) called the LIBERTY extension study. The LIBERTY extension study is a long-term study looking at how well a medicine called relugolix combination therapy worked in reducing blood loss during menstrual periods in women with uterine fibroids with heavy menstrual periods. Women were included in the extension study if they finished the 24-week LIBERTY 1 or LIBERTY 2 studies. Heavy menstrual periods were considered to be menstrual blood loss of about one-third of a cup of blood (80ml) per cycle for two cycles or about two-thirds of a cup of blood (160ml) during one cycle. The LIBERTY extension study also looked at whether relugolix combination therapy was safe to take for up to 1year. What were the results? Out of 770 total women with uterine fibroids with heavy menstrual bleeding who took part in the LIBERTY 1 and LIBERTY 2 studies, 476 took part in the LIBERTY extension study. From the start of the LIBERTY 1 and LIBERTY 2 studies through the end of the LIBERTY extension: 163 women took relugolix combination therapy for 52weeks 149 women took relugolix alone for 12weeks followed by relugolix combination therapy for 40weeks 164 women took placebo for 24weeks followed by relugolix combination therapy for 28weeks The LIBERTY extension study showed that most women in all three treatment groups responded to relugolix combination therapy by having less bleeding during their menstrual periods, having improved anemia symptoms, and having stable bone mineral loss. Side effects were similar across treatment groups, and the most common side effects were headaches and hot flushes. What do the results mean? Women with uterine fibroids with heavy menstrual bleeding taking relugolix combination therapy may have fewer uterine fibroid bleeding symptoms for up to 1year of treatment. Clinical Trial Registration: NCT03049735 (ClinicalTrials.gov) (LIBERTY 1) Clinical Trial Registration: NCT03103087 (ClinicalTrials.gov) (LIBERTY 2) Clinical Trial Registration: NCT03412890 (ClinicalTrials.gov) (LIBERTY extension study).

Orofacial manifestations in Brazilian people living with HIV/AIDS under long-term antiretroviral therapy: a cross-sectional study

The aim of this study was to assess the prevalence of orofacial manifestations in a Brazilian cohort of people living with HIV/AIDS (PLWHIV) using long-term combined antiretroviral therapy (cART) and to correlate the presence of these manifestations with clinical and laboratory characteristics. A cross-sectional observational study evaluated 101 Brazilian PLWHIV. Demographic characteristics, medical history, and laboratory data were collected. Physical examination and measurement of stimulated salivary flow were performed. The study included 101 participants who were mainly male (61%) and White (73%), with an average age of 48 years, using long-term cART. The most common oral manifestations were facial lipoatrophy (33%), xerostomia (30%), and salivary gland enlargement (12%). Facial lipoatrophy was linked to a longer duration of cART use (P=.002), whereas hairy leukoplakia was linked to a detectable viral load (P=.031). The salivary flow of <0.7 mL/min was associated with an HIV infection time >20 years (P=.023). People living with HIV/AIDS who use cART often experience facial lipoatrophy, xerostomia, and bilateral enlargement of the parotid glands. Although opportunistic infections and malignant neoplasms are not frequent occurrences, they can still arise.

Impact of the first-line antiretroviral therapy on soluble markers of inflammation in cohort of human immunodeficiency virus type 1 in Moroccan patients: a prospective study.

Chronic inflammation and immune activation are a hallmark of HIV-1 infection. In this study, we assessed inflammation biomarkers in a cohort of people living with HIV-1 (PLWH) before and after long-term suppressive combined antiretroviral therapy (cART). A single-center prospective cohort study was conducted to assess inflammatory biomarkers in 86 cART-naive PLWH and after receiving suppressive cART and 50 uninfected controls. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and soluble CD14 (sCD14) were measured using enzyme-linked immunosorbent assay (ELISA). No significant difference was found in IL-6 levels between cART-naïve PLWH and controls (p = 0.753). In contrast, TNF-α level showed a significant difference between cART naïve-PLWH and controls (p = 0.019). Interestingly, IL-6 and TNF-α levels were significantly decreased in PLWH after cART (p < 0.0001). The sCD14 showed no significant difference between cART-naïve patients and controls (p = 0.839) and similar levels were observed in pre- and post-treatment (p = 0.719). Our results highlight the critical importance of early treatment to reduce inflammation and its consequences during HIV infection.

Isavuconazole Breakthrough Disseminated *Fusarium fujikuroi* Infection in a Patient with Allogeneic Hematopoietic Stem Cell Transplant: Diagnostic and Therapeutic Challenges – A Case Report

# Introduction This case report illustrates the diagnostic challenges and complexities in the treatment of disseminated fusariosis. # Case An 18-year-old patient received a second allogeneic hematopoietic stem cell transplant (HSCT) 5 months after the first HSCT. Two days post-transplant, the patient presented neutropenic fever with diffuse multiple cutaneous papular lesions under isavuconazole prophylaxis. A diagnosis of disseminated fusariosis due to *Fusarium fujikoroi* was established. Antifungal therapy had to be adapted multiple times for efficacy and safety issues. Long-term combination therapy with posaconazole and terbinafine efficiently controlled the infection and was well tolerated. # Discussion This case report illustrates three major teaching points: (i) high clinical suspicion based on typical clinical and microbiologic findings is a key factor for the diagnosis of fusariosis; (ii) treatment is challenging due to variable antifungal agent minimal inhibitory concentrations (MICs); and (iii) long-term administration of voriconazole can be associated with multiple, less frequently seen adverse events. # Conclusion Typical skin lesions and positive blood cultures for molds should promptly rise suspicion of fusariosis. Amphotericin-B and voriconazole are the first-line agents for the treatment of fusariosis. Second-line agents such as posaconazole and terbinafine can be used.

Long-term field study of lispro and neutral protamine Hagedorn insulins treatment in dogs with diabetes mellitus.

The long-term clinical and biofhemical effects of basal-bolus insulin treatment with lispro and NPH in dogs with diabetes mellitus are undocumented. To perform a prospective pilot field study of the long-term effects of lispro and NPH on clinical signs and serum fructosamine concentrations (SFC) in dogs with diabetes mellitus. Twelve dogs received combined lispro and NPH insulins treatment twice a day and were examined every 2 weeks for 2 months (visits 1-4), and every 4 weeks for up to 4 additional months (visits 5-8). Clinical signs and SFC were recorded at each visit. Polyuria and polydipsia (PU/PD) were scored as absent (0) or present (1). Median (range) PU/PD scores of combined visits 5-8 (0, 0-1) were significantly lower than median scores of combined visits 1-4 (1, 0-1, p = 0.03) and at enrolment (1, 0-1, p = 0.045). Median (range) SFC of combined visits 5-8 (512mmol/L, 401-974mmol/L) was significantly lower than SFC of combined visits 1-4 (578mmol/L, 302-996mmol/L, p = 0.002) and at enrolment (662mmol/L, 450-990mmol/L, p = 0.03). Lispro insulin dose was significantly and negatively, albeit weakly, correlated with SFC concentration during visits 1 through 8 (r = -0.3, p = 0.013). Median duration of follow up was 6 months (range 0.5-6) and most dogs (8, 66.7%) were followed for 6 months. Four dogs withdrew from the study within 0.5-5 months because of documented or suspected hypoglycaemia, short NPH duration or sudden unexplained death. Hypoglycaemia was noted in 6 dogs. Long-term lispro and NPH combination therapy may improve clinical and biochemical control of some diabetic dogs with comorbidities. Risk of hypoglycaemia should be addressed with close monitoring.

Clinical outcomes of withdrawing one medication from long-term combination therapy comprising α-blocker and 5α-reductase inhibitor for benign prostatic hyperplasia.

To assess adherence to combination therapy comprising α-adrenergic blocker (AB) and 5α-reductase inhibitor (5ARI) for benign prostatic hyperplasia (BPH) in a real-world setting and whether lower urinary tract symptoms (LUTS) will relapse after discontinuing one medication from long-term combination therapy. BPH/LUTS patients receiving initial AB +5ARI combination therapy for at least 1 year between January 2012 and January 2017 were retrospectively analyzed. The patients were classified into DC-AB group (n = 65, AB discontinued) and DC-5ARI group (n = 77, 5ARI discontinued) and followed up. Clinical effects were assessed at baseline and annually using the International Prostatic Symptoms Score (IPSS), quality of life (QoL) index, total prostate volume (TPV), maximal flow rate (Qmax), and prostate-specific antigen (PSA) level. Of total 1783 patients, 809 (45.4%) patients were identified with more than 1-year combination therapy. After withdrawal of one medication from combination therapy, the TPV progression (27.6% vs. - 10.8%; P < 0.001) and the requirement for prostate surgery (14.3% vs. 6.1%; P = 0.038) were significantly higher in the DC-5ARI group than in the DC-AB group. The rate of resuming combination therapy was significantly higher in the DC-5ARI group than in the DC-AB group (38.9% vs. 23.0%; P = 0.009). Adherence to combination BPH therapy is relatively low. Although patients adhered to combination therapy for more than 1 year, a higher risk of requiring prostate surgery or resuming combination therapy was observed in patients who discontinued 5ARI.

Clinical outcomes of withdrawing one medication from long-term combination therapy comprising α-blocker and 5α-reductase inhibitor for benign prostatic hyperplasia

Clinical outcomes of withdrawing one medication from long-term combination therapy comprising α-blocker and 5α-reductase inhibitor for benign prostatic hyperplasia

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial

The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. European Union's Horizon 2020.

A Case Report on the Management of Pityriasis rubra pilaris (PRP) in Ayurveda

Pityriasis rubra pilaris (PRP) is an uncommon chronic papulosquamous illness of unknown cause. Contemporary treatments for PRP are arduous since no FDA (United States Food and Drug Administration) approved protocol exists and there is a chance of systemic toxicity by long-term combination therapy as recommended by several experts. Ayurveda can be used to treat PRP. A 51-year-old homemaker female from Delhi NCR was approached by OPD with exfoliative dermatitis, impending erythroderma, and a substantially impaired quality of life. The treatment protocol was designed with the goal of dissolving Samprapti of Pitta kapha pradhana kushtha with interventions such as Avipattikar Churna 3gm BD, Sutshekhar Rasa 250mg BD, Chandrakala Rasa 250mg BD orally and Shatdhauta Ghrita, Kailash Jeevan for topical application for around seven months along with Panchakrma therapies like Sarvang Abhyanga with Eladi oil, Bashpa Swedana, Panchatiktaksheer Basti, Shirodhara with Dashmula Siddha ksheer, and Raktamokshan. Changes in signs and symptoms and PASI (Psoriasis area severity index) scoring were used to determine the outcome. The patient reported steady improvement and total remission of cutaneous lesions after three months of treatment. The PASI score changed from 67.3 to zero, and the DLQI (Dermatology Life Quality Index) score changed from 30 to 2. After seven months, the medications were discontinued. Two years after discontinuing the medicine, no recurrences were found. This case study demonstrates the scope of further research in this field.

Successful rescue of disseminated Nocardia infection with multiple abscesses in a patient with membranous nephropathy after cardiopulmonary resuscitation: A three-year follow-up.

Nocardiosis manifests as an opportunistic infection, primarily affecting individuals who are immunocompromised and susceptible to the infection. We present a case study of one patient with nephrotic syndrome and membranous nephropathy, who underwent treatment with prednisone and cyclosporine in 2016. In early 2017, the patient was diagnosed with a "fungal infection" and discontinued the use of cyclosporine. After one month of anti-infection therapy, a cranial magnetic resonance imaging scan showed multiple abscesses in the right temporal region. The diagnosis of nocardiosis was confirmed based on the presence of metastatic abscess masses, multiple lung and brain lesions, and a positive culture of Nocardia in the drainage. We changed the anti-infection therapy to a combination of trimethoprim-sulfamethoxazole (TMP-SMX), minocycline, and voriconazole. However, the patient experienced a sudden cardiac arrest and subsequently recovered after cardiopulmonary resuscitation. During the five-month follow-up period following the discharge, the patient displayed an enhanced nutritional status and stable renal function. The focal infection ultimately resolved during the subsequent three years. Neuro-infection caused by Nocardia should be considered in immunocompromised patients, and TMP-SMX is the preferred initial therapy; however, because of the high mortality rate, a long-term combination therapy with imipenem, cefotaxime, amikacin, and TMP-SMX is suggested.

Effectiveness of Different Antimicrobial Strategies for Staphylococcal Prosthetic Joint Infection: Results From a Large Prospective Registry-Based Cohort Study

BackgroundTreatment of staphylococcal prosthetic joint infection (PJI) usually consists of surgical debridement and prolonged rifampicin combination therapy. Tailored antimicrobial treatment alternatives are needed due to frequent side effects and drug-drug interactions with rifampicin combination therapy. We aimed to assess the effectiveness of several alternative antibiotic strategies in patients with staphylococcal PJI.MethodsIn this prospective, multicenter registry-based study, all consecutive patients with a staphylococcal PJI, treated with debridement, antibiotics and implant retention (DAIR) or 1-stage revision surgery between January 1, 2015 and November 3, 2020, were included. Patients were treated with a long-term rifampicin combination strategy (in 2 centers) or a short-term rifampicin combination strategy (in 3 centers). Antimicrobial treatment strategies in these centers were defined before the start of the registry. Patients were stratified in different groups, depending on the used antimicrobial strategy. Cox proportional hazards models were used to compare outcome between the groups.ResultsTwo hundred patients were included and stratified in 1 long-term rifampicin group (traditional rifampicin combination therapy) or 1 of 3 short-term rifampicin groups (clindamycin or flucloxacillin or vancomycin monotherapy, including rifampicin for only 5 postoperative days). Adjusted hazard ratios (aHRs) for failure in patients treated with short-term rifampicin and either flucloxacillin or clindamycin were almost equal to patients treated with long-term rifampicin combination therapy (aHR = 1.21; 95% confidence interval, .34–4.40).ConclusionsA short-term rifampicin strategy with either clindamycin or flucloxacillin and only 5 days of rifampicin was found to be as effective as traditional long-term rifampicin combination therapy. A randomized controlled trial is needed to further address efficacy and safety of alternative treatment strategies for staphylococcal PJI.