Multidrug Regimens Research Articles

Re-Evaluation of Combinational Efficacy and Synergy of the Italian Protocol In Vitro: Are We Truly Optimizing Benefit or Permitting Unwanted Toxicity?

Introduction: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, with very poor prognosis as a majority of the patients have advanced disease at the time of diagnosis. Currently, adjuvant therapy for most patients consists of either mitotane (M) alone or in combination with multi-drug chemotherapeutics such as etoposide (E), doxorubicin (D), and cisplatin (P), known as the Italian protocol (IP; EDPM). This multi-drug treatment regimen, however, carries significant toxicity potential for patients. One way to improve toxicity profiles with these drugs in combination is to understand where their synergy occurs and over what dosing range so that lower dose regimens could be applied in combination with equal or improved efficacy. We hypothesize that a better understanding of the synergistic effects as well as the regulation of steroidogenic enzymes during combination therapy may provide more optimized combinational options with good potency and lower toxicity profiles. Methods: Two human ACC cell lines, NCI-H295R (hormonally active) and SW13 (hormonally inactive), were grown in 2D culture in appropriate growth medium. The viability of the cells after treatment with varying concentrations of the drugs (E, D, and P) either alone or in combinations with M was determined using the CellTiter Glow assay after 72 h, and the combination index for each was calculated using Compusyn by the Chou–Talalay method. The expression levels of enzymes associated with steroidogenesis were evaluated by RT-PCR in NCI-H295R. Results: When both cell lines were treated with M (ranging 25–50 μM), +E (ranging 18.75–75 μM), and +D (ranging 0.625–2.5 μM) we observed a synergistic effect (CI < 1) with potency equivalent to the full Italian protocol (IP), whereas combining M + P + D had an antagonistic effect (CI > 1) indicating the negative effect of adding cisplatin in the combination. Comparing the hormonally active and inactive cell lines, M + P + E was antagonistic in NCI-H295R and synergistic in SW13. Treatment of NCI-H295R cells with antagonistic combinations (M + P + D, M + P + E) resulted in a significant decrease in the levels of steroidogenic enzymes STAR, CYP11A1, and CYP21A2 compared to IP (p < 0.05) while M + E + D resulted in increased expression or no significant effect compared to IP across all genes tested. Conclusions: The synergistic effect for M + E + D was significant and equivalent in potency to the full IP in both cell lines and resulted in a steroidogenic gene expression profile similar to or better than that of full IP, warranting further evaluation. Future in vivo evaluation of the combination of M + E + D (with removal of P from the IP regimen) may lower toxicity while maintaining anticancer efficacy in ACC.

Management dilemmas in Nocardia brain infection.

Brain nocardiosis is a rare but severe infection mostly occurring among immunocompromised patients. In this review, we present recent data on this infection and address some of the common clinical dilemmas encountered in patients with brain nocardiosis. Strategies used to approach a patient with suspected brain nocardiosis include the 'conservative strategy' (without early neurosurgery) and the 'neurosurgical strategy' (with early aspiration or excision of brain abscess[es]). The advantages and disadvantages of both strategies are summarised. Our opinion is that the use of the 'conservative strategy' should be limited to well-selected patients presenting with an easily accessible extra-neurological lesion(s) and have brain abscesses at low risk of treatment failure. In terms of antimicrobial therapy, we summarise the data supporting the use of a multidrug regimen in patients with brain nocardiosis.Last, we list possible reasons for treatment failure in patients with brain nocardiosis and suggest interventions to overcome them. Literature is scarce regarding brain nocardiosis, as a consequence of the rarity of this disease. A multidisciplinary and individualised management is required to optimise the outcome of patients with brain nocardiosis.

Pure Neuritic Leprosy with Bilateral Foot Drop and Central Nervous Involvement: A Clinical, Electrophysiological, and MR Correlation.

Central nervous system (CNS) involvement in leprosy is sparsely documented. Neurophysiological tests and magnetic resonance imaging (MRI) helps in demonstrating CNS involvement in the patient of pure neuritic leprosy. To demonstrate CNS involvement in pure neuritic leprosy. Detailed clinical presentation and skin lesions were evaluated. Sural nerve biopsy, MRI diffusion tensor imaging of spinal cord and optic nerve were performed. Visual evoked potential and tibial somatosensory evoked potential were done. Their clinical, electrophysiological, and MRI were done at follow-up visits. We report three patients of pure neuritic leprosy with bilateral foot drop as the initial presentation. MRI T2W sequence of cervico dorsal cord showed dorsal column hyperintensity in two patients. Diffusion-weighted MR revealed decrease fractional anisotropy and an increase in the apparent diffusion coefficient. Similar findings were also noted in the optic nerves. The patients were managed with multidrug therapy multibacillary regimen and steroid in tapering dose. At follow-up, they showed clinical improvement in vision and power of ankle dorsiflexor. Patients of pure neuritic leprosy may manifest with bilateral foot drop with the involvement of posterior column and cranial nerves.

Abstract P133: Prevalence Of Medication Non-adherence Via Therapeutic Drug Monitoring In Patients With Uncontrolled Hypertension Treated At A Safety Net Hospital

Background: Medication nonadherence presents one of the greatest challenges to hypertension management. Previous studies from our group have shown therapeutic drug monitoring (TDM), biochemical monitoring of drug levels, is more accurate than self-report, detailed questionnaires, or prescription fill rate in detecting nonadherence. Prior studies have also shown a prevalence of nonadherence from 45% to 80% among insured patients with uncontrolled hypertension despite having been prescribed a multi-drug regimen. Previous studies have not assessed adherence to antihypertensive drugs in a safety net population by TDM. Methods: We performed a cross-sectional study in patients with uncontrolled hypertension in the primary care Internal Medicine and Cardiology Clinics at Parkland Health&amp; Hospital System (PHHS). Patients with BP of 130/80 mmHg, prescribed ≥2 antihypertensive medications, and self-reporting medication adherence were enrolled after informed consent. Plasma samples were obtained for measurement of 44 cardiovascular drugs using liquid chromatography mass spectrometry. Results: Among 77 patients with uncontrolled hypertension (57% female, 65% Black, 12% Hispanic), 13 (17%) were nonadherent to at least one anti-hypertensive drug by TDM. There was no difference in baseline characteristics between the two groups. The adherent and nonadherent groups had similar systolic (146±13 vs 148±18, p=0.67) and diastolic (83±9 vs 88±10 mmHg, p=0.13) BP. All patients had either medical insurance or some form of prescription financial assistance. 15 patients had prescription financial assistance, while 62 patients had medical insurance. Nonadherence rates for patients on financial assistance programs did not significantly differ from patients with medical insurance (13% vs 18%, p&gt;0.999). Conclusions: We found a surprisingly low prevalence of anti-hypertensive medication nonadherence in this uncontrolled hypertension population despite many barriers to treatment. Our study suggests a lesser role of medication nonadherence in uncontrolled hypertension in the safety net population.

Vincristine in Combination Therapy of Cancer: Emerging Trends in Clinics.

Simple SummaryVincristine is a vinca alkaloid naturally occurring in Catharanthus roseus. It belongs to antimitotic compounds, which arrest the cell cycle via disrupting microtubule dynamics. This property makes vincristine a useful compound in anticancer therapies, however, due to its unspecific biological action, vincristine causes severe side effects, mainly neurotoxicity. Nevertheless, at low concentrations, it is still a beneficial and widely used drug in combinatorial regimens of cancer treatment. Most commonly, it is administered with cyclophosphamide, doxorubicin, and prednisone but also with methotrexate or procarbazine, and dacarbazine. Currently, anticancer research focuses on targeted therapies and the development of antibodies specific to cancer cells. An example of such a drug combination broadly used in clinics is vincristine and rituximab, an antibody binding cancer cell surface receptor CD20. Combining vincristine with monoclonal antibodies is an emerging approach, which has been currently evaluated in clinical trials. This review article reports on the most commonly used vincristine-based drug combinations and summarizes currently running clinical trials. The number of ongoing studies shows that vincristine has its stable place in anticancer therapies and despite all its limitations, it has remained an essential part of anticancer therapies.Treatment of blood malignancies and other cancer diseases has been mostly unfeasible, so far. Therefore, novel treatment regimens should be developed and the currently used ones should be further elaborated. A stable component in various cancer treatment regimens consists of vincristine, an antimitotic compound of natural origin. Despite its strong anticancer activity, mostly, it cannot be administered as monotherapy due to its unspecific action and severe side effects. However, vincristine is suitable for combination therapy. Multidrug treatment regimens including vincristine are standardly applied in the therapy of non-Hodgkin lymphoma and other malignancies, in which it is combined with drugs of different mechanisms of action, mainly with DNA-interacting compounds (for example cyclophosphamide), or drugs interfering with DNA synthesis (for example methotrexate). Besides, co-administration of vincristine with monoclonal antibodies has also emerged, the typical example of which is the anti-CD20 antibody rituximab. Although in some combination anticancer therapies, vincristine has been replaced with other drugs exhibiting lesser side effects, though, in most cases, it is still irreplaceable. This is strongly evidenced by the number of active clinical trials evaluating vincristine in combination cancer therapy. Therefore, in this article, we have reviewed the most common cancer treatment regimens employing vincristine and bring an overview of current trends in the clinical development of this compound.

Drug resistance against 5-fluorouracil and cisplatin in the treatment of head and neck squamous cell carcinoma: A systematic review.

Head and neck cancers are highly prevalent worldwide. Most of these lesions are diagnosed in the advanced stages of the disease. Thus, they do not often have a good long-term prognosis. Like other cancer types, head and neck cancers are managed by surgery, radiotherapy, and chemotherapy. Despite significant advances in the treatment of oral squamous cell carcinoma (OSCC), physicians encounter several challenges in the course of treatment. Various mechanisms mediate the clinical responses of a certain cancer to medications. Thus, efficient treatment planning requires adequate knowledge about the genes involved in drug resistance and the evaluation of the frequency percentage of resistance. Several studies have evaluated the causes and frequency percentages of 5-fluorouracil (5-FU) and cisplatin resistance. In this systematic review, all the relevant articles published until November 30, 2019, were retrieved from the Scopus, Embase, Medline, ISI, Web of Science, and Cochrane databases using certain MeSH and EMTTree keywords. A total of 2164 articles were retrieved of which, 18 were included in the review since they had reported the frequency percentages of drug resistance. Of all, 10 articles had evaluated cisplatin (1317 samples). A meta-analysis of the results revealed a frequency of 33% for cisplatin resistance. Eight studies had evaluated 5-FU (476 samples). A meta-analysis of the results revealed a frequency of 40.2 % for 5-FU resistance. Overcoming cisplatin resistance or 5-FU resistance can significantly enhance recovery in advanced HNSCC. Attempts should be made to eliminate the cause and use multi-drug regimens to increase the success rate of treatment.

The role of autologous stem-cell transplantation in multiple myeloma in 2021.

In this review, we discuss the most important aspects of the role of high-dose melphalan (HDM) and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM). Almost 40 years after the publication of the first study on safety and efficacy of HDM and ASCT in MM patients, and despite the introduction of several drugs and combinations with various targets on the plasma cell and the surrounding microenvironment, HDM-ASCT still stands as a standard of care for the upfront treatment of newly diagnosed MM patients. Indeed, all attempts to replace HDM-ASCT with novel-agent-based, non-transplant strategies have failed to demonstrate their efficacy, at least in terms of progression-free survival. Despite such a long history in MM, a number of open issues regarding HDM-ASCT still exist, from the choice between using transplant in first-line therapy or at relapse to the use of tandem HDM-ASCT in high-risk patients. With the introduction of more and more effective multidrug regimens and of novel immunotherapeutic approaches, the challenge between transplant and non-transplant is not over yet.

Outcomes of Resectional Thoracic Surgery for the Treatment of Pulmonary Nontuberculous Mycobacterial Disease in 105 Patients in the United States

Outcomes of Resectional Thoracic Surgery for the Treatment of Pulmonary Nontuberculous Mycobacterial Disease in 105 Patients in the United States

Spectrum of anti tubercular therapy induced cutaneous adverse drug reactions and its management through rechallenge: A prospective study at a Tertiary Care Centre

IntroductionThe use of multi-drug regimens including 1st and 2nd line anti tubercular drugs in management of tuberculosis (TB) has been associated with undesirable adverse drug reactions including cutaneous one. Re-challenge remains the only option to restart the safe therapy and combat the tuberculous infection simultaneously. Materials and methodologyThis cross-sectional study was conducted via prospective review of outpatients as well as indoor patients who presented with cutaneous adverse drug reactions to ATT between March 2020 and March 2021. Data were analysed regarding demographic profile, site of TB, ATT regimen, pattern of cutaneous lesions, offending drugs, past history of drug allergy, and reinstitution of ATT after re-challenge. ResultsOut of total 56 registered tubercular patients presented with cutaneous adverse drug reaction 30 were females (53.57%). The most common site of TB was pulmonary followed by cervical lymph node TB. The three most common adverse drug reaction detected were maculopapular rash 32 (57.1%) followed by lichenoid drug eruptions in 6 (10.7%) and urticaria in 2 (3.6%). Ethambutol was found to be common offending drug followed by other first line anti-tubercular drugs. 5 patients developed multiple drug hypersensitivity on re-challenging and have to introduce steroids along with ATT. ConclusionAdverse cutaneous drug reactions to ATT is like a double-edged sword as stopping ATT and starting treatment with systemic steroids can further flare up the infection with increased risk of disseminated and multidrug resistant tuberculosis. Re-challenge was found out to be safest way in identifying culprit drug and hence to restart a safer alternate ATT regimen for better management.

Clinical outcomes among patients with tuberculous meningitis receiving intensified treatment regimens.

SETTING: National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.OBJECTIVE: To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent.DESIGN: Prospective cohort of patients aged ≥16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed.RESULTS: Among 77 patients with median follow-up time of 363 days (IQR 269-374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively.CONCLUSION: Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.

Modulation of Quorum Sensing and Biofilms in Less Investigated Gram-Negative ESKAPE Pathogens.

Pathogenic bacteria have the ability to sense their versatile environment and adapt by behavioral changes both to the external reservoirs and the infected host, which, in response to microbial colonization, mobilizes equally sophisticated anti-infectious strategies. One of the most important adaptive processes is the ability of pathogenic bacteria to turn from the free, floating, or planktonic state to the adherent one and to develop biofilms on alive and inert substrata; this social lifestyle, based on very complex communication networks, namely, the quorum sensing (QS) and response system, confers them an increased phenotypic or behavioral resistance to different stress factors, including host defense mechanisms and antibiotics. As a consequence, biofilm infections can be difficult to diagnose and treat, requiring complex multidrug therapeutic regimens, which often fail to resolve the infection. One of the most promising avenues for discovering novel and efficient antibiofilm strategies is targeting individual cells and their QS mechanisms. A huge amount of data related to the inhibition of QS and biofilm formation in pathogenic bacteria have been obtained using the well-established gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa models. The purpose of this paper was to revise the progress on the development of antibiofilm and anti-QS strategies in the less investigated gram-negative ESKAPE pathogens Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter sp. and identify promising leads for the therapeutic management of these clinically significant and highly resistant opportunistic pathogens.

Reductive Power Generated by Mycobacterium leprae Through Cholesterol Oxidation Contributes to Lipid and ATP Synthesis.

Upon infection, Mycobacterium leprae, an obligate intracellular bacillus, induces accumulation of cholesterol-enriched lipid droplets (LDs) in Schwann cells (SCs). LDs are promptly recruited to M. leprae-containing phagosomes, and inhibition of this process decreases bacterial survival, suggesting that LD recruitment constitutes a mechanism by which host-derived lipids are delivered to intracellular M. leprae. We previously demonstrated that M. leprae has preserved only the capacity to oxidize cholesterol to cholestenone, the first step of the normal cholesterol catabolic pathway. In this study we investigated the biochemical relevance of cholesterol oxidation on bacterial pathogenesis in SCs. Firstly, we showed that M. leprae increases the uptake of LDL-cholesterol by infected SCs. Moreover, fluorescence microscopy analysis revealed a close association between M. leprae and the internalized LDL-cholesterol within the host cell. By using Mycobacterium smegmatis mutant strains complemented with M. leprae genes, we demonstrated that ml1942 coding for 3β-hydroxysteroid dehydrogenase (3β-HSD), but not ml0389 originally annotated as cholesterol oxidase (ChoD), was responsible for the cholesterol oxidation activity detected in M. leprae. The 3β-HSD activity generates the electron donors NADH and NADPH that, respectively, fuel the M. leprae respiratory chain and provide reductive power for the biosynthesis of the dominant bacterial cell wall lipids phthiocerol dimycocerosate (PDIM) and phenolic glycolipid (PGL)-I. Inhibition of M. leprae 3β-HSD activity with the 17β-[N-(2,5-di-t-butylphenyl)carbamoyl]-6-azaandrost-4-en-3one (compound 1), decreased bacterial intracellular survival in SCs. In conclusion, our findings confirm the accumulation of cholesterol in infected SCs and its potential delivery to the intracellular bacterium. Furthermore, we provide strong evidence that cholesterol oxidation is an essential catabolic pathway for M. leprae pathogenicity and point to 3β-HSD as a prime drug target that may be used in combination with current multidrug regimens to shorten leprosy treatment and ameliorate nerve damage.

Effect of Dosage Reduction of Hypoglycemic Multidrug Regimens on the Incidences of Acute Glycemic Complications in People With Type 2 Diabetes Who Fast During Ramaḍān: A Randomized Controlled Trial

ObjectiveWe aimed to investigate the effect of dosage reduction of four hypoglycemic multidrug regimens on the incidences of acute glycemic complications in people with type 2 diabetes who fast during Ramaḍān.MethodsWe conducted an open-label, parallel-group, randomized controlled trial at a tertiary care center in Amman, Jordan. We recruited adults with type 2 diabetes who expressed an intention to fast during Ramaḍān and were adherent to one of four regimens—namely: metformin and glimepiride; metformin and vildagliptin; metformin and insulin glargine U100; or, metformin, insulin glargine U100, and human regular insulin. We randomly assigned participants in a 2:1 ratio to low- or regular-dosage therapy. The primary outcomes were the incidences of hypoglycemia and hyperglycemia during the 29 days of Ramaḍān 2017, and the secondary outcomes were the incidences of diabetic ketoacidosis and hyperosmolar hyperglycemic state during the same period.ResultsWe randomly assigned 687 participants to low-dosage therapy (n = 458) or regular-dosage therapy (n = 229) and included 678 (452 and 226, respectively) in the final analysis. The incidence of hypoglycemia was lower in the low-dosage group compared with the regular-dosage group (19 [4.2%] vs. 52 [23.0%], respectively; OR, 0.15 [95% CI, 0.08–0.26]; P < 0.001). The incidence of hyperglycemia did not differ between the low- and regular-dosage groups (319 [70.6%] vs. 154 [68.1%], respectively; OR, 1.12 [95% CI, 0.79–1.58]; P = 0.5). No participants experienced diabetic ketoacidosis or hyperosmolar hyperglycemic state. Each 1% decrease in the baseline HbA1c concentration was associated with a 19.9-fold (95% CI, 9.6–41.5; P < 0.001) increase in the odds of hypoglycemia, and each 1% increase in the baseline HbA1c concentration was associated with a 15.7-fold (95% CI, 10.0–24.6; P < 0.001) increase in the odds of hyperglycemia.ConclusionDosage reduction decreases the incidence of hypoglycemia without a concomitant increase in the incidences of hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state in people with type 2 diabetes who fast during Ramaḍān.Clinical Trial Registration www.ClinicalTrials.gov, identifier NCT04237493.

Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb’s differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host’s antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.

Vulvar pseudotumoral acyclovir-resistant herpes in an HIV-negative, non-immunosuppressed patient: A therapeutic challenge.

BackgroundVulvar pseudotumoral herpes infections have been reported in HIV-positive patients. A 32-year-old HIV-negative woman presented with a 6-month history of a vulvar pseudotumor that had been unresponsive to oral acyclovir and valacyclovir, as well as topical imiquimod.ObjectiveThis study aimed to evaluate the therapeutic efficacy of a multidrug regimen for vulvar pseudotumor herpes infection in an HIV-negative patient.MethodsHistology revealed multinucleated giant cells, consistent with a herpes infection. The patient's herpes simplex virus type 2 was resistant to acyclovir. Immunomodulatory agents (thalidomide and topical imiquimod) were started.ResultsThe lesion enlarged after 6 weeks of treatment. Topical cidofovir 1% gel was added. There was gradual decrease in the pseudotumor size. After 7 months, the Pseudotumor had resolved.ConclusionThis is the first reported case of vulvar pseudotumoral herpes in an immunocompetent, HIV-negative patient. Oral thalidomide, in association with topical imiquimod and topical cidofovir, was effective in treating acyclovir-resistant pseudotumoral herpes of the vulva.

All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings.

Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen. Patients with a positive baseline culture were included. 6-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods. Culture conversion was observed in 83.8% (526 out of 628) of patients receiving an all-oral regimen and 85.5% (425 out of 497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95% CI 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients. Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.

Personalized prediction of overall survival in patients with AML in non-complete remission undergoing allo-HCT.

Allogenic hematopoietic stem cell transplantation (allo‐HCT) is the standard treatment for acute myeloid leukemia (AML) in non‐complete remission (non‐CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non‐CR AML undergoing allo‐HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo‐HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266–0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia‐free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c‐indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi‐drug conditioning regimens in patients undergoing CBT.

Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents

The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including initial viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic anti-blood clotting agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found hydroxychloroquine-based multidrug regimens were associated with a statistically significant > 60% reduction in mortality. Going forward, we conclude that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients e.g. LTF or ALF) has a reasonable probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus prior to symptoms worsening. Given the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of acute COVID-19 patients is a reasonable strategy to reduce the risks of hospitalization and death. If elderly high-risk patients in such congregated nursing home type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. The issue is timing of therapeutics, and we argue that early treatment before hospitalization, is the right time and can potentially save lives, especially among our higher-risk elderly populations hit hardest by severe illness and death from COVID-19. We must reiterate, we are talking about ‘early’ treatment before the disease is far along in the disease sequelae where the patient then needs hospitalization and aggressive interventions. We are referring to the initial days e.g. day one, post infection when symptoms emerge or there is strong clinical suspicion. This early therapeutic option deserves serious and urgent consideration by the medical establishment and respective decision-makers. Doctors must be allowed their clinical discretion in how they optimally treat their patients. Doctors must be brave and trust their skilled judgements and do all to save the lives of their patients.We therefore hypothesize that early outpatient ambulatory treatment, once initiated as soon as symptoms begin in high-risk positive persons, would significantly reduce hospitalizations and prevent deaths. Specifically, the provision of early multi-drug sequenced therapy with repurposed drugs will reduce hospitalization and death in elderly patients being cared for in long-term-care facilities.The most important implications of our hypothesis are: 1) hospitalizations and deaths would be reduced 2) transmission would be reduced due to the mitigation of symptoms and 3) recovery following infection and treatment provides for natural exposure immunity that is broad based, durable, and robust (helping towards natural immunity within the population). The end result is reduced strain on hospitals and systems that would allow for other non-COVID illnesses to receive care.

Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date.

Tuberculosis (TB) is the most deadly infectious disease globally. Although most individuals achieve a cure, a substantial portion develop multi-drug resistant TB which is exceedingly difficult to treat, and the number of effective agents is dwindling. Development of new anti-tubercular medications is imperative to combat existing drug resistance and accelerate global eradication of TB. Pretomanid (PA-824) represents one of the newest drug classes (ie, nitroimidazooxazines) approved in 2019 by the United States Food and Drug Administration as part of a multi-drug regimen (with bedaquiline and linezolid, BPaL) and recommended by the World Health Organization (WHO) to treat extensively-resistant (XR-TB) and multi-drug resistant tuberculosis (MDR-TB). Approval was granted through the FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs, which accelerates approval for antimicrobial drugs used to treat life-threatening or serious infections in a limited population with unmet need. This review details the pharmacology, efficacy, and safety of this new agent and describes evidence to date for its role in the treatment of drug resistant TB including published, ongoing, and planned studies.

Pharmacist-Managed Helicobacter pylori Treatment Service Within a Gastroenterology Clinic: Workflow and Real-World Experiences.

Treatment eradication rates of Helicobacter pylori, a gastrointestinal infection, are 70% to 90% in clinical studies but lower in real-world settings. Potential barriers include multidrug regimen complexity or prescribing/administration errors. A pharmacist-managed H pylori treatment service was implemented to address these barriers and optimize treatment outcomes. The clinical pharmacist provided 2 services: (1) treatment education and monitoring for treatment-naïve patients and (2) treatment initiation, education, and monitoring for treatment-experienced patients. We aimed to evaluate the impact of a pharmacist-managed H pylori treatment service within a gastroenterology clinic. We conducted a retrospective observational cohort study of all patients referred to and seen in the pharmacist-managed H pylori treatment service from July 10, 2019, to December 31, 2020. Patient demographics, prior treatment history, course(s) of treatment prescribed, frequency of follow-ups, and outcomes posttreatment were collected. The clinical pharmacist managed 60 referrals for 55 unique patients over a mean of 5 ± 2 visits. Five patients failed H pylori treatment and were re-referred. Identified barriers included prescribing/dispensing and administration errors. Posttreatment, 38 referrals tested for H pylori eradication, of which 100% of treatment-naïve patients and 69% of treatment-experienced patients were cured, and 13 (22%) referrals were lost to follow-up. This study described and assessed the impact of a pharmacist-managed H pylori treatment service in a gastroenterology clinic, in which various barriers were effectively addressed to optimize treatment outcomes. Future studies should focus on long-term outcome, impact on health care costs, and patient satisfaction with this service.