Antimicrobial innovation: a current update and perspective on the antibiotic drug development pipeline

As bacteria continue to develop resistance to our existing treatment options, antibiotic innovation remains overlooked. If current trends continue, then we could face the stark reality of a postantibiotic era, whereby routine bacterial infections could once again become deadly. In light of a warning signaled by the WHO, a number of new initiatives have been established in the hope of reinvigorating the antibiotic drug development pipeline. In this perspective, we aim to summarize some of these initiatives and funding options, as well as providing an insight into the predicament that we face. Using clinical trials data, company website information and the most recent press releases, a current update of the antibiotic drug development pipeline is also included.

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The drug development pipeline for glioblastoma - a cross sectional assessment of the FDA Orphan Drug Product designation database

10.1101/2021.01.01.21249120 ◽

2021 ◽

Author(s):

Pascal Johann ◽

Dominic Lenz ◽

Markus Ries

Keyword(s):

Drug Development ◽

Orphan Drug ◽

Mechanism Of Action ◽

Drug Product ◽

Treatment Options ◽

Orphan Drugs ◽

Cross Sectional ◽

Therapeutic Mechanism ◽

Development Pipeline ◽

Insight Into

Abstract Background: Glioblastoma multiforme (GBM) is the most common malignant brain tumor among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest. Objectives: To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM. Methods: Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected. Results: Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline. Conclusion: Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

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The drug development pipeline for glioblastoma—A cross sectional assessment of the FDA Orphan Drug Product designation database

PLoS ONE ◽

10.1371/journal.pone.0252924 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0252924

Author(s):

Pascal Johann ◽

Dominic Lenz ◽

Markus Ries

Keyword(s):

Drug Development ◽

Orphan Drug ◽

Mechanism Of Action ◽

Drug Product ◽

Treatment Options ◽

Orphan Drugs ◽

Cross Sectional ◽

Therapeutic Mechanism ◽

Development Pipeline ◽

Insight Into

Background Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest. Objectives To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM. Methods Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected. Results Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline. Conclusion Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

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Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.14.239 ◽

2018 ◽

Vol 14 ◽

pp. 2607-2617 ◽

Cited By ~ 20

Author(s):

Matthew B Calvert ◽

Varsha R Jumde ◽

Alexander Titz

Keyword(s):

Bacterial Infections ◽

Rapid Development ◽

World Health ◽

Resistance Development ◽

New Approach ◽

Bacterial Communication ◽

Current Trends ◽

If Current ◽

New Strategy ◽

Health Organization

The rapid development of antimicrobial resistance is threatening mankind to such an extent that the World Health Organization expects more deaths from infections than from cancer in 2050 if current trends continue. To avoid this scenario, new classes of anti-infectives must urgently be developed. Antibiotics with new modes of action are needed, but other concepts are also currently being pursued. Targeting bacterial virulence as a means of blocking pathogenicity is a promising new strategy for disarming pathogens. Furthermore, it is believed that this new approach is less susceptible towards resistance development. In this review, recent examples of anti-infective compounds acting on several types of bacterial targets, e.g., adhesins, toxins and bacterial communication, are described.

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Current Trends in the Training and Utilization of Paraprofessionals in Speech and Language Programs

Language Speech and Hearing Services in Schools ◽

10.1044/0161-1461.2202.51 ◽

1991 ◽

Vol 22 (2) ◽

pp. 51-59 ◽

Cited By ~ 6

Author(s):

Kathy L. Coufal ◽

Allen L. Steckelberg ◽

Stanley F. Vasa

Keyword(s):

Selection Criteria ◽

Job Descriptions ◽

Paraprofessional Training ◽

Language Programs ◽

Program Administrators ◽

Current Trends ◽

Training And Supervision ◽

Communicative Disorders ◽

Supervision Practices ◽

A Current

Administrators of programs for children with communicative disorders in 11 midwestern states were surveyed to assess trends in the training and utilization of paraprofessionals. Topics included: (a) current trends in employment, (b) paraprofessional training, (c) use of ASHA and state guidelines, and (d) district policies for supervision. Selection criteria, use of job descriptions, training programs, and supervision practices and policies were examined. Results indicate that paraprofessionals are used but that standards for training and supervision are not consistently applied across all programs. Program administrators report minimal training for supervising professionals.

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A Review of Phytochemical and Pharmacological Studies of Inula Species

Current Bioactive Compounds ◽

10.2174/1573407215666190207093538 ◽

2020 ◽

Vol 16 (5) ◽

pp. 557-567

Author(s):

Aparoop Das ◽

Anshul Shakya ◽

Surajit Kumar Ghosh ◽

Udaya P. Singh ◽

Hans R. Bhat

Keyword(s):

Bacterial Infections ◽

Chemical Constituents ◽

Valuable Insight ◽

Important Ingredient ◽

Pharmacological Activities ◽

Medicinal Uses ◽

The Family ◽

Pharmacological Studies ◽

Perennial Herbs ◽

Insight Into

Background: Plants of the genus Inula are perennial herbs of the family Asteraceae. This genus includes more than 100 species, widely distributed throughout Europe, Africa and Asia including India. Many of them are indicated in traditional medicine, e.g., in Ayurveda. This review explores chemical constituents, medicinal uses and pharmacological actions of Inula species. Methods: Major databases and research and review articles retrieved through Scopus, Web of Science, and Medline were consulted to obtain information on the pharmacological activities of the genus Inula published from 1994 to 2017. Results: Inula species are used either alone or as an important ingredient of various formulations to cure dysfunctions of the cardiovascular system, respiratory system, urinary system, central nervous system and digestive system, and for the treatment of asthma, diabetes, cancers, skin disorders, hepatic disease, fungal and bacterial infections. A range of phytochemicals including alkaloids, essential and volatile oils, flavonoids, terpenes, and lactones has been isolated from herbs of the genus Inula, which might possibly explain traditional uses of these plants. Conclusion: The present review is focused on chemical constituents, medicinal uses and pharmacological actions of Inula species and provides valuable insight into its medicinal potential.

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Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524920666201021164805 ◽

2020 ◽

Vol 20 ◽

Author(s):

Tanay Dalvi ◽

Bhaskar Dewangan ◽

Rudradip Das ◽

Jyoti Rani ◽

Suchita Dattatray Shinde ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Development ◽

Molecular Targets ◽

Drug Repurposing ◽

Phase Iii ◽

Complex Nature ◽

New Drug ◽

Development Pipeline ◽

Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

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Current Trends in Anti-Candida Drug Development

Current Topics in Medicinal Chemistry ◽

10.2174/156802661928191206162925 ◽

2019 ◽

Vol 19 (28) ◽

pp. 2525-2526

Author(s):

Ashok K. Dubey ◽

Rajeev K. Singla

Keyword(s):

Drug Development ◽

Current Trends

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Bloodstream infection with Acinetobacter baumanii in a Plasmodium falciparum positive infant: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-020-02648-7 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Charity Wiafe Akenten ◽

Kennedy Gyau Boahen ◽

Kwadwo Sarfo Marfo ◽

Nimako Sarpong ◽

Denise Dekker ◽

...

Keyword(s):

Case Report ◽

Bacterial Infections ◽

Treatment Options ◽

Female Child ◽

Correct Choice ◽

Blood Cultures ◽

Microbial Culture ◽

Acinetobacter Baumanii ◽

Inappropriate Use ◽

History Of

Abstract Background The increasing incidence of multi-antibiotic-resistant bacterial infections, coupled with the risk of co-infections in malaria-endemic regions, complicates accurate diagnosis and prolongs hospitalization, thereby increasing the total cost of illness. Further, there are challenges in making the correct choice of antibiotic treatment and duration, precipitated by a lack of access to microbial culture facilities in many hospitals in Ghana. The aim of this case report is to highlight the need for blood cultures or alternative rapid tests to be performed routinely in malaria patients, to diagnose co-infections with bacteria, especially when symptoms persist after antimalarial treatment. Case presentation A 6-month old black female child presented to the Agogo Presbyterian Hospital with fever, diarrhea, and a 3-day history of cough. A rapid diagnostic test for malaria and Malaria microscopy was positive for P. falciparum with a parasitemia of 224 parasites/μl. The patient was treated with Intravenous Artesunate, parental antibiotics (cefuroxime and gentamicin) and oral dispersible zinc tablets in addition to intravenous fluids. Blood culture yielded Acinetobacter baumanii, which was resistant to all of the third-generation antibiotics included in the susceptibility test conducted, but sensitive to ciprofloxacin and gentamicin. After augmenting treatment with intravenous ciprofloxacin, all symptoms resolved. Conclusion Even though this study cannot confirm whether the bacterial infection was nosocomial or otherwise, the case highlights the necessity to test malaria patients for possible co-infections, especially when fever persists after parasites have been cleared from the bloodstream. Bacterial blood cultures and antimicrobial susceptibility testing should be routinely performed to guide treatment options for febril illnesses in Ghana in order to reduce inappropriate use of broad-spectrum antibiotics and limit the development of antimicrobial resistance.

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Using syndromic measures of mortality to capture the dynamics of COVID-19 in Java, Indonesia, in the context of vaccination rollout

BMC Medicine ◽

10.1186/s12916-021-02016-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Bimandra A. Djaafara ◽

Charles Whittaker ◽

Oliver J. Watson ◽

Robert Verity ◽

Nicholas F. Brazeau ◽

...

Keyword(s):

Rural Areas ◽

Vaccination Campaign ◽

Control Measures ◽

Additional Insight ◽

Short Term ◽

If Current ◽

Vaccine Impact ◽

Potential Impact ◽

The Impact ◽

Insight Into

Abstract Background As in many countries, quantifying COVID-19 spread in Indonesia remains challenging due to testing limitations. In Java, non-pharmaceutical interventions (NPIs) were implemented throughout 2020. However, as a vaccination campaign launches, cases and deaths are rising across the island. Methods We used modelling to explore the extent to which data on burials in Jakarta using strict COVID-19 protocols (C19P) provide additional insight into the transmissibility of the disease, epidemic trajectory, and the impact of NPIs. We assess how implementation of NPIs in early 2021 will shape the epidemic during the period of likely vaccine rollout. Results C19P burial data in Jakarta suggest a death toll approximately 3.3 times higher than reported. Transmission estimates using these data suggest earlier, larger, and more sustained impact of NPIs. Measures to reduce sub-national spread, particularly during Ramadan, substantially mitigated spread to more vulnerable rural areas. Given current trajectory, daily cases and deaths are likely to increase in most regions as the vaccine is rolled out. Transmission may peak in early 2021 in Jakarta if current levels of control are maintained. However, relaxation of control measures is likely to lead to a subsequent resurgence in the absence of an effective vaccination campaign. Conclusions Syndromic measures of mortality provide a more complete picture of COVID-19 severity upon which to base decision-making. The high potential impact of the vaccine in Java is attributable to reductions in transmission to date and dependent on these being maintained. Increases in control in the relatively short-term will likely yield large, synergistic increases in vaccine impact.

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Polyvinyl Chloride Modified Carbon Paste Electrodes for Sensitive Determination of Levofloxacin Drug in Serum, Urine, and Pharmaceutical Formulations

Sensors ◽

10.3390/s21093150 ◽

2021 ◽

Vol 21 (9) ◽

pp. 3150

Author(s):

Fatehy M. Abdel-Haleem ◽

Sonia Mahmoud ◽

Nour Eldin T. Abdel-Ghani ◽

Rasha Mohamed El Nashar ◽

Mikhael Bechelany ◽

...

Keyword(s):

Bacterial Infections ◽

Pharmaceutical Preparation ◽

Pharmaceutical Formulations ◽

Selectivity Coefficient ◽

Pvc Membrane ◽

Carbon Paste ◽

Serum Samples ◽

Carbon Paste Electrodes ◽

Antibiotic Drug

Levofloxacin (LF) is a medically important antibiotic drug that is used to treat a variety of bacterial infections. In this study, three highly sensitive and selective carbon paste electrodes (CPEs) were fabricated for potentiometric determination of the LF drug: (i) CPEs filled with carbon paste (referred to as CPE); (ii) CPE coated (drop-casted) with ion-selective PVC membrane (referred to as C-CPE); (iii) CPE filled with carbon paste modified with a plasticizer (PVC/cyclohexanone) (referenced as P-CPE). The CPE was formulated from graphite (Gr, 44.0%) and reduced graphene oxide (rGO, 3.0%) as the carbon source, tricresyl phosphate (TCP, 47.0%) as the plasticizer; sodium tetrakis[3,5-bis(trifluoromethyl)phenyl] borate (St-TFPMB, 1.0%) as the ion exchanger; and levofloxacinium-tetraphenylborate (LF-TPB, 5.0%) as the lipophilic ion pair. It showed a sub-Nernstian slope of 49.3 mV decade−1 within the LF concentration range 1.0 × 10−2 M to 1.0 × 10−5 M, with a detection limit of 1.0 × 10−5 M. The PVC coated electrode (C-CPE) showed improved sensitivity (in terms of slope, equal to 50.2 mV decade−1) compared to CPEs. After the incorporation of PVC paste on the modified CPE (P-CPE), the sensitivity increased at 53.5 mV decade−1, indicating such improvement. The selectivity coefficient (log KLF2+,Fe+3pot.) against different interfering species (Na+, K+, NH4+, Ca2+, Al3+, Fe3+, Glycine, Glucose, Maltose, Lactose) were significantly improved by one to three orders of magnitudes in the case of C-CPE and P-CPE, compared to CPEs. The modification with the PVC membrane coating significantly improved the response time and solubility of the LF-TPB within the electrode matrix and increased the lifetime. The constructed sensors were successfully applied for LF determination in pharmaceutical preparation (Levoxin® 500 mg), spiked urine, and serum samples with high accuracy and precision.

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