Two-photon polymerization of microneedles for transdermal drug delivery

Importance of the field: Microneedles are small-scale devices that are finding use for transdermal delivery of protein-based pharmacologic agents and nucleic acid-based pharmacologic agents; however, microneedles prepared using conventional microelectronics-based technologies have several shortcomings, which have limited translation of these devices into widespread clinical use.

Areas covered in this review: Two-photon polymerization is a laser-based rapid prototyping technique that has been used recently for direct fabrication of hollow microneedles with a wide variety of geometries. In addition, an indirect rapid prototyping method that involves two-photon polymerization and polydimethyl siloxane micromolding has been used for fabrication of solid microneedles with exceptional mechanical properties.

What the reader will gain: In this review, the use of two-photon polymerization for fabricating in-plane and out-of-plane hollow microneedle arrays is described. The use of two-photon polymerization-micromolding for fabrication of solid microneedles is also reviewed. In addition, fabrication of microneedles with antimicrobial properties is discussed; antimicrobial microneedles may reduce the risk of infection associated with the formation of channels through the stratum corneum.

Take home message: It is anticipated that the use of two-photon polymerization as well as two-photon polymerization-micromolding for fabrication of microneedles and other microstructured drug delivery devices will increase over the coming years.     

Role of old antimicrobial agents in the management of urinary tract infection

Introduction: Urinary tract infection (UTI) is a common infection worldwide. The increase in multidrug resistance together with the paucity of new antibiotics highlights the need for alternative antimicrobials for management of UTI. Among which are older antimicrobials that had been used in the past and now were stopped.

Areas covered: In this article, we examine the evidence in literature for the value of use of various antimicrobial agents in UTI. We conducted systematic Pubmed search and journal literature review including early research work on older agents addressed in relation to recent clinical data. Antimicrobials reviewed include temocillin, fosfomycin, mecillinam, methenamine and cycloserine. We review mechanisms of action, spectrum of activity, effect on multidrug resistance, cure rates and patient tolerance.

Expert commentary: Rational use of current agents and rehabilitation of older drugs will both be needed, combined with antibiotic stewardship, in order to contain the march of antibiotic resistance.     

New antibiotics for the treatment of serious infections in intensive care unit patients

Objective: Nowadays, the infections of patients admitted to intensive care units (ICUs) are a major public health problem; this is due to several factors, in primis an increase in antibiotic resistance and the inappropriate use of antibiotics.

Methods: We briefly focus on on both new antibiotics approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in the last decade (2010–2019), and on agents in an advanced phase of development that have been developed, or are already approved, for the treatment of serious infections due to multidrug-resistant bacteria, both Gram-positive and Gram-negative bacteria.

Results: An adequate knowledge of the new antibiotics will reduce their inappropriate use with the consequent reduction in the onset of new resistance and decreasing health care costs.

Conclusion: Antimicrobial stewardship programs to optimize antimicrobial prescribing and to preserve the effectiveness of the new antimicrobial agents are urgently needed'.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 1: IV options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a predominant pathogen resulting in significant morbidity and mortality. Optimal dosing of anti-MRSA agents is needed to help prevent the development of antimicrobial resistance and to increase the likelihood of a favorable clinical outcome.

Areas covered: This review summarizes the available data for antimicrobials routinely used for MRSA infections that are not administered orally or topically. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: Improvements in MIC determination and therapeutic drug monitoring are needed to fully implement individualized dosing that optimizes antimicrobial pharmacodynamics.Additional data will become available for these agents in regards to effectiveness for severe MRSA infections and pharmacokinetic data for special patient populations.     

Targeting the subtypes of breast cancer: rethinking investigational drugs

Importance of the field: Antibiotic resistance in bacterial pathogens has increased worldwide leading to treatment failures. Concerns have been raised about the use of biocides as a contributing factor to the risk of antimicrobial resistance (AMR) development. In vitro studies demonstrating increase in resistance have often been cited as evidence for increased risks. It is therefore important to understand the mechanisms of resistance employed by bacteria toward biocides used in consumer products and their potential to impart cross-resistance to therapeutic antibiotics.

Areas covered: In this review, the mechanisms of resistance and cross-resistance reported in the literature toward biocides commonly used in consumer products are summarized. The physiological and molecular techniques used in describing and examining these mechanisms are reviewed and application of these techniques for systematic assessment of biocides for their potential to develop resistance and/or cross-resistance is discussed.

Expert opinion: The guidelines in the usage of biocides in household or industrial purpose should be monitored and regulated to avoid the emergence of any MDR strains. The genetic and molecular methods to monitor the resistance development to biocides should be developed and included in preclinical and clinical studies.     

An update on repurposed medications for the treatment of drug-resistant tuberculosis

Introduction: Drug-resistant forms of tuberculosis are a major public health problem with a serious global impact. Although there have recently been two new drugs introduced for the treatment of drug-resistant TB (bedaquiline and delamanid), the current therapeutic armamentarium is limited. Because treatment of drug-resistant TB requires the use of a multidrug-regimen, there has been growing interest in the use of antibiotics developed for other infectious pathogens but that have shown efficacy in the treatment of TB.

Areas covered: This paper will review these ‘re-purposed’ agents – including the beta-lactams, clarithromycin, clofazimine, the fluoroquinolones, and linezolid – with a focus on their efficacy, safety, and pharmacokinetic properties.

Expert commentary: There is growing evidence on the efficacy and safety of repurposed drugs for the treatment of drug-resistant TB, supporting their program-wide inclusion in treatment regimens as recommended in revised WHO guidelines. However, additional work is needed to define optimum dosing as well as describe their role in regimen optimization.     

Programmed cell death in human pathogenic fungi – a possible therapeutic target

ABSTRACT

Introduction: Diseases caused by pathogenic fungi are increasing because of antibiotic overuse, the rise of immunosuppressive therapies, and climate change. The limited variety of antimycotics and the rapid adaptation of pathogenic fungi to antifungal agents serve to exacerbate this issue. Unfortunately, about 1.6 million people are killed by fungal infections annually.

Areas covered: The discovery of the small antimicrobial proteins produced by microorganisms, animals, humans, and plants will hopefully overcome challenges in the treatment of fungal infections. These small proteins are highly stable and any resistance to them rarely evolves; therefore, they are potentially good candidates for the treatment and prevention of infections caused by pathogenic fungi. Some of these proteins target the programmed cell death machinery of pathogenic fungi; this is potentially a novel approach in antimycotic therapies. In this review, we highlight the elements of apoptosis in human pathogenic fungi and related model organisms and discuss the possible therapeutic potential of the apoptosis-inducing, small, antifungal proteins.

Expert opinion: Small antimicrobial proteins may establish a new class of antimycotics in the future. The rarity of resistance and their synergistic effects with other frequently used antifungal agents may help pave the way for their use in the clinic.     

Evolution of antimicrobial resistance among Enterobacteriaceae (focus on extended spectrum β-lactamases and carbapenemases)

Introduction: Bacteria within the family Enterobacteriaceae are important pathogens in nosocomial and community settings. Over the past two decades, antimicrobial resistance among Enterobacteriaceae dramatically escalated worldwide. The authors review the mechanisms of antimicrobial resistance among Enterobacteriaceae, epidemiology and global spread of resistance elements and discuss therapeutic options.

Areas covered: An exhaustive search for literature relating to Enterobacteriaceae was performed using PubMed, using the following key words: Enterobacteriaceae; Klebsiella pneumoniae; Escherichia coli; antimicrobial resistance; plasmids; global epidemiology; carbapenemases (CPEs); extended spectrum β-lactamases (ESBLs) and multidrug resistance (MDR).

Expert opinion: Enterobacteriaceae are inhabitants of intestinal flora and spread easily among humans (via hand carriage, contaminated food or water or environmental sources). Antimicrobial resistance may develop via plasmids, transposons or other mobile resistance elements. Mutations conferring resistance typically increase over time; the rate of increase is amplified by selection pressure from antibiotic use. Factors that enhance spread of antimicrobial resistance include: crowding; lack of hygiene; overuse and over-the-counter use of antibiotics; tourism; refugees and international travel. Clonal spread of resistant organisms among hospitals, geographic regions and continents has globally fueled the explosive rise in resistance. The emergence and widespread dissemination of MDR clones containing novel resistance elements (particularly ESBLs and CPEs) has greatly limited therapeutic options. In some cases, infections due to MDR Enterobacteriaceae are untreatable with existing antimicrobial agents. The authors discuss current and future therapeutic options for difficult-to-treat infections due to these organisms.     

Otitis media: an update on current pharmacotherapy and future perspectives

Introduction: Acute otitis media (AOM) is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Currently, there is an urgent need for developing novel therapeutic agents for treating AOM.

Areas covered: Structured search of current literature. PubMed was searched for published literature in areas of pharmacotherapeutics, preventive therapies and complementary treatments for OM. The intent of this review is to provide a comprehensive evaluation of therapeutics for AOM, including preventive modalities and complementary medicine.

Expert opinion: the management of AOM in young children is still evolving and depends on patterns of bacterial colonization and antimicrobial resistance in the community. The introduction of vaccinations against potential respiratory tract pathogens has altered the frequency of recovery of pathogens causing ear infections in children. Even though not all patients require antimicrobial therapy to overcome their infection, these agents improve symptoms faster and lead to fewer treatment failures. Further studies are warranted to evaluate which patients would best benefit from antimicrobial therapy.     

Ceftazidime for respiratory infections

Introduction: Ceftazidime is a third-generation cephalosporin that has activity against Gram-negative bacilli, including Pseudomonas aeruginosa. The increasing prevalence of antimicrobial resistance and the limited number of antimicrobial agents in development have necessitated a review of the current status of treatments involving ceftazidime.

Areas covered: This review focuses on studies examining the in vitro antibacterial activity of ceftazidime against recent clinical isolates and recent randomized controlled trials studying the clinical efficacy of ceftazidime, and discusses strategies for the optimal use of ceftazidime for treating respiratory tract infections, mainly hospital-acquired pneumonia (HAP).

Expert opinion: Although ceftazidime remains an important option for HAP treatment, its role as an effective antimicrobial agent has been compromised by the sharp increase in resistance rates over the last decade, especially in P. aeruginosa and Acinetobacter baumannii. To maintain or improve the clinical use of ceftazidime in patients with severe HAP, it will be essential to gain a thorough understanding of local resistance patterns, reserve ceftazidime use when pathogens are susceptible to other third-generation cephalosporins, optimize ceftazidime therapy using prolonged or continuous infusion, determine the effectiveness of the combination of ceftazidime with inhibitors of broad-spectrum β-lactamases and role of combination therapy for P. aeruginosa infections, and judiciously use antimicrobial agents through individualization of antimicrobial therapy for HAP.     

New molecules and adjuvants in the treatment of infections by Acinetobacter baumannii

Introduction: The current problems of the treatment of infections by Acinetobacter baumannii are linked with the increase of multidrug- and extensive-drug resistance and the lack of development of new antimicrobial drugs for Gram-negative bacilli. For these reasons, new alternatives for the treatment and control of severe infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents.

Areas covered: In the present review, the authors describe the main results in the development of adjuvant drugs as well as new data on antimicrobial peptides, in monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising preclinical results in vitro and in vivo.

Expert opinion: The preclinical evaluation of adjuvants and antimicrobial peptides, in monotherapy or in combination therapy, for A. baumannii infections has shown promising results. However, caution is needed and further extensive in vivo studies and clinical trials have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives.     

The pharmacological management of severe influenza infection – ‘existing and emerging therapies’

Introduction: Over the last century several influenza outbreaks have traversed the globe, most recently the influenza A(H1N1) 2009 pandemic. On each occasion, a highly contagious, virulent pathogen has emerged, leading to significant morbidity and mortality amongst those affected.

Areas covered: Early antiviral therapy and supportive care is the mainstay of treatment. Treatment should be started as soon as possible and not delayed for the results of diagnostic testing. Whilst oseltamivir is still the first choice, in case of treatment failure, oseltamivir resistance should be considered, particularly in immunosuppressed patients. Here we review the antivirals currently used for management of influenza and explore a number of investigational agents that may emerge as effective antivirals including parenteral agents, combination antiviral therapy and novel agents in order to adequately target influenza virulence.

Expert Commentary: New tools for rapid diagnosis and susceptible strains will help if a patient is not improving because of a resistant strain or an inadequate immune response. Further randomized control trials will be conducted to investigate the use of new antivirals and co-adjuvant therapies that will help to elucidate the process of immune modulation, particularly in immunocompetent patients.     

Clinical and investigational use of proteasome inhibitors for transplant rejection

Introduction: The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) in patients experiencing acute cellular rejection and antibody-mediated rejection (AMR) is associated with poor renal allograft survival in kidney transplant recipients. Traditional therapies for AMR provide variable results, and do not deplete the cellular source of antibody production, that is, the plasma cell.

Areas covered: Physiologic effects of proteasome inhibitors (PIs) are reviewed in the context of recent clinical reports of PI therapy in solid organ transplantation for AMR and desensitization.

Expert opinion: PI-based therapy is a novel approach for treating AMR that is being employed with increasing frequency in transplantation. Initial reports of PI-based regimens for treating AMR have demonstrated the ability of bortezomib to significantly reduce DSA levels and improve histology and allograft function. Use of PI agents have recently been evaluated in a large multicenter collaborative consisting of over 100 solid organ transplant recipients treated with a common PI-based regimen. Increasing experience with PI-based regimens for AMR have indicated that PI therapy (similar to other AMR therapies) provides excellent results in early AMR, with late AMR demonstrating a greater degree of therapeutic resistance. A substantial number of strategies exist for enhancement of therapeutic results with PI therapy for AMR.     

The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy

Importance of the field: The macrolides are a class of antibiotics widely prescribed in infectious disease. More recently, there has been considerable interest in potential indications for these agents, in addition to their simple antibacterial indications, in a number of lung pathophysiologies.

Areas covered in this review: Demonstrated clinical efficacy of macrolides in diseases such as diffuse panbronchiolitis was difficult to ascribe to a direct antimicrobial action. More recently, positive experiences in dealing with post-transplant bronchiolitis obliterans syndrome suggests that other chronic lung diseases may benefit from macrolide therapy. This is important, as the treatment options for such diseases are often very limited. In this review, potential antibiotic and non-antibiotic beneficial actions of macrolide therapy are discussed and conclusions drawn from a limited but growing literature.

What the reader will gain: The reader will gain an overview of lung diseases that may benefit from macrolides, and a consideration of the possible mechanisms underlying such benefit.

Take home message: The key message from our review is that this class of agents may prove to be a useful therapeutic option for a range of respiratory diseases, but that further trials and mechanistic studies are required to clarify their role.     

Aminoacyl-tRNA synthetase inhibitors as antimicrobial agents: a patent review from 2006 till present

Introduction: Aminoacyl-tRNA synthetases (aaRSs) are one of the leading targets for development of antimicrobial agents. Although these enzymes are well conserved among prokaryotes, significant divergence has occurred between prokaryotic and eukaryotic aaRSs, which can be exploited in the discovery of broad-spectrum antibacterial agents. Although several aaRS inhibitors have been reported before, they failed as a result of poor selectivity and limited cell penetration.

Areas covered: This review covers January 2006 to April 2012 wherein several new analogues were claimed as aaRS inhibitors. Anacor Pharmaceuticals patented several boron-containing derivatives inhibiting the function of the editing domain of aaRSs. Two patents describe the combination of aaRS inhibitors with other antibacterial agents. Patents disclosing aaRS inhibitors for indications other than antimicrobial agents are not considered for review here.

Expert opinion: Several recently disclosed leads may form the foundation for development of potent and selective bacterial aaRS inhibitors. In comparison with, for example, terbinafine and itraconazole, compound C10 (AN2690) is a very promising candidate for treatment of ungual and periungual infections with improved nail penetration and low keratin binding. In addition, Raplidyne, Inc. reported bicyclic heteroaromatic compounds as potent and selective inhibitors of bacterial MetRS. These have proven to be particularly effective for treatment of Clostridium difficile-associated diarrhea. Finally, combination of aaRS inhibitors to attenuate resistance looks as a viable strategy to expand the lifespan of existing antibiotics.     

The use of cephalosporins for gonorrhea: an update on the rising problem of resistance

Introduction: Over the last several years, Neisseria gonorrhoeae has developed decreased susceptibility to extended-spectrum cephalosporins worldwide. Gonococcal antimicrobial surveillance programs in multiple regions have documented the rise in N. gonorrhoeae isolates' minimum inhibitory concentrations to cephalosporins, and the first cases of ceftriaxone treatment failure have been reported. These developments have prompted the use of the term ‘superbug’ and concerns about the emergence of untreatable gonococcal infections.

Areas covered: Since the publication of the last detailed review of the use of cephalosporins for gonorrhea in 2009, several new developments have occurred, which are detailed in this review. A variety of treatment strategies have been proposed in response to this ‘superbug’ threat, including increasing the dose or providing multiple doses of cephalosporins, multidrug therapy, rotating therapeutic regimens and individualized treatment based on susceptibility testing.

Expert opinion: A robust public health response is needed that includes better diagnosis and treatment of pharyngeal gonorrhea, improved surveillance of antimicrobial resistance, informed treatment approaches and reduction of the global burden of gonococcal infections.     

Predicting and preventing antimicrobial resistance utilizing pharmacodynamics: Part I gram positive bacteria

Introduction: Antimicrobial resistance is a potentially inevitable consequence of widespread use of antibiotics in the healthcare system. An enhanced understanding of pharmacodynamic (PD) targets that prevent antimicrobial resistance development will improve currently availably therapies and help to guide future drug development strategies. Current in vitro methods to predict bacterial resistance to antimicrobials consist of serial dilution experiments, determination of the mutant prevention concentration (MPC), mutant selection window (MSW), and human simulated pharmacodynamics studies. Clinical trial data and real -world surveillance studies can help validate or disprove in vitro modeling.

Areas covered: This review will discuss methods of predicting development of resistance and how the use of pharmacodynamics can reduce or eliminate the emergence of resistance among Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus species.

Expert opinion: Pharmacodynamic targets can be used successfully to guide antimicrobial therapy to prevent resistance development. Currently, PD targets do not take into consideration horizontal resistance gene transfer and various factors may lead to different PD targets based on sites of infection. Further research is necessary to guide future drug development strategies and optimize new drug therapies.     

Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials

Introduction: Antimicrobial resistance is a well-recognized global threat; thus, the development of strong infection control policies coupled with antimicrobial stewardship strategies and new therapies is required to reverse this process. In its 2013 report on antimicrobial resistance, the Centers for Disease Control and Prevention focused on this problem while presenting estimated annual rates of infections with antimicrobial-resistant organisms and their related mortality rates. Whereas some resistant pathogens were considered less threatening, others such as carbapenem-resistant Enterobacteriaceae were associated with higher mortality rates owing to limited treatment options.

Areas covered: An overview of the most common antimicrobial-resistant pathogens, focusing on risk factors for acquisition, clinical and economic outcomes, as well as current treatment options. Strategies to optimize antimicrobial therapy with currently available agents, in addition to newly developed antimicrobials are also discussed.

Expert opinion: The emergence of pathogens with a variety of resistance mechanisms has intensified the challenges associated with infection control and treatment strategies. Therefore, prudent use of currently available antimicrobial agents, as well as implementing measures to limit spread of resistance is paramount. Although several new antimicrobials have been recently approved or are in the pipeline showing promise in the battle against resistance, the appropriate use of these agents is required as the true benefits of these treatments are to be recognized in the clinical care setting.     

Genome database mining for the discovery of novel lantibiotics

Introduction: The effectiveness of lantibiotics against MDR pathogens and the progression of agents MU1140, NAI-107, NVB302 and duramycin into pre-clinical and clinical trials have highlighted their potential in the fight against bacterial resistance. The number of known lantibiotics and knowledge of their biosynthetic pathways has increased in recent years due to higher quality genomic data being delivered by next generation sequencing technologies combined with the development of specific genome mining tools, enabling the prediction of lantibiotic clusters.

Areas covered: In this review, the author describes how the increase of high quality genomic data has increased the discovery of novel lantibiotics.

Expert opinion: Novel apparatus such as the iChip enabling the isolation of uncultable bacteria will undoubtedly increase the identification rate of novel antimicrobial peptides including lantibiotics. The ability to then assess the lantibiotic clusters via recombinant production or synthesis using a high throughput method is one of the next challenges for developing these agents into the clinical environment.