Frontiers in Anti-infective Agents

Antimicrobial agents are considered one of the most useful and successful forms of chemotherapeutics in the history of medicine. Unfortunately, resistance to such antimicrobial agents is widespread globally which represents a major challenge faced by the health authorities. Some species of microorganisms are intrinsically resistant to the effects of certain antimicrobial agents whereas the selective pressure of antimicrobials can cause others to acquire the resistance due to mutation of the target sites or horizontal gene transfer. The increased dissemination of microbes resistant to antibiotics may be caused by misuse/overuse of antibiotics, non-human use of antimicrobials or pharmaceutical manufacturing effluents. The emergence and spread of antimicrobial resistance influence many sectors in the healthcare system which will be negatively reflected on the whole community and can lead to many consequences which include high morbidity and mortality rates, loss of protection for patients and increased healthcare costs. The continuously increasing rate of antibiotic resistance to almost all traditional antimicrobial agents boosted the urgent need for the development of new non-traditional therapeutics. In addition, innovative strategies should be applied to reduce the emergence of new resistant pathogens. There are many alternative approaches and treatment options at different stages of investigation and development to combat multidrug-resistant pathogens including: development of new antibiotics, phage therapy, monoclonal antibodies, probiotics and anti-virulence factors. Because antibiotic resistance is a cross-border problem and microbes travel freely, international cooperation and coordination are required to solve such a problem. The use of antimicrobial agents should be optimized and misuse and overuse of such vital drugs should be avoided, and stewardship antibiotic programs should be implemented for the proper utilization of antibiotics. In addition, the non-human use of antimicrobial agents in agriculture and animal husbandry should be as limited as possible to reduce the unnecessary use that accelerates the development of antimicrobial resistance. In addition, global public awareness programs are urgently needed to educate everyone about the hazards and consequences of antimicrobial resistance and how such problems could be countered.

In the era of superbugs and antimicrobial resistance to conventional antibiotics, there is an urgent need for alternative drug delivery systems to optimize antimicrobial administration. Traditionally, routes of antimicrobial administration include oral, intravenous, intramuscular, intracerebroventricular, aerosol, rectal, and topical methods. However, more innovative drug delivery systems are required for the treatment of antimicrobial resistance at the cellular level. With recent advances, hefty research has been underway, including the use of nanotechnology and antimicrobial peptides in the fight against multi drug-resistant microorganisms (MDROs). Metal and polymer nanoparticles with or without surface functionalization and antimicrobial peptides act through different mechanisms of actions than conventional antibiotics. Some of these mechanisms of actions are included but are not limited to oxidative and non-oxidative stress, binding to the bacterial membrane, altering cell permeability and integrity, and activation of adaptive immune pathways. This chapter encompasses the cause and effect of multidrug resistance in addition to the nanoparticles, antimicrobial peptides, and gene editing techniques as an alternative or combinatorial antimicrobial combat mechanism for the 21st century.

Antimicrobial administration requires drug therapy to target the site of infection. Traditionally, commercial oral and intravenous agents are the first route of administration for systemic infections. The use of alternative routes of administration is often required to optimize both pharmacokinetic and pharmacodynamic properties of antimicrobials that may not be achieved with oral or intravenous products. Optimizing both pharmacokinetic and pharmacodynamic properties help achieve adequate penetration of the target drug into the site of infection by maintaining antibiotic serum concentration in a time or concentration-dependent manner. The result is the achievement of drug concentrations above the minimum inhibitory concentration of a targeted organism resulting in both clinical and microbiological cure. In addition, pharmaceutically compounded antimicrobials must also be an option to target infections that may not be achieved with commercial antibiotics. A description of the various routes of antimicrobial administration is presented in this chapter including current evidence, guidelines for use and new and novel administrative methods.

This section of the treatise discussed the molecular basis of bacteria resistance exhibited phenotypically as a result of an inherent genotypic makeup of the bacterial cell (intrinsic). It could also result from mutational changes of the bacterial genes or through a process by which resistance genes are acquired through transfer from one bacterial cell to another (acquired). Some of the mechanisms of resistance discussed result from the encoding genes of the enzymes responsible for the enzymatic destruction of antibiotics. For example, virginiamycin acetyltransferases (VATs), which inactivate the type A streptogramins; aminoglycoside phosphotransferases (APHs), also known as aminoglycoside kinases, which inactivate aminoglycosides and the thioltransferases, a fosfomycin resistance enzyme (mediated by fos B). All of these have been located in some Gram-positive pathogens. Bacteria resistance due to alteration of binding sites is evident in penicillin-binding proteins (PBP), which is mediated by the mecA gene of methicillin-resistant S. aureus (MRSA). This gives elevated resistance levels against methicillin amongst other β-lactam antibiotics. Similarly, in vancomycin-resistant enterococci (VRE), the gene clusters of VanA and VanB are responsible for encoding the enzymes which catalyze the production of the modified peptidoglycan precursor in Enterococcus faecium and Enterococcus faecalis. Fluoroquinolone antibiotic resistance results from a situation whereby two enzymes are inhibited in the process of synthesis of bacterial DNA. These are DNA gyrase with 2 subunits encoded in the gyrA and gyrB genes and the Topoisomerase IV with subunits encoded in the parC and parE genes. The macrolide, lincosamide and streptogramin B resistance are observed following a transcriptional modification of the 23S rRNA portion of the 50S ribosomal subunit of the resistant organism. Meanwhile, trimethoprim resistance, due to mutation in the dhfr gene, is known in Gram-positive bacteria. Resistance in Staphylococcus aureus strains is known to be due to mutations to varying levels in Isoleucyl-tRNA synthetase genes, mupA and ileS. The resistance to fusidic acid through point mutations has been identified in the fusA gene, which is chromosomally located in clinical isolates and laboratory selected resistant isolates of Gram-positive organisms.

The other form of resistance observed in Gram-positive and some other bacteria is due to the activities of bacterial antibiotic efflux transporters. These are categorized into five different groups otherwise known as families: The small multidrug resistance (SMR) family, the major facilitator superfamily (MFS), the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily, the resistance-nodulation-cell division (RND) superfamily and the Multidrug and toxic compound extrusion (MATE) family. Concisely, having a good knowledge of the efflux pump inhibitors (EPI) is important in the development of combination drugs, which can improve the activity of otherwise ineffective antibiotics. Therefore, based on the above discourse, this chapter will be discussing the molecular basis of resistant Gram-positive bacteria to antibiotics based on drug inactivation and modifications and how this constitutes a great challenge to the control of infectious diseases by these organisms.

Evolution of microbial resistance, particularly in Gram-negative bacteria, became a nightmare for the healthcare professionals and contributed effectively to high treatment failures as well as infection-related mortality rates. Understanding the diverse mechanisms by which the organisms acquire and transmit these resistance trends is a key determining step in any research endeavors aiming to develop either new drug molecules or treatment guidelines.

Gram-negative bacteria develop resistance through several mechanisms that render it less susceptible or even absolutely resistant to clinically relevant antibiotics. Enzymatic deactivation is the most common bacterial defense mechanism, in addition to other molecular mechanisms like decreased cell wall permeability through down-regulation of its porins, or over-expression of efflux pumps responsible for the decreased intracellular minimum inhibitory concentration of antibiotics, biofilm construction which is a protective barrier against threatening from bacterial surroundings, and antibiotic-specific target modification that leads to impaired drug-target fitting resulting inferior or prohibited clinical response.

The rapid evolvement of fungal resistance to therapeutic agents merits a thorough understanding of the molecular and genetic basis of this deleterious phenomenon. Accumulating efforts expanded our understanding of potential resistance mechanisms that fungi utilize to combat Antifungal therapy like modification of biological targets, gene overexpression, efflux pumps, and regulation of transcriptional factors in response to stress and biofilm formation. The tremendous genomic plasticity of fungi added to the involvement of a multitude of molecular resistance determinants and the paucity of novel targets for therapy mandate utilizing innovative approaches to therapy in parallel to relentless research to develop effective antifungal agents surmounting rapidly increasing resistance. In this chapter, we illustrate a myriad of resistance mechanisms along with other relevant topics like the mechanism of action of antifungal classes, laboratory methods for detecting resistance, clinical susceptibility testing and future insights.

The increasing threat of resistant bacterial phenotypes, leading to increased rates of treatment failure as well as prolonged hospitalization, necessitate early detection and more targeted therapy to improve clinical outcomes. Traditional microbiology laboratory diagnostic testing has been used for decades to identify the pathogens causing the infectious diseases and its susceptibility to antibiotics but these techniques are flawed particularly with long turnaround time. Rapid diagnostic platforms are able to identify the infective organisms as well as antibiotics susceptibility pattern within a significantly shorter period of time, which guides targeted antimicrobial treatment and limit the exposure to broad-spectrum antibiotics, the main trigger for bacterial resistance. Immuno-assay-based, nucleic acid probebased, nucleic acid amplification-based and spectrometry-based techniques, in addition to the future development of whole genome sequencing and microfluidics are technological solutions that can be used by microbiology laboratories to minimize sample-to-answer time. This chapter aims to illustrate the rapid diagnostic testing platforms, discussing their scientific principle of operation, advantages and limitations. Also, the importance of effective incorporation of these techniques in patient care process.

The therapy of multidrug-resistant Gram-positive, Gram-negative, and Candida auris is challenging and has emerged as a major threat to human health. Commonly used drugs have become increasingly resistant, which has led to an absence of reliable options and use of current agents in combination. While this has led to the development of newer drugs, most of them are not available in the United States or are yet to be approved by the FDA. Described here is a comprehensive overview of antimicrobial resistance and recent developments in therapy for methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp, extended-spectrum β- lactamases (ESBL's), carbapenemase-producing Enterobacteriaceae (CRE), multi-drug resistant Pseudomonas aeruginosa (PSA), multi-drug resistant Acinetobacter (ACB), and Candida auris.

Therapeutic Drug Monitoring (TDM) is the art of measuring the levels of a therapeutic agent in body fluids, most commonly plasma, and interpreting the results in order to adjust dosing such that therapeutic benefit is maximized and toxic effects are prevented. With respect to antibiotics, TDM was traditionally viewed as a method to curtail the side effects of agents with narrow therapeutic indices. However, with improved understanding of pharmacokinetic differences in various patient populations, TDM is evolving to a method by which to ensure adequate benefit in patients whose pharmacokinetic status is in question. Moreover, the ever-increasing surge in antimicrobial-resistant organisms is calling for this practice once more, this time to ensure that drug concentrations are maintained sufficiently large in order to combat infections with such organisms. This book chapter details the use of TDM in different patient populations and for different antimicrobials, with emphasis on how reference PK/PD parameters and drug levels are determined.

Antimicrobials are a cornerstone of the medical armamentarium due to the increased prevalence of infectious diseases, particularly those caused by drug-resistant pathogens. As organisms that infect humans become smarter through the development of different resistance mechanisms to some of the currently available antimicrobials, the development of new agents with novel mechanisms of action becomes imperative. Many antimicrobials, including antibacterials, antifungals, and antiparasitics, have recently been approved for clinical use or are currently at some stage in the pipeline. This chapter provides a brief description of these antimicrobials with regards to their mechanisms of action, spectra of activity, indications, and pharmaceutical formulations and describes whether they were recently approved or are currently under development or in clinical trials. The wise use of these antimicrobials is essential to maintain their effectiveness for more tenacious infections.

Antimicrobial resistance (AMR) remains one of the major global public health threats today. Infections due to multi-drug resistant organisms have been shown to not only increase healthcare costs but also be a significant cause of morbidity and mortality in patients. Global efforts have been employed to combat the issue of AMR. Specifically, the World Health Organization’s global action plan on antimicrobial resistance recognizes key areas to be addressed including: increased awareness and understanding of AMR, infection prevention and control, enhanced structure with the use of antimicrobials in animals, research, and economic investment in intervention methods. Several approaches exist to help mitigate this issue such as the development of antimicrobial stewardship programs (ASPs), clinician education, improved infection control practices and judicious antibiotic use in animals. This chapter will outline many of the current strategies proposed to counter and prevent the global concern of AMR.

Antimicrobial dosing in patients with acute kidney injury requiring renal replacement therapies is challenging. Generally, renal replacement therapy is either diffusive or convective. The most commonly used modalities are: Intermittent Hemodialysis (IHD), Continuous Renal Replacement Therapy - CRRT (continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF)), Prolonged Intermittent Renal Replacement Therapies (PIRRT), and Peritoneal Dialysis (PD). Several factors affect the transport of the drugs in these dialysis modalities, such as; the drug’s molecular weight, membrane properties (high-flux or low-flux), protein binding, blood flow rate, and dialysate flow rate, and dialyzer surface area. The Food and Drug Administration (FDA) does not mandate manufacturers to provide dosing in different renal replacement therapy modalities, which overwhelmingly complicate the dosing strategies of antimicrobials in this population. Furthermore, different CRRT modalities complicate the dosing with variable prescriptions in which the blood flow rate, dialysate flow rate, and effluent flow rate might significantly differ based on patients' needs. Additionally, extrapolation of pharmacokinetics (PK) from normal patient population and extending it to patients utilizing RRT is a questionable practice. In addition, the situation gets more complicated when those patients require extracorporeal membrane oxygenation (ECMO). Predicting the plasma concentrations of drugs during ECMO is difficult because many factors simultaneously impact the PK and because inconsistent results have been obtained in PK studies and the significant heterogeneity of data including medical and surgical patients or patients under venovenous and venoarterial ECMO in variable proportion. In conclusion, dosing of antimicrobials in patients receiving RRT or ECMO would require comprehensive understanding of the antimicrobials’ PK/PD as well as thorough understanding of the RRT and ECMO techniques and their effects on PK/PD.

Antimicrobial stewardship in inpatient, as well as outpatient settings, is crucial for preserving antimicrobial susceptibility, combating antibiotic resistance, and reducing unnecessary antibiotic use. The Centers for Disease Control and Prevention, as well as the World Health Organization, and various infectious diseases and government organizations have developed guidance on how to implement stewardship in different settings. A wide variety of practices are in place depending on the setting. Examples include educational activities, antibiotic recommendations and restriction, and facility guidelines. Stewardship practices are mandated in most healthcare settings, and tracking of antibiotic use is important in maintaining good practices.

• In the US, the Centers for Disease Control and Prevention has estimated that 2 million patients a year suffer from infections due to drug resistant bacteria and antimicrobial resistance is predicted to result in 10 million deaths worldwide by 2050.

• Growing antimicrobial resistance combined with a dry antibiotic pipeline has led clinicians to utilize older antibiotics that can be more toxic and/or ineffective.

• There has been development and regulatory progress made, but this is leading to an increasing number of antibiotics that will be reaching the market with limited datasets. Clinicians should understand how to best interpret and incorporate the data into clinical decision-making.

• Clinicians should understand the various challenges for the decline in antibiotic development and understand the initiatives that are currently in place to help fix the issues as well as further potential solutions.