Combination Therapy Against Multidrug Resistance

By Aijaz Ahmad

Combination Therapy against Multidrug Resistance explores the potential of combination therapy as an efficient strategy to combat multi-drug resistance. Multidrug resistance (MDR) occurs when microorganisms such as bacteria, fungi, viruses, and parasites are excessively exposed to antimicrobial drugs such as antibiotics, antifungals, or antivirals, and in response the microorganism undergoes mutations or develops different resistance mechanisms to combat the drug for its survival. MDR is becoming an increasingly serious problem in both developed and developing nations. Bacterial resistance to antibiotics has developed faster than the production of new antibiotics, making bacterial infections increasingly difficult to treat, and the same is true for a variety of other diseases. Combination therapy proves to be a promising strategy as it offers potential benefits such as a broad spectrum of efficacy, greater potency than the drugs used in monotherapy, improved safety and tolerability, and reduction in the number of resistant organisms. This book considers how combination therapy can be applied in multiple situations, including cancer, HIV, tuberculosis, fungal infections, and more. Combination Therapy Against Multidrug Resistance gathers the most relevant information on the prospects of combination therapy as a strategy to combat multridrug resistance and helping to motivate the industrial sector and government agencies to invest more in research and development of this strategy as a weapon to tackle the multidrug resistance problem. It will be useful to academics and researchers involved in the development of new antimicrobial or antiinfective agents and treatment strtategies to combat multidrug resistance. Clinicians and medical nurses working in the field of infection prevention and control (IPC) will also find the book relevant

• Explores strategic methods with investigation of both short- and long-term goals to combat multidrug resistance
• Presents a broad scope to understand fully the ways to apply combined therapy to multidrug resistance
• Provides an overview of combination therapy, but also includes specific cases such as cancer, tuberculosis, HIV and malaria

• Language: English
• Publisher: Academic Press
• Release date: Apr 30, 2020
• ISBN: 9780128205785

Book preview

Federation

Preface

Mohmmad Younus Wani; Aijaz Ahmad

Humans have been plagued by dreadful diseases for centuries, but during the last few centuries tremendous advances have been made that have either completely cured or minimized the impact of many diseases. Today, hundreds of thousands of powerful medicines are used to treat and often cure conditions that were thought to be incurable or untreatable a couple of decades ago. But, sadly enough, the misuse, overuse, and abuse of these drugs have resulted in the development of multidrug resistance (MDR), which is a global problem of great concern that needs immediate attention and action. New resistance mechanisms are developing and spreading globally, more rapidly than the development of new drugs, therefore threatening our ability to treat any multidrug resistant pathogen or disease. In 2016, 490,000 people globally developed multidrug-resistant TB, and drug resistance has also started to complicate the fight against other diseases like malaria, HIV, and cancer. In recent decades, bacterial resistance to antibiotics has developed faster than the production of new antibiotics, making bacterial infections increasingly difficult to treat. In addition, pharmaceutical companies are showing less interest in developing new antibiotics. Scientists worry that a particularly virulent and deadly superbug could one day join the ranks of existing untreatable bacteria, causing a public health catastrophe.

Among the various strategies to combat MDR, combination therapy shows great promise, as it offers potential benefits such as a broad spectrum of efficacy, greater potency than the drugs used in monotherapy, improved safety and tolerability, and reduction in the number of resistant organisms. Combination therapy (or polytherapy) is the use of a combination of drugs to treat a drug-resistant infection or disease, on the theory that if one drug can do something, two or three could accomplish more. While it typically denotes the use of two or more drugs, it can also include immunotherapy and nonmedical therapies, including psychological therapy and other means of therapy or treatment. Combination therapy has been a standard treatment for infections of human immunodeficiency virus (HIV), Plasmodium falciparum, Mycobacterium tuberculosis, and Pseudomonas aeruginosa, and in cystic fibrosis (CF) patients. The growing clinical studies and the recent FDA approval of different combination drugs and regimes for the treatment of different diseases clearly argues that combination therapy affords great opportunities for the discovery and development of novel medicines in the 21st century.

The time is right to provide a state-of-the-art study of MDR and therapeutic strategies against it. Although a plethora of material is currently available in the form of research articles and reviews covering the multidrug resistance problem, there is no comprehensive coverage of the potential of combination therapy as an efficient strategy to combat multidrug resistance in the form of a book. Previous works on combination therapies are either a chapter in a book or a section in a book chapter. Therefore a comprehensive book devoted entirely to combination therapy against multidrug resistance will be an important addition to the literature.

This book is intended to bring to its audience crucial information on multidrug resistance and the potential of combination therapy as an efficient strategy to combat it. The book will enlighten readers on the views of experts, from different countries and having a wide spectrum of backgrounds, who have made significant contributions in understanding drug resistance and handling it with different combination therapies.

This book will also serve as a comprehensive literature guide for beginning researchers and as reference material for the academic and research community involved in tackling the multidrug resistance problem. This book is especially aimed at focusing the attention of researchers in the pharmaceutical industry toward making use of combination therapy as a treatment strategy to tackle the drug-resistance problem. This strategy has already been quite successful in combating drug-resistance in many cases, but work is still needed, both from the research community and industrial sectors, to streamline efforts and understand the need to develop treatment strategies to augment the therapies currently being used. We hope the readers of this book will find in its pages valuable information and views on MDR and combination therapies, and will use it to develop new treatment strategies.

Chapter 1

Combination therapy: Current status and future perspectives

Manzoor Ahmad Malika; Mohmmad Younus Wanib; Athar Adil Hashmia    a Bioinorganic Lab., Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi, India

b Department of Chemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia

Abstract

A one-size-fits-all approach to treating diseases of current concern seems increasingly ineffective, more difficult, and unrealistic. Due largely to resistant strains of disease-causing pathogens and genetic differences in patients, modern medicine is beginning to change its approach. This shift is seen in the attention being paid toward personalized medicine, attempts at fewer side effects, broad spectrum activity, and ongoing research into gene therapy and immunotherapy. One method gaining attention is the use of combination drugs or combination therapy, sometimes referred to as polytherapy, which is a broad term for the use of multiple medications or therapies to fight the same condition. While it typically denotes the use of two or more drugs, it can also include immunotherapy, nonmedical therapies, including psychological therapy, and other means of therapy or treatment. The practice may not be new, but there has been a large increase in the number of approved and researched combination therapies over the past decade. The one drug-one target or magic bullet model has limited viability, and combination therapy is now the norm in the treatment of many cancers, viral infections such as HIV, and tuberculosis treatment. Overall, current data support that combination therapy with two or more drugs appears to be more effective than monotherapy to combat the multidrug resistance problem.

Keywords

Combination therapy; Drugs; Multidrug resistance; Synergy

Abbreviations

AIDS 

acquired immunodeficiency syndrome

AMP 

antimicrobial peptides

ART 

antiretroviral therapy

ARVs 

antiretroviral drugs

CDC 

Centers for Disease Control

DNA 

deoxyribose nucleic acid

FDA 

Food and Drug Administration

FDC 

fixed dose combination

HIV 

human immunodeficiency virus

MBL 

metallo-beta-lactamase

MDR 

multidrug resistance

MRSA 

methicillin-resistant Staphylococcus aureus

WHO 

World Health Organization

1.1 Introduction

Our bodies are equipped with natural (specific and nonspecific) defense mechanisms to fight off invading microbes or unwanted changes that may cause disease. An infection or a disease occurs when the body’s defense system gives up or loses the battle and that is when drugs come to our rescue. Possibly the earliest written accounts of medical therapeutics used by humans are found in the famous Ebers papyrus, which is an almost 20-m long, 110-page medical scroll named after the German Egyptologist Georg Ebers, who acquired it in 1872. Hundreds of treatment options are described in the Ebers papyrus for diseases afflicting ancient Egyptians in ∼   1500 BC, and these treatments involved mixing various herbs, leaves, shrubs, minerals, and animal excreta—forming a combination (Jones, 2011).

The isolation and characterization of the active principles in medicinal plants signified a major challenge, which was later met by the development of synthetic drugs. Today we have 10,000   + ever-more targeted and increasingly powerful high-tech medicines that can treat and often cure conditions that have confounded healers for thousands of years. These drugs, particularly antibiotics, have moved us from being helpless victims of epidemics to being able to fight off potentially deadly diseases. However, sadly enough, with these new medicines has come an increase in the misuse, overuse, and abuse of some of them, which has led to the emergence of multidrug resistance (MDR), a global problem of great concern.

The upsurge in microbial resistance has become a significant threat worldwide. Development of resistance to the available drug candidates has resulted in considerable patient mortality and morbidity (Tamma, Cosgrove, & Maragakis, 2012). Although researchers are involved in the development of new drug candidates for combating the serious problems created by rising multidrug resistance (MDR), the situation appears to be far more complex. During the past two decades, only two new classes of antibiotics have been introduced into clinical use, but none of them is assuredly active against gram-negative bacteria. Daptomycin, which was offered clinically in 2003, lost ground a year later due to the development of resistance in patients with Enterococcus faecium and MRSA infections (Worthington & Melander, 2013). Multidrug resistance against other life-threatening diseases such as malaria, tuberculosis, cancer, and viral diseases such as HIV/AIDS is already ringing alarm bells; it is feared that we may lose the battle if new treatment modalities or strategies are not discovered. Among the various strategies that could augment the current treatment regimen and add to the armament against multidrug resistance is combination therapy. It is imperative to examine the influence of drugs beyond what they can accomplish alone. A combination of drug candidates can act as a multiplier and thereby increase the sum of their benefits.

Drug combinations have been discussed for the treatment of diagnosed conditions for some time, such as aspolol (a combination of atenolol and aspirin) for patients diagnosed with cardiovascular disease. For preventive use, Wald and Law proposed the use of a combination of well-known and inexpensive medications in one pill (called a polypill) for defense against cardiovascular disease (Wald & Law, 2003). Based on the emerging and ongoing clinical studies and research outcomes it is now clear that the use of drug combinations is an effective approach for the treatment of complicated and refractory diseases. The Drug Combination Database (DCDB) has a collection of 1363 drug combinations (330 approved and 1033 investigational, including 237 unsuccessful usages), involving 904 individual drugs and 805 targets; the purpose of the database is to facilitate in-depth analyses and to provide a basis for theoretical modeling and simulation of such drug combinations (Yanbin et al., 2014). Almost 10,000 clinical trials are presently registered in the United States alone, exploring combination therapies for the successful eradication of cancer, infectious diseases, and cardiovascular, neurological, autoimmune, and metabolic disorders. Numerous research articles contain details on drug combinations. Yet, these numbers are quite modest relative to all possible and potent combinations that could be tested (Rationalizing combination therapies, 2017). The numbers of US Food and Drug Administration (FDA) approvals of different classes of combination drugs have, however, increased since the approval of the first combination drugs in the 1940s (Fig. 1.1). Between the 1940s and 1950s the highest growth rate (37.5%) occurred, while the lowest growth rate occurred between the 1960s and 1970s (9%). This initial surge followed by the slowed approval rate of combination drugs was due to the FDA’s new strict criteria and support guidelines announced in 1971. Since 1971, a strong indication has been required to show that a combination drug offers a therapeutic benefit in comparison to each individual drug entity (Finland, 1974). In 1943, the combination drug hycodan (homatropine + hydrocodone), which has been discontinued, was the earliest combination to be approved. Cafergot, a combination of ergotamine and caffeine, was approved in 1948, and since then more than 400 new drug combinations have been approved. The FDA approval of drug combinations for different classes of diseases, including HIV, cancer, and infectious diseases, is now on the rise, with the majority of drug combinations approved for treating infectious diseases (Fig. 1.1).

Fig. 1.1 FDA approval of combination drugs by decade (1940s–2019).

Drug combinations can have synergistic or even additive effects. However, it is imperative to note that not all seemingly rational combinations of drugs will yield better efficacy or safety. For example, a 2004 trial disclosed that torcetrapib could raise HDL and lower LDL both with and without an added statin (Brousseau et al., 2004). However, its combination with atorvastatin (Lipitor) led to a 60% increase in deaths (Nissen et al., 2007). Therefore, in-depth investigations of the known cases of successful and unsuccessful drug combinations are needed to recognize the patterns of valuable drug interactions and to deliver the bases for rational design of efficient drug combinations.

1.2 Combination rule

A combination drug is a fixed-dose combination (FDC) of two or more pharmaceutically active ingredients combined in a single dosage form. As one or both drugs are typically already FDA approved, there might appear to be no need for approval of many drug combinations. However, since the FDA approval is for the drugs alone and not for the combination, FDA approval for the combination is therefore required. For example, to develop an aztreonam-avibactum combination drug, which involves the FDA-approved beta-lactamase resistant aztreonam and a non-beta-lactam-beta-lactamase inhibitor, avibactum, which also restores aztreonam’s activity against isolates expressing multiple beta-lactamases, phase II and phase III clinical studies were required for FDA approval. Another example is the combination of naltraxone HCl and bupropion HCl for weight management, for which similar clinical trials were required for approval. In many cases, additional studies beyond those required for the original approval of the two component drugs are required because the FDA must apply what is commonly referred to as the combination rule. This rule states that two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.

In order to fulfill the requirements of the combination rule, a combination must demonstrate that each component contributes to the safety or efficacy of the product. This typically requires a multifactorial study in which each component is compared separately and in combination with a placebo control. For example, if the product aims to combine Drug A and Drug B, clinical studies with the following treatment arms may be required to demonstrate that each component contributes to the overall effect of the drug:

Placebo

Drug A

Drug B

Drug A and Drug B combined.

Developing a triple combination (three-drug combination) may require eight treatment arms. However, the complexity increases even more when one considers that the dose of each drug must be justified in terms of dosing frequency, amount of each drug, and duration of each effect. If the dosage requires clinical justification, the required studies may be so numerous or so large that they may not be logistically or financially possible.

1.3 Combination therapy: Current status

In combination therapy, two or more drug candidates are used together to achieve better results than the routinely used monotherapy. Typically, combination therapy has one or more of the following aims: (i) decreasing the rate at which acquired resistance arises by combining drugs with minimal cross-resistance, such that emergence of resistance requires attainment of multiple mutations in rapid succession—an unlikely event; (ii) lowering the doses of drugs with nonoverlapping toxicity and similar therapeutic profile so as to attain efficiency with fewer side effects; (iii) sensitizing cells to the action of a drug through the use of another drug (chemosensitization) or radiation (radiosensitization), often by altering cell-cycle stage or growth properties (cytokinetic optimization); and (iv) achieving enhanced potency by exploiting additivity, or better yet, greater-than-additive effects, in the biochemical activities of two drugs. The objectives of combination therapy are not mutually exclusive, and good combinations like ABV (doxorubicin, bleomycin, vinblastine) or BEP (bleomycin, etoposide, cisplatin) accomplish several objectives, including positive cytokinetic and biological interaction (with and without surgery), and reduced toxicity (Fitzgerald, Schoeberl, Nielsen, & Sorger, 2006). Combination therapy has been a standard treatment for infections of human immunodeficiency virus (HIV) and in cystic fibrosis (CF), Plasmodium falciparum, Mycobacterium tuberculosis, and Pseudomonas aeruginosa patients (Vestergaard et al., 2016). Previous studies have endorsed that the advantage of combination therapy against MDR P. aeruginosa infections was mainly due to an increased possibility of selecting an effective agent rather than an in vitro synergy among antimicrobials or prevention of resistance (Garnacho-Montero, Sa-Borges, Sole-Violan, et al., 2007). Against other MDR gram-negative bacteria, however, quite a few studies have revealed higher efficiency and lesser levels of resistance for combination treatment in comparison to monotherapy (Batirel, Balkan, Karabay, et al., 2014; Daikos, Petrikkos, Psichogiou, et al., 2009; Zarkotou, Pournaras, Tselioti, et al., 2011). An upsurge in the survival rate was detected when colistin was administered as part of combination treatments with tigecycline (an aminoglycoside) or meropenem (particularly for carbapenem, minimal inhibitory concentration (MIC) below 4 mg/L). Higher elimination rates were also confirmed for the combination of colistin with rifampin compared to colistin monotherapy against A. baumannii (Durante-Mangoni, Signoriello, Andini, et al., 2013). Similarly, synergistic effects of fosfomycin have been established with carbapenems (along with a decrease in the appearance of resistance), aminoglycosides, and quinolones (Samonis, Maraki, Karageorgopoulos, et al., 2012). Lower mortality rates were observed in Klebsiella pneumoniae carbapenemase (KPC)-associated infections on using a triple combination therapy containing a carbapenem, tigecycline, and colistin. A recent metaanalysis, including studies carried out in the United States, Greece, and Italy, has related the clinical results of combination therapy versus monotherapy for treating carbapenemase-producing Enterobacteriaceae infections, primarily KPC bloodstream infections (BSIs) (Tzouvelekis, Markogiannakis, Piperaki, et al., 2014). A significant difference in the mortality rates for carbapenem-containing regimens (18.8%) compared to the noncarbapenem- containing regimens (30.7) signifies that the presence of a carbapenem in the combination may afford a better survival benefit. Overall, current data backs the usage of combination therapy involving colistin and/or tigecycline along with a carbapenem in the therapy of invasive infections caused due to carbapenem-resistant K. pneumoniae, specifically in severe infections.

1.3.1 Bacterial infections

The overuse and misuse of antibiotics in the healthcare and agricultural industries has resulted in the spread of bacterial resistance worldwide. The recent rise of multidrug resistant (MDR) bacteria, particularly the strains of earlier susceptible bacteria (notably staphylococci) and other bacterial species (like those of aerobacter, proteus, and pseudomonas) resistant to the commonly used antibacterial agents has resulted in a call for the adoption and development of new strategies to tackle this global issue. The rise of extended-spectrum beta-lactamase (ESBL)-producing bacteria, carbapenem-hydrolyzing beta-lactamases, or carbapenemases including metallo-beta-lactamases (MBLs; e.g., New Delhi metallo-β-lactamases, plasmid-mediated imipenem-type carbapenemases, Verona integron-encoded metallo-β-lactamases) and the oxacillinase group of β-lactamases (OXA)-type carbapenemases (e.g., OXA-23 in A. baumannii and OXA-48 in K. pneumoniae) has significantly increased the need for new antibiotics. The delay in the evolution of new antibiotics led to the successful use of combination drugs to treat multidrug-resistant bacterial infections, which began with the use of a combination of tetracycline and oleandomycin. Several new combinations or some mixtures of antibiotics with several sulfonamides and with other drugs exhibiting pharmacologic properties have been introduced. Since the FDA approval of third-generation cephalosporin and the β-lactamase inhibitor combination ceftazidime/avibactam in 2015, the combination of meropenem with the β-lactamase inhibitor vaborbactam in 2017 represented a paradigm shift from the development of new antibiotics to the use of already available drugs in combination (Table 1.1). As of July 2018, a total of about 48 antibiotics (along with some combinations) and 10 biologicals that target the WHO priority pathogens Mycobacterium tuberculosis and Clostridium difficile were in the pipeline (Table 1.2) (WHO, 2018). Quite recently the FDA approved the antibacterial injection drug Recarbrio, a combination of imipenem, cilastatin, and relebactum, to treat adults suffering from complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs) (FDA, 2019).

Table 1.1

Table 1.2

Combination therapy has largely been used to fight MDR bacterial infections and the current focus on their applications using antimicrobial peptides (AMPs) may permit antibiotics to be potent against resistant bacterial strains. Research on a wide range of AMPs displayed promising activity against some resistant strains. Increased understanding of the mode of action of AMPs has revealed similarity and complementarity to conventional antibiotics and the combination of both has led to synergistic effects in some cases. By joining an antibiotic with an AMP, a new compound may be obtained with possibly superior activity and reduced side-effects and toxicity. Such antimicrobial peptide conjugates can act as unique adjuvants for the antibiotic by disturbing the resistance mechanisms of bacteria, thereby permitting the antibiotic to once again be effective (Sheard, O’Brien-Simpson, Wade, & Separovic,