ReviewKeynoteNovel approaches for the treatment of methicillin-resistant Staphylococcus aureus: Using nanoparticles to overcome multidrug resistance
Introduction
Staphylococcus aureus is a Gram-positive bacterium responsible for many complex infections, including skin and soft tissue, pneumonia, bone and joint infections, osteomyelitis, and infective endocarditis [1]. A high mortality rate resulting from S. aureus was observed when antibiotic treatments were not available [2]. Penicillin came into use as a treatment for these infections, but resistance developed to this antibiotic within 2 years. Soon, ∼80% of S. aureus were penicillin resistant [3]. Following this development, methicillin was introduced, with stability against degradation by the penicillinase enzyme. However, methicillin resistance began as soon as it was used to treat the infections [4] and became a major clinically relevant concern from 1960 onwards [5]. MRSA infection is acquired predominately in two settings: secondary to exposure in a healthcare facility, such as hospitals, nursing homes, or dialysis centers [termed health care-associated MRSA (HA-MRSA)]; or exposure acquired in otherwise healthy individuals in the community [termed community-associated MRSA (CA-MRSA)]. In 2017, the Center for Disease Control (CDC) recorded 323 700 cases and 10 600 deaths as ‘incident hospitalized positive clinical cultures, including hospital- & community-onset MRSA infections’ [6]. Chamber and DeLeo illustrated the trends of this resistance, which was first identified during the 1940s and is ongoing [3] (Fig. 1). The most recent wave of vancomycin resistance was first identified during the 2000s and remains prevalent. Although treatment of MRSA remains challenging, the much needed progress in MRSA infection management has slowed significantly [7].
Section snippets
Resistance mechanisms
Resistance to antimicrobial agents is a major reason for the failure of MRSA treatment. There are various mechanisms that contribute to antimicrobial resistance. These can be inherent to MRSA or acquired with the time and length of treatment. Each antibiotic combats MRSA by different mechanisms of action characteristic of the antibiotic class. Similarly, the subsequent resistance mechanisms against each of these drug classes in MRSA can also manifest by different mechanisms (Fig. 2). Table 1
Drawbacks of current conventional therapies
There are various treatment options available clinically for MRSA. Although vancomycin remains the frontline treatment option, it has several limitations, such as high dosage, longer treatment duration, renal toxicity, and low oral absorption, with intravenous injection, although inconvenient, the only available treatment method 31, 32. In addition to vancomycin, there are other drugs available on the market that could circumvent the drug resistance seen in MRSA therapy. However, when
Nanoparticles for the delivery of anti-MRSA agents
Given that current treatment strategies for MRSA are either rendered ineffective or have shown severe adverse effects, there is a need to find alternative strategies besides novel drug discovery and repurposing of current drugs. This alternative strategy could also contribute to improving the bioavailability and safety of current treatments. Research endeavors have been made in this direction to enhance the bioactivity and bioavailability of different pharmaceutical agents by using nanoparticle
Photodynamic therapy
The use of nontoxic dyes or photosensitizers (PS) in conjunction with harmless visible light, known as photodynamic therapy (PDT), has become popular [111] and can be used successfully to eradicate the growth of tumors. A similar strategy was used to suppress the growth of bacterial cells. Perni described the implementation of light-activated NPs to enhance the delivery of agents to the infection site [112].
Liposomes have been widely explored for PDT using hematoporphyrin to enhance activity
Challenges for nanodrug delivery for MRSA treatment
The success of any nanoparticulate treatment method depends on the ability of the formulation to translate to the clinical setting. However, there are many obstacles in the clinical translation of therapies to the clinic. The first is standardization of the in vitro analyses that are applied at every step of the development of a formulation. These include a variety of experimental methods, from the evaluation of MIC of an antibiotic to toxicity assays, biofilm imaging assays, and so on [120].
Prospects and applications of nanotechnology
A characteristic feature of nanotechnology is its ability to make existing products more efficient by introducing new functionality. Nanodrugs are now available in the clinic to treat various cancers, fungal infections, iron deficiency, and macular degeneration, have also been used as image contrast agents, vaccines, and anesthesia, and have successfully demonstrated greater efficacy compared with conventional models of therapy [126]. Increasing research, development, and translation of novel
Concluding remarks
MRSA treatment faces several challenges with limited therapeutic options. Although some drugs have been introduced to replace or work in synergy with the most widely used drugs, such as vancomycin, all have seen developing resistance by MRSA and, hence, increasing MIC values and dosage required. Moreover, these drugs are also associated with other adverse effects, such as renal toxicity and hepatotoxicity, in addition to their ineffectiveness against bacterial biofilms, which remain one of the
Acknowledgments
K.V. would like to acknowledge the Department of Pharmaceutical Sciences, Wayne State University for a Frank O Taylor scholarship. A.K.I. acknowledges the Michigan Translational Research and Commercialization (MTRAC) award (#380121), EACPHS FRAP award (#477482) and Wayne State University start-up award (#176575) for funding the MRSA projects in his lab.
Kushal Vanamala is pursuing a MSc in the Iyer lab in the Department of Pharmaceutical Sciences at Wayne State University (WSU). His current research focuses on developing targeted nanoparticle delivery systems for infectious diseases and cancers.
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Cited by (0)
Kushal Vanamala is pursuing a MSc in the Iyer lab in the Department of Pharmaceutical Sciences at Wayne State University (WSU). His current research focuses on developing targeted nanoparticle delivery systems for infectious diseases and cancers.
Marc Scheetz is a professor at Midwestern University in the Chicago College of Pharmacy and holds a joint appointment in the Department of Pharmacology, College of Graduate Studies. Dr Scheetz was awarded a Doctorate of Pharmacy from Butler University, earned a MSc in Clinical Investigation at Northwestern University, and completed his pharmacy practice residency and an infectious diseases fellowship at Northwestern Memorial Hospital. Dr Scheetz is also the Director of the Pharmacometric Center of Excellence at Midwestern University. He currently practices clinically as an infectious diseases pharmacist at Northwestern Memorial Hospital in Chicago, IL and serves as the Director for the Post-Doctoral Fellowship Program in Infectious Diseases Pharmacotherapy.
Michael J. Rybak is a professor of pharmacy in the Department of Pharmacy Practice, adjunct professor of pharmaceutical sciences in, and Director of the Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences, WSU. He is also adjunct Professor of Medicine, Division of Infectious Diseases, School of Medicine, WSU and adjunct Clinical Professor of Pharmacy, College of Pharmacy, University of Michigan. His research focus is antimicrobial pharmacokinetics and pharmacodynamics and the assessment of infectious diseases outcomes, including their relationship to bacterial resistance. His most recent work focuses on the use of combination therapy, including the use of bacteriophages plus antibiotics to prevent resistance.
David Andes is the William Craig Professor in the Departments of Medicine and Medical Microbiology, Head of the Division of Infectious Diseases, and Director of the Wisconsin Antimicrobial Drug Discovery and Development Center. His research strives to identify strategies to combat antimicrobial drug resistance. His study tactics span from the bench to the clinic, including delineating the optimal dosing strategies for the treatment of drug-resistant infections, identifying new resistance mechanisms, discovering new antimicrobial drugs and targets, and clinical study of resistance epidemiology.
Arun K. Iyer is an associate professor and the Director of the U-BiND Systems Laboratory at the Department of Pharmaceutical Sciences, WSU. Dr. Iyer received his PhD from Sojo University, Japan, under Hiroshi Maeda. In 2012, Dr. Iyer received the prestigious CRS T. Nagai Research Achievement Award. He has authored >100 publications in peer-reviewed international journals and books and has wide expertise in biomaterials and nanomedicine for treating diseases such as infection, dementia, and cancer.