Elsevier

Journal of Controlled Release

Volume 349, September 2022, Pages 338-353
Journal of Controlled Release

Review article
Nano delivery systems to the rescue of ciprofloxacin against resistant bacteria “E. coli; P. aeruginosa; Saureus; and MRSA” and their infections

https://doi.org/10.1016/j.jconrel.2022.07.003Get rights and content

Abstract

Ciprofloxacin (CIP) a broad-spectrum antibiotic, is used extensively for the treatment of diverse infections and diseases of bacteria origin, and this includes infections caused by E. coli; P. aeruginosa; S. aureus; and MRSA. This extensive use of CIP has therefore led to an increase in resistance by these infection causing organisms. Nano delivery systems has recently proven to be a possible solution to resistance to these organisms. They have been applied as a strategy to improve the target specificity of CIP against infections and diseases caused by these organisms, thereby maximising the efficacy of CIP to overcome the resistance. Herein, we proffer a brief overview of the mechanisms of resistance; the causes of resistance; and the various approaches employed to overcome this resistance. The review then proceeds to critically evaluate various nano delivery systems including inorganic based nanoparticles; lipid-based nanoparticles; capsules, dendrimers, hydrogels, micelles, and polymeric nanoparticles; and others; that have been applied for the delivery of CIP against E. coli; P. aeruginosa; S. aureus; and MRSA infections. Finally, the review highlights future areas of research, for the optimisation of various nano delivery systems, to maximise the therapeutic efficacy of CIP against these organisms. This review confirms the potential of nano delivery systems, for addressing the challenges of resistance to caused by E. coli; P. aeruginosa; S. aureus; and MRSA to CIP.

Introduction

Nature generally allows the co-existence of mankind and microorganisms. Microorganisms have taken advantage of this gift of nature to express themselves in various forms that are both beneficial and harmful to mankind, serving as a root cause of diverse infectious diseases that have plagued humans from time immemorial and continues to do so, emerging as a current global crisis. Infectious diseases can generally be defined as any disease induced by microbial pathogens, which include fungi, viruses, and bacteria, that can be transmitted from one organism to another, either primarily or secondarily [1,2]. Infections caused by bacteria have been identified as a significant course of morbidities over the years and are associated with high mortality rates [1,3]. Globally, there are alarming mortality rates reported in various geographical regions, with recent reports showing the Asian region accounting for the highest rate of 4,730,000 deaths per year, followed by Africa with 4,150,000; and other regions which includes Latin America, estimated to be 392,000; Europe, estimated to be 390,000; North America and Oceania estimated to be 317,000 and 22,000, respectively [4].

Antimicrobial resistance (AMR) has been on the increase over the past two decades and has been ruled by the World Health Organization (WHO) to be one of the top ten threats to public health globally [4]. The discovery of antibiotics was regarded as a therapeutical miracle that has been saving lives globally. However, the abuse and misuse of these antimicrobials for treatment in animal and human medicine have escalated AMR globally [5]. The continuing increase in drug-resistant infections caused by bacteria which have been detected, diagnosed, and cured can be attributed to AMR, which threatens public health worldwide [6]. The noteworthy annual mortality caused by diverse infectious diseases globally, includes but is not limited to community-acquired pneumonia (CAP), estimated to be 2.5 million [7]; typhoid fever, which is estimated to be 75,000–208,000 [8]; and leptospirosis (58,900) [9]. Bacterial infections are associated with two current leading causes of death. Sepsis has emanated as a serious danger to the general health of the public across the globe and is life-threatening due to organ dysfunction emanating from a dysregulation in the immune reaction of the host to infections that could lead to death, when not unmasked and properly managed in the preliminary stages [1]. Bacterial infections have been reported to be a major cause of sepsis, which was recently reported by Pant et al. (2021) to be 48 million known cases, with a related mortality rate of 11 million worldwide [10]. Therapeutic mitigation of this disease condition (sepsis) includes making use of a broad-spectrum antibiotics proven to be effective in eliminating the causative bacteria, with importance laid on source control [11]. Furthermore, with the recent global pandemic, there was a widespread and long-term use of steroids, which lowered the immunity of COVID-19 patients [12]. This resulted in the emergence of pan resistance infections that needed treatment with multiple or higher generation antibiotics such as CIP. Moreover, the spread of COVID-19 around the globe resulted in the increased consumption of antibiotics and misuse [13].

Bacteria species are both beneficial and pathogenic to mankind. The majority of Escherichia coli (E. coli) strains are normal flora and are known to be of great benefit to healthy individuals, since they are harmless, and are contained in the large intestines where they help supply vitamin K to the host organism [14]. Unfortunately, there exist some pathogenic strains of E. coli which are disease efficient, and are known to be the leading cause of infections which could result in intestinal infections [15,16], and urinary tract infections (UTI) [17]. There has been a rapid spread of the recently discovered quinolone-resistant E. coli (QREC) in the last two decades [18], with a European case study which reported that 30% of the recorded invasive E. coli isolates were fluoroquinolone (FQ) resistant [19], limiting the established therapy with FQ class antimicrobials. An example of an opportunistic pathogen which could leverage on the compromised immune system or comorbidities of an individual is Pseudomonas aeruginosa (P. aeruginosa). This pathogenic organism con cause a variety of acute or chronic infections [20]. As one of the most commonly known causes of nosocomial infections, it can spread to most of the host body tissues [21], causing chronic lung infections in patients with cystic fibrosis (CF), thereby contributing to the deterioration in the health of the patient [22]. These chronic infections caused by P. aeruginosa can persist for a long period (possibly for decades), during which they grow and replicate with thousands of generations while they face the challenges of iron deprivation, treatment with antibiotics, and inter-species competition [23]. Staphylococcus aureus (S. aureus), in particular, continually spearheads the course and transmission of infectious diseases linked with increased mortality rate [1,24]. Most of the community- and hospital-acquired infections and diseases owing to antibiotic-resistance such as sepsis; pneumonia; impetigo and endocarditis are reported to be associated with S. aureus infections [1,25,26]. Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant danger to the general health of humans either in the hospital or the community neighborhood [27]. They, like many other bacteria, have the capacity to shield themselves from the reach of therapeutic agents with the help of a biofilm which they form around themselves, thereby shielding themselves from the response of the immune system of their host [28]. The Centers for Disease Control and Prevention (CDC) has, in a recent report, ruled MRSA-related infections and death (estimated to be 80,461 and 11,285, annually, respectively) as the arrowhead amongst other bacterial infections in the United States of America (USA) [29]. The high occurrence of MRSA has also been recorded across other continents, with Asia, South and North America recording over 50%; Europe 18 to 49%; and Africa and Australia 20 to 50% of recorded infections and bacteria-related diseases attributed to MRSA [1,30,31]. Therefore, strategies to improve the treatment of the diseases caused by these bacteria are urgently needed.

Fluoroquinolones are arguably one of the most prestigious classes of antibiotics, and having a wide spectrum of activity, means they are active against both the Gram negative and Gram positive bacteria [32]. Some members of this antibiotic class include moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin, which are used for the therapy of infections such as UTI; CAP; bacteremia; sexually transmitted diseases (STDs); respiratory infections; bone infections; skin and soft tissues infections [[32], [33], [34]]. Fluoroquinolones, and specifically ciprofloxacin, have seen their clinical use and applications increased, relative to other antibiotic classes, because of their wide spectrum activity and cost effectiveness, which made it an essential drug in many health care settings, including the Low-or-Middle-Income Countries (LMIC). This attribute is considered to be of great public health importance, because of the large increase in the number of seriously ill patients with impaired or defective immune systems admitted to clinics, and treated with vital antibiotics [35]. Ciprofloxacin (CIP) invades the mammalian tissues and cells, and its mechanism of action includes; binding to the deoxyribonucleic acid (DNA) gyrase, topoisomerase IV and the type II topoisomerase enzymes of the bacteria [34,36]. Mechanism of action of CIP is its Achilles heel, as the drug must penetrate the bacterial membranes, to act centrally in the nucleus, inhibiting DNA replication. Unfortunately, the conventional dosage forms of CIP, like other members of its class of antibiotics, lack the ability to deliver the drug to the bacterial nucleus. Moreover, bacteria have developed resistance mechanism, such as mutating target sites, alteration of drug permeation through the outer membrane of the cell, and creation of efflux pumps; and CIP is not immune to this resistance. Due to such resistance mechanisms, CIP antibacterial efficacy has been reduced significantly in recent years, and the number of CIP-resistant bacteria is on the rise. This is of serious concern, because CIP is an affordable essential drug used by the masses globally, to treat bacterial infections [37,38]. Therefore, the need for effective delivery systems which can help increase their solubility, rate of active site binding, specificity in targeting, and overcoming the efflux pumps of these resistant pathogens, to effectively increase the antibacterial efficacy of fluoroquinolone antibiotics such as CIP cannot be over emphasised.

Nanotechnology has shown its usefulness in serving as a bridge to the barriers confronting both biological and physical sciences, owing to increasing use of nanostructures and nanophases in different fields of science [1,39]. Noteworthy, is the application in nanomedicine, because of the smaller particle sizes, which can range from 1 nm to 100 nm, and their use in drug delivery which improves drug solubility, stability and specificity in drug targeting of disease causing organisms [40,41]. There have been various nano delivery systems for antibiotics which includes emulsions; polymeric nanoparticles; micelles; metallic nanoparticles; nanoplexes; hydrogels; dendrimers; niosomes; cubosomes; and nano capsules, used for specific drug targeting against E. coli; P. aeruginosa; S. aureus; and MRSA and has seen their efficacy and antibacterial efficiency increased relative to the conventional forms of the drug [1,42,43]. More specifically, the potential of CIP loaded nano delivery systems to maximise therapeutic efficacy and overcome bacterial resistance is being increasingly reported.

Various reviews have been published focusing solely on the different mechanisms of resistance of E. coli [44], P. aeruginosa [22], S. aureus and MRSA [45] to CIP. However, despite the emerging potential of nano drug delivery systems for enhancing and maximising the efficacy of CIP, in the treatment of infections caused by E. coli, P. aeruginosa, S. aureus and MRSA, there exists no review to date, to the best of our knowledge, that comprehensively reviews and critically evaluates the various nano drug delivery systems employed to improve CIP efficacy against these organisms.

Herein, an overview of CIP antibiotic; the resistance mechanisms against ciprofloxacin; the causes of this resistance; and the various approaches that have been employed to resolve this resistance are briefly highlighted. Thereafter, the review presents and critically evaluates the various nano delivery systems that have been applied to potentially overcome the resistance posed to CIP antibiotic. Lastly, we proffer some future perspectives of research, for the optimisation of various nano delivery systems, to maximise the therapeutic efficacy of CIP against these organisms.

Section snippets

Ciprofloxacin

Ciprofloxacin (CIP), a broad–spectrum antibiotic, and a member of the fluoroquinolones class of antibiotics has, right from 1987 when it was first introduced into the market, been the most generously used antibiotic globally for chemotherapeutic applications [46,47]. It has been included by the WHO in the essential drug list due to its essential use in therapeutics of various types of infectious diseases induced by various bacteria, including E. coli; P. aeruginosa; S. aureus; and MRSA, which

Nano delivery systems used for CIP delivery against E. coli, P. aeruginosa, S. aureus and MRSA

This section critically discusses the various nano delivery systems that have been applied in CIP delivery against E. coli, P. aeruginosa, and S. aureus, according to different subcategories such as inorganic nanoparticles; lipid-based nanoparticles; general nanoparticles; and others: capsules; dendrimers; micelles; hydrogels; nano fibers and polymeric nanoparticles.

Future perspectives

The evolution of AMR, specifically in E. coli, P. aeruginosa, S. aureus and MRSA, presage a loss of faith in the efficacy of conventional dosage forms for broad-spectrum antibiotics such as CIP. Nanotechnology and nano particles could be a game-changer, due to their different advantageous peculiarities in providing a suitable carrier for drugs and bioactive compounds, thereby overcoming AMR and, in turn, improving the antibacterial efficacy of existing drugs and drug-like molecules, including

Conclusion

Nano drug delivery systems have diverse, advantageous and distinctive features as drug or bioactive agent carriers, which empowers them to deliver drug and drug-like molecules for the therapy of infections and diseases caused by E. coli, P. aeruginosa, S. aureus, and MRSA. Currently, nano drug delivery systems remain one of the best approaches to curbing AMR in E. coli, P. aeruginosa, S. aureus, and MRSA against CIP and antimicrobials, generally. Various studies have shown that encapsulating

Declaration of Competing Interest

The authors declare no conflicts of interest.

Acknowledgements

The authors wish to acknowledge the College of Health Sciences of the University of KwaZulu–Natal (UKZN) and the UKZN Novel Drug Delivery Research Group, the National Research Foundation (NRF Grant No. 106040, 103664 and 116652) South Africa and the Medical Research Council (MRC) of South Africa for the funding of this work.

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