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Review

From Polymeric Nanoformulations to Polyphenols—Strategies for Enhancing the Efficacy and Drug Delivery of Gentamicin

by
Ance Bārzdiņa
1,2,*,
Aiva Plotniece
1,3,
Arkadij Sobolev
3,
Karlis Pajuste
3,
Dace Bandere
1,2 and
Agnese Brangule
1,2
1
Department of Pharmaceutical Chemistry, Riga Stradins University, 21 Konsula Str., LV-1007 Riga, Latvia
2
Baltic Biomaterials Centre of Excellence, Headquarters at Riga Technical University, LV-1007 Riga, Latvia
3
Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., LV-1006 Riga, Latvia
*
Author to whom correspondence should be addressed.
Antibiotics 2024, 13(4), 305; https://doi.org/10.3390/antibiotics13040305
Submission received: 6 March 2024 / Revised: 25 March 2024 / Accepted: 27 March 2024 / Published: 28 March 2024
(This article belongs to the Special Issue Nanocarriers-Based Antimicrobial Drug Delivery)
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Abstract

:
Gentamicin is an essential broad-spectrum aminoglycoside antibiotic that is used in over 40 clinical conditions and has shown activity against a wide range of nosocomial, biofilm-forming, multi-drug resistant bacteria. Nevertheless, the low cellular penetration and serious side effects of gentamicin, as well as the fear of the development of antibacterial resistance, has led to a search for ways to circumvent these obstacles. This review provides an overview of the chemical and pharmacological properties of gentamicin and offers six different strategies (the isolation of specific types of gentamicin, encapsulation in polymeric nanoparticles, hydrophobization of the gentamicin molecule, and combinations of gentamicin with other antibiotics, polyphenols, and natural products) that aim to enhance the drug delivery and antibacterial activity of gentamicin. In addition, factors influencing the synthesis of gentamicin-loaded polymeric (poly (lactic-co-glycolic acid) (PLGA) and chitosan) nanoparticles and the methods used in drug release studies are discussed. Potential research directions and future perspectives for gentamicin-loaded drug delivery systems are given.

Graphical Abstract

1. Introduction

Due to the alarming rate of increase in antibacterial resistance, common broad-spectrum antibiotics often fail to treat infections. More and more often opportunistic and nosocomial pathogens, especially bacterial strains with a tendency to form biofilms, like Pseudomonas aeruginosa, are the cause of high-morbidity and high-mortality infections that require high-dosage and longer antibacterial treatments [1,2,3]. This again leads to increased antibacterial resistance, creating a vicious cycle. The majority of nosocomial infections are caused by six multidrug-resistant bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). This group of bacteria is commonly referred to as ESKAPE pathogens [4]. All of these bacteria can also be found on the World Health Organization’s (WHO) priority list for research on and the development of new antibiotics for antibiotic-resistant bacteria at either critical or high-priority levels [5]. As there has been a serious shortage of new antimicrobials entering the market in recent years, a search for ways to enhance the efficacy and drug delivery of already known and widely used antibacterial agents like gentamicin is essential.
Gentamicin is a broad-spectrum, bactericidal, aminoglycoside antibiotic. It is effective against a wide range of aerobic Gram-negative bacteria, as well as Gram-positive Staphylococcus species [6]. Of special importance is its potential activity against ESKAPE pathogens. Although it was discovered in the early 1960s [7], gentamicin still is a part of the essential medicines list of the World Health Organization [8]. Because of its wide activity spectrum, gentamicin is used to treat over 40 different clinical conditions, including bacterial sepsis, peritonitis, meningitis, the urinary tract and respiratory tract, eye, ear, bone, and surgical site infections, and others, proving its important role in modern medicine [6,8,9,10]. Figure 1 summarizes United States (US) Food and Drug Administration (FDA) approved, prevalent indications treated with gentamicin.
Gentamicin represents class III of the Biopharmaceutical Classification System due to its high solubility in water and low cellular penetration [11]. Consequently, drug delivery of this active agent alone may be hindered. As gentamicin is used to fight serious infections, often caused by multi-drug-resistant pathogens, ways to lower the needed concentration of gentamicin and ultimately minimize the chance of the development of resistance against it are one of the top priorities.
Therefore, this review paper provides an overview of the chemical and pharmacological properties of gentamicin and offers six different strategies (the isolation of specific types of gentamicin, encapsulation in polymeric nanoformulations, hydrophobization of the gentamicin molecule, and combinations of gentamicin with other antibiotics, polyphenols, and natural products) that aim to enhance the drug delivery and antibacterial activity of gentamicin.

2. The Components and Properties of Gentamicin Complex

Gentamicin is produced by the Micromonospora species of bacteria, as a mixture of multiple components, but mainly consists of five structurally different C-subtypes (C1, C1a, C2, C2a, and C2b) with structural modifications at position 6′ of moiety I (Figure 2A) [12]. The structural differences in the major components are related by the level of methylation—a methyl or hydrogen substitution in two R groups on the 2-amino-hexose residue (I). In gentamicin C1a, methyl groups are missing, whereas both in C1 and C2, a methyl group is present at the 6′ position; gentamicin C1 is N-methylated at this position, while C1a and C2 have free amines. The C2 component consists of two stereoisomers [13]. The ratio of the gentamicin components varies depending on the drug’s manufacturing method, the fermentation conditions, and the purification procedure [14,15].
The major components constitute 92–99% of the gentamicin complex. Other gentamicin derivatives (Figure 2B), as the minor components, are found in the range between 0.8 and 5.3% [15,16].
According to the European Medicine Agency (EMA), the gentamicin composition consists of 10–30% C1a, 25–45% C1, and 35–55% C2, C2a, and C2b [17,18]. The ratio of gentamicin components has been studied using several methods based on paired-ion, high-performance liquid chromatography (HPLC) [19,20] and coupled liquid chromatography–NMR to compare the composition of different batches from various sources [15].
The clinical mechanism of action of the mixture is unclear; it is unknown whether the broad spectrum of antimicrobial action is due to multiple components. In other terms, it is unclear whether each component works across a narrower range of bacterial strains or species than the entire mixture [21]. Numerous research groups worldwide are working on the characterization of the structure–activity relationships of gentamicin components, studying the activity of the difficult-to-separate components of the commercial gentamicin samples, and characterizing specially prepared single components [21,22]. The relative toxicity and activity of the individual components in the commercial gentamicin samples have been studied since the 1970s [16,17]. These studies suggest that gentamicin C2 is less nephrotoxic than the other gentamicin constituents [23]; gentamicin C1 and C1a are less ototoxic than C2 [24]. In more recent studies evaluating the ototoxicity, it was indicated that gentamicin C1a was less ototoxic than a commercial gentamicin mixture. The minimum inhibitory concentration (MIC50 and MIC90) values of both the gentamicin complex and gentamicin C1a against clinical isolates of five bacterial species from E. coli, K. pheumoniae, A. baumannii, P. aeruginosa, and S. aureus were comparable; however, a two-fold increase in MIC50 was observed for the gentamicin C1a isomer compared to the gentamicin complex. However, these two compounds showed rather different in vitro activities against a larger portion of 61 isolates from E. coli, K. pheumoniae, A. baumannii, P. aeruginosa, and S. aureus [25].
Further research on the activity–toxicity relationship of the gentamicin components is necessary to draw concrete conclusions regarding the potential gains of isolating and applying individual gentamicin subtypes.

3. Pharmacology, Stability, and Administration of Gentamicin

Gentamicin belongs to the 4,6-disubstituted-2-deoxystreptamine class of aminoglycosides [26]. Clinically, gentamicin has been used as a sulfate salt. It contains five basic nitrogens and requires five sulfuric acid equivalents per mole of every gentamicin base [27].
The mechanism of action prevents the synthesis of bacterial proteins through electrostatic binding with negatively charged phospholipids’ head groups. Afterwards, the antibiotic binds to the specific ribosomal proteins, resulting in the formation of inactive complexes that cause misreadings in mRNA [28,29]. Gentamicin is a cationic antibiotic with a narrow therapeutic index [30,31]. Its antibacterial activity can be influenced by the pH. A low pH is associated with a decrease in activity [30]. The pharmacological action of gentamicin is concentration-dependent [6].
The pharmacokinetics of gentamicin are comparable to those of other aminoglycosides. Gentamicin is a polar molecule and is poorly absorbed when taken orally (less than 1%); therefore, systemic use requires parenteral administration [31,32,33]. In certain infections, topical and local administration is needed [34]. The local delivery of antibiotics might reduce potential toxic side effects and be of particular use in infections that require the long-term, sustained release of antibiotics, like osteomyelitis [35].
It has been suggested that the standard intravenous gentamicin starting dose of 7 mg/kg based on total body weight appears to optimize the chance of reaching the exposure target after the first administration in both adults and children older than 1 month, including critically ill patients. However, despite numerous recent population pharmacokinetic studies, the optimal pharmacokinetic–pharmacodynamic target for efficacy is still unclear [36]. If patients suffer from renal failure, the dosage of gentamicin needs to be lowered [37].
Gentamicin binds to serum proteins very poorly; in most cases, the binding to serum proteins is under 15% [38]. In the cerebrospinal fluid of patients with uninflamed meninges, it is found in very low concentrations [37]. Gentamicin does not easily penetrate cells; instead, it is mostly distributed in the extracellular fluid [33]. Pinocytosis is the main mechanism of free gentamicin uptake [39]. Gentamicin does not undergo metabolism in the body, and, through glomerular filtration, unchanged gentamicin is quickly eliminated [33,40]. Since gentamicin has a short plasma half-life of around 2 h, frequent administration is needed [31]. The biodistribution of gentamicin causes its most common side effects—nephrotoxicity and ototoxicity [41,42]. The half-life in the renal cortex is estimated to be around 100 h [43]. The pharmacokinetics of gentamicin are dependent on the overall health status of the patient. Altered pharmacokinetic parameters like the volume of distribution, peak concentrations, and renal clearance are affected by conditions like sepsis, heart failure, peritonitis, and renal impairment [33,44].
Gentamicin sulfate sterile solutions should be kept between 2 and 8 °C. Gentamicin solutions have proven to be stable when kept at room temperature and in boiling aqueous buffers with pH values ranging from 2 to 14 [27,45]. Recommendations under the auspices of the International Society for Peritoneal Dialysis (ISPD) underlined that gentamicin is stable for 14 days at all temperatures [46]. A protocol used for microbe–epithelium cocultures states that gentamicin is stable at 4 °C for 1 month [47]. The good stability of gentamicin over a wide range of storage conditions makes it a promising candidate for encapsulation in novel drug delivery systems like nanoparticles.

4. Polymeric Nanoformulations of Gentamicin

In the last two decades, nanoformulations have emerged as one of the frontrunners for the encapsulation and delivery of a wide range of active agents, including antibiotics. Nanoformulations for enhanced drug delivery have provided formulation scientists with the opportunity to achieve a higher bioavailability and biocompatibility, a controlled release, and increased target selectivity [48]. Although the use of nanoformulations in terms of their toxicity and distribution in the body is still under investigation, the potential gains of this approach drive further research in this field [14].
In the case of antibiotics, the main hope for the use of nanoformulations is that they will lower the chance of the development of antimicrobial resistance and achieve the targeted delivery of antibiotics with the lowest effective dose to avoid unwanted side effects for the patient [49,50]. For more than two decades, various lipids, polymers, and other materials have been applied to create micro- and nanoformulations, including nanoparticles, nanofibers, nanocomposites, and others, for the delivery of a wide range of antibiotics [50]. Gentamicin is no exception. In addition to polymeric nanoformulations, gentamicin has been successfully encapsulated into liposomes [51,52,53] and mesoporous silica nanoparticles [54,55,56], as well as being tested for synergic effects in combination with metallic nanoparticles [57,58,59]. A detailed overview of all nanoformulation types for the delivery of gentamicin has been thoroughly evaluated in a recent review paper by Athauda et al. [14]. The use of lipid-based nanoparticles for the delivery of antibiotics and the treatment of infections has already been reviewed in detail by Ferreira et al. [60,61]. Therefore, this review will only focus on recent advances in polymeric formulations, in particular, poly (lactic-co-glycolic acid) (PLGA) and chitosan-based systems, their potential applications, and the main variables impacting the systems and their kinetics. The sustained release properties of gentamicin-loaded nanoformulations and the possibility of enhancing the bioavailability of gentamicin are of particular importance; therefore, these topics will be discussed in detail in further subsections.

4.1. Gentamicin-Loaded PLGA Nanoparticles

PLGA is a polyester copolymer composed of lactic acid (PLA) and glycolic acid (PGA) in varying ratios. It is biodegradable, biocompatible, non-toxic, approved for parenteral use by both FDA and EMA, and allows for a wide range of surface modifications [62]. An overview of gentamicin-loaded PLGA nanoparticles and their main parameters can be found in Table 1.
Since gentamicin is highly hydrophilic, its penetration into cells might be hindered and the clearance of the drug is fast [11,31]. Hence, higher doses should be administered more frequently. In the case of gentamicin, the chance of developing side effects increases accordingly [31]. Low cellular penetration is especially associated with intracellular infections [64]. The encapsulation of gentamicin in polymeric nanoparticles like PLGA and chitosan could offer a solution to the problems caused by the high water-solubility of gentamicin. Drug-loaded nanoparticles have an improved bioavailability and permanence time at the site of infection, in addition to offering a sustained release and protection of premature degradation [11]. Polymers offer a wide variability of parameters, like molecular weight and the ratio between monomers, which can be applied to develop nanoformulations with optimal drug release properties.
In comparison to other polymers, like chitosan and alginate, PLGA nanoparticles can have controlled release properties without a chemical modification [67]. The sustained release of gentamicin from PLGA nanoparticles may be the most important advantage compared to using a free drug. The ratio between PLA and PGA is crucial to the hydrophobicity of the formulation [70]. A higher lactic acid content increases the hydrophobicity of the system and prolongs the release of drugs [64,70]. In addition, a sustained release of the drug can also be achieved by using a polymer with a higher molecular weight [71]. In case of chronic, long-lasting infections, a sustained release will determine the efficacy of the therapy. To date, PLGA 50:50 is the most commonly used PLA:PGA ratio in nanoformulations due to its favorable physiochemical properties and release kinetics [72].
The small molecular weight and the high water-solubility of gentamicin make it challenging to encapsulate it into nanocarriers [11]. One key advantage of using PLGA as a nanocarrier is its ability to encapsulate both hydrophobic and hydrophilic substances. However, different formulation methods need to be applied. For a hydrophilic drug (like gentamicin) encapsulation, multiple emulsions are needed so that the aqueous core containing the drug is coated by a polymer shell [65]. Therefore, the majority of published methods use the double emulsion w/o/w solvent evaporation method, with only a few authors reporting on the use of the s/o/w method [11,65]. A schematic illustration of the solvent evaporation method can be found in Figure 3.
Cao et al. provide an in-depth overview of the influence of various parameters in the w/o/w method on the morphology and physiochemical properties of PLGA particles [73]. In short, the study determined that PLGA concentration and the colostrum emulsification speed are the most influential factors impacting the size of the particles. Lower PLGA concentration levels (10–20 mg/mL) produce particles with a narrow size distribution; however, the shape of the nanoparticles can be rather uneven. A higher PLGA concentration (30–40 mg/mL) allows for the formation of particles with round shapes, although the size distribution of the particles in this case is significantly larger. Up to a certain concentration, an increase in the PLGA concentration increases the drug loading. A higher polymer concentration leads to a higher viscosity and the particles solidify faster. As a consequence, less of the drug can escape from the particles, and the encapsulation efficiency (EE%) and drug loading (DL%) increase [73]. Regarding DL%, the second emulsification step is just as important. Higher emulsification speeds lead to the increased volatilization of solvents like DCM or chloroform, restricting the escape of drugs from particles [73].
Another factor significantly impacting the performance of the formulation method is the pH of the external aqueous phase. Increasing the pH of the external aqueous phase from 5 to 7.4 can increase the EE% up to three times [65]. This phenomenon is based on the deprotonation of the amino groups in the gentamicin molecule, making the molecule less hydrophilic [65].
Poly (vinyl alcohol) (PVA) is the most commonly used surfactant in PLGA-gentamicin nanoformulations. With increasing concentrations of PVA, it is possible to decrease the particle size as well as the polydispersity index (PDI) [66]. A study by Sun et al. suggests that a higher concentration of PVA (9%, 12%) is associated with a more uniform, spherical particle shape [69]. In addition, the hydrophilic nature of PVA could be responsible for the porous surface structures of nanoparticles due to the diffusion processes [69]. The pore size decreases with a higher PLGA concentration [69].
It has been determined that the size of nanoparticles will heavily impact their fate in biological systems. Nanocarriers under 100 nm are prone to endocytosis, while carriers larger than 500 nm will face phagocytosis [74]. The endocytosis of nanoparticles could be more efficient than the pinocytosis of free gentamicin, leading to an increase in the efficiency of the therapy [75]. In practice, most gentamicin-loaded PLGA nanoparticles range between 200 nm and 400 nm (see Table 1). PLGA nanoparticles are internalized using both pinocytosis- and clathrin-mediated endocytosis [76]. After internalization, the PLGA nanoparticles escape the lysosomes and enter the cytoplasm approximately 10 min after incubation [77,78]. It has been suggested that the naturally negative/anionic surface charge of PLGA nanoparticles (due to the carboxylic acid end groups) reverses to cationic with the low pH of endo-lysosomes (pH ≈ 4) [78]. The surface cationization allows for nanoparticles to escape into the cytosol, where the encapsulated drug is released [78]. Moreover, the sustained release of the drug is achievable intracellularly. Since the PLGA nanoparticles are only cationic in the endosomal compartment, and therefore do not cause lysosomal destruction, they could be less toxic in comparison to cationic lipids and cationic polymers [78].
The disadvantages of unmodified PLGA use are the lack of specific targeting properties and response to environmental stimuli, as well as vulnerability to aggregates during freeze-drying [79].
Since, without surface modifications, PLGA has no active targeting properties, it has to rely on passive targeting after intravenous administration. Passive targeting will be more effective against conditions that exhibit enhanced permeability and retention effects, such as cancers and inflammatory processes [80]. If no surface modifications to PLGA nanocarriers are applied, opsonization by macrophages usually occurs at high rates [65]. Due to the previously mentioned reasons and the chance of the development of antibacterial resistance, nanoformulations with gentamicin are most often applied for topical or local delivery.
However, in the case of systemic application, it is possible to apply surface modifications to PLGA to avoid clearance by phagocytes, limit opsonization, and prolong circulation time. The surface of PLGA is most often modified using polyethylene glycol (PEG), different lipids, and target-specific agents, like antibodies and bisphosphonates [81]. To the best of our knowledge, only one publication to date has explored the use of PLGA-PEG for the encapsulation of gentamicin [11].
Three main targets for PLGA–gentamicin nanoparticles can be differentiated—surgical site infections, osteomyelitis, and intracellular infections.
In the case of osteomyelitis, poor vascularization around bone tissues makes drug delivery to the site of infection very difficult [82]. For both surgical site infections and osteomyelitis, which are commonly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, as well as more resistant strains like Methicillin-resistant Staphylococcus aureus, up to 6 weeks of the sustained delivery of gentamicin might be needed to eliminate the infections and their biofilms [66,83,84]. Although non-biodegradable bone cements, like poly (methyl methacrylate) (PMMA), possess several advantages for osteomyelitis treatment, the need for a second surgical intervention to remove them hinders their wider use [85,86]. Biodegradable PLGA-based nanocarrier administration via injection at the site of infection is a great alternative [66].
Another group of infections targeted by gentamicin-loaded PLGA nanoparticles are intracellular infections. Intracellular infections act as a reservoir of bacteria and lead to chronic conditions that can also be lethal. Targeting intracellular infections is much harder due to the poor cellular penetration of gentamicin [64,68]. To overcome this challenge, it is possible to turn to nanoformulations, which, in general, are often taken up by macrophages via phagocytosis. This strategy allows for the passive targeting of intracellular infections and enhances the efficacy of the therapy [68]. To date, gentamicin-loaded PLGA nanoparticles have been effectively explored against two intracellular infections—Klebsiella pneumoniae and Brucella melitensis [64,68]. Not only can gentamicin-loaded PLGA nanoparticles be taken up by infected macrophages, but they also reduce bacterial viability without inducing an inflammatory or apoptotic response on the macrophages [68].
The current evidence of the antibacterial effectiveness of PLGA nanoparticles loaded with gentamicin compared to the use of a free drug is mixed. Empty PLGA nanoparticles do not possess antibacterial properties; therefore, their effect is dependent on the drug content and the drug release mechanisms [65,69]. Some in vitro tests against P. aeruginosa, S. aureus, and E. coli have shown that the MIC and MBC levels of nanoparticles compared to a free drug are equal or one dilution higher [11,65]. Lower effective concentrations of nanoparticles compared to the free drug have been reported against S. aureus [11,67]. However, when Jiang et al. tested the use of gentamicin-loaded nanoparticles against K. pneumoniae in vitro, the MIC and MBC values for the nanoparticles were significantly higher than those of a free drug [68]. The MIC/MBC values of nanoparticles lowered when tested after a longer period (up to 120 h), while, for the free gentamicin, the values stayed the same. This observation suggests that simple in vitro antibacterial tests might not be suitable for testing nanoparticles with sustained release. Instead, nanoformulations should be tested in more complex physiological environments in vivo for a longer period of time. It was further proven in vivo that gentamicin-loaded nanoparticles were more effective, providing longer protective effects against the infection than the free form of the drug due to the sustained release of the gentamicin from nanoparticles [68]. An increased effectiveness in vivo was also observed with P. aeruginosa infection [65]. In addition, in terms of antibiofilm activity, the sustained release of gentamicin proves an advantage over a single dose of free gentamicin [65].
To alleviate the application of prepared nanoparticles and to further modify the release profile of the drugs, it is possible to incorporate the nanoparticles in various other drug delivery forms. For local application, gentamicin-loaded PLGA nanoparticles have been incorporated into transdermal patches and pullulan films [67,87,88].
In sum, the main advantages provided by PLGA nanoparticles are the sustained release of gentamicin for up to 35 days and an enhanced possibility of targeting intracellular infections and infections needing long-term treatment, leading to an increase in their bioavailability. The challenges regarding PLGA–gentamicin nanoparticles are that they require further process optimization to obtain reproducible results, in addition to a quite limited EE%. More studies on the antibacterial efficiency of these nanoparticles using in vivo tests are needed. Gentamicin-loaded PLGA nanoparticles with various surface modifications are an underexplored research field, with future potential for more targeted treatments of infections.

4.2. Gentamicin-Loaded Chitosan Nanoparticles

Chitosan is a natural, linear polysaccharide with wide use in the biomedical industry due to its physiochemical properties, biocompatibility, biodegradability, and antibacterial and antifungal activity [89,90]. It is composed of β-1,4 glucose amine and β-1,4-N-acetyl glucose amine units [91]. The antimicrobial properties of chitosan are explained by the electrostatic interaction between the positive charge of chitosan and the negatively charged bacterial cell walls [92,93]. Without the polycationic nature, the antibacterial properties of chitosan are reduced [93]. In addition, other factors, like molecular weight, positive charge density, and pH, can influence the antibacterial properties of chitosan [93,94]. The antimicrobial properties of chitosan make it a desirable polymer for nanoparticle formation and the encapsulation of antibiotics. Gentamicin-loaded chitosan nanoparticles have largely been explored only in the last 5 years. An overview of gentamicin-loaded chitosan nanoparticles and their main parameters can be found in Table 2.
Both physical and chemical crosslinking can be applied to form chitosan nanoparticles [100]. The ionic gelation method, which is a type of physical crosslinking, has been most widely used to form gentamicin-loaded nanoparticles due to the simplicity and mild conditions of the method [96,99]. Sodium tripolyphosphate (TPP), in most cases, is used as a cross-linker. TPP is a non-toxic agent with negatively charged phosphate groups; therefore, it can react with the positively charged amino groups of chitosan, leading to gelling [101,102].
The cellular uptake of chitosan nanoparticles is dependent on their attachment to the negatively charged cell membranes due to electrostatic interactions. The chitosan nanoparticles are then transported via endocytosis, with subsequent release in subcellular compartments like lysosomes [103]. The “proton sponge effect” promotes chitosan nanoparticle escape from endosomes, meaning that the amino groups are more protonated in the acidic pH of endosomes. Subsequently, water and chloride ions enter the endosomes to balance out the osmotic imbalance. The volume increase ruptures the endosomes, allowing the nanoparticles to enter cytoplasm [104]. The same mechanism is also responsible for lysosome rupture [103]. In terms of their possible application, the use of gentamicin-loaded chitosan nanoparticles against intracellular bacteria and biofilms has been examined, as well as explored their potential as wound healing agents [75,95,98,105].
Regarding their antibacterial activity, gentamicin-loaded chitosan nanoparticles have shown promising results. Gentamicin-loaded chitosan nanoparticles have shown equal or better antibacterial properties compared to gentamicin in a free drug form [75,97,99,105]. The authors suggest that the higher antibacterial efficiency is observed due to the sustained release of gentamicin [75]. When tested in combination with other agents, like ascorbic acid, the dual-therapy chitosan particles show enhanced antibacterial activity and possible synergy between the components [99].
A disadvantage of using chitosan to encapsulate gentamicin is the positive charge of both molecules, which leads to electrostatic repulsion and, therefore, lower drug loading [95]. In addition, gentamicin release from the nanoparticles is rather short in comparison to that of gentamicin-loaded PLGA nanoparticles, with authors reporting drug release lasting up to 1 week and, in most cases, only around 3 days [75,95,96,97,99,105]. The release profile of chitosan nanoparticles could prohibit their potential use in hard-to-combat infections that require several weeks of treatment.
In recent years, novel publications can be found on chitosan nanoparticles that combine gentamicin with other active agents, like ascorbic acid, salicylic acid, and proanthocyanidin, to minimize the side effects of gentamicin and enhance the antibacterial activity, with promising results [96,97,99]. As strong antioxidants, these molecules could minimize the toxicity to cells created by reactive oxygen species (ROS) [99].
To further maximize the advantages of both polymeric and lipid drug delivery systems, combined hybrid nanoparticles are currently being researched. In the case of chitosan, Qiu et al. developed novel phosphatidylcholine–chitosan nanoparticles and coated the particles with gentamicin to enhance the drug delivery to biofilms and intracellular pathogens, with promising results [105].

4.3. The Release of Gentamicin from Polymeric Nanoparticles

The in vitro release study is crucial in evaluating drug delivery systems’ safety, effectiveness, and quality when utilizing nanoparticles. However, despite its importance, no universally recognized standards or regulations currently govern this type of testing [106,107].
Various mechanisms are employed to assess the release of drugs from nanoparticles depending on the drug’s physical and chemical properties and the matrix. These mechanisms include diffusion, erosion, swelling, and osmosis [108,109,110,111,112]. The effectiveness of drug release from biodegradable polymeric microspheres is determined by various factors, including drug loading efficiency, solubility, biodegradability, diffusion, and microsphere size [113].
As highlighted by the literature, gentamicin release studies involving the quantification of gentamicin face several challenges. Firstly, gentamicin is a complex mixture of five structurally distinct components (see Section 2). Secondly, gentamicin lacks chromophore groups, which means that it cannot absorb UV light and can be indirectly determined through chemical derivatization methods with o-phthaldialdehyde, phenyl isocyanate, 9-fluorenylmethyl chloroformate, 1-fluoro-2,4-dinitrobenzene, and others, which are time-consuming and produce unstable derivatives [114,115]. Most of the literature on gentamicin release from PLGA and chitosan mentions derivatization with o-phthaldialdehyde or ninhydrin [11,30,63,65,66,67]. The obtained fluorescent product can be determined through multiple methods. One of the most popular is the more rapid and cost-effective UV/VIS method. Alternatively, the most reliable method is high-performance liquid chromatography (HPLC), which enables UV, fluorescence, electrochemical, or MS detection [114,115].
The drug release profiles of nanoparticle-based formulations can be obtained through three methods: dialysis membrane, sample and separate methods, and the continuous-flow method [106,116,117]. For gentamicin-loaded PLGA and chitosan nanoparticles, the most commonly used methods are the first two.
One of the major challenges in comparing research findings in the field of gentamicin release is the absence of standardization in experimental methods. This leads to variations in the type of membranes used, stirring speed (50–200 rpm), medium (NaCl or PBS with pH 6.4–7.4), temperature (37 °C or 32 °C), and volume (500–900 mL) [11,30,63,65,66,67,69]. Even when the same techniques, such as UV/VIS, are employed, different wavelengths are often used to detect fluorescence or absorbance [11,30,69]. Fluorescence has been measured at 360/460 nm [63,65,68]. UV absorbance has been detected at 332 nm [66], 334 nm [75], 335 nm [67], and 400 nm [11]. Due to the variability in drug release profiles (Higuchi, first or zero order), it can be challenging to compare the published results and draw meaningful conclusions. This can lead to different interpretations of the drug release times and concentrations [69,113,118].

5. Hydrophobization of the Gentamicin Molecule

To increase the efficacy of antimicrobial drug activity against various infectious diseases, it is necessary to increase antimicrobial activity in the intracellular environment or prolong the presence of the antibiotic to produce a therapeutic effect. Gentamicin sulfate is a polar antimicrobial drug and, due to its hydrophilic nature, penetration into infected cells is limited. Moreover, as gentamicin shows a concentration-dependent bactericidal activity and post-antibiotic effect, it requires regular and high doses, which lead to increases in side effects [31]. Nanotechnology has developed a promising approach for the treatment of intracellular infections by providing the intracellular targeting and sustained release of encapsulated drugs inside the infected cells [119]. Initially, hydrophilic gentamicin sulfate was encapsulated in PLGA particles, and its encapsulation efficiency was achieved at 19.2% at 9.2 µg/mg of the polymer. However, drug release tests revealed that most of the gentamicin was released within the first hour. This can be explained by the possible absorption of gentamicin on the surface of PLGA particles [63]. Therefore, a highly efficient drug encapsulation strategy is required. The hydrophobic ion pairing of gentamicin with anionic surfactants without losing antimicrobial activity serves well for this purpose [120]. This method is well known to convert polar drugs into non-polar complexes and improve their encapsulation efficiency. For this purpose, active substances such as docusate sodium salt (AOT), sodium dodecyl sulfate, sodium oleate, and sodium deoxycholate sulfate are used [121]. Docusate sodium salt is one of the most promising anionic surfactants for gentamicin. The chemical structure of gentamicin and AOT are presented in Figure 4.
The ionic complex of the Gent–AOT ratio is 1:5, and the stoichiometric complexation of the five ionizable amino groups of gentamicin is neutralized with the AOT sulfate group. The lipophilic alkyl chains of AOT make this complex soluble in organic solvents [122]. The obtained complexes form particles with a size of 1000 nm [123], followed by further encapsulation of the hydrophobic Gent–AOT complex in a biodegradable water-insoluble polymer (PLGA), making it possible to obtain nanoparticles with a size of 200–300 nm [122,123,124]. This strategy allows for a gentamicin encapsulation efficacy close to quantitative yields and up to 60 µg/mg of the PLGA polymer compared to instances where sulfate is used as an ion pairing agent [125]. In addition, encapsulated gentamicin is released from PLGA particles much more slowly in drug release tests due to the hydrophobic gentamicin AOT complex. It was observed that only 10% of gentamicin was released during the first hour, but an almost linear sustained release of the drug over 10 weeks was observed later [122]. Other biodegradable polymers are also used for the encapsulation of hydrophobic Gent–AOT, for example, poly (ε-caprolactone) and poly (D,L-lactic acid) [126], polyvinyl alcohol [122], poly (aspartic acid) [127] or poly (methyl vinyl ether-co-maleic anhydride) [128]. The variation in surfactants is another tool to construct a drug delivery system, as the interactions of the gentamicin complex with the AOT that was entrapped into PLGA are known to provide a more efficient drug delivery than occurs in the absence of AOT [31].
The antibacterial properties of nanoparticles that contain Gent–AOT are superior. However, the toxicity of Gent–AOT should also be considered, and more research is needed to evaluate gentamicin nanoformulations [124,125].

6. Gentamicin Combinations with Other Antibiotics

Early studies started investigating the synergic effects of gentamicin, together with other antibiotics, like β-lactams, in the 1970s, reporting better outcomes for the combination approach [129,130,131]. Currently, gentamicin is co-prescribed with a range of penicillins (amoxicillin, ampicillin, and benzylpenicillin) for the treatment of serious infections like sepsis, bacterial pneumonia, and peritoneal abscess [8]. The World Health Organization recommends gentamicin + azithromycin dual treatment for gonococcal infections in case treatment with cephalosporins fails, although this is a conditional recommendation with very low-quality evidence [132]. In the last decade, several studies have searched for new potential synergic combinations. Synergy has been observed when combining gentamicin with azithromycin [133,134], mitomycin C [135], fosfomycin [136,137], ciprofloxacin [136], daptomycin [138], and cefepime [139].
Recent tests on gentamicin in combination with other antibiotics have largely focused on its antibacterial activity against P. aeruginosa [134,135,136,139] and Enterococci species [137,138]. In addition, the combinational approach has also been tested against uncomplicated gonorrhea [133] and E. coli strains [136]. The synergic effects of combinations against biofilms of both E. coli (fosfomycin/gentamicin [136]) and P. aeruginosa (ciprofloxacin/gentamicin [136] and cefepime/gentamicin [139]) may be particularly important. A fosfomycin/gentamicin combination even retained its synergic effects against a gentamicin-resistant strain of E. coli [136].
The mechanisms behind the synergic effects of the two antibacterial agents are still largely unknown and underexplored. It has been suggested that the synergy of the azithromycin/gentamicin combination might be due to the suppression of trans-translation by gentamicin, enhancing the efficacy of azithromycin [134]. In addition, a bacterolytic effect of gentamicin has been hypothesized to explain the efficacy of the fosfomycin/gentamicin combination against a gentamicin-resistant strain [136]. Due to the high clinical significance, understanding the mechanism behind the synergic effects responsible for action against biofilms is critical.
Reports have been presented on the increased development of resistance after using the gentamicin combination compared to monotherapy [140]. Furthermore, the increased toxicity, especially the nephrotoxicity, of this approach is particularly concerning [29,140,141,142]. For example, a study of patients with gonorrhea revealed a strong adverse gastrointestinal effect rate in patients, which would likely limit the application of the azithromycin/gentamicin combination in clinical practice [133].
Further studies, including randomized controlled trials, should be executed to evaluate the risks and benefits of gentamicin + other antibiotic approaches. A search for alternative antibacterial agents, which have safer profiles and a lower likelihood of the development of resistance, like substances derived or isolated from natural products, is needed.

7. Gentamicin Combinations with Polyphenols

The used combination should lower the effective dose of antibiotic, as well as minimize the potential side-effects of the treatment [2,143]. These criteria could potentially be met by natural products like individual phytochemicals or herbal extracts.
Polyphenols are one of the largest groups of natural bioactive substances and are present in a very wide variety of plants [144]. Polyphenols possess not only antimicrobial but also antioxidant and anti-inflammatory properties [144,145]. Even though the effective concentrations of polyphenols often are much higher than those of antibiotics, their overall properties and potential for synergism make them attractive candidates for the combination approach [146].
A wide range of polyphenols, mainly flavonoids, have been tested together with gentamicin in the last 20 years. For the most part, more flavonoid aglycones than glycosides have been tested. Aglycones are known to have more potent biological activity than their respective glycosides [147]. An overview of studies with positive conclusions regarding synergy is found in Table 3. Polyphenols that, to date, have not shown any synergistic effects together with gentamicin have not been included in Table 3.
Three main mechanisms of polyphenol and gentamicin synergy can be distinguished. First, polyphenols inhibit the bacterial wall biosynthesis, allowing gentamicin to reenter the cells and leading to increased sensitivity [146,152,153]. Second, polyphenols can inhibit different bacterial efflux pumps; for example, AbeM and AdeABC [146,153]. Since these efflux pumps can be responsible for the development of resistance, their inhibition could increase bacterial sensitivity against antibiotics [146]. Third, polyphenols can inhibit quorum sensing, consequently regulating the bacterial population density [2,155,158]. Quorum sensing plays a significant role in biofilm production, hindering optimal drug delivery to pathogens. The inhibition of quorum sensing disrupts the biofilm structure, allowing gentamicin to reach and kill the pathogens [2,153,155].
Overall, most of the research focused on members of the ESKAPE group of pathogens, providing potential future alternatives to current approaches. To date, the lowest amount of evidence of synergy was found for E. coli, with only two papers finding synergy or additive effects using reference strains [3,143], and the rest reporting no or minimal effect [146,148,154,159].
In terms of the tested bacterial strains, it is advisable to use not only commercially available reference strains but also clinical isolates, since different strains may exhibit different synergic effects due to their diverse genetic and resistance mechanisms [2]. The synergic activity of polyphenols with gentamicin against reference strains does not always translate to clinical isolates [143].
In addition to the synergic effects, polyphenols have also been investigated to minimize the toxic effects of oxidative stress subsequent to the use of gentamicin [143,159].

8. Gentamicin Combinations with Natural Products

Another approach to enhance the antibacterial properties of gentamicin is to test multicomponent natural products like herbal extracts. Herbal extracts contain up to hundreds of bioactive substances and, therefore, could simultaneously act on multiple targets and enhance each other’s antibacterial activity [160]. In addition, the use of multi-component products could lower the chances of antibacterial resistance development [161]. An overview of studies with positive conclusions regarding the synergy between natural products and gentamicin is found in Table 4. Natural products that, to date, have not shown any synergistic effects together with gentamicin are not included in Table 4.
Most positive outcomes regarding the synergy between natural products and gentamicin were obtained using bacterial reference strains, raising the question of whether the same observation could be seen using clinical isolates. If using medicinal plant extracts, the preparation method of the extract is crucial to the chemical composition of the extract. Furthermore, the wide variability in the chemical profiles and concentrations of bioactive substances in plants has to be kept in mind. Therefore, studies on the potential synergy between herbal extracts and antibiotics should also provide results on the chemical composition of the extract.
A concrete conclusion regarding the mechanisms responsible for the synergic activity of natural products together with antibiotics cannot be obtained [161,162,163,164]. Some authors have suggested that synergic effects could be observed due to changes in the efflux system, damage to cell membranes, and the inhibition of protein synthesis. Further research is needed to clearly understand the mechanisms [161,162,164]. A study using propolis revealed that the concentration of natural products is also crucial to the synergic activity [161]. Higher concentrations of propolis and antibiotics lead to a surprising loss of synergy [161]. This finding accentuates the important role of the ratio of components to produce synergic activity [161].
Table 4. Synergy between gentamicin and natural products.
Table 4. Synergy between gentamicin and natural products.
Natural ProductBacteriaBacterial Strain TypeAntibacterial Effect on GentamicinFICISynergy/Partial SynergyRef.
Aniba rosaeodora essential oilB. cereusReferenceMIC reduction from 0.50 μg/mL to 0.12 μg/mL0.30Synergy[40]
B. subtilisReferenceMIC reduction from 0.25 μg/mL to 0.06 μg/mL0.34Synergy[40]
S. aureusReferenceMIC reduction from 0.50 μg/mL to 0.12 μg/mL and from 0.06 μg/mL to 0.01 μg/mL0.30Synergy[40]
E. coliReferenceMIC reduction from 0.50 μg/mL to 0.12 μg/mL0.35Synergy[40]
A. baumanniiReferenceMIC reduction from 4.00 μg/mL to 0.24 μg/mL0.11Synergy[40]
S. marcescensReferenceMIC reduction from 0.50 μg/mL to 0.12 μg/mL0.30Synergy[40]
Y. enterocoliticaReferenceMIC reduction from 0.25 μg/mL to 0.01 μg/mL0.11Synergy[40]
Clinopodium vulgare L. extractsB. subtilisClinical isolatesReduction in MIC0.395–0.44Synergy[164]
Daphne genkwa extractS. aureus
(methicillin-resistant)		ReferenceReduction in MIC0.750Partial synergy[165]
Magnolia officinalis extractS. aureus
(methicillin-resistant)		ReferenceReduction in MIC0.750Partial synergy[165]
Kaempferia parviflora extractsK. pneumoniaeClinical isolatesReduction in MIC0.141–0.625Synergy/Partial synergy[162]
P. aeruginosaClinical isolatesReduction in MIC0.133–0.625Synergy/Partial synergy[162]
A. baumanniiClinical isolatesReduction in MIC0.133–0.563Synergy/Partial synergy[162]
Mentha piperita L. essential oilB. cereusReferenceMIC reduction from 2.00 μg/mL to 0.06 μg/mL0.08Synergy[163]
B. subtilisReferenceMIC reduction from 0.50 μg/mL to 0.01 μg/mL0.07Synergy[163]
S. aureusReferenceMIC reduction from 2.0 μg/mL to 0.06 μg/mL; from 0.5 μg/mL to 0.06 μg/mL; from 8.0 μg/mL to 2.0 μg/mL0.103–0.3Synergy[163]
E. faecalisReferenceMIC reduction from 8.0 μg/mL to 1.0 μg/mL0.32Synergy[163]
E. coliReferenceMIC reduction from 1.0 μg/mL to 0.03 μg/mL0.43Synergy[163]
K. pneumoniaeReferenceMIC reduction from 32.0 μg/mL to 1.0 μg/mL0.43Synergy[163]
A. baumanniiReferenceMIC reduction from 8.00 μg/mL to 0.5 μg/mL0.46Synergy[163]
P. aeruginosaReferenceMIC reduction from 2.00 μg/mL to 0.06 μg/mL0.08Synergy[163]
Pelargonium graveolens essential oilB. cereusReferenceMIC reduction from 0.50 μg/mL to 0.125 μg/mL0.30Synergy[40]
B. subtilisReferenceMIC reduction from 0.25 μg/mL to 0.06 μg/mL0.34Synergy[40]
S. aureusReferenceMIC reduction from 0.50 μg/mL to 0.01 μg/mL and from 0.12 to 0.04 μg/mL0.28–0.35Synergy[40]
E. coliReferenceMIC reduction from 0.50 μg/mL to 0.12 μg/mL0.30Synergy[40]
A. baumanniiReferenceMIC reduction from 4.00 μg/mL to 0.24 μg/mL0.11Synergy[40]
S. marcescensReferenceMIC reduction from 0.50 μg/mL to 0.12 μg/mL0.45Synergy[40]
Y. enterocoliticaReferenceMIC reduction from 0.25 μg/mL to 0.03 μg/mL0.22Synergy[40]
PropolisB. subtilisReferenceMIC reduction from 1.25 μg/mL to 0.05 μg/mLNASynergy[161]
B. cereusReferenceMIC reduction from 1.25 μg/mL to 0.05 μg/mLNASynergy[161]
B. megateriumReferenceMIC reduction from 0.25 μg/mL to 0.01 μg/mLNASynergy[161]
S. aureus
(methicillin sensitive)		ReferenceMIC reduction from 1.5 μg/mL to 0.5 μg/mLNASynergy[161]
S. aureus
(methicillin-resistant)		ReferenceMIC reduction from >1.5 μg/mL to 0.5 μg/mLNASynergy[161]
E. coliReferenceMIC reduction from >1.5 μg/mL to 0.5 μg/mLNASynergy[161]
NA—not available; FICI—fractional inhibitory concentration index; MIC—minimum inhibitory concentration.

9. Conclusions and Future Perspectives

Even after 60 years on the market, gentamicin plays an important role in combating serious infections, especially those originating from the nosocomial ESKAPE pathogens. Several strategies, including encapsulation in nanoformulations, hydrophobization of the molecule, and combinations with various agents, have been investigated to enhance both the activity and drug delivery of gentamicin. Current evidence indicates that polymeric nanoformulations, especially PLGA nanoparticles, could provide a sustained release of gentamicin and offer higher bioavailability. Hydrophobization of the gentamicin molecule can significantly increase the encapsulation efficiency in nanoparticles and enhance the antibacterial properties of the system. Nevertheless, the currently used in vitro drug release methods lack standardization, hindering adequate comparison between studies. Further research on the toxicology of these nanoformulations is needed. Research on the synergic effects between gentamicin and polyphenols is an exciting research direction. Testing on a wider range of clinical isolates, not only reference strains of bacteria, will allow us to see if the results of synergy can be translated to clinical practice. The possible encapsulation of gentamicin–polyphenol combinations in drug delivery systems should be further investigated. As gentamicin is applied to treat hard-to-reach infections like osteomyelitis, target-specific surface modifications of drug delivery systems hold great potential for future research.

Author Contributions

Conceptualization, A.B. (Ance Bārzdiņa) and A.B. (Agnese Brangule); writing—original draft preparation, A.B. (Ance Bārzdiņa), A.B. (Agnese Brangule), A.P., A.S. and K.P.; writing—review and editing, A.B. (Ance Bārzdiņa), A.B. (Agnese Brangule), A.P., A.S., K.P. and D.B.; visualization, A.B. (Ance Bārzdiņa), A.P. and K.P.; supervision, A.B. (Agnese Brangule) and D.B.; project administration, A.B. (Agnese Brangule). All authors have read and agreed to the published version of the manuscript.

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation program under the grant agreement No. 857287 (BBCE—Baltic Biomaterials Centre of Excellence).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors acknowledge the access to the infrastructure and expertise of the BBCE—Baltic Biomaterials Centre of Excellence (European Union’s Horizon 2020 research and innovation programme under the grant agreement No. 857287) and the SPRINGBOARD project (European Union’s Horizon 2020 research and innovation programme under grant agreement No. 951883).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Chen, J.W.; Lau, Y.Y.; Krishnan, T.; Chan, K.G.; Chang, C.Y. Recent Advances in Molecular Diagnosis of Pseudomonas aeruginosa Infection by State-of-the-Art Genotyping Techniques. Front. Microbiol. 2018, 9, 1104. [Google Scholar] [CrossRef]
  2. Vipin, C.; Saptami, K.; Fida, F.; Mujeeburahiman, M.; Rao, S.S.; Athmika; Arun, A.B.; Rekha, P.D. Potential synergistic activity of quercetin with antibiotics against multidrug-resistant clinical strains of Pseudomonas aeruginosa. PLoS ONE 2020, 15, e0241304. [Google Scholar] [CrossRef] [PubMed]
  3. Cruz, B.G.; dos Santos, H.S.; Bandeira, P.N.; Rodrigues, T.H.S.; Matos, M.G.C.; Nascimento, M.F.; de Carvalho, G.G.C.; Braz-Filho, R.; Teixeira, A.M.R.; Tintino, S.R.; et al. Evaluation of antibacterial and enhancement of antibiotic action by the flavonoid kaempferol 7-O-β-D-(6″-O-cumaroyl)-glucopyranoside isolated from Croton piauhiensis müll. Microb. Pathog. 2020, 143, 104144. [Google Scholar] [CrossRef] [PubMed]
  4. Santajit, S.; Indrawattana, N. Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens. Biomed. Res. Int. 2016, 2016, 2475067. [Google Scholar] [CrossRef] [PubMed]
  5. Tacconelli, E.; Carrara, E.; Savoldi, A.; Harbarth, S.; Mendelson, M.; Monnet, D.L.; Pulcini, C.; Kahlmeter, G.; Kluytmans, J.; Carmeli, Y.; et al. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 2018, 18, 318–327. [Google Scholar] [CrossRef]
  6. Chen, C.; Chen, Y.; Wu, P.; Chen, B. Update on new medicinal applications of gentamicin: Evidence-based review. J. Formos. Med. Assoc. 2014, 113, 72–82. [Google Scholar] [CrossRef]
  7. Alapi, M.E.; Fisher, J. Analogue-Based Drug Discovery; Fischer, J., Ganellin, C.R., Eds.; Wiley-VCH Verlag GmbH & Co.: Weinheim, Germany; KgaA: Weinheim, Germany, 2006; p. 507. ISBN 9783527607495. [Google Scholar]
  8. WHO Electronic Essential Medicines List. Gentamicin. Model List of Essential Medicines. Available online: https://list.essentialmeds.org/medicines/229 (accessed on 19 February 2024).
  9. Gentamicin sulfate. In Merative Micromedex® DRUGDEX® (Electronic Version); Merative Healthcare Solutions/EBSCO Information Services: Greenwood Village, CO, USA; Cambridge, MA, USA; Available online: https://www.dynamed.com/drug-monograph/gentamicin-sulfate (accessed on 16 March 2024).
  10. Elsevier Drug Information. Drug Monograph. Gentamicin. In ClinicalKey; Elsevier: Amsterdam, The Netherlands, 2024; Available online: https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-275 (accessed on 16 March 2024).
  11. Dorati, R.; DeTrizio, A.; Spalla, M.; Migliavacca, R.; Pagani, L.; Pisani, S.; Chiesa, E.; Conti, B.; Modena, T.; Genta, I. Gentamicin Sulfate PEG-PLGA/PLGA-H Nanoparticles: Screening Design and Antimicrobial Effect Evaluation toward Clinic Bacterial Isolates. Nanomaterials 2018, 8, 37. [Google Scholar] [CrossRef]
  12. Weinstein, M.J.; Luedemann, G.M.; Oden, E.M.; Wagman, G.H.; Rosselet, J.P.; Marquez, J.A.; Coniglio, C.T.; Charney, W.; Herzog, H.L.; Black, J. Gentamicin, a new antibiotic complex from micromonospora. J. Med. Chem. 1963, 6, 463–464. [Google Scholar] [CrossRef] [PubMed]
  13. Isoherranen, N.; Lavy, E.; Soback, S. Pharmacokinetics of gentamicin C1, C1a, and C2 in beagles after a single intravenous dose. Antimicrob. Agents Chemother. 2000, 44, 1443–1447. [Google Scholar] [CrossRef]
  14. Athauda, I.D.; Shetty, M.G.; Pai, P.; Hegde, M.; Gurumurthy, S.C.; Babitha, K.S. Enhanced Bactericidal Effects and Drug Delivery with Gentamicin-Conjugated Nanoparticles. J. Clust. Sci. 2023, 35, 371–390. [Google Scholar] [CrossRef]
  15. Deubner, R.; Schollmayer, C.; Wienen, F.; Holzgrabe, U. Assignment of the major and minor components of gentamicin for evaluation of batches. Magn. Reson. Chem. 2003, 41, 589–598. [Google Scholar] [CrossRef]
  16. Friesen, W.J.; Johnson, B.; Sierra, J.; Zhuo, J.; Vazirani, P.; Xue, X.; Tomizawa, Y.; Baiazitov, R.; Morrill, C.; Ren, H.; et al. The minor gentamicin complex component, X2, is a potent premature stop codon readthrough molecule with therapeutic potential. PLoS ONE 2018, 13, e0206158. [Google Scholar] [CrossRef] [PubMed]
  17. O’Sullivan, M.E.; Song, Y.; Greenhouse, R.; Lin, R.; Perez, A.; Atkinson, P.J.; MacDonald, J.P.; Siddiqui, Z.; Lagasca, D.; Comstock, K.; et al. Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes. Proc. Natl. Acad. Sci. USA 2020, 117, 32423–32432. [Google Scholar] [CrossRef] [PubMed]
  18. Eren, E.; Parkin, J.; Adelanwa, A.; Cheneke, B.; Movileanu, L.; Khalid, S.; van den Berg, B. Toward understanding the outer membrane uptake of small molecules by Pseudomonas aeruginosa. J. Biol. Chem. 2013, 288, 12042–12053. [Google Scholar] [CrossRef] [PubMed]
  19. Claes, P.J.; Busson, R.; Vanderhaeghe, H. Determination of the component ratio of commercial gentamicins by high-performance liquid chromatography using pre-column derivatization. J. Chromatogr. A 1984, 298, 445–457. [Google Scholar] [CrossRef] [PubMed]
  20. Kohlhepp, S.J.; Loveless, M.O.; Kohnen, P.W.; Houghton, D.C.; Bennett, W.M.; Gilbert, D.N. Nephrotoxicity of the Constituents of the Gentamicin Complex. J. Infect. Dis. 1984, 149, 605–614. [Google Scholar] [CrossRef] [PubMed]
  21. Jana, S.; Rajasekaran, P.; Haldimann, K.; Vasella, A.; Böttger, E.C.; Hobbie, S.N.; Crich, D. Synthesis of Gentamicins C1, C2, and C2a and Antiribosomal and Antibacterial Activity of Gentamicins B1, C1, C1a, C2, C2a, C2b, and X2. ACS Infect. Dis. 2023, 9, 1622–1633. [Google Scholar] [CrossRef] [PubMed]
  22. Gu, Y.; Ni, X.; Ren, J.; Gao, H.; Wang, D.; Xia, H. Biosynthesis of Epimers C2 and C2a in the Gentamicin C Complex. ChemBioChem 2015, 16, 1933–1942. [Google Scholar] [CrossRef] [PubMed]
  23. Sandoval, R.M.; Reilly, J.P.; Running, W.; Campos, S.B.; Santos, J.R.; Phillips, C.L.; Molitoris, B.A. A Non-Nephrotoxic Gentamicin Congener That Retains Antimicrobial Efficacy. J. Am. Soc. Nephrol. 2006, 17, 2697–2705. [Google Scholar] [CrossRef]
  24. Kobayashi, M.; Sone, M.; Umemura, M.; Nabeshima, T.; Nakashima, T.; Hellström, S. Comparisons of cochleotoxicity among three gentamicin compounds following intratympanic application. Acta Otolaryngol. 2008, 128, 245–249. [Google Scholar] [CrossRef]
  25. Ishikawa, M.; García-Mateo, N.; Čusak, A.; López-Hernández, I.; Fernández-Martínez, M.; Müller, M.; Rüttiger, L.; Singer, W.; Löwenheim, H.; Kosec, G.; et al. Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use. Sci. Rep. 2019, 9, 2410. [Google Scholar] [CrossRef]
  26. Recht, M.I.; Puglisi, J.D. Aminoglycoside resistance with homogeneous and heterogeneous populations of antibiotic-resistant ribosomes. Antimicrob. Agents Chemother. 2001, 45, 2414–2419. [Google Scholar] [CrossRef]
  27. Rosenkrantz, B.E.; Greco, J.R.; Hoogerheide, J.G.; Oden, E.M. Gentamicin Sulfate. In Analytical Profiles of Drug Substances; Florey, K., Ed.; Academic Press: Cambridge, MA, USA, 1981; Volume 9, pp. 295–340. [Google Scholar] [CrossRef]
  28. Tangy, F.; Moukkadem, M.; Vindimian, E.; Capmau, M.L.; Le Goffic, F. Mechanism of action of gentamicin components. Characteristics of their binding to Escherichia coli ribosomes. Eur. J. Biochem. 1985, 147, 381–386. [Google Scholar] [CrossRef]
  29. Beganovic, M.; Luther, M.K.; Rice, L.B.; Arias, C.A.; Rybak, M.J.; LaPlante, K.L. A Review of Combination Antimicrobial Therapy for Enterococcus faecalis Bloodstream Infections and Infective Endocarditis. Clin. Infect. Dis. 2018, 67, 303–309. [Google Scholar] [CrossRef]
  30. Prior, S.; Gamazo, C.; Irache, J.M.; Merkle, H.P.; Gander, B. Gentamicin encapsulation in PLA/PLGA microspheres in view of treating Brucella infections. Int. J. Pharm. 2000, 196, 115–125. [Google Scholar] [CrossRef] [PubMed]
  31. Duran, S.; Anwar, J.; Moin, S.T. Interaction of gentamicin and gentamicin-AOT with poly-(lactide-co-glycolate) in a drug delivery system—Density functional theory calculations and molecular dynamics simulation. Biophys. Chem. 2023, 294, 106958. [Google Scholar] [CrossRef] [PubMed]
  32. Crcek, M.; Zdovc, J.; Kerec Kos, M. A review of population pharmacokinetic models of gentamicin in paediatric patients. J. Clin. Pharm. Ther. 2019, 44, 659–674. [Google Scholar] [CrossRef] [PubMed]
  33. Craig, W.A. Optimizing aminoglycoside use. Crit. Care Clin. 2011, 27, 107–121. [Google Scholar] [CrossRef]
  34. Pisani, S.; Dorati, R.; Chiesa, E.; Genta, I.; Modena, T.; Bruni, G.; Grisoli, P.; Conti, B. Release Profile of Gentamicin Sulfate from Polylactide-co-Polycaprolactone Electrospun Nanofiber Matrices. Pharmaceutics 2019, 11, 161. [Google Scholar] [CrossRef]
  35. Wassif, R.K.; Elkayal, M.; Shamma, R.N.; Elkheshen, S.A. Recent advances in the local antibiotics delivery systems for management of osteomyelitis. Drug Deliv. 2021, 28, 2392–2414. [Google Scholar] [CrossRef]
  36. Hodiamont, C.J.; van den Broek, A.K.; de Vroom, S.L.; Prins, J.M.; Mathôt, R.A.A.; van Hest, R.M. Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review. Clin. Pharmacokinet. 2022, 61, 1075–1094. [Google Scholar] [CrossRef] [PubMed]
  37. Scholar, E. Gentamicin. In xPharm: The Comprehensive Pharmacology Reference; Enna, S.J., Bylund, D.B., Eds.; Elsevier: New York, NY, USA, 2007; pp. 1–6. [Google Scholar] [CrossRef]
  38. Bailey, D.N.; Briggs, J.R. Gentamicin and Tobramycin Binding to Human Serum In Vitro. J. Anal. Toxicol. 2004, 28, 187–189. [Google Scholar] [CrossRef] [PubMed]
  39. Drevets, D.A.; Canono, B.P.; Leenen, P.J.; Campbell, P.A. Gentamicin kills intracellular Listeria monocytogenes. Infect. Immun. 1994, 62, 2222–2228. [Google Scholar] [CrossRef] [PubMed]
  40. Rosato, A.; Piarulli, M.; Corbo, F.; Muraglia, M.; Carone, A.; Vitali, M.E.; Vitali, C. In vitro synergistic antibacterial action of certain combinations of gentamicin and essential oils. Curr. Med. Chem. 2010, 17, 3289–3295. [Google Scholar] [CrossRef] [PubMed]
  41. Lopez-Novoa, J.M.; Quiros, Y.; Vicente, L.; Morales, A.I.; Lopez-Hernandez, F.J. New insights into the mechanism of aminoglycoside nephrotoxicity: An integrative point of view. Kidney Int. 2011, 79, 33–45. [Google Scholar] [CrossRef] [PubMed]
  42. Fu, X.; Wan, P.; Li, P.; Wang, J.; Guo, S.; Zhang, Y.; An, Y.; Ye, C.; Liu, Z.; Gao, J.; et al. Mechanism and Prevention of Ototoxicity Induced by Aminoglycosides. Front. Cell Neurosci. 2021, 15, 692762. [Google Scholar] [CrossRef] [PubMed]
  43. Dorati, R.; DeTrizio, A.; Genta, I.; Grisoli, P.; Merelli, A.; Tomasi, C.; Conti, B. An experimental design approach to the preparation of pegylated polylactide-co-glicolide gentamicin loaded microparticles for local antibiotic delivery. Mater. Sci. Eng. C 2016, 58, 909–917. [Google Scholar] [CrossRef]
  44. Abbasi, M.Y.; Chaijamorn, W.; Wiwattanawongsa, K.; Charoensareerat, T.; Doungngern, T. Recommendations of Gentamicin Dose Based on Different Pharmacokinetic/Pharmacodynamic Targets for Intensive Care Adult Patients: A Redefining Approach. Clin. Pharmacol. 2023, 15, 67–76. [Google Scholar] [CrossRef]
  45. Cepec, E.; Trček, J. Antimicrobial Resistance of Acetobacter and Komagataeibacter Species Originating from Vinegars. Int. J. Environ. Res. Public. Health 2022, 19, 463. [Google Scholar] [CrossRef]
  46. Li, P.K.T.; Szeto, C.C.; Piraino, B.; de Arteaga, J.; Fan, S.; Figueiredo, A.E.; Fish, D.N.; Goffin, E.; Kim, Y.L.; Salzer, W.; et al. ISPD Peritonitis Recommendations: 2016 Update on Prevention and Treatment. Perit. Dial. Int. 2016, 36, 481–508. [Google Scholar] [CrossRef]
  47. Puschhof, J.; Pleguezuelos-Manzano, C.; Martinez-Silgado, A.; Akkerman, N.; Saftien, A.; Boot, C.; de Waal, A.; Beumer, J.; Dutta, D.; Heo, I.; et al. Intestinal organoid cocultures with microbes. Nat. Protoc. 2021, 16, 4633–4649. [Google Scholar] [CrossRef] [PubMed]
  48. Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.D.P.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71. [Google Scholar] [CrossRef] [PubMed]
  49. Adeniji, O.O.; Nontongana, N.; Okoh, J.C.; Okoh, A.I. The Potential of Antibiotics and Nanomaterial Combinations as Therapeutic Strategies in the Management of Multidrug-Resistant Infections: A Review. Int. J. Mol. Sci. 2022, 23, 15038. [Google Scholar] [CrossRef] [PubMed]
  50. Mamun, M.M.; Sorinolu, A.J.; Munir, M.; Vejerano, E.P. Nanoantibiotics: Functions and Properties at the Nanoscale to Combat Antibiotic Resistance. Front. Chem. 2021, 9, 687660. [Google Scholar] [CrossRef] [PubMed]
  51. Alhariri, M.; Majrashi, M.A.; Bahkali, A.H.; Almajed, F.S.; Azghani, A.O.; Khiyami, M.A.; Alyamani, E.J.; Aljohani, S.M.; Halwani, M.A. Efficacy of neutral and negatively charged liposome-loaded gentamicin on planktonic bacteria and biofilm communities. Int. J. Nanomed. 2017, 12, 6949–6961. [Google Scholar] [CrossRef] [PubMed]
  52. Jia, Y.; Joly, H.; Omri, A. Liposomes as a carrier for gentamicin delivery: Development and evaluation of the physicochemical properties. Int. J. Pharm. 2008, 359, 254–263. [Google Scholar] [CrossRef]
  53. Rukholm, G.; Mugabe, C.; Azghani, A.O.; Omri, A. Antibacterial activity of liposomal gentamicin against Pseudomonas aeruginosa: A time–kill study. Int. J. Antimicrob. Agents 2006, 27, 247–252. [Google Scholar] [CrossRef]
  54. Mosselhy, D.A.; Ge, Y.; Gasik, M.; Nordström, K.; Natri, O.; Hannula, S.-P. Silica-Gentamicin Nanohybrids: Synthesis and Antimicrobial Action. Materials 2016, 9, 170. [Google Scholar] [CrossRef]
  55. Perni, S.; Martini-Gilching, K.; Prokopovich, P. Controlling release kinetics of gentamicin from silica nano-carriers. Colloids Surf. A: Physicochem. Eng. Asp. 2018, 541, 212–221. [Google Scholar] [CrossRef]
  56. Purcar, V.; Rădiţoiu, V.; Nichita, C.; Bălan, A.; Rădiţoiu, A.; Căprărescu, S.; Raduly, F.M.; Manea, R.; Şomoghi, R.; Nicolae, C.A.; et al. Preparation and Characterization of Silica Nanoparticles and of Silica-Gentamicin Nanostructured Solution Obtained by Microwave-Assisted Synthesis. Materials 2021, 14, 2086. [Google Scholar] [CrossRef]
  57. Katva, S.; Das, S.; Moti, H.S.; Jyoti, A.; Kaushik, S. Antibacterial Synergy of Silver Nanoparticles with Gentamicin and Chloramphenicol against Enterococcus faecalis. Pharmacogn. Mag. 2018, 13, S828–S833. [Google Scholar] [CrossRef] [PubMed]
  58. Birla, S.S.; Tiwari, V.V.; Gade, A.K.; Ingle, A.P.; Yadav, A.P.; Rai, M.K. Fabrication of silver nanoparticles by Phoma glomerata and its combined effect against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Lett. Appl. Microbiol. 2009, 48, 173–179. [Google Scholar] [CrossRef]
  59. Feizi, S.; Cooksley, C.M.; Nepal, R.; Psaltis, A.J.; Wormald, P.-J.; Vreugde, S. Silver nanoparticles as a bioadjuvant of antibiotics against biofilm-mediated infections with methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa in chronic rhinosinusitis patients. Pathology 2022, 54, 453–459. [Google Scholar] [CrossRef] [PubMed]
  60. Ferreira, M.; Aguiar, S.; Bettencourt, A.; Gaspar, M.M. Lipid-based nanosystems for targeting bone implant-associated infections: Current approaches and future endeavors. Drug Deliv. Transl. Res. 2021, 11, 72–85. [Google Scholar] [CrossRef]
  61. Ferreira, M.; Ogren, M.; Dias, J.N.R.; Silva, M.; Gil, S.; Tavares, L.; Aires-da-Silva, F.; Gaspar, M.M.; Aguiar, S.I. Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance. Molecules 2021, 26, 2047. [Google Scholar] [CrossRef]
  62. Danhier, F.; Ansorena, E.; Silva, J.M.; Coco, R.; Le Breton, A.; Préat, V. PLGA-based nanoparticles: An overview of biomedical applications. J. Control. Release 2012, 161, 505–522. [Google Scholar] [CrossRef]
  63. Lecaroz, C.; Gamazo, C.; Renedo, M.J.; Blanco-Prieto, M.J. Biodegradable micro- and nanoparticles as long-term delivery vehicles for gentamicin. J. Microencapsul. 2006, 23, 782–792. [Google Scholar] [CrossRef]
  64. Lecaroz, M.C.; Blanco-Prieto, M.J.; Campanero, M.A.; Salman, H.; Gamazo, C. Poly(D,L-lactide-coglycolide) particles containing gentamicin: Pharmacokinetics and pharmacodynamics in Brucella melitensis-infected mice. Antimicrob. Agents Chemother. 2007, 51, 1185–1190. [Google Scholar] [CrossRef]
  65. Abdelghany, S.M.; Quinn, D.J.; Ingram, R.J.; Gilmore, B.F.; Donnelly, R.F.; Taggart, C.C.; Scott, C.J. Gentamicin-loaded nanoparticles show improved antimicrobial effects towards Pseudomonas aeruginosa infection. Int. J. Nanomed. 2012, 7, 4053–4063. [Google Scholar] [CrossRef]
  66. Posadowska, U.; Brzychczy-Włoch, M.; Pamuła, E. Gentamicin loaded PLGA nanoparticles as local drug delivery system for the osteomyelitis treatment. Acta Bioeng. Biomech. 2015, 17, 41–48. [Google Scholar] [CrossRef]
  67. Dhal, C.; Mishra, R. Formulation development and in vitro evaluation of gentamicin sulfate-loaded PLGA nanoparticles based film for the treatment of surgical site infection by Box–Behnken design. Drug Dev. Ind. Pharm. 2019, 45, 805–818. [Google Scholar] [CrossRef] [PubMed]
  68. Jiang, L.; Greene, M.K.; Insua, J.L.; Pessoa, J.S.; Small, D.M.; Smyth, P.; McCann, A.P.; Cogo, F.; Bengoechea, J.A.; Taggart, C.C.; et al. Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles. J. Control. Release 2018, 279, 316–325. [Google Scholar] [CrossRef]
  69. Sun, Y.; Bhattacharjee, A.; Reynolds, M.; Li, Y.V. Synthesis and characterizations of gentamicin-loaded poly-lactic-co-glycolic (PLGA) nanoparticles. J. Nanoparticle Res. 2021, 23, 155. [Google Scholar] [CrossRef]
  70. Rezvantalab, S.; Drude, N.I.; Moraveji, M.K.; Güvener, N.; Koons, E.K.; Shi, Y.; Lammers, T.; Kiessling, F. PLGA-Based Nanoparticles in Cancer Treatment. Front. Pharmacol. 2018, 9, 1260. [Google Scholar] [CrossRef] [PubMed]
  71. Xu, Y.; Kim, C.-S.; Saylor, D.M.; Koo, D. Polymer degradation and drug delivery in PLGA-based drug–polymer applications: A review of experiments and theories. J. Biomed. Mater. Res. B Appl. Biomater. 2017, 105, 1692–1716. [Google Scholar] [CrossRef]
  72. Lü, J.M.; Wang, X.; Marin-Muller, C.; Wang, H.; Lin, P.H.; Yao, Q.; Chen, C. Current advances in research and clinical applications of PLGA-based nanotechnology. Expert. Rev. Mol. Diagn. 2009, 9, 325–341. [Google Scholar] [CrossRef]
  73. Cao, X.; Dai, L.; Sun, S.; Ma, R.; Liu, X. Preparation and performance of porous hydroxyapatite/poly(lactic-co-glycolic acid) drug-loaded microsphere scaffolds for gentamicin sulfate delivery. J. Mater. Sci. 2021, 56, 15278–15298. [Google Scholar] [CrossRef]
  74. Sivaraman, B.; Ramamurthi, A. Multifunctional nanoparticles for doxycycline delivery towards localized elastic matrix stabilization and regenerative repair. Acta Biomater. 2013, 9, 6511–6525. [Google Scholar] [CrossRef] [PubMed]
  75. Razei, A.; Cheraghali, A.M.; Saadati, M.; Fasihi Ramandi, M.; Panahi, Y.; Hajizade, A.; Siadat, S.D.; Behrouzi, A. Gentamicin-Loaded Chitosan Nanoparticles Improve Its Therapeutic Effects on Brucella-Infected J774A.1 Murine Cells. Galen. Med. J. 2019, 8, e1296. [Google Scholar] [CrossRef]
  76. Shakya, A.K.; Al-Sulaibi, M.; Naik, R.R.; Nsairat, H.; Suboh, S.; Abulaila, A. Review on PLGA Polymer Based Nanoparticles with Antimicrobial Properties and Their Application in Various Medical Conditions or Infections. Polymers 2023, 15, 3597. [Google Scholar] [CrossRef]
  77. Vasir, J.K.; Labhasetwar, V. Biodegradable nanoparticles for cytosolic delivery of therapeutics. Adv. Drug Deliv. Rev. 2007, 59, 718–728. [Google Scholar] [CrossRef] [PubMed]
  78. Panyam, J.; Zhou, W.-Z.; Prabha, S.; Sahoo, S.K.; Labhasetwar, V. Rapid endo-lysosomal escape of poly(DL-lactide-coglycolide) nanoparticles: Implications for drug and gene delivery. FASEB J. 2002, 16, 1217–1226. [Google Scholar] [CrossRef] [PubMed]
  79. Kosinski, A.M.; Brugnano, J.L.; Seal, B.L.; Knight, F.C.; Panitch, A. Synthesis and characterization of a poly (lactic-co-glycolic acid) core + poly (N-isopropylacrylamide) shell nanoparticle system. Biomatter 2012, 2, 195–201. [Google Scholar] [CrossRef] [PubMed]
  80. Acharya, S.; Sahoo, S.K. PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv. Drug Deliv. Rev. 2011, 63, 170–183. [Google Scholar] [CrossRef]
  81. El-Hammadi, M.M.; Arias, J.L. Recent Advances in the Surface Functionalization of PLGA-Based Nanomedicines. Nanomaterials 2022, 12, 354. [Google Scholar] [CrossRef] [PubMed]
  82. Nandi, S.K.; Bandyopadhyay, S.; Das, P.; Samanta, I.; Mukherjee, P.; Roy, S.; Kundu, B. Understanding osteomyelitis and its treatment through local drug delivery system. Biotechnol. Adv. 2016, 34, 1305–1317. [Google Scholar] [CrossRef] [PubMed]
  83. Owens, C.D.; Stoessel, K. Surgical site infections: Epidemiology, microbiology and prevention. J. Hosp. Infect. 2008, 70, 3–10. [Google Scholar] [CrossRef]
  84. Worku, S.; Abebe, T.; Alemu, A.; Seyoum, B.; Swedberg, G.; Abdissa, A.; Mihret, A.; Beyene, G.T. Bacterial profile of surgical site infection and antimicrobial resistance patterns in Ethiopia: A multicentre prospective cross-sectional study. Ann. Clin. Microbiol. Antimicrob. 2023, 22, 96. [Google Scholar] [CrossRef]
  85. Liu, Y.; Li, X.; Liang, A. Current research progress of local drug delivery systems based on biodegradable polymers in treating chronic osteomyelitis. Front. Bioeng. Biotechnol. 2022, 10, 1042128. [Google Scholar] [CrossRef]
  86. Flores, C.; Degoutin, S.; Chai, F.; Raoul, G.; Hornez, J.-C.; Martel, B.; Siepmann, J.; Ferri, J.; Blanchemain, N. Gentamicin-loaded poly(lactic-co-glycolic acid) microparticles for the prevention of maxillofacial and orthopedic implant infections. Mater. Sci. Engineering C 2016, 64, 108–116. [Google Scholar] [CrossRef]
  87. Akhtar, B.; Muhammad, F.; Aslam, B.; Saleemi, M.K.; Sharif, A. Biodegradable nanoparticle based transdermal patches for gentamicin delivery: Formulation, characterization and pharmacokinetics in rabbits. J. Drug Deliv. Sci. Technol. 2020, 57, 101680. [Google Scholar] [CrossRef]
  88. Dhal, C.; Mishra, R. In vitro and in vivo evaluation of gentamicin sulphate-loaded PLGA nanoparticle-based film for the treatment of surgical site infection. Drug Deliv. Transl. Res. 2020, 10, 1032–1043. [Google Scholar] [CrossRef]
  89. Aranaz, I.; Alcántara, A.R.; Civera, M.C.; Arias, C.; Elorza, B.; Heras Caballero, A.; Acosta, N. Chitosan: An Overview of Its Properties and Applications. Polymers 2021, 13, 3256. [Google Scholar] [CrossRef]
  90. Kou, S.; Peters, L.; Mucalo, M. Chitosan: A review of molecular structure, bioactivities and interactions with the human body and micro-organisms. Carbohydr. Polym. 2022, 282, 119132. [Google Scholar] [CrossRef] [PubMed]
  91. El-Alfy, E.A.; El-Bisi, M.K.; Taha, G.M.; Ibrahim, H.M. Preparation of biocompatible chitosan nanoparticles loaded by tetracycline, gentamycin and ciprofloxacin as novel drug delivery system for improvement the antibacterial properties of cellulose based fabrics. Int. J. Biol. Macromol. 2020, 161, 1247–1260. [Google Scholar] [CrossRef]
  92. Yan, D.; Li, Y.; Liu, Y.; Li, N.; Zhang, X.; Yan, C. Antimicrobial Properties of Chitosan and Chitosan Derivatives in the Treatment of Enteric Infections. Molecules 2021, 26, 7136. [Google Scholar] [CrossRef]
  93. Yilmaz Atay, H. Antibacterial Activity of Chitosan-Based Systems. In Functional Chitosan: Drug Delivery and Biomedical Applications; Jana, S., Jana, S., Eds.; Springer: Singapore, 2019; pp. 457–489. [Google Scholar]
  94. Chandrasekaran, M.; Kim, K.D.; Chun, S.C. Antibacterial Activity of Chitosan Nanoparticles: A Review. Processes 2020, 8, 1173. [Google Scholar] [CrossRef]
  95. Lu, E.; Franzblau, S.; Onyuksel, H.; Popescu, C. Preparation of aminoglycoside-loaded chitosan nanoparticles using dextran sulphate as a counterion. J. Microencapsul. 2009, 26, 346–354. [Google Scholar] [CrossRef] [PubMed]
  96. Ji, J.; Hao, S.; Wu, D.; Huang, R.; Xu, Y. Preparation, characterization and in vitro release of chitosan nanoparticles loaded with gentamicin and salicylic acid. Carbohydr. Polym. 2011, 85, 803–808. [Google Scholar] [CrossRef]
  97. Alfaro-Viquez, E.; Esquivel-Alvarado, D.; Madrigal-Carballo, S.; Krueger, C.G.; Reed, J.D. Antimicrobial proanthocyanidin-chitosan composite nanoparticles loaded with gentamicin. Int. J. Biol. Macromol. 2020, 162, 1500–1508. [Google Scholar] [CrossRef]
  98. Asgarirad, H.; Ebrahimnejad, P.; Mahjoub, M.A.; Jalalian, M.; Morad, H.; Ataee, R.; Hosseini, S.S.; Farmoudeh, A. A promising technology for wound healing; in-vitro and in-vivo evaluation of chitosan nano-biocomposite films containing gentamicin. J. Microencapsul. 2021, 38, 100–107. [Google Scholar] [CrossRef]
  99. Abdel-Hakeem, M.A.; Abdel Maksoud, A.I.; Aladhadh, M.A.; Almuryif, K.A.; Elsanhoty, R.M.; Elebeedy, D. Gentamicin-Ascorbic Acid Encapsulated in Chitosan Nanoparticles Improved In Vitro Antimicrobial Activity and Minimized Cytotoxicity. Antibiotics 2022, 11, 1530. [Google Scholar] [CrossRef]
  100. Jafernik, K.; Ładniak, A.; Blicharska, E.; Czarnek, K.; Ekiert, H.; Wiącek, A.E.; Szopa, A. Chitosan-Based Nanoparticles as Effective Drug Delivery Systems—A review. Molecules 2023, 28, 1963. [Google Scholar] [CrossRef] [PubMed]
  101. Abdelgawad, A.M.; Hudson, S.M. Chitosan nanoparticles: Polyphosphates cross-linking and protein delivery properties. Int. J. Biol. Macromol. 2019, 136, 133–142. [Google Scholar] [CrossRef]
  102. Pan, C.; Qian, J.; Zhao, C.; Yang, H.; Zhao, X.; Guo, H. Study on the relationship between crosslinking degree and properties of TPP crosslinked chitosan nanoparticles. Carbohydr. Polym. 2020, 241, 116349. [Google Scholar] [CrossRef] [PubMed]
  103. Aibani, N.; Rai, R.; Patel, P.; Cuddihy, G.; Wasan, E.K. Chitosan Nanoparticles at the Biological Interface: Implications for Drug Delivery. Pharmaceutics 2021, 13, 1686. [Google Scholar] [CrossRef]
  104. Cao, Y.; Tan, Y.F.; Wong, Y.S.; Liew, M.W.J.; Venkatraman, S. Recent Advances in Chitosan-Based Carriers for Gene Delivery. Mar. Drugs 2019, 17, 381. [Google Scholar] [CrossRef] [PubMed]
  105. Qiu, Y.; Xu, D.; Sui, G.; Wang, D.; Wu, M.; Han, L.; Mu, H.; Duan, J. Gentamicin decorated phosphatidylcholine-chitosan nanoparticles against biofilms and intracellular bacteria. Int. J. Biol. Macromol. 2020, 156, 640–647. [Google Scholar] [CrossRef] [PubMed]
  106. Weng, J.; Tong, H.H.Y.; Chow, S.F. In Vitro Release Study of the Polymeric Drug Nanoparticles: Development and Validation of a Novel Method. Pharmaceutics 2020, 12, 732. [Google Scholar] [CrossRef]
  107. Gao, J.; Karp, J.M.; Langer, R.; Joshi, N. The Future of Drug Delivery. Chem. Mater. 2023, 35, 359–363. [Google Scholar] [CrossRef]
  108. Kapoor, D.N.; Bhatia, A.; Kaur, R.; Sharma, R.; Kaur, G.; Dhawan, S. PLGA: A unique polymer for drug delivery. Ther. Deliv. 2015, 6, 41–58. [Google Scholar] [CrossRef] [PubMed]
  109. Herdiana, Y.; Wathoni, N.; Shamsuddin, S.; Muchtaridi, M. Drug release study of the chitosan-based nanoparticles. Heliyon 2022, 8, e08674. [Google Scholar] [CrossRef] [PubMed]
  110. Fredenberg, S.; Wahlgren, M.; Reslow, M.; Axelsson, A. The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems—A review. Int. J. Pharm. 2011, 415, 34–52. [Google Scholar] [CrossRef] [PubMed]
  111. Hines, D.J.; Kaplan, D.L. Poly(lactic-co-glycolic) acid-controlled-release systems: Experimental and modeling insights. Crit. Rev. Ther. Drug Carrier Syst. 2013, 30, 257–276. [Google Scholar] [CrossRef] [PubMed]
  112. Chavan, Y.R.; Tambe, S.M.; Jain, D.D.; Khairnar, S.V.; Amin, P.D. Redefining the importance of polylactide-co-glycolide acid (PLGA) in drug delivery. Ann. Pharm. Fr. 2022, 80, 603–616. [Google Scholar] [CrossRef] [PubMed]
  113. Trang, T.T.T.; Mariatti, M.; Badrul, H.Y.; Masakazu, K.; Nguyen, X.T.T.; Zuratul, A.A.H. Drug Release Profile Study of Gentamicin Encapsulated Poly (lactic Acid) Microspheres for Drug Delivery. Mater. Today Proc. 2019, 17, 836–845. [Google Scholar] [CrossRef]
  114. Ivković, B.; Milutinović, I.; Čudina, O.; Marković, B. A new simple liquid chromatographic assay for gentamicin in presence of methylparaben and propylparaben. Acta Chromatogr. 2023, 35, 81–87. [Google Scholar] [CrossRef]
  115. Ismail, A.F.H.; Mohamed, F.; Rosli, L.M.M.; Shafri, M.A.M.; Haris, M.S.; Adina, A.B. Spectrophotometric Determination of Gentamicin Loaded PLGA Microparticles and Method Validation via Ninhydrin-Gentamicin Complex as a Rapid Quantification Approach. J. Appl. Pharm. Sci. 2016, 6, 007–014. [Google Scholar] [CrossRef]
  116. D’Souza, S. A Review of In Vitro Drug Release Test Methods for Nano-Sized Dosage Forms. Adv. Pharm. 2014, 2014, 304757. [Google Scholar] [CrossRef]
  117. D’Souza, S.S.; DeLuca, P.P. Methods to Assess in Vitro Drug Release from Injectable Polymeric Particulate Systems. Pharm. Res. 2006, 23, 460–474. [Google Scholar] [CrossRef]
  118. Gosau, M.; Müller, B.W. Release of gentamicin sulphate from biodegradable PLGA-implants produced by hot melt extrusion. Pharmazie 2010, 65, 487–492. [Google Scholar] [CrossRef] [PubMed]
  119. Hetta, H.F.; Ramadan, Y.N.; Al-Harbi, A.I.; Ahmed, E.A.; Battah, B.; Abd Ellah, N.H.; Zanetti, S.; Donadu, M.G. Nanotechnology as a Promising Approach to Combat Multidrug Resistant Bacteria: A Comprehensive Review and Future Perspectives. Biomedicines 2023, 11, 413. [Google Scholar] [CrossRef] [PubMed]
  120. Imbuluzqueta, E.; Gamazo, C.; Lana, H.; Campanero, M.; Salas, D.; Gil, A.G.; Elizondo, E.; Ventosa, N.; Veciana, J.; Blanco-Prieto, M.J. Hydrophobic gentamicin-loaded nanoparticles are effective against Brucella melitensis infection in mice. Antimicrob. Agents Chemother. 2013, 57, 3326–3333. [Google Scholar] [CrossRef] [PubMed]
  121. Kwiecień, K.; Brzychczy-Włoch, M.; Pamuła, E. Antibiotics modified by hydrophobic ion-pairing—A solution world’s problems with resistant bacteria? Sustain. Mater. Technol. 2023, 37, e00662. [Google Scholar] [CrossRef]
  122. Imbuluzqueta, E.; Elizondo, E.; Gamazo, C.; Moreno-Calvo, E.; Veciana, J.; Ventosa, N.; Blanco-Prieto, M.J. Novel bioactive hydrophobic gentamicin carriers for the treatment of intracellular bacterial infections. Acta Biomater. 2011, 7, 1599–1608. [Google Scholar] [CrossRef] [PubMed]
  123. Imbuluzqueta, E.; Lemaire, S.; Gamazo, C.; Elizondo, E.; Ventosa, N.; Veciana, J.; Van Bambeke, F.; Blanco-Prieto, M.J. Cellular pharmacokinetics and intracellular activity against Listeria monocytogenes and Staphylococcus aureus of chemically modified and nanoencapsulated gentamicin. J. Antimicrob. Chemother. 2012, 67, 2158–2164. [Google Scholar] [CrossRef] [PubMed]
  124. Pudełko, I.; Moskwik, A.; Kwiecień, K.; Kriegseis, S.; Krok-Borkowicz, M.; Schickle, K.; Ochońska, D.; Dobrzyński, P.; Brzychczy-Włoch, M.; Gonzalez-Julian, J.; et al. Porous Zirconia Scaffolds Functionalized with Calcium Phosphate Layers and PLGA Nanoparticles Loaded with Hydrophobic Gentamicin. Int. J. Mol. Sci. 2023, 24, 8400. [Google Scholar] [CrossRef] [PubMed]
  125. Kwiecień, K.; Pudełko, I.; Knap, K.; Reczyńska-Kolman, K.; Krok-Borkowicz, M.; Ochońska, D.; Brzychczy-Włoch, M.; Pamuła, E. Insight in Superiority of the Hydrophobized Gentamycin in Terms of Antibiotics Delivery to Bone Tissue. Int. J. Mol. Sci. 2022, 23, 12077. [Google Scholar] [CrossRef]
  126. Rotman, S.G.; Thompson, K.; Grijpma, D.W.; Richards, R.G.; Moriarty, T.F.; Eglin, D.; Guillaume, O. Development of bone seeker–functionalised microspheres as a targeted local antibiotic delivery system for bone infections. J. Orthop. Translat 2020, 21, 136–145. [Google Scholar] [CrossRef] [PubMed]
  127. Rotman, S.G.; Moriarty, T.F.; Nottelet, B.; Grijpma, D.W.; Eglin, D.; Guillaume, O. Poly(Aspartic Acid) Functionalized Poly(ϵ-Caprolactone) Microspheres with Enhanced Hydroxyapatite Affinity as Bone Targeting Antibiotic Carriers. Pharmaceutics 2020, 12, 885. [Google Scholar] [CrossRef]
  128. Elizondo, E.; Sala, S.; Imbuluzqueta, E.; González, D.; Blanco-Prieto, M.J.; Gamazo, C.; Ventosa, N.; Veciana, J. High loading of gentamicin in bioadhesive PVM/MA nanostructured microparticles using compressed carbon-dioxide. Pharm. Res. 2011, 28, 309–321. [Google Scholar] [CrossRef] [PubMed]
  129. Sande, M.A.; Courtney, K.B. Nafcillin-gentamicin synergism in experimental staphylococcal endocarditis. J. Lab. Clin. Med. 1976, 88, 118–124. [Google Scholar] [PubMed]
  130. Andriole, V.T. Antibiotic synergy in experimental infection with Pseudomonas. II. The effect of carbenicillin, cephalothin, or cephanone combined with tobramycin or gentamicin. J. Infect. Dis. 1974, 129, 124–133. [Google Scholar] [CrossRef] [PubMed]
  131. Archer, G.; Fekety, F.R., Jr. Experimental Endocarditis Due to Pseudomonas aeruginosa. II. Therapy with Carbenicillin and Gentamicin. J. Infect. Dis. 1977, 136, 327–335. [Google Scholar] [CrossRef] [PubMed]
  132. World Health Organization. WHO Guidelines for the Treatment of Neisseria Gonorrhoeae. Available online: https://www.who.int/publications/i/item/9789241549691 (accessed on 19 February 2024).
  133. Kirkcaldy, R.D.; Weinstock, H.S.; Moore, P.C.; Philip, S.S.; Wiesenfeld, H.C.; Papp, J.R.; Kerndt, P.R.; Johnson, S.; Ghanem, K.G.; Hook, E.W., III; et al. The Efficacy and Safety of Gentamicin Plus Azithromycin and Gemifloxacin Plus Azithromycin as Treatment of Uncomplicated Gonorrhea. Clin. Infect. Dis. 2014, 59, 1083–1091. [Google Scholar] [CrossRef] [PubMed]
  134. Ren, H.; Liu, Y.; Zhou, J.; Long, Y.; Liu, C.; Xia, B.; Shi, J.; Fan, Z.; Liang, Y.; Chen, S.; et al. Combination of Azithromycin and Gentamicin for Efficient Treatment of Pseudomonas aeruginosa Infections. J. Infect. Dis. 2019, 220, 1667–1678. [Google Scholar] [CrossRef] [PubMed]
  135. Svedholm, E.; Bruce, B.; Parcell, B.J.; Coote, P.J. Repurposing Mitomycin C in Combination with Pentamidine or Gentamicin to Treat Infections with Multi-Drug-Resistant (MDR) Pseudomonas aeruginosa. Antibiotics 2024, 13, 177. [Google Scholar] [CrossRef]
  136. Wang, L.; Di Luca, M.; Tkhilaishvili, T.; Trampuz, A.; Gonzalez Moreno, M. Synergistic Activity of Fosfomycin, Ciprofloxacin, and Gentamicin against Escherichia coli and Pseudomonas aeruginosa Biofilms. Front. Microbiol. 2019, 10, 2522. [Google Scholar] [CrossRef]
  137. Oliva, A.; Tafin, U.F.; Maiolo, E.M.; Jeddari, S.; Bétrisey, B.; Trampuz, A. Activities of Fosfomycin and Rifampin on Planktonic and Adherent Enterococcus faecalis Strains in an Experimental Foreign-Body Infection Model. Antimicrob. Agents Chemother. 2014, 58, 1284–1293. [Google Scholar] [CrossRef]
  138. Luther, M.K.; Arvanitis, M.; Mylonakis, E.; LaPlante, K.L. Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin against Biofilm-Forming Enterococcus faecalis or E. faecium in an In Vitro Pharmacodynamic Model Using Simulated Endocardial Vegetations and an In Vivo Survival Assay Using Galleria mellonella Larvae. Antimicrob. Agents Chemother. 2014, 58, 4612–4620. [Google Scholar] [CrossRef]
  139. Usman, M.; Marcus, A.; Fatima, A.; Aslam, B.; Zaid, M.; Khattak, M.; Bashir, S.; Masood, S.; Rafaque, Z.; Dasti, J.I. Synergistic Effects of Gentamicin, Cefepime, and Ciprofloxacin on Biofilm of Pseudomonas aeruginosa. Infect. Drug Resist. 2023, 16, 5887–5898. [Google Scholar] [CrossRef] [PubMed]
  140. Tamma, P.D.; Cosgrove, S.E.; Maragakis, L.L. Combination Therapy for Treatment of Infections with Gram-Negative Bacteria. Clin. Microbiol. Rev. 2012, 25, 450–470. [Google Scholar] [CrossRef] [PubMed]
  141. Fernández-Hidalgo, N.; Almirante, B.; Gavaldà, J.; Gurgui, M.; Peña, C.; de Alarcón, A.; Ruiz, J.; Vilacosta, I.; Montejo, M.; Vallejo, N.; et al. Ampicillin Plus Ceftriaxone Is as Effective as Ampicillin Plus Gentamicin for Treating Enterococcus faecalis Infective Endocarditis. Clin. Infect. Dis. 2013, 56, 1261–1268. [Google Scholar] [CrossRef] [PubMed]
  142. Pericas, J.M.; Cervera, C.; del Rio, A.; Moreno, A.; Garcia de la Maria, C.; Almela, M.; Falces, C.; Ninot, S.; Castañeda, X.; Armero, Y.; et al. Changes in the treatment of Enterococcus faecalis infective endocarditis in Spain in the last 15 years: From ampicillin plus gentamicin to ampicillin plus ceftriaxone. Clin. Microbiol. Infect. 2014, 20, O1075–O1083. [Google Scholar] [CrossRef] [PubMed]
  143. Bustos, P.S.; Deza-Ponzio, R.; Páez, P.L.; Cabrera, J.L.; Virgolini, M.B.; Ortega, M.G. Flavonoids as protective agents against oxidative stress induced by gentamicin in systemic circulation. Potent protective activity and microbial synergism of luteolin. Food Chem. Toxicol. 2018, 118, 294–302. [Google Scholar] [CrossRef] [PubMed]
  144. Rana, A.; Samtiya, M.; Dhewa, T.; Mishra, V.; Aluko, R.E. Health benefits of polyphenols: A concise review. J. Food Biochem. 2022, 46, e14264. [Google Scholar] [CrossRef] [PubMed]
  145. Daglia, M. Polyphenols as antimicrobial agents. Curr. Opin. Biotechnol. 2012, 23, 174–181. [Google Scholar] [CrossRef] [PubMed]
  146. Buchmann, D.; Schultze, N.; Borchardt, J.; Böttcher, I.; Schaufler, K.; Guenther, S. Synergistic antimicrobial activities of epigallocatechin gallate, myricetin, daidzein, gallic acid, epicatechin, 3-hydroxy-6-methoxyflavone and genistein combined with antibiotics against ESKAPE pathogens. J. Appl. Microbiol. 2022, 132, 949–963. [Google Scholar] [CrossRef] [PubMed]
  147. Xiao, J. Dietary flavonoid aglycones and their glycosides: Which show better biological significance? Crit. Rev. Food Sci. Nutr. 2017, 57, 1874–1905. [Google Scholar] [CrossRef]
  148. Lima, V.N.; Oliveira-Tintino, C.D.M.; Santos, E.S.; Morais, L.P.; Tintino, S.R.; Freitas, T.S.; Geraldo, Y.S.; Pereira, R.L.S.; Cruz, R.P.; Menezes, I.R.A.; et al. Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: Gallic acid, caffeic acid and pyrogallol. Microb. Pathog. 2016, 99, 56–61. [Google Scholar] [CrossRef]
  149. Parvez, M.A.K.; Saha, K.; Rahman, J.; Munmun, R.A.; Rahman, M.A.; Dey, S.K.; Rahman, M.S.; Islam, S.; Shariare, M.H. Antibacterial activities of green tea crude extracts and synergistic effects of epigallocatechingallate (EGCG) with gentamicin against MDR pathogens. Heliyon 2019, 5, e02126. [Google Scholar] [CrossRef] [PubMed]
  150. Lee, Y.S.; Kang, O.H.; Choi, J.G.; Oh, Y.C.; Chae, H.S.; Kim, J.H.; Park, H.; Sohn, D.H.; Wang, Z.T.; Kwon, D.Y. Synergistic effects of the combination of galangin with gentamicin against methicillin-resistant Staphylococcus aureus. J. Microbiol. 2008, 46, 283–288. [Google Scholar] [CrossRef] [PubMed]
  151. Macedo, I.; Silva, J.; Silva, P.; Cruz, B.; Vale, J.; Santos, H.; Bandeira, P.; Souza, E.; Xavier, R.; Coutinho, H.; et al. Structural and Microbiological Characterization of 5-Hydroxy-3,7,4′-Trimethoxyflavone: A Flavonoid Isolated from Vitex gardneriana Schauer Leaves. Microb. Drug Resist. 2019, 25, 434–438. [Google Scholar] [CrossRef] [PubMed]
  152. Cunningham-Oakes, E.; Soren, O.; Moussa, C.; Rathor, G.; Liu, Y.; Coates, A.; Hu, Y. Nordihydroguaiaretic acid enhances the activities of aminoglycosides against methicillin- sensitive and resistant Staphylococcus aureus in vitro and in vivo. Front. Microbiol. 2015, 6, 1195. [Google Scholar] [CrossRef] [PubMed]
  153. Luo, S.; Kang, X.; Luo, X.; Li, C.; Wang, G. Study on the inhibitory effect of quercetin combined with gentamicin on the formation of Pseudomonas aeruginosa and its bioenvelope. Microb. Pathog. 2023, 182, 106274. [Google Scholar] [CrossRef]
  154. Elssaig, E.; Alnour, T.; Ahmed, E.; Ullah, M.; Abu-Duhier, F. Antimicrobial synergistic effects of dietary flavonoids rutin and quercetin in combination with antibiotics gentamicin and ceftriaxone against E. coli (MDR) and P. mirabilis (XDR) strains isolated from human infections: Implications for food–medicine interactions. Ital. J. Food Sci. 2022, 34, 34–42. [Google Scholar] [CrossRef]
  155. Gupta, P.; Sarkar, A.; Sandhu, P.; Daware, A.; Das, M.C.; Akhter, Y.; Bhattacharjee, S. Potentiation of antibiotic against Pseudomonas aeruginosa biofilm: A study with plumbagin and gentamicin. J. Appl. Microbiol. 2017, 123, 246–261. [Google Scholar] [CrossRef]
  156. Sathiya Deepika, M.; Thangam, R.; Sakthidhasan, P.; Arun, S.; Sivasubramanian, S.; Thirumurugan, R. Combined effect of a natural flavonoid rutin from Citrus sinensis and conventional antibiotic gentamicin on Pseudomonas aeruginosa biofilm formation. Food Control 2018, 90, 282–294. [Google Scholar] [CrossRef]
  157. Mun, S.H.; Kang, O.H.; Joung, D.K.; Kim, S.B.; Seo, Y.S.; Choi, J.G.; Lee, Y.S.; Cha, S.W.; Ahn, Y.S.; Han, S.H.; et al. Combination Therapy of Sophoraflavanone B against MRSA: In Vitro Synergy Testing. Evid. Based Complement. Alternat Med. 2013, 2013, 823794. [Google Scholar] [CrossRef]
  158. Das, M.C.; Sandhu, P.; Gupta, P.; Rudrapaul, P.; De, U.C.; Tribedi, P.; Akhter, Y.; Bhattacharjee, S. Attenuation of Pseudomonas aeruginosa biofilm formation by Vitexin: A combinatorial study with azithromycin and gentamicin. Sci. Rep. 2016, 6, 23347. [Google Scholar] [CrossRef]
  159. Bustos, P.S.; Deza-Ponzio, R.; Páez, P.L.; Albesa, I.; Cabrera, J.L.; Virgolini, M.B.; Ortega, M.G. Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity. Environ. Toxicol. Pharmacol. 2016, 48, 253–264. [Google Scholar] [CrossRef] [PubMed]
  160. Caesar, L.K.; Cech, N.B. Synergy and antagonism in natural product extracts: When 1 + 1 does not equal 2. Nat. Prod. Rep. 2019, 36, 869–888. [Google Scholar] [CrossRef] [PubMed]
  161. Freitas, A.S.; Cunha, A.; Oliveira, R.; Almeida-Aguiar, C. Propolis antibacterial and antioxidant synergisms with gentamicin and honey. J. Appl. Microbiol. 2022, 132, 2733–2745. [Google Scholar] [CrossRef] [PubMed]
  162. Sookkhee, S.; Sakonwasun, C.; Mungkornasawakul, P.; Khamnoi, P.; Wikan, N.; Nimlamool, W. Synergistic Effects of Some Methoxyflavones Extracted from Rhizome of Kaempferia parviflora Combined with Gentamicin against Carbapenem-Resistant Strains of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Plants 2022, 11, 3128. [Google Scholar] [CrossRef] [PubMed]
  163. Rosato, A.; Carocci, A.; Catalano, A.; Clodoveo, M.L.; Franchini, C.; Corbo, F.; Carbonara, G.G.; Carrieri, A.; Fracchiolla, G. Elucidation of the synergistic action of Mentha piperita essential oil with common antimicrobials. PLoS ONE 2018, 13, e0200902. [Google Scholar] [CrossRef] [PubMed]
  164. Stefanovic, O.; Stankovic, M.; Čomić, L. In vitro antibacterial efficacy of Clinopodium vulgare L. extracts and their synergistic interaction with antibiotics. J. Med. Plant Res. 2011, 5, 4074–4079. [Google Scholar]
  165. Kuok, C.F.; Hoi, S.O.; Hoi, C.F.; Chan, C.H.; Fong, I.H.; Ngok, C.K.; Meng, L.R.; Fong, P. Synergistic antibacterial effects of herbal extracts and antibiotics on methicillin-resistant Staphylococcus aureus: A computational and experimental study. Exp. Biol. Med. 2017, 242, 731–743. [Google Scholar] [CrossRef]
Antibiotics 13 00305 g001
Figure 1. Applications of gentamicin. Created with BioRender.com (accessed on 29 February 2024).
Figure 1. Applications of gentamicin. Created with BioRender.com (accessed on 29 February 2024).
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Figure 2. Structures of Gentamicin derivatives: (A): main C-subtypes; (B): minor components.
Figure 2. Structures of Gentamicin derivatives: (A): main C-subtypes; (B): minor components.
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Antibiotics 13 00305 g003
Figure 3. Synthesis, common characterization methods, and possible applications of gentamicin-loaded PLGA nanoparticles. Created with BioRender.com (accessed on 21 March 2024).
Figure 3. Synthesis, common characterization methods, and possible applications of gentamicin-loaded PLGA nanoparticles. Created with BioRender.com (accessed on 21 March 2024).
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Figure 4. Structures of (A): gentamicin; (B): docusate sodium salt (AOT).
Figure 4. Structures of (A): gentamicin; (B): docusate sodium salt (AOT).
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Table 1. Gentamicin-loaded PLGA nanoparticles.
Table 1. Gentamicin-loaded PLGA nanoparticles.
PLGA TypeSurfactantFormulation MethodSize (nm)PDIZeta Potential (mV)Particle
Characterization Methods		EE (%)Drug LoadingDrug Release (In Vitro)Bacteria
(In Vitro Tests)		Potential
Application		Ref.
50:50
(13.7 kDa)		PVA
(15 kDa)		w/o/w
solvent evaporation		320NA−15.5 ± 0.2DLS
ELS
SEM
XRD
DSC		13.12–58.763.24–7.35 #28 daysNTIntracellular pathogens[63]
50:50
(13.7 kDa)		PVA
(15 kDa)		w/o/w
solvent evaporation		310 ± 2.00NANTDLSNT6.2 *NTNTIntracellular pathogens[64]
50:50
(12 kDa)		PVAw/o/w
s/o/w
solvent evaporation		241.3–358.50.10–0.23−0.4–2.3DLS
ELS		NT6.4–22.4 *Over 16 daysP. aeruginosaPlanktonic- and
biofilm-based infections		[65]
85:15
(80 kDa)		PVA
(31 kDa)		w/o/w
solvent evaporation		219–3910.21–0.38−7.2–−1.1DLS
ELS
AFM		2.7–52.40.06–10.28%35 daysS. aureus
S. epidermidis		Osteomyelitis[66]
50:50
(7–17 kDa)		PVA
(85–124 kDa)		w/o/w
solvent evaporation		280 ± 12.040.15 ± 0.01−4.9 ± 0.84DLS
ELS
SEM
TEM		NT60%216 hP. aeruginosa
S. aureus		Surgical site infections[67]
50:50
(7–17 kDa)		PVAw/o/w
solvent evaporation		2270.162−1.67DLS
ELS
SEM		NT135 *120 hK. pneumoniaeIntracellular pathogens[68]
PLGA-PEG
(70 kDa)		PVA
(85–124 kDa)		s/o/w
solvent evaporation		140.0–919.30.104–1.230−5.54–0.36DLS
ELS
TEM		43.97–64.612.9–7.9%10 hP. mirabilis
E. coli
P. aeruginosa
S. aureus		Intracellular pathogens[11]
75:25
(4–15 kDa)		PVA
(89–98 kDa)		w/o/w
solvent evaporation		32–2400NANTDLS
SEM		NTNT10 hE. coliWound
treatment		[69]
#—µg gentamicin/mg particles; *—µg gentamicin/mg polymer; NA—not available; NT—not tested; PVA—poly (vinyl alcohol); PDI—polydispersity index; DLS—dynamic light scattering; ELS—electrophoretic light scattering; AFM—atomic force microscopy; TEM—transmission electron microscopy; SEM—scanning electron microscopy; DSC—differential scanning calorimetry; XRD—X-ray diffraction analysis.
Table 2. Gentamicin-loaded chitosan nanoparticles.
Table 2. Gentamicin-loaded chitosan nanoparticles.
Chitosan TypeCrosslinkerDrugsFormulation MethodSize (nm)PDIZeta Potential (mV)Particle Characterization MethodsEE (%)Drug Loading (%)Bacteria
(In Vitro Tests)		Potential ApplicationRef.
150 kDa, deacetylation degree 85.6%TPPGentamicinIonic gelation779.37 ± 51.79NT1.9 ± 0.5DLS
ELS		78.06 ± 2.1363.10 ± 1.54NTIntracellular pathogens[95]
80 kDa, deacetylation degree 95%TPPGentamicin + salicylic acidIonic gelation148–3450.234–0.42832.45–42.43DLS
ELS
TEM
SEM
FTIR
XRD		61.70–87.2013.56–26.64NTReduction in toxicity[96]
140 kDa, deacetylation degree 85%TPPGentamicinIonic gelation100NT28DLS
ELS
SEM		7222B. abortus
B. melitensis		Intracellular pathogens[75]
304 kDa, deacetylation degree >84%-Gentamicin + proanthocyanidinHydrogen bonding242.9–277.40.344–0.39134.5–38.5DLS
ELS
SEM
FTIR
TGA		94NTE. coli
S. aureus
P. aeruginosa		Enhanced antimicrobial activity[97]
Low molecular weight, deacetylation ≥ 75%TPPGentamicinIonic gelation151–2120.21–0.2937.2–51.1DLS
ELS
TEM
SEM
DSC		36.6–42.7NTNTWound healing[98]
NATPPGentamicin + ascorbic acidIonic gelation278NT30.01DLS
ELS
TEM
FTIR		8922S. aureus
P. aeruginosa		Reduction in toxicity[99]
NA—not available; NT—not tested; TPP—sodium tripolyphosphate; DLS—dynamic light scattering; ELS—electrophoretic light scattering; TEM—transmission electron microscopy; SEM—scanning electron microscopy; TGA—thermogravimetric analysis; DSC—differential scanning calorimetry; FTIR—Fourier-transform infrared spectroscopy; XRD—X-ray diffraction analysis.
Table 3. Synergy between gentamicin and individual polyphenols.
Table 3. Synergy between gentamicin and individual polyphenols.
PolyphenolBacteriaBacterial Strain TypeAntibacterial Effect on GentamicinFICISynergy/Partial SynergyRef.
Caffeic acidP. aeruginosaClinical isolatesMIC reduced from 625 μg/mL to 24.61 μg/mLNASynergy[148]
Epigallocatechin gallateA. baumanniiReferenceMIC reduced from 27 μg/mL to 4 μg/mL0.65Partial synergy[146]
S. aureusClinical isolatesMIC reduced from 32 μg/mL to 6.4 μg/mL0.325Synergy[149]
E. coliClinical isolatesMIC reduced from 32 μg/mL to 6.4 μg/mL0.325Synergy[149]
DaidzeinA. baumanniiReferenceMIC reduced from 27 μg/mL to 8 μg/mL0.42Synergy[146]
GalanginS. aureus
(methicillin-resistant)		Clinical isolates/referenceReduced MIC0.18–0.25Synergy[150]
Gallic acidS. aureusClinical isolatesMIC reduced from 49.21 μg/mL to 2.44 μg/mLNASynergy[148]
GenisteinA. baumanniiReferenceMIC reduced from 27 μg/mL to 4 μg/mL0.4Synergy[146]
5-Hydroxy-3,7,4′-trimethoxyflavoneS. aureusClinical isolatesReduced MICNASynergy[151]
E. coliClinical isolatesReduced MICNASynergy[151]
Kaempferol 7-O-β-D-(6″-O-cumaroyl)-glucopyranosideS. aureusReferenceMIC reduced from 16 μg/mL to 4 μg/mLNASynergy[3]
E. coliReferenceMIC reduced from 16 μg/mL to 8 μg/mLNASynergy[3]
LuteolinS. aureusReferenceMIC reduced 4-fold0.258Synergy[143]
E. coliReferenceReduced MIC0.504Additive[143]
Nordihydroguaiaretic acidS. aureus
(methicillin-sensitive)		Clinical isolatesSeveral-fold MIC reduction<0.5Synergy[152]
S. aureus
(methicillin-resistant)		Clinical isolatesSeveral-fold MIC reduction<0.5Synergy[152]
QuercetinP. aeruginosaClinical isolatesMIC reduced from 128 μg/mL to 32 μg/mL0.28–0.53Synergy/Partial synergy[153]
P. aeruginosaClinical isolates/referenceReduced MIC0.375–0.75Synergy/Partial synergy[2]
P. mirabilisClinical isolatesRestored antibacterial activityNASynergy[154]
PlumbaginP. aeruginosaReferenceReduced MIC0.152–0.485Synergy[155]
PyrogallolS. aureusClinical isolatesMIC reduced from 49.21 μg/mL to 2.44 μg/mLNASynergy[148]
RutinP. aeruginosaReferenceMIC reduced from 10 μg/mL to 2.5 μg/mL0.5Synergy[156]
Sophoraflavanone BS. aureus
(methicillin-resistant)		Clinical isolates/referenceMIC reduced 8- to 32-fold0.25–0.375Synergy[157]
VitexinP. aeruginosaReferenceReduced MIC0.078Synergy[158]
NA—not available; FICI—fractional inhibitory concentration index; MIC—minimum inhibitory concentration.
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Bārzdiņa, A.; Plotniece, A.; Sobolev, A.; Pajuste, K.; Bandere, D.; Brangule, A. From Polymeric Nanoformulations to Polyphenols—Strategies for Enhancing the Efficacy and Drug Delivery of Gentamicin. Antibiotics 2024, 13, 305. https://doi.org/10.3390/antibiotics13040305

AMA Style

Bārzdiņa A, Plotniece A, Sobolev A, Pajuste K, Bandere D, Brangule A. From Polymeric Nanoformulations to Polyphenols—Strategies for Enhancing the Efficacy and Drug Delivery of Gentamicin. Antibiotics. 2024; 13(4):305. https://doi.org/10.3390/antibiotics13040305

Chicago/Turabian Style

Bārzdiņa, Ance, Aiva Plotniece, Arkadij Sobolev, Karlis Pajuste, Dace Bandere, and Agnese Brangule. 2024. "From Polymeric Nanoformulations to Polyphenols—Strategies for Enhancing the Efficacy and Drug Delivery of Gentamicin" Antibiotics 13, no. 4: 305. https://doi.org/10.3390/antibiotics13040305

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