Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

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Gruppo Italiano di Studio sulle Infezioni Gravi – GISIG 3: controversial issues of severe bacterial infections due to multidrug-resistant Gram-positive bacteria: introduction by the National Coordinators

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2010.05.001 ◽

2010 ◽

Vol 14 ◽

pp. S1

Author(s):

Giuseppe Ippolito ◽

Mauro Moroni ◽

Giampiero Carosi

Keyword(s):

Bacterial Infections ◽

Multidrug Resistant ◽

Controversial Issues ◽

Gram Positive ◽

Gram Positive Bacteria

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Bacteriocins, Antimicrobial Peptides from Bacterial Origin: Overview of Their Biology and Their Impact against Multidrug-Resistant Bacteria

Microorganisms ◽

10.3390/microorganisms8050639 ◽

2020 ◽

Vol 8 (5) ◽

pp. 639 ◽

Cited By ~ 13

Author(s):

Alexis Simons ◽

Kamel Alhanout ◽

Raphaël E. Duval

Keyword(s):

Antimicrobial Resistance ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Multidrug Resistant Bacteria ◽

Gram Negative ◽

Gram Positive Bacteria ◽

Further Development

Currently, the emergence and ongoing dissemination of antimicrobial resistance among bacteria are critical health and economic issue, leading to increased rates of morbidity and mortality related to bacterial infections. Research and development for new antimicrobial agents is currently needed to overcome this problem. Among the different approaches studied, bacteriocins seem to be a promising possibility. These molecules are peptides naturally synthesized by ribosomes, produced by both Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB), which will allow these bacteriocin producers to survive in highly competitive polymicrobial environment. Bacteriocins exhibit antimicrobial activity with variable spectrum depending on the peptide, which may target several bacteria. Already used in some areas such as agro-food, bacteriocins may be considered as interesting candidates for further development as antimicrobial agents used in health contexts, particularly considering the issue of antimicrobial resistance. The aim of this review is to present an updated global report on the biology of bacteriocins produced by GPB and GNB, as well as their antibacterial activity against relevant bacterial pathogens, and especially against multidrug-resistant bacteria.

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Redox-active cationic organoiron complex: a promising lead structure for developing antimicrobial agents with activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium

RSC Advances ◽

10.1039/c5ra16613f ◽

2015 ◽

Vol 5 (105) ◽

pp. 86421-86427 ◽

Cited By ~ 9

Author(s):

Alaa S. Abd-El-Aziz ◽

Christian Agatemor ◽

Nola Etkin ◽

David P. Overy ◽

Russell G. Kerr

Keyword(s):

Antimicrobial Agents ◽

Methicillin Resistant Staphylococcus Aureus ◽

Multidrug Resistant ◽

Gram Positive ◽

Lead Structure ◽

Gram Positive Bacteria ◽

Redox Active ◽

Vancomycin Resistant ◽

Organoiron Complexes ◽

Multidrug Resistant Strain

A redox-active, cationic organoiron complexes active against multidrug-resistant strain of Gram-positive bacteria is presented as a potential new lead structure for the design of antimicrobial agents.

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Baseline Study To Determine In Vitro Activities of Daptomycin against Gram-Positive Pathogens Isolated in the United States in 2000-2001

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.5.1689-1693.2003 ◽

2003 ◽

Vol 47 (5) ◽

pp. 1689-1693 ◽

Cited By ~ 59

Author(s):

Ian A. Critchley ◽

Renée S. Blosser-Middleton ◽

Mark E. Jones ◽

Clyde Thornsberry ◽

Daniel F. Sahm ◽

...

Keyword(s):

United States ◽

Outpatient Care ◽

Antimicrobial Agents ◽

The United States ◽

Multidrug Resistant ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Oxacillin Resistance ◽

Positive Spectrum

ABSTRACT The activity of daptomycin was assessed by using 6,973 gram-positive bacteria isolated at 50 United States hospitals in 2000 and 2001. Among the isolates of Streptococcus pneumoniae (n = 1,163) collected, the rate of penicillin resistance was 16.1%; rates of oxacillin resistance among Staphylococcus aureus isolates (n = 1,018) and vancomycin resistance among Enterococcus faecium isolates (n = 368) were 30.0 and 59.5%, respectively. Multidrug-resistant (MDR) phenotypes (isolates resistant to three or more different chemical classes of antimicrobial agents) accounted for 14.2% of S. pneumoniae isolates, 27.1% of S. aureus isolates, and 58.4% of E. faecium isolates. For all gram-positive species tested, MICs at which 90% of the isolates tested were inhibited (MIC90s) and MIC ranges for directed-spectrum agents (daptomycin, quinupristin-dalfopristin, and linezolid) were identical or highly similar for isolates susceptible or resistant to other agents or MDR. Daptomycin had a MIC90 of 0.12 μg/ml for both penicillin-susceptible and -resistant isolates of S. pneumoniae. Against oxacillin-resistant S. aureus daptomycin had a MIC90 of 0.5 μg/ml, and it had a MIC90 of 4 μg/ml against both vancomycin-susceptible and -resistant E. faecium. The MIC90s for daptomycin and other directed-spectrum agents were unaffected by the regional or anatomical origin of isolates or patient demographic parameters (patient age, gender, and inpatient or outpatient care). Our results confirm the gram-positive spectrum of activity of daptomycin and that its activity is independent of susceptibility or resistance to commonly prescribed and tested antimicrobial agents. This study may serve as a baseline to monitor future changes in the susceptibility of gram-positive species to daptomycin following its introduction into clinical use.

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New Insights in Design and Development of Antitubercular Drugs

Current Bioactive Compounds ◽

10.2174/1573407215666190409153756 ◽

2020 ◽

Vol 16 (1) ◽

pp. 13-23

Author(s):

Snehlata Yadav ◽

Balasubramanian Narasimhan

Keyword(s):

Treatment Options ◽

Latent Tuberculosis ◽

Multidrug Resistant ◽

Current Treatment ◽

Extensive Literature ◽

Antitubercular Drugs ◽

Treatment Regimens ◽

Resistant Tuberculosis ◽

Recent Developments ◽

Long Course

Background: Tuberculosis, an infectious disease caused mainly by the Mycobacterium tuberculosis accounts for the highest number of deaths worldwide. Despite curing millions, the currently used drug regimens are bounded by various limitations such as long course of therapy, emergence of resistance and permanent tissue damage. The treatment of multidrug-resistant and extremely drugresistant tuberculosis is a challenging task due to its reliance on second-line drugs which are less potent and more toxic than those used in the clinical management of drug-susceptible tuberculosis. Therefore, the major challenges in the upcoming years are to overcome the emergence of increased number of multidrug-resistant as well as extensively drug-resistant strains and the ineptness of the current treatment regimens against latent tuberculosis. Bedaquiline and Delamanid are the only new anti-TB drugs that have been currently approved since more than 40 years after discovery of isoniazid. Bedaquiline is the first diarylquinoline derivative that has showed resilient culture conversion at 24 weeks in phase IIb trials. Methods: Extensive literature search on the topic was undergone using a focused question. Results: Fifty-eight research articles from journals of repute are included in the review. The vaccine and peptide-based conjugates are recent developments against Mycobacterium for selective and specific targeting to the desired tissues. Conclusion: In this review, we have focused on the different classes of chemical as well as plant based compounds as potent antitubercular agents against multidrug-resistant tuberculosis strains. This review falls light on the importance of research been undergoing in different parts of the world to combat the ever increasing problem of mycobacterial resistance and the various treatment options available for the treatment of tuberculosis.

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Antibacterial Activity of Colloidal Silver against Gram-Negative and Gram-Positive Bacteria

Antibiotics ◽

10.3390/antibiotics9010036 ◽

2020 ◽

Vol 9 (1) ◽

pp. 36 ◽

Cited By ~ 4

Author(s):

Andrea Vila Domínguez ◽

Rafael Ayerbe Algaba ◽

Andrea Miró Canturri ◽

Ángel Rodríguez Villodres ◽

Younes Smani

Keyword(s):

Bacterial Infections ◽

Antimicrobial Properties ◽

Multidrug Resistant ◽

Colloidal Silver ◽

Ros Production ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria ◽

Kill Curve

Due to the emergence of antimicrobial resistance, new alternative therapies are needed. Silver was used to treat bacterial infections since antiquity due to its known antimicrobial properties. Here, we aimed to evaluate the in vitro activity of colloidal silver (CS) against multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria. A total of 270 strains (Acinetobacter baumannii (n = 45), Pseudomonas aeruginosa (n = 25), Escherichia coli (n = 79), Klebsiella pneumoniae (n = 58)], Staphylococcus aureus (n = 34), Staphylococcus epidermidis (n = 14), and Enterococcus species (n = 15)) were used. The minimal inhibitory concentration (MIC) of CS was determined for all strains by using microdilution assay, and time–kill curve assays of representative reference and MDR strains of these bacteria were performed. Membrane permeation and bacterial reactive oxygen species (ROS) production were determined in presence of CS. CS MIC90 was 4–8 mg/L for all strains. CS was bactericidal, during 24 h, at 1× and 2× MIC against Gram-negative bacteria, and at 2× MIC against Gram-positive bacteria, and it did not affect their membrane permeabilization. Furthermore, we found that CS significantly increased the ROS production in Gram-negative with respect to Gram-positive bacteria at 24 h of incubation. Altogether, these results suggest that CS could be an effective treatment for infections caused by MDR Gram-negative and Gram-positive bacteria.

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Current Perspectives on Treatment of Gram-Positive Infections in India: What Is the Way Forward?

Interdisciplinary Perspectives on Infectious Diseases ◽

10.1155/2019/7601847 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Atul P. Kulkarni ◽

Vasant C. Nagvekar ◽

Balaji Veeraraghavan ◽

Anup R. Warrier ◽

Deepak TS ◽

...

Keyword(s):

Mortality Rate ◽

Antimicrobial Agents ◽

Treatment Options ◽

Pharmacokinetic Profile ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Tolerability Profile ◽

Drug Resistant ◽

Gram Positive ◽

Favourable Pharmacokinetic Profile

The emerging antimicrobial resistance leading to gram-positive infections (GPIs) is one of the major public health threats worldwide. GPIs caused by multidrug resistant bacteria can result in increased morbidity and mortality rates along with escalated treatment cost and hospitalisation stay. In India, GPIs, particularly methicillin-resistant Staphylococcus aureus (MRSA) prevalence among invasive S. aureus isolates, have been reported to increase exponentially from 29% in 2009 to 47% in 2014. Apart from MRSA, rising prevalence of vancomycin-resistant enterococci (VRE), which ranges from 1 to 9% in India, has raised concerns. Moreover, the overall mortality rate among patients with multidrug resistant GPIs in India is reported to be 10.8% and in ICU settings, the mortality rate is as high as 16%. Another challenge is the spectrum of adverse effects related to the safety and tolerability profile of the currently available drugs used against GPIs which further makes the management and treatment of these multidrug resistant organisms a complex task. Judicious prescription of antimicrobial agents, implementation of antibiotic stewardship programmes, and antibiotic policies in hospitals are essential to reduce the problem of drug-resistant infections in India. The most important step is development of newer antimicrobial agents with novel mechanisms of action and favourable pharmacokinetic profile. This review provides a synopsis about the current burden, treatment options, and the challenges faced by the clinicians in the management of GPIs such as MRSA, Quinolone-resistant Staphylococcus, VRE, and drug-resistant pneumococcus in India.

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Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

Microorganisms ◽

10.3390/microorganisms9102104 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2104

Author(s):

Sunil Kumar ◽

Razique Anwer ◽

Arezki Azzi

Keyword(s):

Acinetobacter Baumannii ◽

Virulence Factors ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Treatment Options ◽

Outer Membrane Proteins ◽

Multidrug Resistant ◽

High Rate ◽

World Health ◽

Tract Infections

Acinetobacter baumannii is an opportunistic pathogen which is undoubtedly known for a high rate of morbidity and mortality in hospital-acquired infections. A. baumannii causes life-threatening infections, including; ventilator-associated pneumonia (VAP), meningitis, bacteremia, and wound and urinary tract infections (UTI). In 2017, the World Health Organization listed A. baumannii as a priority-1 pathogen. The prevalence of A. baumannii infections and outbreaks emphasizes the direct need for the use of effective therapeutic agents for treating such infections. Available antimicrobials, such as; carbapenems, tigecycline, and colistins have insufficient effectiveness due to the appearance of multidrug-resistant strains, accentuating the need for alternative and novel therapeutic remedies. To understand and overcome this menace, the knowledge of recent discoveries on the virulence factors of A. baumannii is needed. Herein, we summarized the role of various virulence factors, including; outer membrane proteins, efflux pumps, biofilm, penicillin-binding proteins, and siderophores/iron acquisition systems. We reviewed the recent scientific literature on different A. baumannii virulence factors and the effective antimicrobial agents for the treatment and management of bacterial infections.

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Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance

Molecules ◽

10.3390/molecules26072047 ◽

2021 ◽

Vol 26 (7) ◽

pp. 2047

Author(s):

Magda Ferreira ◽

Maria Ogren ◽

Joana N. R. Dias ◽

Marta Silva ◽

Solange Gil ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Bacterial Infections ◽

Private Investment ◽

Therapeutic Index ◽

Multidrug Resistant ◽

Current Treatment ◽

Delivery Systems ◽

Resistant Bacteria ◽

Bacterial Cells ◽

Antimicrobial Drugs

Antimicrobial drugs are key tools to prevent and treat bacterial infections. Despite the early success of antibiotics, the current treatment of bacterial infections faces serious challenges due to the emergence and spread of resistant bacteria. Moreover, the decline of research and private investment in new antibiotics further aggravates this antibiotic crisis era. Overcoming the complexity of antimicrobial resistance must go beyond the search of new classes of antibiotics and include the development of alternative solutions. The evolution of nanomedicine has allowed the design of new drug delivery systems with improved therapeutic index for the incorporated compounds. One of the most promising strategies is their association to lipid-based delivery (nano)systems. A drug’s encapsulation in liposomes has been demonstrated to increase its accumulation at the infection site, minimizing drug toxicity and protecting the antibiotic from peripheral degradation. In addition, liposomes may be designed to fuse with bacterial cells, holding the potential to overcome antimicrobial resistance and biofilm formation and constituting a promising solution for the treatment of potential fatal multidrug-resistant bacterial infections, such as methicillin resistant Staphylococcus aureus. In this review, we aim to address the applicability of antibiotic encapsulated liposomes as an effective therapeutic strategy for bacterial infections.

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