Infections by multidrug-resistant Gram-negative Bacteria: What's new in our arsenal and what's in the pipeline?

The spread of multidrug-resistant bacteria is an ever-growing concern, particularly among Gram-negative bacteria because of their intrinsic resistance and how quickly they acquire and spread new resistance mechanisms. Treating infections caused by Gram-negative bacteria is a challenge for medical practitioners and increases patient mortality and cost of care globally. This vulnerability, along with strategies to tackle antimicrobial resistance development, prompts the development of new antibiotic agents and exploration of alternative treatment options. This article summarises the new antibiotics that have recently been approved for Gram-negative bacterial infections, looks down the pipeline at promising agents currently in phase I, II, or III clinical trials, and introduces new alternative avenues that show potential in combating multidrug-resistant Gram-negative bacteria.     

New antibiotic agents for bloodstream infections

Infections due to multidrug-resistant pathogens have shown a dramatic worldwide increase in prevalence. Bloodstream infections (BSIs) represent an important cause of morbidity and mortality in hospitalised patients. Research in the field led to the introduction of several novel antibiotic agents in the fight against bacterial pathogens. New antibiotics used against Gram-positive bacteria, mainly meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, include daptomycin, linezolid, quinupristin/dalfopristin and semisynthetic lipoglycopeptides. Among the Gram-negative bacteria, extended-spectrum beta-lactamase-producing Enterobacteriaceae as well as highly resistant Pseudomonas and Acinetobacter isolates are of particular concern. Doripenem is a recently approved carbapenem. Polymyxins are reconsidered as valuable therapeutic options for Gram-negative infections. Tigecycline, a glycylcycline, and ceftobiprole, a novel cephalosporin under investigation, have activity both against Gram-positive and Gram-negative organisms. In addition to the above agents, alternative treatment approaches that require further investigation have also been introduced into clinical practice. These include antibiotic lock therapy and continuous intravenous administration of antibiotics. In this article, we review the above treatment options for BSIs based on current clinical evidence. Comparative trials specifically focusing on patients with bacteraemia were generally not performed; however, a proportion of patients from the reported studies did have bacteraemia.     

Tigecycline: first of a new class of antimicrobial agents

Tigecycline is the first commercially available member of the glycylcyclines, a new class of antimicrobial agents. The glycylcyclines are derivatives of the tetracycline antibiotics, with structural modifications that allow for potent gram-positive, gram-negative, and anaerobic activity, including certain multidrug-resistant strains. The enhanced activity can be attributed to stronger binding affinity and enhanced protection against several mechanisms of resistance that affect other antibiotic classes such as tetracyclines. Tigecycline exhibits generally bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein translation. In vitro activity has been demonstrated against multidrug-resistant gram-positive pathogens including methicillin-resistant and glycopeptide-intermediate and -resistant Staphylococcus aureus, as well as vancomycin-resistant enterococci. Multidrug-resistant gram-negative pathogens, such as Acinetobacter baumannii and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli, are typically highly susceptible to tigecycline. The drug also has displayed significant activity against many clinically important anaerobic organisms. This agent demonstrates a predictable pharmacokinetic profile and minimal drug interactions, and is generally well tolerated, with nausea being the most common adverse event. It was approved in June 2005 for the treatment of complicated skin and skin structure infections (SSSIs) and complicated intraabdominal infections. Currently, a limited number of broad-spectrum antimicrobials are available to combat multidrug-resistant organisms. The addition of new agents is essential to limiting the spread of these pathogens and improving outcomes in patients with these types of infections. Tigecycline has demonstrated promising results in initial in vitro and clinical studies for SSSIs and complicated intraabdominal infections; however, further clinical experience will clarify its role as a broad-spectrum agent.     

Practical applications and feasibility of efflux pump inhibitors in the clinic--a vision for applied use

The world of antibiotic drug discovery and development is driven by the necessity to overcome antibiotic resistance in common Gram-positive and Gram-negative pathogens. However, the lack of Gram-negative activity among both recently approved antibiotics and compounds in the developmental pipeline is a general trend despite the fact that the plethora of covered drug targets are well-conserved across the bacterial kingdom. Such intrinsic resistance in Gram-negative bacteria is largely attributed to the activity of multidrug resistance (MDR) efflux pumps. Moreover, these pumps also play a significant role in acquired clinical resistance. Together, these considerations make efflux pumps attractive targets for inhibition in that the resultant efflux pump inhibitor (EPI)/antibiotic combination drug should exhibit increased potency, enhanced spectrum of activity and reduced propensity for acquired resistance. To date, at least one class of broad-spectrum EPI has been extensively characterized. While these efforts indicated a significant potential for developing small molecule inhibitors against efflux pumps, they did not result in a clinically useful compound. Stemming from the continued clinical pressure for novel approaches to combat drug resistant bacterial infections, second-generation programs have been initiated and show early promise to significantly improve the clinical usefulness of currently available and future antibiotics against otherwise recalcitrant Gram-negative infections. It is also apparent that some changes in regulatory decision-making regarding resistance would be very helpful in order to facilitate approval of agents aiming to reverse resistance and prevent its further development.     

Prospects and challenges of developing new agents for tough Gram-negatives

Historically, the medical profession has been successful in treating most bacterial infections in humans with synthetic second- and third-generation antibiotics. Recently, the prospects for continued success have dimmed with the increase in multidrug-resistant stains of bacteria. Infections caused by the Gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter spp. in particular have increased in frequency and severity, and become progressively more difficult to treat. Contributors to disease severity include chronic infections due to mutator strains, persister cells and biofilms. The worst-case scenario of infections susceptible only to toxic polymixins is now a reality. The need to address the treatment of multidrug-resistant pathogens with innovative combination approaches and/or novel antibacterial agents is occurring in the context of reduced investment in antimicrobial drug discovery by the pharmaceutical industry.     

Current challenges in antimicrobial chemotherapy: the impact of extended-spectrum beta-lactamases and metallo-beta-lactamases on the treatment of resistant Gram-negative pathogens

Gram-negative bacteria that produce extended-spectrum- and metallo-beta-lactamases are being discovered at an alarming rate, while the development of new antimicrobial agents has almost ground to a standstill. A body of experience exists with the detection and treatment of extended-spectrum beta-lactamase-producing organisms (Klebsiella pneumoniae and Escherichia coli), suggesting that knowledge of their existence and dissemination might have an impact on therapeutic choices and patient outcomes via targeted empirical antimicrobial selection and infection control practices. It is unclear whether the same mandate exists for the detection of metallo-beta-lactamases. As dictated by local susceptibility patterns, in many settings worldwide empirical therapy in serious nosocomial infections now requires the use of carbapenems alone or in combination with a second antibiotic that is also effective against Gram-negative pathogens; colistin is advocated as the empirical drug of choice in the setting of multidrug-resistant Pseudomonas aeruginosa infections, although high doses of beta-lactams might prove to be effective.     

New antibiotics for the treatment of serious infections in intensive care unit patients

Objective: Nowadays, the infections of patients admitted to intensive care units (ICUs) are a major public health problem; this is due to several factors, in primis an increase in antibiotic resistance and the inappropriate use of antibiotics.

Methods: We briefly focus on on both new antibiotics approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in the last decade (2010–2019), and on agents in an advanced phase of development that have been developed, or are already approved, for the treatment of serious infections due to multidrug-resistant bacteria, both Gram-positive and Gram-negative bacteria.

Results: An adequate knowledge of the new antibiotics will reduce their inappropriate use with the consequent reduction in the onset of new resistance and decreasing health care costs.

Conclusion: Antimicrobial stewardship programs to optimize antimicrobial prescribing and to preserve the effectiveness of the new antimicrobial agents are urgently needed'.     

Plasmid-mediated resistance in Enterobacteriaceae: changing landscape and implications for therapy

Antimicrobial resistance is increasing worldwide, and pathogenic microorganisms that are resistant to all available antimicrobial agents are increasingly reported. Emerging plasmid-encoded extended-spectrum β-lactamases (ESBLs) and carbapenemases are increasingly reported worldwide. Carbapenemase production encoded by genes located on mobile genetic elements is typically accompanied by genes encoding resistance to other drug classes, often but not necessarily located on the same mobile element. Multiple plasmid-mediated mechanisms of resistance against the fluoroquinolones and aminoglycosides have been described, and the combination of plasmid-mediated resistance with chromosomally encoded resistance mechanisms of multiple drug classes now results in strains that are resistant to all of the main classes of commonly used antimicrobial drugs. Clinical studies of antimicrobial therapy and outcome of patients infected with ESBL- or carbapenemase-producing strains of Enterobacteriaceae compared with patients infected with susceptible strains are limited in their design but suggest a worse outcome after infection with resistant strains. Alternative options for the treatment of infections caused by carbapenem-resistant strains of Enterobacteriaceae are limited. Current strategies include colistin, fosfomycin, tigecycline and temocillin. Although in vitro testing suggests strong activity for each of these drugs against a large proportion of carbapenem-resistant strains of Enterobacteriaceae, clinical evaluations do not provide strong evidence for equivalent or improved outcome. Oral treatment with fosfomycin tromethamine is effective against lower urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli. Intravenous fosfomycin may be beneficial and safe for patients when used as part of a combination therapy in the management of severe infections caused by carbapenem-resistant Klebsiella pneumoniae. Tigecycline is only indicated for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections in Europe, and is also approved for treatment of community-acquired pneumonia in the US. Clearly, further research on the clinical and safety outcomes in the treatment of multidrug-resistant Enterobacteriaceae with these existing alternative drugs, and the development of new and unrelated drugs, are urgently warranted.     

Daptomycin

Daptomycin, the first in a class of agents known as lipopeptides, is a novel antimicrobial agent used for the treatment of gram-positive infections. The compound has a distinctive mechanism of action that exerts its bactericidal activity by disrupting plasma membrane function without penetrating into the cytoplasm. The agent has received much interest because of its activity against multidrug-resistant, gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and glycopeptide-intermediate and -resistant S. aureus. Daptomycin demonstrates concentration-dependent killing and is eliminated primarily by glomerular filtration. It was approved in September 2003 for the treatment of complicated skin and soft tissue infections. It has a safety profile similar to other agents commonly administered to treat gram-positive infections. Daptomycin is a welcome addition to the antimicrobial armamentarium for the treatment of bacterial infections. Further clinical experience with this compound will help define its role in the treatment of resistant gram-positive organisms.     

新型抗菌药物研究进展

抗菌药物的研究开发处于相对低谷,而耐药菌感染治疗急需新型抗菌药物,由此所产生的矛盾需要企业、政府与科研部门协调解决。现阶段新型抗菌药物的研究与开发主要在三个方面进行:①通过结构修饰,继续对已有抗菌药物进行深入开发,获得新产品;②利用基础科学研究成果,寻找新的抗菌靶位,设计新的先导化合物,研究全新抗菌药物;③研究抗感染治疗的全新方法,如抗菌肽、噬菌体等。这些有望为耐药菌感染控制提供有效方法。     

Bacteroides fragilis: current susceptibilities, mechanisms of drug resistance, and principles of antimicrobial therapy

The Bacteroides fragilis group of organisms includes the most clinically important anaerobic bacteria. Optimal therapy of infections in which these organisms are involved includes adequate and timely surgical drainage of all collections, debridement of necrotic tissue, optimal nutritional support, and administration of appropriate empiric antibiotics to cover both the aerobic and anaerobic bacterial components of these mixed infections. Special attention must be paid to the B. fragilis group because of its high rate of resistance to many of the commonly used antibiotics. Of the currently available beta-lactam antibiotics, piperacillin has the lowest rate of resistance. Successful antimicrobial agents include clindamycin, chloramphenicol, and metronidazole plus an aminoglycoside. Piperacillin, cefoxitin, and moxalactam can be used with an aminoglycoside or alone if no resistant organisms are revealed on culture and susceptibility testing. Beta-lactam-based regimens are potentially less toxic and may be less costly than those that contain one or more non-beta-lactam antibiotics.     

Linezolid: a new antibiotic

The U.S. Food and Drug Administration recently approved linezolid for the treatment of patients with methicillin-resistant staphylococcal and vancomycin-resistant enterococcal infections. This oxazolidinone antibacterial agent represents the first approved antibiotic of a new structural class in 35 years. Linezolid is a synthetic compound that acts by inhibiting the initiation complex formation in bacterial protein synthesis, a mechanism of action distinct from other commercially available antibiotics. Thus, cross-resistance between linezolid and other current antimicrobial agents has not been demonstrated to date. Linezolid has a wide spectrum of in vitro activity against Gram-positive organisms, including methicillin-resistant staphylococci, penicillin-resistant pneumococci and vancomycin-resistant enterococci. Some anaerobes, such as Clostridium spp., Peptostreptococcus spp. and Prevotella spp. are also susceptible to linezolid. In addition, linezolid has exhibited good efficacy in experimental animal models of acute otitis media, endocarditis and meningitis due to many common aerobic Gram-positive bacteria. In clinical trials involving hospitalized patients with skin/soft tissue infections, community-acquired pneumonia and serious Gram-positive bacterial infections, linezolid appeared to be an effective treatment option, comparable in efficacy to vancomycin.     

Investigational antimicrobial drugs for bloodstream infections

Bloodstream infections, especially those arising from multidrug-resistant strains, are an alarming public health threat requiring continuous efforts for new drug development. In this review, antibiotics at an advanced development stage for the treatment of patients with bloodstream infections are identified through a search of the available literature sources. Eight compounds currently undergoing phase II and/or phase III trials were identified. Isavuconazole, a triazole, is undergoing a phase III trial for the potential treatment of candidemia. Ceftobiprol medocaril, which belongs to the cephalosporin class, is undergoing regulatory review for the treatment of skin infections. Three lipoglycopeptides, oritavancin, dalbavancin and telavancin, are being tested against Gram-positive cocci in clinical trials. Also, human lactoferrin peptide 1-11, which appears to be a promising agent, is being tested in patients with Staphylococcus epidermidis bacteremia and in patients with candidemia. Iclaprim, a novel dihydrofolate reductase inhibitor, has completed two phase III trials for complicated skin and skin structure infections. The revival of an old class of antibiotics, polymyxins, in an effort to combat resistance, has also necessitated further investigation of these agents; colistin (polymyxin E) is at the forefront of this class of compounds, and is being assessed in a phase III efficacy trial. This overview of investigational antibiotics for bloodstream infections highlights that the pace of antimicrobial drug research and development is slower than the evolution of resistance. Only eight relevant compounds were identified in the pipeline of antibiotic research, none of which demonstrate a novel mechanism of action.     

Antimicrobial and biofilm inhibiting diketopiperazines

Diketopiperazines are the smallest cyclic peptides known. 90% of Gram-negative bacteria produce diketopiperazines and they have also been isolated from Gram-positive bacteria, fungi and higher organisms. Biosynthesis of cyclodipeptides can be achieved by dedicated nonribosomal peptide synthetases or by a novel type of synthetases named cyclopeptide synthases. Since the first report in 1924 a large number of bioactive diketopiperazines was discovered spanning activities as antitumor, antiviral, antifungal, antibacterial, antiprion, antihyperglycemic or glycosidase inhibitor agents. As infections are of increasing concern for human health and resistances against existing antibiotics are growing this review focuses on the antimicrobial activities of diketopiperazines. The antibiotic bicyclomycin is a diketopiperazine and structure activity studies revealed the unique nature of this compound which was finally developed for clinical applications. The antimicrobial activities of a number of other diketopiperazines along with structure activity relationships are discussed. Here a special focus is on the activity-toxicity problem of many compounds setting tight limitations to their application as drugs. Not only these classical antimicrobial activities but also proposed action in modulating bacterial communication as a new target to control biofilms will be evaluated. Pathogens organized in biofilms are difficult to eradicate because of the increase of their tolerance for antibiotics for several orders. Diketopiperazines were reported to modulate LuxR-mediated quorum-sensing systems of bacteria, and they are considered to influence cell-cell signaling offering alternative ways of biofilm control by interfering with microbial communication. Concluding the review we will finally discuss the potential of diketopiperazines in the clinic to erase biofilm infections.     

Oritavancin and tigecycline: investigational antimicrobials for multidrug-resistant bacteria

The advent of multidrug-resistant gram-positive aerobes such as Staphylococcus aureus, Streptococcus pneumoniae, and the enterococci, which are resistant to beta-lactams, vancomycin, and a host of other commonly used antimicrobials, has complicated our approach to antibiotic therapy. Despite marketing of the first oxazolidinone, linezolid, and the streptogramin combination, quinupristin-dalfopristin, an urgent need exists for more agents to combat these pathogens. Two such agents, the glycopeptide oritavancin (LY333328) and the glycylcycline tigecycline (GAR-936), are in phase III clinical trials. These agents, which require parenteral administration, exhibit substantial in vitro activity against a variety of gram-positive aerobes and anaerobes, including the multidrug-resistant organisms listed previously. Only tigecycline demonstrates useful activity against gram-negative organisms. Combination therapy of these agents with ampicillin or aminoglycosides frequently leads to synergistic in vitro activity against multidrug-resistant staphylococci and streptococci. These agents are also active in a variety of animal models of systemic and localized infections. Few published efficacy and tolerability data are available in humans. If controlled clinical trial data verify these agents' efficacy and tolerability, both drugs should become welcome additions to the available antimicrobials. However, restricting their use to the treatment of infections caused by bacteria resistant to other antimicrobials, especially multidrug-resistant staphylococci and streptococci, may prolong their clinical utility by retarding the development of resistance. Careful surveillance of bacterial sensitivity to these agents should be undertaken to assist clinicians in the decision whether or not to use these agents empirically to treat infections caused by suspected multidrug-resistant gram-positive pathogens.     

Advances in MRSA drug discovery: where are we and where do we need to be?

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) have been on the increase during the past decade, due to the steady growth of the elderly and immunocompromised patients, and the emergence of multidrug-resistant (MDR) bacterial strains. Although there are a limited number of anti-MRSA drugs available, a number of different combination antimicrobial drug regimens have been used to treat serious MRSA infections. Thus, the addition of several new antistaphylococcal drugs into clinical practice should broaden clinician's therapeutic options. As MRSA is one of the most common and problematic bacteria associated with increasing antimicrobial resistance, continuous efforts for the discovery of lead compounds as well as development of alternative therapies and faster diagnostics are required.

Areas covered: This article summarizes the FDA-approved drugs to treat MRSA infections, the drugs in clinical trials, and the drug leads for MRSA and related Gram-positive bacterial infections. In addition, the article discusses the mode of action of antistaphylococcal molecules and the resistant mechanisms of some molecules.

Expert opinion: The number of pipeline drugs presently undergoing clinical trials is not particularly encouraging. There are limited and rather expensive therapeutic options for MRSA infections in the critically ill. Further research efforts are required for effective phage therapy on MRSA infections in clinical use, which seem to be attractive therapeutic options for the future.     

Metal nanobullets for multidrug resistant bacteria and biofilms

Infectious diseases were one of the major causes of mortality until now because drug-resistant bacteria have arisen under broad use and abuse of antibacterial drugs. These multidrug-resistant bacteria pose a major challenge to the effective control of bacterial infections and this threat has prompted the development of alternative strategies to treat bacterial diseases. Recently, use of metallic nanoparticles (NPs) as antibacterial agents is one of the promising strategies against bacterial drug resistance. This review first describes mechanisms of bacterial drug resistance and then focuses on the properties and applications of metallic NPs as antibiotic agents to deal with antibiotic-sensitive and -resistant bacteria. We also provide an overview of metallic NPs as bactericidal agents combating antibiotic-resistant bacteria and their potential in vivo toxicology for further drug development.     

Pharmacokinetic and pharmacodynamic evaluation of tigecycline

INTRODUCTION: As the spread of multidrug-resistant (MDR) and extensive drug-resistant (XDR) organisms constitutes a real threat for patients, new antimicrobials are needed. Tigecycline, the first-in-class glycylcycline, possesses an extended spectrum of antimicrobial activity including MDR and XDR organisms, which holds promise as a treatment option beyond currently approved indications and deserves expanded evaluation of its pharmacokinetics/pharmacodynamics (PK/PD). AREAS COVERED: This review highlights the areas where our knowledge on PK/PD of tigecycline has been both strengthened and questioned during the recent years. New information has become available on the PK of tigecycline in patients with complicated skin and skin structure infections, complicated intra-abdominal infection, community- and nosocomial-acquired pneumonia. Human PD data from clinical trials linking tigecycline drug exposure to clinical, microbiological and toxicological outcomes are also of great interest. EXPERT OPINION: Tigecycline remains one of our last resorts against MDR pathogens; its clear role has to be re-defined through intense PK/PD applications; dose escalation and exploration of combinations with other antibiotics seem to be the first step towards an expansion of its currently approved indications. The lung remains the most controversial and challenging site regarding the PK/PD standpoint due to the predominance of Acinetobacter baumannii and carbapenemase-producing Klebsiella pneumoniae among ventilator-associated pneumonia infections, for which tigecycline is mostly used off-label.     

Linezolid in children: recent patents and advances

Linezolid is the first approved member of a new generation of antibiotics, the synthetic oxazolidinones, to become available, with a broad spectrum of in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium. It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children. With regards to its antimicrobial action, linezolid has a predominantly bacteriostatic action, rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics. Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections, both in the community and in a hospital setting. Clinical indications so far include skin and soft tissue infections, community-acquired or nosocomial pneumonia due to MRSA, VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae. We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far, such as VRE- associated endocarditis, bone and joint multi-drug resistant infections and possibly central nervous system infections, both in adult and children populations. Some patents on linezolid are also discussed in this review.     

Strategies for new antimicrobial proteins and peptides: lysozyme and aprotinin as model molecules

The increasing development of bacterial resistance to traditional antibiotics has reached alarming levels, thus necessitating the strong need to develop new antimicrobial agents. These new antimicrobials should possess both novel modes of action as well as different cellular targets compared with the existing antibiotics. Lysozyme, muramidase, and aprotinin, a protease inhibitor, both exhibit antimicrobial activities against different microorganisms, were chosen as model proteins to develop more potent bactericidal agents with broader antimicrobial specificity. The antibacterial specificity of lysozyme is basically directed against certain Gram-positive bacteria and to a lesser extent against Gram-negative ones, thus its potential use as antimicrobial agent in food and drug systems is hampered. Several strategies were attempted to convert lysozyme to be active in killing Gram-negative bacteria which would be an important contribution for modern biotechnology and medicine. Three strategies were adopted in which membrane-binding hydrophobic domains were introduced to the catalytic function of lysozyme, to enable it to damage the bacterial membrane functions. These successful strategies were based on either equipping the enzyme with a hydrophobic carrier to enable it to penetrate and disrupt the bacterial membrane, or coupling lysozyme with a safe phenolic aldehyde having lethal activity toward bacterial membrane. In a different approach, proteolytically tailored lysozyme and aprotinin have been designed on the basis of modifying the derived peptides to confer the most favorable bactericidal potency and cellular specificity. The results obtained from these strategies show that proteins can be tailored and modelled to achieve particular functions. These approaches introduced, for the first time, a new conceptual utilization of lysozyme and aprotinin, and thus heralded a great opportunity for potential use in drug systems as new antimicrobial agent.