Newer developments in the treatment of Gram-positive infections

Gram-positive organisms are continually a major cause of infection. These organisms are ever-evolving and exhibit resistance to nearly all available agents. Historically, vancomycin was crowned the drug of choice for many of these organisms including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and penicillin-resistant Enterococcus spp. Many of these organisms have exhibited reduced susceptibility or frank resistance to vancomycin which has resulted in treatment failure. For this reason, new strategies in treating Gram-positive infections are a hot topic. There are two general approaches to waging this war: i) development of new antimicrobial agents; and ii) reinvigorating old antibiotics that still retain appreciable activity against Gram-positives. We review both antibiotic groupings with a focus on S. aureus, S. pneumoniae and Enterococcus spp.     

Repurposing niclosamide for intestinal decolonization of vancomycin-resistant enterococci

Enterococci are commensal micro-organisms present in the gastrointestinal tract of humans. Although normally innocuous to the host, strains of enterococcus exhibiting resistance to vancomycin (VRE) have been associated with high rates of infection and mortality in immunocompromised patients. Decolonization of VRE represents a key strategy to curb infection in highly-susceptible patients. However, there is a dearth of decolonizing agents available clinically that are effective against VRE. The present study found that niclosamide, an anthelmintic drug, has potent antibacterial activity against clinical isolates of vancomycin-resistant Enterococcus faecium (minimum inhibitory concentration 1–8?µg/mL). E. faecium mutants exhibiting resistance to niclosamide could not be isolated even after multiple (10) serial passages. Based upon these promising in-vitro results and the limited permeability of niclosamide across the gastrointestinal tract (when administered orally), niclosamide was evaluated in a VRE colonization-reduction murine model. Remarkably, niclosamide outperformed linezolid, an antibiotic used clinically to treat VRE infections. Niclosamide was as effective as ramoplanin in reducing the burden of vancomycin-resistant E. faecium in the faeces, caecal content and ileal content of infected mice after only 8 days of treatment. Linezolid, in contrast, was unable to decrease the burden of VRE in the gastrointestinal tract of mice. The results obtained indicate that niclosamide warrants further evaluation as a novel decolonizing agent to suppress VRE infections.     

Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic

The emergence and spread of antimicrobial resistance have led to a global public health emergency requiring development of new antimicrobial classes. Lefamulin (formally BC‐3781) is a novel pleuromutilin antibiotic currently undergoing Food and Drug Administration review for community‐acquired bacterial pneumonia (CABP) as intravenous (IV) and oral (PO) formulations. Although pleuromutilin antibiotics were first developed in the 1950s, lefamulin is the first to be used for systemic treatment of bacterial infections in humans. Lefamulin exhibits a unique mechanism of action through inhibition of protein synthesis by binding to the peptidyl transferase center of the 50S bacterial ribosome, thus preventing the binding of transfer RNA for peptide transfer. Lefamulin displays activity against gram‐positive and atypical organisms associated with CABP (i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae), with an expanded gram‐positive spectrum including Staphylococcus aureus (i.e., methicillin‐resistant, vancomycin‐intermediate, and heterogeneous strains) and vancomycin‐resistant Enterococcus faecium. Lefamulin was also shown to retain activity against multidrug‐resistant Neisseria gonorrhoeae and Mycoplasma genitalium. Lefamulin exhibits time‐dependent killing, and the pharmacodynamic target best associated with antibacterial activity is ?AUC_0–24/MIC (minimum inhibitory concentration [MIC]). Preclinical and phase II trials indicate that lefamulin concentrates in lung tissue are well tolerated at an IV dose of 150 mg twice/day over 1 hour or a PO dose of 600 mg twice/day, and preliminary phase III data suggest similar efficacy when compared with moxifloxacin with or without linezolid in CABP. Documented resistance and cross‐resistance with other gram‐positive antibacterials remains low. Additional published in vitro, in vivo, and preclinical trial data suggest further exploration of lefamulin in various infectious disease states (e.g., acute bacterial skin and skin structure infections, and sexually transmitted infections). This review discusses the pertinent bacterial spectrum of activity, preclinical and ongoing clinical data, and potential roles in therapy for lefamulin.     

Enhancement of Vancomycin Activity by Phenothiazines against Vancomycin‐Resistant Enterococcus Faecium in vitro

Abstract: The antimicrobial and resistance‐reversal activities of seven phenothiazine derivatives were evaluated against vancomycin‐sensitive Enterococcus faecalis ATCC 29212, vancomycin resistant E. faecalis ATCC 51299 and ten vancomycin‐resistant E. faecium strains originating from human infections. Minimum inhibitory concentrations (MIC) of the compounds were determined by agar dilution method, and synergy between phenothiazines and vancomycin was investigated using Checkerboard (microbroth dilution) technique. We found that all enterococci strains, regardless of their susceptibility to vancomycin, were inhibited by phenothiazines at concentrations varying from 8 to 256 μg/ml, with thiethylperazine being the most potent inhibitory agent. Besides, all the phenothiazines showed partial synergy with vancomycin and could lessen MIC of vancomycin from 512 to 8 μg/ml at their sub‐inhibitory concentrations. The highest reduction in MIC was observed with chlorpromazine (32 times); however, thiethylperazine and promethazine stood next (24 times). Although resistance modification was observed at concentrations higher than those that phenothiazines reach in vivo, the potential offered by non‐antibiotics justify further animal experiments as well as clinical trials to establish their clinical relevance.     

Current and prospective treatments for multidrug-resistant gram-positive infections

Introduction: Staphylococcus aureus and Enterococcus spp. are two of the most common organisms causing nosocomial infections today; and are consistently associated with high mortality rates (approximately 20 and 44%, respectively). Resistance among these pathogens to first line agents such as methicillin and vancomycin continues to rise while isolates with reduced susceptibility to newer agents including linezolid and daptomycin continue to emerge, representing a serious concern for clinicians.

Areas covered: Mechanisms of action and resistance as well as in vitro and clinical experience in the treatment of resistant staphylococci and enterococci with currently available agents are discussed. Additionally, novel combination regimens showing enhanced efficacy and available data pertaining to prospective therapies including solithromycin, tedizolid, dalbavancin and oritavancin will be covered.

Expert opinion: With an increase in organisms displaying reduced susceptibility to vancomycin and the associated treatment failures, the significance of alternative therapies such as daptomycin, linezolid, ceftaroline, and prospective anti-gram-positive agents is on the rise. As our understanding of antimicrobial pharmacokinetic-pharmacodynamics principles continues to evolve, the selection of highly effective agents and optimization of dosages may lead to improved patient outcomes and delay the development of resistance.     

Synthesis and In Vitro Activity of Polyhalogenated 2‐phenylbenzimidazoles as a New Class of anti‐MRSA and Anti‐VRE Agents

A series of novel polyhalogenated 2‐phenylbenzimidazoles have been synthesized and evaluated for in vitro antistaphylococcal activity against drug‐resistant bacterial strains (methicillin‐resistant Staphylococcus aureus, and vancomycin‐resistant Enterococcus faecium. Certain compounds inhibit bacterial growth perfectly. 11 was active than vancomycin (0.78  μ g/mL) with the lowest MIC values with 0.19  μ g/mL against methicillin‐resistant Staphylococcus aureus, 8 and 35 exhibited best inhibitory activity against vancomycin‐resistant Enterococcus faecium (1.56  μ g/mL). The mechanism of action for this class of compounds appears to be different than clinically used antibiotics. These polyhalogenated benzimidazoles have potential for further investigation as a new class of potent anti‐methicillin‐resistant Staphylococcus aureus and anti‐vancomycin‐resistant Enterococcus faecium agents.     

Management of cSSTIs:the role of daptomycin

ABSTRACT

Background: Skin and soft tissue infections (SSTIs) and complicated SSTIs (cSSTIs), particularly those caused by Gram-positive pathogens, are among the most common human bacterial infections The emergence of resistance to antibiotics such as methicillin and vancomycin has compromised treatment options for these infections and stimulated the search for new antimicrobial therapies. Daptomycin, the first in a class of agents known as cyclic lipopeptides, is a novel antibiotic with potent activity against most Grampositive pathogens, including methicillin‐ resistant Staphylococcus aureus.

Scope: This review examines the novel properties of daptomycin and describes its therapeutic efficacy and tolerability, particularly in the treatment of cSSTIs. The data search strategy included identification of original research papers, review articles, meeting reports and editorials by searches of MEDLINE and references from relevant articles.

Findings: In vitro studies have demonstrated that daptomycin has superior bactericidal activity compared with vancomycin and the newer anti-Gram-positive agents, quinupristin/dalfopristin and linezolid. Robust, randomised, phase III clinical trials have shown daptomycin to be effective and well tolerated for the treatment of cSSTIs caused by Gram-positive bacteria, with equivalent clinical success rates and a similar safety profile to those of comparator agents. Data from these studies suggest a trend toward shorter duration of therapy and faster resolution of symptoms with daptomycin.

Conclusions: Given the pressing need for new antibiotics to combat infections caused by Gram-positive organisms, and to overcome the problem of resistance to conventional antibiotics, daptomycin is a welcome addition to the treatment options for the management of cSSTIs.     

Vancomycin-Resistant Enterococci

Vancomycin-resistant enterococci (VRE) are a major problem in numerous institutions in the United States. Most VRE are resistant to all available antimicrobial agents, resulting in serious therapeutic dilemmas. The resistance genes are transmitted on transposons, so the potential for dissemination to other species is significant. Risk factors associated with VRE infection and colonization are vancomycin and cephalosporin use, but numerous patient-related factors also contribute. Although resistant strains appear to arise from the patient's endogenous flora, VRE may be spread through direct contact with contaminated environmental surfaces and hands of caregivers. Published guidelines for preventing such spread suggest implementing infection-control practices and vancomycin restrictions. The ideal drug regimen for the treatment of VRE is unknown. Various drug combinations have been studied in the laboratory, but patient treatment data are scarce. There is an urgent need for new antimicrobial agents.     

2017年福州市第二医院病原菌的分布及耐药性分析

目的 了解2017年福州市第二医院临床分离病原菌的分布及对抗菌药物的敏感性,为临床用药提供指导。方法 共收集2 720株非重复分离菌,采用纸片扩散法或自动化仪器法进行药敏试验,按CLSI标准判读药敏结果。结果 2 720株细菌中,标本主要来源于伤口分泌物（989株）,占36.3%。革兰阴性菌1 786株,占65.7%,主要为大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、嗜麦芽窄食单胞菌和阴沟肠杆菌;革兰阳性菌934株,占34.3%,主要为金黄色葡萄球菌、粪肠球菌和凝固酶阴性葡萄球菌。耐甲氧西林耐药株金黄色葡萄球菌、凝固酶阴性葡萄球菌的检出率分别为42.7%、84.2%。未发现对万古霉素、替考拉宁和利奈唑胺耐药的葡萄球菌。粪肠球菌对大多数抗菌药物的耐药率明显低于屎肠球菌。肠球菌属中未发现万古霉素、利奈唑胺、替考拉宁耐药的肠球菌。除对黏菌素100%敏感外,铜绿假单胞菌对其他常见抗菌药物的耐药率均较低,鲍曼不动杆菌除对黏菌素敏感外,对其他药物的耐药性均较高,均达46.2%以上。结论 2017年福州市第二医院病原菌耐药形势依旧严峻,应加强合理用药,避免交叉感染。     

Combatting resistant enterococcal infections: a pharmacotherapy review

Introduction: The role of enterococci in infectious diseases has evolved from a gut and urinary commensal to a major pathogen of concern. Few options exist for resistant enterococci, and appropriate use of the available agents is crucial.

Areas covered: Herein, the authors discuss antibiotics with clinically useful activity against Enterococcus faecalis and E. faecium. The article specifically discusses: antibiotics active against enterococci and their mechanism of resistance, pharmacokinetic and pharmacodynamic principles, in vitro combinations, and clinical studies which focus on urinary tract, intra-abdominal, central nervous system, and bloodstream infections due to enterococci.

Expert opinion: Aminopenicillins are preferred over all other agents when enterococci are susceptible and patients can tolerate them. Daptomycin and linezolid have demonstrated clinical efficacy against vancomycin-resistant enterococci (VRE). Synergistic combinations are often warranted in complex infections of high inoculum and biofilms while monotherapies are generally appropriate for uncomplicated infections. Although active against resistant enterococci, the pharmacokinetics, efficacy and safety of tigecycline and quinupristin/dalfopristin can problematical for severe infections. For cystitis, amoxicillin, nitrofurantoin, or fosfomycin are ideal. Recently, approved agents such as tedizolid and oritavancin have good in vitro activity against VRE but clinical studies against other resistant enterococci are lacking.     

2017-2018年南京市儿童医院儿科重症监护病房感染病原菌的分布及耐药性分析

目的 了解南京市儿童医院儿科重症监护病房（PICU）病原菌的分布及耐药性,为临床合理选用抗菌药物提供依据。方法 对2017年1月-2018年12月南京市儿童医院PICU住院患儿送检标本所分离的病原菌及其耐药性进行回顾性分析。结果 共分离出306株病原菌,主要来自痰液,共191例,构成比为62.41%。革兰阳性菌120株,构成比为39.21%,主要为金黄色葡萄球菌、肺炎链球菌和屎肠球菌;革兰阴性菌166株,构成比为54.25%,主要为肺炎克雷伯菌、流感嗜血杆菌、大肠埃希菌、铜绿假单胞菌和鲍曼不动杆菌;真菌20株,构成比为6.54%。金黄色葡萄球菌对环丙沙星、替加环素、万古霉素、左氧氟沙星、喹努普汀/达福普汀、利福平、利奈唑胺、莫西沙星和庆大霉素完全敏感;金黄色葡萄球菌对青霉素G的耐药率高达93.88%。肺炎链球菌对克林霉素、红霉素完全耐药,耐药率为100.00%,未发现对氯霉素、青霉素G、万古霉素的耐药菌株。屎肠球菌对氨苄西林和青霉素G完全耐药,耐药率为100.00%,未发现对喹努普汀/达福普汀、利奈唑胺、替加环素和万古霉素的耐药菌株。肺炎克雷伯菌对氨苄西林完全耐药,耐药率为100.00%,未发现对左氧氟沙星、环丙沙星的耐药菌株;流感嗜血杆菌对头孢曲松和美洛培南的耐药率较低,均为3.70%。大肠埃希菌对阿米卡星完全敏感。铜绿假单胞菌对左氧氟沙星、环丙沙星、妥布霉素、庆大霉素、阿米卡星完全敏感。鲍曼不动杆菌除了对头孢噻肟完全耐药外,对其他抗菌药物的耐药率均较低,且对左氧氟沙星完全敏感。结论 南京市儿童医院PICU医院感染菌耐药性严重,应加强病原菌耐药性的监测,为临床合理应用抗菌药物提供依据。     

Newer treatment options for skin and soft tissue infections

In recent years, serious skin and soft tissue infections (SSTIs) caused by multidrug resistant pathogens have become more common. While the majority of SSTIs are caused by Staphylococcus aureus or beta-haemolytic streptococci that are methicillin/oxacillin susceptible, the emergence of methicillin-resistant and vancomycin-resistant community-acquired and nosocomial Gram-positive pathogens has created a need for different therapeutic agents, such as linezolid, quinupristin/dalfopristin, daptomycin, and newer generation carbapenems and fluoroquinolones. This review focuses on agents presently in clinical development for the treatment of SSTIs caused by Gram-positive pathogens such as staphylococci, streptococci and enterococci including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). Newer-generation carbapenems, such as meropenem and ertapenem, are characterised by a broad-spectrum of activity against Gram-positive and -negative aerobes and anaerobes, and are resistant to hydrolysis by many beta-lactamases. Current-generation fluoroquinolones, such as levofloxacin, moxifloxacin and gatifloxacin, have demonstrated better eradication rates for S. aureus than conventional penicillin and cephalosporins. These antimicrobial agents can be used to treat methicillin-susceptible staphylococcal and streptococcal strains. Oxazolidinones, streptogramin combinations and cyclic lipopeptides have novel mechanisms of action and have been studied in several multinational phase III clinical trials in the treatment of complicated and uncomplicated SSTIs. They possess a broad spectrum of activity against multidrug-resistant pathogens, including MRSA and VRE. Linezolid has been shown to be active against a wide variety of community-acquired and nosocomial antimicrobial-resistant pathogens with comparability to vancomycin, as well as resulting in reduced lengths of hospital stay. Cyclic lipopeptides such as daptomycin have a unique mechanism of action by disruption of bacterial membrane electric potentials with less likelihood for development of cross-resistance. Daptomycin has recently been US FDA approved for the treatment of complicated SSTI. However, rapid development of resistance to some of these newer agents has already been reported and this trend magnifies the importance of further need for effective antimicrobial agents. Several investigational agents, such as dalbavancin, oritavancin and tigecycline, are in advanced stages of development and are likely to proceed to licensing in the next few years. With their long half-lives, these agents have an advantage of less frequent dose administration with more rapid bactericidal activity and less likelihood for development of resistance. However, because of their proven activity against highly resistant organisms, these antibacterial agents should be reserved only for life-threatening situations and/or when resistant pathogens are suspected. Rational antimicrobial use coupled with awareness of infection control measures is paramount to avert the emergence of multidrug-resistant organisms.     

Transfert de la résistance à la vancomycine entre entérocoques d’origine animale et humaine

Enterococci are a dominant bacterial group in the intestinal flora of humans and animals. They have emerged as important nosocomial pathogens over the last two decades, at least in part because of their intrinsic and acquired resistance to many antimicrobial agents, including vancomycin. Two main reservoirs of vancomycin resistant enterococci were described: the hospital and the animal reservoirs. It should be noted that glycopeptide avoparcin has been used as a growth promoter in animal husbandry in Europe since 1970 and an association between the incidence of vancomycin resistance in humans and avoparcin usage in animals has been suggested. In recent years, transfer of resistance genes from animal bacteria to human bacteria causes great concern. By using the vancomycin resistant enterococci, we studied genetic transfers between bacteria in vitro and in vivo in the digestive tract of germ-free mice.The horizontal transfer of vanA gene from Enterococcus faecium strains of animal origin towards E. faecium of human origin within the digestive tract is possible and occurs at high frequencies. This transfer is also possible towards Enterococcus faecalis, the predominant enterococcal species of human digestive tract, at lower frequencies. Early transfer of the vanA operon suggests that even a brief transit of enterococci of animal origin would allow resident human bacteria to acquire glycopeptide resistance, as well as other resistance genes. This transfer occurs at a lower rate in the presence of complex flora.     

Overview perspective of bacterial resistance

The rapidly escalating prevalence of antimicrobial resistance is a global concern. This reduced susceptibility to currently available antimicrobial agents coupled with the progressive shortage of newly approved compounds is a worrisome situation. Major problems are encountered for a growing number of Gram-positive (i.e., Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp.) and Gram-negative pathogens (i.e., Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae). We provide an overview of bacterial resistance focusing on the most common pathogens responsible for infection in both the community and healthcare settings. In addition, several strategies to curb antimicrobial resistance are also discussed. It is increasingly evident that without the introduction of novel antimicrobial agents, a return to the clinical outcomes associated with the pre-antibiotic era are inevitable.     

Daptomycin for the treatment of enterococcal bacteraemia: results from the Cubicin Outcomes Registry and Experience (CORE)

Enterococcal infections are a common cause of nosocomial bloodstream infections. Vancomycin resistance and the emergence of linezolid resistance necessitate alternative therapies. Studies in vitro as well as animal and case studies suggest that daptomycin may be effective in enterococcal infections. Patients with positive blood cultures for enterococci in the Cubicin^® Outcomes Registry and Experience (CORE) 2005–2006 were identified. Patients with endocarditis, intracardiac foreign body infections or non-speciated enterococci were excluded. Outcome was assessed using protocol-defined criteria. Of 159 patients included in the efficacy population, Enterococcus faecium and Enterococcus faecalis were isolated in 120 (75.5%) and 39 (24.5%) patients, respectively. Vancomycin resistance was detected in 91% and 23% of patients with E. faecium and E. faecalis infections, respectively. Prior to daptomycin, 94/159 (59.1%) and 35/159 (22.0%) patients had received vancomycin and linezolid, respectively. Daptomycin was first-line therapy in 27/159 cases (17%). Success was observed in 139/159 patients (87%) and in 104/120 (87%) and 35/39 (90%) patients with E. faecium and E. faecalis infections, respectively. Among the safety population (n = 211), 20 (9.5%) experienced 28 adverse events possibly related to daptomycin, 8 of which were considered serious. Daptomycin may be a useful agent for treating enterococcal bacteraemia caused by E. faecium or E. faecalis. Further studies are warranted.     

New drugs for Gram-positive uropathogens

Complicated urinary tract infections (UTIs) are frequent nosocomial infections. The bacterial spectrum encompasses Gram-negative but also Gram-positive pathogens in up to 30-40%. The existing treatment for Gram-positive pathogens is not always optimal. Antimicrobials for the treatment of Gram-positive uropathogens comprise older agents, such as aminopenicillins with or without beta-lactamase inhibitors and vancomycin, as well as newer fluoroquinolones, such as levofloxacin or gatifloxacin. However, resistant bacteria such as vancomycin-resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) (except vancomycin-resistant) are generally also not susceptible to the fluoroquinolones. Therefore new agents need to be assessed in the treatment of UTI. Daptomycin and linezolid are new antimicrobial agents with good efficacy against Gram-positive uropathogens as shown by their minimal inhibitory concentrations. In a phase II study the urinary bactericidal activity of linezolid versus ciprofloxacin in volunteers showed comparable activity of both drugs against fluoroquinolone susceptible Gram-positive uropathogens, whereas linezolid was also as active against fluoroquinolone resistant ones. The pharmacokinetics and the mode of action of these two antibiotics are discussed together with some clinical data in the context of therapeutic use in patients with complicated UTIs.     

Gram positive infection in trauma patients: new strategies to decrease emerging Gram-positive resistance and vancomycin toxicity

Bacterial resistance to antibiotics has become a serious problem in medicine. Particularly worrisome is the increasing incidence of multi-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Not surprisingly, in view of the high incidence of life-threatening infections and heavy antibiotic use, resistance has become very frequent and problematic in intensive care units. The standard approach for the treatment of MRSA is vancomycin or teicoplanin. Long-term therapeutic and unrestricted prophylactic use of vancomycin has given rise to VRE which in turn may lead to the emergence of vancomycin-resistant S. aureus (VRSA) through plasmid mediated transmission. In order to reduce the incidence of VRE and to avoid the emergence of VRSA, vancomycin use should be restricted and alternative antibiotic strategies should be developed. Using those antibiotics to which MRSA are still generally sensitive, perhaps in combination with new ones, such as, quinupristin/dalfopristin, should be entertained. We performed a retrospective review of the Gram-positive infections in our Level 1 Trauma Center Intensive Care Unit, and an analysis of the resistance patterns of the NMSA infections showed that additional resistance rarely develops within less than 5 days. We then designed a new strategy for the treatment of MRSA infections. This strategy consists of the sequential use of a range of antibiotics with activity against MRSA in short 5-7 day pulses until the full clinical course is completed. Studies validating the benefit of this approach are currently in preparation.     

Safety profiles of old and new antimicrobials for the treatment of MRSA infections

ABSTRACT

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of severe nosocomial and community-acquired infections. Various adverse effects have been associated with compounds that are commonly used in the treatment of MRSA.

Areas covered: Prolonged use of high-dose vancomycin has been linked with nephrotoxicity. Linezolid use has been associated with lactic acidosis in regimens longer than 14 days and occurrence of thrombocytopenia in patients with renal impairment. Daptomycin use correlates with reversible and often asymptomatic myopathy. Among new compounds, telavancin has shown increased toxicity compared to vancomycin, especially in patients with severe renal impairment, while a low rate of adverse effects was reported others glycolipopeptides such as dalbavancin and oritavancin and for new cephalosporins. Recently studied oxazolidinones (tedizolid and radezolid) also showed mild adverse effects in Phase 2 and 3 clinical trials.

Expert opinion: Due to the constant increase in antimicrobial resistance, the use of higher doses and prolonged regimens of antibiotics employed in the treatment of Gram-positive infections has become more common and linked to increased toxicity. Furthermore, new compounds with MRSA activity have been recently approved and will be regularly employed in clinical practice. The knowledge of the adverse effects and risk factors for the development of toxicity associated with anti-MRSA antimicrobials is paramount for the correct use of old and new compounds, especially in the treatment of severe infections.     

Rational design of α-helical antimicrobial peptides to target Gram-negative pathogens, Acinetobacter baumannii and Pseudomonas aeruginosa: utilization of charge, 'specificity determinants,' total hydrophobicity, hydrophobe type and location as design parameters to improve the therapeutic ratio

The rapidly growing problem of increased resistance to classical antibiotics makes the development of new classes of antimicrobial agents with lower rates of resistance urgent. Amphipathic cationic α‐helical antimicrobial peptides have been proposed as a potential new class of antimicrobial agents. The goal of this study was to take a broad‐spectrum, 26‐residue, antimicrobial peptide in the all‐D conformation, peptide D1 (K13) with excellent biologic properties and address the question of whether a rational design approach could be used to enhance the biologic properties if the focus was on Gram‐negative pathogens only. To test this hypothesis, we used 11 and 6 diverse strains of Acinetobacter baumannii and Pseudomonas aeruginosa, respectively. We optimized the number and location of positively charged residues on the polar face, the number, location, and type of hydrophobe on the non‐polar face and varied the number of ‘specificity determinants’ in the center of the non‐polar face from 1 to 2 to develop four new antimicrobial peptides. We demonstrated not only improvements in antimicrobial activity, but also dramatic reductions in hemolytic activity and unprecedented improvements in therapeutic indices. Compared to our original starting peptide D1 (V13), peptide D16 had a 746‐fold improvement in hemolytic activity (i.e. decrease), maintained antimicrobial activity, and improved the therapeutic indices by 1305‐fold and 895‐fold against A. baumannii and P. aeruginosa, respectively. The resulting therapeutic indices for D16 were 3355 and 895 for A. baumannii and P. aeruginosa, respectively. D16 is an ideal candidate for commercialization as a clinical therapeutic to treat Gram‐negative bacterial infections.     

New molecules and adjuvants in the treatment of infections by Acinetobacter baumannii

Introduction: The current problems of the treatment of infections by Acinetobacter baumannii are linked with the increase of multidrug- and extensive-drug resistance and the lack of development of new antimicrobial drugs for Gram-negative bacilli. For these reasons, new alternatives for the treatment and control of severe infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents.

Areas covered: In the present review, the authors describe the main results in the development of adjuvant drugs as well as new data on antimicrobial peptides, in monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising preclinical results in vitro and in vivo.

Expert opinion: The preclinical evaluation of adjuvants and antimicrobial peptides, in monotherapy or in combination therapy, for A. baumannii infections has shown promising results. However, caution is needed and further extensive in vivo studies and clinical trials have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives.