Linezolid: a review of its use in the management of serious gram-positive infections

Linezolid is the first of a new class of antibacterial drugs, the oxazolidinones. It has inhibitory activity against a broad range of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. The drug also shows activity against certain anaerobes, including Clostridium perfringens, C. difficile, Peptostreptococcus spp. and Bacteroidesfragilis. In controlled phase III studies, linezolid was as effective as vancomycin in the treatment of patients with infections caused by methicillin-resistant staphylococci and also demonstrated efficacy against infections caused by VRE. Further phase III studies have demonstrated that linezolid is an effective treatment for patients with nosocomial pneumonia, for hospitalised patients with community-acquired pneumonia, and for patients with complicated skin or soft tissue infections (SSTIs). In these studies, linezolid was as effective as established treatments, including third-generation cephalosporins in patients with pneumonia, and oxacillin in patients with complicated SSTIs. Oral linezolid 400 or 600mg twice daily was as effective as clarithromycin 250mg twice daily or cefpodoxime proxetil 200mg twice daily in the treatment of patients with uncomplicated SSTIs or community-acquired pneumonia. Linezolid is a generally well tolerated drug. The most frequently reported adverse events in linezolid recipients were diarrhoea, headache, nausea and vomiting. Thrombocytopenia was also documented in a small proportion (about 2%) of patients treated with the drug. CONCLUSIONS: Linezolid has good activity against gram-positive bacteria, particularly multidrug resistant strains of S. aureus (including GISA), Enterococcus faecium and E. faecalis (including VRE). In controlled clinical trials, linezolid was as effective as vancomycin in eradicating infections caused by methicillin-resistant Staphylococcus spp. and has demonstrated efficacy against infections caused by VRE. As the level of resistance to vancomycin increases among S. aureus and enterococci, linezolid is poised to play an important role in the management of serious gram-positive infections.     

Antivirulence activity of auranofin against vancomycin-resistant enterococci: in vitro and in vivo studies

Introduction: Vancomycin-resistant enterococci (VRE) are a leading cause of nosocomial infections because of the limited number of effective therapeutic options. In an effort to repurpose FDA-approved drugs against antibiotic-resistant bacteria, auranofin has been identified as a potent drug against VRE.Methods and ResultsThe present study determined that auranofin's antibacterial activity was not affected when evaluated against a higher inoculum size of VRE (~10⁷ CFU/mL), and auranofin successfully reduced the burden of stationary phase VRE cells via a time-kill assay. In addition, auranofin reduced VRE production of key virulence factors, including proteases, lipase and haemagglutinin. The promising features of auranofin prompted evaluation of its in vivo efficacy in a lethal mouse model of VRE septicaemia. All mice receiving auranofin at 0.125 mg/kg orally, 0.125 mg/kg subcutaneously (SC) or 0.0625 mg/kg (SC) survived the lethal VRE challenge. Additionally, auranofin was superior to linezolid, the current drug of choice, in reducing VRE burden in the liver, kidneys and spleen of mice. Remarkably, auranofin successfully reduced VRE below the limit of detection in murine internal organs after 4 days of oral or subcutaneous treatment.ConclusionThese results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections.     

Role of Combination Antimicrobial Therapy for Vancomycin‐Resistant Enterococcus faecium Infections: Review of the Current Evidence

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front‐line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin‐resistant Enterococcus (VRE) faecium including daptomycin, linezolid, quinupristin‐dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti‐VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β‐lactams and fosfomycin, and the promising results from in vitro, animal studies, and clinical experience in the treatment of VRE faecium will be discussed.     

Vancomycin-resistant enterococcal urinary tract infections

Enterococci are a common cause of urinary tract infections (UTIs) among hospitalized patients. The rising prevalence of vancomycin-resistant enterococci (VRE) is of particular concern within many institutions because of its association with increased mortality and health care costs, as well as limited treatment options. Clinicians need to differentiate between VRE-associated urinary colonization, asymptomatic bacteriuria, and UTIs in order to determine the need for treatment, optimal therapeutic options, and length of therapy. Unnecessary use of antibiotics in patients simply colonized and not infected with VRE in the urine has become a large problem in both hospitals and long-term care facilities. A PubMed-MEDLINE search was conducted to identify all English-language literature published between January 1975 and March 2010 in order to summarize diagnostic criteria and treatment options for VRE UTIs. Several antimicrobials are discussed, with the specific focus on those with the potential to treat VRE UTIs and susceptibility patterns of VRE from urinary sources: ampicillin, amoxicillin, daptomycin, doxycycline, fosfomycin, imipenem-cilastatin, linezolid, nitrofurantoin, penicillin, piperacillin, quinupristin-dalfopristin, tetracycline, and tigecycline. Recommendations for empiric treatment of enterococcal UTIs and definitive treatment of VRE UTIs, including an evidence-based treatment algorithm, are proposed. Ampicillin generally is considered the drug of choice for ampicillin-susceptible enterococcal UTIs, including VRE. Nitrofurantoin, fosfomycin, and doxycycline have intrinsic activity against enterococci, including VRE, and are possible oral options for VRE cystitis. Linezolid and daptomycin should be reserved for confirmed or suspected upper and/or bacteremic VRE UTIs among ampicillin-resistant strains. Use of other antimicrobials, such as quinupristin-dalfopristin and tigecycline, should be evaluated on a case-by-case basis due to concerns of toxicity, resistance, and insufficient supportive data. Additional clinical data are needed to determine the optimal management and duration of therapy for VRE UTIs.     

New agents in development for the treatment of bacterial infections

New antibacterial agents to treat infections caused by antibiotic-susceptible and antibiotic-resistant pathogens are in various stages of clinical development. In this review are compounds with demonstrated activity against methicillin-resistant staphylococci including investigational cephalosporins, carbapenems, and a new tetracycline, as well as glycopeptides effective against vancomycin-resistant enterococci (VRE), and fluoroquinolones with improved potency against respiratory pathogens and multidrug-resistant Gram-positive bacteria. Although most recent progress has occurred in the identification of agents for Gram-positive infections, broad-spectrum carbapenems are described for the treatment of multidrug-resistant Gram-negative pathogens. Also discussed are agents with mechanisms of action other than inhibition of protein synthesis, penicillin-binding proteins, and DNA topoisomerases; among these are inhibitors of bacterial fatty acid biosynthesis, peptidoglycan synthesis, and dihydrofolate reductase.     

Glycopeptide antibiotics: from conventional molecules to new derivatives

Vancomycin and teicoplanin are still the only glycopeptide antibiotics available for use in humans. Emergence of resistance in enterococci and staphylococci has led to restriction of their use to severe infections caused by Gram-positive bacteria for which no other alternative is acceptable (because of resistance or allergy). In parallel, considerable efforts have been made to produce semisynthetic glycopeptides with improved pharmacokinetic and pharmacodynamic properties, and with activity towards resistant strains. Several molecules have now been obtained, helping to better delineate structure-activity relationships. Two are being currently evaluated for skin and soft tissue infections and are in phases II/III. The first, oritavancin (LY333328), is the 4'-chlorobiphenylmethyl derivative of chloroeremomycin, an analogue to vancomycin. It is characterised by: i) a spectrum covering vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and to some extent glycopeptide-intermediate S. aureus (GISA); ii) rapid bactericidal activity including against the intracellular forms of enterococci and staphylococci; and iii) a prolonged half-life, allowing for daily administration. The second molecule is dalbavancin (BI397), a derivative of the teicoplanin analogue A40926. Dalbavancin has a spectrum of activity similar to that of oritavancin against vancomycin-sensitive strains, but is not active against VRE. It can be administered once a week, based on its prolonged retention in the organism. Despite these remarkable properties, the use of these potent agents should be restricted to severe infections, as should the older glycopeptides, with an extension towards resistant or poorly sensitive bacteria, to limit the risk of potential selection of resistance.     

In vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci

Tigecycline is a glycylcycline with promising broad-spectrum activity, including resistant Gram-positive organisms. This study characterizes in vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae (QRSP), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). An in vitro pharmacodynamic model generated specific bacterial kill profiles for tigecycline against clinical isolates of QRSP, MRSA and VRE. Tigecycline produced a 6.6 log total reduction and cleared QRSP from the pharmacodynamic model by 18 h. Tigecycline and vancomycin were unable to achieve 3-log reductions in the MRSA and VRE isolates; log reductions in MRSA and VRE were 1.5 and 1.2 logs for tigecycline and 2.8 and zero for vancomycin, respectively. Area under the concentration time curve to minimum inhibitory concentration (AUC/MIC) values for tigecycline ranged from 79 to 158 microg h/mL and tigecycline concentrations remained above the MIC (T>MIC) throughout the simulated dosing interval. Tigecycline showed in vitro activity against the QRSP, MRSA and VRE isolates studied. Low MIC values, prolonged elimination half-life and the associated post-antibiotic effect (PAE) observed with tigecycline are desirable attributes that make it a potentially attractive option for treating resistant Gram-positive organisms.     

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.     

Antimicrobial and clinical effect of linezolid (ZYVOX), new class of synthetic antibacterial drug

Linezolid (ZYVOX), a novel synthesized antibacterial drug, was first approved in April 2001, as an antibacterial against vancomycin (VCM)--resistant enterococci in Japan. LZD has a wide spectrum of antibacterial activity against gram-positive bacteria with MIC90 of 0.5-4 mcg/mL. These antibacterial activities of LZD are similar to those of vancomycin (VCM). LZD also has similar antibacterial activities against drug-resistant bacteria including VRE and MRSA. Protein-synthesis inhibitors, e.g., macrolides, tetracycline, aminoglycosides, and chloramphenicol, are known to bind the 30S and 50S subunits of ribosomes and inhibit the elongation cycle of protein synthesis. In contrast, LZD was found to inhibit the process of formation of the 50S, 30S-mRNA, and fMet-tRNA complex in the ribosome cycle, but not the elongation cycle. Due to this novel mechanism of action, LZD does not have a cross-resistance to drug-resistant bacteria and development of its resistance is quite slow. The antibacterial activity of LZD against VRE is bacteriostatic. In vivo antibacterial activity of orally administered LZD was demonstrated in a mouse model of systemic infection by VRE. When administered orally prior to the abscess formation in a mouse model of soft tissue infection by VRE, LZD showed similar antibacterial activity against VRE infection to that against VCM-susceptible enterococci. LZD is rapidly absorbed following oral administration and bioavailability when compared with intravenous administration is almost 100%. LZD administered orally twice-daily showed excellent efficacy in clinical trials with VRE-infected patients.     

头孢类新药ceftaroline

Ceftaroline(CPT)是一种新型注射用广谱头孢菌素,体内外实验表明,CPT对革兰阳性菌包括耐甲氧西林金葡菌(MRSA)、多重耐药肺炎链球菌(MDRSP)、耐万古霉素肠球菌(VRE)等具有优良的杀菌活性,对常见革兰阴性菌也有效;同时CPT还具有较佳的安全耐受性和药动学预测性强等特点.该药现处于Ⅲ期临床开发阶段,适用于MRSA和多种病原菌混合感染的治疗.     

Antibacterial activity of calozeyloxanthone isolated from Calophyllum species against vancomycin-resistant Enterococci (VRE) and synergism with antibiotics

Calozeyloxanthone ( 1) was re-isolated from the root bark of Calophyllum moonii, an endemic species of Sri Lanka, and found to be active against vancomycin-resistant Enterococci (VRE) and vancomycin-sensitive Enterococci (VSE) with MIC values of 6.25 microg/ml and 12.5 microg/ml, respectively. Further, a marked synergism between 1 and vancomycin hydrochloride (VCM) against VRE was also observed. These findings suggest that 1 in combination with VCM against VRE may be useful in controlling VRE infections.     

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.     

Daptomycin: a new drug class for the treatment of Gram-positive infections

Daptomycin is the first member of a new class of bactericidal antibiotics, the cyclic lipopeptides. In September 2003, daptomycin was approved for the treatment of Gram-positive infections associated with complicated skin and skin structure infections. A key feature of daptomycin is its rapid, concentration-dependent bactericidal activity against significant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, glycopeptide-intermediate and -resistant S. aureus and vancomycin-resistant Enterococcus faecalis and Enterococcus faecium (VRE). Daptomycin also has a unique mechanism of action, no cross-resistance with any other class of antibiotic and a relatively prolonged concentration-dependent postantibiotic effect in vitro. In the United States, daptomycin has been approved for use at a dose of 4 mg/ kg once daily in the treatment of S. aureus (including methicillin-resistant strains), three beta-hemolytic streptococci (S. pyogenes, S. agalactiae and S. dysgalactiae subsp. equisimilis) and E. faecalis associated with complicated skin and skin structure infections. In addition, daptomycin is undergoing a phase III evaluation for the treatment of bacteremia and endocarditis due to S. aureus. With its once-daily dosing, favorable safety profile and low potential for resistance, daptomycin is a powerful new antibiotic therapy against Gram-positive infections.     

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.     

Studies for the development of novel anti-MRSA/VRE drugs

The widespread emergence of multidrug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) is a high threat for human health. In the course of screening for active compounds against the above drug-resistant bacteria from microbial metabolites, we discovered three kinds of novel compounds designated tripropeptins, pargamicin, and amycolamicin. Tripropeptin C (TPPC), major component of tripropeptins, is the most promising compound because it is efficacious against MRSA and VRE both in vitro and in a mouse septicemia model, and shows no cross-resistance to available drugs including vancomycin. Studies of incorporation of radioactive macromolecular precursors and accumulation of UDP-MurNAc-pentapeptide in the cytoplasm in S. aureus Smith revealed that TPPC is a cell wall synthesis inhibitor. Antimicrobial activity of TPPC was weakened by addition of prenylpyrophosphates but not with prenylphosphates, UDP-linked sugars, or the pentapeptide of peptidoglycan. Direct interaction between TPPC and undecaprenyl pyrophosphate (C(55)-PP) was observed by mass spectrometry and thin layer chromatography, and TPPC inhibits C(55)-PP phosphatase, which plays a crucial role in peptidoglycan synthesis at an IC(50) of 0.03-0.1 μM in vitro. From the analysis of accumulation of lipid carrier-related compounds, TPPC caused accumulation of C(55)-PP in situ, leading to the accumulation of a glycine-added lipid intermediate, suggesting a distinct mode of action from that of clinically important drugs such as vancomycin, daptomycin, and bacitracin. TPPC might represent a promising novel class of antibiotic against MRSA and VRE infections.     

Identification ofLactobacillus ruminus SPM0211 isolated from healthy Koreans and its antimicrobial activity against some pathogens

The intestinal microbiota are important to the host with regard to resistance they impart against bacterial infections and their involvement in mediating metabolic functions. Lactic acid producing bacteria such as Lactobacillus play an important physiological role in these matters. The aim of the present study was to isolate Lactobacillus sp. that inhibits enteric pathogens. Initially, 17 isolates from healthy Koreans were collected on Lactobacillus selective medium. Resistance of the isolates to antibiotics including rifampicin, streptomycin, clindamycin and vancomycin was measured. One of the isolate was identified as Lactobacillus ruminus on the basis of bacterial cell morphology, cultural characteristic and biochemical characteristics, 16S rRNA sequence analysis and PCR-RAPD. Antimicrobial activity of the bacterium against Vancomycin Intermediate Resistant Staphylococcus aureus (VISA) and Vancomycin-Resistant Enterococci (VRE) was measured. About 10(4) cells of VISA or VRE were mixed with 1, 5, and 9 mL of L. ruminus SPM 0211 and the final volume was adjusted to 10 mL with brain heart infusion (BHI) broth. The cell suspension was incubated for 3, 6, 9, and 24 h, serially diluted and then plated on BHI agar plates. As numbers of L. ruminus SPM 0211 were increased, viable cell count of VISA and VRE decreased. The strongest antimicrobial activity of SPM 0211 was observed after 9 h incubation in any mixture, almost completely inhibiting the growth of these two bacteria. The results suggest that the freshly isolated L. ruminus SPM 0211 may be used as a pro-biotic microbe that prevents the colonization of enteric pathogens and can thereby promote good gastrointestinal health.     

Treatment options for vancomycin-resistant enterococcal infections

Serious infection with vancomycin-resistant enterococci (VRE) usually occurs in patients with significantly compromised host defences and serious co-morbidities, and this magnifies the importance of effective antimicrobial treatment. Assessments of antibacterial efficacy against VRE have been hampered by the lack of a comparator treatment arm(s), complex treatment requirements including surgery, and advanced illness-severity associated with a high crude mortality. Treatment options include available agents which don't have a specific VRE approval (chloramphenicol, doxycycline, high-dose ampicillin or ampicillin/sulbactam), and nitrofurantoin (for lower urinary tract infection). The role of antimicrobial combinations that have shown in vitro or animal-model in vivo efficacy has yet to be established. Two novel antimicrobial agents (quinupristin/ dalfopristin and linezolid) have emerged as approved therapeutic options for vancomycin-resistant Enterococcus faecium on the basis of in vitro susceptibility and clinical efficacy from multicentre, pharmaceutical company-sponsored clinical trials. Quinupristin/dalfopristin is a streptogramin, which impairs bacterial protein synthesis at both early peptide chain elongation and late peptide chain extrusion steps. It has bacteriostatic activity against vancomycin-resistant E. faecium [minimum concentration to inhibit growth of 90% of isolates (MIC(90)) = 2 microg/ml] but is not active against Enterococcus faecalis (MIC(90 )= 16 microg/ml). In a noncomparative, nonblind, emergency-use programme in patients who were infected with Gram-positive isolates resistant or refractory to conventional therapy or who were intolerant of conventional therapy, quinupristin/dalfopristin was administered at 7.5 mg/kg every 8 hours. The clinical response rate in the bacteriologically evaluable subset was 70.5%, and a 65.8% overall response (favourable clinical and bacteriological outcome) was observed. Resistance to quinupristin/dalfopristin on therapy was observed in 6/338 (1.8%) of VRE strains. Myalgia/arthralgia was the most frequent treatment-limiting adverse effect. In vitro studies which combine quinupristin/dalfopristin with ampicillin or doxycyline have shown enhanced killing effects against VRE; however, the clinical use of combined therapy remains unestablished. Linezolid, an oxazolidinone compound that acts by inhibiting the bacterial pre-translational initiation complex formation, has bacteriostatic activity against both vancomycin resistant E. faecium (MIC(90) = 2 to 4 microg/ml) and E. faecalis (MIC(90) = 2 to 4 microg/ml). This agent was studied in a similar emergency use protocol for multi-resistant Gram-positive infections. 55 of 133 evaluable patients were infected with VRE. Cure rates for the most common sites were complicated skin and soft tissue 87.5% (7/8), primary bacteraemia 90.9% (10/11), peritonitis 91.7% (11/12), other abdominal/pelvic infections 91.7% (11/12), and catheter-related bacteraemia 100% (9/9). There was an all-site response rate of 92.6% (50/54). In a separate blinded, randomised, multicentre trial for VRE infection at a variety of sites, intravenous low dose linezolid (200mg every 12 hours) was compared to high dose therapy (600 mg every 12 hours) with optional conversion to oral administration. A positive dose response (although statistically nonsignificant) was seen with a 67% (39/58) and 52% (24/46) cure rate in the high- and low-dose groups, respectively. Adverse effects of linezolid therapy have been predominantly gastrointestinal (nausea, vomiting, diarrhoea), headache and taste alteration. Reports of thrombocytopenia appear to be limited to patients receiving somewhat longer courses of treatment (>14 to 21 days). Linezolid resistance (MIC > or = 8 microg/ml) has been reported in a small number of E. faecium strains which appears to be secondary to a base-pair mutation in the genome encoding for the bacterial 23S ribosome binding site. At present a comparative study between the two approved agents for VRE (quinupristin/dalfopristin and linezolid) has not been performed. Several investigational agents are currently in phase II or III trials for VRE infection. This category includes daptomycin (an acidic lipopeptide), oritavancin (LY-333328; a glycopeptide), and tigilcycline (GAR-936; a novel analogue of minocycline). Finally, strategies to suppress or eradicate the VRE intestinal reservoir have been reported for the combination of oral doxycyline plus bacitracin and oral ramoplanin (a novel glycolipodepsipeptide). If successful, a likely application of such an approach is the reduction of VRE infection during high risk periods in high risk patient groups such as the post-chemotherapy neutropenic nadir or early post-solid abdominal organ transplantation.     

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.     

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.     

Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents

A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6'-acylgalactoside, and quercetin 2',6'-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 μg/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure-activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent.