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PubMed2006

Optimizing antimicrobial therapy for gram-positive bloodstream infections in patients on hemodialysis.

Infections with gram-positive organisms are highly prevalent in hemodialysis patients and are a major cause of morbidity and mortality in this population. Antimicrobial therapy is widely used to treat these infections, and prolonged therapy with these agents is often necessary. Extensive use of antimicrobials in hemodialysis patients has resulted in a growing threat of resistance, especially among gram-positive bacteria such as Enterococcus spp and Staphylococcus aureus. Vancomycin-resistant enterococci and S. aureus isolates with reduced susceptibility to vancomycin are increasingly being reported in hemodialysis patients. Additionally, resistance of these organisms to newer agents, such as linezolid and daptomycin, has been documented. Appropriate utilization of antimicrobial therapy to treat these organisms requires an understanding of the pharmacokinetic and pharmacodynamic principles to optimize therapy and avoid adverse drug events. The pharmacokinetic and pharmacodynamic profile of antimicrobial agents can be significantly altered in patients with chronic kidney disease. This review will describe mechanisms of antimicrobial resistance among common gram-positive organisms. The pharmacokinetic and pharmacodynamic principles of cephalosporins, vancomycin, aminoglycosides, linezolid, and daptomycin and applications for use of these agents in the treatment of patients with bloodstream infections on hemodialysis are discussed.

Anti-Bacterial Agents↗
PubMed1993

Trends in gram-positive bloodstream organism resistance: a seven-year audit of five glycopeptides and other drugs at a large university hospital.

Gram-positive pathogens (n = 525) isolated from bloodstream infections were tested by a reference broth microdilution method to establish antibiotic susceptibility trends (1985 to 1991). Cefazolin, ciprofloxacin, gentamicin, novobiocin, oxacillin, rifampin, teicoplanin, vancomycin, trimethoprim/sulfamethoxazole, daptomycin and two investigational glycopeptides (LY264826 and MDL62873) were investigated. Strains were selected without bias (first two isolates each month/species; no patient duplicates) as follows: 132 Staphylococcus aureus, 129 Staphylococcus epidermidis, 72 Staphylococcus haemolyticus, 130 Enterococcus faecalis and 62 other enterococci. All isolates were susceptible to vancomycin and teicoplanin except for Staphylococcus haemolyticus which had a resistant teicoplanin MIC90 of 64 micrograms/mL. The susceptibilities to vancomycin and teicoplanin were unchanged over the monitored period. Daptomycin, LY264826 and MDL62873 also demonstrated consistent activity; MDL62873 being superior with a MIC90 of 0.12 micrograms/mL. In 1990-1991 a significantly increased resistance to ciprofloxacin was observed among oxacillin-resistant strains of staphylococci. Our data suggest that the emergence of invasive vancomycin-resistant strains in Gram-positive isolates remains a rare phenomenon. However, we have experienced an emergence of numerous ciprofloxacin-resistant strains among staphylococci that precludes its empirical use at our institution.

Anti-Bacterial Agents↗
PubMed2005

Antimicrobial management of complicated skin and skin structure infections in the era of emerging resistance.

BACKGROUND: Complicated skin and skin structure infections (cSSSIs) are among the most common infections treated in the hospital setting. The mainstays of treatment continue to be antimicrobial therapy combined with appropriate surgical intervention. Due to increasing resistance among pathogens commonly implicated in cSSSIs, the objectives of this review were to describe the potential pathogens causing skin infections, the implications of resistance to currently used drug therapy, and the role of new antibiotics with activity for pathogens causing cSSSIs. METHODS: Relevant information from the primary literature and review articles were identified through a MEDLINE search of the medical literature (1980 to the present) using the terms abscess, wound infection, skin and skin structure infection, antibiotics, resistance, quinupristin- dalfopristin, linezolid, daptomycin, tigecycline, oritavancin, and dalbavancin. Meeting posters and slides were identified from the Interscience Conference of Antimicrobial Agents and Chemotherapy (1998-2004) for supplemental data. RESULTS: The most commonly implicated pathogens in cSSSIs include gram-positive bacteria, specifically Staphylococcus aureus. Gram-negative and mixed organisms are additionally encountered in serious cSSSI. Antimicrobial resistance among both gram-positive and gramnegative bacteria has increased significantly during the last decade, with methicillin resistance among S. aureus approaching 60% in hospitals and becoming more frequent in the community as well. As a result, resistance is the driving factor for treatment failure and rising costs for infection management. Few antimicrobial agents are available currently to treat resistant bacteria in cSSSIs; vancomycin is currently the drug of choice against resistant grampositive cocci; however, resistance to this agent has appeared in enterococci and S. aureus. Several new antibiotics such as linezolid and daptomycin are now available for the management of cSSSIs. Other agents such as tigecycline are under investigation and should be available soon to increase treatment options for cSSSIs caused by resistant bacteria. CONCLUSIONS: Although the resistance of cSSSI pathogens is problematic, new antibiotics with broad-spectrum activity against resistant gram-positive and gram-negative bacteria are promising for the management of severe cSSSIs.

Anti-Bacterial Agents↗
PubMed2006

New agents for Staphylococcus aureus endocarditis.

PURPOSE OF REVIEW: The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) as well as newly discovered S. aureus strains with reduced susceptibility to vancomycin mandates development of new antistaphylococcal agents. This review summarizes currently available and forthcoming antimicrobials for treatment of S. aureus endocarditis. RECENT FINDINGS: No new antimicrobial has been proven superior to antistaphylococcal penicillins for treatment of methicillin-sensitive S. aureus (MSSA) endocarditis. Vancomycin has become standard treatment for MRSA but poor outcomes have been reported, both with susceptible and intermediately resistant S. aureus strains (VISA). Linezolid has successfully treated individual cases of MRSA endocarditis, but limitations include long-term safety. Daptomycin has recently been proven effective and well tolerated for MSSA and MRSA bacteremia, including right-sided endocarditis. New glycopeptides, including dalbavancin and telavancin, as well as the new cephalosporin ceftobiprole, have not yet been studied for treatment of endocarditis but appear active against MRSA and potentially VISA. SUMMARY: Antistaphylococcal penicillins remain the treatment of choice for MSSA. Of the currently available newer agents, daptomycin appears to have the most rapid bactericidal activity and provides a much-needed alternative to vancomycin for treatment of MRSA or MSSA bacteremia and right-sided endocarditis.

Anti-Bacterial Agents↗
PubMed1990

Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus, and Lactobacillus species.

Eighty-five strains of vancomycin-resistant gram-positive bacteria from three genera, Leuconostoc, Pediococcus, and Lactobacillus, were tested to determine susceptibility to 24 antimicrobial agents by broth microdilution and to 10 agents by disk diffusion. The MICs of vancomycin and teicoplanin ranged from 64 to greater than 512 micrograms/ml; however, the MICs of daptomycin, a new lipopeptide, were all less than or equal to 0.25 micrograms/ml. None of the organisms were resistant to imipenem, minocycline, chloramphenicol, gentamicin, or daptomycin. The MICs of penicillin were in the moderately susceptible range for all but three strains. Susceptibility to the other agents varied by genus and, in some cases, by species. When disk diffusion results were compared with MICs for drugs recommended for streptococci by the National Committee for Clinical Laboratory Standards, Villanova, Pa., few very major or major errors were obtained, but the number of minor errors was 19.3%. Therefore, we recommended that MIC testing be used instead of disk diffusion testing for these organisms.

Anti-Bacterial Agents↗
PubMed2003

In vitro activities of a new lipopeptide, HMR 1043, against susceptible and resistant gram-positive isolates.

The purpose of this study was to compare the activity of HMR 1043 with those of daptomycin and teicoplanin against gram-positive isolates. Susceptibility tests were performed for 52 strains, 26 parental strains, including staphylococcal, streptococcal, enterococcal, and listerial strains, and 26 HMR 1043-resistant mutants obtained from parental strains by using the Szybalski method. Agar dilution and disk diffusion susceptibility tests were performed by the procedures outlined by the NCCLS. HMR 1043 demonstrated good activity against susceptible and resistant gram-positive bacteria. The activity of HMR 1043 in vitro was less influenced by the presence of calcium ions than that of daptomycin. Susceptibility test breakpoints were not defined because of the poor correlation coefficients obtained with the different disks tested.

Anti-Bacterial Agents↗
PubMed2005

Antipneumococcal activity of ceftobiprole, a novel broad-spectrum cephalosporin.

Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC(50) and MIC(90) values (microg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1x and 2x the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2x the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2x the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.

Cephalosporins↗
PubMed1991

Recovery of vancomycin-resistant gram-positive cocci from pediatric liver transplant recipients.

Between November 1988 and October 1989, 49 first-time pediatric liver transplant recipients at the Children's Hospital of Pittsburgh were prospectively monitored for the presence of stool colonization and the development of disease caused by vancomycin-resistant gram-positive cocci (VRGPC). Quantitative stool culturing was done on a weekly basis, and cultures were planted onto a selective medium for VRGPC. Isolates for which the MIC was greater than or equal to 8 were considered resistant to vancomycin. Patients were monitored clinically for the development of infection, and their charts were systematically reviewed for the use of antibiotics. Eighty-six isolates were recovered from 36 of the 49 patients. Enterococcal species were isolated from 31 patients and included Enterococcus gallinarum (n = 28), E. casseliflavus (n = 14), E. faecium (n = 9), E. faecalis (n = 2), E. mundtii (n = 2), and E. durans (n = 1). Stool colonization with vancomycin-resistant enterococci was noted to increase steadily during the first month after transplantation. Only 9 of 31 patients demonstrated clearance of these organisms in serial repeat cultures. Additional isolates of VRGPC included Lactobacillus confusus (n = 13), Lactobacillus spp. (n = 12), and Pediococcus pentosaceus (n = 4). Infection due to VRGPC developed in three patients: a urinary tract infection in two and peritonitis in one. E. faecium was the pathogen in each of these cases. The ranges of MICs of vancomycin were 8 to 32 micrograms/ml for all enterococcal isolates and greater than 128 micrograms/ml for Lactobacillus and Pediococcus isolates. All Lactobacillus and Pediococcus isolates were resistant to teicoplanin, although they were susceptible to daptomycin. All other isolates were susceptible to both teicoplanin and daptomycin. This study demonstrates that stool colonization with VRGPC may be a common and early finding among pediatric liver transplant recipients. However, infection appears to be uncommon.

Adolescent↗
PubMed2005

The search for new antimicrobials: why we need new options.

The increasing identification of antibiotic-resistant pathogens that cause serious infections cannot be ignored. Although the future cannot be predicted with certainty, it is surely possible that an extensive epidemic of resistant bacterial infections could potentially harm millions of people. Given that it takes more than 10 years to establish the efficacy and safety of new compounds, there is an urgent need to restock the antibiotic pipeline. Only a few new antibacterial agents have received approval by the US Food and Drug Administration in the last 5 years, including linezolid in 2001, cefditoren, pivoxil and ertapenem in 2002, gemifloxacin and daptomycin in 2003, and telithromycin in 2004. Many of these agents are improved derivatives from established classes of antibiotics, and several are directed primarily at resistant Gram-positive bacteria (e.g., linezolid and daptomycin). One promising new addition is the recent approval of tigecycline (Tigacyl, Wyeth) in June 2005.

Animals↗
PubMed1988

Therapeutic update on glycopeptide and lipopeptide antibiotics.

Glycopeptide antibiotics in the form of vancomycin have been available for almost 30 years. In the past, vancomycin usually was reserved as an alternative agent to treat staphylococcal and streptococcal infection in patients with a penicillin allergy or hemodialysis shunt infection. With the increasing frequency of both methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, now it is often used as a first-line agent. Over a 10-year period, vancomycin sales have increased by almost $1 hundred million. Several new glycopeptide and lipopeptide antibiotics are in various stages of evaluation. While vancomycin resistance to date is a rare phenomenon, these drugs represent a potentially more potent and safer antibiotic alternative to vancomycin. Teicoplanin and daptomycin are two of these investigational agents.

Bacterial Infections↗
PubMed1991

Mechanisms and implications of glycopeptide resistance in enterococci.

Glycopeptide resistance is recent in enterococci and its expression is inducible by glycopeptides. Two phenotypes can be distinguished: (a) resistance to high levels of vancomycin and teicoplanin, and (b) resistance to low levels of vancomycin only. There is no cross-resistance between glycopeptides, glycolipodepsipeptides (ramoplanin), and lipopeptides (daptomycin). The determinants conferring low-level resistance are nontransferable and presumably chromosomal. High-level resistance is plasmid-mediated and the plasmids range from 34 to 40 kb, are self-transferable, and encode various resistance combinations. All plasmids share the same glycopeptide resistance determinant, which is distinct from that conferring low-level resistance. Induction of resistance is associated with induction of about a 40 kDa protein. We have determined the sequence of the vanA gene encoding one such resistance protein designated VANA. Amino acid sequence similarity was detected between VANA and D-Ala: D-Ala ligases from Enterobacteriaceae. Complementation analysis in Escherichia coli indicated that VANA possesses D-Ala: D-Ala ligase activity and is therefore related to enzymes that catalyze synthesis of glycopeptide target, i.e., terminal D-Ala-D-Ala of peptidoglycan precursors. The contribution of VANA to synthesis of peptidoglycan in the presence of glycopeptides is unknown: VANA could bind to D-Ala-D-Ala, preventing the binding of the drugs; could modify the target of the drug; and could be a ligase with novel specificity.

Anti-Bacterial Agents↗
PubMed1989

Lower autolytic activity in a homogeneous methicillin-resistant Staphylococcus aureus strain compared to derived heterogeneous-resistant and susceptible strains.

It has been proposed that in addition to production of a penicillin-binding protein with low affinity for beta-lactam antibiotics, control of autolysin activity is involved in the mechanism of staphylococcal methicillin resistance. A homogeneous methicillin-resistant Staphylococcus aureus strain (DU4916) had lower rates of unstimulated, NaCl- and Triton X-100-stimulated autolysis, and daptomycin (LY146032)-induced lysis than a heterogeneous methicillin-resistant strain (DU4916-K7) and a methicillin-susceptible strain (DU4916S) derived from DU4916.

Bacteriolysis↗
PubMed2004

Current and new antimicrobial agents.

BACKGROUND: Infections may complicate cardiovascular surgery or may require surgery as an adjunct to successful treatment. Staphylococci, which are among the major pathogenic bacteria causing such infections, can be resistant to many of the older antibiotics. METHODS: The properties of several newer antimicrobial agents, recently approved or still investigational, were reviewed, with an emphasis on in vitro activities against staphylococci. RESULTS: The 2 approved agents, linezolid and quinupristin-dalfopristin, and several investigational agents being developed demonstrate in vitro antimicrobial activity against staphylococci. Three of these agents, daptomycin, which was approved by the US Food and Drug Administration in September 2003, and oritavancin and dalbavancin, which are in advanced stages of clinical development, are discussed. CONCLUSIONS: Although clinical studies are required, the in vitro anti-staphylococcal activities of several agents suggest that these antimicrobial agents might be useful options for some infections in patients who are intolerant of older antibiotics or who are infected with organisms that are resistant to older agents.

Acetamides↗
PubMed2003

Array synthesis of novel lipodepsipeptide.

Synthetic array technology was utilized to rapidly synthesize and analyze a diverse set of reductive alkylation analogues of daptomycin. Analysis of the array suggested the use of polar functionality such as sulfonamides or amide or polar spaces such as piperazine would beneficially affect activity.

Alkylation↗
PubMed2006

Clinical experience with recently approved antibiotics.

The advent of vancomycin-resistant enterococci in the 1990s and the threat posed by vancomycin resistance in Staphylococcus aureus led to the development of several new antimicrobial agents active against these pathogens. Quinupristin/dalfopristin was the first such drug to be commercially available but adverse effects have meant that the drug is now rarely used. Linezolid, the first antimicrobial of the oxazolidinone class, has met with more widespread use and has both an intravenous and an oral formulation. Daptomycin is a lipopeptide antimicrobial that is rapidly bactericidal against S. aureus. It is effective in the therapy of S. aureus bloodstream infections but is inactivated by pulmonary surfactant, making it of no use in the therapy of pneumonia. Tigecycline, by contrast, is bacteriostatic against most pathogens but has a broad spectrum of antimicrobial activity and has enhanced penetration into many tissues. Other new antibiotics (dalbavancin, telavancin, ceftobiprole and doripenem) are currently under clinical development and hold promise for widespread clinical use in the next decade.

Acetamides↗
PubMed2004

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.

Acetamides↗
PubMed2004

Novel antibacterial agents for skin and skin structure infections.

UNLABELLED: With the continuing development of clinical drug resistance among bacteria and the advent of resistance to the recently released agents quinupristin-dalfopristin and linezolid, the need for new, effective agents to treat multidrug-resistant gram-positive infections remains important. With treatment options limited, it has become critical to identify antibiotics with novel mechanisms of activity. Several new drugs have emerged as possible therapeutic alternatives. This review focuses on agents newly introduced and those presently in clinical development for the treatment of skin and skin structure infections. Linezolid, quinupristin-dalfopristin, and daptomycin have been approved by the Food and Drug Administration for the treatment of skin and skin structure infections. Two newer compounds, oritavancin and dalbavancin, are in clinical development for this indication. In addition, the quinolones moxifloxacin and gatifloxacin recently were approved for cutaneous infections. LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should be familiar with the modes of action, clinical indications, dosage regimens, and contraindications and cautions for several novel antibacterial agents for skin and skin structure infections.

Acetamides↗
PubMed1991

Treatment of infection and colonization caused by methicillin-resistant Staphylococcus aureus.

The mechanism of methicillin resistance confers resistance to all available beta-lactam antibiotics; consequently, beta-lactam antibiotics have no role in therapy of methicillin-resistant Staphylococcus aureus (MRSA) infections. Vancomycin remains the drug of choice. Teicoplanin and daptomycin are two investigational antibiotics related to vancomycin in structure and in spectrum of activity. In clinical trials employing relatively low doses, neither was as effective as vancomycin. Trials at higher doses are on-going. Quinolones, ciprofloxacin in particular, have been used successfully to treat infections caused by MRSA; however, the usefulness of quinolones may be limited by the tendency of resistance to emerge during therapy. Quinolones probably should be used only in combination with another active agent, such as rifampin, when treating serious infections caused by MRSA. Other agents may be active in vitro against MRSA, but clinical data showing their effectiveness are lacking. Rifampin combination regimens appear most effectively to eradicate colonization with MRSA.

4-Quinolones↗