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PubMed1990

Selection for vancomycin resistance in clinical isolates of Staphylococcus haemolyticus.

Killing curves were used to characterize Staphylococcus haemolyticus isolates previously reported to contain subpopulations showing increased resistance to vancomycin. Results suggested that vancomycin and teicoplanin were ineffective at a concentration of 8 micrograms/ml and growth was seen between 24 and 48 h. Conversely, the lipopeptide antibiotic daptomycin at the same concentration rapidly killed tested strains by 6 h. Various staphylococcal strains were examined to determine if vancomycin resistance could be selected in all strains of staphylococci, was specie(s) restricted, or was unique to this patient's clinical isolates. About 1 x 10(8) colony-forming units were added to melted brain-heart infusion agar plates containing 12 micrograms/ml of vancomycin. Plates were examined after 48 h for presence of resistant clones. Results indicated that selection for vancomycin resistance was restricted to S. haemolyticus strains. Further, all S. haemolyticus isolates that displayed a double zone of growth around imipenem agar diffusion discs (Impdz) contained stably resistant subpopulations. Vancomycin resistance could not be selected in imipenem-sensitive derivative clones. Impdz isolates that were recovered from geographically distinct locations displayed nearly identical SDS-PAGE protein profiles. It appears that a characteristic susceptibility pattern displayed by clinical isolates of S. haemolyticus may provide a marker for those strains that contain subpopulations having increased resistance to vancomycin.

Bacterial Proteins↗

PubMed2025

Antimicrobial resistance among Gram-positive agents of bacteraemia in the UK and Ireland: trends from 2001 to 2019.

OBJECTIVES: The BSAC Bacteraemia Resistance Surveillance collected isolates from UK and Irish hospitals for central testing. Concurrent UKHSA surveillance collated English hospitals' own susceptibility data. Results were collated and compared. METHODS: BSAC Surveillance collected quotas of isolates per site annually from 2001 to 2019. MIC testing was by BSAC agar dilution, with resistance mechanisms identified by synergy tests, interpretive reading and PCR. The UKHSA sought hospitals' data on all bacteraemia isolates. RESULTS: Both surveillance systems recorded dramatic falls in MRSA, from c. 40% of bloodstream Staphylococcus aureus in 2001 to <10% by 2019. Both noted rises in the proportion of MRSA (especially) and MSSA resistant to fusidic acid, along with declines of ciprofloxacin and macrolide resistance amongst MRSA. Methicillin resistance also fell among coagulase-negative staphylococci, albeit only modestly; fusidic acid resistance rose. Shifts for pneumococci were complex, reflecting vaccine-contingent serotype displacements; resistance rates remained low, with high-dose penicillin almost universally active. Enterococcus faecium became more prevalent relative to Enterococcus faecalis; vancomycin resistance averaged 29% among E. faecium versus 2% in E. faecalis, without trend. Erythromycin resistance rose among groups B, C and G (but not group A) streptococci. Oxazolidinones, tigecycline, daptomycin and anti-PBP2' cephalosporins retained near-universal activity against target species, except that tigecycline has been compromised by breakpoint reductions for streptococci. CONCLUSIONS: Gram-positive pathogens were the dominant historical pathogens of bacteraemia. The trends seen here-with many near-universally active antibiotics-indicate little hazard of this situation returning. Nevertheless, few treatments exist in some settings, notably multi-resistant E. faecium endocarditis.

Humans↗

PubMed2003

Therapeutic and preventative options for the management of vancomycin-resistant enterococcal infections.

Enterococci are naturally resistant to a wide range of antimicrobial agents. In addition, some enterococci, known as vancomycin-resistant enterococci (VRE) have become resistant to glycopeptide antibiotics. The therapeutic options for VRE infections are therefore very limited. New antimicrobials have been developed that are active against VRE, such as linezolid and quinupristin/dalfopristin. Others, e.g. tigecycline, daptomycin and oritavancin, are in the later stages of development. However, resistance has already been detected to some of these agents. Some success has been enjoyed through the application of older antibiotics against VRE. The lack of therapeutic options has led to the consideration of measures to prevent infection with VRE. In addition to standard infection control procedures such as isolation and hand washing, decolonization of the gastrointestinal tract has been investigated as a method for the prevention of VRE infection in vulnerable patient groups. Several decolonization regimens have been investigated. These include the use of ramoplanin, a new glycolipodepsipeptide antibiotic that has features that particularly suit it for decolonization. Ramoplanin is not absorbed from the gastrointestinal tract, has potent bactericidal activity against Gram-positive organisms and limited side effects. These features and current clinical evidence suggest that ramoplanin may have a role in future gastrointestinal decolonization regimens.

Anti-Bacterial Agents↗

PubMed2003

Antibacterial susceptibility of a vancomycin-resistant Staphylococcus aureus strain isolated at the Hershey Medical Center.

Staphylococcus aureus strain HMC3 isolated at the Hershey Medical Center, was resistant to vancomycin (VRSA) through the presence of the vanA resistance gene; it also contained mecA, erm(A), erm(B), tet(K) and aac(6')-aph(2"), conferring resistance to licensed beta-lactams, macrolides, tetracycline and aminoglycosides. HMC3 also had alterations in GyrA and GrlB and was resistant to available quinolones. Experimental drugs with low MICs (<2 mg/L) for VRSA HMC3 included cephalosporins BAL9141 and RWJ-54428; glycopeptides oritavancin and dalbavancin; the lipopeptide daptomycin; the glycolipodepsipeptide ramoplanin; new fluoroquinolones WCK 771 A, WCK 1153, DK-507k and sitafloxacin; and the DNA nanobinder GS02-02. These agents were all bactericidal as were trimethoprim/sulfamethoxazole and teicoplanin (MIC 4 mg/L). Oxazolidinones linezolid and ranbezolid; the injectable streptogramin quinupristin/dalfopristin; DNA nanobinders GS2-10547 and GS02-104; peptide deformylase inhibitors NVP-PDF713 and GS02-12; tetracycline derivative tigecycline; the antifolate iclaprim; mupirocin and fusidic acid were all active in vitro but bacteriostatic.

Aged↗

PubMed2004

Approaches to vancomycin-resistant enterococci.

PURPOSE OF REVIEW: This article reviews recent publications regarding new antimicrobial drugs for the treatment of vancomycin-resistant enterococci. RECENT FINDINGS: Newer drugs against vancomycin-resistant enterococci are now available or will soon be available. Quinupristin-dalfopristin, a streptogramin, and linezolid, an oxazolidinone, are effective and safe but only bacteriostatic against enterococi. Bacterial isolates resistant to either antibiotic have been described. Daptomycin, a lipopeptide antimicrobial, has good in-vitro bactericidal activity against enterococci, but very limited clinical data exist regarding the treatment of serious enterococcal infection with this compound. Ramoplanin, the first glycolipodepsipeptide antimicrobial in clinical trials, is not systemically absorbed after oral administration, and is being evaluated for the prevention of bloodstream infection in patients colonized with vancomycin-resistant enterococci. Oritavancin and dalbavancin (both glycopeptides) and tigecycline (a monocycline derivative) are being evaluated in phase II and III trials and are not yet commercially available. SUMMARY: Treatment of vancomycin-resistant enterococci continues to be problematical although these new drugs offer some hope. The rational use of antibiotics, strict guidelines for the use of new compounds, and adherence to infection control practices continue to be essential components of the management of vancomycin-resistant enterococci colonization and infection.

Anti-Bacterial Agents↗

PubMed2005

Community-acquired methicillin-resistant Staphylococcus aureus, a new player in sports medicine.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a major pathogen, with distinct clinical characteristics and target populations. It has a striking ability to infect the young and the healthy. Persons in crowded conditions are at risk, including athletes, military personnel, jail inmates, and children in daycare. Most CA-MRSA infections are composed of simple and complicated skin and soft tissue infections; invasive disease occurs in 6% to 10% of cases. CA-MRSA infections can be treated with trimethoprim-sulfamethoxazole, doxycycline, or clindamycin. For severe infections, vancomycin, daptomycin, quinupristin/dalfopristin, or linezolid can be used. Infection control should be an integral part of any CA-MRSA treatment program.

Community-Acquired Infections↗

PubMed2005

Newer antistaphylococcal agents.

PURPOSE OF REVIEW: As antibiotic resistance in staphylococci continues to evolve, the ability to treat infections in children with confidence using first-generation cephalosporins, penicillins, and macrolides is decreasing. Knowledge of the local trends in resistance is important in making decisions of empiric antibiotic therapy. The antibiotic resistance pattern for the child's pathogen should be assessed whenever possible, to allow the practitioner to properly judge the risks and benefits of alternative antibiotic agents, should they be required for definitive therapy. RECENT FINDINGS: Options for therapy of most methicillin-resistant and macrolide-resistant community-acquired strains of Staphylococcus aureus include vancomycin, linezolid, and, in communities with a high proportion of susceptible strains, clindamycin. Daptomycin, a lipopeptide antibiotic with activity against virtually all strains of S. aureus, was recently approved by the United States Food and Drug Administration for adults. Second-generation glycopeptide antibiotics similar to vancomycin are in clinical trials in adults, including dalbavancin and oritavancin. Several new compounds, including cephalosporins active against methicillin-resistant S. aureus, are in preclinical development as well. SUMMARY: The recent worldwide emergence and rapid spread of community-acquired methicillin-resistant S. aureus has prompted a change in the approach to therapy of staphylococcal infections in both the outpatient clinic and the hospital. Newer agents active against methicillin-resistant S. aureus such as linezolid have been recently approved for children and other agents recently approved for adults are under investigation in children. Older agents for which relatively few data from prospective, controlled, comparative studies exist in the treatment of staphylococcal infections may also offer effective and less costly options for therapy.

Acetamides↗

PubMed2005

Treatment approaches for community-acquired methicillin-resistant Staphylococcus aureus infections.

PURPOSE OF REVIEW: This review addresses therapeutic approaches to community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections, focusing on recently published data in the English-language medical literature dating from June 2004 to July 2005. RECENT FINDINGS: During the reviewed time period, the overall understanding of the epidemiology and virulence of community-acquired MRSA has continued to advance. This same period has also seen numerous works dealing with the newer and emerging anti-staphylococcal antimicrobial agents. Important clinical trials involving linezolid, daptomycin, tigecycline, dalbavancin, and telavancin have been completed. At the same time, owing to the cost of newer agents and the broad susceptibility pattern of community-acquired MRSA, many older antimicrobial agents (long-acting tetracyclines, fluoroquinolones, rifampin, trimethoprim-sulfamethoxazole, and clindamycin) have also been reexamined. SUMMARY: As data accumulates, the newer antimicrobial agents active against community-acquired MRSA continue to demonstrate their value. Despite the appeal and abundant publications involving newer agents, older antimicrobials certainly retain a therapeutic role. Considerable work needs to be done prospectively evaluating older agents for community-acquired MRSA disease. The most important therapeutic intervention for the majority of community-acquired MRSA infections is adequate drainage of purulent fluid collections. Antimicrobial selection for community-acquired MRSA infections should be governed by disease severity, susceptibility patterns (especially based on timely clinical specimen culture), clinical response to therapy, and cost.

Acetamides↗

PubMed2006

Infections associated with orthopedic implants.

PURPOSE OF REVIEW: We review recent advances in the prevention, diagnosis and treatment of infections associated with joint prostheses and internal fixation devices. RECENT FINDINGS: The perioperative antimicrobial prophylaxis should be administered 60-30 min before incision or before inflation of the tourniquet. New diagnostic approaches include sonication of removed implants to dislodge adherent microorganisms growing in biofilms and the use of molecular techniques to improve diagnostic yield. Treatment of implant-associated infections without removal of the device is an established option for selected patients. Treatment with rifampin combinations in staphylococcal infections is crucial for success. As demonstrated in vitro, in animal studies and in clinical trials, quinolones are suitable combination agents with rifampin against susceptible staphylococci, but increasing antimicrobial resistance requires evaluation of alternative combination agents, such as quinpristin-dalfopristin, linezolid, and daptomycin, although clinical experience is limited. New antimicrobial agents, such as dalbavancin, tigecycline, iclaprim, and novel rifamycin derivatives are studied. SUMMARY: Better understanding of the interaction between microorganisms, the implant and the host may improve our current approach to the diagnosis and treatment of implant-associated infections. The treatment modality depends on duration of infection, stability of the implant, antimicrobial susceptibility of the pathogen and condition of the surrounding soft tissue.

Antibiotic Prophylaxis↗

PubMed2005

Structure of the lipopeptide antibiotic tsushimycin.

The amphomycin derivative tsushimycin has been crystallized and its structure determined at 1.0 A resolution. The asymmetric unit contains 12 molecules and with 1300 independent atoms this structure is one of the largest solved using ab initio direct methods. The antibiotic is comprised of a cyclodecapeptide core, an exocyclic amino acid and a fatty-acid residue. Its backbone adopts a saddle-like conformation that is stabilized by a Ca2+ ion bound within the peptide ring and accounts for the Ca2+-dependence of this antibiotic class. Additional Ca2+ ions link the antibiotic molecules to dimers that enclose an empty space resembling a binding cleft. The dimers possess a large hydrophobic surface capable of interacting with the bacterial cell membrane. The antibiotic daptomycin may exhibit a similar conformation, as the amino-acid sequence is conserved at positions involved in Ca2+ binding.

Anti-Bacterial Agents↗

PubMed2026

Antimicrobial Resistance in Nontyphoidal Salmonella and Clinically Relevant Enterococcus From Faecal Samples of Conservation-Priority Captive Ungulates in a United Arab Emirates Urban Zoo: A Cross-Sectional Baseline Study.

Antimicrobial resistance (AMR) is a One Health challenge driven by microbial exchange among humans, animals and the environment. Zoological institutions offer useful settings for environmental AMR surveillance. This single-zoo cross-sectional study examined the occurrence, antimicrobial susceptibility and genomic characteristics of nontyphoidal Salmonella enterica (NTS) and clinically relevant Enterococcus spp. in faecal samples from 101 clinically healthy captive ungulates representing seven conservation-priority species at a major urban zoo in the United Arab Emirates. NTS was detected in 4/101 samples (3.9%), including serovars Schwarzengrund (n = 2), Kentucky (n = 1) and Chester (n = 1). Among the four recovered NTS isolates, all met the study MDR definition within the tested panel, including a Salmonella Kentucky ST198 isolate carrying multiple resistance genes and quinolone-associated mutations. Enterococcus spp. were detected in 77/101 samples (76.2%), dominated by Enterococcus faecium and Enterococcus casseliflavus (each 41.5%). Among 33 E. faecium/Enterococcus faecalis isolates tested phenotypically, resistance was generally low, with erythromycin and ciprofloxacin resistance each observed in 9.1%. One clinically important E. faecium isolate showed glycopeptide resistance and genetic markers associated with reduced daptomycin susceptibility. These single-institution cross-sectional data provide an initial regional baseline for AMR-relevant enteric bacteria in conservation-managed ungulates and identify priorities for broader longitudinal and interface-based surveillance.

Animals↗

PubMed2006

The importance of the development of antibiotic resistance in Staphylococcus aureus.

Hospital- and community-acquired Staphylococcus aureus infections pose a substantial burden in terms of morbidity, mortality and health care costs. The introduction of new antibiotics to counter this pathogen has frequently been closely followed by the emergence of resistant strains. Most significantly, S. aureus isolates resistant to beta-lactams have become common, and many of these are also resistant to beta-lactamase-resistant penicillins. The rapid spread of methicillin-resistant S. aureus (MRSA) clones across the world often results in hospital outbreaks, but implementation of appropriate control measures usually reduces prevalence to sporadic levels. However, the recent emergence of MRSA infections in the community, affecting patients with no established risk factors for MRSA acquisition, is likely to impact significantly on future strategies for control of nosocomial MRSA. In contrast to other antibiotic classes, S. aureus resistance to glycopeptides did not emerge until nearly 40 years after their clinical introduction, and as a result this drug class has remained the mainstay of treatment for MRSA infections. However, a number of vancomycin-intermediate S. aureus isolates have emerged worldwide and four fully resistant S. aureus isolates have been reported in the USA. This raises the concern that the current first-line treatment for MRSA infection may become ineffective in an increasing proportion of cases in the near future. New classes of antibiotic are urgently needed to treat infections with this growing population of multidrug-resistant S. aureus, and the recently introduced oxazolidinone linezolid and the cyclic lipopeptide daptomycin are welcome additions to the ever-narrowing range of therapies effective against this pathogen.

Aminoglycosides↗

PubMed2006

In vitro activities of dalbavancin and 12 other agents against 329 aerobic and anaerobic gram-positive isolates recovered from diabetic foot infections.

Tests of dalbavancin's in vitro activity against 209 aerobic and 120 anaerobic isolates from pretreatment diabetic foot infections showed an MIC(90) of < or =0.125 microg/ml against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and 120 anaerobes (Clostridium perfringens, other clostridia, Peptoniphilus asaccharolyticus, Finegoldia magna, and Anaerococcus prevotii), compared to respective MIC(90)s for MSSA and MRSA of 0.5 and 1 microg/ml for vancomycin, 4 and 4 microg/ml for linezolid, 0.5 and 0.5 microg/ml for daptomycin, and 0.25 and >8 microg/ml for clindamycin.

Anti-Bacterial Agents↗

PubMed2007

Sequencing and analysis of the biosynthetic gene cluster of the lipopeptide antibiotic Friulimicin in Actinoplanes friuliensis.

Actinoplanes friuliensis produces the lipopeptide antibiotic friulimicin, which is a cyclic peptide with one exocyclic amino acid linked to a branched-chain fatty acid acyl residue. The structural relationship to daptomycin and the excellent antibacterial performance of friulimicin make the antibiotic an attractive drug candidate. The complete friulimicin biosynthetic gene cluster of 24 open reading frames from A. friuliensis was sequenced and analyzed. In addition to genes for regulation, self-resistance, and transport, the cluster contains genes encoding peptide synthetases, proteins involved in the synthesis and linkage of the fatty acid component of the antibiotic, and proteins involved in the synthesis of the nonproteinogenic amino acids pipecolinic acid, methylaspartic acid, and 2,3-diaminobutyric acid. By using heterologous gene expression in Escherichia coli, we provide biochemical evidence for the stereoselective synthesis of L-pipecolinic acid by the deduced protein of the lysine cyclodeaminase gene pip. Furthermore, we show the involvement of the dabA and dabB genes in the biosynthesis of 2,3-diaminobutyric acid by gene inactivation and subsequent feeding experiments.

Aminobutyrates↗

PubMed2007

Antimicrobial activities of ceragenins against clinical isolates of resistant Staphylococcus aureus.

The rise in the rates of glycopeptide resistance among Staphylococcus aureus isolates is concerning and underscores the need for the development of novel potent compounds. Ceragenins CSA-8 and CSA-13, cationic steroid molecules that mimic endogenous antimicrobial peptides, have previously been demonstrated to possess broad-spectrum activities against multidrug-resistant bacteria. We examined the activities of CSA-8 and CSA-13 against clinical isolates of vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), as well as vancomycin-resistant S. aureus (VRSA) and compared them to those of daptomycin, linezolid, and vancomycin by susceptibility testing and killing curve analysis. We also examined CSA-13 for its concentration-dependent activity, inoculum effect, postantibiotic effect (PAE), and synergy in combination with various antimicrobials. Overall, the MICs and minimal bactericidal concentrations of CSA-13 were fourfold lower than those of CSA-8. Time-kill curve analysis of the VRSA, VISA, and hVISA clinical isolates demonstrated concentration-dependent bactericidal killing. An inoculum effect was also observed when a higher starting bacterial density was used, with the time required to achieve 99.9% killing reaching 1 h with a 6-log10-CFU/ml starting inoculum, whereas it was>or=24 h with a 8- to 9-log10-CFU/ml starting inoculum with 10x the MIC (P<or=0.001). A concentration-dependent PAE was demonstrated with CSA-13, nearly doubling from 2x to 4x the MIC (P=0.03). With respect to the CSA-13 antimicrobial combinations, time-kill curve analysis showed no difference in the log10 CFU/ml at 24 h for the majority of the organisms tested. However, early synergy at 4 to 8 h was detected against the VRSA Pennsylvania strain (2002) when CSA-13 was tested in combination with gentamicin, while early additivity was demonstrated against all of the other organisms.

Anti-Bacterial Agents↗

PubMed1989

Transferable vancomycin and teicoplanin resistance in Enterococcus faecium.

Enterococcus faecium BM4165 and BM4178, isolated from immunocompromised patients, one treated with vancomycin, were inducibly resistant to high levels of the glycopeptide antibiotics vancomycin and teicoplanin but susceptible to the new lipopeptide daptomycin (LY146032). Strain BM4165 was also resistant to macrolidelincosamide-streptogramin B-type (MLS) antibiotics. The genes conferring resistance to glycopeptides and to MLS antibiotics in strain BM4165 were carried on plasmids pIP819 and pIP821, respectively; pIP819 also carried genes that encoded resistance to MLS antibiotics. The two plasmids, which were distinct although related, were self-transferable to other E. faecium strains. Plasmid pIP819 could also conjugate to E. faecalis, Streptococcus sanguis, S. pyogenes, S. lactis, and Listeria monocytogenes, in which it conferred inducible glycopeptide resistance, but not to S. aureus. Glycopeptide-inactivating activity was not detected, and the biochemical mechanism of resistance remains unknown. Based on this first report of transferable resistance to glycopeptides, we anticipate dissemination of resistance to these antibiotics in gram-positive cocci and bacilli in which it can be phenotypically expressed.

Adult↗

PubMed1989

Susceptibility and bactericidal activity studies of four beta-lactamase-producing enterococci.

beta-Lactamase-producing (Bla+) enterococci are rare but have been reported from several areas. We report another Bla+ enterococcus with high-level gentamicin resistance. Susceptibility and bactericidal activity studies of four Bla+ enterococci against potential alternative antibiotics, including ampicillin-sulbactam, daptomycin, teicoplanin, and vancomycin, are presented.

Anti-Bacterial Agents↗

PubMed1989

Antibacterial activity of the new glycopeptide antibiotic SKF104662.

The inhibitory activity of the new glycopeptide antibiotic SKF104662 was generally equivalent (+/- 1 concentration increment) to the activities of vancomycin, teicoplanin, and daptomycin against selected gram-positive bacteria. However, SKF104662 demonstrated greater activity against Staphylococcus epidermidis and S. haemolyticus than did teicoplanin and was more active than the other drugs against Clostridium difficile isolates. SKF104662 possessed bactericidal activity quite similar to that of vancomycin against selected isolates of Staphylococcus, Streptococcus, and Enterococcus species.

Anti-Bacterial Agents↗