Glycopeptide-intermediate Staphylococcus Aureus Research Articles

New therapeutic approach for the treatment for staphylococcal bacteremia and sepsis

Introduction. Staphylococcal bacteremia is an early and dangerous manifestation of infection, it indicates to the presence of the source of infection in the bloodstream or the dissemination ofgerms from otherfoci, is the cause of high mortality rate. In that the approaches to the treatment for bacteremia/sepsis caused by S.aureus, have surprisingly low conclusiveness and require the optimization of antibiotic therapy, duration of treatment, criteria for cure. The aim of this study was to perform the systematic analysis of the current literature devoted to the problem of antibiotic treatment for staphylococcal infection, primarily followed by bacteremia and sepsis. Objectives of the study: the detection of the problem factors having the negative impact on the effectiveness of the antibiotic treatment of severe staphylococcal infections followed by bacteremia, and prospects for the use of new antibiotics. For the solution of the designated objectives in the scientific medical databases Medscape and Pubmed there was performed the search for the publications on subject headings, covering these problems Conclusion. Bacteremia and sepsis caused by S.aureus is not uncommon and severe infection which occurs everywhere, but remains to be poorly understood. The single isolation of S.aureus from the blood always is to be considered as clinically significant due to the high pathogenicity, high probability of infection and complications, rarity of contamination of blood samples with S.aureus. In cases of the isolation of staphylococci from the blood there is required an immediate and thorough search for any focus of invasion and deep metastatic foci of infection. There are strong evidences that the removal of the origin or the drainage of the locus of infection improves the results of the treatment. There is substantially less certainty about the patients with uncomplicated infections that can receive short courses of ABT. There is discussed the optimal choice of antibiotics, the duration and method of administration for the treatment of S. aureus bacteremia (SAB). Available data indicate to the more higher efficiency of f-lactams compared with glycopeptides for the treatment for infections caused by methicillin-sensitive SAB, the emergence of glycopeptide-intermediate Staphylococcus aureus (GISA) or hetero-GISA reduces the role of glycopeptides in the treatment of bacteremia caused by MRSA. Daptomycin showed the high efficacy in the treatment for severe staphylococcal infections accompanied by bacteremia and sepsis, especially when using in a dose of 6 mg/kg/ day and above. There is insufficient data for the assertion that cephalosporins are also effective as penicillins for treating SAB, but they are probably more effective than vancomycin for the treatment of methicillinsensitive SAB. The optimal duration of treatment is considered to be 10-14 days of intravenous administration for most cases of uncomplicated SAB associated with vascular catheterization, upon condition of the removal of the catheter and low risk of endocarditis.

Synergistic Activity of Ceftobiprole and Vancomycin in a Rat Model of Infective Endocarditis Caused by Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus

The therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) or glycopeptide-intermediate Staphylococcus aureus (GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 μg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 μg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log(10) CFU/g MRSA or 6 log(10) CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. In in vitro time-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, and in vivo synergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.

Efficacy of telavancin against glycopeptide-intermediate Staphylococcus aureus in the neutropenic mouse bacteraemia model

The aim of the study was to compare the efficacies of telavancin and vancomycin against glycopeptide-intermediate Staphylococcus aureus (GISA) and heterogeneous vancomycin-intermediate S. aureus (hVISA) in a neutropenic murine bacteraemia model. Immunocompromised mice (female non-Swiss albino, 18-30 g) were inoculated intraperitoneally with 10(7) cfu/mL of GISA (strain HIP-5836 or Mu50) or hVISA (strain Mu3). Infected mice received a subcutaneous dose of telavancin (40 mg/kg) or vancomycin (110 mg/kg) at 4 and 16 h post-inoculation. Control animals received a subcutaneous dose of vehicle at 4 h post-inoculation only. Blood and spleen bacterial titres were quantified in drug-treated mice at 16, 28 and 52 h post-inoculation. Telavancin was 8-fold more potent than vancomycin against HIP-5836 (MIC 1 versus 8 mg/L), 16-fold more potent against Mu50 (MIC 0.5 versus 8 mg/L) and 8-fold more potent against Mu3 (MIC 0.25 versus 2 mg/L). Telavancin produced significant (P < 0.05) and sustained reductions in blood and spleen titres from pre-treatment levels in mice infected with HIP-5836, Mu50 or Mu3. Vancomycin lowered blood and spleen HIP-5836 counts transiently, but did not lower blood or spleen Mu50 or Mu3 counts significantly at any timepoint. Reductions in blood and spleen HIP-5836 and Mu3 titres and in spleen Mu50 titres at 52 h post-inoculation were significantly greater with telavancin than vancomycin (P < 0.05). Telavancin was more efficacious than vancomycin in clearing infections caused by GISA strains HIP-5836 and Mu50 and hVISA strain Mu3 in a neutropenic mouse bacteraemia model. Further evaluation of telavancin for GISA and hVISA bacteraemia is warranted.

Efficacy of the Arbekacin and Teicoplanin Combination on Glycopeptide Intermediate Staphylococcus aureus in a Rabbit Model of Endocarditis

Background : There have been no reports to evaluate the usefulness of combination therapy with glycopeptide and arbekacin in endocarditis by in vivo model. Materials and Methods : We investigated the efficacy of the arbekacin and teicoplanin combination on glycopeptide intermediate Staphylococcus aureus (GISA) in rabbit model of endocardits. GISA Mu50 strain was used for the experiment. The rabbit model of aortic valve endocarditis as described previously was used. Treatment was started 20h later inoculation with teicoplanin alone (at 20 mg/kg of body weight intramuscularly every 12 hours for 4 days after loading dose of 40 mg/kg of body weight intramuscularly), arbekacin alone (5 mg/kg of body weight intramuscularly every 12h for 4 days), or teicoplanin plus arbekacin. Results : The results of therapy for experimental endocarditis due to Mu50 showed that teicoplanin and arbekacin combination was more effective than the administration of both drugs alone in reducing the log10CFU/g of aortic vegetation (P<0.05). Conclusion : The combination of teicoplanin and arbekacin was more effective against GISA (Mu50) than both drugs alone in vivo endocarditis model.

Evaluation of Fourier transform infrared spectroscopy for the rapid identification of glycopeptide-intermediate Staphylococcus aureus

To evaluate Fourier transform infrared (FTIR) spectroscopy as a rapid method for distinguishing glycopeptide-intermediate Staphylococcus aureus (GISA) from glycopeptide-susceptible methicillin-resistant S. aureus (MRSA) and to compare three data analysis methods. First-derivative normalized spectra of dried films of bacterial growth on Que-Bact Universal Medium No. 2 were examined by singular value decomposition to identify key spectral regions. Region selection was analysed by principal component analysis (PCA), self-organizing maps (SOMs) and the K-nearest neighbour (KNN) algorithm. The initial data set included 35 GISA (including GISA Mu50 and heterogeneous GISA Mu3) and 25 epidemic MRSA. The regions were then tested using enlarged data sets that included 22 sporadic and 85 additional epidemic MRSA. Epidemic MRSA and GISA/hGISA were separated into two distinct clusters on the basis of spectral data from regions 1352-1315 and 1480-1460 cm(-1), the former providing 100% correct classification by all three analyses and the latter providing 96.67% correct by PCA, 98.34% by SOM and 100% by KNN. The 1480-1460 cm(-1) region was more effective for distinguishing GISA/hGISA from a set combining sporadic and epidemic MRSA, with two GISA/hGISA and four sporadic MRSA misclassified by PCA and SOM (92.69% correct), while the KNN method misclassified three of the four sporadic MRSA (93.90% correct). The addition of 85 other epidemic MRSA this set increased the fraction of correctly classified isolates to 96.41% and 97.01% by PCA, SOM and KNN, respectively. As only 6 of 167 isolates were misclassified, FTIR spectroscopy may provide means of rapid and accurate identification of GISA and hGISA among isolates of MRSA.

Autolytic Properties of Glycopeptide-Intermediate Staphylococcus aureus Mu50

Whole-cell autolytic activity of prototypical glycopeptide-intermediate Staphylococcus aureus (GISA) Mu50 was reduced versus that of hetero-GISA Mu3 and glycopeptide-susceptible S. aureus, consistent with other GISA strains. In contrast, autolytic activity was relatively high in Mu50 crude cell walls and autolysin extracts against purified cell walls, reflecting the complexities of autolytic activity regulation.

146 GISA (Glycopeptide-intermediate Staphylococcus aureus) selected by vancomycin treatment of experimental endocarditis persist after treatment arrest in vivo, but are not detected by vegetation cultures in vitro

146 GISA (Glycopeptide-intermediate Staphylococcus aureus) selected by vancomycin treatment of experimental endocarditis persist after treatment arrest in vivo, but are not detected by vegetation cultures in vitro

Control and Outcome of a Large Outbreak of Colonization and Infection with Glycopeptide-Intermediate Staphylococcus aureus in an Intensive Care Unit

Glycopeptide-intermediate Staphylococcus aureus (GISA) is emerging as a cause of nosocomial infection and outbreaks of infection and colonization in intensive care units (ICUs). We describe an outbreak of GISA colonization/infection and the ensuing control measures in an ICU and investigate outcomes of the affected patients. We describe an outbreak of GISA colonization and infection that affected 21 patients in a medical ICU at a tertiary care teaching hospital, as well as the measures taken to eradicate the GISA strain. Recognition of the outbreak was difficult. Infections, all of which were severe, were diagnosed in 11 of 21 patients. Patient isolation and barrier precautions failed when used alone. Addition of a stringent policy of restricted admissions, twice daily environmental cleaning, and implementation of hand decontamination with a hydroalcoholic solution led to outbreak termination. This was associated with increases in workload, despite a marked decrease in the number of admissions. This first description of a large outbreak of GISA colonization and infection underlines the importance of routine GISA-strain detection when methicillin-resistant S. aureus is isolated. Outbreak control may be difficult to achieve.

Expression of tcaA and mprF and glycopeptide resistance in clinical glycopeptide-intermediate Staphylococcus aureus (GISA) and heteroGISA strains

Two genes recently associated with glycopeptide intermediate resistance in Staphylococcus aureus (GISA) are mprF and tcaA, with inactivation causing shifts in vancomycin resistance. This study reveals that expression levels of both genes are similar in groups of clinical GISA, heteroGISA and glycopeptide susceptible strains, suggesting no association with clinical isolates.

Reduced expression of the atl autolysin gene and susceptibility to autolysis in clinical heterogeneous glycopeptide-intermediate Staphylococcus aureus (hGISA) and GISA strains

To assess a link between resistance to Triton X-100 induced autolysis (TIA) and lowered atl expression in a collection of clinical glycopeptide-intermediate Staphylococcus aureus (GISA) and heterogeneous GISA (hGISA). Nine clinical GISA, 11 hGISA and 11 glycopeptide-susceptible S. aureus (GSSA), including three pairs of related isolates, were analysed using TIA assays. Lysostaphin MICs were determined by a broth microdilution technique and reverse transcriptase PCR was used to compare atl expression levels in all isolates. Eight of nine clinical GISA and six of 11 hGISA exhibited lower susceptibility to TIA and higher MICs of lysostaphin than GSSA. Eight of nine GISA and all hGISA strains had lowered atl expression levels compared with GSSA. The majority of GISA and hGISA isolates exhibited lowered susceptibility to TIA and lysostaphin and reduced atl expression when compared with GSSA isolates. These factors could contribute to, or predispose to the development of, a thickened cell wall and glycopeptide-intermediate resistance.

Cell wall composition and decreased autolytic activity and lysostaphin susceptibility of glycopeptide-intermediate Staphylococcus aureus.

The cell wall composition and autolytic properties of passage-selected glycopeptide-intermediate Staphylococcus aureus (GISA) isolates and their parent strains were studied in order to investigate the mechanism of decreased vancomycin susceptibility. GISA had relatively modest changes in peptidoglycan composition involving peptidoglycan interpeptide bridges and somewhat decreased cross-linking compared to that of parent strains. The cell wall phosphorus content of GISA strains was lower than that of susceptible parent strains, indicating somewhat lower wall teichoic acid levels in the GISA strains. Similar to whole cells, isolated crude cell walls retaining autolytic activity of GISA had drastically reduced autolytic activity compared to that of parent strains, and this arose early in the development of the GISA phenotype. This was due to an alteration in the autolytic enzymes of GISA as revealed by normal susceptibility of GISA-purified cell walls to parental strain autolysin extract and lower activity and altered peptidoglycan hydrolase activity profiles in GISA autolysin extracts compared to those of parent strains. Northern blot analysis indicated that expression of atl, the major autolysin gene, was significantly downregulated in a GISA strain compared to that of its parent strain. In contrast to whole cells, which showed decreased lysostaphin susceptibility, purified cell walls of GISA showed increased susceptibility to lysostaphin. We suggest that in our GISA strains, decreased autolytic activity is involved in the tolerance of vancomycin and the activities of endogenous autolysins are important in conferring sensitivity to lysostaphin on whole cells.

False synergy between vancomycin and β-lactams against glycopeptide-intermediate Staphylococcus aureus (GISA) caused by inappropriate testing methods

The combination of vancomycin and beta-lactams is often considered synergistic and has been recommended for the treatment of glycopeptide-intermediate Staphylococcus aureus (GISA) infections. In this study, the combination of vancomycin or teicoplanin with different beta-lactams was tested. When using NaCl 4% w/v, for better expression of heterogeneous resistance to beta-lactams, with a longer (48-h) incubation period and a higher (10(7) CFU/mL) inoculum, the association of vancomycin with beta-lactams was antagonistic. However, a synergistic effect was observed for teicoplanin under the same conditions.

Trimethoprim-sulfamethoxazole activity and pharmacodynamics against glycopeptide-intermediate Staphylococcus aureus.

To determine the activity of trimethoprim-sulfamethoxazole (TMP-SMX) against glycopeptide-intermediate Staphylococcus aureus (GISA). In vitro study. University laboratory. Minimum inhibitory concentrations (MICs) of TMP-SMX were determined for three GISA strains. Time-kill assays were conducted at 1 x MIC and at simulated peak serum concentrations (Cmax). Two dosing regimens of TMP-SMX were investigated: TMP-SMX 8 mg (TMP)/kg/day and TMP-SMX 15 mg/kg/day, each divided into two doses/day Both dosages were studied against each strain in a two-compartment in vitro model to determine concentration-related activity. All isolates were susceptible to TMP-SMX. In time-kill studies at 1 x MIC, TMP-SMX was bacteriostatic against all isolates and bactericidal against two of three strains at simulated Cmax. The 15 mg/kg/day (divided-dose) regimen provided the best overall reduction in colony-forming units/ml. All GISA strains were susceptible to TMP-SMX. In addition, it appears that TMP-SMX may have concentration-dependent antibacterial activity against these organisms. As an option in the management of GISA infection, TMP-SMX merits further study.

Structural and topological differences between a glycopeptide-intermediate clinical strain and glycopeptide-susceptible strains of Staphylococcus aureus revealed by atomic force microscopy.

Novel cell surface topography was revealed on cocci from a glycopeptide-intermediate Staphylococcus aureus (GISA) clinical strain by using atomic force microscopy. The GISA isolate and its revertant had two parallel circumferential surface rings. One equatorial surface ring was observed in control strains. In vancomycin-susceptible strains, additional rings were formed in the presence of vancomycin. Ring depth measurements also revealed striking differences between the GISA strain and susceptible strains grown with or without vancomycin.

Streptogramins: an answer to antibiotic resistance in gram-positive bacteria

The past 15 years have seen the emergence of grampositive microorganisms as major nosocomial pathogens, and a corresponding increase in their antibiotic resistance. Penicillin-resistant pneumococci, meticillinresistant staphylococci, and vancomycin-resistant enterococci have been reported worldwide. 1 Gold HS Moellering Jr, RC Antimicrobial-drug resistance. N Engl J Med. 1996; 335: 1445-1453 Crossref PubMed Scopus (375) Google Scholar In addition, certain species, such as Enterococcus faecium and glycopeptide-intermediate Staphylococcus aureus (GISA), have become resistant to so many antibiotics that they have been described as “untreatable” pathogens. 2 Leclercq R Courvalin P Resistance to glycopeptides in enterococci. Clin Infect Dis. 1997; 24: 545-554 Crossref PubMed Scopus (198) Google Scholar , 3 Hiramatsu K Hanaki H Ino T Yabuta K Oguri T Tenover FC Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother. 1997; 40: 135-136 Crossref PubMed Scopus (1646) Google Scholar However, the clinical consequences of such resistance should not be exaggerated. Extensive spread of resistant enterococci seems to be limited to the USA or to particular hospital ecosystems, and the number of publications on GISA greatly exceeds that of clinical isolates. Nevertheless, where present, these strains cause infections impossible to treat, and they would pose a substantial threat worldwide if they were to be disseminated.