The management of infections due to drug-resistant gram-positive bacteria.
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Animals↗
Biomedical subjects
R C Moellering
Publications and source records attributed to R C Moellering.
In vitro activity of an oral streptogramin antimicrobial, XRP2868, against gram-positive bacteria.
The comparative in vitro potency of XRP2868, a new oral semisynthetic streptogramin antibiotic, was evaluated against gram-positive bacteria. XRP2868 inhibited all staphylococci at < or = 1 microg/ml and all non-pneumococcal streptococci at < or = 0.25 microg/ml and was fourfold more potent than quinupristin-dalfopristin against Staphylococcus aureus and Enterococcus faecium.
Administration, Oral↗
Clinical and public health implications of macrolide-resistant Streptococcus pneumoniae.
Macrolide resistance among Streptococcus pneumoniae is a growing global concern, although its specific impact on public health is not currently well defined. A Consensus Working Group was convened in March 2001 to address whether credible, scientific data substantiate macrolide resistance in S. pneumoniae as: (i) producing significant morbidity; (ii) creating attendant health and economic burdens; (iii) constituting a public health threat; and (iv) warranting intervention, including development of new antibiotics with efficacy against these strains. Despite the limitations of available clinical data, concern about the possibility of treatment failure with macrolides is being expressed in clinical practice and in formal treatment guidelines, threatening the important role of these agents in the treatment of respiratory tract infections. Further studies are required to monitor and control macrolide resistance and evaluate settings in which macrolide treatment failures are occurring, and new therapeutic interventions are needed.
Adolescent↗
In vitro activity of the new oxazolidinone AZD2563 against Enterococci.
The activity of a new oxazolidinone antimicrobial, AZD2563, was assessed against >500 clinical isolates of enterococci representing six species. All isolates, including those resistant to other antibiotic classes, were inhibited by AZD2563 at concentrations </=2 micro g/ml, except for four strains resistant to linezolid. In most cases, AZD2563 was twofold more active than linezolid against enterococci.
Acetamides↗
Molecular characterization of vancomycin-resistant Enterococci repopulating the gastrointestinal tract following treatment with a novel glycolipodepsipeptide, ramoplanin.
We characterized baseline and repopulating stool isolates recovered during a phase II trial of ramoplanin for the treatment of patients with stool carriage of vancomycin-resistant enterococci (VRE). Repopulation with a strain with a related genotype was found in 74, 60, and 53% of individuals in groups treated with placebo, 100 mg of ramoplanin, and 400 mg of ramoplanin, respectively. All ramoplanin-treated patients with a culture positive for VRE at day 7 had a relapse caused by a genotypically related isolate. In ramoplanin-treated patients, antibiotics with activities against anaerobic organisms were associated with positive cultures on day 7 (relative risk [RR] = 8.8; P = 0.004), and the avoidance of such antibiotics was significantly associated with culture negativity through day 21 (RR = 0.16; P = 0.02).
Anti-Bacterial Agents↗
Prevalence of the fsr locus in Enterococcus faecalis infections.
The fsr locus of Enterococcus faecalis confers virulence in animal models. A retrospective analysis of fsr prevalence in diverse E. faecalis clinical isolates demonstrated fsr in all endocarditis isolates versus 53% of stool isolates (P = 0.005). This supports a role for fsr-mediated virulence in the pathogenesis of enterococcal infections in humans.
Animals↗
Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin.
Clinicians caring for patients with vancomycin-resistant Enterococcus faecium (VREF) infections face severe constraints in the selection of treatment. Quinupristin/dalfopristin (Synercid) is active in vitro against VREF, with a MIC(90) of 1.0 microg/mL. We investigated the clinical efficacy and safety of this agent in a multicenter, prospective, noncomparative, emergency-use study of 396 patients. Patients were included if they had signs and symptoms of active infection, including bacteremia of unknown origin, intra-abdominal infection, and skin and skin-structure infection, with no alternative antibiotic therapy available. The mean duration of treatment was 20 days (range, 4-40 days). The clinical response rate was 68.8% in the evaluable subset, and the overall response rate was 65.6%. The most common adverse events related to quinupristin/dalfopristin were arthralgias and myalgias. Related laboratory abnormalities were rare. In this severely ill patient population, quinupristin/dalfopristin was efficacious and demonstrated an acceptable safety profile in the treatment of VREF infection.
Anti-Bacterial Agents↗
Prolonged colonization with vancomycin-resistant Enterococcus faecium in long-term care patients and the significance of "clearance".
Little is known about the persistence of colonization with vancomycin-resistant Enterococcus faecium (VRE) in the nononcologic, non-intensive care unit patient. We studied all patients who had VRE isolated on > or =2 occasions of > 1 year apart (Study A) and those who had been "cleared" of VRE colonization after 3 negative stool cultures (Study B). Twelve patients had stored VRE isolates recovered > 1 year apart (Study A), and 58% of paired isolates were genotypically related according to pulsed field gel electrophoresis patterns. In Study B, stool samples were obtained weekly from 21 "cleared" patients for 5 weeks, which revealed that 24% were VRE positive. For these culture-positive patients, 72% of the cultures failed to detect VRE. Recent antibiotic use was significantly more common in the culture-positive patients, as compared with culture-negative patients (P=.003). Colonization with VRE may persist for years, even if the results of intercurrent surveillance stool and index site cultures are negative. Cultures for detection of VRE in stool samples obtained from patients declared "cleared" are insensitive.
Culture Media↗
Linezolid resistance in a clinical isolate of Staphylococcus aureus.
The new oxazolidinone antimicrobial, linezolid, has been approved for the treatment of infections caused by various gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Although instances of linezolid resistance in VRE have been reported, resistance has not been encountered among clinical isolates of S aureus. We have characterised an MRSA isolate resistant to linezolid that was recovered from a patient treated with this agent for dialysis-associated peritonitis.
Acetamides↗
Chloramphenicol treatment for vancomycin-resistant Enterococcus faecium bacteremia.
OBJECTIVE: To evaluate the results of treating vancomycin-resistant Enterococcus faecium (VREF) bacteremia with chloramphenicol. METHODS: We retrospectively reviewed the charts of all adult patients with VREF bacteremia treated with chloramphenicol during the calendar year 1998 at a 522-bed tertiary referral center in New York City. Patients were identified by reviewing microbiology laboratory records. Patients with clinically significant VREF bacteremia who received chloramphenicol for at least 48 h were included in the study. Clinical and microbiological outcomes were determined. Microbiological and molecular tests were performed on a small representative sample of isolates to identify the presence of resistance mechanisms and to look for similarity among the isolates. RESULTS: Seven episodes of significant VREF bacteremia occurred in six patients. Mean age was 54 years. All patients had cancer and three had severe neutropenia. Five of seven episodes were associated with chronic indwelling devices, but in only one of these cases was the device removed. All isolates were susceptible to chloramphenicol in vitro. All six microbiologically evaluable episodes had a favorable response to chloramphenicol treatment, and four of seven (57%) clinically evaluable episodes had favorable outcomes. Only one death may have been due to VREF bacteremia, so the maximal attributable mortality was 14%. The three representative samples that were tested further were indistinguishable from one another and they displayed no evidence of resistance mechanisms. CONCLUSIONS: In a cohort of severely ill cancer patients, chloramphenicol was effective in treating VREF bacteremia. The use of chloramphenicol should be considered in treating infections with this highly resistant organism, where therapeutic options are limited.
Adult↗
Restoration of vancomycin susceptibility in Enterococcus faecalis by antiresistance determinant gene transfer.
We assessed the ability of gene transfer to reverse vancomycin resistance in class A (VanA) glycopeptide-resistant Enterococcus faecalis. Recombinant shuttle vectors containing a vanH promoter-vanA antisense gene cassette fully restored vancomycin susceptibility through a combined transcriptional activator binding domain decoy and inducible vanA antisense RNA effect.
Anti-Bacterial Agents↗
SME-type carbapenem-hydrolyzing class A beta-lactamases from geographically diverse Serratia marcescens strains.
Three sets of carbapenem-resistant Serratia marcescens isolates have been identified in the United States: 1 isolate in Minnesota in 1985 (before approval of carbapenems for clinical use), 5 isolates in Los Angeles (University of California at Los Angeles [UCLA]) in 1992, and 19 isolates in Boston from 1994 to 1999. All isolates tested produced two beta-lactamases, an AmpC-type enzyme with pI values of 8.6 to 9.0 and one with a pI value of approximately 9.5. The enzyme with the higher pI in each strain hydrolyzed carbapenems and was not inhibited by EDTA, similar to the chromosomal class A SME-1 beta-lactamase isolated from the 1982 London strain S. marcescens S6. The genes encoding the carbapenem-hydrolyzing enzymes were cloned in Escherichia coli and sequenced. The enzyme from the Minnesota isolate had an amino acid sequence identical to that of SME-1. The isolates from Boston and UCLA produced SME-2, an enzyme with a single amino acid change relative to SME-1, a substitution from valine to glutamine at position 207. Purified SME enzymes from the U. S. isolates had beta-lactam hydrolysis profiles similar to that of the London SME-1 enzyme. Pulsed-field gel electrophoresis analysis revealed that the isolates showed some similarity but differed by at least three genetic events. In conclusion, a family of rare class A carbapenem-hydrolyzing beta-lactamases first described in London has now been identified in S. marcescens isolates across the United States.
Anti-Bacterial Agents↗
Diversity of domain V of 23S rRNA gene sequence in different Enterococcus species.
The highly conserved central loop of domain V of 23S RNA (nucleotides 2042 to 2628; Escherichia coli numbering) is implicated in peptidyltransferase activity and represents one of the target sites for macrolide, lincosamide, and streptogramin B antibiotics. DNA encoding domain V (590 bp) of several species of Enterococcus was amplified by PCR. Twenty enterococcal isolates were tested, including Enterococcus faecium (six isolates), Enterococcus faecalis, Enterococcus avium, Enterococcus durans, Enterococcus gallinarum, Enterococcus casseliflavus (two isolates of each), and Enterococcus raffinosus, Enterococcus mundtii, Enterococcus malodoratus, and Enterococcus hirae (one isolate of each). For all isolates, species identification by biochemical testing was corroborated by 16S rRNA gene sequencing. The sequence of domain V of the 23S rRNA gene from E. faecium and E. faecalis differed from those of all other enterococci. The domain V sequences of E. durans and E. hirae were identical. This was also true for E. gallinarum and E. casseliflavus. E. avium differed from E. casseliflavus by 23 bases, from E. durans by 16 bases, and from E. malodoratus by 2 bases. E. avium differed from E. raffinosus by one base. Despite the fact that domain V is considered to be highly conserved, substantial differences were identified between several enterococcal species.
Animals↗
A novel antimicrobial agent joins the battle against resistant bacteria.
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Acetamides↗
A cluster of VanD vancomycin-resistant Enterococcus faecium: molecular characterization and clinical epidemiology.
VanD-mediated glycopeptide resistance has been reported for an isolate of Enterococcus faecium, BM4339. Three clinical isolates of vancomycin-resistant E. faecium collected from 3 patients during a 6-week period in 1993 had agar dilution MICs of vancomycin and teicoplanin of 128 and 4 microg/mL, respectively. Polymerase chain reaction (PCR) using degenerate primers complementary to genes encoding d-Ala-d-X ligases yielded a 630-bp product that was similar to the published partial sequence of vanD. By use of inverse PCR, vanD, vanHD, and two partial flanking open-reading frames were sequenced. The deduced amino acid sequence of VanD showed 67% identity with VanA and VanB. vanD appeared to be located on the chromosome and was not transferable to other enterococci. The 3 isolates were indistinguishable by pulsed-field gel electrophoresis and differed from BM4339. No other isolates carrying vanD were found in a subset of 875 recent US isolates of vancomycin-resistant enterococci.
Amino Acid Sequence↗
Editorial response: Staphylococci vs. glycopeptides--how much are the battle lines changing?
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Humans↗
The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-Use Study Group.
A progressive increase in the incidence of vancomycin resistance in strains of Enterococcus faecium (VREF) has severely constrained treatment options for patients with infection caused by this emerging pathogen. Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic, is active in vitro against VREF, with an MIC90 of 1.0 mg/L. We studied the clinical efficacy and safety of quinupristin/dalfopristin in the treatment of VREF infection. Two prospective studies were conducted simultaneously. The first enrolled only patients with VREF infection; the second included patients with infection caused by other gram-positive bacterial pathogens in addition to VREF. Patients were enrolled if they had signs and symptoms of active infection and no appropriate alternative antibiotic therapy. The recommended treatment regimen of quinupristin/dalfopristin was 7.5 mg/kg i.v. every 8 h for a duration judged appropriate by the investigator. A total of 396 patients with VREF infection were enrolled. The most frequent indications for treatment included intra-abdominal infection, bacteraemia of unknown origin, urinary tract infection, catheter-related bacteraemia, and skin and skin structure infection. This patient population had a high prevalence of severe underlying illness, including a history of diabetes mellitus, transplantation, mechanical ventilation, dialysis, chronic liver disease with cirrhosis and oncological disorders. The mean (+/- S.D.) duration of treatment was 14.5 +/- 10.7 days (range: 1-108). The majority of patients (82.1%) were treated every 8 h, as assessed on day 2 of treatment, while 15.9% were treated every 12 h. The clinical success rate was 73.6% [142/193 clinically evaluable patients; 95% confidence interval (CI): 67.4%, 79.8%], the bacteriological success rate 70.5% (110/156 bacteriologically evaluable patients; 95% CI: 63.4%, 77.7%) and the overall success (both clinical and bacteriological success) rate 65.8% (102/156 bacteriologically evaluable patients; 95% CI: 57.9%, 72.9%). VREF bacteraemia at entry, mechanical ventilation and laparotomy were associated with a worse outcome. Quinupristin/dalfopristin was generally well tolerated. The most common systemic adverse events related to treatment were arthralgias (9.1%) and myalgias (6.6%). Related laboratory abnormalities were infrequent. In these severely ill patients with VREF infection and no other clinically appropriate therapeutic alternatives, quinupristin/dalfopristin demonstrated substantial efficacy and a good nervous system, cardiovascular, gastrointestinal, renal and hepatic tolerability.
Adolescent↗
Quinupristin/dalfopristin: therapeutic potential for vancomycin-resistant enterococcal infections.
Vancomycin-resistant Enterococcus faecium (VREF) is an opportunistic pathogen, which causes infections among severely ill, hospitalized patients, in whom it is likely to increase the risk of progressive local or systemic disease and to worsen the prognosis. Because these organisms are often highly resistant to penicillin, ampicillin and many other antimicrobials including the glycopeptides, there are few proven therapeutic alternatives for the treatment of infection caused by VREF. Quinupristin/dalfopristin is highly active against VREF in vitro. A prolonged post-antibiotic effect, good polymorphonuclear leucocyte/macrophage penetration and slow release, and active metabolites allow this agent to be used with an 8 or 12 h dosing interval. The combined results from a Phase III non-comparative study and an emergency-use study of quinupristin/dalfopristin for the treatment of VREF infection produced a clinical response rate (cure or improvement) in 142 (73.6%) of 193 clinically evaluable patients. The baseline pathogen was eradicated or presumed eradicated from 110 of 156 (70.5%) bacteriologically evaluable patients. Fifty-two per cent of the severely ill patients in these two studies died, but no death was attributed to quinupristin/dalfopristin therapy. The most common adverse event was arthralgia (9.1%). Quinupristin/dalfopristin has demonstrated efficacy for the treatment of serious VREF infections, including those that have failed conventional therapy.
Anti-Bacterial Agents↗