Glycopeptide resistance in gram-positive pathogens.
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Anti-Bacterial Agents↗
Biomedical subjects
D M Shlaes
Publications and source records attributed to D M Shlaes.
Vancomycin resistance in the enterococcus. Relevance in pediatrics.
Enterococci are nosocomial pathogens intrinsically resistant to a variety of commonly used antimicrobial agents. The frequent use of antimicrobial agents such as cephalosporins has been associated with the increased isolation of enterococci in pediatric hospitals. In addition to their intrinsic resistance traits, the enterococci have rapidly accumulated a variety of acquired resistance determinants. Strains that are resistant to all currently available antibiotics are now being isolated from infected children. The threat of untreatable enterococcal infection and the possibility that vancomycin resistance may spread from the enterococci to the more virulent pneumococci or staphylococci argue for vigilant surveillance for resistant strains, isolation and barrier precautions for infected patients, increased research into the mechanisms of resistance, and a reinvigorated effort to identify new classes of antimicrobial agents.
Child↗
Bacteremia due to vancomycin-dependent Enterococcus faecium.
A recipient of small-bowel and liver transplants developed recurrent fever and polymicrobial bacteremia due to multiply resistant Enterobacter cloacae and an inducible VanB strain of Enterococcus faecium while receiving therapy with amikacin, imipenem, and vancomycin. These organisms could not be subcultured onto blood agar but did grow around the vancomyin disk on a direct-susceptibility test plate. Additional testing confirmed the strain as E. faecium, which would not grow in the absence of vancomycin. Growth around a disk containing D-alanyl-D-alanine was demonstrated. Spontaneous vancomycin-independent revertants were obtained at a frequency of approximately 1 x 10(-6). Two classes of vancomycin-independent revertants were obtained: one that was constitutively vancomycin resistant and one that was nonconstitutively vancomycin resistant. We hypothesize that the normal D-ala ligase is not expressed in the vancomycin-dependent strain; thus survival of these strains is dependent on expression of the VanB ligase, which produces a depsipeptide precursor that is resistant to vancomycin binding. This is the second reported case involving a clinically important vancomycin-dependent enterococcal strain. Awareness of the existence of these strains is important, especially when clinical and microbiological data are consistent with infection due to a fastidious or nutritionally-deficient organism.
Bacteremia↗
Teicoplanin selects for Staphylococcus aureus that is resistant to vancomycin.
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Drug Resistance, Microbial↗
Decreased teicoplanin susceptibility of methicillin-resistant strains of Staphylococcus aureus.
Between February 1992 and February 1993, 12 patients were seen who were infected or colonized with methicillin-resistant strains of Staphylococcus aureus. The strains had decreased susceptibility to teicoplanin (MICs, 8-16 micrograms/mL). Field inversion gel electrophoresis showed the strains belonged to three related clones (A1, A2, and A3). The patients were though to have acquired the strains nosocomially. Consistent with results of laboratory studies of teicoplanin-resistant S. aureus, all but 1 strain expressed a 35-kDa membrane protein, and 9 strains expressed increased levels of penicillin-binding protein 2 complex. Six strains were isolated from patients treated with glycopeptides. These data suggest that nosocomial transmission of S. aureus with decreased teicoplanin susceptibility may occur during glycopeptide use and that such strains develop resistance by a mechanism associated with the appearance of a 35-kDa membrane protein. Surveillance is necessary to monitor for the potential selection of resistant clones that may be capable of dissemination.
Adult↗
DNA hybridization and contour-clamped homogeneous electric field electrophoresis for identification of enterococci to the species level.
In this study, 113 Enterococcus faecium, 37 Enterococcus faecalis, 24 Enterococcus gallinarum, 15 Enterococcus raffinosus, and 13 Enterococcus casseliflavus clinical isolates and American Type Culture Collection (ATCC) strains were evaluated by contour-clamped homogeneous electric field electrophoresis. Thirty-one of the E. faecium, 22 of the E. faecalis, 24 of the E. gallinarum, 15 of the E. raffinosus, and 13 of the E. casseliflavus isolates were also evaluated by DNA-DNA hybridization. Genomic DNAs from type strains E. faecalis ATCC 19433, E. faecium ATCC 19434, E. gallinarum ATCC 49573, E. raffinosus ATCC 49427, and E. casseliflavus ATCC 25788 were labeled with biotin for use as probes. E. faecalis differed from all other species in always having a largest fragment of > 400 kb. E. gallinarum was different from all other species in having all SmaI fragments of < 200 kb. Biotin-labeled probes showed a high degree of hybridization with genomic DNA from the same species and a low degree of hybridization when hybridized to genomic DNA from different species for all isolates tested except for four isolates identified as E. faecium by conventional biochemical methods. The DNA from these four isolates hybridized strongly to DNA from E. gallinarum ATCC 49573 and weakly to E. faecium ATCC 19434 DNA and had all SmaI fragments of < 200 kb in size. These data suggest that these isolates are nonmotile E. gallinarum. DNA from each ATCC type strain hybridized strongly with itself and had only a low degree of hybridization with DNA from other ATCC type strains tested. These results suggest that contour-clamped homogeneous electric field electrophoresis patterns and DNA-DNA hybridization with biotin-labeled probes may be of use for species differentiation of some enterococci.
Blotting, Southern↗
Epidemiologic perspectives on Enterobacter for the infection control professional.
Enterobacter species have emerged as important nosocomial pathogens. Common reservoirs for these organisms include wounds and the gastrointestinal, urinary, and respiratory tracts. Enterobacter bacteremia typically occurs in patients with long-standing underlying illnesses who received antimicrobial agents before their bacteremia. The wide use of broad-spectrum antibiotics has contributed to the increased prominence of Enterobacter infections. Enterobacter species have a propensity to emerge resistant to the antibiotic therapy administered. Plasmid analysis, restriction endonuclease analysis of total cellular DNA, pulsed-field electrophoresis, and ribotyping can be valuable in investigating the spread of antibiotic-resistant strains.
Anti-Bacterial Agents↗
Bacterial resistance to the cyclic glycopeptides.
Cyclic-glycopeptide antibiotics, such as vancomycin and teicoplanin, have been almost uniformly active against pathogenic Gram-positive bacteria since their discovery in the 1950s. Resistance is now emerging among enterococci and staphylococci by acquisition of novel genes or by mutation, respectively. The mechanism of resistance for enterococci appears to be synthesis of an altered cell-wall precursor with lower affinity for the antibiotics.
Amino Acid Sequence↗
Intraabdominal infection: differences in presentation and outcome between younger patients and the elderly.
Although the elderly account for a disproportionate number of patients with intraabdominal infections, few studies have compared these patients with younger patients in terms of presentation and outcome. Therefore, we conducted a retrospective cohort study of 131 patients at an urban university hospital that included 88 patients (67%) < or = 65 years of age and 43 (33%) > 65 years of age, all of whom had culture-proven intraabdominal infections. Geriatric patients presented more frequently without the typical symptoms and signs of abdominal pain, nausea and vomiting, diarrhea, and fever and had symptoms for a longer period before presentation. Diagnosis on admission was more often unknown or considered to be of an extraabdominal nature for the elderly patients, and sources of infection were more commonly biliary or pancreatic. Mortality was not significantly different between the groups, but length of stay and duration until normalization of body temperature were longer for the older patients. We concluded that elderly patients with intraabdominal infections frequently present atypically and have a more-protracted course of illness than their younger counterparts.
Abdominal Abscess↗
Piperacillin/tazobactam compared with ticarcillin/clavulanate in community-acquired bacterial lower respiratory tract infection.
The efficacy and safety of a new combination parenteral antibiotic, piperacillin/tazobactam, was compared with that of parenteral ticarcillin/clavulanate in the treatment of adult patients with community-acquired lower respiratory tract infections. A total of 299 patients were enrolled in this multicentre, double-blind, comparative study; 177 received piperacillin/tazobactam and 122 received ticarcillin/clavulanate. Of these, 119 met the evaluability criteria (69, piperacillin/tazobactam and 50, ticarcillin/clavulanate). The study drugs (piperacillin/tazobactam 3 g/375 mg or ticarcillin/clavulanate 3 g/100 mg) were given every 6 h by slow iv infusion for a minimum of 5 days. The favourable clinical response (cured and improved) rates of evaluable patients were 84% and 64% at endpoint (P < 0.01) for piperacillin/tazobactam and ticarcillin/clavulanate, respectively. The favourable bacteriological response at the early follow-up (eradicated and presumed eradicated) were 91% and 67% for piperacillin/tazobactam and ticarcillin/clavulanate, respectively (P < 0.01). At endpoint, 84% and 64%, respectively (P = 0.02) had a favourable response. The most common adverse experiences involved the gastrointestinal tract and occurred in 31.6% of the piperacillin/tazobactam group compared with 20.5% in the ticarcillin/clavulanate group (P = 0.02). These events were mild and generally did not affect therapy. Piperacillin/tazobactam appears to be more effective than ticarcillin/clavulanate in this patient population and is generally well tolerated.
Adolescent↗
In vivo efficacies of beta-lactam-beta-lactamase inhibitor combinations against a TEM-26-producing strain of Klebsiella pneumoniae.
We examined the efficacies of the beta-lactam-beta-lactamase inhibitor combinations ampicillin-sulbactam and piperacillin-tazobactam in the treatment of intra-abdominal abscesses caused by a TEM-26-producing strain of Klebsiella pneumoniae. At lower doses, both combinations reduced abscess colony counts by more than 3 log10 CFU/g from that of untreated controls, but treatment with these drugs was inferior to treatment with imipenem. Increasing the doses of the combinations resulted in a further decrease in abscess CFU to a level where both were similar to imipenem in efficacy. These results suggest that the beta-lactam-beta-lactamase inhibitor combinations ampicillin-sulbactam and piperacillin-tazobactam may be viable alternatives for the treatment of serious infections caused by susceptible extended-spectrum beta-lactamase-producing strains of K. pneumoniae.
Ampicillin↗
Colonization and cross-colonization of nursing home patients with trimethoprim-resistant gram-negative bacilli.
A prospective study of 67 patients in a nursing home and a subpopulation of 31 patients who were stratified according to functional level--a general measure of the amount of nursing care required by the patients--was performed. The goals of this study were (1) to determine whether antibiotic selection of resistant variants from within endogenous flora of hosts or horizontal transmission is more important in the development of colonization with trimethoprim-resistant gram-negative bacilli (TRGNB) in a nursing home; (2) to identify the mode(s) of transmission if horizontal transmission is more important; and (3) to identify risk factors for colonization and cross-colonization with TRGNB. Although a number of variables were associated with colonization, only a decreased functional level appeared to be independently associated with colonization. Isolates from the subpopulation were subtyped by restriction endonuclease digestion of cellular DNA, as were isolates from personnel of the nursing home. Results revealed that 16 of 21 staff members had 48 positive cultures for TRGNB. Of 25 typeable isolates, 12 from seven of the 21 staff members were identical to patient strains. Analysis of acquisition of new strains of TRGNB by members of the subpopulation showed that 67.5% were the result of cross-colonization. Our data are consistent with, but do not prove, the hypothesis that nurses' hands are the primary mode of transmission of TRGNB in this nursing home and suggest that most colonization could be prevented by interdicting horizontal transmission.
DNA, Bacterial↗
Emerging antimicrobial resistance and the immunocompromised host.
Infections caused by gram-positive bacteria have become the most important cause of infectious morbidity among some groups of immunocompromised patients over the last decade. Among the gram-positive bacteria, the emerging problems of resistance to antimicrobial agents include the development of resistance to beta-lactam and aminoglycoside drugs among the enterococci, making synergistic bactericidal therapy impossible; the continued spread of methicillin-resistant staphylococci; resistance to both vancomycin and teicoplanin among enterococci and staphylococci; the emergence of intrinsically vancomycin-resistant species as important pathogens; and resistance to the fluoroquinolones. It is unlikely that new therapeutic classes of antibacterial drugs will be released this decade. Therapeutic alternatives now include unusual combinations of antibiotics to which the strains may appear resistant but that exhibit synergistic activity, although this area has not yet been thoroughly explored. Therefore, control of emergence and spread of resistance through the more judicious use of existing agents, good infection control practices, and the use of imaginative combination therapy for those infected with resistant strains seem to be our best alternatives.
Aminoglycosides↗
Teicoplanin-resistant Staphylococcus aureus expresses a novel membrane protein and increases expression of penicillin-binding protein 2 complex.
In the recent clinical trials of teicoplanin therapy of endocarditis caused by Staphylococcus aureus, at least one instance of the emergence of teicoplanin-resistant strains during therapy has been reported (G.W. Kaatz, S. M. Seo, N. J. Dorman, and S. A. Lerner, J. Infect. Dis 162:103-108, 1990). We have confirmed, using conventional electrophoresis of EcoRI-digested chromosomal DNA and pulsed-field gel electrophoresis of SmaI-digested chromosomal DNA, that the resistant strain (12873) (MIC, 16 micrograms/ml) is genetically very similar to the susceptible parent (12871) (MIC, 4 micrograms/ml). Kaatz et al. were able to select spontaneous teicoplanin-resistant mutants (10(-9)), suggesting that a single gene might be involved. We have shown that the mutation is highly stable during growth in the absence of teicoplanin. Using Tn551, we have selected insertion mutants of 12873 that become teicoplanin susceptible. We have examined a number of aspects of cell wall physiology in strains 12871 and 12873 and the teicoplanin-susceptible Tn551 mutants of 12873. 12873 was more susceptible to lysostaphin lysis than 12871 and the susceptible Tn551 derivatives of 12873. Autolysis in phosphate buffer (pH 7.5) and cell wall turnover rates were similar in 12871 and 12873. An analysis of membrane proteins revealed the expression of a ca. 35-kDa protein and increased expression of both polypeptides of penicillin-binding protein (PBP) 2 (PBP2) in 12873 relative to 12871 and the Tn551 mutants of 12873. This increased expression was not related to PBP2', since both strains were susceptible to oxacillin in 2% NaCl (MIC, < or = 0.25 microgram/ml) and cellular DNA from neither strain hybridized with a specific mec gene probe. Two independent Tn551 inserts have been mapped to a ca. 117-kb SmaI fragment of the chromosome. These data suggest the possibility that the mutation resulting in resistance to teicoplanin involves the regulation of expression of both polypeptides of PBP2 and a 35-kDa membrane protein.
Autolysis↗
Efficacy of ampicillin-sulbactam versus that of cefoxitin for treatment of Escherichia coli infections in a rat intra-abdominal abscess model.
We examined the efficacy of ampicillin-sulbactam (2:1) and cefoxitin in the treatment of infections caused by Escherichia coli strains exhibiting increasing levels of beta-lactamase-mediated resistance to ampicillin-sulbactam in the rat intra-abdominal abscess model. Cefoxitin was superior to ampicillin-sulbactam in the treatment of infections caused by all strains. Treatment with ampicillin-sulbactam resulted in a statistically significant decrease in CFU per gram of abscess in comparison with treatment with ampicillin alone for both the moderately resistant and the resistant strains, with an inverse correlation between the MIC and the absolute decrease in CFU per gram of abscess.
Abdomen↗
Resistance to cefoperazone-sulbactam in Klebsiella pneumoniae: evidence for enhanced resistance resulting from the coexistence of two different resistance mechanisms.
We investigated the in vitro activity and the in vivo efficacy of the beta-lactam-beta-lactamase inhibitor combination cefoperazone-sulbactam against an isogenic series of Klebsiella pneumoniae strains. Both cefoperazone and cefoperazone-sulbactam were active in vitro against a susceptible clinical strain, and the combination was highly effective in the treatment of rat intra-abdominal abscesses. Loss of expression of a 39-kDa outer membrane protein resulted in at least a fourfold increase in the MICs of cefoperazone and cefoperazone-sulbactam but did not appreciably affect the in vivo efficacy of either regimen. Introduction of plasmid RP4, which encodes the TEM-2 beta-lactamase, into the susceptible strain resulted in the loss of in vitro activity and in vivo efficacy for cefoperazone. The in vitro activity of cefoperazone-sulbactam against this strain was diminished, but the antibiotic combination remained highly active in vivo. Introduction of RP4 into the strain lacking the 39-kDa outer membrane protein resulted in a fourfold increase in the in vitro MIC of cefoperazone-sulbactam in comparison with the beta-lactamase-producing susceptible strain and resulted in a loss of in vivo efficacy against infections caused by this strain. These results suggest that the combination of different resistance mechanisms, neither of which alone results in substantially diminished cefoperazone-sulbactam efficacy in vivo, can cause in vivo resistance to the beta-lactam-beta-lactamase inhibitor combination in K. pneumoniae.
Abscess↗
Constitutively vancomycin-resistant Enterococcus faecium resistant to synergistic beta-lactam combinations.
Vancomycin resistance among enterococci has recently been recognized. Synergy between vancomycin and penicillin has been shown in vitro for isolates of Enterococcus faecium resistant to both of these antibiotics. We describe three isolates of vancomycin-resistant E. faecium which demonstrate unique phenotypic characteristics. The isolates exhibited high-level resistance to both vancomycin and teicoplanin, consistent with the VanA phenotype. However, resistance in these isolates could not be induced or cured, and mating experiments failed to detect a transfer of resistance. The combination of vancomycin and penicillin did not significantly change the MIC of penicillin for any of the three isolates. Immunoblotting with polyclonal anti-VanB antibody showed no reaction with the cellular proteins of these strains. Probing with a vanA oligonucleotide revealed hybridization with chromosomal but not plasmid DNA. The mechanism of constitutive resistance of those strains remains unclear. A second mutational change, perhaps involving PBP 5, may explain the presence of resistance to synergistic combination penicillin-vancomycin therapy. In vitro evaluation of penicillin-vancomycin should be carried out in all clinical cases where this therapeutic regimen is being considered.
Adult↗
Clonal spread of vancomycin-resistant Enterococcus faecium between patients in three hospitals in two states.
The DNAs of 3* vancomycin-resistant Enterococcus faecium isolates from five hospitals in three states were analyzed by contour-clamped homogeneous electric field electrophoresis and plasmid analysis. There were 22 strain types. One strain type was common to patients in three hospitals in two states. These results suggest the apparent intra- and interhospital spread of vancomycin-resistant E. faecium.
Bacterial Typing Techniques↗