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Biomedical subjects

K Bush

Publications and source records attributed to K Bush.

At least 37 records · Page 2Linked to original sources
PubMed1999

Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes.

CONTEXT: Infections caused by ceftazidime sodium-resistant gram-negative bacteria that harbor extended-spectrum beta-lactamases (ESBLs) are increasing in frequency in hospitals in the United States. OBJECTIVES: To report a citywide nursing home-centered outbreak of infections caused by ESBL-producing gram-negative bacilli and to describe the clinical and molecular epidemiology of the outbreak. DESIGN: Hospital-based case-control study and a nursing home point-prevalence survey. Molecular epidemiological techniques were applied to resistant strains. SETTINGS: A 400-bed tertiary care hospital and a community nursing home. PATIENTS: Patients who were infected and/or colonized with ceftazidime-resistant Escherichia coli, Klebsiella pneumoniae, or both and controls who were admitted from nursing homes between November 1990 and July 1992. MAIN OUTCOME MEASURES: Clinical and epidemiological factors associated with colonization or infection by ceftazidime-resistant E coli or K pneumoniae; molecular genetic characteristics of plasmid-mediated ceftazidime resistance. RESULTS: Between November 1990 and October 1992, 55 hospital patients infected or colonized with ceftazidime-resistant E coli, K pneumoniae, or both were identified. Of the 35 admitted from 8 nursing homes, 31 harbored the resistant strain on admission. All strains were resistant to ceftazidime, gentamicin, and tobramycin; 96% were resistant to trimethoprim-sulfamethoxazole and 41% to ciprofloxacin hydrochloride. In a case-control study, 24 nursing home patients colonized with resistant strains on hospital admission were compared with 16 nursing home patients who were not colonized on hospital admission; independent risk factors for colonization included poor functional level, presence of a gastrostomy tube or decubitus ulcers, and prior receipt of ciprofloxacin and/or trimethoprim-sulfamethoxazole. In a nursing home point-prevalence survey, 18 of 39 patients were colonized with ceftazidime-resistant E coli; prior receipt of ciprofloxacin or trimethoprim-sulfamethoxazole and presence of a gastrostomy tube were independent predictors of resistance. Plasmid studies on isolates from 20 hospital and nursing home patients revealed that 17 had a common 54-kilobase plasmid, which conferred ceftazidime resistance via the ESBL TEM-10, and mediated resistance to trimethoprim-sulfamethoxazole, gentamicin, and tobramycin; all 20 isolates harbored this ESBL. Molecular fingerprinting showed 7 different strain types of resistant K pneumoniae and E coli distributed among the nursing homes. CONCLUSIONS: Nursing home patients may be an important reservoir of ESBL-containing multiple antibiotic-resistant E coli and K pneumoniae. Widespread dissemination of a predominant antibiotic resistance plasmid has occurred. Use of broad-spectrum oral antibiotics and probably poor infection control practices may facilitate spread of this plasmid-mediated resistance. Nursing homes should monitor and control antibiotic use and regularly survey antibiotic resistance patterns among pathogens.

Aged↗
PubMed1999

Clinical characteristics and molecular epidemiology associated with imipenem-resistant Klebsiella pneumoniae.

Eight patients were infected or colonized with imipenem-resistant Klebsiella pneumoniae (IRKP) from December 1994 to November 1995. Initial Klebsiella isolates were susceptible to imipenem but resistant to all cephalosporins, aminoglycosides, and beta-lactam inhibitor combinations. All patients had been in the surgical intensive care unit and had undergone abdominal surgery or tracheostomy during hospitalization. The average age of the patients was 71 years (range, 41-81 years). All patients were treated with imipenem for 5 to 36 days, and IRKP was recovered from each during or after therapy. Pulsed-field gel electrophoresis (PFGE) of the IRKP isolates revealed three distinct clonal patterns. Paired sequential isolates of imipenem-susceptible K. pneumoniae and IRKP from two patients had identical PFGE patterns, suggesting the development of clonal stepwise resistance to imipenem during therapy. Thus, imipenem resistance in Klebsiella may occur when this agent is used for treatment of infection due to ceftazidine- and aminoglycoside-resistant strains.

Adult↗
PubMed1999

Biochemical characterization of novel tetrahydrofuranyl 1beta-methylcarbapenems: stability to hydrolysis by renal dehydropeptidases and bacterial beta-lactamases, binding to penicillin binding proteins, and permeability properties.

The biochemical properties of tetrahydrofuranyl (THF) carbapenems, carbapenems with THF substituents, were evaluated with respect to enzyme stability, binding to penicillin-binding proteins (PBPs), and penetration into gram-negative organisms. THF carbapenems showed increased stability to hog renal dehydropeptidases (DHPs) compared to that of imipenem or meropenem and were more stable to human DHP than imipenem (<10% hydrolysis compared to that for imipenem). THF carbapenems were stable to hydrolysis by all serine beta-lactamases tested. CL 191,121, a prototype THF carbapenem, was more stable to hydrolysis by carbapenem-hydrolyzing serine beta-lactamases such as IMI-1 and Sme-1 than imipenem, with a relative k(cat) value of <20% for imipenem. Similar to imipenem and meropenem, THF carbapenems were not stable to the metallo beta-lactamases CcrA and L1. However, CL 191,121 bound to all Staphylococcus aureus PBPs at concentrations that were less than or equal to the MICs. The THF carbapenems bound to PBPs from Escherichia coli and Pseudomonas aeruginosa, with the highest affinities being for PBPs 2 and 4, as noted with imipenem. The affinities for PBPs 1a and 1b in E. coli were reduced for the THF carbapenems compared to that for imipenem, even though the MICs of the THF carbapenems for E. coli strains were lower than those of imipenem. The penetrability of the THF carbapenems into Serratia marcescens S6, which produces the Sme-1 carbapenem-hydrolyzing beta-lactamase, was 2.4 to 7.8 times less than that of imipenem. Compounds CL 190,294 and CL 188,624 showed good penetrability, with permeability coefficient values comparable to those of the rapidly penetrating agents cephaloridine, imipenem, meropenem, and biapenem. Decreased penetration into wild-type P. aeruginosa was suggested by the high MICs of the THF carbapenems (MICs, 16 to 32 microg/ml), despite equivalent or better binding to P. aeruginosa PBPs than that of imipenem. However, the MICs of the THF carbapenems for wild-type P. aeruginosa compared to that for an OprD2 mutant generally varied no more than 2-fold, but those of imipenem and other carbapenems differed 16-fold. These data indicated that THF carbapenems do not appear to enter through protein OprD2. In conclusion, the THF carbapenems exhibited stability to hydrolysis by renal DHPs and serine beta-lactamases, exhibited strong binding to essential PBPs from E. coli and S. aureus, and penetrated gram-negative enteric bacteria at rates comparable to those for meropenem and biapenem.

Animals↗
PubMed1999

Multiple mechanisms of action for inhibitors of histidine protein kinases from bacterial two-component systems.

Many pathogenic bacteria utilize two-component systems consisting of a histidine protein kinase (HPK) and a response regulator (RR) for signal transduction. During the search for novel inhibitors, several chemical series, including benzoxazines, benzimidazoles, bis-phenols, cyclohexenes, trityls, and salicylanilides, were identified that inhibited the purified HPK-RR pairs KinA-Spo0F and NRII-NRI, with 50% inhibitory concentrations (IC50s) ranging from 1.9 to >500 microM and MICs ranging from 0.5 to >16 microg/ml for gram-positive bacteria. However, additional observations suggested that mechanisms other than HPK inhibition might contribute to antibacterial activity. In the present work, representative compounds from the six different series of inhibitors were analyzed for their effects on membrane integrity and macromolecular synthesis. At 4x MIC, 17 of 24 compounds compromised the integrity of the bacterial cell membrane within 10 min, as measured by uptake of propidium iodide. In this set, compounds with lower IC50s tended to cause greater membrane disruption. Eleven of 12 compounds inhibited cellular incorporation of radiolabeled thymidine and uridine >97% in 5 min and amino acids >80% in 15 min. The HPK inhibitor that allowed >25% precursor incorporation had no measurable MIC (>16 microg/ml). Fifteen of 24 compounds also caused hemolysis of equine erythrocytes. Thus, the antibacterial HPK inhibitors caused a rapid decrease in cellular incorporation of RNA, DNA, and protein precursors, possibly as a result of the concomitant disruption of the cytoplasmic membrane. Bacterial killing by these HPK inhibitors may therefore be due to multiple mechanisms, independent of HPK inhibition.

Animals↗
PubMed1999

beta-Lactamases of increasing clinical importance.

Resistance to b-lactam-containing antimicrobial agents continues to increase, frequently due to the presence of b-lactamases in Gram-negative bacteria. Over the past twenty-five years broad-spectrum enzymes such as TEM- and SHV-variants and the metallo-b-lactamases have become more prolific. As a result of the ability of plasmids to continue to acquire additional resistance determinants, many of the b-lactamase-producing Gram-negative pathogens have become multi-drug resistant. In combination with decreased permeability, the organisms can become virtually untreatable with current therapies. The major groups of b-lactamases that pose the most serious therapeutic problems include the extended-spectrum b-lactamases, the plasmid-mediated cephalosporinases, the inhibitor-resistant TEM- or SHV-derived b-lactamases and the carbapenem-hydrolyzing b-lactamases. Those enzymes that can be transferred on mobile elements are the most serious of the newer b-lactamases, and include enzymes in each of the four groups outlined above.

Anti-Bacterial Agents↗
PubMed1998

The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test.

OBJECTIVE: To evaluate the 3 alcohol consumption questions from the Alcohol Use Disorders Identification Test (AUDIT-C) as a brief screening test for heavy drinking and/or active alcohol abuse or dependence. METHODS: Patients from 3 Veterans Affairs general medical clinics were mailed questionnaires. A random, weighted sample of Health History Questionnaire respondents, who had 5 or more drinks over the past year, were eligible for telephone interviews (N = 447). Heavy drinkers were oversampled 2:1. Patients were excluded if they could not be contacted by telephone, were too ill for interviews, or were female (n = 54). Areas under receiver operating characteristic curves (AUROCs) were used to compare mailed alcohol screening questionnaires (AUDIT-C and full AUDIT) with 3 comparison standards based on telephone interviews: (1) past year heavy drinking (>14 drinks/week or > or =5 drinks/ occasion); (2) active alcohol abuse or dependence according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria; and (3) either. RESULTS: Of 393 eligible patients, 243 (62%) completed AUDIT-C and interviews. For detecting heavy drinking, AUDIT-C had a higher AUROC than the full AUDIT (0.891 vs 0.881; P = .03). Although the full AUDIT performed better than AUDIT-C for detecting active alcohol abuse or dependence (0.811 vs 0.786; P<.001), the 2 questionnaires performed similarly for detecting heavy drinking and/or active abuse or dependence (0.880 vs 0.881). CONCLUSIONS: Three questions about alcohol consumption (AUDIT-C) appear to be a practical, valid primary care screening test for heavy drinking and/or active alcohol abuse or dependence.

Aged↗
PubMed1998

Bacterial enzymatic resistance: beta-lactamases and aminoglycoside-modifying enzymes.

Numerous novel beta-lactamases and aminoglycoside-modifying enzymes with altered substrate profiles continue to be identified. Plasmid-mediated transmission of many of these enzymes readily occurs due to inclusion of the encoding genes in mobile gene cassettes. Recent crystallographic determinations of the structures of metallo-beta-lactamases and aminoglycoside-modifying enzymes provide the opportunity for the rational design of inhibitors.

Acetyltransferases↗
PubMed1998

Medical risks for women who drink alcohol.

OBJECTIVE: To summarize for clinicians recent epidemiologic evidence regarding medical risks of alcohol use for women. METHODS: MEDLINE and PsychINFO, 1990 through 1996, were searched using key words "women" or "woman," and "alcohol." MEDLINE was also searched for other specific topics and authors from 1980 through 1996. Data were extracted and reviewed regarding levels of alcohol consumption associated with mortality, cardiovascular disease, alcohol-related liver disease, injury, osteoporosis, neurologic symptoms, psychiatric comorbidity, fetal alcohol syndrome, spontaneous abortion, infertility, menstrual symptoms, breast cancer, and gynecologic malignancies. Gender-specific data from cohort studies of general population or large clinical samples are primarily reviewed. MAIN RESULTS: Women develop many alcohol-related medical problems at lower levels of consumption than men, probably reflecting women's lower total body water, gender differences in alcohol metabolism, and effects of alcohol on postmenopausal estrogen levels. Mortality and breast cancer are increased in women who report drinking more than two drinks daily. Higher levels of alcohol consumption by women are associated with increased menstrual symptoms, hypertension, and stroke. Women who drink heavily also appear to have increased infertility and spontaneous abortion. Adverse fetal effects occur after variable amounts of alcohol consumption, making any alcohol use during pregnancy potentially harmful. CONCLUSIONS: In general, advising nonpregnant women who drink alcohol to have fewer than two drinks daily is strongly supported by the epidemiologic literature, although specific recommendations for a particular woman should depend on her medical history and risk factors.

Alcohol Drinking↗
PubMed1998

Metallo-beta-lactamases: a class apart.

Metallo-beta-lactamases have recently become more prominent among the beta-lactam-hydrolyzing enzymes. Two major functional groups of enzymes have been identified, with little structural similarity among the groups. One group is a set of enzymes with broad substrate specificities capable of hydrolyzing most beta-lactams except monobactams. A second group is composed of the "true" carbapenemases, enzymes that exhibit poor hydrolysis of penicillins and cephalosporins. This latter group has been found primarily in Aeromonas species. To date, only a small number of carbapenem-resistant isolates have been reported to produce metallo-beta-lactamases, in part because of the ease with which this resistance can be acquired by other means: permeability changes and an increase in chromosomal cephalosporinase production. However, the appearance of these enzymes on plasmids in Japan poses a worrisome problem. It is anticipated that plasmid-mediated resistance to carbapenems will continue to increase, perhaps compromising the use of these agents.

Humans↗
PubMed1998

The AUDIT alcohol consumption questions: reliability, validity, and responsiveness to change in older male primary care patients.

OBJECTIVES: To determine the reliability, validity, and responsiveness to change of AUDIT (Alcohol Use Disorders Identification Test) questions 1 to 3 about alcohol consumption in a primary care setting. PATIENTS: Randomly selected, male general medical patients (n = 441) from three VA Medical Centers, who had 5 or more drinks containing alcohol in the past year and were willing to be interviewed about their health habits. MEASURES: Three self-administered AUDIT consumption questions were compared with a telephone-administered version of the trilevel World Health Organization interview about alcohol consumption. RESULTS: Of 393 eligible patients, 264 (67%) completed interviews. Test-retest reliability--Correlations between baseline and repeat measures 3 months later for four dimensions of consumption according to the AUDIT, ranged from 0.65 to 0.85, among patients who indicated they had not changed their drinking (Kendall's Tau-b). Criterion validity--Correlations between AUDIT and interview for four dimensions of alcohol consumption ranged from 0.47 to 0.66 (Kendall's Tau-b). Discriminative validity--The AUDIT questions were specific (90 to 93%), but only moderately sensitive (54 to 79%), for corresponding criteria for heavy drinking. Responsiveness to change--The AUDIT consumption questions had a Guyatt responsiveness statistic of 1.04 for detecting a change of 7 drinks/week, suggesting excellent responsiveness to change. CONCLUSIONS: AUDIT questions 1 to 3 demonstrate moderate to good validity, but excellent reliability and responsiveness to change. Although they often underestimate heavy alcohol consumption according to interview, they performed adequately to be used as a proxy measure of consumption in a clinical trial of heavy drinkers in this population.

Adult↗
PubMed1998

Ceftazidime-resistant Klebsiella pneumoniae and Escherichia coli isolates producing TEM-10 and TEM-43 beta-lactamases from St. Louis, Missouri.

Ceftazidime-resistant Escherichia coli and Klebsiella pneumoniae (49 and 102 isolates, respectively) were collected from Barnes-Jewish Hospital, St. Louis, Mo., from 1992 to 1996. They were uniformly resistant to ceftazidime, generally resistant to aztreonam, and variably susceptible to cefotaxime. Four representative E. coli strains and 15 Klebsiella strains were examined. From one to four beta-lactamases were produced per strain, with three possible enzymes related to ceftazidime resistance: enzymes with pI values of 5.6, 6.1, or 7.6. By pulsed-field gel electrophoresis there were at least 13 different Klebsiella strain types and 3 different E. coli strain types, indicating that the outbreak was not clonal. After cloning and sequencing of the beta-lactamase-encoding genes, the enzyme with a pI of 5.6 was identified as TEM-10. The enzyme with a pI of 6.1 was a novel TEM variant (TEM-43) with Lys at 104, His at 164, and Thr at 182. TEM-43 showed broad-spectrum hydrolytic activity against all penicillins, with the highest hydrolysis rate for ceftazidime compared to those for the other expanded-spectrum cephalosporins. Aztreonam was also a good substrate for TEM-43, with hydrolytic activity similar to that of ceftazidime and affinity higher than that of ceftazidime. The TEM-43 beta-lactamase was well inhibited by clavulanic acid and tazobactam at concentrations of < 10 nM. Sulbactam was less effective than the other inhibitors. The Thr182 mutation previously reported in an inhibitor-resistant beta-lactamase did not cause the TEM-43 enzyme to become resistant to any of the inhibitors.

Ceftazidime↗
PubMed1997

Xanthine oxidase binding to glycosaminoglycans: kinetics and superoxide dismutase interactions of immobilized xanthine oxidase-heparin complexes.

Xanthine oxidoreductase (XDH + XO, EC 1.2.3.2) is released into the circulation from organs rich in XO activity. Herein we report the specific high affinity binding of XO to glycosaminoglycans (GAGs) and the preferential association of XO with heparin, compared with heparan sulfate, chondroitin sulfate, and dematan sulfate. The binding of XO to Sepharose 6B-conjugated heparin (HS6B) occurs at physiological ionic strength and increased with pH, with Scatchard analysis revealing a nonlinear binding pattern at pH 7.4. The dissociation constant (Kd) for XO binding was 0.4 to 1.8 x 10(-7) M, similar to the heparin-reversible binding of lipoprotein lipase to vascular endothelium. The binding energy of 9-13 kcal/mol was concordant with noncovalent electrostatic interactions. Xanthine oxidase immobilization to HS6B rendered a catalytically active enzyme from that had kinetic characteristics distinct from XO in free solution. While the Km and Ki for xanthine in phosphate buffer at pH 7.4 were 3 microM and 1.6 mM, respectively, for free XO, they were 15 microM and 2.8 mM for immobilized XO. Inhibition constants for guanine and uric acid were also increased upon XO binding to HS6B. Changes in kinetic parameters were related to a real and not apparent decrease in binding affinity for substrate and inhibitors and were not due to diffusion-controlled processes within the gel matrix. Changes in Km and Ki for xanthine also had a significant influence on the relative quantities of O2.- and H2O2 generated by a given substrate concentration. Superoxide formed by HS6B-bound XO was partially consumed within the gel microenvironment which electrostatically excluded CuZn SOD. Immobilization of XO increased the half-life of enzyme activity in buffer and in the absence of substrate from 67 to 120 h at 4 degrees C. These data indicate that binding to cell surfaces will strongly influence the catalytic properties, oxidant producing capacity, and stability of XO.

Animals↗
PubMed1997

The pathomorphologic changes that accompany the resolution of cervical radiculopathy. A prospective study with repeat magnetic resonance imaging.

STUDY DESIGN: A prospective study with independent clinical and radiologic review. OBJECTIVE: To assess whether regression of cervical intervertebral disc herniations accompanied and correlated with clinical improvement in patients recovering from cervical radiculopathy without undergoing surgical intervention. SUMMARY OF BACKGROUND DATA: The study subjects were 13 consecutive patients, nine men (69%) and four women (31%), presenting with cervical radiculopathy. All patients but one had objective neurologic signs. All patients had large posterolateral cervical intervertebral disc herniations demonstrated by magnetic resonance imaging. METHODS: Pain was controlled by serial periradicular and epidural corticosteroid injections. Patients were finally examined and discharged from care because of sustained pain control at an average of 6 months (range, 2-12 months). They were interviewed subsequently over the telephone by an independent clinician and rescanned at an average of 12 months (range, 4-31 months). The scans were reviewed by an independent radiologist masked to the sequence of the scans. RESULTS: Regression of cervical disc herniations was demonstrated in 12 of the 13 patients. All patients had made a satisfactory clinical recovery, but the one with the herniation that had not regressed suffered from persistent minor symptoms. CONCLUSIONS: Most cervical disc herniations regress with time and without the need for surgical resection. Thus, surgical intervention can be avoided with adequate pain control, allowing the herniation time to regress.

Adrenal Cortex Hormones↗
PubMed1997

Crystal structures of the cadmium- and mercury-substituted metallo-beta-lactamase from Bacteroides fragilis.

The metallo-beta-lactamases require zinc or cadmium for hydrolyzing beta-lactam antibiotics and are inhibited by mercurial compounds. To data, there are no clinically useful inhibitors of this class of enzymes. The crystal structure of the Zn(2+)-bound enzyme from Bacteroides fragilis contains a binuclear zinc center in the active site. A hydroxide, coordinated to both zinc atoms, is proposed as the moiety that mounts the nucleophilic attack on the carbonyl carbon atom of the beta-lactam ring. To study the metal coordination further, the crystal structures of a Cd(2+)-bound enzyme and of an Hg(2+)-soaked zinc-containing enzyme have been determined at 2.1 A and 2.7 A, respectively. Given the diffraction resolution, the Cd(2+)-bound enzyme exhibits the same active-site architecture as that of the Zn(2+)-bound enzyme, consistent with the fact that both forms are enzymatically active. The 10-fold reduction in activity of the Cd(2+)-bound molecule compared with the Zn(2+)-bound enzyme is attributed to fine differences in the charge distribution due to the difference in the ionic radii of the two metals. In contrast, in the Hg(2+)-bound structure, one of the zinc ions, Zn2, was ejected, and the other zinc ion, Zn1, remained in the same site as in the 2-Zn(2+)-bound structure. Instead of the ejected zinc, a mercury ion binds between Cys 104 and Cys 181, 4.8 A away from Zn1 and 3.9 A away from the site where Zn2 is located in the 2-Zn(2+)-bound molecule. The perturbed binuclear metal cluster explains the inactivation of the enzyme by mercury compounds.

Bacteroides fragilis↗
PubMed1997

Antimicrobial agents.

Antimicrobial agents active against multi-resistant Gram-positive bacteria are considered to be of major commercial potential. Commercially viable agents that have been included in recent successful trials include the streptogramins, novel glycopeptides, oxazolidinones and potent quinolones. Cationic peptides have generated much interest, but their utility as successful drug candidates remains questionable. Novel compound classes for possible exploitation include non-beta-lactam beta-lactamase inhibitors, inhibitors of lipid A biosynthesis and tRNA synthetase inhibitors.

Anti-Bacterial Agents↗
PubMed1997

Antimicrobial resistance in anaerobes.

The development of antibiotic resistance in anaerobic bacteria has a tremendous impact on the selection of antimicrobial agents for empirical therapy. Susceptibility studies have documented the emergence of antimicrobial resistance and indicate distinct differences in resistance patterns related to individual hospitals, geographic regions, and antibiotic-prescribing regimens. Resistance to beta-lactam drugs, clindamycin, tetracyclines, and 5-nitroimidazoles (metronidazole) has been observed. The prime mechanism for resistance to beta-lactam agents is the production of beta-lactamases. Resistance to clindamycin is mediated by modification of the ribosome. Tetracycline resistance is mediated by both tetracycline efflux and ribosomal protection. 5-Nitroimidazole resistance appears to be caused by a combination of decreased antibiotic uptake and decreased nitroreductase activity. The level of chloramphenicol susceptibility remains quite high, whereas uniform resistance to aminoglycosides and quinolones is observed. Understanding the mechanisms of resistance is critical for both informed selection of antimicrobial therapy and the design of new antimicrobial agents.

Bacteria, Anaerobic↗