Search PubMed⌕ Search

Biomedical subjects

H C Neu

Publications and source records attributed to H C Neu.

At least 37 records · Page 2Linked to original sources
PubMed1993

Probenecid-resistant J774 cell expression of enhanced organic anion transport by a mechanism distinct from multidrug resistance.

Macrophages possess organic anion transporters that carry membrane-impermeant fluorescent dyes, such as lucifer yellow (LY) and carboxy-fluorescein, from the cytoplasm into endosomes and out of the cells. Probenecid, an organic anion transport inhibitor, blocks these processes. Prolonged incubation of J774 cells in medium containing 2.5 mM probenecid eventually kills most of these cells. To identify J774 variants that express increased organic anion transport activity, we selected probenecid-resistant (PBR) J774 cells by growing them in medium containing increasing concentrations of probenecid. When PBR and unselected J774 cells were loaded with LY by ATP4- permeabilization, the amount of LY accumulated by the PBR cells was about half that in the unselected cells. This difference was abolished by adding 10 mM probenecid to the medium in which the cells were loaded, suggesting that the diminished LY accumulation in PBR cells was due to enhanced LY secretion and that the PBR cells expressed increased organic anion transport activity. Direct comparison of LY efflux from J774 and PBR J774 cells showed a faster initial rate of secretion of LY from PBR J774 cells than from unselected J774 cells. To determine whether LY efflux is mediated by P-glycoprotein, we compared LY efflux in unselected J774 cells, PBR J774 cells, and multidrug-resistant J774 cells (J7.C1). LY efflux from J7.C1 cells was not sensitive to verapamil, which inhibits multidrug-resistance transporters, and reverses the multidrug-resistant phenotype of J7.C1 cells. The rates of LY efflux from unselected J774 and J7.C1 cells were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Infection problems for the 1990's--do we have an answer?

There is and has been continued change in organisms causing infection in the hospital. In the past few years, although Gram-negative bacteria have remained a major cause of mortality, Gram-positive bacteria and fungi have become increasingly important. This has caused organisms such as methicillin-resistant staphylococci, enterococci, Xanthomonas maltophilia and multiply resistant Pseudomonas aeruginosa to be common pathogens. Can this difficult state of affairs be changed by better antimicrobial prescribing practices? Yes and no. Virtually any agent will select MRSA and MRSE since the chromosomal location of the resistance of multiple-antibiotics makes such selection common and explains the rapid rate of the fluoroquinolones as therapy of MRSA. Restriction of oral vancomycin will markedly reduce the pressure to select Enterococcus faecium and thus limit the spread of the organisms and delay transmission of glycopeptide resistance to S. aureus. Judicious use of antibiotics in the intensive care environment will be major factor in "saving" antibiotics for other patients since the ICU patient goes to other parts of the hospital carrying with him/her the baggage of resistant Staphylococcus haemolyticus, klebsiella, P. aeruginosa, acinetobacter, enterobacter, xanthomonas and Pseudomonas cepacia. All of these organisms have the potential to become resistant to the agents heretofore used to treat them and are common in ICU patients.

Anti-Bacterial Agents↗
PubMed1992

Gemfibrozil enhances the listeriacidal effects of fluoroquinolone antibiotics in J774 macrophages.

J774 macrophage-like cells express organic anion transporters that promote the efflux of fluoroquinolone antibiotics such as norfloxacin (NFX) from these cells. Gemfibrozil (GFZ) blocks organic anion transport in J774 cells, thereby facilitating the intracellular accumulation of NFX (Cao, C., H.C. Neu, and S.C. Silverstein. 1991. J. Cell Biol. 115:467a [Abstr.]). To determine whether GFZ enhances the efficacy of fluoroquinolone antibiotics against intracellular bacterial pathogens, J774 cells were infected with Listeria monocytogenes and incubated in medium containing a fluoroquinolone antibiotic in the presence or absence of GFZ. Intracellular growth of L. monocytogenes was evaluated by lysing J774 cells and assaying for colony-forming units of Listeria. GFZ intensified the bacteriostatic effect of 4 micrograms/ml NFX and rendered 8 micrograms/ml bactericidal for L. monocytogenes. GFZ had a similar potentiating effect when used in combination with 2 micrograms/ml ciprofloxacin (CFX). CFX plus GFZ was bactericidal for intracellular L. monocytogenes. Treatment of J774 cells with NFX plus GFZ markedly reduced the cytotoxic effect of the bacteria on these cells. Over 55% of cells treated with 8 micrograms/ml NFX alone were dead 16 h after infection, whereas only 5% of cells treated with 8 micrograms/ml NFX plus GFZ were dead at 16 h. Similarly, GFZ potentiated the ability of 2 micrograms/ml to protect J774 cells against the cytocidal effect of Listeria. NFX in combination with GFZ limited cell-to-cell spread of L. monocytogenes. In antibiotic-free medium, > 99% of J774 cells contained intracellular L. monocytogenes at 14 h after infection. NFX alone in the medium did not change this outcome. However, 4 micrograms/ml NFX plus GFZ decreased bacterial spread by approximately 40% at 24 h postinfection, and 8 micrograms/ml NFX plus GFZ prevented all spread beyond the initially infected cell population. These results suggest that GFZ could be used clinically to enhance the efficacy of fluoroquinolone and of other anionic antibiotics against bacteria that grow and/or reside within macrophages and/or other cells.

Animals↗
PubMed1992

The crisis in antibiotic resistance.

The synthesis of large numbers of antibiotics over the past three decades has caused complacency about the threat of bacterial resistance. Bacteria have become resistant to antimicrobial agents as a result of chromosomal changes or the exchange of the exchange of genetic material via plasmids and transposons. Streptococcus pneumoniae, Streptococcus pyogenes, and staphylococci, organisms that cause respiratory and cutaneous infections, and members of the Enterobacteriaceae and Pseudomonas families, organisms that cause diarrhea, urinary infection, and sepsis, are now resistant to virtually all of the older antibiotics. The extensive use of antibiotics in the community and hospitals has fueled this crisis. Mechanisms such as antibiotic control programs, better hygiene, and synthesis of agents with improved antimicrobial activity need to be adopted in order to limit bacterial resistance.

Anti-Bacterial Agents↗
PubMed1992

Pharmacokinetics, microbiology, cost: interrelated problems for the 1990s that impact on the use of fluoroquinolone antimicrobial agents.

Correlation of pharmacokinetic and pharmacodynamic properties of antimicrobial agents with in vitro activity is critical to proper use of antibiotics. Knowledge of minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) is essential for life-threatening infections and has increased relevance with regard to development of resistance when treating selected urinary tract and wound infections. Factors that decrease absorption of oral agents profoundly affect clinical efficacy. The dose and frequency of dosing programs of the new oral fluoroquinolones should be correlated with the body site of infection, the organism being treated, and the propensity of the organism to become resistant. The long elimination half-life and high urine concentrations of newer fluoroquinolones permit once-daily therapy in many infections.

4-Quinolones↗
PubMed1992

Urinary tract infections.

The populations at risk for urinary tract infection include the newborn, particularly the premature, prepubertal girls, young boys, sexually active young women, elderly males, and elderly females. Risk factors that contribute to lower tract infection in women include sexual intercourse, diaphragm-spermicide use, and voiding behavior. Host factors, more than bacterial virulence, are probably the most important contributors to infection. The genetic factors that are important contributors are secretor status and P blood group phenotype. Which patients to culture, when to culture, and the number of organisms required to define infection have changed in the past decade. A concentration of 10(2) colony forming units/mL can cause an acute urinary tract infection in the healthy woman. The presence of leukocytes in the urine is of increasing diagnostic importance. Complicated urinary tract infections occur in neonates with such congenital anomalies of the urinary tract as urethral valves or in patients with neurologic disease resulting in urinary stasis. In older men or women, complicated urinary tract infections occur with obstruction, instrumentation, surgery, anatomic abnormalities, or stones. Single-dose therapy of uncomplicated urinary tract infection is useful in only a small subset of patients, specifically in patients less than 45 years of age who have short duration of symptoms. The majority of patients with uncomplicated infections should receive treatment for 3-5 days. Response to therapy and long-term cure rates in complicated urinary tract infection are related both to the type of underlying abnormality and to the species of the infecting organism. Complicated urinary tract infections should be treated for 7-14 days.

Bacteriuria↗
PubMed1992

Can fluoroquinolones be considered once-daily therapy?

Fluoroquinolone antimicrobial agents inhibit most Enterobacteriaceae at extremely low concentrations, less than or equal to 0.5 microgram/mL. The half-lives of the agents range from 4 to 18 hours. Most of the available fluoroquinolones can be administered once daily to treat urinary tract and diarrheal infections. Newer agents with long half-lives that inhibit gram positive organisms at lower concentrations than the older fluoroquinolones, less than or equal to 1 microgram/mL, and have a long post-antibiotic effect have the potential to be used once daily as treatment of respiratory, skin-structure and selected bone infections as well. Careful clinical studies are needed to establish the efficacy of once daily use of fluoroquinolones, to determine that clinical efficacy is equivalent to multiple doses, and that once-daily dosing does not select more resistant bacteria. Single-dose therapy with quinolones would be an improvement in cost and patient compliance.

4-Quinolones↗
PubMed1992

Plasma bactericidal activity of a new C-5 methyl fluoroquinolone after oral doses of 400 and 800 mg.

The plasma bactericidal activity of a new C-5 methyl fluoroquinolone, OPC-17116, was determined after once-daily oral ingestion of 400 mg and 800 mg in normal, healthy volunteers. OPC-17116 at a 400-mg dose produced plasma bactericidal titers greater than or equal to 1:16 at 12 hours against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Haemophilus influenzae, and Moraxella catarrhalis. OPC-17116 bactericidal titers against Pseudomonas aeruginosa were 1:2 or 1:4 at 6 and 12 hours. The plasma bactericidal titers against Streptococcus pyogenes and Streptococcus pneumoniae were 1:4 or greater, but bactericidal titers against Staphylococcus aureus were 1:2 at 12 hours and less than 1:2 at 24 hours. The 800-mg dose of OPC-17116 produced bactericidal titers of at least 1:32 at 12 hours for the Enterobacteriaceae, Haemophilus, and Moraxella, and 1:4 for S. pyogenes and S. pneumoniae, but bactericidal titers against S. aureus were 1:2. These data would suggest that an 800-mg dose of OPC-17116 taken orally once daily would provide adequate concentrations to treat infections due to the pathogens examined in this study.

Administration, Oral↗
PubMed1992

Optimal characteristics of agents to treat uncomplicated urinary tract infections.

The optimal characteristics of agents to treat uncomplicated urinary tract infection must include activity against the major pathogens involved in these infections as well as a low potential for development of bacterial resistance. High urinary levels should be present for an adequate period to eliminate the organisms. Side effects should be minimal with minimal effect on the bacterial flora of the community. Treatment programs of single-dose, three days, or five days can be developed depending upon the agent.

Anti-Bacterial Agents↗
PubMed1992

Post-antibiotic effect of the new streptogramin RP 59500.

The post-antibiotic effect (PAE) of RP 59500, a new streptogramin antibiotic, was determined for Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus pneumoniae, and Streptococcus pyogenes. A 30 min exposure of Staphylococcus aureus to 5 micrograms/ml of RP 59500 produced a PAE of 1.9-6.9 h, and a 60 min exposure of 2.5 micrograms/ml produced a PAE of 3.2-8 h. A 30 min exposure of 5 micrograms/ml of RP 59500 of coagulase-negative staphylococci produced a PAE of 2.5-7.5 h. PAEs of constitutively erythromycin-resistant staphylococcal isolates were shorter than were the PAEs of highly susceptible isolates. A 30 min exposure to 5 micrograms/ml of RP 59500 produced a PAE of 7.5-9.5 h for Streptococcus pneumoniae and a PAE of greater than 18 h for Streptococcus pyogenes. RP 59500 produced a longer PAE with Staphylococcus aureus than did vancomycin, oxacillin or erythromycin. These results suggest that RP 59500 may be administered less frequently than would be suggested by its half-life.

Clindamycin↗
PubMed1992

Comparative in vitro activity and beta-lactamase stability of RU29246, the active metabolite of HR916B.

HR 916B is a new orally absorbed cephalosporin. In tests its active metabolite, RU29246, inhibited Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus pneumoniae at less than or equal to 0.12 micrograms/ml, which is similar to the antibacterial activity of cefuroxime, and was more active than cefaclor. It was also more active (MIC 2 micrograms/ml) than cefixime, cefuroxime, cefaclor and cefotaxime against staphylococci. RU29246 inhibited Escherichia coli, Klebsiella pneumoniae, Citrobacter diversus, Klebsiella oxytoca, Proteus mirabilis, Providencia stuartii and Salmonella spp. at less than or equal to 1 microgram/ml, thus being more active than cefuroxime and cefaclor, but was less active than cefixime and cefotaxime. It did not inhibit Pseudomonas aeruginosa and other Pseudomonas spp., Enterobacter spp., Serratia marcescens or Bacteroides fragilis. RU29246 was not hydrolyzed by TEM-1, Staphylococcus aureus TEM-2 or Moraxella catarrhalis beta-lactamases, but was hydrolyzed by TEM-3 and the chromosomal beta-lactamases of Proteus vulgaris and Morganella morganii. Plasmid and chromosomal beta-lactamases were inhibited by RU29246.

Cephalosporins↗
PubMed1992

In vitro activity of the new glycopeptide decaplanin.

The activity of decaplanin, a new glycopeptide, was compared to that of vancomycin, teicoplanin and daptomycin. Decaplanin was two- to four-fold less active than vancomycin, telcoplanin and daptomycin against Staphylococcus aureus and Staphylococcus epidermidis, with an MIC90 of 2 micrograms/ml for methicillin-susceptible and 4 micrograms/ml for methicillin-resistant isolates. Decaplanin had activity similar to that of vancomycin against Streptococcus pyogenes, Streptococcus agalactiae, group C and G streptococci, with an MIC90 of 0.12 micrograms/ml. It was less active than the other agents against the viridans group streptococci (MIC90 4 micrograms/ml). The activity of decaplanin against enterococci (MIC90 4 micrograms/ml) was similar to that of vancomycin. Clostridium spp. were inhibited by 0.5 micrograms/ml, peptostreptococci and peptococci by 0.25 microgram/ml. Decaplanin was active from pH 5.5 to 7.5. Inoculum size had a minimal effect on MICs, and increased concentrations of Ca2+ and Mg2+ and 50% serum did not alter MICs or MBCs.

Anti-Bacterial Agents↗
PubMed1992

In vitro antimicrobial activity of the new antibiotic vermisporin.

The antimicrobial activity of vermisporin, a new antibiotic produced by fermentation of the fungus Ophiobolus vermisporis, was tested in vitro. Vermisporin inhibited 90% of Bacteroides fragilis and other Bacteroides spp. at 1 microgram/ml (range 0.25-1 micrograms/ml). Clostridium perfringens were inhibited by 1 microgram/ml (range 0.25-2 micrograms/ml). Vermisporin inhibited 90% of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, at 0.5 micrograms/ml (range 0.12-0.5 micrograms/ml). Vermisporin MICs for group A, B, C, F and G streptococci were < 1 microgram/ml when tested in Haemophilus Test Medium but > or = 8 micrograms/ml in the presence of blood. Vermisporin MICs for Enterobacteriaceae, Pseudomonas aeruginosa and Haemophilus influenzae exceeded 64 micrograms/ml. Inhibited organisms had MBCs 16- to 32-fold above the MICs.

Alkaloids↗
PubMed1992

The activity of metal compounds against aerobic and anaerobic bacteria.

We evaluated the antimicrobial activity of two metal compounds, JM-1397 (OsO2[xylyl]2) and JM-2469 (AuCl[S2CPEt3]). Both inhibited methicillin-susceptible and methicillin-resistant Staphylococcus aureus at concentrations of 0.5-2 micrograms/ml, with a minimum inhibitory concentration (MIC90) of 1 microgram/ml for JM-1397 and 0.5 microgram/ml for JM-2469. Similar concentrations inhibited methicillin-susceptible and -resistant coagulase-negative staphylococci (S. epidermidis, S. haemolyticus, and S. saprophyticus). JM-2469 inhibited group A, B, C, F, and G beta-hemolytic streptococci and viridans group streptococci at 1-8 micrograms/ml (MIC90 4 micrograms/ml) but Enterococcus faecalis and E. faecium had MICs of 8-16 micrograms/ml. JM-1397 had MICs for these organisms of greater than 64 micrograms/ml. Bacteroides fragilis, other Bacteroides, and Clostridium species were inhibited by less than or equal to 0.12-4 micrograms/ml (MIC90, 0.5 microgram/ml). MICs of both compounds for Enterobacteriaceae and Pseudomonas spp. were greater than 64 micrograms/ml. These studies show that osmium and gold compounds have potential as topical agents against Gram-positive and anaerobic species.

Anti-Bacterial Agents↗
PubMed1992

J774 macrophages secrete antibiotics via organic anion transporters.

Mouse macrophages and J774 macrophage-like cells express probenecid-inhibitable organic anion transporters that remove anionic dyes from the cells' cytoplasmic matrix and secrete these dyes into the extracellular medium. The present studies show that these transporters also secrete antibiotics from J774 macrophages. Penicillin G permeates J774 cells poorly, but after it was introduced into the cell cytoplasm, it was secreted in a probenecid-inhibitable fashion. The quinolone norfloxacin enters macrophages readily. Probenecid retarded the secretion of intracellular norfloxacin by J774 cells and enhanced norfloxacin accumulation three- to fourfold. Thus the intracellular accumulation of norfloxacin is regulated in part by organic anion transporters that secrete norfloxacin (and penicillin G) from J774 cells. This transport process may have clinical significance, as fluoroquinolones inhibit growth of intracellular pathogens such as mycobacteria and Brucella organisms in vitro but fail to arrest infections with these organisms in vivo.

Adenosine Triphosphate↗