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Biomedical subjects

F P Tally

Publications and source records attributed to F P Tally.

At least 19 recordsLinked to original sources
PubMed2000

Drug target validation: lethal infection blocked by inducible peptide.

Genome projects are generating large numbers of potential new targets for drug discovery. One challenge is target validation, proving the usefulness of a specific target in an animal model. In this paper, we demonstrate a new approach to validation and assay development. We selected in vitro specific peptide binders to a potential pathogen target. By inducing the expression of a selected peptide in pathogen cells causing a lethal infection in mice, the animals were rescued. Thus, by combining in vitro selection methods for peptide binders with inducible expression in animals, the target's validity was rigorously tested and demonstrated. This approach to validation can be generalized and has the potential to become a valuable tool in the drug discovery process.

Amino Acid Sequence↗
PubMed2000

Once-daily dosing in dogs optimizes daptomycin safety.

Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.

Animals↗
PubMed1999

Daptomycin: a novel agent for Gram-positive infections.

The alarming increase in the incidence of Gram-positive infections, including those caused by resistant bacteria, has sparked renewed interest in novel antibiotics. One such agent is daptomycin, a novel lipopeptide antibiotic with proven bactericidal activity in vitro against all clinically relevant Gram-positive bacteria. These include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide intermediately susceptible Staphylococcus aureus (GISA), coagulase-negative staphylococci (CNS) and penicillin-resistant Streptococcus pneumoniae (PRSP), for which there are very few therapeutic alternatives. Daptomycin provides rapid, concentration-dependent killing and a relatively prolonged concentration-dependent post-antibiotic effect in vitro. Spontaneous acquisition of resistance to daptomycin occurs rarely. Daptomycin exhibits linear pharmacokinetics, minimal accumulation with once-daily dosing, and low plasma clearance and volume of distribution. Phase II clinical trials indicate that daptomycin at doses of 2 mg/kg q24 h and 3 mg/kg q12 h is efficacious against skin and soft tissue infections and bacteremia, respectively. In addition, results in endocarditis suggested potential efficacy with higher doses. On the basis of clinical trials to date, it appears that daptomycin has an excellent safety profile, with the incidence and nature of serious adverse events comparable to those observed with conventional therapy. Adverse events associated with other classes of antimicrobials (nephrotoxicity, local irritation, ototoxicity, hypersensitivity, and gastrointestinal effects) were uncommon with daptomycin. Minimal skeletal muscle toxicity was seen at only the highest dose tested (4 mg/kg q12 h), predicted by elevations in serum creatinine phosphokinase, and readily reversible upon discontinuation of treatment. There were no signs of toxicity in cardiac or smooth muscle. Phase II and III clinical trials are underway to evaluate daptomycin for the treatment of Gram-positive bacteremia and complicated skin and soft tissue infections, respectively. Daptomycin holds promise as a rapidly acting and highly effective antibiotic for Gram-positive infections.

Journal Article↗
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↗
PubMed1994

Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines.

This report describes the discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". These agents are notable for their activity against a broad spectrum of tetracycline-susceptible and -resistant Gram-negative and Gram-positive aerobic and anaerobic bacteria possessing various classes of tetracycline-resistant determinants [tet B (efflux), tet M (ribosomal protection)]. The design and synthesis of a number of 7-substituted 9-substituted-amido 6-demethyl-6-deoxytetracyclines are described.

Anti-Bacterial Agents↗
PubMed1994

Inhibition of protein synthesis occurring on tetracycline-resistant, TetM-protected ribosomes by a novel class of tetracyclines, the glycylcyclines.

One of the two major mechanisms of tetracycline resistance is ribosomal protection. Of this resistance type, tet(M) is the best characterized. Although the mechanism of tet(M) resistance has not yet been fully elucidated, it has been demonstrated that ribosomes isolated from a tet(M) strain are resistant to inhibition of protein synthesis by tetracycline. A new generation of tetracycline compounds, the glycylcyclines, that are able to inhibit protein synthesis occurring on tetracycline-resistant, TetM-protected ribosomes, as well as wild-type, tetracycline-sensitive ribosomes, have been identified.

Anti-Bacterial Agents↗
PubMed1993

Antimicrobial resistance in Bacteroides.

Antimicrobial resistance in Bacteroides species has a direct impact on the selection of chemotherapy for anaerobic infections. Multiple studies have documented differences in susceptibility patterns related to individual hospitals, geographic areas, and antibiotic-prescribing practices. Resistance to beta-lactam antibiotics, tetracycline, clindamycin, and metronidazole has been documented in Bacteroides species. The prime mechanism for beta-lactam resistance is the production of beta-lactamases, including penicillinases, cephalosporinases, and the metallo-beta-lactamases that can hydrolyze imipenem. Resistance to tetracycline is mediated by ribosomal protection by the tetQ class. Resistance to clindamycin is mediated by ribosomal modification. Metronidazole resistance may be caused by a combination of decreased antibiotic uptake, decreased nitroreductase activity, and decreased pyruvate:ferredoxin oxidoreductase activity accompanied by increased lactate dehydrogenase activity. Most disturbing is the appearance of resistance to multiple agents in the same organism. Understanding the mechanisms of resistance and the mechanisms of action of these drugs not only will lead to the design of new antimicrobial agents but will permit informed selection of therapy for bacteroides infections.

Anti-Bacterial Agents↗
PubMed1993

Safety profile of piperacillin/tazobactam in phase I and III clinical studies.

The safety of piperacillin/tazobactam was investigated in Phase I and Phase III clinical studies. In 22 Phase I pharmacokinetic studies, 242 healthy subjects and 232 patients were given single and multiple doses of piperacillin/tazobactam, piperacillin alone, tazobactam alone, and/or placebo. Interaction with tobramycin and vancomycin was also studied. Of 1201 patients enrolled in Phase III trials, 944 received piperacillin 4 g plus tazobactam 500 mg every 8 h for lower respiratory tract infections, complicated urinary tract infections, skin and soft tissue infections, and intra-abdominal infections, or piperacillin 2 g plus tazobactam 500 mg 8 hourly for less severe infections; 90 patients received imipenem/cilastatin as a comparative regimen. Piperacillin 4 g and tazobactam 500 mg were also administered every 6 h with an aminoglycoside to 167 patients with pulmonary infection or neutropenia and bacterial infection. In all trials, piperacillin/tazobactam was found to be safe and well tolerated. One death was deemed possibly drug-related. Thirty-eight patients were withdrawn from the trials because of adverse experiences, most often diarrhoea and allergic skin reactions. The commonest laboratory abnormalities related to liver function. The safety of piperacillin/tazobactam appears similar to that of other beta-lactam/beta-lactamase inhibitor combinations.

Bacterial Infections↗
PubMed1993

In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines.

N,N-Dimethylglycylamido (DMG) derivatives of minocycline and 6-demethyl-6-deoxytetracycline are new semisynthetic tetracyclines referred to as the glycylcyclines. The in vitro activities of the glycylcyclines were evaluated in comparison with those of minocycline and tetracycline against strains carrying characterized tetracycline resistance determinants and against 995 recent clinical isolates obtained from geographically distinct medical centers in North America. The glycylcyclines were active against tetracycline-resistant strains carrying efflux [tet(A), tet(B), tet(C), and tet(D) in Escherichia coli and tet(K) in Staphylococcus aureus] and ribosomal protection [tet(M) in S. aureus, Enterococcus faecalis, and E. coli)] resistance determinants. Potent activity (MIC for 90% of strains, < or = 0.5 microgram/ml) was obtained with the glycylcyclines against methicillin-susceptible and methicillin-resistant S. aureus, E. faecalis, Enterococcus faecium, and various streptococcal species. The glycylcyclines exhibited good activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to minocycline and tetracycline. The activities of the glycylcyclines against most organisms tested were comparable to each other. The in vivo efficacies of the glycylcyclines against acute lethal infections in mice when dosed intravenously were reflective of their in vitro activities. The glycylcyclines had efficacies comparable to that of minocycline against infections with methicillin-susceptible and methicillin-resistant S. aureus strains, a strain carrying tet(K), and a tetracycline-susceptible E. coli strain but exceeded the effectiveness of minocycline against infections with resistant isolates, including strains harboring tet(M) or tet(B). Levels of DMG-6-deoxytetracycline in serum were higher and more sustained than those of DMG-minocycline or minocycline. Our results show that the glycylcyclines have potent in vitro activities against a wide spectrum of gram-positive and gram-negative, aerobic and anaerobic bacteria, including many resistant strains. On the basis of their in vitro and in vivo activities, the glycylcyclines represent a significant advance to the tetracycline class of antibiotics and have good potential value for clinical efficacy.

Animals↗
PubMed1991

Escherichia coli chromosomal mutations that permit direct cloning of the Bacteroides fragilis metallo-beta-lactamase gene, ccrA.

The class B, metallo-beta-lactamase genes ccrA (carbapenem- and cephamycin resistance) from three Bacteroides fragilis isolates--QMCN3, QMCN4, and TAL3636--were cloned and expressed in Escherichia coli. Cloning of the genes, by selecting for ampicillin resistance, was facilitated by two classes of Escherichia coli chromosomal mutations which resulted in at least a 5-10-fold increase in metallo-beta-lactamase enzymatic activity. The observed increase in enzymatic activity is due to either increased translation of the ccrA gene or an effect on localization or stability of the protein. Comparison of the DNA sequences of the three ccrA genes revealed that their protein-coding sequences shared greater than 97% DNA sequence identity. However, the 5' upstream sequence for the TAL3636 ccrA gene was unrelated to that of the other two genes.

Amino Acid Sequence↗
PubMed1991

Molecular basis of tetracycline action: identification of analogs whose primary target is not the bacterial ribosome.

Tetracycline analogs fell into two classes on the basis of their mode of action. Tetracycline, chlortetracycline, minocycline, doxycycline, and 6-demethyl-6-deoxytetracycline inhibited cell-free translation directed by either Escherichia coli or Bacillus subtilis extracts. A second class of analogs tested, including chelocardin, anhydrotetracycline, 6-thiatetracycline, anhydrochlortetracycline, and 4-epi-anhydrochlortetracycline, failed to inhibit protein synthesis in vitro or were very poor inhibitors. Tetracyclines of the second class, however, rapidly inhibited the in vivo incorporation of precursors into DNA and RNA as well as protein. The class 2 compounds therefore have a mode of action that is entirely distinct from the class 1 compounds, such as tetracycline that are used clinically. Although tetracyclines of the second class entered the cytoplasm, the ability of these analogs to inhibit macromolecular synthesis suggests that the cytoplasmic membrane is their primary site of action. The interaction of class 1 and class 2 tetracyclines with ribosomes was studied by examining their effects on the chemical reactivity of bases in 16S rRNA to dimethyl sulfate. Class 1 analogs affected the reactivity of bases to dimethyl sulfate. The response with class 2 tetracyclines varied, with some analogs affecting reactivity and others (chelocardin and 4-epi-anhydrotetracycline) not.

Bacteria↗
PubMed1990

Candidal meningitis following bacterial meningitis.

Patients with bacterial meningitis and posttraumatic and/or postsurgical access to the CSF are at risk for superinfection with Candida species. Patients who are not improving on appropriate antimicrobial chemotherapy for bacterial meningitis or are deteriorating after initial improvement should have a CSF reexamination for Candida superinfection.

Adult↗
PubMed1990

Imipenem resistance in Bacteroides distasonis mediated by a novel beta-lactamase.

Imipenem is a highly active drug against the Bacteroides fragilis group of organisms. On the basis of a nationwide survey of over 500 isolates, it was found that the frequency of imipenem resistance was less than 0.1%. We have a highly resistant Bacteroides distasonis isolate, TAL7860, for which the following MICs (micrograms per milliliter) were determined by agar dilution: cefoxitin, greater than 128; moxalactam, greater than 128; piperacillin, greater than 128; imipenem, 16; and SCH34343, 16. Resistance was shown to involve both a beta-lactamase and an outer membrane permeability barrier. beta-Lactamase kinetics studies with several beta-lactams, including imipenem, revealed similar hydrolytic efficiency in comparison with those found for the B. fragilis strains. An imipenem outer membrane permeability barrier was detected for TAL7860, which was approximately sixfold more effective for B. fragilis TAL3636 and TAL2480. Significant inhibition of nitrocefin destruction was also shown with sulbactam and clavulanic acid at 10 mumol and dithiothreitol at 10 mM. No inhibition was seen with 10 mM EDTA. Differences in physicochemical properties and inhibition studies suggest that this beta-lactamase is different from the imipenem-inactivating metallo-beta-lactamase previously described in B. fragilis. We demonstrated a significant permeability barrier to clavulanic acid and sulbactam, which resulted in loss of synergism between these clinically employed beta-lactamase inhibitors and beta-lactam drugs. The novel beta-lactamase activity in conjunction with a limited permeability in TAL7860 resulted in resistance to all commonly employed beta-lactams, including the newest and most potent beta-lactam drugs.

Bacterial Proteins↗
PubMed1990

Comparative activities of newer beta-lactam agents against members of the Bacteroides fragilis group.

A nationwide susceptibility survey of 557 isolates of the Bacteroides fragilis group was continued in 1986. The most active beta-lactam drugs were imipenem and ticarcillin-clavulanic acid, which had 0.2 and 1.7% resistance, respectively. The rank order of activity of beta-lactam drugs was imipenem, ticarcillin-clavulanic acid, cefoxitin, piperacillin, moxalactam, ceftizoxime, cefotetan, cefotaxime, cefoperazone, and ceftazadime.

Anti-Bacterial Agents↗