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At least 1,153 records · Page 64Linked to original sources
PubMed1991

Antimicrobial activity of isepamicin (SCH21420, 1-N-HAPA gentamicin B) combinations with cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, imipenem, mezlocillin and piperacillin tested against gentamicin-resistant and susceptible gram-negative bacilli and enterococci.

Isepamicin, formerly SCH21420 or 1-N-HAPA gentamicin B, is an aminoglycoside that was tested alone or in combination with one of seven broad spectrum drugs against 80 clinical isolates. Half of the strains were gentamicin-resistant but only one isolate (1.3%) was resistant to isepamicin. The broadest spectrum comparison drugs tested alone (ciprofloxacin at 3.8% resistance and imipenem at 5.0% resistance) were associated with the lowest synergy rates when combined with isepamicin. The rank order of synergy (complete or partial) was; cefotaxime = ceftazidime = ceftriaxone = mezlocillin = piperacillin (75% to 80%) greater than imipenem (66%) greater than ciprofloxacin (38%). Isepamicin/ampicillin combinations produced synergistic killing of those enterococci not having high-grade resistance to gentamicin or kanamycin. Enterococcus faecium strains were also refractory to isepamicin/ampicillin synergy. Isepamicin appears to be widely useable against gentamicin-resistant gram-negative bacilli either alone or combined with most commonly used broad spectrum beta-lactams.

Cefotaxime↗
PubMed1992

In vitro interactions of aminoglycosides with imipenem or ciprofloxacin against aminoglycoside resistant Acinetobacter baumannii.

The in vitro interactions between gentamicin, tobramycin, netilmicin and amikacin with imipenem and ciprofloxacin were evaluated by the killing curve technique against 20 clinical isolates of Acinetobacter baumannii highly resistant to aminoglycosides which were susceptible or moderately susceptible to imipenem and resistant or moderately susceptible to ciprofloxacin. Imipenem enhanced killing by gentamicin, tobramycin, netilmicin and amikacin in tests with 9, 12, 10 and 15 strains (45-75%) while ciprofloxacin with 3, 7, 5 and 6 strains (15-35%) respectively. Interaction results were influenced by the height of aminoglycoside minimum bactericidal concentrations (MBCs) but were independent of imipenem or ciprofloxacin MBCs and the presence of aminoglycoside modifying enzymes. It is concluded that enhanced killing after aminoglycoside interaction with imipenem or ciprofloxacin versus A. baumannii cannot be predicted but it should be carefully tested in vitro. The in vivo significance of the reported findings mandates clinical studies in humans.

Acinetobacter↗
PubMed1998

Efficient trial designs for studying combination antiretroviral treatments in patients with various resistance profiles.

Selecting antiretroviral therapies for human immunodeficiency virus type 1-infected persons is complicated by the availability of a vast number of potentially useful drug combinations and by extensive variation among patients in their resistance to various drugs. AIDS clinical trials have used designs in which a handful of drug regimens in a few patient classes can be compared. Here is proposed implementation of innovative designs with factorial structure that permit assessment of many treatment arms and patient classes in a single trial; when and how they can be appropriately used are discussed. These designs are efficient, permit systematic investigation of correlations between genetic mutations and in vivo drug resistance, and provide insight into important drug interactions in people that conventional designs are unable to provide. Through creative application of these designs, identification of superior drug combinations and the science of understanding in vivo joint drug dynamics and genotypic resistance will progress at an optimum pace.

Anti-HIV Agents↗
PubMed1999

The rabbit study: ritonavir and saquinavir in combination in saquinavir-experienced and previously untreated patients.

Thirteen protease inhibitor-naive patients with HIV-1 infection, and 12 patients with a median of 58 months prior treatment with saquinavir (SQV) monotherapy, were treated with SQV (400 mg twice daily) and ritonavir (RIT, 500 mg twice daily) in a study designed to assess the effect of prior treatment with SQV monotherapy on the antiretroviral activity of RIT-SQV combination therapy. Median baseline viral load and CD4+ cell counts were 155,000 and 262,000 copies/ml and 333 and 225 cells/mm3 in the naive and experienced groups, respectively. Mean viral load changes at 24 weeks were -1.63 and -0.27 log copies/ml in the naive and SQV-experienced groups, respectively (intent-to-treat analysis). Baseline genotype by point mutation assay and sequencing in the SQV-experienced group was highly predictive of virological response. Eight of 11 SQV-experienced patients had evidence of phenotypic resistance to RIT at baseline, despite previous treatment with SQV only. There was strong correlation between phenotypic resistance to RIT and the presence of the L90M mutation. We conclude that prolonged prior treatment with saquinavir monotherapy may produce cross-resistance to ritonavir and reduce the subsequent response to ritonavir-saquinavir in combination. In this study, both phenotypic resistance to ritonavir and presence of the L90M mutation predicted the viral load response to ritonavir-saquinavir.

Adult↗
PubMedDate not supplied

Efficacy, safety, and potential economic benefits of oral ciprofloxacin in the treatment of infections.

Ciprofloxacin is a new 4-quinolone carboxylic acid derivative with a broad spectrum of activity against gram-positive and gram-negative bacteria, chlamydiae, rickettsiae, and related organisms. The drug has been administered orally to 2,018 patients, primarily in the United States. In open trials oral ciprofloxacin has been shown to constitute effective therapy for osteomyelitis, gonorrhea, and infections of the urinary and gastrointestinal tracts, respiratory tree, and skin and soft tissues. In controlled comparative trials, most of which were doubly blinded, oral ciprofloxacin was equal in terms of safety and therapeutically equal or superior to oral trimethoprim-sulfamethoxazole in urinary and gastrointestinal infections, to oral ampicillin in respiratory infections, and to parenteral cefotaxime in skin and soft tissue disease. Adverse reactions were infrequent and generally mild. The emergence of resistance was encountered rarely; the organisms implicated were usually those for which initial minimal inhibitory concentrations were high, albeit in the sensitive range (such as Pseudomonas aeruginosa). Ciprofloxacin potentiates the toxicity of theophylline. Concurrent administration of antacids may diminish gastrointestinal absorption of the drug.

Bacterial Infections↗
PubMedDate not supplied

Potential role of fluoroquinolones in pediatric infections.

The fluoroquinolones are new, broad-spectrum, bactericidal antimicrobial agents structurally related to nalidixic acid. They are well absorbed after oral administration, with serum and tissue levels generally in excess of the minimal inhibitory concentrations for susceptible organisms. Their spectrum of activity includes serious pediatric pathogens such as Haemophilus influenzae, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The potential uses of fluoroquinolones in pediatric diseases include acute and chronic pulmonary infections in children with cystic fibrosis, methicillin-resistant staphylococcal infections, meningitis with resistant bacteria, and prophylaxis in leukemic and immunocompromised children. The toxicity of some quinolone derivatives that involve developing cartilage in sensitive animal species has to be studied further. Clinical trials of fluoroquinolones from Europe and the United States in children show no cartilage or joint toxicity. For the time being and until more clinical experience with fluoroquinolones in children is obtained, their use should be limited to specific cases of therapeutic failure or multiple resistance to other antibiotics.

4-Quinolones↗
PubMedDate not supplied

Interactions of rifampin and trimethoprim in vitro.

Combination of rifampin and trimethoprim (TMP) has been suggested as a means of preventing the emergence of bacterial resistance to the individual agents and of achieving synergistic antimicrobial activity. By means of standard techniques of antimicrobial susceptibility testing, combinations of rifampin and TMP were tested against clinical isolates of a variety of aerobic bacteria. Synergism was defined as a fourfold or greater decrease in the minimal inhibitory concentration (MIC) of the more active agent in the combination. Antagonism was defined as a fourfold or greater increase in the MIC of the more active agent. No change or, at most, a twofold change was considered to represent indifference. Combinations of rifampin and TMP in ratios of 7:1, 7:2, and 1:1 demonstrated synergistic activity against 12%, 13%, and 28% of 440 isolates, respectively. Antagonism was observed in 10%, 9%, and 8% of strains tested against the above ratios. Killing curves determined with selected organisms failed to demonstrate synergistic antibacterial activity. Combinations of rifampin and TMP failed to prevent the emergence of resistance to both drugs when selected strains of various bacteria were exposed to serial, subinhibitory concentrations. Thus, synergism of rifampin and TMP was observed in only a minority of strains tested, and combination of the two agents failed to prevent the emergence of drug resistance in vitro.

Bacteria↗
PubMedDate not supplied

Discovery and development of the monobactams.

A novel procedure designed to detect naturally occurring beta-lactam-containing molecules led to isolation of the monobactams - structurally unique, bacterially produced, monocyclic beta-lactam antibiotics. Although none of these monobactams exhibited impressive antimicrobial activity, side-chain variation - as with the penicillins and cephalosporins - resulted in potently active compounds. Aztreonam was chosen from hundreds of compounds for extended laboratory studies. In addition to a unique chemical structure, aztreonam has biologic properties that are unique in comparison with those of the classical penicillins and cephalosporins. Aztreonam is relatively inactive against gram-positive bacteria and anaerobes but is extremely effective against aerobic gram-negative bacteria, including Pseudomonas aeruginosa. The drug is highly resistant to enzymatic hydrolysis by beta-lactamases, particularly those known to be mediated by R plasmids, and is a poor inducer of chromosomal beta-lactamases. In the majority of drug combinations tested, aztreonam exhibits additive or synergistic activity. In a series of animal-model infections, the drug showed a high degree of efficacy that was consistent with findings in studies in vitro. In a hamster model for Clostridium difficile-induced pseudomembranous colitis, aztreonam did not induce any significant changes.

Animals↗
PubMed1975

Combined activity of amphotericin B and 5-fluorocytosine against Cryptococcus neoformans in vitro and in vivo in mice.

The in vitro and in vivo activities of amphotericin B and 5-fluorocytosine (5-FC) alone and in combination were studied to determine possible drug interactions against two strains of Cryptococcus neoformans, one sensitive to 5-FC and one resistant to 5-FC. In vitro tube dilution studies demonstrated only additive effects with the 5-FC-sensitive organism but antagonism with eth 5-FC-resistant organism. A mouse model of cryptococcal meningitis allowed comparative drug trails in a new model for the detection of drug interactions. Drug combinations were no more effective against meningitis caused by the 5-FC-sensitive organism than the additive effects of the individual drugs. However, meningitis caused by the 5-FC-resistant Cryptococcus responded less to drug combinations than to either drug alone. Serum levels of amphotericin B and 5-FC were comparable in all groups. No evidence of toxicity from the drug combinations was found. No inhibition of development of resistance to 5-FC by the combination with amphotericin B was detected.

Amphotericin B↗
PubMed1987

Effects of antifungal agents and gamma interferon on macrophage cytotoxicity for fungi and tumor cells.

The activated macrophage may play a central role in host effector mechanisms against invading fungi. Here we demonstrate the importance of the activation state of murine macrophages for both fungistatic and fungicidal activity. Host factors such as gamma interferon and microbial products such as endotoxin can interact synergistically to initiate this cytotoxicity. This activated state may be aided by antifungal agents such as amphotericin B. Both a methyl ester derivative of amphotericin B and liposomal amphotericin B Both a methyl ester derivative of amphotericin B and liposomal amphotericin B potentiated macrophage activation but were less potent than amphotericin B. Other available antifungal agents such as azole compounds and flucytosine did not possess this ability to interact with the intrinsic macrophage effector mechanisms. However, ketoconazole and itraconazole avidly bind to macrophages as the biologically active drug. The azole-loading of macrophages may be a factor in macrophage cytotoxicity for fungi.

Animals↗
PubMed1990

A novel chromosomal TEM derivative and alterations in outer membrane proteins together mediate selective ceftazidime resistance in Escherichia coli.

A clinical Escherichia coli isolate (MG32) resistant to ceftazidime but susceptible to other third-generation cephalosporins was previously examined and found to harbor TEM-1 and exhibit alterations in outer membrane proteins. Reexamination of this isolate revealed the additional presence of a novel TEM-1 derivative, now designated TEM-12. Evaluation of ceftazidime and cefotaxime minimum inhibitory concentrations for isogenic derivatives demonstrated a major role for TEM-12 in the decreased susceptibility observed. This was selectively enhanced for ceftazidime resistance by the altered porins of E. coli MG32. TEM-12 appeared identical to TEM-101, an in vitro TEM derivative, in both isoelectric point (pI 5.25) and substrate profile. Hybridization and cloning of the TEM-12 determinant revealed that, unlike other TEM derivatives, TEM-12 is chromosomally encoded, not plasmid-encoded.

Bacterial Outer Membrane Proteins↗
PubMed1992

Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro.

Protease inhibitor Ro 31-8959, a compound that interrupts human immunodeficiency virus (HIV)-specific formation of infectious virions, was evaluated in two-drug combined regimens with zidovudine, 2',3'-dideoxycytidine (ddC), or recombinant interferon-alpha A (rIFN-alpha A) against HIV-1 replication in vitro. By using peripheral blood mononuclear cells infected with HIV-1, drug interactions were evaluated by the median-effect principle and the isobologram technique. A zidovudine-sensitive and -resistant HIV-1 isolate pair was studied. Additive to synergistic anti-HIV-1 interactions were seen with 7.5-30 nM Ro 31-8959 and 0.005-0.02 microM zidovudine (for the zidovudine-sensitive HIV-1 isolate), 0.25-1.0 microM zidovudine (for the zidovudine-resistant HIV-1 isolate), 0.025-0.1 microM ddC, and 8-32 units/mL rIFN-alpha A, without additive toxicity. Phase I/II clinical trials of Ro 31-8959 for therapy of HIV-1 infection are in progress. If results are favorable, combined regimens including Ro 31-8959 deserve consideration for future clinical trials.

Cells, Cultured↗
PubMed1983

Determination of serum 5-fluorocytosine concentrations in the presence of ketoconazole.

Because in-vitro antifungal synergism has been shown between the imidazoles and 5-fluorocytosine, we have evaluated the accuracy of a standard disc diffusion assay for serum 5-fluorocytosine levels in the presence of ketoconazole. In the usual clinical concentrations, ketoconazole does not interfere with the determination of serum 5-fluorocytosine levels by this standard test.

Candida↗