bluuebunny/crossref_metadata_2025 huggingface dataset:
Binding affinities of structurally related human rhinovirus capsid-binding compounds are related to their activities against human rhinovirus type 14
Authors: Fox M P , McKinlay M A , Diana G D , Dutko F J
Published: June 2012

The binding affinities (Kds) and the rates of association and dissociation of members of a chemical class of antiviral compounds at their active sites in human rhinovirus type 14 (HRV-14) were determined. On the basis of analysis by LIGAND, a nonlinear curve-fitting program, of saturation binding experiments with HRV-14, the Kds for Win 52084, Win 56590, disoxaril (Win 51711), and Win 54954 were found to be 0.02, 0.02, 0.08, and 0.22 microM, respectively. The independently determined kinetic rates of association and dissociation resulted in calculated Kd values which were in agreement with the Kd values determined in saturation binding experiments. Scatchard plots of each of four compounds for the binding data indicated that approximately 40 to 60 molecules were bound per HRV-14 virion. Hill plots showed no evidence of cooperativity in binding. Furthermore, the antiviral activities (MICs in plaque reduction assays with HRV-14) for this limited series of compounds (n = 4) correlated well (r = 0.997) with the observed Kds. Likewise, the absence of detectable binding of Win 54954 to the drug-resistant mutant HRV-14 (Leu-1188) corresponded to a lack of antiviral activity. The positive relationship between the antiviral activities and the Kds that were determined may have implications for the molecular design of capsid-binding antirhinovirus drugs.
Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients
Authors: Takagi K , Yamaki K , Nadai M , Kuzuya T , Hasegawa T
Published: June 2012

Recently, it has become evident that some quinolones affect the processing of theophylline in the human system. The effect of a new quinolone, sparfloxacin, on the pharmacokinetics and metabolism of theophylline was investigated in six asthmatic patients receiving chronic theophylline therapy (a sustained-release theophylline tablet formulation of 200 to 300 mg twice daily at 12-h intervals). To these patients, sparfloxacin (200 mg once daily) was coadministered for 1 week. Plasma and urine samples were analyzed by high-performance liquid chromatography for theophylline and its metabolites. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of sparfloxacin were compared. The total body clearance of theophylline after coadministration of sparfloxacin, 42.81 +/- 6.64 ml/h/kg (mean +/- standard error of the mean), was not significantly different from that after the administration of theophylline alone, 47.11 +/- 7.61 ml/h/kg. Also, no significant change in the urinary excretion of theophylline and its metabolites was observed for subjects receiving or not receiving sparfloxacin. These findings indicate that a once-daily dose of 200 mg of sparfloxacin has no significant effect on the pharmacokinetics and metabolism of theophylline and that it would be safe to coadminister this quinolone to asthmatic patients receiving chronic theophylline therapy.
Beta-lactam antibiotics potentiate magainin 2 antimicrobial activity in vitro and in vivo
Authors: Darveau R P , Cunningham M D , Seachord C L , Cassiano-Clough L , Cosand W L , Blake J , Watkins C S
Published: June 2012

The ability of magainin 2 to augment antibiotic therapy was examined. Susceptibility to magainin 2 was determined on Escherichia coli incubated in the presence and absence of sublethal concentrations of antibiotics both in vitro and in vivo. Experiments in buffer and normal human serum revealed that E. coli exposed to sublethal amounts of cefepime, a beta-lactam antibiotic, was significantly more susceptible to the antimicrobial activity of magainin 2. Bacteria incubated with subinhibitory concentrations of other beta-lactam type antibiotics, but not amikacin (an aminoglycoside) or ciprofloxacin (a quinolone), were also more susceptible to magainin 2 in normal human serum. Bacteria were less susceptible to magainin 2 when they were examined in heat-inactivated serum. Complement was shown to be required for magainin 2 activity in serum by using C8-deficient sera. The combination of magainin 2 and cefepime was shown to be more antimicrobial in normal human serum for a variety of bacterial strains. Magainin 2 was completely inactive as a therapeutic agent when it was administered alone (2 mg per mouse) but significantly increased the survival of mice when it was administered with a low level of cefepime.
Metabolic disposition and pharmacokinetics of the antiviral agent 6-methoxypurine arabinoside in rats and monkeys
Authors: Burnette T C , Koszalka G W , Krenitsky T A , De Miranda P
Published: June 2012

The metabolism and pharmacokinetics of 6-methoxypurine arabinoside (ara-M), a potent and selective inhibitor of varicella-zoster virus, were investigated in rats and monkeys. In Long Evans rats, orally administered [8-14C]ara-M (10 mg/kg) was well absorbed but extensively metabolized to hypoxanthine arabinoside (ara-H), hypoxanthine, xanthine, uric acid, and allantoin. Only 4% of an oral dose was recovered in the urine as unchanged drug, compared with 40% of an intravenous dose, indicating significant presystemic metabolism. Pretreatment of rats with 1-aminobenzotriazole, an inhibitor of cytochrome P-450, did not alter this metabolism. Pretreatment with deoxycoformycin or erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride, inhibitors of adenosine deaminase, resulted in a marked decrease in ara-M metabolism, indicating that adenosine deaminase plays a major role in the biotransformation of ara-M. In cynomolgus monkeys, [8-14C]ara-M (10 mg/kg) administered intravenously or orally was extensively metabolized to ara-H. Several minor urinary metabolites were detected in both rats and monkeys. However, adenine arabinoside was not found in urine or plasma from either rats or monkeys after administration of ara-M, except for a very low level detected in the urine of rats pretreated with deoxycoformycin. The elimination half-lives of intravenously administered ara-M in rats and monkeys were 29 and 45 min, respectively. The corresponding half-lives of the primary metabolite, ara-H, were 44 min and 2.3 h. Plasma profiles of orally administered ara-M in both rats and monkeys demonstrated the poor oral bioavailability of this arabinoside. The results of these studies indicate that ara-M is not well suited for oral administration because of extensive presystemic metabolism.
In vitro susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum to sparfloxacin and PD 127391
Authors: Waites K B , Duffy L B , Schmid T , Crabb D , Pate M S , Cassell G H
Published: June 2012

The in vitro activities of two investigational quinolones, sparfloxacin (previously designated AT 4140) and PD 127391, were determined for 30 strains each of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum and compared with those of ciprofloxacin, tetracycline, clindamycin, and erythromycin. Erythromycin was the most active compound against M. pneumoniae (maximum MIC, less than 0.008 microgram/ml). PD 127391 (MICs, less than 0.008 to 0.031 microgram/ml), sparfloxacin (MICs, less than 0.008 to 0.25 microgram/ml), clindamycin (MICs, less than 0.008 to 0.5 microgram/ml), and tetracycline (MICs, 0.063 to 0.25 microgram/ml) were superior to ciprofloxacin (MICs, 0.5 to 2 microgram/ml). Sparfloxacin and PD 127391 were active against M. hominis (MICs, less than 0.008 to 0.031 microgram/ml for each) at concentrations comparable to those of clindamycin (MICs, less than 0.008 to 0.063 microgram/ml) and at concentrations lower than those of ciprofloxacin (MICs, 0.125 to 0.5 microgram/ml). As expected, M. hominis was resistant to erythromycin (MICs, 32 to greater than or equal to 256 micrograms/ml). For U. urealyticum, PD 127391 (MICs, 0.031 to 0.5 microgram/ml) and sparfloxacin (MICs, 0.063 to 1 microgram/ml) were superior to erythromycin (MICs, 0.25 to 4 micrograms/ml), ciprofloxacin (MICs, 0.5 to 8 micrograms/ml), and clindamycin (MICs, 0.25 to 64 micrograms/ml. Both new quinolones were equally active against tetracycline-susceptible as well as resistant strains of M. hominis and U. urealyticum. The possible influence of medium components and/or pH on MICs was evaluated by testing a Staphylococcus aureus reference strain with each antibiotic in SP-4 broth and 10-B broth and comparing the results with published MICs for this strain. MICs determined in 10-B broth for erythromycin were affected most. This study shows that the activities of sparfloxacin and PD 127391 are similar to one another and comparable or superior to those of other drugs used to treat mycoplasmal infections. The MICs of both new quinolones were consistently 2 to several dilutions lower than those of ciprofloxacin for each species.
Kinetics and dynamics of tobramycin action in patients with bacteriuria given single doses
Authors: Peloquin C A , Cumbo T J , Schentag J J
Published: June 2012

We studied the effect of a single intravenous dose of tobramycin on the rate of bacterial eradication from urine in 10 patients with bladder catheters. The catheter was replaced 4 to 6 h after the tobramycin dose. Pseudomonas aeruginosa was found in 7 of the 10 patients, while members of the family Enterobacteriaceae accounted for the remaining pathogens. The MIC for each bacterium was determined in both broth and urine. Tobramycin eradicated the bacteria from eight patients. Bacteriuria resolved in 21.8 +/- 18.0 h, and urine bactericidal activity persisted for 43.4 +/- 20.3 h after the dose of tobramycin. Most patients were recolonized by another bacterial species if use of Foley catheters was resumed on a continuous basis. Two patients required additional doses of tobramycin to eradicate the original pathogen. There were significant temporal relationships between the pharmacokinetics of tobramycin and the change in colony count of bacteria in urine.
In vitro activities of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae
Authors: Franzblau S G
Published: June 2012

The in vitro activities of a variety of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae were evaluated with the BACTEC 460 system. At 20 micrograms/ml, gentamicin, kanamycin, tobramycin, streptomycin, and amikacin were inactive. Lincomycin was active at 20 micrograms/ml, and clindamycin was active at 0.31 micrograms/ml. Rifamycin SV, rifabutin, and rifampin were active at 3.1, 3.1 to 12.5, and 200 ng/ml, respectively. The in vitro assay correlates well with the in vivo response of M. leprae to antimicrobial agents, with the exception of the aminoglycosides.
In vitro susceptibility testing procedures for fosfomycin tromethamine
Authors: Barry A L , Fuchs P C
Published: June 2012

Fosfomycin tromethamine (previously fosfomycin trometamol) is an orally administered fosfomycin which may be used for single-dose therapy of uncomplicated urinary tract infections. Fosfomycin tromethamine, norfloxacin, and trimethoprim-sulfamethoxazole inhibited greater than 90% of 352 bacterial isolates representing 25 different species; trimethoprim and nalidixic acid had narrower spectrums of activity. Strains of Escherichia, Citrobacter, Enterobacter, and Klebsiella species were much more susceptible when glucose-6-phosphate was added to the test medium, but isolates belonging to other genera were not affected.
Differential inhibition of 2'-deoxycytidine salvage as a possible mechanism for potentiation of the anti-human immunodeficiency virus activity of 2',3'-dideoxycytidine by dipyridamole
Authors: Patel S S , Szebeni J , Wahl L M , Weinstein J N
Published: June 2012

Dipyridamole, a commonly used coronary vasodilator and antithrombotic drug, was recently shown to potentiate the activity of 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine against the human immunodeficiency virus type 1 (HIV-1) in human monocyte-macrophages in vitro. We report in the present paper that in uninfected monocyte-macrophages dipyridamole significantly inhibits cellular salvage of [3H]deoxycytidine, whereas it does not affect the salvage of [3H]dideoxycytidine. Similar differential inhibition by dipyridamole of the salvage of thymidine, as opposed to 3'-azido-3'-deoxythymidine, was reported previously (G. V. Betageri, J. Szebeni, K. Hung, S. S. Patel, L. M. Wahl, M. Corcoran, and J. N. Weinstein, Biochem. Pharmacol. 40:867-870, 1990). Taken together, these observations suggest that inhibition of the salvage of competing physiological nucleosides may explain or contribute to the potentiating effect of dipyridamole on these antiviral dideoxynucleoside drugs.
Synergy between cilofungin and amphotericin B in a murine model of candidiasis
Authors: Hanson L H , Perlman A M , Clemons K V , Stevens D A
Published: June 2012

The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. Therapy groups included those given cilofungin at 6.25 or 62.5 mg/kg/day (given twice daily), amphotericin B at 0.625 mg/kg/day (given once daily), cilofungin at 6.25 mg/kg/day plus amphotericin B, and cilofungin at 62.5 mg/kg/day plus amphotericin B. Mice were observed through 30 days postinfection. All infected untreated mice died of infection between days 6 and 18. Eighty-five percent of mice receiving cilofungin at 6.25 mg/kg/day died between days 13 and 30. All other mice survived. Quantitative determination of the number of CFU of C. albicans in the spleens and kidneys of all survivors revealed that mice that had received both drugs had lower residual burdens of C. albicans. All mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B had sterile spleens, whereas 42 to 58% of mice given cilofungin or amphotericin B monotherapy had sterile spleens. All kidneys were infected in mice which had received cilofungin at 62.5 mg/kg/day or amphotericin B. Neither organ was infected in 17% of each group receiving combination therapy with cilofungin and amphotericin B. The number of CFU in the kidneys of mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B was lower than those cultured from mice treated with cilofungin at 62.5 mg/kg/day (P less than 0.001, Mann-Whitney) or amhotericin B (P less than 0.05). Modest synergy was noted in inhibition of the C. albicans isolate in vitro. Pharmacokinetic studies showed elevated levels of cilofungin but not amphotericin B in sera of mice treated with combined therapy compared with those in mice given monotherapy. No overt toxicity was evident with any regimen. The mechanism of increased efficacy may be altered cilofungin distribution, excretion, or metabolism; antifungal synergy; or both. These results indicate that concurrent cilofungin-amphotericin B therapy has synergistic or additive efficacy in vivo.
Radiolabeling of Mycobacterium leprae lipids within schwannoma cells, a potential drug screening system
Authors: Mistry Y , Antia N H , Mukherjee R
Published: June 2012

This study describes a novel method which could be developed into a test system of evaluating the efficacy of antileprosy drugs. The method estimates incorporation of [14C]acetate into lipids of Mycobacterium leprae maintained within the 33B Schwannoma cell line. Schwannoma cell-resident M. leprae cells incorporated significant levels of radiolabel within their lipids during 12 days of incubation in vitro. This incorporation was markedly reduced by 5 micrograms of rifampin per ml (decrease, 81.62%); this decrease was observed within 24 h of addition of the drug. Dapsone also reduced the radiolabel incorporation into the lipids, but to a lesser extent (decrease, 27.58%). This system was also able to differentiate between rifampin-sensitive and -resistant strains of mycobacteria. It is suggested that since the effect of bacteriostatic (dapsone) and bactericidal (rifampin) drugs could be detected by using this technique, it may prove useful in screening novel drugs acting against M. leprae.
Translocation of antibiotic resistance determinants including an extended-spectrum beta-lactamase between conjugative plasmids of Klebsiella pneumoniae and Escherichia coli
Authors: Sirot D , De Champs C , Chanal C , Labia R , Darfeuille-Michaud A , Perroux R , Sirot J
Published: June 2012

The extended-spectrum beta-lactamase CAZ-7, derived from TEMs, was produced by two different strains of the family Enterobacteriaceae, Klebsiella pneumoniae and Escherichia coli, isolated from the same patient. Both isolates were resistant to amikacin. In addition, the K. pneumoniae strain was TEM-1 producing and resistant to gentamicin. An E. coli HB101 transconjugant obtained from K. pneumoniae, selected on ceftazidime, showed that CAZ-7 and amikacin resistance were encoded by an 85-kb Inc7 or M plasmid, while an E. coli HB101 transconjugant obtained from E. coli under the same conditions showed that CAZ-7 and amikacin resistance were encoded by a greater than 150-kb Inc6 or C plasmid. Two other E. coli HB101 transconjugants obtained from K. pneumoniae, selected on gentamicin or chloramphenicol, showed that TEM-1 and gentamicin resistance could be encoded either by a greater than 150-kb Inc6 or C plasmid or by an 85-kb Inc7 or M plasmid. It was hypothesized that the genes for beta-lactam and aminoglycoside resistances were located on translocatable sequences. EcoRI digestion and hybridizations obtained with blatem, aacA4, and IS15 probes demonstrated that the CAZ-7 gene, amikacin resistance gene, and IS15 element were clustered on an approximately 20-kb fragment common to 85- and greater than 150-kb plasmids. E. coli HB101 transconjugants from K. pneumoniae and E. coli isolates were used to obtain translocations of CAZ-7 and amikacin resistance and of TEM-1 and gentamicin resistance between the 85- and greater than 150-kb plasmids. This study shows a typical example of in vivo gene dissemination involving transposable elements which translocate multiresistance genes, including an extended-spectrum beta-lactamase.
Role of intestinal excretion in the effect of subcutaneously administered sedecamycin on cecal infection caused by Treponema hyodysenteriae in mice
Authors: Hayashi T , Okada J , Kondo S , Yamazaki T
Published: June 2012

The therapeutic effects of subcutaneously administered sedecamycin on experimental Treponema hyodysenteriae infection in mice were evaluated. Sedecamycin was more active than tiamulin and lincomycin. The efficacy of sedecamycin upon subcutaneous administration was similar to that upon oral administration. Sedecamycin given subcutaneously provided similar degrees of protection in bile duct-ligated and intact mice. Pharmacokinetic studies utilizing a liquid chromatographic technique were carried out to determine the concentration of sedecamycin in the cecum, the site of T. hyodysenteriae infection in mice. Little sedecamycin was found; however, lankacidinol, a major metabolite of sedecamycin, was found in the cecal contents of intact mice after subcutaneous or oral administration of sedecamycin. Lankacidinol was also found in the cecal contents of bile duct-ligated mice, although the concentration found after subcutaneous administration of sedecamycin was much lower than that found after subcutaneous or oral administration to intact mice. These results indicate that sedecamycin is excreted directly into the intestinal tract as an active metabolite by a route other than the bile duct. It is suggested that this intestinal excretion plays an important role in the efficacy of subcutaneously administered sedecamycin against cecal infection of mice by T. hyodysenteriae.
Eradication of colonization by methicillin-resistant Staphylococcus aureus by using oral minocycline-rifampin and topical mupirocin
Authors: Darouiche R , Wright C , Hamill R , Koza M , Lewis D , Markowski J
Published: June 2012

In an attempt to control the spread of methicillin-resistant Staphylococcus aureus (MRSA) within a spinal cord injury unit, we investigated the mode of transmission and implemented a multidisciplinary approach for control that consisted of grouping of patients into cohorts, contact isolation, and antibiotics. Surveillance cultures of patients and nose and hand cultures of medical personnel were performed. Of 11 colonized patients, 6 had MRSA isolates that shared a similar plasmid profile and antibiogram, raising the possibility of interpatient spread of the organism. Medical personnel had no evident role in transmitting MRSA. All patients' pretherapy MRSA isolates were susceptible to minocycline and, except for one, to rifampin. Time-kill studies showed an indifferent interaction of these two antibiotics. Ten colonized patients received a 2-week oral course of 100 mg of minocycline twice daily and 600 mg of rifampin once daily, while the 11th patient was treated for only 1 week. Patients with colonization of the nares also had twice daily nasal application of 2% mupirocin for 5 days. Colonization with MRSA cleared in 10 of 11 patients (91%) and 20 of 21 sites (95%). When the individual circumstances of a medical facility justify eradication of MRSA colonization, a multidisciplinary approach that includes antibiotic therapy with oral minocycline and rifampin, along with topical mupirocin for those with nasal carriage, may be successful.
Quinolone resistance-determining region in the DNA gyrase gyrB gene of Escherichia coli
Authors: Yoshida H , Bogaki M , Nakamura M , Yamanaka L M , Nakamura S
Published: June 2012

Thirteen spontaneous quinolone-resistant gyrB mutants of Escherichia coli KL16, including two that were examined previously, were divided into two types according to their quinolone resistance patterns. Type 1 mutants were resistant to all the quinolones tested, while type 2 mutants were resistant to acidic quinolones and were hypersusceptible to amphoteric quinolones. Nucleotide sequence analysis disclosed that all nine type 1 mutants had a point mutation from aspartic acid to asparagine at amino acid 426 and that all four type 2 mutants had a point mutation from lysine to glutamic acid at amino acid 447.
Physical mapping of the mec region of an American methicillin-resistant Staphylococcus aureus strain
Authors: Dubin D T , Matthews P R , Chikramane S G , Stewart P R
Published: June 2012

We mapped part of the mec region of a locally prevalent strain of Staphylococcus aureus. The mec region was found to harbor an insert of the transposon Tn554, which encodes spectinomycin and macrolide-lincosamide-streptogramin B resistance, and a 4.6-kb segment of DNA that contains the kanamycin resistance gene aadD. This 4.6-kb segment appears to be an integrated form of a previously described plasmid, pUB110, and is flanked by copies of the insertion sequence IS257. The integration event may be an example of processes that have led to accretion of resistance determinants in the mec region of S. aureus.
Synergistic activity of azithromycin and gamma interferon in murine toxoplasmosis
Authors: Araujo F G , Remington J S
Published: June 2012

A dose of 75 mg of azithromycin per kg of body weight per day combined with a dose of 2 micrograms of gamma interferon per day and administered for 10 days protected at least 40% of mice infected with a lethal inoculum of Toxoplasma gondii. Azithromycin administered alone protected less than 10% of the mice; gamma interferon had no protective effect.
Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine
Authors: Hayden F G , Sperber S J , Belshe R B , Clover R D , Hay A J , Pyke S
Published: June 2012

The therapeutic activity of rimantadine and its relationship to the shedding of drug-resistant influenza A virus were assessed in two randomized, double-blind, placebo-controlled trials involving patients with laboratory-documented influenza A virus (H3N2 subtype) illness of 2 days' duration or less. In a family-based study, rimantadine treatment for 10 days (24 children and adults) was associated with significant decreases in the number of days to a 50% reduction in symptoms (mean difference, 2.5 days), days of fever (1.6 days), and days of restricted activity (1.5 days) compared with the results obtained with placebo-treated patients (32 children and adults). Drug-resistant virus was recovered from eight (33%) of the rimantadine recipients on day 5. No differences in patient demographics or illness severity at the time of enrollment in the study were apparent between those who shed resistant virus and those who did not. Illness resolution tended to be slower in those who shed resistant virus compared with that in those who did not. In a study of adults treated for 5 days (six treated with rimantadine, six treated with placebo), resistant virus was recovered in three rimantadine recipients by day 3 of treatment. The results indicate that drug-resistant influenza A virus (H3N2) can be recovered from rimantadine-treated children and adults as early as 2 days after starting treatment, but that rimantadine retains a net therapeutic benefit compared with that of placebo.
Comparative inactivation of isepamicin, amikacin, and gentamicin by nine beta-lactams and two beta-lactamase inhibitors, cilastatin and heparin
Authors: Walterspiel J N , Feldman S , Van R , Ravis W R
Published: June 2012

This study was undertaken to compare the susceptibility to inactivation of isepamicin with amikacin and gentamicin when exposed to different beta-lactams, beta-lactamase inhibitors, and heparin. The aminoglycosides (5, 10, 20, and 50 micrograms/ml) were incubated in human serum with ampicillin, azlocillin, aztreonam, carbenicillin, ceftazidime, piperacillin, and ticarcillin (100 and 600 micrograms/ml) and with clavulanate, cilastatin, 1:1 imipenemcilastatin, oxacillin, and sulbactam (20 and 120 micrograms/ml) for 48 h at 37 degrees C. Aminoglycoside concentrations were measured by fluorescence polarization immunoassay (FPI) after 0, 8, and 48 h of incubation and by radial diffusion bioassay after 48 h of incubation. Each of the three aminoglycosides was also added to whole blood containing either heparin (100 U/ml) or 0.5% EDTA as a control and assayed after 6 h by FPI. The degree of inactivation of isepamicin by the beta-lactams was significantly less than that by amikacin (P less than 0.003) and gentamicin (P less than 0.0002) when determined by bioassay. Piperacillin, carbenicillin, and azlocillin produced the greatest amount of inactivation, and cilastatin and oxacillin produced the least. A similar pattern was observed when the degree of inactivation was measured by FPI. A significant difference in the degree of inactivation was noted between isepamicin and gentamicin (P less than 0.003 at 8 h and P less than 0.006 at 48 h) but not between isepamicin and amikacin (P greater than 0.7 at 8 h and P greater than 0.08 at 48 h). Aminoglycoside determinations by FPI were not influenced by the presence of heparin. In summary, isepamicin was found to be at least as stable as amikacin against inactivation by beta-lactam compounds and beta-lactamase inhibitors. Heparin (100 U/ml) did not influence aminoglycoside determinations by FPI.
Species identification and antibiotic susceptibility testing of enterococci isolated from hospitalized patients
Authors: Gray J W , Stewart D , Pedler S J
Published: June 2012

A total of 236 enterococci from hospitalized patients were identified to the species level, and their susceptibilities to 11 antibiotics were determined. Overall, 195 (82.6%) and 38 (16.1%) isolates were identified as Enterococcus faecalis and E. faecium, respectively, but the species distribution as determined from blood culture isolates differed markedly. A total of 27 (63.2%) E. faecium isolates, but no E. faecalis strains, were ampicillin resistant (MIC, greater than 8 micrograms/ml). High-level gentamicin resistance (MIC, greater than 500 micrograms/ml) was found in 8.2% of E. faecalis isolates but was not seen in other species.
In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity
Authors: Andries K , Dewindt B , Snoeks J , Willebrords R , van Eemeren K , Stokbroekx R , Janssen P A
Published: June 2012

Pirodavir (R 77975) is the prototype of a novel class of broad-spectrum antipicornavirus compounds. Although its predecessor, R 61837, a substituted phenyl-pyridazinamine, was effective in inhibiting 80% of 100 serotypes tested (EC80) at concentrations above 32 micrograms/ml, pirodavir inhibits the same percentage of viruses at 0.064 micrograms/ml. Whereas R 61837 was active almost exclusively against rhinovirus serotypes of antiviral group B, pirodavir is broad spectrum in that it is highly active against both group A and group B rhinovirus serotypes. Pirodavir is also effective in inhibiting 16 enteroviruses, with an EC80 of 1.3 micrograms/ml. Susceptible rhinovirus serotypes were rendered noninfectious by direct contact with the antiviral compound. Their infectivity was not restored by dilution of virus-drug complexes, but was regained by organic solvent extraction of the compound for most serotypes. Neutralized viruses became stabilized to acid and heat, strongly suggesting a direct interaction of the compounds with viral capsid proteins. Mutants resistant to R 61837 (up to 85 times the MIC) were shown to bear some cross-resistance (up to 23 times the MIC) to the new compound, indicating that pirodavir also binds into the hydrophobic pocket beneath the canyon floor of rhinoviruses. Pirodavir acts at an early stage of the viral replication cycle (up to 40 min after infection) and reduces the yield of selected rhinoviruses 1,000- to 100,000-fold in a single round of replication. The mode of action appears to be serotype specific, since pirodavir was able to inhibit the adsorption of human rhinovirus 9 but not that of human rhinovirus 1A. Pirodavir is a novel capsid-binding antipicornavirus agent with potent in vitro activity against both group A and group B rhinovirus serotypes.
Antimicrobial susceptibility changes in Enterococcus faecalis following various penicillin exposure regimens
Authors: Hodges T L , Zighelboim-Daum S , Eliopoulos G M , Wennersten C , Moellering R C
Published: June 2012

Penicillin-"virgin" strains of Enterococcus faecalis collected from a population of individuals with no previous antibiotic exposure were subjected in vitro to penicillin delivered as repeated pulses, stepwise increasing concentrations, or sustained levels of a single concentration. Changes in resistance to penicillin were assessed by determination of MICs, and time-kill studies were performed to evaluate changes in tolerance to the bactericidal effects of penicillin. Isogenic clones, derived from various exposure regimens, which exhibited changes in either resistance or tolerance were further examined for changes in penicillin-binding proteins. Exposure to repeated pulses of penicillin resulted in the development of tolerance to penicillin without changes in the level of resistance. Clones derived from a regimen of stepwise increases in the penicillin concentration acquired both increased penicillin resistance and tolerance. Clones selected after prolonged continuous exposure to a fixed concentration of penicillin displayed minimally increased resistance to penicillin, but they retained the lytic, nontolerant response to the bactericidal effect of penicillin. Clones which acquired tolerance to the bactericidal effect of penicillin without changes in penicillin resistance exhibited a penicillin-binding protein pattern identical to that of the parental strain. Increased labeling of several penicillin-binding proteins accompanied the development of increased penicillin resistance in both penicillin-tolerant and nontolerant strains. Exposure of E. faecalis to penicillin in repeated pulses of brief duration, for prolonged periods at a constant concentration, or in stepwise graded concentrations can result in the selection of clones with increased resistance to the inhibitory or bactericidal effects of penicillin, or both. These observations may be relevant to the selection of dosing regimes for penicillin in the treatment of enterococcal infections, when bactericidal synergism cannot be achieved with penicillin-aminoglycoside combinations.
Disposition of cefpodoxime proxetil in healthy volunteers and patients with impaired renal function
Authors: St Peter J V , Borin M T , Hughes G S , Kelloway J S , Shapiro B E , Halstenson C E
Published: June 2012

The disposition of cefpodoxime in 24 subjects with various degrees of renal function after administration of a single oral dose of 200 mg of cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime activity) was studied. Subjects were assigned to one of four groups (six per group): group I, normal renal function (creatinine clearance [CLCR], greater than ml/min); group II, mild renal impairment (CLCR, 50 to 80 ml/min); group III, moderate renal impairment (CLCR, 30 to 49 ml/min); or group IV, severe renal impairment (CLCR, 5 to 29 ml/min). Although cefpodoxime terminal elimination half-life in group I (2.55 +/- 0.25 h [mean +/- standard deviation]) was not significantly different from that in group II (3.53 +/- 0.74 h), the half-life values for group III (5.90 +/- 1.67 h) and group IV (9.80 +/- 1.21 h) were significantly prolonged compared with those of group I. The mean absorption rate constant was similar among groups and ranged from 0.68 to 0.85 h-1. All groups exhibited absorption lag-times which were comparable (0.30 to 0.41 h), and the apparent volume of distribution was similar among groups. Cefpodoxime apparent total body clearance (CLP/F) values in groups II, III, and IV (132 +/- 29, 112 +/- 41, and 55.7 +/- 9.9 ml/min, respectively) were significantly lower than that in group I (238 +/- 44 ml/min). Cefpodoxime CLP/F was positively correlated with CLCR (r2 = 0.79; P less than 0.05): CLP/F = (1.9 CLCR) + 18.4. Renal clearance also declined with decreasing renal function. Adjustments in cefpodoxime organism and on the site and severity of infection. Simulated plasma concentration-time data from this study suggest that 200 mg of cefpodoxime proxetil administered every 12 to 24 h to subjects with CLcr between 30 and 49 ml/min and 200-mg dose taken every 24 h by subjects with CLcr between 5 and 29 ml/min will maintain cefpodoxime concentration in plasma similar to those in subjects with normal renal function who receive a standard dosage mg every 12 h.
Efficacy of ciprofloxacin for treatment of Brucella melitensis infections
Authors: al-Sibai M B , Halim M A , el-Shaker M M , Khan B A , Qadri S M
Published: June 2012

The effectiveness of treatment of human brucellosis caused by Brucella melitensis with ciprofloxacin alone was investigated in a prospective nonrandomized study. Subjects with central nervous system involvement, endocarditis, or severe renal dysfunction; children under 16 years of age; and pregnant women were excluded from the study. Of 19 patients, 16 completed the study; 7 were diagnosed as having acute systemic brucellosis, and 9 had acute brucella arthritis-diskitis. A rapid response to ciprofloxacin was seen in all 16 patients, but the blood cultures of 1 patient remained positive and the treatment was changed. During a 104-week follow-up period, 4 of the 15 responding patients relapsed or were reinfected within 8 to 32 weeks after completion of therapy. We conclude that treatment with ciprofloxacin alone, although effective for the acute symptoms, is associated with an appreciable rate of relapse; therefore, it should be given with other agents for treatment of brucellosis.
Activities of four macrolides, including clarithromycin, against Mycobacterium fortuitum, Mycobacterium chelonae, and M. chelonae-like organisms
Authors: Brown B A , Wallace R J , Onyi G O , De Rosas V , Wallace R J
Published: June 2012

Susceptibilities to erythromycin by broth microdilution were compared with those to the newer macrolide clarithromycin for 223 isolates of rapidly growing mycobacteria belonging to seven taxonomic groups. Seventy-nine random isolates were also tested against azithromycin and roxithromycin. The MIC of clarithromycin for 90% of strains tested (MIC90) was 0.25 microgram/ml for isolates of Mycobacterium chelonae subsp. chelonae and 0.5 microgram/ml for M. chelonae subsp. abscessus, with 100% of strains inhibited by less than or equal to 1 microgram/ml. Clarithromycin was 10 to 50 times more active than erythromycin and four- to eightfold more active than the other newer macrolides against M. chelonae. MICs of clarithromycin frequently increased with prolonged incubation with isolates of M. chelonae subsp. abscessus but not M. chelonae subsp. chelonae. MICs of clarithromycin were much higher for M. fortuitum bv. fortuitum (MIC50, 2.0 microgram/ml; MIC90, greater than 8.0 microgram/ml). The three newer macrolides had comparable activity against M. fortuitum bv. peregrinum (MIC90s of 0.5 to 2.0 microgram/ml compared with erythromycin MIC90s of greater than 8.0 microgram/ml). Overall, clarithromycin was the most active agent, inhibiting all isolates of M. chelonae subsp. chelonae, M. chelonae subsp. abscessus, M. fortuitum bv. peregrinum, and the M. chelonae-like organisms and 35% of M. fortuitum bv. fortuitum at less than or equal to 1 microgram/ml. Clinical trials of the newer macrolides, especially clarithromycin, against these environmental mycobacterial species appear to be warranted.
Efficacy of cilofungin therapy administered by continuous intravenous infusion for experimental disseminated candidiasis in rabbits
Authors: Rouse M S , Tallan B M , Steckelberg J M , Henry N K , Wilson W R
Published: June 2012

Cilofungin has potent in vitro activity against Candida albicans, but previous in vivo models using twice daily intermittent dosing regimens have not consistently demonstrated in vivo efficacy. Because of the pharmacokinetics of cilofungin in rabbits, it has been suggested that administration by continuous intravenous infusion might be more effective. We compared the in vivo efficacy of continuous intravenous infusion of cilofungin with that of amphotericin B in a rabbit model of disseminated candidiasis. Cilofungin prepared as previously described in phosphate-buffered 33% polyethylene glycol was lethal to infected rabbits in this model, as was phosphate-buffered 33% polyethylene glycol alone. In contrast, cilofungin in 26% polyethylene glycol and sterile water administered by continuous intravenous infusion was tolerated by rabbits, was significantly more effective than amphotericin therapy in reducing candida colony counts in kidney tissue, and was as effective as amphotericin therapy in lung and spleen tissue and in cardiac valvular vegetations. The dosage regimen and diluent used in some previous studies may have adversely affected outcome of treatment with cilofungin.
Induction of calf thymus topoisomerase II-mediated DNA breakage by the antibacterial isothiazoloquinolones A-65281 and A-65282
Authors: Kohlbrenner W E , Wideburg N , Weigl D , Saldivar A , Chu D T
Published: June 2012

A number of quinolones and related antibacterial compounds were screened for activity against calf thymus topoisomerase II by using the P4 unknotting and DNA breakage assays. Several compounds from different structural classes which inhibited DNA unknotting with 50% inhibitory concentrations ranging from 8 to 25 micrograms/ml were identified. Two experimental isothiazoloquinolones from this group, designated A-65281 and A-65282, were also found to induce considerable DNA breakage mediated by calf thymus topoisomerase II, with 32P-end-labeled pBR322 as the substrate. These compounds were nearly as potent as teniposide, with DNA breakage activity evident at concentrations as low as 4 micrograms/ml. However, some differences in DNA cleavage patterns from those with teniposide were evident. These studies have thus identified a new class of agents which have activity against both bacterial and eukaryotic type II topoisomerases. The implications of these data for the selectivity of topoisomerase-directed compounds and the potential toxicity of such compounds developed as antibacterial agents are discussed.
Pharmacokinetic-interaction study of didanosine and ranitidine in patients seropositive for human immunodeficiency virus
Authors: Knupp C A , Graziano F M , Dixon R M , Barbhaiya R H
Published: June 2012

The potential pharmacokinetic interactions between didanosine, an acid-labile antiretroviral agent, and ranitidine, an H2-receptor antagonist, were evaluated by a crossover study of 12 male patients seropositive for the human immunodeficiency virus. Single oral doses of 375 mg of didanosine, formulated as a citrate-phosphate-buffered sachet, or of 150 mg of ranitidine were administered alone or in combination (ranitidine was given 2 h prior to didanosine). Serial blood samples and total urinary output were collected after each treatment and analyzed for didanosine and/or ranitidine by validated high-performance liquid chromatography-UV assay methods. Pharmacokinetic parameters were calculated by noncompartmental methods. There were significant increases in mean area under the curve from time zero to infinity and mean urinary recovery for didanosine given in combination with ranitidine compared with those for didanosine alone. There were no significant differences between didanosine coadministered with ranitidine and didanosine alone in the respective mean peak concentrations in plasma, times to peak, elimination half-lives, or renal clearances. The mean area under the curve for ranitidine given with didanosine was significantly less than that for ranitidine given alone. There were no significant differences between the mean peak concentrations in plasma, times to peak, elimination half-lives, renal clearances, or urinary recovery values for ranitidine coadministered with didanosine and values for ranitidine given alone. These data demonstrate that administration of didanosine 2 h after ranitidine will result in a minor increase in the bioavailability of didanosine. A modification in the dose of didanosine or ranitidine is not necessary if the dose of ranitidine precedes that of didanosine by 2 h.
CP-72,588, a semisynthetic analog of the polyether ionophore UK-58,582 with increased anticoccidial potency
Authors: Ricketts A P , Chappel L R , Frame G M , Glazer E A , Migaki T T , Olson J A
Published: June 2012

We have employed semisynthesis to enhance the anticoccidial potency of a polyether ionophore. CP-72,588 is the alpha-methyl analog of the fermentation-derived polyether ionophore UK-58,852. The parent ionophore required a dose of 15 ppm to achieve anticoccidial efficacy in chickens equivalent to that of salinomycin at 60 ppm. CP-72,588 demonstrated substantially improved potency, with efficacy at 5 to 7.5 ppm. The intrinsic antimicrobial potencies of the two ionophores are similar; however, CP-72,588 was found in chicken tissues at higher levels than those of the parent ionophore when each was administered at the same dose (8 ppm). The enhanced potency of CP-72,588 may be partially due to enhanced uptake into tissues.
Activities of WIN-57273, minocycline, clarithromycin, and 14-hydroxy-clarithromycin against Mycobacterium avium complex in human macrophages
Authors: Cohen Y , Perronne C , Truffot-Pernot C , Grosset J , Vilde J L , Pocidalo J J
Published: June 2012

The activities of the fluoroquinolone WIN-57273, 14-OH clarithromycin (a human metabolite of clarithromycin), and minocycline against two virulent strains of Mycobacterium avium complex were evaluated in a model of intracellular infection and compared with that of clarithromycin. Human monocyte-derived macrophages were infected at day 6 of culture. Intracellular CFU at 60 min and intracellular and supernatant CFU on days 4 and 7 were counted after inoculation. The concentrations used, which were equal to peak levels in serum, were 3 micrograms of WIN-57273 per ml (MICs for the two strains, 1 microgram/ml), 4 microgram of 14-OH clarithromycin per ml (MICs, 8 and 2 micrograms/ml, respectively, at pH 7.4), 4 micrograms of minocycline per ml (MICs, 64 and 32 micrograms/ml, respectively), and 4 micrograms of clarithromycin per ml (MICs, 2 and 0.5 micrograms/ml, respectively, at pH 7.4). On day 7, compared with controls, WIN-57273, minocycline (P less than 0.02), clarithromycin, or different combinations of clarithromycin and the other drugs (P less than 0.001) slowed the intracellular replication of strain MO-1. 14-OH clarithromycin (P less than 0.02), clarithromycin (P less than 0.02), 14-OH clarithromycin plus clarithromycin (P less than 0.01), clarithromycin plus minocycline, or clarithromycin plus minocycline plus 14-OH clarithromycin (P less than 0.001) slowed the intracellular replication of strain LV-2. WIN-57273 was less effective than clarithromycin against strain MO-1 (P less than 0.05). Clarithromycin plus 14-OH clarithromycin plus minocycline (P less than 0.02) was more effective than clarithromycin alone against strain LV-2. Thus, clarithromycin plus minocycline, which corresponds in humans to three active molecules, may exhibit a better efficacy than clarithromycin in this model.
Characterization of DNA topoisomerase I from Candida albicans as a target for drug discovery
Authors: Fostel J M , Montgomery D A , Shen L L
Published: June 2012

Candida albicans is an opportunistic pathogen responsible for life-threatening infections in persons with impaired immune systems. Topoisomerase I is a potential target for novel antifungal agents; however, in order for this enzyme to be a therapeutically useful target, it needs to be demonstrated that the fungal and human topoisomerases differ sufficiently as to allow the fungal topoisomerase to be selectively targeted. To address this question, we isolated the topoisomerase I from C. albicans and compared its biochemical properties with those of the mammalian enzyme. Similar to other eukaryotic type I topoisomerases, the C. albicans type I topoisomerase has an apparent molecular mass of 102 kDa and covalently links to the 3' end of DNA, as shown after the reaction is interrupted by sodium dodecyl sulfate. Topoisomerase poisons such as camptothecin act by stabilizing the cleavage complex formed by the topoisomerase I and DNA. We observed that the C. albicans and mammalian type I topoisomerases differ in that the C. albicans cleavage complex is approximately 10-fold less sensitive to camptothecin than the mammalian cleavage complex is. In addition, we found that the antifungal agent eupolauridine can stabilize the cleavage complex formed by both the C. albicans and human topoisomerases and that the response of the C. albicans topoisomerase I to this drug is greater than that of the human enzyme. Thus, the topoisomerase I from C. albicans is sufficiently distinct from the human enzyme as to allow differential chemical targeting and will therefore make a good target for antifungal drug discovery.