bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapy of multidrug-resistant tuberculosis: lessons from studies with mice
Authors: Klemens S P , DeStefano M S , Cynamon M H
Published: June 2012

The activities of antituberculosis agents were evaluated in a murine tuberculosis model using a drug-resistant isolate. A multidrug-resistant clinical isolate from a recent outbreak of tuberculosis in the New York State correctional system was used for infection. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 49967 (strain CNL) organisms were given intravenously to 4-week-old female outbred mice. Treatment was started 1 day after infection and given for 4 weeks. Spleens and lungs were homogenized, and viable cell counts were determined. Statistical analysis indicated that ethionamide, sparfloxacin, ofloxacin, capreomycin, clarithromycin, and clofazimine are active in the murine test system with this multidrug-resistant tuberculosis isolate. Sparfloxacin is the most active quinolone. Despite in vitro resistance, isoniazid has moderate activity. In vitro susceptibility data coupled with evaluation of agents against drug-resistant isolates in the murine system should provide information necessary to design clinical trials for treatment of infections with these organisms.
Toxoplasma gondii: susceptibility and development of resistance to anticoccidial drugs in vitro
Authors: Ricketts A P , Pfefferkorn E R
Published: June 2012

Anticoccidial drugs were evaluated for activity and for the development of resistance in a model of Toxoplasma gondii growing in human fibroblast cultures. Of 13 anticoccidial drugs tested, 9 had selective antitoxoplasma activity (50% inhibitory concentration, in micrograms per milliliter): decoquinate (0.005), arprinocid-N-oxide (0.015), robenidine (0.03), the aryl triazine CP-25,415 (0.2), toltrazuril (0.4), clopidol (1), dinitolmide (Zoalene; Dow) (10), and the carboxylic acid ionophores monensin (0.001) and salinomycin (0.04). Glycarbylamide, amprolium, nicarbazin, and the 6-(p-bromophenoxy)-7-chloro analog of halofuginone (Stenorol; Roussel-UCLAF) (CP-63,567) were toxic for the fibroblasts. Since Eimeria tenella has a similar drug susceptibility profile, anticoccidial durgs can be viewed as a potential source of new antitoxoplasma therapies. The development of resistance has limited the usefulness of most of these drugs as anticoccidial agents; in coccidia, resistance to all except the ionophores occurs readily in vivo. We explored the development of resistance in T. gondii by attempting to select mutants in vitro from parasites mutagenized with ethylnitrosourea. Mutants that had 20- to 50-fold-reduced susceptibility to decoquinate, arprinocid-N-oxide, and CP-25,415 were obtained. Ionophore-resistant T. gondii mutants were also selected in vitro; however, there was only a twofold difference in susceptibility between these mutants and the wild type. For three drugs (clopidol, robenidine, and toltrazuril), we were unable to select resistant mutants. For experimental anticoccidial drugs, there is currently no in vitro method for assessing the risk of development of resistance in Eimeria species. Our results suggest that T. gondii may offer a useful surrogate for this assessment.
Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans
Authors: Blasi E , Mazzolla R , Pitzurra L , Barluzzi R , Bistoni F
Published: June 2012

We have studied the effects of picolinic acid (PLA), a product of tryptophan degradation, on mouse susceptibility to intracerebral infection with Candida albicans. We show that intraperitoneal administration of PLA significantly enhances the median survival time of mice inoculated with the lethal challenge. Furthermore, intracerebral administration of this agent induces a protective state against the local lethal infection, the phenomenon depending upon the administration schedule and doses of PLA employed. According to survival data, yeast growth in the brain as well as yeast colonization of the kidneys are drastically reduced in PLA-treated mice compared with those for untreated controls. Northern (RNA) blot analysis of brain tissues demonstrates that mRNA levels specific for tumor necrosis factor and interleukin 1 are augmented and induced, respectively, after inoculation of PLA. These results indicate that PLA has a protective effect likely involving elicitation of a cytokine response in vivo against fungal infections.
Teicoplanin-resistant Staphylococcus aureus expresses a novel membrane protein and increases expression of penicillin-binding protein 2 complex
Authors: Shlaes D M , Shlaes J H , Vincent S , Etter L , Fey P D , Goering R V
Published: June 2012

In the recent clinical trials of teicoplanin therapy of endocarditis caused by Staphylococcus aureus, at least one instance of the emergence of teicoplanin-resistant strains during therapy has been reported (G.W. Kaatz, S. M. Seo, N. J. Dorman, and S. A. Lerner, J. Infect. Dis 162:103-108, 1990). We have confirmed, using conventional electrophoresis of EcoRI-digested chromosomal DNA and pulsed-field gel electrophoresis of SmaI-digested chromosomal DNA, that the resistant strain (12873) (MIC, 16 micrograms/ml) is genetically very similar to the susceptible parent (12871) (MIC, 4 micrograms/ml). Kaatz et al. were able to select spontaneous teicoplanin-resistant mutants (10(-9)), suggesting that a single gene might be involved. We have shown that the mutation is highly stable during growth in the absence of teicoplanin. Using Tn551, we have selected insertion mutants of 12873 that become teicoplanin susceptible. We have examined a number of aspects of cell wall physiology in strains 12871 and 12873 and the teicoplanin-susceptible Tn551 mutants of 12873. 12873 was more susceptible to lysostaphin lysis than 12871 and the susceptible Tn551 derivatives of 12873. Autolysis in phosphate buffer (pH 7.5) and cell wall turnover rates were similar in 12871 and 12873. An analysis of membrane proteins revealed the expression of a ca. 35-kDa protein and increased expression of both polypeptides of penicillin-binding protein (PBP) 2 (PBP2) in 12873 relative to 12871 and the Tn551 mutants of 12873. This increased expression was not related to PBP2', since both strains were susceptible to oxacillin in 2% NaCl (MIC, < or = 0.25 microgram/ml) and cellular DNA from neither strain hybridized with a specific mec gene probe. Two independent Tn551 inserts have been mapped to a ca. 117-kb SmaI fragment of the chromosome. These data suggest the possibility that the mutation resulting in resistance to teicoplanin involves the regulation of expression of both polypeptides of PBP2 and a 35-kDa membrane protein.
Susceptibilities of Norwegian Candida albicans strains to fluconazole: emergence of resistance. The Norwegian Yeast Study Group
Authors: Sandven P , Bjørneklett A , Maeland A
Published: June 2012

All Candida albicans isolates in Norwegian microbiological laboratories in 1991 judged clinically important (except vaginal isolates) were collected. The isolates were tested for susceptibility to fluconazole with an agar dilution test and a commercially available agar diffusion test. A total of 212 strains (95%) were susceptible to fluconazole, and MICs for most of the strains (92%) were < or = 1.56 micrograms/ml. The agar diffusion test using a 15-micrograms tablet and a 48-h incubation period separated resistant from susceptible strains with a wide margin. The only exception was a strain for which the MIC was 6.25 micrograms/ml. The difference in zone size between the resistant and the susceptible populations of strains was 11 mm. Accordingly, it appears that the agar diffusion test is an appropriate method for detecting fluconazole resistance. The 12 fluconazole-resistant isolates originated from eight AIDS patients with oral or esophageal Candida infections. Seven of the patients had been given fluconazole for 1 month or more, often as self medication. Four had infections that were clinically resistant to fluconazole; one additional patient responded only when the dose was increased. All isolates recovered from these patients were analyzed by multilocus enzyme electrophoresis. The 12 C. albicans isolates belonged to five electrophoretic types, but three of four patients attending one hospital had isolates belonging to one electrophoretic type. One possible explanation for this finding could be that a nosocomial spread of resistant strains has occurred.
Evaluation of activity of temafloxacin against Bacteroides fragilis by an in vitro pharmacodynamic system
Authors: Zabinski R A , Vance-Bryan K , Krinke A J , Walker K J , Moody J A , Rotschafer J C
Published: June 2012

An in vitro pharmacodynamic system has been successfully adapted to simulate in vivo antimicrobial pharmacokinetics under anaerobic conditions. This system was used to perform time-kill kinetic studies which were designed to compare the activity of temafloxacin to ciprofloxacin and cefotetan against two strains of Bacteroides fragilis (ATCC 25285 and ATCC 23745). All experiments were performed as single-dose, 24-h, duplicate runs. Starting bacterial inocula of 10(7) CFU/ml were exposed to starting antimicrobial concentrations of 5 micrograms of temafloxacin per ml, 5 micrograms of ciprofloxacin per ml, and 100 micrograms of cefotetan per ml. Terminal half-lives of 8, 4, and 4 h were simulated for each antimicrobial agent. Temafloxacin was rapidly bactericidal against B. fragilis. Ciprofloxacin was not bactericidal (< 3 log10 unit decline in bacterial numbers) to either strain of B. fragilis. Cefotetan was bactericidal (> or = 3 log10 unit decline in bacterial numbers) to each strain but killed at a slower rate than temafloxacin. Times to 3 log10 unit declines of strain ATCC 25285 were 2, 4, and > 24 h, whereas those of strain ATCC 23745 were 4, 4, and > 24 h for temafloxacin, cefotetan, and ciprofloxacin, respectively. Total logarithmic declines of strain ATCC 25285 were > 4.5, > 4.5, and 2.9 log10 CFU/ml, whereas those of strain ATCC 23745 were 4.1, > 4.5, and 1.2 log10 CFU/ml for each drug, respectively. These and other studies demonstrated that temafloxacin showed potential as an agent that could have been further developed for use in the treatment of anaerobic infections. However, the drug was removed from the market by its manufacturer because of toxicity issues. Although the release of newer fluoroquinolones that possess significant activity against anaerobic bacteria does not appear imminent, the time-kill studies performed in this study demonstrate that further research is warranted in the development of fluoroquinolones which possess significant antianaerobic activity.
Reduced susceptibilities of Shigella sonnei strains isolated from patients with dysentery to fluoroquinolones
Authors: Horiuchi S , Inagaki Y , Yamamoto N , Okamura N , Imagawa Y , Nakaya R
Published: June 2012

Seven clinical isolates of Shigella sonnei with reduced susceptibilities to fluoroquinolones (sparfloxacin, ciprofloxacin, and ofloxacin) were obtained. The MICs of fluoroquinolones against these S. sonnei strains were 16 to 32 times higher than those obtained against typical strains that are highly susceptible to these agents. The kinetics of [14C]ofloxacin accumulation in these clinical strains were not different from those in the fully susceptible strains. However, DNA synthesis was much less inhibited by ofloxacin in the strains with reduced susceptibility. Analysis of the in vitro activity of the partially purified DNA gyrase from these isolates showed that the decreased quinolone susceptibility of the S. sonnei strains was likely due to mutation of the DNA gyrase subunit A gene.
Increased susceptibility of Pseudomonas aeruginosa to ciprofloxacin in the presence of vancomycin
Authors: Day C A , Marceau-Day M L , Day D F
Published: June 2012

Vancomycin in combination with ciprofloxacin exhibited synergy against 7 of 10 strains of Pseudomonas aeruginosa. MICs for the microbial strains used in this study ranged from 0.0325 to 3.0 micrograms/ml for ciprofloxacin and from 23.5 to > 188 micrograms/ml for vancomycin. Combinations of these antibiotics, tested in a checkerboard pattern, gave fractional inhibitory concentrations of 0.5 or less for 7 of the 10 strains tested.
Biliary excretion of rufloxacin in humans
Authors: Privitera G , Nicastro G , Imbimbo B P , Cesana M , Visconti M , Lombardi F , Tagliabue G , Faleschini E , Colturani F , Franzini P
Published: June 2012

Rufloxacin is a new once-daily antibacterial fluoroquinolone with a long half-life. The aim of the present study was to evaluate the plasma and biliary kinetics and biliary and urinary excretion of rufloxacin in patients with extrahepatic cholestasis. Twelve patients with total external percutaneous transhepatic biliary drainage were given a single oral dose of 400 mg of rufloxacin. Plasma, bile, and urine samples and fractions were collected over 72 h after drug administration. Rufloxacin and its major metabolite, the N-desmethyl derivative, were measured by high-performance liquid chromatography. Maximum rufloxacin concentrations in plasma and bile (means +/- standard deviations) were 4.05 +/- 1.38 micrograms/ml and 8.24 +/- 7.16 micrograms/ml, respectively, and were reached in 4.2 +/- 3.0 h and 4.2 +/- 3.5 h, respectively. The terminal elimination half-life of rufloxacin in plasma was 45.1 +/- 13.5 h. Apparent plasma clearance was 31.3 +/- 10.5 ml/min, while biliary clearance was 0.4 +/- 0.2 ml/min and renal clearance was 12.7 +/- 6.0 ml/min. In 72 h, 0.9% +/- 0.8% of the dose given was recovered in bile and 27.2% +/- 12.0% was recovered in urine. Biliary concentrations exceeded the MICs of most common biliary tract pathogens for at least 24 h after administration. The broad antibacterial spectrum of rufloxacin and its high and prolonged biliary concentrations suggest that this drug may be useful for treatment of biliary tract infections.
Study of heterogeneity of chloramphenicol acetyltransferase (CAT) genes in streptococci and enterococci by polymerase chain reaction: characterization of a new CAT determinant
Authors: Trieu-Cuot P , de Cespédès G , Bentorcha F , Delbos F , Gaspar E , Horaud T
Published: June 2012

An assay based on the utilization of degenerate primers that enable enzymatic amplification of an internal fragment of cat genes known to be present in gram-positive cocci was developed to identify the genes encoding chloramphenicol resistance in streptococci and enterococci. The functionality of this system was illustrated by the detection of cat genes belonging to four different hydridization classes represented by the staphylococcal genes catpC221, catpC194, catpSCS7, and the clostridial gene catP, and by the characterization of a new streptococcal cat gene designated catS. A sequence related to the clostridial catQ gene, which was present in one streptococcal strain, was not detected by this assay. These results reveal that these six cat genes account for chromosomal-borne chloramphenicol resistance in 12 group A, B, and G streptococci tested. By contrast, only three of these six cat genes (catpC221, catpC194, and catpSCS7) were detected on the 10 enterococcal plasmids studied here that encode resistance to chloramphenicol.
Biological characterization of cyclothialidine, a new DNA gyrase inhibitor
Authors: Nakada N , Shimada H , Hirata T , Aoki Y , Kamiyama T , Watanabe J , Arisawa M
Published: June 2012

Cyclothialidine is a new DNA gyrase inhibitor isolated from Streptomyces filipinensis NR0484. Structurally, it belongs to a new class of natural products containing a unique 12-membered lactone ring that is partly integrated into a pentapeptide chain. Cyclothialidine was found to be one of the most active of all the DNA gyrase inhibitors tested in the DNA supercoiling reaction of Escherichia coli DNA gyrase; 50% inhibitory concentrations (in micrograms per milliliter) of 0.03 (cyclothialidine), 0.06 (novobiocin), 0.06 (coumermycin A1), 0.66 (norfloxacin), 0.88 (ciprofloxacin), and 26 (nalidixic acid) were found. In addition, DNA gyrases from gram-positive species were inhibited equally as well as DNA gyrase from E. coli. Cyclothialidine also inhibited the in vitro DNA replication directed from oriC of E. coli. Among the bacterial species tested, only Eubacterium spp. were inhibited by cyclothialidine, suggesting that it can enter the cells of Eubacterium and exert antibacterial activity through interference with the DNA gyrase within the cells, although its penetration into most bacterial cells appears to be poor. These results provide a basis for cyclothialidine to be a lead structure for novel antibacterial agents with DNA gyrase inhibitory activities.
Ro 09-1470 is a selective inhibitor of P-450 lanosterol C-14 demethylase of fungi
Authors: Aoki Y , Yoshihara F , Kondoh M , Nakamura Y , Nakayama N , Arisawa M
Published: June 2012

Ro 09-1470 is a new antifungal agent that belongs to a series of compounds characterized by a tetrahydropyran skeleton with glycine and alkenyl side chains and that inhibits P-450 lanosterol C-14 demethylase (P-450(14DM)) of fungi (Y. Aoki, T. Yamazaki, M. Kondoh, Y. Sudoh, N. Nakayama, Y. Sekine, H. Shimada, and M. Arisawa, J. Antibiot. 45:160-170, 1992; S. Matsukuma, T. Ohtsuka, H. Kotaki, H. Sawairi, T. Sano, K. Watanabe, N. Nakayama, Y. Itezono, M. Fujiu, N. Shimma, K. Yokose, and T. Okuda, J. Antibiot. 45:151-159, 1992). We have studied the compound's mode of interaction with fungal P-450(14DM) and its selectivity for the fungal versus mammalian P-450 enzymes. Ro 09-1470 bound to the Saccharomyces cerevisiae P-450(14DM) by coordinating to the heme with one-to-one stoichiometry. Unlike the azole compounds, it interacted with both ferric and ferrous heme. It was active also against the P-450(14DM) of Candida albicans. Ro 09-1470 preferentially inhibited the yeast P-450(14DM), showing a 50% inhibitory concentration (IC50) of 0.47 to approximately 1.1 microM, which is much lower than the IC50s for rat hepatic P-450s catalyzing cholesterol biosynthesis (IC50 = 341 microM), p-nitroanisol O-demethylation (> 1,000 microM), aniline hydroxylation (> 1,000 microM), and aminopyrine N-demethylation (920 microM). The degree of selectivity for yeast P-450 was higher than that of ketoconazole.
Immunosuppressive activity of fosfomycin on human T-lymphocyte function in vitro
Authors: Morikawa K , Oseko F , Morikawa S , Sawada M
Published: June 2012

Recent investigations have shown that some antibiotics also work as immunomodulators. We have recently reported that fosfomycin (FOM) has an immunomodulatory effect on human B-cell activation. FOM is a unique antibiotic which is chemically unrelated to any other known antibacterial agent. In the present study, we examined the effect of FOM on human T-cell function. FOM inhibited the proliferation of human lymphocytes induced by polyclonal T-cell mitogens in a dose-dependent manner. FOM also strongly suppressed mixed lymphocyte reaction and interleukin-2 (IL-2) production by T cells. Moreover, FOM inhibited the expressions of IL-2 receptor (CD25) and transferrin receptor (CD71) on the activated T-cell surfaces. These data suggest that FOM may block the T-cell division during the transition from G1 to S phase of the cell cycle. Combined treatment with FOM and low-dose cyclosporin A or FK506 caused additive or synergistic suppression of T-cell proliferation, but not on IL-2 receptor expression. It seems that the mode of action of FOM on T-cell function involves a specific suppression of IL-2 production.
Chromosomally mediated high-level gentamicin resistance in Streptococcus mitis
Authors: Kaufhold A , Potgieter E
Published: June 2012

Four blood culture isolates of Streptococcus mitis were found to be resistant to penicillin (MIC, 16 to 32 micrograms/ml) and gentamicin (MIC, 128 or 1,000 micrograms/ml), and the two antibiotics demonstrated a lack of in vitro synergy. As shown by polymerase chain reaction assays, the structural gene known to encode high-level gentamicin resistance in Enterococcus faecalis, Enterococcus faecium, and Streptococcus agalactiae was also present in all four S. mitis strains. Attempts to isolate plasmids were unsuccessful, but an oligonucleotide probe derived from the gentamicin resistance gene hybridized to distinct restriction fragments of genomic DNA, suggesting that the resistance genes in these strains are integrated into the bacterial chromosome.
In vitro activity of DU-6859a, a new fluorocyclopropyl quinolone
Authors: Marshall S A , Jones R N
Published: June 2012

DU-6859a was tested against 844 recent clinical isolates (most from bacteremias) by using reference MIC determination procedures. The activity of DU-6859a against members of the family Enterobacteriaceae was comparable to that of ciprofloxacin (range of MICs for 90% of isolates [MIC90], < or = 0.015 to 1 microgram/ml), and the highest MICs were observed among Serratia marcescens and Providencia rettgeri isolates. The DU-6859a MIC90 for Pseudomonas aeruginosa and Xanthomonas maltophilia was 0.5 microgram/ml. Pneumococci (MIC90, 0.06 microgram/ml), Haemophilus influenzae (MIC90, < or = 0.004 microgram/ml), Moraxella catarrhalis (MIC90, < or = 0.015 microgram/ml), and pathogenic neisseriae (MIC90, 0.015 to 0.03 microgram/ml) were very susceptible to DU-6859a. All staphylococci had DU-6859a MICs of < or = 1 microgram/ml, including oxacillin- and ciprofloxacin-resistant strains. DU-6859a was very active against isolates resistant to ceftazidime (MIC90, < or = 0.12 microgram/ml), ciprofloxacin (MIC90, < or = 8 micrograms/ml), and gentamicin (MIC90, < or = 1 microgram/ml).
Effect of scrubbing and irrigation on staphylococcal and streptococcal counts in contaminated lacerations
Authors: Howell J M , Dhindsa H S , Stair T O , Edwards B A
Published: June 2012

We studied the effects of scrubbing with poloxamer 188 (SCR), irrigating with povidone iodine (PI), and scrubbing followed by irrigation (SCR-PI) on staphylococcal and streptococcal counts in inoculated guinea pig lacerations. PI irrigation and SCR-PI significantly lowered streptococcal counts (P < 0.05). Staphylococcal counts were not different from those in controls.
In vitro activity of a new carbapenem antibiotic, BO-2727, with potent antipseudomonal activity
Authors: Nakagawa S , Hashizume T , Matsuda K , Sanada M , Okamoto O , Fukatsu H , Tanaka N
Published: June 2012

BO-2727, a new 1-beta-methyl-carbapenem, was active at concentrations of 6.25 micrograms/ml or less against gram-positive and gram-negative bacteria, including some imipenem- and/or meropenem-resistant (MICs, > or = 12.5 micrograms/ml) Pseudomonas aeruginosa strains, against which it proved generally fourfold more active than imipenem and meropenem. BO-2727's antipseudomonal activity and its broad spectrum merit further investigation for clinical use by itself, since it was stable in the presence of renal dehydropeptidase I.
Sequences of MGH-1, YOU-1, and YOU-2 extended-spectrum beta-lactamase genes
Authors: Rice L B , Marshall S H , Carias L L , Sutton L , Jacoby G A
Published: June 2012

Genes for MGH-1, YOU-1, and YOU-2 extended-spectrum beta-lactamases have been cloned and sequenced. The gene for MGH-1 has the sequence of blaTEM-10, YOU-2 has that of blaTEM-12, and YOU-1 has that of blaTEM-26. All have evolved from blaTEM-1b but have the strong dual promoter sequence of blaTEM-2.
Low neurotoxicity of LJC 10,627, a novel 1 beta-methyl carbapenem antibiotic: inhibition of gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in relation to lack of central nervous system toxicity in rats
Authors: Hikida M , Masukawa Y , Nishiki K , Inomata N
Published: June 2012

The toxicity of LJC 10,627 to the central nervous system of rats was evaluated by examining the effects of the compound on gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in rat synaptic membranes and on the induction of behavioral convulsions by intraventricular administration to rats. The concentrations of this compound needed to inhibit specific [3H]muscimol binding, specific [3H]diazepam binding, and specific [3H]strychnine binding were greater than those of imipenem, as demonstrated by the 50% inhibitory concentrations (IC50S of LJC 10,627, greater than 10 mM for each; IC50S of imipenem, 0.6, 1.9, and 0.2 mM, respectively). These results reflect the fact that LJC 10,627 does not evoke severe convulsions or cause death, even when it is administered intraventricularly at a high dose (300 micrograms per rat), and suggest that the low neurotoxic potential of LJC 10,627 may be attributed to the chemical structure of this compound, which has a methyl radical at the 1 beta site and a triazolium radical at the side chain of the second site.
Synergistic activity of ceftriaxone combined with netilmicin administered once daily for treatment of experimental streptococcal endocarditis
Authors: Francioli P B , Glauser M P
Published: June 2012

We have conducted experiments to determine if one daily injection of netilmicin (NET) would be synergistic with the broad-spectrum cephalosporin ceftriaxone (CRO) in the treatment of experimentally induced endocarditis. Rats with catheter-induced aortic vegetations were infected intravenously with 3 x 10(7) CFU of a beta-lactam-sensitive strain of Streptococcus sanguis or a beta-lactam-resistant strain of Streptococcus mitis. Treatment with the antibiotics alone (CRO, 10 mg/kg of body weight every 8 h; NET, 18 mg/kg every 24 h) or in combinations which had proved synergistic in in vitro time-kill curves was commenced 48 h postinfection and continued for 72 h. The results show that the combination was markedly effective against S. sanguis and moderately effective against S. mitis, while, with the protocol used here, the agents alone were not. The results suggest that CRO-NET should be an effective combination for treating streptococcal endocarditis in humans and may permit a shorter duration of treatment and once-a-day dosing to be used.
Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with end-stage renal disease
Authors: Chimata M , Nagase M , Suzuki Y , Shimomura M , Kakuta S
Published: June 2012

The pharmacokinetics of meropenem were studied after intravenous infusion in 13 patients grouped according to the impairment of their renal function. Creatinine clearance (CLCR) was greater than 50, 50 to 30, and less than 30 ml/min in groups I, II, and III, respectively. Two other groups, groups IV and V, each comprising four patients with end-stage renal disease (CLCR, < 5 ml/min), were also studied, the former on days off of hemodialysis and the latter on days of hemodialysis. The elimination half-lives of meropenem were 1.54 +/- 0.70 h in group I patients, 3.36 +/- 1.02 h in group II patients, and 5.00 +/- 1.05 h in group III patients. Cumulative urinary excretion accounted for 48.5% of the dose in group I patients and decreased progressively with a decline in renal function. Hemodialysis shortened the elimination half-life of meropenem from 7.0 h to 2.9 h. H-4295, the main metabolite of meropenem, had a peak level in plasma of 0.5 to 1.0 h in patients with renal failure. The level of H-4295 decreased with hemodialysis. The dosing interval of meropenem should be prolonged in a regular proportion to the decline in CLCR (12 h in group II patients and 24 h in group III patients). In patients receiving hemodialysis, dosing after each hemodialysis session is recommended.
Decimal assay for additivity of drugs permits delineation of synergy and antagonism
Authors: Sanders C C , Sanders W E , Moland E S
Published: June 2012

Although there are many in vitro tests for drug interactions, few possess a linear, predictable dose-dependent end point or have a precise definition for additivity. Therefore, a new test with both of these features, the decimal assay for additivity, was developed. This test is based on a disk diffusion assay and the strict linear relationship between drug mass and size of the inhibition zone. When the decimal assay for additivity was applied to combinations known on a mechanistic basis to be additive, synergistic, or antagonistic, results of the new test always reflected the expected drug interaction. For example, synergy between trimethoprim and sulfamethoxazole was detected in tests with Escherichia coli and Haemophilus influenzae, as was antagonism between cefoxitin and cefotaxime in tests with Enterobacter cloacae. Quinolones plus chloramphenicol appeared to be antagonistic. In addition to correctly identifying the drug interaction, the decimal assay for additivity identified the drug ratio producing the maximal drug interaction. These results suggest that the decimal assay for additivity should prove very useful in future studies of drug interactions.
Effects of new quinolones on Mycoplasma pneumoniae-infected hamsters
Authors: Arai S , Gohara Y , Akashi A , Kuwano K , Nishimoto M , Yano T , Oizumi K , Takeda K , Yamaguchi T
Published: June 2012

The efficacies of the new quinolones temafloxacin, ofloxacin, and ciprofloxacin were investigated against Mycoplasma pneumoniae in an experimental hamster pneumonia model. Hamsters were infected intratracheally with M. pneumoniae and sacrificed 18 h after the final medication, and their lungs were aseptically removed, homogenized, and cultured quantitatively. The efficacies of these drugs were determined by the CFU of M. pneumoniae in lungs. Temafloxacin and ofloxacin, but not ciprofloxacin, were active when the oral administration of 200 mg/kg of body weight per day (once per day) for 5 days was initiated 24 h after infection. Although no effect on the elimination of M. pneumoniae was observed after the administration of these drugs at 200 mg/kg/day at 5 days after infection, the continuous administration for 15 days of temafloxacin, but not ofloxacin or ciprofloxacin, significantly reduced viable M. pneumoniae in the lungs. These results suggest that temafloxacin and ofloxacin are effective in the acute phase of infection and, moreover, that temafloxacin is effective in the late stage of infection during which progressive lung alterations and continuous increases in mycoplasmal growth occurred. The peak levels of temafloxacin in sera and lungs after oral administration were similar to those of ofloxacin and higher than those of ciprofloxacin. The areas under the curve of temafloxacin in the lung tissue, however, were higher than those of ofloxacin and ciprofloxacin. On the basis of these results, temafloxacin and ofloxacin might be promising antimicrobial agents for the treatment of mycoplasmal infection.
Efficacy of ceftazidime and aztreonam alone or in combination with amikacin in experimental left-sided Pseudomonas aeruginosa endocarditis
Authors: Pefanis A , Giamarellou H , Karayiannakos P , Donta I
Published: June 2012

The in vivo efficacies of ceftazidime, aztreonam, and the combinations of ceftazidime with amikacin and aztreonam with amikacin were studied in the rabbit left-sided endocarditis model by using two strains of Pseudomonas aeruginosa, one multisusceptible and one multiresistant, in a total of 156 animals. Antibiotics were given intramuscularly for 10 days, as follows: amikacin, 7 mg/kg of body weight every 8 h, and ceftazidime and aztreonam, 50 mg/kg every 8 h. All regimens except amikacin alone significantly reduced the number of CFU per gram of vegetation (P < or = 0.008), but only for the multisusceptible strain for which sterile vegetations were obtained in 20, 25, 21, 75, and 53% of the groups treated with amikacin, ceftazidime, aztreonam, and the combination groups ceftazidime-amikacin and aztreonam-amikacin, respectively (ceftazidime plus amikacin versus controls, P = 0.001). Regarding the decrease in the numbers of colonies in vegetations, (i) all regimens significantly reduced the number of CFU per gram of vegetation (P < 0.001), (ii) results with ceftazidime-amikacin compared with those with monotherapy were significantly different (P < or = 0.007), and (iii) results with aztreonam-amikacin, although better than those with monotherapy, were marginally not statistically significant. At 1 h postdose, mean amikacin, aztreonam, and ceftazidime levels in serum were 35 +/- 19.4, 89.6 +/- 8.16, and 92.61 +/- 11.52 micrograms/ml, respectively. It was concluded that the combination of ceftazidime, and possibly aztreonam, with amikacin given at high doses and short intervals could have a place in the therapy of patients with left-sided endocarditis caused by P. aeruginosa.
Pharmacokinetics of azithromycin in pediatric patients after oral administration of multiple doses of suspension
Authors: Nahata M C , Koranyi K I , Gadgil S D , Hilligoss D M , Fouda H G , Gardner M J
Published: June 2012

Azithromycin is an azalide antibiotic. On the basis of data in adults, azithromycin appears to have a greater distribution into tissues, a longer elimination half-life, and a lower incidence of adverse effects than the macrolide antibiotic erythromycin. However, little about the pharmacokinetics of azithromycin in children is known. The objective of our study was to characterize the pharmacokinetics of azithromycin after oral administration of multiple doses of suspension to children with streptococcal pharyngitis. Fourteen children (6 to 15 years of age) received a single oral dose of 10 mg of azithromycin per kg of body weight on day 1 followed by single daily doses of 5 mg/kg on days 2 to 5. Each child fasted overnight before receiving the final dose on day 5. Blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 h after this last dose. Concentrations of azithromycin in serum were measured by a specific high-performance liquid chromatography-mass spectrometry method. The mean +/- standard deviation for maximum concentration of drug in serum, time to maximum concentration of drug in serum, and area under the curve (0 to 24 h) were 383 +/- 142 ng/ml, 2.4 +/- 1.1 h, and 3,109 +/- 1,033 ng.h/ml, respectively. Concentrations in serum at 0 h (predose) and at 24, 48, and 72 h after the final dose were 67 +/- 31, 64 +/- 24, 41 +/- 17, and 29 +/- 14 ng/ml, respectively. Thus, once-daily administration of azithromycin resulted in sustained systemic exposure to the drug.
Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine
Authors: Balzarini J , Holy A , Jindrich J , Naesens L , Snoeck R , Schols D , De Clercq E
Published: June 2012

The (S)- and (R)-enantiomers of acyclic purine nucleoside phosphonate analogs (i.e., 3-hydroxy-2-phosphonomethoxypropyl [HPMP] derivatives, 3-fluoro-2-phosphonomethoxypropyl [FPMP] derivatives, and 2-phosphonomethoxypropyl [PMP] derivatives of adenine [A], 2-aminopurine, 2,6-diaminopurine [DAP], and guanine [G]) have been synthesized and evaluated for antiviral activity. As a rule, the HPMP derivatives proved effective against DNA viruses but not RNA viruses or retroviruses. In particular, (S)-HPMPA, (S)-HPMPDAP, and (R)- and (S)-HPMPG were exquisitely inhibitory to herpes simplex virus type 1 (50% effective concentrations, 0.63, 0.22, 0.10, and 0.66 microM, respectively). The FPMP and PMP derivatives showed marked inhibitory activities against retroviruses but not DNA viruses. The (S)-enantiomer of FPMPA and the (R)-enantiomer of PMPA were approximately 30- to 100-fold more effective against human immunodeficiency virus and Moloney murine sarcoma virus (MSV) than their enantiomeric counterparts. In contrast, both (S)- and (R)-enantiomers of the DAP and G derivatives proved equally effective against retroviruses, except for (R)-PMPDAP, which was 15- to 40-fold more inhibitory than (S)-PMPDAP. (R)-PMPDAP emerged as the most potent and selective inhibitor of MSV-induced transformation of murine C3H/3T3 cells and human immunodeficiency virus-induced cytopathicity in MT-4 and CEM cells (50% effective concentration, approximately 0.1 to 0.6 microM). When administered intraperitoneally at a single dose as low as 2 mg/kg, (R)-PMPDAP efficiently decreased MSV-induced tumor formation in newborn NMRI mice and significantly increased the survival time of MSV-infected mice. In addition, upon oral administration to MSV-infected mice, (R)-PMPDAP showed marked antiretroviral efficacy.
Pharmacologic limits of the protective effect of polyaspartic acid on experimental gentamicin nephrotoxicity
Authors: Swan S K , Gilbert D N , Kohlhepp S J , Kohnen P W , Bennett W M
Published: June 2012

Polyaspartic acid (PAA) ameliorates experimental gentamicin nephrotoxicity despite marked accumulation of gentamicin in the renal cortex. The experiments described here probe the extent of PAA's nephroprotective action when increasing doses of gentamicin, in excess of an established nephrotoxic dose (40 mg/kg of body weight per day), are administered. After 10 days, virtually complete nephroprotection was conferred by PAA coadministered to animals receiving three times the nephrotoxic dose (120 mg/kg/day) of gentamicin.
Anti-Trichophyton mentagrophytes activity and percutaneous permeation of butenafine in guinea pigs
Authors: Arika T , Hase T , Yokoo M
Published: June 2012

We examined anti-Trichophyton mentagrophytes activity, cutaneous penetration, and skin localization of butenafine, a novel benzylamine antifungal agent. The following results were obtained. (i) In the guinea pig dorsal skin trichophytosis model, butenafine produced complete eradication of fungi from infected sites. Clotrimazole was active when animals were infected with 10(4) or 10(5) cells but was almost inactive when the inoculum size was 10(6) cells. (ii) The MICs of butenafine and clotrimazole against arthrospores of T. mentagrophytes KD-04 were 0.025 and 0.39 microgram/ml, respectively. (iii) When 0.2 ml of a 1% 14C-butenafine solution was applied for 23 h/day for 7 days, high radioactivity corresponding to 250 to 500 micrograms of butenafine per g of skin in the epidermis, including the horny layer, was observed. (iv) Butenafine penetrates through transepidermal and transfollicular routes. The excellent therapeutic efficacy of butenafine on experimental dermatophytosis may be attributed to its low MIC and good penetration and distribution in the horny layer and hair follicles, where fungi reside.
Effects of two magainin peptides on eicosanoid release from rat peritoneal macrophages
Authors: Matera G , Cook J A , Geisel J , Ashton S H , Wise W C , Focá A , Berkowitz B A , Halushka P V
Published: June 2012

Magainins are novel polycationic peptides with broad-spectrum antimicrobial activity, including activity against gram-negative bacteria. Gram-negative bacteremia can elicit endotoxic shock that is associated with the increased formation of eicosanoids. Inhibition of eicosanoid synthesis has been shown to improve the outcome of experimental endotoxic shock. The aim of the present study was to test the in vitro effects of two magainin peptides, MSI-97 (M1) and MSI-98 (M2), on eicosanoid synthesis by rat peritoneal macrophages (M phi) stimulated by Salmonella enteritidis lipopolysaccharide (LPS; 50 micrograms/ml) and Salmonella minnesota lipid A (5 micrograms/ml) and to compare their effects on LPS reactivity with a metachromatic dye. M1 (100 micrograms/ml) significantly (P < 0.05) reduced LPS-stimulated synthesis of thromboxane B2 (TXB2), without changing 6-keto-prostaglandin F1 alpha in M phi. Similarly, M2 (10 micrograms/ml) significantly attenuated M phi synthesis of TXB2 stimulated by either LPS or lipid A. However, at a higher concentration (100 micrograms/ml), M2 but not M1 significantly augmented LPS-induced increases in TXB2 and 6-keto-prostaglandin F1 alpha. Polymyxin B (40 micrograms/ml) inhibited LPS production and lipid A-stimulated TXB2 production. M1 (100 micrograms/ml) and polymyxin B (10 and 40 micrograms/ml) also inhibited calcium ionophore A23187 (10 microM)-induced synthesis of TXB2. The lipid A moiety of LPS reacts with dimethylmethylene blue dye, providing a metachromatic assay of LPS. This metachromatic reaction with lipid A was significantly reduced by polymyxin B and M2 at all concentrations. M1 was effective only at the highest M1:lipid A concentration ratio (2:1). Thus, M1 and M2 share some similarities with polymyxin B in inhibiting lipid A reactivity with the dye, which suggests that these magainins may also bind to lipid A. However, M1 was devoid of any inhibitory effects on dye reactivity with S. enteritidis LPS and M2 was inhibitory at only one concentration ratio (1:5). In conclusion, the varied effects of the magainin peptides on LPS, lipid A, and M phi eicosanoid synthesis appear to depend on the type of peptide used and on its concentration.
Pharmacokinetics of intravenous fusidic acid in patients with cholestasis
Authors: Peter J D , Jehl F , Pottecher T , Dupeyron J P , Monteil H
Published: June 2012

The pharmacokinetics of fusidic acid and 3-ketofusidic acid were investigated in cholestatic and noncholestatic patients after intravenous administration of single and multiple doses of 500 mg of sodium fusidate. The patients, all with low serum albumin levels, were divided into three groups. Group I consisted of six noncholestatic patients; group II consisted of nine mildly cholestatic patients with mild hepatic impairment (conjugated bilirubin, 47 mumol liter-1; alkaline phosphatase, 280 IU liter-1; gamma-glutamyltranspeptidase, 190 IU liter-1); group III consisted of six benign intrahepatic cholestatic patients with high isolated conjugated hyperbilirubinemia (98.1 mumol liter-1). Assays were performed by high-pressure liquid chromatography. At steady state, the mean peak concentrations in serum were 63.7, 44.9, and 92.2 micrograms ml-1 in groups I, II, and III, respectively; over a dosage interval, areas under the concentration-time curve were 411.1, 238.7, and 603.4 micrograms.h ml-1 and the mean body clearances were 0.34, 0.53, and 0.25 ml min kg-1 in groups I, II, and III, respectively. The accumulation ratio of fusidic acid increased from 2.8 and 2.4 in groups I and II to 4.2 in group III. At steady state, the ratios of the areas under the concentration-time curve from 0 to 8 h for 3-ketofusidic acid/fusidic acid were 0.11, 0.09, and 0.10 in the three groups, respectively. Only very small amounts of fusidic acid and 3-ketofusidic acid were found in urine. These results substantiate the following hypotheses. In group I and II patients the clearance is higher than that in healthy volunteers because of the increased free, unbound fraction of fusidic acid, a consequence of lower serum albumin concentrations, resulting in increased distribution in tissue and hepatic metabolism. In group III patients, the higher bilirubinemia results in competition with fusidic acid for the limited glucuronidation, thus compensating for the increased elimination with fusidic acid because of the low serum albumin concentration. These results suggest that fusidic acid can be administered normally even to patients with high bilirubinemia because the postoperative serum albumin concentration is usually low.
Relative efficacies of broad-spectrum cephalosporins for treatment of methicillin-susceptible Staphylococcus aureus experimental infective endocarditis
Authors: Steckelberg J M , Rouse M S , Tallan B M , Osmon D R , Henry N K , Wilson W R
Published: June 2012

The effects of treatment with broad-spectrum parenterally administered cephalosporins and cefuroxime, cefazolin, or nafcillin were compared in an experimental model of Staphylococcus aureus infective endocarditis, and the results in vivo were compared with the activities of the study drugs in vitro. After 3 days of treatment, all antimicrobial agents tested were more effective than no treatment in reducing the number of surviving bacteria in cardiac valve vegetations. Nafcillin was the most effective agent studied and was significantly more active than was ceftizoxime, ceftriaxone, cefotaxime, cefoperazone, cefuroxime, or cefazolin (P < or = 0.05). Cefpirome and ceftazidime were the most effective broad-spectrum cephalosporins. The outcome of treatment with cefpirome or ceftazidime was similar to that of treatment with nafcillin and significantly better than that of treatment with ceftizoxime or cefotaxime (P < or = 0.05). Treatment outcome correlated closely with the MICs of the antimicrobial agents for the study strain with the exception of ceftazidime, which was significantly more active in vivo in comparison with other agents than predicted by its MIC (P < or = 0.0003). When ceftazidime was excluded as an outlier, treatment outcome correlated with the MICs of the remaining study drugs (Spearman's correlation coefficient, 0.95; P < or = 0.0004), as well as with the estimated percentage of time during which the concentration of total drug (correlation coefficient, -0.85; P < or = 0.007) or free drug (correlation coefficient, -0.90; P < or = 0.003) exceeded the MIC. A consideration of total or free drug concentrations in relation to MICs did not significantly improve the correlation with outcome observed with the MICs alone.
In vitro activity and beta-lactamase stability of FK-037, a parenteral cephalosporin
Authors: Neu H C , Chin N X , Huang H B
Published: June 2012

The in vitro activity of FK-037, 5-amino-2-[[(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2- methoxyimino) acetyl] amino]-2-carboxy-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-(2-hydroxyethyl)-1H-pyrazoli um hydroxide, inner salt, sulfate (1:1), a new parenteral cephem, was compared with those of cefepime, ceftazidime, imipenem, and ciprofloxacin. FK-037 inhibited methicillin-susceptible staphylocci at < or = 4 micrograms/ml. Of 98 isolates of homogenous methicillin-resistant Staphylococcus aureus, 55 (56.1%) were inhibited by 8 micrograms of FK-037 per ml, compared to 3.1% for cefepime. Imipenem was the most active beta-lactam tested against staphylococci. The MIC of FK-037 for 90% of the strains tested (MIC90) was 0.06 micrograms/ml for hemolytic streptococci, Streptococcus pneumoniae, viridans group streptococci, and Streptococcus bovis. The MIC90 for many of the members of the family Enterobacteriaceae was 1 microgram/ml, similar to that of cefepime and lower than those of ceftazidime and imipenem. The MIC90 for Klebsiella pneumoniae and Enterobacter cloacae was 8 micrograms/ml, similar to that for cefepime, but all isolates were inhibited by 2 micrograms of imipenem per ml. K. pneumoniae isolates with cefotaxime and ceftazidime MICs of > 32 micrograms/ml with Bush type 2b' beta-lactamases were inhibited by 4 micrograms of FK-037 per ml. E. cloacae, Citrobacter freundii, and S. aureus stably resistant to FK-037 could be selected by repeated transfer in the presence of FK-037. The FK-037 MIC90 for Pseudomonas aeruginosa was 4 microgram/ml, compared to 32 microgram/ml for cefepime and ceftazidime and 8 microgram/ml for imipenem. Xanthomonas maltophilia, Pseudomonas cepacia, Acinetobacter anitratus, and Bacteroides species were resistant to FK-037 (MIC, more than or equal 32 microgram/ml). MBCs were identical to or within twofold of the MICs except for a 32-fold greater MBC for P. aeruginosa. Inoculum size and acid environment did not lower the activity of FK-037. FK-037 was not appreciably hydrolyzed by Bush group 1, 2a, 2b, and 2e beta-lactamases but was hydrolyzed by 2b' and 2d enzymes at rates comparable to that of ceftazidime. Nonetheless, FK-037 inhibited bacteria possessing TEM-3, -5, and -7 and SHV -5 at less than or equal 8 microgram/ml. Overall, FK-037 has lower MICs against staphylococci and P. aeruginosa than the currently available iminomethoxy aminothiazolyl cephalosporins and has activity against members of the family Enterobacteriaceae comparable to that of cefepime.