bluuebunny/crossref_metadata_2025 huggingface dataset:
Mode of action of the dual-action cephalosporin Ro 23-9424
Authors: Georgopapadakou N H , Bertasso A , Chan K K , Chapman J S , Cleeland R , Cummings L M , Dix B A , Keith D D
Published: June 2012

Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biological properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decomposition product, desacetyl cefotaxime, Ro 23-9424 bound at less than or equal to 2 micrograms/ml to the essential penicillin-binding proteins 1b and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureus. In E. coli, Ro 23-9424 produced filaments exclusively and decreased cell growth; cefotaxime produced both filaments and lysis. Like its decomposition product fleroxacin but unlike quinolone esters, Ro 23-9424 also inhibited replicative DNA biosynthesis in E. coli. In an E. coli strain lacking OmpF, growth continued after addition of Ro 23-9424, decreased after addition of cefotaxime, and stopped immediately after addition of fleroxacin. The results, together with the chemical stability of Ro 23-9424 (half-life, approximately 3 h at pH 7.4 and 37 degrees C), suggest that in E. coli the compound acts initially as a cephalosporin with intrinsic activity comparable to that of cefotaxime but with poorer penetration. Subsequent to the decomposition of Ro 23-9424 to fleroxacin and desacetyl cefotaxime, quinolone activity appears. The in vitro antibacterial activity reflects both mechanisms of action.
In vitro activity of S-ofloxacin
Authors: Neu H C , Chin N X
Published: June 2012

S-Ofloxacin, the optically active form of ofloxacin, was twice as active as the S,R mixture of ofloxacin against members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and gram-positive species. Of the Enterobacteriaceae, 90% were inhibited by less than or equal to 1 microgram/ml and 90% of Staphylococcus aureus and Streptococcus pyogenes isolates were inhibited by 0.5 microgram/ml. Bacteroides fragilis was inhibited by 4 micrograms/ml. Organisms resistant to ofloxacin were resistant to S-ofloxacin. Like ofloxacin activity, the activity of S-ofloxacin was reduced by Mg2+ and by acid pH. Spontaneous mutational resistance to S-ofloxacin was similar to that to ofloxacin.
Nucleotide sequence of the aacC2 gene, a gentamicin resistance determinant involved in a hospital epidemic of multiply resistant members of the family Enterobacteriaceae
Authors: Vliegenthart J S , Ketelaar-van Gaalen P A , van de Klundert J A
Published: June 2012

A gentamicin resistance determinant of a conjugative plasmid from Enterobacter cloacae was cloned on a 3.2-kilobase fragment in the PstI site of pBR322. Substrate profiles for eight aminoglycosides at three concentrations showed that the resistance was due to aminoglycoside-(3)-N-acetyltransferase isoenzyme II. Insertion mapping by the gamma-delta transposon revealed that the size of the gene was approximately 1 kilobase. Nucleotide sequencing of the aacC2 gene identified an open reading frame of 858 base pairs, preceded by a promoter and a ribosome-binding site. From these data the molecular mass of the protein was calculated to be 30.6 kilodaltons. A comparison of the nucleotide sequence of the aacC2 gene with those published for the aacC3 and aacC4 genes showed complete homology of the aacC2 gene and the presumed aacC3 gene. An internal restriction fragment of the gene used as a probe in colony hybridization demonstrated the presence of the aacC2 gene in 86% of 86 multiply resistant isolates of the family Enterobacteriaceae obtained during an 18-month hospital epidemic. This corroborates our earlier data on the enzyme identification by the susceptibility profiling method.
Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis
Authors: Kaatz G W , Seo S M , Barriere S L , Albrecht L M , Rybak M J
Published: June 2012

The therapeutic activities of ciprofloxacin (25 mg/kg every 8 h), rifampin (10 mg/kg every 24 h), ciprofloxacin plus rifampin, and vancomycin (17.5 mg/kg every 6 h) were compared by using the rabbit model of Staphylococcus aureus endocarditis. Animals infected with one of two test strains (SA1199 or SA487) were randomized into treatment groups and received 6 days of therapy. For SA1199, ciprofloxacin plus rifampin was most effective at reducing vegetation bacterial counts. For SA487, ciprofloxacin plus rifampin was as effective as vancomycin but less effective than ciprofloxacin alone. Resistance to ciprofloxacin at 5- and 10-fold the MIC emerged in the test strain in 82 and 55%, respectively, of rabbits infected with SA1199 and receiving ciprofloxacin monotherapy. The combination of ciprofloxacin and rifampin decreased these frequencies to 60% (P = 0.27) and 10% (P = 0.04). No resistance to ciprofloxacin was found in rabbits infected with SA487. We conclude that ciprofloxacin and ciprofloxacin plus rifampin are as efficacious as vancomycin in this model and that combining rifampin with ciprofloxacin may decrease the frequency at which high-level resistance to ciprofloxacin emerges. However, with respect to improved efficacy, the combination of ciprofloxacin and rifampin is unpredictable and may be detrimental.
Comparison of bactericidal activities of streptomycin, amikacin, kanamycin, and capreomycin against Mycobacterium avium and M. tuberculosis
Authors: Heifets L , Lindholm-Levy P
Published: June 2012

The bactericidal activities of four injectable antituberculosis drugs, streptomycin, amikacin, kanamycin, and capreomycin, against Mycobacterium avium and M. tuberculosis were tested. All four drugs were highly bactericidal against M. tuberculosis, with low MBC/MIC ratios and MBCs significantly lower than the maximum achievalbe concentrations in serum (Cmax). In contrast, all four drugs had very low bactericidal activities against M. avium: the broth-determined MBCs were significantly higher than the Cmax. On a basis of comparisons with the broth-determined MICs found for susceptible M. tuberculosis strains and with the Cmax, about one-third of 100 M. avium strains tested can be tentatively considered as susceptible to three aminoglycosides (streptomycin, amikacin, and kanamycin) but not to capreomycin. In regard to the MBCs and MICs, the three aminoglycosides tested have about identical potentials as drugs of choice in combination with other drugs for chemotherapy of M. avium disease. The low bactericidal activities of these drugs against M. avium in vitro do not exclude their therapeutic usefulness, because they may produce a synergistic effect in combination with other drugs. Such an option is especially promising for patients whose isolates can be considered susceptible on the basis of the MIC. We found no differences in susceptibility to the four drugs tested for M. avium strains (identified by Gen-Probe) isolated from 50 patients with and 50 patients without acquired immune deficiency syndrome.
Pefloxacin versus ceftazidime in the treatment of a variety of gram-negative-bacterial infections
Authors: Giamarellou H , Perdikaris G , Galanakis N , Davoulos G , Mandragos K , Sfikakis P
Published: June 2012

In a prospective open randomized trial, pefloxacin was given to 53 patients and ceftazidime was given to 50 patients suffering from bronchopneumonia (n = 29), deep soft tissue infection (n = 19), urinary tract infection (n = 28), chronic osteomyelitis in exacerbation (n = 15), chronic otitis media in exacerbation (n = 3), malignant external otitis (n = 3), abdominal abscess (n = 2), septic arthritis (n = 1), acute cholangitis (n = 1), bacterial endocarditis (n = 1), and subacute sinusitis (n = 1). Underlying aggravating factors coexisted in 45 and 41 patients in the pefloxacin and ceftazidime groups, respectively, with 32 and 33 infections characterized as nosocomial and severe in each group, respectively. Pefloxacin was given at a dose of 400 mg intravenously (i.v.) (n = 16) or per os (n = 23) every 8 or 12 h, as well as i.v. followed by per os (n = 14), for 7 to 180 days; and ceftazidime was given at 2 g i.v. every 8 h (n = 45) or 1 g intramuscularly every 8 h (n = 5) for 7 to 56 days. Pseudomonas aeruginosa and various members of the family Enterobacteriaceae predominated in culture specimens. Clinical cure was observed in 38 and 39 patients given pefloxacin and ceftazidime, respectively; 10 and 7 patients were improved; and in 5 and 4 patients treatment failed. Pathogen eradication was observed in 42 and 39 patients, respectively; persistence was observed in 8 and ll patients, respectively, followed by the emergence of resistance in five and four P. aeruginosa strains, respectively (P = not significant). With the exception of photosensitivity rash in seven patients given pefloxacin, all side effects observed in eight and three patients in the pefloxacin and ceftazidime groups, respectively (P < 0.01), were not important and were self-limited. It is concluded that pefloxacin is as effective as ceftazidime in moderate to severe gram-negative-bacterial infections, with similar trends toward development of resistance during therapy.
Cross-resistance of Pseudomonas aeruginosa to ciprofloxacin, extended-spectrum beta-lactams, and aminoglycosides and susceptibility to antibiotic combinations
Authors: Chow A W , Wong J , Bartlett K H , Shafran S D , Stiver H G
Published: June 2012

The susceptibilities of 270 clinical isolates of Pseudomonas aeruginosa from diverse sources (82 burn patients, 76 cystic fibrosis [CF] patients, and 112 other sources) to ciprofloxacin and three other quinolones, nine extended-spectrum beta-lactams, and three aminoglycosides were determined by an agar dilution method in cation-supplemented Mueller-Hinton medium. Ciprofloxacin, ceftazidime, imipenem, and aztreonam were the most active. MICs for burn isolates were consistently higher than those for other isolates for most antibiotics, whereas those for CF strains were consistently lower. Multidrug resistance to aminoglycosides and beta-lactams occurred in 21% of the burn isolates, 2.6% of the CF isolates, and 8.9% of the other isolates. Ninety percent of these strains remained susceptible to ciprofloxacin. Seven percent of the isolates were resistant to ciprofloxacin (MIC, greater than or equal to 2 micrograms/ml). Concurrent resistance to ciprofloxacin and beta-lactams or aminoglycosides was rare (1.8 to 4%). Analysis by Spearman rank correlation revealed a high degree of correlation of MICs among antibiotics within the same class, except for imipenem. An inoculum effect was observed for all antibiotics between 10(6) and 10(4) CFU (P less than 0.05), with those for piperacillin and cefoperazone being the most pronounced (16-fold and 8-fold differences, respectively), and was least apparent for the quinolones, aminoglycosides, imipenem, and aztreonam (twofold differences). Selected strains for which there were high MICs of ciprofloxacin (greater than or equal to 1 micrograms/ml) were tested against ciprofloxacin in combination with other agents in a checkerboard agar dilution assay. Synergistic (summated fractional inhibitory concentration, </=0.5) interactions at clinically achievable concentrations were most frequent with mezlocillin (33%), piperacillin (21%), and (7.6%), aztreonam (3.7%), and the aminoglycosides (3.7%). Antagonism (summated fractional inhibitory concentration, >/= 4) was observed in only one instance (with gentamicin).
Evaluation of cilofungin, a lipopeptide antifungal agent, in vitro against fungi isolated from clinical specimens
Authors: Hanson L H , Stevens D A
Published: June 2012

Cilofungin (LY121019) is a new lipopeptide antifungal drug. We tested this drug against 141 pathogenic fungal isolates. All fungal species were tested by broth dilution at 35 degrees C. Malassezia furfur was tested by agar dilution. The results demonstrate the specificity of cilofungin activity. Candida albicans, Candida tropicalis, and Malassezia pachydermatis were highly susceptible, whereas Candida parapsilosis, Candida pseudotropicalis, Candida krusei, Torulopsis glabrata, Blastomyces dermatitidis, Cryptococcus neoformans, Aspergillus species, M. furfur, and Paracoccidioides brasiliensis were more resistant.
New directions for macrolide antibiotics: pharmacokinetics and clinical efficacy
Authors: Kirst H A , Sides G D
Published: June 2012

Erythromycin and related macrolide antibiotics have recently enjoyed a resurgence of clinical interest. This is a result of activity against organisms which are becoming more prevalent, particularly in immunocompromised hosts and, in addition, better understanding of the unique tissue penetration properties and potential immunomodulating properties of macrolides. Other features of clinical interest possessed by certain of the newer macrolides include the potential for once-daily dosing, resistance to acid degradation in the stomach without enteric coating, and possibly reduced gastrointestinal side effects. The new macrolides are expected to retain the clinical indications of erythromycin, which include upper and lower respiratory tract infections, skin and skin structure infections, and genital tract infections caused by erythromycin-susceptible organisms. In addition, enhanced activity has been demonstrated in animal models and in vitro against toxoplasma, Legionella, Haemophilus, and Campylobacter spp. New macrolide derivatives also show promise to expand the antimicrobial spectrum of erythromycin to include Mycobacterium and Borrelia spp.
Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis
Authors: Takayama K , Kilburn J O
Published: June 2012

Ethambutol at 3.0 micrograms/ml inhibited the transfer of label from D-[14C]glucose into the D-arabinose residue of arabinogalactan in whole cells of a drug-susceptible strain of Mycobacterium smegmatis. This inhibition began almost immediately after exposure of the cells to the drug. When drug-resistant M. smegmatis was used in a similar experiment, no such drug inhibition was detected. A much higher concentration of ethambutol (greater than 50 micrograms/ml) was required to show this inhibition. The drug also inhibited synthesis of arabinose-containing oligosaccharides when a cell-free enzyme system was used. These results suggest that the site of action of ethambutol is somewhere on the pathway between the conversion of D-glucose to D-arabinose and the transfer of arabinose into arabinogalactan. The primary mode of action of ethambutol appears to be inhibition of arabinogalactan synthesis.
Antibacterial and immunostimulatory properties of chemotactic N-formyl peptide conjugates of ampicillin and amoxicillin
Authors: Bycroft B W , Lockey P M , Penrose A , Grout R J , Williams P
Published: June 2012

N-Formyl dipeptide conjugates of ampicillin and amoxicillin related to the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine were synthesized and assessed for antibacterial activity and affinity for the chemotactic peptide receptor of differentiated human promyelocytic leukemia (HL-60) cells. The conjugates and parent beta-lactam antibiotics showed similar antibacterial activities against Escherichia coli and Staphylococcus aureus. The affinity of each conjugate for the chemotactic peptide receptor was determined in a competitive binding assay, using 3H-labeled N-formyl-L-methionyl-L-leucyl-L-phenylalanine. All conjugates bound to the receptor, but with affinities ranging from 1/3 to 1/100 that of the tritiated substrate. There was good correlation between receptor affinity and stimulation of chemotaxis. The peptide-antibiotic conjugates also stimulated the oxidative metabolism of the HL-60 cells by inducing the production of superoxide and hydrogen peroxide as determined by Luminol- and Lucigenin-enhanced chemiluminescence. These conjugates, based on N-formyl-L-methionyl-L-leucyl-L-phenylalanine, thus combine both potent antibacterial and immunostimulatory properties within the same molecule.
In vitro and in vivo activities of clarithromycin against Mycobacterium avium
Authors: Fernandes P B , Hardy D J , McDaniel D , Hanson C W , Swanson R N
Published: June 2012

There is no effective therapy to treat Mycobacterium avium complex infection in patients with acquired immune deficiency syndrome. Clarithromycin (A-56268; TE-031) is a new macrolide which is twofold more active than erythromycin against most aerobic bacteria. In addition, higher levels in serum and tissue are achieved with clarithromycin than with erythromycin. In this study, clarithromycin, erythromycin, difloxacin, temafloxacin, ciprofloxacin, rifampin, amikacin, and ethambutol were tested in vitro and in vivo against the M. avium complex. The MICs for 90% of strains tested were 4 micrograms/ml for clarithromycin, 64 micrograms/ml for erythromycin, 32 micrograms/ml for difloxacin, 8 micrograms/ml for temafloxacin, 4 micrograms/ml for ciprofloxacin, 4 micrograms/ml for rifampin, 32 micrograms/ml for amikacin, and 32 micrograms/ml for ethambutol. Beige mice were infected intravenously with 10(7) CFU of M. avium ATCC 25291. Treatment was started on day 6 after infection and was administered twice a day at 8-h intervals for 9 days. Clarithromycin was the most effective compound in these tests and was effective in reducing the viable bacterial counts in the spleen when it was administered subcutaneously or orally at a dose of 25 mg/kg. Amikacin was the only other compound which showed activity in vivo. The peak concentration in serum at which clarithromycin was active was approximately 1.0 microgram/ml.
Susceptibility of Haemophilus influenzae type b to ampicillin-sulbactam
Authors: Azimi P H , Dunphy M G
Published: June 2012

Seventy-five strains of Haemophilus influenzae type b, including 45 beta-lactamase-positive strains, were tested by MIC and time kill studies for susceptibility to ampicillin-sulbactam at various ratios. beta-Lactamase-negative strains were inhibited by lower concentrations of ampicillin-sulbactam than beta-lactamase-positive organisms. beta-Lactamase-negative strains showed a decrease in CFU per milliliter by a factor of 10(4) after a 24-h incubation with ampicillin-sulbactam. beta-Lactamase-positive isolates showed an initial decrease by a factor of up to 10(2) CFU per milliliter, but by the end of incubation these isolates grew to approximately the same cell density as the antibiotic-free control regardless of ampicillin-sulbactam ratios. Caution should be exercised in the use of this combination in treatment of meningitis, in which a high bacterial density is commonly encountered.
Restriction maps of the regions coding for methicillin and tobramycin resistances on chromosomal DNA in methicillin-resistant staphylococci
Authors: Ubukata K , Nonoguchi R , Matsuhashi M , Song M D , Konno M
Published: June 2012

Chromosomal BamHI DNA fragments containing both the mecA gene encoding the penicillin-binding protein responsible for methicillin resistance and the aadD gene encoding 4',4"-adenylyltransferase responsible for tobramycin resistance were cloned from three methicillin- and tobramycin-resistant strains of Staphylococcus aureus and one strain of Staphylococcus epidermidis. Physical maps of the fragments were similar, suggesting their unique origin.
Penetration of ciprofloxacin into saliva and nasal secretions and effect of the drug on the oropharyngeal flora of ill subjects
Authors: Piercy E A , Bawdon R E , Mackowiak P A
Published: June 2012

The pharmacokinetics of ciprofloxacin and its effect on the oropharyngeal bacterial flora were examined in 21 ill patients being treated for methicillin-resistant Staphylococcus aureus infections or colonization or both. Oral ciprofloxacin (750 mg twice a day) produced peak and trough concentrations in serum of 2.56 +/- 1.80 and 0.97 +/- 0.81 micrograms/ml and steady-state salivary and nasal secretory concentrations of 1.29 +/- 1.0 and 1.84 +/- 0.91 micrograms/ml, respectively. Because of technical problems, nasal secretory concentrations were felt to represent rough approximations of true values. Oral ciprofloxacin therapy did not promote colonization of the oropharynx by gram-negative bacilli.
Topical delivery of liposomally encapsulated interferon evaluated by in vitro diffusion studies
Authors: Egbaria K , Ramachandran C , Kittayanond D , Weiner N
Published: June 2012

The topical delivery of several liposomal interferon formulations was evaluated by in vitro diffusion experiments in an effort to understand the effects of liposomal composition and method of preparation on the deposition of interferon into the stratum corneum and deeper strata of the skin. Application of liposomes prepared from lipids with a composition similar to that of the stratum corneum resulted in almost twice the amount of interferon being deposited in the deeper skin layers than did application of liposomes prepared from phospholipids. Topical application of "skin lipid" liposomes prepared by the dehydration-rehydration method was twice as effective as was topical application of liposomes prepared by the reverse-phase evaporation method with respect to their ability to deposit interferon into the skin strata where the basal cell layers reside. These results are consistent with the effects of liposomal composition and method of preparation on the ability of the formulation to reduce lesion scores in the cutaneous herpes simplex virus type 1 guinea pig model.
Production of cyclosporins by Tolypocladium niveum strains
Authors: Isaac C E , Jones A , Pickard M A
Published: June 2012

Nine strains of Tolypocladium niveum (= inflatum) were compared for their production of cyclosporins. Two of the strains, which were originally from the parental NRRL 8044 strain, were among the lower producers, while seventeen Tolypocladium strains belonging to seven other species produced no detectable cyclosporins. Variable cyclosporin production was observed initially. Once extraction and quantitation methods had been established, spore inoculum density and cultural morphology and carbon and nitrogen sources were found to be among the variables affecting cyclosporin production. Cyclosporin A was identified by cochromatography by using high-performance liquid chromatography, and cyclosporins A, B, and C were identified by gas chromatography-mass spectroscopy; all three compounds exhibited biological activity. They were routinely produced as a mixture in the ratio 7:1:2 in T. niveum UAMH 2472, which was selected on the basis of single-spore isolate total cyclosporin production and was used for most studies. This strain routinely produced total cyclosporin levels of 150 to 200 mg.liter-1 after 12 days of growth on a 2% sorbose-1% vitamin assay Casamino Acids medium.
Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease
Authors: Halstenson C E , Hirata C A , Heim-Duthoy K L , Abraham P A , Matzke G R
Published: June 2012

The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were biexponential. The terminal elimination half-life (t1/2 beta) of tobramycin was markedly reduced (59.62 +/- 25.18 [mean +/- standard deviation] versus 24.71 +/- 5.41 h) and total body clearance (CLP) was significantly increased in the presence of piperacillin (3.45 +/- 1.61 versus 7.16 +/- 1.64 ml/min). In contrast, the t1/2 beta (41.80 +/- 13.24 versus 40.07 +/- 10.37 h) and CLP (5.11 +/- 2.15 versus 5.55 +/- 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.
Pharmacokinetics of lomefloxacin in healthy volunteers: comparison of 400 milligrams once daily and 200 milligrams twice daily given orally for 5 days
Authors: Gros I , Carbon C
Published: June 2012

We evaluated the effect of repeated oral doses (5 days of treatment) on the kinetics of lomefloxacin in volunteers and compared the kinetics after two different regimens, i.e., 400 mg once daily and 200 mg twice daily. After 400 mg of lomefloxacin was given once daily, no significant modification in the pharmacokinetic parameters was noted between the first and the fifth dose (maximum concentration of drug in serum, about 4 mg/liter; elimination half-life, about 6.3 h). After a dose of 200 mg every 12 h, a significant increase in the minimum concentration of drug in serum (0.49 +/- 0.1 and 0.72 +/- 0.2 mg/litter at days 1 and 5, respectively) and the area under the concentration-time curve (about 20%) was noted. The 400-mg regimen is probably adequate for therapeutic use.
In vitro susceptibilities of Plesiomonas shigelloides to 24 antibiotics and antibiotic-beta-lactamase-inhibitor combinations
Authors: Clark R B , Lister P D , Arneson-Rotert L , Janda J M
Published: June 2012

The antibiotic susceptibilities of 29 isolates of Plesiomonas shigelloides were studied with 24 antibiotics and antibiotic-inhibitor combinations. Results indicated that all isolates were susceptible to the cephalosporins, penicillins combined with a beta-lactamase inhibitor, aztreonam, and ciprofloxacin. Most isolates were resistant to the penicillins, possibly via production of a penicillinase.
Pharmacokinetics of a novel quinolone, AT-4140, in animals
Authors: Nakamura S , Kurobe N , Ohue T , Hashimoto M , Shimizu M
Published: June 2012

The pharmacokinetics of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1- piperazinyl)-4-oxoquinoline-3-carboxylic acid (AT-4140) in experimental animals given a single oral dose of 5 mg/kg were studied. The mean peak levels of AT-4140 in plasma of mice, rats, dogs, and monkeys were 0.25, 0.50, 1.14, and 0.49 micrograms/ml, respectively, with mean elimination half-lives of 5.0, 3.8, 8.0, and 11.7 h, respectively. The oral bioavailability of AT-4140 calculated from the ratio of the areas under the concentration-time curve after oral and intravenous administration was 77% in dogs. The levels of AT-4140 in tissue in mice and rats were 1 to 11 times higher than the levels in plasma and 4 to 9 times higher than those of ciprofloxacin in mice. The mean 24-h biliary recovery of AT-4140 in rats was 5.6% of the dose and became 21.3% after beta-glucuronidase treatment. The mean 48-h urinary recoveries of AT-4140 in mice, rats, dogs, and monkeys were 6.7, 12.9, 8.6, and 12.7%, respectively, of the dose and were 7.8, 16.3, 8.9, and 18.9%, respectively, after beta-glucuronidase treatment. The pharmacokinetics of AT-4140 may be characterized by its good tissue penetration and its long half-life in plasma and tissues.
Significance of "extravascular" protein binding for antimicrobial pharmacodynamics in an in vitro capillary model of infection
Authors: Dudley M N , Blaser J , Gilbert D , Zinner S H
Published: June 2012

The effect of protein binding in an "extravascular" space on antimicrobial pharmacodynamics was studied in an in vitro capillary model of infection. Simulated 500-mg oral doses of dicloxacillin (approximately 96% bound) or cephalexin (less than 5% bound) were administered every 6 h for four doses. A 10-fold-higher dose of dicloxacillin was also studied to determine the effect of drug concentration on the reduction of bacterial killing in the presence of protein. Staphylococcus aureus ATCC 25923 was inoculated into peripheral chambers filled with either Mueller-Hinton broth or Mueller-Hinton broth plus 25% human serum. Serial samples for bacterial counts were collected over 24 h. The presence of serum in the chambers significantly reduced bacterial killing by dicloxacillin but not by cephalexin during the first 6 h (two-way analysis of variance, F = 6.04, P less than 0.05) but not at 24 h. Reduction of dicloxacillin activity in serum-containing chambers persisted with the higher dose. These data suggest that despite attaining higher total drug concentrations in protein-containing extravascular spaces with highly bound drugs, protein binding reduces bactericidal activity during the early stages of treatment in this model.
Pharmacokinetics of Ro 23-9424, a dual-action cephalosporin, in animals
Authors: Christenson J G , Chan K K , Cleeland R , Dix-Holzknecht B , Farrish H H , Patel I H , Specian A
Published: June 2012

Ro 23-9424 is a dual-action cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position. The new compound has broad and potent antibacterial activity in vitro and in vivo, reflecting contributions from both the beta-lactam moiety and the quinolone moiety. In animals, the ester bond potentially could be hydrolyzed enzymatically or nonenzymatically, to yield the active metabolites desacetylcefotaxime and fleroxacin. The extent to which Ro 23-9424 acts in vivo as a true dual-action cephalosporin, or acts as a combination of active metabolites, is therefore a function of its pharmacokinetic properties. To investigate these properties, Ro 23-9424 was administered as a single intravenous dose of 20 mg/kg of body weight to mice, rats, dogs, and baboons. Timed plasma samples were assayed by an ion-paired high-pressure liquid chromatography method that allowed detection of both intact Ro 23-9424 and fleroxacin. The pharmacokinetic parameters of Ro 23-9424 were similar to published results for cefotaxime, while concentrations of fleroxacin in plasma were low and fairly constant (about 1 to 3 micrograms/ml) in all species, suggesting that excretion of the intact molecule is a major route of elimination for Ro 23-9424, as it is for cefotaxime. For technical reasons, urinary recovery of Ro 23-9424 was not quantitated, but intact Ro 23-9424 was found in high concentrations (greater than 400 micrograms/ml) in mouse urine aspirated directly from the bladder. In all species, low concentrations of free fleroxacin in plasma persisted after the elimination of Ro 23-9424 was complete, but fleroxacin did not accumulate unduly in a 14-day multiple-dose experiment in baboons. Thus, it seems likely that the activity seen in vivo is primarily due to intact Ro 23-9424, although the low levels of free fleroxacin may also have some therapeutic significance.
Antimicrobial properties of N-carboxybutyl chitosan
Authors: Muzzarelli R , Tarsi R , Filippini O , Giovanetti E , Biagini G , Varaldo P E
Published: June 2012

N-Carboxybutyl chitosan, a modified chitin of crustacean origin, displayed inhibitory, bactericidal, and candidacidal activities when tested against 298 cultures of various pathogens. Examination by electron microscopy showed that microbial cells exposed to N-carboxybutyl chitosan underwent marked morphological alterations. The data are of importance in defining the suitability of N-carboxybutyl chitosan as a wound dressing.
Loracarbef concentrations in middle ear fluid
Authors: Kusmiesz H , Shelton S , Brown O , Manning S , Nelson J D
Published: June 2012

Loracarbef concentrations in plasma and middle ear fluid (MEF) were measured in specimens obtained approximately 2 h after doses of 7.5 or 15 mg/kg. The mean +/- standard deviation concentrations in MEF were 2.0 +/- 2.6 mg/liter (48% of the concentration in plasma) after the smaller dose and 3.9 +/- 2.6 mg/liter (42% of the concentration in plasma) after the larger dose. With the larger dose, the concentrations in MEF were greater than the MIC for 90% of strains of the usual pathogens of acute otitis media tested in 16 of 17 specimens.
Effect of Oral Antacid Administration on the Pharmacokinetics of Oral Fluconazole
Authors: Thorpe John E. , Baker Nigel , Bromet-Petit Maguy
Published: June 2012

Absorption and elimination of fluconazole after oral administration of a 100-mg capsule were unaffected by concomitant administration of an antacid containing aluminum and magnesium hydroxides.
Ceftriaxone-sulbactam combination in rabbit endocarditis caused by a strain of Klebsiella pneumoniae producing extended-broad-spectrum TEM-3 beta-lactamase
Authors: Caron F , Gutmann L , Bure A , Pangon B , Vallois J M , Pechinot A , Carbon C
Published: June 2012

We studied the activity of the combination of sulbactam and ceftriaxone against a Klebsiella pneumoniae strain producing TEM-3, a new extended-broad-spectrum beta-lactamase, in an endocarditis model. In vitro, ceftriaxone was strongly inactivated in the presence of TEM-3 (MBC, 128 micrograms/ml with an inoculum of 5 x 10(5) CFU/ml). A marked inoculum effect was demonstrated with sulbactam: effective concentrations of inhibitor needed to reduce the MIC and MBC of ceftriaxone to similar levels increased from 1 microgram/ml in the presence of an inoculum of 5 x 10(5) CFU/ml to 20 micrograms/ml in the presence of an inoculum of 1 x 10(7) CFU/ml. In vivo, sulbactam given at 200 mg/kg of body weight every 12 h, a dosage higher than that previously reported to be effective against rabbit endocarditis caused by other microorganisms, was not sufficient to restore the complete activity of ceftriaxone given at 30 mg/kg once daily for 4 days. This insufficient activity may be correlated with the presence of a high level of beta-lactamase inside the vegetations, as indicated by a quantitative in vitro assay of beta-lactamase activity in the cardiac vegetation, suggesting an insufficient inactivation of the extended-broad-spectrum beta-lactamase in vivo.
Safety and pharmacokinetics of rimantadine small-particle aerosol
Authors: Atmar R L , Greenberg S B , Quarles J M , Wilson S Z , Tyler B , Feldman S , Couch R B
Published: June 2012

The safety and pharmacokinetics of rimantadine administered by small-particle aerosol were assessed in healthy adults and adults with acute influenza virus infection. Aerosolized rimantadine delivered at a concentration of 40 micrograms/liter of air was associated with nasal burning and irritation in normal volunteers. A concentration of 20 micrograms/liter of air was well tolerated for up to 12 h by normal volunteers and was not associated with any changes in pulmonary function, as measured by routine spirometry, plethysmography, or diffusion capacity of carbon monoxide. Mean peak levels of drug in serum were approximately 10-fold lower after 12 h of aerosol administration than they were after oral administration of 200 mg (29.7 versus 255 ng/ml, respectively), while mean nasal wash levels were approximately 100-fold higher (6,650 versus 66.6 ng/ml, respectively). Elimination half-lives were similar after both aerosol and oral administration (24.1 and 25.2 h, respectively), and rimantadine urinary excretion was less than 1% per 24 h in both groups. Twenty micrograms of aerosolized rimantadine per liter of air given 12 h daily for 3 days to nine adults with acute influenza virus infection was well tolerated. Levels in plasma after 12 h of aerosol inhalation were similar to those in normal volunteers, but were higher at the end of the third treatment than they were at the end of the first treatment (88.3 versus 47.9 ng/ml, respectively). Thus, rimantadine delivered via small-particle aerosol at a dose of 20 micrograms/liter of air was well tolerated in normal volunteers and in those with acute influenza and was associated with high local concentrations.
In vitro activities of cefoperazone and sulbactam singly and in combination against cefoperazone-resistant members of the family Enterobacteriaceae and nonfermenters
Authors: Fass R J , Gregory W W , D'Amato R F , Matsen J M , Wright D N , Young L S
Published: June 2012

Among 28,000 isolates of the family Enterobacteriaceae and nonfermenters isolated at multiple medical centers, 1,084 (4%) were resistant to cefoperazone (MIC, greater than or equal to 64 micrograms/ml) and 1,711 (6%) exhibited cefoperazone MICs of 2 to 32 micrograms/ml. Ninety-six percent of these 2,795 isolates produced beta-lactamase, as determined by the nitrocefin test. Sulbactam alone (8 micrograms/ml) was inactive against 99.6% of the isolates other than Acinetobacter calcoaceticus and Pseudomonas cepacia. Sulbactam enhanced the activity of cefoperazone against 56% of the isolates of the family Enterobacteriaceae and 44% of the nonfermenters. In the presence of sulbactam concentrations of less than or equal to 8 micrograms/ml, 65% of the cefoperazone-resistant isolates had reductions in cefoperazone MICs of greater than or equal to 2 log2 dilution steps and were susceptible to less than or equal to 32 micrograms/ml. Antagonism was not observed.
Intraoperative concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue
Authors: Chin A , Okamoto M P , Gill M A , Sclar D A , Berne T V , Yellin A E , Heseltine P N , Appleman M D
Published: June 2012

To evaluate concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue after intravenous administration, patients greater than or equal to 16 years old diagnosed with acute cholecystitis were randomly assigned to receive ofloxacin (400 mg) intravenously every 12 h or ceftazidime (2 g) intravenously every 8 h. Doses of each regimen were given preoperatively. Serum, bile fluid, and gallbladder wall tissue samples of consecutive patients in the ofloxacin group were obtained intraoperatively. The samples were frozen at -70 degrees C until analyzed by high-pressure liquid chromatography. Twenty-three patients (6 males and 17 females) were evaluated. The mean (+/- the standard deviation) ofloxacin concentrations in serum, bile fluid, and gallbladder wall tissue were 2.9 +/- 2.4 and 6.0 +/- 7.9 micrograms/ml and 3.1 +/- 2.9 micrograms/g, respectively. The mean number of doses each patient received before surgery was 5.3 +/- 3.0, and the mean delta time (time elapsed between last antibiotic administration and when intraoperative samples were obtained) was 9.6 +/- 7.5 h. The mean tissue-to-serum ratio was 1.2 +/- 0.5, and the mean bile-to-serum ratio was 2.3 +/- 1.4. The mean serum ofloxacin concentrations were not statistically different from the concentrations in bile (P = 0.1) and tissue (P = 0.7) at the mean delta time. The study revealed that concentrations of ofloxacin in serum, bile fluid, and gallbladder tissue after intravenous dosing were adequate against susceptible organisms found in the biliary tract.
Comparative evaluation of the pharmacokinetics of N-methylthiotetrazole following administration of cefoperazone, cefotetan, and cefmetazole
Authors: Welage L S , Borin M T , Wilton J H , Hejmanowski L G , Wels P B , Schentag J J
Published: June 2012

The comparative pharmacokinetics and in vivo production of N-methylthiotetrazole (NMTT) were evaluated following administration of cefoperazone, cefotetan, and cefmetazole. In a randomized-crossover manner, 11 healthy male volunteers received single 2-g intravenous doses of each agent and serial blood and urine samples were collected. Concentrations of NMTT and the parent compound in plasma, urine, and the reconstituted antibiotic solution were determined by high-pressure liquid chromatography. The amounts of NMTT administered were 6.06 +/- 0.46, 14.4 +/- 0.87, and 17.4 +/- 1.06 mg for cefoperazone, cefotetan, and cefmetazole, respectively (P less than 0.05). The mean NMTT plasma concentration-time profiles following administration of each cephalosporin were markedly different. Six hours after dosing, NMTT concentrations in plasma following cefoperazone administration were higher than those following administration of cefmetazole and cefotetan. Urinary recoveries of NMTT averaged 137.0 +/- 37.1, 38.3 +/- 6.98, and 25.2 +/- 5.95 mg following administration of cefoperazone, cefotetan, and cefmetazole, respectively (P less than 0.01). The apparent amount of NMTT produced in vivo, calculated by subtracting the amount of NMTT administered from the amount of NMTT excreted in urine, was significantly lower following cefmetazole administration than after administration of cefoperazone and cefotetan (P less than 0.01). The discrepancy between in vitro NMTT production (cefmetazole greater than cefotetan greater than cefoperazone) and the amount of NMTT formed in vivo and excreted unchanged (cefoperazone greater than cefotetan greater than cefmetazole) suggests that in vivo production of NMTT is dependent on the disposition of the parent cephalosporin. These results further suggest that cephalosporins which undergo extensive biliary excretion, such as cefoperazone, are associated with the greatest amount of in vivo NMTT release, whereas cephalosporins which are primarily renally excreted, such as cefmetazole, are associated with the lowest in vivo production of NMTT.
Treatment of bone, joint, and vascular-access-associated gram-positive bacterial infections with teicoplanin
Authors: Greenberg R N
Published: June 2012

Teicoplanin, a glycopeptide antibiotic, was evaluated for safety and efficacy in the treatment of vascular-access-associated bacteremias and of bone and joint infections due to susceptible gram-positive organisms. Of 35 patients enrolled, 26 had osteomyelitis, 8 had vascular-access-associated bacteremias, and 1 had a joint infection. A total of 38 gram-positive isolates were identified: 23 Staphylococcus aureus and 6 coagulase-negative staphylococcus and 9 streptococcus isolates. After at least 6 months of follow-up, 17 patients were evaluable for efficacy: 10 of 14 (71%) with osteomyelitis and 3 of 3 with vascular-access-associated bacteremias had full resolution of their infections. Inadequate debridement, the presence of metal, and inadequate dosing were likely causes of two failures and two relapses in patients with osteomyelitis. For all but two organisms, teicoplanin MICs were less than or equal to 2 micrograms/ml. Patients who responded had median peak and trough serum bactericidal levels at serum dilutions of 1:64 and 1:16; trough levels of teicoplanin in serum were greater than 30 micrograms/ml. Patients did not respond as expected to daily doses of 4 mg/kg of body weight, which consequently were increased to greater than or equal to 15 mg/kg. Audiology testing of 20 patients found 2 with a mild loss of high-frequency hearing; 1 patient complained of tinnitus. Patients tolerated peak levels in serum as high as 127 micrograms/ml and trough levels of 49 micrograms/ml. However, 5 of 18 patients (28%) whose daily dose was greater than or equal to 12 mg/kg developed drug fever and rash and had teicoplanin discontinued. Further study of the antibiotic at such higher doses is needed.
Inhibition of Amphotericin B (Fungizone) Toxicity to Cells by Egg Lecithin-Glycocholic Acid Mixed Micelles
Authors: Brajtburg Janina , Elberg Svetlana , Kobayashi George S. , Medoff Gerald
Published: June 2012

Mixed micelles prepared from egg lecithin and the sodium salt of glycocholic acid markedly inhibited amphotericin B toxicity to mammalian cells without significantly affecting the antifungal effects of the drug.
Pharmacokinetics and in vivo activity of liposome-encapsulated gentamicin
Authors: Swenson C E , Stewart K A , Hammett J L , Fitzsimmons W E , Ginsberg R S
Published: June 2012

Gentamicin sulfate was encapsulated in liposomes composed solely of egg phosphatidylcholine and administered via intravenous injection to rats and mice. The total gentamicin activity (regardless of whether it was free or liposome associated) in serum and selected tissues was determined for 24 h (serum) or up to 15 weeks (tissues) by using a microbiological assay. The mean half-lives in serum of a single 20-mg/kg dose of free (nonencapsulated) gentamicin in mice and rats were estimated to be 1.0 and 0.6 h, respectively, whereas a similar dose of encapsulated drug had apparent mean half-lives of 3.8 h in mice and 4.0 h in rats. In both species, the apparent half-life in serum of the liposomal formulation increased as the dose increased. Liposome encapsulation resulted in higher and more prolonged activity in organs rich in reticuloendothelial cells (especially spleen and liver). In acute septicemia infections in mice, the liposomal formulation showed enhanced prophylactic activity (as determined by calculation of the 50% protective dose). In a model of murine salmonellosis, liposomal gentamicin greatly enhanced survival when given as a single dose (10 mg/kg) at 1 or 2 days after infection as well as up to 7 days before infection.
Analysis of acquired ciprofloxacin resistance in a clinical strain of Pseudomonas aeruginosa
Authors: Masecar B L , Celesk R A , Robillard N J
Published: June 2012

Decreasing susceptibility to ciprofloxacin was investigated in sequential clinical isolates of Pseudomonas aeruginosa from a patient on ciprofloxacin therapy. All isolates were verified as the same strain by DNA probe. MICs of all quinolones tested were 16- to 32-fold higher for the posttherapy isolates; nonquinolone MICs were unchanged. The isolates were compared by analyses of outer membrane proteins and lipopolysaccharide composition, antimicrobial susceptibilities, measurement of accumulation of ciprofloxacin, and inhibition of DNA gyrase activity by ciprofloxacin and nalidixic acid. No significant changes in outer membrane proteins or ciprofloxacin accumulation were observed; however, both posttherapy isolates lost the long chain O-polysaccharide component of lipopolysaccharide. Preparations of DNA gyrase from the quinolone-resistant posttherapy isolates were 16- to 32-fold less sensitive to inhibition of supercoiling by ciprofloxacin and nalidixic acid than was gyrase from the pretherapy isolate. Inhibition studies on combinations of heterologous gyrase subunits showed that decreased inhibition was conferred by the resistant gyrase A subunits. Thus, acquired resistance to ciprofloxacin in this strain involved an alteration in the A subunit of DNA gyrase and was associated with changes in lipopolysaccharide.
In vitro evaluation of WIN 57273, a new broad-spectrum fluoroquinolone
Authors: Jones R N , Barry A L
Published: June 2012

WIN 57273 is a new fluoroquinolone that has an expanded spectrum of activity against Staphylococcus spp. (MIC for 90% of isolates [MIC90], 0.008 microgram/ml), Enterococcus faecalis (MIC90, 0.06 microgram/ml), Bacillus spp. (MIC90, 0.03 micrograms/ml), Listeria monocytogenes (MIC90, 0.06 microgram/ml), Streptococcus spp. (MIC90, 0.03 microgram/ml), and Bacteroides fragilis group strains (MIC90, 0.5 microgram/ml). Like other fluoroquinolone compounds, WIN 57273 was active against members of the family Enterobacteriaceae (97% of strains inhibited by less than or equal to 2 micrograms/ml), Haemophilus, Branhamella, and Neisseria strains (100% susceptible), Acinetobacter spp. (100% susceptible), and Pseudomonas aeruginosa (68% susceptible). We observed that WIN 57273 was very active against cephalosporin- or aminoglycoside-resistant gram-negative strains but shared cross-resistance with other fluoroquinolones. Increasing inoculum concentrations had minimal effects on WIN 57273 MICs, and the drug was considered to be bactericidal based on reference MBC and kill curve analyses. Unlike most previously studied drugs in this class, WIN 57273 had increased activity (three- to fourfold) at low pH. Rates of mutation to WIN 57273 resistance at eight times its MIC were in the range of 5.6 x 10(-8) to greater than 1.4 x 10(-9). This new compound possesses a wide potential spectrum of use, and it should be evaluated further by in vitro and in vivo studies.