bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of DL-alpha-difluoromethylornithine in a rat model of Pneumocystis carinii pneumonia
Authors: Clarkson A B , Williams D E , Rosenberg C
Published: June 2012

Pneumocystis carinii pneumonia is often the terminal event for patients with the acquired immunodeficiency syndrome. Eflornithine (DL-alpha-difluoromethylornithine [DFMO]; Ornidyl; Merrell Dow Research Institute, Cincinnati, Ohio) has been used successfully against this protozoan disease in limited clinical trials, although not all patients respond to therapy. In contrast, results of the only reported experiments with DFMO in an animal model were negative. We retested DFMO against P. carinii in an immunosuppressed rat model by inclusion of 3% DFMO in the drinking water, a dose rate about twice that used previously. A combination of trimethoprim and sulfamethoxazole, a proven anti-P. carinii agent, was used as a positive control. After 3 weeks of anti-P. carinii pneumonia therapy, the surviving rats were sacrificed and the degree of parasitosis was judged by examination of lung sections stained with silver methenamine to reveal cysts. In three separate experiments, DFMO showed definite anti-P. carinii pneumonia activity; the parasitosis of DFMO-treated animals was significantly less than that of control animals (P less than 0.001 for all experiments). DFMO was not as active as trimethoprim-sulfamethoxazole, however. Several other experimental therapies were tested, including dapsone and two additional antiprotozoal agents: suramin and diminazene aceturate (Berenil; Farbwerke Hoechst, Frankfurt, Federal Republic of Germany). Diminazene aceturate, a veterinary drug related to the standard anti-P. carinii pneumonia agent pentamidine, was very active (P less than 10(-10]. Suramin and dapsone were weakly active. The combinations suramin-diminazene aceturate and suramin-DFMO were tested, but they were antagonistic rather than synergistic.
DNA gyrase of Staphylococcus aureus and inhibitory effect of quinolones on its activity
Authors: Takahata M , Nishino T
Published: June 2012

DNA gyrase from Staphylococcus aureus FDA 209P was partially purified by lysostaphin treatment, saturation with ammonium sulfate, and affinity chromatography on heparin-Sepharose and with a concentrator (Centricon 30). It was found to consist of two subunits: alpha and beta. The ability of new quinolone antibacterial agents such as norfloxacin, ofloxacin, and ciprofloxacin to inhibit DNA gyrase activity and cell growth was investigated. The inhibitory effects of the new quinolones against the activity of S. aureus DNA gyrase were in parallel with their antibacterial activities. The 50% inhibitory doses of norfloxacin, ofloxacin, and ciplofloxacin were 0.34, 0.31, and 0.24 micrograms/ml, respectively, while the 50% inhibitory doses of nalidixic acid and cinoxacin, which were less active against S. aureus FDA 209P, were 100 micrograms/ml or more.
Plasma bactericidal activity after administration of erythromycin estolate and erythromycin ethylsuccinate to healthy volunteers
Authors: Bérubé D , Kirouac D , Croteau D , Bergeron M G , Lebel M
Published: June 2012

In a crossover design study, we compared the plasma bactericidal activities of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) after administration of a single oral dose to 12 healthy volunteers. Both erythromycin esters displayed very good plasma bactericidal activities against Streptococcus pneumoniae. The median bactericidal titers produced in plasma against Streptococcus pyogenes and Streptococcus pneumoniae were significantly higher with erythromycin estolate than with the ethylsuccinate ester at both 2 and 8 h after dosing (P less than 0.05 by Student's t test). Both erythromycin esters showed rather weak bactericidal activity against Branhamella catarrhalis; a further look at these results indicated that erythromycin estolate presented 50% of the plasma samples at 2 h with bactericidal titers superior or equal to 1:8, versus 11% for the ethylsuccinate ester. Of the 60 plasma bactericidal activity tests performed against Staphylococcus aureus, only 6 (10%) and 3 (5%) exhibited titers of 1:8 or greater for erythromycin estolate and erythromycin ethylsuccinate, respectively. Clinical trials are warranted in which these products are compared in infections other than Streptococcus pyogenes pharyngitis, for which the clinical superiority of erythromycin estolate has been demonstrated.
Tetracycline resistance and TetM in oral anaerobic bacteria and Neisseria perflava-N. sicca
Authors: Roberts M C , Moncla B J
Published: June 2012

Tetracycline-resistant organisms isolated from six patients with periodontal disease included Bacteroides spp., Eubacterium spp., Fusobacterium nucleatum, Neisseria perflava-N. sicca, Peptostreptococcus anaerobius, Veillonella parvula, and facultative streptococci. All but the Bacteroides spp. and Eubacterium spp. hybridized with the TetM determinant. An additional 417 bacterial strains were screened, and 4% of both the oral streptococci and the Fusobacterium spp. hybridized with the TetM probe.
Heterogeneity of 6'-N-acetyltransferases of type 4 conferring resistance to amikacin and related aminoglycosides in members of the family Enterobacteriaceae
Authors: Tran Van Nhieu G , Collatz E
Published: June 2012

DNA-DNA hybridization and immunoblotting were used to assess the relatedness between the 6'-N-acetyltransferases of type 4 encoded by plasmid pAZ007 from a clinical isolate of Serratia marcescens and those encoded by NR79 and R5. The absence of detectable DNA-DNA homology and of immunological cross-reactivity suggests the existence of at least two distinct 6'-N-acetyltransferase type 4 genes that mediate amikacin resistance in gram-negative bacilli.
Ribavirin prophylaxis and therapy for experimental argentine hemorrhagic fever
Authors: McKee K T , Huggins J W , Trahan C J , Mahlandt B G
Published: June 2012

Junin virus-infected rhesus macaques received prophylactic and therapeutic ribavirin to assess the potential of this drug for treating humans with Argentine hemorrhagic fever. When ribavirin was administered intramuscularly at the time of experimental infection with the lethal P3790 strain of Junin virus, all animals were protected from clinical disease. A delay in the initiation of therapy until after the onset of illness resulted in improvement and resolution of systemic signs of disease; however, survivors subsequently developed a late-onset central nervous system infection which was fatal in two of three animals. Side effects of ribavirin included thrombocytosis and severe anemia, both of which resolved promptly on withdrawal of drug therapy. Results of this study suggest that ribavirin may prove useful in treating humans with Argentine hemorrhagic fever.
Beta-lactam resistance in Aeromonas spp. caused by inducible beta-lactamases active against penicillins, cephalosporins, and carbapenems
Authors: Bakken J S , Sanders C C , Clark R B , Hori M
Published: June 2012

Use of cefoperazone in a patient with Aeromonas caviae in the respiratory tract selected a mutant that constitutively produced beta-lactamase. This mutant, in contrast to its parental strain with an inducible beta-lactamase, showed enhanced resistance to newer cephalosporins and aztreonam. This observation suggested that species of Aeromonas, like those of other genera with inducible beta-lactamases, may pose therapeutic problems associated with the rapid development of multiple beta-lactam resistance. Thus, a study was designed to identify the beta-lactamases in 12 strains representing four species of Aeromonas and assess their role in drug resistance. Eleven strains possessed inducible beta-lactamases. One strain showed no detectable activity. An analysis of substrate and inhibitor profiles, isoelectric points, and beta-lactam susceptibility patterns revealed the presence of at least four distinguishable inducible beta-lactamases. These enzymes were involved in the resistance of strains within the genus to penicillins, cephalosporins, aztreonam, and imipenem but not cefoxitin. Unlike most other organisms with inducible beta-lactamases, all four strains of A. caviae, one of four strains of A. sobria, and one of three strains of A. hydrophila possessed two distinct inducible beta-lactamases. Furthermore, substrate and inhibitor profiles revealed that many of these Aeromonas beta-lactamases were distinct from inducible enzymes that have been characterized in other genera of gram-negative bacteria.
Vancomycin concentrations in infected and noninfected human bone
Authors: Graziani A L , Lawson L A , Gibson G A , Steinberg M A , MacGregor R R
Published: June 2012

Concentrations of vancomycin in bones of 14 patients undergoing total hip arthroplasty (group 1) and 5 patients with osteomyelitis (group 2) were studied. Group 1 received vancomycin, 15 mg/kg intravenously, 1 h prior to anesthesia. Group 2 received doses adjusted to achieve peak levels in serum of 20 to 30 micrograms/ml and trough levels of less than 12 micrograms/ml; bone specimens were collected during surgical debridement. The specimens were pulverized and eluted into phosphate buffer, and the supernatants were analyzed for vancomycin content by fluorescence polarization immunoassay. In group 1, vancomycin was detectable in all cancellous specimens with a mean concentration of 2.3 +/- 4.0 micrograms/g (range, 0.5 to 16 micrograms/g); 10 of 14 cortical specimens had detectable vancomycin; the mean cortical concentration was 1.1 +/- 0.8 micrograms/g (range, not detectable to 2.6 micrograms/g). In group 2, vancomycin was detectable in only two of five cortical bone specimens (mean concentration, 5.9 +/- 3.5 micrograms/g). Cancellous bone was obtained in one patient; the vancomycin concentration was 3.6 micrograms/g. In most patients the vancomycin levels in bones were higher than the MIC for susceptible staphylococci following single prophylactic doses. In the few infected patients studied, penetration was variable and deserves further study.
Randomized, double-blind comparison of ciprofloxacin and trimethoprim-sulfamethoxazole for complicated urinary tract infections
Authors: Allais J M , Preheim L C , Cuevas T A , Roccaforte J S , Mellencamp M A , Bittner M J
Published: June 2012

In a prospective, randomized, double-blind study, the effect of ciprofloxacin (250 mg orally, twice daily) was compared with that of trimethoprim-sulfamethoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole orally, twice daily) on 45 patients with complicated urinary tract infections. Pretherapy isolates were all members of the family Enterobacteriaceae. Isolates were eradicated from 18 (82%) of 22 patients treated with ciprofloxacin and 12 (52%) of 23 patients treated with trimethoprim-sulfamethoxazole during and 5 to 9 days after therapy (P = 0.035). Both groups had similar relapse and reinfection rates at 4 to 6 weeks posttherapy. Adverse effects were mild and reversible, occurring in 1 of 22 in the ciprofloxacin group and 6 of 23 in the trimethoprim-sulfamethoxazole group. Disk diffusion susceptibility tests correlated better with broth macrodilution for ciprofloxacin than for trimethoprim-sulfamethoxazole. Ciprofloxacin is a safe, effective alternative to trimethoprim-sulfamethoxazole for the treatment of complicated urinary tract infections.
Mechanism of action and in vitro and in vivo activities of S-6123, a new oxazolidinone compound
Authors: Daly J S , Eliopoulos G M , Willey S , Moellering R C
Published: June 2012

The in vitro activity of S-6123, a synthetic antimicrobial compound of the new oxazolidinone series, was compared with those of other orally administered agents against 328 clinical isolates. The compound was moderately active (MICs, 16 to 64 micrograms/ml) against 90% of staphylococci, nonenterococcal streptococci, and Haemophilus influenzae, including strains resistant to beta-lactam antibiotics. S-6123 was minimally active against enterococci and facultative gram-negative bacilli. Nevertheless, the compound had significant activity in a lethal rat Escherichia coli peritonitis model at serum concentrations of one-tenth the MIC against the infecting organism. The drug demonstrated only bacteriostatic activity against susceptible organisms. Studies to define the mechanism of antibacterial action revealed that S-6123 inhibited ribosomal protein synthesis without inhibiting DNA or RNA synthesis. This compound represents a new series of antibacterial agents not related to any other antibacterial compound of natural or synthetic origin.
Rapid determination of MICs of 15 antichlamydial agents by using an enzyme immunoassay (Chlamydiazyme)
Authors: Bianchi A , Scieux C , Salmeron C M , Casin I , Perol Y
Published: June 2012

An enzyme immunoassay (EIA), Chlamydiazyme (Abbott Laboratories), was evaluated for its determination of MICs of 15 antimicrobial agents against Chlamydia trachomatis (MRC-1, LB, TRIC/GB/MRC-1 Gf [ATCC VR-1]). The inoculum size, incubation time, and enhancers were defined for the assessment of chlamydial antigen synthesis in HeLa 229 cells seeded as monolayers in 96-well plates. MICs were determined and defined as the lowest antibiotic concentrations required to inhibit, after 24 or 48 h of incubation, antigen production as determined by the EIA. The MICs (after 48 h) were similar to those determined by the peroxidase-antiperoxidase staining of inclusions. MIC determinations after 24 h were suitable for screening the activities of quinolones, but less so for measuring the susceptibility of C. trachomatis to macrolides and tetracyclines. MIC determination by EIA was rapid, appropriate for standardization, and less cumbersome than determination by quantification of inclusions.
Resistance to ticarcillin-potassium clavulanate among clinical isolates of the family Enterobacteriaceae: role of PSE-1 beta-lactamase and high levels of TEM-1 and SHV-1 and problems with false susceptibility in disk diffusion tests
Authors: Sanders C C , Iaconis J P , Bodey G P , Samonis G
Published: June 2012

Thirty-four clinical isolates of the family Enterobacteriaceae from the University of Texas M. D. Anderson Cancer Center appeared resistant to ticarcillin-potassium clavulanate in agar dilution and broth macrodilution tests. Among those isolates producing a single non-class I beta-lactamase, resistance was due to production of high levels of TEM-1, SHV-1, or class IV enzymes. In five Escherichia coli isolates, production of low levels of PSE-1 was responsible for resistance which seemed due to rapid hydrolysis of ticarcillin rather than diminished susceptibility of PSE-1 to inhibition by potassium clavulanate. Comparisons of dilution and disk diffusion tests revealed major discrepancies, with 65% false susceptibility in the disk test. Revision of the interpretive criteria used for disk diffusion tests from less than or equal to 11 to less than or equal to 18 mm for resistance is proposed to resolve these discrepancies until clinical data are obtained which can be used to determine which in vitro test is most predictive of therapeutic outcome. These new criteria would diminish false susceptibility without introducing false resistance.
Distribution of cefpirome (HR 810) to exudate in the croton oil-induced rat granuloma pouch and its therapeutic effects on experimental infections in the pouch
Authors: Arai S , Kobayashi S , Hayashi S , Sakaguchi T
Published: June 2012

Therapeutic effects of intravenously administered cefpirome on experimental bacterial infections in croton oil-induced rat granuloma pouches were compared with those of ceftazidime, moxalactam, cefoperazone, and cefotaxime. Its pharmacokinetic profile in pouch exudate was also examined. Cefpirome showed bactericidal effects and long-lasting bacterial growth-inhibitory effects in granuloma pouches infected in Escherichia coli Ec-7, and its effects were almost equal to those of the other antibiotics. Against Pseudomonas aeruginosa TM-11 infection, cefpirome was more active than moxalactam, cefoperazone, and cefotaxime and comparable to ceftazidime. Cefpirome had the strongest activity against Staphylococcus aureus Smith infection among the five antibiotics, showing bactericidal effects and long-lasting bacterial growth-inhibitory effects. The level of cefpirome in pouch exudate peaked at 1 h after administration, with a value of 16.4 micrograms/ml, and declined in a pattern similar to that of ceftazidime. When compared in peak level, the exudate level of cefpirome was 1.8 to 2.6 times higher than the values of moxalactam, cefoperazone, and cefotaxime. The in vitro exudate protein binding of cefpirome was 8.8%, which was the lowest among the antibiotics used.
Transposon-mediated amikacin resistance in Klebsiella pneumoniae
Authors: Tolmasky M E , Chamorro R M , Crosa J H , Marini P M
Published: June 2012

A multiresistant Klebsiella pneumoniae strain isolated from neonates in Mendoza, Argentina, harbored a 48-kilobase-pair (kbp) plasmid, pMET1, with genetic determinants for resistance to amikacin and also ampicillin, kanamycin, streptomycin, and tobramycin. This plasmid was compared with pJHCMW1, a previously isolated 11-kbp plasmid carrying transposon Tn1331, which encodes resistance to amikacin, as well as ampicillin, kanamycin, streptomycin, and tobramycin, and which was originally present in a K. pneumoniae strain that caused an outbreak in a hospital in Buenos Aires, Argentina. The comparison demonstrated that the replication regions of the two plasmids are unrelated. However, in pMET1 an 11-kbp transposition element, Tn1331.2, was identified; it was closely related to Tn1331, with the difference that a 3-kbp BamHI DNA fragment carrying the aminoglycoside resistance genes was duplicated in tandem.
Transfer of beta-lactamase plasmids from Neisseria gonorrhoeae to Neisseria meningitidis and commensal Neisseria species by the 25.2-megadalton conjugative plasmid
Authors: Roberts M C , Knapp J S
Published: June 2012

Two highly tetracycline-resistant, beta-lactamase-producing Neisseria gonorrhoeae strains were used as donors for conjugation with Neisseria meningitidis and commensal Neisseria species. We found that both strains were able to transfer the 4.4- and 3.2-megadalton beta-lactamase plasmids to the recipients tested, with frequencies between 10(-1) and 10(-9).
Roxithromycin disposition in tonsils after single and repeated administrations
Authors: Galioto G B , Ortisi G , Mevio E , Sassella D , Bartucci F , Privitera G
Published: June 2012

Levels of roxithromycin in serum and tissue were investigated in 29 subjects undergoing tonsillectomy. A total of 13 subjects received a single oral dose of 300 mg, and 16 received four oral doses 12 h apart as follows: a 300-mg loading dose followed by three 150-mg doses. Measurable levels of roxithromycin were present in tonsil samples of 11 of 13 subjects in the first group. The mean levels in tonsils and serum were 0.8 microgram/g and 6.7 micrograms/ml, resulting in a mean tissue/serum ratio of 0.16. In the multiple-dose group, roxithromycin was found in 14 of 16 subjects at mean levels in tonsils and serum of 1.6 micrograms/g and 8.7 micrograms/ml, and the tissue/serum ratio was 0.23.
Transferable vancomycin and teicoplanin resistance in Enterococcus faecium
Authors: Leclercq R , Derlot E , Weber M , Duval J , Courvalin P
Published: June 2012

Enterococcus faecium BM4165 and BM4178, isolated from immunocompromised patients, one treated with vancomycin, were inducibly resistant to high levels of the glycopeptide antibiotics vancomycin and teicoplanin but susceptible to the new lipopeptide daptomycin (LY146032). Strain BM4165 was also resistant to macrolidelincosamide-streptogramin B-type (MLS) antibiotics. The genes conferring resistance to glycopeptides and to MLS antibiotics in strain BM4165 were carried on plasmids pIP819 and pIP821, respectively; pIP819 also carried genes that encoded resistance to MLS antibiotics. The two plasmids, which were distinct although related, were self-transferable to other E. faecium strains. Plasmid pIP819 could also conjugate to E. faecalis, Streptococcus sanguis, S. pyogenes, S. lactis, and Listeria monocytogenes, in which it conferred inducible glycopeptide resistance, but not to S. aureus. Glycopeptide-inactivating activity was not detected, and the biochemical mechanism of resistance remains unknown. Based on this first report of transferable resistance to glycopeptides, we anticipate dissemination of resistance to these antibiotics in gram-positive cocci and bacilli in which it can be phenotypically expressed.
Comparative in vitro activities of six new fluoroquinolones and other oral antimicrobial agents against Campylobacter pylori
Authors: Simor A E , Ferro S , Low D E
Published: June 2012

The in vitro susceptibilities of 56 clinical isolates of Campylobacter pylori to six new fluoroquinolones and other oral antimicrobial agents were determined by an agar dilution technique. Ciprofloxacin was the most active of the fluoroquinolones (MIC for 90% of strains tested [MIC90], 0.05 microgram/ml). Other fluoroquinolones had variable activities, although most isolates were moderately susceptible to fleroxacin (MIC90, 4 micrograms/ml) and lomefloxacin (MIC90, 4 micrograms/ml).
Zidovudine antagonizes the action of pyrimethamine in experimental infection with Toxoplasma gondii
Authors: Israelski D M , Tom C , Remington J S
Published: June 2012

The effect of zidovudine (azidothymidine; AZT) on the action of pyrimethamine against Toxoplasma gondii was investigated. Zidovudine was found to antagonize the toxoplasmacidal effect of low concentrations of pyrimethamine in vitro, and in vitro synergism of pyrimethamine and sulfadiazine against T. gondii was reversed by zidovudine. Zidovudine also antagonized the therapeutic effect of pyrimethamine in mice acutely infected with T. gondii.
In vitro activities of quinolones against enterococci resistant to penicillin-aminoglycoside synergy
Authors: Sahm D F , Koburov G T
Published: June 2012

The MICs and MBCs of CI-934, ciprofloxacin, difloxacin (A-56619), A-56620, norfloxacin, enoxacin, amifloxacin, and coumermycin were determined for 43 clinical isolates of Enterococcus faecalis known to be resistant to penicillin-aminoglycoside synergy. Results were compared with those obtained for 37 synergy-susceptible E. faecalis and 22 Enterococcus faecium strains. Although no substantial differences in quinolone activities were observed between synergy-resistant and -susceptible E. faecalis strains, CI-934 and ciprofloxacin were the drugs that demonstrated the greatest bactericidal activity against both types of E. faecalis. The MBCs of the other quinolones were generally within a single twofold dilution of the MICs, but their antienterococcal activity did not approach that of CI-934 or ciprofloxacin. The MBCs for 90% of the isolates of CI-934 for synergy-resistant and -susceptible E. faecalis strains were 1 and less than or equal to 0.5 microgram/ml, respectively. The ciprofloxacin MBC for 90% of the E. faecalis strains tested was 1 microgram/ml. For E. faecium isolates the CI-934 and ciprofloxacin MBCs for 90% of the isolates were 8 and 4 micrograms/ml, respectively. Time-kill assays performed with synergy-susceptible enterococcal strains showed that the bactericidal activities of both CI-934 and ciprofloxacin were less than those of the penicillin-aminoglycoside combinations tested. However, against synergy-resistant isolates the activities of these two quinolones were comparable with and sometimes greater than those of penicillin-aminoglycoside combinations.
Fatty acid alterations and polymyxin B binding by lipopolysaccharides from Pseudomonas aeruginosa adapted to polymyxin B resistance
Authors: Conrad R S , Galanos C
Published: June 2012

Lipopolysaccharides were extracted from freeze-dried cells of Pseudomonas aeruginosa PAO1 (polymyxin B susceptible), isolate A (polymyxin B resistant), and isolate A-reverted (polymyxin B intermediate resistance) by either the phenol-chloroform-petroleum ether or the modified phenol-water method. Isolate A and isolate A-reverted had drastic losses of 2-hydroxydodecanoic acid and significant decreases in 3-hydroxydecanoic acid. Concentrations of amide-linked 3-hydroxydecanoic acid were similar in all three strains. Minor alterations were noted in the composition of 3-deoxy-D-manno-2-octulosonic acid, heptose, phosphate, neutral sugars, and amino compounds. The concentrations of rhamnose in isolate A and of rhamnose and glucose in isolate A-reverted were significantly different from those in PAO1. Trace amounts of mannose and other minor unidentified carbohydrates were detected in all strains. Polymyxin B included in isolate. A growth medium complexed with lipopolysaccharides and remained bound throughout purification. PAO1 lipopolysaccharides bound more polymyxin B than did isolate A lipopolysaccharides. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated minor differences in smooth- and rough-form lipopolysaccharides of the different strains. We propose that loss of hydroxy fatty acids from lipopolysaccharides perturbs outer membrane hydrophobicity and is a contributing factor to polymyxin B adaptive resistance.
Selection of an oral prodrug (BRL 42810; famciclovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine; penciclovir]
Authors: Vere Hodge R A , Sutton D , Boyd M R , Harnden M R , Jarvest R L
Published: June 2012

The limited oral absorption in rodents of the antiherpesvirus agent 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine (BRL 39123 [penciclovir; British approved name]) prompted a search for oral prodrugs. The 6-deoxy derivative of penciclovir (BRL 42359) and the corresponding diacetyl and dipropionyl 6-deoxy derivatives (BRL 42810 [famciclovir; British approved name] and BRL 43599) were tested as oral prodrugs. The in vivo absorption (dose, 0.2 mmol/kg) and the conversion to the active compound, penciclovir, were determined in rats. Compared with the sodium salt of penciclovir given intravenously, the bioavailabilities of penciclovir from orally administered penciclovir, BRL 42359, famciclovir, and BRL 43599 were 1.5, 9, 41, and 27%, respectively. These prodrugs and 6-deoxyacyclovir were tested for stability in rat duodenal contents and for metabolism in rat intestinal wall homogenate, liver homogenate, and blood and in the corresponding human fluids and tissues. Famciclovir was much more stable than BRL 43599 in human duodenal contents (half-lives, greater than 2 h and 7 min, respectively) yet was efficiently converted to penciclovir by the tissue homogenates. The major metabolic pathway was by deacetylation followed by oxidation at the 6 position. The rate of oxidation was comparable to that of 6-deoxyacyclovir, which is known to be converted efficiently to acyclovir in humans. Famciclovir was selected for further evaluation and progression to studies in humans. These subsequent studies confirmed that, after oral dosing with famciclovir, more than half the dose was absorbed and rapidly converted to penciclovir.
Dose-ranging study of fleroxacin for treatment of uncomplicated Chlamydia trachomatis genital infections
Authors: Bowie W R , Willetts V , Megran D W
Published: June 2012

Men and women with suspected or proven genital infections caused by Chlamydia trachomatis were enrolled in a double-blind study to evaluate the efficacy and tolerability of fleroxacin. Patients received either 400, 600, or 800 mg once daily for 7 days and were monitored approximately 2, 4, and 7 weeks after initiation of therapy. In men monitored for at least 6 weeks or until failure of the therapy, fleroxacin failed to eradicate C. trachomatis in three of eight on the 400-mg regimen, in one of four on the 600-mg regimen, and in four of seven on the 800-mg regimen. All five women monitored for at least 6 weeks became culture negative. There was no association between in vitro susceptibility of C. trachomatis to fleroxacin and outcome, with MICs being 4 to 8 migrograms/ml for almost all isolates tested. Among those with positive cultures for Ureaplasma urealyticum initially, the first follow-up cultures remained positive in 8 (29%) of 28 men and 8 (50%) of 16 women. Independent of culture results, men with nongonococcal urethritis receiving 800 mg of fleroxacin were significantly more likely to show a clinical response than men receiving 400 or 600 mg (93 versus 54%). Adverse events were frequent, often severe, and dose related. Insomnia and photosensitivity reactions were the most important. The adverse reactions and unacceptably high rates of microbiologic failure resulted in premature termination of the study.
Adverse reactions in a dose-ranging study with a new long-acting fluoroquinolone, fleroxacin
Authors: Bowie W R , Willetts V , Jewesson P J
Published: June 2012

New fluoroquinolones have generally been well tolerated. In a double-blind evaluation of oral fleroxacin, using 400, 600, or 800 mg once daily for 7 days in an ambulatory setting for treatment of uncomplicated genital infections, we encountered unexpectedly high rates of adverse reactions. The objective of this analysis was to determine whether any factors in addition to dose could be found to account for our observations. Adverse reactions developed in 66 (84%) of 79 individuals, and severe reactions arose in 38 (48%). Most frequent were central nervous system reactions (70%), with insomnia being especially frequent (49%); gastrointestinal reactions (39%) and photosensitivity reactions (10%) were also common. Development of any reaction (central nervous system reactions, insomnia, and severe intestinal reactions) was dose related. Development of photosensitivity reactions correlated with an outdoor occupation. No other factors, including usual daily caffeine use, correlated with the development of adverse reactions. In our study, fleroxacin taken as a single daily 600- or 800-mg dose was associated with an unacceptably high rate of adverse reactions. Other studies are required to determine whether this problem is unique to fleroxacin or will occur with higher doses of other fluoroquinolones possessing similar chemical modifications and/or good tissue penetration and very long half-lives.
Ex vivo study of serum bactericidal titers and killing rates of daptomycin (LY146032) combined or not combined with amikacin compared with those of vancomycin
Authors: Van der Auwera P
Published: June 2012

Twelve volunteers, in two groups of six, received daptomycin at a dose of 1 or 2 mg/kg. In addition, they received in a randomly allocated order amikacin (500 mg), daptomycin-amikacin, and vancomycin (500 mg). Thirty-five clinical isolates, including Staphylococcus aureus, S. epidermidis, Corynebacterium sp. group JK, and Enterococcus faecalis, were tested in vitro for the measure of the serum bactericidal titers and killing rates. The mean peak concentrations of daptomycin in serum 1 h after the administration of 1 and 2 mg/kg were 11 and 20 micrograms/ml, respectively. At 24 h after the administration of 2 mg/kg, the mean level in serum was 1.9 micrograms/ml, which is higher than the MICs for susceptible pathogens. Daptomycin and amikacin provided identical concentrations in serum whether given alone or in combination. Among the six regimens tested, those including daptomycin provided the highest and the most prolonged serum bactericidal titers against S. aureus, S. epidermidis, and E. faecalis. The killing rates measured by the killing curves were correlated with the concentration/MIC and concentration/MBC ratios of daptomycin for all strains tested. Significant killing occurred once the concentration of daptomycin in the serum 4- to 6-fold the MIC or 1- to 1.2-fold the MBC. The combination of daptomycin and amikacin had no effect on either the serum bactericidal titers or the rates of killing. Only vancomycin provided significant killing of the strains of Corynebacterium sp. group JK.
Teicoplanin metabolism in rats
Authors: Zerilli L F , Cavenaghi L , Bernareggi A , Assandri A
Published: June 2012

This study was done to see whether teicoplanin undergoes metabolic transformation in rats. Sprague-Dawley rats were given 7.6 mg of [14C]teicoplanin (904 U/mg, 7.6 muCi/mg) per kg intravenously; 73.2 +/- 4.0% of the administered radioactivity and 59.1 +/- 4.8% of the administered microbiological activity were recovered in the 24-h urine samples. The difference between these two values was due to adsorption of teicoplanin to the urinary sediment, making some of the antibiotic not available for microbiological determination. In fact, after a sample or urine was filtered through an Acrodisc (0.45 micron pore size), radiochemical and microbiological data for the filtrate were very similar. Possible metabolites were looked for by high-performance liquid chromatographic analysis of the teicoplanin complex composition in the urine samples, with both UV and radioactivity detection. The quantitation, based on the 14C percentage in each peak, showed that no more than 3 to 5% of the [14C]teicoplanin underwent metabolic and/or chemical transformation.
Bioequivalence assessment of zidovudine (Retrovir) syrup, solution, and capsule formulations in patients infected with human immunodeficiency virus
Authors: Drew R H , Weller S , Gallis H A , Walmer K A , Bartlett J A , Blum M R
Published: June 2012

The objectives of this open-labeled, multiple-dose, three-way-crossover trial were to evaluate the safety and tolerance of zidovudine (Retrovir) oral syrup and to assess the bioequivalence of this formulation relative to zidovudine solution and capsule formulations in human immunodeficiency virus-infected patients. Over the 7-day study, 12 adult male subjects received 12 administrations each of the capsule, solution, and syrup formulations every 4 h (six times daily) in a randomized sequence. Frequent blood samples were collected over the 4-h period after dose 12 was administered. Zidovudine concentrations in plasma were determined by a specific and sensitive radioimmunoassay. Results from statistical analyses indicated that all three formulations were bioequivalent with respect to systemic availability (area under the time-concentration curve) and that the syrup was also equivalent to the solution with respect to the maximum peak concentration in serum. The lower relative maximum peak concentration in serum (approximately 81%) and small delays in time to peak concentration (less than 30 min) of the capsule formulation as compared with the liquid formulations are thought to be due to the additional processes of disintegration and dissolution associated with capsule administration. All three preparations were well tolerated during the 7-day study.
Gentamicin pharmacokinetics, nephrotoxicity, and prediction of mortality in febrile neutropenic patients
Authors: Bianco T M , Dwyer P N , Bertino J S
Published: June 2012

The pharmacokinetics of gentamicin in 34 febrile neutropenic patients (40 courses) were compared with those in 40 nonneutropenic patients receiving the drug. No pharmacokinetic differences were seen in half-life, volume of distribution (liter per kilogram; total and ideal body weight), or clearance (milliliter per minute per 1.73 m2). The incidences of nephrotoxicity in the two groups were not statistically different. Because of the small number of patients with positive cultures, no relationship between initial peak serum gentamicin concentration and mortality could be determined. Mortality risk factors that were determined to be statistically important included presence of pneumonia, persistent fever in the presence of anti-infective therapy of more than 1 week duration, and peak serum creatinine of greater than 1.2 mg/dl. Initial aminoglycoside dosing in the febrile neutropenic patient should be similar to that in the nonneutropenic patient, with concentrations in serum monitored and doses adjusted accordingly.
In vitro and in vivo antibacterial activities of KB-5246, a new tetracyclic quinolone
Authors: Kotera Y , Mitsuhashi S
Published: June 2012

The in vitro and in vivo antibacterial activities of KB-5246, a tetracyclic quinolone, were compared with those of ciprofloxacin, ofloxacin, and norfloxacin. KB-5246 demonstrated a broad antibacterial spectrum. The in vitro activity of KB-5246 against gram-negative bacteria was higher than that of ofloxacin or norfloxacin and was comparable to that of ciprofloxacin. KB-5246 demonstrated the greatest activity against gram-positive bacteria of the four agents tested. Among Streptococcus pyogenes strains resistant to 1.56 micrograms of norfloxacin per ml, there were 26 strains susceptible to 0.2 micrograms of KB-5246 per ml. Similarly, among the Staphylococcus aureus and Staphylococcus epidermidis strains resistant to 3.13 micrograms of norfloxacin per ml, there were 23 S. aureus and 11 S. epidermidis strains susceptible to 0.39 micrograms of KB-5246 per ml. Among the Streptococcus pneumoniae and Enterococcus faecalis strains resistant to 12.5 micrograms of norfloxacin per ml, there were 5 S. pneumoniae and 10 E. faecalis strains susceptible to 0.39 micrograms of KB-5246 per ml. KB-5246 had bactericidal activity at the MIC. KB-5246 demonstrated excellent antibacterial activity against various systemic infections in mice. After oral administration, KB-5246 was as active as ofloxacin and about two times more active than norfloxacin.
Phosphanilic acid inhibits dihydropteroate synthase
Authors: Eagon R G , McManus A T
Published: June 2012

Intact cells of Pseudomonas aeruginosa were more susceptible to phosphanilic acid (PA) than cells of Escherichia coli. In cell extracts, the dihydropteroate synthases of P. aeruginosa and E. coli were about equally susceptible to inhibition by PA. These results suggest that cells of P. aeruginosa are more permeable to PA than cells of E. coli. Although a weak inhibitor, PA acted on dihydropteroate synthase in the same manner as the sulfonamides with which PA is structurally related. Inhibition of E. coli by PA in a basal salts-glucose medium was prevented by p-aminobenzoic acid (pABA). However, pABA did not protect P. aeruginosa from PA under these conditions, possibly because pABA itself exhibited an inhibitory effect. PA also appeared to have a second mode of action. The mechanism was not elucidated.
ampG is essential for high-level expression of AmpC beta-lactamase in Enterobacter cloacae
Authors: Korfmann G , Sanders C C
Published: June 2012

Mutants of Enterobacter cloacae 55 were studied to delineate more completely the genetics of inducible expression of AmpC beta-lactamase. E. cloacae 55M-L, derived by mutagenesis from a mutant with high-level cefotaxime resistance (MIC, greater than 64 micrograms/ml), E. cloacae 55M, demonstrated a novel phenotype by producing only low levels of AmpC constitutively. Neither the parental phenotype of E. cloacae 55M nor the wild-type phenotype of E. cloacae 55 could be restored in E. cloacae 55M-L by the introduction of functional ampR, ampC, or ampD genes. Cloning each of these genes from E. cloacae 55M-L confirmed the same genotype for this mutant as for its parental strain. Mutation of E. cloacae 55M-L to the E. cloacae 55M phenotype was found to occur spontaneously at a frequency of 10(-8). All such revertants demonstrated an inducible wild-type phenotype after introduction of a functional ampD. These results suggested that the E. cloacae 55M-L phenotype was due to a mutation in an as yet unrecognized gene, designated ampG. Verification of this gene was obtained by the restoration of the E. cloacae 55M phenotype in E. cloacae 55M-L by introduction of a cloned 2.9-kilobase BamHI fragment from the E. cloacae 55 chromosome. Transformation of both ampG and ampD into E. cloacae 55M-L reconstituted the inducible wild-type phenotype. These results indicate that ampG is required for the activation of ampC by AmpR. Without ampG, neither induction nor high-level expression of AmpC is possible. It is likely that the ampG gene product and AmpD together modulate the ability of AmpR to activate ampC expression.
Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency
Authors: Kneer J , Tam Y K , Blouin R A , Frey F J , Keller E , Stathakis C , Luginbuehl B , Stoeckel K
Published: June 2012

The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLS), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min per kg to 0.14 +/- 0.04 and 0.04 +/- 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 +/- 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 +/- 0.74 versus 14.8 +/- 6.14 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 0.05). Based on these observations, it is recommended that patients with CLcr of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily. Patients with CLcr between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLcr of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.
Biliary excretion and choleretic effect of cefmetazole in rats
Authors: Gonzalez J , Fernandez C , Marińo E , Morales A , Jimenez R
Published: June 2012

The effect of cefmetazole, a broad-spectrum cephalosporin, on bile flow and composition in rats was studied. Intravenous injection of cefmetazole at doses ranging from 40 to 400 mumol/kg of body weight led to an increase in its biliary concentration and excretion rate, with a maximum at 30 min after injection. Excretion of cefmetazole into bile was associated with a marked choleresis. The magnitude of the increase in bile flow was dose dependent, with a maximal increase at a dose of 200 mumol/kg. Cefmetazole administration did not affect the secretion of bile acids or their osmotic activities, whereas the bile acid-independent bile flow increased by 49% at a dose of 200 mumol/kg. Cefmetazole administration at a dose of 200 mumol/kg significantly increased the biliary outputs of sodium, potassium, chloride, and bicarbonate (+36, +56, +28, and +31%, respectively) compared with outputs of controls. A linear relationship was observed between bile flow and cefmetazole excretion, 44 microliters of bile being produced per mumol of cefmetazole excreted into bile. Our results demonstrate that cefmetazole induces choleresis by stimulating bile acid-independent bile flow. This effect appears to be partly due to the osmotic properties of cefmetazole transported into bile.
In vitro activity of AT-4140 against clinical bacterial isolates
Authors: Kojima T , Inoue M , Mitsuhashi S
Published: June 2012

The activity of AT-4140, a new fluoroquinolone, was evaluated against a wide range of clinical bacterial isolates and compared with those of existing analogs. AT-4140 had a broad spectrum and a potent activity against gram-positive and -negative bacteria, including Legionella spp. and Bacteroides fragilis. The activity of AT-4140 against gram-positive and -negative cocci, including Acinetobacter calcoaceticus, was higher than those of ciprofloxacin, ofloxacin, and norfloxacin. Its activity against gram-negative rods was generally comparable to that of ciprofloxacin. Some isolates of methicillin-resistant Staphylococcus aureus (MIC of methicillin, greater than or equal to 12.5 micrograms/ml) were resistant to existing quinolones, but many of them were still susceptible to AT-4140 at concentrations below 0.39 micrograms/ml. The MICs of AT-4140, ciprofloxacin, ofloxacin, and norfloxacin for 90% of clinical isolates of methicillin-resistant S. aureus were 0.2, 12.5, 6.25, and 100 micrograms/ml, respectively. AT-4140 was bactericidal for each of 20 clinical isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa at concentrations near the MICs. AT-4140 inhibited the supercoiling activity of DNA gyrase from E. coli.
Teicoplanin pharmacokinetics in patients undergoing continuous ambulatory peritoneal dialysis after intravenous and intraperitoneal dosing
Authors: Guay D R , Awni W M , Halstenson C E , Kenny M T , Keane W F , Matzke G R
Published: June 2012

The pharmacokinetics of teicoplanin after single 6-mg/kg intravenous and intraperitoneal doses were studied in five noninfected patients undergoing continuous ambulatory peritoneal dialysis. Biological samples were assayed for teicoplanin content by a microbiological assay technique. Terminal disposition half-life (266.4 +/- 51.9 h [mean +/- standard error of the mean]) was prolonged and total body clearance (0.040 +/- 0.004 ml/min per kg) was reduced compared with values previously reported in subjects with normal renal function. The volume of distribution at steady state (1.15 +/- 0.19 liters/kg) was higher than values previously reported in subjects with normal renal function (0.56 to 0.72 liter/kg). Peritoneal dialysis clearance (0.007 +/- 0.001 ml/min per kg) accounted for only 16.1% of total body clearance. The absolute systemic bioavailability of teicoplanin after intraperitoneal administration was 81.5 +/- 10.7%.
Reactivation of peptidoglycan synthesis in ether-permeabilized Escherichia coli after inhibition by beta-lactam antibiotics
Authors: Talbot M K , Schaefer F , Brocks V , Christenson J G
Published: June 2012

The recovery of peptidoglycan-synthesizing activity after inhibition by beta-lactam antibiotics was investigated in ether-permeabilized cells of Escherichia coli B. Such cells synthesize sodium dodecyl sulfate-insoluble peptidoglycan when provided with UDP-linked precursors and Mg2+. The ability of beta-lactam antibiotics to inhibit the synthesis of peptidoglycan was correlated with their affinity for penicillin-binding proteins 1A and 1Bs. Penicillin-binding protein 1Bs is thought to be the major peptidoglycan synthetase in E. coli and is a major lethal target for beta-lactam antibiotics. Ether-treated bacteria were preincubated with concentrations of beta-lactams sufficient to completely inhibit peptidoglycan synthesis and then treated with beta-lactamases to inactivate free antibiotic prior to measurement of peptidoglycan synthesis. At 40 min after beta-lactamase treatment, the rate of peptidoglycan synthesis was about 74% of the control rate in cells pretreated with ampicillin, but only 15% of the control in cells pretreated with penicillin G or azlocillin. Reversal of inhibition by several other antibiotics fell between these extremes. When cross-linking of peptidoglycan was measured specifically, reversal of inhibition by ampicillin also occurred more readily than that by penicillin G. Reactivation of peptidoglycan synthesis was not due to de novo synthesis of penicillin-binding proteins since it occurred under conditions that did not allow incorporation of [14C]leucine. We conclude that there is considerable variation in the stability of the inactive acyl enzymes formed between various beta-lactams and penicillin-binding protein 1Bs, with those formed by penicillin G being relatively long-lived.