bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful therapy of experimental chronic foreign-body infection due to methicillin-resistant Staphylococcus aureus by antimicrobial combinations
Authors: Chuard C , Herrmann M , Vaudaux P , Waldvogel F A , Lew D P
Published: June 2012

We compared the efficacy of a long-duration (3-week) therapy of vancomycin, fleroxacin, fleroxacin plus rifampin, and vancomycin plus fleroxacin and rifampin in a recently developed rat model of chronic staphylococcal foreign-body infection. Subcutaneous tissue cages containing polymethylmethacrylate coverslips were infected with 1 x 10(5) to 5 x 10(5) CFU of methicillin-resistant Staphylococcus aureus. Three weeks later, a quantitative culturing of the fluid that had accumulated in the cages was done (mean, 6.72 log10 CFU/ml; n = 110) and treatment was initiated after randomization. The CFUs in the cage fluid were counted on days 11 and 22 and 1 week after the termination of treatment; in addition, a final culture of coverslips (surface-bound microorganisms) was performed. The three-drug therapy was significantly superior to the other treatments on day 11 (a 5.16 log10 decrease of bacterial counts versus a 2.12 log10 to 2.94 log10 decrease for vancomycin, fleroxacin, and fleroxacin plus rifampin; P less than 0.01). On day 22, count decreases were 4.16 log10 for vancomycin, 4.91 log10 for fleroxacin (vancomycin versus fleroxacin, not significant), 6.14 log10 for two-drug therapy, and 6.34 log10 for three-drug therapy (vancomycin-fleroxacin-rifampin versus fleroxacin-rifampin, not significant; fleroxacin-rifampin versus monotherapies, P less than 0.01); the numbers of CFU in most cage fluids were under the detection limit (20 CFU/ml) in combination groups. One week after the end of treatment, 92% of fluids and coverslips (detection limit, 1 CFU) were culture negative with tritherapy, 88% of fluids and 41% of coverslips were negative with bitherapy, and less than 12% of fluids and coverslips were negative with single drugs (for coverslips, P was <0.01 for vancomycin-fleroxacin-rifampin versus fleroxacin-rifampin and P was <0.001 for fleroxacin-rifampin versus the monotherapies). No mutants resistant to rifampin or fleroxacin were detected. In conclusion, antimicrobial combinations were highly effective and superior to single drugs in treating a chronic staphylococcal foreign-body infection for 3 weeks. The three-drug therapy decreased bacterial counts more rapidly than the two-drug therapy under study and appeared to be curative in most cases.
Effects of quinolones on nucleoid segregation in Escherichia coli
Authors: Georgopapadakou N H , Bertasso A
Published: June 2012

The effects of quinolone antibiotics on nucleoid segregation in growing Escherichia coli were examined by using fleroxacin (Ro 23-6240, AM 833) as a prototype compound. At levels that were close to its MIC and induced growth arrest and filamentation, fleroxacin caused large nucleoids to appear in midcell, suggesting inhibition of nucleoid segregation. With increasing fleroxacin concentrations, nucleoids became progressively smaller, suggesting inhibition of DNA replication. Removal of fleroxacin restored normal cell and nucleoid morphology in filaments with large nucleoids but not in filaments with small nucleoids. The results are consistent with inhibition of chromosome decatenation at low quinolone concentrations (bacteriostatic effect) and DNA supercoiling at high concentrations (bactericidal effect).
In vitro activities of lytic peptides against the sporozoites of Cryptosporidium parvum
Authors: Arrowood M J , Jaynes J M , Healey M C
Published: June 2012

Cryptosporidium parvum is a protozoan parasite that causes mild to severe diarrheal disease in animals and humans. There are currently no effective chemotherapeutic agents available for the treatment of cryptosporidiosis. Recent studies have described small, naturally occurring antimicrobial lytic peptides with antiprotozoal activities. In the present study, the anticryptosporidial activities of three synthetic lytic peptides were determined in an in vitro sporozoite susceptibility assay. Sporozoite viability was assessed microscopically by the uptake of the vital dyes fluorescein diacetate and propidium iodide. Sporozoite viability was reduced by 93.5% following a 60-min exposure to 10 microM Hecate-1 at 37 degrees C. Shiva-10 reduced sporozoite viability by approximately 74.0% after a 60-min exposure at 100 microM and 37 degrees C. The cecropin-b analog SB-37 reduced sporozoite viability by 6.0% following a 60-min exposure at 100 microM and 37 degrees C. A control peptide showed no anticryptosporidial activity.
D-lactic acid production as a monitor of the effectiveness of antimicrobial agents
Authors: Smith S M
Published: June 2012

Most bacteria at an infection site obtain energy by the breakdown of glucose via microaerophilic or anaerobic pathways and in the process yield various end products. In this study, production of D-lactic acid by Staphylococcus aureus and Escherichia coli was correlated with glucose utilization by bacteria during exposure to antibiotics at subinhibitory, inhibitory, and suprainhibitory concentrations. D-Lactic acid production was further correlated with production of a tissue-destroying enzyme, hyaluronidase, by S. aureus. For E. coli, all agents tested showed dose-related bacterial killing, with the most noticeable being with ampicillin, piperacillin, and ciprofloxacin. Imipenem, ciprofloxacin, and chloramphenicol had the most dose-related effects on D-lactic acid production. With few exceptions, hyaluronidase production correlated well with D-lactic acid production in S. aureus. Subinhibitory concentrations of erythromycin and clindamycin effectively decreased accumulation of D-lactic acid and hyaluronidase. Determination of D-lactic acid production may perhaps serve as a means of independently monitoring the effects of antimicrobial agents on bacterial metabolic activity, which is an important aspect of antimicrobial action that remains relatively unexplored.
In vitro activity and beta-lactamase stability of GR69153, a new long-acting cephalosporin
Authors: Chin N X , Gu J W , Fang W , Neu H C
Published: June 2012

GR69153, a new parenteral cephalosporin, inhibited 90% of Escherichia coli, Klebsiella oxytoca, Proteus mirabilis, Citrobacter diversus, shigellae, and salmonellae at less than 0.25 micrograms/ml (MIC90). It had activity comparable to those of ceftazidime, cefpirome, cefepime, and E-1040. Against cephalosporinase-producing Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens, MICs ranged from 0.12 to greater than 32 micrograms/ml, and cefpirome and cefepime were the most active agents against these species. Pseudomonas aeruginosa was highly susceptible to GR69153, and for this organism the MIC90 was less than or equal to 2 micrograms/ml, which was similar to the E-1040 MIC90, but most Pseudomonas cepacia and Xanthomonas maltophilia isolates were resistant. GR69153 inhibited Haemophilus influenzae and Moraxella branhamella at less than or equal to 0.5 micrograms/ml. For Staphylococcus aureus GR69153 MICs were similar to those of ceftazidime and E-1040. Enterococci and listeriae were resistant to GR69153, but Streptococcus pyogenes and Streptococcus pneumoniae were inhibited by 0.5 micrograms/ml. The activity of GR69153 was not affected by serum. GR69153 was not inactivated by the beta-lactamases of Staphylococcus aureus, TEM-1, TEM-2, SHV-1, and BRO-1, but it was hydrolyzed by TEM-3, TEM-9, and morganellae. GR69153 had overall activity comparable to those of commercially available parenteral cephalosporins or those found in clinical investigations. It is more active against bacteroides than most available aminothiazolyl parenteral cephalosporins are. GR69153 is hydrolyzed by the new plasmid beta-lactamases, and thus, its primary value may be related to its pharmacological properties.
8-Aminoquinolines from Walter Reed Army Institute for Research for treatment and prophylaxis of Pneumocystis pneumonia in rat models
Authors: Bartlett M S , Queener S F , Tidwell R R , Milhous W K , Berman J D , Ellis W Y , Smith J W
Published: June 2012

Three 8-aminoquinolines from the Walter Reed Army Institute for Research (WRAIR), WR6026, WR238605, and WR242511, strongly inhibited Pneumocystis carinii growth in vitro at 1 microgram/ml. This activity was similar to that of primaquine. In rat therapy models, the WRAIR compounds affected Pneumocystis pneumonia at doses as low as 0.25 mg/kg (WR242511) or 0.5 mg/kg (WR6026 and WR238605). At these doses, primaquine alone was ineffective as therapy. In a rat prophylaxis model, all three WRAIR 8-aminoquinolines were extremely effective at daily doses of 0.57 mg/kg, showing activity greater than that of primaquine at this dosage and comparable to that of trimethoprim-sulfamethoxazole at 50/250 mg/kg.
Novel quinolone resistance mutations of the Escherichia coli DNA gyrase A protein: enzymatic analysis of the mutant proteins
Authors: Hallett P , Maxwell A
Published: June 2012

Using the techniques of gap misrepair mutagenesis and site-directed mutagenesis, we have generated two novel quinolone resistance mutations of the Escherichia coli DNA gyrase A protein. DNA sequencing showed these mutations to be Ser-83----Ala and Gln-106----Arg. The mutant proteins were overproduced and purified, and their enzymatic properties were analyzed and compared with those of the wild-type enzyme. With ciprofloxacin and other quinolones, the inhibition of DNA supercoiling, relaxation, and decatenation and the induction of DNA cleavage were investigated for both wild-type and mutant enzymes. In each assay, the mutant enzymes were found to require approximately 10 times more drug to inhibit the reaction or induce cleavage than was the wild-type enzyme. However, the Ca2(+)-directed DNA cleavage reaction was indistinguishable for wild-type and mutant gyrases. We discuss models for the gyrase-mediated bactericidal effects of quinolone drugs.
Differing activities of quinolones against ciprofloxacin-susceptible and ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus
Authors: Maple P A , Hamilton-Miller J M , Brumfitt W
Published: June 2012

The in vitro activities of nine quinolones (seven fluoroquinolones, nalidixic acid, and acrosoxacin) against methicillin-resistant Staphylococcus aureus (MRSA) were compared with those of the glycopeptides teicoplanin and vancomycin. MICs against 160 strains of ciprofloxacin-susceptible (MIC, less than 2.0 micrograms/ml) MRSA and 40 strains of ciprofloxacin-resistant (MIC, greater than or equal to 2.0 micrograms/ml) MRSA were determined. The following MICs for 50% of the strains tested (in micrograms per milliliter) were obtained for ciprofloxacin-susceptible and -resistant strains, respectively: tosufloxacin, 0.06 and 2.0; ofloxacin, 0.25 and 16; ciprofloxacin, 0.5 and 16; pefloxacin, 0.5 and 32; acrosoxacin, 1.0 and greater than 256; enoxacin, 1.0 and 64; fleroxacin, 1.0 and 32; norfloxacin, 2.0 and 64; nalidixic acid, 64 and 512; teicoplanin, 1.0 and 1.0; vancomycin, 2.0 and 2.0. In mutation rate studies using a range of antibiotic concentrations to reflect those achievable in vivo, resistant mutants grew only on plates containing nalidixic acid (rate of mutation to resistance, 10(-7) to 10(-8) and on plates containing low concentrations of ciprofloxacin, enoxacin, and norfloxacin (rate of mutation to resistance, 10(-8) to 10(-9). In time-kill studies, 99.9% killing was found within 8 h for all of the quinolones tested (norfloxacin and nalidixic acid were not tested). Teicoplanin and vancomycin were less rapidly bactericidal. For the clinical isolates of ciprofloxacin-resistant MRSA, different levels and patterns of quinolone resistance were found. Generally, cross-resistance among the fluoroquinolones was complete; however, incomplete cross-resistance did occur with the nonfluorinated quinolone acrosoxacin.
Altered phenotypes associated with ampD mutations in Enterobacter cloacae
Authors: Korfmann G , Sanders C C , Moland E S
Published: June 2012

A study was done to determine the genetic locus responsible for altered expression of AmpC beta-lactamase in Enterobacter cloacae 1194E and several mutants derived from E. cloacae 029. These phenotypes were defined by units of enzyme activity found in sonic extracts of cells before and after induction with cefoxitin and included (units uninduced/units induced) the wild-type (7/219), high-level constitutive (10,911/10,862), temperature-sensitive (at 30 degrees C 82/706 and at 42 degrees C 5,031/6,020), and hyperinducible (19/1,688) phenotypes. When the ampD region of each E. cloacae strain was cloned and introduced into an ampD mutant Escherichia coli strain, the altered phenotypes were found to reside within this locus. Furthermore, transformants containing wild-type ampD were poorly inducible at 42 degrees C while those with high-level constitutive or hyperinducible ampD were unaffected by temperature. Since the source of ampD was the only variable in these E. coli transformants, these results suggested that ampD encodes a protein that is involved in sensing the inducer. To test this possibility, the responses to different inducers of E. coli transformants containing various ampD regions were assessed. In the presence of wild-type ampD, transformants responded equally to cefoxitin and cefotetan, regardless of temperature. In the presence of temperature-sensitive ampD, induction by cefotetan was similar to that by cefoxitin at 30 degrees C but greater than that by cefoxitin at 42 degrees C. These results suggest that ampD encodes a protein involved in induction of AmpC beta-lactamase in E. cloacae.
Penetration of ofloxacin into human lung tissue following a single oral dose of 200 milligrams
Authors: Serour F , Dan M , Gorea A , Yellin A , Lieberman Y , Berger S A
Published: June 2012

The penetration of ofloxacin into lung tissue was studied in 10 patients subjected to pulmonary surgery. Samples of blood and lung tissue were obtained 3 to 8 h (mean, 5 h) after oral administration of 200 mg. The mean level in tissue was 2.17 +/- 0.5 micrograms/g, while the mean level in serum was 0.85 +/- 0.23 micrograms/ml. The mean lung tissue/serum concentration ratio was 2.55 +/- 0.30. The achievable levels of ofloxacin in lung tissue are above the MICs for most pulmonary pathogens.
Ciprofloxacin-induced inhibition of topoisomerase II in human lymphoblastoid cells
Authors: Bredberg A , Brant M , Jaszyk M
Published: June 2012

The antibacterial activities of the fluorinated 4-quinolones (e.g., ciprofloxacin) have been ascribed to a marked inhibition of bacterial DNA gyrase. In contrast, the influence on purified mammalian DNA enzymes, including topoisomerases, has been reported to be several orders of magnitude weaker, occurring at concentrations higher than 100 micrograms of ciprofloxacin per ml. In this study, using a nondenaturing filter elution method, a marked induction of double-strand DNA breaks in human lymphoblastoid cells exposed to 80 micrograms of ciprofloxacin per ml was seen. The proportion of single-strand versus double-strand DNA breaks was similar to that seen with the topoisomerase II inhibitory antitumor agent VP-16. The cellular recovery was more rapid after treatment with ciprofloxacin than after treatment with VP-16, displaying a normal elution profile within 15 min at 37 degrees C (60 min for VP-16). These data indicate that ciprofloxacin has an effect on intracellularly located topoisomerase II in humans.
Preferential hydrolysis of cis configuration compounds at the 3,4 position of monobactams by beta-lactamase from Morganella morganii
Authors: Matsuda K , Sanada M , Nakagawa S , Inoue M , Mitsuhashi S
Published: June 2012

Carumonam and BO-1166 (cis configuration) were inactivated by beta-lactamase of Morganella morganii more rapidly than were aztreonam and BO-1165 (trans configuration), as demonstrated by spectrophotometric analysis and microbiological assay. An active enzyme was recovered more rapidly from the inactivated enzyme-monobactam complex derived from the cis form of monobactams than from the complex derived from the trans form of monobactams. This result suggests that the configuration at the 3,4 position on the azetidinone ring of monobactams, together with the chemical structure of the side chains attached to the azetidinone ring, may play an important role in the stability of monobactams to the beta-lactamase of M. morganii.
Influence of growth media on Escherichia coli cell composition and ceftazidime susceptibility
Authors: Malouin F , Chamberland S , Brochu N , Parr T R
Published: June 2012

Cell composition and surface properties of Escherichia coli were modified by using various growth media to investigate the role of yet uncharacterized components in ceftazidime susceptibility. An eightfold dilution of Luria broth was used as the basic growth medium and was supplemented with up to 4% phosphate, 5% glucose, or 12% L-glutamate. Decreases in cephaloridine and ceftazidime susceptibility, of two- and eightfold, respectively, were observed only in the glucose-enriched medium. The outer membrane permeability to ceftazidime and cephaloridine was evaluated by crypticity indices. Indices were unchanged under all growth conditions. Fluorometry of whole cells with 1-N-phenylnaphthylamine showed that glucose does not affect the interaction of this hydrophobic probe with the membranes but showed that elevated concentrations of phosphate or glutamate cause a marked increase in cell hydrophobicity, which, in turn, correlates with an increase in the susceptibility of E. coli to nalidixic acid. Growth in phosphate- or glutamate-enriched media caused an augmentation in major phospholipid species and may explain the increased hydrophobicity and susceptibility of E. coli to nalidixic acid. These data showed that E. coli susceptibility to ceftazidime is not influenced by cell surface hydrophobicity and suggested that the contribution of a nonspecific lipophilic diffusion route for entry of ceftazidime into cells is not likely to occur or is distinct from that of more hydrophobic molecules such as nalidixic acid. Finally, the penicillin-binding proteins of the E. coli cells were also investigated. Penicillin-binding protein 8 was only markedly labeled with 125I-penicillin V in inner membranes extracted from cells grown with glucose. Results of this study suggest that the unexpected change in penicillin-binding protein 8 observed in the presence of glucose may be responsible for the increase in MICs of cephaloridine and ceftazidime.
Lansoprazole, a novel benzimidazole proton pump inhibitor, and its related compounds have selective activity against Helicobacter pylori
Authors: Iwahi T , Satoh H , Nakao M , Iwasaki T , Yamazaki T , Kubo K , Tamura T , Imada A
Published: June 2012

The activities of various types of antiulcer agents against Helicobacter pylori (formerly called Campylobacter pylori) strains were determined by an agar dilution method. Among the compounds tested, two benzimidazole proton pump inhibitors, lansoprazole (AG-1749) and omeprazole, were found to have significant activities against this organism. The activity of lansoprazole was comparable to that of bismuth citrate, with MICs ranging from 3.13 to 12.5 micrograms/ml, and fourfold more potent than that of omeprazole. A major metabolite and two acid-converted rearrangement products of lansoprazole also exhibited good activities comparable or superior to that of the parent compound. Exposure to lansoprazole of H. pylori growing in a liquid medium led to an extensive loss of viability without a reduction in culture turbidity and produced an aberrant bacterial morphology characterized by the irregular constriction of cells and the collapse of cell surface structures. The antibacterial activity of lansoprazole and its related compounds was selective against H. pylori; common aerobic and anaerobic bacteria and Campylobacter jejuni were not inhibited by 100 micrograms/ml.
In vitro activity of sparfloxacin
Authors: Chin N X , Gu J W , Yu K W , Zhang Y X , Neu H C
Published: June 2012

Sparfloxacin, a new fluoroquinolone, inhibited the majority of members of the family Enterobacteriaceae at less than or equal to 1 microgram/ml. It was less active than ciprofloxacin but more active than ofloxacin. Against Pseudomonas aeruginosa, it was less active than ciprofloxacin but twofold more active than ofloxacin. It inhibited Staphylococcus aureus and most Streptococcus pneumoniae and Streptococcus pyogenes isolates at 0.25 micrograms/ml, whereas ciprofloxacin and ofloxacin inhibited these isolates at 2 micrograms/ml. Bacteroides fragilis was inhibited by less than or equal to 2 micrograms/ml. Sparfloxacin was less active at an acidic pH and in the presence of Mg2+. Resistance to sparfloxacin was produced by repeated exposure, although the frequency of single-step mutants was less than 10(-9).
Inhibition of rabies virus infection in cultured rat cortical neurons by an N-methyl-D-aspartate noncompetitive antagonist, MK-801
Authors: Tsiang H , Ceccaldi P E , Ermine A , Lockhart B , Guillemer S
Published: June 2012

A noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 (0.5 to 2.0 mM), inhibits rabies virus infection in rat primary cortical neurons, whereas the competitive NMDA antagonist AP5 has no effect. The results suggest that MK-801-mediated inhibition of rabies virus replication, although selective, is not operating through the high-affinity binding site mechanism.
Susceptibility of Mycoplasma pneumoniae to several new quinolones, tetracycline, and erythromycin
Authors: Kenny G E , Cartwright F D
Published: June 2012

Mycoplasma pneumoniae (39 strains) was most susceptible to two quinolones, WIN 57273 and sparfloxacin, with MICs for 90% of the strains (MIC90S) of 0.125 and 0.25 micrograms/ml, respectively. It was susceptible to ofloxacin and ciprofloxacin at 2 micrograms/ml and to lomefloxacin and fleroxacin at 4 micrograms/ml. The MIC90 of erythromycin was 0.062 microgram/ml, and that of tetracycline was 1 microgram/ml.
Multiple mechanisms of methicillin resistance and improved methods for detection in clinical isolates of Staphylococcus aureus
Authors: de Lencastre H , Sá Figueiredo A M , Urban C , Rahal J , Tomasz A
Published: June 2012

The mec gene of a number of clinical methicillin-resistant Staphylococcus aureus isolates exhibiting a variety of heterogeneous expression modes was selectively inactivated by allelic replacement mutagenesis. While the resistance level of each of the transformants was reduced, the methicillin MIC for these transformants was well above the MIC for susceptible laboratory strains of S. aureus and was similar to the methicillin MIC for many contemporary clinical isolates which did not react with the mec-specific DNA probe but which showed a low or borderline level of resistance to methicillin. A number of those strains had no detectable beta-lactamase, and for about half of the isolates that did carry plasmid-borne beta-lactamase, elimination of the plasmid caused only partial reduction of the methicillin MIC or no reduction at all. The findings suggest that many contemporary strains of staphylococci harbor a combination of at least three distinct beta-lactam resistance mechanisms: (i) the mechanism related to the acquisition of the foreign mec gene and (ii) a beta-lactamase-dependent and (iii) a beta-lactamase-independent mechanism, each one of which can provide a certain degree of resistance against penicillinase-resistant beta-lactam antibiotics.
Global and regional cerebral metabolic rate of 2-[18F]fluoro-2-deoxy-D-glucose in the presence of ofloxacin, a gamma-aminobutyric acid a receptor antagonist
Authors: Camargo E E , Sostre S , Sadzot B , Shafique I , Szabo Z , Links J M , Dannals R F , Wagner H N
Published: June 2012

We investigated the effects of ofloxacin, a new antibacterial quinolone gamma-aminobutyric acid A receptor antagonist, on the global and regional cerebral metabolic rates of glucose (cMRgl). Twelve healthy normal male volunteers (mean age, 26.7 years) were studied in a double-blind, placebo-controlled protocol of 11 days' duration. Results of a total of 42 positron emission tomography studies were obtained for these subjects: 12 base line, 18 during placebo, and 12 during ofloxacin administration. The conditions under which repeat positron emission tomography studies of the same subject were performed were reproduced as closely as possible. cMRgl was measured in 24 brain regions. The global cMRgl for base line, placebo, and ofloxacin were 8.82 +/- 1.17, 8.24 +/- 1.17, and 8.79 +/- 1.18 mg/min/100 g, respectively (mean +/- 1 standard deviation). The mean global differences between base line and placebo and between ofloxacin and placebo were 5.1 and 6.6%, respectively. Analysis of variance of both the global and the regional cMRgl showed no statistical difference between base-line, placebo, and ofloxacin studies. Variations in cMRgl found in this study were not related to the presence of ofloxacin. Results of our study demonstrate that ofloxacin does not increase or decrease cMRgl beyond the limits of variability of the study.
Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans
Authors: Foulds G , Knirsch A K , Lazar J D , Tensfelt T G , Gerber N
Published: June 2012

CP-65,207 is a new broad-spectrum penem antimicrobial agent that is a 1:1 mixture of two stereoisomers. Five minutes after a 10-min intravenous infusion of 1 g of CP-65,207 to volunteers, mean concentrations in serum were 33 micrograms of the R isomer per ml and 29 micrograms of the S isomer per ml. Following rapid distribution, half-lives of the isomers were 53 and 55 min, respectively. Concentrations in urine exceeded 800 micrograms of each isomer per ml. Recovery of the S isomer in urine (46%) was much greater than recovery of the R isomer (26%). The serum kinetics of the S isomer (volume of distribution, 319 ml/kg; total clearance, 315 ml/min; elimination rate constant, 0.80 h-1 were similar when it was given alone and when it was contained in CP-65,207, demonstrating that the presence of the R isomer has little effect on the serum kinetics of the S isomer. However, when the S isomer was given alone, the urinary recovery of intact S isomer (36%) was substantially lower than that when it was given with the R isomer as CP-65,207 (57%). Administration of the S isomer alone did not produce the unpleasant sulfurous odor in urine that was observed following administration of CP-65,207. Oral doses of a prodrug, which contained 1 g of CP-65,207, produced peak concentrations in serum of 1.6 micrograms of the R isomer per ml and 1.8 micrograms of the S isomer per ml. Approximately 36% of the S-isomer component was absorbed, and 20% of this isomer was recovered in urine. A 1-g oral dose of the prodrug of the single S isomer provides concentrations in serum above 1.0 microgram/ml (the MIC for 90% of over 1,000 hospital pathogens) for 3.5 h, suggesting that the drug given orally will prove to be efficacious against many infections.
Hyperoxia prolongs the aminoglycoside-induced postantibiotic effect in Pseudomonas aeruginosa
Authors: Park M K , Muhvich K H , Myers R A , Marzella L
Published: June 2012

The objective of this study was to determine whether hyperoxia enhances aminoglycoside activity against Pseudomonas aeruginosa. The existence of tobramycin-oxygen synergy was determined by using the in vitro postantibiotic effect (PAE). P. aeruginosa strains were incubated for 1 h in medium containing tobramycin at four times the MIC in the following gas mixtures: normoxia (21% O2), hyperoxia (100% O2, 101.3 kPa), or hyperbaric oxygen (100% O2, 274.5 kPa). Tobramycin was removed after 1 h and bacteria were incubated under normoxic conditions; growth rates were measured for 5 h. Exposure of three P. aeruginosa strains to hyperoxia prolonged the PAE of tobramycin approximately twofold compared with the PAE after exposure to normoxia (P less than 0.05). Exposure of P. aeruginosa ATCC 27853 to tobramycin and hyperbaric oxygen prolonged the time required for bacteria to increase 1 log10 CFU/ml compared with the time after exposure for this increase to occur in tobramycin-treated, normoxic or hyperoxic groups (P less than 0.02). Pulse-chase labeling of bacteria with L-[35S]methionine, immediately after removal of tobramycin, showed that protein synthesis rates were decreased compared with those in controls (P = 0.0001). Moreover, in tobramycin-treated groups, hyperoxia and hyperbaric oxygen induced 2- and 16-fold decreases, respectively, in protein synthesis rates compared with normoxia; these results did not achieve statistical significance. In the absence of tobramycin, hyperoxia increased bacterial growth (134%; P less than 0.01) and protein synthesis (24%; not significant) compared with normoxia. Hyperbaric oxygen, however, delayed the growth recovery of bacteria (P less than 0.05). We conclude that hyperoxia enhances the bacteriostatic effects of tobramycin in a synergistic manner.+
Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice
Authors: De Clercq E , Holý A
Published: June 2012

The phosphonylmethoxyalkyl derivative (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) was evaluated for its in vivo efficacy in several model infections for herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and thymidine kinase-deficient (TK-) HSV-1 in mice. In hairless mice infected intracutaneously with HSV-1 or HSV-2, HPMPC completely suppressed all manifestations of the disease (skin lesions, paralysis of the hind legs, and mortality) if it was administered topically at a concentration of as low as 0.1, 0.3, or 1%. Similarly, HPMPC completely suppressed TK- HSV-1 infection in athymic nude mice if it was administered topically at 0.1 or 0.3% or intraperitoneally at 100 or 250 mg/kg/day. HPMPC was also effective against intraperitoneal HSV infection if it was given orally at a dose of 50 mg/kg/day or higher. In mice inoculated intracerebrally with HSV-2, intraperitoneal HPMPC treatment achieved a significant and dose-dependent protection at doses ranging from 5 to 400 mg/kg/day. The protective effect of HPMPC (at 200 mg/kg/day) was accompanied by a complete inhibition of virus multiplication in the brain. In all models of infections studied, the efficacy of HPMPC proved to be superior to that of acyclovir. The most remarkable feature of HPMPC was that a single administration of the compound, even as late as 4 days after infection, conferred significant protection against HSV-1 or HSV-2 infection. Topical or systemic HPMPC treatment is efficacious in murine models of HSV-1, HSV-2, and TK- HSV infections.
Combined therapy with fluconazole and flucytosine in murine cryptococcal meningitis
Authors: Allendoerfer R , Marquis A J , Rinaldi M G , Graybill J R
Published: June 2012

To assess the possible beneficial effects of combined therapy (fluconazole and flucytosine) in the treatment of cryptococcal meningitis in the immunocompromised host, we compared therapy with fluconazole and flucytosine, individually and combined, in the experimental murine model. BALB/c athymic (nu/nu) mice were infected intracerebrally with 150 to 300 CFU of Cryptococcus neoformans. In mortality studies, treatment was initiated 24 h postinfection and continued for 10 to 14 days with either fluconazole (1 to 15 mg/kg of body weight per day), flucytosine (60 to 120 mg/kg/8 h), both drugs, or 0.3% Noble agar (control). Combined therapy delayed mortality significantly when compared with controls and single-drug regimens. This was observed over a broad range of doses. Quantitative determinations of CFU in brain tissue demonstrated a significantly lower burden of C. neoformans in mice receiving combined therapy. The results indicate that combined therapy with fluconazole and flucytosine is superior to single-drug therapy.
Killing of nongrowing and adherent Escherichia coli determines drug efficacy in device-related infections
Authors: Widmer A F , Wiestner A , Frei R , Zimmerli W
Published: June 2012

Antimicrobial therapy of device-related infections often fails, despite the in vitro susceptibility of the infecting strain. Therefore, alternative laboratory-based in vitro tests are required to predict the outcome. Fleroxacin, ciprofloxacin, aztreonam, and co-trimoxazole were tested against Escherichia coli ATCC 25922 in vitro and in the tissue-cage animal model. The importance of early treatment was evaluated by starting the drugs either 30 min before or 4, 12, and 24 h after bacterial challenge. Results were compared with the in vitro drug efficacy against nongrowing and adherent Escherichia coli ATCC 25922. The alternative in vitro tests correlated highly with the outcome in the tissue-cage animal model. In the prophylaxis group (drug given 30 min before bacterial challenge), co-trimoxazole was less efficacious than the other three drugs (P less than 0.001). In delayed treatment, ciprofloxacin showed the highest cure rate. It was also more potent than the other drugs against nongrowing and adherent E. coli ATCC 25922. The efficacies of aztreonan, fleroxacin, and ciprofloxacin dropped significantly (P less than 0.01) when the time interval between bacterial challenge and the start of treatment was delayed to greater than 4 h. These data emphasize (i) the need for proper timing of prophylaxis in patients undergoing implant surgery, and (ii) the possibility of successful treatment of established device-related infections with drugs which kill not only growing but also nongrowing and adherent bacteria.
Activities of various macrolide antibiotics against Mycobacterium leprae infection in mice
Authors: Gelber R H , Siu P , Tsang M , Murray L P
Published: June 2012

We evaluated the activities of several macrolide antibiotics against M. leprae infections in mouse footpads. Erythromycin and azithromycin were inactive, while both roxithromycin and clarithromycin were found to be consistently active and, in fact, bactericidal. By both methods, clarithromycin was found to be superior to roxithromycin, a finding which, at least in part, may be a consequence of the higher levels of clarithromycin at the site of infection.
Multicenter evaluation of the in vitro activities of three new quinolones, sparfloxacin, CI-960, and PD 131,628, compared with the activity of ciprofloxacin against 5,252 clinical bacterial isolates
Authors: Fuchs P C , Barry A L , Pfaller M A , Allen S D , Gerlach E H
Published: June 2012

The in vitro activities of three new quinolones (sparfloxacin, CI-960, and PD 131,628) were compared with that of ciprofloxacin against 5,252 routine clinical aerobic and facultatively anaerobic bacterial isolates. Overall, CI-960 was the most active drug in vitro (MIC for 90% of the strains tested, 0.13 micrograms/ml); ciprofloxacin and sparfloxacin were the least active (MIC for 90% of the strains tested, 1.0 micrograms/ml). All three new quinolones, but particularly CI-960 and PD 131,628, exhibited significantly greater activity than ciprofloxacin against enterococci and staphylococci.
Susceptibilities of Mycobacterium fortuitum biovar. fortuitum and the two subgroups of Mycobacterium chelonae to imipenem, cefmetazole, cefoxitin, and amoxicillin-clavulanic acid
Authors: Wallace R J , Brown B A , Onyi G O
Published: June 2012

MICs of imipenem, cefoxitin, cefmetazole, and amoxicillin-clavulanic acid were determined against 100 strains of Mycobacterium fortuitum and 200 strains of Mycobacterium chelonae. Imipenem and cefmetazole were more active against M. fortuitum than cefoxitin was, and imipenem (which inhibited 39% of strains at 8 micrograms/ml) was the only beta-lactam active against M. chelonae subsp. chelonae.
Effect of staggered dose of calcium on the bioavailability of ciprofloxacin
Authors: Lomaestro B M , Bailie G R
Published: June 2012

The effect on ciprofloxacin's bioavailability (F) of calcium carbonate given 2 h before ciprofloxacin administration in 12 male volunteers was studied. The relative F with calcium was 0.98, maximum concentration of drug in serum increased significantly from 1.98 to 2.42 mg/liter (P = 0.039), and time to maximum concentration of drug in serum decreased from 1.82 to 1.26 h (P = 0.038). Thus, a single calcium carbonate dose, administered 2 h before ciprofloxacin, does not alter the F of this quinolone.
Liposomal amphotericin B inhibits in vitro T-lymphocyte response to antigen
Authors: Boggs J M , Chang N H , Goundalkar A
Published: June 2012

The effects of free amphotericin B (as Fungizone) and amphotericin B (AMB) incorporated into liposomes on the proliferation of lymphocytes were determined. Freshly obtained guinea pig and rat antigen-specific lymphocytes were compared with rat T-lymphocyte cell lines cultured for a long period of time. Incorporation of AMB into multilayered vesicles significantly reduced its effect relative to that of Fungizone on cultured T-cell lines, as reported by others for mammalian cells. In contrast, the effects on freshly obtained antigen-specific lymphocytes were different. Fungizone inhibited proliferation of antigen-specific lymph node cells freshly obtained from immunized guinea pigs at fungicidal concentrations, and incorporation into multilayered lipid vesicles did not have much of a protective effect. Higher concentrations of Fungizone were required to inhibit proliferation of fresh rat lymph node cells, but incorporation into multilayered lipid vesicles still did not have much of a protective effect. Some T lymphocytes in the peripheral circulation of guinea pigs and in the lymph nodes of rats were more resistant to liposomal AMB than another more sensitive T-lymphocyte population was. Proliferation of lymphocytes in response to mitogens was inhibited less than that in response to specific antigen was. Thus, sensitivity to AMB depended on the species, the strength of the stimulus used to activate the lymphocytes, and on some other property of the lymphocytes, possibly their state of differentiation. Regardless of the reason for the difference in effects on freshly obtained lymph node lymphocytes and cultured line cells, the former may be more relevant to effects in vivo and should be considered in a complete evaluation of the in vivo toxicity of these forms of the drug. Incorporation into sonicated unilamellar vesicles had more of a protective effect, while equimolar drug-lipid complexes had even more of a protective effect. These forms of AMB might have less of an immunosuppressive potential than multilayered vesicles containing low amounts of AMB do.
Comparative activity of macrolides against Toxoplasma gondii demonstrating utility of an in vitro microassay
Authors: Chamberland S , Kirst H A , Current W L
Published: June 2012

The utility of spiramycin for preventing transplacental transmission of toxoplasmosis and the efficacy of conventional macrolides against Toxoplasma gondii are subjects of active debate. An in vitro microassay was developed to determine the relative inhibitory activity against T. gondii of 24 conventional macrolides derived from erythromycin and tylosin (14- and 16-membered macrolides, respectively). Macrolides and T. gondii RH tachyzoites were added to monolayers of BT cells grown in 96-well plates. Plates were incubated for 20 h at 37 degrees C, and the growth of T. gondii was then measured by the selective incorporation of [3H]uracil in trichloroacetic acid-precipitable material during an additional incubation of 20 h. Dose-response curves and 50 and 90% inhibitory concentrations (IC50 and IC90, respectively) were determined for each drug. Microscopic examination was performed on stained replicates of the infected monolayers, and the relative toxicities of the drugs for host cells were determined. Spiramycin and tylosin showed only limited activity against T. gondii (IC50 of 20.16 and 20.00 micrograms/ml, respectively). Erythromycin and azithromycin had a better anti-Toxoplasma activity with IC50 of 14.38 and 8.61 micrograms/ml, respectively, whereas drugs like desmycosin, dirithromycin, and roxithromycin had no detectable activity. Although many macrolides inhibited intracellular proliferation of T. gondii, azithromycin was the only macrolide demonstrating prolonged inhibitory activity on the replication of intracellular tachyzoites. We conclude that conventional 14- and 16-membered macrolides often interfere with the growth of, but may not kill, T. gondii RH tachyzoites in vitro.
Amikacin pharmacokinetics in patients receiving high-dose cancer chemotherapy
Authors: Davis R L , Lehmann D , Stidley C A , Neidhart J
Published: June 2012

We retrospectively analyzed amikacin pharmacokinetics in 28 patients (mean age, 47.4 +/- 13.6 years) who received high-dose chemotherapy during a neutropenic febrile episode. Patients received an experimental protocol of high-dose anticancer chemotherapy. Amikacin pharmacokinetic parameters were calculated from two or more concentrations in serum around a single dose by the method of Sawchuck and Zaske (J. Pharmacokinet. Biopharm. 4:183-195, 1976). Predicted parameters were calculated by using standard methods. The observed amikacin volume of distribution and clearance were significantly greater and the elimination half-life was longer than predicted (0.38 +/- 0.13 versus 0.25 liter/kg [P = 0.0001], 1.51 +/- 0.92 versus 1.17 +/- 0.38 liters/h/kg [P = 0.012], and 3.8 +/- 2.4 versus 2.9 +/- 1.1 h [P = 0.011], respectively). Multivariate analysis revealed that albumin correlated negatively and creatinine correlated positively with the volume of distribution and the elimination half-life. Creatinine and the percentage below the ideal body weight correlated negatively and hematocrit correlated positively with clearance. Administration of dosage regimens based on predicted pharmacokinetic parameters yielded subtherapeutic amikacin concentrations in serum in our patients. Because of the increased dosage requirements and the need for adequate antibiotic treatment in this population, we suggest guidelines for empiric dosing for patients with advanced cancer receiving intensive chemotherapy.
Mechanisms that may account for differential antibiotic susceptibilities among Coxiella burnetii isolates
Authors: Yeaman M R , Baca O G
Published: June 2012

The Nine Mile, S Q217, and Priscilla isolates, representative of the three major genetic groups of Coxiella burnetii, are known to differ in their susceptibilities to antibiotics. Mechanisms potentially responsible for these differences were investigated. Accumulation of antibiotics by infected L929 cells and purified isolates was measured. In addition, C. burnetii plasmid-transformed Escherichia coli HB101 cells were used to study the possibility that different C. burnetii plasmids are responsible for disparate antibiotic susceptibilities of the isolates. L929 cells recently or persistently infected with the Priscilla isolate exhibited a significantly reduced accumulation of [3H]tetracycline as compared with that in L929 cells infected with either the Nine Mile or S Q217 isolates; accumulation of this drug was greater in cells recently infected each isolate. In contrast, L929 cells recently or persistently infected with the different isolates accumulated [3H]norfloxacin to an equivalent extent. [3H]tetracycline accumulation was approximately the same among the purified isolates. However, as measured by both scintillation and spectrofluorometry, norfloxacin accumulation was significantly diminished in the purified Priscilla isolate. pH had no apparent effect upon isolate permeabilities. The presence of C. burnetii QpH1 or QpRS plasmids did not alter the antibiotic susceptibility of E. coli. Collectively, these results indicate that differential susceptibilities to tetracyclines or fluoroquinolones in C. burnetii isolates may be the result of distinct mechanisms involving altered host-cell (tetracyclines) or isolate-specific (fluoroquinolones) permeabilities.
Synergistic effects between amoxicillin, metronidazole, and the hydroxymetabolite of metronidazole against Actinobacillus actinomycetemcomitans
Authors: Pavicić M J , van Winkelhoff A J , de Graaff J
Published: June 2012

Interactions between metronidazole and amoxicillin, metronidazole and its hydroxymetabolite, and amoxicillin and the hydroxymetabolite of metronidazole were investigated with checkerboard titrations in combination with accurately determined MICs and MBCs. Actinobacillus actinomycetemcomitans was used as the test organism. Synergism was found for all three combinations. Fractional inhibitory concentration indices and fractional bactericidal concentration indices varied from 0.3 to 0.7. These synergistic interactions between these antibiotics may explain the efficacy of the combination of metronidazole and amoxicillin in various bacterial infections, including periodontal disease.
Modulation of the intestinal flora of mice by parenteral treatment with broad-spectrum cephalosporins
Authors: van Ogtrop M L , Guiot H F , Mattie H , van Furth R
Published: June 2012

A study was performed to determine the effect of parenteral treatment with four broad-spectrum cephalosporins (cefoperazone, ceftriaxone, ceftazidime, and cefepime) on the number of aerobic gram-negative rods and on the outgrowth of Candida albicans and a multiresistant strain of Citrobacter freundii in the feces of mice. The estimated fractions of a parenteral dose that were excreted into the gastrointestinal tract were 0.37 for cefoperazone, 0.11 for ceftriaxone, 0.03 for ceftazidime, and 0.002 for cefepime. All four cephalosporins significantly decreased the number of aerobic gram-negative rods in the feces, and virtually all gram-negative rods were eliminated at high doses of cefoperazone, ceftazidime, and ceftriaxone. Furthermore, at high doses these three compounds led to a significant increase of the outgrowth of resistant Citrobacter freundii. The outgrowth of Candida albicans was increased at high doses of cefoperazone and ceftriaxone, whereas ceftazidime and cefepime did not have this effect. The most profound changes in the gastrointestinal ecology were observed during treatment with high doses of cefoperazone. The results suggest that the colonization resistance of the gastrointestinal tract can be substantially decreased by parenteral treatment with cefoperazone and, to a lesser extent, with ceftriaxone and ceftazidime.
Biological comparison of wild-type and zidovudine-resistant isolates of human immunodeficiency virus type 1 from the same subjects: susceptibility and resistance to other drugs
Authors: Rooke R , Parniak M A , Tremblay M , Soudeyns H , Li X G , Gao Q , Yao X J , Wainberg M A
Published: June 2012

We used a viral endpoint dilution assay to show changes in the proportion of zidovudine (azidothymidine; AZT)-resistant viruses within a heterogeneous mixture of human immunodeficiency virus type 1 (HIV-1) quasispecies isolated from patients on long-term AZT therapy. Several HIV-1 isolates, which could replicate in 10 microM AZT, were susceptible to both 2',3'-dideoxycytidine and a novel cytosine analog BCH-189, in which a sulfur atom replaces the 3' carbon of the pentose ring. In certain instances, cross-resistance was seen with 3'-didehydro-2',3'-dideoxythymidine. Although most strains of AZT-resistant HIV-1 displayed reduced susceptibility to 3'-azido-2',3'-dideoxyuridine, two strains were identified for which this was not the case.