bluuebunny/crossref_metadata_2025 huggingface dataset:
Orofacial infection of athymic mice with defined mixtures of acyclovir-susceptible and acyclovir-resistant herpes simplex virus type 1
Authors: Ellis M N , Waters R , Hill E L , Lobe D C , Selleseth D W , Barry D W
Published: June 2012

Infection of athymic mice with defined populations of acyclovir-susceptible (thymidine kinase [TK]-positive) and acyclovir-resistant (TK-deficient or TK-altered) herpes simplex virus type 1 strains was used to simulate herpetic skin disease of the immunocompromised host. In vitro characterization of the defined virus mixtures revealed that the dye uptake method was quite sensitive in the detection of small amounts (3 to 9%) of acylovir-resistant virus. Mice infected with homogeneous virus populations exhibited a good correlation between clinical response and the in vitro drug susceptibility of the infecting virus. Animals infected with defined mixtures of viruses exhibited varied patterns of infection and responses to acyclovir treatment. However, disease severity was useful in predicting the TK phenotype of virus recovered from lesions. Pathogenic, TK-altered virus was responsible for progressive disease in animals receiving low-dose (0.25-mg/ml) prophylactic acyclovir or high-dose (1.25-mg/ml) delayed therapy. Although this mutant was recovered infrequently, it was responsible for clinically significant disease in the animals from which it was isolated.
In vitro effects of beta-lactams combined with beta-lactamase inhibitors against methicillin-resistant Staphylococcus aureus
Authors: Kobayashi S , Arai S , Hayashi S , Sakaguchi T
Published: June 2012

The effects of combinations of beta-lactams with two beta-lactamase inhibitors, sulbactam and clavulanic acid, were determined in vitro against 22 clinical isolates of methicillin-resistant Staphylococcus aureus. Combinations of cefpirome, cefotaxime, and cefazolin with sulbactam (10 micrograms/ml) showed synergistic effects against more than 70% of the strains. Combinations of methicillin and penicillin G with sulbactam also showed synergistic effects against 50 and 68% of the strains, respectively, while cefotiam, moxalactam, flomoxef, and cefmetazole in combination with sulbactam showed such effects against only 40% or fewer. Clavulanic acid was synergistic only when combined with penicillin G, the effect probably being due to the beta-lactamase inhibition by the inhibitor. Sulbactam did not improve the antimicrobial activities of the beta-lactams against methicillin-susceptible S. aureus strains. At 42 degrees C the MICs of cefotaxime, methicillin, and flomoxef alone were markedly decreased from the values at 35 degrees C, and no synergy between these beta-lactams and sulbactam appeared. The resistance to penicillin G was not inhibited by incubation at 42 degrees C, and combinations of penicillin G with sulbactam and clavulanic acid showed synergy. The amounts of beta-lactamase produced were not related to the decreases in the MICs of the beta-lactams, except for penicillin G combined with sulbactam. Clavulanic acid showed slightly stronger beta-lactamase-inhibiting activity than sulbactam did. These results suggest that the synergy between sulbactam and the beta-lactams, except for penicillin G, may not be due to beta-lactamase inhibition but to suppression of the methicillin-resistant S. aureus-specific resistance based on other factors.
Study of the effects of liposomal amphotericin B on Candida albicans, Cryptococcus neoformans, and erythrocytes by using small unilamellar vesicles prepared from saturated phospholipids
Authors: Jullien S , Contrepois A , Sligh J E , Domart Y , Yeni P , Brajtburg J , Medoff G , Bolard J
Published: June 2012

We compared the anticellular effects of liposomal amphotericin B (AmB) formed from AmB and small unilamellar vesicles. The small unilamellar vesicles with or without cholesterol were prepared from three L-alpha-phosphatidylcholines with saturated acyl chains of different lengths: distearoyl (C18), dipalmitoyl (C16), and dimyristoyl (C14). We found that the anticellular potency of liposomal AmB, compared with that of free AmB, decreased with decreasing length of the acyl chain of the phospholipid and increased with the addition of cholesterol. In a parallel study (S. Jullien, A. Vertut-Croquin, J. Brajtburg, and J. Bolard, Anal. Biochem. 172:197-202, 1988), we found that binding of AmB to vesicles decreased with increasing length of the acyl chain of the phospholipid and decreased with the addition of cholesterol. We conclude that the anticellular effects of liposomal AmB preparations are due to the levels of AmB remaining free (unbound to the lipids) in these preparations.
Tissue concentrations and bioactivity of amphotericin B in cancer patients treated with amphotericin B-deoxycholate
Authors: Collette N , van der Auwera P , Lopez A P , Heymans C , Meunier F
Published: June 2012

We have studied amphotericin B concentrations in tissues of 13 cancer patients who died after having received 75 to 1,110 mg (total dose) of amphotericin B-deoxycholate for suspected or proven disseminated fungal infection. Amphotericin B concentrations were measured by high-pressure liquid chromatography (HPLC) and by bioassay, the latter being done on tissue homogenates as well as on tissue methanolic extracts. The fungistatic and fungicidal titers of the tissue homogenates were also tested against three strains of Candida albicans and one strain of Aspergillus fumigatus. Tissue concentrations of amphotericin B measured by HPLC varied with the tested tissues as well as with the total dose of amphotericin B-deoxycholate administered and ranged from 0.4 to 147.1 micrograms/g. A mean of 38.3% (range, 23.0 to 51.3%) of the total dose was recovered by HPLC from all of the tested organs. Bioassay of tissue methanolic extracts reached 58 to 81% of the concentration measured by HPLC, whereas only 15 to 41% was recovered from the homogenates. Overall, 27.5% of the total dose was recovered from the liver, 5.2% was recovered from the spleen, 3.2% was recovered from the lungs, and 1.5% was recovered from the kidneys. The median concentration in bile was 7.3 micrograms/ml, suggesting that biliary excretion could contribute to amphotericin B elimination to an estimated range of 0.8 to 14.6% of the daily dose. Fungicidal titers were seldom measured in tissues, but fungistatic titers were observed and were linearly correlated with amphotericin B concentration measured by HPLC. In conclusion, only a small proportion of the amphotericin B administered as amphotericin B-deoxycholate to patients seems diffusible and bioactive.
Interaction of cefpirome and a cephalosporinase from Citrobacter freundii GN7391
Authors: Satake S , Hiraoka M , Mitsuhashi S
Published: June 2012

The interaction of cefpirome and a cephalosporinase from Citrobacter freundii, including hydrolysis and inhibition, was studied in comparison with those of cefotiam, cefotaxime, and ceftazidime. Cefpirome was hydrolyzed by the enzyme more rapidly at Vmax than were cefotaxime and ceftazidime. However, the low affinity of the enzyme for cefpirome caused a reduction in the hydrolytic rate of cefpirome at a low drug concentration (0.1 microM). The high stability of cefpirome at a low concentration explains the high antimicrobial activity of the agent against cephalosporinase-producing bacteria.
Antibacterial activities of the antiparasitic drugs nifurtimox and benznidazole
Authors: Hof H
Published: June 2012

Both nifurtimox and benznidazole, which are used for the treatment of Chagas' disease, also display marked antibacterial activities. Characteristically for nitroheterocyclic compounds, they are much more active against anaerobic and microaerophilic bacteria than against aerobic bacteria. Nitroreductase-deficient aerobes are completely resistant, whereas SOS-repair-deficient strains are moderately susceptible. Those strains are rapidly killed.
Effects of microamperage, medium, and bacterial concentration on iontophoretic killing of bacteria in fluid
Authors: Davis C P , Weinberg S , Anderson M D , Rao G M , Warren M M
Published: June 2012

Prevention of nosocomial urinary tract infections by iontophoresis is addressed. An iontophoretic generator was used to provide microamperage (10 to 400 microA) to vials containing either synthetic urine or supplemented synthetic urine. Bacteria were added to vials, and parameters of growth, bacterial killing, and multiple electrode materials were examined. Escherichia coli and Proteus species were both inhibited and killed at various microamperages and with several electrode types, the most efficient being gold-gold as the anode-cathode combination. Klebsiella pneumoniae in supplemented synthetic urine was least inhibited in growth, and higher microamperage (200 to 400 microA) was most effective in killing the bacteria. Bacterial growth reduction and killing were directly related to increasing microamperage and were inversely related to bacterial concentration.
Reactions catalyzed by purified L-glutamine: keto-scyllo-inositol aminotransferase, an enzyme required for biosynthesis of aminocyclitol antibiotics
Authors: Lucher L A , Chen Y M , Walker J B
Published: June 2012

Dialyzed extracts of the gentamicin producer Micromonospora purpurea catalyze reactions which represent transaminations proposed for 2-deoxystreptamine biosynthesis. To determine whether these transaminations were catalyzed by a single aminotransferase or by multiple enzymes, we purified and characterized an L-glutamine:keto-scyllo-inositol aminotransferase from M. purpurea. This enzyme was purified 130- to 150-fold from late-log-phase mycelia of both wild-type M. purpurea and a 2-deoxystreptamine-less idiotroph. The cofactor pyridoxal phosphate was found to be tightly bound to the enzyme, and spectral analysis demonstrated its participation in the transamination reactions of this enzyme. The major physiological amino donor for the enzyme appears to be L-glutamine; the keto acid product derived from glutamine was characterized as 2-ketoglutaramate, indicating that the alpha amino group of glutamine participates in the transamination. We found that crude extracts contained omega-amidase activity, which may render transaminations with glutamine irreversible in vivo. The substrate specificity of the aminotransferase was shown to be restricted to deoxycyclitols, monoaminocyclitols, and diaminocyclitols, glutamine, and 2-ketoglutaramate, which contrasts with the broader substrate specificity of mammalian glutamine aminotransferase. The appearance of the enzyme in late-log phase, coupled with its narrow substrate specificity, indicates that it participates predominantly in 2-deoxystreptamine biosynthesis rather than in general metabolism. The enzyme catalyzes reactions which represent both transamination steps of 2-deoxystreptamine biosynthesis. Although copurification of two aminotransferases cannot be ruled out, our data are consistent with the participation of a single aminotransferase in the formation of both amino groups of 2-deoxystreptamine during biosynthesis by M. purpurea. We propose that this aminotransferase participates in a key initial step in the biosynthesis of most aminocyclitol antibiotics.
Do double-beta-lactam combinations prolong neutropenia in patients undergoing chemotherapy or bone marrow transplantation for hematological disease?
Authors: Kibbler C C , Prentice H G , Sage R J , Hoffbrand A V , Brenner M K , Noone P
Published: June 2012

The total period of neutropenia was assessed in 174 episodes after chemotherapy or bone marrow transplantation in which patients received antibiotics for fever in a randomized prospective trial. Log rank analysis demonstrated no significant difference in the total duration of neutropenia between patients receiving netilmicin plus either piperacillin or azlocillin and those given ceftazidime plus either piperacillin or azlocillin. Of 86 patients in the single-beta-lactam group, 27 had a persistent neutrophil count of 0.1 x 10(9) per liter during treatment compared with 27 of 88 patients in the double-beta-lactam group, and 29 of 68 patients treated with the single-beta-lactam combination had a total period of neutropenia greater than 30 days versus 36 of 75 in the double-beta-lactam group. The use of two beta-lactam antibiotics rather than one does not appear to prolong neutropenia in patients undergoing treatment of hematological malignancy. However, in order to determine the effect of a single-beta-lactam combination, a similar carefully controlled prospective randomized study in which such treatment is compared with a non-beta-lactam-containing regimen is required.
Pharmacokinetics of single-dose cefmetazole following intramuscular administration of cefmetazole sodium to healthy male volunteers
Authors: Ko H , Novak E , Peters G R , Bothwell W M , Hosley J D , Closson S K , Adams W J
Published: June 2012

The tolerance and pharmacokinetics of cefmetazole were studied in healthy male volunteers who received a placebo (sterile saline) or a single dose of cefmetazole sodium intramuscularly. Drug-treated volunteers received one of four doses, 0.375, 0.750, 1, or 2 g. The drug was well tolerated, with no adverse medical events or laboratory changes observed during the study that could affect the pharmacokinetic interpretation of the data. Cefmetazole concentrations were determined by using a specific high-performance liquid chromatographic method. Serum cefmetazole concentrations were well described by a one-compartment open model with first-order absorption and elimination. Cefmetazole was rapidly absorbed in most volunteers, with a mean time to maximum concentration in serum of 1.24 +/- 0.12 h (+/- standard error of the mean), and the mean maximum concentration in serum increased from 17.0 +/- 1.6 to 74.2 +/- 9.5 micrograms/ml over the 0.375- to 2-g dose range. Maximum concentrations in serum, areas under serum concentration-time curve, and urinary excretion of intact drug increased in proportion to cefmetazole sodium dose. Times at which maximum concentrations in serum occurred, apparent volumes of distribution, steady-state volumes of distribution, absorption and elimination half-lives, and systemic clearances did not change significantly (P greater than 0.05) with drug dose. Although absorption and elimination half-lives were not significantly different in 10 of 40 volunteers (P greater than 0.05), in a majority of subjects elimination half-lives were approximately 10 times longer than absorption half-lives. The mean recovery of intact drug in urine ranged from 68.8 to 86.0% over the dose range studied, with a mean recovery over all doses of 77.1 +/- 2.4%. Rental clearances were significantly lower (P < 0.05) for the two lowest doses (93.0 and 84.3 versus 115.0 and 118.0 ml/min); these differences are not considered clinically important. The results of this study indicate that cefmetazole pharmacokinetics are linear after administration of single intramuscular doses ranging from 0.375 to 2 g, that clinically relevant concentrations of cefmetazole in serum (1 to 2 micrograms/ml) persist in a majority of volunteers for more than 8 h after administration of 0.750-g or higher doses, and that clinically relevant concentrations of cefmetazole continue to be excreted in urine 8 to 12 h after administration of 0.375- to 2-g doses.
In vitro bone marrow toxicity of nucleoside analogs against human immunodeficiency virus
Authors: Inoue T , Tsushita K , Itoh T , Ogura M , Hotta T , Saneyoshi M , Yoshida S , Saitoh H , Tomoda Y , Nagai Y
Published: June 2012

3'-Azido-2',3'-dideoxythymidine is known to cause severe anemia and neutropenia. Although these are rare for 2',3'-dideoxycytidine, it frequently impairs thrombocytogenesis. These differential myelossuppressive features correlated well with the in vitro toxicities of the drugs for a megakaryoblastic cell line and for colony formation of erythroid and granulocytic cells.
Activities of daptomycin and teicoplanin against Staphylococcus haemolyticus and Staphylococcus epidermidis, including evaluation of susceptibility testing recommendations
Authors: Low D E , McGeer A , Poon R
Published: June 2012

The in vitro activities of daptomycin, teicoplanin, and three other antimicrobial agents were determined against 105 strains of Staphylococcus haemolyticus and 92 strains of Staphylococcus epidermidis. The MICs for 90% of strains tested (MIC90s) of fusidic acid and rifampin were less than or equal to 0.25 microgram/ml. The MIC90s of daptomycin and vancomycin were less than or equal to 4 micrograms/ml. Teicoplanin had a comparable MIC90 of less than or equal to 4 micrograms/ml for isolates of S. epidermidis. However, MIC90s were 8 and 16 micrograms/ml for oxacillin-susceptible and oxacillin-resistant S. haemolyticus, respectively. Disk diffusion tests were evaluated for daptomycin and teicoplanin. Disks with 30 micrograms of teicoplanin performed satisfactorily when S. epidermidis was tested, but when S. haemolyticus was tested, there was a very major error rate of 10% and a minor error rate of 38%.
Enhanced elimination of ciprofloxacin after multiple-dose administration of rifampin to rabbits
Authors: Barriere S L , Kaatz G W , Seo S M
Published: June 2012

The combination of ciprofloxacin and rifampin is potentially useful for the treatment of selected infections. However, rifampin may induce the metabolism of ciprofloxacin. Ciprofloxacin was given in single doses to healthy rabbits before and after six daily doses of intramuscular rifampin. Total clearance of ciprofloxacin increased from 0.96 +/- 0.32 (standard deviation) to 1.57 +/- 0.63 liters/h per kg (P less than 0.05). This change in elimination is potentially significant for the outcome of experimental infections in rabbits.
Comparative antimycobacterial activities of difloxacin, temafloxacin, enoxacin, pefloxacin, reference fluoroquinolones, and a new macrolide, clarithromycin
Authors: Gorzynski E A , Gutman S I , Allen W
Published: June 2012

The activities of fluoroquinolones and a new macrolide against 30 clinical isolates of Mycobacterium tuberculosis were determined in vitro by agar diffusion. In order of relative potencies against M. tuberculosis, temafloxacin (MIC for 90% of isolates [MIC90], 2.3 micrograms/ml) was at least as active as the reference quinolones ofloxacin (MIC90, 2.4 micrograms/ml) and ciprofloxacin (MIC90, 4.3 micrograms/ml). Less active were difloxacin (MIC90, 4.7 micrograms/ml), pefloxacin (MIC90, 6.7 micrograms/ml), and enoxacin (MIC90, 8.3 micrograms/ml). The macrolide clarithromycin was more potent than erythromycin but less potent than the fluoroquinolones. Our results suggest that the newer fluoroquinolones and clarithromycin should be included with ciprofloxacin and ofloxacin in pharmacokinetic studies that may lead to trials in human subjects with mycobacterial infections.
Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital
Authors: Shalit I , Berger S A , Gorea A , Frimerman H
Published: June 2012

Ofloxacin and ciprofloxacin resistance (MIC, greater than 4 micrograms/ml) was encountered in 45 of 50 clinical isolates of methicillin-resistant Staphylococcus aureus. None of 20 methicillin-susceptible strains was resistant to the quinolones (P less than 10(-6). Quinolone-susceptible and -resistant isolates did not differ with respect to culture source or bacteriophage type. The future usefulness of quinolones for S. aureus infection may be limited.
Comparison of intramuscular recombinant alpha interferon (rIFN-2A) with topical acyclovir for the treatment of first-episode herpes genitalis and prevention of recurrences
Authors: Levin M J , Judson F N , Eron L , Bryson Y J , Corey L , Murray M , Scheer R R
Published: June 2012

Intramuscular recombinant alpha interferon (rIFN-2A; 9 million IU given for 5 days during a 9-day treatment period) was compared with topical acyclovir in a double-blind, placebo-controlled trial for the treatment of first-episode genital herpes simplex virus (HSV) infection and for subsequent alteration of the frequency of recurrences. rIFN-2A (within 96 h of onset of the first episode) was not superior to topical acyclovir in a well-matched group of 105 patients. The early use of rIFN-2A also did not alter the frequency or severity of genital HSV recurrences within either the first or second 6 months following therapy. Separate analyses by HSV type and by type of infection (primary versus nonprimary) did not change this conclusion. Furthermore, there was significant toxicity associated with rIFN-2A therapy. rIFN-2A is not indicated for the treatment of genital HSV infections.
Isolation and characterization of an Escherichia coli strain exhibiting partial tolerance to quinolones
Authors: Wolfson J S , Hooper D C , Shih D J , McHugh G L , Swartz M N
Published: June 2012

Quinolone antimicrobial agents rapidly kill bacteria by largely unknown mechanisms. To study this phenomenon, a strain of Escherichia coli inhibited but inefficiently killed by (i.e., partially tolerant to) norfloxacin was isolated and characterized. E. coli KL16 (norfloxacin MIC, 0.10 microgram/ml; MBC, 0.20 microgram/ml) was mutagenized with nitrosoguanidine and cyclically exposed to 3 micrograms of norfloxacin per ml. After five cycles, a bacterial strain (DS1) which was killed 1,000-fold less than KL16 during 3 h of drug exposure was isolated. The MIC and MBC of norfloxacin for DS1 were 0.20 and 1.5 micrograms/ml, respectively. Over a range of norfloxacin concentrations, DS1 was killed 2 to 4 orders of magnitude less than KL16. DS1 grew more slowly than KL16 but after normalization for growth rate was killed four times less rapidly than KL16 at drug concentrations 10-fold higher than respective MICs. DS1 and KL16 cells filamented similarly upon exposure to norfloxacin. DS1 exhibited tolerance to other DNA gyrase A subunit antagonists (ofloxacin and ciprofloxacin) and DNA gyrase B subunit antagonists (novobiocin and coumermycin) but not to the aminoglycoside gentamicin, suggesting involvement of DNA gyrase. DS1 also appeared to be minimally tolerant to the beta-lactam cefoxitin. DS1 exhibited increased susceptibility to the mutagen methyl methanesulfonate, implying a defect in DNA repair. This report describes the first use of quinolone enrichment for isolation of a bacterial strain partially tolerant to quinolones. The study of defects in such tolerant strains offers an approach to an increased understanding of the mechanisms of bacterial killing by quinolones.
Pharmacokinetic comparison of 5 g of azlocillin every 8 h and 4 g every 6 h in healthy volunteers
Authors: Lander R D , Henderson R P , Pyszczynski D R
Published: June 2012

To compare the multiple-dose pharmacokinetics of two dosage regimens of azlocillin, we studied 12 healthy volunteers via a randomized, crossover design with a 2-week washout phase between regimens. Serum and urine samples were collected for 8 h following the fifth dose of a regimen of 4 g every 6 h and the fourth dose of a regimen of 5 g every 8 h. Data for concentrations in serum were fitted to a two-compartment open model by nonlinear regression. Statistically significant differences (P less than 0.05) were observed in the following parameters (mean +/- standard deviation) for the 4- and 5-g regimens, respectively: area under the serum concentration-time curve during the dosing interval, 592 +/- 140 versus 772 +/- 151 micrograms.h/ml; terminal elimination rate constant, 0.5364 +/- 0.0912 versus 0.4758 +/- 0.0486 h-1; renal clearance, 87.6 +/- 16.1 versus 76.1 +/- 13.5 ml/min; maximum drug concentration in serum, 381 +/- 89 versus 473 +/- 90 micrograms/ml; and minimum drug concentration in serum, 19 +/- 10 versus 8 +/- 4 micrograms/ml. No significant differences were seen in the following parameters: V1, V beta, k10, k12, k21, total systemic clearance, and nonrenal clearance. These data support the presence of saturable renal elimination of azlocillin, as well as the feasibility of an 8-h dosing interval.
Assay of fluconazole by megabore capillary gas-liquid chromatography with nitrogen-selective detection
Authors: Harris S C , Wallace J E , Foulds G , Rinaldi M G
Published: June 2012

A megabore column gas-liquid chromatographic method which uses nitrogen-phosphorus detection was developed for the analysis of fluconazole in plasma, serum, cerebrospinal fluid, or urine. The assay was linear from 0.2 to 200 micrograms/ml and had an average coefficient of variation of 7%. The suitability of the assay for pharmacokinetic studies was demonstrated.
Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome
Authors: Jacobson M A , O'Donnell J J , Mills J
Published: June 2012

Ten patients with acquired immunodeficiency syndrome with newly diagnosed cytomegalovirus (CMV) retinitis were treated with an induction regimen of intravenous foscarnet, 60 mg/kg of body weight, administered as a 2-h infusion and repeated every 8 h for 14 days. At the end of induction, 9 of 10 patients had stabilized (no new retinal lesions and stable old lesions [7 patients]) or improved (decreased retinal opacification [2 patients]). All eight patients with CMV in urine or blood upon entry into the study had negative urine and blood cultures at the end of induction. After induction therapy, seven patients continued maintenance foscarnet therapy, 60 mg/kg as a single daily infusion, 5 days/week. In six patients, retinal lesions increased in size after 2 to 32 weeks of maintenance therapy. One was invaluable because a retinal detachment developed. Only 9 of 42 blood and urine cultures obtained during maintenance foscarnet therapy yielded CMV, compared with 7 of 14 obtained prior to the initiation of foscarnet induction therapy (P = 0.04). Foscarnet toxicity was mild and infrequent: elevation in serum creatinine by 0.5 to 1.3 mg/dl over the base line (two patients), muscle twitching (three patients), hemoglobin decrease by 1 mg/dl (two patients), nausea (two patients), absolute neutrophil count decrease by 50% (one patient), rise in serum phosphorus to greater than 5.5 mg/dl (four patients), and proteinuria (two patients). Intermittently administered intravenous foscarnet appears to be an effective, relatively nontoxic therapy for CMV retinitis. Additional studies to determine the optimal dosage for maintenance therapy are needed, as are comparative trials with ganciclovir.
Comparative pharmacokinetics of clarithromycin (TE-031), a new macrolide antibiotic, and erythromycin in rats
Authors: Kohno Y , Yoshida H , Suwa T , Suga T
Published: June 2012

Clarithromycin (TE-031) is a newly synthesized macrolide with high stability in acidic conditions. In the present study, the pharmacokinetics of [N-methyl-14C]clarithromycin were compared with those of [N-methyl-14C]erythromycin in rats by radioassay and bioassay. Both radioactivity and bioactivity of [14C]clarithromycin in plasma and tissues were found to be significantly higher than those of [14C]erythromycin at the same oral dose of 20 mg/kg (body weight). Among the tissues, the peak level of [14C]clarithromycin in the lung was especially high. Levels of radioactivity and bioactivity amounted to 15 and 73 times the corresponding levels of [14C]erythromycin. In the urine, bioactivity recovered after administration of [14C]clarithromycin was sevenfold higher than that for [14C]erythromycin. This accounted for about 60 and 20% of the total radioactivity in the urine for [14C]clarithromycin and [14C]erythromycin, respectively. An examination of metabolites in the urine for [14C]clarithromycin revealed appreciable amounts of bioactive unchanged clarithromycin. These results indicate that clarithromycin has pharmacokinetic properties superior to those of erythromycin. The desirable properties of clarithromycin include high levels in plasma resulting from its high stability in gastric acid; a high tissue affinity, especially to the lung; and favorable urinary excretion.
Efficacy of ciprofloxacin against Leptospira interrogans serogroup icterohaemorrhagiae
Authors: Shalit I , Barnea A , Shahar A
Published: June 2012

Ciprofloxacin activity against Leptospira interrogans serogroup icterohaemorrhagiae was studied in vitro and in an animal model. The MBC of ciprofloxacin was 0.6 microgram/ml. Three of three Syrian hamsters died 8 to 9 days after intraperitoneal challenge with 10(6) leptospires. In contrast, five of six animals given ciprofloxacin 3 or 5 days after challenge survived.
Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones
Authors: Cullen M E , Wyke A W , Kuroda R , Fisher L M
Published: June 2012

Nalidixic acid, enoxacin, and other antibacterial 4-quinolones inhibit DNA gyrase activity by interrupting DNA breakage and reunion by A subunits of the A2B2 gyrase complex. Despite their clinical importance, the mode of quinolone action and mechanisms of resistance are poorly understood at the molecular level. Using a DNA fragment enrichment procedure, we isolated the gyrA gene from a uropathogenic Escherichia coli strain that encodes a gyrase A protein cross-resistant to a variety of quinolones. When complemented with gyrase B subunit, the purified A protein reconstituted DNA supercoiling activity approximately 100-fold more resistant to inhibition by enoxacin than the susceptible enzyme and failed to mediate quinolone-dependent DNA cleavage. Nucleotide sequence analysis revealed that the gene differed at 58 nucleotide positions compared with the K-12 gyrA sequence. The 875-amino-acid residue-resistant gyrase A protein differed at three positions from its wild-type E. coli K-12 counterpart: tryptophan, glutamate, and serine replaced serine, aspartate, and alanine residues at positions 83, 678, and 828, respectively. By genetic analysis of chimeric gyrA genes in a gyrA(Ts) background, we showed that the Ser-83----Trp mutation in the gyrase A protein was solely responsible for high-level bacterial resistance to nalidixic acid and fluoroquinolones.
In vitro and in vivo antibacterial activities of BMY 40062, a new fluoronaphthyridone
Authors: Fung-Tomc J , Desiderio J V , Tsai Y H , Warr G , Kessler R E
Published: June 2012

The in vitro and in vivo activities of a new naphthyridone, BMY 40062, were compared with those of ciprofloxacin and ofloxacin. BMY 40062 showed about threefold more activity than ciprofloxacin showed and four- to eightfold more activity than ofloxacin showed against staphylococci, streptococci, and enterococci. BMY 40062 showed generally twofold less activity than ciprofloxacin showed against most species of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter spp. but twofold more activity than ofloxacin showed against these organisms. BMY 40062 and ofloxacin were more active than ciprofloxacin against Bacteroides fragilis and Clostridium difficile. The antiureaplasmal and antichlamydial activities of BMY 40062 were similar to those of the tetracyclines and were 4- and 16-fold, respectively, higher than those of ciprofloxacin. The in vitro activities of BMY 40062 were influenced by pH and magnesium, although these factors appeared to affect the activity of BMY 40062 against P. aeruginosa to a lesser extent than those of ciprofloxacin and ofloxacin. BMY 40062 was found to be bactericidal, and cross-resistance with other fluoroquinolones was observed. In mouse protection tests, the efficacy of BMY 40062 reflected its in vitro potency. BMY 40062 exhibited longer half-life, higher maximum concentration in serum, greater area under the curve, and better bioavailability in mice after oral dosing than ciprofloxacin. Compared with ofloxacin, BMY 40062 had a lower maximum concentration in serum but a much longer half-life in mice. BMY 40062 was more effective than ciprofloxacin and ofloxacin in penetrating mouse macrophages and killing macrophage-associated Staphylococcus aureus.
Diffusion of ofloxacin into cerebrospinal fluid of patients with purulent meningitis or ventriculitis
Authors: Pioget J C , Wolff M , Singlas E , Laisne M J , Clair B , Regnier B , Vachon F
Published: June 2012

The penetration of ofloxacin was studied in 22 patients with purulent meningitis or ventriculitis treated with conventional antibiotics. Three successive doses of 200 mg were infused at 12-h intervals during the acute stage of the disease. Ten patients received three additional doses when the meninges were considered to be healed. Cerebrospinal fluid (CSF) was drawn 0.5, 3, 6, or 12 h after the last infusion. Serial plasma and CSF samples were also obtained from patients with ventricular drainage. Concentrations in CSF ranged from 0.96 +/- 0.15 to 1.80 +/- 0.29 microgram/ml, depending on sampling time. The percentage of penetration in ventricular fluid, expressed as the ratio of the CSF area under the curve from 0 to 12 h to the plasma area under the curve from 0 to 12 h, was 73 +/- 6. Ofloxacin readily diffuses into CSF of patients with meningitis or ventriculitis and may be useful for treatment of CSF infections caused by susceptible pathogens.
In vitro susceptibilities of Entamoeba histolytica to azithromycin, CP-63,956, erythromycin, and metronidazole
Authors: Ravdin J I , Skilogiannis J
Published: June 2012

Current therapy of Entamoeba histolytica infection requires use of multiple agents effective at different body sites, including the intestinal lumen, intestinal tissue, and liver. Azithromycin and CP-63,956, new extended-half-life macrolides which reach high levels in tissue, exhibit in vitro antiamebic activity at 18 or 48 h of incubation at concentrations comparable to that of erythromycin and slightly higher than that of metronidazole. Azithromycin and CP-63,956 have the potential to be useful therapeutic agents for all types of E. histolytica infection.
Comparison of the in vitro activities of fenticonazole, other imidazoles, metronidazole, and tetracycline against organisms associated with bacterial vaginosis and skin infections
Authors: Jones B M , Geary I , Lee M E , Duerden B I
Published: June 2012

The in vitro antibacterial activity of the antifungal compound fenticonazole was compared with those of clotrimazole, miconazole, tetracycline, and metronidazole against 177 strains of bacterial species associated with either bacterial vaginosis (BV) or skin infections by agar dilution MIC determinations. BV-associated Bacteroides isolates of the Bacteroides melaninogenicus-B. oralis group, Gardnerella vaginalis, Mobiluncus spp., and anaerobic, gram-positive cocci were highly susceptible to fenticonazole, clotrimazole, and miconazole; but Bacteroides spp. not associated with BV, Bacteroides ureolyticus and the Bacteroides fragilis group, were resistant. All Bacteroides strains were susceptible to metronidazole, but the susceptibility of G. vaginalis and Mobiluncus spp. varied. Among the skin bacteria, Staphylococcus aureus, coryneforms, and streptococci were highly susceptible to the imidazoles; but Staphylococcus epidermidis strains were generally resistant. This antibacterial activity may give fenticonazole a useful role in the topical treatment of vaginal discharge and in mycotic skin infections that are superinfected with bacteria.
In vitro activity and beta-lactamase stability of a new carbapenem, SM-7338
Authors: Neu H C , Novelli A , Chin N X
Published: June 2012

SM-7338, a new carbapenem, inhibited most members of the family Enterobacteriaceae at MICs of 0.015 to 0.25 microgram/ml, including Klebsiella oxytoca, Citrobacter freundii, Enterobacter cloacae, and Proteus vulgaris isolates resistant to cefotaxime, ceftazidime, piperacillin, and gentamicin. It was two- to eightfold more active than imipenem, but it inhibited Pseudomonas aeruginosa at 1 to 8 micrograms/ml, which was comparable to the activity of imipenem. Haemophilus, Neisseria, and Branhamella species were inhibited by less than or equal to 0.25 microgram/ml, which was superior to the activity of imipenem. SM-7338 inhibited Staphylococcus aureus and coagulase-negative staphylococci at 0.25 microgram/ml, but for methicillin-resistant isolates MICs were 4 to 16 micrograms/ml. Group A, B, and C streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.03 microgram/ml. Bacteroides species, including clindamycin-resistant isolates, were inhibited by 0.25 microgram/ml. There was no major inoculum size effect, and the MBCs were within a dilution of the MICs. SM-7338 was more active than imipenem at an acid pH under anaerobic conditions. Plasmid beta-lactamases of TEM-1, TEM-2, TEM-3, TEM-5, SHV-1, SHV-2, PSE-1, PSE-2, PSE-3, OXA-2, OXA-3, OXA-4, OXA-5, and OXA-7; Staphylococcus aureus enzymes; and the chromosomal beta-lactamases P-99 and K-1; Morganella species; and Proteus vulgaris did not hydrolyze SM-7338. The repeated transfer of organisms increased the MICs of SM-7338, as it did the MICs of imipenem.
Antibiotic susceptibilities of two Coxiella burnetii isolates implicated in distinct clinical syndromes
Authors: Yeaman M R , Roman M J , Baca O G
Published: June 2012

Antibiotic susceptibility testing of two isolates of the Q-fever agent, Coxiella burnetii, was performed with recently and persistently infected L929 fibroblast cells. The two genetically distinct isolates, Nine Mile and Priscilla, are implicated in two different clinical disease syndromes, acute and chronic Q fever, respectively. We compared the efficacies of rifampin, doxycycline, and five 4-quinolone compounds (ciprofloxacin, difloxacin, ofloxacin, norfloxacin, and pefloxacin) in reducing persistent C. burnetii infection of L929 fibroblasts. In persistently infected cells, the Priscilla isolate was less susceptible to all antibiotics tested when compared with the Nine Mile isolate. The most effective antibiotics against the Priscilla isolate were ofloxacin, pefloxacin, and ciprofloxacin (50% inhibitory concentrations of 0.5, 2.2, and 2.5 micrograms/ml, respectively). In persistently infected cells, the Nine Mile isolate was highly susceptible to all antibiotics tested except doxycycline. In contrast, the Priscilla and Nine Mile isolates in recently infected cells were somewhat susceptible to doxycycline; the Priscilla isolate was significantly more susceptible to ofloxacin and rifampin in recently infected host cells than in persistently infected cells. Persistently infected L929 cells were also treated with antibiotic combinations. Although ciprofloxacin and doxycycline had no synergistic effect on the Priscilla isolate, ciprofloxacin and rifampin acted synergistically. Collectively, these in vitro results are in accord with the fact that chronic Q fever in humans is generally not successfully managed with antibiotics. They also indicate that early diagnosis may be essential and that combination antibiotic therapy that includes quinolones may be effective in treating chronic Q fever.
Characterization of vancomycin resistance in Enterococcus faecium and Enterococcus faecalis
Authors: Nicas T I , Wu C Y , Hobbs J N , Preston D A , Allen N E
Published: June 2012

Vancomycin resistance in Enterococcus faecium 180, a clinical isolate from England, was studied. Resistance to vancomycin was transferable by conjugation to other enterococci. Expression of resistance was inducible and coincided with the appearance of a new membrane protein.
Treatment of Clostridium difficile-associated disease with teicoplanin
Authors: de Lalla F , Privitera G , Rinaldi E , Ortisi G , Santoro D , Rizzardini G
Published: June 2012

Forty-seven patients affected by Clostridium difficile-associated disease were treated orally with either vancomycin (patients hospitalized from February 1984 to February 1987) or teicoplanin (from March 1987 to December 1988). All patients given teicoplanin remained asymptomatic after discontinuation of treatment, and all but one were also cleared of C. difficile. In the vancomycin group, clinical symptoms recurred in 3 of 23 evaluable patients, and follow-up cultures were positive in another asymptomatic case.
In vitro postantibiotic effect of daptomycin (LY146032) against Enterococcus faecalis and methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains
Authors: Bush L M , Boscia J A , Wendeler M , Pitsakis P G , Kaye D
Published: June 2012

The suppression of bacterial growth that persists after brief exposure to antimicrobial agents has been termed the postantibiotic effect (PAE). This pharmacodynamic interaction varies for each microorganism-antimicrobial agent combination. Daptomycin (LY146032) is a new lipopeptide antibiotic with activity against gram-positive organisms. We studied the in vitro bactericidal activities and PAEs of the following drugs: daptomycin compared with penicillin G and vancomycin, without and with gentamicin against Enterococcus faecalis strains; daptomycin compared with nafcillin and vancomycin against methicillin-susceptible Staphylococcus aureus strains; and daptomycin compared with vancomycin against methicillin-resistant S. aureus strains. Daptomycin, alone and when used in combination with gentamicin, exhibited greater bactericidal activity and in general produced a longer PAE than standard effective regimens against the organism strains studied.
Isolation and characterization of dihydrofolate reductase from trimethoprim-susceptible and trimethoprim-resistant Pseudomonas cepacia
Authors: Burns J L , Lien D M , Hedin L A
Published: June 2012

Trimethoprim resistance was investigated in cystic fibrosis isolates of Pseudomonas cepacia. Determination of the MIC of trimethoprim for 111 strains revealed at least two populations of resistant organisms, suggesting the presence of more than one mechanism of resistance. Investigation of the antibiotic target, dihydrofolate reductase, was undertaken in both a susceptible strain and a strain with high-level resistance (MIC, greater than 1,000 micrograms/ml). The enzyme was purified by using ammonium sulfate precipitation, gel filtration, and ion-exchange chromatography. Specific activities, molecular weights, isoelectric points, and substrate kinetics were similar for both enzymes. However, the dihydrofolate reductase from the trimethoprim-resistant strain demonstrated decreased susceptibility to inhibition by trimethoprim and increased susceptibility to inhibition by methotrexate, suggesting that these two enzymes are not identical. We conclude that the mechanism of trimethoprim resistance in this strain with high-level resistance is production of a trimethoprim-resistant dihydrofolate reductase.
Activity and penetration of antituberculosis drugs in mouse peritoneal macrophages infected with Mycobacterium microti OV254
Authors: Dhillon J , Mitchison D A
Published: June 2012

The activities of some commonly used antituberculosis drugs were investigated within unstimulated peritoneal macrophages and in 7H-9 medium without Tween 80 using Mycobacterium microti OV254 as the target organism. In macrophage cultures, serial concentrations of isoniazid, rifampin, pyrazinamide, or streptomycin were added after a 2.5-h phagocytosis period. Viable counts were carried out at daily intervals for 5 or 6 days. The patterns of susceptibility to the four drugs were similar for M. microti and Mycobacterium tuberculosis. To ensure comparability with daily drug replacements in the macrophage experiments, the period of exposure to drugs in 7H-9 medium was kept to only 3 days. With in vitro culture at pH 6.4, drug penetration, measured as the ratio of MICs in macrophages to MICs in 7H-9 medium, was approximately 5 for isoniazid, 5 for rifampin, and 10 for streptomycin. With in vitro culture at pH 7.4, drug penetration was 100 for streptomycin, and at pH 5.6 it was 1 for pyrazinamide. Pyrazinamide was only bacteriostatic in macrophages but weakly bactericidal during the first day of exposure in vitro.
In vitro activity of ME1228, a new parenteral cephalosporin
Authors: Neu H C , Saha G , Chin N X
Published: June 2012

ME1228 is a new cephalosporin with an iminocarboxymethyl moiety on the acyl side chain and a novel pyridiniumthiomethyl group at position 3 of the bicyclic ring. Its activity was compared with those of ceftazidime, imipenem, piperacillin, and gentamicin. ME1228 inhibited most members of the family Enterobacteriaceae, except for some Enterobacter spp. and Citrobacter freundii, at less than or equal to 0.25 micrograms/ml, and it inhibited gentamicin- and piperacillin-resistant isolates. It had MICs for Pseudomonas aeruginosa between 1 and 32 micrograms/ml, comparable to those of ceftazidime, and it inhibited piperacillin- and gentamicin-resistant isolates. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.25 micrograms/ml. Enterococci and listeriae were resistant (MICs, 64 to 128 micrograms/ml). The MICs for staphylococci were 4 to 8 micrograms/ml, and methicillin-resistant Staphylococcus aureus was resistant. There was a minimal inoculum effect and no effect of the medium. ME1228 was not hydrolyzed by TEM-1, TEM-2, SHV-1, and S. aureus plasmid beta-lactamases and was stable against hydrolysis by Richmond-Sykes type 1a, 1c, 1d, and IV chromosomal beta-lactamases. It was hydrolyzed by TEM-3 and Xanthomonas maltophilia beta-lactamases. Overall, ME1228 had activity comparable or superior to that of ceftazidime.
Influence of daptomycin on staphylococcal abscesses and experimental tobramycin nephrotoxicity
Authors: Wood C A , Finkbeiner H C , Kohlhepp S J , Kohnen P W , Gilbert D N
Published: June 2012

The antibacterial efficacies of daptomycin and vancomycin were compared in male Fischer rats with subcutaneous abscesses caused by either methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant S. aureus (MRSA). The influence of daptomycin on tobramycin nephrotoxicity was also assessed. MSSA or MRSA abscesses were treated with subcutaneous daptomycin (10 mg/kg every 12 h), vancomycin (125 mg/kg every 12 h), or diluent (every 12 h) for 5 to 10 days. Rats in both antibiotic treatment groups had lower abscess bacterial counts than did controls at days 5 and 10 (P less than 0.0025). The daptomycin treatment groups had lower abscess bacterial counts than did the vancomycin treatment groups for MSSA at day 5 (P less than 0.0025) and day 10 (P less than 0.025) and for MRSA at day 10 (P less than 0.0025). Nephrotoxicity treatment groups included animals treated for 3, 7, 10, 14, and 17 days with subcutaneous diluent (every 12 h), daptomycin (20 mg/kg every 12 h), tobramycin (40 mg/kg every 12 h), and the combination of daptomycin and tobramycin. Compared with controls, animals treated with daptomycin alone exhibited no detectable nephrotoxicity. Rats given tobramycin alone developed functional and histopathologic abnormalities from days 7 through 17. Animals treated with daptomycin and tobramycin for 14 days had a lower mean concentration of creatinine in serum (P less than 0.005), higher mean creatinine clearance values (P less than 0.05), and less cortical tubular cell regeneration (P less than 0.05) than did rats treated with tobramycin alone. In rats with staphylococcal subcutaneous abscesses, daptomycin was superior to vancomycin in treating both MSSA and MRSA. Daptomycin alone caused no detectable renal injury, and in rats given daptomycin combined with tombramycin, there was less histologic and functional renal injury than in animals given tobramycin alone.