bluuebunny/crossref_metadata_2025 huggingface dataset:
Enzyme immunoassay to assess effect of antimicrobial agents on Toxoplasma gondii in tissue culture
Authors: Derouin F , Chastang C
Published: June 2012

Toxoplasma gondii grown on MRC5 fibroblasts in 96-well tissue culture plates was tested for susceptibility to five antimicrobial agents. T. gondii growth was quantitated by an enzyme-linked immunosorbent assay, which was performed directly on the fixed cultures, using a rabbit anti-T. gondii immunoglobulin G as the first antibody and a phosphatase-labeled anti-rabbit immunoglobulin G as the second antibody. Optical density values were highly correlated with the number of T. gondii organisms in the Giemsa-stained cultures (r = 0.89), and an enzyme-linked immunosorbent assay was used to assess the effect of antimicrobial agents at various concentrations. For each drug, regression models were used to quantify the relationship between optical density values and antimicrobial agent concentrations in the cultures. A significant inhibitory effect was found with pyrimethamine and sulfadoxine for concentrations greater than or equal to 0.05 and 30 micrograms/ml, respectively. With spiramycin, a progressive increase in inhibition of T. gondii was observed for increasing concentrations from 1 to 100 micrograms/ml. Ornidyl (difluoromethylornithine) and (2R,5R)-6-heptyne-2,5-diamine, which are ornithine decarboxylase inhibitors, were found to have a marked inhibitory effect for concentrations greater than or equal to 25 and 2 mM, respectively. This proposed method was sensitive and easy to perform and does not require the use of radiolabeled compounds; since it allows experimental design on replicate cultures and can be partially automated, it thus may prove useful for the systematic screening of the activity of new compounds against T. gondii.
Interference with effects of amphotericin B on Candida albicans cells by 2-chloroethyl-1-nitrosoureas
Authors: Brajtburg J , Elberg S , Kobayashi G S , Medoff G
Published: June 2012

Two nitrosoureas, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), with strong carbamoylating and weak alkylating activities, interfered with the induction of potassium leakage and lethal action of amphotericin B (AmB) on Candida albicans. 2-Cyclohexyl isocyanate, the product of decomposition of CCNU, and 2-chloroethyl isocyanate, the product of decomposition of BCNU, also interfered with the anticandidal actions of AmB. In contrast, two nitrosoureas with weak carbamoylating and strong alkylating activities, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperydyl)-1-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose, did not affect AmB action against C. albicans. These results indicate that the inhibitory action of CCNU and BCNU on the anticandidal effects of AmB is associated with the carbamoylating activity of these nitrosoureas.
Cycloheximide efflux in antibiotic-adapted cells of the fungus Mucor racemosus
Authors: Shearer G , Sypherd P S
Published: June 2012

Mucor racemosus cells adapted to either cycloheximide or trichodermin were approximately 40-fold more resistant to cycloheximide than nonadapted cells. Ribosomes isolated from adapted and nonadapted cells were equally sensitive to cycloheximide in an in vitro poly(U) translation assay. There was no detectable modification of cycloheximide by adapted cells. Uptake of drug by nonadapted and adapted cells was characterized by a rapid initial accumulation during the first 2 min of incubation with [3H]cycloheximide, followed by a steady-state intracellular drug concentration well below that of the medium. The steady-state drug concentration was approximately 10-fold lower in adapted cells than in nonadapted cells. Treatment of cells with sodium azide or dinitrophenol abolished the difference between uptake of drug by nonadapted and adapted cells and resulted in intracellular drug levels equal to that of the medium. Direct efflux measurements showed that adapted cells loaded with cycloheximide were able to excrete the drug far more rapidly than nonadapted cells. These results suggest that both nonadapted and adapted cells possess an energy-dependent efflux mechanism for transporting cycloheximide and that resistance in adapted cells is due to increased efficiency of transport.
Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis
Authors: Tucker R M , Williams P L , Arathoon E G , Levine B E , Hartstein A I , Hanson L H , Stevens D A
Published: June 2012

The pharmacokinetics of fluconazole, a new oral azole, were evaluated in cerebrospinal fluid and sera of eight patients with coccidioidal meningitis. At a dose of 50 mg/day, peak concentrations of 2.5 to 3.5 and 2.0 to 2.3 micrograms/ml occurred at 2 to 6 and 4 to 8 h in serum and cerebrospinal fluid, respectively. At 100 mg/day, peak concentrations of 4.5 to 8.0 and 3.4 to 6.2 micrograms/ml occurred at 2 to 4 and 4 to 12 h, respectively. The mean ratios of the concentration in cerebrospinal fluid to that in serum were 73.8% at 50 mg/day and 88.7% at 100 mg/day. Results suggested that there was a prolonged half-life in both cerebrospinal fluid and serum and that it was slightly longer in the former. Minimal toxicity was noted in 34 patient months of therapy (12 months on 50 mg daily; 22 months on 100 mg daily). After a mean of 4.5 months of therapy, five patients responded to therapy and three were unevaluable. The penetration of fluconazole into cerebrospinal fluid was substantial, toxicity was minimal, and early clinical experience was encouraging. Fluconazole holds promise as the sole or adjunctive therapy for fungal meningitis.
In vitro activity of amiloride combined with tobramycin against Pseudomonas isolates from patients with cystic fibrosis
Authors: Cohn R C , Jacobs M , Aronoff S C
Published: June 2012

The diuretic amiloride has been under recent investigation as adjunctive therapy for pulmonary disease in children with cystic fibrosis (CF). In preliminary studies, the antimicrobial activity of this agent alone or combined with beta-lactam agents against reference strains of Pseudomonas aeruginosa and P. cepacia was poor; however, amiloride was markedly synergistic with tobramycin against P. cepacia. The purpose of this study was to determine the extent of amiloride-tobramycin synergy against CF respiratory isolates of P. aeruginosa, P. cepacia, and P. maltophilia. The MICs of tobramycin and amiloride alone against the Pseudomonas test strains were determined by agar dilution. Synergy was determined by combining each of four subinhibitory concentrations of amiloride (at least fourfold below the MIC) with doubling dilutions of tobramycin and comparing the MIC of tobramycin alone and in combination for each strain. At the highest concentration tested, the drug combination synergistically inhibited 50% of the P. cepacia strains tested; the combination was synergistic against fewer isolates of P. aeruginosa and P. maltophilia. Only P. cepacia was inhibited by tobramycin combined with amiloride at achievable airway concentrations. We conclude that the combination of tobramycin and amiloride may be potentially useful in the treatment of P. cepacia infections in children with CF.
Novel mechanisms of resistance to lincosamides in Staphylococcus and Arthrobacter spp
Authors: Quiros L M , Fidalgo S , Mendez F J , Hardisson C , Salas J A
Published: June 2012

Clinical isolates of Staphylococcus and Arthrobacter spp. were screened for lincosamide resistance. Six different patterns of resistance were found. Strains designated SF27 and SF28 showed low-level resistance to lincosamides: one was susceptible to erythromycin (SF27) and the other was resistant (SF28). Analysis of ribosomes from the resistant strains in an in vitro poly(U)-dependent protein-synthesizing system showed that ribosomes of both strains were sensitive to lincomycin and clindamycin. Four patterns of high-level resistance to lincosamides were observed (strains SF4, SF19, SF30, and SF31). All of these except SF30 had ribosomes which were highly resistant in vitro to the antibiotics and showed a close correlation with results of the in vivo experiments. In vivo protein synthesis by strain SF30 was resistant to lincomycin and sensitive to clindamycin, whereas the ribosomes were sensitive when assayed in vitro. Lincosamide-inactivating enzymes were not detected in cell extracts of the six resistant strains. Strains SF19 and SF31 demonstrated two ribosome-mediated lincosamides resistance mechanisms that were not previously reported. Both strains were highly resistant to lincosamides and susceptible to erythromycin, but SF19 was also highly resistant to oleandomycin and partially resistant to various macrolides.
Synergistic activity between vancomycin or teicoplanin and gentamicin or tobramycin against pathogenic diphtheroids
Authors: Spitzer P G , Eliopoulos G M , Karchmer A W , Moellering R C
Published: June 2012

The in vitro activities of vancomycin and teicoplanin alone and in combination with gentamicin or tobramycin were studied by time-kill techniques with 11 strains of pathogenic diphtheroids (Corynebacterium group JK). The activities of vancomycin and teicoplanin were similar (MIC for 90% of strains tested [MIC90], 1 microgram/ml), as were those of gentamicin and tobramycin (the MIC90 was 1 microgram/ml for five aminoglycoside-susceptible strains, and the MIC90 was greater than 1,024 micrograms/ml for six aminoglycoside-resistant strains). No consistent synergistic killing could be demonstrated by the combination of glycopeptide and aminoglycoside antibiotics at arbitrarily chosen concentrations within the range of clinically achievable levels. However, by careful adjustment of both vancomycin and gentamicin concentrations within a narrow range below the MIC of each antibiotic, synergistic killing could be seen with an aminoglycoside-susceptible strain but not with an aminoglycoside-resistant strain. Synergism between glycopeptide and aminoglycoside antibiotics occurs with some diphtheroid organisms, but it may not be clinically relevant.
Early stages of in vitro killing curve of LY146032 and vancomycin for Staphylococcus aureus
Authors: Flandrois J P , Fardel G , Carret G
Published: June 2012

The early stages of the time-killing curves of vancomycin and LY146032 have been studied, by use of short sampling intervals, for three strains of Staphylococcus aureus. Both vancomycin and LY146032 killed S. aureus, but the time-killing curves differed: the effect of vancomycin was slow, limited, and not related to the concentration of the drug, whereas that of LY146032 was rapid, extensive, and related to concentration. When strains ATCC 25923 and CIP 6525 were exposed to LY146032, the population decreased exponentially with time. The killing rate was constant and linked to the concentration by a Michaelis-Menten relationship. The maximum killing rate and the affinity constant of LY146032, estimated from the data transformed by the Lineweaver-Burk method, differed for the two strains. The concentration of the antibiotic at which killing theoretically begins (estimated by linear regression using the logarithm of the concentration) is of the same magnitude as the MIC of LY146032, which indicates the pure bactericidal mode of action of the drug. S. aureus ATCC 12600 was more resistant to the bactericidal effect of the two drugs, and its killing curve did not conform to the model described here.
Stage-selective inhibition of rodent malaria by cyclosporine
Authors: Murphy J R , Baqar S , Baker R H , Roberts E , Nickell S P , Cole G A
Published: June 2012

The relative susceptibility of different developmental stages of Plasmodium berghei to cyclosporine was investigated in vivo. Within 12 h of receiving a single 25-mg/kg (body weight) dose of cyclosporine, mice with patent P. berghei infections uniformly exhibited a rapid fall in asexual parasite stages. Initially, ring forms and mature schizonts disappeared. Subsequently, trophozoites disappeared between 21 and 24 h, whereas gametocytes persisted for 36 h. In contrast, when cyclosporine was administered to mice 1 day before inoculation (100 mg/kg) with P. berghei sporozoites and for 2 consecutive days after inoculation (25 mg/kg), infections developed normally. When mice with patent infections were placed on prolonged cyclosporine therapy (25 mg/kg per day), parasitemia initially disappeared but often recrudesced. Recrudescent parasites were frequently resistant to cyclosporine (Csr). The Csr phenotype remained stable after serial passage of parasites in mice and after transmission through Anopheles stephensi mosquitoes, in which the capacity to produce oocysts was reduced. When infections of untreated mice were initiated with equal numbers of Csr and cyclosporine-susceptible (Css) parasites and then carried through two serial cycles of mosquito-to-mouse transmission without cyclosporine treatment, the Csr phenotype was lost. The results indicate that cyclosporine selectively inhibits asexual blood stages of P. berghei and favors the emergence of Csr parasites with diminished infectivity for mosquitoes.
Host range of the conjugative 25.2-megadalton tetracycline resistance plasmid from Neisseria gonorrhoeae and related species
Authors: Roberts M C , Knapp J S
Published: June 2012

High-level tetracycline resistance in strains of Neisseria gonorrhoeae, Neisseria meningitidis, Kingella denitrificans, and Eikenella corrodens has recently been described. The resistance in each species is due to the acquisition of 25.2-megadalton conjugative plasmids that carry the tetracycline resistance determinant TetM. We examined the ability of commensal Neisseria species to serve as recipients in conjugation for these new plasmids. Most of the recipients (n = 21) tested had detectable conjugation frequencies (greater than 10(-9] with one or more of the donor strains. Transfer was not detected in Branhamella catarrhalis. Transconjugants were able to maintain the plasmids and act as donors in subsequent matings.
Pharmacokinetics of cefoperazone (2.0 g) and sulbactam (1.0 g) coadministered to subjects with normal renal function, patients with decreased renal function, and patients with end-stage renal disease on hemodialysis
Authors: Reitberg D P , Marble D A , Schultz R W , Whall T J , Schentag J J
Published: June 2012

The single-dose pharmacokinetics of intravenously administered cefoperazone (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of renal failure. In an open, parallel experimental design, six normal subjects (creatinine clearance, greater than 90 ml/min), two patients with mild renal failure (creatinine clearance, 31 to 60 ml/min), eight patients with moderate renal failure (creatinine clearance, 7 to 30 ml/min), and four functionally anephric patients (creatinine clearance, less than 7 ml/min) were studied. The functionally anephric patients were given two test doses to allow study of drug disposition both on and off hemodialysis. Serial blood and urine samples were collected from time zero to 12 h after dosing in normal subjects and from 0 to 72 h in renal patients. Serum concentrations of both drugs declined biexponentially. For cefoperazone, the terminal elimination half-lives averaged from 1.6 to 3.0 h and were similar in subjects and patients. No cefoperazone pharmacokinetic parameters were appreciably altered by renal failure or hemodialysis, and there was no correlation between the total body clearance of cefoperazone and estimated creatinine clearance. In contrast, the sulbactam total body clearance was highly correlated with estimated creatinine clearance (r = 0.92, P less than 0.01) and was significantly higher in normal volunteers than in the renally impaired groups (P less than 0.01). The sulbactam terminal elimination half-life in functionally anephric patients (9.7 +/- 5.3 h) differed significantly from that of normal volunteers (1.0 +/- 0.2 h) and patients with mild renal failure (1.7 +/- 0.7 h, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin [CP-62,993], and A-56268) on Toxoplasma gondii
Authors: Chang H R , Pechère J C
Published: June 2012

The effect of four macrolides against intracellular Toxoplasma gondii was determined in three different in vitro systems. Unactivated murine peritoneal macrophages were infected with the virulent RH strain of T. gondii. The activity of the macrolides was first measured with [3H]uracil, which is incorporated by the parasite but not the host cell. The 50% inhibitory concentrations (IC50s) and 95% confidence limits were calculated at 54 (38 to 73), 140 (98 to 201), 147 (101 to 214), and 246 (187 to 325) micron for roxithromycin, azithromycin (CP-62,993), A-56268, and spiramycin, respectively. Inhibition of Toxoplasma growth was confirmed by microscopic examination of the infected macrophages after treatment with roxithromycin. Compared with untreated controls, roxithromycin concentrations near the IC50s decreased the number of infected cells, the number of tachyzoites per vacuole, and the number of cells containing rosettes (i.e., clusters of more than eight tachyzoites). After treatment with the four macrolides, tachyzoites were released from the macrophages and subcultured in HeLa cells, which are nonprofessional phagocytes, to assess the viability of the remaining parasites. This showed that the macrolides at concentrations corresponding to four times their 90% inhibitory concentrations (IC90s) had no significant killing effect. At 8 times the IC90, roxithromycin showed an incomplete killing effect, similar to that of the combination of pyrimethamine (0.41 microM)-sulfadiazine (99.42 microM). All macrolides tested showed inhibitory effects against intracellular T. gondii, but amounts of azithromycin and A-56268 corresponding to the IC90 appeared to be toxic against the host macrophages, which might have had nonspecific activity against Toxoplasma metabolism.
Pharmacokinetics of imipenem-cilastatin in patients with renal insufficiency undergoing continuous ambulatory peritoneal dialysis
Authors: Somani P , Freimer E H , Gross M L , Higgins J T
Published: June 2012

In six patients with end-stage renal disease, a single bolus of imipenem-cilastatin (500 mg each) was given either intravenously or intraperitoneally in a randomized crossover protocol such that each patient received the drug by both routes at a 2- to 3-week interval. Drug levels in plasma and the peritoneal dialysis fluid were analyzed at frequent intervals, and various pharmacokinetic variables were calculated for a one-compartment open model. Data obtained in the present study suggest that while no significant difference in peak plasma levels or volume of distribution were noted, the following variables were significantly different for imipenem as compared with cilastatin: elimination half-life, total plasma clearance, area under the concentration-time curve, and percent drug excretion in the peritoneal dialysis fluid. The elimination half-life of imipenem (3.28 h) or cilastatin (8.84 h) in our patients was in the same range as observed in patients with minimal renal function undergoing hemodialysis. The dose of imipenem-cilastatin should be reduced appropriately in patients with end-stage renal disease undergoing peritoneal dialysis.
Genetic and physiological characterization of ciprofloxacin resistance in Pseudomonas aeruginosa PAO
Authors: Robillard N J , Scarpa A L
Published: June 2012

Spontaneous ciprofloxacin-resistant mutants of Pseudomonas aeruginosa PAO2 were isolated on ML agar containing 0.5 microgram of ciprofloxacin per ml (2 times the MIC). The mutants were 8- to 64-fold more resistant to ciprofloxacin and showed complete cross resistance to nalidixic acid, ofloxacin, enoxacin, and norfloxacin. Two chromosomal resistance genes, cfxA and cfxB, were mapped between eda-9001 and phe-2 and near pyrB52 distal to proC130, respectively. The cfxB mutation was identical to a nalB mutation and conferred cross resistance to novobiocin, tetracycline, carbenicillin, and chloramphenicol, suggesting that there is an effect on permeability. DNA gyrase A and B subunits were purified from strain PAO2 (wild type), PAO236 nalA2, PAO4704 cfxA2, and PAO4700 cfxA1 cfxB1. Inhibition of gyrase-mediated DNA supercoiling by ciprofloxacin or nalidixic acid was greatly reduced in preparations derived from each of the mutants. Inhibition studies on reconstituted heterologous gyrase subunits showed that decreased inhibition was dependent on the mutant gyrase A subunit. We conclude that ciprofloxacin resistance in P. aeruginosa PAO2 can occur by mutation in the nalB gene or the gene for DNA gyrase A (formerly nalA).
Disposition of amopyroquin in rats and rabbits and in vitro activity against Plasmodium falciparum
Authors: Pussard E , Verdier F , Faurisson F , Clavier F , Simon F , Gaudebout C
Published: June 2012

The disposition of amopyroquin was studied in rats after a single 50-mg/kg (body weight) oral dose of amopyroquin base. After a rapid absorption phase, the drug concentrations decreased in the plasma, with a terminal half-life of 14.5 h. The drug was widely distributed in the liver and lungs and, to a lesser extent, in the kidneys and spleen. In rabbits, the kinetic parameters were compared after a single 10-mg/kg dose of amopyroquin base through intravenous, intramuscular (i.m.), and oral routes. The similar bioavailability values (0.67 and 0.69) suggested that the drug could be used through i.m. or oral administration. Clearance and distribution volume did not differ significantly among the three modes of administration, and the terminal half-lives were 18.1 +/- 3.3, 23.9 +/- 6.7, and 25.7 +/- 5.4 h for intravenous, i.m., and oral routes, respectively. The ratio of concentrations in erythrocytes and plasma was about 5 in rats and rabbits. Three metabolites were detected in both animal species (one was tentatively identified as the primary amine derivative). The amopyroquin in vitro activity was tested against four chloroquine-susceptible and 11 chloroquine-resistant African Plasmodium falciparum strains. For all isolates, the 50% inhibitory concentrations of amopyroquin were much lower than those of chloroquine and monodesethylamodiaquine.
Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans
Authors: Koup J R , Dubach U C , Brandt R , Wyss R , Stoeckel K
Published: June 2012

This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.
Activities of Nigerian chewing stick extracts against Bacteroides gingivalis and Bacteroides melaninogenicus
Authors: Rotimi V O , Laughon B E , Bartlett J G , Mosadomi H A
Published: June 2012

The in vitro activities of extracts of Nigerian chewing sticks against Bacteroides gingivalis and B. melaninogenicus are presented. The greatest inhibitory action was produced by Serindeia werneckei, whereas Fagara zanthoxyloides produced no appreciable inhibitory effect. A generally good correlation was found between the killing curves and MICs. Only extracts of Anogeissus leiocarpus showed acute toxicity in mice.
In vitro activity of cefotetan compared with that of other antimicrobial agents against anaerobic bacteria
Authors: Wexler H M , Finegold S M
Published: June 2012

The activity of cefotetan against 430 strains of anaerobic bacteria was compared with that of cefoxitin, ceftizoxime, clindamycin, metronidazole, and chloramphenicol. Percent susceptible values for the Bacteroides fragilis group were 60, 80, 29, 86, 100, and 100%, respectively. Percent susceptible values for the B. fragilis species were 91, 92, 46, 98, 100, and 100%, respectively. Non-B. fragilis-group Bacteroides species were inhibited very well (90 to 100%) by all drugs except ceftizoxime (80%). Cefotetan and metronidazole were the most active agents against Clostridium difficile. Percent susceptible values for all strains were 72, 79, 44, 82, 93, and 98%, respectively.
Novel plasmid-mediated beta-lactamase in clinical isolates of Klebsiella pneumoniae more resistant to ceftazidime than to other broad-spectrum cephalosporins
Authors: Petit A , Sirot D L , Chanal C M , Sirot J L , Labia R , Gerbaud G , Cluzel R A
Published: June 2012

Multiresistant Klebsiella pneumoniae strains isolated from three patients in the same intensive care unit were more resistant to ceftazidime than to cefotaxime and aztreonam but remained susceptible to moxalactam and imipenem. Resistance to beta-lactams, kanamycin, streptomycin, sulfonamides, and tetracyclines was transferable to Escherichia coli by conjugation and was lost en bloc after treatment with ethidium bromide. Agarose gel electrophoresis of wild types and transconjugants indicated that these resistances were mediated by a 150-kilobase plasmid, pCFF14. The strains constitutively produced a beta-lactamase with isoelectric point close to 5.6 and which had a higher Vmax for ceftazidime and cephalothin than for cefotaxime. The substrate profile and isoelectric point of this enzyme thus differ from those of other known plasmid-mediated beta-lactamases, including the broad-spectrum enzyme CTX-1. Hybridization studies support the derivation of the novel enzyme from a TEM-type beta-lactamase.
Interaction between rifabutin and human immunodeficiency virus type 1: inhibition of replication, cytopathic effect, and reverse transcriptase in vitro
Authors: Anand R , Moore J L , Curran J W , Srinivasan A
Published: June 2012

Rifabutin (ansamycin; LM427), a semisynthetic rifamycin derivative, inhibits the replication of human immunodeficiency virus type 1, the virus etiologically linked to acquired immunodeficiency syndrome. The inhibition of virus production was observed in human immunodeficiency virus type 1-infected peripheral blood mononuclear cells both by reverse transcriptase assay and virus-antigen assay. In addition, rifabutin effectively reduced human immunodeficiency virus type 1-associated cytopathic effect to OKT4-positive cells. Virion-associated reverse transcriptase was also markedly inhibited by rifabutin. The inhibitory dose of rifabutin was nontoxic to lymphoid cells, which further suggests that it might serve as a useful agent in the therapeutic modalities of acquired immunodeficiency syndrome.
Effect of ursodeoxycholate on the biliary excretion of cefotiam and sulbenicillin in patients with percutaneous transhepatic biliary drainage
Authors: Higashi K , Hayakawa T , Katagiri K , Tsukada K , Ito K , Hoshino M , Miyaji M , Takeuchi T , Yamamoto T
Published: June 2012

The effects of ursodeoxycholate administration on the biliary excretion of the antibiotics cefotiam and sulbenicillin were studied in five patients with stable hepatic function receiving percutaneous transhepatic biliary drainage for obstructive jaundice. Cefotiam (I g) and sulbenicillin (2 g) were administered intravenously before and after ursodeoxycholate administration, and the maximum concentrations of the antibiotics in the bile and total amounts excreted in the bile during the 4 h after administration were determined. After ursodeoxycholate administration, both the maximum concentration of cefotiam in the bile and the amount excreted increased significantly. Ursodeoxycholate also increased the peak concentration and total excretion of sulbenicillin. For both cefotiam and sulbenicillin, the amount of antibiotic excreted in the bile during the 4 h after administration showed a significant correlation with the amount of bile acids excreted in the bile. This strongly suggests a common mechanism for the biliary excretion of these antibiotics and bile acids. Ursodeoxycholate administration is a benign way to increase both the concentration and the total amount of antibiotic excreted in the bile. Therefore, it may be useful in the treatment of serious biliary tract infections, especially in patients receiving biliary drainage.
Synergistic interactions of ciprofloxacin and extended-spectrum beta-lactams or aminoglycosides against multiply drug-resistant Pseudomonas maltophilia
Authors: Chow A W , Wong J , Bartlett K H
Published: June 2012

The susceptibility of 28 clinical isolates of Pseudomonas maltophilia to 16 antimicrobial agents was determined in vitro by a standard agar dilution method with inoculum sizes of 10(4) and 10(6) CFU. All isolates exhibited multiple drug resistance. Nine isolates were selected for studies of combinations of ciprofloxacin with seven antipseudomonal beta-lactams and three aminoglycosides by a checkerboard agar dilution technique. Synergistic or additive combinations of ciprofloxacin in clinically achievable concentrations were most frequent with mezlocillin (89%), followed by cefoperazone (67%), piperacillin (56%), cefsulodin (56%), and ceftazidime (33%), and were infrequent with aztreonam (11%), the aminoglycosides (0 to 14%), or imipenem (0%). Antagonism was not observed in any combination. These data suggest that combinations of ciprofloxacin with these agents may be useful for some nosocomial multiply drug-resistant P. maltophilia infections.
Bone penetration of enoxacin in patients with and without osteomyelitis
Authors: Fong I W , Rittenhouse B R , Simbul M , Vandenbroucke A C
Published: June 2012

Enoxacin concentrations in bone were measured in 24 patients without infection and in 7 with osteomyelitis after one or two doses of 400 mg of enoxacin administered orally or intravenously. Enoxacin concentrations were measured in serum and bone (cortical and cancellous) by high-pressure liquid chromatography. The mean concentration in serum was 2.4 +/- 1.0 micrograms/ml (range, 1.3 to 5.2 micrograms/ml) and was highest after two intravenous doses (3.1 +/- 0.9 micrograms/ml). The mean concentration in cortical bone was 1.0 +/- 0.9 micrograms/g (range, 0.4 to 4.8 micrograms/g) and was highest in patients with osteomyelitis (1.3 +/- 1.6 micrograms/g), but this was not statistically significant. The concentration of enoxacin in cancellous bone was significantly higher than that in cortical bone, with a penetration of 82 versus 40%. Oral enoxacin in practical doses can provide significant levels in bone, and further studies are warranted to determine its therapeutic efficacy in osteomyelitis.
Comparative study of cephalexin hydrochloride and cephalexin monohydrate in the treatment of skin and soft tissue infections
Authors: Kumar A , Murray D L , Hanna C B , Kreindler T G , Jacobson K D , Bundy J M , Waxman K , Finnerty E F , Folan D W , Drucker W R
Published: June 2012

In two prospective, randomized multicenter double-blind studies with a dosage of either 250 mg given four times a day (study A) or 500 mg given two times a day (study B), the comparative efficacy and safety of cephalexin hydrochloride (LY061188; Keftab) and cephalexin monohydrate (Keflex) for treatment of skin and soft tissue infections were determined. In study A, 97 patients received cephalexin hydrochloride and 101 patients received cephalexin monohydrate. In study B, 75 patients received cephalexin hydrochloride and 70 patients received cephalexin monohydrate. Diagnoses included abscesses, cellulitis, wound infections, and infected dermatitis, and were comparable in the different treatment groups. Pathogens were isolated from 82% of patients enrolled; the majority of isolates were of Staphylococcus aureus, Streptococcus pyogenes, other staphylococcal species, and a few gram-negative bacteria. In study A, 68 of 71 (95.7%) evaluable patients who received cephalexin hydrochloride responded satisfactorily; 73 of 81 (90%) patients who received cephalexin monohydrate also responded satisfactorily. In study B, 56 of 58 (96.5%) evaluable patients who received cephalexin hydrochloride responded satisfactorily; 47 of 50 (94%) patients who received cephalexin monohydrate also responded satisfactorily. An adverse clinical event leading to discontinuation of the treatment drug developed in 17 of 343 (4.95%) patients in both studies. No differences were noted between the two drugs. Skin eruptions, pruritis, and mild gastrointestinal symptoms were the common adverse effects. These data suggest that cephalexin hydrochloride, a new formulation of cephalexin, is a safe and effective antimicrobial agent for treatment of a variety of skin and subcutaneous infections in a dosage of either 250 mg four times a day or 500 mg twice a day.
Comparative activities of several nucleoside analogs against influenza A, B, and C viruses in vitro
Authors: Shigeta S , Konno K , Yokota T , Nakamura K , De Clercq E
Published: June 2012

A set of 20 nucleoside analogs were examined for their inhibitory effects on the cytopathogenicity and growth of influenza virus type A, B, and C strains in Madin-Darby canine kidney (MDCK) cells. Among the compounds evaluated, pyrazofurin, 3-deazaguanine, ribavirin, carbodine, and cyclopentenyl cytosine inhibited viral cytopathogenicity at concentrations that were lower than those found cytotoxic for the MDCK cells. No differences were observed in the 50% effective doses (based on inhibition of viral cytopathogenicity) of these five compounds for a number of influenza virus type A (subtypes H1N1 and H3N2), B, and C strains. Pyrazofurin showed the lowest 50% effective dose (0.15 microgram/ml), which was about 20- to 30-fold lower than those of the other four compounds. The selectivity indices of the five compounds, calculated as the ratio of the 50% cytotoxic dose (determined by trypan blue exclusion) to the 50% effective dose, were greater than 100. When the selectivity indices were calculated as the ratios of the 50% inhibitory doses for cellular RNA synthesis to the 50% effective doses, they were greater than 100 for ribavirin, pyrazofurin, and 3-deazaguanine but less than 2 for carbodine and cyclopentenyl cytosine. All five compounds inhibited the growth of influenza virus types A and B in MDCK cells at a concentration which was well below their cytotoxicity threshold for MDCK cells and, therefore, deserve further exploration for their potential in the treatment of influenza virus type A, B, and C infections.
Efficacy of pefloxacin-fosfomycin in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus
Authors: Thauvin C , Lemeland J F , Humbert G , Fillastre J P
Published: June 2012

The efficacies of pefloxacin, fosfomycin, and both of these agents in combination against methicillin-resistant Staphylococcus aureus were assessed in a rat endocarditis model. The combination prevented emergence of the fosfomycin and pefloxacin resistance seen in 36 and 4%, respectively, of animals receiving either agent alone and was more effective than either agent in sterilizing cardiac vegetations.
Activities of five new fluoroquinolones against Pseudomonas pseudomallei
Authors: Winton M D , Everett E D , Dolan S A
Published: June 2012

Thirty-four isolates of Pseudomonas pseudomallei were tested by a broth microdilution technique for susceptibility to amifloxacin, ciprofloxacin, enoxacin, norfloxacin, and ofloxacin. Ciprofloxacin was the most active agent tested, with an MIC for 90% of the strains tested of 8 micrograms/ml. These in vitro results suggest that the fluoroquinolones tested would not be optimal for therapy of melioidosis.
Determination of pyrazinamide MICs for Mycobacterium tuberculosis at different pHs by the radiometric method
Authors: Salfinger M , Heifets L B
Published: June 2012

The MICs of pyrazinamide (PZA) were determined for Mycobacterium tuberculosis cultivated under different pH conditions in 7H12 liquid medium. Mycobacterial growth was monitored by the radiometric method (BACTEC system; Johnston Laboratories, Inc., Towson, Md.). We observed a predictable eightfold difference between the MICs determined at pH 5.5 and those determined at pH 5.95. The highest MICs for 21 susceptible strains were 50.0 micrograms/ml at pH 5.5 and 400 micrograms/ml at pH 5.95. This eightfold difference enabled us to predict MICs at pH 5.5 from the values observed at pH 5.95. The use of 7H12 broth at pH 5.95 simplified the radiometric PZA susceptibility test by avoiding the addition of acid solutions in the course of cultivation, which was required when the test was performed at pH 5.5. An additional benefit of using pH 5.95 instead of pH 5.5 was that all tested strains grew at pH 5.95, while some of them, especially PZA-resistant strains, did not grow at pH 5.5.
Gentamicin penetration into cerebrospinal fluid in experimental Haemophilus influenzae meningitis
Authors: Smith A L , Daum R S , Siber G R , Scheifele D W , Syriopoulou V P
Published: June 2012

We studied the effect of meningitis and the method of parenteral gentamicin administration (intramuscular injection, a 30-min intravenous infusion, or intravenous bolus administration) on achievable concentrations of drug in cerebrospinal fluid (CSF). In normal animals, only intravenous bolus administration of 2 to 8 mg/kg produced a gentamicin concentration of greater than 0.1 microgram/ml in CSF in some animals. All CSF samples contained less than the limit of detection (0.1 microgram/ml) after the intramuscular administration of 6 mg/kg. In animals with meningitis, gentamicin penetration into cisternal CSF was increased significantly after a bolus administration of 6 mg/kg (mean, 0.197 +/- 0.063 microgram/ml in normal animals versus 1.68 +/- 0.38 micrograms/ml in animals with meningitis; P less than 0.01). In meningitic animals that received 6 mg/kg as an intravenous bolus, lumbar CSF had the highest maximum concentration (4.25 +/- 1.08 micrograms/ml), in comparison with ventricular CSF (3.10 +/- 0.66 micrograms/ml). The gentamicin concentration in cisternal CSF decreased more slowly than it did in serum (elimination half-life, 238.70 +/- 64.56 min in cisternal CSF versus 82.73 +/- 2.91 min in serum), yielding a relative increase in the percentage of penetration. We conclude that maximum penetration by gentamicin into CSF occurs after intravenous bolus administration and that the maximum concentration occurs in lumbar CSF.
Selective inhibition of human cytomegalovirus replication by a novel nucleoside, oxetanocin G
Authors: Nishiyama Y , Yamamoto N , Takahash K , Shimada N
Published: June 2012

A novel nucleoside with an oxetanosyl-N-glycoside has been recently isolated from a culture filtrate from Bacillus megaterium and named oxetanocin A (N. Shimada, S. Hasegawa, T. Harada, T. Tomisawa, A. Fujii, and T. Takita, J. Antibiot. 39:1623-1625, 1986). In this study, we evaluated the antiherpesvirus activity of oxetanocin A and its derivatives and found that 9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanosyl)guanine (OXT-G) was very potent and selective in inhibiting the replication of human cytomegalovirus (HCMV) in vitro. The median effective concentration for HCMV strain AD169 was 1.0 microgram/ml, and that for herpes simplex virus type 2 strain 186 was 3.5 micrograms/ml. The selectivity index, based on the ratio of the median inhibitory concentration for cell growth of human diploid fibroblasts to the median effective concentration for HCMV plaque formation, was more than 300. The synthesis of HCMV-induced late polypeptides such as the 150,000-molecular-weight capsid and the 68,000-molecular-weight major matrix proteins was strongly suppressed when OXT-G (5 micrograms/ml) was added to the cultures at the beginning of infection. At this concentration of OXT-G, the amount of HCMV DNA detected in the drug-treated infected cells was less than 1/10 of that detected in the infected control cells. The results suggest that the mode of action of OXT-G is inhibition of viral replication by impairing the viral DNA synthesis.
In vitro activities of T-3262, NY-198, fleroxacin (AM-833; RO 23-6240), and other new quinolone agents against clinically isolated Chlamydia trachomatis strains
Authors: Maeda H , Fujii A , Nakata K , Arakawa S , Kamidono S
Published: June 2012

The in vitro activities of three newly developed quinolone drugs (T-3262, NY-198, and fleroxacin [AM-833; RO 23-6240]) against 10 strains of clinically isolated Chlamydia trachomatis were assessed and compared with those of other quinolones and minocycline. T-3262 (MIC for 90% of isolates tested, 0.1 microgram/ml) was the most active of the quinolones. The NY-198 and fleroxacin MICs for 90% of isolates were 3.13 and 62.5 micrograms/ml, respectively.
In vitro activity of U-76,252 (CS-807), a new oral cephalosporin
Authors: Fass R J , Helsel V L
Published: June 2012

U-76,252 is the prodrug of U-76,253. MICs of U-76,253 were 0.015 to 0.06 microgram/ml for greater than or equal to 90% of the strains of Streptococcus spp., Haemophilus influenzae, and Proteus mirabilis; 0.25 to 1 microgram/ml for Branhamella catarrhalis, Escherichia coli, Klebsiella spp., and Citrobacter diversus; 1 to 8 micrograms/ml for Staphylococcus spp.; and 2 to greater than 16 micrograms/ml for other members of the family Enterobacteriaceae and Aeromonas hydrophila; for 72% of the latter group, MICs were less than or equal to 4 micrograms/ml. MICs for Pseudomonas aeruginosa and Enterococcus faecalis were greater than 16 micrograms/ml.
Influence of hydrocortisone on gentamicin-induced nephrotoxicity in rats
Authors: Beauchamp D , Pettigrew M
Published: June 2012

Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans and experimental animals. They include an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of therapy, liver disease, and renal infection. The concomitant administration of steroids has never been investigated. We evaluated the role of hydrocortisone on gentamicin-induced nephroxicity in a model of infused rats. We showed that hydrocortisone given over 3 days after the infusion did not modify the gentamicin half-life in the renal cortex, gentamicin-induced lysosomal phospholipidosis, or histopathology but did reduce significantly the 3H/DNA ratio on day 4 after gentamicin infusion. We concluded that hydrocortisone interferes with the postnecrotic cellular regeneration process, an important step that is responsible for the recovery of normal kidney structure following toxic injuries associated with aminoglycoside therapy.
Effects of amodiaquine, chloroquine, and mefloquine on human polymorphonuclear neutrophil function in vitro
Authors: Labro M T , Babin-Chevaye C
Published: June 2012

This study concerns the in vitro interaction with human polymorphonuclear neutrophils (PMNs) of amodiaquine, chloroquine, and mefloquine, three antimalarial drugs currently in use for the treatment and prophylaxis of malaria. It was found that mefloquine (100 and 50 micrograms/ml) significantly altered PMN viability while the other two drugs did not. Neutrophil chemotaxis was impaired by chloroquine (100 micrograms/ml) and mefloquine (greater than 10 micrograms/ml) but not by amodiaquine. Phagocytosis was decreased by about 50% in the presence of chloroquine (100 micrograms/ml) or mefloquine (10 micrograms/ml). The three antimalarial drugs altered neutrophil oxidative metabolism as assessed by luminol-amplified chemiluminescence. The strongest effect was observed with mefloquine, which abolished almost completely the neutrophil burst at concentrations of greater than 10 micrograms/ml whatever the stimulus used. This effect was not reversed by washing. Chloroquine and amodiaquine also impaired this PMN response by approximately 80 and 50%, respectively, but only at the highest concentration used (100 micrograms/ml). In the case of amodiaquine, the neutrophil response was restored by washing, except for stimulation with opsonized particles. After washing, the depressive effect of chloroquine was reversed completely in the case of phorbol myristate acetate stimulation and partly in the case of opsonized particle stimulation, but the formylmethionyl-leucyl-phenylalanine-induced response was not restored. These data show that although they are structurally related, amodiaquine and chloroquine exhibit qualitatively and quantitatively different depressive effects on PMN function and probably interfere at different points of cell activation, although the precise mechanisms are as yet unresolved.
MIC as a quantitative measurement of the susceptibility of Mycobacterium avium strains to seven antituberculosis drugs
Authors: Heifets L
Published: June 2012

MICs of isoniazid, rifampin, ethionamide, streptomycin, amikacin, kanamycin, and capreomycin were determined for Mycobacterium avium complex strains by two methods: broth dilution in 7H12 medium radiometrically and agar dilution on 7H10 agar plates. The broth-determined MICs of all drugs with the exception of isoniazid were two to eight times lower than the agar-determined MICs for most of the tested M. avium strains, which is probably due to the higher absorption and degradation of the drugs in solid media. The MICs, especially those determined in broth, are suggested as quantitative measurements of the degree of susceptibility of M. avium complex strains. For a certain percentage of the M. avium strains the broth-determined MICs were within the limits of MICs found for wild susceptible Mycobacterium tuberculosis strains. These M. avium strains were classified as presumably susceptible. In contrast to M. tuberculosis, the MICs for M. avium strains had a wide range. When the MICs for M. avium strains were only one dilution higher than those for M. tuberculosis, they were tentatively classified as moderately susceptible. The designation moderately resistant or resistant, respectively, is suggested for those M. avium strains for which the MICs were at or above the concentrations achievable in blood. The quantitation of the degree of susceptibility by the MICs and the tentative interpretation of the MICs are suggested for future use in clinical trials as a means of evaluating the patients' responses to chemotherapy compared with the degree of susceptibility of the initial strain isolated before treatment.