bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of cefmenoxime in experimental Escherichia coli bacteremia and meningitis
Authors: Kim K S
Published: June 2012

Cefmenoxime, a new semisynthetic cephalosporin structurally similar to cefotaxime, was evaluated for its activities in vitro and in vivo against a K1 Escherichia coli strain in comparison with activities of cefotaxime and ampicillin. In vitro the MICs and MBCs of both cefmenoxime and cefotaxime were the same, 1/16th and 1/32nd those of ampicillin, respectively. The efficacies of cefmenoxime and cefotaxime against experimentally induced E. coli bacteremia and meningitis in newborn rats were similar and significantly better than that of ampicillin as judged by bactericidal titers of blood and cerebrospinal fluid, rapidity of clearance of bacteria from blood and cerebrospinal fluid, and incidence of meningitis in animals with bacteremias. The efficacy of cefmenoxime or cefotaxime measured by impact on mortality was influenced by the size of bacterial populations. The mortality was significantly greater in rats with bacterial counts before therapy of greater than or equal to 10(6) CFU/ml of blood than in animals with lower counts. Overall, the in vivo efficacy of cefmenoxime was similar to that of cefotaxime; thus it could be useful in the therapy of neonatal E. coli infection.
Pharmacokinetics and tissue penetration of carumonam, a new synthetic monobactam
Authors: McNulty C A , Garden G M , Ashby J , Wise R
Published: June 2012

The pharmacokinetics of the monobactam carumonam (Ro 17-2301) as derived from serial measurement of the concentrations of this agent in serum, blister fluid, and urine were studied in six male volunteers subsequent to intravenous infusion of a single 2-g dose. Drug levels in serum in excess of 75 micrograms/ml were achieved 0.5 h after the end of infusion, declining to 2.9 micrograms/ml at 8 h. The mean serum and blister fluid elimination half-lives were 1.68 and 1.7 h, respectively. The urinary recovery of the drug by 24 h was 80.6% (range, 68.3 to 91.1%). Carumonam penetrated blister fluid well, the mean percentage penetration (as measured by the ratio of areas under curves) being 101.6%.
Comparison of ciprofloxacin with azlocillin plus tobramycin in the therapy of experimental Pseudomonas aeruginosa endocarditis
Authors: Strunk R W , Gratz J C , Maserati R , Scheld W M
Published: June 2012

The efficacy of ciprofloxacin (Bay o 9867), a promising new quinolone, was compared with the efficacy of azlocillin plus tobramycin in rabbits with experimentally induced Pseudomonas aeruginosa endocarditis. The MBCs of ciprofloxacin, azlocillin, and tobramycin against the test strain were 0.5, 8, and 4 micrograms/ml respectively. Ciprofloxacin at a concentration of 50 mg/kg or azlocillin at a concentration of 200 mg/kg in combination with tobramycin at a concentration of 5 mg/kg was administered intramuscularly at 8-h intervals for 4 days. Both regimens produced median peak serum bactericidal titers of 1:8. The concentrations of ciprofloxacin, azlocillin, and tobramycin in serum, 1.8 +/- 0.7, 154 +/- 48, and 9.1 +/- 2.4 micrograms/ml (mean +/- standard deviation), respectively, closely approximated concentrations found in humans after accepted dosages. At the end of treatment, the titers of P. aeruginosa were 3.0 +/- 1.6 log10 CFU/g of vegetation (mean +/- standard deviation) for recipients of ciprofloxacin and 3.2 +/- 1.3 log10 CFU/g of vegetation for recipients of azlocillin plus tobramycin. These values compared with control titers of 7.3 +/- 1.6 CFU/g. These data indicate that at the doses used, ciprofloxacin was as effective as azlocillin plus tobramycin in the treatment of P. aeruginosa endocarditis in rabbits. Since the latter drug combination has proven efficacy, ciprofloxacin deserves further evaluation in the therapy of systemic infections in animal models and in humans.
Synergistic effect of human leukocyte interferon and nonoxynol 9 against herpes simplex virus type 2
Authors: Rapp F , Wrzos H
Published: June 2012

The nonionic surfactant nonoxynol 9 (NP9), in combination with human alpha interferon, synergistically reduced the titer of herpes simplex virus type 2 (HSV-2) in vitro. The degree of synergy was highest at an interferon concentration of 10(3) IU/ml and an NP9 dilution of 1:1,500. We postulate that NP9 inactivates extracellular HSV-2, whereas interferon inhibits HSV-2 replication at the intracellular level.
Oscillating tolerance in synchronized cultures of Staphylococcus aureus
Authors: Holzhoffer S , Süssmuth R , Haag R
Published: June 2012

Cells of synchronized cultures of Staphylococcus aureus showed an oscillating MBC/MIC ratio when tested with penicillin G. Although the MICs did not differ significantly throughout the cell cycle, the MBC was at its maximum when actively dividing cells were inoculated.
Vancomycin-resistant streptococci or Leuconostoc sp
Authors: Buu-Hoï A , Branger C , Acar J F
Published: June 2012

Two strains of gram-positive cocci highly resistant to vancomycin (MICs of 512 and 1,024 micrograms/ml) were isolated from blood cultures in two compromised patients. These organisms were identified as Leuconostoc spp. Leuconostoc spp. are gram-positive cocci found in vegetables and dairy products; they had not been isolated previously from clinical specimens. The susceptibility of eight Leuconostoc spp. strains, including the two clinical isolates, to 23 antimicrobial agents was determined.
Comparative effects of gentamicin and tobramycin on excretion of N-acetyl-beta-D-glucosaminidase
Authors: Donta S T , Lembke L A
Published: June 2012

Patients receiving gentamicin or tobramycin were studied to determine whether there were differences in the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) between the two groups. The average daily increases in NAG excretion were significantly higher in the group receiving gentamicin. In individual patients, the best correlation with nephrotoxicity was with high initial rates of NAG excretion. If abnormally high initial rates of increase can serve as a prognosticator of nephrotoxicity, it may be possible to alter aminoglycoside therapy and to avoid renal damage.
In vitro activities of the quinolone antimicrobial agents A-56619 and A-56620
Authors: Eliopoulos G M , Moellering A E , Reiszner E , Moellering R C
Published: June 2012

The in vitro activities of two new quinolone antimicrobial agents, A-56619 and A-56620, were compared with those of norfloxacin, ciprofloxacin, and other antimicrobial agents. The activity of A-56620 was comparable to that of ciprofloxacin against Escherichia coli, Enterobacter cloacae, and Aeromonas hydrophila (MICs for 90% of the strains were less than or equal to 0.06 micrograms/ml); Acinetobacter anitratus and Staphylococcus aureus (MIC for 90% of the strains was 0.5 micrograms/ml); and most streptococci. Against other gram-negative strains, A-56620 demonstrated activity comparable to that of norfloxacin, but the new drug was two to eight times more active than norfloxacin against gram-positive isolates. A-56620 was more active than A-56619 against most gram-negative organisms tested. Of the members of the family Enterobacteriaceae examined, 88% were inhibited by A-56619 and 99% by A-56620 at concentrations of less than or equal to 1.0 microgram/ml. By time-kill methods, the new quinolones were bactericidal against gram-negative bacilli during the first 6 h of incubation, but against S. aureus and enterococci the drugs were primarily bacteriostatic during this period. The frequency of spontaneous resistance to 10 micrograms of these drugs per ml was less than 10(-8) for all species tested except E. cloacae, but by serial passage through incremental concentrations of the antimicrobial agents, colonies many-fold more resistant than the initial isolate could be selected. However, resistance to concentrations of the drug greater than 100 micrograms/ml remained stable after passage on antibiotic-free media in only 1 of 35 strains tested.
Evaluation of the in vitro bactericidal action of ciprofloxacin on cells of Escherichia coli in the logarithmic and stationary phases of growth
Authors: Zeiler H J
Published: June 2012

Cells of Escherichia coli Neumann and E. coli KL16 were suspended in phosphate-buffered saline pH 7.4 and allowed to reach stationary growth conditions. Ciprofloxacin was added at different concentrations, and time-kill curves were constructed. It could be demonstrated that the number of viable cells was reduced quickly by several logs for E. coli Neumann, whereas a weak and slow killing effect was observed with E. coli KL16. When ciprofloxacin or norfloxacin was added to logarithmically growing cultures of E. coli Neumann or E. coli KL16, no principal differences in the killing rate for the two strains could be observed. Ciprofloxacin, however, was more bactericidal than norfloxacin. It was also demonstrated that the bactericidal action of ciprofloxacin on cells in the stationary growth phase was better at pH 7.4 than at pH 8.6. This dependence is different from that observed in MIC studies, in which the MIC were lower at pH 8.0 than at pH 7.2. It was also found that the bactericidal action of ciprofloxacin or norfloxacin on cells of E. coli Neumann in the stationary phase of growth could not be reduced by the addition of chloramphenicol, whereas under conditions of logarithmic growth the rapid killing effect of ciprofloxacin was reduced in the presence of chloramphenicol.
Differential effect of sinefungin and its analogs on the multiplication of three Leishmania species
Authors: Paolantonacci P , Lawrence F , Robert-Géro M
Published: June 2012

Sinefungin and seven analogs were evaluated in vitro for activity against promastigote multiplication of Leishmania donovani, L. tropica, and L. enrietti. Of these compounds, sinefungin, the cyclic derivative, and A9145C were leishmanicidal at concentrations ranging from 0.13 to 2.6 microM. Sinefungin was the most active of these three compounds against L. donovani, and A9145C was most active against L. enrietti. None of the remaining derivatives exhibited significant activity against any one of the three species at the highest dose tested. All agents were assayed for activity against protein methylases I and III. The results of these tests showed that there is no relationship between the inhibition of growth and inhibition of protein methylases I and III.
Ceftriaxone therapy in bacteremic typhoid fever
Authors: Ti T Y , Monteiro E H , Lam S , Lee H S
Published: June 2012

The efficacy and safety of ceftriaxone in the treatment of bacteremic typhoid fever was studied in 14 patients. Ceftriaxone at a dosage of 50 to 60 mg/kg per day was administered intravenously in two divided doses in 13 patients and as a single dose in 1 patient. When the two patients with medical complications causing persistent fever and the patient who was febrile during therapy were excluded from the calculations, the mean period of defervescence was 4 days. Five to eight days of ceftriaxone therapy was adequate for the patients who were cured. The 14 patients treated with ceftriaxone included 13 patients who were considered cured, although 1 was a convalescent carrier, and one patient who was a treatment failure. There were no relapses in the 11 patients who were monitored for 1 to 8 months. Both peak and trough concentrations of ceftriaxone were well above the ceftriaxone MICs for the Salmonella typhi strains isolated from the patients. We have demonstrated that ceftriaxone can be used successfully in the treatment of typhoid fever in some patients. The advantages of its use include rapid clinical response, short course of treatment, and lack of serious adverse drug reactions.
Pharmacokinetics of cefmetazole administered intramuscularly and intravenously to healthy adults
Authors: Rodriguez-Barbero J , Mariño E L , Dominguez-Gil A
Published: June 2012

The pharmacokinetics of cefmetazole, a new parenteral cephalosporin, administered intravenously and intramuscularly at a dose of 30 mg/kg to two groups of seven healthy volunteers were studied. Concentrations in serum were monitored over 8 h by a high-pressure liquid chromatography technique. The plasma concentration-time data were statistically fitted to a biexponential equation for both administration routes, and the data were analyzed by a two- and one-compartment kinetic model, respectively. For the dose range and the administration routes used, the pharmacokinetics of cefmetazole proved to be essentially linear, with clearances from plasma ranging between 3.8 and 12.5 liters/h. The mean maximum concentration in plasma after intramuscular administration of the drug was 90.1 micrograms/ml at 0.7 h. The elimination half-life, about 1.3 h, did not show statistically significant differences for the two routes of administration studied.
Comparative trial of rifampin-doxycycline versus tetracycline-streptomycin in the therapy of human brucellosis
Authors: Ariza J , Gudiol F , Pallarés R , Rufí G , Fernández-Viladrich P
Published: June 2012

In an attempt to compare the efficacy of rifampin-doxycycline with tetracycline-streptomycin for the treatment of human brucellosis, we administered both combinations for a 30-day period, similar to the period recommended by the World Health Organization in a prospective, randomized trial. Forty-six patients were included in the final study (36 men and 10 women); 41 had blood cultures positive for Brucella melitensis. The 28 patients in group A received tetracycline hydrochloride at doses of 0.5 g every 6 h or doxycycline at 100 mg every 12 h for 30 days plus 1 g of streptomycin a day for 21 days. The 18 patients in group B received rifampin at 15 mg/kg per day in a single morning dose plus 100 mg of doxycycline every 12 h for 30 days. For patients with focal disease from both groups, therapy was prolonged to 45 days. All patients underwent rigorous clinical and bacteriological long-term follow-up. There were no therapeutic failures in either group, and the defervescence period was similar for both groups (3.1 days for group A, 2.6 days for group B). Two patients (7.1%) from group A had relapses, as did seven (38.8%) from group B (P = 0.024), and blood cultures again became positive for B. melitensis in all of them. In both groups treatment was generally well tolerated. The results strongly suggest that the rifampin-doxycycline combination is a less efficacious mode of therapy for brucellosis to prevent relapses than is the classical tetracycline-streptomycin combination when both are administered for 30 days. A more prolonged period of administration of the rifampin-doxycycline combination may be required to obtain the same low relapse rate as that achieved with the classical tetracycline-streptomycin treatment.
Inoculum effect of beta-lactam antibiotics on Enterobacteriaceae
Authors: Eng R H , Cherubin C , Smith S M , Buccini F
Published: June 2012

Seven beta-lactam antibiotics were studied for both their antimicrobial activity and the degree to which they produced inoculum effect on Escherichia coli, Klebsiella pneumoniae, and Salmonella typhimurium. Aztreonam, cefoperazone, and ceftazidime were poorly bactericidal, caused marked bacterial filamentation, and exhibited a large inoculum effect on E. coli, K. pneumoniae, and S. typhimurium. Cefotaxime and ceftriaxone were more rapidly bactericidal, caused only a moderate amount of filamentous forms, and exhibited a modest inoculum effect, while cefoxitin and imipenem both were rapidly bactericidal and exhibited only a minimal-to-no-inoculum effect. The inoculum effect did not correlate with drug stability during incubation with the bacteria. Inoculum effect on these species of the family Enterobacteriaceae appears to be a manifestation of increase in optical density secondary to the development of filamentous bacterial forms with an increase in bacterial mass during exposure to antibiotics which are not rapidly bactericidal. These observations have a clear significance for the susceptibility testing of beta-lactam antibiotics when turbidity is used as a parameter to determine presence of bacterial growth.
Antibacterial activities of erythromycins A, B, C, and D and some of their derivatives
Authors: Kibwage I O , Hoogmartens J , Roets E , Vanderhaeghe H , Verbist L , Dubost M , Pascal C , Petitjean P , Levol G
Published: June 2012

The MICs of erythromycins A, B, C, and D and some of their derivatives were determined against 21 gram-positive and 15 gram-negative microorganisms. Antibacterial activity was confined to gram-positive and very few gram-negative bacteria. Erythromycin B was somewhat less active than erythromycin A, and erythromycin C and D showed about half that activity or even less. Most other derivatives had negligible activity. Determination of potency by diffusion and turbidimetric assays were in line with MICs. The examination of the results of these assays, however, revealed that there are differences between the data of different laboratories, depending on the microorganisms and conditions used.
Effect of the imidazole derivative lombazole on the ultrastructure of Staphylococcus epidermidis and Candida albicans
Authors: Barug D , de Groot K
Published: June 2012

Lombazole, an antimicrobial agent of the imidazole class, induced profound ultrastructural changes in Staphylococcus epidermidis and Candida albicans, as observed by freeze fracture electron microscopy. In S. epidermidis cells, the primary effect on ultrastructure was characterized by a distinct change in the morphology of the plasma membrane. Secondary effects of lombazole were cell wall thickening, accumulations of lipidlike material, abnormal cell division, severe change of shape, separation of the plasma membrane from the cell wall, and disruption of cells. The alterations in C. albicans were characterized by the deformation of and a decrease in the number of invaginations in the protoplasmic fracture face and corresponding ridges on the exoplasmic fracture face and by separation of the plasma membrane from the cell wall, leaving a gap which frequently contained small vesicles. Moreover, a considerable thickening of the cell wall occurred at localized regions. These structural alterations are discussed in relation to biochemical changes which may correlate with these phenomena.
Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans
Authors: Humphrey M J , Jevons S , Tarbit M H
Published: June 2012

The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.
Relevance of serum protein binding of cefoxitin and cefazolin to their activities against Klebsiella pneumoniae pneumonia in rats
Authors: Bakker-Woudenberg I A , van den Berg J C , Vree T B , Baars A M , Michel M F
Published: June 2012

An experimental Klebsiella pneumoniae pneumonia in rats was used to study the effect of protein binding of cefoxitin and cefazolin on their therapeutic activity. Both cephalosporins were similar with respect to their antimicrobial activity against the K. pneumoniae in vitro, but they differed in their degree of protein binding, being 34% for cefoxitin and 89 to 93% for cefazolin in uninfected rats and 24 and 71 to 83%, respectively, in infected rats. Various doses of these agents were administered by continuous infusion, which started 5 h after bacterial inoculation and continued for 65 h. Antimicrobial response was evaluated with respect to the numbers of bacteria recovered from lung and blood at the end of treatment. An inhibitory effect of protein binding on the in vivo antimicrobial activity was demonstrated. Cefoxitin was therapeutically effective at a constant plasma level that reached the MIC. To obtain a similar effect with cefazolin the plasma level of that drug had to be increased to a concentration more than three times the MIC.
Transition from resistance to hypersusceptibility to beta-lactam antibiotics associated with loss of a low-affinity penicillin-binding protein in a Streptococcus faecium mutant highly resistant to penicillin
Authors: Fontana R , Grossato A , Rossi L , Cheng Y R , Satta G
Published: June 2012

Penicillin-binding protein (PBP) 5 of Streptococcus faecium has been shown to have a very low affinity for penicillin, and this PBP was suggested to be responsible for both the natural low susceptibility and high resistance to the antibiotic in this species (R. Fontana, R. Cerini, P. Longoni, A. Grossato, and P. Canepari, J. Bacteriol. 155:1343-1350, 1983). In this study, an S. faecium mutant (Rev 14) hypersusceptible to penicillin was derived from the highly resistant S. faecium R40 treated with novobiocin, and its properties were compared with those of the parent and S. faecium PS, a relatively susceptible strain from which R40 was isolated. The hypersusceptible strain did not synthesize PBP 5, but it did resemble the parent in cell morphology, growth rate, and autolytic activity. In addition, it was highly susceptible to other beta-lactams but remained as susceptible as R40 and PS to antibiotics of a different mechanisms of action. The affinity of individual PBPs for the beta-lactams tested was the same in all the strains. This finding suggested that Rev 14 hypersusceptibility was due to the lack of PBP 5 and strongly supported the role of this protein in the mechanism of both natural low susceptibility and high-level resistance to beta-lactams in S. faecium.
In vitro antibacterial activity of Sch 34343 and its stability to beta-lactamases and renal dehydropeptidase 1
Authors: Matsuda K , Sasaki K , Inoue K , Kondo H , Inoue M , Mitsuhashi S
Published: June 2012

The in vitro antibacterial activity of Sch 34343 against 1,328 strains of clinical isolates was compared with those of imipenem and ceftazidime. Sch 34343 had a broad spectrum of antibacterial activity against both gram-positive and gram-negative bacteria but was inactive against Pseudomonas aeruginosa and Pseudomonas maltophilia. Sch 34343 was quite stable to hydrolysis by beta-lactamases, including both penicillinases and cephalosporinases. However, Sch 34343 was slightly hydrolyzed by a new type of beta-lactamase (oxyiminocephalosporin beta-lactamase), as was imipenem. Sch 34343 was slightly hydrolyzed by renal dehydropeptidase 1 but was somewhat more stable than other carbapenems.
Elimination of plasmids by new 4-quinolones
Authors: Weisser J , Wiedemann B
Published: June 2012

Nalidixic acid and six of the new 4-quinolones eliminated F'lac and various native R plasmids from Escherichia coli at one half or one quarter the MIC. Four of eight plasmids tested were cured by all derivatives, with frequencies from 10 to 98%. Quinolones did not eliminate all plasmids that were cured by novobiocin, and vice versa.
beta-Lactamases and beta-lactam resistance in Escherichia coli
Authors: Jacoby G A , Sutton L
Published: June 2012

Escherichia coli strains determining 17 different plasmid-determined beta-lactamases were tested for resistance to new broad-spectrum beta-lactam antibiotics. Several beta-lactamases demonstrated enhanced resistance to cefamandole but only low-level resistance to other agents. High production of cloned E. coli chromosomal beta-lactamase, however, provided resistance to cefamandole, cefoxitin, cefotaxime, ceftazidime, and aztreonam but not to BMY-28142 or imipenem.
Effect of a lactobacillus preparation on the absorption of oral ampicillin
Authors: Yost R L , Gotz V P
Published: June 2012

Lactobacillus preparations have been demonstrated to be beneficial in the prevention of antibiotic-associated diarrhea resulting from ampicillin. Since the bioavailability of oral ampicillin is known to be affected by food and fluid volume, a study to evaluate the influence of a lactobacillus product on ampicillin bioavailability was performed. Twelve healthy volunteers, male and female, were studied in a randomized three-way cross-over study. Each received ampicillin alone, ampicillin with a lactobacillus preparation, and ampicillin followed 1 h later by the lactobacillus preparation. Blood was sampled over a 6-h time period. Ampicillin content was determined by high-pressure liquid chromatography. Area under the concentration-time curve, area under the first moment of the concentration-time curve, maximum concentration of drug in plasma, time to maximum concentration of drug in plasma, and mean residence time were determined for each study interval. No differences in maximum concentration of drug in plasma, time to maximum concentration of drug in plasma, area under the concentration-time curve, or mean residence time were seen for either males or females or the combined group. The lactobacillus preparation as used in this study did not appear to interfere with the bioavailability of oral ampicillin.
In vitro and in vivo antipicornavirus activity of some phenoxypyridinecarbonitriles
Authors: Kenny M T , Dulworth J K , Torney H L
Published: June 2012

Nineteen phenoxypyridinecarbonitriles were initially evaluated for their in vitro activity against rhinoviruses (RV) 1A, 2, and 64 and coxsackievirus (Cox) A21 and for their oral prophylactic and therapeutic activity in Swiss albino mice challenged with Cox A21. On the basis of the results of these studies, one compound, 6-(3,4-dichlorophenoxy)-3-(ethylthio)-2-pyridinecarbonitrile, was selected for further evaluation. Expanded in vitro spectrum of activity studies showed that the MIC causing a 50% reduction in viral cytopathic effect in infected cultures (MIC50) was 3.0 micrograms/ml or less against 11 of 20 RV serotypes tested. The compound was only moderately active (MIC50, 5 to 7 micrograms/ml) against four of the RV serotypes evaluated, while RV 4, 5, 8, 13 and Hank's were relatively resistant to compound inhibition. Of the nine enteroviruses studied, only Cox A21, echovirus 12, poliovirus 2, and enterovirus 70 were inhibited at compound concentrations of less than 2.0 micrograms/ml. The compound provided significant protection to mice infected with a normally lethal dose of Cox A21 when administered in a single oral dose of 150 mg/kg (P less than 0.01) and during a regimen of continuous oral doses of 37.5 mg/kg per day (P less than 0.001). Mechanism of action studies indicated that the compound inhibited picornavirus uncoating or some earlier virus-host cell-associated event.
Correlation between growth curve and killing curve of Escherichia coli after a brief exposure to suprainhibitory concentrations of ampicillin and piperacillin
Authors: Yourassowsky E , Van der Linden M P , Lismont M J , Crokaert F , Glupczynski Y
Published: June 2012

Escherichia coli strains that were susceptible to multiple antibiotics were exposed to suprainhibitory concentrations of ampicillin and piperacillin. As with the majority of beta-lactam antibiotics, the growth curves showed an increase in optical density (OD) before lysis during the first hours. This increase in OD depended on the concentration of ampicillin and was independent of the concentration of piperacillin. A good correlation was found between the prelytic increase in OD and the killing curve. During the prelytic increase in OD, the number of CFU per milliliter remained constant. The decrease in the number of CFU per milliliter depended on the concentration of ampicillin and was independent of the concentration of piperacillin. pH variations gave rise to similar effects on growth curves and killing curves.
Antibacterial activity of phosphanilic acid, alone and in combination with trimethoprim
Authors: Misiek M , Buck R E , Pursiano T A , Chisholm D R , Tsai Y H , Price K E , Leitner F
Published: June 2012

We explored the antibacterial activity of phosphanilic acid (P), an analog of sulfanilic acid, alone and in combination with trimethoprim (T; TP, 1:5) with sulfamethoxazole (S) and co-trimoxazole, the combination of this sulfonamide with trimethoprim (TS, 1:5) as the reference. P resembled S in spectrum but, in addition, had significant activity against Pseudomonas aeruginosa. The overall frequency and degree of synergism with TP were lower than with co-trimoxazole. P, like S, was strongly affected by changes in inoculum size and was not bactericidal. P was well absorbed parenterally but not orally in mice. Despite low (but prolonged) blood levels, P, given orally to mice, was effective in treating infections caused by P. aeruginosa. However, against most experimental infections the therapeutic effectiveness of P, as well as that of TP, administered either intramuscularly or orally was unimpressive. Based on in vivo data, the therapeutic application of P or TP would appear to be limited.
Concentration-dependent effects of foscarnet on the cell cycle
Authors: Stenberg K , Skog S , Tribukait B
Published: June 2012

The mechanism of toxicity of foscarnet was studied by monitoring its effects on the cell cycle of exponentially growing, semisynchronous human embryo cells in culture. The effects of foscarnet on the cell cycle were dependent on the concentration of drug used. At 1 mM, cell division was reduced by 50%, whereas the cell flow was mainly reduced in the G2 phase of the cell cycle, leading to an increase in the proportion of G2+M cells. The minor reduction of thymidine incorporation in S phase cells provided additional evidence that 1 mM foscarnet did not specifically inhibit DNA synthesis. Cell division was greatly reduced at 2.5 mM foscarnet, and the G2 phase was markedly affected, whereas S cell flow was less reduced. S cell flow was 10% per h and thymidine incorporation was 25% that of control cells, while a block in the G2+M phase was evident. On the other hand, at a concentration of 5 mM foscarnet, the cell flow was greatly reduced in the G1 and S phases, with less reduction of G2 cell flow and cells accumulated in the S phase. The effects of foscarnet on the cell cycle were more pronounced with increasing times up to 72 h, which could not be explained by the slow penetration of foscarnet which required only 4 to 8 h to achieve constant levels. At 2.5 and 5 mM foscarnet, there was the additional effect of the cell membranes becoming more leaky as a result of foscarnet toxicity which might contribute to the toxic effects of the drug at high concentrations. When foscarnet was removed from the medium, the effects on the cell cycle were rapidly reversed, in the time needed for foscarnet to diffuse out from the cells, which indicates the reversible nature of the toxic effects of foscarnet.
Concentrations of metronidazole and tinidazole in male genital tissues
Authors: Viitanen J , Haataja H , Männistö P T
Published: June 2012

The steady-state concentrations of metronidazole and tinidazole in male genital tissues were analyzed in patients subjected to elective gonadal surgery. The nitroimidazoles were administered orally at 500 mg every 8 h, beginning 5 days before the operation. Eight hours after the last dose, the concentrations of tinidazole were 24.1 +/- 2.5 micrograms (mean +/- standard error of the mean)/g of prostatic tissue, 29.1 +/- 2.9 micrograms/g of vas deferens, 22.1 +/- 2.1 micrograms/g of epididymis, and 18.6 +/- 2.3 micrograms/g of testis. The corresponding values of metronidazole were 14.3 +/- 1.8 micrograms/g, 15.9 +/- 1.2 micrograms/g, 14.0 +/- 1.2 micrograms/g, and 12.5 +/- 1.7 micrograms/g, respectively.
Pharmacokinetics and dosage requirements of netilmicin in cystic fibrosis patients
Authors: Bosso J A , Townsend P L , Herbst J J , Matsen J M
Published: June 2012

The pharmacokinetics of netilmicin were determined in 10 patients with cystic fibrosis. Mean (+/- standard error of the mean) values for total body clearance and volume of distribution were 2.62 (+/- 0.18) ml/min per kg of body weight and 0.38 (+/- 0.01) liter/kg, respectively, and were considerably larger than the same parameters reported for patients without cystic fibrosis.
In vitro activity of carumonam
Authors: Fass R J , Helsel V L
Published: June 2012

The in vitro activities of carumonam and eight comparative antimicrobial agents were studied. MICs of carumonam were less than or equal to 0.5 microgram/ml for 91% of members of the family Enterobacteriaceae and less than or equal to 16 micrograms/ml for 88% of nonfermenters; gram-positive cocci and anaerobic bacteria were resistant. Combinations of carumonam with piperacillin, nafcillin, or clindamycin were usually indifferent, although synergy between carumonam and piperacillin was observed with 20 (13%) of 155 strains.
Effects of norfloxacin on DNA metabolism in Pseudomonas aeruginosa
Authors: Benbrook D M , Miller R V
Published: June 2012

Norfloxacin is a quinolone (pyridonecarboxylic acid derivative) effective against Pseudomonas aeruginosa infections. We studied the effects of this drug on DNA metabolism in P. aeruginosa. Norfloxacin inhibits DNA replication immediately on its addition to a logarithmically growing culture of P. aeruginosa. It inhibits the ability of P. aeruginosa DNA gyrase to supercoil relaxed, closed circular DNA in vitro. At intermediate concentrations of the drug, inhibition of DNA replication in vivo is followed by secondary (recovery) synthesis. Both recovery synthesis and the bactericidal effects of norfloxacin are dependent on continued protein synthesis, suggesting that these are inducible functions. Neither norfloxacin nor nalidixic acid induces Weigle-reactivation (inducible DNA repair) or mutagenesis in P. aeruginosa.
Imipenem-cilastatin in the treatment of methicillin-sensitive and methicillin-resistant Staphylococcus aureus infections
Authors: Fan W , del Busto R , Love M , Markowitz N , Cendrowski C , Cardenas J , Quinn E , Saravolatz L
Published: June 2012

Imipenem-cilastatin was evaluated for efficacy and toxicity as an antistaphylococcal agent in 23 patients; 11 of these patients were infected with methicillin-resistant Staphylococcus aureus (MRSA), and 12 were infected with methicillin-susceptible S. aureus (MSSA). There were 15 soft tissue, 5 endovascular, and 3 skeletal infections and a total of nine patients with bacteremia. As determined by in vitro susceptibility testing, the MICs for 90% of the MRSA and MSSA isolates tested were 6.25 and 0.39 micrograms/ml, respectively. Two MRSA isolates were resistant to a concentration of greater than 16 micrograms/ml. When 11 MRSA isolates and 7 MSSA isolates were incubated for 48 h the MICs for 90% of the isolates increased to greater than 50 micrograms/ml for the MRSA isolates and 6.25 micrograms/ml for the MSSA isolates. Three S. aureus isolates emerged resistant. Ten of 11 (91%) MRSA infections and 11 of 12 (92%) MSSA infections were clinically cured. Adverse reactions occurred in 25% of the imipenemcilastatin-treated patients. These reactions included gastrointestinal intolerance (7% of the patients), rash or pruritis (6%), eosinophilia (6%), thrombocytosis (4%), and a positive, direct Coomb test without hemolysis (3%). One of the two patients for whom therapy was discontinued because of gastrointestinal intolerance had antibiotic-associated colitis. Imipenem appears to be an effective antistaphylococcal agent against both MRSA and MSSA infections.
Hydrophobic polyoxins are resistant to intracellular degradation in Candida albicans
Authors: Smith H A , Shenbagamurthi P , Naider F , Kundu B , Becker J M
Published: June 2012

Two novel polyoxins, N-epsilon-(octanoyl)-lysyl-uracil polyoxin C (Oct-Lys-UPOC) and N-gamma-(octyl)-glutaminyluracil polyoxin C (Oct-Gln-UPOC), were synthesized by reacting uracil polyoxin C with the appropriate amino acid p-nitrophenyl ester. Oct-Lys-UPOC and Oct-Gln-UPOC were strong inhibitors (Kis = 1.7 X 10(-6)M) of chitin synthetase from Candida albicans membrane preparations. In a permeabilized-cell assay, Oct-Gln-UPOC had a 10-fold-lower inhibitory activity toward chitin synthetase than did the Oct-Lys-UPOC analog. Both compounds were resistant to hydrolysis by a cell extract of C. albicans H317; however, Oct-Gln-UPOC was hydrolyzed with a half-life of 23 min by a permeabilized-cell preparation. Oct-Lys-UPOC was resistant to hydrolysis by permeabilized cells. Oct-Gln-UPOC and Oct-Lys-UPOC did not compete with the transport of peptides or uridine into the cell. At concentrations up to 2 mM these two new polyoxins were ineffective in the inhibition of cell growth or reduction of cell viability, but they induced aberrant morphologies in C. albicans at a concentration of 0.25 mM. These data suggest that polyoxins containing hydrophobic amino acids retain strong chitin synthetase inhibitory activity and are resistant to cellular hydrolysis. They provide the first example of effective synthetic chitin synthetase inhibitors which are stable inside C. albicans.
An influenza virus inhibitor that acts late in the replication cycle
Authors: Antonelli G , Dianzani F , Coppenhaver D H , Baron S , Calandra P , Folchitto G
Published: June 2012

An inhibitor which is active against influenza A virus was found in Neuramide, a complex tissue extract that is used as an anti-herpes zoster virus treatment. Kinetic studies showed that significant inhibition of virus production occurred when the inhibitor was added to infected cultures up to 5 h after virus penetration. Molecular sieving fractionation showed that the antiviral activity was contained in a low-molecular-weight fraction (molecular weight, less than 1,000).
Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses
Authors: Tartaglione T A , Raffalovich A C , Poynor W J , Espinel-Ingroff A , Kerkering T M
Published: June 2012

The pharmacokinetics and safety of orally administered ciprofloxacin (Bay o 9867) were examined in 12 healthy male volunteers who received sequential doses of 250, 500, 750, and 1,000 mg. The individual and mean data were best described by biexponential disposition and elimination, assuming an apparent zero-order rate of absorption. The peak serum concentrations determined from the individual data occurred at approximately 1.5 h after each dose and ranged from 0.42 to 4.2 micrograms/ml; the mean peak concentrations increased in proportion to the dose. The areas under the curve determined from the mean data were also proportional with respect to dose. The mean elimination half-lives calculated from pooled data were 4.1, 4.1, 6.9, and 6.3 h for doses of 250, 500, 750, and 1,000 mg, respectively. Longer half-lives but proportional area-under-the-curve values after the 750- and 1,000-mg doses implied that smaller fractions of ciprofloxacin were absorbed after these doses, although nonlinear kinetics could not be ruled out. The mean serum concentrations 12 and 24 h following each dose were greater than or equal to 0.08 and 0.01 micrograms/ml, respectively. The urinary concentrations ranged from 30 to 500 micrograms/ml for at least 12 h after administration and were greater than or equal to 9 micrograms/ml at 24 h following each dose. The urinary recovery level of unchanged ciprofloxacin over a 24-h period ranged from 28 to 44%. The mean renal clearances for each dose ranged from 300 to 500 ml/min. Ciprofloxacin was well tolerated, and no significant clinical or laboratory abnormalities were observed.
Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin
Authors: Bergeron M G , Bergeron Y
Published: June 2012

Multiple factors may modify the pharmacokinetics of aminoglycosides and increase their nephrotoxic potential. In this study, we investigated the influence of Escherichia coli endotoxin on the renal handling of several aminoglycosides and one cephalosporin. Drug levels in the renal parenchyma, as well as several parameters of renal function and histology, were compared in rats treated with endotoxin (0.25 mg/kg) and normal rats treated with either gentamicin (10 mg/kg), netilmicin (10 mg/kg), tobramycin (10 mg/kg), amikacin (50 mg/kg), or cephalothin (100 mg/kg). Blood pressure and pulse rate were recorded. Endotoxin was associated with a decrease in the half-life and in the apparent volume of distribution of gentamicin. The endotoxin-injected animals accumulated significantly (P less than 0.05) more aminoglycosides in their kidneys than the normal animals. The amount of cephalothin recovered in the renal parenchyma was identical in both groups. Slight decreases in the glomerular filtration rate and renal plasma flow were observed after endotoxin treatment. Blood pressure and cardiac frequency were minimally affected by endotoxin. No histological lesions were observed by light microscopy in animals receiving endotoxin. Thus, endotoxin modifies the renal handling of aminoglycosides in the absence of any major physiological disturbance or histological change. By increasing the total amount of drug within the kidneys, endotoxin might increase the nephrotoxic potential of aminoglycosides.
Emergence of trimethoprim resistance in relation to drug consumption in a Finnish hospital from 1971 through 1984
Authors: Huovinen P , Pulkkinen L , Helin H L , Mäkilä M , Toivanen P
Published: June 2012

Emergence of trimethoprim resistance among urinary tract Escherichia coli strains, isolated mostly from long-term patients in the Turku City Hospital, Turku, Finland, was studied from 1971 through 1984. Emergence of resistance to trimethoprim was associated with changes in the consumption of both trimethoprim-sulfamethoxazole and trimethoprim, with occurrence of high-level trimethoprim resistance and sequences homologous to trimethoprim resistance transposon Tn7. Since 1971, resistance of E. coli to trimethoprim-sulfamethoxazole increased from 8 to between 32 and 35% in 1983 and 1984; resistance to sulfamethoxazole varied from 39 to between 40 and 44%. The frequency of DNA sequence homology with our Tn7 probe among trimethoprim-resistant E. coli strains was 42% from 1980 to 1981 and 64% in 1983 (P less than 0.005). Fourteen years after the introduction of trimethoprim therapy in this hospital, resistance has reached the level of resistance to sulfonamide.
Imipenem pharmacokinetics and body fluid concentrations in patients receiving high-dose treatment for serious infections
Authors: MacGregor R R , Gibson G A , Bland J A
Published: June 2012

Serum, urine, tissue, and body fluids were collected from 40 adult patients who were receiving imipenem/cilastatin treatment for serious infections. Thirty-two patients were given 1 g every 6 h (4 g/day), and eight received 500 mg (2 g/day). Mean peak concentrations in serum were 34.9 +/- 4.0 micrograms/ml for the 1-g dose and 26.6 +/- 2.5 micrograms/ml for the 500-mg dose. Trough levels were 3.1 and 1.0 micrograms/ml, respectively. No evidence of drug accumulation was found after comparing peaks measured early in the treatment with those measured late. Peak levels were only marginally increased when infusions were given over 30 versus 60 min. The mean serum half-life was 82.0 +/- 25.3 min, with a range of 50 to 138 min. The apparent volume of distribution was 0.35 +/- 0.13 liter/kg, and the mean total body clearance was 0.183 +/- 0.067 liter/kg per h. Creatinine clearance correlated directly with the plasma elimination rate and inversely with the serum half-life. Moreover, total body clearance fell as the age of the patient rose. The mean urinary recovery was 39.1 +/- 12.8% (range, 15.0 to 59.2%) and did not correlate with creatinine clearance until it was below 15 ml/min. Of 20 specimens of various gastrointestinal secretions, 13 had imipenem concentrations that were low, but above the MIC for most resident flora. Pus, sputum, and bone all had concentrations of the drug sufficient to inhibit the infecting organisms, and these levels reflected generally excellent clinical responses.
An animal source for the ROB-1 beta-lactamase of Haemophilus influenzae type b
Authors: Medeiros A A , Levesque R , Jacoby G A
Published: June 2012

The most common cause of ampicillin resistance in Haemophilus influenzae type b is production of TEM-1 beta-lactamase; however, a novel enzyme with a similar substrate profile but a quite different isoelectric point has also been described. This beta-lactamase, designated ROB-1, has not been found previously in any other organism. In a survey of 46 ampicillin-resistant H. influenzae type b isolates, we found a second human isolate that produces ROB-1 and discovered that ampicillin-resistant isolates of the porcine pathogen Haemophilus pleuropneumoniae also produced ROB-1. In both Haemophilus species ROB-1 production was determined by plasmids that had considerable DNA sequence homology. However, the ROB-1 and TEM-1 beta-lactamase genes were not related. Our findings suggest that this form of ampicillin resistance has an animal reservoir and that conditions fostering its prevalence in animal strains may play a role in the spread of resistance to human pathogens.
The effect of antimicrobial agents on fecal flora of children
Authors: Sakata H , Fujita K , Yoshioka H
Published: June 2012

Influences of antibiotics on the fecal flora in children were studied for oral ampicillin, penicillin V, erythromycin, cefaclor, and gentamicin and for intravenous ampicillin, methicillin, cefpiramide, and ceftazidime. All antibiotics affected the normal flora, although the quality and quantity of the changes were variable. No substantial differences were noted between the oral and intravenous use of ampicillin with regard to its effect on the flora. Three penicillins, ampicillin, penicillin V, and methicillin, caused remarkable changes. The characteristic pattern observed was the considerable suppression of Bifidobacterium, Streptococcus, and Lactobacillus species. Although enterobacteria did not significantly change in number, Klebsiella spp. frequently replaced Escherichia coli. In patients given erythromycin and cefaclor, the reduction in the number of Bifidobacterium spp. was 1 log10 and that of members of the family Enterobacteriaceae was 3 log10. Gentamicin administered orally caused a drastic change, including a remarkable decline of E. coli to less than 2 log10/g of feces. Cefpiramide, a parenteral expanded-spectrum cephalosporin, suppressed normal flora so markedly that almost all species of organisms were eradicated, and the active growth of yeasts was promoted (2.6 log10 increase). Ceftazidime caused similar changes as cefpiramide, but the changes were less extensive. Yeasts increased after treatment with most antibiotic groups. This increase was particularly prominent in patients given oral penicillins and expanded-spectrum cephalosporins.