bluuebunny/crossref_metadata_2025 huggingface dataset:
Tobramycin inactivation by carbenicillin, ticarcillin, and piperacillin
Authors: Konishi H , Goto M , Nakamoto Y , Yamamoto I , Yamashina H
Published: June 2012

The in vitro and in vivo inactivation of tobramycin by carbenicillin, ticarcillin, or piperacillin was investigated by the enzyme immunoassay method in clinically employed dosages. After the addition of an 80-mg dose of tobramycin to 4- to 5-g doses of a penicillin in 100 ml of 0.9% saline or distilled water, the degradation profile of tobramycin appeared to follow a biexponential pattern of decay. Remarkable losses (30 to 40%) of tobramycin combined with carbenicillin or ticarcillin were observed within 1 h, as compared with the later decline. The combination of tobramycin with piperacillin was least inactivating. When the admixture of tobramycin with carbenicillin or piperacillin used in the in vitro study was infused to six volunteers over 1 h, the observed maximum concentrations of tobramycin were on the average 66 and 74% for carbenicillin and piperacillin, respectively, of that observed after tobramycin alone was given. In contrast, the value obtained for tobramycin in combination with piperacillin was close to 90% of the control value. The elimination half-lives of tobramycin combined with the penicillins were slightly shorter than those of tobramycin alone, indicating that the interaction occurs even in patients with normal renal function.
Therapeutic activity of enviroxime against rhinovirus infection in volunteers
Authors: Phillpotts R J , Wallace J , Tyrrell D A , Tagart V B
Published: June 2012

The therapeutic effect of intranasal 2-amino-1-(isopropylsulphonyl)-6-benzimidazole phenyl ketone oxime (enviroxime) against human rhinovirus type 9 was evaluated in a double-blind, placebo-controlled volunteer trial. Enviroxime given 6 times a day was well tolerated, producing a reduction in clinical evidence of infection which coincided with the start of medication (44 h after virus challenge). Although there was a statistically significant reduction in clinical score in the enviroxime group on day 5 after virus challenge, reductions in total clinical score accumulated during the trial and reductions in the quantity of nasal secretions were not significant. A separate analysis was performed on data from volunteers who did not have symptoms when medication began (and who might have been expected to benefit more from enviroxime therapy). No apparent enhancement of the effects of enviroxime could be demonstrated in this group.
Pharmacokinetics of sulbactam in humans
Authors: Foulds G , Stankewich J P , Marshall D C , O'Brien M M , Hayes S L , Weidler D J , McMahon F G
Published: June 2012

Sulbactam, a new beta-lactamase inhibitor, has pharmacokinetic characteristics in humans similar to those of ampicillin and amoxicillin. Its half-life in humans is approximately 1 h. In a two-compartment pharmacokinetic model, the apparent volume of distribution for the central compartment is approximately 12 liters, and half of the dose is found in the central compartment in the postdistributive phase. Approximately 75% of a parenteral dose is excreted unchanged in urine. The coadministration of sulbactam with ampicillin, penicillin G, or cefoperazone has essentially no effect upon the kinetics of either the beta-lactam antibiotic or sulbactam.
Comparative pharmacokinetics of metronidazole and tinidazole as influenced by administration route
Authors: Mattila J , Männistö P T , Mäntylä R , Nykänen S , Lamminsivu U
Published: June 2012

Serum kinetics of metronidazole and tinidazole were compared in four separate randomized crossover studies. Single doses of each drug were given to healthy volunteers through intravenous infusion (500 mg over 20 min, six persons), by mouth (500 mg, nine persons), by rectum (1,000 mg, six persons), or intravaginally (500 mg, six persons). Concentrations of the unchanged drugs in serum, measured by high-pressure liquid chromatography, were similar after oral and intravenous administration, with mean peaks of 9.0 and 9.4 micrograms/ml for metronidazole and 7.5 and 10.1 micrograms/ml for tinidazole. Concentrations of tinidazole were significantly higher than those of metronidazole from 4 h onwards after intravenous infusion, and from 3 h onwards after administration by mouth. After rectal administrations, a significant difference was seen only at 48 h. After vaginal dosing, however, concentrations of metronidazole were significantly higher than those of tinidazole between 1.5 and 12 h. Bioavailability of either drug, calculated according to the formula (area under the curve for oral administration)/(area under the curve for infusion), was practically complete after oral administration and was poorer after rectal and especially vaginal administration. Whenever the parameters were calculable, the elimination half-life of tinidazole (range of means, 14.0 to 14.7 h) was significantly longer and total clearance (40.3 to 47.6 ml/min) was lower than the corresponding values of metronidazole (7.9 to 8.8 h and 71.8 to 80.1 ml/min, respectively).
Ceftriaxone therapy of bone and soft tissue infections in hospital and outpatient settings
Authors: Eron L J , Park C H , Hixon D L , Goldenberg R I , Poretz D M
Published: June 2012

Ceftriaxone, a broad-spectrum cephalosporin with a markedly extended half-life, was administered to 100 patients with 56 bone and 44 soft tissue infections. Sixty-eight received 1 g twice daily, and 32 received 2 g once daily intravenously. Overall, 91% had a satisfactory clinical response, with similar efficacies in both treatment regimens. In six patients, failure to achieve a cure correlated well with the development of resistance to ceftriaxone during therapy in Enterobacter and Pseudomonas species (two cases) and with superinfection with Bacteroides fragilis (four cases). In 41 patients, intravenous drug therapy was continued after discharge from the hospital. In this group, 1,093 patient-days of hospitalization were saved, amounting to $150,020 in cost savings. The prolonged half-life facilitated the administration of ceftriaxone in this setting.
Effects of penicillinase on bactericidal and complement activities in normal human serum
Authors: Biggs W H , Wunderlich A C , Corbeil L C , Davis C E , Curd J G
Published: June 2012

During routine addition of penicillinase (beta-lactamase) to patients sera, we found that the capacity of some of these sera to kill serum-sensitive gram-negative organisms was significantly decreased. Further controlled studies showed that penicillinase decreased both the bactericidal activity of normal human sera and the total hemolytic activity (CH50) of complement in these sera. The decreased bactericidal activity correlated significantly (r = 0.57, P less than 0.05) with the reduction of CH50 in eight normal sera. These effects of penicillinase were time and temperature dependent. Measurement of individual complement component activities showed that penicillinase decreased the activity of C2, C4, and C3-C9, suggesting that the penicillinase preparation activated the classical pathway. These results cast doubts on the validity of bactericidal determinations when sera are pretreated with penicillinase.
Use of a temperature-sensitive, protoplast-forming Neurospora crassa strain for the detection of antifungal antibiotics
Authors: Selitrennikoff C P
Published: June 2012

Protoplasts of the temperature-sensitive osmotic-1 mutant of Neurospora crassa grew and divided as cell wall-less cells when incubated under certain conditions at 37 degrees C. Each protoplast regenerated cell wall and formed a mycelium when the temperature was shifted to 22 degrees C. Cell wall regeneration, but not cell growth, was prevented by the inhibition of cell wall assembly functions. Thus, the inhibition of cell wall regeneration could serve as an indicator of the mode of action of antibiotic drugs. A method for detecting cell wall-inhibiting antifungal compounds with osmotic-1 protoplasts is described.
Safety and tolerance of recombinant leukocyte A interferon in bone marrow transplant recipients
Authors: Winston D J , Ho W G , Schroff R W , Champlin R E , Gale R P
Published: June 2012

Five bone marrow transplant recipients with cytomegalovirus infections were treated with pure recombinant leukocyte A interferon produced by recombinant DNA technology from Escherichia coli. All five patients had documented interstitial pneumonia. The daily intramuscular dose of interferon ranged from 18 X 10(6) to 50 X 10(6) U; the mean duration of therapy was 11.0 days (range, 5 to 18 days). Two patients recovered, one improved, and two died. Clinical side effects (usually fever and chills) occurred in three patients. A 60% or greater reduction in the pretherapy peripheral granulocyte counts occurred in four patients, and four patients had a 37 to 80% reduction in their pretherapy platelet counts. Hematological toxicity was reversible, and there was no loss of marrow graft function. The toxicity of pure recombinant leukocyte A interferon in marrow transplants is similar to that of partially pure leukocyte interferon derived from human cells. Further controlled studies to establish the efficacy of recombinant leukocyte A interferon in marrow transplants are warranted but may be limited by hematological toxicity.
Inhibition of glycosylation of bovine herpesvirus 1 glycoproteins by the thymidine analog (E)-5-(2 Bromovinyl)-2'-deoxyuridine
Authors: Misra V , Nelson R C , Babiuk L A
Published: June 2012

(E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVdU) was phosphorylated by the bovine herpesvirus 1 (BHV-1)-induced thymidine kinase and subsequently incorporated into viral DNA, resulting in DNA that was more dense than DNA from untreated cells. Incorporation of the drug did not result in the termination of replicating BHV-1 DNA molecules since radioactively labeled DNA synthesized in drug-treated and untreated cells sedimented at similar rates in alkaline sucrose gradients. No differences were observed in the electrophoretic mobility of [35S]methionine-labeled viral polypeptides synthesized in treated and untreated cells, although [3H]glucosamine-labeled viral glycoproteins synthesized in treated cells were of a lower molecular weight than those in untreated cells. In BVdU-treated cells, unlike untreated cells, immature neutral and basic precursors of the mature viral glycoproteins accumulated. Although BVdU-treated and untreated cells contained similar amounts of virus, very little virus was released into the culture supernatant from BVdU-treated cells. Our results suggest that BVdU partially inhibits the glycosylation of BHV-1 glycoproteins. BVdU-sensitive glycosylation, however, is not necessary for expression of these glycoproteins on the surface of infected cells since the glycoproteins could be labeled on intact cells with 125I and because BVdU-treated cells remained sensitive to antibody-dependent, cell-mediated cytotoxity mediated by anti-BHV-1 serum. The phosphorylation of BVdU was a prerequisite for its effect on glycosylation since the glycoproteins of a thymidine kinase-deficient mutant of BHV-1 were not affected.
Effects of AC-1370, a new semisynthetic cephalosporin, on phagocyte functions
Authors: Ohnishi H , Kosuzume H , Inaba H , Okura M , Mochizuki H , Suzuki Y , Fujii R
Published: June 2012

The effects of a new semisynthetic cephalosporin, AC-1370, on phagocyte functions were compared with those of cefoperazone. AC-1370 augmented phagocytosis by mouse macrophages in vitro and in vivo, by mouse neutrophils in vivo, and by human neutrophils in vitro. Cefoperazone suppressed phagocytosis by mouse macrophages and neutrophils. Random migration and chemotaxis of mouse and human neutrophils were increased by the addition of AC-1370. Nitroblue tetrazolium reduction by human neutrophils was enhanced by the addition of AC-1370. Intracellular killing of bacteria by macrophages was also enhanced by AC-1370. Further, bactericidal effects of AC-1370 against Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae were augmented when they were each cultured with mouse or human leukocytes. These results suggest that AC-1370 is an unique beta-lactam antibiotic which has a potentiating effect on phagocyte functions as well as a bactericidal effect.
Early synergistic interaction between semisynthetic penicillins and aminoglycosidic aminocyclitols against Enterobacteriaceae
Authors: Glew R H , Pavuk R A
Published: June 2012

Time-kill curves were used to assess the relative in vitro efficacy of the early interaction of three semisynthetic penicillins with two aminoglycosides against 48 Enterobacteriaceae strains. The most efficacious combinations were piperacillin plus amikacin, which demonstrated synergism (greater than or equal to 2 logs of increased kill after 7 h of incubation) against 43 of 48 (90%) strains, and piperacillin plus gentamicin, which exhibited synergism against 25 of 48 (52%) strains. With the combinations of carbenicillin or ticarcillin plus amikacin or gentamicin, early synergistic killing was demonstrated against only 12 to 29% of the strains.
In vitro activity and beta-lactamase stability of cefodizime, an aminothiazolyl iminomethoxy cephalosporin
Authors: Scully B E , Jules K , Neu H C
Published: June 2012

Cefodizime, an iminomethoxy aminothiazolyl cephalosporin similar to moxalactam and ceftazidime, was less active (minimal inhibitory concentration, 1.6 to 12 micrograms) than cefazolin or cefotaxime against Staphylococcus aureus and Staphylococcus epidermidis. It inhibited Haemophilus and Neisseria spp. at less than 0.5 microgram/ml. It did not inhibit methicillin-resistant staphylococci, enterococci, or Listeria spp. and was 8- to 32-fold less active than cefotaxime, moxalactam, or ceftazidime against Escherichia coli, Citrobacter spp., Klebsiella pneumoniae, Providencia spp., and Serratia spp. Cefotaxime-resistant Enterobacter cloacae, Citrobacter freundii, and Proteus vulgaris were resistant to cefodizime. Cefodizime was less active than cefoxitin or moxalactam against Bacteroides fragilis. Cefodizime was not hydrolyzed by common plasmid or chromosomal beta-lactamases, and it inhibited type I beta-lactamases.
Chromosomal beta-lactamases of Enterobacter cloacae are responsible for resistance to third-generation cephalosporins
Authors: Seeberg A H , Tolxdorff-Neutzling R M , Wiedemann B
Published: June 2012

About 70% of all Enterobacter cloacae strains tested possessed one of two species-specific beta-lactamases. These enzymes, E. cloacae beta-lactamase A and E. cloacae beta-lactamase B, with isoelectric points of 8.8 and 7.8, respectively, had the same pH and temperature optima. Both showed similar enzyme kinetics and were inhibited by cloxacillin but not by p-chloromercuribenzoate. E. cloacae beta-lactamase B appeared to be identical with the enzyme of E. cloacae P99. By a mutation in a regulatory gene, inducible enzyme production could be converted into constitutive expression. In E. cloacae, both enzymes did not hydrolyze third-generation cephalosporins, but they were solely responsible for resistance toward these drugs. This was demonstrated by the characterization of Escherichia coli strains expressing an identical resistance pattern after transfer of the corresponding Enterobacter gene.
Cefmenoxime penetration into gallbladder bile and tissue
Authors: Smith B R , LeFrock J , Carr B B
Published: June 2012

Cefmenoxime concentrations in gallbladder bile and tissue were assessed in patients undergoing cholecystectomy. A 0.5-g intravenous dose produced mean concentrations in bile of 54.1 micrograms/ml at 62.9 min and 56.3 micrograms/ml at 194 min after the dose was given. A 1.0-g intravenous dose produced concentrations in bile of 117.9 micrograms/ml at 53 min and 169.7 micrograms/ml of 194 min after the dose was given. Mean concentrations in tissue ranged from 6.1 to 17.9 micrograms/g. Biliary tree penetration was dose and time dependent. Therapeutic concentrations were achieved.
Moxalactam concentrations in human prostatic tissue
Authors: Smith R P , Wilbur H , Sutphen N T , Baltch A L
Published: June 2012

The concentrations of moxalactam in human prostatic tissue, obtained by enucleation or transurethral resection, were measured in 10 patients after the intramuscular administration of two 500-mg doses. The average concentrations of moxalactam in prostatic tissue in the enucleated and transurethral resection specimens were 4.0 micrograms/g and 5.2 micrograms/ml, and the ratios of the moxalactam concentrations in prostate to those in plasma were 0.24 and 0.31, respectively. The concentrations of moxalactam achieved in prostatic tissue after the administration of relatively low doses were greater than the minimum inhibitory concentrations of moxalactam for most common gram-negative pathogens. Concentrations of moxalactam in carefully obtained transurethral resection specimens were similar to those found in the enucleated specimens.
Kinetic studies on inactivation of Citrobacter freundii cephalosporinase by sulbactam
Authors: Yamaguchi A , Hirata T , Sawai T
Published: June 2012

The inactivation kinetics for inhibition by sulbactam (CP45,899) of Citrobacter freundii GN346 cephalosporinase were studied in detail and compared with those of type Ib penicillinase or TEM-2 beta-lactamase mediated by R plasmid RGN823. The rate constant for progressive inactivation of the cephalosporinase was significantly larger than that measured with the penicillinase. The number of sulbactam molecules required to cause complete inactivation of one cephalosporinase molecule (turnover number) was 80. The turnover number for the penicillinase was 5,200. The powerful inhibition by sulbactam of this cephalosporinase is similar to clavulanic acid inhibition of the penicillinase (turnover number, 115; reported by others). The affinity of sulbactam for the cephalosporinase, expressed as Ki, was 500 microM; this value was much higher than that for the penicillinase, which was estimated to be 0.5 microM. These results indicated that sulbactam is an effective progressive inactivator but a poor competitive inhibitor for the cephalosporinase. Our study also revealed that the cephalosporinase and sulbactam formed a long-lived inhibitor-enzyme complex which we termed the pseudo-irreversible complex. The half-life of the complex was 550 min at pH 7.0 and 30 degrees C.
In vitro evaluation of Augmentin by broth microdilution and disk diffusion susceptibility testing: regression analysis, tentative interpretive criteria, and quality control limits
Authors: Fuchs P C , Barry A L , Thornsberry C , Gavan T L , Jones R N
Published: June 2012

Augmentin (Beecham Laboratories, Bristol, Tenn.), a combination drug consisting of two parts amoxicillin to one part clavulanic acid and a potent beta-lactamase inhibitor, was evaluated in vitro in comparison with ampicillin or amoxicillin or both for its inhibitory and bactericidal activities against selected clinical isolates. Regression analysis was performed and tentative disk diffusion susceptibility breakpoints were determined. A multicenter performance study of the disk diffusion test was conducted with three quality control organisms to determine tentative quality control limits. All methicillin-susceptible staphylococci and Haemophilus influenzae isolates were susceptible to Augmentin, although the minimal inhibitory concentrations for beta-lactamase-producing strains of both groups were, on the average, fourfold higher than those for enzyme-negative strains. Among the Enterobacteriaceae, Augmentin exhibited significantly greater activity than did ampicillin against Klebsiella pneumoniae, Citrobacter diversus, Proteus vulgaris, and about one-third of the Escherichia coli strains tested. Bactericidal activity usually occurred at the minimal inhibitory concentration. There was a slight inoculum concentration effect on the Augmentin minimal inhibitory concentrations. On the basis of regression and error rate-bounded analyses, the suggested interpretive disk diffusion susceptibility breakpoints for Augmentin are: susceptible, greater than or equal to 18 mm; resistant, less than or equal to 13 mm (gram-negative bacilli); and susceptible, greater than or equal to 20 mm (staphylococci and H. influenzae). The use of a beta-lactamase-producing organism, such as E. coli Beecham 1532, is recommended for quality assurance of Augmentin susceptibility testing.
Pharmacokinetics of AT-2266 Administered Orally to Mice, Rats, Dogs, and Monkeys
Authors: Nakamura Shinichi , Kurobe Nobuyuki , Kashimoto Shigeki , Ohue Tomio , Takase Yoshiyuki , Shimizu Masanao
Published: June 2012

The pharmacokinetics of AT-2266 (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine- 3-carboxylic acid) were studied in various experimental animals and compared in a number of aspects with those of norfloxacin. Both agents were administered orally. The mean peak plasma levels of AT-2266 in mice, rats, and dogs (given a single dose of 50 mg/kg for mice and rats and 25 mg/kg for dogs) were 2.39, 1.63, and 5.00 μg/ml, respectively, with elimination half-lives of 2.24, 2.81, and 5.76 h. The respective mean plasma levels of norfloxacin at similar dosages were 0.510, 0.410, and 0.700 μg/ml; elimination half-lives were 1.40, 2.35, and 6.06 h. In dogs repeatedly dosed with 25 mg of AT-2266 per kg every 12 h, the mean peak plasma levels after the third and fifth doses were about 1.4 times those after the first dose. The binding rates of AT-2266 and norfloxacin to plasma of mice, rats, and dogs and to human serum ranged from 27.6 to 40.2% and 39.8 to 44.2%, respectively. In rats receiving a single dose of 50 mg/kg, the respective mean peak levels of AT-2266 in plasma, lung, muscle, and kidney were 2.47, 4.60, 5.35, and 33.9 μg/ml or g, whereas those of norfloxacin were 0.234, 0.390, 0.272, and 2.05 μg/ml or g. AT-2266 was widely distributed in tissues of dogs and monkeys after repeated dosage. The respective 24-h recoveries of AT-2266 from urine of mice, rats, and dogs after single doses of 50, 50, and 25 mg/kg were 56.6, 40.5, and 64.1%, and recoveries of norfloxacin at these doses were 4.40, 2.91, and 5.34%. The respective 24-h recoveries of AT-2266 from bile and feces of rats given a single dose of 50 mg/kg were 2.47 and 52.7%. Bioautography of plasma and urine indicated that AT-2266 was metabolized to but a slight degree. The results indicate that AT-2266 is better than norfloxacin in oral absorption and similar to the latter in stability to metabolic inactivation.
Occurrence and expression of imipemide (N-formimidoyl thienamycin) resistance in clinical isolates of coagulase-negative staphylococci
Authors: Blumenthal R M , Raeder R , Takemoto C D , Freimer E H
Published: June 2012

More than 500 clinical isolates were screened for resistance to a number of antibiotics, including imipemide (N-formimidoyl thienamycin [MK0787]). Of the 25 coagulase-negative staphylococcal isolates present in the screening sample, almost one-third showed one of two patterns of imipemide resistance. One pattern apparently involves constitutive expression of drug resistance, whereas the other pattern seems to result from an inducible resistance having an apparent induction threshold higher than the minimal inhibitory concentration of imipemide. The mechanism(s) responsible for this imipemide resistance is unclear, but may be distinct from the more common staphylococcal mechanisms of resistance to beta-lactam antibiotics. Only two of the patients from whom imipemide-resistant staphylococci were cultured had actually been treated with the antibiotic.
Comparative in vitro activities of teichomycin and other antibiotics against JK diphtheroids
Authors: Jadeja L , Fainstein V , LeBlanc B , Bodey G P
Published: June 2012

The in vitro susceptibilities of 98 isolates of JK diphtheroids to teichomycin, vancomycin, and eight other antibiotics was investigated. Teichomycin and vancomycin were extremely active against all the isolates tested. The 90% minimal inhibitory concentrations for teichomycin and vancomycin were 1.56 and 0.78 micrograms/ml, respectively. The majority of the isolates were resistant to ticarcillin, methicillin, erythromycin, tetracycline, chloramphenicol, clindamycin, and cephalothin.
Identification of DNA homologies among H incompatibility group plasmids by restriction enzyme digestion and Southern transfer hybridization
Authors: Whiteley M , Taylor D E
Published: June 2012

Plasmids belonging to the three HI plasmid incompatibility subgroups were characterized by the use of restriction enzymes and Southern transfer hybridization. A diversity of restriction enzyme patterns was noted among the HI subgroups, and a small amount of DNA homology was observed by probing these digests with a nick-translated HI1 plasmid. Within a single subgroup (HI1 and HI2), similar restriction enzyme patterns were noted. Plasmids of all three HI subgroups and the HII group had a guanine plus cytosine content of 49 to 50 mol%. The IncHII plasmid pHH1508a also showed some homology with the HI1 probe. The DNA homology observed is probably responsible for common phenotypic properties encoded by these plasmids.
Substrate-labeled fluorescent immunoassay for measuring dibekacin concentrations in serum and plasma
Authors: Place J D , Thompson S G
Published: June 2012

We have developed a homogeneous substrate-labeled fluorescent immunoassay for the measurement of dibekacin concentrations in serum and plasma. The fluorogenic enzyme substrate beta-galactosyl-umbelliferone was covalently attached to tobramycin, an aminoglycoside structurally similar to dibekacin, to prepare a fluorogenic drug reagent (FDR). The FDR is nonfluorescent under assay conditions, but fluoresces upon hydrolysis by beta-galactosidase. However, binding of the FDR by antiserum to the cross-reactive drug kanamycin prevents enzyme hydrolysis. The fixed level of FDR competes with dibekacin within the sample for the limiting number of antibody-binding sites in the reaction mixture. Unbound FDR is hydrolyzed by beta-galactosidase to release a fluorescent product that is proportional to the dibekacin concentration in the sample. The assay exhibits good precision, standard curve reproducibility, recovery, sensitivity, and correlation with a comparative method. Additionally, the substrate-labeled fluorescent immunoassay is rapid and easy to perform.
Gentamicin substrate-labeled fluorescent immunoassay containing monoclonal antibody
Authors: Place J D , Thompson S G , Clements H M , Ott R A , Jensen F C
Published: June 2012

The current substrate-labeled fluorescent immunoassay for gentamicin has been modified by substituting monoclonal antibodies for conventional antiserum to gentamicin. The standard curve generated with gentamicin monoclonal antibody was essentially linear from 0 to 12 micrograms/ml, could detect 0.4 micrograms of gentamicin per ml, and had overall intra- and interassay precision values (coefficients of variation) of 1.9 and 5.0%, respectively. The substrate-labeled fluorescent immunoassay produced with gentamicin monoclonal antibody gave results with clinical specimens comparable (r = 0.991) to those obtained with the commercially available substrate-labeled fluorescent immunoassay and also with an enzyme immunoassay, a radioimmunoassay, and a fluorescent immunoassay. This technologically state-of-the-art assay employs both a nonisotopic label and monoclonal antibodies. It offers excellent precision, sensitivity, lot-to-lot reproducibility, linearity, and reagent stability.
Fosfomycin inactivates its target enzyme in Escherichia coli cells carrying a fosfomycin resistance plasmid
Authors: León J , García-Lobo J M , Ortiz J M
Published: June 2012

The target enzyme for fosfomycin antibiotic action, enolpyruvyl transferase, was synthesized in similar amounts and with similar kinetic and inhibition constants for phosphoenolpyruvate and fosfomycin, respectively, by an Escherichia coli strain containing the fosfomycin resistance plasmid pOU900 and by plasmid-free strains. Neither phosphoenolpyruvate level nor murein synthesis was altered by pOU900.
Comparative activities of ciprofloxacin (Bay o 9867), norfloxacin, pipemidic acid, and nalidixic acid
Authors: Muytjens H L , van der Ros-van de Repe J , van Veldhuizen G
Published: June 2012

An agar dilution method was used to measure the minimal inhibitory concentrations of ciprofloxacin (Bay o 9867), norfloxacin, pipemidic acid, and nalidixic acid against 496 clinical isolates. Ciprofloxacin and norfloxacin were active against all species tested (90% minimal inhibitory concentrations less than or equal to 8 micrograms/ml), although ciprofloxacin was somewhat more active, e.g., against gram-positive cocci. Pipemidic acid and nalidixic acid were active against most of the members of the Enterobacteriaceae, but Klebsiella species and Providencia stuartii were only inhibited by a high concentration of nalidixic acid.
In vitro antibacterial activity and beta-lactamase stability of E-0702, a new cephalosporin
Authors: Neu H C , Labthavikul P
Published: June 2012

The in vitro activity of E-0702 was compared with the in vitro activity of cefotaxime, ceftazidime, moxalactam, and aztreonam against 600 gram-positive and gram-negative aerobic and anaerobic isolates. E-0702 had a minimal inhibitory concentration for 50% of isolates (MIC50) of 25 micrograms for Staphylococcus aureus, 50 micrograms for Staphylococcus epidermidis, and 1.6 to 3.1 micrograms for streptococci, with Streptococcus faecalis resistant. E-0702 had MIC50s against Escherichia coli, Klebsiella pneumoniae, and Enterobacter aerogenes comparable to those of cefotaxime, ceftazidime, moxalactam, and aztreonam, but MIC90S were higher than those of the other agents. It was as active as the other agents against Proteus mirabilis, Salmonella spp., and Shigella spp., but was four- to eightfold less active against Citrobacter freundii, Enterobacter cloacae, Providencia spp., Morganella spp., and Proteus vulgaris, with isolates in each species resistant. Activity against Bacteroides fragilis was fourfold less than that of cefoxitin. E-0702 was hydrolyzed by plasmid beta-lactamases and was only a weak inhibitor of plasmid and chromosomal beta-lactamases. There was an inoculum effect for E. cloacae, Serratia spp., Morganella spp., and Pseudomonas spp.
Resistance of gram-negative bacilli as related to hospital use of antimicrobial agents
Authors: Ma M Y , Goldstein E J , Friedman M H , Anderson M S , Mulligan M E
Published: June 2012

The development of resistance of gram-negative bacilli, which are common nosocomial pathogens, is an increasing problem. It is generally accepted that this resistance may directly reflect the frequency of use of various antimicrobial agents. Because our institution experienced in 1976 a dramatic change in the pattern of antimicrobial use, primarily a marked decrease in prescribing cephalosporins, we attempted to evaluate retrospectively the effects of this change upon the resistance of gram-negative bacilli that are common nosocomial pathogens. Susceptibilities of Klebsiella and Providencia spp., Pseudomonas aeruginosa, and Serratia marcescens were determined for the years 1975 to 1979. Not unexpectedly, we observed a substantial decrease in cephalosporin resistance. An unexpected finding was a decrease in aminoglycoside resistance, despite increased use of these agents. The possibility that decreased cephalosporin use may lead to decreased aminoglycoside resistance is an intriguing and provocative thesis which can only be speculative at this time but which would seem worthy of additional formal investigation.
In vitro activity and beta-lactamase stability of U-63196E, a novel cephalosporin
Authors: Neu H C , Labthavikul P
Published: June 2012

The in vitro activity of U-63196E, a new broad-spectrum cephalosporin antibiotic, was studied against various gram-positive and gram-negative bacteria and compared with the in vitro activities of cefotaxime, moxalactam, cefoperazone, ceftazidime, and aztreonam. Although U-63196E inhibited many ampicillin-resistant bacteria and its activity against gram-negative species was similar to cefoperazone, it was much less active than the other agents. U-63196E was less active than cefazolin against gram-positive species, and it was less active than cefoxitin or moxalactam against Bacteroides fragilis. U-63196E did not inhibit most cefoperazone- or cefsulodin-resistant Pseudomonas aeruginosa. There was a difference between minimal inhibitory concentrations and minimal bactericidal concentrations for isolates which contained beta-lactamases. Plasmid beta-lactamases of the TEM, HSV, OXA, and PSE types hydrolyzed U-63196E. But U-63196E was relatively stable against hydrolysis by the chromosomal beta-lactamases.
Inhibitory effect of cerulenin and sodium butyrate on germination of Candida albicans
Authors: Hoberg K A , Cihlar R L , Calderone R A
Published: June 2012

Candida albicans germination in liquid medium was inhibition by the antilipogenic agent cerulenin and the fatty acid sodium butyrate. Although these inhibitors prevented germ tube emergence at concentrations of 1 microgram/ml and 20 mM, respectively, neither significantly affected cell viability as judged by trypan blue staining or the rate of protein biosynthesis throughout the time course of the experiments. Cerulenin treatment resulted in inhibition of lipid biosynthesis, but lipid biosynthetic capabilities remained unaltered in sodium butyrate-supplemented cultures. Because each inhibitor blocks germination by different mechanisms, their utility in distinguishing events directly correlated to germination was examined. In this context, chitin synthase activity was inhibited by both compounds, confirming the importance of chitin biosynthesis in C. albicans germination.
Comparative analysis of conjugative plasmids mediating gentamicin resistance in Staphylococcus aureus
Authors: Goering R V , Ruff E A
Published: June 2012

Five gentamicin-resistant clinical isolates of Staphylococcus aureus were found to contain self-transmissible plasmids of 32 to 37 megadaltons in size. Restriction endonuclease digests of the plasmids were markedly similar to those of reference plasmids of unrelated geographical origin, thus suggesting the significant contribution of common conjugal plasmids to the emergence of gentamicin resistance in S. aureus populations.
Pharmacokinetics of aztreonam in rabbit eyes
Authors: Barza M , McCue M
Published: June 2012

Subconjunctival injection of 100 mg of aztreonam in rabbits with Pseudomonas aeruginosa endophthalmitis produced transiently high antibiotic concentrations in most intraocular sites. Concentrations of approximately 2.5 micrograms/ml were achieved in the vitreous humor 15 min after injection and persisted for 6 h. Repeated intramuscular injections in dosages of 25 mg/kg every 4 h resulted in drug concentrations in the vitreous humor of 2.4 micrograms/ml in infected eyes. These levels might be adequate for the treatment of intraocular infections caused by highly susceptible organisms. Direct intravitreal injection of 100 micrograms of aztreonam in normal rabbit eyes produced an estimated peak concentration in the vitreous humor of 62 micrograms/ml, with a half-life of 7.5 h, which declined to 6 micrograms/ml by 48 h. The pharmacokinetic indices suggest that, like other beta-lactam antibiotics, aztreonam is eliminated from the vitreous humor by the retinal route. This novel antibiotic warrants further study of its efficacy and toxicity to determine whether it may be a useful alternative to the aminoglycosides for selected cases of ocular infection.
Inhibition by ketoconazole of mitogen-induced DNA synthesis and cholesterol biosynthesis in lymphocytes
Authors: Buttke T M , Chapman S W
Published: June 2012

The effects of ketoconazole on mitogen-induced DNA synthesis and cholesterol biosynthesis in human and murine lymphocytes have been examined. Ketoconazole concentrations which do not affect cell viability (0.1 to 10 micrograms/ml) in culture led to a dose-dependent inhibition of DNA synthesis, as measured by [3H]thymidine incorporation, induced by either T-cell or B-cell mitogens. At drug concentrations 5- to 10-fold lower, ketoconazole inhibited the incorporation of [14C]acetate into cholesterol, with a resultant accumulation of [14C]lanosterol. The suppressive effects of ketoconazole on DNA synthesis were reversed by increasing the concentration of human serum in the culture medium from 5 to 20%. The depletion of lipoproteins in human serum by density centrifugation reduced the cholesterol content by 90% but did not affect the ability of the serum to overcome the inhibition by ketoconazole of DNA synthesis. Unlike DNA synthesis, cholesterol biosynthesis was not restored by 20% fresh human serum or lipoprotein-depleted human serum. These results demonstrate that ketoconazole potently inhibits DNA synthesis and cholesterol synthesis in mitogen-stimulated lymphocytes at drug concentrations obtained therapeutically. Further, the uncoupling of endogenous cholesterol synthesis and DNA synthesis indicates at least two levels of action of ketoconazole in mammalian lymphocytes.
Agar disk elution method for susceptibility testing of Mycobacterium marinum and Mycobacterium fortuitum complex to sulfonamides and antibiotics
Authors: Stone M S , Wallace R J , Swenson J M , Thornsberry C , Christensen L A
Published: June 2012

An agar disk elution method using round well plates, supplemented Mueller-Hinton agar, and commercial drug disks is described for susceptibility testing of Mycobacterium marinum and the rapidly growing mycobacteria to antibiotics and sulfonamides. By this method, 14 of 14 strains of M. marinum were susceptible to rifampin, doxycycline, minocycline, and trimethoprim-sulfamethoxazole. Identical results were obtained with Middlebrook 7H10 agar and drugs prepared from standard powders. With 58 isolates of Mycobacterium fortuitum and Mycobacterium chelonei, this method had a 92% correlation with broth minimal inhibitory concentration determinations for cefoxitin and greater than 98% for doxycycline, kanamycin, amikacin, and the sulfonamides. Sixty-nine percent of isolates of M. chelonei susceptible to amikacin on supplemented Mueller-Hinton agar were resistant on 7H10 agar, and 15 of 16 M. chelonei isolates susceptible to erythromycin in broth were resistant by disk elution when an endpoint of no growth was used with either agar. The agar disk elution method offers a practical method for testing of most antibacterial agents against these mycobacterial species.
Comparison of moxalactam and gentamicin in the treatment of complicated urinary tract infections
Authors: Penn R G , Preheim L C , Sanders C C , Giger D K
Published: June 2012

Moxalactam and gentamicin were compared in a prospective, randomized study of 49 hospitalized patients with complicated urinary tract infections. Patients received parenteral moxalactam, 250 mg every 12 h, or gentamicin, 1 mg/kg every 8 h. The average duration of therapy (moxalactam, 7.5 days; gentamicin, 8.6 days) was similar for both groups. Sixty-two percent of patients treated with moxalactam and 57% of those receiving gentamicin were cured of their infection, as defined by a negative culture after therapy. No side effects required discontinuation of either drug. An enterococcus caused two superinfections and three reinfections in patients treated with moxalactam. Moxalactam resistance developed in Pseudomonas aeruginosa isolates from three patients treated with moxalactam. Moreover, two of these isolates showed decreased susceptibility to gentamicin, tobramycin, and amikacin. An additional 10 patients with gentamicin-resistant but moxalactam-susceptible isolates were treated with moxalactam. Forty percent of these patients were cured of their infections. Moxalactam appears to be a safe, effective drug for complicated urinary tract infections caused by susceptible bacteria, including those resistant to gentamicin. However, patients receiving moxalactam should be carefully monitored to detect enterococcal superinfections or development of resistance to moxalactam in isolates of P. aeruginosa.
Randomized comparison of ceftazidime versus clindamycin-tobramycin in the treatment of obstetrical and gynecological infections
Authors: Blanco J D , Gibbs R S , Duff P , Castaneda Y S , St Clair P J
Published: June 2012

A randomized comparison of ceftazidime versus clindamycin-tobramycin was performed for the treatment of obstetrical and gynecological infections. Entry criteria were an oral temperature of greater than or equal to 38 degrees C and a clinical diagnosis of endometritis, salpingitis, or pelvic cellulitis after hysterectomy. All patients with endometritis had cultures of intrauterine material obtained via a transcervical single-lumen catheter. The patients with pelvic cellulitis had material from the vaginal apex aspirated for culture, and all patients with salpingitis had a culdocentesis for culture of intraperitoneal material. Of 38 patients who received ceftazidime, 34 had endometritis after cesarean section, 3 had endometritis after abortion, and 1 had pelvic cellulitis. Of 39 patients who received clindamycin-tobramycin, 35 had endometritis after cesarean section, 3 had salpingitis, and 1 had pelvic cellulitis. The most common bacterial isolates were Lactobacillus sp., Bacteroides bivius, Escherichia coli, other gram-negative aerobic bacilli, group B streptococci, and other aerobic streptococci. Bacteremia occurred in 9.0% of the patients. Of the patients receiving clindamycin-tobramycin and ceftazidime, 34 (87.2%) and 34 (89.5%), respectively, responded to therapy. All the clinical failures occurred in patients with endometritis after cesarean section. Clinical failures had persistent fever despite 3 or more days of treatment. One of the patients receiving clindamycin-tobramycin developed an urticarial rash after her infection had resolved. No patient in either group developed diarrhea. In these small groups of patients, there were no significant differences in cure rate, side effects, or length of hospital stay.
Susceptibility of 40 Haemophilus ducreyi strains to 34 antimicrobial products
Authors: Slootmans L , Vanden Berghe D A , Van Dyck E , Piot P
Published: June 2012

A study was performed to examine compounds that might improve the selectivity of the primary isolation medium for Haemophilus ducreyi. The susceptibility of 40 H. ducreyi strains to 34 antimicrobial agents, including 10 antibiotics, 3 quaternary ammonium compounds, 3 phenolic derivatives, 3 acridines, and 15 heavy metal compounds, was investigated by using an agar plate dilution technique. Results were compared with the susceptibilities of other gram-negative rods which may be contaminants on isolation media. The minimal inhibitory concentration range for colistin (16 to 128 micrograms/ml) indicated that this antibiotic might be of use as a selective agent. H. ducreyi was susceptible to spectinomycin (minimal inhibitory concentration range, 16 to 64 micrograms/ml), thiamphenicol (0.12 to 1 microgram/ml), chloramphenicol (0.12 to 0.5 micrograms/ml), and streptomycin (4 to 32 micrograms/ml) and moderately susceptible to kanamycin (2 to 8 micrograms/ml). For the heavy metal compounds, a high susceptibility was seen with copper(II) chloride (2 to 8 micrograms/ml, corresponding to a concentration of 0.75 to 3 micrograms of Cu2+ ions per ml), sodium selenite (1 to 4 micrograms/ml, or 0.45 to 1.83 micrograms of Se- ions per ml), and phenylmercury acetate (0.12 to 0.5 micrograms/ml). The minimal inhibitory concentrations of quaternary ammonium compounds, acridines, and phenolic derivatives were between 1 and 32 micrograms/ml, 8 and 32 micrograms/ml, and 8 and 250 micrograms/ml, respectively.
Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats
Authors: Laurent G , Maldague P , Carlier M B , Tulkens P M
Published: June 2012

Kidney cortex DNA synthesis was studied in female rats treated with a low dose of gentamicin (10 mg/kg) up to 14 days. Synthesis was measured by incorporation of [3H]thymidine into DNA 1 h after intraperitoneal injection of the labeled precursor (200 muCi per animal). Gentamicin given in one injection per day resulted in a greater incorporation of [3H]thymidine into DNA after both 7 and 14 days of treatment as compared with control animals. When the daily dose was divided into three equal injections given at 8-h intervals, a statistically significant increase in thymidine incorporation was observed as early as 4 days after starting gentamicin administration. Excellent agreement was found between DNA specific radioactivity and kidney cortex nuclear labeling, as measured by histoautoradiography. The greatest amount of [3H]thymidine incorporation occurred within proximal tubular cells and interstitial cells. We conclude that a finite duration of gentamicin treatment at low dosage induces an increased DNA synthesis in vivo in rat kidney cortex. We suggest that this reaction results from cellular proliferation and could reflect a regenerative process after focal necrosis induced by gentamicin at low doses. The demonstrated early increase in DNA synthesis could be a useful tool to measure kidney cortex alterations caused by various aminoglycosides at low, therapeutic doses.
Susceptibility of Mycobacterium tuberculosis to pyrazinamide and its relationship to pyrazinamidase activity
Authors: Butler W R , Kilburn J O
Published: June 2012

Pyrazinamidase activity has been associated with pyrazinamide-susceptible Mycobacterium tuberculosis strains. The detection of pyrazinamidase activity by the Wayne method was found to be of limited value when compared with the results of standard pyrazinamide susceptibility tests, especially when a high level of pyrazinamide resistance was found. When resistance to pyrazinamide reached a level of 150 to 200 micrograms/ml, there was too much variability in Wayne test results to accurately define pyrazinamide susceptibility.
Value of serum tests in combined drug therapy of endocarditis
Authors: Drake T A , Hackbarth C J , Sande M A
Published: June 2012

Two in vitro tests, the serum killing level and the serum bactericidal rate assays, were evaluated for correlation with therapeutic efficacy in the rabbit model of Staphylococcus aureus endocarditis. Animals were treated with nafcillin alone and in combination with tobramycin or gentamicin. Both were effective therapies, but rapidity of vegetation sterilization by the single and combined regimens was shown by the serum bactericidal rate assay but not the serum killing level assay. As a direct measure of bactericidal activity in serum during therapy, the serum bactericidal rate assay may be a clinically useful supplemental test for providing information that the serum killing level assay cannot.
Metabolism and metronidazole uptake in Trichomonas vaginalis isolates with different metronidazole susceptibilities
Authors: Müller M , Gorrell T E
Published: June 2012

Three Trichomonas vaginalis isolates with low in vivo susceptibilities to metronidazole (95% curative dose, greater than 3 X 100 mg kg-1 in subcutaneous infections in mice) were compared with strain ATCC 30001 and with four isolates exhibiting high in vivo susceptibilities (95% curative dose, less than 3 X 15 mg kg-1). Activity of pyruvate:ferredoxin oxidoreductase, anaerobic fermentation, and anaerobic intracellular accumulation of [14C]metronidazole label showed no significant isolate-dependent differences which could be correlated with drug susceptibility. The results suggest that processes providing electrons for metronidazole activation are not defective in the resistant strains. Aerobiosis, known to inhibit the antimicrobial action of metronidazole, inhibited accumulation of label more strongly in resistant isolates than in susceptible ones. No differences were detected, however, between resistant and susceptible isolates in respiration, aerobic fermentation, and the specific activity of NADH and NADPH oxidases, the main terminal oxidases of T. vaginalis. These findings suggest that the production of electrons is not diminished under aerobic conditions. The inhibitory effect of aerobic conditions on metronidazole activation, possibly due to competition for the electrons, is markedly enhanced in the resistant isolates compared to the susceptible ones. The mechanism of this effect, however, remains unknown.