bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolism of acyclovir in virus-infected and uninfected cells
Authors: Furman P A , de Miranda P , St Clair M H , Elion G B
Published: June 2012

The metabolism of acyclovir to its mono-, di-, and triphosphate derivatives was examined in uninfected and virus-infected cells. The level of phosphorylation of acyclovir was dependent upon virus type, cell line, exogenous drug concentration, and exposure time. Acyclovir phosphorylation was inhibited by exogenously added nucleosides. The order of inhibition was deoxythymidine greater than deoxycytidine greater than guanosine greater than or equal to deoxyguanosine. Acyclovir triphosphate persisted in infected cells after removal of the drug from the medium. The initial half-life of the triphosphate was 1.2 h in the absence of the drug in the medium, but triphosphate levels reached a plateau after 6 h. The presence of low concentrations of the drug in the medium resulted in a longer persistence of the intracellular triphosphate and a higher plateau level.
Cefsulodin: antibacterial activity and tentative interpretive zone standards for the disk susceptibility test
Authors: Barry A L , Jones R N , Thornsberry C
Published: June 2012

Cefsulodin (SCE-129) is a cephalosporin with a spectrum of antibacterial activity largely limited to Pseudomonas aeruginosa and Staphylococcus aureus. Cefsulodin was compared with carbenicillin, ticarcillin, mezlocillin, and piperacillin against 779 nonenteric gram-negative bacilli and staphylococci collected from five geographically separate institutions. Against P. aeruginosa, cefsulodin was somewhat more active than piperacillin and much more active than other penicillins. In addition, cefsulodin was active against penicillinase-producing strains of S. aureus. Collaborative efforts in three laboratories led to the following tentative zone size breakpoints for 30-micrograms cefsulodin disks: susceptible greater than or equal to 18 mm (minimal inhibitory concentration) [MIC] less than or equal to 16 micrograms/ml) and resistant less than or equal to 14 mm (MIC greater than or equal to 64 micrograms/ml). These zone standards are still tentative since the dosage schedule has not yet been defined and sufficient clinical experience has not yet been gathered to support the validity of these MIC breakpoints.
Activities of New Beta-Lactam Antibiotics Against Isolates of
Pseudomonas aeruginosa
from Patients with Cystic Fibrosis
Authors: Prince Alice S. , Neu Harold C.
Published: June 2012

The in vitro activities of gentamicin, tobramycin, amikacin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, cefotaxime, ceftizoxime, cefoperazone, cefsulodin, moxalactam, ceftazidime, ceftriaxone, and
N
-formimidoyl thienamycin were measured against 62 isolates of
Pseudomonas aeruginosa
obtained from patients with cystic fibrosis. Ceftazidime and
N
-formimidoyl thienamycin were the most active of these agents.
Use of pyrazinamidase activity on Mycobacterium tuberculosis as a rapid method for determination of pyrazinamide susceptibility
Authors: McClatchy J K , Tsang A Y , Cernich M S
Published: June 2012

Pyrazinamidase activity in clinical isolates of Mycobacterium tuberculosis has been previously found to correlate with susceptibility to the antituberculosis drug pyrazinamide. The Wayne method for determining pyrazinamidase activity, a technique also utilized as an aid in identification of mycobacteria, and thin-layer chromatography method were found to be useful screening methods for susceptibility testing, since resistant strains are pyrazinamidase negative. These simple methods overcome the difficulty in growing M. tuberculosis at pH 5.5, as is required in the conventional method of susceptibility testing.
Effect of subinhibitory concentrations of antibiotics on the adhesion of Streptococcus pyogenes to pharyngeal epithelial cells
Authors: Tylewska S , Hjertén S , Wadström T
Published: June 2012

The hydrophobicity and charge of the cell surface of M protein-positive (M+) and the less virulent M protein-negative (M-) strains of type 12 Streptococcus pyogenes have been studied, respectively, by hydrophobic interaction chromatography and free zone electrophoresis. The M+ strain had a more hydrophobic and a more negatively charged surface than the M- strain. When the M+ strain was cultivated in the presence of sub-minimum inhibitory concentrations of different antibiotics, its hydrophobicity either decreased or did not change. The M+ organisms adhered to pharyngeal epithelial cells more avidly than M+; however, cultivation of both strains with sub-minimum inhibitory concentrations of penicillin and rifampin led to the decrease in adhesion. Tetracycline caused a decrease in adhesion for the M+ strain only, whereas cephalothin and polymyxin (to which the strains are resistant) did not affect adhesion or hydrophobicity of the M+ organisms. The negative surface charge of the M+ bacteria increased considerably upon exposure to rifampin and penicillin, and the M- bacteria exhibited small or no change. The contributions of these changes to suppression of infections are discussed.
Comparative Multiple-Dose Pharmacokinetics of Cefotaxime, Moxalactam, and Ceftazidime
Authors: Lüthy Ruedi , Blaser Jürg , Bonetti Antonio , Simmen Hanspeter , Wise Richard , Siegenthaler Walter
Published: June 2012

The pharmacokinetics of cefotaxime, moxalactam, and ceftazidime were investigated in six human volunteers who received in a crossover fashion doses of 0.5, 1.0, and 2.0 g of each drug by a 5-min infusion. Doses of 1.0 g were repeated after the administration of probenecid. Serum and urine concentrations were assayed with an agar diffusion method. Serum concentrations of moxalactam exceeded those of ceftazidime at all times and were distinctly higher than those of cefotaxime. The normalized area under the concentration time curve (defined as the ratio of the area under the curve per dose) reflects this relationship: compared with cefotaxime the normalized area under the curve of moxalactam was 3 to 4 times higher, and that of ceftazidime was 2 to 3 times higher. By intra-individual comparisons, the area under the curve of moxalactam was 44% larger than that of ceftazidime. With increasing doses, cefotaxime exhibited a nonlinear increase of the area under the curve. The half-lives of moxalactam, ceftazidime, and cefotaxime were 2.34, 1.95, and 1.16 h, respectively. The volume of distribution averaged 0.20 ± 0.03, 0.23 ± 0.02, and 0.25 ± 0.04 liters per kg, and the mean total body clearance was 84, 131, and 328 ml/min for moxalactam, ceftazidime, and cefotaxime, respectively. The 24-h urinary recovery was highest for moxalactam (75 ± 4%) followed by ceftazidime (68 ± 11%) and cefotaxime (53 ± 6%). The influence of probenecid on serum concentrations, half-life, area under the curve, and clearance was most apparent with cefotaxime, whereas the pharmacokinetics of moxalactam and ceftazidime were only slightly affected. After the 0.5− and 2.0− g doses of cefotaxime, desacetyl-cefotaxime activity (determined by high-pressure liquid chromatography) reached a peak of 2.7 and 9.9 μg/ml and declined with a half-life of 1.9 and 1.4 h. The ratio of the R(−) and S(−) epimers of moxalactam, which could be differentiated by high-pressure liquid chromatography, fell rapidly from 0.81 at 0.17 h to 0.5 at 5 h, indicating the presence of twice as much of the microbiologically less active S(−) epimer. From a pharmacokinetic standpoint it appears reasonable to conclude that moxalactam and possibly ceftazidime could be administered twice daily and that cefotaxime could be administered three or even four times daily.
Quantitation of herpes simplex virus type 1 shed in preocular tear film of rabbits treated with acyclovir
Authors: Green M T , Dunkel E C , Morris B L
Published: June 2012

The quantity and duration of herpes simplex virus type 1 shedding in the preocular tear film of rabbits were measured before, during, and after administration of acyclovir topically, intravenously, and by these routes. Topical administration reduced shedding significantly, Intravenous administration was without effect and in the combination regimen added nothing to the effectiveness of local application. The effects of acyclovir were temporary because there were significant increase in preocular tear film virus shedding after cessation of treatment.
In vitro activity, efficacy, and pharmacology of moxalactam, a new beta-lactam antibiotic
Authors: Snepar R , Poporad G , Romano J , Levison M E
Published: June 2012

Moxalactam, a potent new beta-lactam antibiotic with a relatively wide spectrum of activity against facultative and anaerobic gram-negative bacilli, was evaluated in vitro and in 28 patients with a variety of severe infections with moxalactam-susceptible organisms (minimum inhibitory concentration less than or equal to 31 microgram/ml). Although therapy was successful in most of these patients, caution is suggested because of the development of resistance on therapy in one patient, persistence of Bacteroides fragilis endocarditis in another, and for certain organisms, a significant inoculum effect on the minimum inhibitory concentration and minimum bactericidal concentration of moxalactam.
Ketoconazole, amphotericin B, and amphotericin B methyl ester: comparative in vitro and in vivo toxicological effects on neutrophil function
Authors: Marmer D J , Fields B T , France G L , Steele R W
Published: June 2012

We investigated a number of parameters for host defense after the in vitro addition of the antifungal agents ketoconazole, amphotericin B (AMB), and amphotericin B methyl ester (AME). Similar assays were repeated before and after patients received the former two drugs. Viability by trypan blue exclusion, adherence by nylon wool columns, chemotaxis by the under-agarose technique, phagocytosis and killing by chemiluminescence, colony counts, and acridine orange direct visualization were assayed. In striking contrast to AMB and AME, ketoconazole demonstrated no significant effect on neutrophils. Adherence in the presence of therapeutic plasma levels of AMB and AME was decreased (P less than or equal to 0.005) at low drug concentrations, whereas at higher concentrations, adherence was increased (P less than 0.001). The chemotactic responses of cells incubated with AMB and AME demonstrated marked suppression. Phagocytic capacity and killing were decreased (P less than or equal to 0.005) with AMB as compared with control assays and assays performed in the presence of ketoconazole and AME. However, no difference were observed between two patients who received AMB and two other treated with ketoconazole.
Comparative efficacy of piperacillin and penicillin G in treatment of gonococcal urethritis
Authors: Landis S J , Ramphal R , Mansheim B J , Rand K H , Shands J W
Published: June 2012

The comparative efficacy of 2 g of piperacillin and 4.8 X 10(6) U of penicillin G in the treatment of uncomplicated gonococcal urethritis was assessed in a randomized prospective study. Sixty-five evaluable patients received piperacillin, and 55 received penicillin G. All patients received either therapy were cured of gonorrhea. We conclude that piperacillin is as efficacious as aqueous procaine penicillin G in the therapy of uncomplicated gonococcal urethritis.
Predicted tissue accumulation of netilmicin in patients
Authors: Edwards D J , Mangione A , Cumbo T J , Schentag J J
Published: June 2012

The two-compartment pharmacokinetics of netilmicin were investigated in 11 patients with stable renal function who were being treated for gram-negative infections. The initial dosage of netilmicin ranged from 2.5 to 5.0 mg/kg per day, with subsequent changes made on the basis of serum concentrations. Venous blood samples were obtained every 2 to 4 days during therapy and daily for an average of 10 days after the final dose. Serum concentrations were measured by both microbiological assay and radioimmunoassay. Peak and trough netilmicin concentrations were significantly greater (P less than 0.01) at the end of therapy than at the first dose, even though renal function was stable throughout treatment in all patients. After the final dose, serum concentrations declined in a biphasic manner, with a first-phase half-life of 5.4 h and a terminal half-life of 198 h. The total body clearance averaged 31 ml/min. An average of 99 mg of netilmicin (approximately 5% of the total dose) was predicted to be in the tissue compartment at the end of therapy. A comparison of these pharmacokinetic parameters with those obtained in a previously reported but similar study with gentamicin showed no significant differences between the two aminoglycosides with respect to peak and trough concentrations (initially or at the end of therapy), volumes of distribution, total body clearance, or amount of drug in the tissue compartment at the end of therapy. The terminal half-life of netilmicin was significantly greater than that of gentamicin, whereas the rate constant of netilmicin for tissue influx (k12) was significantly less.
Cefoxitin pharmacokinetics: relation to three different renal clearance studies in patients with various degrees of renal insufficiency
Authors: Kampf D , Schurig R , Korsukewitz I , Brückner O
Published: June 2012

The pharmacokinetics of cefoxitin were examined in 4 healthy volunteers, 6 patients with normal renal function (inulin clearance, greater than 80 ml/min per 1.73 m2), and 35 patients with various degrees of renal insufficiency (inulin clearance, 80 to less than 5 ml/min per 1.73 m2). A single dose of 30 mg of cefoxitin per kg of body weight was injected intravenously over 3 min. Antibiotic concentrations in plasma were determined by the agar diffusion technique. The cefoxitin half-life increased progressively from 39 min in subjects with normal renal function to 23.5 h in oligoanuric patients. Correspondingly, total body clearance decreased from 340 to 13 ml/min per 1.73 m2. In addition to the study of cefoxitin kinetics, in 29 of the 41 patients, three different renal clearance tests were performed (inulin, p-aminohippurate, and creatinine clearances). Of these, p-aminohippurate clearance showed the best correlation with the elimination rate constant beta as well as total body clearance of cefoxitin; but with respect to beta, the differences between the p-aminohippurate and creatinine clearances were quantitatively negligible. Therefore, even in substances which are eliminated predominantly by active tubular secretion, creatinine clearance could be recommended for dosage adjustments.
Evaluation of carbodine, the carbocyclic analog of cytidine, and related carbocyclic analogs of pyrimidine nucleosides for antiviral activity against human influenza Type A viruses
Authors: Shannon W M , Arnett G , Westbrook L , Shealy Y F , O'Dell C A , Brockman R W
Published: June 2012

Carbodine, the carbocyclic analog of cytidine, was found to possess significant antiviral activity against influenza virus types A0/PR-8/34 and A2/Aichi/2/68 (Hong Kong) in vitro. The compound selectively inhibited PR-8 influenza virus-induced cytopathogenic effects in Madin-Darby canine kidney and inhibited Hong Kong influenza virus replication in primary rhesus monkey kidney cell cultures. The 50% minimum inhibitory concentration for inhibition of human influenza type A viruses by carbodine was approximately 2.6 microgram/ml (i.e., in the range of antiviral potency of ribavirin, but less potent than amantadine hydrochloride in concomitant assays). The fact that carbodine is metabolized to carbodine triphosphate in mammalian cells makes interference with the viral ribonucleic acid-dependent ribonucleic acid polymerase reaction a likely possibility for its principal mode of action. The carbocyclic analogs of uridine (the deamination product of carbodine), 2'-deoxycytidine, 3'-deoxycytidine, N,N-dimethylcytidine, N-methylcytidine, and some related carbocyclic analogs of pyrimidine nucleosides were inactive against PR-8 influenza virus in vitro. The combination of carbodine plus tetrahydrouridine was no more effective in vitro than carbodine alone, thus indirectly indicating that deamination of carbodine probably did not occur to a significant degree during the cell culture experiments. Although reproducibly active in vitro, carbodine did not exhibit any efficacy against lethal influenza virus infections in mice when administered by either the intraperitoneal or intranasal routes up to dose-limiting toxic levels.
Susceptibility of Pittsburgh pneumonia agent (Legionella micdadei) and other newly recognized members of the genus Legionella to nineteen antimicrobial agents
Authors: Pasculle A W , Dowling J N , Weyant R S , Sniffen J M , Cordes L G , Gorman G M , Feeley J C
Published: June 2012

The susceptibilities of 11 strains representing the five recognized species of Legionella were determined by agar dilution testing on buffered charcoal-yeast extract agar. All of the legionellae tested were susceptible to rifampin, erythromycin, rosaramycin, chloramphenicol, and the aminoglycosides and were resistant to clindamycin and vancomycin. Susceptibilities to penicillins and cephalosporins were variable. Legionella micdadei, Legionella bozemanii, and Legionella gormanii were susceptible to these agents, but minimal inhibitory concentrations for each species were different. Legionella dumoffii resembled Legionella pneumophila in being resistant to penicillin, cephalothin, and cephamandole and susceptible to moxalactam and cefoxitin. All species except L. micdadei produced beta-lactamase.
Dose-Ranging Study of Ceftriaxone for Uncomplicated Gonorrhea in Men
Authors: Handsfield H. Hunter , Murphy Victory L. , Holmes King K.
Published: June 2012

Uncomplicated gonorrhea in men was successfully treated with ceftriaxone in single intramuscular doses of 125 mg (15 patients), 250 mg (16 patients), or 500 mg (15 patients). All 45 pretreatment gonococcal isolates tested were inhibited by ≤0.016 μg of ceftriaxone per ml. Treatment was well tolerated and caused no toxicity.
Double-blind controlled study of central nervous system side effects of amantadine, rimantadine, and chlorpheniramine
Authors: Millet V M , Dreisbach M , Bryson Y J
Published: June 2012

A total of 52 healthy, adult volunteers were randomly assigned to five treatment groups to be treated twice daily for 4 days with 100 mg of amantadine, 100 mg of rimantadine, 4 mg of chlorpheniramine or placebo alone, or 100 mg of amantadine in combination with chlorpheniramine. The results of tests measuring performance on tasks of attention, reasoning, and memory were unaffected by treatment. Subjective side effects in recipients of amantadine, rimantadine, and chlorpheniramine were comparable and minimal. Side effects appeared to be enhanced in subjects receiving both amantadine and chlorpheniramine.
Derivatives of 4-dihydro-4-deoxy-4(R)-amino spectinomycin and their activity against susceptible and resistant Escherichia coli strains
Authors: Werner R G , Lechner U L , Goeth H
Published: June 2012

A number of alkyl and acyl derivatives of 4-dihydro-4-deoxy-4(R)-amino spectinomycin were tested against various Escherichia coli strains, possessing different susceptibilities to spectinomycin. The influence of the lipophilicity and the length of the side chain substituents of the derivatives was compared to both minimal inhibitory concentration values and stability to adenyltransferase. Derivatives with a chain length of more than 10 carbon atoms demonstrated a significantly higher activity against all investigated strains, whether susceptible or resistant. The same inhibitory effect was achieved with short-chain aminoacyl derivatives only against susceptible strains. Other short-chain derivatives possessed no advantage to spectinomycin. A 10-fold decrease in the affinity for adenyltransferase was achieved in compounds with a high lipophilicity (log P), i.e., in aliphatic substituted derivatives with a log P greater than 4 and in benzoyl-substituted derivatives with a log P greater than 2. Derivatives with branched alkyl chains and long side chains displayed a different mode of action than spectinomycin. They possessed strong activity against strains with an altered ribosomal binding site and a decreased influence of pH on antimicrobial activity.
Intramuscular and intravenous pharmacokinetics of cefmenoxime, a new broad-spectrum cephalosporin, in healthy subjects
Authors: Granneman G R , Sennello L T , Steinberg F J , Sonders R C
Published: June 2012

This study was concerned with the single-dose, pharmacokinetics of cefmenoxime after intramuscular (i.m.) injections of 250, 500 and 1,000 mg; 1-h intravenous (i.v.) infusions of 500, 1,000, and 2,000 mg; and 5-min i.v. injections of 500, 1,000, and 2,000 mg of cefmenoxime. A total of 15 subjects were used, each receiving all three doses for one route of administration. Mean calculated peak plasma levels after the 250-, 500-, and 1,000-mg i.m. doses were 9.07, 14.68, and 26.73 micrograms/ml, respectively, occurring about 40 min after dosing. The biphasic decline in plasma levels after i.v administration was usually not apparent after i.m. dosing, because absorption of the drug from the injection depot was slower than distribution of the drug. Mean calculated peak levels from the 500-, 1,000-, and 2,000-mg i.v. doses were 22.8, 41.6, and 94.5 micrograms/ml, respectively, after the 1-h infusions and 64.1, 100.9, and 198.2 micrograms/ml, respectively after the 5-min injections. Small but statistically significant trends of decreasing alpha and increasing volume of distribution (central compartment) with increasing dose size were noted; however, this distribution phenomenon was self-compensating, resulting in no overall effect on plasma clearance. For practical purposes, the pharmacokinetics were linear. The mean 0- to 24-h urinary recoveries of cefmenoxime after the i.m. injections, i.v. infusions, and i.v. injections were 72.1, 67.5, and 74.5% respectively. Overall, the pharmacokinetics of cefmenoxime were best described by a two-compartment open model with a beta-phase half life of 0.91 h. Plasma clearance of the drug was dosage level and route independent, averaging 254 ml/min; thus, there was an excellent linear relationship between the area under the plasma level curve and the dose. The results of this study indicated that most of the drug is removed by renal mechanisms, with tubular secretion predominating.
Effect of acyclovir and interferon on human hematopoietic progenitor cells
Authors: Parker L M , Lipton J M , Binder N , Crawford E L , Kudisch M , Levin M J
Published: June 2012

Continuous in vitro exposure of human bone marrow cells to acyclovir (approximately 200 microM) or human leukocyte interferon (approximately 250 U/ml) caused 50% inhibition of granulocyte colony-forming cell differentiation. Colonies expressed in the presence of either agent were reduced both in size and number. Erythroid progenitors were more resistant than granulocyte progenitors to the antiproliferative effects of acyclovir. Progenitor cells of patients recovering from cytotoxic chemotherapy were no more sensitive to the effects of acyclovir or interferon than were cells obtained from patients before chemotherapy.
Disposition of ketoconazole, an oral antifungal, in humans
Authors: Brass C , Galgiani J N , Blaschke T F , Defelice R , O'Reilly R A , Stevens D A
Published: June 2012

The pharmacology of ketoconazole was studied in patients with fungal infections. After administration of 50-, 100-, and 200-mg doses of ketoconazole, there was a linear increase in the area under the curve of serum concentrations; this was not apparent when higher doses of ketoconazole were given. An increase in the area under the curve occurred in patients receiving 200 mg daily who were restudied after 1 to 12 months of therapy. However, normalized area under the curve appeared to decrease after higher doses were administered chronically. The half life ranged from 2.0 to 3.3 h. Peak serum concentrations up to 50 micrograms/ml were detected in this study, and potentially therapeutic concentrations were detectable up to 26 h after high doses. Ketoconazole penetrated the saliva and inflamed joint fluid and meninges, although variably, and could be demonstrated in some other tissue compartments. In the presence of renal failure, ketoconazole disposition was not altered, whereas in the presence of hepatic insufficiency, an alteration in disposition was suggested. The interactions of ketoconazole and other drugs were studied. Of note, antacids did not significantly affect ketoconazole pharmacokinetics (nor did meals), and ketoconazole and warfarin did not appear to affect the pharmacokinetics of the other.
N-formimidoyl thienamycin (MK0787): in vitro activity against anaerobic bacteria
Authors: Martin D A , Sanders C V , Marier R L
Published: June 2012

The in vitro activity of N-formimidoyl thienamycin (MK0787) was tested against 239 anaerobic bacteria clinical isolates: 70 of Bacteroides fragilis, 18 of B. distasonis, 16 of B. thetaiotaomicron, 10 of B. vulgatus, 24 of Bacteroides spp., 22 of B. melaninogenicus (all three subspecies), 26 of Fusobacterium spp., 10 of Peptococcus spp., 15 of Peptostreptococcus spp., 15 of Clostridium perfringens, and 13 of Clostridium spp. Ninety-five percent of the isolates were inhibited by less than or equal to 0.125 microgram/ml, and all were inhibited by less than or equal to 4 micrograms/ml.
Cefaclor pharmacokinetic parameters: serum concentrations determined by a new high-performance liquid chromatographic technique
Authors: Rotschafer J C , Crossley K B , Lesar T S , Zaske D , Miller K
Published: June 2012

Pharmacokinetic parameters of cefaclor were studied in eight patients after an oral dose of 250 mg. Serum samples were obtained before and on 19 occasions after oral administration. Cefaclor serum concentrations were determined by a new high-performance liquid chromatographic technique.
Induction of cell lysis in Escherichia coli: cooperative effect of nocardicin A and mecillinam
Authors: Berenguer J , de Pedro M A , Vázquez D
Published: June 2012

Nocardicin A and mecillinam are two beta-lactam antibiotics with poor bacteriolytic activity against Escherichia coli. However, the combined use of these drugs resulted in the induction of a fast lytic response in E. coli cells. For this cooperative effect to take place, the formation of a complex between penicillin-binding protein 2 and mecillinam is apparently necessary. This suggests that penicillin-binding protein 2 might be actively involved in the response of E. coli to bacteriolytic beta-lactam antibiotics.
Comparative antipseudomonal activity of some newer beta-lactam agents
Authors: Greenwood D , Eley A
Published: June 2012

The antipseudomonal activities of cefotaxime, ceftizoxime, ceftazidime, ceftriaxone, cefoperazone, and moxalactam were tested in conventional minimum inhibitory concentration titrations and according to morphological and turbidimetric criteria. Three groups of pseudomonal strains were tested: carbenicillin hypersusceptible, carbenicillin susceptible, and carbenicillin resistant. In minimum inhibitory concentration titrations, the carbenicillin-hypersusceptible strains did not differ greatly in their susceptibility to other beta-lactam agents, although moxalactam appeared to be rather less active than the other drugs. When tested against the remaining strains, ceftazidime was the most active compound, followed by cefoperazone and ceftriaxone. The turbidimetric experiments supported by microscopical observations, all of the agents induced bacterial lysis in the carbenicillin-hypersusceptible strains, but cefoperazone appeared to be less actively bacteriolytic than the rest of the antibiotics. None of the agents was able to prevent growth of the remainder of the Pseudomonas aeruginosa strains in the first few hours of drug exposure, during which time the bacteria elongated to form long filaments. However, the various agents differed in the length of time which elapsed before growth was completely halted. Judged in this way, moxalactam was the most active compound in relation to its minimum inhibitory concentration, but in comparative experiments in which the same concentration of each drug (64 microgram/ml) was used regardless of the minimum inhibitory concentration, ceftazidime appeared to be the most active antibiotic, followed by ceftriaxone and cefotaxime.
Pharmacokinetics of fosmidomycin, a new phosphonic acid antibiotic
Authors: Murakawa T , Sakamoto H , Fukada S , Konishi T , Nishida M
Published: June 2012

The pharmacokinetics of fosmidomycin was investigated in animals and humans after parenteral and oral dosing. In dogs the serum concentration was 54.8 microgram/ml at 0.25 h after an intravenous dose of 20 mg/kg, and the half-life was 1.14 h. Peak concentration was 41.4 microgram/ml after an intramuscular dose of 20 mg/kg and 16.6 microgram/ml after an oral dose of 40 mg/kg. In volunteers, the serum concentrations 0.25 h after dosing was 157 microgram/ml after an intravenous dose of 30 mg/kg, 12.3 microgram/ml after an intramuscular dose of 7.5 mg/kg, and 2.45 microgram/ml after an oral dose of 500 mg. More than 90% of the given dose was excreted in the 24-h urine in rats and dogs after parenteral dosing with 20 mg/kg. The 24-h urinary recovery was 45.8% of the given dose in rats after oral dosing with 100 mg/kg and 37.8% in dogs after oral dosing with 40 mg/kg. In volunteers 85.5% of the intravenous dose (30 mg/kg), 66.4% of the intramuscular dose (7.5 mg/kg), and 26.0% of the oral dose (500 mg) were excreted unchanged in the 24-h urine. In the multiple-dose study, there was no accumulation of fosmidomycin in the serum even after 21 consecutive intramuscular dosings of 1 g every 6 h or 29 consecutive 0.5-h drip infusions of 2 g every 6 h. Biliary excretion was extremely low in rats. Fosmidomycin was well distributed to the tissues of rats after parenteral and oral dosing. The lymph concentrations in dogs were nearly the same as serum concentrations. Serum protein binding was low (4% or less) to mouse, rat, dog, and human serum.
Membrane transport of clindamycin in alveolar macrophages
Authors: Hand W L , King-Thompson N L
Published: June 2012

The use of antibiotics which can penetrate phagocytic cells and kill intracellular organisms is desirable in the treatment of chronic facultative bacterial infections. Recently, we reported that several antibiotics were selectively concentrated by rabbit alveolar macrophages. Clindamycin accumulation was especially marked. In the present study we evaluated the plasma membrane transport (initial uptake) of clindamycin in alveolar macrophages. The transport of clindamycin is an active process, as documented by requirements for cellular viability, elevated environmental temperature, metabolic energy, and establishment of the 40- to 50-fold cellular/extracellular gradient. Energy for membrane transport of the drug depended at least in part upon mitochondrial oxidative respiration and cell membrane Na-K pump activity. Kinetic analysis of active clindamycin transport revealed it to be saturable, with a high binding affinity (Km = 1 mM) and a high velocity of uptake (Vmax = 15.8 nmol/45 s per 10(6) cells). Clindamycin uptake was not influenced by the presence of hexose or amino acids, but was inhibited by nucleosides (adenosine, puromycin). Decreased clindamycin transport in the presence of puromycin was typical of competitive inhibition (increased Km, unchanged Vmax). Conversely, competitive inhibition of adenosine transport by clindamycin was documented. Thus, clindamycin is transported into alveolar macrophages via the nucleoside system. The potential biological consequences of this unique antibiotic transport mechanism are of interest.
Penetration of cephalosporins and corresponding 1-oxacephalosporins through the outer layer of Gram-negative bacteria and its contribution to antibacterial activity
Authors: Murakami K , Yoshida T
Published: June 2012

1-Oxacephalosporins had a higher ability to penetrate through the outer layer of the envelope of gram-negative bacteria than the corresponding cephalosporins. In spite of the liability of 1-oxa congeners to beta-lactamases, they attained higher periplasm concentrations at a given concentration outside the cells. The replacement of sulfur in the cephem nucleus by oxygen was accompanied by an increment of the hydrophilic character of the molecule, which suggests that this character was favorable for outer layer penetration. 1-Oxacephalosporins showed enhanced antibacterial activity in short-term measurement and exerted their antibacterial action at lower periplasm concentrations. Thus, the enhanced antibacterial activity of 1-oxacephalosporins seems to be due to their higher penetrability and their intrinsic inhibitory activity against the peptidoglycan biosynthesis system.
Pharmacokinetics of intramuscular ceforanide in infants, children, and adolescents
Authors: Dajani A S , Thirumoorthi M C , Bawdon R E , Buckley J A , Pfeffer M , Van Harken D R , Smyth R D
Published: June 2012

We studied the pharmacokinetics of intramuscular ceforanide in 46 infants, children, and adolescents, ranging in age from 1 month to 17 years. After the subjects were given 20-mg doses of ceforanide per kg, the mean peak plasma concentration was 56.3 microgram/ml (range, 27.0 to 95.0), the mean 8-h level was 5.9 microgram/ml (range, 1.5 to 13.5), and the mean 12-h level was 1.5 microgram/ml (range, 0.2 to 4.2). Ceforanide half-life varied with the ages of the patients: in 1- to 2-year-old children, in half-life was significantly shorter (1.5 h) than in younger or older children. Plasma concentrations at 8 and 12 h after a dose were lowest in 1- to 2-year-old children. There was no relationship between the area under the curve, the volume of distribution, or the body clearance of ceforanide to the ages of the patients. Within 6 h of administration of the drug, a mean of 77.5% of a dose was excreted in urine, and at the end of 12 h, virtually all (93.9%) of the administered dose was recovered in urine samples. The administration of ceforanide every 12 h did not result in drug accumulation. A dose of 20 mg of ceforanide per kg every 12 h is recommended for most pediatric patients. Dosage recommendations for 1- to 2 year-old children are presented.
Comparative in vitro bactericidal activity of cefonicid, ceftizoxime, and penicillin against group B streptococci
Authors: Bayer A S , Morrison J O , Kim K S
Published: June 2012

The minimal inhibitory and bactericidal concentrations for 108 group B streptococcal strains were determined for two new cephalosporins, cefonicid and ceftizoxime, and compared to those of penicillin G. Penicillin G was the most active inhibitory and bactericidal agent. Ceftizoxime was a significantly more active inhibitory and bactericidal agent than cefonicid (P less than 0.0005, P less than 0.025, respectively.
Combined activity of ketoconazole and 5-fluorocytosine on potentially pathogenic yeasts
Authors: Beggs W H , Sarosi G A
Published: June 2012

In vitro studies based on periodic viable count determinations indicated that the two antifungal drugs ketoconazole and 5-fluorocytosine generally were at least additive in their combined effect on various opportunistic yeast pathogens, including some resistant to 5-fluorocytosine.
Effect of rifampin, levamisole, and cytoplasmic protein antigen from Mycobacterium microti on 5'-nucleotidase production by guinea pig macrophages
Authors: Bautista A P
Published: June 2012

A decline in 5'-nucleotidase production was observed in short-term tissue culture of guinea pig alveolar, peritoneal, splenic, and liver macrophages during exposure to 10(2) microM rifampicin, 1 microM levamisole, or 10 micrograms of cytoplasmic protein antigen extracted from Mycobacterium microti. Liver macrophage 5'-nucleotidase production was more significantly inhibited by the three agents. Cytoplasmic protein antigen from M. microti was the most potent inhibitor of 5'-nucleotidase production.
Effect of systemic antimicrobial prophylaxis on microbial flora
Authors: Bodey G P , Rosenbaum B , Valdivieso M , Bolivar R
Published: June 2012

Fifteen patients undergoing intensive chemotherapy for oat cell carcinoma of the lung in a protected environmental unit received antimicrobial prophylaxis with oral trimethoprim-sulfamethoxazole and short courses of parenteral ticarcillin, tobramycin, and miconazole. Altogether, 58 (65%) of 89 strains of aerobic bacteria and 28 (60%) of 47 strains of anaerobic bacteria present before prophylaxis were no longer cultured from stool specimens during prophylaxis. Ten strains of bacteria and four fungi were acquired in the stools during prophylaxis. Most fungi persisted in the throat and stools during prophylaxis. Bacterial infections occurred infrequently, but three patients developed Candida esophagitis. The regimen was well tolerated with minimal side effects.
Pharmacokinetics and tolerance of acyclovir, a new anti-herpesvirus agent, in humans
Authors: Laskin O L , Longstreth J A , Saral R , de Miranda P , Keeney R , Lietman P S
Published: June 2012

The pharmacokinetics and tolerance of acyclovir administered intravenously in single doses of 2.5, 5.0, 10.0, and 15.0 mg/kg were studied in 13 volunteers. The mean concentrations (+/- standard deviations) at the end of infusion as measured by radioimmunoassay were 4.52 +/0 0.31, 8.28 +/- 2.61, 14.6 +/- 2.30, and 22.7 +/- 10.4 microgram/ml, respectively. Drug elimination during and after the infusion of acyclovir was well described by a two-compartment open model. The mean terminal plasma half-life for each of the groups was 2.85, 2.80, 3.30, and 2.38 h, respectively. Within 72 h after the start of the infusion, 70% of the administered drug was recovered in the urine as unchanged acyclovir. The renal clearance of acyclovir accounted for about 77% of the total clearance and was about threefold greater than the creatinine clearance. This confirms that acyclovir is eliminated predominantly by the kidneys in patients with normal renal function and suggests that renal secretion and glomerular filtration may both be involved. The only adverse effect found by clinical and laboratory monitoring was irritation at he intravenous site after extravasation (in two cases), which resolved without significant sequelae.
Assay of netilmicin, using enzyme immunoassay for gentamicin
Authors: Larson T , Gerding D N , Peterson L R , Eckfeldt J H
Published: June 2012

A homogenous enzyme immunoassay for the quantitative determination of netilmicin in serum was developed. The procedure utilizes a commercially available assay for gentamicin (EMIT; Syva Co., Palo Alto, Calif.). The method was adapted to a microcentrifugal analyzer, and log-logit regression analysis was performed with a computer. The results of samples assayed by this method correlate well with microbioassay (r2 = 0.985) and radioimmunoassay (r2 = 0.986). This method is not only precise and accurate, but also very rapid and economical and compares favorably to other available methods of netilmicin assay.
In vitro activity of N-formimidoyl thienamycin against 98 clinical isolates of Brucella melitensis compared with those of cefoxitin, rifampin, tetracycline, and co-trimoxazole
Authors: Gutiérrez Altés A , Díez Enciso M , Peña García P , Campos Bueno A
Published: June 2012

IN vitro susceptibilities of 98 isolates of Brucella melitensis to N-formimidoyl thienamycin, tetracycline, co-trimoxazole, rifampin, and cefoxitin were determined. N-Formimidoyl thienamycin showed good activity which was similar to those of tetracycline and rifampin and different from that of the other beta-lactam antibiotic tested (cefoxitin), which showed poor activity. Co-trimoxazole showed good activity.
Comparison of the in vitro activities of teichomycin A2 and vancomycin against staphylococci and enterococci
Authors: Cynamon M H , Granato P A
Published: June 2012

The in vitro activity of teichomycin A2 was compared with that of vancomycin by standardized agar dilution testing against clinical isolates of staphylococci and enterococci. Both antibiotics had similar activities against staphylococci. However, teichomycin A2 was significantly more active against enterococci.
Agar disk diffusion for the quality control testing of Autobac elution disks
Authors: Gaydos J M , Harrington B J
Published: June 2012

The standard disk diffusion method of Bauer et al. (Am. J. Clin. Pathol. 45:493-496, 1966; National Committee for Clinical Laboratory Standards, Performance standards for antimicrobial disc susceptibility tests, approved standard ASM-2, 2nd ed., 1979) was used to monitor the potency of 16 Autobac antibiotic elution disks over an 8-month period. Results obtained by using the three recommended Autobac control strains showed excellent reproducibility. Zones sizes were all within a 5-mm range, and standard deviations ranged from 0.6 to 1.3 mm.
High-level potentiation of lysostaphin anti-staphylococcal activity by lysozyme
Authors: Cisani G , Varaldo P E , Grazi G , Soro O
Published: June 2012

The purpose of this study was to determine whether lysostaphin would enhance its anti-staphylococcal efficacy in combination with lysozyme. Minimum inhibitory concentrations (MICs) of lysostaphin and lysozyme were separately determined for 41 strains belonging to 10 different species of human staphylococci. Lysozyme was virtually inactive and showed MICs of 15 mg/ml. On the contrary, all strains were susceptible to lysostaphin and showed MICs ranging from 2.5 to 60 micrograms/ml for the different Staphylococcus species. When the MIC of lysostaphin was determined in media containing submultiples of the MIC of lysozyme, the values obtained were much lower. The reduction of the lysostaphin MIC ranged from 16- to 200-fold in the different species tested. In Staphylococcus aureus, in particular, the combination of lysostaphin with 1.5 mg of lysozyme per ml reduced the MIC of lysostaphin by 25-fold. The activities of two combinations of the two enzymes were evaluated: one combination was expected to be active on S. aureus only, and the other combination was expected to inhibit all Staphylococcus strains. The first combination (0.5 micrograms of lysostaphin plus 0.5 mg of lysozyme per ml) was inhibitory to all of the 84 S. aureus strains tested, whereas 137 of 151 strains of other Staphylococcus species were unaffected. On the contrary, all of the 235 Staphylococcus strains tested were inhibited by the second combination (4 micrograms of lysostaphin plus 5 mg of lysozyme per ml). The possible mechanisms of lysostaphin potentiation by lysozyme are considered, and the potential use of a lysostaphin-lysozyme combination for topical therapy of staphylococcal infections resistant to other antibiotics is discussed.
Clinical experience with Moxalactam in the treatment of pseudomonal and nonpseudomonal infections
Authors: Murphy T F , Barza M
Published: June 2012

A total of 38 patients with 39 infections involving a variety of organ systems were treated with moxalactam. The overall cure rate was 79.5%. Most of the failures occurred in patients with severe underlying disease such as peripheral vascular disease. The cure rate for infections with Pseudomonas aeruginosa was 62.5% (10 of 16) and for nonpseudomonal infections was 91% (21 of 23). However, excluding the six infections involving organisms which were initially resistant to moxalactam, the cure rate for pseudomonal infections was 77% (10 of 13) compared with 90% (18 of 20) for nonpseudomonal infections. Two patients with gram-negative bacillary meningitis were cured, as were seven of eight with mixed aerobic-anaerobic infections. There were no serious adverse drug effects. Three patients became colonized with the enterococcus and two became colonized with Candida albicans; one other patient developed candida vaginitis. These results suggest that moxalactam will be a valuable drug in therapy of gram-negative bacillary and anaerobic infections.
Modulation of bleomycin cytotoxicity
Authors: Moore C W
Published: June 2012

Lethal effects of a 75-microgram/ml concentration (approximately 5 X 10-5 M) of bleomycin on stationary-phase haploid or diploid cells of the eucaryote Saccharomyces cerevisiae were negated in the presence of 0.05 M phosphate buffer (pH 7). High cell densities (2 X 10(8) cells per ml) further inhibited killing. Multiphasic survival curves resulting after treatments in deionized water (pH 6.7) suggested the presence of cells with differing susceptibilities either at the start of treatment periods or as a result of resistance which developed during exposure to antibiotic. To identify a delayed effect, prolonged lethal consequences of the action of bleomycin were investigated under liquid-holding conditions. Survival of untreated early-stationary-phase yeast cells was not significantly affected by incubation without antibiotic for 6 or 36 h in non-nutrient buffer or water. However, increased killing resulted after bleomycin-treated cells were incubated in the absence of bleomycin or buffer. Moreover, cells which had never been exposed to the antibiotic lost considerable colony-forming ability as a result of incubation with bleomycin-treated cells, indicating the efflux of bleomycin or a reaction product. The findings have implications for both experimental cell studies and cancer therapy, as well as for the chemical mechanisms by which a metal bleomycin complex could cause killing.
Comparative penetration of metronidazole, clindamycin, chloramphenicol, cefoxitin, ticarcillin, and moxalactam into bone
Authors: Summersgill J T , Schupp L G , Raff M J
Published: June 2012

The concentrations of metronidazole, clindamycin, chloramphenicol, cefoxitin, ticarcillin, and moxalactam in the serum, femurs, and scapulae of normal rats were measured microbiologically 0.5, 1, 1, and 4 h after intravenous injection of 15-, 15-, 20-, 40-, 75-, and 30-mg/kg doses of the respective drugs. By 0.5 h metronidazole reached levels of 3.0 micrograms/g in compact femoral bone and 2.7 micrograms/g in cancellous scapular bone. Clindamycin and chloramphenicol reached levels of 8.1 and 6.1 micrograms/g, respectively, at 0.5 h. Cefoxitin penetrated bone to a level of 2.6 micrograms/g, whereas ticarcillin and moxalactam failed to reach significant levels in bone after single intravenous doses.
Fosfomycin resistance plasmids do not affect fosfomycin transport into Escherichia coli
Authors: León J , García-Lobo J M , Ortiz J M
Published: June 2012

Escherichia coli cells carrying fosfomycin resistance plasmids were able to take up fosfomycin from the medium to the same extent as plasmid-free bacteria. The antibiotic entered the plasmid-harboring cells by means of the glpT and uhp transport systems, as is the case with susceptible bacteria. Active fosfomycin could be detected in soluble extracts of cells which had previously been incubated in the presence of the antibiotic. Furthermore, fosfomycin resistance plasmids did not confer on E. coli cells resistance to the novel antibiotic FR-31564, which is incorporated by the same transport systems as fosfomycin. We conclude that, in contrast to chromosomal resistance mutants, altered transport does not play a role in the plasmid-encoded fosfomycin resistance mechanism.
Potent cephalosporinase inhibitors: 7 beta-[2-(1, 3-dithiolan-2-ylidene) acetamido] cephalosporins and related compounds
Authors: Ohya S , Miyadera T , Yamazaki M
Published: June 2012

Cephalosporins possessing a 1, 3-dithiolane, 1, 3-dithiane, or 1, 3-dithietane ring on their 7 beta-substituents showed potent inhibitory activity against cephaloridine hydrolysis by cephalosporinases purified from proteus morganii, Proteus rettgeri, and Proteus inconstans, which were not inhibited by clavulanic acid, a well-known beta-lactamase inhibitor. The mode of inhibition was competitive. The dithiolane cephalosporins themselves were stable against hydrolysis by the beta-lactamases tested. A combination of a dithiolane cephalosporin and cephaloridine synergistically inhibited in vitro growth of strains of P. morganii, P. rettgeri, P. inconstans, Enterobacter aerogenes, Enterobacter cloacae, and Serratia marcescens.