bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug combinations for treatment of mice infected with acyclovir-resistant herpes simplex virus
Authors: Schinazi R F
Published: June 2012

The purpose of this study was to determine whether acyclovir resistance in mice infected with herpes simplex virus could be overcome by using high doses of acyclovir or vidarabine alone or by using a combination of the two drugs. The results indicate that the mice infected intracerebrally were refractory to acyclovir alone but responded to vidarabine or a combination of vidarabine and acyclovir. These observations have major implications for the clinical management of severe herpetic infections, particularly if attempts are to be made to devise means of circumventing drug resistance.
Different patterns of inhibition of avian myeloblastosis virus reverse transcriptase activity by 3'-azido-3'-deoxythymidine 5'-triphosphate and its threo isomer
Authors: Eriksson B , Vrang L , Bazin H , Chattopadhyaya J , Oberg B
Published: June 2012

The two isomers 3'-azido-3'-deoxythymidine 5'-triphosphate (erythro-AZT-TP) and 1-(3'-azido-2',3'-dideoxy-beta-D-xylofuranosyl)thymine 5'-triphosphate (threo-AZT-TP) were studied as inhibitors of the reverse transcriptase activity of avian myelobastosis virus. Kinetic analysis of the (rA)n X (dT)12-18 (a standard template primer complex of polyriboadenylate and oligodeoxythymidylate of indicated length)-directed reaction revealed that erythro-AZT-TP was a competitive inhibitor with respect to dTTP, whereas threo-AZT-TP was a noncompetitive inhibitor. The apparent Ki values, as calculated from Dixon plots, were 0.48 and 5.5 microM, respectively, compared with a Km value for dTTP of about 70 microM. These results indicate that erythro-AZT-TP had an approximately 150-times-higher affinity to the enzyme than dTTP had and that the avian myeloblastosis virus reverse transcriptase had different binding sites for the two isomers.
In vitro activity of zinc salts against human rhinoviruses
Authors: Geist F C , Bateman J A , Hayden F G
Published: June 2012

The antiviral activity of zinc salts against rhinovirus types 1A and 39 was assayed by yield reduction and inhibition of cytopathic effect in cell culture. The findings indicate that the zinc salts tested have low in vitro therapeutic indices and suggest that the possible beneficial effects of zinc lozenges in reducing cold symptoms may not be related to selective antirhinovirus activity.
Synergism of the combinations of imipenem plus ciprofloxacin and imipenem plus amikacin against Pseudomonas aeruginosa and other bacterial pathogens
Authors: Bustamante C I , Drusano G L , Wharton R C , Wade J C
Published: June 2012

The combinations of imipenem plus ciprofloxacin and imipenem plus amikacin were investigated for their activity against Pseudomonas aeruginosa and other bacterial pathogens. For imipenem-susceptible P. aeruginosa, synergy of imipenem plus ciprofloxacin and imipenem plus amikacin was observed against 36 and 45% of the strains, respectively. The incidence of synergy against imipenem-resistant isolates of P. aeruginosa was 10% for both combinations. Antagonism was not observed with either combination.
In vitro activity of BMY-28100, a new oral cephalosporin
Authors: Eliopoulos G M , Reiszner E , Wennersten C , Moellering R C
Published: June 2012

The activity of BMY-28100, a new orally administered cephalosporin, was compared with those of cephalexin and cefaclor. BMY-28100 was the most active drug against Staphylococcus aureus (MIC for 90% of strains tested [MIC90], 1.0 microgram/ml), streptococci (MIC90S, less than or equal to 0.125 microgram/ml), and Klebsiella pneumoniae (MIC90, 2 micrograms/ml). The drug was active against Haemophilus influenzae and gonococci but not against other organisms generally resistant to cephem antibiotics.
Effect of peritoneal dialysis fluid and pH on bactericidal activity of ciprofloxacin
Authors: McCormick E M , Echols R M
Published: June 2012

Ciprofloxacin is active in vitro against most bacteria that cause peritonitis associated with peritoneal dialysis. We compared the effects of pH (5.5 and 7.4) and medium (dialysis fluid) on the bactericidal activity of ciprofloxacin, tobramycin, vancomycin plus rifampin, and rifampin against Pseudomonas aeruginosa, Escherichia coli, and three strains of staphylococci. The bactericidal activity of ciprofloxacin was not significantly affected by pH or medium, in contrast to the activity of tobramycin, which was decreased by low pH.
Inducible macrolides-lincosamides-streptogramin B resistance in Bacteroides species
Authors: Reig M , Campello M G , Baquero F
Published: June 2012

The first evidence is presented for the presence of inducible macrolides-lincosamides-streptogramin B resistance in Bacteroides species. Different macrolides induced clindamycin resistance in Bacteroides vulgatus RYC18F6, an erythromycin-resistant and clindamycin-susceptible strain. A study of 144 Bacteroides isolates indicated that erythromycin resistance was linked to diminished clindamycin susceptibility.
Serum bactericidal rate as measure of antibiotic interactions
Authors: Briceland L L , Pasko M T , Mylotte J M
Published: June 2012

The serum bactericidal rate (SBR) assay was used to assess the antipseudomonal activity of gentamicin with or without piperacillin. Heat-inactivated donor serum was spiked with gentamicin, piperacillin, or a combination at concentrations representative of levels in serum and tested against five P. aeruginosa strains isolated from blood. The SBR assay was performed as follows: colony counts in test samples (control, gentamicin, piperacillin, and combination) were determined at 0, 2, 4, 6, and 8 h after inoculation of a test strain. Log10 CFU per milliliter was plotted versus time, and linear regression analysis was performed; the slope of the regression line was defined as the SBR. The SBRs of agents alone and in combination were compared statistically. The SBR of gentamicin was dependent on the serum concentration. The combination of gentamicin and piperacillin always resulted in a higher SBR than did either drug alone. However, this difference was not statistically significant for highly gentamicin-susceptible strains (MIC, less than or equal to 2 micrograms/ml) until the gentamicin concentration was reduced below the MIC. For a gentamicin-resistant strain (MIC, 8 micrograms/ml), the combination of gentamicin and piperacillin produced mean SBRs similar to that found with gentamicin-susceptible strains. These results provide evidence that the SBR assay may be a useful method of evaluating antibiotic interactions, since it can be done by using serum and since it compares the antibacterial activity of drugs statistically rather than requiring arbitrary criteria to define interactions.
Use of recombinant bovine alpha 1 interferon in reducing respiratory disease induced by bovine herpesvirus type 1
Authors: Babiuk L A , Lawman M J , Gifford G A
Published: June 2012

Intranasal or intramuscular treatment of calves with recombinant bovine alpha 1 interferon before challenge with bovine herpesvirus type 1 and Pasteurella haemolytica reduced clinical signs, number of sick days, lung lesions, and weight loss. The effective dose was determined to be relatively broad within the range of 1 to 50 mg per animal. No adverse effects were observed even at high doses of interferon (50 mg per animal). Administration before virus infection was more effective than administration at the same time as virus infection. Although interferon administration had dramatic effects on the survival of animals, it did not have much effect on virus secretion in the upper respiratory tract. Therefore, the mechanism by which interferon reduces the susceptibility of animals to viral-bacterial synergy was postulated to be via its immunomodulatory effects.
Influence of antibiotics on formylmethionyl-leucyl-phenylalanine-induced leukocyte chemiluminescence
Authors: Briheim G , Dahlgren C
Published: June 2012

The effect of three antimicrobial agents, penicillin G, ampicillin, and chloramphenicol, on luminol-enhanced chemiluminescence of polymorphonuclear leukocytes stimulated by the chemoattractant formylmethionyl-leucyl-phenylalanine was studied. An inhibitory effect of penicillin G and of ampicillin was demonstrated, whereas chloramphenicol gave rise to an enhancement of the chemiluminescence response from polymorphonuclear leukocytes. These effects could be due to interaction between the drugs and the polymorphonuclear leukocytes, but they could also be the result of interference with the generation of light without any effect on the cells. Therefore, the effects of the same antimicrobial agents on the chemiluminescence generated from a cell-free system consisting of myeloperoxidase and hydrogen peroxide were investigated in parallel. The results obtained in the cell-free system were almost identical to those obtained in the cell system; i.e., penicillin G and ampicillin caused an inhibition and chloramphenicol caused an enhancement of the light emission. These results indicate that observed effects induced by drugs in a chemiluminescence assay are not necessarily due to interaction between the drug and polymorphonuclear leukocytes but may be caused by interference with other components of the assay. In view of these findings, the conflicting data reported in the literature on the effects of antimicrobial agents on phagocyte function are discussed.
Prooxidative activities of 10 phenazine derivatives relative to that of clofazimine
Authors: Zeis B M , Anderson R , O'Sullivan J F
Published: June 2012

The objective of this study was to investigate the relationship between the antimycobacterial properties of the antileprosy drug clofazimine and its stimulatory effect on the release of reactive oxidants by polymorphonuclear leukocytes by using a variety of phenazine derivatives. The effects of these compounds on myeloperoxidase-mediated iodination, luminol-enhanced chemiluminescence, and the release of superoxide anion by polymorphonuclear leukocytes were investigated. Dissociation of the antimycobacterial and prooxidative effects of clofazimine was possible by manipulation of the chemical group in position 2 of the phenazine molecule. When nitrogen-containing substituents in this position were replaced by oxygen, the mode of the prooxidative action of the compounds was altered.
Pharmacokinetics of intravenously administered ciprofloxacin in patients with various degrees of renal function
Authors: Drusano G L , Weir M , Forrest A , Plaisance K , Emm T , Standiford H C
Published: June 2012

We examined the pharmacokinetic behavior of 200 mg of ciprofloxacin administered intravenously to 32 volunteers whose renal function as measured by creatinine clearance ranged from 0 to 8.99 liters/h per 1.73 m2. Serum clearances (mean +/- standard deviation) were 26.8 +/- 5.7 and 15.4 +/- 4.3 liters/h per 1.73 m2 in normal and anephric volunteers, respectively. The half-life (mean +/- standard deviation) increased from 4.3 +/- 0.8 h in normal volunteers to 8.6 +/- 3.3 h in anephric volunteers. There was good correlation between normalized creatinine clearance and both normalized serum and renal clearance. The regression equation for serum clearance (CLS) versus creatinine clearance (CLCR) was CLS = 1.97 X CLCR + 13.23, where r = 0.697; for renal clearance versus creatinine clearance, the equation was CLR = 2.26 X CLCR, where r = 0.845. On the basis of these data, we recommend a maximum 50% reduction in dose when ciprofloxacin is instituted at a renal function of 1.2 to 1.8 liters/h per 1.73 m2 (20 to 30 ml/min per 1.73 m2). Because of the observed variation in ciprofloxacin half-life in our anephric volunteers, we also recommend that a schedule of administration every 12 h be maintained, even for patients without urine output.
Paradoxical antibacterial activity of cefmenoxime against Proteus vulgaris
Authors: Ikeda Y , Nishino T , Tanino T
Published: June 2012

The growth-inhibitory effect of cefmenoxime against Proteus vulgaris was studied by using the broth dilution and paper disk diffusion methods. Cefmenoxime showed growth-inhibitory activity against Proteus vulgaris at low concentrations but not at high concentrations up to a certain limit. This paradoxical antibacterial activity was not observed with cefoperazone and cefbuperazone. The induction of beta-lactamase by cefmenoxime and the rate of hydrolysis of cefmenoxime in the culture broth were proportional to the initial concentration of this antibiotic. At high initial concentrations, cefmenoxime was rapidly inactivated. On the other hand, neither cefoperazone nor cefbuperazone was inactivated irrespective of concentration. We conclude that cefmenoxime induces beta-lactamase in P. vulgaris, perhaps accounting for its paradoxical antibacterial effect.
Ampicillin versus cefamandole as initial therapy for community-acquired pneumonia
Authors: Weber D J , Calderwood S B , Karchmer A W , Pennington J E
Published: June 2012

One hundred seven patients with community-acquired pneumonia thought to be of bacterial etiology by the admitting physician but whose initial sputum Gram stain was inadequate to direct specific therapy were randomized to receive either intravenous ampicillin or cefamandole as empiric therapy. Patients were excluded if the initial sputum Gram stain was highly suggestive of infection with Streptococcus pneumoniae, Staphylococcus aureus, or an enteric gram-negative bacillus. The two study groups had comparable demographic and presenting clinical features. The mean age of the patients evaluable for determination of clinical efficacy was 69 years, and greater than 75% had at least one serious underlying medical disorder. In the 90 evaluable patients, there were 11 therapeutic failures (12%), including 5 deaths (5%). Cefamandole, a broad-spectrum antibiotic, was not more efficacious than ampicillin in producing a satisfactory clinical response or in shortening the duration of parenteral therapy. Patients received an average of only 4 days of intravenous antibiotics before changeover to oral therapy and were hospitalized for a mean of 7 days. No patient experienced a relapse of pneumonia following successful completion of parenteral drug therapy. We conclude that cefamandole is not a more effective agent than ampicillin for empiric therapy of community-acquired bacterial pneumonia of uncertain etiology.
Methylation of demethylavermectins
Authors: Schulman M D , Ruby C
Published: June 2012

Demethylavermectins, which lack methyl groups on the oleandrose moiety, were fed to wild-type "Streptomyces avermitilis," which produces the normal avermectin components, and the bioconversion products were identified. The oleandrose units of the demethylavermectins were not methylated by the wild-type strain, but the C-5 of the macrolide ring was methylated. This demonstrates that methylation of the oleandrose units is not a terminal step in avermectin biosynthesis and that it occurs before attachment of the sugars to the macrolide ring. Avermectin biosynthesis thus differs from that of tylosin and erythromycin, in which methylation of the hexose moieties is a terminal reaction.
Isolation and molecular characterization of beta-lactamase-producing Haemophilus parainfluenzae from the genital tract
Authors: Martel A Y , Gosselin P , Ouellette M , Roy P H , Bergeron M G
Published: June 2012

Three Haemophilus parainfluenzae strains isolated from the urogenital tract harbored a beta-lactamase-coding 3.2-megadalton plasmid identical, by restriction endonuclease digestion and hybridization with radioactive and biotin-labeled probes specific for the TEM-1 beta-lactamase and TnA sequences, to the 3.2-megadalton "African-type" plasmid found in Neisseria gonorrhoeae.
Bactericidal activity and killing rate of serum in volunteers receiving teicoplanin alone or in combination with oral or intravenous rifampin
Authors: Van der Auwera P , Klastersky J
Published: June 2012

A total of 10 volunteers, in two groups of 5 each, received the following on separate days: group 1,200 mg of teicoplanin intravenously (i.v.), 600 mg of rifampin orally, or teicoplanin-rifampin; group 2,400 mg of teicoplanin i.v., 300 mg of rifampin i.v. in 60 min, or teicoplanin-rifampin. Blood samples were obtained before, at the end, and at 1 and 6 h after the administration of the antibiotics. Bactericidal activity in serum (SBA) was measured in microtiter plates against 20 clinical isolates (five strains each) of oxacillin-susceptible and-resistant Staphylococcus aureus and Staphylococcus epidermidis. The endpoint of the SBA corresponded to 99.9% killing. Killing rates were measured in serum obtained at 1 and 6 h. The concentrations of each antibiotic were measured by bioassay. The antibiotic concentrations in serum obtained at the peak and at 1 and 6 h after the end of administration were as follows: group 1, teicoplanin, 26, 15.6, and 8.4 mg/liter; rifampin, not determined, 8.3, and 3.8 mg/liter; group 2, teicoplanin, 66, 29.4, and 11.5 mg/liter; rifampin, 14.8, 3.8, and 1.2 mg/liter. Higher median SBAs were obtained after treatment with rifampin than after that with teicoplanin. No interaction was observed between rifampin and teicoplanin. This was confirmed by determination of the killing rate in serum. Teicoplanin killed more slowly than rifampin. The combination had the same killing rate as rifampin alone. Rifampin neither improved nor antagonized the bactericidal activity of teicoplanin, as determined by the SBAs or the rate of killing.
Inhibition of peptidoglycan biosynthesis in gram-positive bacteria by LY146032
Authors: Allen N E , Hobbs J N , Alborn W E
Published: June 2012

LY146032, a cyclic lipopeptide antibiotic, is an inhibitor of cell wall peptidoglycan biosynthesis in gram-positive bacteria. Although LY146032 at relatively high concentrations inhibited the in vitro polymerization of UDP-linked sugar precursors, inhibition of cell wall formation in intact Staphylococcus aureus and Bacillus megaterium cells did not lead to the accumulation of UDP-N-acetyl-muramyl (MurNAc)-peptide(s). Experiments that measured formation of UDP-MurNAc-peptides revealed that LY146032 inhibited the formation of these nucleotide-linked intermediates. This antibiotic had a disruptive effect on membrane permeability as evidenced by the loss of intracellular potassium immediately after exposure to the drug. The lack of any major disruption of the phosphoenolpyruvate:sugar phosphotransferase system indicated that the membrane is not likely a lethal target for this antibiotic. The findings are consistent with a mechanism by which LY146032 inhibits the formation of precursor molecules utilized in peptidoglycan biosynthesis. The observed membrane effects likely result from transit of the inhibitor to its lethal target site.
In vitro and in vivo antibacterial activities of T-2588, a new oral cephalosporin, compared with those of other oral beta-lactam antibiotics
Authors: Okamoto S , Hamana Y , Inoue M , Mitsuhashi S
Published: June 2012

T-2588, the pivaloyloxymethyl ester of T-2525, [6R, 7R]-7-[(z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoamido] -3- [(5-methyl-2H-tetrazol-2-yl)methyl]-3-cephem-4-carboxylic acid, is a new oral cephalosporin. T-2525 had a widely expanded antibacterial spectrum against gram-negative and gram-positive bacteria. T-2525 was more active in vitro than cefaclor, cephalexin, and amoxicillin against members of the family Enterobacteriaceae and Branhamella catarrhalis. Moreover, it exhibited superior in vitro activity against Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae. T-2525 was highly stable to various beta-lactamases, which were classified as Richmond and Sykes types Ia, Ib, Ic, III, IV, and Vc. It had high affinities for the lethal (essential) penicillin-binding proteins of Escherichia coli, Clostridium perfringens, and Bacteroides fragilis. T-2588 had excellent therapeutic effect on systemic infections in mice with various species of gram-negative bacteria, including beta-lactamase-producing bacteria.
Clinical isolate of herpes simplex virus type 2 that induces a thymidine kinase with altered substrate specificity
Authors: Ellis M N , Keller P M , Fyfe J A , Martin J L , Rooney J F , Straus S E , Lehrman S N , Barry D W
Published: June 2012

In vitro and in vivo studies were done on a herpes simplex virus type 2 strain recovered from a patient on acyclovir (ACV) which was ACV resistant but expressed thymidine (dThd) kinase (EC 2.7.1.21) activity. Plaque-purified clones derived from the original clinical sample were heterogeneous with respect to plaque size and drug susceptibility. The heterogeneity of this viral mixture was also evident from varied 125I-labeled 5-iodo-2'-deoxycytidine autoradiographic patterns and from varied expression of dThd kinase-associated phosphorylating activities. Four clones from this mixture were 1-beta-D-arabinofuranosylthymine (ara-T) susceptible and ACV resistant. Extracts of cells infected with these clones catalyzed the phosphorylation of ara-T but little of ACV. The virus-coded dThd kinase was purified from one of these clones to determine whether its substrate specificity was altered. The amount of virus-coded dThd phosphorylating activity with the cell extracts was estimated to be sevenfold lower with the resistant clone than with the MS strain of herpes simplex virus type 2. The dThd kinase eluted from a dThd-agarose affinity column under the same conditions with extracts from both sources and substrate saturations of both enzymes by acyclic nucleoside analog phosphate acceptors were classical hyperbolic functions. However, there were significant differences in the kinetic parameters of substrates between the two enzymes. Apparent Km (Km') values for dThd, deoxycytidine, ara-T, ACV, and the acyclic guanosine analog 9-[[2-hydroxyl-1-(hydroxymethyl)ethoxy]methyl]guaine (BW B759U) were 2- to 60-fold higher with the variant enzyme than with the enzyme from laboratory strain MS. Comparing these two enzymes, relative maximal phosphorylation rates (Vm) were eightfold lower for ACV but unchanged for BW B759U. In contrast, the relative rates for deoxycytidine and ara-T were eight- and twofold higher, respectively. The surprisingly good substrate activity with BW B759U compared with that of ACV (Vm/Km' = 0.39 versus 0.01) coincided with susceptibility of the ACV-resistant virus to BW B759U. This clinical variant retained its pathogenicity for mice and was only moderately less neurovirulent than wild-type virus. Although such mutants have the potential to induce illness less responsive to therapy, the recurrence from which the isolate was obtained was typical for this patient in severity and duration. Since this episode, the patient has been treated successfully with ACV.
Effects of cefonicid and other cephalosporin antibiotics on male sexual development in rats
Authors: Manson J M , Zolna L E , Kang Y J , Johnson C M
Published: June 2012

The purpose of this study was to determine whether cefonicid, a cephalosporin antibiotic with a modified N-methylthiotetrazole (MTT) side chain, caused testicular toxicity when subcutaneously administered to Sprague-Dawley male rats from days 6 to 36 postpartum at doses of 50 to 1,000 mg/kg per day. Moxalactam (a cephamycin antibiotic which will be referred to as a cephalosporin for convenience throughout), which contains the MTT side chain, was used as a positive control and was administered at 100 to 1,000 mg/kg per day, and cephalothin, which lacks an MTT side chain, was used as the negative control at 1,000 mg/kg per day. Moxalactam caused a significant reduction in testicular and seminal vesicle weights in 37-day-old animals, and histological examination revealed bilateral multifocal atrophy of the seminiferous tubules at all dose levels. Animals reared to reproductive maturity had significant deficits in fertility, and histological examination revealed multifocal or diffuse atrophy of the seminiferous tubules at all doses with a severity greater than that observed in the 37-day-old animals. The histological findings were confirmed by marked reductions in testicular sperm production rates and cauda epididymal sperm numbers. Cephalothin and cefonicid had no treatment-related adverse effects on the sexual maturation of prepubertal, juvenile, or adult males. The absence (in cephalothin) or modification (in cefonicid) of the MTT side chain was not associated with adverse reproductive effects. The relevance of these findings to humans in prenatal and prepubertal stages of life cannot be determined at this time.
Recent analytical methods for cephalosporins in biological fluids
Authors: Toothaker R D , Wright D S , Pachla L A
Published: June 2012

Since 1980, RP chromatography has been the principal analytical technique used for cephalosporins. This technology offers selectivity, accuracy, and ease of use. Most of the methods rely on protein precipitation and, to a lesser extent, solid-phase isolation or extraction procedures. The proper selection of a method depends on the analytical constraints imposed by the overall objective of the study. For example, pharmacokinetic datum interpretation mandates that the method be validated and provide specific and accurate results. LC is the preferred technique, since it not only meets these specifications but may also distinguish between the drug and metabolites. Those chromatographic methods which quantify several different cephalosporins are not desirable for pharmacokinetic datum interpretation, since accuracy and precision are usually compromised in order that many different drugs may be quantified in a single analysis. The proper selection of sample preparation method is dependent on the presence of potential interferences and the acceptable lower limit of quantitation. Protein precipitation methods offer ease of sample preparation but may suffer from nonselectivity. Solid-phase isolation and extraction procedures may increase selectivity and improve the limit of quantitation. Although LC provides specific and accurate results, clinical laboratories may prefer to use the less specific methods for therapeutic drug monitoring. In this case, microbiological, enzymatic, and fluorimetric methods offer improved sample throughput but less specificity. However, these methods should not be used for drugs that may have a low margin of safety or if the patient is on multiple-antibiotic therapy. Future methods may involve incorporating solid-phase isolation columns to enhance the specificity of chromatographic, microbiological, enzymatic, and fluorescence methods. Advancements in microbore column technology may allow improvements in the selectivity and sensitivity of LC methods. Many investigators prefer to use simple protein precipitation procedures for sample preparation because of sample throughput constraints. However, advances in robotic sample preparation may allow the more cumbersome solid-phase isolation or extraction techniques to be used to improved sample throughput and specificity.
Disposition of moxalactam and N-methyltetrazolethiol in rats and monkeys
Authors: Mizojiri K , Norikura R , Takashima A , Tanaka H , Yoshimori T , Inazawa K , Yukawa T , Okabe H , Sugeno K
Published: June 2012

The disposition of moxalactam (MOX) and N-methyltetrazolethiol (NMTT) in rats and monkeys after intravenous injection was investigated, focusing on the in vivo liberation of NMTT, by using [NMTT-14C]MOX and [14C]NMTT. After [NMTT-14C]MOX injection, MOX levels in plasma quickly became high in both rats and monkeys and then declined, with half-lives at the beta phase of 18.8 and 67.1 min, respectively. The levels of NMTT liberated from MOX were much lower than those of MOX, but the apparent elimination was significantly slow. The levels of MOX and NMTT in rat liver were almost comparable but lower than those in plasma. With [14C]NMTT administration, the level of NMTT in plasma declined, with half-lives at the beta phase of 21.5 min in rats and 54.0 min in monkeys. After [NMTT-14C]MOX injection, most of the radioactivity was excreted in urine as MOX, with 11% of the dose in rats and 8% of the dose in monkeys eliminated as NMTT until 24 h. Total biliary excretion was 26% of the injected radioactivity in rats, and most of it was due to MOX. In one monkey, the total biliary excretion was only 0.2% of the injected radioactivity. With [14C]NMTT administration, most radioactivity was excreted in the urine as unchanged NMTT in both animals. Oral administration in rats showed that part of the biliary-excreted MOX was degraded to NMTT in the intestine and then absorbed. Repeated administration of [NMTT-14C]MOX to rats did not change the levels of MOX and NMTT in plasma or liver nor did it change the excretion profiles. Thus, accumulation of MOX and NMTT did not occur.
Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds
Authors: Farr B M , Conner E M , Betts R F , Oleske J , Minnefor A , Gwaltney J M
Published: June 2012

The therapeutic efficacy of zinc gluconate lozenge therapy in experimentally induced rhinovirus infection was assessed in two randomized controlled trials in susceptible adult volunteers. In trial 1, lozenges containing either zinc gluconate (23 mg of elemental zinc) or placebo were given 36 h after nasal inoculation of rhinovirus type 39 and administered eight times per day for 5 days. All of the volunteers had early cold symptoms at the time that treatment was begun. In trial 2, the same lozenge regimen was used, beginning 2 h after nasal inoculation with rhinovirus type 13, and continued for 7 days. Zinc therapy did not reduce the severity or duration of cold symptoms or the frequency or duration of viral shedding in either trial. Viral titers were measured in trial 2 and were shown to be unaffected by zinc therapy. Nasal mucus weights and the numbers of paper tissues used were slightly higher in zinc recipients. A statistically significant increase in levels of zinc in serum was documented in zinc recipients after 5 days of therapy. These data suggest that zinc gluconate lozenge therapy is not therapeutically useful in the treatment of rhinovirus colds.
Determination of teicoplanin concentrations in serum by high-pressure liquid chromatography
Authors: Joos B , Lüthy R
Published: June 2012

An isocratic reversed-phase high-pressure liquid chromatographic method for the determination of six components of the teicoplanin complex in biological fluid was developed. By using fluorescence detection after precolumn derivatization with fluorescamine, the assay is specific and highly sensitive, with reproducibility studies yielding coefficients of variation ranging from 1.5 to 8.5% (at 5 to 80 micrograms/ml). Response was linear from 2.5 to 80 micrograms/ml (r = 0.999); the recovery from spiked human serum was 76%. An external quality control was performed to compare this high-pressure liquid chromatographic method (H) with a standard microbiological assay (M); no significant deviation from slope = 1 and intercept = 0 was found by regression analysis (H = 1.03M - 0.45; n = 15).
Inhibitory effects of antiviral compounds on respiratory syncytial virus replication in vitro
Authors: Kawana F , Shigeta S , Hosoya M , Suzuki H , De Clercq E
Published: June 2012

We examined the inhibitory effect of 20 antiviral compounds, including ribavirin, on the replication of respiratory syncytial virus in HeLa and HEp-2 cell cultures. Of the compounds studied, pyrazofurin and 3-deazaguanine emerged as more potent inhibitors of respiratory syncytial virus than ribavirin. Based on their inhibitory effect on the cytopathogenicity of respiratory syncytial virus in HeLa cells, the average 50% effective dose of pyrazofurin and 3-deazaguanine for eight strains was 0.07 and 1.65 micrograms/ml, respectively; that of ribavirin was 5.82 micrograms/ml. The cytotoxicity of these compounds for HeLa cells was examined by monitoring the incorporation of radiolabeled uridine into cellular RNA. The selectivity indexes of pyrazofurin and 3-deazaguanine exceeded that of ribavirin by 70- and 11-fold, respectively. Pyrazofurin, 3-deazaguanine, and ribavirin inhibited both viral antigen expression and syncytium formation in HeLa cell cultures, as assessed by an indirect immunofluorescence assay. In these assays, pyrazofurin and 3-deazaguanine again proved more potent than ribavirin. 2,5-Diamidinoindole and carbodine were less potent than ribavirin. Various other compounds, i.e., 3-adenin-9-yl-2-hydroxypropanoic acid isobutyl ester, 3-deazauridine, 3'-C-methyluridine, 5'-deoxy-5-fluorouridine, 5-cyanoimidazole-4-carboxamide, and its ribofuranosyl derivative, did not inhibit the cytopathic effect of the Long strain of respiratory syncytial virus at concentrations greater than or equal to 125 micrograms/ml. Tubercidin, 5-chlorotubercidin, xylotubercidin, neplanocin A, thiosemicarbazone R, and 3-methylquercetine were too toxic to HeLa cells for their inhibitory effects on respiratory syncytial virus to be examined.
Entry of five antifungal agents into the ovine lung
Authors: Hoeprich P D , Merry J M , Gunther R , Franti C E
Published: June 2012

The passage of antifungal agents into pulmonary parenchyma was studied in normal sheep prepared by cannulation of the right external jugular vein and the efferent duct of the right caudal mediastinal lymph node. Five sheep were given single, sequential, intravenous injections of flucytosine, ketoconazole, BAY n 7133, amphotericin B methyl ester, and amphotericin B. Venous blood plasma and pulmonary lymph were collected before infusion and from 5 min to 24 h postinfusion; the concentrations of the drugs were assayed by a well-agar diffusion method. All drugs appeared promptly in the pulmonary lymph and disappeared at approximately exponential rates from both liquids. The lymph/plasma ratios of the drug concentrations did not differ between flucytosine and the two azoles but were lower for both polyenes. Binding by plasma proteins did not appear to be a determinant of pulmonary entry.
Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults
Authors: Douglas R M , Miles H B , Moore B W , Ryan P , Pinnock C B
Published: June 2012

Effervescent lozenges containing 10 mg of zinc acetate were evaluated as a treatment of upper respiratory tract infections in a double-blind randomized trial by using a placebo which was indistinguishable to most observers in taste and appearance from the active material. Of the 70 treatment courses used by 55 individuals in 34 families, 63 (33 zinc and 30 placebo) were considered evaluable, in that the volunteer used the medication at least four times daily for at least 3 days, the average utilization being 5.4 days at an average dose of six lozenges daily. Six users of zinc reported nausea (versus no placebo users), and eight reported an unpleasant taste or aftertaste (versus one placebo user). No benefit was observed among the users of zinc acetate. The mean duration of symptoms in users of the zinc was 12.1 days, compared with 7.7 days in those who used the placebo. Nor was any beneficial effect of zinc evident among the four zinc-treated versus the two placebo-treated individuals from whom rhinovirus was grown.
Improved sensitivity in assays for binding of novel beta-lactam antibiotics to penicillin-binding proteins of Escherichia coli
Authors: Bush K , Smith S A , Ohringer S , Tanaka S K , Bonner D P
Published: June 2012

Tigemonam and temocillin, but not aztreonam, bound to penicillin-binding proteins (PBPs) 1a and 3 of Escherichia coli with apparent improved affinity when challenged with benzylpenicillin at lowered temperatures. Half times for deacylation of the tigemonam-PBP complexes were shorter than were those of the corresponding aztreonam-PBP complexes. The implications of the routine testing of PBP affinities are discussed.
Pharmacokinetics and bacteriological efficacy of ticarcillin-clavulanic acid (timentin) in experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis
Authors: Syrogiannopoulos G A , Al-Sabbagh A , Olsen K D , McCracken G H
Published: June 2012

The pharmacokinetics and bacteriological efficacy of ticarcillin and clavulanic acid administered individually or in combination were assessed in rabbits with experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis. The mean penetrations into the cerebrospinal fluid (CSF) of infected animals after a single dose of ticarcillin-clavulanic acid were approximately 11 and 28% for ticarcillin and clavulanic acid, respectively. In continuous-infusion experiments, the mean penetrations into CSF were 14.6 and 35% for ticarcillin and clavulanic acid, respectively, in rabbits with E. coli meningitis and 6.1 and 24%, respectively, in rabbits with H. influenzae meningitis. In animals that received a continuous infusion of the two drugs alone or in combination, the median CSF bactericidal titers for E. coli were less than 1:2, less than 1:2, and 1:2 for ticarcillin, clavulanic acid, and ticarcillin-clavulanic acid, respectively, and for H. influenzae the titers were less than 1:2, less than 1:2, and 1:4, respectively. The addition of clavulanic acid potentiated significantly the bacteriological efficacy of ticarcillin in reducing the number of bacteria in CSF of infected rabbits. Additional studies in animals and humans are required before recommendations can be made regarding the use of ticarcillin-clavulanic acid for treatment of meningitis.
Synergism between 9-deazainosine and DL-alpha-difluoromethylornithine in treatment of experimental African trypanosomiasis
Authors: Bacchi C J , Berens R L , Nathan H C , Klein R S , Elegbe I A , Rao K V , McCann P P , Marr J J
Published: June 2012

Kinetoplastid hemoflagellates are sensitive to growth inhibition by various purine analogs. In this study the activities of 9-deazainosine (9-DINO), formycin B, and sinefungin were compared in experimental murine Trypanosoma brucei subsp. brucei infections, both singly and in combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO, eflornithine). Used singly, all of the purine analogs were able to suppress an acute T. brucei subsp. brucei infection. 9-DINO and formycin B were the most active. None of the purine analogs was curative when used singly against a strain causing chronic central nervous system infection. 9-DINO was highly effective when used in combination with DFMO in curing this central nervous system infection and another more stringent experimental infection. Neither sinefungin nor formycin B was active in combination with DFMO in curing the central nervous system experimental infection. 9-DINO was metabolized to phosphorylated derivatives of 9-deazaadenosine and 9-deazaguanosine by bloodstream trypomastigotes, but not by murine erythrocyte suspensions or kidney or liver homogenates--a potential rationale for the selectivity of the analog. These studies indicate that 9-DINO is a potent, nontoxic purine analog which, in combination with DFMO, is capable of late-stage cures of African trypanosomiasis.
Effects of polymyxin B nonapeptide on Aeromonas salmonicida
Authors: McCashion R N , Lynch W H
Published: June 2012

In contrast to polymyxin B-susceptible gram-negative bacteria of human origin, the fish pathogen Aeromonas salmonicida was resistant to sensitization by polymyxin B nonapeptide (PMBN) to hydrophobic antibiotics. Similarly, sensitization of A. salmonicida strains by PMBN to the bactericidal action of brook trout (Salvelinus fontinalis) serum complement was less pronounced than the similar effect of PMBN against other gram-negative bacteria in certain mammalian sera. The surface array protein (A layer), overlying the outer membrane of virulent A. salmonicida strains, did not appear to cause resistance to PMBN sensitization since an A-layer-deficient mutant showed similar responses to PMBN as its parent strain. Electron micrographs of PMBN-treated A. salmonicida cells revealed very little visible outer membrane disruption when compared with the extensive blebbing on the outer membrane surface caused by PMBN in certain enteric bacteria, including Escherichia coli K-37. However, small extracellular vesiclelike components, which may have been derived from the outer membrane, were numerous around PMBN-treated A. salmonicida cells. In this connection, PMBN caused disruption of the A layer in the form of bulges, breaks, and detached fragments which appeared to be associated with the accumulation of these vesicles underneath the A layer of wild-type A. salmonicida strains.
Comparative trial of cefuroxime axetil in recurrent urinary tract infections illustrating importance of 6-week follow-up
Authors: Brumfitt W , Hamilton-Miller J M , Smith G W
Published: June 2012

Women with recurrent urinary tract infections treated with cefuroxime axetil (500 or 250 mg twice daily) for 7 days had a higher relapse rate when tested 6 weeks after the start of treatment than those given amoxycillin (250 mg three times daily). The poor performance of cefuroxime axetil is explained by variable bioavailability.
Antimycobacterial activities in vitro and in vivo and pharmacokinetics of dihydromycoplanecin A
Authors: Haneishi T , Nakajima M , Shiraishi A , Katayama T , Torikata A , Kawahara Y , Kurihara K , Arai M , Arai T , Aoyagi T
Published: June 2012

The in vitro activity of dihydromycoplanecin A (DHMP A), a new cyclic peptide antibiotic, was compared with those of antimycobacterial drugs such as streptomycin, isoniazid (INH), rifampin, and ofloxacin against several clinically isolated species of mycobacteria, including Mycobacterium tuberculosis, M. intracellulare, and M. kansasii. DHMP A demonstrated stronger activities than other drugs against all species of mycobacteria tested at concentrations of less than 0.0125 to 25 microgram/ml. A marked synergism between DHMP A and INH was demonstrated by the checkerboard technique against M. tuberculosis, M. intracellulare, and M. smegmatis, and the synergistic effect was observed by treatment of the culture of M. smegmatis with DHMP A for at least 3 h prior to treatment with INH. It was also shown that both absorption and excretion of INH in mice were faster than those of DHMP A. On the basis of these results, combination therapy with DHMP A and INH was successfully carried out in experimental tuberculosis in mice infected with M. bovis Ravenel. After a single intravenous administration of 10 mg of DHMP A per kg, its half-life in serum in mice was about 0.5 h and in dogs it was 5.5 h. A single oral administration to dogs of 12.5 mg/kg gave a peak of 5.0 micrograms/ml at 3 h. In these experiments, urinary recoveries within 48 h were 21.0% in mice and 25.2% in dogs. The tissue distribution level of DHMP A in mice after oral administration was in the order of liver greater than kidney greater than serum greater than spleen = lung. The 50% lethal doses of DHMP A for mice were more than 6,000 mg/kg orally and 1,840 mg/kg intraperitoneally.
Pharmacokinetics of ribavirin aerosol in mice
Authors: Gilbert B E , Wyde P R
Published: June 2012

The pharmacokinetics of ribavirin administered in single or multiple treatments to mice by small-particle aerosol were monitored in lung, serum, and brain tissues. ribavirin aerosol was administered with a standard drug concentration (20 mg/ml) in the reservoir for 12 h or a high dose (60 mg/ml) for 2 or 4 h. After single or 3-day treatments, ribavirin rapidly accumulated in the lungs at concentrations sufficient to inhibit influenza virus or respiratory syncytial virus (1 to 5 mM). While peak levels of ribavirin in the lungs after the high-dose administration were about three times those found with the standard dose, ribavirin was rapidly cleared from the lungs. There was no accumulation of drug in the lungs after multiple treatments. Ribavirin cleared from the lungs was detected in the blood within 15 min. Concentrations in the serum were similar (20 to 30 microM) for standard- and high-dose treatments with either single or multiple treatments. Ribavirin clearance from the serum after treatment was similar for each regimen. Ribavirin also rapidly accumulated in the brain to a similar level (ca. 6 nmol per brain) after standard- or high-dose treatment for 3 days. In contrast to ribavirin in the serum, ribavirin in the brain appeared to be slowly cleared, allowing levels to remain relatively constant during and after treatment. With the interest in viral encephalopathies, further evaluation of the possible advantages of this method of drug administration is warranted.
Characterization and comparison of two penicillinase-producing strains of Streptococcus (Enterococcus) faecalis
Authors: Patterson J E , Masecar B L , Zervos M J
Published: June 2012

We identified two beta-lactamase-positive enterococci. One strain was high-level (MIC, greater than 2,000 microgram/ml) gentamicin resistant; the other was not (MIC, 12.5 microgram/ml). beta-Lactamase production was extrachromosomally mediated in both strains, and both strains showed an inoculum effect reversed by beta-lactamase inhibitors. The strain lacking high-level gentamicin resistance showed synergistic killing with a combination of penicillin, clavulanic acid, and gentamicin.
Antimicrobial susceptibilities of Bordetella species isolated in a Multicenter Pertussis Surveillance Project
Authors: Kurzynski T A , Boehm D M , Rott-Petri J A , Schell R F , Allison P E
Published: June 2012

MICs for 90% (MIC90s) of 75 Bordetella pertussis strains for amoxicillin, erythromycin, rifampin, and sulfamethoxazole-trimethoprim were 1, less than or equal to 0.12, 1, and 4 micrograms/ml, respectively. Susceptibility rates were all greater than or equal to 93%. Only 17% of the strains were susceptible to tetracycline. The MIC90s of ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and roxithromycin were less than or equal to 0.06, 0.5, 0.25, 0.12, and 0.5 micrograms/ml, respectively. For B. parapertussis, the MIC90s were 16-fold higher with amoxicillin and rifampin and 2- to 4-fold higher with the fluoroquinolones and roxithromycin.
In vitro activities of five new quinolones against 88 genital and neonatal Haemophilus isolates
Authors: Quentin R , Koubaa N , Cattier B , Gavignet M , Goudeau A
Published: June 2012

In vitro activities of five new quinolones against 88 strains of Haemophilus influenzae and H. parainfluenzae isolated from genitourinary or neonatal infections were studied. All strains were susceptible, and MICs were similar to those for respiratory tract isolates. However, H. influenzae biotype IV appeared to be more susceptible to norfloxacin, enoxacin, and ciprofloxacin than the other biotypes were.
Transferable amikacin resistance in Acinetobacter spp. due to a new type of 3'-aminoglycoside phosphotransferase
Authors: Lambert T , Gerbaud G , Courvalin P
Published: June 2012

Acinetobacter baumannii BM2580 resistant to kanamycin and structurally related antibiotics, including amikacin, was isolated from a clinical specimen. A phosphocellulose paper-binding assay and DNA annealing studies indicated that resistance to aminoglycosides in BM2580 was due to synthesis of a new type of 3'-aminoglycoside phosphotransferase. The gene conferring resistance to kanamycin-amikacin in this strain was carried by a 63-kilobase plasmid, pIP1841, self-transferable to A. baumannii, A. haemolyticus, and A. lwoffii but not to Escherichia coli. The aminoglycoside resistance gene of pIP1841 was cloned in E. coli, where it was expressed.
Enterohepatic circulation of NY-198, a new difluorinated quinolone, in rats
Authors: Saito A , Nagata O , Takahara Y , Okezaki E , Yamada T , Ito Y
Published: June 2012

Enterohepatic circulation of NY-198 in rats was studied. NY-198 glucuronide in the bile was rapidly hydrolyzed to NY-198 by the intestinal contents. Hydrolyzed and parent NY-198 in the bile were reabsorbed from the intestine. The amount of NY-198 in enterohepatic circulation was 59.8% of that excreted in the bile.