bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between human lactoferrin binding and colicin susceptibility in Escherichia coli
Authors: Gadó I , Erdei J , Laszlo V G , Pászti J , Czirók E , Kontrohr T , Tóth I , Forsgren A , Naidu A S
Published: June 2012

Escherichia coli H10407 demonstrated low 125I-human lactoferrin (HLf) binding (7%) and was insusceptible to group A (A, E1, E2, E3, E6, and K) and group B (B, D, Ia, Ib, and V) colicins. Conversely, a spontaneous HLf high-binding (44%) variant, H10407(Lf), demonstrated an increase susceptibility to both colicin groups. Colicin-insusceptible E. coli wild-type strains 75ColT, 84ColT, and 981ColT showed a low degree of HLf binding, i.e., 4, 8, and 10%, respectively. The HLf binding capacity was high in the corresponding colicin-susceptible mutants 75ColS (43%), 84ColS (32%), and 981ColS (43%). Furthermore, HLf low- (less than 5%) and high- (greater than 35%) binding E. coli clinical isolates (10 in each category) were tested for susceptibility against 11 colicins. Colicin V susceptibility did not correlate with HLf binding in either categories. However, with the remaining colicins, three distinct HLf-binding, colicin susceptibility patterns were observed; (i) 10 of 10 HLf low-binding strains were colicin insusceptible, (ii) 6 of 10 HLf high-binding strains were also colicin insusceptible, and (iii) the remaining HLf high binders were highly colicin susceptible. Certain proteins in the cell envelope and outer membrane of wild-type H10407 (HLf low binder, colicin insusceptible) showed a lower mobility in sodium dodecyl sulfate-polyacrylamide gel electrophoresis compared to the corresponding proteins of mutant H10407(Lf) (HLf high binder, colicin susceptible). These mobility differences were also associated with HLf-binding proteins in Western blot (ligand blot) analysis. The wild type showed a smooth form of lipopolysaccharide (LPS) with a distinct ladder of O-chains, compared to the rough LPS of the mutant.(ABSTRACT TRUNCATED AT 250 WORDS)
Treatment of encrusted cystitis caused by Corynebacterium group D2 with norfloxacin, ciprofloxacin, and teicoplanin in an experimental model in rats
Authors: Soriano F , Rodriguez-Tudela J L , Castilla C , Avilés P
Published: June 2012

Oral doses of norfloxacin (80 mg/kg of body weight per day) and ciprofloxacin (25 and 80 mg/kg/day) and intramuscular doses of teicoplanin (5 mg/kg/day), all administered once a day for 10 days, were evaluated as a means of preventing encrusted cystitis caused by Corynebacterium group D2. Zinc disks dipped into a 24-h broth culture of these microorganisms were inserted into the bladders of female Wistar rats, and treatment was started 14 days after bacterial challenge. The appearance of encrusted cystitis was directly related to a documented urinary tract infection by these coryneforms (71.7 and 0% for rats with positive and negative urine cultures, respectively). All rats that died between days 18 to 43 after bacterial challenge presented very severe encrusted cystitis, which was prevented by teicoplanin and high doses of ciprofloxacin. Rats surviving up to day 44 after bacterial challenge were sacrificed; they presented a lower incidence of encrusted cystitis which was also less severe, with teicoplanin and a high dose of ciprofloxacin being more active in reducing the rate of positive cultures (78.8 and 65.7% reduction, respectively). All antibiotics and doses used were active in vivo at preventing encrusted cystitis by Corynebacterium group D2, but the best therapeutic effect was obtained with teicoplanin.
Long-term protection of polyaspartic acid in experimental gentamicin nephrotoxicity
Authors: Swan S K , Kohlhepp S J , Kohnen P W , Gilbert D N , Bennett W M
Published: June 2012

Polyaspartic Acid (PAA) protects the kidney from experimental gentamicin nephrotoxicity despite large increases in renal cortical gentamicin content. In these experiments, prominent cytoplasmic vacuoles were noted in all animals that received PAA with or without gentamicin. The present study showed that there were no renal structural or functional consequences of PAA given alone or with gentamicin for up to 14 days, followed by a 16-week washout period. Creatinine clearance was similar to that of controls in animals that received gentamicin and in those that received PAA alone. Thus, complete functional protection was conferred by PAA and gentamicin, confirming previous reports from our laboratory. There was no protection by PAA from the nephrotoxic effects of mercuric chloride and cis-platinum.
Impact of pH and cationic supplementation on in vitro postantibiotic effect
Authors: Gudmundsson A , Erlendsdottir H , Gottfredsson M , Gudmundsson S
Published: June 2012

Most studies on pharmacodynamic variables in vitro, including the postantibiotic effect (PAE), are performed at pH 7.4 in noncationic-supplemented media, a situation which may differ significantly from the true microenvironment in most infected foci. We studied the impact of five different pH levels (pH 5, 6, 7, 7.4, and 8) on the duration of the PAE, the MIC, and bactericidal activity. Acid pH was found to have in general a deleterious effect on the activity of aminoglycosides and ciprofloxacin against Escherichia coli and Pseudomonas aeruginosa, with the MIC being higher, the bactericidal rate being lower, and the PAE being shorter at pH 5 (and to a lesser extent at pH 6) than at more alkaline pH levels. Similar results were observed for imipenem against P. aeruginosa. The PAEs induced by ampicillin against E. coli and dicloxacillin against Staphylococcus aureus were not predictably dependent on the pH, whereas the PAEs induced by ciprofloxacin against S. aureus were longest at either end of the pH spectrum. The bactericidal activity of these agents was, however, pH dependent, being slower at acid pHs. The addition of 50 mg of Ca2+ and 20 mg of Mg2+ per liter of liquid medium at pH 7.4 did not affect the duration of the PAE. Since the pH in abscess cavities may be close to 5, these observations may be of importance for employment of the agents studied in closed or poorly drained infections.
Development of resistance to ciprofloxacin in nutrient-rich and nutrient-limited growth conditions in vitro by Pseudomonas aeruginosa isolates from patients with cystic fibrosis
Authors: Ferguson M I , Scott E M , Collier P S
Published: June 2012

Five serial exposures of mucoid Pseudomonas aeruginosa from patients with cystic fibrosis to subinhibitory concentrations of ciprofloxacin resulted in stepwise increases in the MIC, with a mean proportional increase of 10. MICs were significantly lower in an iron-limited chemically defined medium than in Iso-Sensitest broth. The mucoid phenotype was maintained in chemically defined medium. Acquired resistance was retained either partially or completely in 85% of the isolates following 10 transfers in drug-free media. In cases in which susceptibility was regained, an increase in the MIC was observed on one further exposure to ciprofloxacin.
Sequence and molecular characterization of the ROB-1 beta-lactamase gene from Pasteurella haemolytica
Authors: Livrelli V , Peduzzi J , Joly B
Published: June 2012

The ROB-1 beta-lactamase-encoding plasmids from eight Pasteurella and two Haemophilus strains were compared by restriction endonuclease and hybridization analyses. Two types of ROB-1-encoding plasmids, which differed in size, were detected. One (4.1 kb) was found only in Pasteurella strains. The other (4.4 kb) was found in both Haemophilus influenzae and in one of the eight Pasteurella strains examined. These two plasmids shared multiple homologous fragments, suggesting that one was derived from the other. The ROB-1-encoding gene from Pasteurella haemolytica LNPB 51 was cloned and sequenced. An open reading frame of 915 nucleotides was found; it encoded a 305-amino-acid protein. Analysis of this amino acid sequence confirmed that the enzyme was found; it encoded a 305-amino-acid protein. Analysis of this amino acid sequence confirmed that the enzyme is a class A beta-lactamase. It had 32 to 48% homology with other class A enzymes and exhibited several common features of the gram-positive beta-lactamases. The ROB-1 mature protein, however, contained only one cysteine residue at position 123. These results suggest that ROB-1 is a link between beta-lactamases of gram-negative and gram-positive bacteria. An internal 230-bp DraI fragment from ROB-1 hybridized only with plasmid DNA from ROB-1-producing strains. This specific probe could be useful in epidemiological studies.
Efficacy of halofuginone lactate against Cryptosporidium parvum in calves
Authors: Villacorta I , Peeters J E , Vanopdenbosch E , Ares-Mazás E , Theys H
Published: June 2012

The efficacy of halofuginone lactate against natural Cryptosporidium parvum infection in 150 neonatal market calves of a mixed Belgian breed was tested. The drug was administered orally in the milk replacer over a period of 3 to 14 days at doses ranging from 30 to 500 micrograms/kg of body weight. Over a period of 4 weeks, the animals were examined twice a week for shedding of C. parvum oocysts and were scored semiquantitatively for diarrhea. Weight gain was assessed after 2 and 4 weeks. Subclinical infections by rota-, corona-, and bovine picobirnaviruses were equally distributed in the different groups. In total, 93% of the unmedicated calves eliminated C. parvum within 10 days after arrival at the rearing unit and 62% of them showed diarrhea. Immediately after treatment with halofuginone was started, no more signs of Cryptosporidium-associated diarrhea were established. From the level of 60 micrograms/kg on, oocysts were no longer detected in 98% of animals 5 to 6 days after the start of treatment. Animals remained negative for at least 7 days after withdrawal of the drug. From 7 to 10 days after withdrawal, some animals excreted oocysts again. The number of shedders was closely linked with increasing doses of the drug, which indicates that lower doses do not interrupt infection completely and allow development of immunity. In this respect, a dose of 60 to 125 micrograms/kg over a period of 7 days seems most appropriate in practice. Toxic side effects were noticed only at 500 micrograms/kg.
Uptake of sparfloxacin and norfloxacin by clinical isolates of Staphylococcus aureus
Authors: Yoshida S , Kojima T , Inoue M , Mitsuhashi S
Published: June 2012

The amount of sparfloxacin uptake was higher than that of norfloxacin uptake in Staphylococcus aureus. Moreover, energy-dependent reduction in quinolone uptake, probably due to active efflux of the quinolone, was observed. The reduction in quinolone uptake appeared to be associated with quinolone resistance in S. aureus.
Inter- and intrasubject variabilities in the pharmacokinetics of rufloxacin after single oral administration to healthy volunteers
Authors: Imbimbo B P , Broccali G , Cesana M , Crema F , Attardo-Parrinello G
Published: June 2012

Rufloxacin is a new long-acting, once-daily quinolone antibacterial agent. We evaluated inter- and intrasubject variations in pharmacokinetics of rufloxacin following oral administration of 400 mg (two capsules) under controlled conditions, at an interval of 2 weeks (periods I and II), to 12 healthy male subjects. Plasma and urine samples were collected up to 48 h after drug administration. Plasma drug levels determined by bioassay were higher than those measured by high-performance liquid chromatography, indicating that one or more active metabolites were formed. Individual high-performance liquid chromatography plasma rufloxacin concentrations were fitted with a one-compartment open model with first-order input. There were considerable variations in the plasma concentration-time profiles among subjects; for example, the elimination half-life in plasma varied from 14.6 to 95.5 h. However, pharmacokinetic parameters calculated for the two periods did not differ significantly. These results suggest that the intrasubject variation in the pharmacokinetics of rufloxacin is usually small in spite of the considerable intersubject variation.
Activity of temafloxacin against respiratory pathogens
Authors: Swanson R N , Hardy D J , Chu D T , Shipkowitz N L , Clement J J
Published: June 2012

The activity of the quinolone temafloxacin against respiratory pathogens was compared with those of ciprofloxacin and ofloxacin. MICs for 90% of strains tested indicated that temafloxacin was at least two- to fourfold more potent than the other two quinolones against Staphylococcus aureus, Streptococcus pneumoniae, and Legionella pneumophila. Temafloxacin had potency equal to that of ciprofloxacin and was twofold more active than ofloxacin against Streptococcus pyogenes. Moraxella catarrhalis, and Bordetella pertussis. Against Haemophilus influenzae and Klebsiella pneumoniae, temafloxacin was four- and twofold less potent than ciprofloxacin, respectively. When administered orally in mouse protection tests against S. aureus, S. pneumoniae, and S. pyogenes, temafloxacin was at least eight times more potent than ciprofloxacin and was two to four times more active than ofloxacin. Against H. influenzae, temafloxacin was as active as ofloxacin and was two times less active than ciprofloxacin following oral administration in mice. In treating L. pneumophila in guinea pigs and H. influenzae otitis media in gerbils, temafloxacin and ofloxacin were more effective than ciprofloxacin. Against S. pneumoniae otitis media in gerbils, temafloxacin and ciprofloxacin were more active than ofloxacin. Following subcutaneous administration in mice, temafloxacin achieved higher lung levels than ciprofloxacin or ofloxacin did.
Roxithromycin treatment of mouse chlamydial salpingitis and protective effect on fertility
Authors: Zana J , Muffat-Joly M , Thomas D , Orfila J , Salat-Baroux J , Pocidalo J J
Published: June 2012

We used a mouse model of acute chlamydial salpingitis to evaluate the efficacy of roxithromycin in preventing irreversible inflammatory damage leading to tubal infertility. Female C3H/He mice were genitally inoculated with a human strain of Chlamydia trachomatis and then treated with roxithromycin glutamate subcutaneously. Treatment was initiated either 7 or 10 days postinfection (p.i.) and continued for 7 days at a dosage of 50 or 100 mg/kg of body weight per 24 h. The course of the disease was monitored serologically, bacteriologically, and histologically. At the end of the treatment, the mice were encaged with males and their reproductive capacity was recorded over a 19-week period. The protective effect of roxithromycin was assessed in terms of fertility parameters in comparison with values for noninfected control mice. When treatment was initiated on day 7 p.i. and given in twice-daily 25-mg/kg doses, all the mice remained fertile and the total number of offspring was similar to that of sham-infected mice (17.3 +/- 3.3 versus 17.2 +/- 2.3). When treatment was initiated on day 10 p.i. and given in a single daily dose of 50 or 100 mg/kg, 90 and 70% of the mice, respectively, remained fertile; however, in terms of total offspring, fertility was lower in the group treated with the lower dose (5.6 +/- 1.4 versus 13.0 +/- 3.8). Roxithromycin was found to be effective against C. trachomatis in the mouse genital tract, but fertility was only partially preserved when the time between infection and treatment was prolonged.
Extracellular and intracellular activities of clarithromycin used alone and in association with ethambutol and rifampin against Mycobacterium avium complex
Authors: Rastogi N , Labrousse V
Published: June 2012

Mycobacterium avium complex bacteria are opportunistic human pathogens, and their chemotherapy remains a challenge since these organisms are resistant to a majority of routine antituberculous drugs. Recently, a wide range of new macrolide antibiotics has been developed, among which the drug clarithromycin appears to have a selective action against M. avium bacteria. In the present study, we have investigated the action of clarithromycin alone (MIC and MBC determinations) and in association with the routine antimycobacterial drugs ethambutol and rifampin at sublethal concentrations (1 micrograms/ml; below concentrations obtainable in human serum) against M. avium. Our viable count data showed that clarithromycin was bactericidal against all 10 strains of M. avium studied and that its activity was enhanced by ethambutol (in 8 of 9 strains) and rifampin (in 3 of 9 strains). The use of all three drugs in association resulted in higher bactericidal effects than found with any of the drugs used alone or in two-drug combinations in seven of nine strains. The bactericidal effects of various drugs used alone and in combination at concentrations obtainable in human serum were investigated against the type strain ATCC 15769 by using 7H9 broth and BACTEC radiometry (extracellular action) and a J-774 macrophage cell line (intracellular action). A good agreement between the extracellular and intracellular activities was found. Electron microscopy using a ruthenium red cytochemical staining of the bacteria showed that clarithromycin disorganized the outer wall layer and the cytoplasmic membrane in the mycobacterial cell envelope and resulted in formation of large vacuoles inside the cytoplasm, with solubilization of ribosomal structures and consequent plasmolysis. Its association with ethambutol and rifampin resulted in more drastic alterations in the bacterial morphology than were seen with any of the drugs used alone, leading to the removal of the bacterial outer layer, homogenization of cytoplasm, complete cell lysis, and formation of ghosts.
Comparison of different antibiotic regimens for therapy of 32 cases of Q fever endocarditis
Authors: Levy P Y , Drancourt M , Etienne J , Auvergnat J C , Beytout J , Sainty J M , Goldstein F , Raoult D
Published: June 2012

We studied 32 cases of Q fever endocarditis diagnosed in France between January 1985 and December 1989 to evaluate the efficacies of the different regimens of antibiotics used for treatment. Each patient was monitored during the treatment (range, 12 to 60 months), and clinical and biological information was computerized. Various treatments were prescribed, including doxycycline alone (9 cases) or in association with rifampin (4 cases), quinolones (16 cases), or sulfamethoxazole-trimethoprim (1 case). Two patients died before the beginning of the treatment. Nineteen patients had hemodynamic failure and subsequently underwent valve replacement. Nine valve tissue cultures were positive despite previous antibiotic treatment. In terms of their effects on mortality, the difference between doxycycline alone and doxycycline plus quinolones is statistically significant. We conclude that the addition of quinolones to doxycycline is beneficial. On the basis of clinical, serological, and valve tissue culture results, no treatment was able to cure Q fever endocarditis within 2 years, even with a combination of antibiotics. We advise a minimum duration of treatment of 3 years with therapy combining quinolones and doxycycline.
Ofloxacin versus parenteral therapy for chronic osteomyelitis
Authors: Gentry L O , Rodriguez-Gomez G
Published: June 2012

We conducted a randomized comparison of oral ofloxacin (400 mg twice a day) and parenteral agents (cefazolin, 1.0 g intravenously every 8 h, or ceftazidime, 2.0 g intravenously every 12 h) in biopsy-confirmed, nonprosthesis osteomyelitis. A total of 19 subjects received ofloxacin for an average of 8 weeks, and 14 received parenteral antibiotics for an average of 4 weeks; both therapies were well tolerated. Infections were due to Staphylococcus aureus (40%), Enterococcus spp. (3%), Pseudomonas aeruginosa (15%), and other gram-negative organisms (42%). At the completion of therapy, one P. aeruginosa infection in the ofloxacin group persisted and the organism acquired resistance, accompanied by a resistant Acinetobacter superinfection. In the parenteral group, one S. aureus infection persisted, and there was a resolved superinfection due to S. aureus as well. Eighteen-month follow-up data have been obtained. Among those treated with ofloxacin, four subjects whose initial response to therapy was successful suffered relapses of infection, three due to S. aureus and one due to P. aeruginosa, while in the parenteral group, one subject with a P. aeruginosa infection relapsed. Long-term response to therapy was successful for 14 of 19 (74%) subjects who received ofloxacin and 12 of 14 (86%) who received parenteral antibiotics; the difference was not significant. Oral ofloxacin appears comparable to parenteral antibiotics in chronic osteomyelitis due to susceptible organisms, and oral ofloxacin offers advantages in economics and convenience.
Nonradioactive DNA probe for detection of gene for methicillin resistance in Staphylococcus aureus
Authors: Ligozzi M , Rossolini G M , Tonin E A , Fontana R
Published: June 2012

A DNA probe was developed by inserting, in the SmaI site of pBluescript sK, a 528-bp fragment of the gene responsible for intrinsic resistance to beta-lactam antibiotics in Staphylococcus aureus (mec determinant). The mec probe provided a useful tool for the rapid identification of the intrinsic resistance trait and for establishing guidelines for testing the in vitro susceptibility of S. aureus to beta-lactams.
Effectiveness of clarithromycin and minocycline alone and in combination against experimental Mycobacterium leprae infection in mice
Authors: Ji B , Perani E G , Grosset J H
Published: June 2012

As determined by the proportional bactericide method, clarithromycin had strong bactericidal activity against Mycobacterium leprae. Clarithromycin was administered to mice by gavage as 20 daily doses at dosages of 12.5 to 50 mg/kg of body weight. At a dosage of 25 mg/kg, minocycline was more active than clarithromycin at a dosage of 50 mg/kg. Additive effects were displayed with the combination of clarithromycin (50 mg/kg) and minocycline (25 mg/kg), both of which were administered daily by gavage, and of clarithromycin and minocycline, both of which were administered daily by gavage at dosages of 25 mg/kg each, with rifampin at a single oral dose of 10 mg/kg.
Pharmacokinetics of 2',3'-dideoxyinosine (BMY-40900), a new anti-human immunodeficiency virus agent, after administration of single intravenous doses to beagle dogs
Authors: Kaul S , Knupp C A , Dandekar K A , Pittman K A , Barbhaiya R H
Published: June 2012

The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were investigated in four adult male beagle dogs that received 15-min infusions of 20-, 50-, and 100-mg/kg doses in a randomized crossover study design. Plasma and urine samples were collected for 10 and 24 h, respectively, and assayed for ddI by high-performance liquid chromatographic methods. The mean maximum concentrations of drug in plasma at the end of 15-min infusions for the 20-, 50-, and 100-mg/kg doses were 33.3, 90.0, and 202 micrograms/ml, respectively. Area under the concentration-time curve data deviated significantly from linearity. The mean total clearance for the low dose (250 ml/min) was significantly greater than that for the high dose (190 ml/min). Renal clearance, which averaged between 98 and 116 ml/min, was dose independent. Renal clearance implied that nonrenal clearance decreased at the high dose (92 ml/min) when compared with that of the low dose (134 ml/min). The average urinary recovery of ddI for the high dose (51.2% of dose) was significantly greater than that for the low dose (45.8%). The volume of distribution at steady state averaged between 7.6 and 10.5 liters and decreased with increasing dose; however, it was not statistically significant. The mean half-life and mean residence time were invariant with respect to dose and averaged between 0.94 and 1.07 h and 0.61 and 0.71 h, respectively. In this dose range, ddI pharmacokinetics are dose dependent.
In vitro and in vivo evaluation of Ro 09-1428, a new parenteral cephalosporin with high antipseudomonal activity
Authors: Arisawa M , Sekine Y , Shimizu S , Takano H , Angehrn P , Then R L
Published: June 2012

Ro 09-1428, a new parenteral cephalosporin with a catechol moiety attached at position 7 of the cephalosporin ring, showed high in vitro activity against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and Streptococcus pyogenes, with MICs for 90% of strains tested (MIC90s) of less than or equal to 0.39 micrograms/ml. Morganella morganii, Providencia rettgeri, Citrobacter freundii, Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae were inhibited with MIC90s of less than or equal to 3.13 micrograms/ml. Serratia marcescens was less susceptible to Ro 09-1428, with a MIC90 of 25 micrograms/ml. The most distinctive feature of Ro 09-1428 was its potent activity against Pseudomonas aeruginosa and Acinetobacter calcoaceticus, with MIC90s of 0.39 and 6.25 micrograms/ml, respectively. Most of the ceftazidime-resistant strains of P. aeruginosa, E. cloacae, and C. freundii were inhibited by Ro 09-1428, while those of S. marcescens were resistant at a concentration of 12.5 micrograms/ml. Ro 09-1428 was more active than ceftazidime against staphylococci. PBP 3 was the most sensitive target in E. coli and P. aeruginosa. The response to ferric iron in growth medium suggests that Ro 09-1428 may be taken up by transport mechanisms similar to those of other catechol cephalosporins. In accordance with its in vitro activity, Ro 09-1428 activity was equal to or greater than ceftazidime activity in efficacy against experimental septicemias in mice. The results indicate that Ro 09-1428 is a broad-spectrum cephalosporin with advantages over ceftazidime in its activity against P. aeruginosa, staphylococci, and ceftazidime-resistant strains of C. freundii and E. cloacae.
Antiviral activities of 5-ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide and related compounds
Authors: De Clercq E , Cools M , Balzarini J , Snoeck R , Andrei G , Hosoya M , Shigeta S , Ueda T , Minakawa N , Matsuda A
Published: June 2012

A series of novel compounds, 5-alkynyl-1-beta-D-ribofuranosylimidazole-4- carboxamides, have been identified as broad-spectrum antiviral agents. 5-Ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide (EICAR), the most potent congener of the group, showed antiviral potency about 10- to 100-fold greater than that of ribavirin. Similar in spectrum to ribavirin, EICAR was particularly active (50% inhibitory concentration, 0.2 to 4 micrograms/ml) against poxviruses (vaccinia virus), togaviruses (Sindbis and Semliki forest viruses), arenaviruses (Junin and Tacaribe viruses), reoviruses (reovirus type 1), orthomyxoviruses (influenza A and B viruses), and paramyxoviruses (parainfluenza virus type 3, measles virus, subacute sclerosing panencephalitis virus, and respiratory syncytial virus). EICAR was also cytostatic for rapidly growing cells (50% inhibitory concentration, 0.2 to 0.9 microgram/ml). EICAR inhibited vaccinia virus tail lesion formation at doses that were not toxic to the host. EICAR is a candidate antiviral drug for the treatment of pox-, toga-, arena-, reo-, orthomyxo, and paramyxovirus infections.
Teicoplanin pharmacokinetics in intravenous drug abusers being treated for bacterial endocarditis
Authors: Rybak M J , Lerner S A , Levine D P , Albrecht L M , McNeil P L , Thompson G A , Kenny M T , Yuh L
Published: June 2012

The pharmacokinetics of teicoplanin were determined after multiple 30-min intravenous infusions of 10 to 15 mg/kg every 12 to 24 h in 11 intravenous drug abuse (IVDA) patients being treated for bacterial endocarditis. Multiple serum samples were obtained over 7 to 14 days. Twenty-four-hour urine collections were obtained on days 1 and 5. Serum concentration-time data were analyzed by using multiple-dose pharmacokinetic analysis (NONLIN84). Results were compared with pharmacokinetic parameters derived from previous studies in normal healthy volunteers following multiple intravenous infusions of teicoplanin (3 to 6 mg/kg/day). Total and renal clearances of teicoplanin in IVDA patients were found to be significantly greater and more highly variable than those observed previously in normal healthy volunteers. As a result, predicted steady-state trough concentrations in serum may vary up to fivefold. The mechanism responsible for this variation appears to be related to the glomerular filtration rate. In IVDA patients, individualized teicoplanin dosage may be required in the treatment of bacterial endocarditis.
High-dose itraconazole in the treatment of severe mycoses
Authors: Sharkey P K , Rinaldi M G , Dunn J F , Hardin T C , Fetchick R J , Graybill J R
Published: June 2012

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (less than 2.5 micrograms/ml) in both patients. All other patients had mean trough levels in serum above 5 micrograms/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.
Pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine in rats
Authors: Boudinot F D , Smith S G , Funderburg E D , Schinazi R F
Published: June 2012

Concentrations of 3'-fluoro-3'-deoxythymidine (FDT) and 3'-deoxy-2',3'-didehydrothymidine (D4T) in plasma declined in a biexponential fashion. Total clearance of D4T (1.75 +/- 0.22 liters/h/kg; mean +/- standard deviation) was significantly greater than that of FDT (1.19 +/- 0.19 liters/h/kg) owing to greater renal and nonrenal clearances of the former. Steady-state volumes of distribution of FDT (1.20 +/- 0.12 liters/kg) and D4T (1.07 +/- 0.15 liters/kg) were similar.
Imipenem resistance in pseudomonas aeruginosa PAO: mapping of the OprD2 gene
Authors: Quinn J P , Darzins A , Miyashiro D , Ripp S , Miller R V
Published: June 2012

Carbapenem antibiotics have been shown to penetrate the outer membrane of Pseudomonas aeruginosa through a unique porin protein, OprD2. We mapped the OprD2 gene by conjugation using plasmid FP2 and by transduction using phage F116L. This gene maps between 71 and 75 min on the PAO1 chromosome.
Induction of beta-lactamase production in Pseudomonas aeruginosa biofilm
Authors: Giwercman B , Jensen E T , Høiby N , Kharazmi A , Costerton J W
Published: June 2012

Imipenem induced high levels of beta-lactamase production in Pseudomonas aeruginosa biofilms. Piperacillin also induced beta-lactamase production in these biofilms but to a lesser degree. The combination of beta-lactamase production with other protective properties of the biofilm mode of growth could be a major reason for the persistence of this sessile bacterium in chronic infections.
Lack of ciprofloxacin ototoxicity after repeated ototopical application
Authors: Claes J , Govaerts P J , Van de Heyning P H , Peeters S
Published: June 2012

The possible side effects of ototopically applied ciprofloxacin on inner ear function were investigated. The hearing function of pigmented guinea pigs was evaluated by daily frequency-specific evoked response audiometry after repeated application of the drug to both ears. Ciprofloxacin appeared to have no statistically significant effect on the hearing thresholds of the experimental animals.
Pharmacokinetics of 3'-azido-3'-deoxythymidine and its catabolites and interactions with probenecid in rhesus monkeys
Authors: Cretton E M , Schinazi R F , McClure H M , Anderson D C , Sommadossi J P
Published: June 2012

The pharmacokinetics and metabolism of 3'-azido-3'-deoxythymidine (AZT) were investigated in rhesus monkeys after subcutaneous administration of 33.3 mg of AZT per kg of body weight alone or in the presence of 100 mg of probenecid per kg. In addition to unchanged drug, two catabolites, 5'-O-glucuronide (GAZT) and 3'-amino-3'-deoxythymidine (AMT), were detected in plasma within 30 min. GAZT exhibited a kinetic profile similar to that of AZT, with an elimination half-life of approximately 1 h, while AMT was more variable, with an apparent half-life of 1.6 +/- 1.5 h. Approximately 90% of the total administered dose was recovered in urine within 24 h as AZT, GAZT, AMT, and the 5'-O-glucuronide of AMT. AZT and AMT demonstrated similar cerebrospinal fluid (CSF) penetration 1 h after AZT treatment, while GAZT poorly crossed the blood-brain barrier. Concomitant administration of probenecid greatly altered the pharmacokinetics of AZT, GAZT, and AMT, resulting in prolongation of their apparent elimination half-lives, increased concentrations in plasma, and marked reduction in renal clearances. In addition, the CSF/plasma concentration ratios for AZT and its catabolites were greatly increased, suggesting that probenecid inhibits efflux of AZT and its catabolites from CSF to plasma. The substantial levels of AMT in plasma suggest that this catabolite affects the pharmacodynamic properties of AZT in relation to its activity against human immunodeficiency virus replication and cytotoxicity to host cells. Enhanced AMT levels in plasma in the presence of probenecid may decrease the therapeutic efficacy of the AZT-probenecid combination.
Effect of monodesethyl amodiaquine on human polymorphonuclear neutrophil functions in vitro
Authors: Labro M T , el Benna J
Published: June 2012

We have previously observed that the antimalarial drug amodiaquine impairs the human polymorphonuclear neutrophil (PMN) oxidative burst in vitro. However, the drug acted at a concentration of 100 micrograms/ml, far higher than that which is achievable therapeutically. Since amodiaquine is extensively metabolized into monodesethyl amodiaquine, we investigated whether the metabolite modified PMN functions at lower concentrations than amodiaquine does. Monodesethyl amodiaquine strongly depressed PMN chemotaxis and phagocytosis at concentrations as low as 10 micrograms/ml. This inhibition was reversed by washing out the drug. The PMN oxidative burst was markedly depressed by monodesethyl amodiaquine, whatever the assay technique (luminol-amplified chemiluminescence, lucigenin-amplified chemiluminescence, myeloperoxidase activity) or stimulus used (opsonized zymosan, phorbol myristate acetate, formylmethionyl leucyl phenylalanine). There were extreme interindividual variations in sensitivity to the depressive effect of monodesethyl amodiaquine when the PMN oxidative burst was assayed in terms of luminol-amplified chemiluminescence or lucigenin-amplified chemiluminescence. PMN samples were divided into two groups on the basis of the MIC of the drug: 60% of the samples were "highly sensitive," being strongly inhibited at concentrations as low as 0.1 micrograms/ml (obtained during therapy), whereas the "moderately sensitive" samples were inhibited at concentrations of 10 micrograms/ml and above. The difference between the two groups was highly significant. This PMN sensitivity to the inhibitory effect of the drug was not related to intrinsic oxidative metabolism. Our data indicate that monodesethyl amodiaquine, the main metabolite of amodiaquine, has a far stronger inhibitory effect on various PMN functions in vitro than the parent drug, warranting relevant in vivo studies.
Standardization of a fluconazole bioassay and correlation of results with those obtained by high-pressure liquid chromatography
Authors: Rex J H , Hanson L H , Amantea M A , Stevens D A , Bennett J E
Published: June 2012

An improved bioassay for fluconazole was developed. This assay is sensitive in the clinically relevant range (2 to 40 micrograms/ml) and analyzes plasma, serum, and cerebrospinal fluid specimens; bioassay results correlate with results obtained by high-pressure liquid chromatography (HPLC). Bioassay and HPLC analyses of spiked plasma, serum, and cerebrospinal fluid samples (run as unknowns) gave good agreement with expected values. Analysis of specimens from patients gave equivalent results by both HPLC and bioassay. HPLC had a lower within-run coefficient of variation (less than 2.5% for HPLC versus less than 11% for bioassay) and a lower between-run coefficient of variation (less than 5% versus less than 12% for bioassay) and was more sensitive (lower limit of detection, 0.1 micrograms/ml [versus 2 micrograms/ml for bioassay]). The bioassay is, however, sufficiently accurate and sensitive for clinical specimens, and its relative simplicity, low sample volume requirement, and low equipment cost should make it the technique of choice for analysis of routine clinical specimens.
Prospective randomized evaluation of ciprofloxacin versus piperacillin plus amikacin for empiric antibiotic therapy of febrile granulocytopenic cancer patients with lymphomas and solid tumors. The European Organization for Research on Treatment of Cancer International Antimicrobial Therapy Cooperative Group
Authors: Meunier F , Zinner S H , Gaya H , Calandra T , Viscoli C , Klastersky J , Glauser M
Published: June 2012

Empiric therapy for febrile granulocytopenic patients is mandatory, but whether monotherapy is a safe alternative and whether fluoroquinolones are useful agents for this indication are still controversial issues. The use of monotherapy with intravenous ciprofloxacin (200 to 300 mg every 12 h) was evaluated against combined therapy with piperacillin plus amikacin in febrile granulocytopenic patients with solid tumor or lymphoma. The study was discontinued prematurely because patients treated with ciprofloxacin had a significantly lower overall success rate than patients treated with piperacillin plus amikacin (31 of 48 patients [65%] versus 48 of 53 patients [91%], P = 0.002). Patients with gram-positive coccal bacteremia had a particularly poor outcome: therapy failed for six of eight patients (75%) treated with ciprofloxacin, while therapy failed for none of four patients treated with piperacillin plus amikacin. Death from primary infection during initially randomized protocol therapy occurred in 7 of 48 patients (14.5%) treated with ciprofloxacin and in 3 of 53 (6%) treated with piperacillin plus amikacin. This study does not support the use of this dose of intravenous ciprofloxacin as empiric monotherapy for fever in granulocytopenic patients.
Spontaneous quinolone resistance in Serratia marcescens due to a mutation in gyrA
Authors: Masecar B L , Robillard N J
Published: June 2012

Spontaneous quinolone-resistant mutants of MP050, a quinolone-susceptible clinical strain of Serratia marcescens, were isolated on nutrient agar containing 0.5 microgram of ciprofloxacin per ml. One mutant, designated MP051, was selected for further study. Quinolone MICs for MP051 were 4- to 16-fold higher than those for MP050; nonquinolone MICs were unchanged. The DNA gyrase isolated from MP051 was 24-fold less sensitive to inhibition of supercoiling by ciprofloxacin than the DNA gyrase isolated from MP050 was. Inhibition studies on reconstituted combinations of heterologous gyrase subunits showed that the decreased inhibition was dependent on the A subunit of DNA gyrase from MP051. Further evidence that this decreased inhibition was due to a gyrA mutation was provided by analysis of Escherichia coli gyrA gene expression in S. marcescens heterodiploids containing pNJR3-2, a broad-host-range gyrA gene probe. Quinolone susceptibilities of MP051 heterodiploids containing the wild-type E. coli gyrA gene decreased to those of MP050, while quinolone susceptibilities of MP050 containing the same plasmid were unchanged. These results indicate that spontaneous quinolone resistance in MP051 was due to a mutation in gyrA.
Escherichia coli resistant to cephalosporins and quinolones is still susceptible to the cephalosporin-quinolone ester Ro 23-9424
Authors: Pace J , Bertasso A , Georgopapadakou N H
Published: June 2012

Ro 23-9424 is a broad-spectrum antibacterial agent consisting of a cephalosporin (desacetylcefotaxime) linked through an ester bond to a fluoroquinolone (fleroxacin). Its activity against mutants of Escherichia coli TE18 resistant to both antibacterial components was examined. E. coli TE18 overproduces the AmpC beta-lactamase and is resistant to several cephalosporins, including desacetylcefotaxime (MIC, 50 micrograms/ml), although it is still susceptible to Ro 23-9424 (MIC, 0.2 microgram/ml). Thirty-five spontaneous, two-step mutants of E. coli TE18 which were resistant to fleroxacin (MIC, 50 micrograms/ml) were isolated. In the mutants, replicative DNA biosynthesis (permeabilized cells) was resistant to fleroxacin, and some mutants had porin abnormalities. However, all remained susceptible to Ro 23-9424 (MIC, 0.5 microgram/ml). Examination of beta-lactamase activity in the parent strain revealed that it hydrolyzes desacetylcefotaxime more rapidly than it does Ro 23-9424. Thus, Ro 23-9424 may be less susceptible to the gram-negative, chromosomal beta-lactamases that hydrolyze several broad-spectrum cephalosporins and may be effective in cases in which neither of its two components is active.
In vitro evaluation of GR69153, a novel catechol-substituted cephalosporin
Authors: Erwin M E , Jones R N , Barrett M S , Briggs B M , Johnson D M
Published: June 2012

GR69153 is a C-7 catechol cephalosporin with a broad spectrum of activity against members of the family Enterobacteriaceae (MICs for 50% of strains tested [MIC50s], 0.008 to 0.5 micrograms/ml), Staphylococcus aureus (MIC50, 4 micrograms/ml), Pseudomonas aeruginosa (MIC50, 0.25 micrograms/ml), Haemophilus influenzae (MIC50, 0.03 micrograms/ml), Neisseria gonorrhoeae (MIC50, 0.03 micrograms/ml), and Acinetobacter spp. (MIC50, 2 micrograms/ml). Potent GR69153 activity was also demonstrated against Moraxella catarrhalis, pneumococci, beta-hemolytic streptococci, gram-positive anaerobes, and most species of coagulase-negative staphylococci. The activity of GR69153 was generally two- to fourfold greater than that of ceftazidime. Resistance level GR69153 MICs for 90% of strains tested (greater than or equal to 32 micrograms/ml) were found most often among Citrobacter freundii, Enterobacter spp. and Morganella morganii strains. GR69153 did not significantly inhibit enterococci, Xanthomonas maltophilia, the Bacteroides fragilis group, Corynebacterium jeikeium, or Listeria monocytogenes. GR69153 was bactericidal and was generally beta-lactamase stable, and MICs were only slightly increased by high inoculum concentrations. Activity was enhanced in an iron-deficient medium, and a modest MIC difference attributed to iron availability was noted between standard agar and broth test results. GR69153 was confirmed to be a potent, catechol-substituted cephalosporin with a spectrum slightly wider than that of ceftazidime, but it was less active than cefpirome or imipenem against some gram-positive pathogens and anaerobes.
Comparative evaluation of loracarbef and amoxicillin-clavulanate for acute otitis media
Authors: Gan V N , Kusmiesz H , Shelton S , Nelson J D
Published: June 2012

One hundred five infants and children with acute otitis media were randomized to therapy with loracarbef, an experimental carbacephem antibiotic, or amoxicillin-clavulanate (Augmentin), an approved drug for this disease. Ninety-two were evaluable (46 in each group). Middle ear fluid samples obtained for culture before therapy grew Haemophilus spp. in 30% of cases, pneumococci in 29% of cases, and Moraxella catarrhalis in 15% of cases. beta-Lactamase-producing bacteria were found in 37% of patients. Clinical failure occurred in four loracarbef-treated patients and one amoxicillin-clavulanate-treated patient (P = 0.361). Recurrence of acute otitis media was more common in the 2 to 3 weeks after loracarbef treatment (eight patients) than it was after amoxicillin-clavulanate therapy (three patients), but not significantly so (P = 0.197). Thus, combined failure and recurrence occurred in 12 loracarbef-treated patients and four amoxicillin-clavulanate-treated patients (P = 0.052). Gastrointestinal side effects occurred in 13 loracarbef-treated and 21 amoxicillin-clavulanate-treated patients (P = 0.13). Diaper rash was more common with amoxicillin-clavulanate (22 patients) than with loracarbef (10 patients; P = 0.016). Satisfactory results were achieved with both antibiotics, and adverse effects, although common, were minor.
Single-dose trospectomycin for chlamydial urethritis in men
Authors: Keefer M C , Menegus M A , Nasello M A , Reid J A , Long M , Reichman R C
Published: June 2012

Trospectomycin is an aminocyclitol analog of spectinomycin with significant in vitro activity against Chlamydia trachomatis. A single 1-g intramuscular dose was administered to 10 men with symptomatic, culture-positive chlamydial urethritis. Trospectomycin was well tolerated but failed to eradicate chlamydial infection, as determined by cultures obtained approximately 1 week after treatment.
Isoniazid inhibition of mycolic acid synthesis by cell extracts of sensitive and resistant strains of Mycobacterium aurum
Authors: Quémard A , Lacave C , Lanéelle G
Published: June 2012

Isonicotinic acid hydrazide (isoniazid; INH) inhibition of mycolic acid synthesis was studied by using cell extracts from both INH-sensitive and -resistant strains of Mycobacterium aurum. The cell extract of the INH-sensitive strain was inhibited by INH, while the preparation from the INH-resistant strain was not. This showed that the INH resistance of mycolic acid synthesis was not due to a difference in drug uptake or the level of peroxidase activity (similar in both extracts). As INH did not induce accumulation of any labeled intermediates, it is postulated that the drug acts either on production of labeled chain elongation precursors of mycolic acids or an early step of this elongation. The level of inhibition was not changed by addition of NAD or nicotinamide; thus, INH does not act on mycolic acid synthesis as an NAD antimetabolite. Benzoic or acetic acid hydrazides and known or postulated metabolites of INH (i.e., the corresponding acid, aldehyde, or alcohol) were not inhibitors of cell-free mycolic acid synthesis; the complete structure of INH was required, as already known for inhibition of mycobacterial culture growth. Extracts prepared from INH-treated cells showed reduced mycolic acid synthesis, and the inhibition level was not modified by either extensive dialysis or pyridoxal phosphate. This latter molecule efficiently antagonized INH action by reacting rapidly with INH, as shown by differential spectroscopy. Moreover, pyridoxal phosphate did not release inhibition of INH-treated extracts. It is proposed that INH may covalently react with an essential component of the mycolic acid synthesis system.