bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug susceptibility testing of Mycobacterium leprae in the BACTEC 460 system
Authors: Franzblau S G
Published: June 2012

The susceptibility of Mycobacterium leprae to clinical and experimental antileprosy agents was assessed in the BACTEC 460 system. Nude-mouse-derived M. leprae (10(7) cells), incubated in BACTEC 12B medium at 33 degrees C under reduced oxygen, maintained a fairly constant growth index (14CO2 evolution) for 2 to 3 weeks. At concentrations ranging from 0.031 to 2.0 micrograms/ml, dapsone, rifampin, clofazimine, ethionamide, ofloxacin, clarithromycin, and minocycline all effected reductions in the growth index within 1 to 2 weeks, the extent of inhibition increasing with the incubation time. An in vivo rifampin-resistant isolate displayed markedly reduced susceptibility to rifampin compared with an in vivo-susceptible strain. This system appears to be highly suitable for in vitro drug susceptibility testing of M. leprae.
Susceptibility of anaerobic bacteria to ALP 201
Authors: Nord C E , Lindmark A , Persson I
Published: June 2012

The activity of ALP 201 against 350 strains of anaerobic bacteria was determined by an agar dilution method. Its activity was compared with those of piperacillin, cefoxitin, imipenem, clindamycin, metronidazole, and chloramphenicol. ALP 201 and imipenem were the most active agents tested. Based on these results, ALP 201 appears to be a promising antimicrobial agent for anaerobic infections and warrants further clinical investigations.
In vitro susceptibility of Nocardia spp. to a new fluoroquinolone, tosufloxacin (T-3262)
Authors: Yazawa K , Mikami Y , Uno J
Published: June 2012

The in vitro activity of a new fluoroquinolone, tosufloxacin (T-3262), against 111 pathogenic Nocardia strains was studied by an agar dilution method and compared with the activities of other fluoroquinolones. All strains were susceptible to tosufloxacin, and the drug was 2 to 20 times more active than four other quinolones tested. Nocardia farcinica was the Nocardia species most susceptible to tosufloxacin.
Comparison of electronic and viability counting methods for determination of postantibiotic effect of oxacillin on Staphylococcus aureus
Authors: Nadler H L , Curby W A , Forgacs P , Rosenberg F
Published: June 2012

The postantibiotic effect of oxacillin on Staphylococcus aureus ATCC 6538P was determined under different test conditions by reference (viability counting) and semiautomated (electronic counting) methods. Differences in durations of the postantibiotic effect obtained with the two counting methods were not statistically significant. The semiautomated method provided a more rapid and convenient alternative to viability counting.
Structural features related to hydrolytic activity against ceftazidime of plasmid-mediated SHV-type CAZ-5 beta-lactamase
Authors: Péduzzi J , Barthélémy M , Tiwari K , Mattioni D , Labia R
Published: June 2012

Tryptic peptides of the novel ceftazidimase CAZ-5 were sequenced by manual Edman degradation and aligned according to strong homology (more than 98%) with SHV-1 and SHV-2 beta-lactamase sequences. CAZ-5 differed from SHV-1 by five amino acid substitutions. Unusually high activity of CAZ-5 towards ceftazidime was imputed to substitution of a Lys for a Glu at position 214 of the mature protein.
Mechanism of mupirocin transport into sensitive and resistant bacteria
Authors: Capobianco J O , Doran C C , Goldman R C
Published: June 2012

Pseudomonic acid A (mupirocin) blocks protein synthesis in bacteria by inhibition of bacterial isoleucyl-tRNA synthetase. [16, 17-3H]mupirocin, isolated from a methionine auxotroph of Pseudomonas fluorescens, was used to study transport of this antibiotic into sensitive and resistant strains of Bacillus subtilis, Staphylococcus aureus, and Escherichia coli. The transport of mupirocin into sensitive bacteria was energy independent and temperature dependent (decreased uptake at lower temperatures), indicating non-carrier-mediated passive diffusion. Uptake was also saturable with time or increasing antibiotic concentration. The saturable intracellular binding site, most likely the target isoleucyl-tRNA synthetase as determined by the amount of bound mupirocin (2,700 to 3,100 molecules per cell), caused concentration of the antibiotic within the cell. E. coli transformed with a plasmid containing ileS overproduced the target enzyme and demonstrated greater accumulation of mupirocin than a strain containing a control plasmid. The concentrations needed to half saturate (Kd) these binding sites in B. subtilis and S. aureus were 35 and 7 nM, respectively. In gram-positive organisms trained for mupirocin resistance, uptake was not saturable with increasing antibiotic concentration, and intra- and extracellular concentrations of drug equilibrated with time. Kinetic analysis of crude isoleucyl-tRNA synthetase from trained and untrained B. subtilis strains revealed differences in apparent Ki for mupirocin (resistant strain SB23T, Ki = 71.1 nM; sensitive strain SB23, Ki = 33.5 nM), while the Km for isoleucine remained unchanged (2.7 to 2.9 microM). A Km of 0.4 micromolar isoleucine and Ki of 24 nM mupirocin was demonstrated for isoleucyl-tRNA synthetase from sensitive S. aureus 730a, while no isoleucyl-tRNA synthetase activity was detected in extracts of resistance-trained S. aureus 3000 even at 40 micromolar isoleucine, suggesting instability of the enzyme. Free isoleucine pools differed between sensitive (0.26 micromolar) and resistance-trained (1.06 micromolar) S. aureus. Our results demonstrate that (i) mupirocin enters cells by passive diffusion, (ii) mupirocin concentrates in sensitive bacteria due to binding to isoleucyl-tRNA synthetase, and (iii) resistance to mupirocin involves restricted access to the binding site of isoleucyl-tRNA synthetase.
In vitro antibacterial activity of SM-7338, a carbapenem antibiotic with stability to dehydropeptidase I
Authors: Edwards J R , Turner P J , Wannop C , Withnell E S , Grindey A J , Nairn K
Published: June 2012

SM-7338, a new carbapenem antibiotic, was demonstrated to have potent antibacterial activity against a broad spectrum of aerobes, including Staphylococcus aureus, beta-hemolytic streptococci, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria spp., members of the family Enterobacteriaceae, Pseudomonas spp., and gram-positive and gram-negative anaerobes in a collection of 1,102 unselected clinical isolates. At a concentration of 0.5 micrograms/ml, SM-7338 inhibited 90% of these strains. The spectrum of activity of ceftazidime and cefotaxime was more limited, and many of the Enterobacteriaceae and Pseudomonas spp. were resistant to these agents, piperacillin, or gentamicin. A collection of ofloxacin-resistant strains was inhibited by SM-7338 or imipenem at 4 micrograms/ml. SM-7338 was more active than metronidazole and clindamycin against anaerobes. Of the carbapenems, imipenem had greater activity against staphylococci but SM-7338 was much more active against Haemophilus, Branhamella, and Neisseria spp. and all genera of Enterobacteriaceae tested. The MIC of SM-7338 for 90% of these strains ranged from less than or equal to 0.008 to 0.13 micrograms/ml. When tested against 124 strains of Pseudomonas aeruginosa, SM-7338 inhibited 76% at 0.5 microgram/ml but imipenem inhibited only 15% at this concentration. Both carbapenems exhibited similar activities against Bacteroides spp., but SM-7338 was more active than imipenem against Clostridium spp. The MBC of SM-7338 was most commonly the same as or twice the MIC. SM-7338 and imipenem showed excellent activities against bacteria elaborating chromosome- or plasmid-mediated beta-lactamases, including those conferring resistance to broad-spectrum cephalosporins. The activity of SM-7338 was generally unaffected by the culture medium used, pH, 25% human serum, and inoculum size, but the susceptibility of Xanthomonas maltophilia was medium dependent.
Enhanced gentamicin killing of Escherichia coli by tet gene expression
Authors: Merlin T L , Corvo D L , Gill J H , Griffith J K
Published: June 2012

Time-kill studies were performed to determine the effect of tetracycline resistance (tet) gene expression on gentamicin killing of Escherichia coli. Expression of tet increased gentamicin killing in laboratory strains and clinical isolates. A role for tetracycline in inducing tet expression and increasing the bactericidal activity of aminoglycosides is suggested.
Characterization of a streptomycin-sulfonamide resistance plasmid from Actinobacillus pleuropneumoniae
Authors: Willson P J , Deneer H G , Potter A , Albritton W
Published: June 2012

An Actinobacillus pleuropneumoniae strain contained a plasmid (pHD8.1) conferring resistance to streptomycin and sulfonamide. Restriction endonuclease mapping and DNA-DNA hybridization showed that pHD8.1 is related to RSF1010 from Salmonella panama, which also confers resistance to streptomycin and sulfonamide, and to pHD148 from Haemophilus ducreyi, which confers resistance only to sulfonamide.
Macrolide accumulation by Bacteroides fragilis ATCC 25285
Authors: Muto Y , Bandoh K , Watanabe K , Katoh N , Ueno K
Published: June 2012

The accumulation of macrolide antibiotics in Bacteroides fragilis ATCC 25285 was increased in the order erythromycin, josamycin, and rokitamycin, depending on hydrophobicity. The half-times of efflux were also prolonged in the same order. Furthermore, MICs of the antibiotics were correlated with the extent of hydrophobicity. These findings suggest that the macrolide antibiotics are accumulated in B. fragilis by means of their hydrophobic properties, and the efficient accumulation of the drugs may explain the susceptibility of this gram-negative bacterium to macrolides.
Cell-wall-defective variants of Fusobacterium
Authors: Johnson C C , Wexler H M , Becker S , Garcia M , Finegold S M
Published: June 2012

The activity of antimicrobial agents against Fusobacterium species has been reported as variable in the literature. For some strains, the inconsistency arises from difficulty in determining the endpoint of growth in agar dilution susceptibility tests. Certain strains persist as a subtle haze beyond the levels of antibiotic that permit conventional colonial growth. We have determined by light and electron microscopy that this haze represents the colonial growth of cell-wall-defective (CWD) variants of the parent Fusobacterium. The CWD forms could be propagated indefinitely in hypertonic medium containing the antibiotic inducing agent. However, when the antibiotic was eliminated, the organisms would revert to their native morphology. Formation of CWD variants was observed in the presence of cell-wall-active drugs (e.g., beta-lactam agents) but not with drugs that work by a different mechanism (e.g., clindamycin or chloramphenicol). Fourteen of 22 F. varium strains, 8 of 11 F. mortiferum strains, 2 of 10 F. gonidiaformans strains, and 1 of 4 of F. necrophorum strains could be induced to a CWD form in vitro in the usual agar dilution susceptibility test. Although the clinical significance of CWD variants of Fusobacterium is unknown, they may be a source of confusion in interpreting agar dilution susceptibility tests.
Pharmacokinetics and metabolism of intravenous and oral fleroxacin in subjects with normal and impaired renal function and in patients on continuous ambulatory peritoneal dialysis
Authors: Stuck A E , Frey F J , Heizmann P , Brandt R , Weidekamm E
Published: June 2012

The pharmacokinetics of fleroxacin, including the formation of N-demethyl and N-oxide fleroxacin after the administration of single intravenous (100-mg) and oral (400-mg) doses, was investigated in 26 subjects with various levels of renal function, including 7 patients on continuous ambulatory peritoneal dialysis. Fleroxacin was well tolerated by all subjects. The volume of distribution, systemic availability, and peak concentration after the administration of oral fleroxacin were independent of the glomerular filtration rate. As a consequence of a declining renal clearance but not nonrenal clearance, the total body clearance of fleroxacin declined with decreasing glomerular filtration rate from 1.41 +/- 0.23 ml/min per kg in subjects with normal renal function to 0.58 +/- 0.13 ml/min per kg in patients with end-stage renal disease (r = 0.84, P less than 0.001). The analysis revealed that the N-oxide metabolite exhibited formation-limited kinetics and the N-demethyl metabolite exhibited elimination-limited kinetics. The areas under the curve of both metabolites increased with declining renal function. In patients on continuous ambulatory peritoneal dialysis the mean dialysate/plasma concentration ratio of fleroxacin increased from 0.52 +/- 0.11 to 0.71 +/- 0.13 (P less than 0.001) with increasing dwell time, resulting in a 7.8 +/- 3.6% recovery of unchanged fleroxacin in peritoneal dialysate. In conclusion, (i) a 50% reduction of the maintenance dose is recommended in patients with a renal function below 20 to 30 ml/min per 1.73 m2, and (ii) therapeutic concentrations of fleroxacin in the peritoneal dialysate should be achievable after oral administration in patients on continuous ambulatory peritoneal dialysis.
Penetration of pefloxacin into bronchial secretions
Authors: Bonmarchand G , Grès J J , Lerebours G , Massari P , Mayoux J J , Montay A , Leroy J
Published: June 2012

Twelve patients, intubated for acute exacerbation of chronic obstructive pulmonary disease, received six intravenous doses of 400 mg of pefloxacin at 12-h intervals. Samples of blood and bronchial secretions were taken simultaneously, before the injection and at 0.5, 3, 6, 9, and 12 h after the end of the sixth infusion. There was a large variation in pefloxacin levels in both serum and bronchial secretions. The mean concentrations of pefloxacin in bronchial secretions ranged from 6.51 to 11.1 micrograms/ml and were higher than the corresponding concentrations in serum at all times. Of 61 bronchial specimens, 48 (79%) contained more than 8 micrograms of the antibiotic per ml.
In vitro synergism between daptomycin and fosfomycin against Enterococcus faecalis isolates with high-level gentamicin resistance
Authors: Rice L B , Eliopoulos G M , Moellering R C
Published: June 2012

Daptomycin and fosfomycin are two agents which inhibit different steps in peptidoglycan synthesis. We studied the in vitro activities of these drugs, alone and in combination, by time-kill techniques against 21 clinical isolates of Enterococcus (Streptococcus) faecalis demonstrating high-level resistance to gentamicin. Combinations of fosfomycin and daptomycin exhibited synergistic bactericidal activity (100-fold decrease in CFU per milliliter at 24 h compared with daptomycin alone) against all strains (mean +/- standard deviation of increment in killing = 2.7 +/- 0.7 log10 CFU/ml). In a subgroup of strains against which daptomycin (5 micrograms/ml) alone was bactericidal (greater than 3 log10 killing), synergistic activity was demonstrable only when the concentration of daptomycin was lowered to 0.25 to 0.5 microgram/ml. A 50% dilution of human serum diminished the bactericidal activity of daptomycin alone at 24 h but did not affect killing observed with the daptomycin-fosfomycin combination. The inhibition of peptidoglycan synthesis by the combination was greater than the inhibition observed with either drug alone. The combination of daptomycin and fosfomycin exhibited consistent synergistic bactericidal activity against strains of E. faecalis possessing high-level resistance to gentamicin. This synergism may be the result of sequential inhibition of early steps in peptidoglycan synthesis.
In vivo efficacy of zidovudine (3'-azido-3'-deoxythymidine) in experimental gram-negative-bacterial infections
Authors: Keith B R , White G , Wilson H R
Published: June 2012

The therapeutic efficacy of orally administered zidovuldine (3'-azido-3'-deoxythymidine) was determined in animals infected with Escherichia coli and Salmonella dublin. The 50% effective dose (ED50) of zidovudine (9.6 to 11.8 mg/kg of body weight) compared favorably with that of trimethoprim (19.4 to 22.2 mg/kg) in mice with systemic E. coli infection. At 50 mg/kg, both zidovudine and ampicillin reduced the number of bacteria in the kidneys of mice and prevented lethal infection in mice with ascending pyelonephritis caused by E. coli. Zidovudine prevented a lethal S. dublin infection in calves over a wide dose range (8.0 to 31.0 mg/kg per day). Zidovudine levels in plasma of uninfected mice were 28.2 +/- 4.5 and 7.9 +/- 2.2 micrograms/ml at 30 and 60 min, respectively, exceeding the MICs for the bacteria used in the infections. Few zidovudine-resistant strains were observed. The in vivo data raise the possibility that zidovudine may have an antibacterial effect in patients receiving this therapy.
Efficacy of fleroxacin in experimental methicillin-resistant Staphylococcus aureus endocarditis
Authors: Kaatz G W , Seo S M , Barriere S L , Albrecht L M , Rybak M J
Published: June 2012

The efficacy of fleroxacin versus that of vancomycin was assessed by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Animals were treated with fleroxacin (30 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg every 6 h) for 4 days. These antimicrobial agents were equally effective in clearing bacteremia, reducing bacterial counts in vegetations and tissues, and curing endocarditis. However, resistance to fleroxacin at fivefold the MIC arose in the test strain of S. aureus in 8% of animals that received the drug. We conclude that fleroxacin is as efficacious as vancomycin in this model of a serious systemic S. aureus infection, but modest resistance to fleroxacin may develop during therapy.
Antibacterial activity of the new glycopeptide antibiotic SKF104662
Authors: Jorgensen J H , Redding J S , Maher L A
Published: June 2012

The inhibitory activity of the new glycopeptide antibiotic SKF104662 was generally equivalent (+/- 1 concentration increment) to the activities of vancomycin, teicoplanin, and daptomycin against selected gram-positive bacteria. However, SKF104662 demonstrated greater activity against Staphylococcus epidermidis and S. haemolyticus than did teicoplanin and was more active than the other drugs against Clostridium difficile isolates. SKF104662 possessed bactericidal activity quite similar to that of vancomycin against selected isolates of Staphylococcus, Streptococcus, and Enterococcus species.
Pseudomonas cepacia susceptibility to sulbactam
Authors: Jacoby G A , Sutton L
Published: June 2012

For 25 of 32 Pseudomonas cepacia isolates, predominantly from sputum of adult patients, agar dilution MICs of sulbactam were 2.5 micrograms/ml, and for only one was the MIC more than 80 micrograms/ml. Susceptibility was reliably predicted by response to a commercial sulbactam-ampicillin disk.
Postantibiotic effect of penicillin plus gentamicin versus Enterococcus faecalis in vitro and in vivo
Authors: Hessen M T , Pitsakis P G , Levison M E
Published: June 2012

A persistent suppression of bacterial growth following a brief exposure to an antibiotic (postantibiotic effect [( PAE]) has been described for a variety of antibiotics and microorganisms. If a PAE is present in vivo, antibiotic levels in tissue at the site of infection may decrease below the MIC without bacterial regrowth in the latter portion of the dosing interval. In the present studies, a PAE was sought in vitro and in vivo for penicillin G plus gentamicin versus Enterococcus faecalis. The studies demonstrated that increasing concentrations of gentamicin caused an increased rate of bactericidal action and an increasingly prolonged PAE in vitro. The combination of penicillin and gentamicin, in addition to more rapid killing, exhibited a more prolonged PAE than did penicillin alone. However, unlike these in vitro findings, no PAE could be demonstrated in vivo in rats with experimental left-sided enterococcal endocarditis treated with penicillin plus gentamicin. This suggests that antibiotic vegetation levels should be maintained above the MIC throughout the dosing interval to prevent loss of efficacy as a result of bacterial regrowth.
Pharmacokinetic evaluation of two dosage regimens of clindamycin phosphate
Authors: Plaisance K I , Drusano G L , Forrest A , Townsend R J , Standiford H C
Published: June 2012

Interpretation of the majority of data on the disposition of clindamycin is confounded by the presence of active metabolites, which may interfere with commonly employed bioassays. We undertook a multiple-dose study of the disposition of clindamycin phosphate and clindamycin, given either as 600 mg intravenously every 6 h or 1,200 mg intravenously every 12 h for five and three doses, respectively, in six healthy volunteers. Concentrations in serum and urine were analyzed by a specific gas chromatography assay. Maximum and minimum clindamycin concentrations in serum and the area under the serum concentration-time curve following the first dose were similar to those observed at the steady state. The mean and standard deviation of the maximum, 1-h postdose, and minimum concentrations in serum at steady state for the 600-mg dose given every 6 h were 16.8 +/- 6.0, 7.6 +/- 0.7, and 2.3 +/- 0.9 microgram/ml, whereas for the 1,200-mg dose given every 12 h they were 17.2 +/- 3.5, 9.8 +/- 1.5, and 0.6 +/- 0.3 microgram/ml, respectively. For the 12-h regimen, clindamycin concentrations in serum remained above 2 micrograms/ml for 7 h. The decay of clindamycin phosphate levels in serum was rapid, with virtually 100% of the phosphate eliminated within the first 1.5 h following the dose. Approximately 0.35 and 4.5% of the administered dose were recovered in the urine as clindamycin phosphate and clindamycin, respectively. Further pharmacokinetic evaluation of the 12-hourly dosage regimen should be done before clinical evaluation in infected patients is undertaken.
Characterization of mechanisms of quinolone resistance in Pseudomonas aeruginosa strains isolated in vitro and in vivo during experimental endocarditis
Authors: Chamberland S , Bayer A S , Schollaardt T , Wong S A , Bryan L E
Published: June 2012

Mechanisms of resistance to quinolones were characterized in Pseudomonas aeruginosa strains isolated after Tn5 insertional mutagenesis and in resistant strains that emerged during pefloxacin therapy of experimental aortic endocarditis. Quinolone resistance achieved in in vitro-selected mutants Qr-1 and Qr-2 was associated with cross-resistance to several groups of antimicrobial agents, including beta-lactams, tetracycline, and chloramphenicol. A significant reduction of norfloxacin uptake was also observed. After ether permeabilization of the cells, DNA synthesis of these two isolates was as susceptible to norfloxacin as DNA synthesis of the parent strain (PAO1). These results indicate that alteration of outer membrane permeability is the primary determinant of resistance in these isolates. This altered cell permeability was correlated with reduction of outer membrane protein G (25.5 kilodaltons) and loss of a 40-kilodalton outer membrane protein in strain Qr-1. Resistance to quinolones that emerged during experimental endocarditis therapy was associated with both modification of outer membrane permeability (decreased uptake of norfloxacin) and decreased susceptibility of DNA synthesis to norfloxacin. Resistance was limited to quinolones and chloramphenicol. For these strains, norfloxacin inhibitory doses (50%) for DNA synthesis were identical to the drug MICs, suggesting that despite the identification of a permeability change, perhaps due to changes of lipopolysaccharide, the alteration of the quinolone intracellular target(s) susceptibility constitutes the primary determinant of resistance. Also, two distinct levels of norfloxacin resistance of DNA synthesis were found in these isolates, indicating that at least two distinct alterations of the drug target(s) are possible in P. aeruginosa.
Comparative evaluation of daptomycin (LY146032) and vancomycin in the treatment of experimental methicillin-resistant Staphylococcus aureus osteomyelitis in rabbits
Authors: Mader J T , Adams K
Published: June 2012

A rabbit model for methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis was used to compare treatment with daptomycin, a new peptolide, and vancomycin. Daptomycin (4 mg/kg) and vancomycin (40 mg/kg) were injected subcutaneously every 12 and 6 h, respectively. After treatment, MRSA was found in bone cultures from 18 of 18 control rabbits, 10 of 17 animals treated with daptomycin, and 11 of 18 animals treated with vancomycin. Drug concentrations were measured in serum, uninfected bone, and infected bone 1 h after daptomycin or vancomycin was injected in a group of rabbits that had been infected for 3 to 4 weeks. Vancomycin was present at the highest concentrations in infected and uninfected bone. The results of this study suggest that daptomycin was similar to vancomycin in the eradication of MRSA from infected bone in an experimental model of osteomyelitis.
Simulation of human serum pharmacokinetics of ticarcillin-clavulanic acid and ceftazidime in rabbits, and efficacy against experimental Klebsiella pneumoniae meningitis
Authors: Mizen L , Woodnutt G , Kernutt I , Catherall E J
Published: June 2012

The penetration into cerebrospinal fluid (CSF) and efficacy of ticarcillin-clavulanic acid, ticarcillin alone, and ceftazidime were compared in rabbits with experimentally induced Klebsiella pneumoniae meningitis. The compounds were administered to simulate in rabbit plasma the concentration-versus-time curves observed in humans after 30-min infusions of Timentin (3 g of ticarcillin plus 100 mg of clavulanic acid), ticarcillin (3 g), and ceftazidime (2 g). Single- and multiple-dosing schedules were used. The penetrations of clavulanic acid into CSF (expressed as [area under the concentration-time curve for CSF/area under the curve for plasma] x 100) after the two dosing schedules were 28 and 24.5%, similar to that for ceftazidime (21%; multiple-dosing only) and greater than those for ticarcillin (8.4 and 9.3%). Ticarcillin was ineffective in reducing viable counts in CSF but, in the presence of clavulanic acid, reduced bacterial numbers by approximately 99% at 4 h after a single dose and by 99.99% at 12 h after three doses given at 4-h intervals. Two doses of ceftazidime given 8 h apart were more effective than the three doses of ticarcillin-clavulanic acid, in keeping with the in vitro activities of these compounds against the infecting organism. These results illustrate the ability of clavulanic acid to penetrate the blood-CSF barrier such that concentrations of the inhibitor in CSF potentiate the activity of ticarcillin against the ticarcillin-resistant, beta-lactamase-producing strain of K. pneumoniae.
Penetration of antibiotics into the surgical wound in a canine model
Authors: Rosin E , Ebert S , Uphoff T S , Evans M H , Schultz-Darken N J
Published: June 2012

The dose and timing of antimicrobial agents given for surgical wound prophylaxis should be based on the concentration-time profile of the drug in tissue at the site of contamination. However, concentrations of antimicrobial agents in surgical wounds are difficult to determine accurately. Since a surgical wound is a unique extravascular compartment with increased vascular permeability and a high surface area/volume ratio, antibiotic concentrations in sera and surgical wounds should be similar. To test this hypothesis, the pharmacokinetics of single intravenous doses of cefazolin (40 mg/kg) and gentamicin (4 mg/kg) in sera and surgical wounds in a clinically relevant surgical model using dogs were compared. Drug concentrations were determined in interstitial fluid in muscle biopsies taken randomly from wound surfaces and serial wound fluid samples collected after the incisions were closed. Protein binding of cefazolin and gentamicin in sera and wound fluids was low (less than or equal to 29 +/- 9%) in this canine model. Cefazolin and gentamicin equilibrated rapidly (less than or equal to 30 min) between serum and the surgical wound, and concentrations in the two sites declined in parallel. Values for the area under the concentration-time curve, mean residence time, and terminal half-life in serum and the surgical site for each drug were similar. Cefazolin concentrations in serum underestimated the time during which concentrations in surgical wounds exceeded the susceptibility breakpoint MIC for important pathogens by an average of 58 min (range, 26 to 109 min; P = 0.036); for gentamicin, the underestimation averaged 30 min (range, 10 to 60 min; P = 0.036). These data support the concept that the concentration-time profiles of antimicrobial agents in serum may prove valuable clinically as guides to determining the and timing of antibiotic administration necessary for effective antimicrobial prophylaxis in surgery. Further studies are needed to determine the surgical wound pharmacokinetics of highly protein-bound antibodies.
Antimicrobial susceptibility of Bordetella avium and Bordetella bronchiseptica isolates
Authors: Mortensen J E , Brumbach A , Shryock T R
Published: June 2012

Two veterinary pathogens, Bordetella bronchiseptica and Bordetella avium, were tested for their antimicrobial susceptibilities. Of the 20 antimicrobial agents tested, both species were consistently resistant to penicillin and cefuroxime but susceptible to mezlocillin, piperacillin, gentamicin, amikacin, and cefoperazone.
Inhibition of infectivity of human immunodeficiency virus by a novel nucleoside, oxetanocin, and related compounds
Authors: Seki J , Shimada N , Takahashi K , Takita T , Takeuchi T , Hoshino H
Published: June 2012

Oxetanocin is a novel nucleoside containing a 4-membered sugar, oxetanosyl-N-glycoside, and adenine. The effects of oxetanocin and related compounds on the infectivity of human immunodeficiency virus (HIV) were examined. They inhibited HIV infectivity in vitro. Allopurinol and mycophenolic acid produced additive anti-HIV effects when added with these compounds.
Production and induction of beta-lactamase during growth of Pseudomonas aeruginosa in biological fluids
Authors: Letendre E D , Turgeon P L
Published: June 2012

beta-Lactamase production in biological fluids was evaluated by using an antibiotic-resistant Pseudomonas aeruginosa strain. Enzyme production was low in plasma or ascitic fluid and high in urine. Induction of beta-lactamase by imipenem was studied by using an inducible P. aeruginosa strain. Induction was lower in biological fluids than in Mueller-Hinton broth.
Lincomycin increases the half-life of beta-lactamase mRNA
Authors: Matsushita O , Okabe A , Hayashi H , Kanemasa Y
Published: June 2012

Escherichia coli K-12 strains isolates carrying plasmid pBR322 were grown in the presence of subinhibitory concentrations of lincomycin, which stimulated beta-lactamase synthesis about 2.5-fold, and the effects of the drug on the synthesis and degradation of bla mRNA were studied. The bla mRNA levels determined by 1-min pulse-labeling with [3H]uridine were significantly higher in a lincomycin-containing culture than in the control culture, indicating that stimulation of beta-lactamase synthesis is caused by an increase in the amount of bla mRNA. The enhancing effect of lincomycin was observed in strains harboring pBR322 delta P1 and pBR322 delta P3, which lacked the P1 or P3 promoter, respectively, as well as in the strain harboring pBR322. S1 nuclease analysis showed that the half-life of bla mRNA increased about 2.7-fold when lincomycin was present. These results indicate that the increase in beta-lactamase synthesis caused by lincomycin is due to an increase in the stability of bla mRNA rather than activation of its synthesis.
Ceftriaxone disposition in open-heart surgery patients
Authors: Jungbluth G L , Pasko M T , Beam T R , Jusko W J
Published: June 2012

The effects of cardiopulmonary bypass (CPB) with hypothermia and systemic heparinization on ceftriaxone disposition were evaluated in seven male patients. A bolus dose of drug (14 mg/kg of body weight) was given, and blood and urine specimens were collected before, during, and after CPB for 96 h. Creatinine, albumin, and total and free ceftriaxone concentrations in plasma were measured. The ceftriaxone free fraction (ff) in vitro was estimated by equilibrium dialysis, and the in vivo ff was obtained by the ratio of renal clearance due to filtration to creatinine clearance. Pharmacokinetic parameters were based on concentrations of total drug and free drug. Albumin decreased from 3.10 +/- 0.29 g/dl presurgery to 1.42 +/- 0.17 g/dl and recovered to 2.46 +/- 0.26 g/dl on postoperative day 4. CPB markedly increased the in vitro ff, which was reversed by protamine post-CPB (ff pre-CPB, 0.15 +/- 0.01; during CPB, 0.53 +/- 0.20; post-CPB, 0.16 +/- 0.02). The in vitro ff exceeded the in vivo ff (0.53 +/- 0.20 versus 0.24 +/- 0.07), probably due to continued free fatty acid release caused by heparin during dialysis. Clearances based on free drug decreased, and the renal clearance due to filtration increased (7.6 +/- 2.8 versus 15.0 +/- 4.5 ml/min) while the creatinine clearance decreased (114 +/- 29 versus 72 +/- 28 ml/min) during CPB. Diminished binding owing to low albumin and free fatty acids explain this behavior. Lower binding also increased the volume of distribution (154 +/- 41 ml/kg) and extended the half-life (15 +/- 6 h). In summary, ceftriaxone disposition was significantly altered by CPB, resulting in marked increases in free drug concentrations, half-life, and volume of distribution and in decreased intrinsic clearance.
Effects of a derivative of serotonin (deoxyfructoserotonin) and other antileprosy drugs on attachment and uptake of Mycobacterium leprae by Schwann cells in vitro
Authors: Choudhury A , Mistry N F , Antia N H
Published: June 2012

The association (attachment and/or uptake) of Mycobacterium leprae with cultured Schwann cells was studied at 8 and 72 h in the presence of a new antileprosy compound, deoxyfructoserotonin (DFS), as well as conventional antileprosy drugs such as rifampin (RFP) and 4,4'-diaminodiphenyl sulfone (DDS). DFS significantly inhibited bacterial association with Schwann cells at 8 h. RFP also affected the association of M. leprae but not to the same extent as DFS. A similar inhibition at 8 h was noted when M. leprae but not Schwann cells were pretreated with DFS or RFP for 5 days before infection of cultures, implying that modulation was achieved through some form of drug action on bacteria. DDS had no effect on M. leprae association; however, the combination of DFS and DDS was neither antagonistic nor additive. At 72 h postinfection, when attached but noninternalized bacteria were removed with trypsin-EDTA from Schwann cell cultures containing DFS or RFP, a 50% reduction in the number of bacteria in the drug-treated group was obtained as compared with the numbers in drug-free cultures. This indicated a slow entry of M. leprae into Schwann cells in the presence of these drugs. Collectively, these observations point to differing requirements for late and early association of M. leprae with Schwann cells, besides suggesting a role for DFS and RFP in the prevention and minimization of M. leprae-induced nerve damage in vivo.
Human immunodeficiency virus inhibition is prolonged by 3'-azido-3'-deoxythymidine alternating with 2',3'-dideoxycytidine compared with 3'-azido-3'-deoxythymidine alone
Authors: Spector S A , Ripley D , Hsia K
Published: June 2012

The inhibition of the lymphadenopathy-associated virus strain of human immunodeficiency virus (HIV) by alternating regimens of two dideoxynucleosides, 3'-azido-3'-deoxythymidine (AZT) (zidovudine) and 2',3'-dideoxycytidine (ddC), was determined in CEM cells. Cultures infected with virus for 2 h were treated with clinically achievable concentrations of AZT, ddC, or a 3-day-alternating regimen of AZT and ddC. Media were completely changed every 3 days and replaced with antiviral agent, and virus production was assayed by p24 antigen and virus-specific DNA. Cells treated with no antiviral agent exhibited breakthrough infection by day 6 in culture, whereas cells treated with 0.1, 1.0, or 3.0 microM AZT had a prolonged time to viral breakthrough. For each regimen of AZT alternating with 0.05 or 0.1 microM ddC, there was consistently prolonged HIV inhibition compared with continuous treatment with AZT alone. The viral suppression achieved with the alternating combinations required AZT as well as ddC and was superior to 3 days of treatment with ddC alternating with 3 days of no antiretroviral treatment. Levels of unintegrated HIV DNA paralleled the detection of p24 antigen, with the most prolonged inhibition of virus-specific DNA occurring with AZT alternating with ddC (compared with all regimens except continuous treatment with ddC). These data suggest that alternating regimens of AZT and ddC not only might decrease toxicity associated with the two drugs but may prove to be more efficacious than AZT alone.
Sputum levels of fluconazole in humans
Authors: Ebden P , Neill P , Farrow P R
Published: June 2012

We measured fluconazole levels in sputum samples obtained from 11 bronchiectatic volunteers at 4 and 24 h after a single oral dose of 150 mg of fluconazole. Levels in sputum were similar to levels in plasma at both times.
In vitro activity of SK&F 104662, a new glycopeptide antibiotic
Authors: Yao J D , Eliopoulos G M , Moellering R C
Published: June 2012

The in vitro activity of SK&F 104662, a new glycopeptide antibiotic, against gram-positive bacteria was evaluated. Activity was comparable to those of teicoplanin and vancomycin against most organisms. SK&F 104662 inhibited diphtheroids at concentrations of less than or equal to 0.5 microgram/ml. Addition of human serum to the test medium lowered the inhibitory activity of this glycopeptide against some organisms by as much as eightfold.
Randomized double-blind evaluation of ciprofloxacin and doxycycline for Mediterranean spotted fever
Authors: Gudiol F , Pallares R , Carratala J , Bolao F , Ariza J , Rufi G , Viladrich P F
Published: June 2012

A study of 43 patients with Mediterranean spotted fever showed that a 2-day course of ciprofloxacin or a 2-day course of doxycycline may be an effective mode of therapy. All patients in both arms of the study were cured; however, doxycycline produced a more rapid defervescence.
Effect of lomefloxacin on theophylline pharmacokinetics
Authors: Nix D E , Norman A , Schentag J J
Published: June 2012

A study involving 25 health male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 +/- 3.0 years, and the mean weight was 77.3 +/- 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 +/- 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 +/- 1.63 to 7.02 +/- 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.
Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection
Authors: Sjövall J , Bergdahl S , Movin G , Ogenstad S , Saarimäki M
Published: June 2012

To investigate the pharmacokinetics and effects of intravenous foscarnet, 13 relatively healthy male patients with human immunodeficiency virus infection and a mean CD4+ lymphocyte value of 0.45 x 10(-9) cells per liter were given a continuous intravenous infusion of foscarnet (0.14 to 0.19 mg/kg per min) for 8 to 21 days. Blood and urine samples were taken during and after drug administration to monitor foscarnet concentrations. Lumbar puncture was performed during the infusion in five patients. The concentrations in plasma showed large variations both within and between patients. The disposition of foscarnet could be explained by a triexponential equation (t1/2 lambda 1, 0.40 to 2.52 h; t1/2 lambda 2, 3.20 to 16.7 h; t1/2 lambda 3, 36 to 196 h). Renal clearance accounted for most of the plasma clearance, the difference probably reflecting the passage of foscarnet into bone. Up to 20% of the cumulative dose may have been deposited in bone 7 days postinfusion. Foscarnet was distributed to the cerebrospinal fluid in a concentration varying from 13 to 68% of the simultaneous concentration in plasma. Polyuria and polydipsia were recorded in all patients. There appears to be an association between the degree of malaise, including symptoms such as nausea, vomiting, fatigue, and headache, and concentrations in plasma above 350 mumol/liter.
Comparative in vitro activity of a new quinolone, AM-1091
Authors: Neu H C , Novelli A , Chin N X
Published: June 2012

The in vitro activity of a new quinolone, AM-1091 [7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo- 3-quinoline carboxylic acid hydrochloride], was compared with those of ciprofloxacin, ofloxacin, beta-lactams, and gentamicin. AM-1091 inhibited 90% of the isolates of the family Enterobacteriaceae at less than or equal to 0.12 micrograms/ml. For many species AM-1091 was 2-fold more active than ciprofloxacin and 2- to 32-fold more active than ofloxacin. It inhibited Enterobacter, Citrobacter, and Klebsiella species resistant to ceftazidime and gentamicin. Ninety percent of Pseudomonas aeruginosa isolates were inhibited by 0.5 micrograms/ml, so for this species AM-1091 was twofold less active than ciprofloxacin. AM-1091 was more active against Pseudomonas cepacia and Xanthomonas maltophilia, inhibiting isolates resistant to imipenem and gentamicin. Most Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, and Branhamella catarrhalis isolates were inhibited by less than or equal to 0.06 micrograms/ml. The MICs for 90% of Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecalis isolates were 0.06, 0.06, and 2 micrograms/ml, respectively. AM-1091 inhibited hemolytic streptococci and Streptococcus pneumoniae at 0.25 micrograms/ml and was more active than ciprofloxacin or ofloxacin against gram-positive species. AM-1091 inhibited 90% of the Bacteroides species at 0.5 micrograms/ml. The frequency of spontaneous resistance was less than 10(-10) for most organisms, but resistant strains could be selected by repeated subculturing. Although AM-1091 had lower in vitro activity at pH 5.5 and in the presence of high concentrations of Mg2+, it still inhibited most organisms at </= 0.5 micrograms/ml under these conditions. AM-1091 rapidly killed Escherichia coli and P. aeruginosa and had a prolonged postantibiotic suppressive effect on these bacteria.
Fluconazole (UK-49,858) treatment of candidiasis in normal and diabetic rats
Authors: Fisher M A , Lee P G , Tarry W F
Published: June 2012

Fluconazole (UK-49,858), a new oral bistriazole antifungal agent, was compared with amphotericin B in the treatment of established systemic infection with Candida albicans in normal and diabetic rats. In normal rats, oral fluconazole at 10 mg/kg per day for 7 days reduced Candida colony counts in the kidneys and livers as well as amphotericin B did and was nearly as effective as amphotericin B in a 21-day treatment trial. There was no further reduction in Candida colony counts when normal rats were treated with fluconazole at 40 mg/kg twice a day for 7 days. In streptozotocin-induced diabetic rats, fluconazole at 20 mg/kg per day for either 7 or 21 days compared favorably with amphotericin B in efficacy. Results of our study suggest that oral fluconazole may be useful in the treatment of established disseminated candidiasis in normal as well as diabetic hosts.
Selective activity of 5-fluoroorotic acid against Plasmodium falciparum in vitro
Authors: Rathod P K , Khatri A , Hubbert T , Milhous W K
Published: June 2012

Unlike mammalian cells, malarial parasites are completely dependent on de novo pyrimidine metabolism. Even though these parasites do not use external uracil or uridine, orotic acid, an intermediate of pyrimidine biosynthesis, is successfully transported into the parasite and incorporated into parasite nucleic acids. On this basis, it was hypothesized that 5-fluoroorotate, a cytotoxic derivative of orotic acid, may be a potent and selective antimalarial agent. In vitro, 5-fluoroorotate caused 50% inhibition of the growth of Plasmodium falciparum at a concentration of 6.0 nM. In contrast, 5-fluorouracil, 5-fluorouridine, and 5-fluoro 2'-deoxyuridine were much less effective against malarial parasites. Chloroquine-susceptible and chloroquine-resistant clones of P. falciparum were equally susceptible to 5-fluoroorotate. The toxicity of 5-fluoroorotate was evaluated on four human cell lines (HT-1080, IMR-90, HeLa S3, and HL-60) and one mouse cell line (L-1210). Compared with malarial parasites, the mammalian cells were relatively tolerant of 5-fluoroorotic acid (50% inhibitory concentration, 0.9 to 10 microM). Finally, in the presence of 1 mM uridine, all mammalian cells were partially protected from 5-fluoroorotate cytotoxicity, but uridine offered no protection to P. falciparum.
In vitro susceptibilities of yeasts to a new antifungal triazole, SCH 39304: effects of test conditions and relation to in vivo efficacy
Authors: McIntyre K A , Galgiani J N
Published: June 2012

We used six candidal strains (two Candida albicans and one each of four other species) to study the effects of test conditions on the activity of SCH 39304 compared with that of fluconazole in broth macro- and microdilution assays. Increasing the inoculum from 10(2) to 10(5) yeasts per ml raised the MICs for all isolates up to greater than 512-fold. In contrast, results with a 50% turbidimetric endpoint (50% inhibitory concentration; IC1/2) varied no more than twofold. Similar effects were seen with fluconazole, and both drugs were found to have an associated delay in onset of action. Acidity was found to increase both MICs and IC1/2s. Other effects were observed among four synthetic media, but a consistent pattern was not identified. Incubation temperatures of 37, 35, and 30 degrees C yielded equivalent results. Broth microdilution IC1/2s against most of 40 isolates of C. albicans were 0.31 microgram/ml +/- fourfold for SCH 39304 and 0.16 microgram/ml +/- twofold for fluconazole. Treatment of experimental candidiasis in rats with SCH 39304 and fluconazole resulted in 50% effective doses of 0.33 and 0.49 mg/kg per day, respectively. In contrast, another C. albicans isolate, previously identified as resistant to other azoles, had IC1/2s of 20 micrograms of SCH 39304 per ml and, in vivo, a 50% effective dose of 2.25 mg/kg per day. We conclude that the in vivo efficacy of SCH 39304 correlates with MIC results when broth macrodilution testing is performed with a small inoculum and with IC1/2 results which are independent of inoculum size.