bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of single-dose treatment with norfloxacin and standard 5-day treatment with trimethoprim-sulfamethoxazole for acute shigellosis in adults
Authors: Gotuzzo E , Oberhelman R A , Maguiña C , Berry S J , Yi A , Guzman M , Ruiz R , Leon-Barua R , Sack R B
Published: June 2012

Shigellae have been shown to be highly susceptible to new quinolone agents, with average MICs for 90% of isolates of less than 0.1 microgram/ml. Because these agents also reach high concentrations in the stool after a single dose, the effectiveness of a single 800-mg dose of norfloxacin and of 5-day treatment with trimethoprim-sulfamethoxazole (TMP-SMX) were compared in a randomized trial. Patients with clinical dysentery received one of these treatment regimens, and clinical data and follow-up culture results were analyzed for patients whose stool culture on presentation grew shigellae. When 55 patients with shigellosis (26 treated with TMP-SMX, 29 treated with norfloxacin) whose bacterial isolates were susceptible to the antibiotic given were compared by treatment group, no significant differences were seen in days of illness (mean, 2.5 +/- 0.65 days with TMP-SMX and 2.0 +/- 0.47 days with norfloxacin; P = 0.200) or number of unformed stools after starting treatment (mean, 9.7 +/- 2.37 stools with TMP-SMX and 7.6 +/- 3.19 stools with norfloxacin; P = 0.312). Resistance in vitro to TMP-SMX was seen in 15% of Shigella isolates, whereas none was resistant to norfloxacin. Bacteriologic failure was found in 1 patient among 24 receiving TMP-SMX and in none of 25 patients receiving norfloxacin. One single dose of norfloxacin was as effective as 5 days of treatment with TMP-SMX in these adults with shigellosis.
Relative bioavailability in healthy volunteers of ciprofloxacin administered through a nasogastric tube with and without enteral feeding
Authors: Yuk J H , Nightingale C H , Sweeney K R , Quintiliani R , Lettieri J T , Frost R W
Published: June 2012

The bioavailability of ciprofloxacin after its administration through a nasogastric (NG) feeding tube was studied in six healthy volunteers. Each subject received, on separate occasions, an intact 750-mg ciprofloxacin tablet, a crushed tablet as a suspension through an NG tube, and a crushed tablet as a suspension through an NG tube while receiving enteral feeding. No statistically significant differences were observed in the area under the curve, maximum concentration in serum, and time to peak concentration among these three modes of administration. These findings suggest that ciprofloxacin is well absorbed after administration via an NG tube (compared with an orally administered intact tablet) even in the presence of enteral feeding.
Randomized clinical trial of aztreonam and aminoglycoside antibiotics in the treatment of serious infections caused by gram-negative bacilli
Authors: DeMaria A , Treadwell T L , Saunders C A , Porat R , McCabe W R
Published: June 2012

Aztreonam was compared with aminoglycoside antibiotics (tobramycin and amikacin) in a randomized, prospective, clinical trial in serious infections caused by gram-negative bacilli (GNB). A total of 43 evaluable patients with 47 infected sites were treated with aztreonam, and 41 evaluable patients were treated with aminoglycosides for 43 infections. Of patients treated with aztreonam, 17 were bacteremic, as were 12 of those treated with aminoglycosides. Clinical and microbiologic response rates were similar, except that only 5 of 11 patients with pneumonia were considered to be clinically cured with aminoglycoside therapy, while 5 of 6 patients with pneumonia treated with aztreonam were cured. Renal impairment was observed in 9 of 54 patients who received aminoglycoside antibiotics, but in only 2 of 53 patients treated with aztreonam. Hearing impairment developed in one patient treated with tobramycin. Transient elevations of serum transaminase levels occurred in 9 of 53 patients treated with aztreonam and in only 2 of 54 aminoglycoside-treated patients. Diarrhea and superinfection occurred with equal frequency in both groups. Serum concentrations of bactericidal activity could not be correlated with the outcome of therapy. Aztreonam appears to have comparable clinical efficacy with aminoglycoside antibiotics for the treatment of serious infections caused by aerobic and facultative GNB. Its use as a single agent for the treatment of serious lower respiratory infections caused by GNB warrants further evaluation.
In vitro and in vivo antibacterial activities of AT-4140, a new broad-spectrum quinolone
Authors: Nakamura S , Minami A , Nakata K , Kurobe N , Kouno K , Sakaguchi Y , Kashimoto S , Yoshida H , Kojima T , Ohue T
Published: June 2012

AT-4140, 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5- dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, showed broad and potent antibacterial activity. Its MICs for 90% of the strains tested were 0.1 to 0.78 micrograms/ml against gram-positive organisms, such as members of the genera Staphylococcus, Streptococcus, and Enterococcus, and 0.0125 to 1.56 micrograms/ml against gram-negative organisms, such as members of the family Enterobacteriaceae and the genera Pseudomonas, Branhamella, Campylobacter, Haemophilus, and Neisseria. Its MICs were 0.025 to 0.78 micrograms/ml against glucose nonfermenters, such as members of the genera Xanthomonas, Acinetobacter, Alcaligenes, Moraxella, Flavobacterium, and Brucella; 0.2 to 0.78 micrograms/ml against anaerobes, such as Clostridium perfringens and Bacteroides fragilis; 0.0125 to 0.05 micrograms/ml against Legionella spp.; 0.0125 to 0.2 micrograms/ml against Mycoplasma spp.; 0.031 to 0.063 micrograms/ml against Chlamydia spp.; and 0.1 to 0.3 micrograms/ml against Mycobacterium spp. The potencies of AT-4140 against gram-negative organisms were comparable to those of ciprofloxacin and higher than those of ofloxacin, enoxacin, and norfloxacin. The potencies of AT-4140 against gram-positive organisms, glucose nonfermenters, anaerobes, Mycoplasma spp., Chlamydia spp., and Mycobacterium spp. were generally higher than those of the quinolones with which AT-4140 was compared. AT-4140 showed good oral efficacy against systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa in mice. Its efficacy was better when a daily dose was given once than when it was given in two doses. Good efficacies of the orally administered drug were also observed in pulmonary, dermal, and urinary tract infection models in mice. The in vivo efficacies of AT-4140 were equal to or better than those of ciprofloxacin, ofloxacin, enoxacin, and norfloxacin.
Efficacy of dicloxacillin-coated polyurethane catheters in preventing subcutaneous Staphylococcus aureus infection in mice
Authors: Sherertz R J , Forman D M , Solomon D D
Published: June 2012

In a mouse model, dicloxacillin-coated polyurethane catheters or control (uncoated) catheters were placed subcutaneously and then Staphylococcus aureus was inoculated at the time of insertion, 24 or 48 h later. The in vivo half-life of the antibiotic was 11 to 16 h. When 10(5) CFU of S. aureus were inoculated at the time of catheter insertion, dicloxacillin-coated catheters kept the number of S. aureus removed from catheters by sonication below 10(2) CFU at 12, 24, 48, and 96 h after inoculation compared with titers greater than 10(3.5) CFU for control catheters (P less than 0.05). When S. aureus was inoculated 24 h after catheter insertion, control catheters averaged greater than 10(2) CFU of S. aureus removed compared with less than 10(1.5) CFU for the dicloxacillin-coated catheters (P less than 0.05). No difference was found between coated and control catheters when S. aureus was inoculated 48 h after catheter insertion, but S. aureus titers averaged less than 10(2) CFU for all experimental groups. Our data suggest that in mice, regional prophylaxis of S. aureus subcutaneous space infection is feasible with catheters coated with dicloxacillin and that the presence of antibiotic is only necessary for the first 24 to 48 h.
Liposome-encapsulated-amikacin therapy of Mycobacterium avium complex infection in beige mice
Authors: Cynamon M H , Swenson C E , Palmer G S , Ginsberg R S
Published: June 2012

Efficacy of liposome-encapsulated amikacin and free amikacin against Mycobacterium avium complex was evaluated in the beige mouse (C57BL/6J-bgJ/bgJ) acute infection model. Approximately 10(7) viable M. avium complex serotype 1 cells for which the MIC of amikacin was 8 micrograms/ml were given intravenously. Treatment was started with encapsulated or free amikacin at approximately 110 or 40 mg/kg of body weight 7 or 14 days later. In the former experiment, treatment was given two or three times per week. In the latter experiment, treatment was given daily for 5 days. The animals were sacrificed 5 days after the last dose. Liver, spleen, and lung were homogenized, and viable cell counts were determined on 7H10 agar. An analysis of variance and subsequent Tukey HSD (honestly significant difference) tests indicated that both encapsulated and free amikacin significantly reduced viable cell counts in each of the organs compared with counts in the control group. Compared with free amikacin, encapsulated amikacin significantly reduced viable cell counts in the liver and spleen. Liposome encapsulation of an active agent appears to be a promising therapeutic approach to M. avium complex infection.
Single-dose cefuroxime axetil versus multiple-dose cefaclor in the treatment of acute urinary tract infections
Authors: Iravani A , Richard G A
Published: June 2012

Eighty-nine college women with acute urinary tract infections were treated orally with either 1,000 mg of cefuroxime axetil in a single dose (n = 59) or 250 mg of cefaclor three times a day for 7 days (n = 30). At 1 week posttherapy, 88% of the patients in the cefuroxime axetil group and 97% in the cefaclor group were clinically and bacteriologically cured (P greater than 0.10). There was no statistically significant difference between the cure rates of the two treatment groups. However, this study has only a 50% power to detect a 10% difference. Therefore, there is a substantial possibility of a type II error, i.e., failing to find a difference that is actually present. At 4 weeks posttherapy, 78% of the patients in the cefuroxime group and 80% in the cefaclor group remained cured. By 36 weeks posttherapy, the cumulative rate of recurrence in both treatment groups was 60%. Of the patients with a positive antibody-coated bacteria test, fewer achieved a short-term cure after single-dose treatment with cefuroxime axetil than those with a negative antibody-coated bacteria test (67 versus 96%; P less than 0.01).
Topical delivery of liposomally encapsulated interferon evaluated in a cutaneous herpes guinea pig model
Authors: Weiner N , Williams N , Birch G , Ramachandran C , Shipman C , Flynn G
Published: June 2012

The topical delivery of liposomally encapsulated interferon was evaluated in the cutaneous herpes simplex virus guinea pig model. Application of liposomally entrapped interferon caused a reduction of lesion scores, whereas application of interferon formulated as a solution or as an emulsion was ineffective. The method of liposomal preparation rather than the lipid composition of the bilayers appeared to be the most important factor for reducing lesion scores. Only liposomes prepared by the dehydration-rehydration method were effective. This finding implied that the dehydration and subsequent rehydration of the liposomes facilitate partitioning of the interferon into liposomal bilayers, where the drug is positioned for transfer into the lipid compartment of the stratum corneum. Liposomes do not appear to function as permeation enhancers but seem to provide the needed physicochemical environment for transfer of interferon into the skin.
Comparative effects of the azole-based fungicide flusilazole on yeast and mammalian lanosterol 14 alpha-methyl demethylase
Authors: Trzaskos J M , Henry M J
Published: June 2012

Flusilazole inhibits the 14 alpha-demethylation of [24,25-3H-2]dihydrolanosterol by yeast and rat liver cell-free preparations. The 50% inhibitory concentration of demethylation shows that the yeast system is 100 times more sensitive than the rat system. Purified rat liver P-45014DM is about 10 times more sensitive to flusilazole than crude rat liver microsomes. Binding constants in microsomes indicate that yeast preparations (Kd, 21 nM) bind flusilazole with a higher affinity than rat liver (Kd, 496 nM). Purified rat liver P-45014DM (Kd, 45 nM) binds flusilazole with an affinity similar to that of the yeast enzyme. The P-450-dependent cholesterol 7 alpha-hydroxylase in rat liver microsomes is more sensitive to flusilazole than P-45014DM. The results indicate that selectivity of azole antimycotics is not due to inherent sensitivity differences between fungal and mammalian 14 alpha-demethylase; rather, in crude enzyme systems, a protective effect is afforded by other susceptible isozymes present in mammalian systems.
Comparative in vitro activity of SM7338, a new carbapenem antimicrobial agent
Authors: Sentochnik D E , Eliopoulos G M , Ferraro M J , Moellering R C
Published: June 2012

The comparative in vitro activity of SM7338 was tested against 670 routine clinical isolates and 130 cefoperazone-resistant isolates of bacteria by agar dilution methods. SM7338 was at least as active as imipenem against gram-negative organisms but was slightly less active against gram-positive organisms. SM7338 was particularly active against members of the family Enterobacteriaceae, with MICs for 90% of strains of less than or equal to 0.125 micrograms/ml for all species tested. Differences in activity between SM7338 and imipenem were particularly striking against Proteus vulgaris, Proteus mirabilis, and Morganella morganii, against which MICs of SM7338 and imipenem for 90% of strains were 0.125 and 4 micrograms/ml, respectively. The presence of unique plasmid-mediated beta-lactamases in Pseudomonas aeruginosa PU21 transconjugants did not affect activity substantially, except in the case of OXA-2 (eightfold-increased MIC) and OXA-3 (fourfold-increased MIC). SM7338 was also active against a laboratory-derived strain of P. aeruginosa which hyperproduced chromosomal beta-lactamase, inhibiting both the wild type and the mutant at a concentration of 1.0 micrograms/ml.
Efficacy of SCH39304 in murine cryptococcosis
Authors: Restrepo B I , Ahrens J , Graybill J R
Published: June 2012

Cryptococcal meningitis is increasing in frequency, in large part because of the advent of acquired immune deficiency syndrome. Using the murine cryptococcosis model, a new oral triazole, SCH39304, has been compared with two drugs in clinical use, fluconazole and amphotericin B. BALB/c mice (nu/nu and nu/+) were challenged intracerebrally or intranasally. Oral treatment was given daily with SCH39304 at doses of 1 to 60 mg/kg of body weight or fluconazole at doses of 1 or 5 mg/kg of body weight. Amphotericin B was given intraperitoneally three times weekly, at doses of 3 or 6 mg/kg. After intracerebral challenge, SCH39304 prolonged survival in doses as low as 1 mg/kg, a dose at which fluconazole was ineffective. At equal doses, SCH39304 consistently increased survival more than did fluconazole but not longer than did amphotericin B. SCH39304 significantly lowered colony counts in brains more than did fluconazole but no more than did amphotericin B. SCH39304 was also superior to fluconazole after intranasal challenge at equal doses. SCH39304 appears to be superior to fluconazole in mice when the drugs are given at equal doses. Clinical trials are warranted.
Comparative in vitro activities of piperacillin-tazobactam and ticarcillin-clavulanate
Authors: Fass R J , Prior R B
Published: June 2012

The in vitro activities of ticarcillin, piperacillin, clavulanic acid, tazobactam, ticarcillin-clavulanate, and piperacillin-tazobactam against 819 bacterial isolates were compared. The two beta-lactamase inhibitors, clavulanic acid and tazobactam, had little useful antibacterial activity but enhanced the activities of the penicillins against beta-lactamase-producing strains of Haemophilus influenzae, Branhamella catarrhalis, and methicillin-susceptible Staphylococcus aureus; all strains were susceptible to both combinations. Both enzyme inhibitors also enhanced the activities of the penicillins against most strains of Escherichia coli, Klebsiella spp., Citrobacter diversus, Proteus spp., Providencia spp., and Bacteroides spp. and against occasional strains of Citrobacter freundii, Enterobacter spp., and Serratia marcescens. Clavulanic acid frequently enhanced the activity of ticarcillin against Xanthomonas maltophilia, and tazobactam frequently enhanced the activity of piperacillin against Morganella morganii. Enhancement was observed primarily with strains relatively resistant to the penicillins. In general, clavulanic acid was more effective than tazobactam in enhancing penicillin activity against Klebsiella spp., C. diversus, X. maltophilia, and Bacteroides spp., whereas tazobactam was more effective against Escherichia coli and Proteeae. There was little or no enhancement of activity against Enterococcus faecalis, Aeromonas hydrophila, Pseudomonas aeruginosa, Pseudomonas cepacia, or Acinetobacter anitratus. Clavulanic acid occasionally antagonized the activity of ticarcillin against ticarcillin-susceptible members of the family Enterobacteriaceae, but those strains were still considered susceptible to the combination. Tazobactam never antagonized the activity of piperacillin. In a direct comparison of the activities of ticarcillin-clavulanate and piperacillin-tazobactam, the two were equally active against H. influenzae, B. catarrhalis, and S. aureus; the latter was more active against E. faecalis. For relatively susceptible strains of members of the family Enterobacteriaceae, neither combination was predictably more active than the other, but relatively resistant strains were generally more susceptible to piperacillin-tazobactam. Piperacillin-tazobactam was more active than ticarcillin-clavulanate against A. hydrophila, P. aeruginosa, and P. cepacia, similar in activity against A. anitratus, and less active against X. maltophilia and Bacteroides spp.
Measurement and clinical and pharmacokinetic implications of diffusion coefficients of antibiotics in tissues
Authors: Meulemans A , Paycha F , Hannoun P , Vulpillat M
Published: June 2012

A method for determining diffusion coefficients of four antibiotics in extracellular tissue space according to Fick's law is described. This new method was applied to rat brain tissue and to agar. After diffusion of the antibiotic in one axis, the gradient concentration was determined with microvoltammetric electrodes. These microelectrodes (1 micron at the extreme tip) measured the free diffusible form of electroactive antibiotics in the extracellular brain space. Metronidazole, chloramphenicol succinate, cefsulodin, and piperacillin gave diffusion coefficients ranging from 0.1 x 10(-6) to 0.2 x 10(-6) cm2 . s-1 in tissue; chloramphenicol base, which is positively charged, gave a coefficient of 0.04 x 10(-6) cm2 . s-1. The coefficient ranged from 0.6 x 10(-6) to 1.2 x 10(-6) cm2 . s-1 in agar. These coefficients were used to simulate antibiotic concentrations in infectious sites and between capillaries by using a simple model of plane diffusion.
beta-Lactamase stability and in vitro activity of oral cephalosporins against strains possessing well-characterized mechanisms of resistance
Authors: Sanders C C
Published: June 2012

The in vitro activity of four oral cephalosporins was assessed in dilution tests with 50 isolates of the family Enterobacteriaceae possessing well-characterized mechanisms of resistance to beta-lactam antibiotics. The interaction of the drugs with a broad array of beta-lactamases was also determined in spectrophotometric assays and tests for enzyme induction. Overall, the percentages of strains susceptible to each of the study drugs were 82% for cefixime, 62% for cefuroxime, 58% for cephalexin, and 44% for cefaclor. The poor activity of the older cephalosporins was due to a high degree of susceptibility to hydrolysis by both plasmid-mediated and chromosomally mediated beta-lactamases. For cefaclor, higher MICs were associated with higher levels of plasmid-mediated beta-lactamases in the strains. Resistance to cefuroxime was seen primarily among strains expressing high levels of class I or IV beta-lactamase. Resistance to cefixime was seen only among strains expressing high levels of class I enzymes. Neither cefixime nor cefuroxime was a strong inducer of class I beta-lactamases, although enzyme induction did appear to play a role in cefuroxime resistance in a strain of Serratia marcescens. The consistently greater activity of cefixime over cefuroxime was found not to be due to greater drug permeation into the cell. Rather, it appeared to result from the high affinity of the drug for target enzymes.
Cloning and hybridization analysis of ermP, a macrolide-lincosamide-streptogramin B resistance determinant from Clostridium perfringens
Authors: Berryman D I , Rood J I
Published: June 2012

The erythromycin resistance determinant from Clostridium perfringens CP592 was cloned and shown to be expressed in Escherichia coli. The resultant plasmid, pJIR122 (7.9 kilobase pairs [kb]), was unstable since in both recA+ and recA E. coli hosts spontaneous deletion of 2.7 kb, including the erythromycin resistance determinant, was observed. Subcloning, as well as deletion analysis with BAL 31, localized the erythromycin resistance gene (ermP) to within a 1.0-kb region of pJIR122. A 0.5-kb fragment internal to ermP was 32P labeled and used as an ermP-specific probe in DNA hybridization experiments which used target DNA prepared from representatives of each of the known erm classes and also from erythromycin-resistant isolates of a variety of clostridial species. Hybridizing sequences were detected in DNA from several Clostridium difficile isolates and a Clostridium paraputrificum strain; however, ermP was not widespread in erythromycin-resistant C. perfringens isolates. The ermP determinant hybridized to, and shared significant restriction identity with, the ermB class gene from the streptococcal plasmid pAM beta 1. No hybridization was detected with the other six hybridization classes of erm determinants.
Interaction of the fluoroquinolone antimicrobial agents ciprofloxacin and enoxacin with liposomes
Authors: Bedard J , Bryan L E
Published: June 2012

The interaction between ciprofloxacin and enoxacin and phospholipid-containing bilayers was examined as the initial step in transmembrane diffusion processes. By using cosedimentation, maximal association of liposomes and 14C-labeled enoxacin and ciprofloxacin was detected at acidic and neutral pHs. Aqueous solubility of ciprofloxacin, enoxacin, and norfloxacin was poorest at neutral pH and greater at alkaline or acidic pHs. These investigations suggest that the interaction occurs because of ionic and hydrophobic forces and is nonsaturable up to 20 micrograms/ml.
Single-dose treatment of cholera with furazolidone or tetracycline in a double-blind randomized trial
Authors: Rabbani G H , Islam M R , Butler T , Shahrier M , Alam K
Published: June 2012

To evaluate single doses of 400 mg of furazolidone and 1 g of tetracycline given orally to patients with diarrhea due to Vibrio cholerae, we studied 87 adults in a randomized, double-blind, placebo-controlled trial. All patients received intravenous fluids for rehydration and no other drugs. The total volumes of stool (mean +/- standard deviation) during a 6-day period after treatment were significantly smaller in the tetracycline group (10.5 +/- 8.6 liters) than in the furazolidone group (20.9 +/- 15.9 liters) and the placebo group (19.1 +/- 10.5 liters) (P less than 0.01). The duration of diarrhea and volumes of intravenous fluids were also significantly reduced in the tetracycline group (P less than 0.05). However, there were no differences between the furazolidone and the placebo groups with regard to stool volume, intravenous fluid, and duration of diarrhea. Within 48 h of treatment, tetracycline significantly reduced the number of patients with positive stool cultures for V. cholerae (37%) compared with furazolidone treatment (96%) and the placebo (97%) (P less than 0.001). Although the tetracycline group had a significantly higher incidence (61%) of bacteriologic relapse (negative stool cultures on days 2 and 3, followed by positive cultures afterward) compared with that in the furazolidone group (40%) and the placebo group (33%), this was not associated with clinical relapse. There were no differences between the furazolidone and placebo groups with regard to any of the bacteriologic responses examined. These data indicate that a single dose of 1 g of tetracycline is effective in the treatment of cholera, but it is asymptomatic bacteriologic relapse. A single dose of 400 mg of furazolidone is not therapeutically effective in cholera.
Antipseudomonal activity of simulated infusions of gentamicin alone or with piperacillin assessed by serum bactericidal rate and area under the killing curve
Authors: Tisdale J E , Pasko M T , Mylotte J M
Published: June 2012

The objectives of this study were to (i) determine which of three simulated dosing regimens (gentamicin alone, simultaneous infusions of gentamicin and piperacillin, or staggered infusions of gentamicin and piperacillin) produced the fastest killing rate of Pseudomonas aeruginosa in serum, using the serum bactericidal rate (SBR) assay; and (ii) describe an alternative method of analysis of killing curves, the area under the killing curve (AUKC). Gentamicin alone or combined with piperacillin was added to heat-inactivated human serum to approximate drug concentrations achieved after the above-mentioned types of infusion. By a microdilution technique, seven strains of P. aeruginosa were exposed to no drug (control) and gentamicin alone or with piperacillin; colony counts were determined at hourly intervals for 5 h, and log10 CFU per milliliter was plotted versus time. Linear regression was used to calculate the slope (SBR) of each timed killing curve for each drug concentration tested alone or in combination. In addition, the AUKC for each curve was calculated. To compare simulated infusion regimens further, the cumulative AUKC (the sum of AUKCs for specific time points along the serum concentration-time curve for each simulated regimen) was calculated. With the SBR assay or AUKC determination, there was a significant increase in the rate of killing of all test strains by the combination compared with gentamicin alone only at gentamicin concentrations which exceeded the MIC (8, 5, and 2.5 micrograms/ml). Mean cumulative AUKC of the simultaneous-infusion regimen was significantly less (indicating faster killing) than either the staggered-infusion regimen or the gentamicin infusion alone. Both the SBR and AUKC have the potential for integration of in vitro microbiologic effects and in vivo pharmacokinetics of antimicrobial agents.
Daptomycin (LY146032) for prevention and treatment of experimental aortic valve endocarditis in rabbits
Authors: Kennedy S , Chambers H F
Published: June 2012

The efficacy of daptomycin (LY146032), a vancomycinlike lipopeptide antibiotic, was compared with that of antibiotics commonly in use for prevention and treatment of experimental aortic valve endocarditis in rabbits. Strains of Staphylococcus aureus. S. epidermidis, Streptococcus sanguis, and Enterococcus faecalis were used to establish endocarditis. A single 10-mg/kg dose of daptomycin and a single 25-mg/kg dose of vancomycin were both effective in prevention of endocarditis produced by strains of S. aureus and S. sanguis. Daptomycin was more effective than vancomycin for prevention of endocarditis caused by the strain of S. epidermidis. A single dose of daptomycin also was more effective in prevention of staphylococcal and enterococcal endocarditis than were single-dose regimens of cefazolin (100 mg/kg) and the combination of ampicillin (30 mg/kg) plus gentamicin (3 mg/kg), respectively. For treatment of endocarditis, daptomycin (10 mg/kg) as a single daily dose was as effective as regimens of either vancomycin or beta-lactam antibiotics for staphylococcal and enterococcal endocarditis. Daptomycin, however, was not as effective as a single daily dose of 600,000 U of procaine penicillin for endocarditis caused by the strain of S. sanguis.
Cloning and expression of the norA gene for fluoroquinolone resistance in Staphylococcus aureus
Authors: Ubukata K , Itoh-Yamashita N , Konno M
Published: June 2012

The norA gene for fluoroquinolone resistance in Staphylococcus aureus TK2566 was cloned from chromosomal DNA into fluoroquinolone-susceptible Escherichia coli TG1. The resulting transformant, NY11, contained a recombinant plasmid, designated pTUS1, with a cloned 5.5-kilobase (kb) HindIII fragment of staphylococcal DNA. The MIC of norfloxacin for the strain increased from 0.1 to 3.13 micrograms/ml. Furthermore, when the fragment was recloned into S. aureus, the transformant NY12, containing recombinant plasmid pTUS20, had the same level of resistance to norfloxacin as did the original strain, although it was less resistant to ofloxacin and ciprofloxacin. A single KpnI-HaeIII fragment was found to be the minimum size able to express norfloxacin resistance, suggesting that the norA gene is located within the 2.6- to 3.2-kb region of the original 5.5-kb fragment. The 5.5-kb fragment hybridized to DNA from a fluoroquinolone-susceptible S. aureus strain.
Treatment of experimental salmonellosis in mice with ampicillin-bound nanoparticles
Authors: Fattal E , Youssef M , Couvreur P , Andremont A
Published: June 2012

We tested the effectiveness of ampicillin bound to nanoparticles of polyisohexylcyanoacrylate (PIHCA) in treating C57BL/6 mice experimentally infected with Salmonella typhimurium C5. The diameter of the nanoparticles was 187 +/- 13 nm, and the ampicillin/PIHCA ratio was 0.2/1. The proportion of ampicillin bound was 90 +/- 3%. All control mice and all those treated with nonloaded nanoparticles died within 10 days of infection. By contrast, all mice treated with a single injection of 0.8 mg of nanoparticle-bound ampicillin survived. With free ampicillin, a similar curative effect required three doses of 32 mg each. Lower doses delayed but did not reduce mortality. The sharp increase in the therapeutic index of ampicillin after linkage to PIHCA nanoparticles was explained by studies of the distribution of ampicillin, which showed that when bound to nanoparticles, the ampicillin was concentrated mainly in the liver and spleen, the primary foci of infection in the experimental model that we used. These findings warrant further development of intracellular targeting of antibiotics on biodegradable polymeric carriers such as PIHCA.
In vitro evaluation of BRL 42715, a novel beta-lactamase inhibitor
Authors: Coleman K , Griffin D R , Page J W , Upshon P A
Published: June 2012

The penem BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, is a potent inhibitor of a broad range of bacterial beta-lactamases, including the plasmid-mediated TEM, SHV, OXA, and staphylococcal enzymes, as well as the chromosomally mediated enzymes of Bacteroides, Enterobacter, Citrobacter, Serratia, Morganella, Escherichia, Klebsiella, and Proteus species. The concentration of BRL 42715 needed to reduce the initial rate of hydrolysis of most beta-lactamase enzymes by 50% was less than 0.01 micrograms/ml, which was 10- to 100-fold lower than for other beta-lactamase inhibitors. These potent inhibitory activities were reflected in the low concentrations of BRL 42715 needed to potentiate the antibacterial activity of beta-lactamase-susceptible beta-lactams. Concentrations of 0.25 micrograms/ml or less considerably enhanced the activity of amoxicillin against many beta-lactamase-producing strains. The MIC50 (MIC for 50% of strains tested) of amoxicillin for 412 beta-lactamase-producing members of the family Enterobacteriaceae fell from greater than 128 to 2 micrograms/ml in the presence of 1 microgram of BRL 42715 per ml, whereas 5 micrograms of clavulanic acid per ml brought the MIC50 down to 8 micrograms/ml. Among these 412 strains were 73 Citrobacter and Enterobacter strains, and 1 microgram of BRL 42715 per ml reduced the MIC50 of amoxicillin from greater than 128 to 2 micrograms/ml for the 48 cefotaxime-susceptible strains and from greater than 128 to 8 micrograms/ml for the 25 cefotaxime-resistant strains.
In vitro susceptibility studies of vancomycin-resistant Enterococcus faecalis
Authors: Sahm D F , Kissinger J , Gilmore M S , Murray P R , Mulder R , Solliday J , Clarke B
Published: June 2012

Vancomycin resistance exhibited by Enterococcus faecalis isolates V583, V586, and V587 is described. The vancomycin MICs ranged from 32 to 64 micrograms/ml. Although resistant to vancomycin, the isolates were susceptible to teicoplanin (MIC, less than or equal to 0.5 micrograms/ml). Such a glycopeptide susceptibility profile has not been previously described for E. faecalis. Time kill studies showed that vancomycin resistance adversely affected the synergistic activity that vancomycin and aminoglycoside combinations usually demonstrate against enterococci. However, the ability to detect vancomycin resistance varied with the susceptibility testing method used. Whereas broth microdilution, broth macrodilution, and agar dilution methods detected resistance, disk-agar diffusion and the AutoMicrobic system Gram-Positive GPS-A susceptibility card (Vitek Systems Inc., Hazelwood, Mo.) did not. To detect vancomycin resistance reliably and establish the incidence of such E. faecalis isolates, adjustments in some susceptibility testing methods may be necessary.
Growth phase dependency of chromatin cleavage and degradation by bleomycin
Authors: Moore C W , Jones C S , Wall L A
Published: June 2012

Preferential cleavage of Saccharomyces cerevisiae chromosomes in internucleosomal (linker) regions and nonspecific degradation of chromatin by an anticancer antibiotic which degrades DNA were investigated and found to increase in consecutive stages of growth. Cleavage of DNA in internucleosomal regions and intensities and multiplicities of nucleosomal bands were dependent on drug concentration, growth phase of the cells, and length of incubation. Cellular DNA was least degraded during logarithmic phase. After cells progressed only one generation in logarithmic phase, low concentrations (6.7 x 10(-7) to 3.4 x 10(-6) M) of bleomycin produced approximately three to seven times more DNA breaks. Internucleosomal cleavage was highest, and the most extended oligonucleosomal series and extensive chromatin degradation were observed during stationary phase. It is concluded that the growth phase of cells is critical in determining amounts of the highly preferential cleavage in internucleosomal regions and overall breakage and degradation of DNA. Mononucleosomal bands were most intense, indicating the greatest accumulation of DNA of this size. Mean mononucleosomal lengths were 165.9 +/- 3.9 base pairs, in agreement with yeast mononucleosomal lengths. As high-molecular-weight chromatin was digested by bleomycin, oligonucleosomes and, eventually, mononucleosomes became digested. Therefore, it is also concluded that bleomycin degradation of oligonucleosomes and trimming of DNA linker regions proceed to degradation of the monosomes (core plus linker DNA).
Plasmid-mediated Tet M in Haemophilus ducreyi
Authors: Roberts M C
Published: June 2012

A tetracycline-resistant Haemophilus ducreyi strain isolated in the United States was shown to carry a 34-megadalton plasmid which hybridized with the 1.8-kilobase KpnI-HindIII Tet M probe. The complete Tn916 transposon hybridized with five different bands from this plasmid, suggesting homology throughout the length of the transposon.
Tetracycline and erythromycin resistance among clinical isolates of Branhamella catarrhalis
Authors: Brown B A , Wallace R J , Flanagan C W , Wilson R W , Luman J I , Redditt S D
Published: June 2012

We reviewed tetracycline and erythromycin disk diffusion susceptibility of 457 isolates of Branhamella catarrhalis. Four isolates were resistant to tetracycline, with MICs for two available isolates of 16 micrograms/ml. Sixteen isolates were in the moderately susceptible range for erythromycin, with an MIC for one available isolate being greater than 8 micrograms/ml. These are the first tetracycline- and (by MIC) erythromycin-resistant B. catarrhalis isolates reported from the United States.
Antimicrobial activity of N,N'-dialkylpolymethylenediamines against some dental plaque bacteria
Authors: Murata Y , Mita K , Miyamoto E , Ueda M
Published: June 2012

Twenty N,N'-dialkylpolymethylendiamine derivatives were synthesized, and a study was made of their antimicrobial activities in vitro against four oral microorganisms which are related to dental caries. The maximum activity was shown by N,N'-dinonyl or N,N'-didecyl derivatives among the complete homologous series of compounds studied.
Imipenem resistance in Bacteroides distasonis mediated by a novel beta-lactamase
Authors: Hurlbut S , Cuchural G J , Tally F P
Published: June 2012

Imipenem is a highly active drug against the Bacteroides fragilis group of organisms. On the basis of a nationwide survey of over 500 isolates, it was found that the frequency of imipenem resistance was less than 0.1%. We have a highly resistant Bacteroides distasonis isolate, TAL7860, for which the following MICs (micrograms per milliliter) were determined by agar dilution: cefoxitin, greater than 128; moxalactam, greater than 128; piperacillin, greater than 128; imipenem, 16; and SCH34343, 16. Resistance was shown to involve both a beta-lactamase and an outer membrane permeability barrier. beta-Lactamase kinetics studies with several beta-lactams, including imipenem, revealed similar hydrolytic efficiency in comparison with those found for the B. fragilis strains. An imipenem outer membrane permeability barrier was detected for TAL7860, which was approximately sixfold more effective for B. fragilis TAL3636 and TAL2480. Significant inhibition of nitrocefin destruction was also shown with sulbactam and clavulanic acid at 10 mumol and dithiothreitol at 10 mM. No inhibition was seen with 10 mM EDTA. Differences in physicochemical properties and inhibition studies suggest that this beta-lactamase is different from the imipenem-inactivating metallo-beta-lactamase previously described in B. fragilis. We demonstrated a significant permeability barrier to clavulanic acid and sulbactam, which resulted in loss of synergism between these clinically employed beta-lactamase inhibitors and beta-lactam drugs. The novel beta-lactamase activity in conjunction with a limited permeability in TAL7860 resulted in resistance to all commonly employed beta-lactams, including the newest and most potent beta-lactam drugs.
Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats
Authors: Beauchamp D , Pellerin M , Gourde P , Pettigrew M , Bergeron M G
Published: June 2012

Daptomycin is a new biosynthetic antibiotic which belongs to a new class of drugs known as lipopeptides. The objective of this study was to evaluate the effects of daptomycin and vancomycin on tobramycin-induced nephrotoxicity. Female Sprague-Dawley rats were treated during 4 and 10 days with either saline (NaCl, 0.9%) or tobramycin at doses of 4 and 40 mg/kg per day (given every 12 h [q12h] intraperitoneally). Each treatment was combined with saline, daptomycin at a dose of 20 mg/kg per day (given q12h subcutaneously), and ancomycin at a dose of 50 mg/kg per day (given q12h subcutaneously). Daptomycin and vancomycin had no effect on the intracortical accumulation of tobramycin. Daptomycin did not accumulate in renal tissue even after 10 days of treatment. Tobramycin given at a dose of 40 mg/kg per day during 10 days induced a significant inhibition of sphingomyelinase activity in the renal cortex (P less than 0.01) and increased cellular regeneration (P less than 0.01), as measured by the incorporation of [3H]thymidine into DNA of the renal cortex. These changes were minimal when daptomycin was combined with tobramycin. Histologically, signs of tobramycin toxicity were also less severe in the presence of daptomycin. The intracortical accumulation of vancomycin was not modified by tobramycin. The sphingomyelinase activity was significantly more inhibited (P less than 0.01) when vancomycin was associated with tobramycin (4 and 40 mg/kg) without affecting the rate of [3H]thymidine incorporation into DNA. Histologically, signs of tobramycin toxicity were not affected by vancomuycin, but the cellular vacuolizations which were also observed in vancomycin-treated animals were still present in the proximal tubular cells of animals that were treated with the combination vancomycin-tobramycin. This study strongly suggests that daptomycin protects animals from tobramycin-induced nephrotoxicity but that vancomycin may enhance the effect of tobramycin. We conclude that daptomycin is safe and protects kidney cells from tobramycin-induced nephrotoxicity.
Comparison of ofloxacin and ceftriaxone in the treatment of uncomplicated gonorrhea caused by penicillinase-producing and non-penicillinase-producing strains
Authors: Covino J M , Cummings M , Smith B , Benes S , Draft K , McCormack W M
Published: June 2012

Eighty-nine patients with uncomplicated gonorrhea, including 31 patients (34.8%) infected with penicillinase-producing strains of Neisseria gonorrhoeae, were treated with oral ofloxacin (single 400-mg dose) or intramuscular ceftriaxone (250-mg dose). All 47 patients who received ofloxacin and 41 of 42 patients who received ceftriaxone were cured.
Successful single-dose prophylaxis of Staphylococcus aureus foreign body infections in guinea pigs by fleroxacin
Authors: Bouchenaki N , Vaudaux P E , Huggler E , Waldvogel F A , Lew D P
Published: June 2012

Single-dose administration of fleroxacin was evaluated as a means of preventing foreign body infection due to staphylococci. Tissue cages were implanted into guinea pigs and subsequently infected (100% rate) with 10(2) or more CFU of Staphylococcus aureus Wood 46. When a single dose of 30 mg of fleroxacin or vancomycin per kg of body weight was administered intraperitoneally, bactericidal levels of the antimicrobial agent were found in the tissue cage fluid after 3 h (when guinea pigs were inoculated with S. aureus) and during the next 24 h. Either fleroxacin or vancomycin successfully prevented experimental infection in all tissue cages challenged by 10(2) CFU of S. aureus Wood 46. When tissue cages were challenged with 10(4) CFU of S. aureus Wood 46, however, fleroxacin was more effective than vancomycin (P less than 0.05) in reducing colony counts below the detection limit of 10 CFU/ml in the inflammatory fluid of all tissue cages during the initial 48 h. In contrast to their initially different actions, the effects of the antibiotics were similar after 7 days, mostly because bacterial regrowth occurred more frequently in the fleroxacin-treated than in the vancomycin-treated tissue cages. These data show that experimental infections of subcutaneous tissue cages are a useful model for studying the prophylaxis of foreign body infections with antimicrobial agents.
Two bactericidal targets for penicillin in pneumococci: autolysis-dependent and autolysis-independent killing mechanisms
Authors: Moreillon P , Markiewicz Z , Nachman S , Tomasz A
Published: June 2012

It has been assumed that penicillin (and also other cell wall inhibitors) kill pneumococci predominantly by triggering their major autolytic enzyme (an N-acetylmuramoyl-L-alanine amidase; referred to as amidase), resulting in massive cell wall degradation. Three types of experiments suggest that only part of this killing is due to cell lysis by amidase. (i) Suppression of penicillin-induced lysis by specific inhibitors of amidase protected pneumococci only marginally from killing in spite of prolonged exposure to concentrations of penicillin that were 10x, 20x, or 100x greater than the MIC. (ii) Mutants from which the amidase was completely eliminated by plasmid insertion or deletion (Lyt-) were still killed, albeit at a slower rate than the wild-type Lyt+ strains (3 to 4 log units instead of 4 to 5 log units per 6 h, i.e., about 1 log unit slower than the wild type; P less than 0.001). (iii) A new mutation (cid), which was not related to the amidase gene, further reduced killing of mutants lacking amidase to 1 log unit per 6 h (Lyt- Cid- phenotype). Reintroduction of the amidase gene into Lyt- Cid- cells partially restored penicillin-induced lysis but increased only slightly the rate of killing (from 1 log unit per 6 h in Lyt- Cid- cells to 2 log units per 6 h in Lyt+ Cid- cells). We conclude that penicillin kills pneumococci by two distinct mechanisms: one that involves the triggering of the amidase (about 1 log unit of killing per 6 h) and another, amidase-independent mechanism that is responsible for 3 to 4 log units of killing per 6 h. Triggering of the amidase activity in situ in growing bacteria was significantly reduced in Lyt+ Cid- cells, indicating that there is some regulatory interaction between the cid gene product and the amidase.
Activities of ciprofloxacin and ofloxacin against rapidly growing mycobacteria with demonstration of acquired resistance following single-drug therapy
Authors: Wallace R J , Bedsole G , Sumter G , Sanders C V , Steele L C , Brown B A , Smith J , Graham D R
Published: June 2012

The susceptibility to ciprofloxacin of 548 clinical isolates of rapidly growing mycobacteria belonging to eight subgroups or species was determined. The 170 isolates of Mycobacterium fortuitum biovar.fortuitum were most susceptible; the MIC for 90% of the organisms was 0.125 micrograms/ml. The other biovariants of M. fortuitum, M. smegmatis, and the M. chelonae-like organisms were less susceptible; the modal MIC was 0.5 micrograms/ml, and the MIC for 90% of organisms was 1.0 micrograms/ml. The two subspecies of M. chelonae were generally resistant, with only 8% of 206 isolates falling in the moderately susceptible category (MIC, 2 micrograms/ml) and only 2% falling in the susceptible category (MIC, less than or equal to 1 micrograms/ml). MICs of ofloxacin averaged 1 to 2 dilutions higher than those of ciprofloxacin for all subgroups tested. Three patients with M. fortuitum cutaneous disease relapsed after an initial response to therapy with ciprofloxacin, and their isolate was shown to have acquired drug resistance. Mutational frequencies for M. fortuitum with ciprofloxacin were relatively high (10(-5) to 10(-7), and MICs for single-step mutants were similar to those for the clinically resistant strains. Thus, despite the excellent activity of ciprofloxacin against rapidly growing mycobacterial groups other than M. chelonae, single-drug therapy should be used with caution because of the risk of development of mutational resistance.