bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of experimental salmonellosis in mice with streptomycin entrapped in liposomes
Authors: Tadakuma T , Ikewaki N , Yasuda T , Tsutsumi M , Saito S , Saito K
Published: June 2012

Liposome-entrapped streptomycin (SM) was compared with free SM for therapeutic efficacy against experimental salmonellosis in mice. All of the mice infected with the virulent strain of Salmonella enteritidis 116-54 died between days 5 and 7, and a dose of 20 mg of free SM per kg administered 24 h after the bacterial inoculation did not prolong the survival. In contrast, the same dose of SM entrapped in liposomes prolonged paralleled the dose in the liposomes, and a dose as low as 1.2 mg of SM per kg in liposomes prolonged the survival. The advantage of using liposomes was more pronounced when a larger dose of SM was employed. The liposome-entrapped drug was less toxic than the free drug. A dose of 80 mg of free SM per kg caused convulsions, but the same dose entrapped in liposomes caused no side effects. Furthermore, two doses of liposome-entrapped SM further enhanced the therapeutic effect. The efficacy of the liposome-entrapped drug was still observed in mice infected with a large inoculum of S. enteritidis. A tissue distribution study on SM in various organs demonstrated that liposomal SM was selectively delivered to the spleen and liver with concentrations in these those in mice receiving the free drug. The prolongation of survival was due to suppression of the multiplication of S. enteritidis as demonstrated by viable cell counts in the spleens.
In vitro susceptibility of Campylobacter jejuni to 27 antimicrobial agents and various combinations of beta-lactams with clavulanic acid or sulbactam
Authors: Van der Auwera P , Scorneaux B
Published: June 2012

The in vitro susceptibility of human isolates of Campylobacter jejuni was investigated with 27 antibiotics and 8 combinations of beta-lactams with clavulanic acid or sulbactam. Ansamycin, the new quinolines, erythromycin, and cefpirome were the most active drugs against C. jejuni; amoxicillin, ampicillin, cefotaxime, and ceftazidime 90% of the isolates, greater than or equal to 50 mg/liter). The activity of various beta-lactams was unchanged by the addition of clavulanic acid or sulbactam.
Comparison of three DNA hybridization methods for detection of the aminoglycoside 2"-O-adenylyltransferase gene in clinical bacterial isolates
Authors: Gootz T D , Tenover F C , Young S A , Gordon K P , Plorde J J
Published: June 2012

Two rapid DNA hybridization methods in which whole-cell lysates fixed to nitrocellulose were used were compared with Southern hybridization of purified plasmid or chromosomal DNA for the ability to identify the 2"-O-adenylyltransferase [ANT(2")] gene in 42 enzymatically defined isolates of gram-negative bacilli. A DNA restriction fragment isolated from an ANT(2") gene cloned into pBR322 and radiolabeled with 32P was used as the probe in all three procedures. Under conditions of high stringency, agreement was obtained between the Southern hybridization method and detection of the ANT(2") enzyme by the phosphocellulose paper binding assay or resistance phenotype in 39 of the 42 strains tested. By using these characterized strains, colony hybridization was shown to be unsatisfactory as a rapid technique for detecting the ANT(2") gene, due to the high number of false-positive and -negative signals obtained. Compared with Southern hybridization, however, spot hybridization (SPH) proved highly reliable for detecting the ANT(2") gene in both members of Enterobacteriaceae and Pseudomonas aeruginosa harboring R factors ranging in size from 23 to 150 kilobases. The relatively low copy number of the 150-kilobase plasmids decreased the sensitivity of SPH, necessitating a minimum cell density of 5 X 10(6) cells per spot. SPH proved to be a very useful method for rapidly screening large numbers of clinical isolates for this resistance determinant.
Antagonistic effect of penicillin-amikacin combinations against enterococci
Authors: Thauvin C , Eliopoulos G M , Wennersten C , Moellering R C
Published: June 2012

Amikacin has been shown to antagonize the bactericidal effect of penicillin against strains of Streptococcus faecalis which produce aminoglycoside 3'-phosphotransferase. The mechanism by which this phenomenon occurs was studied with an enzyme-producing strain (8436) and an enzyme-negative strain (8436c) derived by curing the former with novobiocin. Combinations of amikacin with beta-lactam antibiotics were antagonistic against strain 8436 but synergistic against strain 8436c. Against strain 8436 penicillin-amikacin combinations resulted in levels of killing comparable to those seen with high concentrations of penicillin (500 micrograms/ml), which were less bactericidal than lower concentrations of penicillin. No antagonism was observed between amikacin and non-beta-lactam cell wall-active drugs or between penicillin and kanamycin or neomycin, both of which are substrates for the enzyme. At concentrations near the MIC, amikacin was bactericidal against strain 8436c but bacteriostatic against strain 8436 (MIC, 250 micrograms/ml; MBC, 2,000 micrograms/ml). Neither penicillin nor phosphorylated amikacin affected the inhibition of ribosomal protein synthesis by amikacin in a cell-free system. Although antagonism of killing by amikacin in enzyme-positive strains was specific for combinations which included beta-lactam antibiotics, amikacin did not influence the binding of [3H]penicillin to penicillin-binding proteins in isolated bacterial cell membranes or in intact cells and did not detectably affect the autolytic system of cells exposed to penicillin. Antagonism of beta-lactam activity by a bacteriostatic effect of amikacin against the enzyme-producing strain is the most likely explanation for this phenomenon.
Selective in vitro and in vivo activities of 5-(2-haloalkyl)pyrimidine nucleoside analogs, particularly 5-(2-chloroethyl)-2'-deoxyuridine, against herpes simplex virus
Authors: De Clercq E , Rosenwirth B
Published: June 2012

5-(2-Chloroethyl)-2'-deoxyuridine (CEDU), 5-(3-chloropropyl)-2'-deoxyuridine (CPDU), and 5-(2-chloroethyl)-2'-deoxycytidine (CEDC) were evaluated for activity against herpes simplex virus type 1 (HSV-1) and HSV-2 in vitro. Their MICs for HSV-1 in primary rabbit kidney cell cultures were 0.15, 0.20, and 0.60 micrograms/ml, respectively; their MICs for HSV-2 were about 10-fold higher. When tested in parallel, the reference compounds 5-ethyl-2'-deoxyuridine, 5-iodo-2'-deoxyuridine, acyclovir, and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) gave MICs of 0.20, 0.18, 0.04, and 0.015 micrograms/ml, respectively. The antiviral indexes of CEDU, CPDU, and CEDC, as determined by the ratio of the minimum toxic dose for the normal host cell to the minimum inhibitory dose for HSV-1, were about 2,000, 100, and greater than or equal to 400, respectively. The three 5-(2-haloalkyl)pyrimidine derivatives were further evaluated for their antiviral effects in vivo. In hairless mice, CEDU suppressed the development of cutaneous HSV-1 lesions, and associated mortality, when applied topically at a concentration as low as 0.1%. For the treatment of systemic HSV-1 infection in Naval Medical Research Institute mice, a single oral dose per day of 5 mg of CEDU per kg achieved a significant reduction in the mortality rate. Against HSV-1 encephalitis, CEDU exerted a significant protective effect at a dosage of 50 mg/kg per day when administered intraperitoneally. CEDU was effective against systemic HSV-1 infection and HSV-1 encephalitis in mice at a 5- to 15-fold-lower dose than either BVDU or acyclovir. When given orally, CPDU and CEDC were considerably less active than CEDU against systemic HSV-1 infection.
In vitro activities of enoxacin, ticarcillin plus clavulanic acid, aztreonam, piperacillin, and imipenem and comparison with commonly used antimicrobial agents
Authors: Henry D , Skidmore A G , Ngui-Yen J , Smith A , Smith J A
Published: June 2012

A total of 745 gram-negative and 313 gram-positive clinical isolates were tested against enoxacin, ticarcillin plus clavulanic acid, aztreonam, imipenem, and piperacillin and compared with commonly used antimicrobial agents. Ticarcillin plus clavulanic acid, imipenem, and piperacillin were active against Pseudomonas aeruginosa and Acinetobacter spp. and most Pseudomonas spp. Aztreonam was active against members of the family Enterobacteriaceae but was less effective against the nonfermenters. Enoxacin was active against the Enterobacteriaceae, P. aeruginosa, the staphylococci, and most Acinetobacter spp. but was less active against Pseudomonas spp. and streptococci. Imipenem was very active against all gram-positive and -negative organisms tested except for Pseudomonas maltophilia.
Comparison of aminoglycoside resistance patterns in Japan, Formosa, and Korea, Chile, and the United States
Authors: Shimizu K , Kumada T , Hsieh W C , Chung H Y , Chong Y , Hare R S , Miller G H , Sabatelli F J , Howard J
Published: June 2012

The resistance mechanisms of more than 2,000 aminoglycoside-resistant gram-negative aerobic bacteria were estimated by a method that assigned a biochemical mechanism based on susceptibility to selected aminoglycosides. Strains from hospitals in Japan, Formosa, and Korea (the Far East) were compared with strains from Chile and the United States. Of the strains from Chile, 90% had an aminoglycoside resistance pattern indicative of the 3-N-acetyltransferase [AAC(3)-V] enzyme. Of the strains from the Far East, 78% had susceptibility patterns suggesting the presence of AAC(6') enzymes. In contrast, strains from the United States had a wider variety of resistance mechanisms including 2''-O-adenylyltidyltransferase [ANT(2'')], AAC(3), AAC(6'), and AAC(2'). Reflecting these differences in resistance patterns, the frequencies of resistance to gentamicin, tobramycin, dibekacin, and amikacin in strains from the United States were different from those in strains from the Far East. These differences seem to be correlated with different aminoglycoside usage in the two regions. In the United States, where gentamicin was the most widely used aminoglycoside, 92% of the strains were resistant to gentamicin, 81% were resistant to dibekacin, and 8.8% were resistant to amikacin. In the Far East, dibekacin and kanamycin were widely used in the past and more recently amikacin has been frequently used. Of the strains from this region, 99% were resistant to dibekacin, 85% were resistant to gentamicin, and 35% were resistant to amikacin.
Activity of selenazofurin against influenza A and B viruses in vitro
Authors: Sidwell R W , Huffman J H , Call E W , Alaghamandan H , Cook P D , Robins R K
Published: June 2012

Activity of the new antiviral compound selenazofurin was compared with the known active compounds ribavirin and amantadine against influenza A and B viruses. In experiments with Madin Darby canine kidney cells, selenazofurin inhibited the cytopathic effect and yield of influenza A/NWS/33 virus, with 50% effective dose ranges of 0.7 to 1.4 micrograms/ml (virus rating [VR], 1.3 to 1.4). The 50% effective dose range for ribavirin was 1.2 to 1.6 micrograms/ml (VR, 1.0 to 1.3), and for amantadine it was 9 micrograms/ml (VR, 0.9). Selenazofurin and ribavirin were similarly inhibitory to influenza B/Lee/40 virus, whereas amantadine was inactive. Selenazofurin appeared somewhat cytotoxic in these studies at concentrations as low as 1 micrograms/ml.
Reverse transsulfuration and its relationship to thienamycin biosynthesis in Streptomyces cattleya
Authors: Williamson J M , Meyer R , Inamine E
Published: June 2012

Cystathionine gamma-lyase (EC 4.4.1.1) was purified from Streptomyces cattleya, an actinomycete which produces the unusual beta-lactam antibiotic thienamycin. The enzyme displays broad substrate specificity and is similar to gamma-lyases purified from other microorganisms. That the gamma-lyase functions in vivo to provide cysteine for antibiotic synthesis was shown by two types of experiments. First, cystathionine and methionine, as well as cysteine itself, are efficiently utilized by S. cattleya for thienamycin biosynthesis. Second, propargylglycine, a mechanism-based inactivator of cystathionine gamma-lyase in vitro, inhibits the synthesis of thienamycin in vivo. This inhibition can be substantially reversed by providing the cells with another source of cysteine, such as cystine.
Effect of pyrimidinone treatment on lethal and immunosuppressive murine cytomegalovirus infection
Authors: Brideau R J , Wolcott J A
Published: June 2012

The 2-amino-5-halo-pyrimidinones, which are potent interferon inducers and antiviral agents, were found to be protective against lethal cytomegalovirus (CMV) challenge in weanling or neonatal mice when administered before virus challenge. This protection was dependent upon the dosage of pyrimidinone administered. Weanling mice infected with a sublethal challenge of CMV exhibited moderate to severe immunosuppression as measured by reduced splenic cell blastogenic responses in vitro to the mitogen concanavalin A. Treatment of mice with pyrimidinones during the course of CMV immunosuppression resulted in substantial augmentation of splenic cell blastogenic responses. The degree of augmentation appeared to be dependent on the severity of CMV-induced immunosuppression.
Kinetics of gentamicin in plasma of nonpregnant, pregnant, and fetal guinea pigs and its distribution in fetal tissues
Authors: Lelievre-Pegorier M , Sakly R , Meulemans A , Merlet-Benichou C
Published: June 2012

Nonpregnant and pregnant guinea pigs in the last third of gestation were injected intramuscularly with 4 mg of gentamicin per kg, and drug concentrations in plasma were determined by radioimmunoassay at several intervals after injection. The maximum gentamicin concentration was lower in pregnant than in nonpregnant animals (14.6 +/- 0.7 micrograms/ml versus 21.6 +/- 0.7 micrograms/ml), and the peak time occurred significantly later (0.57 +/- 0.12 h versus 0.13 +/- 0.02 h). Four hours after gentamicin injection, drug concentrations in plasma were 2.1 +/- 0.8 and 0.3 +/- 0.1 micrograms/ml in pregnant and nonpregnant animals, respectively. Pregnant animals therefore eliminated the drug from their plasma more slowly. These data provide good evidence that the kinetics of plasma gentamicin varies in pregnant females because its volume of distribution was larger in pregnant than in nonpregnant animals. Detectable but small amounts of gentamicin (less than or equal to 0.50 microgram/ml) were found in the plasma of 46 of 57 fetuses. However, no net variations in these concentrations were observed during the period between 15 min and 6 h after injection to the mother. Gentamicin concentrations were also determined in the kidneys, liver, lungs, heart, and brain of fetal guinea pigs after administration to their mothers of one daily injection of 4 mg/kg for 7 days. Gentamicin was present in all these fetal organs; however, as in the adult organs, the kidneys contained far more than any of the others. Gentamicin concentrations were not significantly different in the kidney cortex and medulla (1.79 +/- 0.16 versus 1.48 +/- 0.92 micrograms/g), indicating that, contrary to what is observed for adults, renal accumulation of gentamicin in the fetus does not occur preferentially in the cortex.
Cilastatin does not alter superoxide dismutase activity
Authors: Proctor R A , Textor J A
Published: June 2012

Cilastatin inhibits dehydropeptidase-I, a zinc metaloenzyme that metabolizes imipenem. Because zinc stabilizes the mammalian superoxide dismutase, we postulated that cilastatin would also inhibit the dismutase. Cilastatin concentrations at levels threefold higher than those expected in urine, however, did not inhibit the superoxide dismutase activity.
Comparative activities of piperacillin, ceftazidime, and amikacin, alone and in all possible combinations, against experimental Pseudomonas aeruginosa infections in neutropenic rats
Authors: Johnson D E , Thompson B , Calia F M
Published: June 2012

This study compared the efficacy of therapy with the double beta-lactam combination of ceftazidime plus piperacillin with that of single-agent therapy with ceftazidime, piperacillin, or amikacin alone and with that of two aminoglycoside-beta-lactam combinations against Pseudomonas aeruginosa peritonitis and bacteremia in neutropenic rats. Rats made severely granulocytopenic with cyclophosphamide became bacteremic secondary to peritonitis which was induced by intraperitoneal challenge with P. aeruginosa. Antibiotic therapy with single agents (amikacin, 20 mg/kg of body weight, intramuscularly; ceftazidime, 20 mg/kg of body weight, subcutaneously; piperacillin, 200 mg/kg of body weight, intramuscularly) or with the various combinations of agents was begun 2 h after bacterial challenge and was continued every 6 to 8 h for 62 h. Therapeutic efficacy was judged on the basis of survival 72 h after bacterial challenge, rate of mortality, incidence of bacteremia, and the emergence of resistant organisms. Based on these criteria, therapy with the double beta-lactam combination had no advantage over single-agent therapy and was in all cases clearly inferior to beta-lactam-aminoglycoside combinations.
Drug resistance patterns of herpes simplex virus isolates from patients treated with acyclovir
Authors: McLaren C , Chen M S , Ghazzouli I , Saral R , Burns W H
Published: June 2012

A decrease in the in vitro sensitivity to acyclovir (ACV) was observed in successive isolates of herpes simplex virus type 1 from three immunocompromised patients during intravenous therapy with this drug. The ACV-resistant isolate from patient 1 was cross-resistant to dihydroxypropoxymethylguanine and bromovinyldeoxyuridine, but still susceptible to three fluoro-substituted pyrimidines, 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC), 2'-fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (FIAU), and 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylthymine (FMAU). The thymidine kinase (TK) from the resistant isolate showed a 50-fold or greater reduction in affinity for thymidine, FIAU, FMAU, and ACV, but the total enzyme activity was similar to that of the sensitive isolate. The ACV-resistant isolate from patient 2 was also resistant to dihydroxypropoxymethylguanine, bromovinyldeoxyuridine, and the fluoro-substituted compounds; TK activity for this isolate was less than 1% of the patient's pretherapy isolate. An isolate obtained during a subsequent recurrence in patient 2 was susceptible to ACV and the other TK-dependent agents. The ACV-resistant isolate from patient 3 was partially resistant to FIAC and FIAU but still susceptible to FMAU; the viral TK had a 10-fold-lower affinity for ACV, FIAU, and FMAU than did the sensitive pretherapy isolate, while the level of TK activity detected was reduced to 6%. In none of the isolates studied was a change in sensitivity to phosphonoformic acid observed. Compared with the corresponding pretherapy ACV-sensitive isolates, there was a 30-fold decrease in neurovirulence for mice of the two drug-resistant isolates with diminished levels of thymidine-phosphorylating activity and no change in virulence for the third isolate. These findings indicate that mixed patterns of drug-resistance to TK-dependent antiviral compounds can occur in clinical isolates, resulting from changes in either the amount or the affinity of viral TK activity.
Cephamycin inactivation due to enzymatic hydrolysis by beta-lactamase from Bacteroides fragilis
Authors: Yotsuji A , Minami S , Kakizawa H , Yasuda T , Takai A , Saikawa I , Inoue M , Mitsuhashi S
Published: June 2012

The susceptibility of 53 clinical isolates of Bacteroides fragilis to cephamycins was examined. Judging from the MICs for 50% of the strains tested, moxalactam was the most active, however, judging from the MICs for 90% of the strains tested, cefbuperazone was more effective than moxalactam. A correlation was observed between in vitro activity of benzylpenicillin and cephaloridine and beta-lactamase production. Inactivation due to enzymatic hydrolysis of cephamycins over a short time was not observed; however, inactivation was detected by a double disk diffusion test, and moxalactam was most easily inactivated. We conclude that inactivation due to enzymatic hydrolysis of cephamycins over a long time may play an important role in resistance to some cephamycins in strains of B. fragilis.
Microbicidal activity of octenidine hydrochloride, a new alkanediylbis[pyridine] germicidal agent
Authors: Sedlock D M , Bailey D M
Published: June 2012

The potential of octenidine hydrochloride (WIN 41464-2) as a topical microbicide was measured both by in vitro death kinetics and reductions in numbers of bacteria on the skin of cynomolgus monkeys. Semilogarithmic survival curves were plotted to measure the microbicidal activity of various concentrations of octenidine against Staphylococcus aureus. The microbicidal activity of octenidine was also determined for Staphylococcus epidermidis, Proteus mirabilis, Streptococcus pyogenes, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens, and Candida albicans. Death rates for the same microbial strains were compared with those obtained by using chlorhexidine gluconate. Octenidine concentrations of less than 1.5 microM (0.94 microgram/ml) caused a greater than 99% reduction of each microbial population within 15 min. Staphylococcus epidermidis was the most susceptible of the test organisms, and E. coli and C. albicans were the least susceptible. Octenidine was more active than chlorhexidine against each test strain. Skin-degerming activities of aqueous and formulated octenidine and formulated chlorhexidine were compared in single and multiple applications of these agents to the hand and foot surfaces of monkeys by using a glove-juice extraction procedure to measure the skin microflora. Aqueous octenidine, at a concentration of 0.2 to 1.6% reduced resident microflora populations from 90 to 99.98%, depending on the concentration and number of applications. Octenidine formulated at 2% in a surfactant-based vehicle exhibited significantly better skin-degerming activity than did either a nonmedicated vehicle or the Hibiclens brand of 4% chlorhexidine gluconate.
Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis
Authors: Trang J M , Jacobs R F , Kearns G L , Brown A L , Wells T G , Underwood F L , Kluza R B
Published: June 2012

The pharmacokinetics and cerebrospinal fluid (CSF) penetration of cefotaxime (Ctx) and desacetylcefotaxime (dCtx) were evaluated in 13 infants and children with meningitis after dose 6 of Ctx in a multiple-dose intermittent intravenous infusion regimen (50 mg/kg every 6 h). Model-dependent and noncompartmental pharmacokinetic parameters were determined and were found to be congruous. The disposition of both Ctx and dCtx was described adequately by a one-compartment, open model. Noncompartmental pharmacokinetic parameters are reported. The mean Ctx serum concentration at 0.25 h postinfusion was 121.2 micrograms/ml, and the mean CSF concentration at 1 h postinfusion was 6.2 micrograms/ml. The CSF/serum ratio was variable (0 to 20%), with a mean penetration of 10.1%. The mean Ctx elimination half-life, apparent steady-state volume of distribution, and total body clearance were 0.8 h, 0.361 liter/kg, and 0.289 liter/h per kg, respectively. For Ctx, 61% of the dose was excreted unchanged in the urine during the 6-h postinfusion period, and the estimated renal clearance was 0.174 liter/h per kg. No significant correlations were observed between Ctx pharmacokinetic parameters and demographic parameters. The mean peak concentration of dCtx in serum (21.6 micrograms/ml) occurred at approximately 1.5 h postinfusion, and the mean concentration in CSF at 1 h postinfusion was 5.6 micrograms/ml. The CSF/serum ratio was extremely variable (0 to 103%), and the mean penetration was 28.8%. The mean apparent elimination half-life for dCtx was 2.1 h. In infants and children with normal renal function, a 50-mg/kg dose of Ctx administered every 6 h should provide adequate concentrations in serum and CSF in the majority of patients with meningitis.
Efficacy of UK-49,858 (fluconazole) against Candida albicans experimental infections in mice
Authors: Troke P F , Andrews R J , Brammer K W , Marriott M S , Richardson K
Published: June 2012

UK-49,858 (fluconazole), a new, orally absorbed bis-triazole derivative, has been evaluated against systemic infections with Candida albicans in normal and immunosuppressed mice and against an intestinal infection with C. albicans in immunosuppressed mice. Orally administered ketoconazole was used as a comparison agent throughout, and orally administered amphotericin B was included for comparative in the experimental intestinal infection. In a 10-day dosage regimen, UK-49,858 was far more active than ketoconazole against systemic infections with C. albicans in normal and immunosuppressed mice. In normal mice, extension of UK-49,858 dosing to 30 days resulted in prolongation of survival to over 90 days, and up to 60% of treated animals had no detectable C. albicans in their kidneys. In addition, over 90% of mice with intestinal candidiasis had culture-negative feces after a 3-day treatment with UK-49,858, but only 62 and 23% of mice gave this response after amphotericin B and ketoconazole therapy, respectively. These data suggest that UK-49,858 may be of value in the treatment of systemic and gastrointestinal infections due to C. albicans in humans.
Cerebrospinal fluid penetration of moxalactam in ventriculostomy patients
Authors: Creger R J , Cowan R I , Nearman H S , Blumer J L , Selman W R , Danziger L H
Published: June 2012

The cerebrospinal fluid penetration of moxalactam was simultaneously investigated in three patients with presumed bacterial meningitis. When ratios of simultaneously drawn ventriculostomy to serum moxalactam levels of 1, 2, 3, and 4 h were examined, the penetration ratios were 7.8 +/- 2.4, 11.2 +/- 1.3, 14.2 +/- 2.5, and 15.0 +/- 4.9%, respectively. These ratios were not statistically different from the penetration of moxalactam calculated by the area under the concentration-time curve technique (8.97 +/- 1.89%).
Comparative in vitro activities of amoxicillin-clavulanic acid and imipenem against anaerobic bacteria isolated from community hospitals
Authors: Goldstein E J , Citron D M
Published: June 2012

The susceptibilities of recent clinical isolates of anaerobic bacteria from two community hospitals were determined. Thirty percent of pigmented Bacteroides species and bile-sensitive, nonpigmented Bacteroides species produced penicillinase and were resistant to amoxicillin. Cefoxitin and clindamycin showed good activity against most strains, with the exception of rare isolates of the Bacteroides fragilis group and some strains of Clostridium species. While amoxicillin was not active against B. fragilis and other members of the B. fragilis group, amoxicillin-clavulanic acid was very active against almost all of these organisms. Imipenem was the most potent agent against all strains tested.
Comparative activities of UK-49,858 and amphotericin B against Blastomyces dermatitidis infections in mice
Authors: Lyman C A , Sugar A M , Diamond R D
Published: June 2012

UK-49,858, a new antifungal triazole derivative, was compared with amphotericin B in the treatment of pulmonary infections by Blastomyces dermatitidis in male BALB/cByJ mice. Administration of UK-49,858 in daily doses of 25 or 50 mg/kg for 21 days gave 30 and 100% survival rates, respectively. These results compared with 100% mortality in infected controls and 100% survival among mice treated with amphotericin B. UK-49,858 did not eradicate the fungus from the lungs of surviving animals, while amphotericin B effected sterilization of the lungs in 66% of the survivors.
In vitro evaluation of A-56619 and A-56620, two new quinolones
Authors: Barry A L , Thornsberry C , Jones R N
Published: June 2012

The in vitro activities of two new aryl-fluoroquinolones (A-56619 and A-56620) were compared with those of ciprofloxacin, ofloxacin, enoxacin, and norfloxacin. All six quinolones had broad spectra of antibacterial activity; the streptococci, Pseudomonas maltophilia, and Pseudomonas cepacia were the least susceptible. A-56619, A-56620, and chloramphenicol had similar activity against anaerobic bacteria. With both drugs, a low frequency of resistant variants (less than 10(-8)) was observed. By regression analysis, A-56619 MICs correlated best with ofloxacin MICs and A-56620 was most similar to ciprofloxacin.
Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora
Authors: Harris B E , Manning B W , Federle T W , Diasio R B
Published: June 2012

The mechanism of toxicity from 5-fluorocytosine chemotherapy is unclear. However, recent evidence suggests that the generation of 5-fluorouracil by a host may play an important role in the development of this toxicity. Using an in vitro semicontinuous culture system to mimic the intestinal microflora, we examined the capacity of this complex microbial community to convert 5-fluorocytosine to 5-fluorouracil. The system was dosed initially and after 2 weeks of chronic exposure to 5-fluorocytosine with radiolabeled 5-fluorocytosine. No detectable production of 5-fluorouracil was observed up to 8 h after the acute dose; however, at 24 h and at all time points thereafter, increasing levels of 5-fluorouracil were detected for 4 days. The chronic dose resulted in an increased rate of 5-fluorouracil production without the 8-h lag time. These findings suggest that the enzyme or enzymes responsible for the deamination of 5-fluorocytosine to 5-fluorouracil by the intestinal microflora can be induced by chronic exposure to 5-fluorocytosine and that this conversion may provide a mechanism through which 5-fluorocytosine toxicity is manifested.
Effects of erythromycin and ciprofloxacin on chronic fecal excretion of Campylobacter species in marmosets
Authors: Goodman L J , Kaplan R L , Petrak R M , Fliegelman R M , Taff D , Walton F , Penner J L , Trenholme G M
Published: June 2012

Ciprofloxacin was compared with erythromycin for the eradication of Campylobacter species that were chronically excreted in the stools of marmosets (Saguinus labiatus labiatus, Saguinus fuscicollis nigrifrons, and Saguinus fuscicollis illigeri). Stool cultures were negative within 48 h of the beginning of treatment with either agent. Within 10 days after the end of therapy, however, Campylobacter species were again isolated from the stools of six animals that had received erythromycin. During an 8-week follow-up period, no animal that had received ciprofloxacin relapsed. High levels of ciprofloxacin in the stool (mean, 49.2 micrograms/g) possibly contributed to the efficacy of this agent.
In vivo evaluation of A-56619 (difloxacin) and A-56620: new aryl-fluoroquinolones
Authors: Fernandes P B , Chu D T , Bower R R , Jarvis K P , Ramer N R , Shipkowitz N
Published: June 2012

A-56619 and A-56620 are two new aryl-fluoroquinolones which are as potent as or more potent than norfloxacin when administered orally and subcutaneously in mouse protection tests against Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. A-56619 and A-56620 were more potent than norfloxacin when administered orally against Escherichia coli, Proteus mirabilis, Serratia marcescens, and Pseudomonas aeruginosa. A-56620 was as potent or two- to threefold more potent than norfloxacin when administered subcutaneously against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Infection with Salmonella typhimurium was more effectively treated with A-56619 (50% effective dose [ED50], 1.4 mg/kg per day) than with norfloxacin (ED50, 62.8 mg/kg per day). E. coli or Pseudomonas pyelonephritis in mice was more effectively treated with A-56619 or A-56620 than with norfloxacin. After oral treatment, the ED50s of A-56619 and A-56620 were less than 12.5 mg/kg per day against E. coli and 62.9 and 38 mg/kg per day against P. aeruginosa pyelonephritis, respectively. Norfloxacin was ineffective at 200 mg/kg per day against E. coli or P. aeruginosa pyelonephritis. A-56619 and A-56620 were also more potent than norfloxacin in treatment of mixed bacterial pyelonephritis caused by E. coli and Streptococcus faecalis. A-56619 was at least 30 times more potent than norfloxacin and A-56620 was 4 to 11 times more potent than norfloxacin when administered against Klebsiella pneumonia in mice. A-56619 and A-56620 were at least 2 to 10 times more potent than norfloxacin against Staphylococcus aureus infections in immunosuppressed mice. A-56619 was equally potent in all in vivo tests when administered orally or subcutaneously, whereas A-56620 was similar to norfloxacin in being more potent when administered subcutaneously. The peak serum levels after subcutaneous and oral administration of A-56619 and A-56620 were higher than that of norfloxacin. The serum hal-lives of A-56619 and A-56620 after subcutaneous and oral administration were longer than the serum half-life of norfloxacin.
New agents active against African swine fever virus
Authors: Sola A , Rodríguez S , Gil-Fernández C , Alarcón B , González M E , Carrasco L
Published: June 2012

Actinobolin, atropine, carrageenan, megalomycin C, suramin, and tetracenomycin C were tested for their activity against African swine fever virus replication. Both viral inhibitory potency and cytotoxicity were investigated. Megalomycin C, suramin, atropine, and carrageenan exhibited significant activity. Megalomycin C was the most active of the four agents with respect to the concentration of compound that blocked the formation of infectious virus by 50%. Suramin was the next most active agent in this respect, but because of its lower cytotoxicity, it had the most favorable therapeutic index.
Comparative study of serum bactericidal activity of cefotaxime alone or in combination with tobramycin
Authors: Bergeron M G , LeBel M , Charest A , Forcier J F , Morin J , Vallée F
Published: June 2012

The objectives of this study were to investigate the bactericidal activity in serum of cefotaxime alone or in combination with tobramycin against clinical strains and to determine the influence of tobramycin on the pharmacokinetics of cefotaxime. The peak bactericidal activity in serum of cefotaxime alone against Klebsiella oxytoca, Enterobacter aerogenes, Serratia marcescens, Pseudomonas cepacia, and Listeria monocytogenes varied between 1:4 and 1:256. Bactericidal activity could still be detected at 6 h against K. oxytoca and L. monocytogenes. The addition of tobramycin increased the bactericidal activity of cefotaxime against E. aerogenes from 1:16 to 1:128 (P less than 0.01). Cefotaxime recovery from urine was significantly decreased when tobramycin was added. Our data are comparable with those of other investigators who have shown a limited increase in the bactericidal activity of cefotaxime when aminoglycosides are added.
Ciprofloxacin concentrations in bone and muscle after oral dosing
Authors: Fong I W , Ledbetter W H , Vandenbroucke A C , Simbul M , Rahm V
Published: June 2012

Ciprofloxacin, a quinoline derivative with marked gram-negative and staphylococcal activity, may be a valuable orally administered agent for use against soft-tissue and bone infections. The concentrations of this antibiotic in serum, bone, and muscle samples were determined in patients undergoing orthopedic surgery. A total of 18 patients undergoing hip or knee replacement surgery or osteotomy were randomized to receive single oral doses of ciprofloxacin (500 mg, 750 mg, or 1 g); 10 patients with osteomyelitis were given single doses of 500 or 750 mg. Mean levels in bone of more than 1 microgram/g were achieved with the 750-mg ciprofloxacin doses in patients with osteomyelitis (1.4 +/- 1 microgram/g) or with the 1-g doses in patients without infections (1.6 +/- 0.6 microgram/g). The levels in muscle were significantly higher with each increasing dose level. Orally administered ciprofloxacin (750 mg given every 12 h) should provide adequate concentrations in bones and soft tissues to treat most osteomyelitis and soft-tissue infections.
Effect of tobramycin on protein synthesis in 2-deoxystreptamine aminoglycoside-resistant clinical isolates of Haemophilus influenzae
Authors: Levy J , Burns J L , Mendelman P M , Wong K , Mack K , Smith A L
Published: June 2012

Clinical isolates of Haemophilus influenzae resistant to a broad range of 2-deoxystreptamine aminoglycosides (2-DAM) were studied. The gene responsible for resistance could be mobilized by transformation into a 2-DAM susceptible laboratory strain of H. influenzae, enabling isogenic comparisons. The transformants had the same resistance phenotype as the parental strains. There was close linkage between 2-DAM resistance and streptomycin resistance, a chromosomal marker, but weak linkage between 2-DAM and erythromycin resistance. Resistant transformants exhibited a decreased accumulation of gentamicin due to the absence of the rapid, energy-dependent phase of uptake. Resistance was not through metabolic inactivation of the antibiotic; no aminoglycoside-acetylating, -adenylylating, or -phosphorylating activity was detected in the wild-type strains or in the 2-DAM-resistant transformants. Protein synthesis in 2-DAM-susceptible H. influenzae strains increased in the presence of low (1 microgram/ml) and moderate (50 micrograms/ml) concentrations of tobramycin. With higher concentrations (100 and 500 micrograms/ml), protein synthesis was progressively inhibited. In contrast, protein synthesis in 2-DAM-resistant clinical isolates and transformants was inhibited by 1 microgram of tobramycin per ml, and inhibition increased with higher drug concentrations. Since the stimulating effect of low concentrations of tobramycin in susceptible H. influenzae strains is probably due to misreading, these findings suggest that 2-DAM-resistant strains of H. influenzae have reduced sensitivity to misreading, indicating that altered ribosomes are responsible for the resistance.
Plasmid-mediated high-level resistance to erythromycin in Escherichia coli
Authors: Andremont A , Gerbaud G , Courvalin P
Published: June 2012

Escherichia coli BM2195 was found to be resistant to high levels of erythromycin. This new resistance phenotype was due to the constitutive synthesis of an erythromycin esterase which inactivates the antibiotic. The gene conferring resistance to erythromycin in this strain is carried on a 61-kilobase self-transferable plasmid, pIP1100, belonging to incompatibility group X.
Effect of ribavirin and tributylribavirin on argentine hemorrhagic fever (Junin virus) in guinea pigs
Authors: Kenyon R H , Canonico P G , Green D E , Peters C J
Published: June 2012

Subcutaneous injections of ribavirin into guinea pigs infected intraperitoneally or intracerebrally with Junin virus significantly increased the mean time to death but did not enhance survival of the animals. We found similar results with tributylribavirin. Virus replication was delayed, but not prevented, in ribavirin-treated infected guinea pigs. The animals usually died with high virus titers in their brains and frequently were paralyzed.
LY164846 in vitro antimicrobial activity testing, including disk diffusion susceptibility tests using 30-microgram disks
Authors: Jones R N , Baker C , Barry A L , Fuchs P C
Published: June 2012

A new oral cephalosporin, LY164846 (Eli Lilly & Co., Indianapolis, Ind.), was found to have a unique antimicrobial spectrum confined to methicillin-susceptible Staphylococcus spp., streptococci (except Enterococcus spp.), Haemophilus influenzae, Branhamella catarrhalis, and some anaerobes. Cephalothin in vitro tests (30-microgram disks or dilution) can represent LY164846 for laboratory testing if comparable interpretive breakpoints are applied to strains within the spectrum of LY164846. Organisms not inhibited by LY164846 (MICs greater than or equal to 32 micrograms/ml) were members of the family Enterobacteriaceae, Pseudomonas spp., Acinetobacter spp., enterococci, and some strains of Staphylococcus haemolyticus and of the Bacteroides fragilis group.
Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli
Authors: Hirai K , Aoyama H , Irikura T , Iyobe S , Mitsuhashi S
Published: June 2012

The mechanism of penetration of quinolones through the bacterial outer membrane was studied with lipopolysaccharide-deficient and porin-deficient mutants. The data indicated that the lipopolysaccharide layer might form a permeability barrier for hydrophobic quinolones such as nalidixic acid but not for hydrophilic quinolones such as norfloxacin and ciprofloxacin. The results also showed that quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a high relative hydrophobicity appeared to permeate through both OmpF porin and phospholipid bilayers.
Trichodermin esterase activity and trichodermin resistance in Mucor racemosus
Authors: Fonzi W A , Sypherd P S
Published: June 2012

Mucor racemosus exhibited inducible phenotypic resistance toward the protein synthesis inhibitor trichodermin. Induction of resistance was elicited by exposure to trichodermin or to cycloheximide. Both adapted and nonadapted cells took up [14C]trichodermin from the medium. Trichodermin was found to be rapidly deacetylated to trichodermol upon entering the cell. Adapted cells deacetylated the drug more rapidly than nonadapted cells both in vivo and in vitro. The trichodermol resulting from deacetylation appeared in the medium, but the growth of adapting cells began well before the total conversion of trichodermin to trichodermol. Based on these data and the observation that trichodermol was a poor inhibitor of Mucor, adaptation appears to result from deacylation of the active antibiotic.
Influence of six antifungal agents on the chemiluminescence response of mouse spleen cells
Authors: Abruzzo G K , Giltinan D M , Capizzi T P , Fromtling R A
Published: June 2012

The luminol-enhanced chemiluminescence (CL) assay is a measure of the early events of phagocytosis, leukocyte activation, and immune cell interactions. Reduction in the CL response of immune cells may be indicative of an inhibition of the immune response. This study was undertaken to examine the effects of antifungal agents tested at concentrations above and below therapeutically achievable levels on the CL response of mouse spleen cells. The effects of six antifungal agents--amphotericin B, ketoconazole, miconazole, 5-fluorocytosine, Bay-n-7133, and ICI 153,066--were studied. Changes in the CL response were assessed in terms of peak intensity and area under the intensity-time curve compared with appropriate diluent controls for each drug. Only amphotericin B and ketoconazole caused statistically significant lowering of the peak intensity at levels that are therapeutically attainable (mean peak plasma levels of 2 to 4 and 3.5 to 16 micrograms/ml, respectively). Although amphotericin B and ketoconazole caused reduction in the CL response, removal of the unbound drug in the preparation by centrifugation, washing, and suspension of cells in fresh drug-free medium resulted in a return of CL activity equivalent to the activity observed in cells not exposed to these agents. These results suggest that amphotericin B and ketoconazole at therapeutic concentrations may cause a reduction in immune cell antimicrobial activity; the clinical significance of these observations remains to be determined.
Hospital distribution, persistence, and reintroduction of related gentamicin R plasmids
Authors: Lee S C , Gerding D N , Cleary P P
Published: June 2012

A single plasmid clone was predominantly responsible for gentamicin resistance at the Minneapolis Veterans Administration Medical Center (MVAMC) for 9 years, although two unrelated R plasmids were found. Epidemiological data and restriction endonuclease analysis of 25 plasmid isolates suggested that the clonally derived plasmid population had persisted at the hospital. However, one case of reintroduction of the original epidemic plasmid from a hospital in another state was documented 4 years after the introduction of the original plasmid to the MVAMC. Resistance by the clonally derived plasmid population was not localized geographically within the MVAMC but rather was a hospital-wide problem. Furthermore, previously described classes of DNA rearrangement of the original plasmid were also widely disseminated in the hospital, implying that spread of strains bearing index-related plasmids was relatively unimpeded within the MVAMC despite extensive barrier isolation and cohorting measures. Potential environmental reservoirs of the plasmids were identified in hospital sinks and drains, but their relation to continued patient infection is not known.
In vitro activity of Ro 23-6240, a new fluorinated 4-quinolone
Authors: Chin N X , Brittain D C , Neu H C
Published: June 2012

The in vitro activity of Ro 23-6240 (AM833), 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7(4-methyl-1-piper azinyl) quinolone-3-carboxylic acid, was compared with those of norfloxacin, enoxacin, ofloxacin, and ciprofloxacin. Ro 23-6240 inhibited the majority of Enterobacteriaceae isolates at a concentration of less than or equal to 0.5 microgram/ml. It was especially active against Shigella sp., Salmonella sp., Escherichia coli, and Yersinia enterocolitica, with an MIC for 90% of the strains of less than or equal to 0.12 microgram/ml. The MIC for 90% of the strains was 1 microgram/ml for Serratia marcescens and 8 micrograms/ml for Pseudomonas aeruginosa. Staphylococcus aureus isolates, including methicillin-resistant strains, were inhibited by less than or equal to 1 microgram/ml. Streptococcal and anaerobic species were inhibited by 8 to 16 micrograms/ml. Ro 23-6240 inhibited beta-lactamase-producing bacteria resistant to broad-spectrum cephalosporins. The overall activity of Ro 23-6240 was similar to those of enoxacin, norfloxacin, and ofloxacin, but less than that of ciprofloxacin. The frequency of spontaneous resistance was low, although resistant bacteria could be isolated by repeated subculture. The activity of Ro 23-6240 was decreased in the presence of magnesium at concentrations similar to those present in urine.
Pharmacokinetics and metabolism of [14C]rosaramicin in dogs
Authors: Lin C C , Kim H K , Marco A , Radwanski E , Symchowicz S
Published: June 2012

The pharmacokinetics and metabolism of [14C]rosaramicin were studied in dogs after intravenous (i.v.; 10 mg/kg [bodyweight]) and oral (25 mg/kg) administration. After i.v. administration, rosaramicin levels in plasma declined rapidly, with half-lives of 0.22 h for the distribution phase and 0.97 h for the elimination phase. The apparent volume of distribution was 3.43 liters/kg, and the total body clearance was 106 mg/min . kg, indicating extensive distribution in tissue or metabolism or both. The absorption of oral solution was 58%, and the absolute bioavailability of rosaramicin was 35%. The plasma area under the curve of unchanged rosaramicin was only 5% that of total radioactivity after oral administration and 8% after i.v. administration, indicating extensive metabolism of the drug. The total radioactivity excreted in urine accounted for only 24% of the i.v. dose and 17% of the oral dose. Fecal radioactivity accounted for 71% of the i.v. dose and 68% of the oral dose. Several metabolites were observed in the plasma and urine. The amount of unchanged rosaramicin in urine (1 to 2% of the dose) was quite small after drug administration by either route.