bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiviral activity of 5-ethyl-2'-deoxyuridine against herpes simplex viruses in cell culture, mice, and guinea pigs
Authors: Schinazi R F , Scott R T , Peters J , Rice V , Nahmias A J
Published: June 2012

The susceptibility of 3 laboratory strains and 24 clinical isolates of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) to 5-ethyl-2'-deoxyuridine was determined in plaque reduction assays in Vero cells. The median effective doses were 8.6 and 7.8 microM, respectively. The drug was less potent than acyclovir and other related antiviral drugs, but it had a high therapeutic index against both HSV-1 and HSV-2. Drug-resistant viruses were readily produced in cell culture. These variants were cross-resistant to acyclovir, 2'-fluoro-5-iodoaracytosine, and 2'-fluoro-5-methylarauracil but were susceptible to vidarabine or phosphonoformate. These findings confirm that the selective antiviral activity of 5-ethyl-2'-deoxyuridine is mediated by the virus-induced thymidine kinase. Oral or intraperitoneal administration of the drug at nontoxic doses was ineffective in protecting mice against intracerebral challenge with virus. Using implanted osmotic minipumps or coadministering the drug with dimethyl sulfoxide failed to decrease the mortality rate. In guinea pigs infected genitally with HSV-2, topical drug treatment was more effective than placebo in reducing lesion severity and other clinical and virological variables. These effects were noted whether the drug treatment was initiated 3 or 24 h after infection (ascertained serologically). Drug-treated animals had a significantly lower herpes antibody titer than did placebo-treated guinea pigs, suggesting that the drug can also reduce the viral antigen load. In this model, the drug appeared to be as effective as topical phosphonoformate or acyclovir.
Prevention of oncogenic viral infections in mice with CGP 11637, a synthetic muramyl dipeptide analog
Authors: Acevedo H F , Raikow R B , Acevedo H O , Delgado T F , Pardo M
Published: June 2012

The efficacy of N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine (nor-MDP) in controlling viral oncogenesis in mice was investigated. The tumors studied were blood cell malignancies induced by Friend leukemia virus in SJL/J mice, spontaneous mammary neoplasms in RIII/Imr and C3H/OuJ mice, and spontaneous lymphocytic leukemia in AKR/J mice. A transplantable tumor, Lewis lung carcinoma, in C57BL/6J mice was used as a nonvirally induced control model. The nor-MDP was dissolved in saline and made into an emulsion with an equal volume of squalene-Arlacel A and injected subcutaneously at 1- to 2-month intervals. Test and control mice were challenged with exogenous virus or tumor transplant 2 weeks after a second injection of nor-MDP. Administration was started at around 2 months of age in mice that develop spontaneous neoplasms. Electron microscopy studies were done on neoplastic tissues of selected test and control mice. This administration of nor-MDP prevented erythroleukemia in SJL/J mice caused by low doses of Friend leukemia virus (although erythroleukemia survivors were not protected from a late-developing lymphoma) and also delayed (possibly prevented) the development of a spontaneous mammary neoplasm in RIII/Imr mice. No antitumor effects were observed on the spontaneous neoplasms of C3H/OuJ and AKR/J mice or on the Lewis lung carcinoma implanted into C57BL/6J mice. Electron microscopic examinations of the various neoplastic tissues indicated that nor-MDP administration eliminated or reduced extracellular viruses. The results suggested that under the experimental conditions used nor-MDP appears to effect the viruses and not the malignant cells per se.
Antimalarial activities and subacute toxicity of RC-12, a 4-amino-substituted pyrocatechol
Authors: Schmidt L H , Rossan R N , Fradkin R , Sullivan R , Schulemann W , Kratz L
Published: June 2012

RC-12 [1,2-dimethoxy-4-(bis-diethylaminoethyl)-amino-5-bromobenzene] was evaluated for prophylactic, radical curative, and suppressive activities against infections with Plasmodium cynomolgi and subacute toxicity in rhesus monkeys. Applied as a prophylactic agent, RC-12, administered in doses of 6.25 to 25.0 mg/kg daily throughout the incubation period, provided near-complete to complete protection against 10(5) to 10(6) times the minimum infective dose of sporozoites. Applied as a suppressive agent, daily doses of 100.0 mg of RC-12 per kg did not eradicate blood schizonts regularly; hence, the need for concomitant administration of a blood schizonticide, such as chloroquine, in assessments of radical curative activity. In such appraisals, daily doses of 6.25 to 25.0 mg of RC-12 per kg for 14 days, in combination with 2.5 mg of chloroquine per kg daily for 7 days, effected cure of 69 and 93% of established infections, respectively. The curative activity of RC-12 was related to the total dose and could be achieved with a regimen as brief as 4 days. With respect to outward expressions of toxicity, daily doses of 50.0 mg/kg or lower for 15 to 225 days evoked no reactions. Doses of 100.0 or 200.0 mg/kg, scheduled for 15 days, evoked convulsions and depression and were, respectively, lethal to 4 of 17 and 7 of 7 recipients. Doses of 25.0 mg/kg or lower evoked no discrete reactions. Doses of 50.0 mg/kg and higher evoked hepatomegaly, vacuolation of hepatocytes, and elevations of glutamic oxalacetic and glutamic pyruvic transferase activities in serum, reactions related in intensity to dose but not duration of dosage.
Cytotoxicity of rabbit macrophage peptides MCP-1 and MCP-2 for mouse tumor cells
Authors: Sheu M J , Baldwin W W , Brunson K W
Published: June 2012

The cytotoxicity of cationic peptides MCP-1 and MCP-2 isolated from rabbit alveolar macrophages was tested against two tumor cell lines of murine lymphosarcoma origin, RAW117-P and RAW117-H10, and a normal mouse connective tissue fibroblast strain, ATCC CCL1.RAW117-H10 is a highly malignant metastatic variant derived from the less malignant RAW117-P. Our results indicate that these peptides possess a cytotoxic activity against the tumor cells tested but not against the normal cells tested. At concentrations of 30 micrograms/ml, these peptides completely killed RAW117-H10 cells in suspension cultures, while inhibiting growth of RAW117-P for but a limited period of time, up to 48 h, after which growth resumed. RAW117-P cells were killed by concentrations of 40 micrograms/ml. These peptides showed little cytotoxicity for normal mouse connective tissue fibroblasts at concentrations of 40 micrograms/ml.
Comparison of the activities of coumermycin, ciprofloxacin, teicoplanin, and other non-beta-lactam antibiotics against clinical isolates of methicillin-resistant Staphylococcus aureus from various geographical locations
Authors: Aldridge K E , Janney A , Sanders C V
Published: June 2012

One hundred clinical isolates of methicillin-resistant (Metr) Staphylococcus aureus from five different geographical origins were tested for their susceptibility to 12 non-beta-lactam antibiotics by the broth microdilution technique recommended by the National Committee for Clinical Laboratory Standards. Coumermycin and rifampin showed the highest activity with of MIC90s of 0.032 micrograms/ml for each compound. No resistance was found to coumermycin, whereas a single Metr S. aureus strain was found to be resistant to rifampin. Ciprofloxacin, vancomycin, and teicoplanin were the next most active compounds with MIC90s of 0.25, 0.5, and 0.5 micrograms/ml, respectively. Norfloxacin was less active, with an MIC90 of 1.0 micrograms/ml. Amikacin was the most active aminoglycoside tested, whereas high levels of resistance were found to tobramycin and gentamicin. Doxycycline and chloramphenicol showed variable results. Geographical variations in results were seen with doxycycline, chloramphenicol, and aminoglycosides. Kill-curve studies showed that coumermycin, ciprofloxacin, teicoplanin, vancomycin, and rifampin were highly bactericidal; more than 90% of the inoculum was killed within 8 h.
Comprehensive evaluation of ciprofloxacin-aminoglycoside combinations against Enterobacteriaceae and Pseudomonas aeruginosa strains
Authors: Haller I
Published: June 2012

The in vitro activities of antibiotic combinations containing ciprofloxacin and either gentamicin, sisomicin, netilmicin, amikacin, or tobramycin were evaluated by checkerboard assay (agar dilution method). A total of 220 strains of Enterobacteriaceae and Pseudomonas aeruginosa (11 species, 20 strains each) were tested. Synergistic or antagonistic effects were observed in less than 1% of the tests performed; they appeared to represent method-dependent fluctuations rather than true antibiotic interactions. No significant differences among the five aminoglycosides tested were seen. Time-kill experiments performed with three representative strains of Escherichia coli and Serratia marcescens showed additive combination effects with respect to the kill rates and inhibition of bacterial regrowth. Exposure of Serratia strains to either ciprofloxacin or gentamicin before the addition of the second drug had little influence on the combination effects observed. No antagonistic drug interactions were seen in vivo when combination therapy with ciprofloxacin and gentamicin was evaluated in a model of E. coli thigh muscle infection in neutropenic mice. Comparable therapeutic effects were obtained, regardless of whether the two compounds were administered simultaneously or sequentially at 1- or 2-h intervals.
Nationwide study of the susceptibility of the Bacteroides fragilis group in the United States
Authors: Tally F P , Cuchural G J , Jacobus N V , Gorbach S L , Aldridge K , Cleary T , Finegold S M , Hill G , Iannini P , O'Keefe J P
Published: June 2012

A nationwide susceptibility survey of the Bacteroides fragilis group was continued at New England Medical Center in 1983. A total of 555 strains were obtained from eight centers in the United States. In addition to the nine antimicrobial agents studied in the two previous years, three other agents were added to the evaluation: cefamandole, cefuroxime, and cefonicid. The results for the strains tested with the original nine drugs in 1983 were compared with those for 1,292 isolates tested in 1981 and 1982. The most active beta-lactam drug was piperacillin, which had an 8% resistance rate. Cefoxitin resistance increased from 10% in 1982 to 16% in 1983. High rates of resistance to cefotaxime, cefoperazone, cefamandole, cefonicid, and cefuroxime were encountered. No metronidazole- or chloramphenicol-resistant isolates were found during the 3 years of the study. Susceptibility patterns varied at the eight hospitals: the outbreak of cefoxitin resistance reported in 1982 at New England Medical Center remitted, while a high clindamycin resistance rate was documented at one hospital in 1983. These data indicate the need for determining the susceptibility patterns for the B. fragilis group of organisms at each hospital.
Randomized comparative study of amoxicillin-clavulanic acid and co-trimoxazole in the treatment of acute urinary tract infections in adults
Authors: Karachalios G N
Published: June 2012

The efficacy and safety of amoxicillin-clavulanic acid were compared with those of co-trimoxazole in the treatment of acute urinary tract infections. A total of 104 patients (mean age, 52 years) with clinical and laboratory evidence of acute urinary tract infection were enrolled in the study. Characteristics and infecting organisms were equivalent in both groups of patients. Escherichia coli was the predominant bacteria pathogen in both groups. Both drugs resulted in clinical improvement in 100% of the patients; bacteriological cure after the termination of therapy was 95% with amoxicillin-clavulanic acid and 83% with co-trimoxazole (P less than 0.001). Side effects were not severe enough to necessitate discontinuation of the antimicrobial agents. Amoxicillin-clavulanic acid is effective and safe therapy for acute urinary tract infections caused by susceptible bacteria.
Semiautomated assessment of in vitro activity of potential antileishmanial drugs
Authors: Berman J D , Gallalee J V
Published: June 2012

We have compared the in vitro activity of six agents against macrophage-contained Leishmania tropica amastigotes determined by the conventional Giemsa staining procedure, with the activity determined by the semiautomated assessment of incorporation of radiolabeled uracil into the nucleic acid of the organisms. Although the mean 50% effective dose of Pentostam by Giemsa staining (4.1 micrograms/ml) was somewhat higher than that by uracil incorporation (2.8 micrograms/ml), the ED50S for the other two clinical agents (pentamidine, 0.035 versus 0.037 micrograms/ml; amphotericin B, 0.67 versus 0.70 micrograms/ml) and for three promising experimental agents (ketoconazole, 11.3 versus 11.3 micrograms/ml; the 8-aminoquinoline WR 6026, 1.6 versus 1.5 micrograms/ml formycin B, 0.018 versus 0.017 micrograms/ml) were virtually identical. The radiolabeling technique has several advantages over the Giemsa staining procedure. These include the need for relatively few macrophages, rapid and objective data generation, and viability of the test organism being measured. The successful application of the radiolabeling technique to at least six different chemical classes of compounds suggests that it would be useful for the routine assessment of antileishmanial activity in vitro.
Comparison of amphotericin B and N-D-ornithyl amphotericin B methyl ester in experimental cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis
Authors: Perfect J R , Durack D T
Published: June 2012

Amphotericin B and N-D-ornithyl amphotericin B methyl ester were compared for therapeutic efficacies against experimentally induced cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis in rabbits. Antifungal activity of the two polyenes in vitro was similar for the yeasts used in these experiments. N-D-ornithyl amphotericin B methyl ester gave a slightly higher concentration in serum than amphotericin B did, but both drugs had similar elimination curves, and penetration into the cerebrospinal fluid was poor for both. Despite these similarities between the two polyenes, amphotericin B was much more effective than N-D-ornithyl amphotericin B methyl ester in the treatment of cryptococcal meningitis in rabbits. For C. albicans endocarditis, both polyenes had similar cure rates, but in vitro measurement of fungicidal activity in serum did not predict treatment outcome. For C. albicans pyelonephritis, both polyenes showed efficacy; because higher doses of the less toxic methyl ester could be used, it sterilized the urinary tract more often than amphotericin B. These studies indicate that in vivo and in vitro experiments may be needed to predict the results of treatment with polyenes.
Antimicrobial susceptibility of five subgroups of Mycobacterium fortuitum and Mycobacterium chelonae
Authors: Swenson J M , Wallace R J , Silcox V A , Thornsberry C
Published: June 2012

Broth microdilution MICs were determined for 258 clinical isolates of Mycobacterium fortuitum (3 biovariants) and M. chelonae (2 subspecies) with amikacin, tobramycin, cefoxitin, doxycycline, erythromycin, and sulfamethoxazole-trimethoprim and with several new beta-lactams and aminoglycosides and ciprofloxacin. Variations in susceptibility by and within species subgroups confirm the need for susceptibility testing against clinically important strains.
Antimicrobial chemotherapy of septicemia due to methicillin-resistant Staphylococcus aureus
Authors: Cafferkey M T , Hone R , Keane C T
Published: June 2012

The outcome of treatment of 48 episodes of septicemia due to methicillin-resistant Staphylococcus aureus (MRSA) in 44 patients was assessed. Twenty-six of the patients died; nineteen of them died of infection, and infection was a major contributing factor to the deaths of the remaining seven patients. Fourteen of fifteen patients treated with inadequate antibiotic therapy died, and the other patient developed a mycotic aneurysm of the femoral artery, for which amputation was necessary. Eight of eleven patients treated with amikacin (alone or combined with another antimicrobial) died, and three recovered slowly; only one recovered fully without sequelae. In an additional two patients who failed to respond to amikacin, treatment was changed to vancomycin. Vancomycin was used to treat 18 episodes of MRSA septicemia in 17 patients. In 14 of these episodes the patients recovered fully. One patient died of uncontrolled infection, and in three, infection was a contributing factor but not the major cause of death. Vancomycin was confirmed as antibiotic of choice in treating MRSA septicemia.
A randomized prospective study of ceftazidime versus ceftazidime plus flucloxacillin in the empiric treatment of febrile episodes in severely neutropenic patients
Authors: de Pauw B , Williams K , de Neeff J , Bothof T , de Witte T , Holdrinet R , Haanen C
Published: June 2012

In a prospective, randomized study, ceftazidime monotherapy was compared with a combination of ceftazidime and flucloxacillin in 100 febrile neutropenic patients. Thirty-four bacteriologically documented infections, of which 26 were bacteremias, in 51 patients were treated with ceftazidime alone. Thirty-four bacteriologically proven infections, of which 29 were bacteremias, in 49 patients were treated with a combination of ceftazidime and flucloxacillin. The clinical response rate for ceftazidime monotherapy was 80%; the bacteriological cure rate was 90%. Efficacy against gram-negative pathogens appeared to be excellent, achieving a 100% cure rate. The clinical response and bacteriological cure rates for the combination were 76 and 86%, respectively. Three superinfections were registered in the ceftazidime group, and four, involving six pathogens, were registered in the combination group. Other side effects of ceftazidime were minimal. It is concluded that ceftazidime is an effective drug for the empiric treatment of febrile neutropenic patients. It offers the opportunity to avoid the aminoglycosides in first-line treatment. It may be appropriate to combine ceftazidime with cephalothin or vancomycin or to modify therapy if resistant gram-positive strains are encountered.
Pharmacokinetic and therapeutic trial of sultamicillin in acute sinusitis
Authors: Jones S , Yu V L , Johnson J T , Wagner R L , Kim H K
Published: June 2012

Sultamicillin, an antibiotic combining ampicillin and the beta-lactamase inhibitor sulbactam, was administered to 13 patients diagnosed as having acute sinusitis. Specimens from sinus were obtained for all 13 patients by transantral puncture. Pharmacokinetics, bacteriology, and therapeutic efficacy were assessed. Eighty-five percent (11 of 13) were cured; two treatment failures were subsequently shown to have chronic (rather than acute) sinusitis during surgical exploration. Diarrhea was frequently encountered, and Clostridium difficile-associated enteritis was documented for one patient. Beta-lactamase-producing organisms were not encountered in this study; however, this study provides impetus for further controlled clinical trials.
In vitro susceptibility of Clostridium difficile to new beta-lactam and quinolone antibiotics
Authors: Chow A W , Cheng N , Bartlett K H
Published: June 2012

The in vitro susceptibilities of 34 to 73 clinical isolates of Clostridium difficile to 24 antimicrobial agents, including 18 beta-lactams, 4 fluoroquinolones, clindamycin, and metronidazole were examined. Metronidazole was the most active (MIC for 90% of the isolates [MIC90], 0.5 microgram/ml), followed by the carbapenems (Sch 34343, 4 micrograms/ml; imipenem, 8 micrograms/ml) and the antipseudomonas penicillins (piperacillin, 8 micrograms/ml; ticarcillin, 32 micrograms/ml; carbenicillin, 32 micrograms/ml). A monobactam (aztreonam) and most cephalosporins were either highly inactive (cefoxitin, cefuroxime, cefotiam, cefsulodin, ceftizoxime, cefbuperazone, and cefotaxime), with an MIC90 of greater than or equal to 128 micrograms/ml, or moderately inactive (ceftriaxone, cefmenoxime, cefoperazone, ceftazidime, and moxalactam), with an MIC90 of greater than or equal to 32 micrograms/ml. Clindamycin (MIC90, 32 micrograms/ml) and the fluoroquinolones (ciprofloxacin, 8 micrograms/ml; A-56619, 8 micrograms/ml; A-56620, 8 micrograms/ml; norfloxacin, 32 micrograms/ml) were only variably active. These in vitro data per se may not necessarily predict the relative risks for C. difficile-associated diarrhea or colitis during therapy with these agents. However, these data, in concert with knowledge of drug bioavailability in feces and the broad-spectrum antimicrobial activity on the resident bowel flora, may provide additional insight into the mechanisms and predictability of this complication with these agents. Careful monitoring for the emergence of C. difficile and fecal cytotoxin and for diarrhea during therapy with these agents is clearly indicated.
Antimicrobial susceptibility of Corynebacterium group D2
Authors: Santamaría M , Ponte C , Wilhelmi I , Soriano F
Published: June 2012

The in vitro susceptibility of 30 Corynebacterium group D2 strains to nine antimicrobial agents was determined. Vancomycin and norfloxacin were the most active agents tested. All strains were resistant to ampicillin and cephalothin, all except one were resistant to gentamicin, and the activity of erythromycin, novobiocin, tetracycline, and rifampin varied.
In vitro activity of ciprofloxacin combined with azlocillin
Authors: Moody J A , Peterson L R , Gerding D N
Published: June 2012

A ciprofloxacin plus azlocillin broth microdilution checkerboard was evaluated against 125 aerobic gram-negative and gram-positive bacteria. Synergism (sigma FIC less than or equal to 0.5) occurred among 56% of Pseudomonas aeruginosa, 30% of Acinetobacter species, and 40% of Staphylococcus aureus studied. Antagonism (sigma FIC greater than or equal to 2) was present in less than 1% of the organisms.
Comparative pharmacokinetics of carumonam and aztreonam in mice, rats, rabbits, dogs, and cynomolgus monkeys
Authors: Kita Y , Fugono T , Imada A
Published: June 2012

The pharmacokinetic properties of carumonam (AMA-1080, Ro 17-2301) were studied in mice, rats, rabbits, dogs, and cynomolgus monkeys and compared with those of aztreonam. Carumonam administered subcutaneously in mice or intramuscularly in rats, rabbits, dogs, and cynomolgus monkeys at a dose of 20 mg/kg was readily absorbed and distributed at high concentrations in the plasma, kidneys, liver, and lungs, as was aztreonam. The peak level of carumonam in plasma, ranging from 41 micrograms/ml in mice to 68 micrograms/ml in monkeys; the area under the plasma concentration-time curve, ranging from 20 micrograms X h/ml in mice to 80 micrograms X h/ml in monkeys; the plasma half-life, ranging from 0.24 h in mice to 1.10 h in dogs; and the plasma clearance, ranging from 4.5 ml/min per kg in monkeys to 16.7 ml/min per kg in mice, resembled respective values of aztreonam. In rats, carumonam was eliminated faster than aztreonam. The levels of both antibiotics in the kidneys and liver were usually higher than respective levels in plasma. The level of carumonam in the kidney was usually higher than that of aztreonam, whereas the level of aztreonam in the liver was usually higher than that of carumonam. Both antibiotics showed similar distribution in the lung and spleen; the levels in these tissues were less than the levels in plasma. Carumonam was excreted mainly in the urine; the recovery ranged from 52% (from dogs) to 73% (from rabbits). The urinary recovery of carumonam from mice, rats, and monkeys was higher, but the recovery of carumonam from rabbits and dogs was lower than that of aztreonam. The biliary excretion of carumonam, amounting to 4.1% from rats and less than 0.3% from rabbits and dogs, was smaller than that of aztreonam, amounting to 19.1% from rats and around 1% from rabbits and dogs. The extent of protein binding at 20 micrograms of carumonam per ml was lower than that of aztreonam. For all species except dogs, which have very low binding in their serum (11% for carumonam and 20% for aztreonam), the binding of carumonam ranged from 21% (in rabbits) to 36% (in rats), whereas that of aztreonam ranged from 55% (in rabbits) to 85% (in rats). Thus, the plasma pharmacokinetics of carumonam and aztreonam were generally similar for all animals tested except dogs, but the two antibiotics differed slightly in their distribution in tissue, excretion, and protein binding in serum.
Production of new hybrid antibiotics, mederrhodins A and B, by a genetically engineered strain
Authors: Omura S , Ikeda H , Malpartida F , Kieser H M , Hopwood D A
Published: June 2012

Hybrid antibiotics mederrhodins A and B were produced by a recombinant strain consisting of the medermycin-producing Streptomyces sp. strain AM7161 containing part of the gene clusters for actinorhodin biosynthesis of Streptomyces coelicolor A3(2). Mederrhodin A has a hydroxyl group at the C-6 position of the medermycin molecule, and mederrhodin B is dihydromederrhodin A. The antimicrobial activity of mederrhodin A resembled that of medermycin. Mederrhodin B was almost devoid of antimicrobial activity.
Contrasts between phagocyte antibiotic uptake and subsequent intracellular bactericidal activity
Authors: Hand W L , King-Thompson N L
Published: June 2012

An ideal antibiotic for therapy of infections due to facultative intracellular organisms would enter phagocytes readily and kill intracellular bacteria. We have examined the consequences of antibiotic uptake by human polymorphonuclear lymphocytes (PMN) on intraphagocytic bactericidal activity, using antibiotics which differ markedly in their ability to enter PMN. After ingestion of Staphylococcus aureus, PMN were evaluated in regard to uptake of antibiotics and survival of intraphagocytic bacteria in the presence or absence of these drugs. Except for erythromycin, the uptake of which was slightly decreased, the entry of tested antibiotics into PMN was increased or unchanged after ingestion of S. aureus. Clindamycin and erythromycin, which achieved high cellular levels in PMN, failed to produce a significant reduction in viable intraphagocytic S. aureus during 3 h of antibiotic exposure. In contrast, rifampin, which was concentrated severalfold by phagocytes, was able to kill intracellular staphylococci. Gentamicin and penicillin G penetrated PMN rather poorly. However, while gentamicin demonstrated efficient intraphagocytic killing of bacteria, penicillin had no intracellular effect during the 3-h incubation period. These observations document that the ability to enter phagocytes is only one of the factors which determine the intracellular antibacterial activity of an antibiotic.
Synthesis and antibacterial activities of optically active ofloxacin
Authors: Hayakawa I , Atarashi S , Yokohama S , Imamura M , Sakano K , Furukawa M
Published: June 2012

Two optically active (100% enantiomeric excess) isomers of ofloxacin [(+/-)-ofloxacin; DL-8280; (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7 H-pyrido[1,2,3-de] [1,4] benzoxazine-6-carboxylic acid] were prepared by use of their optically resolved synthetic intermediates. One of the isomers, (-)-ofloxacin, was 8 to 128 times more potent in inhibiting the multiplication of gram-positive and gram-negative bacteria than the other, (+)-ofloxacin, and approximately two times more active than the racemate, (+/-)-ofloxacin.
Mechanism of resistance to silver ions in Klebsiella pneumoniae
Authors: Kaur P , Vadehra D V
Published: June 2012

The uptake of silver by an experimentally derived silver-resistant Klebsiella pneumoniae strain was three to four times lower than the uptake by a susceptible strain. Spheroplasts of the two strains showed no difference in uptake. AgNO3 at a concentration of 40 micrograms/ml decreased the succinate dehydrogenase activity in susceptible and resistant strains by 100 and 18%, respectively. More than one resistance mechanism may be involved.
In vitro susceptibility of Brucella melitensis to new cephalosporins crossing the blood-brain barrier
Authors: Palenque E , Otero J R , Noriega A R
Published: June 2012

The in vitro susceptibilities of 83 clinical isolates of Brucella melitensis to seven cephalosporins and a monobactam were determined. Ceftizoxime, ceftriaxone, and cefotaxime were the most effective agents tested, with MICs ranging from 0.25 to 2 micrograms/ml. Moxalactam, cefoperazone, cefuroxime, and ceftazidime showed MICs between 4 and 64 micrograms/ml, with moxalactam being the most active agent in this group. Aztreonam showed poor activity, with MICs higher than 64 micrograms/ml.
Role of the cell membrane in pH-dependent fluoride inhibition of glucose uptake by Streptococcus mutans
Authors: Germaine G R , Tellefson L M
Published: June 2012

The effect of pH on the fluoride sensitivity of glucose uptake by whole cells and glucose transport by permeabilized cells of Streptococcus mutans was compared. Whole cells exhibited a marked pH-dependent sensitivity to fluoride over the pH range 7.0 to 5.0. As the pH was decreased, fluoride sensitivity increased. In contrast, no significant effect of pH on the fluoride sensitivity of glucose transport (e.g., phosphorylation) by permeabilized cells energized with 2-phosphoglycerate was noted. The relative effect of pH on the fluoride sensitivity of whole cell glucose uptake and fermentation was similar. These data are consistent with the notion that the cell membrane is impermeable to the fluoride anion and that intracellular accumulation of fluoride depends on translocation of hydrogen fluoride across the membrane.
Expression of methicillin resistance in heterogeneous strains of Staphylococcus aureus
Authors: Hartman B J , Tomasz A
Published: June 2012

The phenotypic expression of methicillin resistance was studied in a number of clinical isolates and laboratory strains of Staphylococcus aureus. The methicillin-resistant S. aureus strains could be divided into three classes, homogeneous, heterogeneous, and thermosensitive heterogeneous methicillin-resistant S. aureus, on the basis of their plating efficiencies at 30 or 37 degrees C on methicillin-containing agar plates. Heterogeneous strains of methicillin-resistant S. aureus were composed of two subpopulations: a small minority of cells (10(-5) to 10(-3); MIC, 600 to 1,000 micrograms/ml) that expressed resistance to high concentrations of methicillin at 37 degrees C, and a majority of cells (MIC, 5 micrograms/ml) that remained susceptible to the drug at 37 degrees C. Cultures of a thermosensitive heterogeneous strain were able to grow in the presence of high concentrations of methicillin, provided that the growth temperature was 30 degrees C. Such cultures lost their phenotypic resistance within 30 min (i.e., in less than one doubling time) after the growth temperature was shifted to the nonpermissive 37 degrees C. Shift of the temperature of the culture in the reverse direction (37 to 30 degrees C) resulted in an equally rapid expression of phenotypic resistance. The majority of the cells in such heterogeneous strains may be considered heat (or salt) conditional in their phenotypic expression of methicillin resistance. Both heterogeneous and thermosensitive heterogeneous strains, irrespective of their temperature of cultivation and degree of phenotypic resistance, contained detectable quantities of the 78-kilodalton penicillin-binding protein 2a (PBP 2a) that previous studies have suggested is a biochemical correlate of methicillin resistance in homogeneous strains of methicillin-resistant S. aureus. However, in contrast to the homogeneous stains, in heterogeneous and thermosensitive heterogeneous isolates the ability to synthesize PBP 2a is apparently not sufficient to provide a resistant phenotype. In these strains some additional, as yet undefined factor(s) is also needed for the expression of methicillin resistance.
Characterization of NPS-1, a novel plasmid-mediated beta-lactamase, from two Pseudomonas aeruginosa isolates
Authors: Livermore D M , Jones C S
Published: June 2012

A novel beta-lactamase, which had a pI of 6.5 and a molecular weight of 25,000, was observed in two Pseudomonas aeruginosa isolates. The enzyme, designated NPS-1, was encoded by a plasmid of molecular weight 41 X 10(6) which also encoded resistance to streptomycin and sulfonamide. This plasmid, designated pMLH50, was freely transmissible to other P. aeruginosa strains, but not to Escherichia coli K-12. The enzyme was purified partially and shown to have activity against both penicillins and cephalosporins. Vmax rates for oxacillin and carbenicillin were less than 50% of the Vmax for benzylpenicillin, and the Vmax for cephaloridine was only 3% of the Vmax for benzylpenicillin. Imipenem, aztreonam, and several antipseudomonal cephalosporins were stable to the enzyme. Hydrolysis of most substrates obeyed Michaelis-Menten kinetics, but cefsulodin induced a reversible reduction in the activity of the enzyme. Transconjugants of the beta-lactamase-producing isolates in P. aeruginosa PU21 acquired beta-lactam resistances which mirrored the hydrolytic activity of the enzyme.
In vitro evaluation of A-56619 (difloxacin) and A-56620: new aryl-fluoroquinolones
Authors: Stamm J M , Hanson C W , Chu D T , Bailer R , Vojtko C , Fernandes P B
Published: June 2012

The in vitro antibacterial potencies of A-56619 and A-56620, two new aryl-fluoroquinolones, were compared with the potency of norfloxacin against a broad spectrum of organisms. Cefotaxime, aztreonam, piperacillin, imipenem, penicillin, and gentamicin were also tested for reference purposes. The MICs required to inhibit at least 90% of the strains tested ranged from 0.25 to 4 micrograms/ml for A-56619 and from 0.06 to 0.5 microgram/ml for A-56620 for members of the Enterobacteriaceae. A-56619 was generally twofold less potent and A-56620 was twofold more potent than norfloxacin against most aerobic gram-negative bacilli, including members of the Enterobacteriaceae and Pseudomonas aeruginosa. Against indole-positive Proteus, Morganella, Providencia rettgeri, and Serratia strains, A-56619 was at least 8- to 16-fold less potent than norfloxacin. A-56619 and A-56620 were four- to eightfold more potent than norfloxacin against Staphylococcus aureus and equally potent to fourfold more potent against Streptococcus species, Haemophilus influenzae, and Neisseria gonorrhoeae. The MICs of A-56619 and A-56620 were only slightly affected by increased inoculum size or by the addition of various cations at physiologic concentrations. A-56619 was three- to fivefold less active at pH 8.0 than at pH 6.5 or 7.2. A-56620 was twofold less active at pH 6.5 than at pH 8.0 or 7.2 against members of the Enterobacteriaceae and Pseudomonas aeruginosa; similar pH variations did not affect A-56620 activity against gram-positive cocci. The potencies of A-56619, A-56620, and norfloxacin were less in urine than in Mueller-Hinton broth; however, this effect was more pronounced with norfloxacin. Human serum at a concentration of 50% caused a 4- to 64- fold decrease in the potency of A-56619 and an average 4-fold decrease in the potency of A-56620, compared with no effect on the potency of norfloxacin. A-56619, A-56620, and norfloxacin were bactericidal and, at four times the MIC, reduced the viable cell counts of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa by approximately 99.9% within 2 h. A-56619, A-56620, and norfloxacin showed no significant synergistic activity and no antagonism when they were aminoglycoside or beta-lactam antimicrobial agents.
High-level amikacin resistance in Escherichia coli due to phosphorylation and impaired aminoglycoside uptake
Authors: Perlin M H , Lerner S A
Published: June 2012

Plasmid pMP1-1 in Escherichia coli L-0 encodes aminoglycoside (AG) 3'-phosphotransferase II [APH(3')-II]. This enzyme modifies and confers high-level resistance to kanamycin. Although amikacin is a substrate for APH(3')-II, strain L-0(pMP1-1) is susceptible to amikacin. Plasmid pMP1-2 is a spontaneous mutant of pMP1-1 which determines increased APH(3')-II activity for amikacin, apparently as a result of an increase in the copy number of the plasmid. From amikacin-susceptible, gentamicin-susceptible transformants and transconjugants that bear the APH(3')-II gene on plasmid pMP1-1 or pMP1-2 or cloned into multicopy plasmid pBR322, we selected spontaneous mutants at concentrations of amikacin or gentamicin that were two to four times higher than the MICs of these antibiotics. In each case, whether they were selected by using amikacin or gentamicin, the mutants exhibited modest (two- to eightfold) increases in the MIC of gentamicin and major (64- to 128-fold) increases in the MIC of amikacin. Using these laboratory strains of E. coli, we examined the effects on AG susceptibility of the interaction of AG-modifying enzyme activity and generalized AG uptake. Increasing the level of activity of an AG phosphotransferase in these strains lowered their susceptibility to AGs which were substrates for which the enzyme had low Kms. However, an increase in AG-modifying activity alone did not result in large increases in the MICs for poor substrates of the enzyme. In strains which lacked AG-modifying enzymes, a decrease in the rate of AG uptake increased the MICs modestly for a broad spectrum of AGs. When a strain bore the phosphotransferase, a decrease in generalized AG uptake could raise the MIC further, not only for low-Km substrates, but even for AG substrates for which the enzyme had high Kms. Thus, increased modifying activity, together with a diminished rate of uptake, could produce even higher MICs for poor AG substrates.
Randomized prospective study comparing moxalactam and cefoxitin with or without tobramycin for the treatment of serious surgical infections
Authors: Tally F P , Kellum J M , Ho J L , O'Donnell T F , Barza M , Gorbach S L
Published: June 2012

The efficacy and toxicity of moxalactam were compared with the efficacy and toxicity of cefoxitin given with or without tobramycin to 109 patients with surgical infections. A total of 66 patients could be assessed for efficacy (33 patients in each group); 13 of the cefoxitin-treated patients also received tobramycin for at least 72 h. Most patients had intraabdominal infections; 17 had peritonitis, 14 had intraabdominal abscesses, and 7 had perforation of a gangrenous appendix. There were 15 patients with necrotizing soft-tissue infections. The predominant pathogens were members of the Enterobacteriaceae and Bacteroides fragilis. The cure rates were 79% (26 of 33 patients) for moxalactam and 88% (29 of 33 patients) for cefoxitin; the difference in cure rates was not statistically significant. In several patients, cultures of purulent intraabdominal exudates were negative, although bacteria were observed after Gram staining; this presumably reflected the potent activity of the antibiotic therapy which had been started before surgical drainage could be carried out. Adverse effects were observed in 18 of 44 assessable patients (41%) in the cefoxitin group and in 12 of 36 patients (33%) in the moxalactam group; the difference in the rates of adverse effects was not statistically significant. Our results suggest that moxalactam is similar in efficacy and toxicity to cefoxitin given with or without tobramycin for the treatment of serious surgical sepsis caused by a mixture of anaerobic and aerobic pathogens.
Characteristics of ethidium uptake by the trypanosomatid flagellates Crithidia fasciculata and Leptomonas seymouri
Authors: Coolbear K P , Midgley M
Published: June 2012

The uptake of the phenanthridinium ethidium by the trypanosomatids Crithidia fasciculata and Leptomonas seymouri was studied. The time course of uptake of ethidium was biphasic for both organisms, consisting of an initial rapid phase and a protracted slow phase. The characteristics of these phases were consistent with the hypothesis that the initial phase represented specific external binding, while the second phase represented transport into the cells. In L. seymouri the transport phase was inhibited by inhibitors of energy transduction and putative inhibitors of a transport ATPase. Ethidium transport could not be saturated over a large concentration range of ethidium. Phenanthridiniums and related compounds displayed both inhibitory and stimulatory effects on ethidium transport.
Plasmid-encoded amikacin resistance in multiresistant strains of Klebsiella pneumoniae isolated from neonates with meningitis
Authors: Woloj M , Tolmasky M E , Roberts M C , Crosa J H
Published: June 2012

Two multiresistant Klebsiella pneumoniae strains isolated from cerebrospinal fluid of human neonates were analyzed for their plasmid content. Two of the plasmids harbored by these strains, pJHCMW1 (11 kilobase pairs) and pJHCMW4 (75 kilobase pairs), carried genetic determinants for amikacin resistance. These plasmids also encoded resistance to kanamycin, tobramycin, and ampicillin which could be transferred to Escherichia coli by conjugation. Extracts from transconjugant derivatives carrying pJHCMW4 produced an acetyltransferase activity that acetylated all three aminoglycosides. Transconjugant derivatives carrying pJHCMW1 encoded both acetylating and phosphorylating activities. Southern blot hybridization analysis indicated considerable DNA homology between these two plasmids.
Possible physiological functions of penicillin-binding proteins in Staphylococcus aureus
Authors: Georgopapadakou N H , Dix B A , Mauriz Y R
Published: June 2012

There are four penicillin-binding proteins (PBPs) in Staphylococcus aureus, of which PBPs 2 and 3 are essential. Cefotaxime binds selectively to PBP 2, and cephalexin binds to PBP 3, each at its respective MIC. The morphology of S. aureus strains grown in the presence of the two antibiotics was examined by phase-contrast and scanning electron microscopy. Exposure of the cells to cefotaxime at concentrations at which it bound selectively to PBP 2 resulted in the extrusion of cytoplasm and cell lysis, whereas exposure to cephalexin at concentrations at which it bound exclusively to PBP 3 resulted in cell enlargement and the cessation of septation. The latter morphological response was very similar to that produced by norfloxacin. The results suggest that in S. aureus, PBP 2 may be the primary peptidoglycan transpeptidase, and PBP 3 may be involved in septation.
Enhanced toxicity of copper for Streptococcus mutans under anaerobic conditions
Authors: Evans S L , Tolbert C , Arceneaux J E , Byers B R
Published: June 2012

Copper inhibition of 11 strains (serotypes a through g) of Streptococcus mutans was increased by anaerobic incubation. Anaerobic toxicity was reversed by cuprous, but not by cupric, chelators. Susceptibility to aerobic copper inhibition was related to serotype; serotypes c, e, and f (biotype I) were most sensitive.
In vitro activities of selected new and long-acting cephalosporins against Pasteurella multocida
Authors: Noel G J , Teele D W
Published: June 2012

The activities of six agents commonly used in treating infections of the skin and soft tissues and the action of selected cephalosporins against 15 isolates of Pasteurella multocida were assessed by a macro-broth dilution method. Broad-spectrum cephalosporins, including ceftriaxone and cefixime, had excellent in vitro activities (MIC less than or equal to 0.098) against the isolates tested.
In vitro inactivation of aminoglycosides by apalcillin
Authors: Wright D N , Hale D C , Saxon B , Matsen J M
Published: June 2012

Apalcillin, at concentrations of 75, 150, 300, and 600 micrograms/ml, was combined in vitro with amikacin, gentamicin, netilmicin, or tobramycin. Incubation at 37 degrees C resulted in an apalcillin concentration-dependent and time-dependent decrease of aminoglycoside activity of up to 60%. Amikacin was the most stable and tobramycin was the least stable aminoglycoside under the conditions tested.
Comparative in vitro susceptibilities of eight Enterobacter species, with special reference to Enterobacter sakazakii
Authors: Muytjens H L , van der Ros-van de Repe J
Published: June 2012

An agar dilution method was used to measure the MICs of 29 antimicrobial agents against Enterobacter sakazakii, E. cloacae, E. aerogenes, E. agglomerans, E. amnigenus, E. gergoviae, E. intermedium, and E. taylorae (formerly Enteric Group 19). E. sakazakii was the most susceptible species. Results showing resistance to ampicillin are likely to exclude E. sakazakii.
Ultrastructural changes in mollicutes induced by the peptide antibiotic herbicolin A
Authors: Birkelund S , Freundt E A , Christiansen G
Published: June 2012

Electron microscopy of negatively stained mycoplasma, ureaplasma, and acholeplasma cells showed ultrastructural changes after 10 min of treatment of the organisms with the peptide antibiotic herbicolin A in concentrations ranging from 10 micrograms/ml for Mycoplasma capricolum to 600 micrograms/ml for Ureaplasma urealyticum. The morphological changes were shown to be reversible at low concentrations of the antibiotic but irreversible at high concentrations.
Synergistic action of nikkomycins X and Z with papulacandin B on whole cells and regenerating protoplasts of Candida albicans
Authors: Hector R F , Braun P C
Published: June 2012

Combinations of nikkomycin X (NX) or nikkomycin Z (NZ), known inhibitors of chitin synthesis in fungi, together with papulacandin B (PB), an inhibitor of beta-glucan synthesis, were tested for synergistic activity against four isolates of Candida albicans by using the broth microdilution checkerboard technique and a method to assess the regeneration of cell wall material in protoplasts. The construction of isobolograms from the data generated by the checkerboard determinations revealed a synergistic effect for the two classes of compounds against all strains. The combination of NX and PB was more effective than the combination of NZ and PB, perhaps reflecting the lower Ki value of NX. While the presence of NX and NZ reduced chitin synthesis, as determined by staining with calcofluor white and assaying with a microfluorimeter, cells treated with PB demonstrated an increased synthesis of chitin. Protoplast regeneration experiments using similar concentrations of the two classes of compounds resulted in comparable findings. The combination of NX and PB resulted in a greater inhibition of chitin synthesis than did equivalent combinations of NZ and PB. These data suggest that combinations of agents active against cell wall synthesis in fungi may prove more useful as chemotherapeutic agents than such compounds used singly.
Single-dose pharmacokinetics of 3-O-demethylfortimicin A in humans after intravenous and intramuscular administration
Authors: Sennello L T , Wilson D S , Afarian J , Holtam L S , Norman G , Rollins D E , Tolman K G
Published: June 2012

The pharmacokinetics of 3-O-demethylfortimicin A were evaluated in 16 healthy adult male volunteers after bolus intramuscular (i.m.) and 30-min intravenous (i.v.) infusion administration of doses ranging from 0.25 to 16 mg/kg. Mean calculated peak levels of the drug in plasma after the 0.25-, 0.5-, 1-, 2-, 4-, 8-, and 16-mg/kg i.m. doses were 1.1, 1.9, 3.5, 4.9, 11.0, 21.8, and 41.3 micrograms/ml, respectively, occurring about 60 min after dosing. The biphasic decline in levels of the drug in plasma after i.v. administration was not apparent after i.m. dosing, presumably because absorption of the drug from the injection site obscured the alpha elimination phase. Mean calculated peak levels for the 1-, 2-, 4-, 8-, and 16-mg/kg 30-min i.v. infusions were 5.9, 12.2, 20.1, 36.7, and 66.4 micrograms/ml, respectively. A statistically significant trend of increasing apparent volume of distribution with increasing dose size was noted for the i.m. dose group only. Plasma drug clearance was dose level and route independent, with an excellent linear relationship between the area under the plasma drug level curve and the dose. The mean 0- to 48-h urinary recoveries of 3-O-demethylfortimicin A after the i.m. injections and i.v. infusions were 90 and 102%, respectively. After the i.m. dosings, the half-life of the drug in plasma averaged 2.0 h, and after the i.v. dosings it averaged 2.7 h. The results of the study indicated that most of the drug was cleared by renal mechanisms.