bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro activity of CI-934, a quinolone carboxylic acid active against gram-positive and -negative bacteria
Authors: Cohen M A , Griffin T J , Bien P A , Heifetz C L , Domagala J M
Published: June 2012

CI-934 is a totally synthetic difluorinated quinolinecarboxylic acid with an ethyl-amino-methyl pyrrolidine side chain, which has broad-spectrum antibacterial activity, including particular potency directed against streptococci and staphylococci. The CI-934 MIC (micrograms per milliliter) for 90% of the strains tested was 0.4 (range, 0.2 to 0.8) for a group of streptococci (pneumococci, viridans streptococci, Streptococcus faecalis, and Lancefield groups A, B, and C), 0.2 (0.05 to 0.2) for staphylococci (including methicillin-resistant Staphylococcus aureus), 0.025 (less than or equal to 0.003 to 0.025) for Haemophilus influenzae and Neisseria gonorrhoeae, 1.6 (0.1 to 25) for Enterobacteriaceae, 25 (3.1 to 25) for Pseudomonas aeruginosa, and 1.6 (0.05 to 3.1) for non-Bacteroides anaerobe species. CI-934 was equally active in vitro against multi-drug-resistant and -sensitive isolates, and cross-resistance was not apparent. Potency increased with alkalinity and was somewhat lower in urine. CI-934 was bactericidal. Inhibitory activity was generally unaffected by anaerobiosis, light, changes in inoculum size or cation concentration, or addition of human serum or sodium cholate.
Decreased biliary excretion of piperacillin after percutaneous relief of extrahepatic obstructive jaundice
Authors: Blenkharn J I , Habib N , Mok D , John L , McPherson G A , Gibson R N , Blumgart L H , Benjamin I S
Published: June 2012

The biliary excretion of piperacillin has been assessed in 11 patients with obstructive jaundice due to hilar cholangiocarcinoma. After a 1-g intravenous dose administered 30 min before preliminary percutaneous transhepatic cholangiography, no drug was detected in the bile of seven patients; in four others, drug concentrations were far below the corresponding level in serum. After a period of external biliary drainage of up to 28 days, levels of antibiotic in bile after intravenous administration were only minimally increased. The results suggest that although the impairment of hepatic function may be improved by external biliary decompression when assessed by a fall in plasma bilirubin, the biliary elimination of piperacillin and related beta-lactam antibiotics may remain impaired for prolonged periods.
Susceptibility of clinical isolates of Campylobacter pyloridis to 11 antimicrobial agents
Authors: McNulty C A , Dent J , Wise R
Published: June 2012

The activities of 11 antimicrobial agents, including two bismuth salts, against 70 strains of Campylobacter pyloridis isolated from gastric biopsy specimens were tested. The isolates were very susceptible to penicillin (the MIC for 90% of the strains tested [MIC90] was 0.03 microgram/ml), erythromycin, cefoxitin (MIC90, 0.12 microgram/ml), gentamicin, and ciprofloxacin (MIC90, 0.25 microgram/ml). The bismuth salts and nalidixic acid had moderate activity (MIC90, 16 to 64 micrograms/ml). Twenty percent of the isolates were resistant to metronidazole (MIC, greater than 1 micrograms/ml), and all were resistant to sulfamethoxazole and trimethoprim (MIC90, greater than 256 micrograms/ml).
Synergistic effects of dicloxacillin or clavulanic acid in combination with penicillin G or cephalothin against Yersinia enterocolitica
Authors: Jimenez-Valera M , Ruiz-Bravo A , Ramos-Cormenzana A
Published: June 2012

Cultures of Yersinia enterocolitica grown at 22 degrees C produced beta-lactamases, whereas cultures grown at 37 degrees C produced these enzymes much less effectively. Both dicloxacillin and clavulanic acid inhibited the beta-lactamase activity of bacterial crude extracts and potentiated the activity of penicillin G or cephalothin against 14 Y. enterocolitica strains. It appeared that the beta-lactamase activity present in Y. enterocolitica cells grown at 37 degrees C was great enough to play a role in bacterial resistance to beta-lactam antibiotics, since combining penicillin G or cephalothin with clavulanic acid or dicloxacillin resulted in synergistic activity against cultures grown at 37 degrees C that was equal to or greater than the activity against cultures grown at 22 degrees C.
Amoxicillin-clavulanic acid versus cefaclor in the treatment of urinary tract infections and their effects on the urogenital and rectal flora
Authors: Iravani A , Richard G A
Published: June 2012

In a double-blind randomized study, amoxicillin-clavulanic acid (AM-CL) was compared with cefaclor for the treatment of acute urinary tract infections in 107 college women. A total of 53 patients received amoxicillin (250 mg) and clavulanic acid as the potassium salt (125 mg), and 54 received cefaclor (250 mg); each drug was administered every 8 h for 10 days. The cure rates at 1 and 4 weeks after treatment were 96 and 78%, respectively, in the AM-CL group and 92 and 75%, respectively, in the cefaclor group (P greater than 0.10). After AM-CL treatment, the prevalence of amoxicillin-resistant Escherichia coli significantly increased in the rectal flora. Also, the frequency of bacterial resistance to amoxicillin, AM-CL, and cefaclor increased among the urinary pathogens causing subsequent urinary tract infections (P less than 0.05). There were no adverse reactions in the cefaclor group; however, six patients in the AM-CL group (12%) experienced diarrhea, nausea, or vomiting (P less than 0.05). Elevated transaminase enzyme levels were observed in 23% of the patients in the AM-CL group and in 6% of the patients in the cefaclor group (P less than 0.05). Symptomatic Candida vaginitis developed in 16 and 13% of the patients in the AM-CL and cefaclor groups, respectively (P greater than 0.10).
Streptomycin accumulation by Bacillus subtilis requires both a membrane potential and cytochrome aa3
Authors: Arrow A S , Taber H W
Published: June 2012

Cytochrome aa3 concentrations in the cytoplasmic membrane of Bacillus subtilis were altered by growth conditions, and the effects on the membrane potential (delta psi) in whole cells were measured. When cytochrome aa3 was absent, the magnitude of delta psi was not diminished by comparison with the delta psi measured in cells containing normal cytochrome aa3 concentrations. In addition, the energy-dependent uptake of proline and glutamate was comparable at both cytochrome aa3 concentrations. However, in the cytochrome aa3-deficient cell preparation, accumulation of the aminoglycoside antibiotic streptomycin was much lower than that of the cytochrome aa3-sufficient cells. When cells were cultured under conditions that stimulated higher than normal concentrations of cytochrome aa3, delta psi was also increased, and enhanced streptomycin accumulation was observed. Phenazine methosulfate-ascorbate was used both in delta psi measurements and in uptake studies to provide high rates of electron transport and maximal delta psi values. These results, taken together with those previously published (A. S. McEnroe and H. W. Taber, Antimicrob. Agents Chemother. 26:507-512, 1984) suggest that the uptake of streptomycin by B. subtilis requires adequate levels both of delta psi and cytochrome aa3.
Effect of moxalactam on human fecal microflora
Authors: Benno Y , Shiragami N , Uchida K , Yoshida T , Mitsuoka T
Published: June 2012

Five healthy male adults received 2 g of moxalactam every 12 h for 7 days. The alterations of fecal microflora were investigated before, during, and after treatment with moxalactam. On day 7 of treatment, the number of total bacteria was decreased in all subjects. There was marked suppression of the obligate anaerobic bacteria and enterobacteria to undetectable levels, but the counts of Streptococcus spp. and Lactobacillus spp. increased. On day 7, two subjects had Clostridium innocuum and Clostridium ramosum in their feces but not Clostridium difficile. On day 7 after treatment, the counts of Streptococcus spp., enterobacteria, Lactobacillus spp., and Clostridium spp. in all subjects were still not normal.
In vitro activity of antibiotics alone and in combination against Actinobacillus actinomycetemcomitans
Authors: Yogev R , Shulman D , Shulman S T , Glogowski W G
Published: June 2012

The MICs for 90% of the organisms tested (MIC90S) of 11 antibiotics against 24 clinical isolates of Actinobacillus actinomycetemcomitans were determined by the MIC 2000 system. The lowest MIC90S (16 micrograms/ml) were observed with ceftriaxone and rifampin. The next lowest MIC90S were found with cephapirin, tetracycline, and chloramphenicol (3.12 micrograms/ml). The MIC90S of penicillin, ampicillin, ticarcillin, piperacillin, and amikacin were each greater than or equal to 12.5 micrograms/ml. Antibiotic synergy was studied by the killing curve method and was defined as a greater than or equal to 2 log10 reduction in CFU when two antibiotics were used in combination at one-fourth the MBC for each compared with the effect of each antibiotic alone at one-half the MBC. Synergism between rifampin and penicillin, cephapirin, or ceftriaxone was tested for with 12 A. actinomycetemcomitans strains. In 7 of 37 instances, synergism was demonstrated for the combinations rifampin plus ceftriaxone (n = 3) or rifampin plus penicillin (n = 4); in 9 instances, an additive effect was noted, and impaired killing with drug combinations compared with the effect of a single antibiotic was suggested in 4 strains. The majority of strains were indifferent to the combinations. Similarly, variable results were observed when the combination of trimethoprim and cephapirin was tested against eight A. actinomycetemcomitans strains. Our data suggest that rifampin and cephapirin are the most active of the 11 antibiotics studied against A. actinomycetemcomitans. In addition, in vitro synergism between rifampin and other antibiotics or between trimethoprim and cephapirin was not consistently demonstrable.
Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2
Authors: Schinazi R F , Fox J J , Watanabe K A , Nahmias A J
Published: June 2012

As measured by plaque and yield reduction assays, several metabolites of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) were highly active against herpes simplex virus types 1 and 2. These metabolites included the 2'-deoxy-2'-fluoroarabinosyl derivatives of 5-iodouracil (FIAU), cytosine (FAC), uracil (FAU), and thymine (FMAU). In mice inoculated intracerebrally with herpes simplex virus type 2, the relative order of potency of these compounds and licensed antiviral drugs was as follows: FMAU much greater than FIAC approximately equal to FIAU greater than acyclovir approximately equal to vidarabine much greater than FAC approximately equal to FAU. One of the main metabolites of FMAU, 2'-fluoro-5-hydroxymethyl-arabinosyluracil, was essentially inactive in vivo. FIAC-, FIAU-, FMAU-, FAC-, and FAU-resistant herpes simplex virus variants prepared in cell culture were found to be (i) devoid of viral thymidine kinase, (ii) cross-resistant to one another and resistant to drugs requiring viral thymidine kinase for activation, and (iii) sensitive to vidarabine or phosphonoformate. These results indicate that FIAC, FIAU, and FMAU require the virally encoded thymidine kinase for activation and suggest that the antiviral activity of FAU and FAC in cell cultures is also mediated by this enzyme. The interaction of the fluoroarabinosyl pyrimidine nucleosides with herpes simplex virus thymidine kinase in a cell-free system is also described.
Emergence of aminoglycoside 3-N-acetyltransferase IV in Escherichia coli and Salmonella typhimurium isolated from animals in France
Authors: Chaslus-Dancla E , Martel J L , Carlier C , Lafont J P , Courvalin P
Published: June 2012

We studied two outbreaks of calf salmonellosis caused by apramycin and gentamicin-resistant Salmonella typhimurium strains. In both cases, the responsible strains were resistant to ampicillin, chloramphenicol, kanamycin, streptomycin, tetracycline, and trimethoprim; one strain was also resistant to nalidixic acid in one outbreak. A systematic survey of the intestinal Escherichia coli strains of calves from the two affected flocks showed that 11 of 24 animals sampled were also colonized by apramycin- and gentamicin-resistant E. coli strains. These isolates belonged to four biotypes and were resistant to ampicillin, chloramphenicol, kanamycin, streptomycin, tetracycline, trimethoprim, and nalidixic acid. All of the strains were resistant to high levels of apramycin (MICs, 512 to 1,024 micrograms/ml) and to gentamicin (MICs, 8 to 32 micrograms/ml), and these resistances were always transferred en bloc. In S. typhimurium, this coresistance was borne by plasmids that were approximately 39 kilobases long (outbreak 1) or 90 kilobases long (outbreak 2), whereas in E. coli, the coresistance was due to plasmids that were approximately 110 kilobases long in both outbreaks. The two plasmids of Salmonella and four plasmids of E. coli encoded type IV aminoglycoside 3-N-acetyltransferases. The intensive use of curative and preventive treatments in calf production could be responsible for the emergence of enzymic resistance to apramycin and gentamicin.
Effects of 2,2'-O-cyclocytidine and acyclovir on latent herpes simplex virus in trigeminal ganglia of mice
Authors: Liu W G , Chen Z J , Song J Z , Ma Z X
Published: June 2012

The effects of 2,2'-O-cyclocytidine (CC) and acyclovir (ACV) on latent herpes simplex virus (HSV) in trigeminal ganglia were studied in an in vitro model using reactivation of HSV type 1 (HSV-1) as a model. It was shown that both CC (10 micrograms/ml) and ACV (2.5 micrograms/ml) significantly inhibited the reactivation of the latent HSV-1 in infected ganglia. The effect of CC (25 micrograms/ml), which was as good as that of ACV (10 micrograms/ml), did not last as long as that of ACV after removal of the drugs. The latent state of HSV-1 in vitro was dependent on the continuous presence of either drug. Even though the latent HSV-1 could not be eliminated completely from the trigeminal ganglia by discontinuous administration of either drug, its titers were markedly reduced. The combination of CC and ACV had a synergistic effect on preventing the reactivation of the latent HSV-1 in vitro.
Penetration of aztreonam into cerebrospinal fluid of patients with bacterial meningitis
Authors: Modai J , Vittecoq D , Decazes J M , Wolff M , Meulemans A
Published: June 2012

The penetration of aztreonam into the cerebrospinal fluid was determined in 16 patients with bacterial meningitis undergoing treatment with other antibiotics. Three aztreonam doses of 30 mg/kg were infused intravenously over 30 to 45 min at 8-h intervals, first between days 2 and 4 and again between days 11 and 20 after onset of the disease. Concentrations of aztreonam in serum and cerebrospinal fluid samples obtained at 60, 90, 120, and 240 min after the third aztreonam dose were measured by high-pressure liquid chromatography. The concentrations of aztreonam in cerebrospinal fluid ranged from 3.5 to 62 micrograms/ml, depending on the sampling time and the time elapsed since the onset of the disease. These concentrations were equal to or higher than the MICs for most of the gram-negative bacilli (including Pseudomonas aeruginosa).
Pharmacokinetics of ciprofloxacin and effect of repeated dosage on salivary and fecal microflora
Authors: Bergan T , Delin C , Johansen S , Kolstad I M , Nord C E , Thorsteinsson S B
Published: June 2012

The pharmacokinetics of ciprofloxacin was studied in 12 volunteers during a 5-day course of 500 mg of ciprofloxacin given orally twice a day. The effects on the microflora of saliva and feces were also examined. Serum and urine samples were assayed for ciprofloxacin microbiologically, and the salivary and fecal microflora were examined quantitatively after processing onto a series of selective media. Fecal samples were also investigated for the presence of Clostridium difficile and its cytotoxin. The MICs for new colonizing bacteria were examined in the salivary and fecal samples. There was no accumulation during the course of 5 days with peak serum concentrations identical (2.8 and 2.3 mg/liter) after the first and final doses, and the areas under the serum curves were similar (9.6 mg/liter). The serum half-life was 2.5 h on both days. The changes in the salivary flora were minor and affected only the neisseriae. In the fecal flora, the numbers of enterobacteria and enterococci decreased markedly, whereas the changes in anaerobic flora (anaerobic cocci, fusobacteria, and bacteroids) were not so pronounced. However, 14 days after the drug was discontinued, the salivary and fecal flora were normalized in all respects. No new colonization of ciprofloxacin-resistant bacteria for which MICs were above 1.0 mg/liter was observed. C. difficile or its cytotoxin was not detected.
Effect of folinic acid on the capacity of trimethoprim-sulfamethoxazole to prevent and treat Pneumocystis carinii pneumonia in rats
Authors: D'Antonio R G , Johnson D B , Winn R E , van Dellen A F , Evans M E
Published: June 2012

Daily administration of 1 mg of folinic acid to immunosuppressed rats with incipient or established Pneumocystis carinii pneumonia did not impair the capacity of trimethoprim-sulfamethoxazole to either prevent or treat this disease. These observations constitute the first experimental support for the use of folinic acid to prevent or control cytopenias that occur in patients with Pneumocystis carinii pneumonia who are under trimethoprim-sulfamethoxazole treatment.
Aztreonam treatment of gram-negative septicemia
Authors: Pierard D , Boelaert J , Van Landuyt H W , Naessens A , Huyghens L , Lauwers S
Published: June 2012

Seventy-five aztreonam treatment courses in 74 patients with gram-negative septicemia resulted in 56 clinical cures (75%), 12 partial clinical cures (16%), and 7 clinical failures (9%). Eradication of the original pathogen from the blood was obtained in all patients but two, who had relapses 1 and 4 days, respectively, after treatment. In nine patients (12%) a superinfection was reported. Significant adverse reactions were limited to one transient urticarial rash. Aztreonam may prove to be an effective alternative for the treatment of gram-negative septicemia, but superinfections should be carefully monitored.
Comparative evaluation of ciprofloxacin, enoxacin, and ofloxacin in experimental Pseudomonas aeruginosa pneumonia
Authors: Kemmerich B , Small G J , Pennington J E
Published: June 2012

The therapeutic activity of ciprofloxacin, enoxacin, and ofloxacin was evaluated in guinea pigs with acute and chronic experimental Pseudomonas aeruginosa pneumonia. Intratracheal instillations of P. aeruginosa resulted in fatal pneumonia in all untreated animals within 36 h. Among treatment groups (80 mg/kg [body weight] per day), cumulative survival rates were: 47%, ciprofloxacin; 55%, enoxacin; and 42%, ofloxacin. These rates were not significantly different. Intrapulmonary killing of P. aeruginosa was equivalent 3 h after a single dose of ciprofloxacin or ofloxacin (20 mg/kg) or enoxacin (40 mg/kg). The combination of ciprofloxacin with azlocillin, ceftazidime, or tobramycin did not increase the efficacy of intrapulmonary killing of P. aeruginosa over that of ciprofloxacin alone. A chronic, nonfatal bronchopneumonia was induced in guinea pigs by intratracheal instillation of microscopic agar beads impregnated with a mucoid strain of P. aeruginosa. Compared with no treatment, ciprofloxacin and enoxacin produced greater than or equal to 99.9% intrapulmonary killing, and ofloxacin sterilized the lungs completely, after 4 days of treatment. In no quinolone-treated animal did resistant strains of P. aeruginosa emerge during 4-day treatment periods. In further studies with the chronic model, oral and parenteral ciprofloxacin treatment were found to be equivalent in efficacy. We conclude that several quinolone derivatives may be effective for the treatment of P. aeruginosa pneumonia and that combinations of quinolones with beta-lactams or aminoglycosides may not increase efficacy against P. aeruginosa pneumonia.
In vitro susceptibility of Rickettsia conorii to ciprofloxacin as determined by suppressing lethality in chicken embryos and by plaque assay
Authors: Raoult D , Roussellier P , Galicher V , Perez R , Tamalet J
Published: June 2012

We tested the susceptibility of Rickettsia conorii to ciprofloxacin, a new quinolone antibiotic. A final concentration of 1 microgram/g of egg was effective in suppressing chicken embryo lethality, and a concentration of 0.25 micrograms/ml inhibited plaque formation in a plaque assay; however, a concentration of 0.5 microgram/ml was necessary to obtain rickettsiacidal activity. These results support the idea that ciprofloxacin could be of clinical use in treating Mediterranean spotted fever.
Novobiocin antagonism of amastigotes of Trypanosoma cruzi growing in cell-free medium
Authors: Pate P G , Wolfson J S , McHugh G L , Pan S C , Swartz M N
Published: June 2012

Inhibitors of the enzyme bacterial topoisomerase II (DNA gyrase) were evaluated for activity against Trypanosoma cruzi (Brazil strain), based on the theoretical need for a topoisomerase II in the replication of the kinetoplast DNA network. Novobiocin (500 micrograms/ml) antagonized amastigotes of T. cruzi growing in a cell-free medium at 37 degrees C, as manifested by inhibition of multiplication, abnormal morphology of Giemsa-stained organisms, and delayed or absent growth of cells upon subculturing in a drug-free medium. In contrast, novobiocin (1,000 micrograms/ml) essentially had no effect on the multiplication and motility of epimastigotes growing in a cell-free medium at 27 degrees C. This resistance of epimastigotes represented a difference in the physiology of this morphologic stage and not in the temperature of experimentation, because novobiocin inhibited multiplication of amastigotes at 27 degrees C as well and accelerated transformation to epimastigotes. With T. cruzi growing within cultured human fibroblasts, novobiocin (200 micrograms/ml) markedly inhibited transformation of intracellular amastigotes to trypomastigotes. Clorobiocin, a structural analog of novobiocin and likewise an inhibitor of the B subunit of bacterial topoisomerase II, was five times more potent on a molar basis than novobiocin was in antagonism of amastigotes growing in a cell-free medium and did not antagonize epimastigotes. Coumermycin A1, another analog of novobiocin, and five 4-quinolone antibacterial agents, antagonists of the A subunit of bacterial topoisomerase II, inhibited neither amastigotes nor epimastigotes. These experiments indicate that novobiocin and clorobiocin represent a new structural class of drugs with activity against T. cruzi. Whether the mechanism of action of these drugs involves antagonism of a T. cruzi topoisomerase II or an unrelated target is yet to be determined.
In vivo target of benzylpenicillin in Gaffkya homari
Authors: Wrezel P W , Ellis L F , Neuhaus F C
Published: June 2012

It has been established that the DD-carboxypeptidase is the primary in vitro target of benzylpenicillin in Gaffkya homari (W. P. Hammes, Eur. J. Biochem. 70:107-113, 1976). To determine whether this enzyme is also the primary target of benzylpenicillin in vivo, we compared the effects of this beta-lactam, cefmenoxime, cephalothin, and cefoxitin on growth with their acylation of penicillin-binding protein (PBP) 9, the DD-carboxypeptidase. Results of three types of experiments with membrane-walls indicated that PBP 9 is this enzyme and that it is the primary in vitro target of these beta-lactams in the synthesis of sodium dodecyl sulfate (SDS)-insoluble peptidoglycan. First, the acylation of PBP 9 by these beta-lactams paralleled the inhibition of DD-carboxypeptidase and the inhibition of SDS-insoluble peptidoglycan synthesis. Second, the rate of benzylpenicillin release from PBP 9 correlated with the recovery of DD-carboxypeptidase. Third, DD-carboxypeptidase activity was detected in a protein with the same apparent molecular weight as PBP 9 after elution from an SDS-polyacrylamide gel. When intact cells were treated with benzylpenicillin, the minimum growth inhibitory concentration (MGIC) correlated with the concentration of [35S]benzylpenicillin required to acylate PBPs 6 and 9 by 50%. When intact cells were treated with cefmenoxime, cephalothin, or cefoxitin, the MGICs correlated with the concentration of unlabeled beta-lactam required to reduce the subsequent binding of [35S]benzylpenicillin by 50% (ED50) for PBP 6. In contrast, the MGICs of these beta-lactams did not correlate with the ED50s for PBP 9. PBP 9 was not acylated by cefmenoxime or cephalothin at their MGICs, whereas this PBP was fully acylated by cefoxitin at one-tenth of its MGIC. It is suggested that PBP 6 may be a primary target of growth inhibition by benzylpenicillin, cefmenoxime, cephalothin, and cefoxitin; PBP 9, the DD-carboxypeptidase, is dispensable for growth under laboratory conditions; and PBP 9 does not appear to be a primary in vivo target of these beta-lactams, even though this PBP is their primary target in vitro.
Charge and lipophilicity govern the pharmacokinetics of glycopeptide antibiotics
Authors: Pitkin D H , Mico B A , Sitrin R D , Nisbet L J
Published: June 2012

The pharmacokinetics and urinary excretion of nine glycopeptide antibiotics with diverse pIs (3.8 to 8.5) and lipophilicities were studied. The disposition of the aridicin antibiotics and their hydrolysis products were examined in male CD-1 mice after subcutaneous and intravenous administration and compared with the disposition of teicoplanin, ristocetin, and vancomycin. The total systemic clearance, half-life, volume of distribution, and urinary excretion were highly correlated with pIs. In general, as the pI decreased, the clearance, urinary recovery, and volume of distribution decreased, whereas the half-life increased. With those glycopeptides that had similar pIs, clearance decreased and half-life increased with increasing lipophilicity. The urinary recovery of the glycopeptides decreased with decreasing pI and increasing lipophilicity. Because vancomycin (pI = 8.0) is cleared by glomerular filtration, increased binding to serum is the likely mechanism of reduced renal clearance for glycopeptides with low pIs. These results are consistent with previous findings concerning the correlation of physical-chemical properties and the drug disposition of small organic molecules. Results of these studies also indicate that desirable pharmacokinetic properties can be incorporated into glycopeptides through semisynthetic modifications.
Lysis of nongrowing Escherichia coli by combinations of beta-lactam antibiotics and inhibitors of ribosome function
Authors: Kusser W , Ishiguro E E
Published: June 2012

It is generally assumed that only actively growing bacteria are killed by inhibitors of peptidoglycan synthesis. Several exceptional examples are described here. As expected, ampicillin did not lyse nongrowing, amino acid-deprived cultures of relA+ strains of Escherichia coli, but the subsequent addition of several ribosome inhibitors (chloramphenicol, tetracycline, gentamicin, and kanamycin) caused various degrees of lysis in such ampicillin-treated cultures. Of the antibiotics tested, only streptomycin was ineffective in this regard. Peptidoglycan synthesis has been shown to be inhibited in amino acid-deprived relA+ bacteria by the stringent control mechanism (E. E. Ishiguro and W. D. Ramey, J. Bacteriol. 127:1119-1126, 1976), and the ribosome inhibitors tested here relaxed peptidoglycan synthesis to various degrees under these conditions. The relative lysis-inducing activities of the ribosome inhibitors on ampicillin-treated, amino acid-deprived bacteria were directly correlated to their relative activities as stringent control antagonists. This phenomenon was not dependent on amino acid deprivation. Cultures treated with growth inhibitory levels of the various ribosome inhibitors alone were lysed by ampicillin, apparently because peptidoglycan synthesis continues uninhibited when growth is arrested by treatment with ribosome inhibitors. These results indicate that autolysis can be triggered by the inhibition of peptidoglycan synthesis occurring in the absence of wall expansion; i.e., active cell growth is unnecessary.
Isolation, characterization, and mode of action on Escherichia coli strains of microcin D93
Authors: Martínez J L , Pérez-Díaz J C
Published: June 2012

Microcin D93 is an antibiotic substance produced by Escherichia coli strains which harbor the 5.5-kilobase plasmid pMccD93. Its production is unaffected by the use of different carbon and ammonia sources, different phosphate concentrations, or mitomycin C. We developed a method for purifying this microcin based on gel permeation chromatography and reverse-phase high-pressure liquid chromatography. The antibiotic appears to be a small, hydrophilic, basic peptide, active on E. coli and Proteus, Citrobacter, and Pseudomonas species and much more active on recA strains than on their isogenic wild type. Diminution of the rate of DNA biosynthesis without any apparent effect on other macromolecules appears to be a primary effect in the action of microcin D93.
A placebo-controlled trial of topical 8% arildone cream early in recurrent genital herpes
Authors: Douglas J M , Judson F N , Levin M J , Bosso J A , Spruance S L , Johnston J M , Corey L , McMillan J A , Weiner L B , Frank J A
Published: June 2012

Arildone is an aryl diketone which is inhibitory in vitro against herpes simplex virus type 2 at a concentration of 2 micrograms/ml or less. One hundred forty-five patients with recurrent genital herpes were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial to evaluate the efficacy and safety of an 8% arildone cream. Patients initiated therapy a mean of 9.9 h and a maximum of 24 h after the reported onset of lesions and applied medication 6 times daily for 7 days. The duration of viral shedding was shorter among women (P less than 0.05) and the duration of local itching was shorter among men (P less than 0.05) in patients that received arildone than in those that received placebo, but there were no significant differences between treatment groups in duration of pain, time to crusting or healing of lesions, or percentage of patients developing new lesions. Mild local irritation after application of ointment was common and occurred equally in both treatment groups. Despite early application, topical arildone cream was ineffective in the therapy of acute recurrences of genital herpes.
Antirhinovirus activity of purine nucleoside analogs
Authors: De Clercq E , Bernaerts R , Bergstrom D E , Robins M J , Montgomery J A , Holy A
Published: June 2012

A wide variety of purine nucleoside (mainly tubercidin and adenosine) analogs, which had previously been shown to inhibit the replication of a broad spectrum of RNA viruses, were evaluated for their antirhinovirus activity in human diploid (WI-38) fibroblasts. Tubercidin, 5-(1-hydroxyethyl)tubercidin, 5-(2-buten-1-yl)tubercidin, toyocamycin, and sangivamycin emerged as the most potent inhibitors. These compounds inhibited the replication of rhinovirus types 1A, 1B, and 9 at an MIC well below 1 microgram/ml. However, these compounds proved cytotoxic for the uninfected host cells at concentrations which were only slightly higher (3- to 10-fold, on the average) than those required for inhibition of rhinovirus replication. The most selective inhibitor of rhinovirus replication was 3-deazaguanine, with a selectivity index of 50. None of the carbocyclic and acyclic analogs of adenosine tested exhibited a potent or selective antirhinovirus activity.
Tissue penetration of ciprofloxacin after single and multiple doses
Authors: LeBel M , Vallée F , Bergeron M G
Published: June 2012

The pharmacokinetics and the suction-induced blister fluid penetration of ciprofloxacin were compared after a single dose (500 mg) and after multiple dosing (500 mg q8h for 13 doses). Significantly higher peak levels of ciprofloxacin in serum were observed after multiple dosing (3.51 versus 2.26 micrograms/ml; P less than 0.01). Increased elimination half-life occurred after multiple dosing; this seems to be mostly related to decreased systemic clearance secondary to a diminished nonrenal clearance (240.0 versus 125.0 ml/min). Ciprofloxacin appeared rapidly in the blister fluid, and the percentage of penetration (AUC0-tBF/AUC0-t serum) yielded values of 88.8 versus 84.7% after single and multiple doses, respectively. Ciprofloxacin levels in serum and blister fluid at the end of the dosing interval (8 h) were superior or almost superior to MICs for sensitive organisms including Pseudomonas aeruginosa. Comparative studies of ciprofloxacin metabolite excretion after multiple doses in healthy subjects and in renal insufficiency patients are needed.
Quinolones affect thymidine incorporation into the DNA of human lymphocytes
Authors: Forsgren A , Bergh A K , Brandt M , Hansson G
Published: June 2012

The incorporation of [3H]thymidine into DNA was increased in phytohemagglutinin-stimulated human lymphocytes exposed to four of the new quinolone derivatives (ciprofloxacin, norfloxacin, ofloxacin, and A 56620) at concentrations achievable in clinical situations. However, proliferation of phytohemagglutinin-stimulated lymphocytes was not influenced by ciprofloxacin at concentrations of 0.5 to 10 micrograms/ml.
Determination of mezlocillin and its penicilloate and penilloate by high-performance liquid chromatography and stability of mezlocillin at different temperatures
Authors: Knöller J , Bremm K D , Schönfeld W , König W
Published: June 2012

A method is described for the determination of mezlocillin and its metabolites penicilloic acid and penilloic acid in biological fluids by high-performance liquid chromatography. The stability of mezlocillin in serum and buffer was studied at different temperatures (4, -20, -70, and -196 degrees C) over a period of 6 months. Mezlocillin remained stable at -70 and -196 degrees C, whereas degradation was observed at -20 and 4 degrees C in serum and buffer.
Broad geographical distribution of homologous erythromycin, kanamycin, and streptomycin resistance determinants among group D streptococci of human and animal origin
Authors: LeBlanc D J , Inamine J M , Lee L N
Published: June 2012

The Emr, Kmr, and Smr determinants of the Streptococcus faecalis R plasmid pJH1 were cloned in Streptococcus sanguis with a streptococcal plasmid vector, pVA380-1. Each cloned determinant was used as a probe in hybridization reactions with dot blots containing plasmid-enriched DNA from 91 group D streptococcal isolates resistant to erythromycin, kanamycin, and streptomycin; the isolates were obtained from animal and human sources in a variety of geographical locations. Nearly 70% of the strains contained DNA that hybridized to each of the three resistance determinants from pJH1. Five plasmids mediating resistance to erythromycin, kanamycin, and streptomycin were examined in more detail. These plasmids varied in size between 26 and 105 kilobase pairs (kbp) and exhibited very different EcoRI restriction patterns. However, each plasmid contained the resistance determinants on a single 13- to 20-kbp EcoRI fragment. Southern blot hybridizations and additional restriction endonuclease digests revealed extensive DNA sequence homology and virtually indistinguishable restriction endonuclease maps within a 9- to 11-kbp region of each plasmid which included the resistance determinants.
Susceptibility of bite wound bacteria to seven oral antimicrobial agents, including RU-985, a new erythromycin: considerations in choosing empiric therapy
Authors: Goldstein E J , Citron D M , Vagvolgyi A E , Finegold S M
Published: June 2012

The susceptibility of 93 aerobic and 59 anaerobic bacteria isolated from human and animal bite wounds was determined by agar dilution. No agent tested (penicillin, oxacillin, cephalexin, sulfamethoxazole-trimethoprim, minocycline, erythromycin, and RU-965) was consistently active against all isolates. A total of 21% of the Bacteroides species, all isolated from human bites, were resistant to penicillin; 14 and 18% of the Pasteurella multocida isolates were resistant to erythromycin and oxacillin, respectively.
In vitro activity of an orally administered cephalosporin, LY164846, against potentially pathogenic respiratory and dermal bacterial isolates
Authors: Lauderdale B L , Yu P K , Washington J A
Published: June 2012

The antibacterial activity of LY164846, a new orally administered semisynthetic cephalosporin, was compared with that of amoxicillin-clavulanic acid against 492 potentially pathogenic respiratory tract and dermal isolates. Against groups A, B, and G streptococci; pneumococci; staphylococci (other than methicillin resistant); Haemophilus influenzae; Branhamella catarrhalis; and meningococci, the MICs for 90% of strains tested of LY164846 and amoxicillin-clavulanic acid were less than or equal to 4 and less than or equal to 1 microgram/ml, respectively. LY164846 was equally active against beta-lactamase-positive and -negative strains of Haemophilus and Staphylococcus. MBC to MIC ratios of LY164846 versus H. influenzae were less than or equal to 2, while those with Staphylococcus aureus were more difficult to determine because of skipped tubes or paradoxic effects. There were minimal inoculum, pH, or serum effects on LY164846 activity against H. influenzae and S. aureus. In time-kill studies, LY164846 and amoxicillin-clavulanic acid at double MICs were 99.9 to 100% bactericidal to H. influenzae in 24 h; two times the MIC of LY164846 and four times the MIC of cephalexin were 99.9 to 100% bactericidal to S. aureus in 24 h. Based on error-rate-bounded analysis, the following interpretative guidelines for 30-micrograms LY164846 disk diffusion test diameters are suggested: greater than or equal to 19 mm, susceptible (MIC, less than or equal to 4 micrograms/ml); 16 to 18 mm, intermediate (MIC, greater than 4 but less than or equal to 8 micrograms/ml); less than or equal to 15 mm, resistant (MIC, greater than 8 micrograms/ml).
Prolonged herpes simplex virus latency in vitro after treatment of infected cells with acyclovir and human leukocyte interferon
Authors: Scheck A C , Wigdahl B , De Clercq E , Rapp F
Published: June 2012

We previously demonstrated that herpes simplex virus type 1 (HSV-1) can be established in a latent form in vitro by the treatment of HSV-infected human cells with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) in combination with human leukocyte interferon (IFN-alpha). We now report that the substitution of BVDU with 9-[(2-hydoxyethoxy)methyl]guanine (acyclovir; ACV) during a combined treatment with IFN-alpha inhibited HSV-1 replication and established in vitro virus latency that could be maintained for a longer period after inhibitor removal and a continued incubation at 37 degrees C. By contrast, the treatment of HSV-1-infected cells with combined IFN-alpha and 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a congener of ACV, failed to establish in vitro virus latency. Furthermore, none of these inhibitors used alone was sufficient to establish in vitro virus latency. The use of nucleoside analogs differing from BVDU in their modes of action has enabled us to initiate studies designed to extend in vitro virus latency.
Inhibition of Micrococcus luteus DNA gyrase by norfloxacin and 10 other quinolone carboxylic acids
Authors: Zweerink M M , Edison A
Published: June 2012

The ability of norfloxacin, amifloxacin, cinoxacin, ciprofloxacin, flumequine, nalidixic acid, ofloxacin (OFL), oxolinic acid, perfloxacin, pipemidic acid, and rosoxacin to inhibit the in vitro supercoiling activity of Micrococcus luteus DNA gyrase was compared with the ability of each drug to inhibit the growth of the M. luteus strain from which the gyrase was purified. The potency of the quinolones as DNA gyrase inhibitors did not always correlate with antimicrobial potency. For example, OFL was a less potent inhibitor of gyrase than rosoxacin, yet the MIC of OFL was 16-fold lower than that of rosoxacin. Similarly, the MICs of norfloxacin and ciprofloxacin (the most potent of the antibiotics tested in these assays) were several hundredfold lower than the MIC of nalidixic acid (the least potent of these antibiotics), but the inhibition of purified gyrase by these two quinolones was only 8- to 16-fold lower than that of nalidixic acid. These results suggest that factors in addition to inhibition of gyrase supercoiling activity are important in determining the potency of these drugs. Further studies indicated that the uptake of norfloxacin, OFL, and amifloxacin by M. luteus cells may not account for the large differences in MICs observed for these drugs (MICs of 0.8, 2.0, and 128 micrograms/ml, respectively).
Activity of coumermycin against clinical isolates of staphylococci
Authors: Guillemin M N , Miles H M , McDonald M I
Published: June 2012

Staphylococci, particularly methicillin-resistant strains of Staphylococcus aureus, are major nosocomial pathogens in large hospitals in eastern Australia. At present vancomycin is the drug of choice for the treatment of life-threatening methicillin-resistant S. aureus infections. A possible alternative drug is coumermycin, a bis-hydroxy coumarin which inhibits DNA gyrase. Coumermycin activity was determined against clinical isolates from the Royal Melbourne Hospital. MICs of 639 staphylococcal isolates were determined by agar dilution. MICs and MBCs of 100 staphylococcal isolates were also determined by microdilution methods. The results showed that coumermycin was bactericidal, with MBCs of less than or equal to 4 micrograms/ml against all isolates tested. The results indicate that coumermycin is a potential alternative to vancomycin in the treatment of severe staphylococcal infections.
Effects of toluene permeabilization and cell deenergization on tetracycline resistance in Escherichia coli
Authors: McMurry L M , Hendricks M , Levy S B
Published: June 2012

Resistance to tetracycline (Tcr) mediated by Tn10 and related Tcr determinants involves an inner membrane protein, TET (similar but not identical for different determinants), and a proton motive force-dependent efflux of tetracycline which keeps the drug away from its intracellular target, the ribosome (L. M. McMurry, R. E. Petrucci, Jr., and S. B. Levy, Proc. Natl. Acad. Sci. USA 77:3974-3977, 1980). However, the amount of tetracycline accumulated by bacteria does not always correlate with their resistance levels, suggesting that an additional resistance mechanism may be present. When we permeabilized susceptible and resistant Tn10-bearing cells with toluene, we found that protein synthesis in the two strains became equally sensitive to tetracycline. Therefore, the protein synthesis machinery was not a source of resistance, and an intact membrane was required for resistance. To determine whether resistance was entirely dependent on energy, we measured susceptibility to tetracycline after inhibition of proton motive force by starvation and specific inhibitors. An 80 to 90% loss of Tcr (measured by protein synthesis) resulted from partial deenergization of resistant cells. A remaining resistance (10- to 20-fold greater than that of susceptible cells) could not be eliminated by further deenergization. These findings indicated that, to a major extent, expression of Tn10 resistance required energy, presumably for tetracycline efflux. They also suggested the existence of a small component of Tcr having little or no energy dependence. Whether this component depends on tetracycline efflux or some other mechanism is not known, but presumably both high- and low-energy components of resistance reflect activity of TET protein.
Failure of vancomycin prophylaxis and treatment for Actinobacillus actinomycetemcomitans endocarditis
Authors: Eng R H , Smith S M , Goldstein E J , Miyasaki K T , Quah S E , Buccini F
Published: June 2012

Reported is a case of Actinobacillus actinomycetemcomitans endocarditis which developed after dental prophylaxis with vancomycin and erythromycin. In vitro results indicated that this isolate and 20 additional isolates were resistant to vancomycin and that potentially useful bactericidal antibiotics for the prophylaxis and treatment of A. actinomycetemcomitans infections included gentamicin, sulfamethoxazole-trimethoprim, cefotaxime, and ciprofloxacin.
Sensitivity of Candida albicans to amphotericin B administered as single or fractionated doses
Authors: Sokol-Anderson M L , Brajtburg J , Medoff G
Published: June 2012

Candida albicans cells were exposed to equal concentrations of amphotericin B (AmB) administered either as a single large dose or as repeated small doses. Toxicity to C. albicans cells was less pronounced when AmB was administered in fractionated doses. Increased catalase activity in C. albicans cells was induced after exposure to fractionated doses of AmB; this increase may have contributed to the greater resistance of cells to AmB used according to this schedule.
Aztreonam penetration into synovial fluid and bone
Authors: MacLeod C M , Bartley E A , Galante J O , Friedhoff L T , Dhruv R
Published: June 2012

Eighteen patients with uncomplicated degenerative joint disease requiring joint replacement (hip or knee) were given a single 2-g intravenous dose of aztreonam over a 5-min period preoperatively. The mean concentration in synovial fluid of 83.0 +/- 9.2 micrograms/ml averaged 0.99 times the concomitant levels in serum. The mean concentration in cancellous bone of 16.0 +/- 4.3 micrograms/g averaged 0.20 times the concomitant levels in serum.
Randomized comparison of cefamandole, cefazolin, and cefuroxime prophylaxis in open-heart surgery
Authors: Slama T G , Sklar S J , Misinski J , Fess S W
Published: June 2012

A total of 337 patients undergoing coronary artery bypass grafting or cardiac valve replacement were randomly assigned to receive cefazolin (1 g every 8 h [q8h]), cefamandole (2 g q6h), or cefuroxime (1.5 g q12h) as an intravenous antibiotic prophylaxis. All drugs were administered within 60 min before the initial incision and were continued for 48 h postoperatively. No adverse effects related to the study drugs were observed. The percentage of patients with postoperative infection was 9% for the cefazolin group, 6% for the cefamandole group, and 5% for the cefuroxime group or 6.5% overall. There were more infection sites in patients treated with cefazolin than in those treated with cefuroxime (P = 0.05) or cefamandole (P = 0.06). Fewer wound infections occurred with cefuroxime (P less than 0.01) and cefamandole (P = 0.06) than with cefazolin. Analyses of the prophylactic regimens used in this study showed cefazolin and cefuroxime to be less costly than cefamandole.
Leakage of periplasmic proteins from Escherichia coli mediated by polymyxin B nonapeptide
Authors: Dixon R A , Chopra I
Published: June 2012

The effects of polymyxin B and polymyxin B nonapeptide (PMBN) on cell envelope integrity in Escherichia coli were compared. Both compounds caused loss of proteins from E. coli K-12 3300(pBR322), although PMBN released less protein than did polymyxin B. The origin of the released protein was determined both by polyacrylamide gel electrophoresis and by using specific enzyme markers (beta-lactamase in periplasm, beta-galactosidase in cytoplasm). The proteins released by both compounds were derived principally from the periplasm, accompanied in the case of polymyxin B by a low level of cytoplasmic proteins. Although polymyxin B and PMBN both caused release of periplasmic proteins, the individual proteins released by the compounds differed. The periplasmic fraction contained six principal polypeptides with molecular weights between 62,000 (polypeptide 1) and 29,000 (polypeptide 6). Polypeptide 6 was identified as the pBR322-encoded beta-lactamase, but the other proteins were not specifically identified. Polymyxin B caused considerable release of polypeptides 1, 2, and 5 with some release of polypeptides 4 and 6. PMBN released polypeptide 1 (trace), 3, 4, and 6 (trace). Scanning electron microscopy showed that polymyxin B and PMBN both caused surface damage in E. coli. However, polymyxin B produced greater morphological changes than PMBN.