bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon
Authors: Hartshorn K L , Vogt M W , Chou T C , Blumberg R S , Byington R , Schooley R T , Hirsch M S
Published: June 2012

Both recombinant alpha A interferon and azidothymidine inhibit the replication of human immunodeficiency virus in peripheral blood mononuclear cells. Combinations of recombinant alpha A interferon and azidothymidine at concentrations that are easily achievable in patients synergistically inhibit human immunodeficiency virus in vitro with minimal toxicity. Combinations of antiretroviral compounds that act by different mechanisms may prove useful in the treatment of acquired immunodeficiency syndrome-related disorders.
Comparative activity of metronidazole and tinidazole against Clostridium difficile and Peptostreptococcus anaerobius
Authors: Jokipii A M , Jokipii L
Published: June 2012

Broth dilution MICs of metronidazole against 38 strains of Clostridium difficile (0.13 microgram/ml) and 11 strains of Peptostreptococcus anaerobius (0.11 microgram/ml) were lower than those of tinidazole (0.16 and 0.17 microgram/ml, respectively). As molar concentrations the nitroimidazoles were equally active. The MICs of the two drugs correlated positively, and the relative activity of tinidazole increased with decreasing susceptibility of both species.
Pharmacokinetics of cefoperazone and tobramycin alone and in combination
Authors: Guglielmo B J , Flaherty J F , Woods T M , LaFollette G , Gambertoglio J G
Published: June 2012

Certain beta-lactams have been shown to increase the clearance of tobramycin. We evaluated the pharmacokinetics of cefoperazone and tobramycin, alone and in combination, in healthy volunteers. No significant alteration in pharmacokinetic behavior was noted for cefoperazone or tobramycin alone or in combination.
In vitro activity of CGP 31608, a new penem
Authors: Wise R , Andrews J M , Piddock L J
Published: June 2012

The in vitro activity of CGP 31608, a semisynthetic penem derivative, was compared with that of Sch 34343, imipenem, cefoxitin, cefuroxime, and ceftazidime and other beta-lactams, when appropriate, against 628 recent isolates and other beta-lactam-resistant strains. The MICs of CGP 31608 against 90% of the members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria spp., Bacteroides spp., Clostridium spp., staphylococci, and Streptococcus pneumoniae were between 0.25 and 8 micrograms/ml. The susceptibility of beta-lactamase-producing strains and known porin mutants of the Enterobacteriaceae suggests that CGP 31608 is resistant to many important beta-lactamases (including the mutationally derepressed chromosomal enzymes) and is not excluded from the bacterial cell in strains expressing these known porin mutations. Generally, CGP 31608 was less active than imipenem, Sch 34343, and the cephalosporins, except against Pseudomonas aeruginosa. The activity of CGP 31608 against Staphylococcus aureus (including methicillin-resistant strains) was greater than that of the cephalosporins. The major target site in Escherichia coli K-12 for CGP 31608 was penicillin-binding protein 2. The serum protein binding of 5 micrograms of CGP 31608 per ml was 14%, and serum had little effect on activity.
Peritoneal transport of cefonicid
Authors: Morse G D , Lane T , Nairn D K , Deterding J , Curry J , Gal P
Published: June 2012

The pharmacokinetic characteristics of cefonicid, a highly protein-bound expanded-spectrum cephalosporin, were examined in six noninfected, clinically stable patients undergoing continuous ambulatory peritoneal dialysis. After a 1.0-g intravenous dose of cefonicid, the mean concentrations in serum were 105 +/- 25 and 35.6 +/- 14.4 micrograms/ml at 3 and 72 h, respectively. Despite a prolonged half-life in serum of 49.7 +/- 18 h, the penetration into peritoneal fluid was low. The average concentration in dialysate over the 72-h study period was 2.7 micrograms/ml. The serum clearance was 2.6 +/- 1.0 ml/min, and the distribution volume was 0.14 +/- 0.02 liter/kg. Dosage recommendations and clinical considerations for cefonicid use in continuous ambulatory peritoneal dialysis patients are discussed.
Acyclic guanosine analogs as inhibitors of human cytomegalovirus
Authors: Wahren B , Larsson A , Rudén U , Sundqvist A , Sølver E
Published: June 2012

The acyclic guanosine analogs R- and S-enantiomers of 9-(3,4-dihydroxybutyl)guanine [(R)- and (S)-DHBG], 9-(4-hydroxybutyl)guanine (HBG), and 9-(2-hydroxyethoxymethyl)guanine (ACV) were examined for their effects on human cytomegalovirus (CMV) replication and on CMV DNA synthesis in cell culture as well as for their ability as triphosphates to interact with CMV DNA polymerase. Production of early CMV antigens was not affected. All analogs inhibited CMV DNA synthesis and late viral antigen synthesis. Primary CMV isolates were less susceptible to all tested analogs than was the laboratory strain CMV Ad.169. The triphosphate of ACV was the most potent inhibitor of CMV DNA polymerase, with an observed Ki of 0.0076 microM. The corresponding Ki values of the triphosphates of (R)-DHBG, (S)-DHBG, and HBG were 3.5, 13.0 and 0.23 microM, respectively. All triphosphates of the analogs given above inhibited CMV DNA polymerase in a competitive manner with respect to dGTP. The triphosphates of the analogs also inhibited reactions when the synthetic template poly(dC)oligo(dG)12-18 was used, whereas no inhibition was observed with poly(dA)oligo(dT)12-18. None of the triphosphate analogs supported DNA synthesis in the absence of dGTP, showing that no analog was an alternative substrate to dGTP.
Inhibition of DNA gyrase by optically active ofloxacin
Authors: Imamura M , Shibamura S , Hayakawa I , Osada Y
Published: June 2012

Inhibition of DNA gyrase activity by optically active ofloxacins was studied and compared with the inhibition of norfloxacin and ciprofloxacin. The (-)-isomer of ofloxacin inhibited the supercoiling activity of gyrase from Micrococcus luteus more effectively than did the (+)-isomer. The 50% inhibitory concentrations of (-)-, (+/-)-, and (+)-ofloxacin; norfloxacin; and ciprofloxacin for gyrase from Escherichia coli were 0.78, 0.98, 7.24, 0.78, and 1.15 microgram/ml, respectively. These values correlated well with the antibacterial activity of each compound against intact bacterial cells.
In vitro activity of LY146032, a new lipopeptide antibiotic, against gram-positive cocci
Authors: Verbist L
Published: June 2012

The activity of LY146032, a new lipopeptide antibiotic, was compared in vitro with those of vancomycin, oxacillin, and ampicillin against 261 staphylococcal and 154 streptococcal isolates. The MICs of LY146032 and vancomycin were similar, but the bactericidal activity and killing kinetics of LY146032 were more pronounced.
Interference by methionine on valine uptake in Acremonium chrysogenum
Authors: Alonso M J , Luengo J M
Published: June 2012

The incorporation of L-[U-14C]valine into delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV), a direct biosynthetic precursor of penicillins and cephalosporins, was studied. When DL-methionine was added to Acremonium chrysogenum culture broths, no labeled ACV was found, while a large amount of radioactive ACV was detected when methionine was not present. DL-Norleucine, a nonsulfur analog of methionine, also inhibited the synthesis of radioactive ACV to some degree. This effect was due to the inhibition of valine transport by methionine and norleucine.
Ion pair high-performance liquid chromatographic assay for ceftriaxone
Authors: Granich G G , Krogstad D J
Published: June 2012

We developed a high-performance liquid chromatographic assay to measure ceftriaxone in serum, urine, and cerebrospinal fluid. Ion pairing was used because ceftriaxone is a relatively polar compound which is poorly retained on C18 columns in standard reverse-phase high-performance liquid chromatography and which produces trailing peaks in the absence of ion-pairing agents. The mobile phase was a combination of acetonitrile and water (46:54), adjusted to pH 9.0 with 10 mM K2HPO4, which contained 10 mM hexadecyltrimethylammonium bromide as the ion-pairing agent. Moxalactam (200 micrograms/ml) was used as the internal standard. A silica-packed precolumn (3 cm long) was used to prevent rapid deterioration of the analytical column (30 by 0.4 cm) by the alkaline pH of the mobile phase, and it significantly extended the life of the analytical column. The assay was linear with ceftriaxone concentrations of 1 to 250 micrograms/ml (r = 0.999) and correlated well with an agar diffusion bioassay (r = 0.990). Reproducibility was good, with intrarun coefficients of variation from 2.3 to 6.4% and interrun coefficients of variation from 3.2 to 21.4%. The absolute recoveries of ceftriaxone and moxalactam were 91 to 97 and 96 to 98%, respectively. No interferences were observed with more than 40 commonly prescribed drugs, including 10 cephalosporins (cefotaxime, cefoperazone, ceftazidime, ceftizoxime, cefoxitin, cefamandole, cephalothin, cefazolin, cephapirin, and cephalexin), or with sera from patients with renal or hepatic disease.
Distribution of erythromycin esterase and rRNA methylase genes in members of the family Enterobacteriaceae highly resistant to erythromycin
Authors: Arthur M , Andremont A , Courvalin P
Published: June 2012

The distribution of nucleotide sequences related to ereA, ereB, and ermAM was studied by colony hybridization in 112 strains of members of the family Enterobacteriaceae that are highly resistant to erythromycin. The ereA and ereB genes encoding erythromycin esterases type I and II, respectively, were detected in strains inactivating the 14-membered macrolides erythromycin and oleandomycin. Because all 52 strains resisting these antibiotics by inactivation were detected by ereA (n = 23), ereB (n = 23), or both probes (n = 6), only two classes of genes accounted for this resistance phenotype. The ermAM gene encoding a streptococcal rRNA methylase was detected in 21 strains of Escherichia coli and two strains of Klebsiella spp. Determination of the MICs of macrolide, lincosamide, and streptogramin (MLS) antibiotics demonstrated a correlation between hybridization with ermAM and the so-called MLS resistance phenotype. The presence of 11 strains coresistant to MLS antibiotics that did not hybridize to the ermAM probe suggests that, as in gram-positive organisms, MLS resistance in members of the family Enterobacteriaceae involves more than one class of rRNA methylase. Numerous strains (n = 18) were found to produce both an erythromycin esterase type II and an rRNA methylase. Physical linkage between ereB and ermAM may be responsible for the codissemination of the genes. Despite their exogenous origin, ereB and ermAM are already disseminated in various genera of the Enterobacteriaceae.
Erythromycin-resistant Campylobacter infections in Thailand
Authors: Taylor D N , Blaser M J , Echeverria P , Pitarangsi C , Bodhidatta L , Wang W L
Published: June 2012

Erythromycin therapy was compared with no treatment in a prospective trial of acute diarrheal disease among 100 infants in an orphanage in Bangkok. Within 24 h of the onset of diarrhea, 50 children received erythromycin ethylsuccinate (40 mg/kg per day) in four divided doses for 5 days. Campylobacter jejuni isolated from 31, Campylobacter coli isolated from 21, and Shigella spp. isolated from 21 of 100 children were the most commonly recognized pathogens; use of a sensitive, nonselective method substantially increased Campylobacter isolation. Treatment with erythromycin had no effect on the duration of diarrhea caused by Campylobacter spp., Shigella spp., or other agents; 37% of the treatment group and 35% of the control group had diarrhea for 1 week. Of 23 Campylobacter strains isolated from the treatment group before treatment, 15 (65%) were resistant (MIC, greater than or equal to 8 micrograms/ml) to erythromycin. Among orphanage-acquired strains, 53% of 43 C. jejuni strains and 91% of 23 C. coli strains were resistant to erythromycin compared with 11% of 114 C. jejuni strains and 46% of 35 C. coli strains that were community acquired. Erythromycin resistance is common among Campylobacter strains in Bangkok, especially in an institutional setting, which may account for the lack of efficacy of erythromycin for treatment of acute diarrheal illnesses.
Comparative in vitro antibacterial activities of two new oral cephalosporins, ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074)
Authors: Chau P Y , Leung Y K , Ng W W , Arnold K
Published: June 2012

The in vitro activities of two new oral cephalosporins, ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074), were tested against 990 clinical bacterial isolates in comparison with that of cephalexin. Both compounds were more active than cephalexin against gram-negative bacteria, inhibiting most isolates of the family Enterobacteriaceae at concentrations of less than or equal to 4 micrograms/ml, but were not active against Acinetobacter species, most Pseudomonas species, Campylobacter jejuni, and Flavobacterium meningosepticum. Ceftetrame was also more active than cephalexin against most streptococcal isolates and as active as cephalexin against methicillin-susceptible Staphylococcus aureus; against the latter cefetamet was ineffective.
Comparative antibacterial activity of a new oral cephalosporin, BMY-28100
Authors: Chin N X , Neu H C
Published: June 2012

BMY-28100 is a new oral cephalosporin which had in vitro activity superior to that of cephalexin and cefaclor against staphylococci, beta-hemolytic streptococcal species, and Streptococcus pneumoniae. It inhibited beta-lactamase-producing Haemophilus influenzae, Neisseria gonorrhoeae, 50% of Streptococcus faecalis isolates, Listeria monocytogenes, and 50 to 75% of Escherichia coli and Klebsiella species at less than or equal to 8 micrograms/ml, but high producers of beta-lactamase were resistant. Enterobacter, Citrobacter, Morganella, Providencia, and Pseudomonas species and Bacteroides fragilis were resistant. BMY-28100 was more stable than cefaclor against hydrolysis by beta-lactamases.
Clindamycin in a murine model of toxoplasmic encephalitis
Authors: Hofflin J M , Remington J S
Published: June 2012

We investigated the efficacy of clindamycin in a murine model of toxoplasmic encephalitis using direct intracerebral inoculation. Clindamycin reduced mortality from 40% in normal mice and 100% in cortisone-treated mice to 0% in both groups. Although we were unable to document appreciable levels of clindamycin in the brains of infected mice, the histological features of cerebral infection were markedly altered. The formation of large numbers of cysts and the intense inflammatory response seen in the brains of normal mice and the unchecked infection and tissue necrosis in the brains of cortisone-treated mice were absent in the brains of clindamycin-treated mice. Enumeration of cysts in the brains of mice 10 weeks after infection revealed a significantly lower number in the clindamycin-treated mice. Spread of infection to other organs was also decreased during clindamycin administration. These observations suggest that clindamycin may have a role in the therapy of toxoplasmic encephalitis.
Killing of Saccharomyces cerevisiae by the lysosomotropic detergent N-dodecylimidazole
Authors: Hussain M , Leibowitz M J , Lenard J
Published: June 2012

The lysosomotropic detergent N-dodecylimidazole (C12-Im) has previously been found to kill mammalian cells by concentrating in lysosomes, followed by lysosomal disruption and release of cytotoxic enzymes into the cytoplasm. The action of C12-Im on Saccharomyces cerevisiae is described in this report. C12-Im prevented growth of colonies when present in 1% yeast extract-2% Bacto-Peptone-2% glucose plates at concentrations of 5 micrograms/ml or above, or when present in a soft agar overlay at 20 micrograms/ml. Treatment of cells suspended in glucose-containing buffer (pH 8.0, 37 degrees C) with C12-Im (6 micrograms/ml) caused greater than 95% cell death within 6 min. Dependence of killing on C12-Im concentration was sigmoidal, suggesting a cooperative mode of action. Killing was pH dependent, being much more effective at pH 8.0 than at pH 5.0. Ammonium sulfate and imidazole protected against killing if added before, but not after, the addition of C12-Im. Sensitivity to C12-Im was strongly growth dependent: the cells were most sensitive at early to mid-logarithmic phase of growth and became progressively less sensitive during progression through late logarithmic and stationary phase. Vacuolar disruption by C12-Im was demonstrated by using cells loaded with lucifer yellow CH or fluoresceinated dextran in their vacuoles; vacuoles of logarithmically growing cells were more sensitive than those of stationary-phase cells. These results suggest that vacuolar disruption by C12-Im may underlie its cytotoxic effects.
Failure of newer beta-lactam antibiotics for murine Yersinia enterocolitica infection
Authors: Scavizzi M R , Alonso J M , Philippon A M , Jupeau-Vessieres A M , Guiyoule A
Published: June 2012

Cefotaxime, imipenem, gentamicin, and doxycycline were active in vitro against the virulent serotype O8 Yersinia enterocolitica WA strain. Amoxycillin was inactive. The in vivo activity of these drugs was evaluated in a standardized and reproducible mouse model of systemic infection. Each single antibiotic was injected intravenously 30 h after intravenous inoculation of Y. enterocolitica WA. In vivo efficacy was measured by counting the viable bacteria recovered from the whole spleens of mice sacrificed at selected times. Doxycycline and gentamicin were active in stopping bacterial proliferation. Cefotaxime and imipenem, even at high doses (250 and 100 mg/kg of body weight, respectively), were totally ineffective, as was amoxycillin. Bacterial inocula (10(7)), recovered from either the in vitro growth or the infected spleens, were plated on cefotaxime or imipenem concentration gradients in agar; no emergence of beta-lactam-resistant organisms was detected. Based on these experiments it is not possible to explain, from any given property of the antibiotic, the bacteria, or the host, the discrepancy between the in vivo and in vitro activities of cefotaxime and imipenem. On the basis of these results, the use of newer beta-lactam antibiotics should be delayed in the therapy of human Y. enterocolitica infections until further investigations are carried out.
Inhibition of R-plasmid transfer in Escherichia coli by 4-quinolones
Authors: Weisser J , Wiedemann B
Published: June 2012

Inhibition of transfer of four conjugative R plasmids by ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and pipemidic acid was investigated in an Escherichia coli mating system. The absolute concentrations needed for inhibition of conjugation varied from 0.12 microgram/ml for ciprofloxacin to 16 micrograms/ml for pipemidic acid, but the relationship to the MICs for the parent strains was identical for all substrates. Concentrations for a 90% reduction of transconjugants were in the range of one to six times the MIC for the parent strains, which also had lethal effects on donors and recipients. A similar effect on conjugation was found with chloramphenicol. These observations question the specificity of transfer inhibition by quinolones and cast doubt on the clinical importance of such an effect.
Pyrrolo[2,3-d]pyrimidine nucleosides as inhibitors of human cytomegalovirus
Authors: Turk S R , Shipman C , Nassiri R , Genzlinger G , Krawczyk S H , Townsend L B , Drach J C
Published: June 2012

Seven arabinosyl, 2'-deoxyribosyl, and ribosyl pyrrolo[2,3-d]pyrimidines were evaluated in vitro for activity against human cytomegalovirus and for cytotoxicity in primary and established cell lines of human origin. The parent ribosyl analogs exhibited little antiviral selectivity owing to high cytotoxicity. In contrast, ara-tubercidin, ara-toyocamycin, ara-sangivamycin, and deoxysangivamycin exhibited selectivity between antiviral effect (measured by plaque or titer reduction or both) and cytotoxicity (measured microscopically and by incorporation of radioactive precursors into DNA, RNA, and protein). The selectivity (in vitro therapeutic indexes) for these four compounds ranged from 2 to 40. The two sangivamycin analogs were the most potent and selective. Ara-sangivamycin, for example, inhibited virus replication 10(5)-fold at a concentration (10 microM) which produced only partial inhibition of cell growth and labeled precursor incorporation. The four arabinosyl and deoxyribosyl nucleosides appeared to act by inhibition of viral DNA synthesis as quantitated by DNA-DNA dot blot hybridization. These four analogs also were tested for activity against two strains of type 1 herpes simplex virus by a plaque reduction assay. Unexpectedly, all compounds inhibited herpes simplex virus to a lesser extent than human cytomegalovirus.
Pharmacokinetics of habekacin in patients with renal insufficiency
Authors: Fillastre J P , Leroy A , Humbert G , Moulin B , Bernadet P , Josse S
Published: June 2012

The pharmacokinetics of habekacin, a new semisynthetic aminoglycoside antibiotic, were investigated in six healthy subjects and 25 uremic patients (six of whom were on hemodialysis) after administration of a single 3-mg/kg dose. Six healthy subjects received the 3-mg/kg dose both intramuscularly (i.m.) and intravenously (i.v.) (1-h infusion). Uremic patients were given the 3-mg/kg dose as an i.m. injection, except for the hemodialysis patients, who received the dose as a 1-h i.v. infusion. After the i.m. injection, the peak concentrations in serum were higher and the times to peak levels were longer in patients with renal impairment than in healthy subjects. The elimination half-life in serum increased in relation to the degree of renal impairment, from 2 h in normal subjects to 32 h in patients with creatinine clearances of less than 10 ml/min. Renal impairment did not significantly modify the apparent volume of distribution. After the same 3-mg/kg dose as a 1-h i.v. infusion in six hemodialysis patients, the elimination half-life averaged 48 and 5 h off and on a 4- to 5-h hemodialysis session, respectively. The habekacin pharmacokinetic data appeared to be similar to those of the other available aminoglycoside antibiotics.
Mutations producing resistance to norfloxacin in Pseudomonas aeruginosa
Authors: Hirai K , Suzue S , Irikura T , Iyobe S , Mitsuhashi S
Published: June 2012

Two genetically distinct classes of norfloxacin-resistant Pseudomonas aeruginosa PAO4009 mutants were isolated spontaneously. Two norfloxacin resistance genes, nfxA and nfxB, were mapped hex-9001 and leu-9005 and between pro-9031 and ilv-9023, respectively, on the P. aeruginosa PAO chromosome. The nfxA gene was shown to be an allele of nalA by transductional analysis with bacteriophage F116L. The nfxB mutant showed a 16-fold increase in resistance to norfloxacin and a slight increase in resistance to nalidixic acid. The nfxB mutant was unique in that it showed hypersusceptibility to beta-lactam and aminoglycoside antibiotics. This mutant had about a threefold-lower rate of norfloxacin uptake than that of the wild-type strain or nfxA mutant. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of outer membrane proteins demonstrated the appearance of a 54,000-dalton protein in the nfxB mutant. These findings suggested that the norfloxacin resistance mechanism in the nfxB mutant might be an alteration in outer membrane permeability to norfloxacin.
Cumulative and acute toxicity of repeated high-dose tobramycin treatment in cystic fibrosis
Authors: Pedersen S S , Jensen T , Osterhammel D , Osterhammel P
Published: June 2012

Forty-six patients with cystic fibrosis and chronic bronchopulmonary Pseudomonas aeruginosa infection entered a study of tobramycin-related chronic and acute nephro- and acousticovestibular toxicity. The patients (mean age, 15.7 years) had previously received 2-week courses of tobramycin therapy, for a mean cumulative total of 279 days each. The cumulative tobramycin dose ranged from 632 to 7,644 mg/kg. The patients were studied before and at the end of a 2-week course of treatment with tobramycin (10 to 20 mg/kg per day) to discriminate between acute and chronic toxicity. In patients studied at the beginning of the present course of treatment, the glomerular filtration rate, measured as 24-h creatinine clearance, did not correlate with the cumulative dose of tobramycin received during previous courses. Eighteen patients (39%) had a reduced glomerular filtration rate compared with normal values (mean, 12.5% reduction) but normal serum creatinine values. Two patients (5%) had a high-frequency hearing deficit (above 8 kHz), but only one deficit was possibly related to tobramycin. No chronic vestibular toxicity was observed. During the course of treatment, no patients developed acute nephrotoxicity. After 2 weeks of treatment 32% had a slightly reduced hearing threshold (15 to 30 dB) in two or more high frequencies, and 28% had a fall in vestibular response greater than 25% of the initial value but remained within normal limits. Thus, the acute and chronic toxicity of repeated high-dose tobramycin treatment in cystic fibrosis patients seems to be very mild.
Absence of ototoxicity of teichomycin A2 in guinea pigs
Authors: Brummett R E , Fox K E , Warchol M , Himes D
Published: June 2012

Teichomycin A2 is a new antibiotic that is similar to vancomycin. Because vancomycin is reported to be ototoxic, teichomycin A2 was tested for ototoxicity. No evidence of ototoxicity was found. Furthermore, ethacrynic acid, a diuretic that augments the ototoxicity of many drugs, did not enhance ototoxicity with teichomycin A2.
Activity of difloxacin (A-56619) and A-56620 against clinical anaerobic bacteria in vitro
Authors: Bansal M B , Thadepalli H
Published: June 2012

We determined the MICs of difloxacin (A-56619) and A-56620 against anaerobic bacteria and assessed the effects of alterations in pH, size of inoculum, addition of human serum, and repeated exposure to subinhibitory levels of antibiotics. We tested for synergism of these drugs with cefoxitin against Bacteroides spp. We found that difloxacin and A-56620 were as active as ciprofloxacin, inhibiting about 90% of B. fragilis (4 micrograms/ml) and other Bacteroides spp. (8 micrograms/ml), A-56620 being more active than difloxacin against several isolates. Increased inoculum size and changes in pH did not alter their MICs much, but human serum and exposure to sub-MICs of antibiotic effected increases in their MICs against Bacteroides spp. Cefoxitin was not synergistic with either difloxacin or A-56620 against B. fragilis.
Alteration of gentamicin and cefazolin kinetics with control of the hypothyroid state in humans
Authors: Chanson P , Joly V , Contrepois A , Garaud J J , Bauchet J , Mohler J , Nguyen P C , Carbon C
Published: June 2012

We studied the effect of the control of the hypothyroid state in humans on the pharmacokinetic parameters of cefazolin and gentamicin after a single intravenous injection. These two antibiotics were chosen because of their different patterns of binding to serum albumin (0% for gentamicin and 82% for cefazolin). In hypothyroidism, the behavior of cefazolin only was altered, with a decrease in the total body clearance, possibly due to reduced urinary excretion, and a decrease in the volume of distribution without a significant alteration of cefazolin binding to serum protein.
In vitro activity of A-56268 (TE-031), a new macrolide antibiotic, compared with that of erythromycin and other antimicrobial agents
Authors: Floyd-Reising S , Hindler J A , Young L S
Published: June 2012

A-56268 is a new macrolide antibiotic that resembles erythromycin in its spectrum of activity. A-56268 and erythromycin had identical activities against Streptococcus pyogenes, group B, C, and G streptococci, and viridans group streptococci. Erythromycin and A-56268 had similar activities against Staphylococcus aureus, coagulase-negative staphylococci, and group D enterococci. Like erythromycin, A-56268 was ineffective in inhibiting oxacillin-resistant S. aureus, oxacillin-resistant, coagulase-negative staphylococci, and penicillin-resistant viridans group streptococci. Haemophilus influenzae, Neisseria gonorrhoeae, and Legionella spp. were inhibited by A-56268 at concentrations similar to those of erythromycin.
In vitro activity of paldimycin (U-70138F) against gram-positive bacteria isolated from patients with cancer
Authors: Rolston K V , LeBlanc B , Ho D H , Bodey G P
Published: June 2012

The in vitro activity of paldimycin, a novel antimicrobial agent, was compared with that of vancomycin against 306 gram-positive isolates (representing 12 bacterial species) obtained from patients with cancer. Paldimycin had lower MICs for 90% of isolates than vancomycin did against most isolates tested. Its activity, however, was medium and pH dependent, being greatest in Nutrient broth at a pH of 6.8.
Effect of phagocyte membrane stimulation on antibiotic uptake and intracellular bactericidal activity
Authors: Steinberg T H , Hand W L
Published: June 2012

Phagocytosis stimulated a substantial increase in clindamycin uptake and a smaller increase in rifampin accumulation by polymorphonuclear leukocytes. The effect of this increased antibiotic uptake on intraphagocytic bactericidal activity was evaluated. Although zymosan stimulated antibiotic uptake by polymorphonuclear leukocytes, neither zymosan nor formyl-methionyl-leucyl-phenylalanine enhanced the ability of clindamycin or rifampin to kill ingested staphylococci. Properties other than antibiotic uptake are important in determining intraphagocytic bactericidal activity.
More than one DNA sequence encodes the 2''-O-adenylyltransferase phenotype
Authors: Lee S C , Cleary P P , Gerding D N
Published: June 2012

Biochemical and phenotypic assays indicate that three enterobacterial R plasmids isolated in a single hospital encode 2''-O-adenylyltransferase [ANT(2'')], and an ANT(2'')-specific probe was developed from one plasmid. Southern hybridization revealed the three plasmids to be unrelated and, further, showed their ANT(2'')-encoding genes to be different.
Chloramphenicol accumulation by Haemophilus influenzae
Authors: Burns J L , Smith A L
Published: June 2012

The mechanism of chloramphenicol transport into susceptible strains of Haemophilus influenzae cells has not been reported previously. We examined apparent uptake of chloramphenicol by bacterial cells by using high-pressure liquid chromatography to quantitate drug disappearance from liquid media. Cell-associated chloramphenicol concentration is 1,000-fold greater than the extracellular drug concentration. Under incubation conditions associated with chloramphenicol disappearance from media, cellular protein synthesis was inhibited; however, if accumulation was inhibited, protein synthesis occurred in the presence of the drug. Chloramphenicol uptake appeared saturable (Km = 0.96 mM, Vmax = 0.9 mumol/min per mg of protein) and energy dependent: disappearance from media was markedly decreased by 2,4-dinitrophenol and carbonyl cyanide m-chlorophenylhydrazone, compounds which disrupt the proton motive force. Uptake occurred only in median which can support growth and was dependent upon temperature and pH. Drug accumulation was minimally affected by inhibitors of electron transport or by gentamicin and puromycin, both inhibitors of protein synthesis. The rate of disappearance was inhibited by SCH24893, a fluorinated chloramphenicol analog which also inhibits protein synthesis. We conclude that chloramphenicol accumulation by H. influenzae occurs by energy-dependent transport.
Imipenem resistance in Pseudomonas aeruginosa resulting from diminished expression of an outer membrane protein
Authors: Büscher K H , Cullmann W , Dick W , Opferkuch W
Published: June 2012

The mechanism of Pseudomonas aeruginosa resistance to imipenem in five imipenem-susceptible clinical isolates and in their resistant counterparts was investigated. The frequency for selecting imipenem-resistant variants ranged from 2.7 X 10(-5) to 2.1 X 10(-8) and was comparable to those for other beta-lactams. Cross-resistance between imipenem and other beta-lactam compounds was not observed. In all imipenem-resistant variants, induction of chromosomal beta-lactamase by imipenem was markedly diminished compared with that in the susceptible parent strain. This was not the case for other inducers such as ampicillin or cefoxitin, suggesting an impaired uptake of imipenem as an explanation for resistance. Analysis of the outer membrane proteins revealed a marked decrease of either a 46- or a 45-kilodalton protein. The lipopolysaccharide of the outer membrane in the imipenem-resistant variants was not altered.
Ciprofloxacin pharmacokinetics in patients with normal and impaired renal function
Authors: Gasser T C , Ebert S C , Graversen P H , Madsen P O
Published: June 2012

The pharmacokinetics of ciprofloxacin following single oral doses of 500 and 750 mg in 32 patients with various degrees of renal function impairment were investigated in an open, randomized crossover fashion. Ciprofloxacin was administered after overnight fasting; the washout time between the two doses was 1 week. Serum and urine samples were collected serially between 0 and 24 h and subjected to bioassay and high-performance liquid chromatography. Pharmacokinetic parameters were analyzed, assuming an open two-compartment model with first-order input and elimination. A distinct difference was observed in pharmacokinetic parameters between patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) and those with normal renal function (creatinine clearance, greater than or equal to 50 ml/min per 1.73 m2). For the former group, the area under the curve of serum concentration versus time was doubled, the renal clearance of ciprofloxacin was cut to one-fourth, the total and nonrenal ciprofloxacin clearance was reduced by 50%, and the elimination half-life was prolonged by a factor of approximately 1.7. The correlation between renal drug clearance and creatinine clearance was highly significant (r = 0.890; P less than 0.001). On the basis of these findings, it appears that a 50% dose reduction of ciprofloxacin in patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) may be indicated to achieve concentrations in serum similar to those observed in normal individuals. As the concentration of ciprofloxacin in urine after 24 h remained above the MIC for most urinary pathogens, this drug appears to be of potential benefit for the treatment of urinary tract infections in patients with impaired renal function.
Penetration of enoxacin into bronchial secretions
Authors: Fong I W , Vandenbroucke A , Simbul M
Published: June 2012

Enoxacin is a potent quinolone derivative with marked activity against gram-negative bacteria and staphylococci. The oral preparation has a potential role in treatment of gram-negative-bacterial lower respiratory infections if found to give adequate bronchial (sputum) concentrations. A study was done to determine the concomitant serum and bronchial concentrations of oral enoxacin after dosing with 600 mg, single dose; 400 mg, single dose; and 400 mg every 12 h, four doses. Blood and bronchial secretions were collected from 20 patients predose and 2, 5, and 9 h postdose. Bronchial secretions were obtained from tracheostomies, endotracheal tubes, or bronchoscopy. Levels of enoxacin in serum and sputum were measured by high-pressure liquid chromatography. Mean peak bronchial secretion levels were similar for the 400-mg dose schedules (2.2 and 2.4 micrograms/ml) but were significantly higher with the 600-mg dose (4.0 micrograms/ml) (P less than 0.05). Significant concentrations in bronchial secretions were still achievable at 9 h postdose (1.3 to 2.3 micrograms of enoxacin per ml). The mean ratios of enoxacin concentrations in sputum to those in serum at various time intervals for all groups were as follows: at 2 h, 0.55 +/- 0.34; at 5 h, 1.04 +/- 0.72; at 9 h, 0.97 +/- 0.62. Considering that most gram-negative bacteria are inhibited by 1.0 microgram of enoxacin per ml in vitro, this study shows that oral enoxacin in practical doses achieves a concentration in bronchial secretions that is adequate to treat most gram-negative-bacterial lower respiratory infections.
Quantitative neutralization assay of fungicidal activity of disinfectants
Authors: Terleckyj B , Axler D A
Published: June 2012

A quantitative assay using a neutralization medium was developed to evaluate fungicidal activity of disinfectants. Concentrated Dey-Engley neutralizing broth was used in this study and was demonstrated to inactivate various chemical agents within 5 min when disinfectant concentrations were reduced to specific levels. Addition of this Dey-Engley broth to test tubes containing fungal cells and disinfectants permitted control of the various interactions times. Subsequent concentration of the disinfectant-treated cells to a 1-ml final volume also permitted examination of a larger population for the presence of resistant cells. After timed exposures of 15, 30, and 60 min, only three of seven disinfectant solutions were found to be lethal for quantitative populations of 11 fungi tested. The recommended use dilution formulations of a quaternary ammonium product and an iodophor product were the least effective agents. Various fungi, including Trichophyton mentagrophytes, Epidermophyton floccosum, and Aspergillus niger, survived 30- to 60-min interactions with these disinfectant solutions. The most resistant organism encountered was Aspergillus fumigatus, which survived 60 and even 90 min of exposure to most disinfectants. Only use dilutions of a chlorine dioxide formulation, a glutaraldehyde formulation, and an ethyl alcohol product were effective against this species and all of the other fungi after a 15-min interaction.
In vitro evaluation of CP-62,993, erythromycin, clindamycin, and tetracycline against Chlamydia trachomatis
Authors: Walsh M , Kappus E W , Quinn T C
Published: June 2012

The antimicrobial activity of CP-62,993 against four Chlamydia trachomatis isolates was compared with those of erythromycin, clindamycin, and tetracycline. The MIC of CP-62,993 was 0.26 to 1.02 micrograms/ml for 100% inclusion inhibition and 0.031 to 0.063 microgram/ml for 50% inclusion inhibition. With pharmacokinetic and antimicrobial studies demonstrating prolonged half-life and in vitro effectiveness, CP-62,993 may make possible a single, short-course treatment regimen for C. trachomatis infection.
Antimicrobial activity of ceftriaxone, cefotaxime, desacetylcefotaxime, and cefotaxime-desacetylcefotaxime in the presence of human serum
Authors: Jones R N , Barry A L
Published: June 2012

Eighty-seven organisms were tested against ceftriaxone, cefotaxime, desacetylcefotaxime, and the combination of cefotaxime and desacetylcefotaxime (1:1 ratio) in broth containing 0, 25, or 50% human serum. In the presence of human serum, ceftriaxone MICs were four- to eightfold higher than those obtained in broth, changing 98% of Staphylococcus aureus strains from the susceptible to the moderately susceptible category and 53% of selected gram-negative strains to a more resistant category. The MICs of cefotaxime, desacetylcefotaxime, and cefotaxime plus desacetylcefotaxime were not adversely affected by human serum; in fact, the bactericidal activity was slightly improved.
Location on RP4 of a tellurite resistance determinant not normally expressed in IncP alpha plasmids
Authors: Taylor D E , Bradley D E
Published: June 2012

The tellurite resistance (Ter) determinant of RP4 is not normally expressed unless variants are selected on medium containing tellurite. The determinant was mapped in the variant plasmid RP4Ter by Tn7 insertion mutagenesis. Based on a 56.4-kilobase (kb) replicon, it covered the region from 56 kb, across the EcoRI site at 0 kb, to 1.5 kb.
Assessment of formulas for calculating critical concentration by the agar diffusion method
Authors: Drugeon H B , Juvin M E , Caillon J , Courtieu A L
Published: June 2012

The critical concentration of antibiotic was calculated by using the agar diffusion method with disks containing different charges of antibiotic. It is currently possible to use different calculation formulas (based on Fick's law) devised by Cooper and Woodman (the best known) and by Vesterdal. The results obtained with the formulas were compared with the MIC results (obtained by the agar dilution method). A total of 91 strains and two cephalosporins (cefotaxime and ceftriaxone) were studied. The formula of Cooper and Woodman led to critical concentrations that were higher than the MIC, but concentrations obtained with the Vesterdal formula were closer to the MIC. The critical concentration was independent of method parameters (dilution, for example).
Concentrations of ticarcillin and clavulanic acid in human bone after prophylactic administration of 5.2 g of timentin
Authors: Adam D , Heilmann H D , Weismeier K
Published: June 2012

The penetration of ticarcillin and clavulanate into their distribution space within human bone was determined after prophylactic administration of 5.2 g of timentin (5 g of ticarcillin plus 0.2 g of clavulanic acid) to 20 patients undergoing hip surgery. All samples were taken 45 to 85 min postadministration. The mean concentrations of ticarcillin in spongiosa and corticalis bone were 57.1 and 70.5 mg/kg, respectively; those of clavulanic acid were 17.8 and 32.5 mg/kg, respectively. No infections occurred in these patients.
In vitro activity of systemic antifungal agents against Malassezia furfur
Authors: Marcon M J , Durrell D E , Powell D A , Buesching W J
Published: June 2012

The activity of four antifungal agents against 15 systemic (blood and vascular catheter) and 10 superficial (skin) Malassezia furfur isolates was evaluated. MIC ranges were similar for the two groups of organisms: amphotericin B, 0.3 to 2.5 micrograms/ml; flucytosine, greater than 100 micrograms/ml; miconazole, 0.4 to 1.5 micrograms/ml; and ketoconazole, 0.025 to 0.4 micrograms/ml.
Erythromycin bioactivity is stable in ophthalmic ointment used for prophylaxis of neonatal gonococcal conjunctivitis
Authors: Bialer M G , Baron E J , Harper R G
Published: June 2012

Erythromycin ophthalmic ointment (E. Fougera & Co., Melville, N.Y.) and erythromycin gluceptate standards prepared in ointment base were stored at room temperature and heated at temperatures up to 45 degrees C for as long as 6 h before being assayed for bioactivity. We were unable to detect any significant loss of antibiotic bioactivity.
Effect of ciprofloxacin on carrier rate of Neisseria meningitidis in army recruits in Finland
Authors: Renkonen O V , Sivonen A , Visakorpi R
Published: June 2012

The efficacy of ciprofloxacin in eradicating pharyngeal colonization of Neisseria meningitidis was studied among army recruits in Finland. Ciprofloxacin (250 mg) or placebo was given twice a day for 2 days to 118 meningococcal carriers. Meningococcal carriage was eradicated in 96% of subjects given ciprofloxacin and in 13% of those given placebos.
9-(1-3-Dihydroxy-2-propoxymethyl)guanine prevents death but not immunity in murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice
Authors: Wilson E J , Medearis D N , Hansen L A , Rubin R H
Published: June 2012

Immunosuppressed (from treatment with cortisone acetate and anti-thymocyte globulin) and control adult female BALB/c mice, latently infected with murine cytomegalovirus (MCMV) or lethally challenged (10(6) PFU) with MCMV intraperitoneally, were treated with 9-(1-3-dihydroxy-2-propoxymethyl)guanine (DHPG) intraperitoneally. A dose of 3 mg/kg reduced mortality by 50% in lethally challenged normal mice; 10 mg/kg was required in immunosuppressed mice. When 15 mg/kg was given, the onset of treatment could be delayed for 64 h after lethal challenge. DHPG did not prevent the establishment of latent MCMV infection or immunosuppression-induced reactivation. The antibody titer to MCMV in DHPG-treated mice which survived lethal challenge was 41 (reciprocal of geometric mean) 4 to 5 weeks after inoculation; such mice survived a second lethal challenge. When antiserum treatment was begun 64 h and DHPG was begun 72 h after a lethal challenge, most mice survived; most did not when either treatment alone was begun at those times. In summary, DHPG effectively treated lethal MCMV infection even in immunosuppressed mice and even when treatment onset was delayed for 64 h. Treatment did not alter the establishment or reactivation of latent infections or the induction of effective immunity. The administration of DHPG coupled with antiserum treatment may be even more effective than the administration of either alone.
Acquisition by a Campylobacter-like strain of aphA-1, a kanamycin resistance determinant from members of the family Enterobacteriaceae
Authors: Ouellette M , Gerbaud G , Lambert T , Courvalin P
Published: June 2012

A Campylobacter-like organism, BM2196, resistant to kanamycin and streptomycin-spectinomycin was isolated from the feces of a patient with acute enteritis. The kanamycin and streptomycin-spectinomycin resistances were not transferable to Camplylobacter sp. or to Escherichia coli, and no plasmid DNA was detected in this strain. The resistance genes were therefore tentatively assigned to a chromosomal locality. Analysis by the phosphocellulose paper-binding assay of extracts from BM2196 indicated that resistance to kanamycin and structurally related antibiotics was due to the synthesis of 3'-aminoglycoside phosphotransferase type I [APH(3')-I], an enzyme specific for gram-negative bacteria, and that resistance to streptomycin-spectinomycin was secondary to the presence of a 3",9-aminoglycoside adenylyltransferase. Homology between BM2196 and an APH(3')-I probe was detected by DNA-DNA hybridization. A 2.2-kilobase BM2196 DNA fragment conferring resistance to kanamycin was cloned in E. coli and was sequenced partially. The resistance gene appeared nearly identical to that of Tn903 from E. coli and was adjacent to IS15-delta, an insertion sequence widespread in gram-negative bacteria, thus indicating that Campylobacter species can act as a recipient for genes originating in members of the family Enterobacteriaceae.
Characterization of a staphylococcal trimethoprim resistance gene and its product
Authors: Coughter J P , Johnston J L , Archer G L
Published: June 2012

Resistance to trimethoprim (Tp) is mediated by a plasmid-encoded gene in staphylococci. The gene is responsible for high-level resistance (MIC, greater than 1,000 micrograms/ml) in both its native host and when cloned on high-copy-number vectors in Escherichia coli. Analysis of subclones of the staphylococcal Tp gene on E. coli expression vectors and estimation of the size of full and truncated proteins produced in E. coli minicells generated an approximate size limit of 505 base pairs for the gene and 18,500 daltons for the gene product. Crude extracts of E. coli containing the cloned gene had dihydrofolate reductase (DHFR) specific activity that was more than 100 times greater than that of control cells and more than 1,000 times more resistant to trimethoprim inhibition. The amount of trimethoprim required for a 50% reduction in the specific activity of staphylococcal DHFR differed from those of cells containing DHFR types I, II, or III, enzymes mediating Tp in members of the family Enterobacteriaceae. In addition, the size of the monomeric staphylococcal DHFR protein was larger than that of any of the gram-negative DHFRs both compared with published sequence data and as observed by direct comparison on polyacrylamide gels. Finally, there was no homology between a DNA fragment containing the cloned staphylococcal gene and DNA encoding any of the gram-negative DHFRs. Thus, the staphylococcal Tp gene codes for a single protein with DHFR activity that appears to be unrelated to DHFR genes that mediate Tp in members of the Enterobacteriaceae.