bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children
Authors: Viganò A , Principi N , Brivio L , Tommasi P , Stasi P , Villa A D
Published: June 2012

The efficacy and safety of netilmicin, 5 mg/kg of body weight once daily or 2 mg/kg thrice daily for 10 days, for the treatment of gram-negative pyelonephritis in children were compared in a prospective, randomized trial. Explicit criteria were used to define the site of infection, treatment outcome, and adverse effects. Netilmicin was given to 74 children once daily and to 70 children three times daily. At 1 week posttreatment, 73 (99%) of 74 children treated with netilmicin once daily and 70 (100%) of 70 children treated with netilmicin three times daily were cured. At 4 weeks posttreatment, no relapse was detected and the rate of reinfection was essentially identical in the two treatment groups. Peak serum netilmicin concentrations were higher in patients given the once-daily regimen, whereas a higher trough level was detected in patients given the three-times-daily regimen. Nephrotoxicity, which was defined as an increase in the serum creatinine level of greater than or equal to 0.3 mg/dl over the baseline, was rare (3%) and reversible and occurred regardless of the treatment regimen. Ototoxicity, which was assessed by pure-tone audiometry (250 to 8,000 Hz) and brain stem-evoked response (6,000 Hz), occurred in 2 of 32 children who were evaluated. In these two children, who were given the once-daily regimen, wave V was not evokable monolaterally below 25 and 40 dB normal hearing level, respectively. Thus, it may be possible to treat childhood pyelonephritis with netilmicin once daily. However, this new approach needs to be confirmed in other studies.
Didanosine pharmacokinetics in patients with normal and impaired renal function: influence of hemodialysis
Authors: Singlas E , Taburet A M , Borsa Lebas F , Parent de Curzon O , Sobel A , Chauveau P , Viron B , al Khayat R , Poignet J L , Mignon F , Humbert G , Fillastre J P
Published: June 2012

The pharmacokinetics of didanosine were investigated following oral administration of a single 375-mg dose to eight human immunodeficiency virus-seropositive patients with normal renal function and eight human immunodeficiency virus-seropositive uremic patients. In uremic patients, the plasma half-life was longer than that in control patients (respectively, 4.5 +/- 2.2 and 1.6 +/- 0.4 h). The ratio of total plasma clearance to absolute bioavailability was four- to fivefold lower in uremic patients than in patients with normal renal function (respectively, 491 +/- 181 and 2,277 +/- 738 ml/min). Because of the decrease in elimination, concentrations in plasma were higher for uremic patients than for control patients; the maximum concentrations of drug in plasma were, respectively, 3,978 +/- 1,607 and 1,948 +/- 994 ng/ml; the areas under the concentration-time curve were, respectively, 14,050 +/- 4,262 and 3,000 +/- 956 ng.h/ml. Didanosine was removed by hemodialysis with an extraction ratio of 53% +/- 8%, a hemodialysis clearance value of 107 +/- 21 ml/min, and a fractional drug removal during a 4-h dialysis of 20% +/- 8% of the dose. Dosage adjustments are necessary in uremic patients.
Intraocular penetration of rifampin in humans
Authors: Outman W R , Levitz R E , Hill D A , Nightingale C H
Published: June 2012

The penetration of rifampin into human aqueous humor was determined in 15 patients undergoing elective cataract surgery. Between 0.9 and 5.5 h after administration of a single 600-mg oral dose, concentrations ranged from 6.0 to 21.5 mg/liter in serum and from less than 0.2 to 1.3 mg/liter in aqueous humor.
Evaluation of cefuroxime axetil and cefadroxil suspensions for treatment of pediatric skin infections
Authors: Jacobs R F , Brown W D , Chartrand S , Darden P , Drehobl M A , Yetman R , Ossi M J
Published: June 2012

A randomized, single-blind, multicenter study was conducted to evaluate the safety and efficacy of cefuroxime axetil and cefadroxil suspensions for the treatment of skin or skin structure infections in 287 children. Each drug was given at a dosage of 30 mg/kg of body weight per day in two divided doses. Staphylococcus aureus and Streptococcus pyogenes, or a combination of the two, were the primary pathogens isolated from infected skin lesions. A satisfactory bacteriological response (cure or presumed cure) was obtained in 97.1 and 94.3% of children in the cefuroxime axetil and cefadroxil groups, respectively (P greater than 0.05). Satisfactory clinical responses (cure or improvement) were more likely to occur in cefuroxime axetil recipients than in cefadroxil recipients (97.8 versus 90.3%; P less than 0.05). Both regimens were equally well tolerated, with adverse events occurring in 7.9 and 6.1% of cefuroxime axetil and cefadroxil recipients, respectively. There were more patients who refused to take cefuroxime axetil (7 of 189) than there were who refused to take cefadroxil (0 of 98), but the difference was not statistically significant (P = 0.1). In this study, cefuroxime axetil was at least as effective as cefadroxil in resolving skin and skin structure infections in children.
Resistance to cefotaxime and seven other beta-lactams in members of the family Enterobacteriaceae: a 3-year survey in France
Authors: Sirot D L , Goldstein F W , Soussy C J , Courtieu A L , Husson M O , Lemozy J , Meyran M , Morel C , Perez R , Quentin-Noury C
Published: June 2012

During the second quarter each of 1988, 1989, and 1990, a French collaborative study group, including 12 university hospital laboratories, surveyed the resistance to beta-lactams of clinical isolates from hospitalized patients: consecutively, 10,641, 10,692, and 9,382 isolates were tested. The distribution of bacterial species over time was similar in each laboratory. The susceptibilities of microorganisms to amoxicillin, ticarcillin, cephalothin, cefoxitin, cefotaxime (CTX), ceftazidime (CAZ), aztreonam (ATM), and imipenem (IPM) were measured by the disk diffusion method in accordance with the recommendations of the Antibiogram Committee of the French Society for Microbiology. Five reference strains were included for quality control. Extended-spectrum beta-lactamases were detected by the synergistic effect of the combination of clavulanic acid-amoxicillin with CTX, CAZ, and ATM in the double-diffusion test. A synergistic effect with CTX, CAZ, and ATM was detected for 1.5% of all strains, mainly those of Klebsiella pneumoniae (13.3%). For this species, the synergy test enabled the detection of roughly 50% of the resistant strains misclassified as susceptible on the basis of interpretative standards. Extended-spectrum beta-lactamases disseminated in 1990 in most enterobacterial species but at a low frequency. Important variations in the percentages of resistant strains were observed in terms of bacterial species, hospitals, and wards. However, when the total number of strains was considered, the percentages of resistance to newer beta-lactams remained low.
Bacteriostatic and bactericidal activities of gentamicin alone and in combination with clarithromycin against Mycobacterium avium
Authors: Heifets L B , Lindholm-Levy P J , Comstock R D
Published: June 2012

The inhibitory activity of gentamicin against Mycobacterium avium depended on the pH of the medium, and the broth-determined MICs for 90% of strains were 5.0 micrograms/ml at pH 7.4, 9.5 micrograms/ml at pH 6.8, and greater than 16.0 micrograms/ml at pH 5.0. The MBCs were two- to eightfold higher than the MICs. The combined effect of gentamicin and clarithromycin was additive, and the MICs and MBCs of each drug were either the same as those in the single-drug tests or reduced twofold.
Increased rate of isolation of penicillin-resistant Streptococcus pneumoniae in a children's hospital and in vitro susceptibilities to antibiotics of potential therapeutic use
Authors: Mason E O , Kaplan S L , Lamberth L B , Tillman J
Published: June 2012

The isolation of Streptococcus pneumoniae with both high and intermediate resistance to penicillin has increased in our institution since 1989 to an average of 12.1% of all isolates. We determined the susceptibilities of 95 isolates (34 susceptible to penicillin, 42 intermediate in resistance to penicillin, and 19 resistant to penicillin) to 16 antimicrobial agents of potential use in the treatment of disease caused by S. pneumoniae. Susceptibility to penicillin was determined by broth macrodilution with Mueller-Hinton broth supplemented with 5% lysed horse blood. Isolates were classified as highly resistant when the MIC was greater than or equal to 2.0 micrograms/ml, intermediate in resistance when the MIC was between 0.1 and 1.0 microgram/ml, and susceptible when the MIC was less than 0.1 microgram/ml. Fifteen of 19 isolates found to be highly resistant to penicillin were recovered from the middle ear of children. None of the isolates recovered from cerebrospinal fluid was highly resistant to penicillin. Fifteen of these isolates highly resistant to penicillin were found to be serogroup 6. Susceptibilities to other antibiotics were determined by the agar dilution method with Mueller-Hinton agar containing 5% lysed horse blood and an inoculum of 10(4) CFU per spot delivered by a replicator device. The MIC for 90% of isolates increased with increasing penicillin resistance for all antibiotics tested, except chloramphenicol, ciprofloxacin, rifampin, and vancomycin. Regardless of the classification of penicillin resistance, all isolates were classified as susceptible to cefotaxime, cefpirome, cefpodoxime, clarithromycin, imipenem, rifampin, and vancomycin on the basis of National Committee for Clinical Laboratory Standards interpretive guidelines. Interpretation of susceptibilities on the basis of currently available guidelines is difficult in that susceptibility guidelines applicable specifically to S. pneumoniae are not available.
Identification by DNA sequence analysis of a new plasmid-encoded trimethoprim resistance gene in fecal Escherichia coli isolates from children in day-care centers
Authors: Singh K V , Reves R R , Pickering L K , Murray B E
Published: June 2012

In our ongoing studies of trimethoprim resistance (Tmpr) in day-care centers (DCC), we have shown a high rate of fecal colonization with Tmpr Escherichia coli and, using total plasmid content analysis, have shown that this is due to a diversity of strains. In the present study, we analyzed 367 highly Tmpr (MIC, greater than or equal to 2,000 micrograms/ml) isolates of E. coli from 72 children over a 5-month period and found at least 83 distinct plasmid patterns, indicating that at least 83 strains were involved. Several strains were particularly common in a given DCC, including one found in 61% of children with Tmpr E. coli; these common strains usually persisted within a DCC for several months. Colony lysates were hybridized with gene probes for dihydrofolate reductases (DHFR) types I, II, III, V, and VII; 21% hybridized under stringent conditions, and all of these were with type I (17%) or type V (4%) probes. Tmpr was cloned from a probe-negative Tmpr transconjugant, and an intragenic probe was prepared from this clone. Approximately 21% of the Tmpr E. coli strains (76 isolates) in the DCC were found to have this new gene, 74 of which were in one DCC. The DNA sequence of this gene was determined, and the predicted amino acid sequence was shown to have between 32% and 39% identity with the amino acid sequences for types I, III, V, VI, and VII and the partial sequence of type IV and approximately 26% identity with types IX and X DHFR. This confirms the uniqueness of this gene, which has tentatively been named dhfrxii, and its translation product, DHFR type XII.
Long-term tolerance and efficacy of 3'-azidothymidine and 3'-fluorothymidine treatment of asymptomatic monkeys infected with simian immunodeficiency virus
Authors: Böttiger D , Ståhle L , Li S L , Oberg B
Published: June 2012

Macaques chronically infected with simian immunodeficiency virus were treated with zidovudine (20 mg/kg of body weight per day for 9 weeks) or 3'-fluorothymidine (5 mg/kg of body weight per day for 9 weeks or three doses of 2 mg/kg per day for 24 days). Hematological changes in the treated animals included macrocytic anemia and leukopenia. Determination of antiviral effects in this model requires improved assay methods.
Increased susceptibility of transfected prokaryotic and eukaryotic cells to antibiotic selection
Authors: Asselbergs F A , van Someren P
Published: June 2012

At 39 to 40 degrees C, selection of antibiotic-resistant transfected mammalian cell lines or Escherichia coli required lower aminoglycoside antibiotic concentrations than at 37 degrees C. The thermosensitivity of antibiotic susceptibility was much more manifest during genetic selection experiments than in conventional growth inhibition assays.
Susceptibilities of ampicillin-resistant strains of Salmonella other than S. typhi to 10 antimicrobial agents
Authors: Alós J I , Gómez-Garcés J L , Cogollos R , Amor E , Pérez-Rivilla A
Published: June 2012

Ampicillin-resistant strains of Salmonella other than S. typhi constitute a health problem. We tested the antimicrobial susceptibilities to 10 antibiotics of 57 of these strains isolated in a 30-month period. The rates of resistance were as follows: chloramphenicol, 40.3%; tetracycline, 33.3%; gentamicin, 5.3%; co-trimoxazole, 5.3%; nalidixic acid, 1.8%; and amoxicillin-clavulanic acid, cefotaxime, ceftriaxone, aztreonam, and ciprofloxacin, 0%. In our experience, there are alternative antibiotics with excellent in vitro activities.
Prediction of human pharmacokinetics of panipenem-betamipron, a new carbapenem, from animal data
Authors: Kurihara A , Naganuma H , Hisaoka M , Tokiwa H , Kawahara Y
Published: June 2012

The pharmacokinetic behavior of panipenem (PAPM)-betamipron (BP), a new carbapenem, in humans was successfully predicted from data collected from six animal species. PAPM and BP were biphasically eliminated from plasma after intravenous (i.v.) administration of PAPM-BP to mice, guinea pigs, rats, rabbits, monkeys, and dogs. Elimination rates of PAPM and BP were correlated with animal size: the larger the animal was, the slower the elimination was. As for PAPM and BP, log-log plots of total plasma clearance (CLtot) versus body weight and log-log plots of distribution volume at steady state (VSS) versus body weight for six animal species were linear, with high correlation coefficients. These allometric equations were extrapolated to predict CLtot and VSS for PAPM and BP in humans. In addition, concentration in plasma-time profiles for humans were predicted by using two-exponent equations fitted to the complex Dedrick plot of animal data. Predicted values for CLtot and VSS for PAPM and BP in humans agreed well with observed values in humans given 750/750 mg of PAPM-BP as an i.v. drip infusion for 30 min. Predicted concentration in plasma-time profiles for humans approximated observed profiles. Thus, the pharmacokinetics of PAPM-BP extrapolated well from animal species to humans when allometric equations and the complex Dedrick plot were used.
Cross-resistance to meropenem, cephems, and quinolones in Pseudomonas aeruginosa
Authors: Masuda N , Ohya S
Published: June 2012

Multiple-drug-resistant mutants were isolated from Pseudomonas aeruginosa PAO1 on agar plates containing ofloxacin and cefsulodin. These mutants were four to eight times more resistant to meropenem, cephems, carbenicillin, quinolones, tetracycline, and chloramphenicol than the parent strain was. In contrast, these mutants showed no significant changes in their susceptibilities to all carbapenems except meropenem. In these mutants, the amounts of an outer membrane protein with an apparent molecular weight of 49,000 (designated OprM) were increased compared with the amount in PAO1. Multiple-drug-resistant mutants of this type were also isolated from PAO1 on agar plates containing meropenem. Approximately 5% of clinical isolates showed cross-resistance to meropenem, cephems, and quinolones, concomitant with overproduction of OprM. Moreover, these two phenotypes, i.e., multiple-drug resistance and overproduction of OprM, were cotransferable by transduction. These data suggest that overproduction of OprM is associated with cross-resistance to meropenem, cephems, and quinolones in P. aeruginosa. The ofloxacin-cefsulodin-resistant mutant required higher concentrations of meropenem to induce beta-lactamase than PAO1 did, indicating the possibility that this mutation involves decreased outer membrane permeability to meropenem.
Detection of extended-spectrum beta-lactamases in members of the family Enterobacteriaceae: comparison of the double-disk and three-dimensional tests
Authors: Thomson K S , Sanders C C
Published: June 2012

The three-dimensional and clavulanate double-disk potentiation tests were compared as procedures for the detection of extended-spectrum beta-lactamase production in 32 strains of Escherichia coli and Klebsiella pneumoniae, 31 of which produced TEM-1, TEM-2, TEM-3, TEM-4, TEM-5, TEM-7, TEM-8, TEM-9, TEM-10, TEM-12, TEM-101, SHV-1, SHV-2, SHV-3, SHV-4, SHV-5, CAZ-2, MIR-1, or an unidentified extended-spectrum beta-lactamase with a pI of 5.95, with some strains producing multiple beta-lactamases. The three-dimensional test, which was performed in conjunction with a routine disk diffusion test, detected extended-spectrum beta-lactamase production in 26 of 28 (93%) of the strains that produced extended-spectrum beta-lactamases. The clavulanate double-disk potentiation test detected extended-spectrum beta-lactamases in only 22 of the 28 strains (79%) when it was performed as currently recommended. The three-dimensional test, when performed in conjunction with the disk diffusion test, offered the advantages of providing simultaneous information about both antibiotic susceptibility and extended-spectrum beta-lactamase production, coupled with a greater sensitivity and earlier detection of extended-spectrum beta-lactamases.
Chitin biosynthesis in Candida albicans grown in vitro and in vivo and its inhibition by nikkomycin Z
Authors: Chapman T , Kinsman O , Houston J
Published: June 2012

An N-acetyl-D-[14C]glucosamine radiolabel incorporation assay has been used to monitor chitin biosynthesis in whole cells of Candida albicans both in vitro and in vivo in two different mouse infection models, one using the peritoneal cavity as a chamber in which to add and retrieve cells and the other using infected kidneys. Specific labeling of chitin in alkali-insoluble material was confirmed by chitinase digestion, analysis of acid hydrolysates, and the use of nikkomycin Z as a probe. Nikkomycin Z was shown to strongly inhibit chitin biosynthesis in C. albicans grown in vitro and in vivo in both models. This demonstrates that nikkomycin Z-susceptible chitin synthase activity is present in C. albicans when the fungus is in its pathogenic state in vivo. The limited use of nikkomycin as a therapeutic agent is discussed.
Tn21-specific structures in gram-negative bacteria from clinical isolates
Authors: Zühlsdorf M T , Wiedemann B
Published: June 2012

A total of 807 gram-negative clinical isolates were treated with five different probes: intragenic segments for the transposase gene tnpA; the resolvase gene tnpR; the modulator of the resolvase, tnpM; the integraselike factor gene tnpI; and a 20-mer oligonucleotide for the recombinational site of action for the integrase. A total of 8% of the isolates hybridized with all five Tn21-related probes, and another 11% represented transposons in which one or more of the tested genes were missing. This 11% included groups whose descriptions have been published as well as groups that have not yet been described. The not-yet-described groups include various deletion products and some precursor structures, as is predicted for the evolution of Tn21-like transposons. The integration system appears to be coupled with Tn21-like structures and yet independent from these structures, implying an independent evolution of this system from Tn21-like transposons. The structures were found with similar incidence levels in all species tested except Pseudomonas aeruginosa, for which a novel separate family of class II transposons has been described before.
Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers
Authors: Efthymiopoulos C , Strolin Benedetti M , Sassella D , Boobis A , Davies D
Published: June 2012

FCE 22891 is a prodrug of the penem antibiotic FCE 22101 and is suitable for oral administration. The pharmacokinetics of FCE 22891 were investigated in four healthy male volunteers following the oral administration of 500 mg of [14C]FCE 22891. Levels of radioactivity in plasma were always higher and persisted for longer than those of FCE 22101. The time to the maximum concentration of radioactivity in plasma generally coincided with that of FCE 22101. The respective values for the maximum concentrations of radioactivity in plasma were, on average, 8.57 +/- 2.95 micrograms equivalent/ml and 2.97 +/- 2.05 micrograms/ml. Over a 5-day period, mean urinary and fecal recovery of radioactivity accounted for 53.2 and 41.0% of the dose, respectively. The average amount of FCE 22101 excreted in urine and feces corresponded to 9.0 and 1.6% of the dose, respectively. The urinary recovery of the open-ring metabolite P1 and of its 5-S epimer P2 accounted for about 6.5 and 1.2% of the dose, respectively. Other chromatographic peaks corresponding to nonidentified compounds accounted for about 14.0% (polar metabolite fraction; peak P), 3.7% (less polar fraction; peak X), and 15.4% (least polar fraction) of the dose. Elimination of radioactivity and FCE 22101 in urine was rapid. Intersubject variability in the kinetics of total radioactivity in plasma was far less than that observed for FCE 22101. The results of the present study support suggestions that presystemic metabolism of FCE 22101 and/or transformation of the prodrug to compounds other than FCE 22101 are the main cause of intersubject variability in the kinetics of FCE 22101 produced in plasma following oral administration of its prodrug.
Activities of clarithromycin against eight slowly growing species of nontuberculous mycobacteria, determined by using a broth microdilution MIC system
Authors: Brown B A , Wallace R J , Onyi G O
Published: June 2012

MICs of clarithromycin against 324 clinical isolates belonging to eight species of slowly growing nontuberculous mycobacteria were determined by using a broth microdilution system. Isolates were inoculated into twofold drug dilutions in Middlebrook 7H9 broth (pH corrected to 7.4) and then incubated at 30 degrees C for 7 days for Mycobacterium marinum and for 14 days for all other species. The MIC for 90% of the strains (MIC90) was less than or equal to 0.5 micrograms/ml for isolates of Mycobacterium gordonae (6 strains), Mycobacterium scrofulaceum (5 strains), Mycobacterium szulgai (6 strains), and Mycobacterium kansasii (35 strains). MICs for M. marinum (25 strains) and Mycobacterium avium complex (237 strains) were higher, but 100% and 89% of the strains, respectively, were susceptible to less than or equal to 4 micrograms/ml. In contrast, MICs for five of six M. simiae strains were greater than 8 micrograms/ml, and the range of MICs for Mycobacterium nonchromogenicum varied from less than or equal to 0.125 to 8 micrograms/ml. For the 237 isolates of M. avium complex, the MIC50 was 2 micrograms/ml and the MIC90 was 8 micrograms/ml. MICs for most isolates (77%) were in the 1- to 4-micrograms/ml range. For the 80 isolates in this group known to be from AIDS patients, the MIC50 was 4 micrograms/ml and the MIC90 was 8 micrograms/ml. These MIC studies combined with preliminary clinical trials suggest that clarithromycin may be useful for drug therapy of most species of the slowly growing nontuberculous mycobacteria except M. simiae.
Presence of Clostridium difficile and antibiotic and beta-lactamase activities in feces of volunteers treated with oral cefixime, oral cefpodoxime proxetil, or placebo
Authors: Chachaty E , Depitre C , Mario N , Bourneix C , Saulnier P , Corthier G , Andremont A
Published: June 2012

Three groups of six healthy adult volunteers were randomly assigned to a treatment with 400 mg of oral cefpodoxime proxetil, oral cefixime, or placebo per day for 10 days. Informed consent was obtained from all volunteers. Clostridium difficile was not detected in the feces of any subject before treatment or at any time in the subjects in the placebo group. C. difficile was, however, detected in all subjects treated with cefpodoxime proxetil and in five of six treated with cefixime. Genomic DNA restriction patterns showed that the strains of C. difficile differed from one volunteer to another. Two subjects both shed different strains at different times during the 25-day surveillance period. All isolates were resistant to cefixime and cefpodoxime (MIC for 90% of strains, 256 and 512 mg/liter, respectively). Antibiotic activity was found in the feces of one volunteer treated with cefpodoxime proxetil and of four volunteers treated with cefixime. It was inversely correlated with the presence of fecal beta-lactamase activity. Intestinal side effects were limited to modifications of stool consistency, which occurred in only 3 of the 12 treated volunteers and did not lead to cessation of treatment. These modifications were significantly associated with the presence of fecal antibiotic activity (P less than 0.05) but not with the shedding of toxigenic or nontoxigenic strains of C. difficile or with the presence of toxin A in feces, which was detected only in one perfectly healthy treated volunteer.
Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653,180) as therapy for experimental recurrent genital herpes
Authors: Bourne N , Bravo F J , Ashton W T , Meurer L C , Tolman R L , Karkas J D , Stanberry L R
Published: June 2012

Herpes simplex virus (HSV)-coded thymidine kinase (TK) is important in efficient reactivation of latent infection. These studies were designed to investigate whether treatment of latently infected animals with a TK inhibitor altered the natural history of recurrent HSV disease. 9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) is a potent and selective nonsubstrate inhibitor of HSV TK which can suppress or delay reactivation of HSV-1 from latently infected cells in vitro without affecting viral replication. In an initial study, six female Hartley guinea pigs were treated with L-653,180 in their diet (25 mg/30 g of food) and water (300 mg/liter) for 7 days. Blood, urine, kidney, liver, spinal cord, and cerebral cortex specimens were collected. L-653,180 was detected in all specimens at concentrations which, although low, were higher than the in vitro 50% inhibitory concentration of the drug against HSV TK. In the second study, 20 female Hartley guinea pigs were randomized into two groups following recovery from primary genital HSV-2 infection. One group received L-653,180 in diet and water for 4 weeks beginning 21 days postinoculation. Animals were examined daily for recurrent lesions for 10 weeks. Treated animals experienced fewer recurrences during the treatment period but the results were not significantly different from results with controls. During the first 2-week posttreatment period, L-653,180-treated animals had significantly fewer recurrences than control animals (P = 0.02). Over the entire 10-week observation period, treated animals experienced fewer recurrences (P = 0.06). These results suggest that inhibitors of viral TK may be useful in limiting reactivation of latent virus and thus recurrent infections. In these experiments, the amount of drug that could be administered to the animals was limited by its poor solubility. Further studies with more potent and soluble inhibitors of HSV TK appear to be warranted.
Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter
Authors: Neyfakh A A , Borsch C M , Kaatz G W
Published: June 2012

The gene of the Staphylococcus aureus fluoroquinolone efflux transporter protein NorA confers resistance to a number of structurally dissimilar drugs, not just to fluoroquinolones, when it is expressed in Bacillus subtilis. NorA provides B. subtilis with resistance to the same drugs and to a similar extent as the B. subtilis multidrug transporter protein Bmr does. NorA and Bmr share 44% sequence similarity. Both the NorA- and Bmr-conferred resistances can be completely reversed by reserpine.
Candidicidal activity of the human recombinant myeloperoxidase system
Authors: Tournay C , Majerus P , Pourtois M , Moguilevsky N , Bollen A
Published: June 2012

The effect of the human recombinant myeloperoxidase (recMPO) system on the viability of Candida albicans blastospores was determined. Cells were incubated in the presence of the enzyme, H2O2, and various substrates. In optimal conditions, 100% mortality was reached with only 41 mU of recMPO per ml, confirming its powerful candidicidal activity.
Neutralizing antibodies against the peptide antibiotic AS-48: immunocytological studies
Authors: Maqueda M , Gálvez A , Martínez-Bueno M , Guerra I , Valdivia E
Published: June 2012

Antisera against the broad-spectrum peptide antibiotic AS-48 produced by Enterococcus faecalis were obtained from immunized rabbits. Appreciable antibody titers were obtained only after repeated immunization, suggesting a feeble antigenicity for AS-48. Upon incubation with AS-48, the antisera neutralized its bacteriolytic action on E. faecalis S-47, although the simultaneous addition of AS-48 and serum did not prevent lysis. Crude serum cross-reacted with outer envelope components of enterococci, although specific anti-AS-48 antibodies, purified by affinity chromatography, reacted only with AS-48-treated cells. Labelling with immunofluorescence and colloidal gold particles was carried out on sensitive and resistant bacterial species to determine the interaction of AS-48 with cell structures.
Prospective evaluation of effects of broad-spectrum antibiotics on gastrointestinal yeast colonization of humans
Authors: Samonis G , Gikas A , Anaissie E J , Vrenzos G , Maraki S , Tselentis Y , Bodey G P
Published: June 2012

This study evaluated the effects of broad-spectrum antibiotics on the gastrointestinal (G.I.) yeast flora of humans and correlated the findings with those obtained from a mouse model of G.I. colonization by Candida albicans. We prospectively studied 46 adult cancer patients who received one of five broad-spectrum antibiotics (ceftriaxone, ceftazidime, ticarcillin-clavulanic acid, imipenem-cilastatin, and aztreonam) as therapy for infections. Quantitative examination of yeast colonization of stools was conducted at the baseline, at the end of antibiotic treatment, and 1 week after discontinuation of therapy. Antibiotics with anaerobic activity (ticarcillin-clavulanic acid) or high G.I. concentrations (ceftriaxone) caused a higher and more sustained increase in G.I. colonization by yeasts than did antibiotics with poor anaerobic activity (ceftazidime and aztreonam) or a low G.I. concentration (imipenem-cilastatin). These results were similar to those obtained with a mouse model of G.I. colonization by C. albicans that involved the same antibiotics. Hence, the mouse model may be useful for evaluation of yeast colonization of the human G.I. tract.
Pharmacokinetics and protein binding of ceftriaxone during pregnancy
Authors: Bourget P , Fernandez H , Quinquis V , Delouis C
Published: June 2012

The purpose of the present work was to study the pharmacokinetics and the protein binding (free fraction of the drug) of ceftriaxone (CTX) during pregnancy. Nine pregnant women (ages, 20 to 34 years) whose gestational ages ranged from 28 4/7 to 40 5/7 weeks were included. The diagnosis of infection was established in all cases; i.e., four women had chorioamnionitis and five women had pyelonephritis. The following triple antibiotic therapy was infused with the aim of achieving cure: CTX, 2 g once every 24 h (constant rate over 60 min); tobramycin, 3 mg/kg of body weight once every 24 h; and ornidazole, 1 g/day. Two series of blood samples were collected, i.e., during the first day of treatment (on day 1), to establish the primary pharmacokinetic profile of CTX, and at the plateau (on day 7), to evaluate a possible accumulation of the drug. This was an open, noncompartmental study, with each patient serving as her own control. Concentrations of total and unbound CTX in serum were measured by a high-performance liquid chromatographic method. Pharmacokinetic analysis was done by a noncompartmental method. Data were compared by a Wilcoxon t test (a P value of < or = 0.05 was considered significant). Data were also compared with those obtained for healthy subjects who received similar treatments. (i) The tolerance to treatment was excellent, and in all cases patients had a complete remission without premature delivery. (ii) No accumulation of CTX was noted during the treatment, and the profiles of the drug determined at days 1 and 7 were not significantly different.(iii) The pharmacokinetic parameters measured in pregnant patients during the third trimester of pregnancy were similar to those measured in healthy subjects. (iv) Residual concentrations of total and unbound CTX measured at 24 h were greater than the MICs for allegedly susceptible organisms, both on day 1 and at steady state. (v) During the final 3 months of pregnancy, the dosage schedule of CTX (2-g infusion per day) required no particular adjustment (i.e., neither a loading dose nor any increase in the maintenance dose.)
Overproduction of 3'-aminoglycoside phosphotransferase type I confers resistance to tobramycin in Escherichia coli
Authors: Menard R , Molinas C , Arthur M , Duval J , Courvalin P , Leclercq R
Published: June 2012

Escherichia coli HM69, isolated from urine, was resistant to high levels of kanamycin (MIC, > 1,000 micrograms/ml) and a low level of tobramycin (MIC, 8 micrograms/ml). Phosphocellulose paper-binding assays and molecular cloning indicated that resistance to both aminoglycosides was due to synthesis of a 3'-aminoglycoside phosphotransferase type I, an enzyme that phosphorylates kanamycin but not tobramycin. The structural gene for the enzyme was borne by an 80-kb conjugative plasmid, pIP1518, and was nearly identical to aphA1 of Tn903. Incubation of extracts of resistant cells with tobramycin or kanamycin led to a decrease (> 80%) of antibiotic activity as determined by a microbiological assay. Heat treatment showed that loss of activity was reversible and dependent upon the native enzyme. In the presence of ATP, only inactivation of kanamycin was reversible. These results suggest that resistance to low levels of tobramycin was due to formation of a complex between the enzyme and the antibiotic.
Comparison of population pharmacokinetic models for gentamicin in spinal cord-injured and able-bodied patients
Authors: Gilman T M , Brunnemann S R , Segal J L
Published: June 2012

Population pharmacokinetic models for gentamicin were developed by using data obtained from 29 spinal cord-injured patients and 11 able-bodied control patients. With a one-compartment model, the population parameters were clearance (CL), volume of distribution (V), and their associated variances. Parameter estimates were found by using the computer program NPEM and by the standard two-stage (STS) method. NPEM uses a nonparametric approach incorporating the expectation maximization algorithm to evaluate a joint probability density function at 900 intersections over a bivariate grid. In contrast, the STS method requires conventional assumptions of normality for the underlying distributions. For NPEM, the mean CL was 97.6 ml/h/kg of body weight (coefficient of variation, 33.0% in the spinal cord-injured patients and 67.8 ml/h/kg +/- 28.2% in the able-bodied patients; the mean V was 0.31 liter/kg +/- 32.3% in the spinal cord-injured patients and 0.23 liter/kg +/- 15.8% in the able-bodied patients. For STS, the mean CL was 101.0 ml/h/kg +/- 37.5% in the spinal cord-injured patients and 65.0 ml/h/kg +/- 33.8% in the able-bodied patients; the mean V was 0.29 liter/kg +/- 34.0% in the spinal cord-injured patients and 0.21 liter/kg +/- 21.0% in the able-bodied patients. Although the means and variances found by NPEM and the STS method were similar, the NPEM analysis revealed that the distributions of CL and V, even after they were linked to weight, were positively skewed and kurtotic. The cumulative distribution functions for CL (P < 0.001) and V (P < 0.001) in spinal cord-injured patients were different from those in able-bodied patients. Unique population models are required for the initial dosage selection for spinal cord-injured patients. Future approaches for developing population models should allow the linkage of structural parameters to multiple patient covariates.
Direct, automated detection of rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis
Authors: Telenti A , Imboden P , Marchesi F , Schmidheini T , Bodmer T
Published: June 2012

A rapid screening test was recently established for the detection of mutations in the rpoB gene of Mycobacterium tuberculosis, a region identified as the locus for rifampin resistance (Rifr). The detection method involved the amplification by polymerase chain reaction (PCR) of the Rifr region and the identification of mutations by single-strand DNA conformation polymorphism analysis (SSCP) of the amplification products. Experience using two different PCR-SSCP formats for the evaluation of BACTEC cultures and sputum is presented here; the previously described manual procedure for the detection for the detection of radiolabelled amplification products and an automated SSCP by which fluorescein-labelled products were detected on a Pharmacia DNA sequencer apparatus. All 17 different Rifr mutations known to date were consistently detected. PCR-SSCP could be used for the evaluation of minimally grown cultures (BACTEC 12B medium with a growth index of < or = 100) and for direct screening of microscopically positive sputa with greater than 10 organisms per field (magnification, x250). Implementation of this technique could result in rapid detection of rifampin resistance in M. tuberculosis, a marker of multidrug-resistant tuberculosis.
Characterization of a new TEM-type beta-lactamase resistant to clavulanate, sulbactam, and tazobactam in a clinical isolate of Escherichia coli
Authors: Blazquez J , Baquero M R , Canton R , Alos I , Baquero F
Published: June 2012

A clinical Escherichia coli strain highly resistant to the combinations of amoxicillin-clavulanate, ampicillin-sulbactam, and piperacillin-tazobactam was isolated from a patient with a community-acquired urinary tract infection who was previously treated with amoxicillin-clavulanate. These resistances were carried by a 45-kb conjugative plasmid encoding for a single beta-lactamase with a pI of 5.4. Cloning and sequencing of the new beta-lactamase, IRT-3, revealed identity with the blaT1 gene encoding the TEM-1 beta-lactamase except for a replacement of the methionine residue at position 67 by isoleucine and of the methionine residue at position 180 by threonine. Both mutations were segregated by the construction of hybrid genes, and only the mutation at methionine at position 67 was related to resistance to the suicide inhibitors. The inhibitory effects of clavulanate, sulbactam, and tazobactam on the TEM-1 enzyme were substantially decreased in comparison with those on IRT-3, as indicated by the 50% inhibitory concentrations.
Treatment of tinea unguium with medium and high doses of ultramicrosize griseofulvin compared with that with itraconazole
Authors: Korting H C , Schäfer-Korting M , Zienicke H , Georgii A , Ollert M W
Published: June 2012

Toenail tinea is a very recalcitrant dermatosis. Griseofulvin at > or = 500 mg/day is the current medication of choice, but it is minimally successful. In a controlled open trial ultramicrosize griseofulvin (UMSG) at doses of 660 and 990 mg/day was compared with itraconazole at 100 mg/day in 109 patients. At 4-week intervals, the patients were evaluated for their clinical and mycological statuses and adverse reactions. Treatment was given for up to 18 months. Compliance was checked by tablet counting. Response (cure, partial cure, marked improvement) was analyzed by the intent-to-treat method. Cured and partially cured patients were followed up. Except for one early dropout, the toenails (mean, 6 to 7) were involved. Cure or partial cure was found in 6% (UMSG at 660 mg), 14% (UMSG at 990 mg), and 19% (itraconazole at 100 mg) of patients (P = 0.2097); marked improvement was found in 36, 44, and 39% of patients in the three treatment groups, respectively. Most patients had to be treated for 18 months. Failure was related to short medication periods (adverse drug reactions, dropout). While stable cure was not obtained with UMSG at 660 mg, the higher dose of UMSG and itraconazole gave stable cures in the other patients. Side effects of nausea, diarrhea, and headache were found in 20, 26, and 11 patients, respectively (P = 0.0028), and the numbers in whom medication had to be discontinued differed, too (P = 0.0137). While there was no major difference with glutamic-pyruvic transaminase and gamma-GT, total and low-density lipoprotein cholesterol levels declined slightly in the itraconazole group (P = 0.0357 and P = 0.0639, respectively, at 3 months). More than 70% of the patients had an average compliance of > or = 90%; four patients (two dropouts) were poor compliers. In conclusion, it appears questionable whether griseofulvin can continue to be considered the "gold standard" in the treatment of toenail tinea. At present, itraconazole at 100 mg shows better efficacy and is better tolerated.
Identification of the satA gene encoding a streptogramin A acetyltransferase in Enterococcus faecium BM4145
Authors: Rende-Fournier R , Leclercq R , Galimand M , Duval J , Courvalin P
Published: June 2012

Enterococcus faecium BM4145, a clinical isolate from urine, was resistant to streptogramin group A antibiotics by inactivation. The strain harbored a plasmid containing a gene, satA, responsible for this resistance; this gene was cloned and sequenced. It encoded SatA, a protein deduced to be 23,634 Da in mass and homologous with a new family of chloramphenicol acetyltransferases described in Agrobacterium tumefaciens, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The similarity of SatA to other acetyltransferases, LacA (thiogalactoside acetyltransferase) and CysE (serine acetyltransferase) from E. coli, and to two putative acetyltransferases, NodL from Rhizobium leguminosarum and Urf1 from E. coli, was also observed in a region considered to be the enzyme's active site. Acetylation experiments indicated that acetyl coenzyme A was necessary for SatA activity and that a single acetylated derivative of pristinamycin IIA was produced. Other members of the streptogramin A group such as virginiamycin M and RP54476 were also substrates for the enzyme. We conclude that resistance to the streptogramin A group of antibiotics in E. faecium BM4145 is due to acetylation by an enzyme related to the novel chloramphenicol acetyltransferase family.
Pharmacokinetics and serum bactericidal titers of ciprofloxacin and ofloxacin following multiple oral doses in healthy volunteers
Authors: Israel D , Gillum J G , Turik M , Harvey K , Ford J , Dalton H , Towle M , Echols R , Heller A H , Polk R
Published: June 2012

Fourteen adult males participated in a randomized three-way crossover study to compare the pharmacokinetics and serum bactericidal titers (SBTs) of 500 mg of ciprofloxacin (regimen A), 750 mg of ciprofloxacin (regimen B), and 400 mg of ofloxacin (regimen C) administered every 12 h for seven doses. Mean steady-state peak concentrations in serum for regimens A, B, and C were 3.0, 4.4, and 6.5 micrograms/ml, respectively (P < 0.01, all comparisons) and mean half-lives were 4.5, 4.3, and 6.5 h, respectively (P < 0.05, C versus A and B). Mean steady-state areas under the concentration-time curve were 14.1, 21.1, and 48.1 micrograms/h/ml for regimens A, B, and C, respectively (P < 0.05, all comparisons). SBTs were determined at different times postdose for three isolates each of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Enterobacter cloacae, and Pseudomonas aeruginosa. Mean steady-state peak SBTs for regimens A, B, and C, respectively, were as follows: S. pneumoniae, < 1:2, 1:8, 1:8, S. aureus, 1:16, 1:16, 1:16; E. coli, 1: > or = 128, 1: > or = 128, 1:64; E. cloacae, 1: > or = 128, 1: > or = 128, 1:64; P. aeruginosa, 1:8, 1:8, 1:2. These differences in SBTs within each genus were statistically significant. The majority of predicted SBTs were within one dilution of measured SBTs. Areas under the serum bactericidal time curves for E. coli, E. cloacae, and P. aeruginosa were significantly higher for ciprofloxacin; areas under the serum bactericidal time curves for S. pneumoniae and S. aureus were significantly greater for ofloxacin. Ofloxacin achieved higher concentrations in serum than ciprofloxacin, but differences in in vitro activity were a more important determinant of SBTs.
Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: studies of interpatient variations in concentrations
Authors: Hostetler J S , Heykants J , Clemons K V , Woestenborghs R , Hanson L H , Stevens D A
Published: June 2012

Pharmacologic studies of itraconazole (IZ), a triazole antifungal, indicated unexplained differences between bioassay and chromatographic determinations and large variations in steady-state blood concentrations. We show that concentrations of a hydroxylated metabolite, hydroxyitraconazole (HIZ), are approximately twofold higher than IZ over a range of concentrations. Though HIZ and IZ appear equipotent against selected pathogens, HIZ is two to three times more active against a commonly used bioassay fungus but minimally affects IZ activity. Hence, HIZ probably contributes importantly to the therapeutic activity attributed to IZ and contributes approximately four to six times the activity of IZ in bioassays, explaining discrepancies observed between assay methods.
Azithromycin inhibition of intracellular Legionella micdadei
Authors: Donowitz G R , Earnhardt K I
Published: June 2012

Legionella micdadei is an intracellular parasite that is ingested, but not killed, by leukocytes. Within monocytes, the organism has been shown to grow 1.0 to 2.0 log10 units over 48 h (D. L. Weinbaum, R. R. Benner, J. N. Dowling, A. Alpern, A. W. Pasculle, and G. R. Donowitz, Infect. Immun. 46:68-73, 1984). Intracellular L. micdadei would appear to be a useful model in which to study the effect of antibiotics which accumulate intracellularly. Azithromycin, a newly introduced azalide, is highly concentrated within leukocytes and was therefore studied to determine its effect on a single strain of L. micdadei that had been ingested by human monocytes. Peripheral blood monocytes were allowed to ingest L. micdadei and extracellular, nonadherent organisms were subsequently removed by washing. Cells and cell-associated bacteria were then incubated at 0, 24, and 48 h in media with serial concentrations of azithromycin at sub-MIC levels (less than 1.0 microgram/ml). L. micdadei in cells not exposed to azithromycin grew 0.8 +/- 0.1 log10 units (mean +/- standard deviation) at 24 h and 1.7 +/- 0.4 log10 units at 48 h. At both 24 and 48 h, the lowest concentrations of azithromycin tested (0.02 microgram/ml) significantly inhibited bacterial growth in monocytes (P = 0.02). A stepwise inhibition of L. micdadei CFUs was noted with increasing azithromycin concentrations. In contrast, when cells were exposed to antibiotic before ingesting L. micdadei, a less effective antibacterial effect was noted. Under certain in vitro conditions, azithromycin is a potent agent against intracellular L. micdadei.