bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized, double-blind comparison of the efficacies, costs, and vaginal flora alterations with single-dose ceftriaxone and multidose cefazolin prophylaxis in vaginal hysterectomy
Authors: Stiver H G , Binns B O , Brunham R C , Cheng N , Dean D M , Goldring A M , Walker J B , Tan E , McLeod J
Published: June 2012

A comparison of efficacies, costs, and effects on vaginal microflora of one preoperative and three postoperative 1-g doses of cefazolin versus those of one preoperative 1-g dose of ceftriaxone was done with 65 and 73 women, respectively, undergoing elective vaginal hysterectomy. Patient infection rates were not statistically different between the cefazolin group (six events in 6 of 73 patients [8.2%]) and the ceftriaxone group (11 events in 9 of 65 patients [13.8%]). Side effects, including diarrhea, were minimal and similar between the two groups. Significant shifts in the cervicovaginal microflora of the patients occurred postoperatively, with a marked increase in enterococci and a drop in nonenterococcal streptococci. No shifts among aerobic, facultative gram-negative rods and staphylococci were observed. Among the anaerobes, a significant decrease in the number of patients harboring nonsporulating, gram-positive rods and a less striking concomitant increase in Bacteriodes species and members of the family Peptococcaceae were noted. No qualitative differences were noted between the two groups that received prophylactic therapy. Aside from enterococci, cefazolin or ceftriaxone resistance among vaginal isolates (greater than or equal to 10(3)/ml) was minimal. Selection of resistant isolates was not different between the treatment groups. We could not detect a difference between a single 1-g dose of ceftriaxone and multidose cefazolin for infection prophylaxis in patients undergoing a vaginal hysterectomy. However, the total acquisition, preparation, and administration costs were greater for the ceftriaxone regimen than they were for the cefazolin regimen. Cefazolin should therefore remain the drug of choice for infection prophylaxis in uncomplicated vaginal hysterectomies.
Phase I study of multiple-dose cefprozil and comparison with cefaclor
Authors: Barbhaiya R H , Shukla U A , Gleason C R , Shyu W C , Wilber R B , Martin R R , Pittman K A
Published: June 2012

The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after administration of multiple doses of the drug, and to compare these pharmacokinetic parameters with those obtained with cefaclor. The volunteers received 28 doses of 250, 500, or 1,000 mg of cefprozil or 500 mg of cefaclor every 8 h for 10 days. Serial blood samples and the total volume of urine voided by each individual were collected for pharmacokinetic evaluation on days 1, 5, and 10. Both cephalosporins were well tolerated after multiple oral dosing. The peak levels in plasma (Cmax) of cefprozil ranged from 5.7 to 18.3 micrograms/ml after oral administration of 250- to 1,000-mg doses. The regression analysis of Cmax on cefprozil dose showed a dose-linear response. The mean Cmax of cefaclor ranged from 15.2 to 16.7 micrograms/ml and did not change significantly on multiple dosing. The overall mean terminal half-life of cefprozil was 1.2 h and was invariant with respect to dose or duration of dosing. The area under the plasma-concentration-versus-time curve from 0 h to infinity (AUC0-infinity) of cefprozil increased in a dose-proportional manner with an increase in dose. The overall urinary recovery (61% of dose) and renal clearance values of cefprozil were generally invariant with respect to dose and duration of dosing. While cefprozil was apparently absorbed less rapidly and achieved lower Cmax values than cefaclor, the AUC0-infinity of cefprozil was nearly twofold greater than that of cefaclor. The half-life of cefprozil was also twofold longer than that observed for cefaclor. Although the urinary recovery of cefaclor (75% of dose) was significantly higher than that of cefprozil (61% of dose), the concentrations of cefprozil in urine remained significantly higher than those of cefaclor from 2 to 8 h postdosing. If the therapeutic concept is maintained that levels of beta-lactam antibiotics in plasma should exceed the MIC for the offending organisms over a period that approximates the dosing interval, then cefprozil would appear to be suitable for twice-daily administration, whereas cefaclor should probably be administered three or even four times a day.
Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users
Authors: Small P M , Chambers H F
Published: June 2012

The clinical courses of 13 consecutive intravenous drug users with Staphylococcus aureus endocarditis treated principally with vancomycin were reviewed. Two patients, one with only right-sided endocarditis and the other with tricuspid and mitral valve endocarditis, had recurrences of positive blood cultures 2 days after completing a 4-week course of vancomycin. Two patients, both of whom eventually were cured, had modifications of therapy because of bacteremia persisting 7 and 16 days into therapy. One patient required an operation for recurrent fevers, and the resected vegetation showed evidence of active infection. Time-kill studies performed with nafcillin and vancomycin for 10 isolates of S. aureus showed that vancomycin was less rapidly bactericidal than nafcillin. Although vancomycin is used as an alternative to penicillinase-resistant penicillins for treatment of staphylococcal endocarditis, these findings raise the question of whether it is equivalent to these drugs in efficacy.
Penetration of SCH-39304, a new antifungal triazole, into cerebrospinal fluid of primates
Authors: Walsh T J , Lester-McCully C , Rinaldi M G , Wallace J E , Balis F M , Lee J W , Pizzo P A , Poplack D G
Published: June 2012

We characterized the cerebrospinal fluid (CSF) penetration and pharmacokinetics of SCH-39304 in adult rhesus monkeys receiving a single oral dose of SCH-39304 (2.0 mg/kg of body weight). The mean CSF-to-plasma area under the curve ratio was 0.63 (+/- 0.18, standard error of the mean); maximum concentrations were 1.34 micrograms/ml (+/- 0.18) in CSF and 1.96 micrograms/ml (+/- 0.43) in plasma. The mean plasma half-life was 45.7 h (+/- 11), and mean CSF half-life was 38.7 h (+/- 3.5). The mean levels of SCH-39304 at 24 h were 1.48 micrograms/ml (+/- 0.3) in plasma and 0.96 microgram/ml (+/- 0.12) in CSF. We conclude that SCH-39304 effectively penetrates into CSF and achieves concentrations considered active against many opportunistic yeasts and that these concentrations are sustained in CSF for greater than or equal to 24 h.
Failure of ceftazidime-amikacin therapy for bacteremia and meningitis due to Klebsiella pneumoniae producing an extended-spectrum beta-lactamase
Authors: Smith C E , Tillman B S , Howell A W , Longfield R N , Jorgensen J H
Published: June 2012

A multiple trauma patient failed treatment with ceftazidime and amikacin for bacteremia and meningitis due to a Klebsiella pneumoniae strain that produced a novel, plasmid-mediated beta-lactamase. Both pre- and posttreatment isolates were resistant to ceftazidime (MIC, greater than or equal to 64 micrograms/ml) and various penicillins but not to other expanded-spectrum cephalosporins. The beta-lactamase had a pI of 5.25 and was encoded on a conjugal plasmid of approximately 150 kilobases. DNA hybridization studies indicated that the enzyme was a TEM derivative.
In vitro activity of tosufloxacin (A-61827; T-3262) against selected genital pathogens
Authors: Segreti J , Hirsch D J , Harris A A , Kapell K S , Orbach H , Kessler H A
Published: June 2012

The in vitro activity of tosufloxacin (A-61827; T-3262) against 15 clinical isolates of Chlamydia trachomatis and 31 recent clinical isolates of Neisseria gonorrhoeae, including 15 spectinomycin-resistant N. gonorrhoeae and 16 penicillinase-producing N. gonorrhoeae, was determined. Tosufloxacin was compared with doxycycline, ciprofloxacin, and temafloxacin against C. trachomatis. Susceptibility testing was performed by using McCoy cell monolayers. The in vitro activity of tosufloxacin against N. gonorrhoeae was compared with that of ciprofloxacin, temafloxacin, doxycycline, ceftriaxone, and spectinomycin by using an agar dilution method. Tosufloxacin was as active as temafloxacin against C. trachomatis (MIC for 90% of strains tested [MIC90], 0.25 microgram/ml; MBC for 90% of strains tested [MBC90], 0.25 microgram/ml) and was almost as active as doxycycline (MIC90, 0.06 microgram/ml; MBC90, 0.125 microgram/ml). Ciprofloxacin, temafloxacin, and tosufloxacin were extremely active against N. gonorrhoeae, including spectinomycin-resistant N. gonorrhoeae and penicillinase-producing N. gonorrhoeae, with MIC90s of 0.004, 0.015, and 0.008 microgram/ml, respectively. Ceftriaxone was slightly less active (MIC90, 0.03 microgram/ml), and doxycycline was the least active drug tested (MIC90, 4.0 micrograms/ml). Tosufloxacin and temafloxacin had excellent activity against the C. trachomatis and N. gonorrhoeae strains tested.
In vivo efficacy of SM-8668 (Sch 39304), a new oral triazole antifungal agent
Authors: Tanio T , Ichise K , Nakajima T , Okuda T
Published: June 2012

SM-8668 (Sch 39304) is a new oral antifungal agent which we evaluated in comparison with fluconazole in various fungal infection models. The prophylactic effect of SM-8668 was excellent against systemic candidiasis, aspergillosis, and cryptococcosis in mice. The 50% effective dose for SM-8668 was assessed at 10 days after infection and was 0.18, 3.7, and 5.9 mg/kg (body weight), respectively, for the above-mentioned fungal diseases. Fluconazole was about four times less effective than SM-8668 against systemic candidiasis and was only slightly effective at doses of 80 and 25 mg/kg against systemic aspergilosis and cryptococcosis, respectively. SM-8668 was also about four to eight times more active than fluconazole against vaginal candidiasis in rats and against dermatophytic infection in guinea pigs. In addition, topical SM-8668 was as effective as topical miconazole or tioconazole against skin mycosis in guinea pigs. After oral administration, SM-8668 showed a maximum concentration in serum similar to that of fluconazole in both mice and rats, but the elimination half-life and area under the serum concentration-time curve for SM-8668 were twice those for fluconazole.
Quantitative analysis of antimicrobial effect kinetics in an in vitro dynamic model
Authors: Firsov A A , Chernykh V M , Navashin S M
Published: June 2012

Variants of the available methods for estimating antimicrobial effect kinetics in an in vitro dynamic model were analyzed. Two integral parameters characterizing antimicrobial effect duration (TE) and intensity (IE) are suggested to define and analyze the concentration-effect relationships in these models, irrespective of the method of recording. TE is defined by the time from the moment of antibiotic administration to the movement when the bacterial count again reaches its initial level. IE is defined by the area between the microbial growth curves in the presence and absence of an antibiotic. TE and IE were used to quantify the antimicrobial effects of sisomicin on Pseudomonas aeruginosa 58, Escherichia coli 93, and Klebsiella pneumoniae 5056, simulating the pharmacokinetic profiles of the drugs observed following intramuscular administration in therapeutic doses, including the variability of aminoglycoside concentrations in human blood.
Comparative activities of several nucleoside analogs against duck hepatitis B virus in vitro
Authors: Yokota T , Konno K , Chonan E , Mochizuki S , Kojima K , Shigeta S , de Clercq E
Published: June 2012

Duck hepatitis B virus (DHBV) replication in primary duck hepatocytes was monitored by examining the synthesis of both DHBV DNA and DHBV core antigen. Several nucleoside analogs which were previously shown to inhibit the replication of DNA viruses (i.e., herpesviruses) and retroviruses were examined for their inhibitory effects on the synthesis of DHBV core antigen in primary duck hepatocytes. (S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine, 2',3'-dideoxyadenosine, and 2',3'-dideoxycytidine inhibited DHBV core antigen synthesis at concentrations that were significantly lower than those found to be toxic to the primary hepatocytes. Of all the compounds tested, (S)-HPMPA showed the lowest 50% effective concentration (0.5 micrograms/ml). The selectivity index or ratio of the 50% cytotoxic concentration to the 50% effective concentration of (S)-HPMPA was greater than 300. (S)-HPMPA not only inhibited DHBV core antigen but also DHBV DNA synthesis in DHBV-infected hepatocytes.
Involvement of a cell wall receptor in the mode of action of an anti-Candida toxin of Pichia anomala
Authors: Sawant A D , Ahearn D G
Published: June 2012

Hanes-Woolf, Dixon, and Hill plots of growth rates of Candida albicans RC1 grown in various concentrations of glucose and a Pichia anomala WC65 toxin suggested the presence of toxin-binding sites. Indirect immunofluorescence microscopy with antitoxin antibodies demonstrated binding of the toxin to the cell wall. Resistance to the toxin of a mutant Saccharomyces cerevisiae deficient in cell wall beta-1-6-D-glucan suggests that the glucan either served as the receptor or influenced the number or composition of the receptor. Immunofluorescence that appeared to be associated with the cell membrane of toxin-treated spheroplasts of C. albicans was also observed. Spheroplasts of the resistant mutant of S. cerevisiae were sensitive to the toxin.
Ceftazidime versus imipenem-cilastatin as initial monotherapy for febrile neutropenic patients
Authors: Liang R , Yung R , Chiu E , Chau P Y , Chan T K , Lam W K , Todd D
Published: June 2012

One hundred febrile episodes in 89 neutropenic patients after cytotoxic chemotherapy were randomized to be treated with either ceftazidime or imipenem as initial monotherapy. The clinical characteristics of the two groups of patients were comparable. The response of the fever in patients who received imipenem was significantly better than that in those who received ceftazidime (77 versus 56%, respectively; P = 0.04), especially in those with microbiologically documented infection (81 versus 33%, respectively; P = 0.02). The in vitro susceptibilities and the clinical responses suggested that, with the possible exception of Pseudomonas spp., imipenem was more effective than ceftazidime in treating neutropenic infections caused by both gram-positive and -negative organisms. An additional 23 and 21% of the patients in the ceftazidime and imipenem groups, respectively, responded to the addition of cloxacillin and amikacin following failure of monotherapy. The majority of the treatment failures, relapses, and superinfections were related to resistant infective organisms such as methicillin-resistant Staphylococcus spp. and Pseudomonas spp. or disseminated fungal infections.
Sequence analysis and evolutionary perspectives of ROB-1 beta-lactamase
Authors: Juteau J M , Levesque R C
Published: June 2012

The nucleotide sequence of the ROB-1 beta-lactamase gene from Haemophilus influenzae plasmid RRob was determined. The structural gene encodes a polypeptide of 305 amino acids, with an estimated molecular mass of 30,424 for the mature form of the protein. The ROB-1 gene showed low homologies with other beta-lactamases at the nucleic acid level. By using two statistical computer methods, assessment of the extent of similarity between ROB-1 and other known beta-lactamase amino acid sequences suggested that ROB-1 is a class A enzyme. Alignment of class A beta-lactamases with ROB-1 identified conserved residues. The use of a mutation matrix for detecting distance relationships indicated that ROB-1 has higher values and homologies with beta-lactamases of gram-positive bacteria, giving insight into its ancestry and divergence.
In vitro activity of E-1040, a 3-substituted cephalosporin, against pathogens from cystic fibrosis sputum
Authors: Stutman H R , Akaniro J C , Vidaurre C E , Marks M I
Published: June 2012

On the basis of preliminary in vitro data, we evaluated E-1040, a new cephalosporin, against 188 cystic fibrosis (CF) sputum isolates obtained from 26 CF centers in the United States. These isolates included mucoid and nonmucoid Pseudomonas aeruginosa, Pseudomonas cepacia, Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli. In addition to MICs measured under standard conditions, selected isolates were tested at various pH values, inoculum sizes, and diluent (CF serum and sputum) conditions. E-1040 activities (MICs for 50 and 90% of the strains) against the isolates were as follows: P. aeruginosa (mucoid and nonmucoid), 1 and 4 micrograms/ml; P. cepacia, 4 and 16 micrograms/ml; S. aureus, 8 and 8 micrograms/ml; H. influenzae, 1 and 4 micrograms/ml; and E. coli, less than or equal to 0.12 and less than or equal to 0.12 microgram/ml. E-1040 activity against mucoid P. aeruginosa was 4-fold greater than that of aztreonam, 16-fold greater than that of ceftazidime, and 32-fold greater than that of piperacillin. E-1040 was similar to other broad-spectrum cephalosporins against S. aureus, H. influenzae, and E. coli. Bactericidal activity was less than or equal to 1 dilution of MIC for 88% of the strains, although kinetic studies with mucoid strains of P. aeruginosa demonstrated effective killing only at eight times the MIC. Variations in pH from 5 to 8, in inoculum size from 10(3) to 10(7) CFU/ml, and in diluent (CF serum or CF sputum) did not affect E-1040 activity.
Antimalarial activity of a combination of 5-fluoroorotate and uridine in mice
Authors: Gómez Z M , Rathod P K
Published: June 2012

Malarial parasites, in contrast to mammalian cells, utilize orotic acid more efficiently than uracil or uridine. Recently, chloroquine-susceptible and chloroquine-resistant clones of Plasmodium falciparum were shown to be inhibited by 5-fluoroorotate, with a 50% inhibitory concentration of 6 nM in vitro. Mammalian cells were far less sensitive to 5-fluoroorotate, particularly in the presence of uridine. In this report, the antimalarial activity of 5-fluoroorotate was tested in vivo. Initially, levels of 5-fluoroorotate in plasma were determined in Swiss mice injected intraperitoneally with radioactive 5-fluoroorotate. On the basis of the pharmacokinetics profile, mice infected with Plasmodium yoelii were treated with 5-fluoroorotate at a dose of 0.2 or 5 mg/kg (body weight) every 4 h for 3 days. At the nontoxic dose of 0.2 mg/kg, the reduction in parasitemia was followed by a temporary resurgence of parasitemia. This second wave of parasitemia cleared without additional 5-fluoroorotate treatment. To radically eliminate P. yoelii from mice and avoid the second wave of parasitemia, a higher dose of 5 mg of 5-fluoroorotate per kg had to be used. In the absence of uridine, repeated doses of 5 mg/kg were toxic to mice, as judged by weight loss, diarrhea, decreased numbers of leukocytes, and increased mortality. However, in the presence of uridine, repeated doses of 5 mg/kg could be used for antimalarial chemotherapy without obvious toxicity. Mice cured with 5-fluoroorotate and uridine were immune to subsequent challenge with a potentially lethal inoculum of P. yoelii.
WIN 57273, a new fluoroquinolone with enhanced in vitro activity versus gram-positive pathogens
Authors: Kaatz G W , Seo S M
Published: June 2012

WIN 57273 is a new fluoroquinolone with excellent in vitro activity versus gram-positive pathogens, including methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis and gentamicin-susceptible and -resistant Enterococcus faecalis. We compared the microdilution MICs and MBCs of this compound to those of other antimicrobial agents for more than 30 clinical isolates of each of these groups of organisms and found that with few exceptions, it was at least 10 times more active than all other drugs tested. Selection for resistance to ciprofloxacin (greater than or equal to 5 micrograms/ml) or WIN 57273 (greater than or equal to 0.16 microgram/ml) by the gradient plate method produced mutants with diminished susceptibility to the other fluoroquinolone; however, the MICs and MBCs of WIN 57273 for such strains were still quite low and remained below the preliminary susceptibility breakpoint (less than or equal to 2 micrograms/ml). Spontaneous mutations conferring resistance to two and five times the WIN 57273 MIC were detectable at low frequencies for S. aureus and S. epidermidis; such mutations were virtually undetectable for E. faecalis. Further testing is necessary to establish if the effectiveness of WIN 57273 is maintained in vivo, first in animals and then in humans with infections caused by methicillin-susceptible and -resistant strains of S. aureus and S. epidermidis or gentamicin-susceptible and -resistant strains of E. faecalis.
In vitro synergy of clindamycin and aminoglycosides against Chlamydia trachomatis
Authors: Pearlman M D , Faro S , Riddle G D , Tortolero G
Published: June 2012

The importance of Chlamydia trachomatis as an etiologic agent in the development of pelvic inflammatory disease (PID) is well documented. Although there are numerous antimicrobial agents that are effective against C. trachomatis, one of the most frequent combinations that is used to treat PID is clindamycin and gentamicin. The efficacy of clindamycin as the sole treatment for chlamydial infections has been questioned. In fact, the Centers for Disease Control (Atlanta, Ga.) has recommended the use of doxycycline following clindamycin and gentamicin treatment of PID confirmed or suspected to be caused by C. trachomatis. This study was designed to determine whether there is any synergistic in vitro activity between clindamycin and gentamicin or tobramycin on inhibition of C. trachomatis replication. In this experiment, the MIC of clindamycin decreased two- to threefold when an aminoglycoside was added. This occurred even though aminoglycosides by themselves had essentially no effect against C. trachomatis. The mechanism of this interaction is uncertain.
In Vitro Susceptibility of
Campylobacter jejuni
to Rokitamycin
Authors: Miyake Yoichiro , Okada Mitsugi , Sasaki Mikiko , Nagasaka Nobuo , Suginaka Hidekazu
Published: June 2012

The susceptibilities of 100 clinical isolates of
Campylobacter jejuni
to rokitamycin, a new macrolide, and eight other oral antibiotics were tested by using a broth microdilution method. Rokitamycin demonstrated antibacterial activity that was higher than those of fosfomycin and the tetracyclines and comparable to those of erythromycin and clindamycin, whereas it was slightly less active than the quinolones.
In vitro inhibition of bacterial DNA gyrase by cinodine, a glycocinnamoylspermidine antibiotic
Authors: Osburne M S , Maiese W M , Greenstein M
Published: June 2012

Cinodine, a broad-spectrum glycocinnamoylspermidine antibiotic, binds to DNA and irreversibly inhibits bacterial and phase DNA synthesis. Cinodine was found to inhibit the activity of Micrococcus luteus DNA gyrase in vitro, but it did not inhibit the activities of two other DNA-binding enzymes, namely, topoisomerase I and BamHI. Although we cannot yet conclude that DNA gyrase is an intracellular target of the drug, in vitro inhibition of the enzyme by cinodine appears to be specific.
Comparative in vitro activity of cefixime against Haemophilus influenzae isolates, including ampicillin-resistant, non-beta-lactamase-producing isolates, from pediatric patients
Authors: Mortensen J E , Himes S L
Published: June 2012

The in vitro activity of cefixime was comparatively tested against 232 non-type b and 102 type b isolates of Haemophilus influenzae derived from clinical specimens of pediatric patients, including 10 non-type b strains that did not produce beta-lactamase and demonstrated resistance to ampicillin. Cefixime was active against the ampicillin-susceptible and ampicillin-resistant, beta-lactamase-producing isolates; however, its activity against some non-beta-lactamase-producing, ampicillin-resistant isolates appeared to be limited.
In vitro cultivation of Cryptosporidium parvum and screening for anticryptosporidial drugs
Authors: McDonald V , Stables R , Warhurst D C , Barer M R , Blewett D A , Chapman H D , Connolly G M , Chiodini P L , McAdam K P
Published: June 2012

Sporozoites of Cryptosporidium parvum which were excysted in vitro from oocysts isolated from calves or patients with acquired immune deficiency syndrome underwent development in monolayers of the mouse fibroblast cell line L929. Asexual multiplication occurred, with the maximum numbers of parasites usually being observed between 24 and 48 h after infection. Gametocytes were also found, but their numbers were relatively small compared with those of the asexual stages. A study was made of the effect on parasite development of 20 antimicrobial agents, most of which were anticoccidial or antimalarial agents. The majority of the drugs had a limited inhibitory effect on parasite development, but usually only at high concentrations. The two most active drugs were monensin and halofuginone, which reduced parasite multiplication by more than 90% at high concentrations. In the case of monensin, however, inhibition of parasite development at higher concentrations was due, at least in part, to a toxic effect of the drug on the host cells.
Genetic diversity of penicillin-binding protein 2 genes of penicillin-resistant strains of Neisseria meningitidis revealed by fingerprinting of amplified DNA
Authors: Zhang Q Y , Jones D M , Sáez Nieto J A , Pérez Trallero E , Spratt B G
Published: June 2012

A 2-kilobase fragment containing the penicillin-binding protein 2 gene (penA) was amplified by using the polymerase chain reaction with DNA prepared from 35 penicillin-resistant strains of Neisseria meningitidis isolated in England, Ireland, and Spain (MICs, 0.16 to 1.28 micrograms of benzylpenicillin per ml) and from 10 penicillin-susceptible strains (MICs, less than or equal to 0.04 micrograms of benzylpenicillin per ml). The penA genes were digested with HpaII or TaqYI; and the resulting fragments were end-labeled, fractionated on a polyacrylamide gel, and autoradiographed, to produce gene fingerprints. The fingerprints of the penA genes of the 10 penicillin-susceptible strains were identical. In contrast, the fingerprints of the penA genes of all but two of the penicillin-resistant strains differed markedly from those of the penicillin-susceptible strains. The altered penA genes of group B penicillin-resistant strains were very diverse, and 14 different fingerprints were found among the 15 strains that we examined. The penA genes of the 19 resistant group C strains were less diverse, and two major fingerprint patterns predominated.
Branched-chain fatty acids produced by mutants of Streptomyces fradiae, putative precursors of the lactone ring of tylosin
Authors: Huber M L , Paschal J W , Leeds J P , Kirst H A , Wind J A , Miller F D , Turner J R
Published: June 2012

Three branched-chain fatty acids (7-hydroxy-4,6-dimethylnona-2,4-dienoic acid [compound 1], its 7-epimer [compound 2], and 7-keto-4,6-dimethylnona-2,4-dienoic acid [compound 3]) and a ketone (9-hydroxy-6,8-dimethylundeca-4,6-dien-3-one [compound 4]) were isolated from the culture broth of mutants of Streptomyces fradiae which were blocked in the biosynthesis of the macrolide antibiotic tylosin. Two phenotypic classes of mutants of this organism which were blocked in the addition of mycaminose to tylactone (compound 6) accumulated these compounds. These compounds were not produced by mutants which were blocked in lactone synthesis, in steps beyond mycaminose addition, or by the wild-type strain. Synthesis of these compounds, like synthesis of tylosin, was inhibited by the addition of cerulenin. Compounds 1, 2, and 3 were partially interconvertible by these mutants; but they were not produced from the degradation of tylactone and they were not directly incorporated into tylosin by intact cells. The structures of compounds 1 and 2 were equivalent to that of a predicted intermediate (S. Yue, J. S. Duncan, Y. Yamamoto, and C. R. Hutchinson, J. Am. Chem. Soc. 109:1253-1255, 1987) in the biosynthesis of tylactone. The ketone (compound 4) reported previously (N. D. Jones, M. O. Chaney, H. A. Kirst, G. M. Wild, R. H. Baltz, R. L. Hamill, and J. W. Paschal, J. Antibiot. 35:420-425, 1982) appears to be the decarboxylation product of the intermediate following that represented by compound 1. This represents the first report of the isolation of putative precursors of tylactone from tylosin-producing organisms.
SCH-39304 in prevention and treatment of disseminated candidiasis in persistently granulocytopenic rabbits
Authors: Walsh T J , Lee J W , Lecciones J , Kelly P , Peter J , Thomas V , Bacher J , Pizzo P A
Published: June 2012

To investigate the potential use of SCH-39304 for the prevention and treatment of disseminated candidiasis in granulocytopenic patients, we studied its in vivo antifungal activity as preventive, early, and late treatments in three models (acute, subacute, and chronic) of disseminated candidiasis in persistently granulocytopenic rabbits. SCH-39304 was an effective as amphotericin B alone and fluconazole alone for the prevention of disseminated candidiasis. SCH-39304 alone and fluconazole alone were as effective as amphotericin B plus flucytosine for early treatment of subacute disseminated candidiasis. When treatment was delayed for 5 days to establish chronic disseminated candidiasis, SCH-39304 was less effective than amphotericin B plus flucytosine. In comparison with different treatment regimens, SCH-39304 was more effective in early and preventive treatment. Thus, SCH-39304 was comparable to treatment control regimens in prevention and early treatment of subacute disseminated candidiasis. SCH-39304 also was most effective in granulocytopenic rabbits with disseminated candidiasis when used for prevention or early treatment.
Emergence of 4',4"-aminoglycoside nucleotidyltransferase in enterococci
Authors: Carlier C , Courvalin P
Published: June 2012

Enterococcus faecium BM4102 was resistant to macrolide-lincosamide-streptogramin B-type (MLS) antibiotics; tetracycline-minocycline; and high levels of kanamycin, neomycin, tobramycin, and dibekacin but not gentamicin. This aminoglycoside resistance phenotype is new in enterococci. The genes conferring resistance to aminoglycosides and MLS antibiotics in this strain were carried on a plasmid, pIP810, that was self-transferable to to other Enterococcus strains. Resistance to tobramycin and structurally related aminoglycosides, kanamycin, neomycin, and dibekacin, was due to synthesis of a 4',4"-aminoglycoside nucleotidyltransferase. Homology was detected by hybridization between pIP810 DNA and a probe specific for a gene encoding an enzyme with identical site specificity in staphylococci. The bacteriostatic activity of amikacin apparently was not affected by the presence of the enzyme, although it was modified in vitro. However, the bactericidal activity of amikacin and the synergism of this aminoglycoside with penicillin were abolished.
Safety and prophylactic efficacy of low-dose rimantadine in adults during an influenza A epidemic
Authors: Brady M T , Sears S D , Pacini D L , Samorodin R , DePamphilis J , Oakes M , Soo W , Clements M L
Published: June 2012

A placebo-controlled, double-blind study to evaluate the safety and prophylactic efficacy of a low dose (100 mg) of rimantadine hydrochloride against naturally occurring influenza in adults was conducted at two sites. After the onset of the influenza season, volunteers (ages, 18 to 55 years) were assigned randomly to receive rimantadine or placebo daily. Subjects were monitored for adverse effects and evidence of influenza virus infection weekly for six weeks. Only 10 (8.7%) of 114 rimantadine recipients and 5 (4.4%) of 114 placebo control recipients reported one or more mild to moderate adverse symptoms, most of which were related to the gastrointestinal or central nervous system. Compared with placebo, low-dose rimantadine was highly effective in the prevention of influenza A virus infection (20 of 110 versus 7 of 112 participants; P less than 0.01) and influenza illness (7 of 110 versus 1 of 112 participants; P = 0.04). Influenza A/Leningrad/87-like (H3N2) virus was recovered from the nasopharynxes of only five placebo recipients. These findings indicate that low-dose rimantadine is well tolerated and highly effective for the prevention of influenza A illness in healthy adults.
Metabolic N-hydroxylation of pentamidine in vitro
Authors: Berger B J , Lombardy R J , Marbury G D , Bell C A , Dykstra C C , Hall J E , Tidwell R R
Published: June 2012

By using high-performance liquid chromatography, the in vitro conversion of pentamidine to the corresponding amidoximes (N-hydroxypentamidine and N,N'-dihydroxypentamidine) was studied in supernatants of rat liver homogenate centrifuged at 9,000 x g. The presence of the two amidoxime peaks in chromatograms was confirmed by liquid secondary ion mass spectrometry and by unequivocal synthesis of the suspected metabolites. The metabolic reactions were found to be catalyzed by the cytochrome P-450 system (mixed-function oxidases). The formation of the monohydroxylated product was found to have a Km of 0.48 mM and a Vmax of 29.50 pmol/min per mg of protein, while the dihydroxylated metabolite had a Km of 0.73 mM and a Vmax of 4.10 pmol/min per mg of protein. N,N'-Dihydroxypentamidine was found to have highly reduced antiprotozoal activity in vitro relative to that of pentamidine, and neither of the hydroxylated metabolites nor pentamidine was found to be significantly mutagenic by the Ames test. Contrary to previous reports, pentamidine is readily metabolized to at least two hydroxylated products, and this conversion may be relevant to the clinical use of the compound and to future drug design.
Trypanosoma cruzi proliferation and differentiation are blocked by topoisomerase II inhibitors
Authors: Gonzales-Perdomo M , de Castro S L , Meirelles M N , Goldenberg S
Published: June 2012

Bacterial topoisomerase II inhibitors (ofloxacin and its commercial derivative Tarivid, nalidixic acid, and novobiocin) were tested as blockers of Trypanosoma cruzi differentiation and proliferation. The transformation of either epimastigotes into metacyclic trypomastigotes or amastigotes into trypomastigotes was inhibited by the drugs in a dose-dependent manner. The inhibition of epimastigote differentiation was also dependent on the time of drug addition to the medium. Proliferation of T. cruzi was also blocked in a dose-dependent manner by the drugs, with the exception of novobiocin, which did not inhibit epimastigote replication and resulted in cell lysis when it was used at high concentrations. On the other hand, the transformation of amastigotes into epimastigotes in axenic culture was not inhibited; this process did not require either kinetoplast (mitochondrial) DNA replication or changes in the DNA network organization. Electron microscopy of cells treated with Tarivid (ofloxacin) showed damage to the kinetoplast, suggesting that this organelle might be the target of the drug. These results indicate that a bacterial-like topoisomerase II plays an important role in T. cruzi proliferation and differentiation.
Clinical isolate of a porinless Salmonella typhi resistant to high levels of chloramphenicol
Authors: Toro C S , Lobos S R , Calderón I , Rodríguez M , Mora G C
Published: June 2012

We studied a clinical isolate of Salmonella typhi (strain 1895) characterized by resistance to 200 micrograms of chloramphenicol per ml despite the absence of chloramphenicol-inactivating activity. The outer membrane protein profile analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated a deficiency of one of the major protein species which may serve as a porin for entry of chloramphenicol. When the strain was transformed with a plasmid encoding chloramphenicol acetyltransferase, chloramphenicol added to the culture was not inactivated, suggesting a drastic reduction of permeability towards the drug. Moreover, transformants bearing a plasmid coding for the Escherichia coli OmpF porin became considerably more susceptible to chloramphenicol (40 micrograms/ml). On the other hand, transformants carrying a plasmid encoding the Salmonella typhi ompC gene remained as resistant to the drug as the parental strain, even though they overexpressed OmpC. These findings indicate that the lack of OmpF plays a major role in the resistance to chloramphenicol in strain 1895.
Influence of antacid and ranitidine on the pharmacokinetics of oral cefetamet pivoxil
Authors: Blouin R A , Kneer J , Ambros R J , Stoeckel K
Published: June 2012

The purpose of this investigation was to assess the influence that treatment with antacid and ranitidine had on the pharmacokinetics of oral cefetamet pivoxil in 18 healthy male volunteers. Each subject received, in an open-labeled, randomized, three-way crossover design, a single oral dose of 1,000 mg (two tablets) of cefetamet pivoxil 10 min after a standard breakfast during each of the following treatments: treatment A, control period; treatment B, antacid (80 ml of suspension; Maalox 70) administered on the evening before cefetamet pivoxil dosing (-12.5 h) and again 2 h before and 2 h after a standard breakfast; treatment C, ranitidine (150 mg) administered twice a day for 4 days and again 1 h and 10 min prior to cefetamet pivoxil dosing. Plasma and urine samples were collected over a 24-h period following cefetamet pivoxil administration. Cefetamet was analyzed by high-performance liquid chromatography. Oral bioavailability parameters (area under the concentration-time curve from 0 to 12 h, area under the concentration-time curve from 0 h to infinity, time to maximum concentration of drug in plasma, and maximum concentration of drug in plasma) were obtained by noncompartmental techniques. The results showed that none of these bioavailability parameters was significantly (P greater than 0.05) affected by antacid or rantidine coadministration. A compartmental analysis showed no significant differences. In addition, the terminal elimination half-life and the fraction of cefetamet excreted unchanged in the urine was also not significantly (P greater than 0.05) affected by antacid or ranitidine exposure. Relatively wide intrasubject variability was observed for time to maximum concentration of drug in plasma and terminal elimination half-life in several of the 18 subjects studied. Although these irregularities did not appear to be strongly associated with a particular treatment, they increased in subjects in both the antacid and H2-receptor antagonist treatment groups compared with those in subjects in the control treatment group. We conclude that antacid and ranitidine treatment likely does not alter the bioavailability of oral cefetamet pivoxil.
New norfloxacin resistance gene in Pseudomonas aeruginosa PAO
Authors: Fukuda H , Hosaka M , Hirai K , Iyobe S
Published: June 2012

A new type of norfloxacin-resistant mutant of Pseudomonas aeruginosa PAO was isolated. This mutant showed cross resistance to imipenem and chloramphenicol and hypersusceptibility to beta-lactam and aminoglycoside antibiotics. The new norfloxacin resistance gene nfxC was mapped near catA (46 min) on the PAO chromosome. Norfloxacin accumulation was decreased in the nfxC mutant; furthermore, the rate of imipenem diffusion through the outer membrane of the nfxC mutant was lower than that of the parent strain. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of outer membrane proteins showed a decrease of a 46-kilodalton protein and an increase of a 50-kilodalton protein in the nfxC mutant. We conclude the nfxC is a new norfloxacin resistance gene that affects outer membrane permeability to quinolones and other antimicrobial agents.
Insertional inactivation of the mec gene in a transposon mutant of a methicillin-resistant clinical isolate of Staphylococcus aureus
Authors: Matthews P , Tomasz A
Published: June 2012

All clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) examined so far contain the mec gene and its product, the penicillin-binding protein (PBP) 2A. Yet the same strains show tremendous variation in the phenotypic expression of antibiotic resistance (MIC), which is under the control of a set of additional, auxiliary genes. Thus, the quantitative contribution of the mec gene to the resistance phenotype of MRSA is not known, and no mutants with the lesion located within the mec gene have been described. We subjected a highly resistant MRSA strain to transposon mutagenesis with the erythromycin resistance transposon Tn551, and a mutant expressing greatly decreased methicillin resistance (RUSA4) was selected to characterize the transposon insertion site. The results indicate that the Tn551 insertion site in mutant RUSA4 is between base pairs 1000 and 1400 of the sequence encoding PBP 2A. Thus, the uniform and greater than 200-fold drop in the methicillin MIC (4 micrograms/ml) for this mutant relative to that for the parent strain (MIC greater than or equal to 800 micrograms/ml) must be related to the inactivation of the PBP 2A gene. The results provide the first unequivocal evidence for the importance of PBP 2A as a quantitative contributor to the MIC for MRSA.
In vitro activities of 15 oral beta-lactams against Klebsiella pneumoniae harboring new extended-spectrum beta-lactamases
Authors: Kitzis M D , Liassine N , Ferré B , Gutmann L , Acar J F , Goldstein F
Published: June 2012

The activities of 15 oral beta-lactams against Klebsiella pneumoniae harboring new extended-spectrum beta-lactamases were studied. All compounds were affected by these enzymes, especially by the SHV derivatives. Except for ceftibuten, the compounds with the greatest intrinsic activity were more affected by the presence of these enzymes than were older compounds with moderate intrinsic activity.
Comparative in vitro activities of newer quinolones against Pseudomonas species and Xanthomonas maltophilia isolated from patients with cancer
Authors: Rolston K V , Messer M , Ho D H
Published: June 2012

The in vitro susceptibilities of three Pseudomonas species (Pseudomonas aeruginosa, Pseudomonas putida, and Pseudomonas fluorescens) and Xanthomonas maltophilia to quinolone antimicrobial agents were determined. Several newer agents, particularly PD117558, PD117596, PD127391, sparfloxacin (AT-4140), A-56620, and temafloxacin, were active against Pseudomonas species. X. maltophilia isolates were generally less susceptible than were Pseudomonas isolates but were inhibited by some of the newer quinolones.
In vitro activity of ciprofloxacin in combination with ceftazidime, aztreonam, and azlocillin against multiresistant isolates of Pseudomonas aeruginosa
Authors: Bustamante C I , Wharton R C , Wade J C
Published: June 2012

The combinations of ciprofloxacin plus ceftazidime, ciprofloxacin plus aztreonam, and ciprofloxacin plus azlocillin were evaluated for the presence of synergy against multiresistant isolates of Pseudomonas aeruginosa. The frequency of synergy was dependent on antibiotic susceptibilities. If the organism was resistant to ciprofloxacin, synergy was observed in more than 50% of the isolates; however, if the organism was resistant to the beta-lactam (with the exception of ceftazidime), synergy was generally observed in less than 10% of the isolates. Antagonism was not observed with any of the combinations. These results may be helpful in making clinical decisions in treating P. aeruginosa infections.
In vitro activity of dirithromycin (LY 237216) compared with activities of other macrolide antibiotics
Authors: Yu K W , Neu H C
Published: June 2012

Dirithromycin inhibited Streptococcus pyogenes, Streptococcus pneumoniae, and other hemolytic streptococci at concentrations of less than or equal to 0.03 to 0.12 micrograms/ml, with 90% inhibition at 0.12 micrograms/ml, which is comparable to results using erythromycin. Group A streptococci, listeriae, and enterococci resistant to erythromycin were resistant to dirithromycin. Erythromycin-susceptible staphylococci were inhibited by 0.5 micrograms/ml, but for erythromycin-resistant isolates MICs were greater than or equal to 8 micrograms/ml. For Haemophilus influenzae, MICs were greater than or equal to 8 micrograms/ml, two- to fourfold greater than for erythromycin. The activity of dirithromycin against staphylococci and streptococci was not decreased by the addition of human serum.
Antistaphylococcal activities of sparfloxacin (CI-978; AT-4140), ofloxacin, and ciprofloxacin
Authors: Chaudhry A Z , Knapp C C , Sierra-Madero J , Washington J A
Published: June 2012

The activity of sparfloxacin (CI-978; AT-4140) was compared with those of ofloxacin and ciprofloxacin against clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis. All 10 ciprofloxacin-resistant staphylococci had reduced susceptibility to sparfloxacin and ofloxacin. Against 105 ciprofloxacin-susceptible strains of S. aureus, the sparfloxacin MIC for 90% of strains tested was at least fourfold lower than those of ciprofloxacin and ofloxacin, while against 104 ciprofloxacin-susceptible strains of S. epidermidis, the MIC of sparfloxacin for 90% of strains tested was twofold lower than that of ciprofloxacin and fourfold lower than that of ofloxacin. MBCs of sparfloxacin were less than or equal to 4 x MICs. The effects of inoculum size and pH variations, as well as the presence of serum, on the MICs of sparfloxacin were minimal. Subinhibitory concentrations of sparfloxacin did reduce adherence of S. epidermidis.
Properties of plasmids responsible for production of extended-spectrum beta-lactamases
Authors: Jacoby G A , Sutton L
Published: June 2012

The extended-spectrum beta-lactamases are believed to arise by mutations which alter the configuration around the active site of TEM- and SHV-type enzymes so as to increase their efficiency with otherwise nonhydrolyzable cephalosporins and monobactams. This hypothesis predicts that the genes for these new enzymes should be found on the same wide variety of plasmids that encode TEM-1, TEM-2, and SHV-1 beta-lactamases and that at least some of them should be mediated by transposons. Fifteen plasmids, each encoding an extended-spectrum beta-lactamase, were examined. Unlike the average TEM plasmid, all were large, ranging in size from 80 to 300 kb. All determined resistance to multiple antimicrobial agents, ranging from 5 to 11, and some conferred resistance to heavy metals and UV radiation as well. The plasmids belonged to a limited number of incompatibility (Inc) groups, including IncC, IncFI, IncHI2, and IncM. Because most of the mutations giving rise to extended-spectrum activity are G.C----A.T transitions and some of the mutant genes have as many as four base substitutions, a plasmid-determined mutator gene was searched for, but no such property was found. Several techniques were used to detect transposition of the extended-spectrum beta-lactamase genes, but a mobile genetic element could not be demonstrated even though eight of the plasmids hybridized with a DNA probe derived from the tnpR gene of Tn3. The genesis of extended-spectrum beta-lactamases may not be as simple as has been supposed.
Identification of a methicillin-resistant strain of Staphylococcus caprae from a human clinical specimen
Authors: Kanda K , Suzuki E , Hiramatsu K , Oguri T , Miura H , Ezaki T , Yokota T
Published: June 2012

The analysis of gel banding patterns of penicillin-binding proteins was used to identify two clinical isolates of a coagulase-negative Staphylococcus species as Staphylococcus caprae, a species originally isolated from goat's milk. One of the isolates was further shown to carry mecA, the structural gene for methicillin resistance.
Contribution of the cell-surface-associated enzyme in the Zimmermann-Rosselet assay of outer membrane permeability of beta-lactam antibiotics
Authors: Liu W , Nikaido H
Published: June 2012

Analysis of beta-lactam hydrolysis by intact cells of several strains of enteric bacteria suggests that a significant fraction of beta-lactamase molecules is present at a location directly accessible for the substrates in the medium. We propose a method to correct for the error introduced by these "surface-exposed" enzymes in the Zimmermann-Rosselet assay of outer membrane permeability.