bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and plasma bactericidal activity of aztreonam in low-birth-weight infants
Authors: Likitnukul S , McCracken G H , Threlkeld N , Darabi A , Olsen K
Published: June 2012

Aztreonam (30 mg/kg) was administered intravenously every 12 h during week 1 and every 8 h during weeks 2 to 4 of life to 26 low-birth-weight (less than 2,000 g) infants, and plasma concentration-time curves were measured on two occasions. The pharmacokinetics were described equally well by one-compartment and noncompartment models, and the values on day 1 were similar to those measured during the steady state on days 3 to 6. The mean peak plasma concentrations at completion of the 10-min infusion were from 65 to 83 micrograms/ml, the higher concentrations being seen in the larger infants. The half-lives of aztreonam ranged from 5.4 to 8.6 h and did not change significantly with birth weight. The median peak and trough plasma bactericidal titer against a strain of Escherichia coli (MBC, 10 micrograms/ml) was 1:16. Against a strain of Pseudomonas aeruginosa (MBC, 16 micrograms/ml), the median peak and trough bactericidal titers were 1:8 to 1:16 and 1:4, respectively. The urinary concentrations of aztreonam on day 1 of therapy were from 24 to 460.7 micrograms/ml (mean +/- 1 standard deviation, 254 +/- 113 micrograms/ml).
Prospective randomized controlled study of ciprofloxacin versus imipenem-cilastatin in severe clinical infections
Authors: Lode H , Wiley R , Höffken G , Wagner J , Borner K
Published: June 2012

In a randomized prospective study, 66 patients with serious bacterial infections--mainly lower respiratory tract infections--were treated with either imipenem plus cilastatin (32 patients) or ciprofloxacin (34 patients); 30 patients in each group were evaluable for efficacy. Substantial underlying disease was present in most of the patients; pathogens isolated prior to treatment (77 isolates) consisted mainly of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and streptococci. Of the etiologic bacteria, 67% were eradicated by ciprofloxacin treatment and 79% by imipenem therapy; however, two patients (6.7%) failed in the ciprofloxacin group, and six patients (20%) did not respond to imipenem treatment (P = 0.25). All patients with therapeutic failures suffered from severe fatal underlying diseases, which had substantial impact on the outcome of treatment. Therapeutic drug monitoring in the ciprofloxacin patients revealed higher concentrations in serum at days 4 and 8 in comparison with day 1 of treatment, indicating that steady-state conditions were reached between days 1 and 4. The total number of side effects was relatively high--eight imipenem patients (25%) and six ciprofloxacin patients (18%) had reactions. Treatment had to be discontinued due to adverse reactions for three ciprofloxacin patients and two imipenem patients. Major side effects in both groups were gastrointestinal and central nervous system-related symptoms. In terms of clinical and bacteriological efficacy and safety, there was no statistical difference between the two groups, and both groups gave good to excellent results for bacterial infections that were difficult to treat.
Comparative activity of CGP 31608, nafcillin, cefamandole, imipenem, and vancomycin against methicillin-susceptible and methicillin-resistant staphylococci
Authors: Sachdeva M , Hackbarth C , Stella F B , Chambers H F
Published: June 2012

The activity of CGP 31608 for 53 strains of Staphylococcus aureus and 48 strains of S. epidermidis, both methicillin susceptible and resistant, was compared with that of vancomycin, nafcillin, cefamandole, and imipenem. Microdilution MICs were determined in Mueller-Hinton broth with or without 2.5% NaCl at an inoculum of 3 x 10(5) CFU/ml with a 20-h, 37 degrees C incubation. The MICs of imipenem and CGP 31608 for methicillin-resistant strains were lower than the MICs of nafcillin or cefamandole for these strains; these differences diminished in the presence of 2.5% NaCl. Subpopulations were detected in strains of methicillin-resistant S. aureus and S. epidermidis that were resistant to all the beta-lactam antibiotics tested at 5 micrograms/ml. This resistant subpopulation produced progeny that were uniformly resistant to high concentrations of each of the beta-lactams.
Comparison of four antiseptic products containing chlorhexidine gluconate
Authors: Larson E L , Laughon B E
Published: June 2012

The purpose of this study was to compare the antimicrobic efficacies of four formulations of chlorhexidine gluconate (CHG) for handwashing under frequent-use conditions. Fifty volunteers were assigned by block randomization to one of five products: one of two liquid detergents containing 4% CHG, a liquid detergent containing 2% CHG, a foam containing 4% CHG, and a nonantiseptic soap (control). Subjects washed their hands by a standardized technique 15 times per day for 5 days. After days 1 and 5 of handwashing, there was a significant reduction in log CFU for subjects using all four CHG-containing products compared with subjects using control soap and for subjects within each group after days 1 and 5 compared with the base-line CFU counts (all P less than 0.05). There were no significant differences between the four CHG products at any testing time. We conclude that all four formulations are satisfactory for clinical use.
Pharmacokinetics of cefpiramide in volunteers with normal or impaired renal function
Authors: Conte J E
Published: June 2012

The pharmacokinetics of a single 2.0-g intravenous dose of cefpiramide in patients with normal or impaired renal function were studied. Serial concentrations in serum and urine were measured by using high-performance liquid chromatography, and the effect of the concentration in serum on protein binding was assessed. Thirty patients (ten with creatinine clearances of greater than 80 ml/min, ten with creatinine clearances between 10 and 80 ml/min, and ten on dialysis) were studied. The concentration-time curve of cefpiramide was best described by an open two-compartment model. The elimination half-lives in patients with normal or impaired renal function or those on dialysis were 5.41 +/- 1.44, 8.3 +/- 2.82, and 8.38 +/- 4.06 h, respectively, and the serum clearances in the same groups were 2.0 +/- 0.84, 1.29 +/- 0.45, and 2.04 +/- 1.10 liters/h, respectively. There were no significant differences in any of the parameters among the three groups of patients. In patients with normal or impaired renal function, protein binding varied between 93.0 +/- 1.3% at 304.4 micrograms/ml and 99.3 +/- 0.8% at 41.1 micrograms/ml and was linearly and inversely related to the cefpiramide concentration in serum. In patients on dialysis, protein binding was significantly lower (P less than 0.05) and varied between 88.5 +/- 7.1% at 173.4 micrograms/ml to 94.9 +/- 4.8% at 46.8 micrograms/ml. In patients with normal or abnormal renal function, renal cefpiramide clearance decreased linearly with declining renal function, whereas plasma clearance was maintained. Therefore, nonrenal elimination becomes more important as renal impairment progresses.
Pharmacokinetics of teicoplanin in critically ill patients with various degrees of renal impairment
Authors: Domart Y , Pierre C , Clair B , Garaud J J , Regnier B , Gibert C
Published: June 2012

The pharmacokinetics of teicoplanin were studied in 15 adult patients in the acute phase of severe infections caused by gram-positive cocci. All the subjects were given a daily intravenous bolus dose of 6 mg of teicoplanin kg-1 (body weight). The pharmacokinetic study was performed over a 48-h period after injection 4. The subjects were categorized according to their mean creatinine clearances (ml.min-1.kg-1) during the study period: group 1 (n = 3), greater than 1.6; group 2 (n = 6), 0.8 to 1.6; and group 3 (n = 6), 0.15 to 0.8. Mean concentrations of teicoplanin in serum at 1, 24, and 48 h were 33 +/- 8, 9 +/- 3, and 6 +/- 2.5 micrograms.ml-1, respectively. The mean half-lives of the concentration-time curve from 12 to 48 h were 28 +/- 4, 44 +/- 24, and 48 +/- 14 h in groups 1, 2, and 3, respectively (group 3 versus group 1: P less than 0.05). The mean area under the serum concentration-time curve from time zero to 24 h was 344 +/- 92 mg.h.liter-1, and the mean hybrid volume of distribution was 1.09 +/- 0.46 liter.kg-1. These values were similar for the three groups, with a trend for larger areas under the curve in group 3. Creatinine clearance correlated directly with the total body clearance of teicoplanin (r = 0.70) and with the renal clearance of teicoplanin (r = 0.82). However, in critically ill patients, the wide interindividual variations in pharmacokinetic parameters are more relevant than those related to the variations in renal function when creatinine clearance is above 0.30 ml.min-1.kg-1. We concluded that, in such conditions, monitoring of concentrations of teicoplanin in serum is mandatory.
In vitro activity of ciprofloxacin against aerobic bacteria isolated in a southern European hospital
Authors: Cornaglia G , Pompei R , Dainelli B , Satta G
Published: June 2012

The activity of ciprofloxacin was evaluated against 1,204 isolates freshly isolated in Southern Europe, including 193 isolates of 10 species never studied before. Ciprofloxacin proved more active than other quinolones and very active in absolute terms against the 10 new species and showed against the other species an activity close to that reported for isolates from other geographic areas.
Recovery of pefloxacin in saliva and feces and its action on oral and fecal floras of healthy volunteers
Authors: Janin N , Meugnier H , Desnottes J F , Woehrle R , Fleurette J
Published: June 2012

Pefloxacin, a new fluoroquinolone, was given to 10 volunteers in single 400-mg oral doses repeated at 12-h intervals during 7 days. Serum, saliva, and feces samples were collected before and at appropriate intervals after the initiation of treatment. Drug concentrations were determined by bioassay. Qualitative and quantitative analyses of the saliva and fecal floras were performed. Mean concentrations in saliva (3.46 micrograms/ml on day 1 and 7.54 micrograms/ml on day 7) were closely related to levels in serum. High concentrations of pefloxacin were found in the feces (645 micrograms/g on day 8). No modification of oral flora was observed. In the fecal flora, members of the family Enterobacteriaceae were eliminated between days 2 and 8. The alterations in streptococci and anaerobic flora were not significant; Bacteroides fragilis was more resistant to pefloxacin after treatment. Clostridium difficile was not detected, and there was no overgrowth by yeasts. No side effects were observed.
DNA probes for identification of tetracycline resistance genes in Campylobacter species isolated from swine and cattle
Authors: Ng L K , Stiles M E , Taylor D E
Published: June 2012

Tetracycline-resistant strains of Campylobacter jejuni and Campylobacter coli from swine and cattle colons were isolated and characterized by hybridization with DNA probes. A probe consisting of the 1.8-kilobase (kb) HincII fragment from pUA466 was highly specific for the detection of tetracycline resistance (Tcr) in C. jejuni and C. coli. The 5-kb tetM DNA probe from Streptococcus agalactiae plasmid pJI3 which has homology with the 1.8-kb HincII fragment from pUA466 could also be used to detect Tcr Campylobacter strains. However, the tetM probe had a much lower sensitivity and required a lower stringency of hybridization. Therefore, the 1.8-kb HincII fragment appeared to be more appropriate for the classification of Tcr in Campylobacter spp. No homology was detected between the Tcr determinant from Campylobacter spp. and the tetL and tetN probes from Streptococcus spp. DNA homology was demonstrated between pUA649, a derivative of plasmid pUA466 which had lost most of the Tcr region, and Tcr plasmids from C. jejuni and C. coli isolated from animal and human sources. There was also homology between pUA649 and the chromosomes of C. jejuni and C. coli strains. In this study, all but one of the tetracycline-resistant C. coli and C. jejuni strains contained plasmids of approximately 50 kb which hybridized with the 1.8-kb HincII probe. In one C. coli strain (UA703), Tcr appeared to be chromosomally mediated.
Penetration of sulbactam and ampicillin into cerebrospinal fluid of infants and young children with meningitis
Authors: Foulds G , McBride T J , Knirsch A K , Rodriguez W J , Khan W N
Published: June 2012

Infusions of 50 mg of sulbactam per kg per day and 400 mg of ampicillin per kg per day in divided doses to infants and children with bacterial meningitis produced levels in cerebrospinal fluid approximately one-third those in serum. Concentrations in cerebrospinal fluid of 5.5 micrograms of sulbactam per ml and 16.0 micrograms of ampicillin per ml declined within a few days of therapy to 1.9 microgram of sulbactam per ml and 5.2 micrograms of ampicillin per ml.
Effects of temperature, NaCl, and methicillin on penicillin-binding proteins, growth, peptidoglycan synthesis, and autolysis in methicillin-resistant Staphylococcus aureus
Authors: Madiraju M V , Brunner D P , Wilkinson B J
Published: June 2012

Methicillin-resistant Staphylococcus aureus strains produce a fifth penicillin-binding protein (PBP), PBP 2', with low affinity for beta-lactam antibiotics that is believed to represent a beta-lactam-insensitive peptidoglycan transpeptidase. In an effort to evaluate the adequacy of PBP 2' as an explanation of methicillin resistance, PBP 2' production and the responses of growth and peptidoglycan synthesis to methicillin under different environmental conditions have been compared. In the heterogeneous methicillin-resistant strain DU4916-K7, less PBP 2' was produced at 40 degrees C than at 30 degrees C, but inclusion of 5% (wt/vol) NaCl in the medium at 40 degrees C boosted PBP 2' production and allowed growth of the organism in the presence of 10 micrograms of methicillin per ml. When exponential-phase cultures were challenged with methicillin, growth and peptidoglycan synthesis were much more resistant at 30 degrees C than at 40 degrees C. Inclusion of NaCl in medium rendered growth and peptidoglycan synthesis more methicillin resistant at 40 degrees C. Hence, there was a good correlation between PBP 2' production and methicillin-resistant peptidoglycan synthesis under these conditions. However, PBP 2' production was increased by NaCl at 30 degrees C without markedly affecting the susceptibilities of growth and peptidoglycan synthesis to methicillin. Pregrowth of cells with methicillin, which was expected to boost PBP 2' production, seemed to increase the susceptibilities of growth and peptidoglycan synthesis to methicillin. Patterns of growth and peptidoglycan synthesis susceptibilities to methicillin which were similar to those described above were found in chloramphenicol-inhibited cultures, in which presumably no induction of PBP 2' could occur during the methicillin challenge period. Complex effects were noted in the combination of subinhibitory methicillin and NaCl. Growth of cells in the presence of NaCl stimulated their autolytic activity, which was further increased by growth with subinhibitory methicillin in addition to NaCl. It appears that NaCl enhances methicillin resistance by stimulating PBP 2' production and providing osmotic support but opposes it by stimulating autolytic activity which is exacerbated by the very low cross-linking of peptidoglycan in methicillin-resistant strains grown in the presence of methicillin.
Isolation and characterization of DNA-dependent RNA polymerase III from Leishmania mexicana and inhibition by purine analogs
Authors: Nolan L L , Fehr T F
Published: June 2012

A DNA-dependent RNA polymerase has been isolated and characterized from the parasitic flagellated protozoan Leishmania mexicana. The initial stages of purification utilized high-ionic-strength extraction and protamine sulfate treatment. The enzyme was further purified by differential elution by heparin-Sepharose, DEAE-Sephadex, and carboxymethyl-Sephadex chromatography. Analysis of the chromatographically purified RNA polymerase on nondenaturing gels revealed two electrophoretic forms. The enzyme isolated had characteristics of true DNA-dependent RNA polymerase since it required DNA and all four nucleoside triphosphates for synthesis of RNase-sensitive products. Analysis of ammonium sulfate and metal ion optima, as well as relative activities of the enzyme with Mn2+ versus Mg2+, gave results similar to those reported for other RNA polymerase IIIs in eucaryotes. Formycin A triphosphate was found to be a noncompetitive inhibitor of RNA polymerase III, and cordycepin triphosphate was found to be inhibitory, although the exact mode of inhibition was not determined.
Bactericidal interactions of a beta-lactam and beta-lactamase inhibitors in experimental Pseudomonas aeruginosa endocarditis caused by a constitutive overproducer of type Id beta-lactamase
Authors: Bayer A S , Selecky M , Babel K , Hirano L , Yih J , Parr T R
Published: June 2012

We investigated the in vitro and in vivo effects of a combination of a beta-lactam (ceftazidime) and a beta-lactamase inhibitor (dicloxacillin) to synergistically kill a ceftazidime-resistant variant, Pseudomonas aeruginosa PA-48, which overproduces type Id cephalosporinase constitutively. In vitro, dicloxacillin plus ceftazidime exerted bactericidal synergy at approximately 10(5) CFU/ml of inoculum (but not at approximately 10(7)-CFU inoculum), whereas other beta-lactamase inhibitors (sulbactam, clavulanic acid) showed no enhanced killing of PA-48 when combined with ceftazidime at clinically achievable levels for each agent. Dicloxacillin was a potent competitive inhibitor of the extracted Id cephalosporinase from strain PA-48 in short-term comixture studies (less than 10 min [Ki = 2 nM]); in contrast, longer-term comixture studies (90 min) indicated that dicloxacillin functions as a competitive substrate for the enzyme. Growth of PA-48 cells in the presence of dicloxacillin (12.5 to 100 micrograms/ml) had no significant effect on the production rates or functional activity of the Id enzyme. In experimental aortic valve endocarditis due to the ceftazidime-resistant variant (PA-48), rabbits received either no therapy, ceftazidime (25 mg/kg intramuscularly, every 4 h), or ceftazidime plus dicloxacillin (200 mg/kg intramuscularly, every 4 h). The combination regimen reduced mean bacterial densities of PA-48 within cardiac vegetations significantly below those in the other groups at both days 3 and 6 of treatment (P less than 0.005). However, mean vegetation bacterial densities remained greater than 6 log10 CFU/g in the combined treatment group. This modest in vivo synergistic effect (as compared to striking in vitro synergy at approximately 10(5)-CFU inoculum) most likely reflects the high densities of PA-48 achieved in vivo within cardiac vegetations (greater than 8 log10 CFU/g).
Effects of antacids and dialysate dwell times on multiple-dose pharmacokinetics of oral ciprofloxacin in patients on continuous ambulatory peritoneal dialysis
Authors: Golper T A , Hartstein A I , Morthland V H , Christensen J M
Published: June 2012

Six stable patients on continuous ambulatory peritoneal dialysis were evaluated for the appearance of ciprofloxacin in their peritoneal dialysate following oral ingestion of 750 mg of the drug every 12 h for four doses. Three subjects participated in this study twice, once while taking and once while abstaining from phosphate-binding aluminum antacids. Subjects tolerated the medication without evidence of toxicity. Food may have delayed or decreased the absorption of ciprofloxacin, whereas antacids definitely decreased the absorption of the drug. Peak concentrations in serum noted in the absence of antacids ranged from 2.9 to 6.4 micrograms/ml, and peak concentrations in dialysate in the absence of antacids ranged from 1.8 to 4.5 micrograms/ml. Peak ciprofloxacin concentrations in serum achieved in subjects taking antacids were 14 to 50% of those achieved in subjects without antacids. The peak concentrations in dialysate achieved in subjects on antacids were 8 to 33% of those observed in subjects off antacids. The clearance of ciprofloxacin by continuous ambulatory peritoneal dialysis represented 2% of the total body (systemic) clearance. Simultaneous ratios of concentration in dialysate to concentration in serum (D/S) were determined at various durations of dialysate dwelling within the peritoneum. A progressive rise of the D/S ratio was noted as dwell time increased. At 4 h D/S was 0.57 +/- 0.07 (mean +/- standard error of the mean; n = 9), and at 8 h it was 0.75 +/- 0.04 (n = 26). Long-dwell exchanges may be necessary to achieve reasonable concentrations of orally ingested ciprofloxacin in dialysate.
Influence of hydrocortisone succinate on intrarenal accumulation of gentamicin in endotoxemic rats
Authors: Bergeron M G , Bergeron Y , Beauchamp D
Published: June 2012

Gentamicin is a commonly used antibiotic in the treatment of gram-negative infections including septicemia and pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy and may lead to endotoxemic shock. Steroids such as hydrocortisone are generally recommended in the treatment of endotoxemic shock. There are very limited data on the influence of endotoxin or corticosteroids on the pharmacology of antibiotics, especially aminoglycosides, which are nephrotoxic. We studied the influence of both Escherichia coli endotoxin and hydrocortisone succinate on the renal uptake of gentamicin in rats. Animals were injected intravenously with endotoxin (0.25 mg/kg) and/or hydrocortisone (25 mg/kg) plus gentamicin (10 mg/kg). Gentamicin levels in the serum and renal parenchyma as well as renal function and histology were evaluated. Both endotoxin and hydrocortisone given alone increased the concentration of gentamicin in the renal cortex (P less than 0.05). Normal values in serum were observed in all groups at most time intervals. When administered together, endotoxin and hydrocortisone did not potentiate each other. The combination of endotoxin and hydrocortisone gave significantly higher levels of gentamicin than endotoxin or hydrocortisone alone when endotoxin was injected 3 h before hydrocortisone (P less than 0.05). Blood pressure and cardiac frequency were normal when gentamicin was given. Endotoxin alone slightly decreased the glomerular filtration rate, and hydrocortisone alone slightly modified renal plasma flow. The combination of both drugs did not significantly affect renal function. No histological lesion was noted on light microscopy in animals receiving endotoxin. Competitive or synergistic activity of endotoxin, gentamicin, and hydrocortisone at the cellular level, especially on membranes or lysosomes, might explain in part our observation on the renal uptake of gentamicin. By increasing the total amount of drug within the kidney, endotoxin and hydrocortisone might increase the risk of nephrotoxicity associated with aminoglycosides.
Cefodizime in serum and skin blister fluid after single intravenous and intramuscular doses in healthy volunteers
Authors: Korting H C , Schäfer-Korting M , Maass L , Klesel N , Mutschler E
Published: June 2012

In gonorrhea therapy, cephalosporins are conventionally administered by intramuscular (i.m.) injection, which rather frequently leads to local side effects. To investigate whether the well-tolerated intravenous (i.v.) injection of cephalosporins may be of comparable gonocidal effect, levels of cefodizime, a new broad-spectrum cephalosporin, in serum and tissue fluid (suction blister and cantharides blister fluid) were determined in six healthy men. Single doses of 1 g of cefodizime were injected i.v. and i.m. according to a randomized crossover design. On i.m. injection the drug was completely bioavailable, and the peak concentration in serum was 75 +/- 8 micrograms/ml. The terminal half-life of serum levels was 2.4 h. Cefodizime concentrations in the blister fluids increased for 1.5 to 3 h after the i.v. dose and for at least 3 h on i.m. administration. The concentrations of non-protein-bound cefodizime in blister fluid already exceeded the MIC for 90% of Neisseria gonorrhoeae strains 10 min after i.v. injection and 20 to 30 min after the i.m. dose. At 6 h after each dose, active concentrations were still present in serum. The results suggest that cefodizime administered i.v. and i.m. has equivalent high cure rates in uncomplicated gonorrhea. This hypothesis should be tested further by a controlled clinical trial. If equivalent, i.v. administration excels because it is better tolerated locally.
Effects of rokitamycin and other macrolide antibiotics on Mycoplasma pneumoniae in L cells
Authors: Misu T , Arai S , Furukawa M , Yamamoto Y , Miyazaki T
Published: June 2012

Fifty strains of Mycoplasma pneumoniae in L cells were tested for susceptibility to macrolide antibiotics. Rokitamycin, a new macrolide antibiotic, was most active against these organisms, with an MIC for 90% of strains of 0.007 microgram/ml. The MICs of erythromycin, josamycin, and kitasamycin for 90% of strains were 0.03, 0.03, and greater than or equal to 0.06 microgram/ml, respectively. Based on these results, rokitamycin is a promising antibiotic for the treatment of mycoplasmal infections, and further clinical investigations are needed.
Predicted and measured aminoglycoside pharmacokinetic parameters in critically ill patients
Authors: Hassan E , Ober J D
Published: June 2012

We conducted a prospective study to determine whether predicted aminoglycoside pharmacokinetic parameters (based on population averages) correlate with measured values in critically ill patients. There was wide interpatient variability for all pharmacokinetic parameters. Only predicted and measured volumes of distribution (18.7 +/- 6.5 versus 22.9 +/- 7.7 liters [mean +/- standard deviation], respectively), with a mean of 0.32 +/- 0.09 liter/kg of dosing body weight, were significantly different. There were no relationships between pharmacokinetic parameters and documented infection, death, or intubation status. The results indicate that volume of distribution is commonly underestimated in intensive care unit patients, whereas elimination rates may be adequately predicted based on population averages. We therefore recommend that aminoglycoside volume of distribution estimates for intensive care unit patients take fluid and adipose excess into account and be based on 0.32 liter/kg rather than the usual 0.25 liter/kg.
Antagonism of wild-type and resistant Escherichia coli and its DNA gyrase by the tricyclic 4-quinolone analogs ofloxacin and S-25930 stereoisomers
Authors: Wolfson J S , Hooper D C , Ng E Y , Souza K S , McHugh G L , Swartz M N
Published: June 2012

The mechanism of action of the quinolone analogs ofloxacin and S-25930, which are unusual because of the presence of a third ring with an asymmetric carbon, was studied. Drug-resistant strains of Escherichia coli were selected by serial passage in the presence of ofloxacin, and a mutation was mapped near the gyrA gene of DNA gyrase. DNA gyrase containing the A subunit purified from this strain as compared with the isogenic wild-type strain exhibited increased resistance to ofloxacin, proving that the mutation was located in the gyrA gene. For S-25930, the S stereoisomer was more potent than the R isomer in inhibiting wild-type E. coli and DNA gyrase containing an A subunit isolated from this strain. Both isomers had decreased potency against the isogenic ofloxacin-resistant (gyrA) strain and its purified enzyme, but the S isomer remained more potent than the R isomer. These studies, using a combined genetic and biochemical approach, demonstrate (i) that DNA gyrase is a target of the tricyclics ofloxacin and S-25930, (ii) that serial exposure to ofloxacin can select resistance to tricyclic quinolone agents by mutation in the gyrA gene, and (iii) that the more potent antibacterial activity of S relative to R S-25930 correlates with increased activity against DNA gyrase for both wild-type and ofloxacin-resistant (gyrA) isogenic strains.
Dideoxynucleosides are less inhibitory in vitro against human immunodeficiency virus type 2 (HIV-2) than against HIV-1
Authors: Richman D D
Published: June 2012

The antiviral activities of various dideoxynucleosides against LAV strains of human immunodeficiency viruses type 1 (HIV-1) and type 2 (HIV-2) were evaluated. Significantly more 3'-azido-3'-deoxythymidine was required to inhibit the replication of HIV-2 than HIV-1 in three human cell lines. HIV-2 also appeared more resistant than HIV-1 to other dideoxynucleosides. These results suggest that dideoxynucleosides may be less effective in vivo for HIV-2 infection and that a broader range of clinical isolates of human retroviruses should be examined for drug susceptibility in vitro.
Phenotypic expression and genetic heterogeneity of lincosamide inactivation in Staphylococcus spp
Authors: Leclercq R , Brisson-Noël A , Duval J , Courvalin P
Published: June 2012

We examined the resistance phenotype and the genetic basis of lincosamide modification in 25 clinical isolates of Staphylococcus spp. inactivating lincomycin and clindamycin. The strains were resistant to high levels of lincomycin but remained susceptible to clindamycin. However, MBCs and inoculum effects showed that the activity of clindamycin was impaired. The distribution in these strains of nucleotide sequences related to linA and linA', the genes encoding lincosamide nucleotidylation in Staphylococcus haemolyticus BM4610 and S. aureus BM4611, respectively, was studied by dot blot hybridization. The genes responsible for lincosamide inactivation in Staphylococcus spp. were found to constitute a family of related sequences which are not species specific.
Gentamicin dosing strategies for dogs with subclinical renal dysfunction
Authors: Frazier D L , Riviere J E
Published: June 2012

Twenty-six subtotally nephrectomized dogs were used as a model for subclinical renal dysfunction to evaluate the nephrotoxic potential of gentamicin administered according to four different dosage regimens. Dosages were individualized based on the pharmacokinetic disposition of drug in each dog. Gentamicin at 3.75 +/- 0.15 mg/kg (mean +/- standard error of the mean, total daily dose) was given for 12 days in two or three divided daily doses (BID and TID, respectively) or in a 2-h or 4-h once-daily variable-rate infusion (2HI and 4HI, respectively) with loading dose. Analyses of serum chemistries and pharmacokinetic data were performed on the ratio of pretreatment versus posttreatment parameters in individual animals. While serum chemistries and histopathology revealed no significant differences in toxicity between treatment groups, pharmacokinetic analysis revealed a significant difference in the ratio of pretreatment versus posttreatment gentamicin clearance (1.35 +/- 0.22, BID; 2.44 +/- 0.52, TID; 0.91 +/- 0.08, 2HI; 0.91 +/- 0.07, 4HI). By using mean population pharmacokinetic parameters (all dogs), predicted times for each treatment group administered 3.75 mg/kg per day to achieve concentrations in serum above the MICs of 2, 4, 6, and 8 micrograms/ml, respectively, were 7.8, 4.2, 2.0, and 0.6 (BID); 6.1, 3.0, 0.5, and 0.2 (TID); 7.1, 5.3, 4.2, and 3.5 (2HI); and 7.4, 5.8, 4.8, and 4.0 (4HI) h daily. This study suggests that decreasing the total daily dosage of drug may decrease the incidence of gentamicin-induced nephrotoxicity. Regardless of the dosage regimen, however, regimens may differ significantly in predicted therapeutic efficacy. Predicted 30-min postdosing concentrations in serum were lowest in dogs administered drug TID, and gentamicin clearance decreased in this group with treatment, suggesting that this regimen may be the least efficacious as well as the most prone to causing future nephrotoxicity.
Revised structure for the phenazine antibiotic from Pseudomonas fluorescens 2-79 (NRRL B-15132)
Authors: Brisbane P G , Janik L J , Tate M E , Warren R F
Published: June 2012

A phenazine antibiotic (mp, 243 to 244 degrees C), isolated in a yield of 134 micrograms/ml from cultures of Pseudomonas fluorescens 2-79 (NRRL B-15132), was indistinguishable in all of its measured physicochemical (melting point, UV and infrared spectra, and gas chromatography-mass spectrometry data) and biological properties from synthetic phenazine-1-carboxylic acid. Gurusiddaiah et al. (S. Gurusiddaiah, D. M. Weller, A. Sarkar, and R. J. Cook, Antimicrob. Agents Chemother. 29:488-495, 1986) attributed a dimeric phenazine structure to an antibiotic with demonstrably similar properties obtained from the same bacterial strain. Direct comparison of the physicochemical properties of the authentic antibiotic obtained from D. M. Weller with synthetic phenazine-1-carboxylic acid and with the natural product from the present study established that all three samples were indistinguishable within the experimental error of each method. No evidence to support the existence of a biologically active dimeric species was obtained. Phenazine-1-carboxylic acid has a pKa of 4.24 +/- 0.01 (25 degrees C; I = 0.09), and its carboxylate anion shows no detectable antimicrobial activity compared with the active uncharged carboxylic acid species. These data suggest that phenazine-1-carboxylic acid is probably not an effective biological control agent for phytopathogens in environments with a pH greater than 7.
In vitro activities of ICI 194008 and ICI 193428, two new cephem antimicrobial agents
Authors: Allan J D , Eliopoulos G M , Reiszner E , Moellering R C
Published: June 2012

The in vitro activities of two new cephem antibiotics, ICI 193428 and ICI 194008, were compared with those of cefpirome, cefotaxime, ceftazidime, and piperacillin. Essentially all strains of the family Enterobacteriaceae were inhibited by both study drugs at concentrations of less than or equal to 4 micrograms/ml. Both new cephems were comparable to ceftazidime against Pseudomonas aeruginosa (MIC for 90% of strains, 8 micrograms/ml) and were the most active agents tested against Pseudomonas maltophilia (MIC for 90% of strains, 16 micrograms/ml).
Molecular epidemiology of OHIO-1 beta-lactamase
Authors: Kron M A , Shlaes D M , Currie-McCumber C , Medeiros A A
Published: June 2012

A total of 31 plasmids, all bearing a gene that encodes a novel, plasmid-mediated Richmond-Sykes class III beta-lactamase designated OHIO-1 and a gene that encodes aminoglycoside 2"-adenyltransferase, have been collected from hospitals in Ohio. By using restriction endonuclease digestion and Southern hybridization, we were able to demonstrate that all these plasmids have a common genetic origin.
Bactericidal activity against Haemophilus influenzae of cerebrospinal fluid of patients given amoxicillin-clavulanic acid
Authors: Decazes J M , Bure A , Wolff M , Kitzis M D , Pangon B , Modai J
Published: June 2012

Patients with purulent meningitis received amoxicillin-clavulanic acid (200/20 mg/kg [body weight] per day). Clavulanic acid levels in cerebrospinal fluid were less than or equal to 0.05 micrograms/ml in 5 of 18 samples and ranged from 0.1 to 0.8 micrograms/ml in the others. Of 12 cerebrospinal fluid samples tested, 10 lacked bactericidal activity in vitro against a beta-lactamase-producing strain of Haemophilus influenzae.
Continuous-infusion ampicillin therapy of enterococcal endocarditis in rats
Authors: Thauvin C , Eliopoulos G M , Willey S , Wennersten C , Moellering R C
Published: June 2012

Intermittent administration of ampicillin alone has resulted in high failure rates in previously described animal models of enterococcal endocarditis. We developed a rat model of enterococcal endocarditis which permits comparison of continuous intravenous infusion of ampicillin with intramuscular therapy. Continuous low-dose ampicillin infusion (450 mg/kg [body weight] per day) was compared with the same dose given intramuscularly in three divided doses and with high-dose infusion (4.5 g/kg per day) of the drug. For the infecting strain of Streptococcus faecalis, the MIC and MBC were 1 microgram/ml. Mean ampicillin levels in serum were 53.9 +/- 4.8 (peak) and less than 1 (trough), 8.7 +/- 1.4, and 244 +/- 29 micrograms/ml for intramuscular, low-dose, and high-dose regimens, respectively. Ampicillin infusion therapy significantly increased the survival rate and sterilization of blood cultures. Continuous infusions were superior to intermittent therapy in eradicating bacteremia. After 5 days of treatment, low-dose ampicillin infusion was more effective than intermittent therapy in sterilizing cardiac vegetations (P less than 0.01). Continuous-infusion therapy at either dose was significantly more effective than intramuscular injection in reducing bacterial titers in cardiac vegetations (5.4 +/- 1.0 log10 CFU/g [low dose], 4.8 +/- 0.3 log10 CFU/g [high dose], and 7.7 +/- 0.3 log10 CFU/g [intramuscular]). However, no statistically significant advantage was found for high-dose compared with low-dose ampicillin infusion in lowering bacterial titers in vegetations (P greater than 0.3).
In vitro and in vivo susceptibility of the Lyme disease spirochete, Borrelia burgdorferi, to four antimicrobial agents
Authors: Johnson R C , Kodner C , Russell M
Published: June 2012

The antimicrobial susceptibility of Borrelia burgdorferi isolated from human spinal fluid was determined in vitro and in vivo. A broth dilution technique was used to determine the MBCs of four antimicrobial agents. The Lyme disease spirochete was most susceptible to ceftriaxone (MBC, 0.04 microgram/ml) and erythromycin (MBC, 0.05 microgram/ml), then tetracycline (MBC, 0.8 microgram/ml), and finally penicillin G (MBC, 6.4 micrograms/ml). Syrian hamsters were used to determine the 50% curative doses (CD50s) of the four antimicrobial agents. Ceftriaxone and tetracycline had the highest activities, with CD50s of 24.0 and 28.7 mg/kg [corrected], respectively. Both erythromycin and penicillin G possessed low activities. The CD50 of erythromycin was 235.3 mg/kg [corrected], and the CD50 of penicillin G was greater than 197.5 mg/kg [corrected].
Randomized prospective study of ceftazidime versus ceftazidime plus cephalothin in empiric treatment of febrile episodes in severely neutropenic patients
Authors: Verhagen C S , de Pauw B , de Witte T , Janssen J , Williams K , de Mulder P , Bothof T
Published: June 2012

In a prospective randomized study, ceftazidime monotherapy was compared with a combination of ceftazidime plus cephalothin in 102 febrile neutropenic patients. Thirty bacteriologically documented infections, of which 23 were bacteremias, in 48 clinically assessable patients were treated with ceftazidime alone. Twenty-four bacteriologically proven infections, of which 18 were bacteremias, in 42 clinically assessable patients were treated with a combination of ceftazidime and cephalothin. The clinical response rates in assessable patients were 77% for ceftazidime monotherapy and 88% for the combination. The bacteriological clearance rate was 70% for ceftazidime monotherapy and 79% for the combination. Efficacy against gram-negative pathogens appeared to be excellent, with 93% clearance for ceftazidime monotherapy and 100% clearance for the combination. The bacteriological clearance of gram-positive infections was only 60% for both regimens, with failures mainly due to Streptococcus faecalis and Streptococcus sanguis, which are primarily resistant to both ceftazidime and cephalothin. After addition of vancomycin to those infections which did not respond to empiric therapy, bacteriological clearance rates of 94% (ceftazidime plus vancomycin) and 90% (ceftazidime and cephalothin plus vancomycin) were achieved. Three superinfections were registered in the ceftazidime group and two were seen in the combination group. Other adverse effects of ceftazidime were minimal and were not enhanced by combination with cephalothin. It is concluded that ceftazidime is an effective drug for the empiric treatment of febrile neutropenic patients, especially if one is prepared to modify therapy if resistant gram-positive strains or mycotic infections are encountered. Neither the clinical nor bacteriological cure rates could be substantially improved by adding cephalothin to ceftazidime in initial empiric treatment of febrile neutropenic patients.
In vivo evaluation of tigemonam, a novel oral monobactam
Authors: Clark J M , Olsen S J , Weinberg D S , Dalvi M , Whitney R R , Bonner D P , Sykes R B
Published: June 2012

Tigemonam, a new monobactam with excellent activity against gram-negative bacteria, was evaluated for in vivo efficacy and absorption after oral administration to laboratory animals. Tigemonam is absorbed when administered orally to mice and dogs. In a variety of gram-negative systemic infections in mice, orally administered tigemonam was efficacious in all infections studied. Comparison drugs such as amoxicillin, cephalexin, and cefaclor were less efficacious, especially in infections caused by beta-lactamase-producing organisms. In localized infections, tigemonam also demonstrated excellent in vivo activity. In acute pyelonephritis in mice caused by Escherichia coli or Proteus sp., tigemonam was very effective. In a rat lung model with Klebsiella pneumoniae, tigemonam was active with a median effective dose of 46 mg/kg compared with 160 mg/kg for cefaclor and over 200 mg/kg for amoxicillin. Tigemonam was well absorbed in laboratory animals and with its excellent gram-negative spectrum of activity should prove of value in oral antibiotic therapy in humans.
Comparative evaluation of A-56619, A-56620, and nafcillin in the treatment of experimental Staphylococcus aureus osteomyelitis
Authors: Mader J T , Morrison L T , Adams K R
Published: June 2012

A rabbit model for Staphylococcus aureus osteomyelitis was used to compare the results of treatment with A-56619 and A-56620, two new aryl-fluoroquinolones, and nafcillin. A-56619 (15 mg/kg) and A-56620 (20 mg/kg), both used for 28 days of treatment, were injected subcutaneously every 12 h, and nafcillin (40 mg/kg) was injected every 6 h. After treatment, S. aureus was found on bone marrow cultures from 19 of 20 control rabbits, 6 of 20 treated with A-56619, 14 of 20 treated with A-56620, and 8 of 20 treated with nafcillin. Drug concentrations in serum and uninfected and infected bone were measured 1 h after A-56619 and A-56620 injection and 30 min after nafcillin injection in a group of rabbits that had been infected for 3 to 4 weeks. The concentrations in infected bone were similar for all three drugs and were significantly higher than in uninfected bone. The results of this study showed that A-56619 had a high rate of eradication of S. aureus from infected bone and compared favorably to nafcillin.
Coagulopathy associated with extended-spectrum cephalosporins in patients with serious infections
Authors: Nichols R L , Wikler M A , McDevitt J T , Lentnek A L , Hosutt J A
Published: June 2012

Patients enrolled in two double-blind multicenter studies were evaluated for the development of hypoprothrombinemia during treatment with cephalosporins. Patients with pneumonia or peritonitis received ceftizoxime, cefotaxime, or moxalactam. The incidence of hypoprothrombinemia was greater in patients with peritonitis (12 of 49) than in those with pneumonia (5 of 96; P less than 0.05). Overall, moxalactam was associated with a higher incidence of hypoprothrombinemia (13 of 52) than either ceftizoxime (1 of 43; P less than 0.05) or cefotaxime (3 of 50; P less than 0.05), and moxalactam patients incurred the highest average increase in prothrombin time (3.7 s) as compared with either ceftizoxime (0.5 s; P less than 0.05) or cefotaxime (0.9 s; P less than 0.05) patients. The occurrence of hypoprothrombinemia in moxalactam patients with peritonitis was not related to dosage, duration of therapy, age, sex, race, or renal or hepatic function. The degree of ileus was, however, strongly related to the development of coagulopathy in moxalactam-treated patients only.
Effect of ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)guanine] on viral DNA and protein synthesis in cells infected with herpes simplex virus
Authors: Chun Y S , Park N H
Published: June 2012

The effect of ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)guanine] on herpes simplex virus type 1 DNA and protein synthesis was studied. Ganciclovir markedly inhibited the synthesis of viral DNA and gamma proteins in a dose-dependent manner. However, the synthesis of viral beta proteins was significantly increased by ganciclovir in the later stage of infection.
Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers
Authors: Healy D P , Polk R E , Garson M L , Rock D T , Comstock T J
Published: June 2012

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.
In vitro and in vivo activity of ciprofloxacin against enterococci isolated from patients with infective endocarditis
Authors: Fernandez-Guerrero M , Rouse M S , Henry N K , Geraci J E , Wilson W R
Published: June 2012

In vitro activity of ciprofloxacin against 27 strains of enterococci was inoculum dependent. Using inocula of 10(5) to 10(6) or 10(7) to 10(8) CFU of enterococci per ml, the MICs for 50 and 90% of strains tested increased from 1 to greater than or equal to 128 micrograms of ciprofloxacin per ml with the higher inoculum compared with the lower inoculum. The MBC for 50% of strains tested increased from 2 to greater than 128 micrograms/ml and the MBC for 90% of strains tested increased from 8 to greater than 128 micrograms of ciprofloxacin per ml with the lower and higher inocula, respectively. The combination of penicillin-gentamicin was more effective in vitro than the combination of ciprofloxacin-gentamicin against the low or high inoculum of enterococci. Using two strains of enterococci, we studied the efficacy of ciprofloxacin in the treatment of enterococcal experimental endocarditis in rabbits. Ciprofloxacin used alone or combined with gentamicin was significantly less effective (P less than 0.01) than procaine penicillin alone or procaine penicillin combined with gentamicin for the treatment of enterococcal experimental endocarditis. The combination of ciprofloxacin-procaine penicillin was not a more effective therapy than procaine penicillin alone.