bluuebunny/crossref_metadata_2025 huggingface dataset:
Action of penicillin on Borrelia hermsii
Authors: Barbour A G , Todd W J , Stoenner H G
Published: June 2012

Borrelia hermsii, a spirochete and an etiological agent of relapsing fever, was cultivated in modified Kelly medium. Studies of the action of penicillin on B. hermsii strain HS1 revealed the following: (i) the in vitro minimum inhibitory concentration and minimum bactericidal concentration of benzylpenicillin for this strain were 0.4 and 3.1 nmol/ml (0.15 and 1.1 micrograms/ml), respectively; (ii) the primary morphological responses at the minimum bactericidal concentration of benzylpenicillin were the formation of spheroplast-like structures and an increased number of small, membranous blebs; (iii) radioactive benzylpenicillin bound to five penicillin-binding proteins in the whole cells of B. hermsii. The 50% binding concentrations of labeled penicillin for the five penicillin-binding proteins were within a factor of five of the minimum inhibitory concentration. More than one-half of the total bound labeled penicillin was associated with penicillin-binding protein 1, the penicillin-binding protein with the largest apparent molecular weight (90,000).
Effects of moxalactam and cefotaxime on rabbit renal tissue
Authors: Luft F C , Aronoff G R , Evan A P , Connors B A , Blase D K , Gattone V H
Published: June 2012

To determine and compare the effects of moxalactam and cefotaxime on kidneys, we gave these drugs in doses of 750 and 1,500 mg/kg to rabbits for 7 days. Cephaloridine was included as a positive control. Neither moxalactam nor cefotaxime at either dose caused lysosomal enzymuria, changes visible by light microscopy or increased plasma creatine. Both drugs caused minor alterations in glomerular ultrastructure at the higher dose. Cephaloridine, on the other hand, caused widespread renal functional and morphological damage. We conclude that in rabbits, both moxalactam and cefotaxime are remarkably nonnephrotoxic.
In Vitro Susceptibility of
Clostridium difficile
Isolates to Cefotaxime, Moxalactam, and Cefoperazone
Authors: Greenfield Ronald A. , Kurzynski Terrence A. , Craig William A.
Published: June 2012

The in vitro susceptibility of 20 isolates of
Clostridium difficile
to cefotaxime, moxalactam, and cefoperazone was determined by a standard agar dilution method. The median minimal inhibitory concentrations were 64, 32, and 32 μg/ml for cefotaxime, moxalactam, and cefoperazone, respectively.
Synergistic interaction of trimethoprim and sulfamethoxazole on Paracoccidioides brasiliensis
Authors: Stevens D A , Vo P T
Published: June 2012

The in vitro interaction of trimethoprim and sulfamethoxazole on clinical isolates of Paracoccidioides brasiliensis was studied. With complete inhibition and a visual endpoint used as the criteria, three of four strains had minimal inhibitory concentrations that indicated resistance to sulfamethoxazole, and all four strains were resistant to trimethoprim. A marked synergism in inhibition was noted with the combination of these drugs against sulfa-resistant strains. A sulfamethoxazole/trimethoprim ratio of 5:1 was the most synergistic. Fifty percent inhibition, determined spectrophotometrically, of the strains could be achieved with sulfamethoxazole alone. In summary, the striking synergy observed suggests that combination chemotherapy with these drugs deserves further study.
Evaluation of Urinary Elimination of
N
-Acetyl-β-Glucosaminidase in Healthy Volunteers Treated with Dibekacin or Gentamicin
Authors: Camí J. , Segura J. , Baños J. E. , Garcia I. , Drobnic L.
Published: June 2012

The urinary excretion of
N
-acetyl-β-glucosaminidase was studied in healthy subjects during and after treatment with aminoglycosides. In terms of this parameter dibekacin appeared to be less nephrotoxic than gentamicin.
In vitro antagonism of beta-lactam antibiotics by cefoxitin
Authors: Sanders C C , Sanders W E , Goering R V
Published: June 2012

We assessed the extent and mechanisms of antagonism of beta-lactam antibiotics by cefoxitin. In tests with 41 gram-negative isolates, cefoxitin antagonized cephalothin, cefamandole, cefsulodin, cefotaxime, moxalactam, ampicillin, carbenicillin, piperacillin, mezlocillin, and azlocillin, but not cephalexin, mecillinam, or N-formimidoyl thienamycin. The extent of antagonism varied with the beta-lactam and genus studied. However, antagonism occurred most often with strains possessing inducible cephalosporinases. Antagonism of cephalothin and cefamandole correlated closely with the induction of beta-lactamases capable of inactivating these drugs. Although antagonism of the remaining drugs occurred more often with strains possessing inducible beta-lactamases, these enzymes did not inactivate the drugs. Morphological studies revealed that cefoxitin inhibited filamentation and lysis produced by various beta-lactam drugs. Results of this investigation suggest that cefoxitin antagonizes beta-lactams via (i) induction of drug-inactivating beta-lactamases, and (ii) the induction of beta-lactamases that cannot inactivate the drug but serve as barriers against access to target proteins. This barrier appears most efficient for drugs that bind to penicillin-binding proteins 1 and 3.
Penicillin-binding proteins in Bacillus subtilis mutants
Authors: Kleppe G , Yu W , Strominger J L
Published: June 2012

The penicillin-binding proteins (PBPs) from mutants of Bacillus subtilis were studied and related to morphology. In a previously described cloxacillin-resistant mutant of B. subtilis strain Porton, PBP 2a had an altered mobility by sodium dodecyl sulfate gel electrophoresis and was present in increased amounts. In addition, PBPs 1a and 1b were missing in this mutant. The only morphological change seen was a decrease in size of about 15%. Studies of two Triton-resistant morphological mutants of B. subtilis 168, Tr49 (small diameter) and Tr61 (helical form), revealed no change in the number of PBPs compared with that of the parent strain. However, PBPs 1a and 1b had an altered mobility in the mutant Tr49.
Comparative biliary excretion of cephalosporins in normal and partially hepatectomized rats
Authors: Humphries N L , Tasker D G , Karran S J
Published: June 2012

The biliary excretion of six cephalosporins was examined in normal and partially hepatectomized rats. Cefamandole, cefazolin, cefuroxime, cefoxitin, and cephradine were excreted well in normal animals. In partially hepatectomized rats, the cumulative percentage of excretion reached only 11 to 36.8% of the control levels. Cephaloridine was excreted poorly in both groups.
Quality control and interpretive criteria for the azlocillin disk diffusion susceptibility test
Authors: Fass R J
Published: June 2012

The standardized disk diffusion test was performed with 75-micrograms azlocillin disks to determine individual test, accuracy, and precision control values with Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 25923. In addition, regression lines for correlating inhibitory zone diameters with the 75-micrograms azlocillin disk and azlocillin minimal inhibitory concentrations were calculated for gram-negative clinical isolates (including Enterobacteriaceae, P. Aeruginosa, other nonfermenters, and Aeromonas hydrophila). Criteria for distinguishing susceptible isolates from resistant isolates, based on an error-rate bound classification scheme, are proposed.
Ceftriaxone (Ro 13-9904) therapy of serious infection
Authors: Bradsher R W
Published: June 2012

Ceftriaxone (Ro 13-9904), a newly developed cephalosporin with a long half-life, was evaluated for efficacy and safety in 19 patients with serious infections. Underlying illnesses were present in 16 patients. Ceftriaxone was given intravenously every 12 h. Infections treated included gram-negative bacillary pneumonias (two cases), staphylococcal and streptococcal soft tissue-skeletal infections (six cases), spontaneous peritonitis (two cases), and complicated urinary tract infections (nine cases). Bacteremia was present in three patients. Microbiological and clinical cures were achieved in all but one case, although three patients with urinary infection had recurrences 6 weeks posttherapy. The only failure occurred in a patient with pneumonia who had a Pseudomonas aeruginosa isolated from sputum with an initial minimal inhibitory concentration of 4 micrograms/ml, but after 9 days of therapy, a repeat isolate had a minimal inhibitory concentration of 32 micrograms/ml. The minimal inhibitory concentrations for the other isolates ranged from less than or equal to 0.6 to 8.0 micrograms/ml. The mean peak plasma level of ceftriaxone was 99.9 micrograms/ml. The only side effects noted were drug fever in one patient, phlebitis in two patients, and thrombocytosis in four patients.
Moxalactam pharmacokinetics in children
Authors: Romagnoli M F , Flynn K , Siber G R , Goldmann D A
Published: June 2012

We measured the serum concentrations of moxalactam in 10 children receiving antibiotic prophylaxis for surgery and in 18 children treated for documented or suspected infections. Moxalactam was administered intravenously at a dose of 50 mg/kg every 8 h. After the first dose in 28 patients, mean moxalactam concentrations 5 min, 30 min, 2 h, and 8 h after infusion were 257, 177, 82.2, and 17.5 micrograms/ml, respectively. The mean half-life (T 1/2) was 2.44 h (range: 0.55 to 7.96 h). The mean distribution volume (VD) was 0.30 liters per kg. No significant accumulation was observed with multiple doses. Prophylactic and therapeutic groups had similar serum levels, T 1/2, and VD. The five infants less than 1 year of age had a lower mean 30-min level (P less than 0.01), larger VD (P less than 0.001) and longer T 1/2 (P less than 0.025) than the children older than 1 year. A dose of 50 mg/kg produced 30-min levels in excess of 64 microgram/ml in all patients studied, but 8-h trough levels were below the minimal inhibitory concentrations breakpoint of 17 mg/ml in 32% of patients.
In vitro activities of trimethoprim and sulfamethoxazole against Listeria monocytogenes
Authors: Winslow D L , Pankey G A
Published: June 2012

The in vitro activities of trimethoprim and sulfamethoxyazole against clinical isolates of Listeria monocytogenes were examined separately and in combination with a microtiter broth dilution system. Sulfamethoxazole demonstrated variable activity and was generally bacteriostatic. Trimethoprim alone was bactericidal against 96% of isolates at less than 0.5 microgram/ml. The bactericidal action of trimethoprim against L. monocytogenes was generally potentiated by sulfamethoxyazole even when isolates were relatively resistant to sulfamethoxyazole alone.
Herpes simplex virus variants restraint to high concentrations of acyclovir exist in clinical isolates
Authors: Parris D S , Harrington J E
Published: June 2012

Acyclovir (ACV) has been shown to inhibit the replication of herpes simplex virus (HSV) in vitro. We examined a wide variety of HSV clinical isolates for the presence of naturally occurring ACV-resistant (ACVr) variants. Although the ACV doses that inhibited 50% of these isolates were within the range of doses inhibiting 50% of the ACV-susceptible wild-type strains, we successfully isolated variants resistant to high ACV concentrations (25 to 75 microM) from each virion population even in the absence of prior drug exposure. Furthermore, we demonstrated, by fluctuation analysis of two encephalitis strains, that the ACVr variants were clonally distributed in the virus populations before exposure to ACV and did not result from rapid adaptation to ACV. All variants isolated after a single exposure to a high dose of ACV were true ACVr variants, as demonstrated by their plating efficiencies in the presence of ACV. We found that 36 and 50% of the ACVr variants of the two strains examined in detail displayed plating efficiencies in phosphonoacetic acid of greater than 0.1, possibly indicating that many of the ACVr variants contained alterations in the DNA polymerase gene locus. Because the distribution of ACVr variants in natural populations is relatively high (10(-4), these results suggest that selection of ACVr strains during ACV therapy is possible.
Susceptibility of Legionella spp. to mycinamicin I and II and other macrolide antibiotics: effects of media composition and origin of organisms
Authors: Edelstein P H , Pasiecznik K A , Yasui V K , Meyer R D
Published: June 2012

Thirty-three strains of Legionella spp., 29 of which were L. pneumophila, were tested for their susceptibilities to erythromycin (EM), rosaramicin, tylosin, mycinamicin I (Sch-27897), and mycinamicin II (Sch-27896). Testing was performed using an agar dilution method with two different types of media: buffered charcoal yeast extract medium supplemented with 0.1% alpha-ketoglutarate (BCYE alpha) and filter-sterilized yeast extract medium with 0.1% alpha-ketoglutarate (BYE alpha). The minimal inhibitory concentrations (MICs) of the drugs tested relative to the MICs of erythromycin were: rosaramicin, MIC approximately equal to 0.2 EM MIC; tylosin, MIC approximately equal to 2 EM MIC; mycinamicin I, MIC approximately equal to 0.5 EM MIC; and mycinamicin II, MIC approximately equal to EM MIC. Both types of media caused equivalent partial inactivation of the macrolides which was apparently due entirely to pH effect. MICs on BCYE alpha were one to five times more than those observed on BYE alpha; this may be due to poorer growth on BYE alpha.
Comparison of standard versus pharmacokinetically adjusted amikacin dosing in granulocytopenic cancer patients
Authors: Finley R S , Fortner C L , deJongh C A , Wade J C , Newman K A , Caplan E , Britten J , Wiernik P H , Schimpff S C
Published: June 2012

The capabilities of two pharmacokinetic amikacin dosing methods were evaluated and compared with the standard amikacin dosage recommended by the manufacturer. Study patients participated in two consecutive prospective randomized double-blind trials of empiric antibiotic therapy for febrile episodes during granulocytopenia. Patients in study 1 received amikacin at a dosage of 15 mg/kg per day in four divided doses in combination with either ticarcillin or piperacillin. Patients in study 2 received either ticarcillin or moxalactam in combination with amikacin. Amikacin dosages in study 2 were adjusted to achieve a 1-h-postinfusion concentration of approximately 25 micrograms/ml and a trough concentration of approximately 8 micrograms/ml. Initial amikacin dosage requirements were established based on the lean body weight and estimated renal function of the patient. If amikacin serum concentrations were not within acceptable ranges, further dosage adjustments were made by using patient-specific pharmacokinetic parameters. The median 1-h-postinfusion concentration of amikacin in study 1 was 13.0 micrograms/ml, with a median trough concentration of 6.1 micrograms/ml. In study 2 the median 1-h-postinfusion concentration was 20.8 micrograms/ml, with a median trough of 6.4 micrograms/ml. Patients in study 2 required a mean dosage of 29.4 mg/kg per day. The incidence of amikacin-induced nephrotoxicity was not increased despite the substantial increase in dosage. Ototoxicity was not evaluated in study 1, but the incidence of ototoxicity in study 2 (17%) exceeded the incidence observed in a previous amikacin-plus-ticarcillin trial in which patients received 15 mg of amikacin per kg per day.
Species differences in susceptibilities of Proteeae spp. to six cephalosporins and three aminoglycosides
Authors: Penner J L , Preston M A , Hennessy J N , Barton L J , Goodbody M M
Published: June 2012

Six cephalosporins and three aminoglycosides were examined for activity against 1,693 isolates belonging to six species of Proteeae. The most notable species-specific differences included the marked susceptibility of Providencia alcalifaciens and Proteus mirabilis to cephalothin, the resistance of Proteus vulgaris to cefamandole, and the resistance of Providencia stuartii to gentamicin and tobramycin. The third-generation cephalosporins cefotaxime and moxalactam were substantially more inhibitory than were cefoperazone, cefamandole, and cefoxitin. P. stuartii, generally the most resistant species, was, however, markedly susceptible to moxalactam and cefotaxime.
Comparative pharmacokinetics of ceftazidime and moxalactam
Authors: Tjandramaga T B , Van Hecken A , Mullie A , Verbesselt R , De Schepper P J , Verbist L
Published: June 2012

The pharmacokinetics of ceftazidime and moxalactam were compared after intravenous and intramuscular administration of single 1-g doses to eight healthy volunteers in a crossover study. The bioavailability of the antibiotics after administration by either route was almost complete. Both drugs had similar areas under the serum curves. Significant differences between ceftazidime and moxalactam were observed with respect to the apparent volume of distribution (18.4 and 24.1 liters, respectively), to the terminal half-life (1.6 versus 2.0 h), and to urinary recovery of the active compound (96 versus 79%). Ceftazidime was almost completely eliminated by renal excretion (greater than 96%), whereas about 20% of the moxalactam was eliminated by nonrenal mechanisms. The concentrations of ceftazidime and moxalactam in serum after a 1-g dose exceeded the concentrations required to inhibit 90% of the Enterobacteriaceae for about 8 and 10 h, respectively. The levels of ceftazidime and moxalactam in serum exceeded the 90% minimal inhibitory concentration of Pseudomonas aeruginosa for about 6 and 1 h, respectively.
Antiviral activity of sodium 5-aminosulfonyl-2,4-dichlorobenzoate (M12325)
Authors: Ohnishi H , Yamaguchi K , Shimada S , Himuro S , Suzuki Y
Published: June 2012

Sodium 5-aminosulfonyl-2,4-dichlorobenzoate (M12325) was evaluated for antiviral activity in tissue culture and infected mice. At concentrations ranging from 2.5 to 75.8 micrograms/ml, M12325 inhibited the cytopathic effects of 10 mean tissue culture infective doses of influenza virus A/WSN, A/FM, A/Kumamoto, and B/Great Lakes; parainfluenza virus; rhinovirus; echovirus; respiratory syncytial virus; and vesicular stomatitis virus. Concentrations up to 150 micrograms/ml did not inhibit the cytopathic effects of herpes simplex virus, vaccinia virus, or adenovirus. Concentrations up to 3,160 micrograms/ml did not inhibit the growth of MDCK, Vero, or HEL cells in culture. Single oral doses of M12325, ranging from 10 to 300 mg/kg, administered 1 h before and 1 h after challenge, reduced mortality in mice inoculated intranasally with influenza A/WSN virus. Twice daily oral doses for 14 days effected significant reductions in the mortality of mice infected intranasally with influenza A/WSN, A/FM, A/Kumamoto, and B/Great Lakes, and parainfluenza virus, but they were not effective in mice infected with herpes simplex virus. Multiple doses of 10 and 30 mg/kg, administered intraperitoneally, reduced lung consolidation and virus titer. M12325 was well tolerated in multiple doses up to 1 g/kg orally. These observations support the conclusions that M12325 has a broad spectrum of activity against RNA viruses in vitro and in vivo, selective toxicity, and a large margin of safety.
Excretion of cephalothin and cefamandole by the normal pancreas and in acute pancreatitis in dogs
Authors: Studley J G , Schentag J J , Schenk W G
Published: June 2012

Nine mongrel dogs were studied to evaluate the excretion of cefamandole (five dogs) and cephalothin (four dogs) in the pancreatic fluid. Each dog was studied before and after the induction of pancreatitis, with 2 weeks between studies. After intravenous administration of a 25-mg/kg dose of either cephalosporin, serum and pancreatic fluid concentrations were monitored for 6 h. Both cephalothin and cefamandole were excreted in bactericidal concentrations in the normal pancreas and in acute pancreatitis. Clearance of cefamandole (290 ml/min) and cephalothin (348 ml/min) were similar pre- and postinduction of pancreatitis. Serum albumin concentration was less during the post-pancreatitis phase compared with the prepancreatitis phase. Penetration of cephalothin was reduced in pancreatitis, whereas cefamandole penetration increased in pancreatitis.
Production, purification, and preliminary characterization of a gonococcal growth inhibitor produced by a coagulase-negative staphylococcus isolated from the urogenital flora
Authors: Beaudet R , Bisaillon J G , Saheb S A , Sylvestre M
Published: June 2012

Coagulase-negative staphylococcus no. 7, isolated from the urogenital flora, was grown on semisolid brain heart infusion medium. Supernatants were obtained by centrifuging frozen and thawed media which had supported the growth of the staphylococci at 37 degrees C. The kinetic of production revealed that the antigonococcal activity was detected at the end of the logarithmic phase of growth and that the maximum activity was obtained after 24 h of incubation. Production of inhibitory activity was detected in cultures grown between 35 and 39 degrees C and in a pH range of 6.9 to 9.4. The inhibitory substance was purified by methanol extraction, acetone fractionation, dialysis, and chromatography on Ultrogel AcA 54. The characterization of the inhibitor showed that it was a lipoprotein or a lipid-associated-protein and that the protein component could be separated from the lipids when chromatographed on Ultrogel AcA 54 in the presence of urea. The inhibitory activity was associated with the protein component which had a molecular weight of approximately 15,900. In polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and urea, the protein component was dissociated in a subunit estimated to be approximately 1,400 daltons.
In vitro activity and beta-lactamase stability of cefmenoxime
Authors: Neu H C , Labthavikul P
Published: June 2012

The activity of cefmenoxime, an aminothiazolyl cephalosporin, was studied against 650 bacteria. It was slightly less active than cefotaxime and more active than moxalactam against staphylococci. It had activity similar to that of cefotaxime and ceftizoxime against group A and B streptococci and Streptococcus pneumoniae. It did not inhibit Streptococcus faecalis or Listeria spp. Cefmenoxime had activity similar to that of cefotaxime, ceftizoxime, ceftazidime, and moxalactam against Escherichia coli, Citrobacter diversus, Klebsiella, Proteus mirabilis, Salmonella, and Shigella. It inhibited beta-lactamase-positive and -negative isolates at less than or equal to 0.4 microgram/ml. Cefmenoxime was somewhat less active than moxalactam or ceftizoxime against Enterobacter cloacae, Enterobacter aerogenes, and Enterobacter agglomerans, but was more active than cefotaxime, ceftizoxime, or ceftazidime against Morganella (minimum inhibitory concentration for 90% of isolates, 0.1 microgram/ml.), Proteus vulgaris and Providencia spp. It was as active as ceftizoxime was against Serratia. Pseudomonas spp. and Bacteroides spp. were relatively resistant (minimum inhibitory concentration for 90% of isolates, greater than 100 micrograms/ml). The compound was stable to the common plasmid beta-lactamases, such as that of TEM. It was stable to most chromosomally mediated beta-lactamases, which act primarily as cephalosporinases, but was hydrolyzed by Bacteroides and Acinetobacter.
High-pressure liquid chromatographic assay of ceftizoxime with an anion-exchange extraction technique
Authors: Fasching C E , Peterson L R , Bettin K M , Gerding D N
Published: June 2012

An anion-exchange extraction method was used in conjunction with high-pressure liquid chromatography for assay of ceftizoxime in 181 serum samples. Comparison of this method with bioassay gave a linear regression line described by Y = 1.11 + 0.98 X, with a correlation coefficient of 0.984. The anion-exchange extraction method is a fast, reliable method of preparing serum samples containing ceftizoxime for assay by liquid chromatography.
Inactivation of amikacin and gentamicin by carbenicillin in patients with end-stage renal failure
Authors: Blair D C , Duggan D O , Schroeder E T
Published: June 2012

Aminoglycosides are inactivated by carbenicillin in vitro and in patients with end-stage renal failure. In vitro, amikacin is inactivated to a lesser extent than is gentamicin. In five patients on chronic hemodialysis, serum levels of amikacin alone and after repeated intravenous carbenicillin infusions were determined. Analogous gentamicin studies were conducted with five different patients. Neither amikacin serum levels nor serum clearances were affected by carbenicillin. The mean gentamicin serum half-life was significantly lower in the presence of carbenicillin: 18.4 +/- 8.2 compared with 61.6 +/- 30.7 h. Serum clearance increased significantly. The inactivation of gentamicin by carbenicillin was both time related (greater than 12 h of exposure) and concentration dependent (molar carbenicillin/gentamicin ratios greater than or equal to 39:1). Amikacin would be preferable to gentamicin in patients with end-stage renal failure.
Antimicrobial susceptibility of Staphylococcus saprophyticus and urethral staphylococci
Authors: Marrie T J , Kwan C
Published: June 2012

The activity of eight antimicrobial agents was determined against 115 isolates of Staphylococcus saprophyticus. All were susceptible to ampicillin, cephalexin, and trimethoprim-sulfamethoxazole and resistant to nalidixic acid and novobiocin. A bimodal pattern of susceptibility to erythromycin was observed: 80% were inhibited by 0.25 microgram/ml, whereas 13% required greater than or equal to 128 micrograms/ml. The following urethral staphylococci were susceptible to ampicillin, cephalexin, and nitrofurantoin but resistant to nalidixic acid: S. epidermidis, S. hominis, S. haemolyticus, S. warneri, S. simulans, and S. cohnii.
Lack of in vivo and in vitro bactericidal activity of N-formimidoyl thienamycin against enterococci
Authors: Auckenthaler R , Wilson W R , Wright A J , Washington J A , Durack D T , Geraci J E
Published: June 2012

The minimal bactericidal concentrations of N-formimidoyl thienamycin (N-f-thienamycin) against 21 strains of enterococci isolated from patients with infective endocarditis were determined by macro- and microdilution methods. By a macrodilution technique with the minimal bactericidal concentration defined as greater than or equal to 99.9% killing of an initial inoculum, all 21 strains of enterococci were found to have minimal bactericidal concentration/minimal inhibitory concentration ratios of greater than or equal to 32. The mean minimal inhibitory concentration was 1.5 micrograms/ml (range, 0.5 to 4 micrograms/ml), and the minimal bactericidal concentration was greater than or equal to 128 micrograms/ml. The disparity between the results of our study and those published elsewhere, which reported that N-f-thienamycin is bactericidal in vitro against enterococci, may represent the relative insensitivity of the microdilution method in determining greater than or equal to 99.9% killing. The lack of in vitro bactericidal activity of N-f-thienamycin against enterococci was confirmed in vivo in the rabbit model of experimental endocarditis. N-f-Thienamycin was no more effective than penicillin alone in the treatment of experimental enterococcal endocarditis and was less effective than the combination of penicillin and gentamicin. The results indicate that N-f-thienamycin should not be used alone in the treatment of enterococcal endocarditis.
Piperacillin distribution into bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue in surgical patients
Authors: Russo J , Thompson M I , Russo M E , Saxon B A , Matsen J M , Moody F G , Rikkers L F
Published: June 2012

The concentrations of piperacillin in serum, bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue were measured simultaneously at various times after the intravenous administration of a single 5-g dose to each of 14 patients undergoing biliary tract surgery. Piperacillin concentrated in the bile with peak levels exceeding 4,000 micrograms/ml. In a single patient with cystic duct obstruction, trace gallbladder bile piperacillin levels were measured. Gallbladder wall concentrations of piperacillin tended to be higher than corresponding serum concentrations, with a correlation observed between tissue values and the degree of acute gallbladder inflammation and gallbladder bile piperacillin concentrations. Mean peak muscle and adipose tissue piperacillin concentrations of 31 and 27 micrograms/g, respectively, were reached at between 2 and 3 h after the start of infusion. These concentrations exceeded the minimum inhibitory concentration for a majority of susceptible organisms. A single 5-g dose of piperacillin achieved therapeutic levels in gallbladder wall, intraabdominal skeletal muscle, and adipose tissue and concentrated in the bile of patients with patent biliary tracts.
Gonococcal opacity variants: susceptibility to antimicrobial agents
Authors: Salit I E , Bond M
Published: June 2012

We tested the susceptibility of 34 pairs of isogenic opaque and transparent colony variants of gonococci to nine antimicrobial agents. Only 20% of the opaque and transparent minimal inhibitory concentrations were discordant, and the mean minimal inhibitory concentrations were not significantly different. Selection of opacity variants is, therefore, not necessary for routine susceptibility testing.
Cloning the gentamicin resistance gene from a Pseudomonas aeruginosa plasmid in Escherichia coli enhances detection of aminoglycoside modification
Authors: Prince A S , Jacoby G A
Published: June 2012

Cloning the gene for gentamicin resistance from Pseudomonas aeruginosa plasmid pMG35 on the high-copy-number Escherichia coli cloning vehicle pMK20 allowed detection of 6'-N-acetyltransferase activity that was not readily detected when the parent plasmid was present either in P. aeruginosa or E. coli.
Antibacterial activity and mechanism of action of phosphonopeptides based on aminomethylphosphonic acid
Authors: Atherton F R , Hall M J , Hassall C H , Lambert R W , Lloyd W J , Ringrose P S , Westmacott D
Published: June 2012

Phosphonopeptides based on aminomethylphosphonic acid as the C-terminal residue linked to L-amino acids possessed antibacterial activity in vitro and in vivo. Analogs in this series were generally less potent than corresponding compounds based on L-1-aminoethylphosphonic acid such as alafosfalin (L-alanyl-L-1-aminoethylphosphonic acid). Significant differences in antibacterial spectra were observed. The mechanism of action involved active transport of the peptide mimetics into the bacterial cells, followed by intracellular release of high concentrations of aminomethylphosphonic acid which inhibited bacterial cell wall biosynthesis. Aminomethylphosphonic acid behaved as a mimetic of both D- and L-alanine and inhibited D-Ala-D-Ala synthetase (EC 6.3.2.4.), alanine racemase (EC 5.1.1.1.), and UDP-N-acetylmuramyl-L-alanine synthetase (EC 6.3.2.8.). The minimal inhibitory concentration of L-norvalyl-aminomethylphosphonic acid was essentially unaffected by the presence of D-alanine, whereas the activity of the corresponding L-norvalyl derivative of L-1-aminoethylphosphonic acid was markedly decreased. Substantial differences in the inhibitory and lytic activity of the L-norvalyl derivatives of aminomethylphosphonic and L-1-aminoethylphosphonic acids were also observed when these agents were combined with other inhibitors of bacterial cell wall biosynthesis.
Antipicornavirus flavone Ro 09-0179
Authors: Ishitsuka H , Ohsawa C , Ohiwa T , Umeda I , Suhara Y
Published: June 2012

Ro 09-0179 (4',5-dihydroxy-3,3',7-trimethoxyflavone), isolated from a Chinese medicinal herb, was found to have potent antiviral activity. It selectively inhibited the replication of human picornaviruses, such as rhinoviruses and coxsackieviruses in tissue culture, but not other DNA and RNA viruses. Ro 09-0298 (4',5-diacetyloxy-3,3',7-trimethoxyflavone), an orally active derivative of Ro 09-0179, prevented coxsackievirus (B1) infection in mice. The critical time for the inhibition of rhinovirus replication by Ro 09-0179 was 2 to 4 h after virus adsorption, i.e., in the early stages of virus replication. It markedly inhibited coxsackievirus and rhinovirus RNA synthesis in infected HeLa cells, but not in a cell-free system using the RNA polymerase complex isolated from the infected cells. In the infected cells, the RNA polymerase complex was not formed in the presence of Ro 09-0179. Therefore, it is suggested that Ro 09-0179 interferes with some process of viral replication which occurs between viral uncoating and the initiation of viral RNA synthesis.
Activity of 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860) against picornaviruses in vitro
Authors: Powers R D , Gwaltney J M , Hayden F G
Published: June 2012

The newly synthesized compound 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860) has been found to inhibit picornavirus replication. In multiple growth cycle experiments, 1 microgram of MDL-860 per ml caused a reduction in virus yield of at least 1.0 log10 50% tissue culture infectious doses per 0.2 ml for 8 of 10 enteroviruses and 72 of 90 rhinovirus serotypes. This antiviral activity was dependent on both compound concentration and virus inoculum size. At concentrations that had no toxic effects on cell cultures, MDL-860 did not inhibit cytopathic effect or hemadsorption activity due to coronavirus 229-E, vesicular stomatitis virus, herpes simplex virus type 1, adenovirus, influenza virus A, or parainfluenza virus 1. Compound concentrations up to 25 micrograms/ml did not cause cytopathic effect in short-term cultures of rhesus monkey, WI-38, or HeLa cells; 10 micrograms/ml did not inhibit the replication of HeLa cells. The mechanism of action of MDL-860 has not been defined, although it was not directly virucidal and appeared to inhibit picornaviruses specifically at an early step in the virus-host cell interaction.
Effects of novobiocin, coumermycin A1, clorobiocin, and their analogs on Escherichia coli DNA gyrase and bacterial growth
Authors: Hooper D C , Wolfson J S , McHugh G L , Winters M B , Swartz M N
Published: June 2012

Novobiocin, coumermycin A1, and clorobiocin, structurally related compounds that antagonize the B subunit of the essential bacterial enzyme DNA gyrase, were compared with 18 of their analogs for the inhibition of Escherichia coli DNA gyrase supertwisting activity in vitro and of bacterial multiplication. This family of compounds has a 4-hydroxy-8-methylcoumarin core substituted in the 7 and 3 positions. Important for enzyme inhibition in vitro is a 7 ether linkage to a 3'-substituted noviose sugar. The 3'-ester-linked 5-methylpyrrole, found in the coumermycin series, conferred at least 10-fold more inhibitory activity than did the similarly linked amide, found in the novobiocin series; lack of the pyrrole and amide results in the loss of inhibitory activity. Of many aryl and alkyl substituents linked as an amide at the 3 position, the 4-hydroxyl-3-(3-methyl-2-butenyl)benzoic acid moiety, found in novobiocin and clorobiocin, and the reduplication of the coumarin-noviose-5-methylpyrrole, found in coumermycin A1, were most effective in gyrase inhibition. In vivo, the ability of these compounds to inhibit the growth of E. coli varied greatly. The enhanced inhibition of gyrase in vitro conferred by a 5-methylpyrrole relative to an amide in the 3'-noviose position was reflected in inhibition of bacterial multiplication. Several substitutions at the 3 position of the coumarin core conferring similar antagonism of gyrase in vitro resulted in substantially different inhibitory activities for E. coli, suggesting that these moieties at the 3 position affect drug access to the intracellular target. This target was shown for isobutyryl PNC-NH2 (PNC-NH2 is 3-amino-4-hydroxy-8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl)noviosyloxy] coumarin) and confirmed for novobiocin, coumermycin A1, and clorobiocin to be in the B subunit of DNA gyrase.
Plasmid-coded ampicillin resistance in Haemophilus ducreyi
Authors: Thomson J A , Bilgeri Y R
Published: June 2012

Seven of the 96 ampicillin-resistant isolates of Haemophilus ducreyi reported in the preceding article (Bilgeri et al., Antimicrob. Agents Chemother. 22:686-688, 1982) were investigated and found to harbor plasmids of 3.95, 5.2, 5.8, and 6.4 megadaltons. All except the 5.8-megadalton plasmid have been shown to code for beta-lactamase. The 6.4- and 5.2-megadalton plasmids of three isolates were conjugally transferable to a streptomycin-resistant mutant of H. ducreyi at high frequencies, perhaps due to the presence in these strains of a high-molecular-weight plasmid.
In vitro and in vivo antibacterial activity of T-1982, a new semisynthetic cephamycin antibiotic
Authors: Tai M , Fukuoka Y , Yotsuji A , Kumano K , Takahata M , Mikami H , Yasuda T , Saikawa I , Mitsuhashi S
Published: June 2012

The activities of T-1982 (sodium 7 beta-[(2R, 3S)-2-(4-ethyl-2, 3-dioxo-1-piperazine-carboxamido)-3-hydroxybutanamido]-7 alpha-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate) against various gram-positive and gram-negative bacteria were compare with those of cefmetazole, cefoxitin, cefazolin, and cefoperazone. T-1982 was active against both gram-positive and gram-negative bacteria, including genera resistant to the other cephalosporins. T-1982 exhibited greater activity than did cefmetazole, cefoxitin, cefazolin, or cefoperazone against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Serratia marcescens and was also highly active against Bacteroides fragilis. T-1982 was as stable to various beta-lactamases as were cefmetazole and cefoxitin. The therapeutic activities of T-1982 in mice experimentally infected with various gram-negative bacteria were superior to those of cefmetazole, cefoxitin, cefazolin, and cefoperazone.
Synergism between aminoglycosides and cephalosporins with antipseudomonal activity: interaction index and killing curve method
Authors: Hallander H O , Dornbusch K , Gezelius L , Jacobson K , Karlsson I
Published: June 2012

Combinations of gentamicin with cefotaxime, moxalactam, and ceftazidime were tested against 43 bacterial strains, most of them blood isolates. With an interaction index of less than or equal to 0.5 as borderline, synergism was demonstrated against 30 to 40% of the strains by the fractional inhibitory concentration index and against 50 to 70% by the fractional bactericidal concentration index. The reproducibility of the index was within +/- 0.2 for two-thirds of 40 repetitive assays and within +/- 0.4 to 0.5 for all of these assays. Similar results were obtained when netilmicin was substituted for gentamicin. The killing curve system for studying antibiotic synergism was standardized to give results comparable to those obtained with the interaction index. This was achieved when one-half of a previously determined minimum bactericidal concentration was used for single drugs and the amount of antibiotic was at least halved again when drugs were used in combination. An initial bacterial concentration of 10(5) to 10(6) colony-forming units per ml is recommended. Given these conditions, synergism could be defined as a 2-log 10 or more decrease in viable count given by both drugs together, as compared with the more active of the pair after 24 h. Prediction of killing curve results could then be obtained with the fractional bactericidal concentration index. When cephalosporins and gentamicin were combined from the start, the beta-lactam antibiotics were less susceptible to inactivation, as demonstrated in time-killing assays. If one of the antibiotics were added after 24 h, synergism was not demonstrable. The results indicate that the new cephalosporins may be advantageously combined with aminoglycosides.
Interactions among amphotericin B, 5-fluorocytosine, ketoconazole, and miconazole against pathogenic fungi in vitro
Authors: Odds F C
Published: June 2012

Interactions among amphotericin B, 5-fluorocytosine, ketoconazole, and micoconazole were tested for all possible paired and triple drug combinations and all four drugs combined against three isolates of Candida albicans, three Candida spp., two isolates of Cryptococcus neoformans, and three isolates Aspergillus fumigatus. An assay for inhibitory activity was developed in which growth in the presence of an antifungal agent was expressed as a percentage of the growth in drug-free cultures. For nearly all of the antifungal combinations, the interaction was additive against most fungal isolates. Drug combinations that included amphotericin B and ketoconazole were most often synergistic, i.e., amphotericin plus ketoconazole, amphotericin plus 5-fluorocytosine plus ketoconazole, and amphotericin plus 5-fluorocytosine plus ketoconazole plus miconazole, whereas the combination of ketoconazole plus miconazole showed the strongest tendency towards antagonism. The data in this screening survey provide a basis for further studies of drug interactions in vivo and in vitro.
Bacteroides fragilis resistance to clindamycin in vitro
Authors: Sosa A , Tally F P , Jacobus N V , Gorbach S L
Published: June 2012

Clindamycin resistance in Bacteroides fragilis was examined in 507 strains isolated from 1973 to 1981. Three groups were recognized: highly susceptible (minimum inhibitory concentration [MIC] less than or equal to 0.125 microgram/ml), intermediately susceptible (MIC = 0.25 to 4 micrograms/ml), and highly resistant to (MIC greater than or equal to 8 microgram/ml). The incidence of high-level resistance (1.8%) had not changed during this period. Only 8 of 17 isolates reputed to be highly clindamycin resistant that were referred to our laboratory proved to be highly resistant (MICs greater than or equal to 32 microgram/ml), whereas the other 9 were intermediately susceptible. Analysis of 2- and 10-microgram clindamycin disks for determining the susceptibility of B. fragilis revealed a high false-resistance rate with the 2-microgram disk, most errors occurring with the intermediate group. There was no false resistance with the 10-microgram disk. When disk diffusion susceptibility of B. fragilis is employed, we recommend the 10-microgram disk to predict accurately the susceptibility of B. fragilis to clindamycin.
Candida albicans resistance to 5-fluorocytosine: frequency of partially resistant strains among clinical isolates
Authors: Defever K S , Whelan W L , Rogers A L , Beneke E S , Veselenak J M , Soll D R
Published: June 2012

Resistance to 5-fluorocytosine was studied in 137 independent Candida albicans clinical isolates. Seventy-eight isolates (57%) were susceptible; 51 isolates (37%) were partially resistant; 8 isolates (6%) were highly resistant. All partially resistant isolates gave rise to variants which were highly resistant. Some susceptible isolates gave rise to variants which were highly resistant; two such isolates were shown to be heterozygous for resistance, and these isolates define a new type of heterozygote. A partially resistant isolate gave rise to resistant variants which were auxotrophic for lysine; this result was interpreted as preliminary evidence that the allele which determined resistance was linked to an allele which determined auxotrophy for lysine. It is suggested that heterozygotes constitute a source of preexisting mutant alleles which determine resistance, and that 5-fluorocytosine treatment of infections due to heterozygotes may result in significant selection for resistant variants. A simple screening procedure is described by which partially resistant strains may be recognized.
In vitro activity of azthreonam, a monobactam antibiotic
Authors: Jacobus N V , Ferreira M C , Barza M
Published: June 2012

We studied the activity of azthreonam (SQ 26,776), a novel monocyclic beta-lactam compound, against a variety of clinical isolates. It was more potent than moxalactam, cefoperazone, cefamandole, cefoxitin, ticarcillin, tobramycin, or amikacin against strains of Klebsiella spp., Serratia spp., and the Proteus group. It was highly effective against Escherichia coli and strains of Salmonella spp. The median minimal inhibitory concentration for all species of Enterobacteriaceae was less than or equal to 2 micrograms/ml. Azthreonam was moderately active against Pseudomonas aeruginosa, including tobramycin-resistant strains, and against Pseudomonas cepacia (median minimal inhibitory concentration, 16 to 32 micrograms/ml), but was weakly active against Pseudomonas maltophilia and strains of Acinetobacter spp. and Achromobacter spp. The drug showed little activity against Staphylococcus aureus, enterococci, and anaerobic bacteria, including Bacteroides fragilis, Clostridium spp., and gram-positive cocci. Like moxalactam and cefoperazone, azthreonam exhibited a considerable inoculum effect with strains of Enterobacter spp. and Pseudomonas spp. Combination with clavulanic acid did not increase the activity of azthreonam against S. aureus but was synergistic for 5 of 15 strains of B. fragilis. Azthreonam is about 50% bound to human serum protein. The selective range of activity of this compound could be of clinical benefit.
Effect of calcium, magnesium, and zinc on ticarcillin and tobramycin alone and in combination against Pseudomonas aeruginosa
Authors: Zuravleff J J , Yu V L , Yee R B , Zaphyr M K , Diven W , Taylor F B
Published: June 2012

Correlation between in vitro and in vivo test results for synergy between carboxypenicillins and aminoglycosides against Pseudomonas aeruginosa is poor. Although the divalent cation content of culture media is known to affect aminoglycoside susceptibility testing for P. aeruginosa, this effect of divalent cations has not been examined for synergy testing of carboxypenicillin-aminoglycoside interaction against P. aeruginosa. The minimal inhibitory concentrations (MICs) of tobramycin and ticarcillin and the interaction of these drugs in combination were studied by a microtitration method for 36 strains of P. aeruginosa in Mueller-Hinton broth with varying supplements of calcium, magnesium, and zinc. The supplementation of Mueller-Hinton broth to 50 or 100 mg of calcium per liter had a significant effect in increasing the tobramycin MIC (P less than 0.01), as well as decreasing the degree of synergy between ticarcillin and tobramycin (P less than 0.01). Supplementation to 20 mg of magnesium per liter, 1.0 mg of zinc per liter, or both did not significantly affect tobramycin MIC or the interaction of tobramycin and ticarcillin. Supplementation to 50 or 100 mg of calcium per liter rendered any additional effect of magnesium and zinc on aminoglycoside MIC and aminoglycoside-carboxypenicillin interaction negligible. If these results for ticarcillin and tobramycin are confirmed for other carboxypenicillins and aminoglycosides, then the Mueller-Hinton broth used for P. aeruginosa aminoglycoside susceptibility and synergy testing may need to be supplemented only with calcium at a concentration of 50 mg/liter.
Effects of a Vancomycin-Rifampin Combination on Enterococci
Authors: Watanakunakorn Chatrchai , Tisone Joann C.
Published: June 2012

By the time-kill curve method, a vancomycin-rifampin combination showed neither synergism nor antagonism against 43 of 48 strains of enterococci. Antagonism was demonstrated against five strains.