bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans
Authors: Contrepois A , Brion N , Garaud J J , Faurisson F , Delatour F , Levy J C , Deybach J C , Carbon C
Published: June 2012

The tubular disposition of five aminoglycosides was studied in humans to establish a possible relationship between tubular reabsorption and the nephrotoxicity that has been described in the literature. Thirty-three healthy male volunteers received a continuous intravenous infusion of isotonic saline with inulin, followed 1 h later by inulin plus gentamicin, dibekacin, tobramycin, netilmicin, or amikacin (1 mg/kg per h) or amikacin (4 mg/kg per h) over a period of 2 h. Brain-stem-evoked response audiometry was performed both before and at the end of each infusion. The latency of wave V remained constant whichever antibiotic was considered. The glomerular filtration rate did not vary significantly during the infusion of each drug. The percent fractional excretion was 79 +/- 6, 81 +/- 22, 85 +/- 5, and 99 +/- 9 for gentamicin, dibekacin, tobramycin, and netilmicin, respectively, and 83 +/- 4 and 124 +/- 13 for amikacin at concentrations of 1 and 4 mg/kg per h, respectively. Net balance and renal clearance were similar for the five aminoglycosides when administered at a rate of 1 mg/kg per h. With gentamicin only, fractional excretion was correlated with the urinary flow rate. We can conclude that (i) gentamicin, generally considered the most nephrotoxic agent, had the highest degree of net reabsorption; (ii) netilmicin exhibited a net zero tubular balance; (iii) amikacin had different patterns of tubular disposition according to the dose, i.e., reabsorption at 1 mg/kg per h and secretion at 4 mg/kg per h, raising the hypothesis of a saturable process of reabsorption; and (iv) these differences in tubular reabsorption could account at least in part for the known different nephrotoxic potentials of these five aminoglycosides in humans.
Quantitation of ciprofloxacin in body fluids by high-pressure liquid chromatography
Authors: Weber A , Chaffin D , Smith A , Opheim K E
Published: June 2012

We describe a reverse-phase high-pressure liquid chromatography method for the quantitation of a new quinoline carboxylic acid antimicrobial agent, ciprofloxacin (Bay o 9867). This assay utilizes the intrinsic fluorescence of ciprofloxacin for primary detection but employs UV absorption as a secondary detection system. Mobile phases contained methanol and phosphate buffer and used a common C18 mu Bondapak column. A single precipitation step of a 50-microliter specimen was the only sample preparation necessary. The assay is linear from 2,000 to 10 ng/ml and sensitive to 5 ng/ml. The mean recovery of ciprofloxacin from serum was 105.7%. The coefficient of variation was less than or equal to 3.1% for same-day precision and less than or equal to 6.3% for assay-to-assay precision. Because the assay requires only small specimen volumes and minimal sample preparation and because of its defined characteristics, this assay would be ideal for clinical trials and pharmacokinetics studies of ciprofloxacin.
Resistance caused by decreased penetration of beta-lactam antibiotics into Enterobacter cloacae
Authors: Bush K , Tanaka S K , Bonner D P , Sykes R B
Published: June 2012

Strains of Enterobacter cloacae were selected on the basis of resistance to aztreonam, ceftazidime, moxalactam, or imipenem. All strains produced the same E2 beta-lactamase, with an isoelectric point greater than 9.5 and with high hydrolytic activity in the presence of cephaloridine. Resistance to beta-lactams could not be correlated with the amount of beta-lactamase present in the various strains. beta-Lactamase activity was induced strongly by moxalactam and imipenem in the wild-type and moxalactam-resistant strains, with beta-lactamase representing as much as 4% of the total cellular protein after induction (2 X 10(5) molecules per cell). Ceftazidime and aztreonam were poor inducers. None of the antibiotics studied was readily hydrolyzed by the E2 beta-lactamase; aztreonam and moxalactam inhibited the enzyme with apparent Ki values of 1.2 and 100 nM, respectively. Aztreonam, which bound covalently to the E2 beta-lactamase with a half-life of 2.3 h at 25 degrees C, was used to measure penetrability of beta-lactam into the periplasmic space of the resistant E. cloacae strains. In all of the E2-producing organisms studied, a significant permeability barrier existed. A maximum concentration of 0.02 microgram of aztreonam per ml should have saturated the periplasmic beta-lactamase in the highest enzyme producers studied. However, fully active beta-lactamase was observed in the periplasm of cells exposed to aztreonam at concentrations at least 1,000-fold higher than that theoretically necessary to inhibit the total enzyme within the cell. Thus, the major cause for resistance to beta-lactam antibiotics in these E. cloacae strains was lack of penetration across the outer membrane.
In vitro studies on the antibacterial activities of YM-13115, a new broad-spectrum cephalosporin
Authors: Toda M , Arao N , Nohara C , Susaki K , Tachibana A
Published: June 2012

The in vitro antibacterial activities of YM-13115, a new parenteral cephalosporin, were compared with those of ceftazidime, cefoperazone, and cefsulodin. The compound was highly active against the common members of the Enterobacteriaceae and 2 to 256 times more active than cefoperazone. YM-13115 was as active as ceftazidime against Citrobacter freundii, Proteus vulgaris, and Morganella morganii and two to four times more active than ceftazidime against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, and Providencia stuartii. The activity of YM-13115 against Pseudomonas aeruginosa (with MICs of 0.78 and 3.13 micrograms/ml for 50 and 90% of the isolates, respectively) was ca. 2 times that of ceftazidime, 4 times that of cefsulodin, and 16 times that of cefoperazone. Against Haemophilus influenzae YM-13115 was more active than ceftazidime. YM-13115 was less active than ceftazidime, cefoperazone, and cefsulodin against Staphylococcus aureus and Staphylococcus epidermidis. The concentrations of YM-13115 required to inhibit the growth of 90% of the isolates of Streptococcus pyogenes and Streptococcus pneumoniae were 0.78 and 1.56 microgram/ml, respectively, but concentrations above 100 micrograms/ml were required to inhibit Streptococcus faecalis. YM-13115 was not hydrolyzed by the common plasmid and chromosomal beta-lactamases. YM-13115 is extremely active against P. aeruginosa and members of the Enterobacteriaceae.
Pharmacokinetics of ceftazidime, alone or in combination with piperacillin or tobramycin, in the sera of cancer patients
Authors: Drusano G L , Joshi J , Forrest A , Ruxer R , Standiford H , Leslie J , Wade J , Schimpff S
Published: June 2012

We administered 2 g of ceftazidime intravenously every 8 h to cancer patients for the empiric therapy of febrile episodes. Ceftazidime was administered as monotherapy for patients with granulocyte counts in excess of 1,000/microliter. Febrile, neutropenic patients were randomized to also receive either piperacillin or tobramycin. The pharmacokinetic profile of ceftazidime during a steady-state dosing interval was ascertained in 21 patients. No differences were seen between groups for any of the pharmacokinetic parameters examined. As expected, the observed half-life was longer, the serum clearance was smaller, and the volumes of distribution were larger than in previously reported studies of volunteers. Serum concentrations remained above the MIC for inhibition of 90% of strains of the most common bacteremic pathogens seen in our cancer center for the entire 8-h dosing interval.
In vitro activities of rifapentine and rifampin, alone and in combination with six other antibiotics, against methicillin-susceptible and methicillin-resistant staphylococci of different species
Authors: Varaldo P E , Debbia E , Schito G C
Published: June 2012

The antistaphylococcal activity of rifapentine, a new rifamycin SV derivative, was evaluated in vitro and compared with that of rifampin. A total of 313 staphylococcal strains freshly isolated from clinical material and including representatives of all currently recognized Staphylococcus species of human origin were used. The susceptibility to methicillin of all the test strains was determined preliminarily. Despite minor differences with some species, the MICs of rifapentine were found to be substantially similar to those of rifampin. Methicillin-resistant strains of all species were most resistant to rifapentine and rifampin than were their methicillin-susceptible counterparts. For most strains tested, the MBCs of both rifamycins exceeded by twofold the respective MICs. Both the checkerboard dilution and time-kill methods were used to determine the interactions of rifapentine or rifampin with six different antibiotics: cefamandole, vancomycin, teicoplanin, gentamicin, erythromycin, and fusidic acid. No significant differences between the two rifamycins in the combinations were observed against either methicillin-susceptible or methicillin-resistant strains. Minor differences were noted depending on the second antibiotic tested or the staphylococcal species examined. Antagonism was never observed, and indifference was the prevalent response. Cases of synergism were observed occasionally with the checkerboard method and slightly more often with the time-kill method.
Comparative activity of the quinolones against anaerobic bacteria isolated at community hospitals
Authors: Goldstein E J , Citron D M
Published: June 2012

The in vitro activity of five quinolone compounds, amoxicillin, and clindamycin against 118 strains of anaerobic bacteria isolated at community hospitals was determined by an agar dilution method. Nalidixic acid and cinoxacin had poor activity, and norfloxacin and enoxacin showed relatively poor activity. Ciprofloxacin was active against Bacteroides fragilis, Fusobacterium species, Clostridium perfringens, and gram-positive cocci. At peak levels achievable in the feces, norfloxacin and enoxacin had moderate activity.
Correlation of aminoglycoside resistance with the KmS and Vmax/Km ratios of enzymatic modification of aminoglycosides by 2''-O-nucleotidyltransferase
Authors: DeHertogh D A , Lerner S A
Published: June 2012

A clinical isolate, Serratia marcescens 75, was found to be susceptible to netilmicin and yet had a high level of aminoglycoside 2''-O-nucleotidyltransferase activity for netilmicin. Kinetic studies of the partially purified enzyme revealed substrate inhibition for gentamicin and tobramycin at concentrations greater than 10(-2) mM, but this was not observed for netilmicin. The MICs of the aminoglycosides tested exhibited a good inverse correlation with the Km values for the enzyme and a direct correlation with the Vmax/Km ratios of the enzyme.
Comparison of a beta-lactamase induction test with a test that detects low-frequency resistance to cefotaxime
Authors: Menzies R E , MacCulloch D
Published: June 2012

A paper strip test that detects cefotaxime-resistant variants of gram-negative bacilli was described and compared with a beta-lactamase induction test. Both tests demonstrated a potential for resistance that is not indicated by standard agar dilution and agar diffusion tests.
Pefloxacin therapy for experimental endocarditis caused by methicillin-susceptible or methicillin-resistant strains of Staphylococcus aureus
Authors: Sullam P M , Täuber M G , Hackbarth C J , Chambers H F , Scott K G , Sande M A
Published: June 2012

The therapeutic efficacy of pefloxacin in experimental endocarditis caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus was evaluated. In rabbits infected with a methicillin-susceptible strain, 4 days of pefloxacin therapy significantly reduced both the number of bacteria per gram of vegetation and the mortality rate compared with untreated controls, and pefloxacin was equivalent to cephalothin. Pefloxacin was also as effective as vancomycin in reducing vegetation titers and mortality rate in animals with endocarditis caused by a methicillin-resistant strain. These results suggest that pefloxacin may be an effective agent in the therapy of serious infections caused by either methicillin-susceptible or -resistant strains of S. aureus.
Activity of ciprofloxacin against methicillin-resistant Staphylococcus aureus
Authors: Smith S M , Eng R H
Published: June 2012

Ciprofloxacin, a carboxy quinolone antibiotic with a broad spectrum of activity, was tested against 54 strains of methicillin-resistant Staphylococcus aureus. The ciprofloxacin MICs for 50 and 90% of the isolates were 0.25 and 0.5 micrograms/ml, respectively, and its MBC for 90% of the isolates was 1.0 microgram/ml. Killing kinetic studies were conducted in vitro with ciprofloxacin and vancomycin individually and in combination. The results of these studies showed that ciprofloxacin at 2 micrograms/ml and vancomycin at 10 micrograms/ml decreased the number of organisms by approximately 1.5 log10 after 6 h. The combination of ciprofloxacin plus vancomycin did not alter the rate of killing over that achieved by ciprofloxacin alone. The in vitro killing of resistant staphylococci was rapid, and the potential use of ciprofloxacin for infections caused by methicillin-resistant S. aureus should be further explored.
Inhibitory effects of chlorpromazine on Candida species
Authors: Wood N C , Nugent K M
Published: June 2012

Chlorpromazine was tested for antifungal activity by using Candida albicans and standard assays. The MIC of chlorpromazine was 35 micrograms/ml; the minimal fungicidal concentration was also 35 micrograms/ml. The minimal effective concentration was 2.2 to 3.5 micrograms/ml (using assays based on quantitative cultures and growth). There was a slight positive interaction between chlorpromazine and amphotericin B but no interaction between chlorpromazine and rifampin. Chlorpromazine also inhibited C. krusei, C. parapsilosis, C. tropicalis, and Torulopsis glabrata. We conclude that phenothiazines have direct anti-Candida activity and that these drugs appear to have a broad antimicrobial spectrum.
Enoxacin compared with cefoperazone for the treatment of experimental Enterobacter aerogenes endocarditis
Authors: Boscia J A , Kobasa W D , Kaye D
Published: June 2012

This study compared enoxacin administered orally with cefoperazone administered intramuscularly for the treatment of Enterobacter aerogenes endocarditis in rabbits. The MICs and MBCs of both enoxacin and cefoperazone for an inoculum of 10(5) CFU/ml of the E. aerogenes strain used were 0.8 micrograms/ml, respectively. With an inoculum of 10(8) organisms per ml, enoxacin at 2 and 5 micrograms/ml and cefoperazone at 60 and 155 micrograms/ml were effective in reducing titers of E. aerogenes in broth. E. aerogenes endocarditis in rabbits was treated with enoxacin (100 or 25 mg/kg orally every 6 h) or cefoperazone (60 mg/kg intramuscularly every 6 h) for 5 or 10 days. Enoxacin at 100 and 25 mg/kg significantly reduced bacterial titers of vegetations compared with those of untreated controls. Enoxacin at 100 mg/kg was significantly more effective than enoxacin at 25 mg/kg and cefoperazone. Enoxacin at 25 mg/kg and cefoperazone did not differ significantly. Cefoperazone and controls did not differ significantly. In uninfected rabbits single doses of cefoperazone achieved much higher concentrations in serum than single doses of enoxacin (25 and 100 mg/kg). The half-lives of enoxacin at 25 and 100 mg/kg were approximately three times longer than that of cefoperazone.
Safety and efficacy of high-dose treatment with imipenem-cilastatin in seriously ill patients
Authors: Zajac B A , Fisher M A , Gibson G A , MacGregor R R
Published: June 2012

Imipenem-cilastatin was given in doses of 1 g intravenously every 6 h to 31 patients. Twenty-five patients, with 27 infections, were clinically evaluable and received 20 to 210 g of imipenem for a duration of 5 to 56 days (average 16.3 days). Infections included seven cases of osteomyelitis, seven of bacteremia, five of cellulitis, two of pneumonia, three of pelvic cellulitis, two of intraabdominal abscess, and one each of empyema, mediastinitis, and endometritis. Fifty-five percent of the infections were caused by gram-negative bacilli, 33% were due to gram-positive organisms, and 10% were caused by anaerobes. Twenty-two patients (81%) were cured, three improved, one relapsed, and one became superinfected with a resistant organism. In 5 of 11 cases with Pseudomonas aeruginosa, the imipenem MIC for organisms isolated by the end of treatment was higher than it was initially, raising concern that imipenem should not be used alone to treat Pseudomonas aeruginosa infections. Twenty-one patients had no adverse reaction; of the remaining 10 patients, 4 had nausea, 1 had urticaria, and 6 had mild abnormalities in hepatic function; three episodes of diarrhea included two with Clostridium difficile toxin in stool and one with pseudomembranous colitis, as determined by sigmoidoscopy. Levels of creatinine, hemoglobin, leukocytes, platelets, prothrombin, and urine components were unchanged. Imipenem-cilastatin is a clinically effective antibiotic with freedom from nephrotoxicity and hematological abnormalities in the large doses used in this study.
In vitro activity of Sch 34343 and cefbuperazone against anaerobic bacteria
Authors: Shafran S D , Wong J , Chow A W
Published: June 2012

The in vitro activities of Sch 34343, a new penem antibiotic, and cefbuperazone, a new cephamycin antibiotic, were determined against 459 clinical anaerobic bacterial isolates and compared with the activities of imipenem and cefoxitin, respectively, by an agar dilution method. Both penems showed potent and similar activity against all anaerobic bacteria tested, particularly Peptococcus spp., Bacteroides fragilis, and Clostridium perfringens. All organisms except a single strain of Fusobacterium necrogenes were inhibited by an 8 micrograms/ml concentration of either Sch 34343 or imipenem. Overall, gram-positive bacilli, particularly Lactobacillus species, Clostridium difficile, and Bifidobacterium and Actinomyces species, were relatively more resistant to either penem than other genera of anaerobic bacteria tested. Cefbuperazone demonstrated only modest activity against a wide spectrum of anaerobic bacteria. It had excellent and selective activity against B. fragilis and Bacteroides vulgatus but was highly inactive against Bacteroides distasonis and Bacteroides thetaiotaomicron within the B. fragilis group. Both cephamycins showed virtually no activity against C. difficile and Lactobacillus spp. Although cefbuperazone was more active against Bifidobacterium spp., it had less activity against Fusobacterium spp., Eubacterium spp., and all Bacteroides spp. other than B. fragilis and B. vulgatus.
In vitro activity of the spermicide nonoxynol-9 against Chlamydia trachomatis
Authors: Kelly J P , Reynolds R B , Stagno S , Louv W C , Alexander W J
Published: June 2012

The in vitro activity of nonoxynol-9 against four serotypes (C, D, H, and K) of Chlamydia trachomatis was investigated. A constant inoculum of each serotype was exposed to serial twofold dilutions (1:100 to 1:800) of Koromex, Conceptrol, or reference preparations (not containing nonoxynol-9) for 4 and 24 h at 37 degrees C. The mixtures of nonoxynal-9 or nonnonoxynol preparations and control inocula were dispensed into triplicate wells containing McCoy cell monolayers. After incubation at 37 degrees C, the monolayers were fixed and stained with iodine and examined for evidence of infection with C. trachomatis. All nonoxynol-9-containing preparations showed marked antichlamydial activity as judged by percent reduction of glycogen-containing intracytoplasmic inclusions. The reference preparations, which did not contain nonoxynol-9, were markedly less active when tested in this in vitro system.
Comparative in vitro activities of cefpiramide and apalcillin individually and in combination
Authors: Allan J D , Eliopoulos G M , Ferraro M J , Moellering R C
Published: June 2012

The in vitro activities of cefpiramide and apalcillin were compared with those of other third-generation cephalosporins and extended-spectrum penicillins against over 1,000 clinical bacterial isolates. The activity of cefpiramide against Pseudomonas aeruginosa was comparable to those of piperacillin and cefoperazone, inhibiting 90% of strains at concentrations less than or equal to 16.0 micrograms/ml. This drug was also active against a broad range of gram-negative organisms but was generally less active than many of the other cephalosporins tested against members of the family Enterobacteriaceae. The activity of cefpiramide against gram-positive organisms was comparable to that of cefoperazone. Apalcillin, along with ceftazidime, was the most active agent tested against P. aeruginosa and Acinetobacter calcoaceticus subsp. anitratus, inhibiting 90% of these strains at concentrations less than or equal to 8 micrograms/ml. Against other gram-negative and gram-positive organisms, its activity was similar to that of piperacillin. The activities of both cefpiramide and apalcillin were significantly reduced by the presence of several plasmid-mediated beta-lactamases in a series of otherwise isogenic strains of P. aeruginosa in comparison with their activities against a parent strain which lacks these enzymes. Many strains of Enterobacter cloacae were synergistically inhibited by the combination of gentamicin with either cefpiramide (5 of 10 strains) or apalcillin (6 of 10 strains). Most strains of P. aeruginosa were synergistically inhibited by the combination of gentamicin with either cefpiramide (8 of 10 strains) or apalcillin (10 of 10 strains). However, cefoxitin antagonized the activity of both cefpiramide and apalcillin against most of these same strains.
In vitro susceptibilities of 126 clinical isolates of Yersinia enterocolitica to 21 beta-lactam antibiotics
Authors: Hornstein M J , Jupeau A M , Scavizzi M R , Philippon A M , Grimont P A
Published: June 2012

The MICs of 21 beta-lactam antibiotics were measured against 126 clinically significant and epidemiologically unrelated Yersinia enterocolitica isolates. The most active antimicrobial agents tested (geometric means of MICs) were ceftriaxone, cefotaxime, ceftizoxime, and cefmenoxime (0.06 to 0.08 micrograms/ml). Mezlocillin (1.36 micrograms/ml) and piperacillin (1.57 micrograms/ml) were the most active penicillins. Aztreonam and imipenem had MICs of 0.44 and 0.24 micrograms/ml. All isolates exhibited some degree of resistance against ampicillin (MICs, greater than or equal to 4 micrograms/ml) and cephalothin (MICs, greater than or equal to 8 micrograms/ml). Cephalosporinase or penicillinase activities were expressed by all isolates. A principal component analysis of MIC data separated the major serotypes (O3, O9, O8, and O5,27). The MCBs of 14 newer beta-lactams were measured against 10 clinical isolates. On the basis of the ratio of MBC to MIC (expressed in dilution factors), a real bactericidal activity was only observed for imipenem (MBC/MIC = 1). For the other newer beta-lactams, the ratios ranged from 4 to 8.
In vitro activity of cefbuperazone compared with that of other new beta-lactam agents against anaerobic gram-negative bacilli and contribution of beta-lactamase to resistance
Authors: Del Bene V E , Carek P J , Twitty J A , Burkey L J
Published: June 2012

Cefbuperazone was compared with other currently available and investigational antibiotics against 278 clinical isolates of anaerobic gram-negative bacilli by an agar dilution method. Cefbuperazone and cefotetan were equally active against Bacteroides fragilis, with 8% of the organisms tested found to be resistant to 32 micrograms of either drug per ml. Cefoperazone, cefotaxime, ceftriaxone, and cefmetazole were less active against these strains; cefoxitin, moxalactam, piperacillin, clindamycin, and metronidazole were more active. None of the agents were consistently active against any of the other anaerobic gram-negative bacilli except imipenem, for which the minimum concentration required to inhibit 90% of all strains tested was 4 micrograms/ml. A 10,000-fold increase in inoculum size caused an increase in the MIC of ceftriaxone, cefotaxime, and cefoperazone but not of cefbuperazone, cefotetan, or cefoxitin. Investigation of the mechanism of resistance to cephalosporin-like agents demonstrated a correlation between the level of resistance and beta-lactamase activity. Cefbuperazone, cefotetan, and cefoxitin were not hydrolyzed, had lower MICs, and were less affected by changes in inoculum size than were cefotaxime, ceftriaxone, and cefoperazone.
Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes
Authors: Richardson K , Brammer K W , Marriott M S , Troke P F
Published: June 2012

The therapeutic potential of UK-49,858, a difluorophenyl bis-triazole derivative, has been assessed by evaluating its activity against systemic infections with Candida albicans in normal mice and rats and in mice with impaired defence mechanisms, against vaginal infections with C. albicans in mice, and against dermal infections with Trichophyton mentagrophytes in guinea pigs. Orally administered ketoconazole was used as a comparative agent throughout, and parenterally administered amphotericin B was included in the study of C. albicans systemic infection in normal mice. The activity of UK-49,858 given orally to mice or rats infected systemically with C. albicans was far superior to that of ketoconazole. In addition, UK-49,858 showed activity comparable to that of amphotericin B when given parenterally, although the latter gave more prolonged protection. UK-49,858 was also effective orally in curing experimental candidal vaginitis in mice and trichophytosis in guinea pigs, against which it was approximately 10 times more active than ketoconazole. These data suggest that UK-49,858 may be of value in the treatment of both C. albicans and dermatophyte fungal infections in man.
Risk factors of ventricular fibrillation during rapid amphotericin B infusion
Authors: Craven P C , Gremillion D H
Published: June 2012

Amphotericin B causes reversible concentration-dependent loss of intracellular potassium in vitro and hyperkalemic ventricular arrhythmias in dogs. Hyperkalemic ventricular arrhythmias associated with amphotericin B infusion have not been well documented in humans. Ventricular fibrillation with progressive hyperkalemia (up to 8 to 8.4 meq/liter) occurred twice in an anuric patient during rapid infusion of high-dose amphotericin B (1.4 mg/kg over 45 min). The peak amphotericin B concentration in serum at the end of infusion was 6.7 micrograms/ml. Prolonged infusion (3 h) and concurrent hemodialysis each prevented the development of hyperkalemia and ventricular arrhythmia. In two anuric patients receiving 4-h infusions of amphotericin B during dialysis (0.7 and 1.0 mg/kg), peak amphotericin B concentrations in serum were lower, 1.6 +/- 0.1 and 2.7 +/- 0.7 micrograms/ml, respectively; serum potassium levels were maintained in the normal range; and venous access for outpatient therapy was convenient. Peak concentrations of amphotericin B in serum were also lower (1.7 +/- 0.7 micrograms/ml) in eight patients with normal renal function who received lower doses (0.7 +/- 0.2 mg/kg) over 45 min; there were only slight increases in the serum potassium level (from 3.9 +/- 0.9 to 4.4 +/- 0.6 meq/liter, P less than 0.05). We recommend that rapid infusion of amphotericin B not be used in patients with impaired potassium excretion unless accompanied by hemodialysis and careful potassium monitoring.
Effects of general and local anesthesia on the pharmacokinetics of cefazolin in patients undergoing orthopedic surgery
Authors: Welch W D , Jantzen J P , Johnson K , Bawdon R E
Published: June 2012

The pharmacokinetics of cefazolin in patients undergoing orthopedic surgery with either general (enflurane) or local (lidocaine or marcaine) anesthesia were studied. No differences in either mean serum levels at 30, 60, or 120 min after the intravenous injection of cefazolin or serum half-lives were seen between the two groups of patients.
Alteration of ribosomes and RNA polymerase in drug-resistant clinical isolates of Mycobacterium tuberculosis
Authors: Yamada T , Nagata A , Ono Y , Suzuki Y , Yamanouchi T
Published: June 2012

The biochemical mechanism of resistance to kanamycin, viomycin, and rifampin in five clinical isolates of Mycobacterium tuberculosis was studied. Resistance to viomycin and kanamycin was attributed to altered ribosomes, whereas resistance to rifampin was attributed to an alteration of RNA polymerase. Ribosomal resistance was, however, not the only way of expressing resistance to viomycin and kanamycin.
Comparative in vitro activities of selected antimicrobial agents against Edwardsiella tarda
Authors: Reinhardt J F , Fowlston S , Jones J , George W L
Published: June 2012

MICs of 14 antimicrobial agents for 29 strains of Edwardsiella tarda were determined by an agar dilution method. Of the agents tested, ciprofloxacin, enoxacin, and norfloxacin were the most active on a weight basis. All strains were also susceptible to clinically achievable concentrations of ampicillin, chloramphenicol, tetracycline, trimethoprim, sulfamethoxazole, trimethoprim plus sulfamethoxazole, cefotaxime, and gentamicin. Ninety percent of the strains demonstrated high-level resistance to polymyxin B and colistin.
In vitro comparative antimicrobial activity of cefpimizole against clinical isolates from five medical centers
Authors: Jones R N , Ayers L W , Gavan T L , Gerlach E H , Sommers H M
Published: June 2012

Cefpimizole was compared with cefoperazone and cefotaxime against 6,599 clinical bacterial isolates from five medical centers. Cefoperazone and cefotaxime were both more active and provided a greater spectrum of antimicrobial coverage than cefpimizole. Some of the cefpimizole minimum concentrations inhibiting 50% of tested strains were as follows: Citrobacter freundii and Enterobacter cloacae, 16 micrograms/ml; Escherichia coli and Klebsiella pneumoniae, 2.0 micrograms/ml; Proteus mirabilis, 1.0 microgram/ml; Pseudomonas aeruginosa, 16 micrograms/ml; Staphylococcus spp., 32 micrograms/ml; and the enterococci, greater than 32 micrograms/ml.
Synergistic activity of combinations of recombinant human alpha interferon and acyclovir, administered concomitantly and in sequence, against a lethal herpes simplex virus type 1 infection in mice
Authors: Connell E V , Cerruti R L , Trown P W
Published: June 2012

The nucleoside analog acyclovir [9-(2-hydroxyethoxymethyl)guanine] and the hybrid recombinant human alpha interferon (rHuIFN-alpha A/D) were evaluated in weanling mice for their efficacy alone and in combination against a lethal systemic infection with herpes simplex virus type 1. Simultaneous parenteral treatment with combinations of both agents at various doses resulted in a higher percentage of survival than when either agent was administered alone, with a synergistic interaction demonstrated at certain dose combinations. Sequential administration of parenteral rHuIFN-alpha A/D and oral acyclovir, administered by gavage or supplied ad libitum in drinking water, resulted in a synergistic interaction at all dose combinations tested. These results suggest that combinations of interferon and acyclovir may be useful in treating primary herpes simplex virus infections in humans.
Transferable plasmid-linked chloramphenicol acetyltransferase conferring high-level resistance in Bacteroides uniformis
Authors: Martínez-Suárez J V , Baquero F , Reig M , Pérez-Díaz J C
Published: June 2012

Bacteroides uniformis RYC3373 resistant to 64 micrograms of chloramphenicol per ml was isolated from a peritoneal pelvic abscess of a patient not previously treated with this drug. Chloramphenicol resistance was transferable at low frequency to a suitable Bacteroides fragilis recipient. The acquisition of resistance was linked to the presence of a 39.5-kilobase plasmid (pRYC3373), which was subsequently transferred to a secondary recipient. The transfer of Cm resistance occurred by a conjugation-like process. Donor and transconjugant strains produced chloramphenicol acetyltransferase constitutively. The Km for chloramphenicol was 40 microM, and its inactivation by 5-5'-dithiobis(2-nitrobenzoic acid) suggested its similarity to the type II enterobacterial enzymes encoded by different conjugative plasmids and also to a previously described enzyme of B. fragilis F47 and F48. The specific activity and the resistance level in pRYC3373-bearing strains were more than 10-fold higher than in the case of the enzyme from B. fragilis strains F47 and F48. The genetic basis of chloramphenicol acetyltransferase synthesis in Bacteroides spp. had not been previously established.
Comparative in vitro evaluation of cefpimizole (U-63196E), a new antipseudomonal cephalosporin
Authors: LeFrock J L , Smith B R , Bihl J
Published: June 2012

The activity of cefpimizole (formerly U-63196E) was compared with that of other broad-spectrum cephalosporins and penicillins. Overall, cefpimizole exhibited limited activity against gram-positive cocci and members of the family Enterobacteriaceae as compared with the other cephalosporins tested. The activity of cefpimizole against Pseudomonas aeruginosa was similar to that of cefoperazone and mezlocillin (90% MIC, 32 micrograms/ml) but poorer than that of ceftazidime (90% MIC, 8 micrograms/ml). Cefpimizole appears to have no in vitro advantage over the cephalosporins with which it was compared.
Pharmacokinetic evaluation of cefoperazone in infants
Authors: Varghese M , Khan A J , Kumar K , Rosenfeld W , Schaeffer H A , Evans H E
Published: June 2012

The pharmacokinetics of cefoperazone were evaluated in 25 infants (mean age, 26 days) after intramuscular and intravenous routes of administration. The levels in blood that were achieved were severalfold higher than those required to inhibit common pathogens. The mean half-life of 240 min was one-half of that observed in 1- to 2-day-old infants but about twice that seen in adults. Further evaluation is needed to study the efficacy of the drug in infants and children.
In vitro susceptibilities of Aeromonas hydrophila, Aeromonas sobria, and Aeromonas caviae to 22 antimicrobial agents
Authors: Motyl M R , McKinley G , Janda J M
Published: June 2012

MICs of 22 antimicrobial agents for 60 strains of three Aeromonas species were determined by a microdilution method. The newer cephalosporins such as moxalactam, cefotaxime, and cefoperazone, the aminoglycosides, and chloramphenicol, tetracycline, nitrofurantoin, and trimethoprim-sulfamethoxazole inhibited most of the strains studied. Within the genus, A. hydrophila was more resistant than either A. caviae or A. sobria to the antibiotics tested.
Imipenem-induced resistance to antipseudomonal beta-lactams in Pseudomonas aeruginosa
Authors: Tausk F , Evans M E , Patterson L S , Federspiel C F , Stratton C W
Published: June 2012

Using clinical isolates of Pseudomonas aeruginosa, we studied the ability of imipenem to antagonize the activity of nine other antipseudomonal beta-lactam antimicrobial agents. Imipenem caused truncation of the zones of inhibition in a disk diffusion test for 91 to 100% of the strains, depending on the beta-lactam tested. Addition of subinhibitory concentrations of imipenem caused a fourfold or greater increase in MICs for 72 of 74 isolates and in 20 to 87% of the tests, again depending on the antibiotic tested. beta-Lactamase assays with both whole-cell suspensions and cell sonicates showed that exposure to subinhibitory concentrations of imipenem resulted in a beta-lactamase production supported the hypothesis that induction of beta-lactamase was responsible for antagonism. In hydrolysis studies with a beta-lactamase extract, most of the antagonized drugs were either not hydrolyzed or only poorly hydrolyzed. We conclude that imipenem induces significantly elevated levels of beta-lactamase in P. aeruginosa. This increase in beta-lactamase is associated with increased resistance of the organism to many other beta-lactam agents.
Involvement of a change in penicillin target and peptidoglycan structure in low-level resistance to beta-lactam antibiotics in Neisseria gonorrhoeae
Authors: Dougherty T J
Published: June 2012

A penicillin-susceptible gonococcus and its low-level resistant penA transformant were examined with regard to their penicillin-binding proteins (PBPs) and their peptidoglycan structures. Treatment of the susceptible strain with its MIC of penicillin (0.01 microgram/ml) led to significant binding to PBPs 2 and 3 and a substantial decrease in the O-acetyl modification on the peptidoglycan. Peptidoglycan synthesis gradually ceased over an extended time. When the penA strain was treated with the same concentration of penicillin, only binding to PBP 3 was observed and there was no O-acetylation decrease, with continued peptidoglycan synthesis. This suggested that PBP 2 was the primary target in penicillin-susceptible gonococci and that this protein participated in the O-acetylation of peptidoglycan. Penicillin concentrations representing the MIC for the penA transformant (0.06 microgram/ml) caused significant binding to PBPs 1, 2, and 3 in the susceptible strain and PBPs 1 and 3 in the penA strain. In both strains the rate of peptidoglycan synthesis and the cross-linkage of the peptidoglycan made declined sharply, suggesting that significant inhibition of PBP 1 interfered with transpeptidation. A model for low-level resistance is proposed in which a decreased PBP 2 affinity leads to assumption of the role of primary target in the resistant transformant by PBP 1. The differences observed in peptidoglycan metabolism are a direct consequence of this change.
Determination of pipemidic acid in plasma by normal-phase high-pressure liquid chromatography
Authors: Ito H , Inoue M , Morikawa M , Tsuboi M , Oka K
Published: June 2012

An improved high-pressure liquid chromatography procedure for determining the concentration of pipemidic acid in human plasma was developed, which uses a normal-phase silica gel column and aqueous mobile solvent system similar to that used in reverse-phase chromatography. Precolumn derivatization of pipemidic acid was achieved by a methylation reaction with boron trifluoride in methanol after extraction from plasma with chloroform containing 4% ethanol. The percent recovery of pipemidic acid was 88.3 +/- 7.7, the variation of which became negligible when quinacrine was used as an internal standard for the determination. High-pressure liquid chromatography analysis was performed by conventional silica gel and mobile solvent mixtures containing 3% of 0.14% HClO4 solution, 19% methanol, and 78% chloroform. The UV detector was set at 265 nm. The detection limit of pipemidic acid methyl ester was as low as 10 ng of the injection amounts or 0.5 micrograms of the plasma per ml, with 0.01 absorbance units (full scale) and a signal-to-noise ratio of 3.
Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses
Authors: Freitas V R , Smee D F , Chernow M , Boehme R , Matthews T R
Published: June 2012

The activities of the purine acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) against two human and five animal strains of cytomegalovirus were compared with those of acyclovir. DHPG was significantly more active than acyclovir against all but one (mouse cytomegalovirus) of the strains tested, with 50% effective doses ranging from 5 to 13 microM, as determined by plaque reduction assays in human embryonic lung (MRC-5) and human embryonic tonsil cells. Both DHPG and acyclovir inhibited virus replication at concentrations considerably lower than those necessary to inhibit cell proliferation. In mode-of-action studies, the triphosphates of DHPG and acyclovir inhibited human cytomegalovirus DNA polymerase. DHPG phosphorylation to the active triphosphate was enhanced in infected cells; however, this enzymatic activity was unrelated to thymidine kinase. In animal studies, DHPG was slightly more effective than acyclovir in reducing mouse cytomegalovirus-induced mortality.
Antiviral activity of 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodocytosine against human cytomegalovirus in human skin fibroblasts
Authors: Colacino J M , Lopez C
Published: June 2012

2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodocytosine (FIAC) was shown to be a selective anti-human cytomegalovirus agent in vitro with a 50% antiviral effective dose of 0.6 microM (J. M. Colacino and C. Lopez, Antimicrob. Agents Chemother. 26:505-508, 1983) and a 50% cell growth inhibitory dose of 8 microM. Antiviral activity was more readily reversed with 10-fold excess thymidine, whereby the 50% effective dose was increased to 11.3 microM. FIAC-induced cytotoxicity was more readily reversed with 10-fold excess of deoxycytidine, whereby the 50% inhibitory dose was increased to greater than 100 microM. Thymidine was unable to reverse completely the antiviral activity of FIAC. Although, the extent of phosphorylation of thymidine, deoxycytidine, and deoxyuridine was 6-, 4-, and 4-fold greater, respectively, in human cytomegalovirus-infected cell lysates than in uninfected cell lysates, the extent of phosphorylation of FIAC was only 1.3-fold greater in human cytomegalovirus-infected cell lysates than in uninfected cell lysates. By comparison, the extent of FIAC phosphorylation was 500 times greater in herpes simplex virus type 1-infected cells than in uninfected cell lysates. Methotrexate was 400 times more effective against human cytomegalovirus replication than it was against herpes simplex virus type 1 replication, indicating that thymidylate synthetase may be important for human cytomegalovirus replication. However, 10 microM FIAC did not inhibit thymidylate synthetase activity in uninfected or virus-infected cells as determined by their metabolism of [6-3H]deoxyuridine in the presence or absence of drug. FIAC at 1 microM suppresses and FIAC at 10 microM completely inhibits human cytomegalovirus DNA replication as indicated by Southern blot analysis. This inhibition was reversible. FIAC incorporation into the DNA of human cytomegalovirus strain AD169-infected cells was stimulated relative to that in nondividing, uninfected cells.
Moxalactam kinetics during continuous ambulatory peritoneal dialysis after intraperitoneal administration
Authors: Jones T E , Milne R W , Mudaliar Y , Sansom L N
Published: June 2012

Moxalactam kinetics during continuous ambulatory peritoneal dialysis (CAPD) was followed in eight patients after a single intraperitoneal dose of 1 g. Approximately 60% of the dose was absorbed after a dwell time of 4 h. Dialysis solutions were exchanged at 4-h intervals with an overnight dwell of 8 h. The mean (+/- standard deviation) elimination half-life was 13.2 +/- 2.9 h, and the mean apparent volume of distribution was 0.22 +/- 0.08 liters/kg. Mean total clearance was 11.5 +/- 2.4 ml/min, with a mean dialysis clearance of 2.3 +/- 0.5 ml/min. The maximum concentration in plasma ranged from 24.5 to 54.1 micrograms/ml. Moxalactam concentrations in the peritoneal dialysis fluid were above 80 micrograms/ml during the first exchange and above 2 micrograms/ml for a further three exchanges. A suggested intraperitoneal dose regimen for patients undergoing CAPD is 1 g initially, followed by 15 to 25% of the recommended dose for normal patients given at the same time intervals, or 30 to 50% of the recommended dose at twice the usual intervals. Moxalactam is suggested for initial treatment of peritonitis in CAPD patients who do not have ready access to the antibiotic of choice.
Ciprofloxacin therapy of infections caused by Pseudomonas aeruginosa and other resistant bacteria
Authors: Eron L J , Harvey L , Hixon D L , Poretz D M
Published: June 2012

Ciprofloxacin was administered orally to 48 patients with 24 Pseudomonas aeruginosa infections and 13 other infections caused by cephalothin-resistant gram-negative bacilli. The types of infections treated included those of skin or skin structure, bone, urinary tract, and respiratory tract. In 83% of P. aeruginosa infections, a favorable clinical outcome occurred, compared with 85% for all infections. Failure to achieve a cure correlated with the emergence of resistant P. aeruginosa and Acinetobacter calcoaceticus strains in four instances and superinfection with Candida (two cases) and Streptococcus (two cases) species. Therapy was discontinued in three patients because of the development of nausea. Ciprofloxacin appears to be safe and effective in the therapy of infections caused by resistant gram-negative bacilli.
Plasmid-mediated aminoglycoside phosphotransferases in Haemophilus ducreyi
Authors: Sanson-le Pors M J , Casin I M , Collatz E
Published: June 2012

Three clinical isolates of Haemophilus ducreyi, representing at least two subtypes, were shown to be resistant to streptomycin and kanamycin. They also produced a beta-lactamase and chloramphenicol acetyltransferase and were resistant to tetracycline. In the three strains the resistance to both aminoglycoside antibiotics was encoded by a plasmid of ca. 4.7 kilobases which apparently did not carry ampicillin, chloramphenicol, or tetracycline resistance genes, as determined after transfer to Escherichia coli by transformation. Resistance to streptomycin and kanamycin was due to the presence of two aminoglycoside phosphotransferases (APH). The enzyme modifying kanamycin was a 3',5"-APH of type I [APH(3',5")-I], as inferred from its substrate profile and immunological cross-reactivity with the APH(3',5")-I encoded by the transposable element Tn903. However, the APH(3',5")-I gene in H. ducreyi did not appear to be carried by Tn903.
Mechanism of selective inhibition of human cytomegalovirus replication by 1-beta-D-arabinofuranosyl-5-fluorouracil
Authors: Suzuki S , Saneyoshi M , Nakayama C , Nishiyama Y , Yoshida S
Published: June 2012

Four kinds of 1-beta-D-arabinofuranosyl-5-halogenouracil were examined for inhibition of human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) replication. 1-beta-D-Arabinofuranosyl-5-fluorouracil (ara-FU) was the most effective against HCMV, whereas 1-beta-D-arabinofuranosyl-5-bromouracil was the most effective against HSV-1 and HSV-2. The mechanism of action of ara-FU on HCMV replication was also studied. The dTTP pool size in human embryonic fibroblasts was increased 33-fold by HCMV infection. However, treatment with ara-FU decreased the size of the dTTP pool by approximately 50%. On the other hand, 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate inhibited HCMV DNA polymerase activity competitively with dTTP. These results suggest that ara-FU acts as a bifunctional inhibitor of HCMV replication. Ara-FU is phosphorylated by cellular thymidine kinase to 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-monophosphate, which inhibits cellular thymidylate synthetase, which in turn decreases the dTTP pool size in infected cells. As the dTTP pool size is reduced, inhibition of viral DNA polymerase by 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate becomes more efficient.
Emergence of trimethoprim resistance in fecal flora
Authors: Huovinen P , Mattila T , Kiminki O , Pulkkinen L , Huovinen S , Koskela M , Sunila R , Toivanen P
Published: June 2012

The emergence of trimethoprim (TMP) resistance in fecal flora was compared in patients with urinary tract infection treated with TMP or TMP-sulfamethoxazole. No significant differences were found in the occurrence of TMP-resistant fecal aerobic bacteria in the two treatment groups before and after treatment.