bluuebunny/crossref_metadata_2025 huggingface dataset:
Potentiation of antiviral activity of acyclovir by polyene macrolide antibiotics
Authors: Malewicz B , Momsen M , Jenkin H M , Borowski E
Published: June 2012

The potentiation of the antiviral activity of acyclovir [9-[(2-hydroxyethoxy)methyl]guanine] by polyene macrolide antibiotics has been studied as a function of the macrolide structure. The 12 polyenes chosen for this study represented the major structural groups of these antibiotics and induced in mammalian cells repairable membrane alterations or irreversible cell damage. The potentiating activity of the polyene macrolides was determined based on the differential decrease of in vitro production of infectious virions in the presence of acyclovir alone or in combination with the polyene. Pseudorabies virus, a representative herpesvirus susceptible to acyclovir, was replicated in BHK-21 cells grown in serum-free medium to avoid the interference of serum factors in the polyene macrolide-cell interaction. The potentiation activity of the polyene antibiotics was concentration dependent. The enhancement of the antiviral activity of acyclovir was observed at polyene concentrations which had no direct effect on pseudorabies virus replication in BHK-21 cells. The optimal potentiating concentrations of polyenes were 2 to 15 times lower than that inducing 50% of potassium efflux from BHK-21 cells. The highest potentiating activity was observed for the methyl ester of the trimethylammonium derivative of aureofacin B, which reduced the pseudorabies virus titer by two orders of magnitude. Potentiation by polyene macrolides appeared to coincide with the K+-dependent membrane repair process. The acyclovir potentiating activity was associated with polyene macrolide antibiotics having a large and rigid macrolide ring (amphotericin B and aureofacin). Polyene antibiotics with small and rigid (pimaricin and filipin) or large but flexible (nystatin A1 and lienomycin) macrolide rings showed no potentiation of the antiviral effect of acyclovir.
Comparative activities of ciprofloxacin, ticarcillin, and tobramycin against experimental Pseudomonas aeruginosa pneumonia
Authors: Schiff J B , Small G J , Pennington J E
Published: June 2012

The therapeutic efficacy of ciprofloxacin, an investigational quinoline derivative, was compared with those of ticarcillin and tobramycin in guinea pigs with experimental Pseudomonas aeruginosa pneumonia. Guinea pigs challenged with tracheal instillations of 10(8) CFU of P. aeruginosa developed acute pneumonia, for which survival rates were: controls, 0%; ticarcillin treatment, 37%; ciprofloxacin treatment, 57%; and tobramycin treatment, 69%. Intrapulmonary killing of P. aeruginosa was greater (P less than 0.05) in animals treated with ciprofloxacin or tobramycin than in groups treated with ticarcillin. A more chronic, nonfatal form of bronchopneumonia caused by P. aeruginosa was induced with agar beads impregnated with bacteria for pulmonary challenge. In this model, ciprofloxacin treatment resulted in significantly (P less than 0.001) greater intrapulmonary killing than did any other therapy. These data suggest that ciprofloxacin may be useful in the treatment of acute and more-chronic forms of pulmonary infection caused by P. aeruginosa.
Safety of prolonged administration of rimantadine hydrochloride in the prophylaxis of influenza A virus infections in nursing homes
Authors: Patriarca P A , Kater N A , Kendal A P , Bregman D J , Smith J D , Sikes R K
Published: June 2012

We evaluated the safety of rimantadine hydrochloride (RH) prophylaxis in a double-blind, placebo-controlled trial in three nursing homes during a community epidemic of influenza A (H3N2). Although daily monitoring of the 35 participants revealed an association between RH administration (100 mg twice a day) and the development of nausea and anxiety (P less than 0.05), these and other potential side effects were transient and were rarely considered to be clinically significant. Serum RH levels measured at the end of the trial (mean, 1,159 ng/ml) were nearly three times higher than those measured previously in younger individuals, suggesting that lower dosages may be indicated for the elderly.
Pharmacokinetics and tissue penetration of enoxacin
Authors: Wise R , Lockley R , Dent J , Webberly M
Published: June 2012

The pharmacokinetics of the quinolone enoxacin were studied after a 600-mg oral dose was given to each of six male volunteers. The levels of the compound were measured in serum, blister fluid, and urine. Absorption was variable, with peak levels (mean, 3.7 micrograms/ml) being attained between 0.75 and 3.0 h (mean, 1.9 h). The serum elimination half-life was 6.2 h, and 71.6% of the drug was recovered in the urine by 48 h. Enoxacin penetrated blister fluid well, the mean percent penetration being 78.4%.
Direct membrane-damaging effect of ketoconazole and tioconazole on Candida albicans demonstrated by bioluminescent assay of ATP
Authors: Anséhn S , Nilsson L
Published: June 2012

Bioluminescent assays of fungal ATP in cultures of Candida albicans exposed to tioconazole and ketoconazole demonstrated that intracellular ATP levels were directly related to cell viability. At high concentrations of drug, a fungicidal effect was indicated by a very rapid and heavy leakage of ATP and a simultaneous, dramatic decrease in intracellular ATP. This leakage was due to direct membrane damage, which was less pronounced after exposure to ketoconazole than to tioconazole. After exposure to lower imidazole concentrations, intracellular ATP indicated growth inhibition without significant leakage of ATP. These findings support the hypothesis that imidazole antifungal agents basically act in the same manner but at different concentrations.
Teicoplanin versus nafcillin and vancomycin in the treatment of experimental endocarditis caused by methicillin-susceptible or -resistant Staphylococcus aureus
Authors: Chambers H F , Sande M A
Published: June 2012

In rabbits with experimentally induced endocarditis, the efficacy of teicoplanin compared favorably both with that of nafcillin for infection by a methicillin-susceptible strain of Staphylococcus aureus and with that of vancomycin for infection by a methicillin-resistant strain of S. aureus. In a 4-day treatment regimen, teicoplanin was as effective as either nafcillin or vancomycin in eliminating organisms from aortic valve vegetations in the respective infection. In a 10-day regimen for methicillin-resistant S. aureus endocarditis, both teicoplanin and vancomycin sterilized the vegetations of some rabbits, but the relapse rate was high for both. These results justify further investigation into the role of teicoplanin for the treatment of serious infections caused by S. aureus.
Determination of imipenem and cilastatin in serum by high-pressure liquid chromatography
Authors: Myers C M , Blumer J L
Published: June 2012

Imipenem and cilastatin concentrations in serum were determined by using reverse-phase high-pressure liquid chromatography. Serum samples were stabilized with 0.5 M morpholineethanesulfonic acid buffer (pH 6.0) and subjected to ultrafiltration before chromatography. The elution solvent consisted of water or potassium phosphate buffered to pH 2.5 and methanol. The imipenem and cilastatin peaks were detected at 300 and 220 nm, respectively. Recovery from serum was 99% for both imipenem and cilastatin, and the limits of detectability for the two compounds were 0.3 and 0.5 microgram/ml, respectively. The assay may be readily applied to pharmacokinetic analysis of imipenem and cilastatin biodisposition in patients.
In vitro activities of norfloxacin and ciprofloxacin against Mycobacterium tuberculosis, M. avium complex, M. chelonei, M. fortuitum, and M. kansasii
Authors: Gay J D , DeYoung D R , Roberts G D
Published: June 2012

The activities of ciprofloxacin and norfloxacin against 100 mycobacteria isolates were studied in vitro by the 1% standard proportion method. Ciprofloxacin was more active against M. tuberculosis and M. fortuitum with MICs of 1.0 and 0.25 microgram/ml, respectively, against 90% of isolates; norfloxacin had MICs of 8.0 and 2.0 micrograms/ml, respectively, against 90% of isolates.
Efficacy of liposome-intercalated amphotericin B in the treatment of systemic candidiasis in mice
Authors: Tremblay C , Barza M , Fiore C , Szoka F
Published: June 2012

We developed a liposome-intercalated preparation of amphotericin B by using small, unilamellar vesicles 0.06 to 0.1 micron in diameter. In contrast to previously described liposomal preparations of amphotericin B, these vesicles have the advantage that they are small enough to be filter sterilized. We compared the efficacy of liposomal amphotericin B with that of the commercial drug given as an intravenous bolus every other day for 13 days (seven doses) in mice with disseminated candidiasis. Survival rates were similar for the two preparations at each dosage of amphotericin B; however, the highest survival rates occurred at dosages of liposomal amphotericin B which would be lethal to these animals if administered as the commercial drug. Viable colony counts of fungi in various organs, particularly the kidneys, tended to be lower with increasing dosage of the drug. However, some organisms persisted even after 13 days. These studies indicate that liposomal formulations of amphotericin B merit further investigation because of their improved therapeutic margins.
MBCs for Staphylococcus aureus as determined by macrodilution and microdilution techniques
Authors: Shanholtzer C J , Peterson L R , Mohn M L , Moody J A , Gerding D N
Published: June 2012

MBC testing of clindamycin, methicillin, cephalothin, gentamicin, and vancomycin with 67 clinical isolates of Staphylococcus aureus was examined by both standard macrodilution tubes and commercial microdilution trays. Standard macrodilution failed to give reproducible (99.9% killing) MBC results, even when a strictly defined protocol was followed. Continuous shaking during incubation resulted in regrowth of more colonies than did stationary incubation. Vortexing of incubated tubes before subculture resulted in regrowth of more colonies than did careful transfer of the contents to sterile tubes before vortexing and subculture. No significant difference in MBCs was demonstrated by the use of log-phase versus stationary-phase inocula. Use of the multiprong inoculator for subculture from commercial microdilution trays was unsatisfactory because, although antibiotics evaluated were inactivated by subculture to a pH 5.5 agar plate coated with a beta-lactamase solution, the volume of broth transferred by the prongs was small and inconsistent, ranging from 0 to 3 microliter. Subcultures of commercial microdilution panels with a 1-microliter loop, 10-microliter pipette, and 100-microliter pipette were also evaluated. Results of MBC testing were most reproducible when the entire 100-microliter volume was aspirated from commercial microdilution wells after stirring and the contents of each well were spread over a separate sheep blood agar plate.
In vitro activity of HR 810, a new cephalosporin
Authors: Bertram M A , Bruckner D A , Young L S
Published: June 2012

The in vitro susceptibility of 409 clinical isolates to HR 810, a new cephalosporin, was evaluated and compared with their susceptibility to aztreonam, cefazolin, ceftazidime, imipenem, moxalactam, piperacillin, and gentamicin. On a weight basis, the activity of HR 810 against gram-negative bacilli was equivalent or superior to that of the other beta-lactam agents except imipenem.
Enterococcal superinfection and colonization with aztreonam therapy
Authors: Chandrasekar P H , Smith B R , LeFrock J L , Carr B
Published: June 2012

Patients were given aztreonam (SQ 26,776) parenterally for the treatment of various gram-negative infections. During or shortly after therapy, 8 (17.8%) of 45 patients became infected with or colonized by enterococcus. These eight cases included eight urinary tract isolates; one of these cases subsequently developed bacteremia. Five patients required further antimicrobial therapy directed against enterococcus. Patients receiving aztreonam are at risk for the development of enterococcal superinfection or colonization.
Azlocillin and cefonicid penetration into bone enhanced by probenecid
Authors: Summersgill J T , Harrod L G , Raff M J
Published: June 2012

Azlocillin (AZL) and cefonicid (CFD) penetration into rabbit humerus and scapula was evaluated with and without concomitantly administered probenecid. Groups of animals received either 70 mg of AZL intravenously or 20 mg of CFD intramuscularly per kg of body weight; other groups were pretreated with 40 mg of probenecid per kg before the administration of antibiotics. Peak levels of AZL in the sera of animals not receiving probenecid were 76.0 micrograms/ml at 30 min and declined to 7.7 micrograms/ml by 2.0 h. Maximum concentrations in bone were 2.7 micrograms/g in the humerus and 7.1 micrograms/g in the scapula at 1 h. Pretreatment with probenecid significantly elevated levels of AZL in both serum and bone while increasing the half-life in serum from 0.44 to 0.65 h. Maximum drug concentrations in bones of probenecid-pretreated animals were 3.9 and 11.7 micrograms/g in the humerus and scapula, respectively, with detectable levels persisting in bone for up to 4 h. The peak level of CFD alone in serum was 36.7 micrograms/ml at 30 min and declined to 0.86 micrograms/ml at 8 h. Maximum concentrations in bone were 0.66 micrograms/g in the humerus at 1 h and 1.8 micrograms/g in the scapula at 2 h. Pretreatment with probenecid significantly elevated levels of CFD in both serum and bone while increasing the half-life in serum from 1.4 to 2.94 h. Pretreatment with probenecid achieved maximum concentrations of 1.7 and 2.8 micrograms/g in the humerus and scapula, respectively. Detectable levels of CFD persisted in the humerus for up to 4 h and in the scapula for 8 h.
Timentin versus piperacillin or moxalactam in the therapy of acute bacterial infections
Authors: File T M , Tan J S , Salstrom S J , Johnson L A , Douglas G F
Published: June 2012

In a randomized comparative study, 116 patients with acute bacterial infections were treated with timentin (ticarcillin plus clavulanic acid) or a comparative agent (piperacillin for respiratory or urinary tract infections, and moxalactam for soft tissue infections). There were 91 clinically evaluated infections (timentin, 46; piperacillin, 29; moxalactam, 16). Twelve patients were bacteremic. A satisfactory clinical response occurred in all 46 patients treated with timentin and in 42 of the 45 treated with a comparative agent. Two clinical failures were due to superinfection (a Staphylococcus aureus pneumonia in the piperacillin group and an enterococcal skin infection in the moxalactam group), and one clinical failure was due to a primary S. aureus skin infection (moxalactam group). One wound isolate of Pseudomonas aeruginosa developed resistance to timentin during therapy (despite clinical improvement). Adverse reactions were uncommon but did include one patient treated with timentin who developed unexplained hallucinations.
Ceftazidime as initial therapy for suspected bacterial infections in hospitalized pediatric patients
Authors: Reed M D , O'Brien C A , Aronoff S C , Klinger J D , Blumer J L
Published: June 2012

Ceftazidime, a new beta-lactam antibiotic, was used to treat 60 children with suspected bacterial infections occurring outside the central nervous system. The patients ranged in age from 0.1 to 21 years and received 30 mg of ceftazidime per kg up to a total single dose of 1 g administered every 8 h. Fifty-three pathogens were isolated from 43 children before the initiation of therapy. All children responded clinically, although one child failed bacteriologically and five children were considered colonized at the end of ceftazidime therapy. Adverse reactions associated with ceftazidime administration were primarily alterations in laboratory parameters and were clinically insignificant. Ceftazidime administered on an 8-h dosing regimen is effective monotherapy for the treatment of childhood infections.
Comparison of antimicrobial susceptibility patterns of Campylobacter jejuni and Campylobacter coli
Authors: Wang W L , Reller L B , Blaser M J
Published: June 2012

To determine whether employing antibiograms is useful to separate Campylobacter jejuni and Campylobacter coli, we determined the MICs of 12 antibiotics for 104 human clinical strains and 74 swine strains. Of 74 swine strains, 5 (7%) were hippurate positive, as were 93 (89%) of 104 human strains. The 12 antimicrobial agents tested were ampicillin, amoxicillin, clindamycin, chloramphenicol, erythromycin, furazolidone, norfloxacin, nalidixic acid, rosoxacin, rosaramicin, tetracycline, and Sch 32063. Isolates from humans were significantly (P less than 0.001) more susceptible than swine strains to clindamycin, erythromycin, rosaramicin, and Sch 32063. Of 11 human hippurate-negative strains, 3 (27%) were resistant to clindamycin, erythromycin, rosaramicin, and Sch 32063, compared with 1 of 93 (1%) hippurate-positive strains. Nearly all human and swine strains were susceptible to furazolidone and nalidixic acid. Campylobacter isolates from humans and swine have different antibiograms, and the susceptibility to certain antibiotics, such as clindamycin, may be helpful for differentiation of C. jejuni from C. coli.
Pharmacokinetics of cefotiam and cefsulodin after simultaneous administration to patients with impaired renal function
Authors: Lecaillon J B , Rouan M C , Binswanger U , Guibert J , Schoeller J P
Published: June 2012

The possible influence of the concomitant administration of cefotiam and cefsulodin on their respective pharmacokinetics was studied in 15 patients with renal insufficiency and 10 anuric patients. Linear relations were found between the clearance of creatinine and the total clearance, as well as the renal clearance, of each drug. These relations for each cephalosporin were not significantly different from previous results obtained after separate administration. In hemodialyzed patients, the two cephalosporins were readily eliminated from the blood after simultaneous administration: ca. 35% of the dose of cefotiam and 30% of the dose of cefsulodin was recovered in the dialysate over 5 h. These results suggest that the pharmacokinetics of the two drugs are not modified by their simultaneous administration and that the dosing schedule previously proposed for administration of the two cephalosporins alone in the presence of renal insufficiency can be applied without modification when they are given together. Patients on hemodialysis should receive a loading dose after each dialysis period, and then reduced doses according to recommendations for anuric patients.
Renal disposition of ceftazidime illustrated by interferences by probenecid, furosemide, and indomethacin in rabbits
Authors: Carbon C , Dromer F , Brion N , Cremieux A C , Contrepois A
Published: June 2012

Excretion of ceftazidime (C), a new cephalosporin antibiotic, has been reported to occur unexpectedly through glomerular filtration only, without being significantly affected by probenecid. We investigated renal tubular disposition of C in rabbits by calculating its rates of fractional excretion, net tubular secretion, and absolute excretion. During continuous intravenous infusion of C, 3 mg of furosemide (F), 15 mg of probenecid (P), or 2 mg of indomethacin (I) per kg was injected intravenously as a bolus. Equilibrium dialysis showed that the percentage of C bound to serum proteins (14 +/- 5%) was not altered by F, P, or I. Fractional excretion of C was 94 +/- 22, 65 +/- 21, 182 +/- 36, and 98 +/- 3% for the drug given alone and after injection of F, P, and I, respectively. For 15 min after P injection, we observed net tubular secretion of C (404 +/- 276 micrograms/min). The C absolute excretion rate was significantly reduced by I compared with the absolute excretion rate for the control (405 +/- 104 versus 696 +/- 157 micrograms/min). We conclude that (i) C undergoes bidirectional transport in the nephron, revealed by the effects of F and P, with a nil net C balance; (ii) F and P have opposite unexpected effects on tubular handling of C, possibly due to competition for C secretion processes; (iii) I reduces C excretion solely by decreasing its glomerular-filtered load; and (iv) tubular handling of C differs from that of previously studied cephalosporins.
Herpes simplex virus mutants resistant to arabinosyladenine in the presence of deoxycoformycin
Authors: Fleming H E , Coen D M
Published: June 2012

Herpes simplex virus mutants PAAr5, AraAr6, AraAr7, AraAr9, and AraAr13, which previously had been shown to be resistant to arabinosyladenine (araA) alone, were found to be resistant to araA in the presence of high concentrations of the adenosine deaminase inhibitor, deoxycoformycin. The marker conferring resistance to araA and deoxycoformycin in mutant PAAr5 was mapped finely to an 0.8-kilobase-pair region in the herpes simplex virus DNA polymerase locus. These results indicate that the mutants are resistant to araA itself rather than to its deamination product and confirm the importance of the viral polymerase in the antiviral action of araA.
Comparative in vitro activities of enoxacin (CI-919, AT-2266) and eleven antipseudomonal agents against aminoglycoside-susceptible and -resistant Pseudomonas aeruginosa strains
Authors: Bassey C M , Baltch A L , Smith R P , Conley P E
Published: June 2012

The in vitro activity of enoxacin (CI 919, AT 2266), a new oral quinolone carboxylic acid compound, was compared with those of gentamicin, tobramycin, amikacin, azlocillin, piperacillin, aztreonam, moxalactam, imipenem, cefsulodin, ceftazidime, and cefoperazone against 101 aminoglycoside-susceptible and 105 aminoglycoside-resistant Pseudomonas aeruginosa strains. Among these 206 P. aeruginosa isolates were 25 strains with known mechanisms of resistance to amikacin. The activity of enoxacin was similar to that of tobramycin against aminoglycoside-susceptible strains, with MICs of 1.0 to 2.0 micrograms/ml and 0.5 to 1.0 microgram/ml, respectively, for 90% of the strains. Enoxacin was the most active agent in this in vitro study against aminoglycoside-resistant P. aeruginosa strains, with MICs of 2.0 to 4.0 micrograms/ml for 90% of the strains. Strains with enzymatic resistance to amikacin were more resistant to beta-lactams (except enoxacin and imipenem) than were strains with decreased permeability.
In vitro activity of WIN 49375 compared with those of other antibiotics in isolates from cancer patients
Authors: Garcia I , Bodey G P , Fainstein V , Ho D H , LeBlanc B
Published: June 2012

The activity of WIN 49375 [6-fluoro-1, 4-dihydro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid], a new synthetic quinolone, was tested in vitro against 587 clinical isolates. The MICs for 90% of isolates of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae were 0.20, 1.56, and 0.39 microgram/ml, respectively. The MICs for 90% of isolates of Pseudomonas aeruginosa and Serratia marcescens were both 3.12 micrograms/ml. WIN 49375 was minimally active against gram-positive cocci. Its in vitro activity suggests that it may be useful for the treatment of gram-negative bacillary infections.
Biliary elimination of apalcillin in humans
Authors: Brogard J M , Arnaud J P , Blickle J F , Lavillaureix J
Published: June 2012

Apalcillin was administered intravenously as a single 1-g dose on day 8 after surgery to 10 cholecystectomized patients with T-tube drainage. A peak of 2,093 +/- standard error of the mean 859 micrograms/ml of bile was attained at 3 h after dosage. Biliary recovery over a 12-h period amounted to 12.2% of the dose. In 20 patients undergoing biliary surgery, apalcillin concentrations 1 h after a 1-g dose were 65.5 +/- 5.0, 3,680 +/- 551, and 2,552 +/- 627 micrograms/ml in serum, choledochal bile, and gallbladder bile, respectively.
Efficacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis carinii pneumonitis
Authors: Hughes W T , Smith B L
Published: June 2012

The purpose of this study was to identify new drugs for the prevention and treatment of Pneumocystis carinii pneumonitis (PCP) induced in rats by continuous daily dosage with dexamethasone. Initially, test drugs were administered prophylactically as a screen for efficacy. Drugs were selected because of their known activity against certain protozoa and their tolerance in human usage. Doses were based on previous studies in rats or estimated from usage in humans and lower animals. Allopurinol (50 mg/kg per day), ketoconazole (25 mg/kg per day), difluoromethylornithine (2.5 g/kg per day), diloxanide (125 mg/kg per day, nifurtimox (100 mg/kg per day), suramin (20 mg/kg per day), melarsoprol (20 mg/kg per day), gentian violet (0.5 mg/kg per week, 5 and 50 mg/kg per day), primaquine (5.6 mg/kg per day) and chloroquine (37.5 mg/kg per day) were ineffective, whereas diaminodiphenylsulfone (daspone) (25 mg/kg per day) was totally effective in preventing the infection. Diaminodiphenylsulfone was then evaluated at dose levels of 5, 25, and 125 mg/kg per day and compared with trimethoprim-sulfamethoxazole (TMP-SMZ), given at 50 per 250 mg/kg per day orally. The two highest dose levels of diaminodiphenylsulfone and TMP-SMZ prevented the infection in all of the animals, and the lowest dose of diaminodiphenylsulfone prevented it in 40% of the rats. All of the untreated controls developed PCP. To determine therapeutic efficacy, animals with extensive PCP were treated for 2.5 weeks with diaminodiphenylsulfone or TMP-SMZ. Based on residual extensive pneumonitis at the completion of treatment, the pneumonitis was reduced to 50% by TMP-SMZ and to 25% by diaminodiphenylsulfone, whereas 100% of untreated controls had extensive PCP. When treatment was begun earlier in the course of the pneumonitis, diaminodiphenylsulfone was totally effective in eradicating the infection. These results suggest that diaminodiphenylsulfone is an effective drug for the treatment and prevention of murine PCP and that it is at least as effective as TMP-SMZ.
Clinical pharmacokinetics of aztreonam in cancer patients
Authors: Jones P G , Bodey G P , Swabb E A , Ho D H , Fainstein V , Pasternak J
Published: June 2012

The pharmacokinetics of aztreonam were studied in 25 adult patients with hematological malignancies. Two groups of nine patients each received aztreonam (1 or 2 g every 8 h) prophylactically, and seven infected patients received a therapeutic regimen of aztreonam (1.5 g every 4 h). The mean peak serum concentration after a 1-g dose of aztreonam (given over 0.5 h on day 1) was 75.5 micrograms/ml; after a 2-g dose it was 177.2 micrograms/ml. The mean peak serum concentration after a 1.5-g dose of aztreonam (given over 2 h on day 1) was 68.5 micrograms/ml. The serum half-life ranged between 1.7 and 2.0 h for all regimens studied. The urinary concentration of the metabolite of aztreonam, SQ 26,992, increased during 1 week of administration of the drug; however, serum levels of the metabolite were barely detectable.
Comparative trial of norfloxacin and trimethoprim-sulfamethoxazole in the treatment of women with localized, acute, symptomatic urinary tract infections and antimicrobial effect on periurethral and fecal microflora
Authors: Haase D A , Harding G K , Thomson M J , Kennedy J K , Urias B A , Ronald A R
Published: June 2012

Forty-three women with acute, symptomatic urinary tract infections were randomized to receive either norfloxacin (400 mg) twice daily or trimethoprim-sulfamethoxazole (160-800 mg) twice daily for 10 days. Of the 43 patients, 7 (16%) had low-count bacteriuria and pyuria and were included in the evaluation. Escherichia coli was isolated in 72% of the infections, whereas coagulase-negative staphylococci were isolated in 14%. All isolates were susceptible to the assigned study drug. The MICs for 90% of the strains susceptible to norfloxacin and trimethoprim-sulfamethoxazole were less than or equal to 2 and less than or equal to 0.8-16 micrograms/ml, respectively. The cure rates for norfloxacin and trimethoprim-sulfamethoxazole were 95 and 90%, respectively. There were 17 patients with presumptive upper tract infections; only 1 of these relapsed after therapy. The effects on the periurethral flora were similar in both groups, but the infecting organism was eradicated from the fecal flora in 93% of the patients treated with norfloxacin and in 57% of the patients treated with trimethoprim-sulfamethoxazole. More early reinfections occurred in the trimethoprim-sulfamethoxazole group, with resistant organisms appearing in urine and in the periurethral and fecal flora in all cases. Three patients in each group experienced adverse clinical effects, but these were more severe in the trimethoprim-sulfamethoxazole group. No adverse hematological or biochemical changes were noted. From these results, we concluded that norfloxacin is at least as effective as trimethoprim-sulfamethoxazole in the therapy of acute, symptomatic urinary tract infections in women.
Resistance of Pseudomonas aeruginosa to new beta-lactamase-resistant beta-lactams
Authors: Godfrey A J , Bryan L E
Published: June 2012

An isogenic set of mutants of Pseudomonas aeruginosa, altered in permeability or permeability plus constitutive production of beta-lactamase, was examined for susceptibility to newer beta-lactam antibiotics. Kinetic data on the chromosomal beta-lactamase and susceptibility studies for the test beta-lactams indicate that permeability was the major mechanism of resistance to the poorly hydrolyzed and nonhydrolyzed antibiotics, e.g., carbenicillin, moxalactam, and cefsulodin. An exception was cefotaxime, with a low Km and a low Vmax, which had reduced efficacy in the permeability mutant and was further affected by the constitutive beta-lactamase. In this case, since the Vmax was low, a nonhydrolytic barrier may provide the additional reduction in susceptibility.
Effects of cirrhosis on kinetics of aztreonam
Authors: MacLeod C M , Bartley E A , Payne J A , Hudes E , Vernam K , Devlin R G
Published: June 2012

Aztreonam was administered as a single, 3-min, 1-g intravenous infusion to 18 subjects, including 6 with biopsy-proven, primary biliary cirrhosis, 6 with biopsy-proven, stable alcoholic cirrhosis, and 6 age- and sex-matched control subjects with normal hepatic functions. Aztreonam was well tolerated by all subjects. Multiple blood samples and timed, cumulative urine samples were taken for assay of aztreonam content and determination of pharmacokinetic profiles. Protein-free filtrates of serum were also assayed for drug levels. Analyses by microbiological and high-pressure liquid chromatographic procedures gave equivalent results. The kinetic data were described by an open, linear, two-compartment model. There were significant differences in elimination half-life (3.2 versus 1.9 h), serum clearance (0.8 versus 1.1 ml/min per kg), and nonrenal clearance (0.2 versus 0.4 ml/min per kg) between the alcoholic cirrhosis group and the normal control group and in elimination half-life (2.2 versus 1.9 h) between the primary biliary cirrhosis group and the normal control group. There was also a difference in nonrenal clearance between the alcoholic cirrhosis and primary biliary cirrhosis groups (0.2 versus 0.5 ml/min per kg). Although the handling of aztreonam differed in the three groups, the magnitude of the difference would warrant a change in aztreonam dosing only for the alcoholic cirrhosis group. In this group, dose adjustment might be required if long-term therapy with high doses of aztreonam is indicated.
Gentamicin uptake in Staphylococcus aureus possessing plasmid-encoded, aminoglycoside-modifying enzymes
Authors: Mandel L J , Murphy E , Steigbigel N H , Miller M H
Published: June 2012

[3H]gentamicin uptake and killing were studied in three strains of gentamicin-resistant Staphylococcus aureus possessing plasmid-encoded, gentamicin-modifying enzymes and in three isogenic, enzyme-free, gentamicin-susceptible derivatives. At low (less than or equal to 2.0 micrograms/ml) concentrations of gentamicin, uptake by resistant organisms was impaired compared with that of susceptible strains, and no killing was noted. In contrast, at higher (2.5 to 10.0 micrograms/ml) concentrations (which were below the MIC for the resistant strains), rapid gentamicin uptake similar to that seen in susceptible isolates was observed. Although growth inhibition at these concentrations was apparent, there was no loss of viability in resistant strains. Consistently, the membrane H+-ATPase inhibitor N,N'-dicyclohexyl carbodiimide caused resistant strains to take up low concentrations (1.0 microgram/ml) of gentamicin at rates comparable to those seen in susceptible organisms without causing an associated loss of viability. These studies show differences between gentamicin uptake in S. aureus and streptomycin uptake in Escherichia coli (Dickie et al., Antimicrob. Agents Chemother. 14:569-580, 1978) regarding the kinetics of uptake in resistant strains with plasmid-encoded aminoglycoside-modifying enzymes. Specifically, they suggest that for 2-deoxystreptamine compounds such as gentamicin, ribosomal binding followed by accelerated uptake and subsequent interference with cell growth may occur without invariably being associated with lethal effect.
Antimicrobial activities of BMY-28142, cefbuperazone, and cefpiramide compared with those of other cephalosporins
Authors: Khan N J , Bihl J A , Schell R F , LeFrock J L , Weber S J
Published: June 2012

The antimicrobial activities of BMY-28142, cefbuperazone (BMY-25182; formerly T-1982), and cefpiramide (WY-44635; formerly SM-1652) were compared with those of cefmenoxime, cefoperazone, cefotaxime, ceftizoxime, and moxalactam. BMY-28142 was the most active cephalosporin against the majority of aerobic and facultatively anaerobic microorganisms studied. Its spectrum of activity was very similar to that of cefotaxime. However, BMY-28142, cefbuperazone, cefmenoxime, cefotaxime, ceftizoxime, and moxalactam were equivalent in activity and rate of killing against members of the family Enterobacteriaceae. Cefpiramide was considerably less active than the other cephalosporins against the Enterobacteriaceae.
Susceptibility of Bordetella pertussis to cephalosporin derivatives and imipenem
Authors: Bannatyne R M , Cheung R
Published: June 2012

The in vitro activities of 16 cephalosporin derivatives and imipenem against 60 strains of Bordetella pertussis were examined. Cefoperazone, imipenem, and ceftriaxone were the most active, with MICs that inhibited 90% of the strains of 0.006, 0.05, and 0.1 microgram/ml, respectively. Cephalexin, cephradine, and cefsulodin were the least active, with MICs of 25 to 125 micrograms/ml. The remainder of the agents demonstrated intermediate activity.
High-pressure liquid chromatographic method for analysis of cephalosporins
Authors: Signs S A , File T M , Tan J S
Published: June 2012

A high-pressure liquid chromatographic method is described for the analysis of a wide range of cephalosporin congeners, using only three reagents for extraction and drug analysis. Plasma was treated with cold methanol-0.1 M sodium acetate to precipitate protein. Cephalosporins were resolved on a C-18 reverse-phase column, utilizing a mobile phase of various percentages of 0.01 M sodium acetate and acetonitrile-methanol. Compounds analyzed included cephalexin, cefamandole, cephalothin, cefotaxime, cefazolin, cephaloridine, cefoxitin, cefaclor, cephapirin, and cefoperazone. Each antibiotic demonstrated excellent linearity throughout the therapeutic range. The method of standard additions revealed recoveries of 93 to 101%, with detection limits ranging from 0.2 to 1.0 micrograms/ml for these drugs. Retention times ranged from 4 to 6 min. This method offers a rapid and simple means by which this group of cephalosporins may be reliably quantitated.
Comparative in vitro activities of apalcillin and piperacillin against gram-negative bacilli
Authors: Fass R J , Helsel V L
Published: June 2012

The susceptibilities of 317 gram-negative bacilli to apalcillin and piperacillin were determined by standardized microdilution and disk diffusion tests. The respective percentages of strains susceptible to less than or equal to 64 micrograms of apalcillin and piperacillin per ml were as follows: members of the family Enterobacteriaceae, 90 and 88%; randomly selected Pseudomonas aeruginosa, 100 and 100%; multi-drug-resistant P. aeruginosa, 100 and 75%; and other nonfermenters and Aeromonas hydrophila, 99 and 97%. The drugs had equal activity against Enterobacteriaceae and A. hydrophila; apalcillin was more active against Pseudomonas species and Acinetobacter calcoaceticus, and piperacillin was more active against other nonfermenters. By using linear regression analysis, we found that the MICs of apalcillin and piperacillin were highly interrelated; the lines of best fit had slopes close to unity, and correlation coefficients (r) were greater than 0.90 for Enterobacteriaceae as a group and for other species individually. With disk diffusion testing, inhibition zone diameters around 100 micrograms apalcillin and 100 micrograms piperacillin disks correlated well with respective MICs for Enterobacteriaceae and P. aeruginosa (r = -0.93 to -0.96). Using an error rate-bound classification scheme, we determined breakpoints for apalcillin susceptibility and confirmed those previously established for piperacillin to be appropriate. The apalcillin disk, with modified breakpoints, could be used to predict piperacillin MICs for all organisms, but the piperacillin disk could not be used to predict apalcillin MICs for nonfermenters.
Ferredoxin-linked reduction of metronidazole in Clostridium pasteurianum
Authors: Lockerby D L , Rabin H R , Bryan L E , Laishley E J
Published: June 2012

Clostridium pasteurianum cell-free extracts enzymatically reduced metronidazole when coupled by hydrogenase via reduced ferredoxin. A 5 mM concentration of methyl viologen, flavin adenine dinucleotide, or flavin mononucleotide could completely replace ferredoxin (0.05 mM) in the in vitro reduction assay system, whereas 5 mM benzyl viologen was less effective. However, when these electron carriers were used at a concentration of 0.05 mM, there was a drastic loss in their abilities to couple the metronidazole reduction system compared with the comparable concentration of ferredoxin. It is not understood why these flavin coenzymes participate in this enzymatic reaction. NAD and NADP had no activity when substituted for ferredoxin in the enzyme system. Two reduced ferredoxin-linked pathways, "metronidazole reductase" and the inducible dissimilatory sulfite reductase system, when combined in a single in vitro competition experiment demonstrated a preferential flow of electrons to metronidazole away from sulfite. A proposed bactericidal mechanism for metronidazole against C. pasteurianum incorporating the above findings is discussed.
Effect of saturable clearance during high-dose mezlocillin therapy
Authors: Drusano G L , Forrest A , Fiore D , Auger F , Caplan E S
Published: June 2012

As mezlocillin has been shown to display nonlinear pharmacokinetics in single-dose evaluations, we evaluated a crossover trial in patients with renal dysfunction the impact on serum clearance of fixed-dose versus fixed-interval administration of identical daily doses of the drug. In four patients with creatinine clearances of 0.00 to 1.78 liters/h per 1.73 m2, equal serum clearances were observed when the calculated daily total dose of mezlocillin was given either as a fixed dose of 5,000 mg at various intervals or every 4 h at various doses. We found that repetitive large daily doses that are equivalent to 30 g/day in patients with normal renal function can be administered to patients with impaired renal function as a reduced dose every 4 h instead of prolonging the dosing interval, as suggested by Mangione et al. (Antimicrob. Agents Chemother. 21:428-435, 1982). The observed serum clearances were equal for the two schedules, probably owing to the degree of continuing saturation of the nonlinear clearance mechanisms of mezlocillin.
Prospective randomized double-blind comparison of nephrotoxicity and auditory toxicity of tobramycin and netilmicin
Authors: Gatell J M , SanMiguel J G , Araujo V , Zamora L , Maña J , Ferrer M , Bonet M , Bohe M , Jimenez de Anta M T
Published: June 2012

Netilmicin or tobramycin was administered to 197 patients in a prospective randomized double-blind trial. Of these patients, 140 recipients of nine or more doses of netilmicin or tobramycin could be evaluated for nephrotoxicity. Fifty-five patients were able to cooperate in the administration of serial audiograms. Nephrotoxicity of similar severity developed in 7 of 73 (9.6%) recipients of tobramycin and in 7 of 67 (10.4%) recipients of netilmicin (P greater than 0.05). Mild or slight auditory toxicity developed in 5 of 28 (17.8%) recipients of tobramycin and in 2 of 27 (7.4%) recipients of netilmicin (P greater than 0.05).
In vitro and in vivo activities of ketoconazole and itraconazole against Pityrosporum orbiculare
Authors: Faergemann J
Published: June 2012

The MICs of ketoconazole and itraconazole against Pityrosporum orbiculare were 0.02 to 0.05 and 0.1 to 0.2 micrograms ml-1, respectively. In a rabbit model, orally administered ketoconazole (1 mg kg-1) afforded protection against experimental pityriasis (tinea) versicolor in all animals. Itraconazole (5 mg kg-1) was effective in four of five rabbits.
Improved micromethod for mezlocillin quantitation in serum and urine by high-pressure liquid chromatography
Authors: Fiore D , Auger F A , Drusano G L , Dandu V R , Lesko L J
Published: June 2012

A rapid, sensitive, and specific method of analysis for mezlocillin in serum and urine by high-pressure liquid chromatography is described. A solid-phase extraction column was used to remove interfering substances from samples before chromatography. Quantitation included the use of an internal standard, nafcillin. Mezlocillin was chromatographed with a phosphate buffer-acetonitrile (73:27) mobile phase and a C-18 reverse-phase column and detected at a wavelength of 220 nm. The assay had a sensitivity of 1.6 micrograms/ml and a linearity of up to 600 micrograms/ml and 16 mg/ml in serum and urine, respectively, with only 0.1 ml of sample. The interday and intraday coefficients of variation for replicate analyses of spiked serum and urine specimens were less than 6.5%.
Concentrations of cefmetazole in plasma and tissue resulting from peri-incisional administration before appendectomy
Authors: Rodríguez J R , Mariño E L , Otero M J , Commes J R , Garcia J , Rodriguez J M , Lozano F , Dominguez-Gil A , Alonso A G
Published: June 2012

The levels of cefmetazole in plasma and tissue were determined after injection of a dose of 30 mg/kg into the zone of the wound of each of 15 patients undergoing appendectomy. The mean plasma levels of cefmetazole at the start and end of surgery (8.9 +/- 2.4 and 31.7 +/- 6.4 min after dosage) were 21.1 and 59.0 micrograms/ml, respectively; concentrations of the drug were 14.6 and 4,486.9 micrograms/g in skin, 9,165.0 and 1,756.4 micrograms/g in subcutaneous tissue, and 8,669.6 and 2,022.9 micrograms/g in muscle.
Pharmacokinetics of cefpimizole in normal humans after single- and multiple-dose intravenous infusions
Authors: Lakings D B , Friis J M , Brown R J , Allen H R
Published: June 2012

The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were determined after single- and multiple-dose 20-min intravenous infusions of 1, 2, and 4 g. The kinetics of single-dose administration of cefpimizole correspond to a two-compartment model with an average apparent volume of distribution of 20.0 +/- 3.5 liters, a distribution rate constant of 2.24 +/- 1.00 h-1, and a terminal rate constant of 0.358 +/- 0.036 h-1 (half-life, 1.9 h). The total body clearance was 118.6 +/- 20.2 ml/min. The primary route of elimination for cefpimizole was the renal route, with approximately 80% of the administered dose excreted as the parent compound. The elimination rate constant, as calculated from urinary excretion data, was 0.339 +/- 0.043 h-1, which is in close agreement with the terminal rate constant for plasma. Renal clearance of cefpimizole was 96.2 +/- 17.3 ml/min. Dose proportionality over the three dose levels was obtained from area under the plasma curve and cumulative urinary excretion data. The results of the multiple-dose study indicated that no apparent change in the distribution or elimination kinetics of cefpimizole occurred after the administration of 1-, 2-, and 4-g doses for 7 days, three times a day. The kinetics from the multiple-dose study were in close agreement with those from the single-dose study. No accumulation of cefpimizole occurred, and nondetectable levels was observed 24 h after administration of the last dose. Peaks that could be attributed to metabolites of cefpimizole were not observed during high-pressure liquid chromatographic analysis of either plasma or urine specimens.
pH-dependent bactericidal effects of acidulated fluoride gels on preformed plaque aggregates of Streptococcus mutans 6715
Authors: Caufield P W , Wannemuehler Y
Published: June 2012

The anticaries action of topically applied sodium fluoride (NaF) preparations has been attributed, at least in part, to the antibacterial effect of fluoride on cariogenic bacteria. In this report we examined the bactericidal activity of acidulated NaF gels against preformed plaque aggregates of Streptococcus mutans 6715. Both commercially available and laboratory-prepared gels were tested. Prepared NaF gels were acidified to various pH levels with HCl, H3PO4, or HF. The aggregates of S. mutans were immersed in the various fluoride gels for 5 min and then monitored for viability. None of the commercially available NaF gels with pHs of 3.5 to 4.5 and fluoride concentrations of 5,000 to 12,300 micrograms/ml were capable of exerting complete bactericidal activity against aggregates of S. mutans. For the laboratory-prepared NaF gels, neither the source of hydrogen ion nor the source of fluoride influenced the outcome when fluoride was present at the appropriate MBC and pH. NaF gels with a fluoride concentration of 37,000 micrograms/ml were bactericidal to S. mutans at pH 3.0. At pH 2.5 and 2.0, approximately 12,000 and 1,100 micrograms of fluoride per ml, respectively, was bactericidal. Results from this study suggest that the bactericidal properties of acidulated NaF gels can be enhanced by lowering their pHs to below 3.0.
Comparison of fortimicins with other aminoglycosides and effects on bacterial ribosome and protein synthesis
Authors: Moreau N , Jaxel C , Le Goffic F
Published: June 2012

Fortimicins are bicyclic aminoglycoside antibiotics that contain a fortamine moiety instead of the deoxystreptamine found in other aminoglysides. Fortimicin A had a bactericidal effect on Escherichia coli and Staphylococcus epidermidis and was found to inhibit protein synthesis in vivo. In vitro, fortimicin A inhibited polyuridylic acid-directed phenylalanine polymerization and induced misreading, as shown by leucine incorporation. In contrast, fortimicin B had no effect on either polymerization or misreading. In assays programmed with natural mRNA, only a weak polymerization inhibition effect was observed with fortimicin A, whereas a strong stimulation was seen in the presence of fortimicin B. Both fortimicins A and B inhibited dissociation of 70S ribosomes into their subunits and neither was able to displace [3H]dihydrostreptomycin, [3H]tobramycin, or [3H]gentamicin from their respective binding sites on the 70S particle.