bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of herbicolin A against Mycoplasma, Acholeplasma, Ureaplasma, and Spiroplasma species
Authors: Freundt E A , Winkelmann G
Published: June 2012

Herbicolin A, a novel acyl peptide antibiotic, inhibits the growth of the sterol-requiring Mycoplasma, Ureaplasma, and Spiroplasma species, with MICs varying from 1.5 to 100 micrograms/ml. With the exception of Acholeplasma modicum, all of the non-sterol-requiring species of the family Acholeplasmataceae were totally resistant to herbicolin A when tested on serum-containing medium but were inhibited to some extent on medium devoid of serum and any other source of sterol or fatty acids.
In vitro studies with R 51,211 (itraconazole)
Authors: Espinel-Ingroff A , Shadomy S , Gebhart R J
Published: June 2012

The in vitro activity of R 51,211 (itraconazole, accepted generic name; Janssen Pharmaceutica, Beerse, Belgium), a new orally active triazole, was compared with those of two existing orally active azoles, ketoconazole and BAY n 7133, and a topical agent, Ro 14-4767/002. An agar dilution procedure (Kimmig agar) was performed with 148 isolates of pathogenic fungi. Incubation was at 30 degrees C from 48 h to 7 days. R 51,211 was dissolved in 0.2 N HCl in absolute ethanol, ketoconazole was dissolved in 0.2 N HCl alone, BAY n 7133 was dissolved in absolute ethanol, and Ro 14-4767/002 was dissolved in dimethyl sulfoxide. R 51,211 and Ro 14-4767/002 were the most active drugs against isolates of Histoplasma capsulatum, and R 51,211 showed the greatest activity in vitro against isolates of Blastomyces dermatitidis and Cryptococcus neoformans. Ro 14-4767/002 was the most active drug against 30 isolates of dermatophytes, followed by R 51,211, ketoconazole, and BAY n 7133. R 51,211 showed the best activity in vitro against 19 isolates of Aspergillus fumigatus and Aspergillus flavus, as well as 19 isolates of dematiaceous fungi. All four drugs had 90% MICs of greater than or equal to 16 micrograms/ml when tested with isolates of zygomycetous fungi.
Mechanisms of action of aminoglycoside antibiotics in eucaryotic protein synthesis
Authors: Eustice D C , Wilhelm J M
Published: June 2012

Tetrahymena thermophila is a eucaryotic organism that is highly susceptible to growth inhibition by aminoglycoside antibiotics. Concentrations of paromomycin, gentamicin G418, and hygromycin B at 22, 10, and 17 microM, respectively, inhibited growth by 50%. A combination of in vitro and in vivo methods was used to determine the mechanisms of action of these aminoglycoside antibiotics on protein synthesis in T. thermophila. Analysis of polysome profiles from paromomycin- and gentamicin G418-treated cells showed clear, progressive depletions of polysomes concomitant with an inhibition of in vivo [14C] lysine incorporation. In vitro, paromomycin and gentamicin G418, which are disubstituted 2-deoxystreptamine-containing molecules, were not very effective inhibitors of either the translocation of peptidyl-tRNA or the elongation of nascent polypeptide chains on polysomes. In contrast, we found that the translocation of phe-tRNA on polyuridylate programmed ribosomes was susceptible to inhibition by paromomycin. We conclude that the primary inhibitory action of paromomycin and gentamicin G418 was at (i) an early stage of elongation after initiation, (ii) the initiation stage of translation, or (iii) a stage of translation before initiation. Hygromycin B, which is a monosubstituted 2-deoxystreptamine-containing aminoglycoside, potently inhibited the elongation of nascent chains during the translation of polysomes. In addition, the in vitro translation of polysomes from two hygromycin B-resistant mutants was resistant to the inhibition of elongation caused by hygromycin B.
Correlation of amikacin concentrations in perilymph and plasma of continuously infused guinea pigs
Authors: Desjardins-Giasson S , Beaubien A R
Published: June 2012

A commercially available radioimmunoassay kit was modified to enable us to measure, in triplicate, the amikacin concentration in 1 microliter of perilymph fluid. Amikacin levels in plasma and perilymph were measured in guinea pigs after continuous intravenous infusion at four different dosing rates. After a 4-h infusion, a good linear correlation was found between the amikacin concentration in plasma and the dosing rate. Likewise, a significant linear relationship was found between concentrations of amikacin in perilymph and plasma (y = 0.21x + 2.56; r = 0.67; n = 45) after 6 h of infusion. These results suggest nonsaturation kinetics at the concentrations used.
Furazolidone versus ampicillin in the treatment of traveler's diarrhea
Authors: DuPont H L , Ericsson C D , Galindo E , Wood L V , Morgan D , Bitsura J A , Mendiola J G
Published: June 2012

Ninety-four U.S. students who acquired diarrhea in Mexico were treated with furazolidone (47 subjects) or ampicillin (47 subjects) on a double-blind random basis. Of 47 students, 26 (55%) who received furazolidone (100 mg four times daily for 5 days) recovered from illness within 48 h after initiation of therapy, in contrast to 15 of 47 (32%) who received ampicillin (500 mg four times daily for 5 days) (P less than 0.05). Altogether, 74% of students treated with furazolidone and 49% of those receiving ampicillin were well within 72 h (P less than 0.05). When furazolidone was compared with ampicillin, clinical illness was shortened on the average from 65 to 61 h for enterotoxigenic Escherichia coli diarrhea, from 83 to 58 h for shigellosis, from 82 to 51 h for diarrhea unassociated with a detectable agent, and from 72 to 57 h for all cases irrespective of etiology. Although not dramatically effective in the current trial, the broad spectrum of activity of furazolidone is of interest. Because of in vitro activity against Campylobacter strains and known effectiveness in treating giardiasis, furazolidone should be considered in therapy for diarrhea of unknown etiology in certain settings when laboratory processing of stools for etiological agent is not feasible.
Treatment of influenza A (H1N1) virus infection with ribavirin aerosol
Authors: Wilson S Z , Gilbert B E , Quarles J M , Knight V , McClung H W , Moore R V , Couch R B
Published: June 2012

In a randomized, controlled study of ribavirin aerosol treatment of influenza A(H1N1) virus infection among college students, treated patients had a significantly shorter duration of fever than control patients. There was a trend of more rapid recovery in treated patients. Virus shedding was similar in treated and control patients, declining gradually from a 50% tissue culture infective dose of 3.5 log10 per ml at admission to 1.8 log10 per ml at 53 h after admission. There was no local or systemic intolerance and no hematological or biochemical abnormalities associated with ribavirin treatment.
Comparison of itraconazole and ketoconazole in the treatment of experimental candidal vaginitis
Authors: Sobel J D , Muller G
Published: June 2012

Comparison of itraconazole (R51,211) and ketoconazole in the treatment of experimental candidal vaginitis in rats on schedules of 3 and 5 days revealed significantly superior results with itraconazole at all dosages (1.0 to 7.5 mg/kg) studied, but was particularly evident at 1.0 and 2.5 mg/kg. A single 25-mg/kg dose of itraconazole was as effective as 5 daily 5-mg/kg doses of itraconazole.
Comparison of antiviral activities of cloned and native human interferons against herpes simplex virus types 1 and 2 and human cytomegalovirus
Authors: Rasmussen L E , Chen P T , Merigan T C
Published: June 2012

Five recombinant alpha interferons and two recombinant beta interferons have been tested for their ability to inhibit yields of herpes simplex virus types 1 and 2 and human cytomegalovirus in human embryonic lung cells. All of the alpha species and both of the beta forms (cysteine and serine) were active against the herpesviruses tested in this study. Neither the recombinant alpha nor the recombinant beta interferons exceeded the activity of the native species against herpes simplex viruses types 1 and 2. However, the recombinant beta interferons inhibited cytomegalovirus more than either the native beta or the alpha interferon species with the exception of interferon alpha K (alpha 6).
Experimental evaluation of chlorhexidine gluconate for ocular antisepsis
Authors: Hamill M B , Osato M S , Wilhelmus K R
Published: June 2012

Chlorhexidine gluconate is a bisguanide germicide currently available with 70% isopropanol (Hibistat, Hibitane) or a detergent (Hibiclens, Hibiscrub) for preoperative skin preparation. As these solvents are toxic to the cornea, we investigated the safety and efficacy of aqueous chlorhexidine solutions for ophthalmic use. Chlorhexidine in Tris-glycine buffer was evaluated for retardation of epithelial regeneration after experimental corneal abrasion in rabbits. Irrigant concentrations of 2.0 and 4.0% chlorhexidine significantly slowed the healing rate (0.546 and 0.076 mm/h, respectively) compared with saline controls (0.938 mm/h). Irrigant concentrations of less than or equal to 1% did not statistically delay healing (P greater than 0.4). In a separate group of animals, the right conjunctivae of pigmented rabbits were inoculated with Staphylococcus epidermidis (approximately 10(7) organisms per eye) and irrigated with 40 microliters of aqueous chlorhexidine in concentrations of 0.1, 0.5, and 1.0%; the left eyes were irrigated with saline or left untreated. Quantitative conjunctival cultures were obtained, and the total number of organisms recovered per eye was calculated. All chlorhexidine-treated eyes showed significant reduction in organisms compared with either untreated or saline-irrigated control eyes (P less than 0.001). In vitro antimicrobial susceptibility testing demonstrated chlorhexidine in concentrations of 0.1 to 4% to be highly active against a variety of gram-positive and gram-negative bacterial pathogens by disk diffusion and broth diffusion assays. Topical aqueous chlorhexidine may be an alternate agent for preoperative conjunctival antisepsis.
Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges
Authors: Dudley M N , Levitz R E , Quintiliani R , Hickingbotham J M , Nightingale C H
Published: June 2012

The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMX) in cerebrospinal fluid (CSF) and serum after a single intravenous infusion of 5 mg of TMP and 25 mg of SMX per kg of body weight over approximately 120 min were studied i nine patients who had uninflamed meninges and were undergoing elective myelography. Peak concentrations of TMP and SMX in CSF were 1 microgram/ml and 13.8 micrograms/ml, respectively. The peak TMP concentration in CSF occurred significantly earlier than the peak SMX concentration (60 versus 480 min postinfusion). At 15 h, there was no detectable TMP in the CSF, and there was 4.7 micrograms of SMX per ml of CSF. In the postdistribution phase (in CSF), simultaneous CSF-to-serum concentration ratios ranged from 0.23 to 0.53 for TMP and from 0.20 to 0.36 for SMX. CSF penetration (measured by comparison of the area under the curve of the composite CSF and serum concentration-time curves) was 18% for TMP and 12% for SMX. A loading dose of TMP-SMX (bases on TMP) of 10 to 12 mg/kg and a maintenance dose of 6 mg/kg every 8 h or 8 mg/kg every 12 h (with a 2-h infusion) should yield steady-state peak concentrations of at least 5 micrograms of TMP per ml of serum and 160 micrograms of SMX per ml of serum. Further studies of TMP-SMX administered in these doses in the treatment of serious bacterial infection, including meningitis, are warranted.
Responses of tolerant and nontolerant Staphylococcus aureus strains to methicillin treatment in an experimental infection in mice
Authors: Goessens W H , Fontijne P , Michel M F
Published: June 2012

Staphylococcus aureus strains can be divided into tolerant and nontolerant strains on the basis of their survival in vitro in the presence of high concentrations of methicillin (greater than or equal to 64 micrograms/ml). A strain is defined as tolerant if more than 2% of the inoculum survives under these conditions. The response of five susceptible and five tolerant S. aureus strains to treatment with methicillin was studied in an experimental thigh infection in mice. Animals were treated with one and two injections of methicillin (2.5 mg per mouse). At the end of treatment, the number of CFUs in the thigh muscles infected with the susceptible strains was found to be significantly lower than that in the thigh muscles infected with the tolerant
Examination of gram-negative bacilli from meningitis patients who failed or relapsed on moxalactam therapy
Authors: Eng R H , Cherubin C , Smith S M , Buccini F
Published: June 2012

One Salmonella and four Escherichia coli isolates from patients with bacterial meningitis who had responded slowly, relapsed, or failed to respond to monotherapy with moxalactam were examined. For purposes of comparison, an E. coli isolate from one patient who had responded promptly to therapy was also studied. On testing, moxalactam had higher MICs and MBCs (two to four times) than cefotaxime or ceftriaxone for all isolates; the rates of killing of the isolates were dependent on the antibiotic concentrations used. At comparable multiples of the MIC, these isolates were generally killed more slowly by moxalactam than by cefotaxime or ceftriaxone. In addition, a reduction of 3 in the logarithm of the number of CFU per milliliter could be attained at far lower concentrations with cefotaxime or ceftriaxone than with moxalactam. The degree of concentration-related killing of bacteria produced by the beta-lactams appeared to correlate with the clinical responses of the patients. Furthermore, real differences appeared to exist among the third-generation cephalosporins, which were not evident by the MIC and MBC points alone but were evident in the concentration-related killing curves: Determination of a reduction of 3 in the logarithm of the number of CFU per milliliter after a 6-h incubation is suggested as the criterion for the screening of antibiotics for the therapy for gram-negative bacillary meningitis.
Gastrointestinal motor-stimulating activity of macrolide antibiotics and analysis of their side effects on the canine gut
Authors: Itoh Z , Suzuki T , Nakaya M , Inoue M , Mitsuhashi S
Published: June 2012

For clarification of the nature of the side effects of macrolide antibiotics on the gastrointestinal tract, the motor-stimulating activity of these agents was studied in unanesthetized dogs. The results showed that erythromycin and oleandomycin, the 14-membered macrolides with two side chain sugars combined at C3 and C5 in a glycosidic linkage in parallel, strongly stimulate gastrointestinal motor activity, an action accompanied by vomiting at large doses. On the other hand, leucomycin, acetylspiramycin, and tylosin, belonging to a 16-membered macrolide with two side chain sugars in series combined at C5 of the lactone ring, did not induce contractions of the gastrointestinal tract. Motor-stimulating activity by erythromycin and oleandomycin was greatly inhibited by atropine sulfate. These results point to structure-physiological activity relationships.
Susceptibility of multiply antibiotic-resistant pneumococci to the new quinoline antibiotics, nalidixic acid, coumermycin, and novobiocin
Authors: Gombert M E , Aulicino T M
Published: June 2012

The susceptibility of 10 multiply antibiotic-resistant strains of Streptococcus pneumoniae to several quinoline antibiotics and to coumermycin, novobiocin, and penicillin was determined. The MIC of penicillin for all test isolates was greater than or equal to 4 micrograms/ml. Ciprofloxacin was the most active quinoline derivative tested, followed by norfloxacin. These isolates of S. pneumoniae were not inhibited by the remaining quinolines at achievable concentrations in serum. Coumermycin and ciprofloxacin were the most active antibiotics tested in this study.
Antibiotic resistance and small R plasmids among Escherichia coli isolates from outpatient urinary tract infections in northern Norway
Authors: Vorland L H , Carlson K , Aalen O
Published: June 2012

Escherichia coli strains from outpatient urinary tract infections in northern Norway over a period of 1 year were examined for resistance to nine commonly used antibiotics. Strains collected during 4.5 months were examined for R plasmid content by using conjugation and in vitro transformation. Of the E. coli strains, 42% were resistant to one or more antibiotics. Resistance was highest to sulfonamide (20.8% of all strains), nitrofurantoin (14.5%), and tetracycline (10.1%), whereas less than 6% of the strains were resistant to ampicillin, carbenicillin, cephalothin, nalidixic acid, or trimethoprim-sulfamethoxazole. No strain was resistant to gentamicin. Tetracycline resistance was more common in men than in women. Resistance to cephalothin, nalidixic acid, and sulfonamide was higher in strains from older people. Resistance to sulfonamide was more frequent in the urban community. These was no seasonal variation in antibiotic resistance, although the incidence of urinary tract infection varied with seasons. Plasmid-determined resistance to ampicillin, streptomycin, sulfonamide, and tetracycline was found. About 18% of the resistant strains from the urban municipality carried R plasmids, most of which were small plasmids mediating resistance to sulfonamide and streptomycin. The overall frequency of resistance in strains collected from rural areas was similar to the urban frequency, but in the rural strains, R plasmids were found in only 5% of the resistant strains.
Determination of in vitro susceptibility of Mycobacterium tuberculosis to cephalosporins by radiometric and conventional methods
Authors: Heifets L B , Iseman M D , Cook J L , Lindholm-Levy P J , Drupa I
Published: June 2012

Among eight cephalosporins and cephamycins tested in preliminary in vitro screening against Mycobacterium tuberculosis, the most promising for further study was found to be ceforanide, followed by ceftizoxime, cephapirin, and cefotaxime. Moxalactam, cefoxitin, cefamandole, and cephalothin were found to be not active enough against M. tuberculosis to be considered for further in vitro studies. The antibacterial activity of various ceforanide concentrations was investigated by three methods: (i) the dynamics of radiometric readings (growth index) in 7H12 broth; (ii) the number of CFU in the same medium; and (iii) the proportion method on 7H11 agar plates. There was a good correlation among the results obtained with these methods. The MIC for most strains ranged from 6.0 to 25.0 micrograms/ml. The BACTEC radiometric method is a reliable, rapid, and convenient method for preliminary screening and determination of the level of antibacterial activity of drugs not commonly used against M. tuberculosis.
Lack of accumulation of exogenous adenylyl dihydrostreptomycin by whole cells or spheroplasts of Escherichia coli
Authors: Garcia-Riestra C , Perlin M H , Lerner S A
Published: June 2012

Accumulation of purified adenylylated dihydrostreptomycin (DHS-AMP) was examined in two strains of Escherichia coli. E. coli JSRO-N was plasmid free and aminoglycoside (AG) susceptible; E. coli JSRO-N(pSAD1) contained a plasmid-encoded AG adenylyltransferase which modifies DHS and streptomycin and confers resistance to both of these drugs. Although both whole cells and spheroplasts of JSRO-N accumulated free DHS, we were not able to demonstrate uptake of DHS-AMP by this strain. Whole cells and spheroplasts of JSRO-N(pSAD1) accumulated DHS at a much slower rate than that observed in JSRO-N. This was presumably due to the activity of the adenylyltransferase in JSRO-N(pSAD1). However, this low rate of accumulation of DHS was still higher than the uptake of DHS-AMP by either JSRO-N or JSRO-N(pSAD1). Thus, the rate of accumulation of DHS-AMP was even lower than that of DHS during the slow, initial, energy-dependent phase of AG uptake seen in JSRO-N(pSAD1). We also found that when either JSRO-N or JSRO-N(pSAD1) was incubated with barely inhibitory or subinhibitory concentrations of DHS, rapid uptake of DHS could be stimulated by the addition of an inhibitory concentration of another AG, such as amikacin. Uptake of DHS-AMP could not be similarly enhanced by the addition of amikacin. Our results indicate that DHS-AMP is not accumulated by whole cells or spheroplasts of E. coli. These results are consistent with the postulated intracellular location of AG-modifying enzymes.
In vitro activity of Sch 34343 against enterococci and other gram-positive bacteria
Authors: Eliopoulos G M , Reiszner E , Moellering R C
Published: June 2012

The in vitro activity of Sch 34343, a new penem antibiotic, was compared with those of imipenem, vancomycin, and eight other antibiotics against gram-positive bacteria. Ninety percent of methicillin-susceptible Staphylococcus aureus and penicillin-susceptible streptococcal isolates were inhibited by Sch 34343 at concentrations of less than or equal to 0.125 micrograms/ml. Listeria monocytogenes isolates were susceptible to the penem at concentrations of less than or equal to 0.25 micrograms/ml. Penicillin-resistant pneumococci and viridans streptococci were relatively resistant to Sch 34343 (MIC for 90% of the isolates, 4 micrograms/ml), as were methicillin-resistant strains of S. aureus (MIC for 90% of the isolates, greater than or equal to 256 micrograms/ml). All 48 strains of Streptococcus faecalis were inhibited by concentrations of less than or equal to 8 micrograms of the drug per ml. Combinations of Sch 34343 with gentamicin demonstrated bactericidal synergism against 5 of 10 enterococcal strains tested in broth media and against 6 of 10 strains tested in 50% pooled human serum. The serum protein binding of Sch 34343 was ca. 65%. The antibacterial activity of Sch 34343 remained stable after 24 h of incubation at 37 degrees C in water or Dextrose-Phosphate broth. However, 63% of bioassayable activity was lost after 24 h of incubation at 37 degrees C in 50% human serum buffered with HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) (pH 7.4).
Single-dose pharmacokinetics of ceftriaxone in healthy Chinese adults
Authors: Zhou H H , Chan Y P , Arnold K , Sun M
Published: June 2012

The pharmacokinetics of ceftriaxone were investigated in six healthy mainland Chinese adults (four males and two females). A single 1.0-g dose was administered intravenously or intramuscularly in a two-way crossover design. Plasma and saliva samples were collected on 11 occasions between 0 and 36 h after dosing. Ceftriaxone was not detected in any saliva samples. The mean volume of distribution and mean elimination half-life of ceftriaxone in plasma were 8.5 liters and 8.1 h, respectively. The mean total body clearance after intravenous administration was 0.68 liter/h. The mean Tmax and Cmax after intramuscular injection were 1.4 h and 131 micrograms/ml, respectively. The area under the plasma concentration-time curves after intravenous and intramuscular administrations were 1,507 and 1,493 micrograms X h/ml, respectively. The bioavailability for a 1.0-g intramuscular dose of ceftriaxone was calculated to be 100%. These pharmacokinetic parameters for ceftriaxone in healthy Chinese adults were very similar to those previously reported in the literature. Thus, ceftriaxone may be administered to treat Chinese patients without any major modification in the standard dosing regimen.
Lack of evidence for interaction between tobramycin and shock in their effect on renal function
Authors: Ambinder R F , Moore R D , Smith C R , Mellits E D , Lietman P S
Published: June 2012

We sought to determine whether there was an interaction between aminoglycoside use and shock in their effect on renal function among seriously ill patients suspected of having gram-negative sepsis. Serial serum creatinine determinations were used to estimate changes in creatinine clearance rates in 179 patients entered onto a prospective randomized trial of tobramycin-nafcillin versus cefotaxime. A 25% decline in estimated creatinine clearance was considered to be clinically important. Univariate chi-square analysis showed that both shock (P less than 0.01) and tobramycin use (P less than 0.001) were independently associated with decline in estimated creatinine clearance. A two-way analysis of variance showed that both shock (F = 10.44, P less than 0.01) and tobramycin use (F = 42.6, P less than 0.001) continued to be significantly associated with renal dysfunction in the presence of each other, but there was no significant interaction between shock and tobramycin in their effect (F = 0.62, P less than 0.43). A multiple logistic regression with an interaction term representing the occurrence of shock and tobramycin use simultaneously yielded similar results. Our study provided no analytic evidence supporting the existence of an interaction between shock and aminoglycoside use in their effect on renal function.
Antimicrobial activity of gentamicin in experimental enterococcal endocarditis
Authors: Sullam P M , Täuber M G , Hackbarth C J , Sande M A
Published: June 2012

The in vitro activity of gentamicin was compared with its therapeutic efficacy in rabbits with Streptococcus faecalis endocarditis. The test strain was resistant to gentamicin as measured by MICs and MBCs determined in Mueller-Hinton broth alone or in broth supplemented with 50% rabbit serum. Gentamicin also failed to manifest anti-enterococcal activity when evaluated by time-kill studies in broth. However, the addition of serum to the medium did enhance the activity of gentamicin. In the therapy of experimental endocarditis, gentamicin used alone demonstrated anti-enterococcal activity equivalent to that of ampicillin used alone. Vegetation titers in animals treated with gentamicin alone were lower than those of untreated controls (P less than 0.01) and comparable to those in animals treated with ampicillin alone. Thus, gentamicin demonstrated anti-enterococcal activity in vivo despite the resistance observed in vitro, as measured by conventional assays to determine MICs and MBCs.
Single-dose tinidazole for the treatment of giardiasis
Authors: Speelman P
Published: June 2012

Sixty-three expatriate residents and travellers in Bangladesh, infected with Giardia lamblia, participated in two studies to compare the therapeutic efficacy of tinidazole and metronidazole. In the first trial 33 randomly selected patients were treated with tinidazole (50 mg/kg of body weight to a maximum of 2 g) or metronidazole (60 mg/kg of body weight to a maximum of 2.4 g) in a single oral dose. Patients were followed for 4 weeks after the end of therapy for the presence of G. lamblia in their stools. Sixteen (94%) of 17 patients receiving tinidazole were free of G. lamblia during that period, compared to only 9 (56%) of 16 patients who had received metronidazole (P less than 0.02). In the second trial patients were randomly allocated to a treatment schedule of either metronidazole as a single dose on 3 successive days (50 mg/kg of body weight to a maximum of 2 g daily) or tinidazole as a single oral dose (50 mg/kg of body weight to a maximum of 2 g). All 15 patients treated with tinidazole and 14 (93%) of 15 patients treated with metronidazole were free of G. lamblia during the 4-week follow-up period. A single oral dose of tinidazole is a highly effective treatment for giardiasis and is equal in efficacy to a 3-day therapy with metronidazole.
In vitro and in vivo comparisons of amphotericin B and N-D-ornithyl amphotericin B methyl ester
Authors: Kobayashi G S , Little J R , Medoff G
Published: June 2012

N-D-Ornithyl amphotericin B methyl ester (N-D-ornithyl AmE) has a lower toxicity for animals than does amphotericin B (AmB), and peak serum levels can be achieved that are fourfold higher than those obtained with an equivalent dose of AmB. However, N-D-ornithyl AmE has one-fourth the in vitro activity and between one-fifth and one-eighth the in vivo activity of AmB. N-D-ornithyl AmE and the corresponding lysyl derivative also lack the immunoadjuvant effects of AmB.
Single-dose pharmacokinetics of imipenem-cilastatin in neonates
Authors: Gruber W C , Rench M A , Garcia-Prats J A , Edwards M S , Baker C J
Published: June 2012

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin), a beta-lactam antibiotic, used in combination with cilastatin, a renal dehydropeptidase I inhibitor, were evaluated in 10 neonates 1 to 8 days of age. The imipenem-cilastatin combination was given intravenously over a 15-min period at a dose of 15 or 25 mg/kg. Drug concentrations in serum, urine, and cerebrospinal fluid (when available) were determined by high-pressure liquid chromatography, and plasma disposition of the drugs was described by a two-compartment open model. The mean peak plasma levels of imipenem 30 min postinfusion were 55.4 and 27.2 micrograms/ml, and the mean t1/2 beta values were 2.1 and 1.8 h at doses of 25 and 15 mg/kg, respectively. The calculated volume of distribution was 0.41 liters/kg. In two patients from whom cerebrospinal fluid was obtained 1.5 h postinfusion, imipenem levels were 5.6 and 1.1 micrograms/ml at doses of 25 and 15 mg/kg, respectively, representing 10 and 4% of the 1-h serum levels. No side effects attributable to a single dose of imipenem-cilastatin were noted.
Binding of polymyxin B nonapeptide to gram-negative bacteria
Authors: Vaara M , Viljanen P
Published: June 2012

The binding of the outer membrane-disorganizing peptide polymyxin B nonapeptide (PMBN) to gram-negative bacteria was studied by using tritium-labeled PMBN. Smooth Salmonella typhimurium had a binding capacity of ca. 6 nmol of PMBN per mg (dry weight) of bacteria, which corresponds to ca. 1 X 10(6) to 2 X 10(6) molecules of PMBN per single cell. The binding was of relatively high affinity (Kd, 1.3 microM). The isolated outer membrane of S. typhimurium bound ca. 100 nmol of PMBN per mg of outer membrane protein (Kd, 1.1 microM), whereas the cytoplasmic membrane bound 9 to 10 times less. Other bacteria which are susceptible to the action of PMBN (Escherichia coli strains, Pseudomonas aeruginosa, Haemophilus influenzae) also bound large amounts of PMBN. The S. typhimurium pmrA mutant, Neisseria gonorrhoeae, and Proteus mirabilis (all known as resistant to polymyxin and PMBN) bound 3.3, 4, and 12 times less than S. typhimurium, respectively. The binding of PMBN to S. typhimurium was effectively inhibited by low concentrations of polymyxin B, compound EM49 (octapeptin), polylysine, and protamine. Spermine, Ca2+, and Mg2+ also inhibited the PMBN binding although they were ca. 160, 700, and 2,400 times less active (based on molarity) than polymyxin B, respectively. No binding inhibition was found at the tested concentrations of streptomycin, tetralysine, spermidine, or cadaverine.
Immunoadjuvant activity of amphotericin B as displayed in mice infected with Candida albicans
Authors: Bistoni F , Vecchiarelli A , Mazzolla R , Puccetti P , Marconi P , Garaci E
Published: June 2012

Mice receiving a single intraperitoneal injection of amphotericin B showed increased resistance to subsequent challenge with either Candida albicans or Staphylococcus aureus. This enhancement of resistance was obvious in terms of both survival criteria and clearance of the intravenously injected organism from different organs. The protective effect of amphotericin B was conditioned by dose, time of drug administration, and size of yeast or bacterial inoculum and was reversed by cyclophosphamide. Effector cells from mice treated with amphotericin B displayed enhanced fungicidal activity in vitro as measured in a short-term 51Cr release assay. Macrophages from intact animals exposed in vitro to amphotericin B also acquired strong candidacidal reactivity.
Relationship between rat renal accumulation of gentamicin, tobramycin, and netilmicin and their nephrotoxicities
Authors: Brier M E , Mayer P R , Brier R A , Visscher D , Luft F C , Aronoff G R
Published: June 2012

Gentamicin, tobramycin, and netilmicin were given to rats in daily doses of either 5 or 20 mg/kg for 30 days to determine the renal accumulation kinetics of the compounds and to correlate steady-state renal parenchymal concentrations with nephrotoxicity. Four rats from each group were sacrificed daily and renal parenchymal tissue concentrations were determined microbiologically. Nephrotoxicity was assessed by changes in creatinine values in serum, renal creatinine clearances, and pathological scores. There was no indication of aminoglycoside-induced nephrotoxicity in any tests performed. The following steady-state levels resulted: 36, 148, and 176 micrograms/g after 5 mg/kg per day and 148, 260, and 510 micrograms/g after 20 mg/kg per day for tobramycin, gentamicin, and netilmicin, respectively. We conclude that aminoglycoside parenchymal accumulation in rats follows this order: tobramycin less than gentamicin less than netilmicin. Therefore, differences in the relative toxicities of gentamicin, tobramycin, and netilmicin do not correlate with the renal parenchymal accumulation of these agents and may be more dependent on intrinsic toxicity to the renal proximal tubule than to the concentration of the aminoglycoside in the kidney.
In vitro and in vivo antibacterial activities of carumonam (AMA-1080), a new N-sulfonated monocyclic beta-lactam antibiotic
Authors: Imada A , Kondo M , Okonogi K , Yukishige K , Kuno M
Published: June 2012

The in vitro and in vivo antibacterial activities of carumonam (AMA-1080), a synthetic sulfazecin derivative, were compared with those of aztreonam, cefoperazone, ceftazidime, and cefsulodin. Carumonam was highly active in vitro against members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Haemophilus influenzae and weakly active against Streptococcus pneumoniae, but it was not active against Staphylococcus aureus. The MICs of carumonam for 90% of 1,156 clinical Enterobacteriaceae isolates were between 0.013 and 25 micrograms/ml, which were the lowest MICs of the antibiotics tested. The MIC of carumonam for 90% of Klebsiella oxytoca was 0.2 micrograms/ml, whereas that of aztreonam was 50 micrograms/ml. The superiority of carumonam to aztreonam and the reference cephalosporins was also demonstrated by their activities against Klebsiella pneumoniae and Enterobacter cloacae. The MIC of carumonam for 90% of P. aeruginosa was 12.5 micrograms/ml, which was comparable to the MICs of aztreonam and ceftazidime. Carumonam showed a high affinity for the penicillin-binding protein 3 of gram-negative bacteria, but not for the penicillin-binding proteins of S. aureus and Bacteroides fragilis. Carumonam was resistant to hydrolysis by 12 plasmid-mediated beta-lactamases and 7 chromosomal beta-lactamases. It was more stable than aztreonam to hydrolysis by the beta-lactamase of K. oxytoca; this stability is related to the superiority of the in vitro and in vivo activities of carumonam to those of aztreonam against this species. In general, the protective activities (50% effective dose) of carumonam and reference antibiotics in mice with experimental intraperitoneal infections correlated with the in vitro activities (MIC); carumonam showed excellent protective activity against most aerobic gram-negative bacteria.
In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug
Authors: Otto M J , Fox M P , Fancher M J , Kuhrt M F , Diana G D , McKinlay M A
Published: June 2012

WIN 51711 (5-[7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl]-3-methylisoxazole), a new antipicornavirus drug, is a potent inhibitor of human entero- and rhinoviruses at concentrations not inhibitory to HeLa cell growth. In plaque reduction assays, WIN 51711 reduced plaque formation by 9 enteroviruses and 33 rhinoviruses, with MICs of 0.004 to 0.17 and 0.004 to 6.2 micrograms/ml, respectively. Addition of WIN 51711 to infected cells at concentrations of 0.02 to 5.0 micrograms/ml reduced the yield of picornaviruses by 90%. Other RNA viruses (nonpicornaviruses) and DNA viruses were unaffected by the compound.
Purification and properties of a novel beta-lactamase from Fusobacterium nucleatum
Authors: Tunér K , Lindqvist L , Nord C E
Published: June 2012

A strain of Fusobacterium nucleatum which produced high levels of beta-lactamase was isolated. The specific activity of the unpurified beta-lactamase was 7.8 U/mg of protein. By Sephacryl S-300 and S-200 column passage and chromatofocusing, the enzyme was purified 450-fold. Sodium dodecyl sulfate-gradient gel electrophoresis revealed a single band. The enzyme hydrolyzed phenoxymethylpenicillin, benzylpenicillin, and ampicillin more rapidly than carbenicillin and piperacillin. Cephaloridine, cefaclor, cephalothin, imipenem, and SCH 34343 had hydrolysis rates of less than or equal to 1% that of phenoxymethylpenicillin. The enzyme was inhibited by clavulanic acid and RO-15-1903/001 but not by p-mercuribenzoate or cefoxitin. Molecular weight by gel filtration was determined to be 21,000 and by sodium dodecyl sulfate-gradient gel electrophoresis was determined to be 26,000. The amino acids aspartic acid-asparagine, glutamic acid-glutamine, serine, glycine, and lysine dominated the amino acid composition.
Antimicrobial susceptibilities of Listeria monocytogenes strains isolated from 1958 to 1982 in Sweden
Authors: Larsson S , Walder M H , Cronberg S N , Forsgren A B , Moestrup T
Published: June 2012

Antibiotic susceptibility was studied in 175 clinical isolates of Listeria monocytogenes. There were no major changes in the susceptibility of strains between 1958 and 1982. Benzylpenicillin and ampicillin had MICs for 90% of the strains (MIC90) of 0.5 micrograms/ml. Gentamicin also had good activity against L. monocytogenes, with an MIC90 of 1.0 microgram/ml. All the new beta-lactamase-stable cephalosporins tested had relatively poor activity against L. monocytogenes. Of the bacteriostatic antibiotics, trimethoprim had by far the lowest MIC90 (0.06 microgram/ml), and in combination with sulfamethoxazole (co-trimoxazole), it had an MIC90 of 0.5 microgram/ml. Both erythromycin and doxycycline had low MIC90s (0.25 microgram/ml).
Comparative in vitro inhibitory and killing activity of cefpirome, ceftazidime, and cefotaxime against Pseudomonas aeruginosa, enterococci, Staphylococcus epidermidis, and methicillin-susceptible and -resistant and tolerant and nontolerant Staphylococcus aureus
Authors: Goldstein E J , Citron D M
Published: June 2012

With a macrotube dilution method, MICs and MBCs were determined for three aminothiazolyl cephalosporins, cefpirome (HR 810), ceftazidime, and cefotaxime, against Pseudomonas aeruginosa, enterococci, Staphylococcus epidermidis, and methicillin-resistant, -susceptible, and -tolerant strains of Staphylococcus aureus. Comparatively, cefpirome was the most active agent against all gram-positive cocci, including enterococci and methicillin-resistant S. aureus, and was as active as ceftazidime against P. aeruginosa. MBCs of cefpirome were within two dilutions of the MICs for 91% of P. aeruginosa and 90% of gram-positive cocci strains tested, except methicillin-resistant S. aureus, for which the MBCs were within three dilutions for 90% of strains.
Plaque autoradiography assay for the detection and quantitation of thymidine kinase-deficient and thymidine kinase-altered mutants of herpes simplex virus in clinical isolates
Authors: Martin J L , Ellis M N , Keller P M , Biron K K , Lehrman S N , Barry D W , Furman P A
Published: June 2012

A plaque autoradiography assay to detect and quantitate thymidine kinase (TK) mutants of herpes simplex virus type 1 (HSV-1) and HSV-2 in clinical samples is described. This method utilizes the selective incorporation of [125I]iododeoxycytidine, a pyrimidine analog selectively phosphorylated by the HSV TK. Only cells infected with TK-competent virus will efficiently incorporate iododeoxycytidine and are the only cells detected by autoradiography. Furthermore, this assay discriminates between TK+ virus (TK competent) and TKA virus (TK altered or reduced). This ability to differentiate TK+ from TKA virus is enhanced when infected cells are labeled with [14C]thymidine in tandem with iododeoxycytidine labeling. Reconstruction experiments with mixtures of TK+ (HSV-1 Patton) virus and TK-deficient (TK-) (B2006) or TKA (IUDRr) mutants were performed to determine the limits of detection of this technique. Ten percent TK- or TKA virus was the lower limit for the detection of TK mutants in a mixed population, whereas 1 in 1,000 TK+ virus revertants could be detected in a TK- virus population. In reconstructed populations and 45 clinical samples, a good correlation existed between the increase in 50% inhibitory dose for acyclovir and the percent TK mutant virus present. Similarly, the results of this technique correlated well with the acyclovir phosphorylating activity of extracts from cells infected with isolates or reconstructed mixtures. Plaque autoradiography with [125I]iododeoxycytidine was able to distinguish mixed populations of TK+ and TK- virus and homogeneous populations of TKA virus. The tandem use of [125I]iododeoxycytidine and [14C]thymidine readily identified TKA virus, which appeared as TK+ virus when labeled with [14C]thymidine alone. This technique provides a sensitive screen for antiviral resistance due to alterations in the viral TK and can be used to analyze clinical samples.
High-pressure liquid chromatographic methods for determining arabinosyladenine-5'-monophosphate, arabinosyladenine, and arabinosylhypoxanthine in plasma and urine
Authors: McCann W P , Hall L M , Siler W , Barton N , Whitley R J
Published: June 2012

New high-pressure liquid chromatographic methods for determining concentrations of arabinosyladenine (Ara-A), its 5'-monophosphate (Ara-AMP), and arabinosylhypoxanthine (Ara-H) in plasma and urine are presented. A fluorescence detector is used for Ara-A and Ara-AMP, which are first converted to highly fluorescent derivatives with chloroacetaldehyde. This increases sensitivity greatly over previous methods. The sensitivities of the methods (in micrograms per milliliter) are as follows: in plasma, Ara-AMP, 0.002; Ara-A, 0.0015; and Ara-H, 0.35; and in urine, 9 times these values, respectively. Drug concentration data are also presented, which were obtained after doses of Ara-AMP were given intramuscularly to two patients treated with this drug for severe herpes zoster. One patient was given 13 mg of Ara-AMP per kg of body weight once daily, and the other was given 6.5 mg/kg twice daily. Peak Ara-AMP and Ara-A levels in plasma occurred within 1 h after the doses, and neither exceeded 2 micrograms/ml. Ara-AMP and Ara-A concentrations in plasma fell to less than 0.01 micrograms/ml in both patients by 4 to 6 h after the doses. Peak Ara-H concentrations in plasma occurred within 1 to 2 h after doses and were 21 micrograms/ml in patient 1 and 2. The highest concentration of Ara-AMP in urine was 0.09 micrograms/ml. The highest Ara-A concentration in urine was 62 micrograms/ml, and the highest Ara-H concentration in urine was 1,080 micrograms/ml. An interfering substance of unknown nature, cochromatographing with Ara-H, was encountered sporadically in urine samples. An algorithm based on differential spectrophotometry to identify and correct for this problem is described. Estimates of the renal clearances of Ara-AMP, Ara-A, and Ara-H are also given.
Antibiotic resistance and serotypes of 100 Streptococcus pneumoniae strains isolated in a children's hospital in Barcelona, Spain
Authors: Latorre C , Juncosa T , Sanfeliu I
Published: June 2012

A total of 100 Streptococcus pneumoniae strains with various penicillin G susceptibilities, isolated in Barcelona, Spain, from different pediatric sources during 1983 and the first 4 months of 1984, were tested for susceptibility to tetracycline, chloramphenicol, erythromycin, clindamycin, vancomycin, and rifampin. The isolates were distributed in nine patterns of antibiotic resistance, and 15 different serotypes were encountered. The high incidence of resistance to multiple antibiotics clearly indicates the need to perform antibiotic susceptibility testing of all pneumococcal isolates with proved pathologic significance to avoid therapeutic failure.
Role of an altered penicillin-binding protein in methicillin- and cephem-resistant Staphylococcus aureus
Authors: Utsui Y , Yokota T
Published: June 2012

About 80% of methicillin- and cefazolin-resistant strains of Staphylococcus aureus isolated clinically in Japan in 1982 retained their resistance even after elimination of penicillinase-encoding plasmids. The penicillin-binding proteins (PBPs) of the penicillinase-free, methicillin- and cephem-resistant subclones of Staphylococcus aureus (MRSA) were compared with those of spontaneous susceptible revertants which had been obtained by the replica method after 10 subcultures in drug-free media. A new PBP fraction (PBP2') having a molecular weight of 78,000 and low binding affinities for various beta-lactam antibiotics was found in MRSA exclusively. The levels of resistance of MRSA strains were reduced markedly by culturing them at 43 degrees C or at pH 5.2 or both. We found that the binding capacity of PBP2' for 14C-labeled penicillin G was decreased by preincubation of the membrane fractions of MRSA strains at 43 degrees C for 60 min and that the amount of PBP2' in MRSA strains grown at pH 5.2 was less than that the amount of PBP2' in MRSA strains grown at pH 7.0. Temperature- and pH-dependent expression of resistance in MRSA is likely to reflect the temperature sensitivity and neutral pH-dependent production of the specific PBP fraction (PBP2'). We suggest that MRSA strains can grow in the presence of beta-lactam antibiotics because of the low affinities of the specific PBP2' fraction for various beta-lactam antibiotics.
Influence of four modes of administration on penetration of aztreonam, cefuroxime, and ampicillin into interstitial fluid and fibrin clots and on in vivo efficacy against Haemophilus influenzae
Authors: Lavoie G Y , Bergeron M G
Published: June 2012

The extravascular penetration and bactericidal activity of aztreonam, cefuroxime, and ampicillin against beta-lactamase-positive and -negative Haemophilus influenzae strains were compared in a rabbit model. All groups of animals received an identical total dose of 100 mg of either antibiotic per kg given by four different intravenous modes of administration including a single large injection, four intermittent injections, a continuous infusion, and an injection followed by an infusion. Aztreonam had a higher degree of penetration in interstitial fluid and fibrin clots and was the most effective agent against beta-lactamase-positive and -negative H. influenzae. A single large injection of either drug resulted in significantly higher peak levels and higher initial area under the curves of concentrations of drugs in serum, the interstitial fluid, and fibrin clots than those by other modes of administration. Continuous infusions of antibiotics resulted in poor in vivo bactericidal activity. Other modes of administration exhibited good antibacterial activity within the first 6 h of the study. Thereafter, a single large injection of aztreonam resulted in a much more rapid killing of H. influenzae than that by injection of the other drugs. Aztreonam and cefuroxime showed good in vivo stability to beta-lactamase produced by H. influenzae while ampicillin was rapidly hydrolyzed in vivo.
Antibacterial activities of antineoplastic agents
Authors: Bodet C A , Jorgensen J H , Drutz D J
Published: June 2012

Fourteen antineoplastic agents were examined for in vitro antibacterial activity against 101 aerobic and anaerobic bacterial isolates representing indigenous human microflora and selected opportunistic pathogens. Only 5-fluorouracil, mitomycin, and etoposide demonstrated inhibitory effects at achievable plasma concentrations, while the remaining drugs lacked appreciable antibacterial activities.