bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of ampicillin-sulbactam in healthy elderly and young volunteers
Authors: Meyers B R , Wilkinson P , Mendelson M H , Walsh S , Bournazos C , Hirschman S Z
Published: June 2012

The pharmacokinetics of ampicillin-sulbactam in elderly subjects (65 to 85 years; group 3, n = 8), compared with those in middle-aged (41 to 64 years; group 2, n = 8) and younger (20 to 40 years; group 1, n = 8) subjects, were investigated. A single 2-g dose of ampicillin combined with 1 g of sulbactam in 60 ml of intravenous solution was administered to each subject over a 30-min period. Blood and urine samples were taken at baseline and serially over an 8.5-h period following the infusion. Ampicillin and sulbactam concentrations were assayed by high-performance liquid chromatography on a reversed-phase C-8 column. The mean levels in serum of both ampicillin and sulbactam were significantly higher for samples from group 3: for ampicillin from 1 through 8.5 h, and for sulbactam for the same time interval except at 5.5 h (P less than or equal to 0.05). The mean urinary excretion of both ampicillin and sulbactam was lowest, and urinary concentrations were highest in group 3. The areas under the serum drug concentration-time curve, the half-lives, and the maximum concentrations in serum were greatest, while the total clearance was lowest, for group 3 for both ampicillin and sulbactam. These results are consistent with a prolongation of antimicrobial activity of ampicillin-sulbactam in the elderly compared with that in younger subjects.
Treatment of murine invasive candidiasis with amphotericin B and cilofungin: evidence for enhanced activity with combination therapy
Authors: Sugar A M , Goldani L Z , Picard M
Published: June 2012

The in vivo interactions of cilofungin, an echinocandin antifungal agent, and amphotericin B, a polyene derivative, in a murine model of disseminated candidiasis have been investigated. While single therapy with either drug alone prolonged survival of infected mice, kidney colony counts were not appreciably reduced. In contrast, combination therapy, especially at higher doses of both drugs, resulted in significant prolongation of survival and suppression of growth of yeast cells in the kidneys. Combination therapy of experimental candidiasis with cilofungin and amphotericin B did not result in antagonism; rather, additive or synergistic effects were seen. Future preclinical work with other echinocandin and polyene derivatives should include studies evaluating the in vivo interactions of both classes of compounds.
Aminoglycosides modify the in vitro metachromatic reaction and murine generalized Shwartzman phenomenon induced by Salmonella minnesota R595 lipopolysaccharide
Authors: Focà A , Matera G , Iannello D , Berlinghieri M C , Liberto M C
Published: June 2012

Endotoxin-neutralizing activity may be an important property for antibiotics to be used in severe sepsis. Several antibiotics, belonging to different classes, were evaluated as to their endotoxin-neutralizing ability, using the inhibition of an in vitro metachromatic assay for lipopolysaccharides and a murine generalized Shwartzman reaction model. Gentamicin, amikacin, and sisomicin have been found to share significant in vitro antiendotoxin activity at an antibiotic/endotoxin ratio as low as 1.0/5 (by weight) and to reduce the murine generalized Shwartzman reaction at an antibiotic/endotoxin ratio of 3.3/5.
Enhanced antiparasitic activity of lipophilic tetracyclines: role of uptake
Authors: Katiyar S K , Edlind T D
Published: June 2012

It was previously noted that the inhibitory activities of lipophilic tetracyclines against the growth of Giardia lamblia in vitro were up to 40-fold greater than those of nonlipophilic tetracyclines (50% inhibitory concentration [IC50] = 1.8 to 71 micrograms/ml) (T. D. Edlind, Antimicrob. Agents Chemother. 33:2144-2145, 1989). We have now extended this observation to Trichomonas vaginalis (IC50 = 2.9 to 200 micrograms/ml), Entaoeba histolytica (IC50 = 3.8 to 36 micrograms/ml), and Leishmania major promastigotes (IC50 = 21 to 250 micrograms/ml; one strain only). The basis for these differential tetracycline activities was investigated with G. lamblia. In a cell-free protein synthesis system, lipophilic and nonlipophilic tetracyclines had similar, relatively low activities (IC50 = 170 to 500 micrograms/ml). On the other hand, tetracycline uptake into intact cells after a 1-h incubation varied dramatically: the ratios of intracellular to extracellular drug concentrations were 1.7 to 7.2 for nonlipophilic tetracyclines and 47 to 112 for lipophilic derivatives. Thus, the variable effects of tetracyclines on the growth of G. lamblia can be fully accounted for by differences in uptake. Passive diffusion probably plays a more important role than active transport in uptake of lipophilic tetracyclines, since similar results were obtained with cells rendered nonviable by metronidazole treatment.
Effect of clavulanic acid on activity of beta-lactam antibiotics in Serratia marcescens isolates producing both a TEM beta-lactamase and a chromosomal cephalosporinase
Authors: Bush K , Flamm R K , Ohringer S , Singer S B , Summerill R , Bonner D P
Published: June 2012

An isolate of Serratia marcescens that produced both an inducible chromosomal and a plasmid-mediated TEM-1 beta-lactamase was resistant to ampicillin and amoxicillin and also demonstrated decreased susceptibility to extended-spectrum beta-lactam antibiotics (ESBAs). Clavulanic acid did not lower the MICs of the ESBAs, but it decreased the MICs of the penicillins. The TEM-1-producing plasmid was transferred to a more susceptible S. marcescens strain that produced a well-characterized inducible chromosomal beta-lactamase. The MICs of the ESBAs remained at a low level for the transconjugant. Ampicillin and amoxicillin which were good substrates for the plasmid-mediated enzyme, were not well hydrolyzed by the chromosomal enzymes; the ESBAs were hydrolyzed slowly by all the enzymes. When each of the S. marcescens strains was grown with these beta-lactam antibiotics, at least modest increases in chromosomal beta-lactamase activity were observed. When organisms were grown in the presence of clavulanic acid and an ESBA, no enhanced induction was observed. The increases in the MICs of the ESBAs observed for the initial clinical isolate may have been due to a combination of low inducibility, slow hydrolysis, and differences in permeability between the S. marcescens isolates. When clavulanic acid and a penicillin were added to strains that produced both a plasmid-mediated TEM and a chromosomal beta-lactamase, much higher levels of chromosomal beta-lactamase activity were present than were observed in cultures induced by the penicillin alone. This was due to the higher levels of penicillin that were available for induction as a result of inhibition of the TEM enzyme by clavulanate.
Double-blind comparison of teicoplanin versus vancomycin in febrile neutropenic patients receiving concomitant tobramycin and piperacillin: effect on cyclosporin A-associated nephrotoxicity
Authors: Kureishi A , Jewesson P J , Rubinger M , Cole C D , Reece D E , Phillips G L , Smith J A , Chow A W
Published: June 2012

A prospective, randomized, and double-blind study comparing teicoplanin with vancomycin in the initial management of febrile neutropenic patients was conducted. Teicoplanin was administered at 6 mg per kg of body weight every 24 h (q24h) intravenously (i.v.) after initial loading at 6 mg/kg q12h for three doses. Vancomycin was administered at 15 mg/kg q12h i.v. Patients also received piperacillin (3 g q4h i.v.) and tobramycin (1.5 to 2.0 mg/kg q8h i.v.). Of 53 patients enrolled, 50 were judged to be evaluable. Among these, 25 received teicoplanin and 25 received vancomycin. At enrollment, both groups were comparable in age, sex, renal function, underlying hematologic condition, and concurrent therapy. Both groups had similar sites of infection and microbial pathogens. Empirical antimicrobial therapy resulted in the cure of or improvement in 23 (92%) teicoplanin patients and 21 (84%) vancomycin patients (P = 0.67). Failures occurred with two vancomycin patients but no teicoplanin patients. Clinical response was indeterminate for two patients in each group. Adverse reactions occurred significantly more often in the vancomycin group than in the teicoplanin group (P = 0.01), and these reactions required the termination of the study regimens of 6 vancomycin versus 0 teicoplanin patients (P = 0.02). Nephrotoxicity was observed more frequently in the vancomycin group (10 versus 2 patients; P = 0.02). Subgroup analysis revealed a significant deterioration of renal function when vancomycin and cyclosporin A, but not teicoplanin and cyclosporin A, were used concurrently (P = 0.02). Among patients who received vancomycin and amphotericin B or teicoplanin and amphotericin B concurrently, deterioration in renal function was equivalent in both groups. Teicoplanin in the dosage employed was tolerated better than vancomycin in the empirical treatment of fever and neutropenia in our patient population.
Daptomycin disrupts membrane potential in growing Staphylococcus aureus
Authors: Alborn W E , Allen N E , Preston D A
Published: June 2012

Daptomycin (LY146032) caused a calcium-dependent dissipation of the membrane potential (delta psi) in Staphylococcus aureus without noticeably affecting the chemical gradient (delta pH) across the membrane. The effect of daptomycin on membrane energization may account for many of the inhibitory effects on macromolecular biosyntheses and membrane function reported for this antibiotic. Our evidence indicates that the bactericidal activity of daptomycin is dependent on an available delta psi.
Petite mutagenesis in Saccharomyces cerevisiae by a series of bis-cationic trypanocidal drugs
Authors: Ferguson L R , Sundberg R J
Published: June 2012

A group of bis-cationic imidazo[1,2-a]pyridinium salts and related compounds, some of which exhibit in vivo trypanocidal activity, have been investigated for induction of petite mutagenesis in Saccharomyces cerevisiae. All of the compounds which are active trypanocides induce mutagenesis. There appears to be a correlation between trypanocidal activity and mutagenic activity which may have its structural origin in the spatial separation of the cationic centers.
In vitro studies with five quinolones: evidence for changes in relative potency as quinolone resistance rises
Authors: Thomson K S , Sanders C C , Hayden M E
Published: June 2012

A panel of 203 staphylococci, Enterobacteriaceae, Pseudomonas aeruginosa, and miscellaneous nonfermentative gram-negative bacilli were chosen for their various susceptibilities to ciprofloxacin. On the basis of agar dilution susceptibilities, each of the four taxonomic groups was divided into ciprofloxacin-susceptible, moderately resistant, and highly resistant subgroups, and each subgroup was then further analyzed for its susceptibility to the fluoroquinolones CI-960, CI-990, sparfloxacin, and ofloxacin. Although the MICs of each quinolone increased as ciprofloxacin resistance increased, the potency of CI-960 appeared to increase relative to the potencies of the other quinolones. Similarly, the MICs of sparfloxacin and ofloxacin appeared to be less affected by ciprofloxacin resistance than were the MICs of ciprofloxacin or CI-990. Single-step mutants of representative clinical isolates with different levels of ciprofloxacin resistance were selected to determine whether the study quinolones differed in their propensity to select resistant mutants and whether the presence of preexisting ciprofloxacin resistance influenced the subsequent development of resistance. Each of the five fluoroquinolones and nalidixic acid selected mutants that exhibited generally modest decreases in quinolone susceptibility (4- to 16-fold). However, CI-960 inhibited significantly more mutants (80%) than did the other quinolones (39 to 59%) at a concentration of 1 microgram/ml. The presence of preexisting ciprofloxacin resistance appeared to be associated with higher mutational frequencies in coagulase-negative staphylococci exposed to each of the fluoroquinolones and in Serratia marcescens exposed to nalidixic acid. Preexisting ciprofloxacin resistance did not influence the development of resistance in the strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa that were studied. The results of this study suggest that quinolones are not affected equally by all resistance mechanisms, and although each one can select mutants, some quinolones may be active against these mutants at clinically achievable concentrations.
Crossover assessment of serum bactericidal activity and pharmacokinetics of ciprofloxacin alone and in combination in healthy elderly volunteers
Authors: Weinstein M P , Deeter R G , Swanson K A , Gross J S
Published: June 2012

To better define the pharmacokinetics and serum bactericidal activity (SBA) of ciprofloxacin and other antimicrobial agents in the elderly, six healthy (greater than 65 years) volunteers with normal renal function were given ciprofloxacin alone orally, ciprofloxacin plus rifampin orally, ciprofloxacin plus clindamycin orally, rifampin alone orally (three volunteers), and, for comparison of SBA against gram-positive cocci, vancomycin intravenously. Mean peak ciprofloxacin concentrations and other pharmacokinetic parameters were not altered significantly by coadministration of either rifampin or clindamycin. Ciprofloxacin had somewhat greater SBA against the oxacillin-susceptible and oxacillin-resistant Staphylococcus aureus strains tested than did vancomycin, but rifampin was by far the most active single agent tested. The SBA of rifampin against S. aureus was modestly antagonized during combination therapy with ciprofloxacin, but substantial SBA still was present. The ciprofloxacin SBA against S. aureus was completely antagonized by clindamycin if the strains were susceptible to the latter agent. Ciprofloxacin had modest SBA against group A streptococci and no SBA against the three pneumococcal strains tested. All of the regimens had poor to absent SBA against Enterococcus faecalis. By contrast, ciprofloxacin had excellent SBA against Escherchia coli and Klebsiella pneumoniae and moderate SBA against Pseudomonas aeruginosa. Combination therapy with rifampin or clindamycin in general enhanced the SBA against the nonenterococcal streptococci and had no effect on the SBA against the gram-negative bacilli.
Effect of isepamicin dosing scheme on concentration in cochlear tissue
Authors: Govaerts P J , Claes J , Van de Heyning P H , Derde M P , Kaufman L , Marquet J F , De Broe M E
Published: June 2012

To investigate the possible effect of the dosing scheme of aminoglycosides on their concentration in the cochlear tissue, we gave two groups of 12 guinea pigs subcutaneous doses of 45 mg of isepamicin (ca. 30 mg of active product) per kg of body weight daily for eight consecutive days. The first group received the drug by continuous infusion, while the second group received it by single daily injection. On the final day of administration, the animals were sacrificed and the cochlear tissue was removed. The tissues from the cochleas of pairs of guinea pigs were pooled. The isepamicin concentrations in the cochlear duct tissue (organ of Corti plus lateral wall) and the cochlear nerve tissue were determined separately. Hearing levels before and after treatment were assessed by means of frequency-specific auditory brain stem responses (ABR). The creatinine level in serum was determined on the last day of the administration. None of the animals in either group showed signs of renal insufficiency or of hearing impairment. The median isepamicin concentration in the cochlear duct was 2.40 micrograms/mg of protein after continuous administration and 2.50 micrograms/mg of protein after once-daily administration, compared with the concentration in the cochlear nerve, where it was 1.93 micrograms/mg of protein after continuous administration and 2.59 micrograms/mg of protein after once-daily administration. These differences are statistically insignificant. The results give evidence for linear uptake kinetics of isepamicin in the inner ear tissue and may be directly relevant to the clinical dosing of the drug.
Interaction of imipenem with erythromycin and tetracycline assessed by microdilution checkerboard techniques
Authors: Gould I M , Wilson D , Milne K , Paterson A , Golder D , Russell D
Published: June 2012

Microdilution methodology was used to study the interaction of imipenem with erythromycin and tetracycline, a combination therapy that might be used for the treatment of serious pelvic inflammatory disease. The combination of imipenem and erythromycin showed no antagonism for Escherichia coli and Haemophilus influenzae but was antagonistic for Staphylococcus aureus, Enterococcus faecalis, and group B streptococci; the combination of imipenem and tetracycline was antagonistic for all strains except H. influenzae. Correlation between the results of kill curves and the measurement of fractional bactericidal concentration (FBC) indices was good, although FBC indices showed less antagonism than kill curves. Fractional inhibitory concentration indices showed poor correlation, rarely showing antagonism, and indeed showed synergy in three cases. If erythromycin or tetracycline is considered necessary in addition to imipenem in the treatment of pelvic inflammatory disease, it is probably more effective when given after the course of imipenem has been completed.
A new trimethoprim resistance gene, dhfrX, in the In7 integron of plasmid pDGO100
Authors: Parsons Y , Hall R M , Stokes H W
Published: June 2012

A new trimethoprim resistance determinant, designated dhfrX, was identified in the In7 integron of pDGO100. The sequence of the dhfrX dihydrofolate reductase is up to 28% identical to the sequences of several known dihydrofolate reductase proteins. The dhfrX gene is adjacent to the second 3'-conserved segment of the In7 integron, but the first 77 bases of this segment are not present.
In vitro antibacterial activity of a new quinolone, NM394
Authors: Ozaki M , Matsuda M , Tomii Y , Kimura K , Kazuno K , Kitano M , Kise M , Shibata K , Otsuki M , Nishino T
Published: June 2012

NM394 is a new 6-fluoroquinolone antibacterial agent with a tricyclic structure which has a bridge that connects the N-1 and C-2 positions of the quinolone. The antibacterial activity of NM394 against clinical isolates of staphylococci, streptococci, enterococci, members of the family Enterobacteriaceae, and Pseudomonas aeruginosa was equal to or one-half that of ciprofloxacin. NM394 was as active as ofloxacin against gram-positive bacteria and was two to eight times more active against gram-negative bacteria, including P. aeruginosa. NM394 was two to eight times more active than enoxacin against gram-positive and gram-negative bacteria. The MICs of NM394 against Escherichia coli and P. aeruginosa at pH 5.5 were reduced 4 to 16 times compared with those at pH 7.0. Ciprofloxacin, ofloxacin, and enoxacin were 2 to 32 times less active against these two bacteria and Staphylococcus aureus at an acidic pH than they were at pH 7.0. In the presence of 5 mM Mg2+, the MICs of all of these drugs increased 2 to 32 times, but they were only slightly affected by 5 mM Ca2+, type of medium, serum, or size of inoculum. NM394 showed potent bactericidal activity and inhibited the supercoiling activity of E. coli DNA gyrase. The in vitro antibacterial profile of NM394 is similar to that of other 6-fluoroquinolones.
In vivo evaluation of NM441, a new thiazeto-quinoline derivative
Authors: Ozaki M , Matsuda M , Tomii Y , Kimura K , Segawa J , Kitano M , Kise M , Shibata K , Otsuki M , Nishino T
Published: June 2012

NM441 is a lipophilic prodrug of a new thiazeto-quinoline carboxylic acid derivative NM394, and when it is administered orally it is readily absorbed and hydrolyzed to its parent compound. After oral administration of NM441 at a dose of 20 mg/kg to dogs, the peak concentration of NM394 in plasma was 2.39 micrograms/ml, whereas it was 0.63 micrograms/ml for NM394 administered alone. The in vivo activity of NM441 was compared with those of ciprofloxacin, ofloxacin, and enoxacin in mouse protection studies. NM441 was as effective as ofloxacin and was twice as effective as ciprofloxacin against systemic infection with Staphylococcus aureus. Against infections with streptococci, NM441 was two to three times as effective as ofloxacin and five times as effective as ciprofloxacin. Against infection with Escherichia coli, NM441 was as effective as ciprofloxacin and ofloxacin, but against infections with Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa, NM441 was two to four times as effective as ciprofloxacin and ofloxacin. NM441 was three to seven times as effective as enoxacin in systemic infections. Against urinary tract infections with E. coli, NM441 reduced the number of bacterial CFU per gram of kidney by 1 to 2 log10 more and, with P. aeruginosa, by 1 to 6 log10 more than did ciprofloxacin and ofloxacin. Against respiratory tract infections with K. pneumoniae, NM441 was as effective as ofloxacin and was twice as effective as ciprofloxacin.
Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection
Authors: Flexner C , Barditch-Crovo P A , Kornhauser D M , Farzadegan H , Nerhood L J , Chaisson R E , Bell K M , Lorentsen K J , Hendrix C W , Petty B G
Published: June 2012

Polysulfated polysaccharides are attractive candidates for antiviral drug development because of their potent in vitro activities against human immunodeficiency virus (HIV), herpesviruses, and other enveloped viruses. To determine the potential anti-HIV activity of a prototypical polysulfated polysaccharide, we administered the maximally tolerated dose of dextran sulfate by continuous intravenous infusion to 10 subjects with symptomatic HIV infection for up to 14 days. Since parenteral dextran sulfate is an anticoagulant, the infusion was adjusted to produce the greatest acceptable increase in activated partial thromboplastin time. Drug concentrations in plasma achieved with this protocol were up to 200-fold greater than the 50% inhibitory concentration for free HIV infectivity in vitro. Despite this, circulating HIV antigen (p24) levels increased in all eight subjects who received the drug for more than 3 days (median proportional increase, 73.5%; range, 32 to 130%); this increase was highly significant when it was compared with that in a large cohort of untreated historical controls (Fisher's exact test, P less than 0.001). Frequent decreases in infusion rate were required in all subjects to maintain a constant activated partial thromboplastin time; plasma dextran sulfate levels did not fall as the infusion rate decreased, suggesting a decline in estimated drug clearance over time. Continuous intravenous dextran sulfate was toxic, producing profound but reversible thrombocytopenia in all eight subjects who received drug for more than 3 days and extensive but reversible alopecia in five of these subjects. Because of its toxicity and lack of beneficial effect on surrogate markers, dextran sulfate is unlikely to have a practical role in the treatment of symptomatic HIV infection.
Pharmacokinetics and tolerability of teicoplanin in healthy volunteers after single increasing doses
Authors: Del Favero A , Patoia L , Rosina R , Buniva G , Danese A , Bernareggi A , Molini E , Cavenaghi L
Published: June 2012

In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.
Phase 1 study of recombinant human CD4-immunoglobulin G therapy of patients with AIDS and AIDS-related complex
Authors: Hodges T L , Kahn J O , Kaplan L D , Groopman J E , Volberding P A , Amman A J , Arri C J , Bouvier L M , Mordenti J , Izu A E
Published: June 2012

The safety and pharmacokinetics of recombinant CD4-immunoglobulin G (rCD4-IgG) were evaluated in a phase 1 study with dose escalation. A total of 16 patients, 6 with AIDS and 10 with AIDS-related complex, were evaluated at two university-affiliated hospital clinics. rCD4-IgG was administered once weekly for 12 weeks to four patients each at doses of 0.03, 0.1, 0.3, and 1.0 mg/kg of body weight. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Pharmacokinetic, toxicity, and immunologic variables were monitored with all patients. Administration of rCD4-IgG was well tolerated, with no important clinical or immunologic toxicities noted. No subjects required dose reduction or discontinuation of therapy due to toxicity. No consistent changes were seen in human immunodeficiency virus antigen levels in serum or CD4 lymphocyte populations. The volume of distribution was small, and compared with that of rCD4, the half-life of the hybrid molecule was markedly prolonged following intramuscular or intravenous administration. The rate and extent of absorption following intramuscular dosing were variable. Intramuscular administration of rCD4-IgG appears to be inferior to intravenous dosing from a pharmacokinetic standpoint, with lower peak concentrations and variable absorption. After intravenous administration, peak concentrations of rCD4-IgG in serum (20 to 24 micrograms/ml) that have shown antiviral activity in vitro against more sensitive clinical isolates of human immunodeficiency virus were achieved. The peak concentrations in serum after intramuscular administration were below these levels. Treatment with rCD4-IgG was well tolerated at the doses administered to patients in this study but did not result in significant changes in CD4 lymphocyte counts or p24 antigen levels in serum.
Stimulation with cytokines enhances penetration of azithromycin into human macrophages
Authors: Bermudez L E , Inderlied C , Young L S
Published: June 2012

An effective intracellular concentration of an antimicrobial agent is essential for therapy of infections caused by organisms of the Mycobacterium avium complex. We previously reported on the effect of the combination of azithromycin and tumor necrosis factor (TNF) against M. avium infection in macrophages. We now report that stimulation of macrophages either with recombinant human gamma interferon (IFN-gamma, 10(2) U/ml) or with recombinant human TNF-alpha (10(2) U/ml) resulted in an increase in the intracellular concentration of azithromycin by approximately 200% within 3 h, compared with the concentration in unstimulated macrophages. Infection of macrophages with M. avium complex led to a decrease in the uptake of [14C]azithromycin by infected cells, compared with that by uninfected controls. Stimulation of infected macrophages with recombinant IFN-gamma or TNF-alpha overcame the inhibitory effect associated with infection. These results suggest that the increased bactericidal activity of the TNF-alpha-azithromycin or IFN-gamma-azithromycin combination against M. avium is related to enhanced uptake of the antibiotic by the stimulated phagocyte.
Hygromycin B inhibits synthesis of murine coronavirus RNA
Authors: Macintyre G , Woods D E , Anderson R
Published: June 2012

The aminoglycoside hygromycin B inhibits the infection of mouse hepatitis virus (MHV) A59 both in vitro and in vivo. In probing the mechanism by which hygromycin B exerts its antiviral effect, we describe here studies which point to inhibition of viral RNA synthesis as the key step in virus replication which is affected by the drug. Cells which are infected with MHV do not take up higher levels of hygromycin B than do uninfected ones. Comparative assays of MHV replication and MHV protein synthesis in the presence of hygromycin B and another aminoglycoside, neomycin, indicate that hygromycin B is the more-effective antiviral agent and that its antiviral activity likely does not involve phosphoinositide-mediated processes such as those inhibited by neomycin.
In vitro susceptibility of the fish pathogen Aeromonas salmonicida to flumequine
Authors: Barnes A C , Lewin C S , Hastings T S , Amyes S G
Published: June 2012

The activity of the fluoroquinolone flumequine was investigated against the fish pathogen Aeromonas salmonicida and was compared with that of oxolinic acid. Flumequine was more active than oxolinic acid in terms of its MIC against oxolinic acid-resistant isolates of A. salmonicida and was as active as oxolinic acid against susceptible isolates. In contrast to oxolinic acid, flumequine was bactericidal, with only 1% of the bacteria surviving 6 h of exposure to the drug at concentrations slightly above the MIC. Mutation to resistance to flumequine was found to occur at a lower frequency than that to oxolinic acid. Hence, in vitro, flumequine appears to possess some advantages over oxolinic acid against this fish pathogen.
Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine
Authors: Derouin F , Piketty C , Chastang C , Chau F , Rouveix B , Pocidalo J J
Published: June 2012

The efficacy of dapsone alone or combined with pyrimethamine against Toxoplasma gondii was investigated experimentally. For in vitro studies, a sensitive immunoassay was used for assessment of Toxoplasma growth in tissue cultures; dapsone was found to have a significant inhibitory effect at a concentration of 0.5 micrograms/ml in the cultures, and the 50% inhibitory concentration was estimated to be 0.55 micrograms/ml. When pyrimethamine and dapsone were combined, an important synergistic effect which was associated with morphological alterations of the parasites was observed. In vivo studies were performed in a murine model of acute toxoplasmosis in which a tissue culture method was used to estimate the parasite burden in the blood, lungs, and brains of infected mice. Dapsone alone, which was administered at 100 mg/kg/day for 10 days from day 1 after infection, was unable to prevent parasite dissemination and only delayed the time to death of treated mice compared with the time of death of untreated controls. When dapsone and pyrimethamine (18.5 mg/kg/day) were administered in combination from day 4 after infection, parasites were cleared from blood and organs within 6 days, but relapses were observed 15 days after the cessation of therapy. When treatment was started at day 1 after infection, 100% of mice survived and relapses were not observed, suggesting a good efficacy of this combination for preventive therapy.
Biochemical properties and purification of metallo-beta-lactamase from Bacteroides fragilis
Authors: Bandoh K , Muto Y , Watanabe K , Katoh N , Ueno K
Published: June 2012

The beta-lactamase from Bacteroides fragilis GAI-30144 hydrolyzed imipenem, oxyiminocephalosporins, cephamycins, and penicillins. Enzyme activity was inhibited by EDTA. Zinc completely reversed inactivation of the enzyme by EDTA. The molecular mass of purified enzyme was estimated to be 33,000 daltons.
Oral acyclovir therapy of recurrent herpes simplex virus type 2 infection of the hand
Authors: Gill M J , Bryant H E
Published: June 2012

Acyclovir was evaluated as treatment of recurrent herpes simplex virus type 2 infection of the hand in a double-blind, placebo-controlled crossover study. In nine fully evaluable patients, oral acyclovir (2 g/day in three doses for 10 days) initiated during the earliest phase of a recurrence reduced the mean durations (+/- standard deviation) of clinical symptoms from 10.1 (+/- 3.6) to 3.7 (+/- 3.0) days (P = 0.008), signs from 11.1 (+/- 3.7) to 6.2 (+/- 3.3) days (P = 0.024), and viral positivity from 5.3 (+/- 3.8) to 0.6 (+/- 1.1) days (P = 0.011).
Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis
Authors: Yokota T , Mochizuki S , Konno K , Mori S , Shigeta S , De Clercq E
Published: June 2012

By using an assay system based on a human hepatoblastoma cell line (HB611) that continuously synthesizes hepatitis B virus DNA, the following compounds were found to inhibit hepatitis B virus DNA synthesis at concentrations that were significantly lower than their minimum cytotoxic concentrations: 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, 9-(phosphonylmethoxyethyl)adenine, 2',3'-dideoxy-2',3'-didehydrocytidine, and 2',3'-dideoxycytidine. The most potent compound was PMEDAP (50% effective concentration, 0.02 micrograms/ml). The selective index, or ratio of the 50% cytotoxic concentration to 50% effective concentration, of PMEDAP was greater than 750.
Pharmacokinetics of temafloxacin in humans after single oral doses
Authors: Granneman G R , Carpentier P , Morrison P J , Pernet A G
Published: June 2012

Temafloxacin (A-63004) is a new quinolone antibacterial agent with a broad spectrum of activity against gram-positive and gram-negative aerobes and anaerobes. The pharmacokinetics and metabolism of temafloxacin were determined in healthy volunteers after administration of single oral doses of 100, 200, 400, 600, 800, and 1,000 mg. The corresponding peak concentrations in plasma (mean +/- standard deviation) were 0.98 +/- 0.26, 1.61 +/- 0.57, 2.43 +/- 0.56, 3.87 +/- 0.64, 4.54 +/- 1.03, and 6.67 +/- 0.74 micrograms/ml. The times that elapsed to attain peak levels ranged from 1.25 to 3.5 h. Statistical analyses of parameters related to the extent of absorption and the linearity of the dispositional pharmacokinetics detected no dose-related trends. Study-wide, total clearance (223 ml/min) and renal clearance (125 ml/min) showed low intersubject variability, with coefficients of variation near 20%. The terminal-phase rate constant of 0.090 +/- 0.008 h-1 corresponds to a half-life of 7.7 h. Temafloxacin was excreted mainly in the urine, with 57 +/- 11% of the dose appearing in the urine unchanged. Conjugated temafloxacin, oxidative metabolites, and conjugates thereof were minor components in urine, collectively accounting for 5 to 8% of the dose. Since intravenously dosed dogs eliminated 50% of the dose by nonrenal processes, urinary recoveries approaching two-thirds of the dose in humans were consistent with high, if not quantitative, absorption. Reported adverse events were generally mild, were randomly distributed between temafloxacin- and placebo-treated subjects, and were not dose related.
Acquired resistance of Nocardia brasiliensis to clavulanic acid related to a change in beta-lactamase following therapy with amoxicillin-clavulanic acid
Authors: Steingrube V A , Wallace R J , Brown B A , Pang Y , Zeluff B , Steele L C , Zhang Y
Published: June 2012

Previous studies have demonstrated that Nocardia brasiliensis is susceptible to amoxicillin-clavulanic acid and that its beta-lactamases are inhibited in vitro by clavulanic acid. A cardiac transplant patient with disseminated infection caused by N. brasiliensis was treated with this drug combination with good response, but relapsed while still on therapy. The relapse isolate was found to be identical to the initial isolate by using genomic DNA restriction fragment patterns obtained by pulsed field gel electrophoresis, but it was resistant to amoxicillin-clavulanic acid. On isoelectric focusing, the beta-lactamase from the relapse isolate exhibited a shift in the isoelectric point (pI) of its major band from 5.10 to 5.04 compared with the enzyme from the pretreatment isolate. As determined by using values of the amount of beta-lactamase inhibitor necessary to give 50 +/- 5% inhibition of beta-lactamase-mediated hydrolysis of 50 microM nitrocefin, the beta-lactamase of the relapse isolate was also 200-fold more resistant than the enzyme from the pretreatment isolate to clavulanic acid and was more resistant to sulbactam, tazobactam, cloxacillin, and imipenem. The beta-lactamase of the relapse isolate exhibited a 10-fold decrease in hydrolytic activity for cephaloridine and other hydrolyzable cephalosporins compared with that for nitrocefin. Acquired resistance to amoxicillin-clavulanic acid in this isolate of N. brasiliensis appears to have resulted from a mutational change affecting the inhibitor and active site(s) in the beta-lactamase.
Comparison of the inoculum effects of members of the family Enterobacteriaceae on cefoxitin and other cephalosporins, beta-lactamase inhibitor combinations, and the penicillin-derived components of these combinations
Authors: Goldstein E J , Citron D M , Cherubin C E
Published: June 2012

We compared the inoculum effects of 105 recent clinical isolates of the family Enterobacteriaceae on cefoxitin, other cephalosporins, aztreonam, and three beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and their penicillin-derived components. Piperacillin and aztreonam showed the largest inoculum effect, and cefoxitin showed the smallest. The other cephalosporins tested (cefotetan, ceftizoxime, and ceftriaxone) showed an intermediate inoculum effect. In general, the inoculum effect was of greater magnitude for the penicillin and beta-lactamase inhibitor combinations than for the cephalosporins tested. Bactericidal activity was assayed and morphologic changes were monitored for selected strains exhibiting a large inoculum effect. MICs correlated with bactericidal activity at an inoculum level of 10(5) CFU/ml, while activity at 10(8) CFU/ml was variable. Cefoxitin demonstrated the least filamentous transformation and the most rapid bactericidal activity. Aztreonam showed the most marked filamentous transformation and was no longer bactericidal at 10(8) CFU/ml. The beta-lactamase inhibitor combinations showed variable bactericidal activity, and regrowth occurred with a number of strains with all three agents tested.
High genetic homology between plasmids of human and animal origins conferring resistance to the aminoglycosides gentamicin and apramycin
Authors: Chaslus-Dancla E , Pohl P , Meurisse M , Marin M , Lafont J P
Published: June 2012

Escherichia coli and Salmonella strains resistant to gentamicin and apramycin were isolated from cattle in France and Belgium and from patients in hospitals. Homology between plasmids of both human and animal origins encoding aminoglycoside 3-N-acetyltransferase was revealed by digestion with several restriction endonucleases and confirmed by hybridization with different replicon-specific probes.
Activity of a new carbapenem antibiotic, meropenem, against Haemophilus influenzae strains with beta-lactamase- and non-enzyme-mediated resistance to ampicillin
Authors: Jorgensen J H , Maher L A , Howell A W
Published: June 2012

Meropenem was 8- to 32-fold more active (MIC for 90% of strains = 0.125 micrograms/ml) than imipenem against a collection of Haemophilus influenzae strains characterized as either susceptible to ampicillin or resistant to that agent by virtue of beta-lactamase or nonenzymatic mechanisms. MBCs and kinetic kill curve tests showed that meropenem (as well as imipenem, several cephalosporins, and amoxicillin-clavulanate) was bactericidal against all strains at or within four times the respective MICs. Thus, meropenem demonstrated greater inhibitory activity than imipenem and activity comparable to that of cefotaxime against these selected strains.
Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children
Authors: Hayton W L , Walstad R A , Thurmann-Nielsen E , Kufaas T , Kneer J , Ambros R J , Rugstad H E , Monn E , Bodd E , Stoeckel K
Published: June 2012

The pharmacokinetics of cefetamet were determined after intravenous (i.v.) administration of cefetamet and oral administration of cefetamet pivoxil syrup to patients between the ages of 3 and 12 years. The patients were hospitalized for reconstructive urological surgery; to prevent infection, prophylactic i.v. cefetamet was administered on the day of surgery and oral cefetamet pivoxil was administered 2 days later. After i.v. administration, the mean (+/- standard deviation) half-life of cefetamet was 1.97 +/- 0.60 h (n = 18), which was different from the 2.46 +/- 0.33 h reported for nine adults (22 to 68 years old) in a previous study. The average values for the mean residence times were 2.35 +/- 0.94 and 2.83 +/- 0.34 h and the average values for the fraction of the dose eliminated unchanged in the urine were 79.9% +/- 8.99% and 80% +/- 11% in children and adults, respectively. Plots of mean systemic clearance and steady-state volume of distribution versus body weight for the children and comparative adults were linear on log-log coordinates, and the slopes of the plots were 0.661 and 0.880, respectively. These slope values suggested that mean systemic clearance values per unit of body surface area were similar in children and adults and that maintenance doses for children should be the adult maintenance dose multiplied by the child's surface area divided by 1.73 m2. The mean (+/- standard deviation) oral bioavailabilities of cefetamet pivoxil were 49.3% +/- 15.7% in 3- to 7-year-old children who received a 500-mg dose and 37.9% +/- 10.0% in 8- to 12-year-old children who received a 1,000-mg dose. These values were not different from that observed in the adult group after two 500-mg tablets. Likewise, the peak concentration of cefetamet in plasma and its time of occurrence in children were in line with the values which have been observed for adults.
Lack of effective bactericidal activity of new quinolones against Brucella spp
Authors: García-Rodriguez J A , García Sánchez J E , Trujillano I
Published: June 2012

The in vitro activities of six fluoroquinolones against 43 Brucella spp. were compared by testing three different inocula at two medium pH values. The influence of the test conditions was moderate. The activities of all quinolones were lower at pH 5 and with a high inoculum size. Results indicate the lack of effective bactericidal activity of quinolones against most strains of Brucella spp., particularly B. abortus.
Comparative activity of cefepime, alone and in combination, against clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients
Authors: Bosso J A , Saxon B A , Matsen J M
Published: June 2012

The comparative in vitro activity and synergy of cefepime were evaluated with clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients. The activity of cefepime, both alone and in combination, was comparable to those of other antibiotics. The clinical efficacy of cefepime in cystic fibrosis patients merits investigation.
Disulfiram inhibits the in vitro growth of methicillin-resistant staphylococcus aureus
Authors: Phillips M , Malloy G , Nedunchezian D , Lukrec A , Howard R G
Published: June 2012

Several antibiotics have disulfiram-like effects; we evaluated disulfiram for its antibiotic-like effects. Disulfiram inhibited the in vitro growth of methicillin-resistant Staphylococcus aureus, with an MIC of 1.33 micrograms/ml, but was not effective against members of the family Enterobacteriaceae or Pseudomonas species.
High-level resistance to cefotaxime and ceftazidime in Klebsiella pneumoniae isolates from Cleveland, Ohio
Authors: Thomson K S , Sanders C C , Washington J A
Published: June 2012

Two isolates of Klebsiella pneumoniae possessing both TEM-1 and SHV-2 beta-lactamases were isolated from patients at the Cleveland Clinic in 1988. The beta-lactamases were discriminated and identified by using substrate hydrolysis data and an isoelectric focusing procedure in which the gel was overlaid with beta-lactamase inhibitors.
Enhancement of macrophage superoxide anion production by amphotericin B
Authors: Wilson E , Thorson L , Speert D P
Published: June 2012

Amphotericin B (AmB) appears to have some important immunomodulatory effects, but its mechanism of action has not been explained. We investigated the effects of AmB on activation of human monocyte-derived macrophages. Macrophages cultured in the presence of AmB had an enhanced capacity to produce superoxide anion after stimulation with phorbol myristate acetate. This enhancement was dose dependent within a therapeutic range of AmB levels (0.1 to 3.0 mg/liter). Macrophages cultured in the presence of AmB had enhanced surface expression of Ia antigen; phagocytosis of unopsonized zymosan, opsonized Staphylococcus aureus, or erythrocytes opsonized with C3bi or immunoglobulin G paradoxically appeared to be reduced, but results did not achieve statistical significance. AmB appears to activate macrophages and may do so via direct effects on the plasma membrane.
Role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents
Authors: Lachance N , Gaudreau C , Lamothe F , Larivière L A
Published: June 2012

We studied the role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents. beta-Lactamase-positive strains were more resistant than beta-lactamase-negative strains to amoxicillin, ampicillin, and ticarcillin (P less than 0.05). With penicillin G, piperacillin, imipenem, and six cephalosporins, the susceptibility levels were similar for both beta-lactamase-positive and -negative strains. By using spectrophotometric and microbiological assays, the beta-lactamase from three strains hydrolyzed ampicillin, amoxicillin, penicillin G, cloxacillin, and, partially, cephalothin. Ticarcillin and piperacillin were partially hydrolyzed in the microbiological assay. There was no activity against five other cephalosporins or imipenem. Isoelectric focusing of the enzyme showed a pI of 8.8. Tazobactam was the best inhibitor of the enzyme, followed by clavulanic acid, sulbactam, and cefoxitin, while EDTA and p-chloromercuribenzoate had no activity. All beta-lactamase-positive strains became susceptible to amoxicillin and ampicillin with 1 micrograms of clavulanic acid per ml. With the same inhibitor, there was a reduced but significant effect for ticarcillin but no effect for penicillin G or piperacillin. Sulbactam had no effect and tazobactam was effective only at 2 micrograms/ml on amoxicillin and ampicillin. The beta-lactamase of C. jejuni seems to be a penicillinase with a role in resistance for only amoxicillin, ampicillin, and ticarcillin.