bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorometric measurement of ofloxacin uptake by human polymorphonuclear leukocytes
Authors: Pascual A , Garcia I , Perea E J
Published: June 2012

A fluorometric assay, based on the natural fluorescence of the quinolone nucleus, was used to determine the uptake of ofloxacin by human polymorphonuclear leukocytes. The ratio of cellular concentration to extracellular concentration (C/E) at 20 min and 37 degrees C was 7.2, using an extracellular concentration of 5 micrograms/ml. Uptake was rapid and was not affected by pH (5 to 9), but required elevated environmental temperature and cell viability. The metabolic inhibitors sodium fluoride and sodium cyanide significantly decreased the uptake of ofloxacin. The penetration of ofloxacin was not affected by the presence of glucose or adenosine, but was decreased by L-amino acids (lysine, leucine, and glycine). These results suggest that ofloxacin could be transported via an amino acid transport system and that the fluorometric assay is a useful method for determining the intracellular penetration of fluoroquinolones, avoiding the use of radiolabeled antimicrobial agents.
Resistance to antimicrobial agents and prevalence of R plasmids in Pasteurella multocida from turkeys
Authors: Hirsh D C , Hansen L M , Dorfman L C , Snipes K P , Carpenter T E , Hird D W , McCapes R H
Published: June 2012

One hundred fifty-three isolates of Pasteurella multocida, representing the causative agent of 95% of all known outbreaks of fowl cholera occurring in California meat and breeder turkeys from August 1985 through February 1987, were examined for susceptibility to antimicrobial agents. Of the 153 isolates, 6 were shown to be resistant to one or more antimicrobial agents. Of the six resistant isolates, five contained R plasmids. All but one of the R plasmids were small (6 to 7 megadaltons) and nonconjugative, encoding resistance to tetracycline or kanamycin, streptomycin, and sulfonamides; the other was large (70 megadaltons) and conjugative, transferring resistance to kanamycin, streptomycin, sulfonamides, and tetracycline to P. multocida and Escherichia coli. The three plasmids encoding resistance to tetracycline alone appeared identical.
Lack of activity of fusidic acid against human immunodeficiency virus in monocytes
Authors: Maehlen T , Degré M
Published: June 2012

The effect of fusidic acid on the multiplication of human immunodeficiency virus in monocyte-derived macrophages was examined in in vitro cultures. Virus titers, measured by reverse transcriptase and by p24 antigen in the supernatants and in lysed cells, were reduced in some experiments by 50 micrograms/ml or more; in other experiments, 10 micrograms of fusidic acid per ml added to the cells simultaneously with the virus inoculation reduced virus titers. The effect was comparable in peripheral blood lymphocytes. The drug was generally toxic to the cells, both macrophages and peripheral blood lymphocytes, in concentrations of 50 micrograms/ml or more.
pH and other effects on the antifungal activity of cilofungin (LY121019)
Authors: McIntyre K A , Galgiani J N
Published: June 2012

We investigated the effects of various test conditions on broth macro- and microdilution susceptibility test results for several species of yeasts with a new antifungal agent, cilofungin. As the pH decreased from 7.4 to 3.0, 50% inhibitory concentrations (IC1/2) increased up to 64-fold. This effect was unrelated to yeast growth rate, solvent concentration, or choice of buffer. Broth microdilution results for 42 Candida albicans isolates at pH 7.4 in synthetic amino acid medium, fungal (SAAMF), showed IC1/2 results from 0.08 to 2.5 micrograms/ml, whereas at pH 3.0 the results were 5.0 or 10.0 micrograms/ml. Fungicidal concentrations were closer to MIC results at the lower pH, i.e., an average of 16-fold above the MIC at pH 3.0, compared with an average 256-fold difference at pH 7.4. Two strains that had very different IC1/2 results at pH 7.4 and identical IC1/2 results at pH 3.0 were found to be equally susceptible to cilofungin therapy in rats. In additional studies, other medium effects were demonstrable, with yeast nitrogen broth and minimal essential medium generally yielding higher results than two other synthetic media (SAAMF and RPMI 1640 medium). However, susceptibility results did not change with inoculum between 10(2) and 10(5) yeast cells per ml or temperature between 30 and 37 degrees C. These studies indicate that pH is an important influence on in vitro rank order susceptibility of pathogenic yeasts to cilofungin.
Plasmid-mediated beta-lactamases in clinical isolates of Klebsiella pneumoniae and Escherichia coli resistant to ceftazidime
Authors: Vuye A , Verschraegen G , Claeys G
Published: June 2012

Low-level transferable resistance to ceftazidime was detected in seven strains of Klebsiella pneumoniae and one strain of Escherichia coli. Six of the Klebsiella strains and the E. coli strain were shown to produce a novel beta-lactamase (CAZ-lo) with a pI of 5.6 that hydrolyzed broad-spectrum cephalosporins at low but comparable levels. One strain of K. pneumoniae was of a serotype different from that of the other strains and produced a plasmid-encoded cefuroximase (FUR) with a pI of 7.5 that mediated moderate levels of resistance to different broad-spectrum cephalosporins. High-level resistance to ceftazidime was detected in one other strain of K. pneumoniae, which produced a beta-lactamase with a pI of 6.5 (CAZ-hi). Apart from its pI, this enzyme differed from CAZ-lo by a specific and high hydrolytic activity against ceftazidime. The epidemiological context suggested that CAZ-hi may be a mutant of CAZ-lo, and this hypothesis was supported by the isolation of laboratory mutants of CAZ-lo showing properties identical to those of the clinical CAZ-hi enzyme.
Clinical comparison of single-oral-dose cefuroxime axetil and amoxicillin with probenecid for uncomplicated gonococcal infections in women
Authors: Baddour L M , Gibbs R S , Mertz G , Cocchetto D M , Noble R C
Published: June 2012

Four hundred sixty-six female patients were enrolled in a randomized study that compared the clinical efficacies of single oral doses of cefuroxime axetil and amoxicillin with probenecid in the treatment of uncomplicated gonorrhea. Two hundred ninety-five patients had culture-positive gonococcal infections and completed the investigation. Cure rates for the patients treated with cefuroxime axetil and those treated with amoxicillin with probenecid were high (greater than 95%) for genitorectal infections. Pharyngeal infections, however, were not uniformly eradicated by either cefuroxime axetil (60%) or amoxicillin with probenecid (64%). Approximately 13% of each patient group suffered adverse events, which were gastrointestinal in the majority and were transient. Compared with amoxicillin plus probenecid, cefuroxime axetil in a single oral dose was an equally safe and effective drug for the treatment of uncomplicated gonorrhea in women caused by penicillin-susceptible strains.
Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis
Authors: el Kouni M H , Diop D , O'Shea P , Carlisle R , Sommadossi J P
Published: June 2012

Host toxicity of the dose regimen of tubercidin (7-deazaadenosine) plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) used in combination therapy of schistosomiasis (M. H. el Kouni, D. Diop, and S. Cha, Proc. Natl. Acad. Sci. USA 80:6667-6670, 1983; M. H. el Kouni, N. J. Messier, and S. Cha, Biochem. Pharmacol. 36:3815-3821, 1987) was examined in vivo in mice and in vitro with human bone marrow progenitor cells. Four successive daily intraperitoneal injections of tubercidin at 5 mg/kg per day produced 100% mortality in mice within 3 to 5 days following the first injection, with massive peritonitis and intestinal obstruction secondary to abdominal adhesions. Coadministration of NBMPR-P (25 mg/kg per day) protected the mice from the lethality of tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection. Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium. In vitro, tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM tubercidin. At higher doses, BFU-E were more sensitive to tubercidin toxicity than CFU-GM. Complete inhibition (99%) of BFU-E colonies occurred at 10 nM tubercidin, while complete inhibition of CFU-GM occurred at 100 nM. NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from tubercidin toxicity in a dose-dependent matter.
Dose-dependent pharmacokinetics of mezlocillin in rats
Authors: Jungbluth G L , Jusko W J
Published: June 2012

The pharmacokinetics of mezlocillin were examined in rats following bolus intravenous doses of 20 or 200 mg/kg. Mezlocillin exhibited bi- or triexponential disposition profiles, and the area under the concentration-time curve increased nonproportionally with dose similar to reported findings in humans. Apparent total, renal, and nonrenal clearances and the volume of distribution at steady-state all decreased by 45 to 50% with the higher dose, and the elimination half-life was longer (8 +/- 2 versus 15 +/- 3 min). Mezlocillin exhibits low saturable binding in rat serum, ranging from 20 to 40% bound. Pharmacokinetic parameters based on free drug demonstrated dose-dependent characteristics similar to those with total drug. Use of the volume of distribution from the low dose allowed calculation of the true mean residence time. The linear relationship between dose and mean residence time from free concentrations yielded pooled Michaelis-Menten parameters. These were used as initial estimates in the simultaneous nonlinear fitting of the low- and high-dose mean free concentrations to a three-compartment model with sequential distribution and Michaelis-Menten elimination to describe the nonlinearity of mezlocillin disposition further.
Feeder layer-free in vitro assay for screening antitrypanosomal compounds against Trypanosoma brucei brucei and T. b. evansi
Authors: Kaminsky R , Zweygarth E
Published: June 2012

A drug-susceptible Trypanosoma brucei brucei stock, a multidrug-resistant T. b. brucei stock, and a T. b. evansi stock resistant to two commercial trypanocides were adapted to a feeder layer-free culture system. Bloodstream forms were grown continuously in a liquid medium at 37 degrees C in 4% CO2 in air. Samples of trypanosome populations in the logarithmic growth phase were incubated with various concentrations of commercial and experimental compounds. Growth inhibition was monitored after a 24-h incubation and quantified by comparing the number of generations between control and drug-treated cultures. Some of the experimental compounds [taxol, formicin B, thioridazine, Ro 15-0216, and DL-alpha-(difluoromethyl)ornithine hydrochloride monohydrate] showed activity against both drug-susceptible and drug-resistant trypanosomes. Other compounds [sinefungin, 1,3,5-triacetylbenzene tris(guanylhydrazone)trimethanesulfonate hydrate, and 9-deazainosine] which inhibited the growth of drug-susceptible trypanosomes showed little or no effect upon drug-resistant parasites. Gossypol, however, had no antitrypanosomal effect on either trypanosome stock. The results obtained in this study correlate with observations obtained from drug screening in mice. The main advantages of the described in vitro screening assay are as follows: (i) lower amounts of drugs are required, (ii) results are obtained more rapidly, (iii) animals are not necessary, and (iv) the method is less labor intensive. These advantages result in an economical and rapid assay for primary drug screening.
Influence of etoposide and cyclophosphamide on the efficacy of cloxacillin and erythromycin in an experimental staphylococcal infection
Authors: Calame W , van der Waals R , Mattie H , van Furth R
Published: June 2012

The effect of monocytopenia and granulocytopenia on the outgrowth of Staphylococcus aureus as well as on antibiotic efficacy was studied in an experimental thigh infection in mice. Pretreatment with etoposide reduced monocyte numbers in blood to 14% and those of granulocytes to 54% at the time of infection. Monocytopenia did not affect the proliferation of bacteria in the infected thigh or the reduction of bacterial numbers after treatment with cloxacillin or erythromycin. Pretreatment with cyclophosphamide reduced monocyte numbers to 15% and granulocyte numbers to 3%. This resulted in a marked increase in the number of bacteria at the site of infection and a decrease in the efficacy of antibiotic treatment.
Binding of novel macrolide structures to macrolides-lincosamides-streptogramin B-resistant ribosomes inhibits protein synthesis and bacterial growth
Authors: Goldman R C , Kadam S K
Published: June 2012

Dimethylation of adenine 2058 in 23S rRNA renders bacteria resistant to macrolides, lincosamides, and streptogramin B (MLS resistance), because the antibiotic binding site on the altered 50S ribosomal subunit is no longer accessible. We now report that certain 6-O-methyl-11,12-cyclic carbamate derivatives of erythromycin are able to bind to dimethylated MLS-resistant 50S ribosomal subunits, thus inhibiting protein synthesis and cell growth. One of these novel structures, an 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic ester) derivative, structure 1a, was studied in detail. It inhibited in vitro protein synthesis in extracts prepared from both susceptible and MLS-resistant Bacillus subtilis with 50% inhibitory concentrations of 0.4 and 20 microM, respectively. The derivative bound specifically to a single site on the 50S subunit of MLS-resistant ribosomes prepared from B. subtilis and Staphylococcus aureus, and no binding to 30S subunits was observed. The association rate constant of derivative 1a with sensitive and resistant ribosomes was 100- and 500-fold slower, respectively, than that of the parent compound, erythromycin, with sensitive ribosomes. The dissociation rate constant of 1a from sensitive and resistant ribosomes was 50- to 100-fold slower than the rate of erythromycin dissociation from sensitive ribosomes. Furthermore, 1a binding to sensitive 50S subunits led to induction of ermC and ermD, while binding to resistant 50S subunits did not, showing that perturbation of sensitive and resistant 50S subunit function by 1a differs. These data demonstrated that 1a is unique in its interaction with MLS-resistant ribosomes and that this interaction causes a novel allosteric perturbation of ribosome function.
Penetration of doxycycline into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis
Authors: Dotevall L , Hagberg L
Published: June 2012

Twelve patients were treated orally with 100 mg of doxycycline twice a day (b.i.d.) and 10 patients were treated with 200 mg b.i.d. for suspected tick-borne neuroborreliosis (Lyme borreliosis). At 5 to 8 days after the start of therapy, the mean concentrations in serum were 4.7 micrograms/ml for the doxycycline dose of 100 mg b.i.d. and 7.5 micrograms/ml for 200 mg b.i.d., 2 to 3 h after the last drug administration. The corresponding levels for cerebrospinal fluid were 0.6 and 1.1 micrograms/ml. Since a doxycycline concentration in cerebrospinal fluid above the estimated MIC for Borrelia burgdorferi (0.6 to 0.7 microgram/ml) is wanted in patients treated for severe neuroborreliosis, the higher dose is preferable.
Penicillin-binding protein 2 is required for induction of the Citrobacter freundii class I chromosomal beta-lactamase in Escherichia coli
Authors: Oliva B , Bennett P M , Chopra I
Published: June 2012

Involvement of Escherichia coli penicillin-binding proteins (PBPs) in induction of the cloned ampC Citrobacter freundii beta-lactamase by 6-aminopenicillanic acid was investigated. The enzyme was not inducible at 42 degrees C in a mutant thermosensitive for expression of PBP 2. The results imply that PBP 2 is involved in the process leading to induction of ampC.
Decreased outer membrane permeability in imipenem-resistant mutants of Pseudomonas aeruginosa
Authors: Trias J , Dufresne J , Levesque R C , Nikaido H
Published: June 2012

The outer membrane of imipenem-resistant mutants of Pseudomonas aeruginosa was shown to have decreased permeability to imipenem but not to cephaloridine. These experiments were performed with intact cells and liposomes containing imipenem-hydrolyzing beta-lactamase derived from Pseudomonas maltophilia, in both cases utilizing an imipenem concentration of 50 microM. In contrast, liposome swelling assays using imipenem at 8 mM detected no significant difference between the imipenem-resistant mutants and their parents. It was found that the outer membrane of P. aeruginosa has a saturable specific channel through which imipenem travels mainly at low concentrations, whereas at high concentrations this pathway is obscured by diffusion through nonspecific porin channels.
Sodium status influences chronic amphotericin B nephrotoxicity in rats
Authors: Ohnishi A , Ohnishi T , Stevenhead W , Robinson R D , Glick A , O'Day D M , Sabra R , Jackson E K , Branch R A
Published: June 2012

The nephrotoxic potential of amphotericin B (5 mg/kg per day intraperitoneally for 3 weeks) has been investigated in salt-depleted, normal-salt, and salt-loaded rats. In salt-depleted rats, amphotericin B decreased creatinine clearance linearly with time, with an 85% reduction by week 3. In contrast, in normal-salt rats creatinine clearance was decreased but to a lesser extent at week 2 and 3, and in salt-loaded rats creatinine clearance did not change for 2 weeks and was decreased by 43% at week 3. All rats in the sodium-depleted group had histopathological evidence of patchy tubular cytoplasmic degeneration in tubules that was not observed in any normal-salt or salt-loaded rat. Concentrations of amphotericin B in plasma were not significantly different among the three groups at any time during the study. However, at the end of 3 weeks, amphotericin B levels in the kidneys and liver were significantly higher in salt-depleted and normal-salt rats than those in salt-loaded rats, with plasma/kidney ratios of 21, 14, and 8 in salt-depleted, normal-salt, and salt-loaded rats, respectively. In conclusion, reductions in creatinine clearance and renal amphotericin B accumulation after chronic amphotericin B administration were enhanced by salt depletion and attenuated by sodium loading in rats.
Pharmacokinetics of rifabutin
Authors: Skinner M H , Hsieh M , Torseth J , Pauloin D , Bhatia G , Harkonen S , Merigan T C , Blaschke T F
Published: June 2012

We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.
Does pyrazinoic acid as an active moiety of pyrazinamide have specific activity against Mycobacterium tuberculosis?
Authors: Heifets L B , Flory M A , Lindholm-Levy P J
Published: June 2012

The commonly accepted hypothesis explaining the mechanism of action of pyrazinamide (PZA) is based on the assumption that PZA-susceptible Mycobacterium tuberculosis strains produce pyrazinamidase, which hydrolyzes PZA to the antibacterial moiety pyrazinoic acid (POA). It is not clear whether POA has specific antimicrobial activity or the inhibition of growth caused by POA is due to its ability to lower the pH of the environment below the limits of tolerance of M. tuberculosis growth. We confirmed in this study that POA, depending on the concentration, lowered the pH of 7H12 broth (pH 6.0), which ranged from 5.8 at 120.0 micrograms/ml to 4.6 at 960.0 micrograms/ml. Therefore, we tested the inhibitory effects of different concentrations of POA in broth in which the final pH was adjusted to 5.6 by adding appropriate amounts of phosphoric acid or dipotassium phosphate. Under these conditions, we found a clear dose-response correlation, proving that POA does have specific antimicrobial activity. The MIC of POA at pH 5.6 was 240 to 480 micrograms/ml, 8- to 16-fold higher than the MIC of PZA under the same conditions and much higher than the concentrations achievable in humans. This suggests that the action of POA in an acid environment is a combined effect of its specific activity and its ability to lower the pH below the limits of tolerance of the target organism.
Ofloxacin versus trimethoprim-sulfamethoxazole for treatment of acute cystitis
Authors: Hooton T M , Latham R H , Wong E S , Johnson C , Roberts P L , Stamm W E
Published: June 2012

We compared the safety and efficacies of ofloxacin and trimethoprim-sulfamethoxazole for the treatment of acute uncomplicated cystitis in women enrolled in a multicenter study. Data from three centers were combined for this report because the study design and study populations were identical, and patients were enrolled within an 18-month period. Cure rates for evaluable patients 4 weeks after treatment were high for all regimens: ofloxacin (200 mg) twice daily for 3 days, 22 of 25 (88%) cured; ofloxacin (200 mg) twice daily for 7 days, 42 of 49 (86%) cured; ofloxacin (300 mg) twice daily for 7 days, 25 of 25 (100%) cured; and trimethoprim-sulfamethoxazole (160/800 mg) twice daily for 7 days, 46 of 52 (88%) cured. Ofloxacin was more effective than trimethoprim-sulfamethoxazole in eradicating Escherichia coli from rectal cultures during and 1 week after treatment. Both ofloxacin and trimethoprim-sulfamethoxazole markedly reduced vaginal colonization with E. coli during and 4 weeks after therapy. Emergence of resistant coliforms in rectal flora was found in 5 (19%) of 27 patients treated with trimethoprim-sulfamethoxazole but none of 50 ofloxacin-treated patients who were studied (P = 0.004). Adverse effects were equally common among the four treatment groups. We conclude that 3 to 7 days of ofloxacin is as safe and effective as trimethoprim-sulfamethoxazole for treatment of uncomplicated cystitis in women and that ofloxacin effectively reduces the fecal and vaginal reservoirs of coliforms in such patients.
Cephalosporin penetration into soft tissue of paralyzed limbs
Authors: Darouiche R , Musher D , Hamill R , Ou C , Rognerud C
Published: June 2012

Poor penetration of antibiotics into paralyzed tissue may contribute to the difficulty of curing soft tissue infections in paralyzed limbs. A novel model of spinal cord hemisection was used to induce paralysis of one hind leg in mice. Five, 10, or 20 days after induction of paralysis, six groups of 10 mice were injected intravenously with a single dose or with four sequential doses of cefepime, a new broad-spectrum cephalosporin, and then sacrificed. High-performance liquid chromatography was used to compare cefepime levels in soft tissue homogenates of paralyzed and normal hind legs; no significant differences were found in any group. Factors other than antibiotic delivery may be responsible for difficulty in curing infections in paralyzed soft tissue.
Influence of indomethacin on the intrarenal uptake of gentamicin in endotoxemic rats
Authors: Bergeron M G , Bergeron Y , Tardif M , Marchand S , Beauchamp D
Published: June 2012

Gentamicin is a commonly used antibiotic for the treatment of gram-negative-bacterial infections. Bacterial endotoxin is liberated during antibiotic therapy, and we have shown that endotoxemic animals accumulate more aminoglycosides in their renal parenchyma than normal animals. Vasoactive mediators, such as prostaglandins and thromboxanes, are released after endotoxin and are involved in inflammation. Indomethacin, a nonsteroidal anti-inflammatory drug known to inhibit the synthesis of these hormones, was infused intravenously as a bolus (3.0 mg/kg) or as a bolus followed by a continuous infusion (0.75 mg/kg per h) to rats given gentamicin. Levels of gentamicin in serum and kidney were increased 2 h post-antibiotic treatment in the endotoxemic animals. Renal function was not significantly disturbed. Indomethacin given as a bolus failed to correct the disturbed intrarenal pharmacokinetics of gentamicin induced by endotoxin. However, a bolus followed by continuous infusion of indomethacin resulted in low cortical and high papillary levels of antibiotic. These changes were correlated with the inhibition of prostaglandin synthesis from the kidney. These observations suggest an important role for prostaglandins in the interaction among endotoxin, aminoglycosides, and the kidney. Specific inhibitors of arachidonic acid metabolites should be investigated to further understand the mechanisms of this interaction.
Efficacy of mupirocin in methicillin-resistant Staphylococcus aureus burn wound infection
Authors: Rode H , Hanslo D , de Wet P M , Millar A J , Cywes S
Published: June 2012

Methicillin-resistant Staphylococcus aureus strains (MRSA) have become increasingly prevalent as nosocomial pathogens, especially in burn wounds. MRSA constituted 38% of all S. aureus isolates in our 25-bed burns unit despite the utilization of a combination of 1% silver sulfadiazine and 0.2% chlorhexidine as topical therapy. Mupirocin, a new antibiotic, has proved in vitro and in vivo to be highly effective in the treatment of MRSA infections. A prospective clinical trial with mupirocin ointment in MRSA burn wound infection was untertaken. Forty-five children with 59 discrete burn wounds and from whom MRSA were isolated were treated with 2% mupirocin ointment under occlusive dressings, applied twice daily for 5 days. The average burned area treated was 8% (range, 2 to 20%) of the total body surface area. The burn wounds were assessed clinically and bacteriologically daily. Mupirocin eliminated MRSA in all 59 wounds treated, with the maximum therapeutic response seen within 4 days. In three wounds, gram-negative organisms persisted after 5 days of topical therapy. Treatment was well tolerated by all children. We recommend that mupirocin in its present polyethylene glycol base should be used only on a selective basis, when current prophylactic topical therapy has failed to control MRSA infection in burns of less than 20% of the total body surface area, and that it should be applied only for a limited period of 5 days. The safety and the efficacy of mupirocin in burns exceeding 20% of the total body surface area need to be established.
Susceptibility of methicillin-resistant Staphylococcus aureus to the selenium-containing compound 2-phenyl-1,2-benzoisoselenazol-3(2H)-one (PZ51)
Authors: Nozawa R , Yokota T , Fujimoto T
Published: June 2012

The growth of Staphylococcus aureus 209P was inhibited by 0.20 micrograms of 2-phenyl-1,2-benzoisoselenazol-3(2H)-one (PZ51) per ml, while strains of the family Enterobacteriaceae were more resistant to the drug. The MIC for 90% of methicillin-resistant S. aureus strains was 1.56 micrograms/ml, and the drug was bactericidal. The selenium in PZ51 was essential, since its sulfur analog (PZ25) lost the antibacterial activity.
Performance characteristics of two bioassays and high-performance liquid chromatography for determination of flucytosine in serum
Authors: St-Germain G , Lapierre S , Tessier D
Published: June 2012

We compared the accuracy and precision of two microbiological methods and one high-pressure liquid chromatography (HPLC) procedure used to measure the concentrations of flucytosine in serum. On the basis of an analysis of six standards, all methods were judged reliable within acceptable limits for clinical use. With the biological methods, a slight loss of linearity was observed in the 75- to 100-micrograms/ml range. Compared with the bioassays, the HPLC method did not present linearity problems and was more precise and accurate in the critical zone of 100 micrograms/ml. On average, results obtained with patient sera containing 50 to 100 micrograms of flucytosine per ml were 10.6% higher with the HPLC method than with the bioassays. Standards for the biological assays may be prepared in serum or water.
In vitro and in vivo antibacterial activities of BO-1341, a new antipseudomonal cephalosporin
Authors: Nakagawa S , Sanada M , Matsuda K , Hashizume T , Asahi Y , Ushijima R , Ohtake N , Tanaka N
Published: June 2012

BO-1341, a new antipseudomonal semisynthetic cephalosporin, was evaluated for in vitro and in vivo antibacterial activities in comparison with ceftazidime, cefotaxime, and cefoperazone. The in vitro activity of BO-1341 was generally superior or comparable to the activities of the reference antibiotics against clinical isolates of the family Enterobacteriaceae. BO-1341 was highly active against Pseudomonas aeruginosa (MIC for 90% of the strains tested, 1.56 micrograms/ml), Pseudomonas maltophilia (MIC for 50% of the strains tested, 1.56 micrograms/ml), and Acinetobacter calcoaceticus (MIC for 90% of the strains tested, 3.13 micrograms/ml). Furthermore, BO-1341 was highly active against P. aeruginosa isolates resistant to the other antibiotics. Of 199 P. aeruginosa isolates tested, only 2 were resistant to BO-1341. These two strains were also resistant to ceftazidime, cefotaxime, and cefoperazone. Haemophilus influenzae, Branhamella catarrhalis, and nonenteric streptococci were also susceptible to BO-1341, but Staphylococcus aureus, Streptococcus faecalis, and Bacteroides fragilis were not susceptible to the compound. The protective efficacy against experimental infections in mice caused by nine strains of gram-negative bacteria, including P. aeruginosa, reflected the potent in vitro activity.
Contribution of permeability and sensitivity to inhibition of DNA synthesis in determining susceptibilities of Escherichia coli, Pseudomonas aeruginosa, and Alcaligenes faecalis to ciprofloxacin
Authors: Bedard J , Chamberland S , Wong S , Schollaardt T , Bryan L E
Published: June 2012

To examine the correlation between bacterial cell susceptibility to ciprofloxacin and the magnitude of uptake and cell target sensitivity, the relative contribution of ciprofloxacin accumulation in intact cells and its ability to inhibit DNA synthesis were investigated among strains of Escherichia coli, Pseudomonas aeruginosa, and Alcaligenes faecalis. Uptake studies of [14C]ciprofloxacin demonstrated diffusion kinetics for P. aeruginosa and E. coli. Ciprofloxacin was more readily removed from E. coli J53 and A. faecalis ATCC 19018 by washing than from P. aeruginosa PAO503. These results indicate that the process of cell accumulation is different for P. aeruginosa in that the drug is firmly bound at an extracellular site. Whatever the washing conditions, A. faecalis accumulated less drug than either of the other two bacteria. Magnesium chloride (10 mM) caused a substantial decrease of ciprofloxacin accumulated and an increase in the MIC, depending upon the nature of the medium. The addition of carbonyl cyanide m-chlorophenylhydrazone caused a variable increase in drug accumulated, depending on the medium and the bacterial strain. The concentration of ciprofloxacin required to obtain 50% inhibition (ID50) of DNA synthesis for P. aeruginosa PAO503 and A. faecalis ATCC 19018 did not correlate with their corresponding MICs but did for E. coli J53. Treatment with EDTA decreased the ID50 of ciprofloxacin for P. aeruginosa PAO503 and its gyrA derivative by 5- and 2-fold, respectively, and decreased the ID50 for E. coli JB5R, a strain with a known decrease in OmpF, by 1.4-fold but did not decrease the ID50 for the normally susceptible E. coli J53. The ID(50) for P. aeruginosa obtained after EDTA treatment or in ether-permeabilized cells was higher than that obtained for the other two strains. The protonophore carbonyl cyanide m-chlorophenylhydrazone prevented killing by low ciprofloxacin concentrtaions, but sodium azide did not. The latter compound did not enhance killing in association with inhibition of a previously described energy-dependent efflux of ciprofloxacin susceptibility being the susceptibility to inhibition of DNA synthesis in E. coli, poor premeability associated with the small pore size of A. faecalis, and a combination of low permeability and reduced susceptibility of DNA synthesis to inhibition for P. aeruginosa.
Hyperoxia and the antimicrobial susceptibility of Escherichia coli and Pseudomonas aeruginosa
Authors: Muhvich K H , Park M K , Myers R A , Marzella L
Published: June 2012

We have tested the ability of hyperoxia (98% O2-2% CO2 at 2.8 atmospheres absolute [ca. 284.6 kPa]) to enhance killing of Escherichia coli (serotype O18 or ATCC 25922) by nitrofurantoin, sulfamethoxazole, trimethoprim, gentamicin, and tobramycin. We have also looked for interactions between hyperoxia and the aminoglycosides against Pseudomonas aeruginosa ATCC 27853. Hyperoxia significantly enhanced bacteriostatic activity of nitrofurantoin and trimethoprim as measured by MIC testing. The possibility exists that these effects might be due to the method required to tests MICs under hyperoxic conditions rather than to the effect of hyperoxia itself. In addition, hyperoxia enhanced killing of bacteria by trimethoprim as measured by MBC testing. Hyperoxia decreased numbers of E. coli by 1.3 log10 and P. aeruginosa by 2.7 log10 in cation-supplemented Mueller-Hinton broth medium. The bacteriostatic effects of hyperoxia did not affect MICs of gentamicin or tobramycin. The lack of interaction between hyperoxia and gentamicin or tobramycin was confirmed by determining the number of viable bacteria remaining after 24 h of exposure to hyperoxia by using a pour plate method. We conclude that hyperoxia potentiates the antimicrobial activity of the reduction-oxidation-cycling antibiotic tested (nitrofurantoin) and of one of the antimetabolites tested (trimethoprim). Hyperoxia does not enhance the bactericidal effects of gentamicin and tobramycin, which require oxidative metabolism for transport into bacterial cells.
In vitro and in vivo studies of the effect of artemether on Schistosoma mansoni
Authors: Xiao S H , Catto B A
Published: June 2012

To determine whether artemether, a derivative of the antimalarial agent qinghaosu, is therapeutically active against Schistosoma mansoni, we determined the in vitro, in vivo, and histopathologic effects of the drug on S. mansoni worms. In vitro, toxic effects of artemether on S. mansoni were not seen at concentrations of less than 100 micrograms/ml. However, in vivo, 30 and 50% reductions in the lengths of male and female worms, respectively, were observed 14 days after treatment. By 56 days worm dimensions had returned to control values. Similar reversible effects on male testes and female ovaries were seen. In vivo, a single oral dose of artemether (300 mg/kg) induced a shift of worms towards the liver within 8 h after treatment. By 3 and 14 days after treatment, 99 and 76%, respectively, of worms were still in the liver. In vivo, the therapeutic effect of artemether on adult S. mansoni treated on day 56 after infection was modest. Doses as high as 1,200 mg (200 mg/kg per day, six doses) resulted in a worm reduction rate of only 39%. However, in infected mice treated on day 14 or 21 after infection, worm reduction rates of 83 to 98% were obtained. Thus, artemether exhibited modest in vitro and in vivo activities against adult S. mansoni but was twofold more active against 2- to 3-week-old liver-stage parasites.
Effect of 2'-nor-cyclic GMP against guinea pig cytomegalovirus infection
Authors: Yang Z H , Lucia H L , Tolman R L , Colonno R J , Hsiung G D
Published: June 2012

Cyclic phosphate derivative of DHPG, 2'-nor-cGMP [9-[(2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl]-guani ne phosphate-oxide] was evaluated for activity against guinea pig cytomegalovirus (GPCMV) infection in cultured guinea pig embryo cells and in guinea pigs. By virus yield reduction and plaque reduction assays, 2'-nor-cGMP was demonstrated to be 15- to 20-fold more potent against GPCMV infection than its parental drug DHPG. The selectivity index of 2-nor-cGMP was 110, which was 10-fold higher than that of DHPG. In cultured cells, 2'-nor-cGMP attained maximal antiviral activity when added to the cells within 12 h postinfection. In the studies on GPCMV infection in guinea pigs, 2'-nor-cGMP administered subcutaneously once daily (5 mg/kg per day) for 8 days, starting 24 after virus inoculation, significantly suppressed GPCMV infectivity titers in the blood, spleen, lung, and salivary gland during acute infection (10 days postinfection) as compared with sham-treated infected animals. A greater reduction of GPCMV infectivity titers in the salivary gland was noted during chronic infection (i.e., 24 days postinfection). Clinically, splenomegaly and peripheral lymphocytosis were significantly modified as compared with the sham-treated animals (P less than 0.05). The drug, administered at this dosage, was reasonably tolerated by the guinea pigs and showed clinical benefit.
Antimicrobial susceptibility of Plesiomonas shigelloides from patients with diarrhea
Authors: Kain K C , Kelly M T
Published: June 2012

Antimicrobial susceptibility testing was performed on 72 fecal isolates of Plesiomonas shigelloides from patients with diarrhea by using a standard agar dilution technique. All isolates were obtained from a single geographic location. Based on the in vitro activities demonstrated in this study, norfloxacin, ciprofloxacin, and trimethoprim may be effective as oral agents in the treatment of P. shigelloides diarrheal disease. For the parenteral treatment of extraintestinal infection, netilmicin and the cephalosporins had the best in vitro activity.
Antimicrobial drug susceptibility of clinical isolates of Acinetobacter species (A. baumannii, A. haemolyticus, genospecies 3, and genospecies 6)
Authors: Traub W H , Spohr M
Published: June 2012

A total of 144 clinical isolates of Acinetobacter species, i.e., A. baumannii (n = 60), genospecies 3 (n = 48), A. haemolyticus (n = 12), and genospecies 6 (n = 24), were examined comparatively with the agar dilution method of the National Committee for Clinical Laboratory Standards for susceptibility to 25 antimicrobial drugs. Only minor species differences were noted.
Characterization of a multiple antibiotic resistance plasmid from Haemophilus ducreyi
Authors: Willson P J , Albritton W L , Slaney L , Setlow J K
Published: June 2012

Plasmid pLS88 from a clinical isolate of Haemophilus ducreyi encoded resistance determinants for sulfonamides and streptomycin related to those of RSF1010 and for kanamycin related to Tn903 but lacked the inverted repeats of the transposon. Its host range included Haemophilus influenzae, Actinobacillus pleuropneumoniae, and Escherichia coli; and it was compatible with pDM2 and RSF1010.
Loss of melanin in Wangiella dermatitidis does not result in greater susceptibility to antifungal agents
Authors: Polak A , Dixon D M
Published: June 2012

Melanized wild-type and melanin-deficient (Mel-) strains of Wangiella dermatitidis (Kano) McGinnis were tested for in vitro susceptibility to amphotericin B, flucytosine, amorolfine, ketoconazole, fluconazole, terbinafine, and itraconazole by using an agar dilution technique. Although the MICs of itraconzole obtained with seven of the eight Mel- strains were lower than those obtained with the melanized wild-type strains, there was no such trend observed with fluconazole, the other triazole tested. Furthermore, there was no apparent difference in MICs when comparing the melanized wild-type and the Mel-strains for the other drugs tested. Thus, no consistent increase in in vitro antifungal activity was found to be associated with a specific class of drug. Therefore, melanin does not appear to confer protection against some of the more important antifungal agents.
Inhibition of growth of the dimorphic fungus Paracoccidioides brasiliensis by ajoene
Authors: San-Blas G , San-Blas F , Gil F , Mariño L , Apitz-Castro R
Published: June 2012

Ajoene, a garlic-derived compound that prevents platelet activation, inhibited the growth of Paracoccidioides brasiliensis, a fungal pathogen for humans, by affecting the integrity of the fungal cytoplasmic membrane. This action may be the basis for the study of ajoene as a possible specific antifungal drug.
In vitro susceptibility of mutans streptococci to antimicrobial substances as determined by a membrane transfer assay
Authors: Childers N K , Caufield P W
Published: June 2012

The in vitro susceptibilities of seven representative strains of mutans streptococci to three topically applied chemotherapeutic agents were determined by a modified membrane transfer assay. The MBCs of chlorhexidine and I2-KI ranged from 0.5 to 1.0%, while SnF2 was sublethal at the highest concentration tested (8%) in all but one strain (AHT; mode MBC, 8.0%). The proposed in vitro assay may be useful for preclinical screening of potential antimicrobial agents prior to use in the oral cavity.
Pharmacokinetics of aerosol amphotericin B in rats
Authors: Niki Y , Bernard E M , Schmitt H J , Tong W P , Edwards F F , Armstrong D
Published: June 2012

The distributions of amphotericin B (AmB) in tissue were compared after intraperitoneal or aerosol administration. Rats were sacrificed 24 h after receiving single or repeated daily doses; AmB concentrations in tissues were determined by high-performance liquid chromatography. After intraperitoneal doses of 4 mg/kg of body weight per day for 7 days, mean concentrations of AmB were 122.7, 55.2, and 4.31 micrograms/g in the spleen, liver, and lung, respectively. After aerosol doses (aero-AmB) of 1.6 mg/kg per day, the mean concentrations of AmB in the lung were 2.79 micrograms/g after a single dose and 9.88 micrograms/g after four doses, while the drug was undetectable (less than 0.1 micrograms/g) in serum, spleen, liver, kidney, and brain. The half-life of elimination of AmB from the lungs was 4.8 days according to serial sacrifices done after a single dose of 3.2 mg of aero-AmB per kg. Treatment with 60 mg of aero-AmB per kg was well tolerated and produced no histopathologic changes in the lungs. The aerosol route was much more efficient than the systemic route in delivering AmB to the lungs, and it limited the accumulation of AmB in other organs. Because AmB is eliminated slowly, infrequent dosing schedules can be used. These pharmacokinetic characteristics and its proven effectiveness in an animal model make aero-AmB a highly promising new method for the prevention of pulmonary aspergillosis. Aero-AmB should also be considered for use as an adjunct to intravenous AmB for treatment of fungal pneumonias.
Renal handling of fleroxacin in rabbits, dogs, and humans
Authors: Shiba K , Saito A , Shimada J , Hori S , Kaji M , Miyahara T , Kusajima H , Kaneko S , Saito S , Ooie T
Published: June 2012

The renal handling of fleroxacin was studied by renal clearance and stop-flow techniques in rabbits and dogs and by analyzing the pharmacokinetics with and without probenecid in humans. In rabbits the excretion ratios (fleroxacin intrinsic renal clearance/glomerular filtration rate) were greater than unity (2.01) without probenecid and were decreased to a value below unity (0.680) with probenecid. In dogs, on the other hand, the excretion ratios were less than unity (0.608 and 0.456) both without and with probenecid, and so were not affected by probenecid. This fact suggested that fleroxacin was excreted into urine by both glomerular filtration and renal tubular secretion in rabbits, but only by glomerular filtration in dogs, accompanied by partial renal tubular reabsorption in both species; these mechanisms were also supported by stop-flow experiments. In humans probenecid treatment induced increases in the elimination half-life and area under the serum concentration-time curve and decreases in apparent serum clearance, renal clearance, and urinary recovery of fleroxacin. The excretion ratio without probenecid was 1.13, which was significantly decreased to 0.750 with probenecid. These results indicated that both renal tubular secretion and reabsorption contributed to renal excretion of fleroxacin in humans. The contribution of tubular secretion was species dependent and was extensive in rabbits, minimal in dogs, and moderate in humans. Renal tubular reabsorption was commonly found in every species. The long elimination half-life of fleroxacin in humans might be explained by its small total serum clearance and small renal clearance, which are attributed to less tubular secretion and more tubular reabsorption.
Multiple-dose pharmacokinetics of ofloxacin in serum, saliva, and skin blister fluid of healthy volunteers
Authors: Warlich R , Korting H C , Schäfer-Korting M , Mutschler E
Published: June 2012

The pharmacokinetics of ofloxacin were determined in six healthy volunteers after oral administration of 200 mg twice daily for 3.5 days. To study the pharmacokinetic behavior at the target site in bacterial infection of the skin, drug concentrations were determined in suction blister fluid (SBF) and cantharides blister fluid (CBF), as well as in serum and saliva. Ofloxacin was measured by a high-performance liquid chromatographic assay. Ofloxacin concentrations in saliva amounted to 61 +/- 3% of levels in serum. After the final dose, ofloxacin concentrations in blister fluid and serum declined in parallel. Terminal half-lives of ofloxacin in blister fluids (SBF, 7.0 h; CBF, 6.3 h) were in accordance with serum half-life (6.6 h). Favorable penetration into the skin is suggested by high area under the concentration-time curve ratios for blister fluid and serum (CBF, 1.1; SBF, 1.3). During repeated ofloxacin intake, drug levels in SBF and CBF at 12 h amounted to 0.94 and 1.10 micrograms/ml. Thus, ofloxacin levels in the skin are well above the MIC for 90% of strains tested for, e.g., Staphylococcus aureus, Staphylococcus epidermidis, Neisseria gonorrhoeae, and various members of the family Enterobacteriaceae. This should also hold true with respect to other tissues.