bluuebunny/crossref_metadata_2025 huggingface dataset:
Target for bacteriostatic and bactericidal activities of beta-lactam antibiotics against Escherichia coli resides in different penicillin-binding proteins
Authors: Satta G , Cornaglia G , Mazzariol A , Golini G , Valisena S , Fontana R
Published: June 2012

The relationship between cell-killing kinetics and penicillin-binding protein (PBP) saturation has been evaluated in the permeability mutant Escherichia coli DC2 in which the antimicrobial activity of beta-lactams has been described as being directly related to the extent of saturation of the PBP target(s). Saturation of a single PBP by cefsulodin (PBP 1s), mecillinam (PBP 2), and aztreonam (PBP 3) resulted in a slow rate of killing (2.5-, 1.5-, and 0.8-log-unit decreases in the number of CFU per milliliter, respectively, in 6 h). Saturation of two of the three essential PBPs resulted in a marked increase in the rate of killing, which reached the maximum value when PBPs 1s and 2 were simultaneously saturated by a combination of cefsulodin and mecillinam (4.7-log-unit decrease in the number of CFU per milliliter in 6 h). Inactivation of all three essential PBPs by the combination of cefsulodin, mecillinam, and aztreonam further increased the killing kinetics (5.5-log-unit decrease in the number of CFU per milliliter), and this was not significantly changed upon additional saturation of the nonessential PBPs 5 and 6 by cefoxitin. Similar relationships between PBP saturation and killing kinetics were obtained with imipenem and meropenem at concentrations which inhibited only one PBP (PBP 2), only two PBPs (PBP 1s and 2), or all three essential PBPs. Saturation of one or more PBPs also resulted in a different rate of bacteriolysis, the highest rate being obtained by the cefsulodin-mecillinam combination and by 5 micrograms of either imipenem or meropenem per ml. All of these conditions caused saturation of PBP 2 and saturation or extensive binding of PBP 1s. However, none of these conditions caused determined the fastest possible rate of killing, which occurred only when all three essential PBPs were saturated. It was concluded that the actual killing effect of beta-lactams is reflected by killing rates that approach the fastest possible rate for the given microorganism and that the targets for the bactericidal activity are precisely those PBPs whose saturation or binding occurs under conditions.
Inducible and constitutive expression of resistance to glycopeptides and vancomycin dependence in glycopeptide-resistant Enterococcus avium
Authors: Rosato A , Pierre J , Billot-Klein D , Buu-Hoi A , Gutmann L
Published: June 2012

A clinical isolate of Enterococcus avium, Ea1, which exhibited inducible, low-level resistance to vancomycin and teicoplanin, and two mutants selected from this strain, Ea3 and Ea31, were studied. Ea3 was vancomycin dependent and derived from Ea1, while Ea31 was not vancomycin dependent, was constitutively resistant, and was derived from Ea3. Hybridization studies revealed that vanA was present in Ea1 and suggested that it was located on a high-molecular-weight plasmid. In the absence of induction, Ea1 synthesized only the natural UDP-MurNAc-pentapeptide precursor, and after induction it synthesized an additional precursor identified as UDP-MurNAc-tetrapeptide-D-lactate. The latter was the only precursor found in Ea3 and Ea31, even after precursor accumulation. From these results, we infer that (i) the low level of resistance to glycopeptides in strain Ea1 may be in part due to the residual synthesis of the normal precursor and (ii) the vancomycin dependence of mutant Ea3 could be due to the fact that this strain does not produce any peptidoglycan precursor in the absence of induction.
Alterations in penicillin-binding protein 2B from penicillin-resistant wild-type strains of Streptococcus pneumoniae
Authors: Smith A M , Klugman K P
Published: June 2012

The 1.5-kb transpeptidase-encoding region (TER) of penicillin-binding protein (PBP) 2B was amplified and sequenced from 18 penicillin-resistant isolates of Streptococcus pneumoniae, with each isolate representing a different DNA fingerprint profile of the TER. PBP 2B TERs from penicillin-resistant isolates revealed extensive sequence divergence from the penicillin-susceptible R6 strain, differing by up to 170 nucleotide substitutions and resulting in up to 38 alterations in the amino acid sequence of the protein. All penicillin-resistant isolates showed sequence divergence within a +/- 300-bp area at the center of the PBP 2B TER. Although a number of amino acid substitutions were found within this central area of PBP 2B, only two substitutions were common to all resistant isolates, namely, Thr-252 replacement by Ala and Glu-282 replacement by Gly. These two substitutions appear to be essentially associated with a decreased affinity of PBP 2B for penicillin. A second block of divergent nucleotide sequence was prominent amongst isolates with high levels of resistance. This was a +/- 100-bp area of the TER around nucleotide 1300 and included the substitution of Gly for Asp-431, which was the only amino acid substitution within this area that was common to all isolates. These data may assist in the definition of the structural changes in the penicillin-binding site of PBP 2B associated with penicillin resistance in S. pneumoniae.
In vitro activity of D0870 compared with those of other azoles against fluconazole-resistant Candida spp
Authors: Wardle H M , Law D , Moore C B , Mason C , Denning D W
Published: June 2012

We compared the in vitro activity of a new triazole, D0870, with those of fluconazole, itraconazole, and ketoconazole against 41 clinical isolates of fluconazole-resistant Candida belonging to nine different species. The 50% inhibitory concentrations (IC50s) were determined by a microdilution method with morpholinopropanesulfonic acid (MOPS)-buffered RPMI medium and an inoculum of approximately 10(4) yeasts per ml. After incubation for 48 h at 37 degrees C the optical density at 550 nm was measured. The IC50 was the lowest drug concentration which reduced the optical density at 550 nm by > or = 50% compared with that for a drug-free control. D0870 had significant activity against many of the isolates. Its activity was comparable to that of ketoconazole, slightly superior to that of itraconazole, and markedly superior to that of fluconazole against Candida albicans. Against Candida glabrata, Candida krusei, and Candida inconspicua, it had activity similar to those of itraconazole and ketoconazole but had activity superior to that of fluconazole. D0870 IC50s for some isolates were increased. This may be due to cross-resistance mechanisms because the IC50s of both itraconazole and ketoconazole for these isolates were often high. When IC50s and IC80s were compared there was a marked organism and drug variation. With C. glabrata much higher endpoints for itraconazole were observed when an IC80 endpoint was used. For C. albicans there was also a significant shift upward in endpoints for itraconazole and ketoconazole. Values were changed little when IC50 and IC80 endpoints of D0870 were compared. For 35 of 41 isolates tested the D0870 IC50 was less than the 2.5-mg/liter breakpoint threshold proposed previously. Therefore, D0870 may be a useful agent for the therapy of infections caused by fluconazole-resistant Candida spp.
Activities of roxithromycin against Mycobacterium avium infections in human macrophages and C57BL/6 mice
Authors: Struillou L , Cohen Y , Lounis N , Bertrand G , Grosset J , Vildé J L , Pocidalo J J , Perronne C
Published: June 2012

The activity of roxithromycin against three clinical isolates of Mycobacterium avium was compared with that of clarithromycin both in a model of infection of human monocyte-derived macrophages and in a model of established infection of C57BL/6 mice. In the cell culture model, roxithromycin and clarithromycin were bactericidal for strains MO-1 and N-92159 and bacteriostatic for strain N-93043. For the three strains, the differences between the intracellular activities of roxithromycin and clarithromycin were not singificant after 7 days of treatment. Mice were infected with the MO-1 strain. Drugs were given by gavage at a dosage of 200 mg/kg of body weight 6 days per week for 16 weeks starting 5 weeks after infection. At the end of treatment, clarithromycin was more effective than roxithromycin in lungs; roxithromycin was as effective as clarithromycin in spleens. Thus, the activity of roxithromycin was comparable to that of clarithromycin both in vitro and in vivo.
Primary structure of OXA-3 and phylogeny of oxacillin-hydrolyzing class D beta-lactamases
Authors: Sanschagrin F , Couture F , Levesque R C
Published: June 2012

We determined the nucleotide sequence of the blaOXA-3(pMG25) gene from Pseudomonas aeruginosa. The bla structural gene encoded a protein of 275 amino acids representing one monomer of 31,879 Da for the OXA-3 enzyme. Comparisons between the OXA-3 nucleotide and amino acid sequences and those of class A, B, C, and D beta-lactamases were performed. An alignment of the eight known class D beta-lactamases including OXA-3 demonstrated the presence of conserved amino acids. In addition, conserved motifs composed of identical amino acids typical of penicillin-recognizing proteins and specific class D motifs were identified. These conserved motifs were considered for possible roles in the structure and function of oxacillinases. On the basis of the alignment and identity scores, a dendrogram was constructed. The phylogenetic data obtained revealed five groups of class D beta-lactamases with large evolutionary distances between each group.
Chlorhexidine susceptibilities of mutans streptococcal serotypes and ribotypes
Authors: Grönroos L , Mättö J , Saarela M , Luoma A R , Luoma H , Jousimies-Somer H , Pyhälä L , Asikainen S , Alaluusua S
Published: June 2012

The susceptibilities of 379 clinical mutans streptococcal isolates to chlorhexidine (CHX) were tested by agar dilution according to the standards of the National Committee for Clinical Laboratory Standards. Isolates were obtained from saliva samples of 34 young mothers who had high or moderate salivary levels of mutans streptococci at baseline. Samples were collected on three occasions, before childbirth, when each child was 6 months old, and 1 year later. Of these isolates, 50% were inhibited at 1 microgram of CHX per ml, 90% were inhibited at 2.0 micrograms/ml, and all were inhibited at 4.0 micrograms/ml. The MICs for Streptococcus mutans isolates (serotypes c, e, and f) were lower than those for Streptococcus sobrinus isolates (serotypes d and g). In some subjects, the MICs for isolates of the same serotype were different. This phenomenon was studied by ribotyping isolates (n = 45) from selected subjects (n = 7). It was found that if there were intraindividual differences in the MICs for isolates of the same serotype, then the ribotypes of these isolates were different. In order to decrease the mutans streptococcal infection risk for children, 24 mothers (test group) brushed their teeth periodically with a gel that contained 0.3% CHX digluconate and 0.2% NaF, pH 5.8, between the second and third sampling occasions. The gel was used twice a day for the first 10 days of each month. Development of resistant strains during CHX-NaF gel use was not detected. The serotype distribution of isolates from the test group after 1 year of periodic CHX-NaF gel use did not differ from that at baseline. Periodic CHX-NaF gel brushing did not lead to lower salivary mutans streptococcal counts.
Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus
Authors: Sumita Y , Nouda H , Kanazawa K , Fukasawa M
Published: June 2012

The in vitro and in vivo antibacterial activities of SM-17466, a new 1 beta-methyl carbapenem, were evaluated against a wide range of clinical bacterial isoaltes and compared with the activities of meropenem, imipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of action against gram-positive bacteria, showing especially potent activity against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinical isolates of methicillin-resistant Staphylococcus aureus were inhibited were 3.13, 50, 100, 1.56, and 3.13 micrograms/ml, respectively. This activity of SM-17466 was almost equivalent to those of the antibiotics used for the treatment of infections caused by this organism. SM-17466 also showed bactericidal activity against methicillin-resistant S. aureus. In contrast, SM-17466 was less active against gram-negative bacteria, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highest activity against Haemophilus influenzae and Bacteriodes fragilis. SM-17466, at a 50% inhibitory concentration of less than 1 microgram/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillin-binding protein 2' in a methicillin-resistant strain (50% inhibitory concentration, 5.9 micrograms/ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-17466 demonstrated excellent in vivo efficacy against methicillin-susceptible and -resistant S. aureus strains in a mouse peritoneal infection model: the efficacy of SM-17466 against methicillin-resistant strains was equal to or one-third that of vancomycin. This activity was comparable to the in vitro activity of SM-17466. The subcutaneous injection of SM-17466 in mice revealed that the half-life of SM-17466 in serum was about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to hydrolysis by swine renal dehydropeptidase I, to an extent comparable to the resistance shown by meropenem.
Effect of testing method on apparent activities of antiviral disinfectants and antiseptics
Authors: Woolwine J D , Gerberding J L
Published: June 2012

This study was designed to evaluate the independent effects of various test methods on the activities of antiviral chemical germicides. The activities of germicides against MS2 and phi 6 bacteriophages in a new porcine tissue carrier model were compared to those obtained by four other methods (suspension, glass carrier, tile carrier, and fingerpad tissue carrier tests). After a 1-min contact followed by neutralization (and elution off the carriers), the residual virus in the treated samples was quantified and the amount was compared with that in the saline controls. Antiviral activity was highly dependent on the test method for both viruses and was always greatest in suspension tests and lowest in tissue carrier tests. Results obtained for hydrophilic MS2 with the porcine tissue carrier were comparable to those from fingerpads, but lipophilic phi 6 was subject to spontaneous inactivation on human skin and proved unsuitable for fingerpad testing. These data indicate that the activities of germicides in tests with nonbiological substrates may overestimate antiviral antiseptic activity on skin surfaces. Products intended for use as antiviral antiseptics or hand-washing agents should be evaluated in a tissue carrier system. The porcine tissue carrier model provides a safe, inexpensive, accurate, and reproducible method for testing the activities of antiseptics.
Treatment of experimental endocarditis due to methicillin-susceptible or methicillin-resistant Staphylococcus aureus with trimethoprim-sulfamethoxazole and antibiotics that inhibit cell wall synthesis
Authors: de Górgolas M , Avilés P , Verdejo C , Fernández Guerrero M L
Published: June 2012

Using two strains of Staphylococcus aureus, one susceptible and one heterogeneously resistant to methicillin, for which MICs and MBCs of trimethoprim-sulfamethoxazole (TMP-SMX) were 0.06 and 0.06 micrograms/ml and 0.06 and 0.25 microgram/ml, respectively (concentrations are those of TMP), we studied the efficacies of TMP-SMX and cloxacillin, teicoplanin, and vancomycin for treatment of experimental staphylococcal endocarditis. Rabbits were treated with dosages of TMP-SMX selected to achieve concentrations in serum equivalent to that obtained in humans treated for Pneumocystis carinii pneumonia. The overall mortality rate of rabbits treated with TMP-SMX was 84% at day 3, not different from that of the control groups (P > 0.1). No sterile vegetations were observed to be present in control groups or in animals treated with TMP-SMX. However, 26, 60, and 75% of rabbits treated with teicoplanin, cloxacillin, and vancomycin, respectively, showed sterile vegetations. For methicillin-susceptible S. aureus (MSSA), the mean vegetation counts were not significantly different between the control group and the group treated with TMP-SMX (P > 0.1). For methicillin-resistant S. aureus (MRSA), treatment with TMP-SMX was more effective than no therapy, decreasing the number of organisms in vegetations (P < 0.01). For both strains, therapy with cloxacillin and therapy with teicoplanin or vancomycin were significantly more effective than therapy with TMP-SMX. Despite high concentrations of teicoplanin in serum which exceeded MBCs for staphylococci more than 50 times at the peak and 10 times at the trough, therapy with cloxacillin or vancomycin was superior to therapy with teicoplanin against both MSSA and MRSA. These data do not support the use of TMP-SMX in treatment of endocarditis and other severe staphylococcal infections with high bacterial counts.
Intracellular activities of roxithromycin used alone and in association with other drugs against Mycobacterium avium complex in human macrophages
Authors: Rastogi N , Labrousse V , Bryskier A
Published: June 2012

Recent reports have shown that roxithromycin possesses significant activity against atypical mycobacteria, including the Mycobacterium avium complex (MAC), and that its extracellular anti-MAC activity is further enhanced in two- or three-drug combinations with ethambutol, rifampin, amikacin, ofloxacin, and clofazimine. In accordance with the above data, the anti-MAC potential of roxithromycin used alone and in combination with the above-mentioned antituberculous drugs was screened intracellularly against five clinical MAC isolates (from both human immunodeficiency virus-positive and human immunodeficiency virus-negative patients), phagocytized by human monocyte-derived macrophages. The results showed that roxithromycin used alone and within clinically achievable levels was active against all of the MAC isolates tested. Screening of two-drug combinations showed that both rifampin and clofazimine further increased the intracellular activity of roxithromycin against all five isolates by 35 to 80% (ethambutol, ofloxacin, and amikacin resulted in increased intracellular activity against one, two, and four isolates, respectively). For the three-drug combinations, the combination of roxithromycin plus ethambutol used with rifampin or clofazimine was the most uniformly active against all five MAC isolates, with activity increases of 42 to 90%, followed by roxithromycin plus ethambutol used with amikacin, which resulted in activity increases of 15 to 90%. The overall level of intracellular killing after 5 days of drug addition, in comparison with growth in untreated controls, varied from 1 to 3 log units depending on the individual MAC isolate and/or drug combination used.
Comparative in vitro activities of L-695,256, a novel carbapenem, against gram-positive bacteria
Authors: Malanoski G , Collins L , Eliopoulos C T , Moellering R C , Eliopoulos G M
Published: June 2012

The in vitro activity of a prototype 2-aryl carbapenem, L-695,256, against gram-positive bacteria was examined. All streptococci and oxacillin-susceptible and -resistant staphylococci were inhibited at concentrations of < or = 0.125, < or = 0.125, and 4 micrograms/ml, respectively. The activity of L-695,256 was superior to that of imipenem against other organisms intrinsically resistant to beta-lactams.
Treatment of murine pulmonary blastomycosis with SCH 51048, a broad-spectrum triazole antifungal agent
Authors: Sugar A M , Picard M
Published: June 2012

The in vitro and in vivo activities of a new broad-spectrum triazole derivative, SCH 51048, against Blastomyces dermatitidis were evaluated. As determined by using the new National Committee for Clinical Laboratory Standards proposed standard for susceptibility testing of yeasts, SCH 51048 was the most active of the four agents tested in vitro against 13 strains of B. dermatitidis. In a well-described murine model of acute pulmonary blastomycosis, SCH 51048 was comparable to amphotericin B and at least 30 times more active than itraconazole. On the basis of these experiments, clinical evaluation of SCH 51048 for the use in treatment of human blastomycosis should proceed.
Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry
Authors: Nair V , Jahnke T S
Published: June 2012

In summary, many isomeric analogs of ddNs of both D-related and L-related absolute stereochemistries have been synthesized and evaluated in vitro for their antiviral activities. A few of these compounds exhibit potent antiviral activity and, interestingly, belong to both the D and L families. The synthetic methodologies developed will allow accessibility to many more novel modified nucleosides. While some structure-activity relationships are emerging from this work, it is clear that these chiral isomeric nucleosides have opened a new chapter in the field of antiviral nucleosides.
Interaction study of lomefloxacin and ciprofloxacin with omeprazole and comparative pharmacokinetics
Authors: Stuht H , Lode H , Koeppe P , Rost K L , Schaberg T
Published: June 2012

To assess whether or not concomitant omeprazole treatment influences the pharmacokinetics of lomefloxacin and ciprofloxacin, a randomized, double-blind four-way-crossover study was performed. Another objective was to compare the pharmacokinetics of lomefloxacin and ciprofloxacin. Twelve healthy volunteers participated. On days 1 to 4 of each study period, each of them took 20 mg of omeprazole or a placebo orally, and on day 4, each took 400 mg of lomefloxacin or 500 mg of ciprofloxacin orally. Blood and urine samples were collected and assayed for the quinolones by high-pressure liquid chromatography. The mean peak concentrations in plasma (Cmax) and the areas under the curves (AUC), respectively, of lomefloxacin and ciprofloxacin, respectively, after prior treatment with placebo were 2.88 +/- 0.73 (mean +/- standard deviation) as against 2.60 +/- 0.76 micrograms/ml and 24.9 +/- 3.13 as against 11.9 +/- 1.89 micrograms.h/ml, and 72.4% +/- 5.10% as against 36.1% +/- 7.50% of the doses of lomefloxacin and ciprofloxacin, respectively, were recovered from the urine. None of the pharmacokinetic parameters differed significantly after prior treatment with omeprazole compared with placebo. The Cmax of lomefloxacin was not significantly higher than that of ciprofloxacin, but lomefloxacin's AUC reached twice that of ciprofloxacin because of its significantly longer half-life in plasma (6.68 +/- 1.94 as against 4.15 +/- 0.92 h, respectively, P < or = 0.01). Concomitant therapy with omeprazole did not alter the pharmacokinetics of lomefloxacin or ciprofloxacin in these single-dose studies.
Therapeutic monitoring of experimental invasive pulmonary aspergillosis by ultrafast computerized tomography, a novel, noninvasive method for measuring responses to antifungal therapy
Authors: Walsh T J , Garrett K , Feurerstein E , Girton M , Allende M , Bacher J , Francesconi A , Schaufele R , Pizzo P A
Published: June 2012

Pulmonary infiltrates in neutropenic hosts with invasive aspergillosis are due to vascular invasion and hemorrhagic infarction. In order to measure the effect of antifungal compounds on this organism-mediated tissue injury, we monitored the course of pulmonary infiltrates by serial ultrafast computerized tomography (UFCT) in persistently granulocytopenic rabbits with experimental invasive pulmonary aspergillosis. The course of pulmonary lesions measured by serial UFCT scans was compared with those measured by conventional chest radiography, histopathological resolution of lesions, and microbiological clearance of Aspergillus fumigatus. Treatment groups included either amphotericin B colloidal dispersion in dosages of 1, 5, and 10 mg/kg of body weight per day intravenously or conventional desoxycholate amphotericin B at 1 mg/kg/day intravenously. Therapeutic monitoring of pulmonary lesions by UFCT demonstrated a significant dose-response relationship. Lesions continued to progress in untreated controls, whereas lesions in treated rabbits initially increased and then decreased in response to antifungal therapy in a dosage-dependent manner (P < or = 0.05 to P < or = 0.005, depending upon the groups compared). This same trend of resolution of lesions in response to antifungal therapy was also demonstrated by postmortem examination and by microbiological clearance of the organism. These data indicated that amphotericin B colloidal dispersion at 5 and 10 mg/kg/day exerted a more rapid rate of clearance of lesions than conventional amphotericin B. UFCT was more sensitive than conventional chest radiography in detecting lesions due to invasive pulmonary aspergillosis (P < 0.05 to P < 0.005, depending upon the groups compared). These findings establish a correlation among UFCT-defined lesions, microbiological response, and resolution of pathologically defined lesions in experimental invasive pulmonary aspergillosis. Serial monitoring of UFCT-defined lesions of aspergillosis provides a novel system for determining the antifungal response of organism-mediated tissue injury.
Effects of MICs and sub-MICs of antibiotics on production of capsular polysaccharide of Klebsiella pneumoniae
Authors: Held T K , Adamczik C , Trautmann M , Cross A S
Published: June 2012

In the present study, we examined whether MICs and sub-MICs of antimicrobial agents belonging to two different classes, ciprofloxacin and ceftazidime, were able to influence the production and release of cell-associated and soluble (extracellular) capsular polysaccharide (CPS), respectively, in a heavily encapsulated strain of Klebsiella pneumoniae (B5055). Using a CPS-specific enzyme-linked immunosorbent assay, we found that the amount of cell-associated CPS increased in a dose-dependent manner by more than 10-fold under the influence of the MIC of ceftazidime and by more than 100-fold under the influence of the MIC of ciprofloxacin. The largest amounts of CPS were measured by using the MIC of either antibiotic substance. Electron microscopic studies showed that the diameter of the capsule was significantly increased compared with the diameter for untreated controls. Thus, both antimicrobial agents genuinely stimulated CPS production.
Pharmacokinetics of dapsone in human immunodeficiency virus-infected children
Authors: Gatti G , Loy A , Casazza R , Miletich F , Cruciani M , Bassetti D
Published: June 2012

Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means +/- standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 +/- 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 +/- 1.3 (2 to 6) h; half-life at elimination phase, 24.2 +/- 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 +/- 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 +/- 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r = 0.614 and P = 0.034), as did V (r = 0.631 and P = 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r = 0.765 and P = 0.004, and for V/F to height, r = 0.748 and P = 0.005). Since oral CL from plasma and V were positively and highly correlated (r = 0.898 and P = 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.
Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi
Authors: Kersten A , Poitschek C , Rauch S , Aberer E
Published: June 2012

Antibiotic therapy with penicillin, doxycycline, and ceftriaxone has proven to be effective for the treatment of Lyme borreliosis. In some patients, however, it was noticed that borreliae can survival in the tissues in spite of seemingly adequate therapy. For a better understanding of this phenomenon, we investigated the different modes of degeneration of Borrelia burgdorferi suspensions during a 96-h exposure to various antibiotics. By dark-field microscopy and ultrastructural investigations, increasing blebbing and the gradual formation of granular and cystic structures could be followed during the exposure time. Although antibiotic concentrations at the MIC at which 90% of organisms are inhibited after 72 h were 80% or even greater, motile organisms were still present after incubation with penicillin and doxycycline but not after incubation with ceftriaxone. By transmission electron microscopy, intact spirochetal parts, mostly situated in cysts, were seen up to 96 h after exposure with all three antibiotics tested. According to experiences from studies with other spirochetes it is suggested that encysted borreliae, granules, and the remaining blebs might be responsible for the ongoing antigenic stimulus leading to complaints of chronic Lyme borreliosis.
Concentration-dependent synergy and antagonism between cefoperazone and imipenem against methicillin-resistant Staphylococcus aureus
Authors: Rand K H , Brown P
Published: June 2012

By the agar dilution checkerboard method, striking synergy between cefoperazone and imipenem was observed with 32 strains of methicillin-resistant Staphylococcus aureus (fractional inhibitory concentration indices, < or = 0.03 to 0.34; mean, 0.12 +/- 0.08). By the double-disk diffusion method, the synergy was confirmed, but about 60% of strains showed antagonism manifest by truncation of the zone of inhibition around cefoperazone. The mechanism may involve auxiliary factors distinct from those essential for the expression of methicillin resistance.
Concentration of pefloxacin in feces during infection prophylaxis in neutropenic patients
Authors: van de Leur J J , Vollaard E J , Janssen A J , Dofferhoff A S
Published: June 2012

Pefloxacin (400 mg twice daily) was administered orally for infection prophylaxis in neutropenic patients. Diffusible fecal pefloxacin concentration was determined by bioassay during 24 neutropenic periods. The median diffusible fecal pefloxacin concentration was 187 micrograms/g. This concentration was comparable with those found in volunteers following oral and intravenous administration of pefloxacin (400 mg twice daily) (median of 171 and 155 micrograms/g, respectively). From this study, it is concluded that pefloxacin administered orally results in a predictable high diffusible fecal concentration which leads to effective elimination of susceptible aerobic gram-negative bacilli from the colonic flora.
Safety and pharmacokinetics of vitamin A therapy for infants with respiratory syncytial virus infections
Authors: Neuzil K M , Gruber W C , Chytil F , Stahlman M T , Graham B S
Published: June 2012

Infants with respiratory syncytial virus infection have low serum vitamin A levels. We treated 21 respiratory syncytial virus-infected children with 12,500 to 25,000 IU of oral vitamin A. Vitamin A levels were normalized at 6 h, and none of the children experienced vitamin A toxicity or exacerbation of respiratory illness. Vitamin A treatment of previously healthy respiratory syncytial virus-infected infants at these doses is safe and well tolerated.
Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide
Authors: Speirs R J , Welch J T , Cynamon M H
Published: June 2012

The mechanism of action of pyrazinamide (PZA) is not known. One hypothesis is that PZA functions as a prodrug of pyrazinoic acid. Susceptibility to PZA correlates with amidase activity of the Mycobacterium tuberculosis isolate in question. PZA-resistant isolates retain susceptibility in vitro to pyrazinoic acid and n-propyl pyrazinoate. Esters of pyrazinoic acid appear to circumvent the requirement for activation by mycobacterial amidase. The MICs of n-propyl pyrazinoate for M. tuberculosis isolates are lower than those of pyrazinoic acid. Further studies to assess the effects of modifications of the alcohol and pyrazine moieties of pyrazinoate esters on in vitro and in vivo antituberculosis activity are under way. This may lead to a candidate compound with enhanced activity against both PZA-susceptible and PZA-resistant M. tuberculosis isolates suitable for clinical development.
Characterization of a conjugative staphylococcal mupirocin resistance plasmid
Authors: Morton T M , Johnston J L , Patterson J , Archer G L
Published: June 2012

We studied conjugative plasmids encoding high-level mupirocin resistance. These plasmids were found in Staphylococcus aureus isolates from two geographic locations in the United States. Transfer genes on three mupirocin resistance plasmids with different restriction endonuclease profiles were indistinguishable by DNA hybridization from those on pG01, a conjugative aminoglycoside resistance plasmid representative of similar plasmids that are prevalent in the United States. One mupirocin resistance plasmid, pG0400 (34 kb), was smaller than pG01 (52 kb) because of the absence from pG0400 of DNA, found on pG01, that contained genes encoding resistance to aminoglycosides, trimethoprim, and quaternary ammonium compounds flanked by directly repeated copies of the insertion sequence (IS)-like element IS431-IS257. The plasmids pG0400 and pG01 were otherwise indistinguishable except for the presence in pG0400 of a 4.5-kb HinDIII fragment encoding mupirocin resistance. The added mupirocin resistance gene was flanked by two directly repeated copies of IS431/257. The nucleotide sequence of DNA contiguous to the outside of the IS elements, as well as those of the elements themselves, was identical in both pG01 and pG0400, and there were no target site duplications flanking either copy of the element. We conclude that the mupirocin resistance gene was added to an existing conjugative plasmid in conjunction with the deletion of other resistance genes by recombination at IS elements. The construction of conjugative plasmids carrying a mupirocin resistance gene may be a model for the mobility of other resistance genes newly acquired by staphylococci.
Evaluation of SCH51048 in an experimental model of pulmonary aspergillosis
Authors: Allendoerfer R , Loebenberg D , Rinaldi M G , Graybill J R
Published: June 2012

The efficacy of a novel triazole, SCH51048, was assessed with a murine model of pulmonary aspergillosis and was compared with those of SCH39304 and itraconazole. A wide range of doses of SCH51048 (5 to 50 mg/kg of body weight) was evaluated. Mortality was significantly delayed in mice treated with doses of 5 mg of SCH51048 per kg or greater in comparison with mortality in controls (P < 0.05). Both SCH51048 and SCH39304 at higher doses (30 and 50 mg/kg) reduced the number of viable Aspergillus fumigatus organisms in lung tissue (P < 0.05). In the present model, itraconazole neither delayed mortality nor significantly reduced the counts in tissue at the doses used. We conclude that SCH51048 is an effective therapy for murine pulmonary aspergillosis.
In vitro antibiotic susceptibility testing of clinical isolates of Mycoplasma penetrans from patients with AIDS
Authors: Hayes M M , Foo H H , Timenetsky J , Lo S C
Published: June 2012

In vitro susceptibilities of Mycoplasma penetrans were determined. MICs and MBCs were determined. The MICs at which 50% of the isolates are inhibited (micrograms per milliliter) for broth dilution testing were as follows: azithromycin, 0.039; chloramphenicol, 0.625; ciprofloxacin, 0.156; clindamycin, 0.078; doxycycline, 0.312; erythromycin, 0.312; gentamicin. > 10; levofloxacin, 0.078; lincomycin, 0.625; streptomycin, > 10; and tetracycline, 1.25. Bactericidal activity was significant only for ciprofloxacin (MBC at which 50% of the isolates are killed, 0.312 microgram/ml) and levofloxacin (MBC at which 50% of the isolates are killed, 0.312 microgram/ml).
Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin
Authors: Kirst H A , Creemer L C , Paschal J W , Preston D A , Alborn W E , Counter F T , Amos J G , Clemens R L , Sullivan K A , Greene J M
Published: June 2012

Dirithromycin is the 9-N,11-O-oxazine adduct formed from 9(S)-erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in which the methoxyethoxymethyl substituent on the oxazine ring possesses the R configuration. Epidirithromycin is its isomer in which the methoxyethoxymethyl substituent has the opposite (S) configuration. Both compounds readily epimerize in solution, reaching an equilibrium ratio of 85:15 in favor of dirithromycin, given sufficient time. The rate of interconversion is dependent upon pH, temperature, and solvent. An enriched sample of epidirithromycin (95% purity) was synthesized by condensing erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in diethyl ether as the reaction solvent, and the product was fully characterized by nuclear magnetic resonance spectroscopy and high-pressure liquid chromatographic (HPLC) analysis. Both oxazine derivatives readily hydrolyze to erythromycylamine, so all three compounds exhibit the same antibiotic activity in vitro. In order to determine whether dirithromycin itself possesses significant antimicrobial activity without initial hydrolysis to erythromycylmine, inhibition of cell-free ribosomal protein synthesis was measured under conditions which were adapted to minimize hydrolysis, as measured by analytical HPLC in parallel experiments. Under these particular conditions, inhibition of ribosomal protein synthesis by dirithromycin was < 10% of the value measured for erythromycylamine.
Response of rat model of Pneumocystis carinii pneumonia to continuous infusion of deferoxamine
Authors: Merali S , Chin K , Grady R W , Weissberger L , Clarkson A B
Published: June 2012

The iron-chelating drug deferoxamine mesylate (DFO) is active against Pneumocystis carinii in vitro and in rat and mouse models of P. carinii pneumonia. Because DFO has a short half-life, daily divided or continuous dosage was expected to improve the dose response, as is the case with DFO treatment of malaria. Therefore, results of single daily intraperitoneal injections were compared with results of an evenly divided four-times-daily dosage and the efficacy of delivery with implanted infusion pumps. The highest bolus dosage (1,000 mg kg-1 of body weight day-1) was as effective as the standard combination of trimethoprim with sulfamethoxazole. Unexpectedly, very little improvement was observed with the divided or continuous dosage, and several mechanisms that could account for this are discussed.
Susceptibilities of nontuberculosis mycobacterial species to amoxicillin-clavulanic acid alone and in combination with antimycobacterial agents
Authors: Utrup L J , Moore T D , Actor P , Poupard J A
Published: June 2012

Neither amoxicillin nor clavulanic acid used alone was active at the highest level tested, i.e., 256.0 micrograms/ml, in vitro against 24 isolates of Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium marinum. However, the MIC of an amoxicillin-clavulanic acid combination of 2:1 was < or = 8.0/4.0 micrograms/ml for 50 percent of the isolates tested, with all isolates being inhibited in the range of 4.0/2.0 to 32.0/16.0 micrograms/ml, respectively. Titration of amoxicillin-clavulanic acid with a fixed 2-micrograms/ml concentration of ethambutol resulted in synergistic activity against 3 of 9 isolates of M. fortuitum, 10 of 10 isolates of M. kansasii, and 5 of 5 isolates of M. marinum. This observation was confirmed in a checkerboard analysis in which fractional inhibitory concentrations were < or = 0.5 for 20 of the 24 isolates. Synergistic activity was observed against the other four isolates in one of two trials. On the other hand, titration of amoxicillin-clavulanic acid in the presence of either one or two fixed concentrations of isoniazid, rifampin, cycloserine, tetracycline, or amikacin failed to result in synergism.
Purification and characterization of a new beta-lactamase from Bacteroides uniformis
Authors: Hedberg M , Lindqvist L , Bergman T , Nord C E
Published: June 2012

A beta-lactam-resistant Bacteroides uniformis strain was isolated from a clinical specimen. The strain produced large amounts of beta-lactamase and was resistant to penicillins and cephalosporins. The specific activity of the unpurified beta-lactamase was 4.8 U/mg of protein with nitrocefin as the substrate. The enzyme was purified 188-fold by Q-Sepharose, Sephacryl S-300, and Mono Q column passages. Kinetic parameters of the enzyme were determined by a micromethod performed in microtiter plates. beta-Lactamase was inhibited by cefoxitin and imipenem and hydrolyzed cephalosporins more rapidly than penicillins. The molecular weight was determined by sodium dodecyl sulfate-gradient gel electrophoresis to be 32,500, and the isoelectric point was 4.5.
Pharmacokinetics of ofloxacin in serum and vitreous humor of albino and pigmented rabbits
Authors: Perkins R J , Liu W , Drusano G , Madu A , Mayers M , Madu C , Miller M H
Published: June 2012

The purpose of this study was to evaluate the pharmacokinetics of ofloxacin in serum and vitreous humor samples from albino and pigmented rabbits by using a recently described animal model which permits robust estimation of parameter values. The drug was administered to rabbits intravenously, multiple vitreous humor and serum samples were taken from each rabbit, and the vitreous humor and serum samples were assayed by high-pressure liquid chromatography. The pharmacokinetic parameters were determined with RSTRIP, an iterative, nonlinear, weighted, least-squares regression program. Eight New Zealand White rabbits and eight Dutch Belted rabbits (split into single-dose and multiple-dose groups) were investigated in this study. The value of penetration into the vitreous humor of albino rabbits (n = 6) was 32.6% +/- 2.12%, with terminal-elimination half-life values of 3.21 and 2.39 h, respectively, for vitreous humor and serum. In pigmented rabbits after a single dose (n = 3) and with a steady-state concentration of drug in serum (n = 4), penetration values were similar, at 30.4% +/- 2.98% and 30.0% +/- 4.12%, respectively (P > 0.10). Following a single dose of ofloxacin, pigmented animals had elimination half-life values from serum and vitreous humor of 2.64 and 4.32 h, respectively. After steady state was achieved, half-life values for serum and vitreous humor were 3.12 and 6.05 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults
Authors: Beutner K R , Friedman D J , Forszpaniak C , Andersen P L , Wood M J
Published: June 2012

Acyclovir treatment of acute herpes zoster speeds rash healing and decreases pain and ocular complications. The limited oral bioavailability of acyclovir necessitates frequent dosing. Valaciclovir, the l-valyl ester of acyclovir, is rapidly and almost completely converted to acyclovir in vivo and gives three- to fivefold increases in acyclovir bioavailability. In a randomized, double-blind, multicenter study, the safety and efficacy of oral valaciclovir given at a dosage of 1,000 mg three times daily for 7 or 14 days and oral acyclovir given at a dosage of 800 mg five times daily for 7 days were compared in immunocompetent adults aged > or = 50 years with herpes zoster. Patients were evaluated for 6 months. The intent-to-treat analysis (1,141 patients) showed that valaciclovir for 7 or 14 days significantly accelerated the resolution of herpes zoster-associated pain (P = 0.001 and P = 0.03, respectively) compared with acyclovir; median pain durations were 38 and 44 days, respectively, versus 51 days for acyclovir. Treatment with valaciclovir also significantly reduced the duration of postherpetic neuralgia and decreased the proportion of patients with pain persisting for 6 months (19.3 versus 25.7%). However, there were no differences between treatments in pain intensity or quality-of-life measures. Cutaneous manifestations resolved at similar rates in all groups. Adverse events were similar in nature and prevalence among groups, and no clinically important changes occurred in hematology or clinical chemistry parameters. Thus, in the management of immunocompetent patients > or = 50 years of age with localized herpes zoster, valaciclovir given at 1,000 mg three times daily for 7 days accelerates the resolution of pain and offers simpler dosing, while it maintains the favorable safety profile of acyclovir.
Influence of pentoxifylline and its derivatives on antibiotic uptake and superoxide generation by human phagocytic cells
Authors: Hand W L , Hand D L
Published: June 2012

Pentoxifylline modulates multiple activities of stimulated polymorphonuclear neutrophils (PMNs), including the respiratory burst response and membrane transport of certain substances (e.g., nucleosides). We found that several weakly basic antibiotics are highly concentrated by human PMNs and that these drugs also inhibit the respiratory burst response (by a mechanism different from that of pentoxifylline). Since both pentoxifylline and antibiotics will be administered to some patients with serious infections, we have evaluated several types of interactions between these drugs and human PMNs and have attempted to identify the mechanisms that produce alterations in cellular function. Roxithromycin, dirithromycin, and clindamycin were avidly concentrated by PMNs. Pentoxifylline and two derivatives (HWA-448 [torbafylline] and HWA-138 [albifylline]) increased the uptake of these antibiotics by PMNs, both in the resting state and during phagocytosis. Pentoxifylline, HWA-448, HWA-138, and the highly concentrated antibiotics each exerted an inhibitory effect on the stimulated respiratory burst response in PMNs. The combination of both pentoxifylline and a modulatory antibiotic (roxithromycin or clindamycin) inhibited superoxide production to a greater extent than either agent alone. This additive effect might be expected, since pentoxifylline and the modulatory antibiotics influence the respiratory burst activation pathway at different sites. The ability of pentoxifylline to augment the entry of antibiotics into neutrophils has important therapeutic implications. The consequences of this phenomenon might include improved intracellular bactericidal activity as well as efficient antibiotic delivery and release at sites of infection.