bluuebunny/crossref_metadata_2025 huggingface dataset:
beta-Lactamase-mediated inactivation and efficacy of cefazolin and cefmetazole in Staphylococcus aureus abscesses
Authors: Fields M T , Herndon B L , Bamberger D M
Published: June 2012

12694668 Clinical reports and animal models have demonstrated that cefazolin may have decreased efficacy against some strains of Staphylococcus aureus because of type A beta-lactamase-mediated hydrolysis. We sought to measure biologically active cefazolin concentrations within abscesses with high concentrations of S. aureus and compare the concentrations with those of cefmetazole, a beta-lactamase-stable cephamycin. A type A beta-lactamase-producing strain of S. aureus with a demonstrated inoculum effect against cefazolin (MIC at an inoculum of 5 x 10(5) CFU/ml, 1.0 micrograms/ml; MIC at an inoculum of 5 x 10(7) CFU/ml, 32.0 micrograms/ml) but not cefmetazole (MICs at inocula of 5 x 10(5) and 5 x 10(7) CFU/ml, 2.0 micrograms/ml) was used. Cefazolin or cefmetazole (100 mg/kg of body weight every 8 h for 8 days) was administered to rabbits with infected tissue cages. No differences in the concentrations of the two drugs in the uninfected tissue cages were observed. Higher concentrations of cefmetazole than cefazolin were found in infected tissue cages at day 3 (5.9 +/- 0.7 versus 2.2 +/- 0.3 micrograms/ml; P < 0.01), day 5 (9.1 +/- 2.6 versus 3.6 +/- 0.7 micrograms/ml; P = 0.02), and day 8 (9.4 +/- 1.4 versus 4.8 +/- 0.9 micrograms/ml; P = 0.01) after infection. Cefazolin and cefmetazole were equally effective in reducing the bacterial concentration in the abscess. In vitro experiments demonstrated greater cefazolin than cefmetazole degradation by S. aureus, but the differences were greater in serum than in abscess fluid supernatants. We conclude that abscess cefazolin concentrations are diminished by type A beta-lactamase-producing S. aureus, but this did not affect drug efficacy in this model.
Rat cytomegalovirus-induced pneumonitis after allogeneic bone marrow transplantation: effective treatment with (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine
Authors: Stals F S , Zeytinoglu A , Havenith M , de Clercq E , Bruggeman C A
Published: June 2012

Two antiviral compounds, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), were evaluated for their effects on rat cytomegalovirus (RCMV)-induced interstitial pneumonitis after allogeneic bone marrow transplantation (BMTx). Eight-week-old Brown Norway rats immunosuppressed by a lethal dose of total body irradiation were inoculated with RCMV and received allogeneic bone marrow cells from Lewis rats. Animals were treated with either HPMPC (20 mg/kg of body weight as a single dose) or DHPG (20 mg/kg as two daily doses for 5 days). The effect of antiviral therapy was monitored by measuring RCMV titers in different organs and the histopathologic changes in lungs at 8 to 10 days postinfection. In RCMV-infected allogeneic BMTx recipients, severe diffuse thickening of alveolar septa (6.02 microns) with a diffuse infiltration of mononuclear cells occurred, whereas in the noninfected allogeneic BMTx recipients, the septal width was on the order of 2 microns (P < 0.01). Treatment with DHPG (20 mg/kg in two daily doses for 5 days) resulted in a decrease in virus titers (log10 PFU per gram of tissue) in lungs and spleens from 3.81 +/- 0.34 and 4.29 +/- 1.07 (untreated animals) to 1.26 +/- 0.53 and 3.22 +/- 0.27 (treated animals), respectively. Treatment with HPMPC (20 mg/kg as a single dose) resulted in a complete reduction of virus titers in all organs to below the detection level (P < 0.01). Furthermore, antiviral treatment resulted in a reduction of the alveolar septal width from 6.02 +/- 1.59 microns (untreated animals) to 4.67 +/- 1.70 and 3.32 +/- 0.63 microns after DHPG and HPMPC treatment, respectively. Treatment with HPMPC (20 mg/kg as a single dose) resulted in a complete reduction of virus titers in all organs to below the detection level (P <0.01). Furthermore, antiviral treatment resulted in a reduction of the alveolar septal width from 6.02 +/- 1.59 micrometre (untreated animals) to 4.67 +/- 0.63 micrometre after DHPG and HPMPC treatment, respectively. Furthermore, the influx of mononuclear cells in the alveolar septa was significantly impaired after treatment with HPMPC (P <0.01). We conclude that in the described rat model, HPMPC is highly effective in suppressing RCMV-induced interstitial pneumonitis after allogeneic BMTx.
Evaluation of the efficacy of ciprofloxacin against Streptococcus pneumoniae by using a mouse protection model
Authors: Sullivan M C , Cooper B W , Nightingale C H , Quintiliani R , Lawlor M T
Published: June 2012

A mouse protection model was used to investigate the association of the pharmacokinetics and pharmacodynamics with the in vivo efficacy of ciprofloxacin compared with that of penicillin G in the treatment of mice infected with Streptococcus pneumoniae ATCC 6303. Mice were inoculated intraperitoneally with 10 times the minimum lethal dose of S. pneumoniae. For determination of the 50% protective dose, subcutaneous antibiotics were begun 1 h after infection and were continued for 24 h. The 50% protective doses of ciprofloxacin and penicillin G were 25.52 +/- 1.95 and 0.307 +/- 0.006 mg/kg of body weight, respectively, an 83-fold difference in efficacy. For 100% protection with penicillin G, the time that the drug concentration needed to remain above the MIC was 51 min, a value easily achieved in most clinical situations. For 100% protection with ciprofloxacin, the peak concentration/MIC ratio must reach a value of 10.6. This ratio is rarely achieved with this drug against S. pneumoniae in clinical practice. These pharmacodynamic differences probably contribute to the reported differences in clinical success between these agents.
Roles of liposome composition and temperature in distribution of amphotericin B in serum lipoproteins
Authors: Wasan K M , Brazeau G A , Keyhani A , Hayman A C , Lopez-Berestein G
Published: June 2012

The role of liposome composition and temperature in the distribution of amphotericin B (AmB) with serum lipoproteins and the role of particle charge in AmB transfer to serum lipoproteins were determined. Serum obtained from healthy volunteers was incubated with known concentrations of AmB or different liposomal formulations of AmB (1 to 100 micrograms/ml) at 37 degrees C for various time intervals (5, 10, 20, 30, 45, and 60 min). After each interval, serum was removed and separated into high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions by an LDL-direct assay. The distribution of AmB (Fungizone) at 5 min through 1 h of incubation at 25 degrees C remained constant and was similar in the HDL and LDL fractions. At 37 degrees C, at 5 through 45 min of incubation, 54 to 61% of AmB was recovered in the HDL fraction; however, at 1 h more than 75% of the AmB concentration was recovered in the HDL fraction. In contrast, 87.5 to 92% AmB was recovered in the HDL fraction throughout the incubation when negatively charged liposomal AmB (dimyristoylphosphatidylcholine [DMPC]:dimyristoylphosphatidylglycerol [DMPG], 7:3 [wt/wt]) was used. With positively charged liposomes, 75 to 87.7% of AmB was recovered in the HDL fraction through the different time points studied. AmB incorporated into DMPC (neutral) and DMPG (negative) liposomes, and AmB was distributed in an HDL:LDL ratio of 6:4 following 1 h of incubation. Ninety percent of AmB and 80% of the lipid were found in the HDL fraction in a 3:1 molar DMPG:AmB ratio and in the LDL fraction in a 6:1 molar ratio. Lipid charge and temperature play a role in AmB distribution into serum lipoproteins. AmB and DMPG may contransfer as an intact drug-lipid complex to serum lipoproteins.
Immunomodulatory effect of fosfomycin on human B-lymphocyte function
Authors: Morikawa K , Oseko F , Morikawa S
Published: June 2012

Fosfomycin (FOM) is an unique antibiotic which is chemically unrelated to any other known antimicrobial agent. Recent investigations have demonstrated that FOM inhibits histamine release from basophils. In this study, we examined the effect of FOM on human B-cell functions. FOM inhibited the proliferative response of resting B cells induced by Staphylococcus aureus Cowan 1 in a dose-dependent manner. FOM interfered with the transition from the G0 to the G1 phase of the cell cycle, leading to cell arrest. The proliferative response of in vivo-activated B cells and lymphokine-induced B-cell proliferation were also affected by FOM. In addition, FOM suppressed immunoglobulin secretion by antibody-producing B cells. Interestingly, FOM did not affect the expression of activation antigens such as the CD25 (interleukin-2 receptor) and CD71 (transferrin receptor) antigens. Moreover, FOM sustained the increased Ia expression on B-cell membranes induced by S. aureus Cowan 1 stimulation, which suggests that FOM may not block the role of B cells in antigen presentation in T-cell-B-cell interaction.
Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients
Authors: Lamer C , de Beco V , Soler P , Calvat S , Fagon J Y , Dombret M C , Farinotti R , Chastre J , Gibert C
Published: June 2012

Vancomycin penetration into the fluid lining the epithelial surface of the lower respiratory tract was studied by performing fiberoptic bronchoscopy with bronchoalveolar lavage on 14 critically ill, ventilated patients who had received the drug for at least 5 days. The apparent volume of epithelial lining fluid (ELF) recovered by bronchoalveolar lavage was determined by using urea as an endogenous marker. Vancomycin levels in ELF ranged from 0.4 to 8.1 micrograms/ml (mean, 4.5 micrograms/ml), while the mean simultaneous level of the drug in plasma was 24 micrograms/ml (range, 9 to 37.4 micrograms/ml). There was a significant relationship (r = 0.64, P < 0.02) between vancomycin levels in plasma and those in ELF, with a correlation whose slope (0.15) indicated that the blood-to-ELF ratio of drug penetration was 6:1. Using the albumin concentration in ELF as a marker of lung inflammation, we found that vancomycin penetration was higher in patients with ELF albumin values of > or = 3.4 mg/ml than in patients with normal values (< 3.4 mg/ml) (P < 0.02). These results suggest that the vancomycin distribution includes the ELF of the lower respiratory tract at a concentration that is dependent upon the levels in blood and the alveolar capillary membrane protein permeability. These concentrations were well above the MICs for most staphylococci and enterococci.
Activities of several benzimidazoles and tubulin inhibitors against Giardia spp. in vitro
Authors: Morgan U M , Reynoldson J A , Thompson R C
Published: June 2012

Previous studies in our laboratory have shown that albendazole is effective against Giardia spp. in vitro and in vivo, prompting an investigation of the effects of several related benzimidazoles (BZs) on the viability of this protozoan parasite. A range of BZs was tested, and their effects were compared with those of a number of microtubule inhibitors. The effects produced by the two types of drugs were markedly similar, namely, trophozoite detachment and distortion of morphology and general structure, indicating a potential antimicrotubule mode of action for BZs. Mebendazole, albendazole, and fenbendazole proved to be among the most effective BZs tested, exhibiting apparent irreversibility. Nocodazole, oxfendazole, and albendazole sulfoxide, among others, produced transient inhibitions only. Further studies are required to evaluate all available BZs and other antigiardial agents to ensure the development of the most effective and safest antigiardial agent possible.
Synergy of levofloxacin (L-ofloxacin) and oxacillin against quinolone-resistant Staphylococcus aureus, measured by the time-kill method
Authors: Patel J A , Pachucki C T , Lentino J R
Published: June 2012

The synergistic activity of levofloxacin and oxacillin against levofloxacin-resistant isolates of methicillin-resistant Staphylococcus aureus was tested by the time-kill method. The combination of levofloxacin at 1/4 the MIC for the isolate plus oxacillin at 8 micrograms/ml (< 1/4 the MIC) was synergistic against seven of nine isolates at 8 h, although no significant synergy was demonstrated at 24 h. This combination may prove to be effective against multidrug-resistant methicillin-resistant S. aureus, and further studies are warranted.
In vitro antimicrobial activity of CP-99,219, a novel azabicyclo-naphthyridone
Authors: Gooding B B , Jones R N
Published: June 2012

CP-99,219 is a trifluoronaphthyridone with significant antibacterial activity that includes the family Enterobacteriaceae (MICs for 90% of the strains tested [MIC90s], < or = 0.015 to 0.5 micrograms/ml), Moraxella catarrhalis, Haemophilus influenzae, and gonococci (MICs, < or = 0.015 micrograms/ml). Legionella spp. were also CP-99,219 susceptible, with MICs of 0.008 to 0.12 micrograms/ml. CP-99,219 demonstrated activity greater than that of ciprofloxacin, ofloxacin, or enoxacin against Pseudomonas aeruginosa (MIC90, 1 microgram/ml), Xanthomonas maltophilia (MIC90, 2 micrograms/ml), Staphylococcus haemolyticus (MIC90, 0.5 micrograms/ml), Enterococcus faecalis (MIC90, 1 microgram/ml), and pneumococci (MIC90, 0.12 micrograms/ml). Numerous ciprofloxacin-resistant isolates were susceptible to CP-99,219, a new compound showing potential value for further in vivo trials.
Acyclovir susceptibilities of herpes simplex virus strains isolated from solid organ transplant recipients after acyclovir or ganciclovir prophylaxis
Authors: Boivin G , Erice A , Crane D D , Dunn D L , Balfour H H
Published: June 2012

We determined the acyclovir (ACV) susceptibilities of herpes simplex virus (HSV) isolates (n = 18) recovered from solid organ transplant patients after antiviral prophylaxis with ACV or ganciclovir. All isolates tested were susceptible to ACV (50% inhibitory concentration, < 1 microM). A clinical review of patients with HSV disease showed that all improved with specific anti-HSV therapy, and no recurrences were reported.
Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats
Authors: Reuhl K R , Vapiwala M , Ryzlak M T , Schaffner C P
Published: June 2012

The intracisternal administration of amphotericin B (AmB) and its mono-methyl ester derivative (AME), via direct intraventricular injection (0.01 to 5 mg/ml, 6 microliters) in adult female Wistar rats, revealed that AmB was significantly more toxic than AME, as measured by weight loss, lethargy, death, and central nervous system histopathology. Light and electron microscopy confirmed a greater neurotoxicity for AmB, manifested as edema and modest gliosis extending along and beyond the injection tract. Neuronal degeneration and myelin damage were present in AmB-treated (1 mg/ml) animals but were present only modestly in animals treated with AME at a fivefold greater concentration. Intravenous administration of AmB to adult female Wistar rats as five daily doses of 5 mg/kg of body weight resulted in significant weight loss and some deaths. Histopathologic examination of the brains, spinal cords, and sural nerves of surviving animals revealed neurotoxicity manifested by neuronal degeneration, gliosis, and myelin edema. In sharp contrast, similar treatment with AME at a 10-fold greater dose resulted in neither death nor significant neurotoxicity. The administration of five daily doses of a mixture of AME-AmB (9:1; wt/wt) at 50 mg/kg of body weight resulted in neurotoxicity. These results indicate that AmB exhibits significantly greater in vivo neurotoxicity than AME.
In vitro activities of ceftriaxone and fusidic acid against 13 isolates of Coxiella burnetii, determined using the shell vial assay
Authors: Torres H , Raoult D
Published: June 2012

The susceptibilities of 13 isolates of Coxiella burnetii to fusidic acid and ceftriaxone were determined by use of the recently described shell vial assay (D. Raoult, H. Torres, and M. Drancourt, Antimicrob. Agents Chemother, 35:2070-2077, 1991). At a concentration of 4 micrograms/ml, ceftriaxone was bacteriostatic for four isolates and slowed the multiplication of the other nine. Fusidic acid at a concentration of 2 micrograms/ml was bacteriostatic for six isolates and slowed the multiplication of three others. These results show that these compounds could be effective in the phagolysosome of C. burnetii-infected cells.
Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex
Authors: Hewitt R G , Morse G D , Lawrence W D , Maliszewski M L , Santora J , Bartos L , Bonnem E , Poiesz B
Published: June 2012

Granulocytopenia is a complication of human immunodeficiency virus disease, as well as a toxic manifestation of zidovudine therapy. To evaluate pharmacokinetic and pharmacodynamic relationships, 11 AIDS-AIDS-related complex patients who had developed zidovudine-associated granulocytopenia (mean absolute neutrophil count, 1,077/mm3) were examined after addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to zidovudine. GM-CSF was administered as a daily (1.0 or 0.3 micrograms/kg) or every-other-day (0.3 micrograms/kg) subcutaneous dose over a 28-day period. Zidovudine was continued at the same daily dosage as was previously being administered. Of 11 patients, 7 (1.0 micrograms/kg, n = 5; 0.3 micrograms/kg, n = 2) had a pharmacologic response to GM-CSF with an increase to a mean absolute neutrophil count of 3,189 cells per mm3 at 4 weeks (P < 0.05). The peak concentration of GM-CSF in plasma ranged from 11.5 to 84.4 pg/ml, and the time to peak ranged from 1 to 3 h. No correlation between GM-CSF disposition and hematologic response was noted. A decreased plasma zidovudine-glucuronide/zidovudine ratio was noted after 1 week of GM-CSF, and an increase in the area under the plasma concentration-versus-time curve for zidovudine was found in three patients after 4 weeks. Low doses of GM-CSF can raise the granulocyte count in patients with zidovudine-induced neutropenia. The use of GM-CSF and zidovudine may represent a viable treatment option for persons with human immunodeficiency virus infection who develop neutropenia while receiving zidovudine but do not tolerate alternative nucleoside analogs. Further studies are needed to assess the complex interaction between these two agents.
The fractional maximal effect method: a new way to characterize the effect of antibiotic combinations and other nonlinear pharmacodynamic interactions
Authors: Li R C , Schentag J J , Nix D E
Published: June 2012

The checkerboard technique leading to the fractional inhibitory concentration indexes and the killing curve method are currently the most widely used methods to study antibiotic combinations. For both methods, experimental conditions and interpretation criteria are somewhat arbitrary. The relevance of the fractional inhibitory concentration index computation, in the classic case of additivity [P = d1/(D1)p + d2/(D2)p, where d1 and d2 are the doses of drugs 1 and 2 in combination to produce an effect at a percent level (P) and (D1)p and (D2)p are the doses required for the two respective drugs alone to produce the same effect] relies on the assumption of a linear relationship between the MIC and the concentration of the test antibiotics. In addition, there is no consensus as to the definition of synergy in killing curve interpretation. The fractional maximal effect (FME) method is a new approach which was developed to handle the nonlinear pharmacodynamics exhibited by antibiotics and other drugs. This method relies on the mathematical linearization of the nonlinear concentration-effect scales and eventual construction of an isobologram-type data plot. The FME method was applied to study interactions between several antibiotic combinations: amoxicillin and tetracycline, ciprofloxacin and erythromycin, and ticarcillin and tobramycin. These combinations were selected because the pharmacologic basis for their interactions has been previously described. The FME method correctly identified antagonism for the first two combinations and synergism for the last combination. Conclusions were reproducible across the range of concentrations studied. Besides providing information on the nature of the interaction, the method can rapidly explore the effect of changing concentration ratios of two antimicrobial agents on the degrees of interaction. The FME method may be applied to interactions between drugs or agents with either a linear or nonlinear endpoint measurement. Methods frequently used for drug combination testing are also discussed in the paper.
Strategic design and three-dimensional analysis of antiviral drug combinations
Authors: Prichard M N , Prichard L E , Shipman C
Published: June 2012

The development of new drugs effective against human viral diseases has proven to be both difficult and time-consuming. Indeed, there are but 10 drugs licensed for such applications in the United States today. An attractive solution to this problem may be to optimize the efficacy and selectivity of existing antiviral drugs by combining them with agents that strategically block carefully selected metabolic pathways. This approach was used in the rational design of a three-drug combination to increase the apparent potency of acyclovir against herpes simplex virus. Recent advances in analytical techniques have made the evaluation of this complex drug strategy both possible and practical. A modified version of a previously described analytical method was used to identify optimal drug concentrations and to quantitate statistically significant synergy. Concentrations of 0.25 microM 5-fluorodeoxyuridine, 3.6 microM 2-acetylpyridine thiosemicarbazone, and 0.3 microM acyclovir were determined to be optimal in terms of antiviral activity. The volume of synergy produced was nearly 2,000 microM3% at a 95% level of confidence (corresponding to a 186-fold decrease in the apparent 50% inhibitory concentration of acyclovir with the addition of 0.25 microM 5-fluorodeoxyuridine and 3.6 microM 2-acetylpyridine thiosemicarbazone). We anticipate that this strategic approach and the supporting three-dimensional analytical method will prove valuable in designing and understanding multidrug therapies.
Reproducibility of the microdilution checkerboard method for antibiotic synergy
Authors: Rand K H , Houck H J , Brown P , Bennett D
Published: June 2012

We assessed the reproducibility of the microdilution checkerboard method for measuring antibiotic synergy. Five strains of Pseudomonas aeruginosa were tested with four antibiotic combinations by using 10 replicates each. Twenty-five percent of replicate sets gave discordant classification results (i.e., a 7:3 or worse split in categorization). Determination of the individual MICs of each antibiotic alone was excellent; all 10 replicates were within 1 twofold dilution for 95% of the 80 sets of 10 replicates. The microdilution checkerboard method either should not be used or should be used with at least five replicates per determination, with > or = 80% agreement among the replicates required for classification.
Comparative activity of penciclovir and acyclovir in mice infected intraperitoneally with herpes simplex virus type 1 SC16
Authors: Sutton D , Boyd M R
Published: June 2012

Penciclovir [PCV; 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] is a potent and selective inhibitor of herpes simplex virus and varicella-zoster virus in human cell culture. We have compared the activities of PCV and acyclovir (ACV) in DBA/2 mice infected intraperitoneally with herpes simplex virus type 1 SC16 by measuring the amount of virus in peritoneal washings. In untreated mice after an eclipse phase, virus titers are maximum at 48 h after infection and decline thereafter. PCV and ACV reduced virus replication to a similar extent when given ad libitum in drinking water, even though ACV had better oral bioavailability and greater potency in murine cells. Thus, PCV was more active than had been predicted. In dose-response experiments, PCV given as a single subcutaneous dose 24 h after infection was active at a 10-fold-lower dose than ACV (P < 0.01). A single subcutaneous dose of PCV at 5 h after infection prevented virus replication for 3 days and was more effective than three doses of ACV given 1, 5, and 20 h after infection (P < 0.05). The superior activity of PCV following discrete dosing is not due to pharmacokinetic differences but is probably a reflection of the known stability of the intracellular triphosphate. In this model, the maintenance of high concentrations in blood is less important for PCV than for ACV and may lead to less-frequent doses in clinical use.
Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme
Authors: Froelich-Ammon S J , McGuirk P R , Gootz T D , Jefson M R , Osheroff N
Published: June 2012

A series of novel C-7 quinolyl-substituted enantiomers of ofloxacin were used to determine the stereospecificity of topoisomerase II for the C-11 methyl group in tricyclic quinolones. In all cases, the S isomer was the most active compound against the eukaryotic enzyme. It was approximately 2.2-fold more potent than the R isomer at inhibiting the overall catalytic activity of topoisomerase II (as monitored by DNA relaxation assays). A markedly greater difference in quinolone activity was observed in enzyme-mediated DNA cleavage reactions. While the S enantiomer stimulated nucleic acid breakage approximately 3.5-fold, the R compound did not enhance and, in fact, decreased initial DNA cleavage levels by approximately 50%. The activity of the racemic mixture more closely resembled that of the R enantiomer. In competition experiments, the DNA cleavage-enhancing effects of the S isomer were attenuated by the R compound. Taken together, these latter results indicate that the R enantiomer is an antagonist of S isomer-promoted topoisomerase II-mediated DNA cleavage. Finally, the cytotoxic potential of quinolyl-substituted ofloxacin analogs correlated with the ability to stimulate enzyme-mediated DNA cleavage. Thus, stereochemistry appears to be a governing factor for the potential development of tricyclic quinolones as topoisomerase II-targeted drugs with antineoplastic activity.
Activities of fluoroquinolone, macrolide, and aminoglycoside drugs combined with inhibitors of glycosylation and fatty acid and peptide biosynthesis against Mycobacterium avium
Authors: Barrow W W , Wright E L , Goh K S , Rastogi N
Published: June 2012

Smooth- and rough-colony variants of Mycobacterium avium serovar 4 were treated with three classes of drugs. The drugs were chosen for their potential inhibitory effects on the biosynthesis of the cell envelope-associated serovar-specific glycopeptidolipid antigens. Growth was monitored radiometrically with a BACTEC 460-TB instrument, and MICs were determined for each drug. Both variants were then treated with inhibitory drugs in combination with antimicrobial agents that have demonstrated effectiveness against M. avium. No growth inhibition was observed with 6-fluoro-6-deoxy-D-glucose or avidin. Inhibitors of glycosylation, i.e., 2-deoxy-D-glucose, bacitracin, and ethambutol, were inhibitory to smooth- and rough-colony variants, whereas drugs that inhibit peptide synthesis, i.e., N-carbamyl-L-isoleucine and m-fluoro-phenylalanine, were more inhibitory for the rough-colony variant. Cerulenin, which affects fatty acid synthesis, was inhibitory for both variants, but it appeared to be more effective at inhibiting the growth of the smooth-colony variant at equivalent concentrations. Generally, when inhibitors of glycosylation were used with sparfloxacin and amikacin, a synergistic effect was observed for only the smooth variant. When drugs that affect peptide synthesis were used in combination with amikacin, a synergistic effect was observed for the rough variant, and when cerulenin was used in combination with sparfloxacin or amikacin, a synergistic effect was observed for both variants. Lipid analysis revealed that although the rough variant lacks the serovar-specific glycopeptidolipid antigens, it does possess a group of phenylalanine-isoleucine-containing lipopeptides that may explain its different susceptibility patterns to m-fluoro-phenylalanine and N-carbamyl-L-isoleucine. The significance of these results is discussed with reference to various components in the cell envelope and their importance in cell wall permeability.
Ciprofloxacin resistance in clinical isolates of Salmonella typhimurium obtained from two patients
Authors: Piddock L J , Griggs D J , Hall M C , Jin Y F
Published: June 2012

Two patients (patients A and B) infected with Salmonella typhimurium failed ciprofloxacin therapy, and the posttherapy isolates had reduced susceptibilities to quinolones; 6 of 11 isolates from patient B were also cross-resistant to chemically unrelated agents. No transferable resistance, chloramphenicol-acetylating enzymes, or beta-lactamases were detected. For 13 of 14 isolates, the concentrations of ciprofloxacin that inhibited DNA synthesis by 50% were similar to the MICs, suggesting a mutation in gyrA. Insertion of pNJR3-2 (gyrA) in the posttherapy isolate from patient A and 5 of 11 of the posttherapy isolates from patient B resulted in lower quinolone MICs, also suggesting that resistance was due to a mutation in gyrA. Three of the five isolates also had reduced levels of accumulation of quinolones. All six cross-resistant isolates from patient B had reduced levels of accumulation of quinolones, but only one isolate had increased susceptibility when pNJR3-2 was inserted. Despite the lack of OmpF seen in five isolates from patient B, there was no correlation with decreased levels of quinolone accumulation. All isolates had identical smooth lipopolysaccharide profiles. The mechanism of apparently reduced accumulation has yet to be determined.
Effects of sub-MICs of erythromycin and other macrolide antibiotics on serum sensitivity of Pseudomonas aeruginosa
Authors: Tateda K , Hirakata Y , Furuya N , Ohno A , Yamaguchi K
Published: June 2012

We examined the effects of sub-MICs of erythromycin (EM) and other macrolide antibiotics on the serum sensitivity of Pseudomonas aeruginosa. P. aeruginosa S-6 grown for 36 and 48 h on agar with 10 micrograms of EM per ml (1/10th the MIC) showed significantly increased sensitivity to human serum bactericidal activity compared with those of bacteria grown on agar without EM (P < 0.05). No changes in serum sensitivity were observed in bacteria grown for less than 24 h. This increased sensitivity was apparent even at a concentration of 1.5 micrograms of EM per ml (1/67th the MIC) in bacteria grown for 48 h (P < 0.01). Among the other macrolide antibiotics tested, clarithromycin also enhanced sensitivity to serum, but there were no changes in the sensitivities of bacteria grown on agar with kitasamycin, josamycin, rokitamycin, or oleandomycin even at a concentration of 12 micrograms/ml (1/16th, 1/16th, 1/8th, and 1/33rd the MICs, respectively). P. aeruginosa S-6 grown on agar with subinhibitory concentrations of EM showed decreased cell surface hydrophobicity in a dose-dependent manner, whereas oleandomycin and rokitamycin, even at a concentration of 12 micrograms/ml, induced a slight decrease in hydrophobicity which was approximately equivalent to that of 1.5 micrograms of EM per ml. Among six other strains of the nonmucoid phenotype, three strains became more sensitive to serum by exposure to 10 micrograms of EM per ml for 48 h. In contrast, no evident correlation between EM treatment and a change in serum sensitivity was observed in six strains of the mucoid phenotype, as judged by the results of experiments with both 2 and 0.4% serum. These results show that EM at subinhibitory concentrations enhances the serum sensitivity of some P. aeruginosa strains. Since induced serum sensitivity was accompanied by a decrease in bacterial cell surface hydrophobicity, EM may render P. aeruginosa more serum sensitive by changing the cell surface structure(s) of this organism.
Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model
Authors: Kernodle D S , Kaiser A B
Published: June 2012

Although some beta-lactams and beta-lactam-beta-lactamase inhibitor combinations exhibit activity against methicillin-resistant Staphylococcus aureus, there remains the concern that therapeutic failures may result from the selection of resistant subpopulations. The prophylactic use of these antibiotics in clean surgery, however, may prove adequate since wound infections arise from the inoculation of small numbers of bacteria. In this clinical setting, heterogeneity in the phenotypic expression of beta-lactam resistance may facilitate antibiotic efficacy. Similarly, beta-lactamase-mediated resistance in S. aureus is dependent on inoculum size, and it may be possible to prevent infection from small inocula with relatively labile beta-lactams. To test this hypothesis, antibiotics were administered to guinea pigs as prophylaxis against infection by two methicillin-resistant strains and one borderline-susceptible strain. Following prophylaxis with sulbactam or placebo, inoculation of only a dozen or fewer bacteria had a 50% probability of creating an abscess (50% infective dose [ID50]). The efficacy of ampicillin was similar to that of cefazolin, exhibiting moderate activity against the borderline-susceptible strain (ID50s, greater than 300 bacteria) and minimal activity against the methicillin-resistant strains (ID50s, fewer than 100 bacteria). Coadministration of sulbactam with ampicillin or cefazolin yielded better results than the beta-lactam alone for five of six strain-beta-lactam combinations, including an 80-fold increase in the efficacy of ampicillin-sulbactam compared with that of ampicillin for one methicillin-resistant strain (ID50s, 2,017 and 25 bacteria, respectively). Prophylaxis with beta-lactams, especially beta-lactam-beta-lactamase inhibitor combinations, reduces the risk of wound infection by beta-lactam-resistant S. aureus.
Therapeutic efficacy of the benzoxazinorifamycin KRM-1648 against experimental Mycobacterium avium infection induced in rabbits
Authors: Emori M , Saito H , Sato K , Tomioka H , Setogawa T , Hidaka T
Published: June 2012

The therapeutic efficacy of the benzoxazinorifamycin KRM-1648 was studied in an experimental rabbit infection system with avian Mycobacterium avium. The infected rabbits died from Yersin type infections, a peculiar type of experimental bovine tuberculosis characterized by a very rapid course, enlargement of the spleen and liver, and septic infection, 14 to 20 days after bacterial challenge, as evidenced by bacteremia and severe bacterial loads in the visceral organs. Histopathologic studies of the visceral organs of the infected rabbits revealed the development of numerous typical granulomatous lesions. This experimental rabbit infection system, features of which resemble certain features of disseminated M. avium complex infections in AIDS patients, was used to evaluate the therapeutic efficacy of KRM-1648, a newly synthesized benzoxazinorifamycin. KRM-1648 given orally at 25 and 50 mg/kg of body weight reduced the incidence and degree of bacteremia in infected rabbits and protected against subsequent death. Moreover, the drug allowed almost complete recovery of infected rabbits by week 7. KRM-1648 cleared infections in the lungs, liver, spleen, and kidneys and restored histopathologic features of healthy tissue in the visceral organs. KRM-1648 exhibited a more potent therapeutic effect against M. avium infection than rifampin and clarithromycin.
Pharmacokinetics and bactericidal activities of one 800-milligram dose versus two 400-milligram doses of intravenously administered pefloxacin in healthy volunteers
Authors: Petitjean O , Pangon B , Brion N , Tod M , Chaplain C , Le Gros V , Louchahi K , Allouch P
Published: June 2012

Pefloxacin pharmacokinetics and serum bactericidal activities (SBA) against Escherichia coli and Staphylococcus aureus were compared after intravenous infusion of either a single 800-mg dose or twice-daily 400-mg doses into 16 healthy volunteers. Plasma pefloxacin concentrations were measured for up to 60 h, and SBAs were determined 1, 12, and 24 h after the start of the infusion. The mean areas under the concentration-versus-time curve for plasma were not different (138 versus 136 h.mg/liter). The mean clearances, volumes of distribution, and half-lives were also comparable. The mean (+/- standard deviation) maximal concentration after the 800-mg infusion was 12.11 +/- 1.35 versus 6.51 +/- 0.73 mg/liter after the first 400-mg infusion and 7.42 +/- 0.76 mg/liter after the second 400-mg infusion. Mean trough concentrations at 24 h were significantly different: 2.77 +/- 0.63 (800 mg) versus 1.93 +/- 0.49 (400 mg twice) mg/liter (P = 0.0007). Mean SBAs against E. coli after 800 mg of pefloxacin were higher than 1/128 (1 h), 1/32 (12 h), and 1/16 (24 h). Mean SBAs against S. aureus under the same conditions were higher than 1/64 (1 h), 1/16 (12 h), and 1/8 (24 h). Mean SBAs at 1 and 12 h were significantly higher after the 800-mg infusion than after the 400-mg infusion but were similar at 24 h for both regimens. Comparison of SBAs according to National Committee for Clinical Laboratory Standards criteria showed a similar adequacy at 24 h for both regimens against both strains. Administration of 800 mg of pefloxacin once a day is bioequivalent to 400 mg twice a day, and bactericidal activity of the 800-mg infusion is not less than that of two 400-mg infusions.
Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers
Authors: Barone J A , Koh J G , Bierman R H , Colaizzi J L , Swanson K A , Gaffar M C , Moskovitz B L , Mechlinski W , Van de Velde V
Published: June 2012

The influence of food on itraconazole pharmacokinetics was evaluated for 27 healthy male volunteers in a single-dose (200 mg) crossover study with capsules containing itraconazole-coated sugar spheres. This study was followed by a study of the steady-state pharmacokinetics for the same subjects with 15 days of administration of itraconazole at 200 mg every 12 h. Concentrations of itraconazole and hydroxyitraconazole, the active main metabolite, were measured in plasma by high-performance liquid chromatography. The results of the food interaction segment showed that a meal significantly enhances the amount of itraconazole absorbed. The mean maximum concentration in plasma of unmetabolized itraconazole after fasting (140 ng/ml) was about 59% that after the standard meal (239 ng/ml). The rate of elimination was not affected (terminal half-life, approximately 21 h). The mean maximum concentration in plasma of hydroxyitraconazole after fasting was about 72% the postmeal concentration (287 and 397 ng/ml, respectively). The terminal half-life of hydroxyitraconazole was approximately 12 h. Steady-state concentrations of itraconazole and hydroxyitraconazole were reached after 14 or 15 days of daily dosing. The average steady-state concentrations were approximately 1,900 ng/ml for itraconazole and 3,200 ng/ml for hydroxyitraconazole. The shape of the elimination curve for itraconazole after the last dose was indicative of saturable elimination. This conclusion was confirmed by the sevenfold increase in the area under the curve from 0 to 12 h at steady state compared with the area under the curve from 0 h to infinity after a single dose. It was furthermore confirmed by the larger-than-expected number of half-lives required to achieve steady-state plasma drug levels.
Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue
Authors: Lupia R H , Ferencz N , Lertora J J , Aggarwal S K , George W J , Agrawal K C
Published: June 2012

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.
In vitro and in vivo antibacterial activities of E-4868, a new fluoroquinolone with a 7-azetidin ring substituent
Authors: Guinea J , Robert M , Gargallo-Viola D , Xicota M A , Garcia J , Tudela E , Esteve M , Coll R , Pares M , Roser R
Published: June 2012

E-4868, (-)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-1-(2,4- difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid, is a new fluoroquinolone with an azetidine moiety at the 7 position. The in vitro activity of E-4868 has been compared with those of ciprofloxacin, ofloxacin, and fleroxacin, while the activity of ciprofloxacin was used as reference for in vivo studies. The MICs of E-4868 for 90% of the isolates tested (MIC90s) were 0.06 to 0.5 microgram/ml against gram-positive organisms, including Staphylococcus, Streptococcus, and Enterococcus spp. In general, the in vitro potency of E-4868 against gram-positive bacteria was higher than those of all of the other fluoroquinolones tested. MIC90s against members of the family Enterobacteriaceae between 0.03 and 1 microgram/ml were observed, with the exception of those against Serratia marcescens and Providencia spp., and a MIC90 of 2 micrograms/ml against Pseudomonas aeruginosa was obtained. E-4868 inhibited 90% of the Clostridium spp. and Bacteroides spp. at 2 micrograms/ml and was twofold more active than ciprofloxacin. An increase in the Mg2+ concentration from 1 to 10 mM increased the MIC between two and three times. Human urine caused a significant decrease in activity of E-4868, which was more pronounced at pH 5.5 than at pH 7.2. The presence of serum also decreased the activity of E-4868. Fifty percent effective dose (ED50) values against experimental Escherichia coli HM-42 infections in mice were 3.9 mg/kg of body weight with E-4868 and 3.5 mg/kg of body weight with ciprofloxacin. Corresponding ED50 values against P. aeruginosa HS-116 were 93.2 and 107.8 mg/kg, respectively, and those against Staphylococcus aureus HS-93 were 6.5 and 44.6 mg/kg, respectively. In experimental infections with Streptococcus pneumoniae 84551, the ED50 value of E-4868 was 154.4 mg/kg, while ciprofloxacin proved totally inactive at a dose of 400 mg/kg. When E-4868 was administered orally at a dose of 50 mg/kg in mice, the area under the concentration-time curve (0 to 4 h) value was 28.4 microgram . h/ml, while an area under the concentration-time curve value of 2.3 microgram . h/ml was observed for ciprofloxacin at the same dose. In these studies, levels of the two agents in blood 1 h postadministration were 7.6 and 1.2 microgram/ml, respectively.
Uptake of itraconazole by alveolar macrophages
Authors: Perfect J R , Savani D V , Durack D T
Published: June 2012

Itraconazole is a broad-spectrum potent triazole antifungal agent. Its efficacy in treatment cannot always be explained by body fluid drug levels. In this study, itraconazole was shown to accumulate into host cells. Its intracellular accumulation in cells is greater than that of the antibacterial agent clindamycin, which is known for intracellular localization, and the uptake process does not appear to be active. This ability to reach high concentrations intracellularly may be an important property for the in vivo efficacy of itraconazole.
In vitro activities of new macrolides and rifapentine against Brucella spp
Authors: García-Rodríguez J A , Muñoz Bellido J L , Fresnadillo M J , Trujillano I
Published: June 2012

We have tested the in vitro activities of streptomycin, rifampin, tetracyclines, trimethoprim-sulfamethoxazole, erythromycin, four new macrolides (roxithromycin, azithromycin, clarithromycin, and dirithromycin), and rifapentine against 62 strains of Brucella spp. Azithromycin and clarithromycin were, respectively, eight- and twofold more active than erythromycins (MIC for 90% of strains = 2, 8, and 16 micrograms/ml, respectively). The activity of rifapentine was similar to that of rifampin (MIC for 90% of strains = 1 microgram/ml).
3'-azido-3'-deoxythymidine (AZT) monophosphate: an inhibitor of exonucleolytic repair of AZT-terminated DNA
Authors: Harrington J A , Reardon J E , Spector T
Published: June 2012

A 3'-exonuclease(s) that excised 3'-azido-3'-deoxythymidine (AZT) monophosphate (AZTMP) from the 3' terminus of DNA was partially purified from two human cell lines. AZTMP inhibited the hydrolysis of AZTMP-terminated single-stranded and double-stranded DNA substrates. Thus, high levels of AZTMP might inhibit the exonuclease and trigger the toxicity of AZT by impairing the repair of AZTMP-terminated DNA.
Effects of subinhibitory concentrations of vancomycin and teicoplanin on adherence of staphylococci to tissue culture plates
Authors: Carsenti-Etesse H , Durant J , Entenza J , Mondain V , Pradier C , Bernard E , Dellamonica P
Published: June 2012

Bacterial adhesion is the first step in infection of medical devices. Staphylococcus aureus and Staphylococcus epidermidis are the pathogens recovered most often. The effects of subinhibitory concentrations of vancomycin and teicoplanin on the adherence of eight clinical strains of S. aureus and eight strains of S. epidermidis to tissue culture plates in vitro were tested. The mean relative inhibitions of adherence at one-fourth and one-eighth the MIC were statistically different for teicoplanin and vancomycin. Slime production seemed not to be involved in adherence.
In vitro activity of cycloguanil against African isolates of Plasmodium falciparum
Authors: Basco L K , Ramiliarisoa O , Ringwald P , Doury J C , Le Bras J
Published: June 2012

The in vitro activity of cycloguanil was assessed against 86 African isolates of Plasmodium falciparum by a semi-micro assay system. A bimodal distribution of susceptibility patterns was observed, with 44% of the isolates being cycloguanil susceptible. Cycloguanil alone retains a high activity against the intraerythrocytic forms of some isolates and, together with its activity against the hepatic stages, may be useful for chemoprophylaxis when combined with chloroquine.